Infectious Diseases

Infectious Diseases
Infectious Diseases
Fourth Edition
Edited by
Jonathan Cohen, William G. Powderly, Steven M. Opal, MD

MB, FRCP, FRCPE, MD, FRCPI Professor of Medicine
Infectious Disease Division
FRCPath, FMedSci J. William Campbell Professor of Medicine
Alpert Medical School of Brown University
Larry J Shapiro Director, Institute for
Emeritus Professor of Infectious Diseases Providence, RI, USA
Public Health
Brighton and Sussex Medical School
Co-director, Division of Infectious Diseases
Brighton, UK
Washington University in St Louis
St Louis, MO, USA
Section Editors
Thierry Calandra, MD, PhD Roy M. Gulick, MD, MPH Didier Raoult, MD, PhD
Chairman, Department of Medicine Rochelle Belfer Professor in Medicine Professor, Faculté de Médecine, Director of
Head, Infectious Diseases Service Chief, Division of Infectious Diseases the Foundation Mediterranee Infection
CHUV (Centre Hospitalier Department of Medicine Unité des Rickettsies
Universitaire Vaudois) Weill Cornell Medical College WHO Collaborative Center for Rickettsial
Lausanne, Switzerland New York, NY, USA Reference and Research
Marseille, France
Nathan Clumeck, MD, PhD Andy I.M. Hoepelman,
Professor of Infectious Diseases MD, PhD Robert T. Schooley, MD
Honorary Head, Department of Professor and Head
Professor in Medicine, Infectious
Infectious Diseases Division of Infectious Diseases
Diseases Specialist
Saint-Pierre University Hospital Academic Vice Chair
Head, Department of Internal Medicine and
Brussels, Belgium Department of Medicine
Infectious Diseases
University of California San Diego
University Medical Center
Jeremy Day, MA, DTM&H, Utrecht, The Netherlands
San Diego, CA, USA
PhD, FRCP Jos W.M. van der Meer,
Head, CNS–HIV Infections Research Group Kieren A. Marr, MD
Oxford University Clinical Research Unit Professor of Medicine and Oncology MD, PhD, FRCP,
Wellcome Trust Major Overseas Director, Transplant and Oncology Infectious FRCP(Edin), FIDSA, MAE
Programme Vietnam Diseases Program
Emeritus Professor of Medicine
Ho Chi Minh City, Vietnam Johns Hopkins University School of Medicine
Radboud University Medical Center
Associate Professor Baltimore, MD, USA
Nijmegen, The Netherlands
Centre for Tropical Medicine
Nuffield Department of Medicine Jeanne Marrazzo, MD, Richard J. Whitley, MD
University of Oxford
Oxford, UK
MPH, FACP, FIDSA Distinguished Professor
Director, Division of Infectious Diseases Loeb Chair in Pediatrics
Jeremy Farrar, FRS, FRCP, Professor of Medicine Professor of Pediatrics, Microbiology,
University of Alabama at Birmingham Medicine and Neurosurgery
FMedSci, DPhil, OBE School of Medicine University of Alabama
Director, The Wellcome Trust Birmingham, AL, USA Birmingham, AL, USA
London, UK
Associate Editors (Educational Content)
Courtney D. Chrisler, MD Bethany Davies, MRCP,

Instructor in Medicine FRCPath
Division of Infectious Diseases
Specialist Registrar in Infectious Diseases and
Washington University in St Louis
Medical Microbiology
St Louis, MO, USA
Brighton and Sussex University Hospitals
NHS Trust
Brighton, East Sussex, UK
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© Henry J. C. de Vries retains copyright of his original figures in Chapter 13.
© David A. Warrell retains copyright of his original figures in Chapter 131 and Chapter 171.
First edition 1999
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Third edition 2010
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CONTENTS
Preface to the Fourth Edition xiv 11 Necrotizing Fasciitis, Gas Gangrene,

List of Contributors xv Myositis and Myonecrosis 95
Dedication xxxv11 DENNIS l. STEVENS I MICHAEL J. ALDAPE I
AMY E. BRYANT
VOLUME 1 12 Arthropod Vectors of Medical

Importance 104
JEAN-MICHEL BERENGER I PHILIPPE PAROLA
SECTION a Introduction to
13 Dermatologic Manifestations of Systemic
Infectious Diseases Infections 113
CHANTAL P. BLEEKER-ROVERS I HENRY J.C. DE VRIES
1 The Evolution of Koch's Postulates
JONATHAN COHEN
14 Superficial Fungal Infections 122
DAVID W. WARNOCK I TOM M. CHILLER
2 Nature and Pathogenicity of
Micro-organisms 4 PPl Management of Infected Diabetic
JOSHUA FIERER I DAVID LOONEY I JEAN-CLAUDE PECHfORE'
Foot Ulcers 130
EDGAR J.G. PETERS I BENJAMIN A. LIPSKY
3 Host Responses to Infection 26
CARA C. WILSON I ROBERT T. SCHOOLEY
PP2 Managing the Patient with Recurring
Skin Infections 133
4 Emerging and Re-emerging Pathogens and THUSHAN I. DE SILVA I STEPHEN T. GREEN
Diseases, and Health Consequences of a
Changing Climate 40 The Lymphatic System 136
PHILIP M. POLGREEN I EVELYN l. POLGREEN
15 Lymphadenopathy 136
5 Mathematical Models in Infectious Disease ETHAN RUBINSTEIN' I YOAV KEYNAN
Epidemiology 49
PETER J. WHITE
PP3 Evaluation and Management
of the Solitary Enlarged
6 Infection Prevention and Control, and
Lymph Node 146
Antimicrobial Stewardship 54 YOAV KEYNAN I ETHAN RUBINSTEIN1
RANDY A. TAPLITZ I MICHELE l. RITIER I FRANCESCA J. TORRIANI
The Eye 150

7 Bacterial Genomes 62
PIERRE-EDOUARD FOURNIER I DIDIER RAOULT
16 Conjunctivitis, Keratitis and
Infections of Periorbital
8 The Microbiome in Infectious Diseases 68
Structures 150
MAKEDONKA MITREVA
MICHEL DRANCOURT I MARIE BOULZE PANKERT I
LOUIS HOFFART
SECTION IJ Syndromes by 17 Endophthalmitis 158

Body System MICHEL DRANCOURT I FREDERIC MATONTI
Skin and Soft Tissue 75 18 Infectious Retinitis and Uveitis 165

MICHEL DRANCOURT
9 Viral Exanthems 75
PP4 Management of Red Eye 175
ADILIA WARRIS I FRANK P. KROON
MICHEL DRANCOURT I LOUIS HOFFART
10 Cellulitis, Pyoderma, Abscesses, and Other

Skin and Subcutaneous Infections 84 The Central Nervous System 177
DENNIS l. STEVENS
19 Acute and Chronic Meningitis 177
1Deceased MATIHIJS C. BROUWER I DIEDERIK VAN DE BEEK
Copyrighted material
vi Contents
20 Encephalitis and Myelitis 189 34 Management of the Infected Cystic

KAREN C. BLOCH I CAROL A. GLASER I ALLAN R. TUNKEL Fibrosis Patient 300
HEATHER STRAH I DANIEL ROSENBLUTH
21 Brain Abscess and Other Focal Pyogenic

Infections of the Central Nervous PP7 Investigation of Pleural
System 198 Discharge/Fluid 303
ITZHAK BROOK SAMI HRAIECH I BENOIT D'JOURNO I LAURENT PAPAZIAN
22 Tetanus and Botulism 208 PP8 When to Use Corticosteroids in Noncentral

AIMEE C. HODOWANEC I THOMAS P. BLECK Nervous System Tuberculosis 306
GUY THWAITES
23 Transmissible Spongiform Encephalopathies

of Humans and Animals 214 PP9 How to Manage a Patient on Anti-TB
SIMON MEAD I JOHN COLLINGE I SARAH J. TABRIZI Therapy with Abnormal Liver
Enzymes 308
24 Infections in Hydrocephalus Shunts 221 L. PETER ORMEROD I THOMAS C. BAILEY
ROGER BAYSTON I IVAN PELEGRIN
PPIO Use of Antibiotics for Exacerbations of

PPS Role of Rapid Viral Detection in COPD 310
Meningitis 225 JOHANNES M.A. DANIELS I MENNO M. VAN DER EERDEN
REMI N. CHARREL
The Gastrointestinal System 312

PP6 Investigation of Psychiatric Manifestations
of Encephalitis 227 35 Orocervical Infection 312
DAVID B. CLIFFORD
ROBERT C. READ
The Respiratory System 229 36 Gastritis, Peptic Ulceration and Related

Conditions 321
25 Laryngitis, Epiglottitis and Pharyngitis 229 JONATHAN R. WHITE I RICHARD J.M. INGRAM I
LUU-LY PHAM I RAFIK BOURAYOU I JOHN C. ATHERTON
VALtRIE MAGHRAOUl-SLIM I ISABELLE KONt-PAUT
37 Food-Borne Diarrheal Illness 328

26 Otitis, Sinusitis and Related Conditions 236 CHRISTOPHER P. CONLON
LUU-LY PHAM I RAFIK BOURAYOU I
VALtRIE MAGHRAOUl-SLIM I ISABELLE KONt-PAUT
38 Acute Diarrhea 335
MICHEL DRANCOURT
27 Bronchitis, Bronchiectasis 243
MARCUS W BUTLER I MICHAEL P. KEANE
39 Chronic Diarrhea 341
FLORENCE FENOLLAR
28 Community-Acquired Pneumonia 251
RICHARD G. WUNDERINK
40 Clostridium difficile Infections in Hospitals
29 Hospital-Acquired, Healthcare-Associated and Community 351
MARTIJIN P. BAUER I ED J. KUIJPER
and Ventilator-Associated Pneumonia 258
ANTOINE ROCH I GUILLEMETIE THOMAS I SAMI HRAIECH I
LAURENT PAPAZIAN I WILLIAM G. POWDERLY 41 Intra-abdominal Sepsis, Peritonitis,
Pancreatitis, Hepatobiliary and Focal
30 Lung Abscesses and Pleural Abscesses 263 Splenic Infection 355
CHRISTINA LISCYNESKY I JULIE E. MANGINO P. RONAN O'CONNELL I GERARD SHEEHAN
31 Tuberculosis 271 42 Clinical Manifestations of Acute and Chronic

REINOUT VAN CREVEL I PHILIP C. HILL Hepatitis 363
DAVID WYLES I JENNIFER LIN
32 Nontuberculous Mycobacterial
Diseases 285 PP11 Travelers' Diarrhea 375
JAKKO VAN INGEN PHILIPPE GAUTRET I PHILIPPE PAROLA
33 Fungal Pneumonias 292 PP12 Febrile Transaminitis of Viral Etiology 377

CAROL A. KAUFFMAN STEVEN J. LAWRENCE
Contents vii
PPB Management of CAPD Peritonitis 380 55 Complications of Pregnancy: Maternal

CARLOS A.Q. SANTOS Perspectives 498
GUILLAUME DURAND I FLORENCE BRETELLE I
FLORENCE FENOLLAR
Bone and Joints 382
43 Infective and Reactive Arthritis 382 56 Feta! Implications of Maternal Infections in

ARJUN GUPTA I ELIE F. BERBARI I JAMES M. STECKELBERG I
Pregnancy 505
DOUGLAS R. OSMON ARI BITNUN I HYTHEM AL-SUM I GREG RYAN
44 Acute and Chronic Osteomyelitis 388 PP16 Treatment of a Positive Toxoplasma Titer in
SHIREESHA OHANIREDDY I SANTIAGO NEME Pregnancy 517
RONALD A. NICHOLS I THEODORE B. JONES
45 Infections of Prosthetic Joints and Related

Problems 399 PP17 A Pregnant Patient with a Previous
SHADI PARSAEI I JAMES KEENEY I JONAS MARSCHALL Pregnancy Complicated by Group B
Streptococcal Disease in the Infant 520
46 Lyme Disease 405 UPTON D. ALLEN
JOHN N. AUCOTT I BENJAMIN J. LUFT
Urinary Tract 523

Bloodstream, Heart and Vessels 415
57 Cystitis and Urethral Syndromes 523

47 Sepsis 415
STEPHEN T. CHAMBERS I SARAH C. METCALF
TOM VAN DER POLL I WILLEM JOOST WIERSINGA
58 Prostatitis, Epididymitis and Orchitis 532

48 Infections Associated with lntravascular
FLORIAN M.E. WAGENLEHNER I ADRIAN PILATZ I
Lines and Grafts 427 WOLFGANG WEIDNER I KURT G. NABER
WINFRIED V. KERN
59 Complicated Urinary Infection, Including

49 Systemic Candidiasis 439 Postsurgical and Catheter-Related
BENOIT PILMIS I ZHl-TAO YANG I FANNY LANTERNIER I
Infections 539
OLIVIER LORTHOLARY
LINDSAY E. NICOLLE
50 Myocarditis and Pericarditis 446

60 Pyelonephritis and Abscesses of the
ADAM Z. BANKS I G. RALPH COREY
Kidney 547
ELODI J. DIELUBANZA I RICHARD S. MATULEWICZ I
51 Endocarditis 456 ANTHONY J. SCHAEFFER
FRANCK THUNY I GILBERT HABIB I DIDIER RAOULT I
PIERRE-EDOUARD FOURNIER
PP18 Tuberculosis of the Urogenital Tract 555
DAVID J. HORNE I ELIZABETH ANN MISCH
52 Rheumatic Fever 471
ABBY DOUGLAS I KUMAR VISVANATHAN
PP19 Urinary Tract Infections in Kidney Transplant
Recipients 557
PP14 Management of Pericardia! Effusion 478
KATHLEEN G. JULIAN I EMILY A. BLUMBERG
FREDERIQUE GOURIET I PIERRE-YVES LEVY
PP15 Mediastinitis and Sternal Sexually Transmitted Diseases 559

Osteomyelitis 481
CHRISTOPH SCHIMMER I RAINER G. LEYH 61 Syphilis 559
KHALIL G. GHANEM
Obstetric and Gynecologic

Infections 483 62 Genital Herpes 567
CHRISTINE JOHNSTON I ANNA WALD
53 Vaginitis, Vulvitis, Cervicitis and Cutaneous

Vulva! Lesions 483 63 Human Papillomavirus Infections 575
JACK D. SOBEL VIKRANT V. SAHASRABUDDHE I STEN H. VERMUND
54 Infections of the Female Pelvis, Including 64 Lymphogranuloma Venereum, Chancroid

Septic Abortion 492 and Granuloma lnguinale 585
PAUL NYIRJESY I K. ASHLEY BRANDT PAUL A. MACPHERSON I D. WILLIAM CAMERON
viii Contents
65 Management of Gonorrhea 592 75 Bioterrorism and Biodefense 670

JEANNE MARRAZZO ANDREW W. ARTENSTEIN
66 Chlamydia trachomatis Infection 597 PP24 Infections Associated with Drowning 680
STEPHEN J. JORDAN I WILLIAM M. GEISLER ALASTAIR MILLER
PP20 Persistent and Recurrent Nongonococcal PP25 Management of Human Bites 682
Urethritis 603 ELENI PATROZOU
REBECCA A. LILLIS I DAVID H. MARTIN
Nosocomial Issues 684
76 Infectious Complications Following Surgery

SECTION II Special Problems in and Trauma 684
Infectious Disease HEATHER L. EVANS I EILEEN M. BULGER
Practice
77 Controlling Transmission of Antibiotic
Fever 605 Resistant Bacteria in ICU Settings 693
MARC J.M. BONTEN
67 Pathogenesis of Fever 605

MOHAMMAD M. SAJADI I PHILIP A. MACKOWIAK
PP26 Infection in Burns 698
DAVID J. BARILLO I KEVIN K. CHUNG I CLINTON K. MURRAY
68 Fever of Unknown Origin (FUO) 611

CHESTON B. CUNHA I BURKE A. CUNHA
PP27 Transfusion-Related Infections 701
NAJAM A. ZAIDI
69 The Potential Role of Infectious

Agents in Diseases of Unknown
Etiology 625
STEVEN M. OPAL
SECTION II Infections in the
lmmunocompromised
70 Chronic Fatigue Syndrome 631 Host
JOS W.M. VAN DER MEER I GIJS BLEIJENBERG
78 Immunodeficiencies 705
PP21 Factitious and Fraudulent Fever 636 STEVEN M. HOLLAND I SERGIO D. ROSENZWEIG I
ALICE CHIJIOKE EZIEFULA RICHARD F. SCHUMACHER I LUIGI D. NOTARANGELO
PP22 Infection-Related Hemophagocytic 79 Infections in the Cancer Patient 723

Syndromes 638 OSCAR MARCHETTI I FREDERIC TISSOT I
THIERRY CALANDRA
DENNIS W. SIMON I JOSEPH A. CARCILLO
80 Infections in Hematopoietic Stem Cell

PP23 Kawasaki Disease 640
Transplant Recipients 739
KARI A. SIMONSEN
KIEREN A. MARR
Environmental and Occupational 81 Heart, Lung and Heart-Lung

Factors 643 Transplantation 746
PATRICIA MU N OZ I MADDALENA GIANNELLA I
EMILIO BOUZA
71 Recreational Infections 643
PAVITHRA NATARAJAN I ALASTAIR MILLER
82 Liver Transplantation 751
RAYMUND R. RAZONABLE
72 Occupational Infections 647
TAR-CHING AW I IAIN BLAIR I HILARY M. BABCOCK
83 Intestinal Transplantation 756
KLARA M. POSFAY-BARBE I MARIAN G. MICHAELS I
73 Infections from Pets 656 MICHAEL D. GREEN
ELLIE J.C. GOLDSTEIN I FREDRICK M. ABRAHAMIAN
84 Kidney and Pancreas Transplant

74 Infections Acquired from Animals Other Recipients 762
Than Pets 663 ORIOL MANUEL I CHRISTIAN TOSO I
DANIEL S. SHAPIRO MANUEL A. PASCUAL
Contents ix
85 Vasculitis and Other Immunologically 94 Opportunistic Infections: Management and

Mediated Diseases 770 Prevention 850
JONATHAN COHEN STEPHANE DE WIT I NAT H AN CLUMECK
86 Splenectomy and Splenic Dysfunction 775 95 Immune Reconstitution Disorders in Patients

STEVEN M. OPAL with HIV Infection 859
MARTYN A. FRENCH I GRAEME MEINTJES
87 Vaccination of the lmmunocompromised

Patient 780 96 Tuberculosis in HIV 865
BERNARD P. VAUDAUX I SILJA B U HLER I STEPHEN D. LAWN I ROBIN WOOD
CH RISTIAN VAN DELDEN I CHRISTOPH BERGER
97 Neoplastic Disease 874

88 Infections Associated with CHRISTIAN HOFFMANN
lmmunobiologics 796
JULIE DELALOYE I CURDIN CONRAD I MICHEL GILLIET I
98 Dermatologic Manifestations of HIV
GIUSEPPE PANTALEO I CAMILLO RIBI
Infection/AIDS 879
MISHA M. MUTIZWA I M I LA N J. ANADKAT
PP28 Infectious Diseases Transmitted by
Grafts 805
ANDREA J. ZIMMER I LORA D. THOMAS
99 HIV/AIDS-Related Problems in Low- and
Middle-Income Countries 888
STEVEN J. REYNOLDS I ALEXANDER C. BILLIOUX I
PP29 Evaluation of the HIV-Uninfected Adult with THOMAS C. QUINN
Suspected Immunodeficiency 808
SARAH K. BROWNE
PP31 How to Manage Hepatitis B Virus in the HIV
Coinfected Patient 896
JURGEN KURT ROCKSTROH I KARINE LACOMBE
VOLUME2
PP32 How to Manage Hepatitis C Virus in the HIV
Coinfected Patient 898
SECTION IJ HIV and AIDS JURGEN KURT ROCKSTROH I KARINE LACOMBE
89 Epidemiology of HIV Infection 812

RENNATUS MDODO I ANDREA A. KIM I KEVIN M. DE COCK AIDS in Women and Infants 900
Prevention 824 100 HIV Infection in Children 900

STEPHANE BLANCHE
90 Bio-behavioral Interventions to Prevent HIV

Transmission 824 101 Special Problems in Women Who Have HIV
KENNETH H. MAYER I MATIHEW J. MIMIAGA I Disease 905
STEVEN A. SAFREN
BEVERLY E. SHA I CONSTANCE A. BENSON
91 HIV Vaccines: Past Failures and Future

Scientific Challenges 829
HIV Therapy 912
BRUCE L. GILLIAM I ROBERT R. REDFIELD I BARRY S. PETERS
102 Principles of Management of HIV in the

PP30 HIV Postexposure Prophylaxis 835
ERNIE-PAUL BARRETIE I GEROME V. ESCOTA I RUPA PATEL
Industrialized World 912
MARK W. H ULL I MARIANNE HARRIS I
JULIO S.G. MONTANER
Pathogenesis 837
103 Antiviral Therapy 918
92 The lmmunopathogenesis of HIV-1 JOSE I. BERNARDINO I J OSE R. ARRIBAS
Infection 837
RACHEL PRESTI I GIUSEP P E PANTALEO 104 Issues in the Aging HIV-Positive
Patient 927
Clinical Presentation 846 PATRICK W. MALLON I WILLIAM G. POWDERLY
93 Primary HIV Infection 846 105 Eradication and Cure of HIV 931
BERNARD HIRSCHEL ST E PHEN J. KENT
X Contents
PP33 Antiretroviral Management in Major Tropical Syndromes: Systemic

Low- and Middle-Income Infections 1014
Countries 936
SOMNUEK SUNGKANUPARPH ll7 Malaria 1014
ARJEN M. DONDORP I LORENZ VON SEIDLEIN
ll8 Schistosomiasis 1026

SECTION m International Medicine ALAN FENWICK
Principles of International ll9 Cestode and Trematode

Health 938 Infections 1032
DAVID J. DIEMERT
106 Geography of Infectious Diseases 938

MARY ELIZABETH WILSON 120 Echinococcosis 1038
BRUNO GOTISTEIN I GUIDO BELDI
107 Travel Medicine 948

JANE N. ZUCKERMAN 12 1 Filarial Infections 1046
THOMAS B. NUTMAN
Major Tropical Syndromes: Skin and

Soft Tissue 954 122 Infections and the Common
Inherited Hemoglobin
108 Leprosy 954 Disorders 1053
THOMAS N. WILLIAMS I DAVID J. WEATHERALL
WARWICK J. BRITION
109 Endemic Treponematoses 961 123 Leishmaniasis 1059

ROBERT N. DAVIDSON
NICK J. BEECHING
124 Chagas Disease (American

Major Tropical Syndromes: The Central
Trypanosomiasis) 1065
Nervous System 966
MICHAEL A. MILES
llO Human African Trypanosomiasis 966

125 Melioidosis 1073
CHRISTIAN BURRI I JOHANNES BLUM
SHARON J. PEACOCK I DIREK LIMMATHUROTSAKUL
lll Eosinophilic Meningitis 971

BRIAN JOHN ANGUS
126 Plague 1078
KENNETH L. GAGE I C. BEN BEARD
1 12 Eye Infections in the Tropics 979

ROBIN BAILEY 127 Tularemia 1085
JEANNINE M. PETERSEN I DAVID T. DENNIS I
C. BEN BEARD
Major Tropical Syndromes: The

Gastrointestinal Tract 984 128 Scrub Typhus and Other Tropical
Rickettsioses 1091
ll3 Approach to Eosinophilia in a Traveler from NICHOLAS P.J. DAY I PAUL N. NEWTON
the Tropics 984

ANDREW P. USTIANOWSKI I JOOP E. ARENDS 129 Brucellosis 1098
NICK J. BEECHING I HAKAN ERDEM
ll4 Parasitic Infections of the Gastrointestinal
Tract 989 130 Leptospirosis 1102
PAUL KELLY I MABLE MUTENGO NICHOLAS P.J. DAY
llS Typhoid Fever and Other Enteric 131 Relapsing Fevers 1105
Fevers 1002 DAVID A. WARRELL
CHRISTIANE DOLECEK
132 Viral Hemorrhagic Fevers 1110

ll6 Amebic Infections 1008 AMANDA ROJEK I GAIL CARSON I YASUYUKI KATO I
DAVID C. WARHURST PETER W. HORBY I HAKAN LEBLEBICIOGLU
Contents xi
133 Dengue and Chikungunya 1119 140 �- Lactam Antibiotics 1203

CAMERON P. SIMMONS I JAMES WHITEHORN I RICHARD R. WATKINS I ROBERT A. BONOMO
KATHERINE ANDERS I VINH CHAU VAN NGUYEN
141 Macrolides, Ketolides, Lincosamides and

134 Anthrax 1123 Streptogramins 1217
MEHMET DOGANAY
JENNIE H. KWON
135 The Patient Returning from the Tropics 142 Oxazolidinones 1230
with Fever 1129 FRANKLIN D. LOWY
CHRISTOPHER J.M. WHITTY
143 Aminoglycosides 1233

PP34 Respiratory Tract Infection in a Traveler JAMES E. LEGGETI
Returning from the Hajj 1132

SHRUTI SRIDHAR I JEAN-CHRISTOPHE LAGIER I 144 Ouinolones 1239
PHILIPPE GAUTRET ETHAN RUBINSTEINt I PHILIPPE LAGAC E -WIENS
PP35 Jaundice in the Traveler Returning from 145 Glycopeptides 1249

Nepal 1134 DIANE M. PARENTE I KERRY L. LAPLANTE
JUSTIN BEARDSLEY
146 Tetracyclines and Chloramphenicol 1256

PP36 Sexually Transmitted Infection in a JASON M. POGUE I MICHAEL N. DUDLEY I
AMBIKA ERANKI I KEITH S. KAYE
Traveler Returning from South
Africa 1137
147 Nitroimidazoles, Metronidazole, Ornidazole
A. WILLEM STURM
and Tinidazole; and Fidaxomicin 1261
MARK H. WILCOX
PP37 Lymphadenopathy, Splenomegaly and
Anemia in a Traveler Returning from
148 Antituberculosis Agents 1264
Sudan 1139
GIOVANNI BATIISTA MIGLIORI I ALIMUDDIN ZUMLA
TOM DOHERTY
149 Miscellaneous Agents: Fusidic Acid,

PP38 What are the Treatment Options Nitrofurantoin and Fosfomycin 1277
for a Pregnant Patient with ANGELA HUTINER I STEPHAN HARBARTH
Malaria? 1141
ROSE MCGREADY I FRAN<;: OIS NOSTEN
150 Folate Inhibitors 1280
EIRINI CHRISTAKI
151 Polymyxins 1285

SECTION fJ Anti-infective Therapy MICHAEL J. SATLIN I STEPHEN G. JENKINS
136 Principles of Anti-infective Therapy and

PP39 Management Strategies for Drug-Resistant
Surgical Prophylaxis 1145
Infections 1289
EVELINA TACCONELLI I FEDERICO FOSCHI I
CHRISTINA FORSTNER I ROGER G. FINCH I GEORGE L. DAIKOS I MARIA SOULI I ANASTASIA ANTONIADOU
MATHIAS W. PLETZ
152 Drugs for HIV Infection 1293

137 Mechanisms of Action 1162 BENJAMIN J. ECKHARDT I ROY M. GULICK
FRAN<;: OISE VAN BAMBEKE I
MARIE-PAULE MINGEOT-LECLERCQ I
YOURI GLUPCZYNSKI I PAUL M. TULKENS 153 Drugs for Herpesvirus Infections 1309
MICHELLE R. SALVAGGIO I JOHN W. GNANN, JR.
138 Mechanisms of Antibacterial

Resistance 1181 154 Antiviral Agents Against Respiratory
GIAN MARIA ROSSOLINI I FABIO ARENA I TOMMASO GIANI Viruses 1318
MICHAEL G. ISON I FREDERICK G. HAYDEN
139 Optimizing the Use of Antimicrobial

Agents: Antimicrobial Stewardship 155 Drugs to Treat Viral Hepatitis 1327
and Outpatient Parenteral Antimicrobial LEAH A. BURKE I KRISTEN M. MARKS
Therapy (OPAT) 1197

MATIHEW S. SIMON I DAVID P. CALFEE tocceascd
xii Contents
156 Systemic Antifungal Agents 1333 172 Influenza Viruses 1465

SHMUEL SHOHAM I ANDREAS H. GROLL I SCOTT H. JAMES I RICHARD J. WHITLEY
VIDMANTAS PETRAITIS I THOMAS J. WALSH
173 Noninfluenza Respiratory Viruses 1472

157 Antiparasitic Agents 1345 MICHAEL G. JSON I NELSON LEE
F. MATTHEW KUHLMANN I JAMES M. FLECKENSTEIN
174 Retroviruses and Retroviral Infections 1483

158 Probiotics 1373 GEORGE B. KYEI I WILLIAM G. POWDERLY
JASMIN !SLAM
175 Zoonotic Viruses 1493

159 Infections Associated with LYLE R. PETERSEN I THOMAS G. KSIAZEK
Biologies 1377
RUSSELL J. MCCULLOH
Bacteria 1509
160 Antibacterial Drugs: Looking Ahead From
the Past 1382 176 Staphylococci and Micrococci 1509
DAVID J. HE TEM I SUZAN H.M. ROOJJAKKERS I
DAVID M. SHLAES
MIQUEL B. EKKELENKAMP
177 Streptococci and Enterococci 1523

SECTION II Clinical Microbiology ANDROULLA EFSTRATIOU I THERESA LAMAGNI I
CLAIRE E. TURNER
General Principles 1386

178 Aerobic Gram-Positive Bacilli 1537
GUY PROD'HOM I JACQUES BILLE
161 Advances in Diagnostic Microbiology 1386
GRt:GORY DUBOURG I PIERRE EDOUARD FOURNIER
-
179 Neisseria 1553

TONE T0NJUM I JOS VAN PUTTEN
Viruses 1390
180 Enterobacteriaceae 1565

162 Acute Gastroenteritis Viruses 1390
CLAIRE JENKINS I ROB J. RENTENAAR I
ARTURO S. GASTANADUY I RODOLF O E. BtGUt:
LUCE LANDRAUD I SYLVAIN BRISSE
163 Measles, Mumps and Rubella Viruses 1399 18 1 Pseudomonas spp., Acinetobacter spp.
SCOTT H. JAMES
and Miscellaneous Gram-Negative
Bacilli 1579
164 Human Enteroviruses 1406 HI L MAR WISPLINGHOFF
JOSE R. ROMERO
182 Curved and Spiral Bacilli 1600

165 Hepatitis Viruses 1417 FRANCIS Mt:GRAUD I DIDIER MUSSO I
STEPHANE CHEVALIEZ I JEAN-MICHEL PAWLOTSKY MICHEL DRANCOURT I PHILIPPE LEHOURS
166 Herpesviruses 1426 183 Gram-Negative Coccobacilli 1611

TYREL T. SMITH I RICHARD J. WHITLEY FIONA J. COOKE I MARY P.E. SLACK
167 Papillomaviruses 1439 184 Anaerobic Bacteria 1628

RAPHAEL P. VISCIDI I PATTI E. GRAVITT ITZHAK BROOK
168 Polyomaviruses 1445 185 Mycobacteria 1645

RAPHAEL P. VISCIDI I CHEN SABRINA TAN JAKKO VAN JNGEN
169 Parvoviruses 1449 186 Mycop/asma and Ureap/asma 1660

ALOYS C.M. KROES J0RGEN SKOV JENSEN
170 Poxviruses 1452 187 Rickettsia and Rickettsia-Like

R. MARK L. BULLER Organisms 1666
EMMANOUIL ANGELAKIS I DIDIER RAOULT
17 1 Rabies and Rabies-Related

Viruses 1458 188 Chlamydia 1676
MARY J. WARRELL I DAVID A. WARRELL MIRJA PUOLAKKAINEN I PEKKA A.I. SAIKKU
Contents xiii
Fungi 1681 192 Intestinal Coccidia and Microsporidia 1734

RAINER WEBER
189 Opportunistic and Systemic

Fungi 1681 193 Protozoa: Free-Living Amebae 1744
CHRIS KOSMIDIS I DAVID W. DENNING JENNIFER RITTENHOUSE COPE I JONATHAN S. YODER I
GOVINDA S. VISVESVARA
190 Superficial and Subcutaneous Fungal

Pathogens 1710
194 Blood and Tissue Protozoa 1751
MARIA-JESUS PINAZO I EDELWEISS ALDASORO I
MALCOLM D. RICHARDSON I CAROLINE B. MOORE
ANTONIA CALVO-CANO I ALBERT PICADO I
JOSE MUNOZ I JOAQUIM GASCON
Parasites 1725
195 Helminths 1763
19 1 Protozoa: Intestinal and Urogenital Amebae, H.D. ALAN LINDQUIST I JOHN H. CROSS'
Flagellates and Ciliates 1725

LYNNE S. GARCIA Index 11
1Deceased
PREFACE TO THE FOURTH EDITION
We live in interesting times. The discipline of infectious diseases has threats. However, nothing has demonstrated our collective vulnerabil-
rarely faced so much promise, and yet such peril. The possibility of an ity to pathogenic infection more than the West African outbreak of
AIDS-free world within the next generation is now seriously contem- Ebola which showed the world the devastating effects of a lethal infec-
plated, based on the intelligent use of combinations of antiretroviral tion. Although ultimately controlled by effective infection prevention,
agents and selected use of pre-exposure prophylaxis, and even without this outbreak reminded us of the continued importance of under-
the benefit of a vaccine that induces sterilizing immunity against standing, preventing and treating infectious diseases.
human immunodeficiency virus (HIV). This would not have seemed It is against this background that we have prepared this fourth
possible even 25 years ago. Similarly, the remarkable success story of edition of Infectious Diseases. In doing this we have been conscious not
possibly curing hepatitis C virus (HCV) with safe, oral, directly acting, only of the extraordinary developments in the science and practice of
antiviral agents is now well within our grasp. Only 30 years ago the infection, but also in the evolving needs of our readers. Scientists and
cause of non-A non-B post-transfusion hepatitis was unknown and no practitioners turn to books like this both for specific information on
serologic test was available to detect carriers and prevent transmission. unfamiliar subjects but also as a source for further education and
Real progress in developing a multistage malaria vaccine has recently training. Mindful of this, we have introduced a variety of exciting new
been made, and a vaccine for dengue is on the horizon. Promising and elements to the book. Alongside our widely acclaimed Practice Points
innovative vaccine strategies using reverse genetic approaches are now offering pithy, practical advice on common management problems we
in development, targeting recalcitrant bacterial, fungal and parasitic have now added several new features designed to assist our readers.
pathogens. Rapid molecular diagnostics are finally making huge These include online mannequins providing a ready reference to phar-
inroads in the clinical microbiology laboratory. Such advances are macokinetic data on antimicrobial agents, which are traditionally dif-
essential if we are to be able to make accurate diagnoses within hours ficult to access in an easily useful form, and also a portfolio of online
and provide optimal care for our patients in this era of precision multiple choice questions, fully supported by reference material, as a
medicine. resource for postgraduate education. We are grateful to our two new
Yet despite these advances, we are constantly reminded of just how Associate Editors in Medical Education, Bethany Davies and Courtney
fragile our dominion over the microbial world really is. The human Chrisler, for their help with this important new addition to the book.
population has swelled to over 7 billion inhabitants; most now reside As ever, we are indebted to the extraordinary commitment and exper-
in crowded cities, often without the benefits of adequate sanitation or tise of our Section Editor colleagues and to the very many expert
reliable nutrition. As Paul Farmer has written, physicians ‘need to contributors who have so graciously agreed to undertake comprehen-
think hard about poverty and inequality, which influence any popula- sive revision of their chapters from the previous edition, and, in many
tion’s morbidity and mortality’, and this is no more so than in the case cases, write completely new chapters. We also wish to express our
of infectious diseases. The global spread of antimicrobial resistance profound thanks to the team at Elsevier who have cajoled, supported
now poses the very real threat of infection for which there are no effec- and encouraged us to get this done, in particular Sharon Nash, Jo
tive treatments. Novel resistance mechanisms in gram-negative bacte- Souch and Belinda Kuhn, and last but by no means least, we thank the
ria have emerged and spread rapidly across the world, challenging the Section Editors from the previous edition, Jack Sobel, Roger Finch,
foundations of the modern era of medicine. Drug-resistant tuberculo- Scott Hammer, Tim Kiehn and Keith McAdam, without whom we
sis, including infection with organisms that are extensively resistant would never have been in a position to prepare this new edition of the
(XDR-TB), continues to challenge global efforts at control. Despite the book. We hope that you, the reader, will find what you are looking for
extensive efforts to provide global access to antiretroviral therapy, new and we welcome feedback on how we can continue to improve Infec-
cases of HIV continue in epidemic numbers, and many continue to tious Diseases.
die from AIDS. The spread of vector-borne pathogens, especially
dengue, chikungunya and Zika, continues and corona virus-related Jon Cohen
Middle Eastern respiratory syndrome has emerged as yet another William Powderly
unexpected challenge. Zika-induced microcephaly is hugely important Steven Opal
and clearly demonstrates our continued vulnerability to new microbial
xiv
LIST OF CONTRIBUTORS
The editors would like to acknowledge and offer grateful thanks for the input of all previous editions’ contributors, without whom this new
edition would not have been possible.
Fredrick M. Abrahamian, DO, FACEP, FIDSA Anastasia Antoniadou, MD

Clinical Professor of Medicine Associate Professor of Medicine and Infectious Diseases
David Geffen School of Medicine at UCLA Fourth Department of Medicine
Los Angeles, CA, USA National and Kapodistrian University of Athens
Director of Education Athens, Greece
Department of Emergency Medicine
Olive View-UCLA Medical Center Fabio Arena, MD
Sylmar, CA, USA Senior Research Fellow in Clinical Microbiology
Department of Medical Biotechnologies
Michael J. Aldape, PhD University of Siena
Research Investigator Siena, Italy
Infectious Disease Section
Department of Research and Development Joop E. Arends, MD, PhD
Veterans Affairs Medical Center Infectious Diseases Physician
Boise, ID, USA Internal Medicine and Infectious Diseases
University Medical Center Utrecht (UMCU)
Edelweiss Aldasoro, MD Utrecht, The Netherlands
Medical Research Fellow
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Jose R. Arribas, MD
Clínic-Universitat de Barcelona Head, Infectious Diseases Unit, Internal Medicine
Barcelona, Spain Hospital La Paz
Madrid, Spain
Upton D. Allen, MB BS, MSc, FAAP, FRCPC, Hon
FRCP(UK), FIDSA Andrew W. Artenstein, MD
Professor of Paediatrics Chair, Department of Medicine
Division of Infectious Diseases Baystate Health
Department of Paediatrics Tufts University School of Medicine Chair of Medicine at Baystate
Hospital for Sick Children Medical Center
University of Toronto Professor of Medicine
Toronto, ON, Canada Tufts University School of Medicine
Springfield, MA, USA
Hythem Al-Sum, MD
Clinical Fellow John C. Atherton, MD, FRCP
Maternal-Fetal Medicine Division Professor of Gastroenterology, Pro-Vice Chancellor and Dean of the
Department of Obstetrics and Gynaecology Faculty of Medicine and Health Sciences
Mount Sinai Hospital-University of Toronto NIHR Biomedical Research Unit in Gastrointestinal and Liver
Toronto, ON, Canada Diseases
Nottingham University Hospitals NHS Trust
Milan J. Anadkat, MD University of Nottingham, Queen’s Medical Centre
Associate Professor of Medicine Nottingham, UK
Division of Dermatology
Washington University School of Medicine in St Louis John N. Aucott, MD
St Louis, MO, USA Assistant Professor of Medicine
Division of Rheumatology
Katherine Anders, MSc, PhD Johns Hopkins University School of Medicine
Epidemiologist and Data Manager Baltimore, MD, USA
Eliminate Dengue Program
Monash University Tar-Ching Aw, MB, PhD, FRCPC, FFOM
Melbourne, Australia Professor (EVP)
PAPRSB Institute of Health Sciences
Emmanouil Angelakis, MD, PhD Universiti Brunei Darussalam
Assistant Unité de Recherche sur les Maladies Infectieuses et Adjunct Professor
Tropicales Emergentes Herbert Wertheim College of Medicine
Aix–Marseille Université Florida International University
Marseille, France Miami, FL, USA
Brian John Angus, MB ChB, MD, DTM&H, FRCP

Associate Professor and Reader in Infectious Diseases
Nuffield Department of Medicine
Oxford, UK
xv
xvi List of Contributors
Hilary M. Babcock, MD, MPH Nick J. Beeching, MA, BM BCh, FRCP, FRACP,
Medical Director FFTM, RCPS(Glasg), DCH, DTM&H
BJC Infection Prevention and Epidemiology Consortium Senior Clinical Lecturer
Medical Director of Occupational Health (Infectious Diseases) Department of Clinical Sciences and NIHR Health Protection
Barnes-Jewish and St Louis Children’s Hospitals Research Unit in Emerging and Zoonotic Infections
Associate Professor of Medicine Liverpool School of Tropical Medicine
Infectious Disease Division Pembroke Place
Department of Medicine Liverpool, UK
Washington University School of Medicine in St Louis
St Louis, MO, USA Rodolfo E. Bégué, MD
Professor of Pediatrics
Robin Bailey, BA, BM, FRCP, PhD, DTMH Department of Pediatrics
Professor of Tropical Medicine Louisiana State University HSC School of Medicine
Department of Clinical Research New Orleans, LA, USA
Faculty of Infectious and Tropical Diseases
London School of Hygiene and Tropical Medicine Guido Beldi, MD
London, UK Professor in Surgery
Department for Visceral Surgery and Medicine
Thomas C. Bailey, MD Bern University Hospital
Professor of Medicine University of Bern
Infectious Diseases Division Bern, Switzerland
Department of Medicine
Washington University School of Medicine in St Louis Constance A. Benson, MD, FACP, FIDSA
St Louis, MO, USA Professor of Medicine and Global Public Health
Infectious Diseases Training Program Director
Adam Z. Banks, MD Divisions of Infectious Diseases and Global Public Health
Resident, PGY-3 Department of Medicine
Department of Internal Medicine University of California, San Diego
Duke University Medical Center San Diego, CA, USA
Durham, NC, USA
Elie F. Berbari, MD
David J. Barillo, MD, FACS, FCCM Professor of Medicine
Colonel (retired) Division of Infectious Diseases
US Army Reserve Section of Orthopedic Infectious Diseases
Disaster Response/Critical Care Consultants, LLC Mayo Clinic College of Medicine
Mount Pleasant, SC, USA Rochester, MN, USA
Ernie-Paul Barrette, MD, FACP Jean-Michel Berenger, MD

Associate Professor of Medicine Medical Entomologist
Department of Internal Medicine Aix–Marseille Université
Division of Infectious Diseases URMITE
Washington University School of Medicine in St Louis Marseille, France
St Louis, MO, USA
Christoph Berger, MD
Martijn P. Bauer, MD, PhD Associate Professor of Pediatrics and Pediatric Infectious Diseases
Senior Medical Specialist, Infectious Diseases Division of Infectious Diseases and Hospital Epidemiology
Center of Infectious Disease University Children’s Hospital
Leiden University Medical Centre Zürich, Switzerland
Leiden, The Netherlands
Jose I. Bernardino, MD
Roger Bayston, MMedSci, MSc, PhD, FRCPath Assistant Physician
Professor of Surgical Infection HIV Unit, Department of Internal Medicine
School of Medicine Hospital Universitario La Paz, IdiPAZ
University of Nottingham Madrid, Spain
Nottingham, UK
Jacques Bille, MD
C. Ben Beard, MS, PhD Honorary Professor of Medical Microbiology
Chief, Bacterial Diseases Branch Institute of Microbiology
Division of Vector-Borne Diseases Lausanne University Hospital Center and University of Lausanne
US Centers for Disease Control and Prevention Lausanne, Switzerland
Fort Collins, CO, USA
Alexander C. Billioux, MD, DPhil
Justin Beardsley, MB ChB Assistant Chief of Service, Thayer Firm
Senior Clinical Research Fellow Department of Medicine
Nuffield Department of Medicine The Johns Hopkins Hospital
Oxford University Clinical Research Unit Baltimore, MD, USA
Ho Chi Minh City, Vietnam
List of Contributors xvii
Ari Bitnun, MD, MSc Marc J.M. Bonten, MD, PhD

Associate Professor Professor of Molecular Epidemiology of Infectious Diseases
Department of Pediatrics Department of Medical Microbiology
Hospital for Sick Children Julius Center for Health Sciences and Primary Care
University of Toronto University Medical Center Utrecht
Toronto, ON, Canada Utrecht, The Netherlands
Iain Blair, MB BChir, MA, MFCM, MRCGP Rafik Bourayou, MD

Associate Professor Hospital Practitioner
Institute of Public Health Department of Pediatrics
College of Medicine and Health Sciences Bicêtre Hospital
United Arab Emirates University Paris, France
Al Ain, Abu Dhabi, United Arab Emirates
Emilio Bouza, MD, PhD
Stéphane Blanche, MD Head, Clinical Microbiology and ID Division
Professor of Pediatrics Hospital Gregorio Marañón
Immunology and Hematology Unit Universidad Complutense de Madrid
Hôpital Necker–Enfants Malades Madrid, Spain
University René Descartes
Paris, France K. Ashley Brandt, DO
Resident Physician
Thomas P. Bleck, MD Department of Obstetrics and Gynecology
Professor of Neurological Sciences, Neurosurgery, Medicine, and Drexel University College of Medicine
Anesthesiology Philadelphia, PA, USA
Rush University Medical Center
Chicago, IL, USA Florence Bretelle, MD, PhD
Professor of Obstetrics and Gynaecology
Chantal P. Bleeker-Rovers, MD, PhD Department of Obstetrics and Gynaecology
Internist-Specialist in Infectious Diseases University of Marseille
Department of Internal Medicine Marseille, France
Radboud University Medical Center Sylvain Brisse, PhD
Nijmegen, The Netherlands Research Director
Microbial Evolutionary Genomics
Gijs Bleijenberg, PhD Institut Pasteur
Professor Emeritus Paris, France
Expert Centre for Chronic Fatigue
Radboud University Medical Center Warwick J. Britton, PhD, MB BS, FAAHMS, FRACP,
Nijmegen, The Netherlands FRCP, FRCPA
Bosch Professor of Medicine and Immunology
Karen C. Bloch, MD, MPH Centenary Institute and Discipline of Medicine
Associate Professor Sydney Medical School
Departments of Medicine (Infectious Diseases) and Health Policy University of Sydney
Vanderbilt University School of Medicine Sydney, Australia
Nashville, TN, USA
Itzhak Brook, MD
Johannes Blum, MD Professor of Pediatrics
Professor Georgetown University School of Medicine
Department of Medical Services and Diagnostics Washington DC, USA
Swiss Tropical and Public Health Institute and University of Basel
Basel, Switzerland Matthijs C. Brouwer, MD, PhD
Neurologist
Emily A. Blumberg, MD Department of Neurology
Professor of Medicine, Director Transplant Infectious Diseases Academic Medical Center
Department of Medicine University of Amsterdam
Perelman School of Medicine at the University of Pennsylvania Amsterdam, The Netherlands
Philadelphia, PA, USA
Sarah K. Browne, MD
Robert A. Bonomo, MD Assistant Clinical Investigator
Chief, Medical Service Division of Intramural Research
Louis Stokes Cleveland Department of Veterans Affairs Medical National Institute of Allergy and Infectious Diseases
Center National Institutes of Health
Professor of Medicine, Pharmacology, Biochemistry, Molecular Bethesda, MD, USA
Biology and Microbiology Division of Vaccines and Related Product Applications
Case Western Reserve University School of Medicine Center for Biologics Evaluation and Research, Food and Drug
Cleveland, OH, USA Administration
Silver Spring, MD, USA
xviii List of Contributors
Amy E. Bryant, PhD D. William Cameron, MD, FRCPC, FACP

Research Career Scientist Professor of Medicine
Infectious Disease Section Divisions of Infectious Diseases and Respirology
Research and Development Service Senior Scientist
Veterans Affairs Medical Center Clinical Epidemiology Program
Boise, ID, USA University of Ottawa at The Ottawa Hospital Research Institute
Ottawa, ON, Canada
Silja Bühler, MD, MSc
Research Scientist Joseph A. Carcillo, MD
Division of Infectious Diseases Professor of Critical Care Medicine and Pediatrics
Epidemiology, Biostatistics and Prevention Institute University of Pittsburgh
University of Zurich Pittsburgh, PA, USA
Zurich, Switzerland
Gail Carson, MB ChB, MRCP, DTM&H
Eileen M. Bulger, MD, FACS Clinical Coordinator and Consultant in Infectious Diseases
Professor, Chief of Trauma International Severe Acute Respiratory and Emerging Infection
Department of Surgery Consortium
Harborview Medical Center, University of Washington Centre for Tropical Medicine and Global Health
Seattle, WA, USA Nuffield Department of Medicine
R. Mark L. Buller, PhD Oxford, UK
Professor of Molecular Microbiology and Immunology
Department of Molecular Microbiology and Immunology Stephen T. Chambers, MB ChB, MSc, MD, FRACP
Saint Louis University Professor
St Louis, MO, USA Department of Pathology
University of Otago, Christchurch
Leah A. Burke, MD Clinical Director
Instructor of Medicine Department of Infectious Diseases
Department of Medicine Christchurch Hospital
Division of Infectious Diseases Christchurch, New Zealand
Weill Cornell Medical College
New York, NY, USA Remi N. Charrel, MD, PhD
Head, Emergence and Genomics of RNA Viruses
Christian Burri, PhD, MPharm IRD French Institute of Research for Development, INSERM U1207
Professor EHESP French School of Public Health,
Department of Medicines Research EPV UMR190 “Emergence des Pathologies Virales”
Swiss Tropical and Public Health Institute IHU Méditerranée Infection, APHM Public Hospitals of Marseille
University of Basel Aix Marseille Université
Basel, Switzerland Marseille, France
Marcus W. Butler, MD, MB BCh, FRCPI Vinh Chau Van Nguyen, MD, PhD
Consultant Respiratory Physician Director of the Hospital for Tropical Diseases
University College Dublin Ho Chi Minh City, Vietnam
School Of Medicine Deputy Head of Infectious Disease Division
St Vincent’s Hospital University of Medicine and Pharmacy
Dublin, Ireland Ho Chi Minh City, Vietnam
Thierry Calandra, MD, PhD Stéphane Chevaliez, PharmD, PhD

Chairman, Department of Medicine Professor of Medicine
Head, Infectious Diseases Service Department of Virology
CHUV (Centre Hospitalier Universitaire Vaudois) Henri Mondor Hospital
Lausanne, Switzerland University of Paris-Est & INSERM U955
Creteil, France
David P. Calfee, MD, MS
Associate Professor Tom M. Chiller, MD
Departments of Medicine and Health Policy and Research Associate Director for Epidemiologic Science
Weill Cornell Medical College Division of Foodborne, Waterborne and Environmental Diseases
New York, NY, USA National Center for Emerging and Zoonotic Infectious Diseases
Centers for Disease Control and Prevention
Antonia Calvo-Cano, MD Atlanta, GA, USA
Medical Research Fellow
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Eirini Christaki, MD
Clínic-Universitat de Barcelona Infectious Diseases Consultant
Barcelona, Spain Department of Medicine
AHEPA University Hospital
Thessaloniki, Greece
Research Associate in Medicine
Alpert Medical School of Brown University
Providence, RI, USA
List of Contributors xix
Kevin K. Chung, MD, FCCM, FACP The late John H. Cross, PhD
Director of Research Professor
US Army Institute of Surgical Research, Fort Sam Tropical Public Health
Houston, TX, USA Department of Preventive Medicine and Biometrics
Uniformed Services University of the Health Sciences
David B. Clifford, MD Bethesda, MD, USA
Melba and Forest Seay Professor of
Clinical Neuropharmacology in Neurology Burke A. Cunha, MD, MACP
Washington University in St Louis Chief, Infectious Disease Division
Saint Louis, MO, USA Winthrop-University Hospital
Mineola, New York
Nathan Clumeck, MD, PhD Professor of Medicine
Professor of Infectious Diseases State University of New York School of Medicine
Honorary Head, Department of Infectious Diseases Stony Brook, NY, USA
Saint-Pierre University Hospital
Brussels, Belgium Cheston B. Cunha, MD
Assistant Professor of Medicine
Jonathan Cohen, MB, FRCP, FRCPE, FRCPath, Medical Director, Antimicrobial Stewardship Program
FMedSci Division of Infectious Disease
Emeritus Professor of Infectious Diseases Brown University Alpert School of Medicine, Rhode Island Hospital
Brighton and Sussex Medical School and Miriam Hospital
Brighton, UK Providence, RI, USA
John Collinge, MRCP, MD, FRCPath Benoit D’Journo, MD, PhD

Professor of Neurology Professor
Head of Department Service de Chirurgie Thoracique
Department of Neurodegenerative Diseases/Director Assitance Publique-Hôpitaux de Marseille
MRC Prion Unit Marseille, France
Institute of Neurology
University College London George L. Daikos, MD
London, UK Professor of Medicine and Infectious Diseases
First Department of Medicine
Christopher P. Conlon, MA, MD, FRCP, FRCPI National and Kapodistrian University of Athens
Professor of Infectious Diseases Athens, Greece
University of Oxford Johannes M.A. Daniels, MD, PhD
Consultant Physician Pulmonologist
Oxford University Hospitals NHS Foundation Trust Department of Pulmonary Diseases
Oxford, UK VU University Medical Center
Amsterdam, The Netherlands
Curdin Conrad, MD, PD&MER
Head of the Psoriasis Center Robert N. Davidson, MD, FRCP, DTM&H
Department of Dermatology Consultant Physician
University Hospital of Lausanne, CHUV Department of Infectious Diseases and Tropical Medicine
Lausanne, Switzerland Northwick Park Hospital
Harrow, UK
Fiona J. Cooke, MA, PhD, MSc, MRCP, FRCPath,
DTM&H Nicholas P.J. Day, MA, BMBCh, DM, FRCP, FMedSci
Consultant Medical Microbiologist Professor of Tropical Medicine
Clinical Microbiology and Public Health Laboratory University of Oxford
Cambridge University Hospitals NHS Foundation Trust Director, Mahidol-Oxford Tropical Medicine Research Unit
Cambridge, UK Faculty of Tropical Medicine
Mahidol University
Jennifer Rittenhouse Cope, MD, MPH Bangkok, Thailand
Medical Epidemiologist
National Center for Emerging and Zoonotic Infectious Diseases Kevin M. De Cock, MD, FRCP (UK), DTM&H
Centers for Disease Control and Prevention Director
Atlanta, GA, USA Division of Global HIV/AIDS-Kenya
G. Ralph Corey, MD Nairobi, Kenya
Professor of Medicine and Pathology
Department of Medicine Thushan I. de Silva, BSc, MB ChB, MRCP, FRCPath,
Duke University Medical Center DTM&H, PhD
Durham, NC, USA NIHR Academic Clinical Lecturer in Infectious Diseases and
Microbiology
Department of Infection and Tropical Medicine
Royal Hallamshire Hospital
Sheffield, UK
xx List of Contributors
Henry J.C. de Vries, MD, PhD Tom Doherty, MD, FRCP, DTM&H
Dermatologist Consultant Physician
Department of Dermatology Hospital for Tropical Diseases
Academic Medical Center (AMC) University College London Hospitals
University of Amsterdam London, UK
Center for Infection and Immunology Amsterdam (CINIMA) Christiane Dolecek, MD, PhD, FRCP
Academic Medical Center (AMC) University Research Lecturer
University of Amsterdam Centre for Tropical Medicine and Global Health
Amsterdam, The Netherlands Nuffield Department of Medicine
STI Outpatient Clinic Spatial Ecology and Epidemiology Group
Public Health Service of Amsterdam (GGD Amsterdam) Department of Zoology
Amsterdam, The Netherlands University of Oxford
Oxford, UK
Stéphane de Wit, MD, PhD
Head of Department Arjen M. Dondorp, MD, PhD
Infectious Diseases Professor of Tropical Medicine
Saint-Pierre University Hospital University of Oxford
Brussels, Belgium Oxford, UK
Julie Delaloye, MD, PhD Abby Douglas, MB BS(Hons), BMedSci

Infectious Disease Specialist Infectious Diseases Registrar
Centre Hospitalier Universitaire Vaudois Department of Infectious Diseases
Lausanne, Switzerland St Vincent’s Hospital Melbourne
Melbourne, Australia
David W. Denning, FRCP, FRCPath, FMedSci
Professor of Infectious Diseases in Global Health Michel Drancourt, MD, PhD
The University of Manchester Professor
Director Unité de Recherches sur les Maladies Infectieuses et Tropicales
National Aspergillosis Centre Emergentes
University Hospital of South Manchester Aix–Marseille Université
Manchester, UK Marseille, France
David T. Dennis, MD, MPH Grégory Dubourg, PharmD

Medical Epidemiologist University Hospital Assistant
Centers for Disease Control and Prevention (Ret.) Unité de Recherche sur les Maladies Infectieuses et Tropicales
Fort Collins, CO, USA Emergentes
Aix-Marseille University
Shireesha Dhanireddy, MD Marseille, France
Associate Professor
Division of Infectious Diseases, Department of Medicine Michael N. Dudley, PharmD, FIDSA
University of Washington Senior Vice President and Chief Scientific Officer (Rempex)
Seattle, WA, USA Health Sciences Lead
Infectious Diseases Global Innovation Group
Elodi J. Dielubanza, MD The Medicines Company
Housestaff Physician San Diego, CA, USA
Department of Urology
Feinberg School of Medicine Northwestern University Guillaume Durand, MD
Chicago, IL, USA Medicine Resident
Unité de Recherche sur les Maladies Infectieuses et Tropicales
David J. Diemert, MD, FRCP(C) Emergentes
Associate Professor University of Marseille
Department of Microbiology Marseille, France
Immunology and Tropical Medicine
George Washington University School of Medicine and Health Benjamin J. Eckhardt, MD
Sciences Infectious Diseases Fellow
Washington, DC, USA Division of Infectious Diseases
Weill Cornell Medical College
Mehmet Doganay, MD New York, NY, USA
Professor of Infectious Diseases
Department of Infectious Diseases Androulla Efstratiou, PhD
Faculty of Medicine, Erciyes University Director
Kayseri, Turkey WHO Collaborating Centre for Reference and Research on
Diphtheria and Streptococcal Infections
Reference Microbiology Division
Public Health England (PHE)
London, UK
List of Contributors xxi
Miquel B. Ekkelenkamp, MD, PhD James M. Fleckenstein, MD

Clinical Microbiologist Associate Professor of Medicine and Molecular Microbiology
Department of Medical Microbiology Department of Medicine, Division of Infectious Diseases
University Medical Center Utrecht Washington University School of Medicine in St Louis
Utrecht, The Netherlands St Louis, MO, USA
Ambika Eranki, MD, MPH Christina Forstner, MD

Assistant Professor Assistant Professor
Division of Infectious Disease Specialist for Internal Medicine
Department of Medicine Department of Medicine I
State University of New York/Upstate Medical Center Division of Infectious Diseases and Tropical Medicine
Syracuse, NY, USA Medical University of Vienna
Vienna, Austria
Hakan Erdem, MD
Professor of Infectious Diseases and Clinical Microbiology Federico Foschi, MD
Gulhane Medical Academy and Infectious Diseases Department Resident Physician
GATA Hospital Department of Internal Medicine I
Etlik, Ankara, Turkey Division of Infectious Diseases
Tübingen University Hospital
Gerome V. Escota, MD Tübingen, Germany
Clinical Instructor of Medicine
Division of Infectious Disease Pierre-Edouard Fournier, MD, PhD
Washington University School of Medicine in Saint Louis Professor of Clinical Microbiology
Saint Louis, MO, USA Institut Hospitalo-Universitaire Méditerranée-Infection
Aix-Marseille Université
Heather L. Evans, MD, MS, FACS Marseille, France
Associate Professor of Surgery
Department of Surgery Martyn A. French, MB ChB, MD, FRCPath, FRCP,
University of Washington FRACP
Seattle, WA, USA Professor in Clinical Immunology
School of Pathology and Laboratory Medicine
Alice Chijioke Eziefula, MA, MB BS, MRCP, FRCPath University of Western Australia
Specialist Registrar in Infectious Diseases and Medical Microbiology Perth, Australia
Department of Infection
Brighton and Sussex University Hospitals NHS Trust Kenneth L. Gage, PhD
Brighton, UK Chief, Entomology and Ecology Activity
Bacterial Diseases Branch
Florence Fenollar, MD, PhD Division of Vector-Borne Diseases
Professor Centers for Disease Control and Prevention
Institut Hospitalo-Universitaire Méditerranée-Infection Fort Collins, CO, USA
Aix–Marseille Université
Marseille, France Lynne S. Garcia, MS, CLS, FAAM
Director
Alan Fenwick, PhD LSG & Associates
Professor of Tropical Parasitology Santa Monica, CA, USA
Department of Infectious Disease Epidemiology
Imperial College London Joaquim Gascon, MD, PhD
London, UK Research Professor
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital
Joshua Fierer, MD Clínic-Universitat de Barcelona
Chief, Infectious Disease Barcelona, Spain
VA San Diego Healthcare System
Professor of Medicine and Pathology Arturo S. Gastañaduy, MD
University of California San Diego Associate Professor of Pediatrics
San Diego, CA, USA Department of Pediatrics
Louisiana State University HSC School of Medicine
Roger G. Finch, MB BS, FRCP, FRCPath, FRCPEd, New Orleans, LA, USA
FFPM
Professor of Infectious Diseases Philippe Gautret, MD, PhD, MSc, DTM&H
School of Molecular Medical Science Director of Travel Clinic
Division of Microbiology and Infectious Disease University Hospital Institute for Infectious Diseases and Tropical
Nottingham University Hospitals NHS Trust Medicine, Méditerranée Infection
Nottingham, UK Aix-Marseille University
Marseille, France
xxii List of Contributors
William M. Geisler, MD, MPH Bruno Gottstein, PhD, AssEVPC

Professor Full Professor of Medical and Veterinary Parasitology
Department of Medicine, Division of Infectious Diseases Institute of Parasitology
The University of Alabama at Birmingham Department of Infectious Diseases and Pathobiology
Birmingham, AL, USA University of Bern
Bern, Switzerland
Khalil G. Ghanem, MD, PhD
Associate Professor of Medicine Frederique Gouriet, MD, PhD
Division of Infectious Diseases Physician
Johns Hopkins University School of Medicine Research Unit of Emerging Infectious and Tropical Diseases
Baltimore, MD, USA Faculty of Medicine
Aix-Marseille University
Tommaso Giani, PhD Marseille, France
Assistant Professor
Department of Medical Biotechnologies Patti E. Gravitt, PhD, MS
University of Siena Professor
Siena, Italy Department of Pathology
University of New Mexico Health Sciences Center
Maddalena Giannella, MD, PhD Albuquerque, NM, USA
ID Consultant
Infectious Diseases Unit, Department of Medical and Surgical Michael D. Green, MD, MPH
Sciences Professor of Pediatrics, Surgery and Clinical and Translational
Sant’Orsola Hospital, University of Bologna Science
Bologna, Italy University of Pittsburgh School of Medicine
Attending Physician
Bruce L. Gilliam, MD Division of Infectious Diseases
Associate Professor of Medicine Children’s Hospital of Pittsburgh of UPMC
Institute of Human Virology Pittsburgh, PA, USA
University of Maryland School of Medicine
Baltimore, MD, USA Stephen T. Green, MD, BSc, MB ChB, FRCP(Lond &
Glas), FFTM, DTM&H
Michel Gilliet, MS Honorary Professor of International Health at Sheffield Hallam
Chief of Service University
Dermatology Consultant Physician in Infectious Diseases and Tropical Medicine
Department of Medicine Department of Infection and Tropical Medicine
Centre Hospitalier Universitaire Vaudois Royal Hallamshire Hospital
Lausanne, Switzerland Sheffield, UK
Carol A. Glaser, DVM, MD Andreas H. Groll, MD

Associate Clinical Professor of Pediatrics Professor of Pediatrics
Division of Pediatric Infectious Diseases Center for Bone Marrow Transplantation and Department of
University of California, San Francisco Pediatric Hematology/Oncology
San Francisco, CA, USA University Children’s Hospital Münster
Münster, Germany
Youri Glupczynski, MD, PhD
Professor and Head of Clinical Microbiology Roy M. Gulick, MD, MPH
Microbiology Laboratory and National Reference Laboratory for Rochelle Belfer Professor in Medicine
Monitoring of Antimicrobial Resistance in Gram-Negative Chief, Division of Infectious Diseases
Bacteria Department of Medicine
CHU Dinant-Godinne, UCL Namur Weill Cornell Medical College
Yvoir, Belgium New York, NY, USA
John W. Gnann, Jr, MD Arjun Gupta, MB BS

Professor of Medicine Internal Medicine PGY1
Department of Medicine, Division of Infectious Diseases University of Texas Southwestern Medical Center
Medical University of South Carolina Dallas, TX, USA
Charleston, SC, USA
Gilbert Habib, MD
Ellie J.C. Goldstein, MD, FSHEA, FIDSA Cardiologist
Clinical Professor of Medicine Department of Cardiology
David Geffen School of Medicine at UCLA La Timone Hospital
Los Angeles, CA, USA Marseille, France
Director, R.M. Alden Research Laboratory
Santa Monica, CA, USA
List of Contributors xxiii
Stephan Harbarth, MD, MS Peter W. Horby, MB BS, FRCP, PhD

Associate Professor of Medicine Associate Professor
Infection Control Programme Centre for Tropical Medicine and Global Health
Department of Medicine University of Oxford
Geneva University Hospitals and Faculty of Medicine Oxford, UK
Geneva, Switzerland
David J. Horne, MD, MPH
Marianne Harris, MD Assistant Professor of Medicine
Clinical Assistant Professor, Department of Family Practice Division of Pulmonary and Critical Care Medicine, Department of
Associate Member, Division of AIDS Medicine
Faculty of Medicine Harborview Medical Center, University of Washington
University of British Columbia Seattle, WA, USA
Vancouver, BC, Canada
Sami Hraiech, MD, PhD
Frederick G. Hayden, MD Assistance Publique–Hôpitaux de Marseille
Stuart S. Richardson Professor of Clinical Virology and Professor of Hôpital Nord
Medicine Réanimation des Détresses Respiratoires et des Infections Sévères
Department of Medicine Aix–Marseille Université
Division of Infectious Diseases and International Health Marseille, France
University of Virginia
Charlottesville, VA, USA Mark W. Hull, MD, MHSc
Clinical Associate Professor
David J. Hetem, MD, PhD Division of AIDS
Clinical Microbiologist Department of Medicine
Department of Medical Microbiology University of British Columbia
University Medical Center Utrecht Vancouver, BC, Canada
Utrecht, The Netherlands
Angela Huttner, MD
Philip C. Hill, BHB, MB ChB, MPH, MD, FranceCP, Instructor
FAFPHM Infection Control Programme
McAuley Professor of International Health Geneva University Hospitals and Faculty of Medicine
Centre for International Health Geneva, Switzerland
University of Otago,
Dunedin, New Zealand Richard J.M. Ingram, BMedSci, BM BS(Hons), MRCP
Clinical Research Fellow in Gastroenterology
Bernard Hirschel, MD NIHR Biomedical Research Unit in Gastrointestinal and Liver
Professor Emeritus Diseases
Division of Infectious Disease Nottingham University Hospitals NHS Trust
Geneva University Hospitals University of Nottingham, Queen’s Medical Centre
Geneva, Switzerland Nottingham, UK
Aimee C. Hodowanec, MD Jasmin Islam, MB BS, PhD, MRCP

Assistant Professor Specialist Registrar Infectious Diseases and Medical Microbiology
Section of Infectious Diseases Department of Infection and Microbiology
Department of Medicine Brighton and Sussex University Hospital
Rush University Medical Center Brighton, UK
Chicago, IL, USA
Michael G. Ison, MD, MS, FIDSA, FAST
Louis Hoffart, MD Associate Professor
Service d’Ophtalmologie Divisions of Infectious Diseases and Organ Transplantation
Hôpital de la Timone Northwestern University Feinberg School of Medicine
Marseille, France Chicago, IL, USA
Christian Hoffmann, MD, PhD Scott H. James, MD

Associate Professor Assistant Professor of Pediatrics
University of Schleswig Holstein Department of Pediatrics
Campus Kiel Hemato-oncologist Infektionsmedizinisches Centrum Division of Infectious Diseases
Hamburg (ICH) ICH Study Center Hamburg University of Alabama at Birmingham School of Medicine
Hamburg, Germany Birmingham, AL, USA
Steven M. Holland, MD Claire Jenkins, PhD

Chief Head of E. coli, Shigella, Yersinia & Vibrio Reference Services
Laboratory of Clinical Infectious Diseases Gastrointestinal Bacteria Reference Unit
National Institute of Allergy and Infectious Diseases, NIH, Public Health England
Bethesda, MD, USA London, UK
xxiv List of Contributors
Stephen G. Jenkins, PhD James Keeney, MD

Adjunct Professor of Pathology and Laboratory Medicine Chief, Adult Hip and Knee Reconstructions Service
Adjunct Professor of Pathology in Medicine Associate Professor, Department of Orthopaedic Surgery
Weill Cornell Medical College University of Missouri
New York, NY, USA Columbia, MO, USA
Jørgen Skov Jensen, MD, PhD, DMedSci Paul Kelly, MD, FRCP
Consultant Physician Professor of Tropical Gastroenterology
Microbiology and Infection Control Blizard Institute
Statens Serum Institut Barts & The London School of Medicine
Copenhagen, Denmark Queen Mary University of London
London, UK
Christine Johnston, MD, MPH
Assistant Professor of Medicine Stephen J. Kent, MB BS, MD, FRACP
Division of Infectious Diseases, Department of Medicine Professor of Microbiology and Immunology
University of Washington Department of Microbiology and Immunology
Seattle, WA, USA University of Melbourne
Melbourne, Australia
Theodore B. Jones, MD, FACOG
Residency Program Director Winfried V. Kern, MD
Obstetrics and Gynecology Professor of Internal Medicine and Infectious Diseases
Department of Obstetrics and Gynecology Division of Infectious Diseases
Beaumont Oakwood University Hospital and Medical Center
Associate Professor Freiburg, Germany
Wayne State University School of Medicine
Dearborn, MI, USA Yoav Keynan, MD, PhD
Assistant Professor
Stephen J. Jordan, MD, PhD Department of Internal Medicine
Clinical Fellow Medical Microbiology and Community Health Sciences
Department of Medicine, Division of Infectious Diseases University of Manitoba
The University of Alabama at Birmingham Winnipeg, Canada
Birmingham, AL, USA
Andrea A. Kim, PhD, MPH
Kathleen G. Julian, MD Chief, Surveillance and Epidemiology Branch
Associate Professor of Medicine Division of Global HIV/AIDS–Kenya
Department of Medicine Centers for Disease Control and Prevention
Division of Infectious Diseases Nairobi, Kenya
Penn State Hershey Medical Center
Hershey, PA, USA Isabelle Koné-Paut, MD
Professor of Medicine
Yasuyuki Kato, MD, MPH, DTM Department of Pediatrics
Chief, Division of Preparedness and Emerging Infections University of Paris Sud
Disease Control and Prevention Centre Paris, France
National Centre for Global Health and Medicine
Tokyo, Japan Chris Kosmidis, MD, PhD
Consultant in Infectious Diseases
Carol A. Kauffman, MD National Aspergillosis Centre
Chief, Infectious Diseases Section University Hospital of South Manchester
Veterans Affairs Ann Arbor Healthcare System Hon. Senior Lecturer
Professor of Internal Medicine The University of Manchester
University of Michigan Medical School Manchester, UK
Ann Arbor, MI, USA
Aloys C.M. Kroes, MD, PhD
Keith S. Kaye, MD, MPH Professor of Medical Microbiology and Clinical Virology
Professor of Medicine Department of Medical Microbiology
Corporate Vice President of Quality and Patient Safety Leiden University Medical Center
Corporate Medical Director, Infection Prevention, Epidemiology and Leiden, The Netherlands
Antimicrobial Stewardship
Detroit Medical Center and Wayne State University Frank P. Kroon, MD PhD
University Health Center Internist-Specialist in Infectious Diseases
Detroit, MI, USA Department of Infectious Diseases
Leiden University Medical Center
Michael P. Keane, MD FRCPI Leiden, The Netherlands
Professor of Medicine
University College Dublin Thomas G. Ksiazek, DVM, PhD
School of Medicine Professor
St Vincent’s Hospital Sealy Center for Vaccine Development
Dublin, Ireland University of Texas Medical Branch
Galveston, TX, USA
List of Contributors xxv
F. Matthew Kuhlmann, MD Kerry L. LaPlante, PharmD, FCCP

Instructor in Medicine Professor of Pharmacy
Division of Infectious Diseases, Department of Medicine Department of Pharmacy Practice
Washington University School of Medicine in St Louis University of Rhode Island
St Louis, MO, USA Kingston, RI, USA
Adjunct Clinical Associate Professor of Medicine
Ed J. Kuijper, MD, PhD Alpert Medical School of Brown University
Professor of Medical Microbiology Providence, RI, USA
Department of Medical Microbiology Director of the Rhode Island Infectious Diseases Research Program
Center of Infectious Disease (RIID) and Infectious Diseases Pharmacotherapy Specialist
Leiden University Medical Centre Veterans Affairs Medical Center
Leiden, The Netherlands Providence, RI, USA
Jennie H. Kwon, DO Stephen D. Lawn, BMedSci MB BS, MD, FRCP,

Senior Clinical Research Fellow DTM&H, DiP HIV MED
Division of Infectious Diseases Professor of Infectious Diseases
Department of Internal Medicine Department of Clinical Research
Washington University School of Medicine in St Louis Faculty of Infectious and Tropical Diseases
St Louis, MO, USA London School of Hygiene & Tropical Medicine
London, UK
George B. Kyei, MB ChB, PhD
Assistant Professor of Medicine Steven J. Lawrence, MD, MSc
Department of Medicine Assistant Professor of Medicine
Washington University School of Medicine in St Louis Department of Medicine
Saint Louis, MO, USA Washington University School of Medicine in St Louis
St Louis, MO, USA
Karine Lacombe, MD, PhD
Associate Professor Hakan Leblebicioglu, MD
Infectious Diseases Department Head of Department of Infectious Diseases & Clinical Microbiology
Hôpital St Antoine Coordinator of ESCMID Study Group for Infections in Travelers
Paris, France and Migrants (ESGITM)
Ondokuz Mayis University
Philippe Lagacé-Wiens, MD, FRCPC, DTM&H Samsun, Turkey
Professor
Department of Medical Microbiology and Infectious Diseases Nelson Lee, MD
University of Manitoba College of Medicine Professor of Infectious Medicine and Therapeutics
Winnipeg, Manitoba, Canada The Chinese University of Hong Kong
Hong Kong, People’s Republic of China
Jean-Christophe Lagier, MD, PhD
Associate Professor of Medicine James E. Leggett, MD
Institut Hospitalo-Universitaire Méditerranée-Infection Associate Professor, Department of Internal Medicine, Oregon
Aix-Marseille Université Health and Sciences University
Marseille, France Infectious Diseases, Department of Medical Education, Providence
Portland Medical Center
Theresa Lamagni, MSc, PhD Portland, OR, USA
Senior Epidemiologist
Healthcare-Associated Infections and Antimicrobial Resistance Philippe Lehours, PharmD, PhD
Department Assistant Professor in Microbiology
Public Health England Department of Bacteriology
London, UK University of Bordeaux
Bordeaux, France
Luce Landraud, MD, PhD
Medical Doctor Pierre-Yves Levy, MD
Microbiology Department Associate Professor of Microbiology
Archet II-Hospital Institut Hospitalier Universitaire Méditerranée Infection
Microbial Toxins in Host Pathogen Marseille, France
Interactions
Sophia Antipolis University Rainer G. Leyh, MD, PhD
Nice, France Professor, Director and Chairman
Department of Thoracic and Cardiovascular Surgery
Fanny Lanternier, MD Universitätsklinikum Würzburg
Researcher Université Paris–Descartes Würzburg, Germany
Hôpital Necker–Enfants Malades
Service des Maladies Infectieuses et Tropicales
Institut Imagine, APHP, Centre d’Infectiologie Necker–Pasteur
Paris, France
xxvi List of Contributors
Rebecca A. Lillis, MD Franklin D. Lowy, MD

Associate Professor of Medicine Professor of Medicine and Pathology and Cell Biology
Department of Medicine, Section of Infectious Diseases Department of Medicine
Louisiana State University School of Medicine Columbia University
New Orleans, LA, USA College of Physicians and Surgeons
New York, NY, USA
Direk Limmathurotsakul, MD, MSc, PhD
Assistant Professor of Epidemiology Benjamin J. Luft, MD
Department of Tropical Hygiene and Edmund D. Pellegrino Professor
Mahidol-Oxford Tropical Medicine Research Unit Department of Medicine
Faculty of Tropical Medicine State University of New York at Stony Brook
Mahidol University Stony Brook, NY, USA
Bangkok, Thailand
Philip A. Mackowiak, MD, MBA, MACP
Jennifer Lin, MD Emeritus Professor of Medicine
Chief, Division of HIV/AIDS Medicine Carolyn Frenkil and Selvin Passen History of Medicine
Santa Clara Valley Medical Center Scholar-in-Residence
San Jose, CA, USA University of Maryland School of Medicine
Clinical Instructor, Affiliated Baltimore, MD, USA
Stanford University Paul A. MacPherson, PhD, MD, FRCPC
Stanford, CA, USA Associate Professor of Medicine
H.D. Alan Lindquist, PhD The Ottawa Hospital
Biologist Ottawa, ON, Canada
Senior Advisor
Water Supply and Water Resources Division Valérie Maghraoui-Slim, MD
National Risk Management Research Laboratory Hospital Practitioner
Office of Research and Development Department of Pediatrics
U.S. Environmental Protection Agency Bicêtre Hospital
Cincinnati, OH, USA Paris, France
Benjamin A. Lipsky, MD, FACP, FIDSA, FRCP Patrick W. Mallon, MB BCh, FRACP, PhD
Emeritus Professor Associate Dean for Research Innovation and Impact
Department of Medicine School of Medicine and Medical Science
University of Washington University College Dublin
Visiting Professor Dublin, Ireland
Department of Medicine (Infectious Diseases)
Geneva University Hospitals and Faculty of Medicine Julie E. Mangino, MD, FSHEA
Teaching Associate Professor of Medicine
Green Templeton College Division of Infectious Diseases
Division of Medical Sciences The Ohio State University College of Medicine
University of Oxford Medical Director
Oxford, UK Clinical Epidemiology at the Ohio State University Wexner Medical
Center
Christina Liscynesky, MD Columbus, OH, USA
Assistant Professor of Internal Medicine
Division of Infectious Disease Oriol Manuel, MD
The Ohio State University College of Medicine Associate Physician
Associate Medical Director Infectious Diseases Service and Transplantation Center
Clinical Epidemiology at the Ohio State University Wexner Medical University Hospital and University of Lausanne
Center Lausanne, Switzerland
Columbus, OH, USA
Oscar Marchetti, MD
David Looney, MD Associate Professor
Staff Physician Infectious Disease Infectious Diseases Service
VA San Diego Healthcare System Department of Medicine
Associate Professor of Medicine Lausanne University Hospital (CHUV)
University of California San Diego Lausanne, Switzerland
San Diego, CA, USA
Kristen M. Marks, MD, MS
Olivier Lortholary, MD, PhD Assistant Professor of Medicine
Professor of Infectious Diseases and Tropical Medicine Weill Cornell Medical College
Centre d’Infectiologie Necker–Pasteur New York, NY, USA
Hospital Necker Enfants Malades
Institut Pasteur
National Reference Center for Invasive Mycoses and Antifungals
Paris, France
List of Contributors xxvii
Kieren A. Marr, MD Rennatus Mdodo, DrPH, MS, MPhil

Professor of Medicine and Oncology Epidemiologist
Director, Transplant and Oncology Infectious Surveillance and Epidemiology Branch
Diseases Program Division of Global HIV/AIDS-Kenya
Johns Hopkins University School of Medicine Centers for Disease Control and Prevention
Baltimore, MD, USA Nairobi, Kenya
Jeanne Marrazzo, MD, MPH, FACP, FIDSA Simon Mead, MD

Director, Division of Infectious Diseases Honorary Consultant Neurologist and Professor of Neurology
Professor of Medicine MRC Prion Unit
University of Alabama at Birmingham School of Medicine Institute of Neurology
Birmingham, AL, USA University College London
London, UK
Jonas Marschall, MD, MSc
Director of Infection Prevention Francis Mégraud, MD
Department of Infectious Diseases Professor of Bacteriology
Bern University Hospital University of Bordeaux
Bern, Switzerland Bordeaux, France
Adjunct Assistant Professor
Division of Infectious Diseases Graeme Meintjes, MB ChB, FRCP(UK), FCP(SA),
Washington University School of Medicine in St Louis MPH, PhD
St Louis, MO, USA Associate Professor of Medicine
David H. Martin, MD University of Cape Town
Harry E. Dascomb Professor of Medicine and Professor of Cape Town, South Africa
Microbiology
Chief, Section of Infectious Diseases Sarah C. Metcalf, MB ChB, FRACP, DTM&H
Department of Internal Medicine Consultant Infectious Diseases Physician
Louisiana State University Health Sciences Center Department of Infectious Diseases
New Orleans, LA, USA Christchurch Hospital
Christchurch, New Zealand
Frédéric Matonti, MD
Ophthalmology Department Marian G. Michaels, MD, MPH
Aix–Marseille Université Professor of Pediatrics and Surgery
APHM, Hôpital Nord Pediatric Infectious Diseases
Marseille, France Children’s Hospital of Pittsburgh of UPMC University of Pittsburgh
School of Medicine
Richard S. Matulewicz, MS, MD Pittsburgh, PA, USA
Resident Physician
Department of Urology Giovanni Battista Migliori, MD, FRCP(Lond), FERS
Northwestern University Feinberg School of Medicine Director, WHO Collaborating Center for Tuberculosis and Lung
Chicago, IL, USA Diseases
Fondazione Salvatore Maugeri, Care and Research Institute
Kenneth H. Mayer, MD Tradate, Italy
Professor of Medicine and Community Health
Brown University Michael A. Miles, MSc, PhD, DSc, FRCPath
Director of Brown University Professor of Medical Protozoology
Infectious Diseases Division Department of Pathogen Molecular Biology
The Miriam Hospital Faculty of Infectious and Tropical Diseases
Providence, RI, USA London School of Hygiene and Tropical Medicine
London, UK
Russell J. McCulloh, MD
Assistant Professor, Infectious Diseases Alastair Miller, MA, FRCP, FRCP(Edin), DTM&H
Department of Pediatrics Honorary Senior Lecturer
Department of Internal Medicine Institute of Infection and Global Health
University of Missouri-Kansas City School of Medicine University of Liverpool
Kansas City, MO, USA Liverpool, UK
Deputy Medical Director
Rose McGready, MB BS, PhD Joint Royal College of Physicians Training Board
Professor of Tropical Maternal and Child Health London, UK
Maternal and Child Health
Shoklo Malaria Research Unit
Mae Sot, Tak, Thailand
xxviii List of Contributors
Matthew J. Mimiaga, ScD, MPH Didier Musso, MD

Professor of Epidemiology and Behavioral & Social Health Sciences Laboratory Director
(tenured) Unit of Emerging Infectious Diseases
Director, Institute for Community Health Promotion (ICHP) Institut Louis Malardé
Brown University, School of Public Health Tahiti, French Polynesia
Adjunct Professor of Epidemiology, Harvard School of Public Health
Senior Research Scientist and Director, Epidemiology and Global Mable Mutengo, MSc
Health Research, The Fenway Institute Chief Biomedical Scientist
Harvard Medical School Department of Pathology and Microbiology
Boston, MA, USA University Teaching Hospital
Lusaka, Zambia
Marie-Paule Mingeot-Leclercq, MSc, PharmD, PhD
Professor Misha M. Mutizwa, MD
Pharmacologie Cellulaire et Moléculaire Assistant Professor, Dermatology
Louvain Drug Research Institute Director, HIV Dermatology
Université Catholique de Louvain Temple University Hospital
Brussels, Belgium Philadelphia, PA, USA
Elizabeth Ann Misch, MD Kurt G. Naber, MD, PhD

Clinical Assistant Professor Associate Professor of Urology
Division of Allergy and Infectious Diseases Department of Urology
Department of Medicine Technical University of Munich
University of Washington Munich, Germany
Seattle, WA, USA
Pavithra Natarajan, BMedSci, BM BS, MCRCP,
Makedonka Mitreva, PhD DTM&H (Hons)
Assistant Professor of Medicine Infectious Diseases Division Specialist Registrar in Infectious Diseases and Tropical Medicine
Assistant Director Tropical and Infectious Diseases Unit
The Genome Institute Royal Liverpool Hospital
Washington University School of Medicine in St Louis Liverpool, UK
St Louis, MO, USA
Santiago Neme, MD, MPH
Julio S.G. Montaner, MD, DSc Medical Director
Professor of Medicine Infection Prevention and Employee Health Services
Faculty of Medicine Northwest Hospital/UW Medicine
University of British Columbia Clinical Instructor and Attending Physician
Vancouver, BC, Canada Division of Allergy and Infectious Diseases
Caroline B. Moore, MSc, PhD, MRSB University of Washington
Principal Clinical Mycologist Seattle, WA, USA
Mycology Reference Centre
University Hospital of South Manchester Paul N. Newton, DPhil, MRCP
University of Manchester Professor of Tropical Medicine, University of Oxford
Manchester, UK Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit
(LOMWRU)
Patricia Muñoz, MD, PhD Microbiology Laboratory
Clinical Microbiology and Infectious Diseases Department Mahosot Hospital
Hospital General Universitario Gregorio Marañón Vientiane
Instituto de Investigación Sanitaria del Hospital Gregorio Marañón Lao PDR
CIBER Enfermedades Respiratorias-CIBERES
Medicine Department Ronald A. Nichols, MD, MPH FACOG
School of Medicine Associate Program Director
Universidad Complutense de Madrid Obstetrics and Gynecology
Madrid, Spain Department of Obstetrics and Gynecology
Beaumont Oakwood
Jose Muñoz, MD, PhD Assistant Clinical Professor
Assistant Research Professor Wayne State University School of Medicine
ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Dearborn, MI, USA
Clínic-Universitat de Barcelona
Barcelona, Spain Lindsay E. Nicolle, MD, FRCPC
Professor
Clinton K. Murray, MD Departments of Internal Medicine and Medical Microbiology
Colonel, Medical Corps University of Manitoba
Professor of Medicine Winnipeg, Manitoba, Canada
Uniformed Service University Corps Specific Branch Proponent
Officer, Medical Corps
Army Medical Department Center and School
Houston, TX, USA
List of Contributors xxix
François Nosten, MD, PhD Laurent Papazian, MD, PhD

Professor of Tropical Medicine Assistance Publique–Hôpitaux de Marseille
Shoklo Malaria Research Unit Hôpital Nord
Mahidol–Oxford University Research Unit Réanimation des Détresses Respiratoires et des Infections Sévères
Mae Sot, Thailand Aix–Marseille Université
Marseille, France
Luigi D. Notarangelo, MD
Prince Turki bin Abdul Aziz al-Saud Professor of Pediatrics Diane M. Parente, PharmD
Harvard Medical School Clinical Pharmacist Specialist, Infectious Diseases
Division of Immunology The Miriam Hospital
Boston Children’s Hospital Providence, RI, USA
Boston, MA, USA Adjunct Assistant Professor
Department of Pharmacy Practice
Thomas B. Nutman, MD University of Rhode Island College of Pharmacy
Head, Helminth Immunology Section Kingston, RI, USA
Head, Clinical Parasitology Section
Laboratory of Parasitic Diseases Philippe Parola, MD, PhD
National Institute of Allergy and Infectious Diseases Professor of Medicine
National Institutes of Health Chief of the Acute infectious Diseases Unit
Bethesda, MD, USA University Hospital Institute For Infectious Diseases and Tropical
Medicine, Méditerranée Infection
Paul Nyirjesy, MD Aix-Marseille University
Professor of Obstetrics and Gynecology and of Medicine Marseille, France
Drexel University College of Medicine
Philadelphia, PA, USA Shadi Parsaei, DO
Instructor
P. Ronan O’Connell, MD, FRCSI, FRCS (Glas), FRCS Division of Infectious Diseases
(Edin) Washington University School of Medicine in St Louis
Professor of Surgery St Louis, MO, USA
Head, Section of Surgery and Surgical Specialties
School of Medicine and Medical Sciences Manuel A. Pascual, MD
University College Dublin Chief and Professor
Consultant Surgeon Transplantation Center
St Vincent’s University Hospital Medicine and Surgery
Dublin, Ireland University Hospital of Lausanne (CHUV)
Lausanne, Switzerland
Steven M. Opal, MD
Professor of Medicine Rupa Patel, MD, MPH
Infectious Disease Division Instructor
Alpert Medical School of Brown University Department of Medicine
Providence, RI, USA Washington University School of Medicine in St Louis
St Louis, MO, USA
L. Peter Ormerod, BSc, MB ChB(Hons), MD,
DSc(Med), FRCP Eleni Patrozou, MD
Professor of Medicine Research Associate
Chest Clinic Department of Medicine
Blackburn Royal Infirmary Alpert Medical School of Brown University
Blackburn, UK Providence, RI, USA
Douglas R. Osmon, MD Jean-Michel Pawlotsky, MD, PhD

Consultant Professor of Medicine
Division of Infectious Diseases Department of Virology
Mayo Clinic Henri Mondor Hospital, University of Paris-Est & INSERM U955
Rochester, MN, USA Créteil, France
Marie Boulze Pankert, MD Sharon J. Peacock, BM, FRCP, FRCPath, PhD

Maisonneuve-Rosemont Hospital Research Center Professor of Clinical Microbiology
Montreal, Québec, Canada Department of Medicine
Département d’ophtalmologie University of Cambridge
Université d’Aix-Marseille Cambridge, UK
Marseille, France
The late Jean-Claude Pechère
Giuseppe Pantaleo, MD Department of Microbiology and Molecular Medicine
Chief of Service University of Geneva
Immunology and Allergy Geneva, Switzerland
Centre Hospitalier Universitaire Vaudois
xxx List of Contributors
Ivan Pelegrin, MD Mathias W. Pletz, MD

Infectious Diseases Research Fellow Full Professor for Infectious Diseases
Infectious Diseases Department Center for Infectious Diseases and Infection Control
Hospital Universitari de Bellvitge Jena University Hospital
Barcelona, Spain Jena, Germany
Barry S. Peters, MB BS, MD, FRCP Jason M. Pogue, PharmD

Reader in Infectious Diseases Clinical Pharmacist, Infectious Diseases
Department of Infectious Diseases Department of Pharmacy Services
Kings College London Sinai-Grace Hospital; Detroit Medical Center
London, UK Detroit, MI, USA
Edgar J.G. Peters, MD, PhD Evelyn L. Polgreen, MS

Internist-Specialist in Infectious Diseases and Acute Medicine Environmental Science Consultant
VU University Medical Center Oxford, UK
Department of Internal Medicine
Amsterdam, The Netherlands Philip M. Polgreen, MD MPH
Associate Professor
Jeannine M. Petersen, PhD Department of Internal Medicine
Research Microbiologist University of Iowa
Division of Vector-Borne Diseases Iowa City, IA, USA
Fort Collins, CO, USA Klara M. Posfay-Barbe, MD, MS
Professor and Head of Pediatric Infectious Diseases Unit
Lyle R. Petersen, MD, MPH Department of Pediatrics
Director Children’s Hospital of Geneva, University Hospitals of Geneva
Division of Vector-Borne Diseases Geneva, Switzerland
Fort Collins, CO, USA William G. Powderly, MD, FRCPI
J. William Campbell Professor of Medicine
Vidmantas Petraitis, MD Larry J Shapiro Director, Institute for Public Health
Senior Research Associate Co-director, Division of Infectious Diseases
Transplantation-Oncology Infectious Diseases Program Washington University in St Louis
Weill Cornell Medicine of Cornell University St Louis, MO, USA
New York, NY, USA
Rachel Presti, MD, PhD
Luu-Ly Pham, MD Assistant Professor of Medicine
Former Senior Registrar Division of Infectious Disease, Department of Medicine
Hospital Practitioner Washington University School of Medicine in St Louis
Department of Pediatrics St Louis, MO, USA
Bicêtre Hospital
University of Paris Sud Guy Prod’hom, MD
Paris, France Head of Bacteriology Unit
Institute of Microbiology
Albert Picado, DVM, MSc, PhD Lausanne University Hospital Center and University of Lausanne
Assistant Research Professor Lausanne, Switzerland
Clínic-Universitat de Barcelona Mirja Puolakkainen, MD, PhD
Barcelona, Spain Adjunct Professor in Medical Microbiology
Department of Virology
Adrian Pilatz, MD University of Helsinki
Consultant Urologist Helsinki, Finland
Department of Urology, Pediatric Urology and Andrology
Justus Liebig University, Giessen Thomas C. Quinn, MD, MSc
Giessen, Germany Professor of Medicine and Pathology
Benoit Pilmis, MD Johns Hopkins School of Medicine
Hospital Practitioner Baltimore, MD, USA
Equipe Mobile d’Infectiologie
Service de Maladies Infectieuses et Tropicales Didier Raoult, MD, PhD
Hôpital Necker–Enfants Malades Professor, Faculté de Médecine, Director of the Foundation
Paris, France Mediterranee Infection Unité des Rickettsies
WHO Collaborative Center for Rickettsial Reference and Research
María-Jesús Pinazo, MD Marseille, France
Medical Doctor
International Health
Clínic-Universitat de Barcelona
Barcelona, Spain
List of Contributors xxxi
Raymund R. Razonable, MD, FIDSA, FAST Jürgen Kurt Rockstroh, MD, JKR
Professor of Medicine Professor of Medicine
Chair, Transplant Infectious Diseases Department of Medicine I
Division of Infectious Diseases Bonn University Hospital
Department of Medicine University of Bonn
William J von Liebig Center for Transplantation and Clinical Bonn, Germany
Regeneration
Mayo Clinic Amanda Rojek, BAppSci(Hons), MB BS, MSc
Rochester, MN, USA Medical Doctor
Doctor of Philosophy Candidate
Robert C. Read, MD, FRCP, FIDSA Epidemic Diseases Research Group, Centre for Tropical Medicine
Professor of Infectious Diseases and Global Health
University of Southampton Medical School University of Oxford
Southampton, UK Oxford, UK
Robert R. Redfield, MD José R. Romero, MD, FAAP

Professor of Medicine Professor of Pediatrics
Institute of Human Virology Horace C. Cabe Endowed Chair in Infectious Diseases
University of Maryland School of Medicine Director, Pediatric Infectious Diseases Section
Baltimore, MD, USA University of Arkansas for Medical Sciences and Arkansas Children’s
Hospital
Rob J. Rentenaar, MD, PhD Little Rock, AR, USA
Clinical Microbiologist
Department of Medica Microbiology Suzan H.M. Rooijakkers, PhD
University Medical Centre Utrecht Associate Professor
Utrecht, The Netherlands Medical Microbiology
University Medical Center Utrecht
Steven J. Reynolds, MD, MPH, FRCP(C) Utrecht, The Netherlands
Senior Clinician
National Institute of Allergy and Infectious Diseases Daniel Rosenbluth, MD
National Institutes of Health Tracey C. and William J. Marshall Professor of Medicine
Bethesda, MD, USA Division of Pulmonary and Critical Care Medicine
Associate Professor of Medicine and Epidemiology Washington University School of Medicine in St Louis
Division of Infectious Diseases St Louis, MO, USA
Johns Hopkins University
School of Medicine Sergio D. Rosenzweig, MD, PhD
Baltimore, MD, USA Deputy Chief, Immunology Service
Clinical Center, NIH
Camillo Ribi, MD Bethesda, MD, USA
Associated Physician
Department of Immunology and Allergy Gian Maria Rossolini, MD
CHUV University Hospital Lausanne Professor of Microbiology and Clinical Microbiology
Lausanne, Switzerland Department of Medical Biotechnologies
University of Siena
Malcolm D. Richardson, PhD, FSB, FRCPath Siena, Italy
Professor and Director Department of Experimental and Clinical Medicine
Mycology Reference Centre University of Florence
University Hospital of South Manchester Florence, Italy
University of Manchester Clinical Microbiology and Virology Unit
Manchester, UK Florence Careggi University Hospital
Florence, Italy
Michele L. Ritter, MD
Associate Clinical Professor of Medicine The late Ethan Rubinstein, MD, LLB
Division of Infectious Diseases Sellers Professor and Head
Department of Medicine Section of Infectious Diseases
University of California Faculty of Medicine, Winnipeg
San Diego, CA, USA Manitoba, Canada
Antoine Roch, MD, PhD Greg Ryan, MB, DCH, FRCOG, FRCSC
Professor of Medicine Staff Perinatologist
Assistance Publique–Hôpitaux de Marseille Director
Hôpital Nord Fetal Medicine Program
Réanimation des Détresses Respiratoires et des Infections Sévères Mount Sinai Hospital
Aix–Marseille Université Professor
Marseille, France Department of Obstetrics & Gynaecology and Medical Imaging
Division of Maternal-Fetal Medicine
University of Toronto
Toronto, ON, Canada
xxxii List of Contributors
Steven A. Safren, PhD, ABPP Richard F. Schumacher, MD

Professor ID Consultant in the Pediatric Hematology-Oncology Unit
Department of Psychology Pediatric Infectious Diseases (DGPI)
University of Miami Pediatric Hematology Oncology Unit
Coral Gables, FL, USA University Children’s Hospital, Spedali Civili
Brescia, Italy
Vikrant V. Sahasrabuddhe, MB BS, MPH, DrPH
Program Director Beverly E. Sha, MD
Division of Cancer Prevention Professor of Medicine
National Cancer Institute Division of Infectious Diseases
Rockville, MD, USA Rush University Medical Center
Chicago, IL, USA
Pekka A.I. Saikku, MD, PhD
Emeritus Professor of Microbiology Daniel S. Shapiro, MD
University of Oulu Professor of Internal Medicine
Oulu, Finland University of Nevada School of Medicine
Reno, NV, USA
Mohammad M. Sajadi, MD
Associate Professor of Medicine Gerard Sheehan, MB, FRCPI
Institute of Human Virology Senior Lecturer
University of Maryland School of Medicine School of Medicine and Medical Sciences
Baltimore, MD, USA University College Dublin
Consultant in Infectious Diseases
Michelle R. Salvaggio, MD Mater Misericordiae University Hospital
Associate Professor Dublin, Ireland
Infectious Diseases Section, Department of Internal Medicine
University of Oklahoma Health Sciences Center David M. Shlaes, MD, PhD
Oklahoma City, OK, USA Retired (from Anti-infectives Consulting, LLC)
Stonington, CT, USA
Carlos A.Q. Santos, MD
Assistant Professor of Medicine Shmuel Shoham, MD
Division of Infectious Diseases Associate Professor of Medicine
Washington University School of Medicine in St Louis Division of Infectious Diseases
Saint Louis, MO, USA Johns Hopkins University School of Medicine
Baltimore, MD, USA
Michael J. Satlin, MD, MS
Assistant Professor of Medicine Cameron P. Simmons, PhD
Department of Internal Medicine Senior Research Fellow
Division of Infectious Diseases Department of Microbiology and Immunology
Weill Cornell Medical College University of Melbourne
New York, NY, USA Carlton, Victoria, Australia
Senior Research Fellow
Anthony J. Schaeffer, MD Nuffield Department of Clinical Medicine
Chair, Department of Urology University of Oxford
Herman L. Kretschmer Professor of Urology Oxford, UK
Professor in Urology
Northwestern University Feinberg School of Medicine Dennis W. Simon, MD
Chicago, IL, USA Assistant Professor
Department of Pediatrics and Critical Care Medicine
Christoph Schimmer, MD Children’s Hospital of Pittsburgh of UPMC
Consultant of Cardiac Surgery Pittsburgh, PA, USA
Department of Cardiac Surgery
University of Würzburg Matthew S. Simon, MD, MS
Würzburg, Germany Assistant Professor of Medicine
Robert T. Schooley, MD Weill Cornell Medical College
Professor and Head New York, NY, USA
Academic Vice Chair Kari A. Simonsen, MD
Department of Medicine Associate Professor of Pediatrics
University of California San Diego Chief, Division of Pediatric Infectious Diseases
San Diego, CA, USA University of Nebraska Medical Center
Omaha, NE, USA
List of Contributors xxxiii
Mary P.E. Slack, MA, MB BChir, FRCPath Evelina Tacconelli, MD, PhD
Professor Professor of Infectious Diseases
School of Medicine Division of Infectious Diseases, Department of Internal Medicine
Gold Coast Campus University of Tübingen
Griffith University Tübingen, Germany
Queensland, Australia
Chen Sabrina Tan, MD
Tyrel T. Smith Assistant Professor of Medicine
Howard Hughes Med-Grad Fellow Beth Israel Deaconess Medical Center
Department of Pediatrics Infectious Diseases Harvard Medical School
University of Alabama at Birmingham School of Medicine Boston, MA, USA
Birmingham, AL, USA
Randy A. Taplitz, MD
Jack D. Sobel, MD Professor of Clinical Medicine
Professor of Medicine Division of Infectious Diseases
Division of Infectious Diseases Department of Medicine
Wayne State University School of Medicine University of California
Detroit, Michigan, USA San Diego, CA, USA
Maria Souli, MD Guillemette Thomas, MD

Assistant Professor of Medicine and Infectious Diseases Assistance Publique–Hôpitaux de Marseille
Fourth Department of Medicine Hôpital Nord
National and Kapodistrian University of Athens Réanimation des Détresses Respiratoires et des Infections Sévères
Athens, Greece Aix–Marseille Université
Marseille, France
Shruti Sridhar, MBBS, MSc, Public Health
Research Assistant Lora D. Thomas, MD, MPH
Department of Tropical Diseases Assistant Professor
Aix-Marseille University Division of Infectious Diseases
Marseille, France Vanderbilt University School of Medicine
Nashville, TN, USA
James M. Steckelberg, MD
Professor of Medicine Franck Thuny, MD, PhD
Division of Infectious Diseases Professor of Cardiology
Mayo Clinic College of Medicine Head of Unit of Heart Failure and Valve Heart Diseases
Rochester, MN, USA Department of Cardiology, University Hospital Nord Aix–Marseille
University of Marseille
Dennis L. Stevens, PhD, MD Marseille, France
Chief, Infectious Disease Section
Veterans Affairs Medical Center Guy Thwaites
Boise, ID, USA Professor of Infectious Diseases
Heather Strah, MD University of Oxford, Oxford, UK
Assistant Professor of Medicine Director
Division of Pulmonary, Critical Care, Sleep and Allergy Oxford University Clinical Research Unit
Department of Internal Medicine Ho Chi Minh City
University of Nebraska Medical Center Vietnam
Omaha, NE, USA
Frederic Tissot, MD
A. Willem Sturm, MD, PhD Chief Resident
Emeritus Professor Medical Microbiology Infectious Diseases Service
Nelson R Mandela School of Medicine Centre Hospitalier Universitaire Vaudois and Lausanne University
University of KwaZulu-Natal Hospital
Congella, South Africa Lausanne, Switzerland
Somnuek Sungkanuparph, MD Tone Tønjum, MD, PhD

Professor of Medicine Professor, Chief Physician
Department of Medicine Department of Microbiology
Faculty of Medicine Ramathibodi Hospital Oslo University Hospital
Mahidol University University of Oslo
Bangkok, Thailand Oslo, Norway
Sarah J. Tabrizi, BSc(Hons), FRCP, PhD Francesca J. Torriani, MD

Professor of Neurology Professor of Clinical Medicine
Department of Neurodegenerative Diseases/MRC Prion Unit Division of Infectious Diseases
Institute of Neurology Department of Medicine
London, UK University of California
San Diego, CA, USA
xxxiv List of Contributors
Christian Toso, MD, PhD Jos W.M. van der Meer, MD, PhD, FRCP,
Assistant Professor FRCP(Edin), FIDSA, MAE
Divisions of Abdominal and Transplantation Surgery Emeritus Professor of Medicine
Geneva University Hospitals and Faculty of Medicine Radboud University Medical Centre
Geneva, Switzerland Nijmegen, The Netherlands
Paul M. Tulkens, MD, PhD Tom van der Poll, MD, PhD
Professor Emeritus Professor of Medicine
Professor Invited Center of Experimental and Molecular Medicine & Division of
Pharmacologie Cellulaire et Moléculaire Infectious Diseases
Louvain Drug Research Institute Academic Medical Center
Université Catholique de Louvain University of Amsterdam
Brussels, Belgium Amsterdam, The Netherlands
Allan R. Tunkel, MD, PhD Jakko van Ingen, MD, PhD

Professor of Medicine Clinical Microbiology Resident
Associate Dean for Medical Education Department of Medical Microbiology
Warren Alpert Medical School of Brown University Radboud University Medical Center
Providence, RI, USA Nijmegen, The Netherlands
Claire E. Turner, PhD Jos van Putten, MD, PhD

Imperial College Junior Research Fellow Professor of Infection Biology
Department of Medicine Infectious Diseases and Immunology
Imperial College London Utrecht University
London, UK Utrecht, The Netherlands
Andrew P. Ustianowski, FRCP, PhD Bernard P. Vaudaux, MD

Consultant in Infectious Diseases and Tropical Medicine Former Head, Unit of Pediatric Infectious Diseases and Vaccinology
NW Regional Infectious Diseases Unit Department of Pediatrics
North Manchester General Hospital Centre Hospitalier Universitaire Vaudois and Hôpital de l’Enfance
Manchester, UK de Lausanne
Françoise van Bambeke, PharmD, PhD
Professor and Senior Research Associate Sten H. Vermund, MD, PhD
Pharmacologie Cellulaire et Moléculaire Assistant Vice Chancellor for Global Health
Louvain Drug Research Institute Amos Christie Chair and Professor of Pediatrics
Université Catholique de Louvain Department of Pediatrics and Vanderbilt Institute for Global Health
Brussels, Belgium Vanderbilt University School of Medicine
Nashville, TN, USA
Reinout van Crevel, MD, PhD
Infectious Diseases Specialist Raphael P. Viscidi, MD
Department of Medicine Professor of Pediatrics
Radboud University Medical Centre Pediatrics
Nijmegen, The Netherlands Johns Hopkins University School of Medicine
Baltimore, MD, USA
Diederik van de Beek, MD, PhD
Professor of Neurology Kumar Visvanathan, MB BS, PhD
Department of Neurology Professor of Medicine
Academic Medical Centre University of Melbourne
University of Amsterdam ID Physician and Clinical Director
Amsterdam, The Netherlands St Vincent’s Hospital
Fizroy, Victoria, Australia
Christian van Delden, MD
Associate Professor of Medicine Govinda S. Visvesvara, PhD
Service of Infectious Diseases, Department of Medical Specialties Microbiologist
Geneva University Hospitals and Faculty of Medicine National Center for Emerging and Zoonotic Infectious Diseases
Geneva, Switzerland Centers for Disease Control and Prevention
Atlanta, GA, USA
Menno M. van der Eerden, MD, PhD
Pulmonologist Lorenz von Seidlein, MD, PhD
Department of Pulmonary Diseases Project Coordinator
Erasmus Medical Center Mahidol-Oxford Tropical Medicine Research Unit (MORU)
Rotterdam, The Netherlands Faculty of Tropical Medicine
Mahidol University
Bangkok, Thailand
List of Contributors xxxv
Florian M.E. Wagenlehner, MD David J. Weatherall, MD, FRCP, FRS

Professor of Urology Regius Professor Emeritus
Clinic for Urology, Pediatric Urology and Andrology Weatherall Institute of Molecular Medicine
Justus-Liebig-University Giessen University of Oxford
Giessen, Germany Oxford, UK
Anna Wald, MD, MPH Rainer Weber, MD

Professor Professor of Infectious Diseases
Department of Medicine, Epidemiology, and Laboratory Medicine Division of Infectious Diseases and Hospital Epidemiology
University of Washington University Hospital
Member, Vaccines and Infectious Diseases Division Zurich, Switzerland
Fred Hutchinson Cancer Research Center
Seattle, WA, USA Wolfgang Weidner, MD, PhD
Professor of Urology
Thomas J. Walsh, MD, PhD (hon), FAAM, FIDSA Clinic for Urology, Pediatric Urology and Andrology
Director, Transplantation-Oncology Infectious Diseases Program Justus-Liebig University Giessen
Professor of Medicine, Pediatrics, and Microbiology & Immunology Giessen, Germany
Weill Cornell Medicine of Cornell University
New York, NY Jonathan R. White, MBChB, MRCP
Clinical Research Fellow in Gastroenterology
David C. Warhurst, BSc, PhD, DSc NIHR Biomedical Research Unit in Gastrointestinal and Liver
Emeritus Professor of Protozoan Chemotherapy Diseases
Department of Pathogen Molecular Biology Nottingham University Hospitals NHS Trust
London School of Hygiene & Tropical Medicine University of Nottingham, Queen’s Medical Centre
London, UK Nottingham, UK
David W. Warnock, BSc, PhD, FAAM, FRCPath Peter J. White, PhD

Honorary Professor of Medical Mycology Head, Modelling and Economics Unit
Faculty of Medical and Human Sciences Public Health England Centre for Infectious Disease Surveillance
University of Manchester and Control, London, UK
Manchester, UK MRC Centre for Outbreak Analysis and Modelling and NIHR HPRU
in Modelling Methodology
David A. Warrell, DM, DSc, FRCP, FRCPE, FMedSci Department of Infectious Disease Epidemiology
International Director (Hans Sloane Fellow), Royal College of Imperial College London
Physicians, London, UK London, UK
Emeritus Professor of Tropical Medicine, Nuffield Department of
Clinical Medicine and Honorary Fellow of St Cross College, James Whitehorn, PhD, MRCP
University of Oxford, Oxford, UK Research Fellow
Principal Fellow, Australian Venom Research Unit, Department of Department of Clinical Research
Pharmacology and Therapeutics, University of Melbourne, London School of Hygiene and Tropical Medicine
Melbourne, Australia London, UK
International Advisor, Australian DFAT Myanmar Snake-Bite Oxford University Clinical Research Unit Vietnam
Project, University of Adelaide, Adelaide, Australia Oxford, UK
Mary J. Warrell, MB, BS, FRCP, FRCPath Richard J. Whitley, MD

Honorary Senior Researcher Distinguished Professor
Oxford Vaccine Group Loeb Chair in Pediatrics
Centre for Clinical Vaccinology & Tropical Medicine Professor of Pediatrics, Microbiology,
University of Oxford Medicine and Neurosurgery
Oxford, UK University of Alabama
Birmingham, AL, USA
Adilia Warris, MD, PhD
Professor of Paediatric Infectious Diseases Christopher J.M. Whitty, FRCP, DTM&H
Institute of Medical Sciences Consultant Physician
University of Aberdeen The Hospital for Tropical Diseases
Aberdeen, UK Professor of International Health
London School of Hygiene & Tropical Medicine
Richard R. Watkins, MD, MS, FACP London, UK
Associate Professor of Internal Medicine
Northeast Ohio Medical University Willem Joost Wiersinga
Rootstown, OH, USA Consultant, Internal Medicine and Infectious Diseases
Division of Infectious Diseases Principal Investigator
Akron General Medical Center Department of Medicine
Akron, OH, USA Division of Infectious Diseases and Center for Experimental
Molecular Medicine (CEMM)
Academic Medical Center
University of Amsterdam
xxxvi List of Contributors
Mark H. Wilcox, BMedSci, BM, BS, MD, FRCPath Zhi-Tao Yang, MD, PhD
Consultant and Professor of Medical Microbiology Doctor in Charge of ICU
Department of Microbiology Emergency Department/Pôle Sino-Français de Recherches en Science
Leeds Teaching Hospitals du Vivant et Génomique
University of Leeds & Public Health England Ruijin Hospital
Leeds, UK Shanghai Jiaotong University, School of Medicine
Shanghai, China
Thomas N. Williams, MB BS, MRCP, PhD
Professor of Haemoglobinopathy Research Jonathan S. Yoder, MSW, MPH
Department of Medicine Water Preparedness and Response Coordinator
Imperial College, National Center for Emerging and Zoonotic Infectious Diseases
London, UK Centers for Disease Control and Prevention
Atlanta, GA, USA
Cara C. Wilson, MD
Professor Najam A. Zaidi, MD, FACP, FIDSA
Infectious Diseases Division Consulting Infectious Disease Attending
University of Colorado School of Medicine Division of Infectious Disease
Denver, CO, USA Roger Williams Medical Center
Providence, RI, USA
Mary Elizabeth Wilson, MD Medical Director
Adjunct Professor Infection Control and Antibiotic Stewardship
Global Health and Population St Luke’s Hospital
Harvard T.H. Chan School of Public Health New Bedford, MA, USA
Boston, MA, USA Assistant Professor of Medicine (Clinical)
Visiting Professor of Epidemiology and Biostatistics Warren Alpert School of Medicine
School of Medicine Brown University
University of California San Francisco Providence, RI, USA
San Francisco, CA, USA
Andrea J. Zimmer, MD
Hilmar Wisplinghoff, MD Assistant Professor of Medicine
Physician Department of Medicine, Division of Infectious Diseases
Institute for Medical Microbiology, Immunology and Hygiene University of Nebraska Medical Center
University of Cologne Omaha, NE, USA
Cologne, Germany
Jane N. Zuckerman, MD, FRCP, FRCPath, FFPH,
Robin Wood, MD, DSC (Med) FFTM
Emeritus Professor of Medicine Consultant in Travel Medicine
Desmond Tutu HIV Centre Department of Infection
Institute of Infectious Disease & Molecular Medicine and Royal Free London NHS Foundation Trust
Department of Medicine Honorary Senior Lecturer
University of Cape Town Department of Infection
Cape Town, South Africa University College London
London, UK
Richard G. Wunderink, MD
Professor of Medicine Alimuddin Zumla, GCDS, FRCP(Lond), FRCP(Edin),
Division of Pulmonary and Critical Care FRCPath(UK), PhD(Lond), FSB(UK)
Northwestern University Feinberg School of Medicine Professor of Infectious Diseases and International Health
Chicago, IL, USA Division of Infection and Immunity
University College London
David Wyles, MD Consultant Infectious Diseases Physician
Associate Professor of Medicine University College London Hospitals NHS Foundation Trust
Division of Infectious Diseases London, UK
University of California San Diego
San Diego, CA, USA
We dedicate this work to our teachers, who inspired and
encouraged us; our students for their enthusiasm and new
ideas; and our families for putting up with us for all
these years.
SECTION 1: Introduction to Infectious Diseases
1
The Evolution of Koch’s Postulates
JONATHAN COHEN
KEY CONCEPTS the emergence of clinical virology as a discipline. Viruses proved to be

particularly challenging to fit into Koch’s structures and a number of
• Robert Koch developed his famous postulates as a way of writers, notably Thomas Rivers1 and Robert Huebner,4 developed alter-
trying to bring some order and scientific rigor into the debate native paradigms to try to get round the problem. By the 1970s the
surrounding the microbial cause of disease. problems had multiplied, not least because of the discovery of ‘slow
• Although his ideas were helpful, even Koch himself recognized viruses’ and the recognition of the possible role of micro-organisms
the limitations of his approach. These limitations became even in some chronic diseases. The British writer Alfred Evans revised the
more apparent with the emergence of clinical virology as a original Koch’s postulates, and Evans’ ideas remain useful5 (Box 1-2).
discipline. Viruses proved to be particularly challenging to fit The advent of molecular microbiology allowed not only the
in to Koch’s structures. identification of micro-organisms without the requirement for their
• The emergence in the 1980s of the field of the molecular cultivation on solid media, but also the notion that ‘virulence’ and
pathogenesis of microbial disease created new challenges, and ‘pathogenicity’ could be attributed to certain microbial genes or gene
led to the idea of ‘molecular’ Koch’s postulates.
• Finally, it was recognized that Koch’s postulates were not
helpful when thinking about immunocompromised patients, or BOX 1-1 KOCH’S POSTULATES
in those cases where infection played an ‘indirect’ role, such as
in the pathogenesis of cancer. Based on Koch’s presentation to the Tenth International Congress of Medi-
cine in Berlin, 1890.
• Today, Koch’s postulates are primarily of historical interest 1. The parasite occurs in every case of the disease in question and under
although they continue to provide a useful framework in which circumstances which can account for the pathological changes and
clinical course of the disease.
to consider the pathogenesis of disease. 2. The parasite occurs in no other disease as a fortuitous and nonpatho-
genic parasite.
3. After being fully isolated from the body and repeatedly grown in pure
culture, the parasite can induce the disease anew.
4. The parasite can be re-isolated from an experimentally inoculated
Introduction host.*
At one time diseases were thought to be caused by the wrath of the
gods, configuration of the stars or miasmas.1 It was not until the latter *The fourth postulate was in fact added by later writers.
part of the 19th century that micro-organisms began to be accepted
– at least by some scientists – as the cause of infectious diseases, and
it was then that Robert Koch developed his famous principles (postu-
lates) as a way of trying to bring some order and scientific rigor into BOX 1-2 EVANS’ PRINCIPLES OF THE CAUSATION
what had become a sometimes difficult debate. Since that time Koch’s OF DISEASE, 19765
postulates have achieved almost totemic significance in biology and
Based on the original Koch’s postulates, Evans’ principles were important
medicine, yet it became clear very quickly that they had serious limita- because they incorporated both the epidemiological principles first devel-
tions. This chapter discusses what role they play, if any, in understand- oped by Sir Austin Bradford Hill, and also the immunological notion of a
ing the modern world of infection. specific host response as providing evidence that an organism was contribut-
ing to the cause of a disease.
• Prevalence of the disease should be significantly higher in those
A Historical Perspective exposed to the putative cause than in control cases not so exposed.
In 1840 the German anatomist Friedrich Henle wrote a paper consid- • Exposure to the putative cause should be present more commonly in
those with the disease than in controls without the disease when all
ering what would be required to confidently attribute causation to risk factors are held constant.
micro-organisms that had been associated with various infectious dis- • Incidence of the disease should be significantly higher in those
eases (for a detailed account of the historical background see reference exposed to the putative cause than in those not exposed, as shown in
2). Robert Koch entered medical school at the University of Göttingen prospective studies.
• Temporally, the disease should follow exposure to the putative agent
in 1862 and came to know Henle well, but it was not until 1882 that with a distribution of incubation periods on a bell-shaped curve.
Koch formulated what have come to be known as Koch’s postulates, or • A spectrum of host responses should follow exposure to the putative
sometimes as Henle–Koch’s postulates. Koch was working at a time agent along a logical biologic gradient from mild to severe.
that has been called the ‘bacteriological revolution’ of 19th century • A measurable host response following exposure to the putative cause
should regularly appear in those lacking this before exposure or should
medicine, although some historians have challenged this.3 What is increase in magnitude if present before exposure.
certainly true is that during the latter part of the 19th century there • Experimental reproduction of the disease should occur in higher inci-
was an explosion of knowledge about micro-organisms and, of course, dence in animals or humans appropriately exposed to the putative
Koch himself was pivotal in demonstrating the microbial etiology of cause than in those not so exposed; this exposure may be deliberate
in volunteers, experimentally induced in the laboratory, or demon-
tuberculosis and anthrax. But it was not always easy to persuade strated in a controlled regulation of natural exposure.
detractors, and he hoped that these principles, presented to a scientific • Elimination or modification of the putative cause or of the vector car-
meeting in Berlin in 1890, would bring some order into the debate rying it should decrease the incidence of the disease.
(Box 1-1). • Prevention or modification of the host’s response on exposure to the
putative cause should decrease or eliminate the disease (e.g., immu-
Koch’s ideas undoubtedly helped, but as we shall see, even Koch nization or drug).
himself recognized the limitations of his approach. These limitations • The whole thing should make biologic and epidemiologic sense.
became even more apparent as the new century dawned and with it
1
2 SECTION 1 Introduction to Infectious Diseases
TABLE The Growing List of Situations in Which It Has Become Difficult or Impossible to Apply Koch’s Postulates as
1-1 Originally Conceived, Despite Very Clear Evidence for Causation
Colonization vs carrier state vs infection Candida albicans; Neisseria meningitidis
Inability to isolate the organism in pure culture Mycobacterium leprae
Inability to isolate the organism in cell-free culture Plasmodium falciparum
Organisms for which humans are the only host Herpes simplex virus
Subclinical infection Mycobacterium tuberculosis
Organisms that cause ‘distant’ infection Streptococcus pyogenes/rheumatic fever; measles virus/SSPE
Disease caused by toxins Staphylococcus aureus/toxic shock syndrome
Diseases that require coinfection Hepatitis D virus/hepatitis B virus

Wucheria and Wolbachia endosymbionts (filariasis)
Organisms associated with tumors EBV (Burkitt lymphoma); HHV-8 (Kaposi’s sarcoma); Helicobacter pylori (gastric cancer)
Bacteria that require phage DNA to acquire virulence Corynebacterium diphtheriae

Organisms identified only by molecular probes Tropheryma whipplei (Whipple’s disease) (subsequently successfully cultivated)
EBV, Epstein–Barr virus; HHV-8, human herpesvirus 8; SSPE, subacute sclerosing panencephalitis.
families. Falkow’s paper in 1988 on ‘molecular Koch’s postulates’ was

an attempt to reconcile 20th century science with 19th century deter- BOX 1-3 ‘MOLECULAR’ KOCH’S POSTULATES
ministic principles,6 and this debate has continued.2,7 An attempt to update the original concepts to create a framework that would
allow the identification of genes associated with bacterial virulence.6
Limitations of Koch’s Postulates • The phenotype or property under investigation should be associated
with pathogenic members of a genus or pathogenic strains of a
It became apparent almost immediately that there were instances species.
where causation was very likely but the postulates could not be made • Specific inactivation of the gene(s) associated with the suspected viru-
to ‘fit’ the evidence. Koch himself believed Vibrio cholerae to be the lence trait should lead to a measurable loss in pathogenicity or viru-
lence, or the gene(s) associated with the supposed virulence trait
cause of cholera, but because the organism had also been isolated from should be isolated by molecular methods. Specific inactivation or dele-
otherwise healthy carriers his second principle was breached. As time tion of the gene(s) should lead to loss of function in the clone.
passed, more and more examples emerged that stretched the utility of • Reversion or allelic replacement of the mutated gene should lead to
Koch’s postulates right up to – and indeed beyond – the limit of plau- restoration of pathogenicity, or the replacement of the modified
gene(s) for its allelic counterpart in the strain of origin should lead to
sibility (Table 1-1). loss of function and loss of pathogenicity or virulence. Restoration of
As others have observed, the problem with Koch’s postulates is not pathogenicity should accompany the reintroduction of the wild-type
that they are wrong, but rather, that they apply only to a very limited gene(s).
number of circumstances. The rapid growth in microbiology led to the
recognition not only of many more bacterial species, but crucially, to
the discovery of the role that viruses play in human disease. As Huebner
trenchantly commented in 1957: relied on them we would not have been in the position of being certain
that human papillomaviruses were implicated in the cause of cervical
it is quite obvious that the clinician seldom if ever knows that the
cancer and we would not today have an effective vaccine against this
illness he describes actually is caused by a virus or, if so, what virus
disease.
is implicated. Similarly, the virologist reporting new and prevalent
Finally, Koch’s postulates are not helpful when it comes to ascribing
agents very often has only slightly more information and, usually, no
causality in immunocompromised patients. We know that recognized
greater certainty about the clinical behavior and importance of his
organisms of very low virulence10 or even entirely unknown bacteria11
viruses than does the clinician.4
can cause clinically significant disease in heavily immunocompromised
The problems remain, and are well illustrated by the difficulties in individuals even though they would certainly not fulfil Koch’s
understanding what role, if any, a newly identified virus such as boca- criteria.
virus might have in causing disease.8
Pari passu with the growth of diagnostic microbiology came an Virulence, Pathogenicity
explosive growth in the understanding of pathogenesis of microbial
disease, the concepts of the carrier state and of colonization, of coinfec- and Causation
tion and the notion that micro-organisms could cause ‘distant’ disease. The emergence in the 1980s of the field of the molecular pathogenesis
Nowadays we accept that Streptococcus pyogenes is the primary cause of microbial disease created new challenges, and led to Falkow develop-
of rheumatic fever, that Reiter’s syndrome can follow an episode ing the idea of ‘molecular’ Koch’s postulates6 (Box 1-3). At that early
of shigellosis, that hepatitis virus can be the antigen of cryoglobuline- stage it seemed reasonable to suppose that it would be possible to
mia, or that Brill–Zinsser disease is a late complication of rickettsial identify single genes that conferred virulence to an organism, and the
infection, but these examples completely overturn the classical concept updated postulates were designed to help identify where this could be
of an ‘infectious disease’. Tumor viruses pose similar challenges. safely imputed from the data. The subsequent explosion of our knowl-
Unequivocal evidence now exists implicating Epstein–Barr virus edge has led to a much more complex picture: we now have complete
(EBV) in the pathogenesis of Burkitt lymphoma, of hepatitis B in genome sequences for a large number of important human pathogens,
hepatoma, and of KSHV (Kaposi’s sarcoma-associated herpesvirus, or we understand that there are groups, or islands of genes associated with
human herpesvirus 8 [HHV-8]) in Kaposi’s sarcoma and multicentric pathogenicity, and we have new experimental models such as the zebra
Castleman’s disease (MCD). Yet Koch’s postulates are completely fish or the fruit fly in which to study molecular virulence factors.7 A
unsuited to proving causality in these situations,9 and indeed if we had detailed discussion of the concepts of virulence, pathogenesis and
Chapter 1 The Evolution of Koch’s Postulates 3
causation is beyond the scope of this chapter and suffice it to say they
are not identical. But as an example, consider a strain of Staphylococcus TABLE Examples of Chronic Diseases in Which
aureus containing TSST-1, the gene for toxic shock syndrome toxin. 1-2 Micro-organisms Have Been Implicated
This same strain might be found as a harmless commensal in the nose, in the Cause*
or causing a simple superficial skin abscess, as a destructive lesion of
Disease Suggested Causative Organisms
the aortic valve in a patient with endocarditis or associated with a
fulminating toxic shock syndrome. TSST-1 is certainly a ‘virulence Kawasaki disease Unknown (multiple candidates: EBV;
gene’ but it is probably only contributing to the disease in the last of Mycoplasma pneumoniae; VZV; adenoviruses)
these scenarios. Kikuchi’s disease Unknown (multiple viral candidates)
Crohn’s disease Mycobacterium paratuberculosis

Beyond Infection: Micro-organisms
Acne Proprionobacterium acnes
and Chronic Disease
Sarcoidosis Mycobacteria; P. acnes; herpesviruses
We have already noted conditions such as rheumatic fever or Reiter’s
disease in which micro-organisms are clearly implicated, and also Type I diabetes mellitus Enteroviruses
several malignancies that are either directly or indirectly caused by Schizophrenia Endogenous retroviruses
tumor viruses. But beyond these relatively clear-cut cases lies a huge
range of conditions in which micro-organisms have been implicated, Multiple sclerosis Measles (and many other viruses)
usually on the basis of either epidemiological evidence (be that sero- Atherosclerosis Chlamydia pneumoniae; CMV
logical or based on prevalence data) or histopathological findings Chronic fatigue Borrellia burgdorferi (‘chronic neuroborrelliosis’);
(Table 1-2). The subject was reviewed exhaustively in a 2004 Institute syndrome Candida albicans (‘Candida syndrome’); EBV;
of Medicine report12 and again more recently in a paper that used XMRV
published data and aligned these with Koch’s and Hill’s criteria to
*Note that in none of these cases has causation been proved, and in most the
gauge the level of evidence supporting a role for micro-organisms in association is tenuous at best. The list is intended simply to demonstrate the
chronic diseases.13 They concluded that there was reasonably strong wide range of diseases and potential causes, and is not exhaustive.
evidence to implicate five organisms (HIV, hepatitis B, hepatitis C, CMV, cytomegalovirus; EBV, Epstein–Barr virus; VZV, varicella-zoster virus;
Helicobacter pylori and Chlamydia pneumoniae) in as many as 37 dif- XMRV, xenotropic murine leukemia virus-related-virus.
ferent chronic conditions.
Most recently, scientists have begun to consider the huge biomass
of bacteria in the human gut and have developed the idea of the gut circumstances in which bacteria can be precisely tied to the cause of a
microbiota and the influence that these organisms can have on condi- particular clinical syndrome. But in a world in which viruses cause
tions as diverse as allergies, irritable bowel disease, Crohn’s disease and cancer and noncultivable bacteria can be demonstrated by molecular
even obesity.14 With a pleasing circularity, Zhao has recently used probes, Koch’s postulates are no longer fit for purpose. What is more,
Koch’s postulates to discuss how we might try to identify causality in used uncritically they have the potential to mislead.16 Their main
this very difficult area.15 purpose now is to provide a framework to ensure that scientific rigor
is applied when proposing an organism as the cause of a disease –
Conclusions – and a Note of Caution exactly as Koch intended when he first conceived them.
Koch’s postulates were invaluable at the time they were developed
and remain largely valid for a relatively small number of defined References available online at expertconsult.com.
KEY REFERENCES
Evans A.S.: Causation and disease: the Henle–Koch postu- Knobler S.L., O’Connor S., Lemon S.M., et al., ed.: The Orrskog S., Medin E., Tsolova S., et al.: Causal inference
lates revisited. Yale J Biol Med 1976; 49(2):175-195. infectious etiology of chronic diseases: defining the relation- regarding infectious aetiology of chronic conditions: a
Falkow S.: Molecular Koch’s postulates applied to bacterial ship, enhancing the research, and mitgating the effects – systematic review. PLoS One 2013; 8(7):e68861.
pathogenicity – a personal recollection 15 years later. Nat Workshop Summary. Washington, DC: National
Rev Microbiol 2004; 2(1):67-72. Acadamies Press; 2004.
Fredericks D.N., Relman D.A.: Sequence-based identifica- Moore P.S., Chang Y.: The conundrum of causality in
tion of microbial pathogens: a reconsideration of Koch’s tumor virology: the cases of KSHV and MCV. Semin
postulates. Clin Microbiol Rev 1996; 9(1):18-33. Cancer Biol 2014; 26:4-12.
Chapter 1 The Evolution of Koch’s Postulates 3.e1
REFERENCES
1. Rivers T.M.: Viruses and Koch’s postulates. J Bacteriol 7. Falkow S.: Molecular Koch’s postulates applied to bacte- 12. Knobler S.L., O’Connor S., Lemon S.M., et al.: eds. The
1937; 33(1):1-12. rial pathogenicity – a personal recollection 15 years infectious etiology of chronic diseases: defining the rela-
2. Fredericks D.N., Relman D.A.: Sequence-based identi- later. Nat Rev Microbiol 2004; 2(1):67-72. tionship, enhancing the research, and mitgating the effects
fication of microbial pathogens: a reconsideration 8. Williams J.V.: Déjà vu all over again: Koch’s postulates – Workshop Summary. Washington, DC: National Acad-
of Koch’s postulates. Clin Microbiol Rev 1996; 9(1): and virology in the 21st century. J Infect Dis 2010; amies Press; 2004.
18-33. 201(11):1611-1614. 13. Orrskog S., Medin E., Tsolova S., et al.: Causal inference
3. Worboys M.: Was there a Bacteriological Revolution in 9. Moore P.S., Chang Y.: The conundrum of causality in regarding infectious aetiology of chronic conditions: a
late nineteenth-century medicine? Stud Hist Philos Biol tumor virology: the cases of KSHV and MCV. Semin systematic review. PLoS ONE 2013; 8(7):e68861.
Biomed Sci 2007; 38(1):20-42. Cancer Biol 2014; 26:4-12. 14. Kau A.L., Ahern P.P., Griffin N.W., et al.: Human nutri-
4. Huebner R.J.: Criteria for etiologic association of prev- 10. Gugliotta J.L., Goethert H.K., Berardi V.P., et al.: tion, the gut microbiome and the immune system.
alent viruses with prevalent diseases; the virologist’s Meningoencephalitis from Borrelia miyamotoi in an Nature 2011; 474(7351):327-336.
dilemma. Ann N Y Acad Sci 1957; 67(8):430-438. immunocompromised patient. N Engl J Med 2013; 15. Zhao L.: The gut microbiota and obesity: from correla-
5. Evans A.S.: Causation and disease: the Henle–Koch pos- 368(3):240-245. tion to causality. Nat Rev Microbiol 2013; 11(9):
tulates revisited. Yale J Biol Med 1976; 49(2):175-195. 11. Greenberg D.E., Ding L., Zelazny A.M., et al.: A novel 639-647.
6. Falkow S.: Molecular Koch’s postulates applied to bacterium associated with lymphadenitis in a patient 16. Miklossy J.: Alzheimer’s disease – a neurospirochetosis:
microbial pathogenicity. Rev Infect Dis 1988; 10(Suppl. with chronic granulomatous disease. PLoS Pathog 2006; analysis of the evidence following Koch’s and Hill’s cri-
2):S274-S276. 2(4):e28. teria. J Neuroinflamm 2011; 8:90.
SECTION 1 Introduction to Infectious Diseases
2
Nature and Pathogenicity of
Micro-organisms
JOSHUA FIERER | DAVID LOONEY | JEAN-CLAUDE PECHÈRE†
KEY CONCEPTS Our intimate symbiosis with microbes is often peaceful and mutu-
ally beneficial (mutualism), as when bacteria shelter in the intestine
• Micro-organisms and higher organisms have evolved together and in turn supply vitamins, aid in digesting endogenous or exogenous
and interact in complex ways. Only a small percentage of carbohydrates, assist in maintaining oral tolerance and the develop-
microbes are inherently pathogenic. ment of the innate immune system.1 Alternatively, if the micro-
• Pathogenicity, the ability of infectious agents to cause disease, organism benefits while the host is indifferent, the relationship (and
must be interpreted in the context of the properties of both organism) is termed commensal. Parasitism occurs when the invad
transmissible agent and host. ing organisms produce harm to the host.
This chapter focuses on the lifestyle of pathogenic micro-organisms
• Understanding this interplay is important to developing
methods to prevent infection and reduce the severity of and how they infect us, reproduce and cause disease. We shall use
disease. the word ‘pathogenicity’ to indicate the capacity to cause disease (or
damage) in nonimmune individuals. Although the word ‘virulence’ is
• The initial step in infection is usually adherence, mediated by often used in the same sense, we mean it to refer to the severity of the
the interaction of surface structures on the pathogen with host illness that is caused. Communicability refers to the transmissibility or
cell membrane proteins or carbohydrates. This often presents
infectiousness of micro-organisms.
excellent targets for immunity.
• Intracellular pathogens have evolved methods to neutralize the
cellular defenses that can destroy invaders. Definition and Comparison of
Infectious Agents
The definition of an ‘infectious agent’ was proposed by Jacob Henle in
Introduction 1840 and refined by Robert Koch. In 1876, Koch reported experiments
The micro-organisms that surround us play roles critical to human on mice with Bacillus anthracis showing that:
existence, through processes as diverse as photosynthesis, nitrogen • B. anthracis could be isolated from all animals suffering from
fixation, production of vitamins in the intestine, and decomposition naturally occurring anthrax;
of organic matter. They are a major driving force behind evolution, • disease could be reproduced in an experimental host by infection
providing organelles for photosynthesis and respiration in present-day with a pure culture of this B. anthracis;
eukaryotes, and facilitating genome rearrangement in infected host • B. anthracis could subsequently be re-isolated from the experi-
cells. The lifestyle of a micro-organism is intimately related to its envi- mental host.
ronment, be it the human body or a polluted riverbed. Some highly As discussed in more detail in Chapter 1, this definition of a patho-
specialized micro-organisms can survive in harsh environmental con- gen is correct but inadequate because many pathogenic microbes have
ditions, while others, such as root-colonizing bacteria and our own never been cultured (e.g. Mycobacterium leprae and Treponema palli-
intestinal flora, take advantage of the abundant resources provided by dum), others lack a suitable animal host in which the infection can be
higher organisms. reproduced (e.g. Salmonella enterica serovar Typhi), and some microbes
cause disease only under specific conditions that may not be reproduc-
THE NORMAL MICROBIAL FLORA OF THE ible in experimental animals (e.g. varicella-zoster virus).
HUMAN HOST Infectious agents can be divided into four groups:
The fetus normally starts acquiring its indigenous microflora from its • Prions, which consist of 2only a single protein (PrP). The
mother during vaginal delivery and nursing. The human body can be infectious form (PrPTSE) is transmissible as spongiform
thought of as an ecosystem for microbes. Each part of the body exposed encephalopathy (see Chapter 23).
to the outside environment has its own characteristic mixture of • Viruses, which contain proteins, lipids and nucleic acids. Viri-
microbes. The microbial population is especially dense in the large oids consist of only nucleic acid. These organisms characteristi-
intestine, where each gram of stool contains ~~1012 bacteria. The cally disassemble after cell entry and then assemble their progeny
normal flora is well adapted to its niche and forms a complex, meta- during replication3 (see Chapters 162 to 175).
bolically interacting community. Although age, diet and exogenous • Bacteria, including archaea and eubacteria. Unlike eukaryotes,
factors such as antibiotic treatment may induce important variations, the DNA genomes of prokaryotes are not separated from the cell
the microbial population of the gastrointestinal tract seems to be stable by a membrane. Unlike viruses, they remain enclosed within
in each individual. The fecal flora is much more diverse in vegetarians their own cell envelope throughout their life cycle (see Chapters
than in omnivores or carnivores, probably reflecting the difficulty of 176 to 188).
digesting complex carbohydrates found in plants. Facultative anaer- • Eukaryotes, including fungi (see Chapters 189 and 190), proto-
obes such as Escherichia coli, which are frequently used as markers for zoa (see Chapters 191 to 194) and multicellular parasites (see
environmental pollution with human feces, represent less than 1% of Chapter 195). These organisms have subcellular compartments,
the normal flora. including the nucleus.
Table 2-1 compares the properties that define prokaryotes with
†
Deceased eukaryotes and Table 2-2 emphasizes the differences between bacteria
4
Chapter 2 Nature and Pathogenicity of Micro-organisms 5
TABLE
2-1 Comparison of Prokaryotes and Eukaryotes
Feature Prokaryotes Eukaryotes
Chromosome Single, circular or linear Yes
Gene organization Operon-polycistronic mRNA Single genes and block of genes
Nucleosomes No Yes
Nuclear membrane No Yes
Mitosis No Yes
Introns in genes No Yes
Transcription Coupled with translation Separate from translation
mRNA No terminal polyadenylation (except archaebacteria); polygenic Terminal polyadenylation; usually monogenic
First amino acid Unstable formylmethionine (except archaebacteria) Methionine
Ribosome 70S (30S + 50S) 80S (40S + 60S)
Cell wall Presence of muramic acid, D-amino acids, peptidoglycan No muramic acid, D-amino acids or peptidoglycan
(except archaebacteria and mycoplasma)
Membrane No sterols or phosphatidyl-choline (except mycoplasma) Sterols and phosphatidyl-choline
Endoplasmic reticulum No Yes
Mitochondria No Yes (Entamoeba histolytica, Giardia and microsporidia

have vestigial remnants of mitochondria)
Lysosomes and peroxisomes No Yes

Movement By flagella, composed of a single fiber Ameboid, by cilia or cilia-like flagella
TABLE is a family of small, non-enveloped RNA viruses containing the Entero-

2-2 Comparison of Bacteria and Fungi virus genus, which in turn includes poliovirus species of serotypes
1, 2 and 3.5 Other schemes emphasize the relationship of the
Characteristics Bacteria Fungi
genetic material of the virus and the viral replication scheme.6 For
Cell volume (/µL) 0.6–5.0 Yeast: 20–50; molds: example, Baltimore group IV contains viruses with single-stranded
greater than yeast (ss) RNA genomes where the mRNA shares the same sense as the
Nucleus No membrane Membrane viral RNA (+ssRNA), including the Picornaviridae, enteroviruses and
poliovirus.
Mitochondria No Yes
Endoplasmic No Yes COMMON STEPS IN VIRAL REPLICATION

reticulum Virus replication involves the following steps:
Sterol in cytoplasmic No (except for Yes
1. Attachment: Virus particles (virions) attach to specific receptor(s)
membrane mycoplasma) on the surface of a host cell.
2. Entry: Virions fuse to the outer cell membrane or are endocy-
Cell wall Muramic acids and Chitin, glucans and
components teichoic acids; no mannans; no
tosed and fuse to endosomal membranes at reduced pH.
chitin, glucans or muramic acids or 3. Uncoating and transport: The virion disassembles, freeing its
mannans teichoic acids nucleic acid and proteins, which are transported into the cyto-
Metabolism Autotropic or Heterotropic
plasm and/or nucleus.
heterotropic 4. Transcription and translation: Viral RNA and proteins are
expressed. Intermediates such as viral complementary RNA or
Sensitivity to No Yes
polyenes integrated proviral DNA may be involved.
5. Assembly and release: New virions are formed and released
Adapted from Kobayashi G.S.: Fungi. In: Davis B.D., Dulbecco R., Elsen H.N., from the cell via lysis, or budding from surface or internal
Ginsberg H.S., ed. Microbiology, 4th ed. Philadelphia: JB Lippincott; membranes.
1990:737–765.
STRUCTURE OF VIRUSES
and fungi, many of which determine the specificity of antimicrobial Virions serve to protect the viral genome and facilitate infection of new
agents. host cells. The smallest viruses are only 25–30 nm in diameter, while
the largest (e.g. mimivirus, an infectious agent of amebae) are 400 nm
General Properties and Classification or more in size.7 The viral genome is tightly associated with
of Viruses nucleoprotein(s) in a highly organized core structure, the nucleocap-
sid. In some virus families, such as negative-strand RNA viruses and
TAXONOMY OF VIRUSES retroviruses, the virion contains enzymes required for early steps in
Viruses are classified into families (-viridae), genera (-virus or -viruses) virus replication. The viral capsid or tegument comprises the outer
and species (-virus), based on the type (DNA or RNA) and nature proteinaceous covering. Some viruses have a surrounding outer lipid
(single-stranded or double-stranded, segmented or nonsegmented) of layer (the envelope) derived from host cell membranes during budding.
genetic material, and structural features4 (size, symmetry and presence Clefts, vertices, or spikes in the capsid or proteins inserted into the
or absence of a lipid envelope; Table 2-3). For example, Picornaviridae envelope layer serve to attach to host receptor molecule(s).8
TABLE
2-3 Classification of Viruses
Genome Size (kb), Polarity
Family Name Example (+ or −) and Segments Morphology Envelope
DNA VIRUSES
Single-stranded (Class II)

Parvoviridae Human parvovirus B19 5 (±) single Icosahedral No
Mixed-stranded (Class VII)

Hepadnaviridae Hepatitis B 3 (±) single Icosahedral Yes
Double-stranded (Class I)
Papovaviridae Wart virus 8 (±) single Icosahedral No
Polyomaviridae JC virus 5 (±) single Icosahedral No
Adenoviridae Adenovirus 36–38 (±) single Icosahedral No
Herpesviridae Herpes simplex 120–220 (±) single Icosahedral Yes
Poxviridae Vaccinia 120–280 (±) single Complex Yes
RNA VIRUSES
Positive-sense (Class IV)

Picornaviridae Poliovirus 7.2–8.4 (+) single Icosahedral No
Togaviridae Rubella 12 (+) single Icosahedral Yes
Flaviviridae Yellow fever 10 (+) single Icosahedral Yes
Coronaviridae Infectious bronchitis 16–21 (+) single Helical Yes
Negative-sense (Class V)
Rhabdoviridae Rabies 13–16 (−) single Helical Yes
Paramyxoviridae Measles 16–20 (−) single Helical Yes
Orthomyxoviridae Influenza 14 (−) 8 Helical Yes
Bunyaviridae California encephalitis 13–21 (−) 3 Helical Yes
Arenaviridae Lassa fever 10–14 (−) 2 Helical Yes
Filoviridae Marburg, Ebola 19 (−) single Helical Yes
Reverse (Class VI)

Retroviridae HIV-1 3–9 (+) diploid Icosahedral Yes
Double-stranded (Class III)

Reoviridae Rotavirus 16–27 (±) 10–12 Icosahedral No
The Viral Genome contrast, the RNA-dependent RNA polymerase of (−)ssRNA viruses
Viral genomes usually consist of either DNA or RNA, though some uses vRNA as a template for mRNA transcription. Negative-strand
contain both: Cytomegalovirus (CMV) virions include viral RNAs that RNA genomes may lack cap structures and poly-A tails, often parasit-
promote infectivity and human immunodeficiency virus (HIV) virions izing cap structures from cellular pre-mRNA or mRNA. Retroviruses
include partially reverse transcribed DNA.9 Genomes range from synthesize a dsDNA copy of the positive-strand RNA genome, which
1.7 kb to 1.2 Mb in size, and may encode only a single gene, or hun- then integrates into cellular DNA.
dreds. For example, Parvoviridae have only two open reading frames,
whereas the vaccinia poxvirus has 263 known genes. Genomes may be The Capsid
linear or circular, segmented or nonsegmented. Genome segmentation The viral genome is protected by one or more protein coats, the
facilitates genetic exchange between coinfecting virions in a process nucleocapsid and/or capsid. The capsid is made of viral protein
known as reassortment. Many viral nucleic acids contain modified structures known as capsomeres, accounting for a large portion of
nucleotides, which inhibit host cell nucleases and/or mediate recogni- the viral mass. Papillomavirus produces only two capsid proteins
tion by viral polymerase. Linear genomes often contain conserved and poliovirus four, but more complex viruses may encode a larger
terminal sequences. When complementary, these allow partial circu- variety.
larization of the genome via formation of panhandle or tube-like struc- Picornaviruses, adenoviruses and papovaviruses have a nucleocap-
tures. Terminal sequences may also allow incomplete replication sid structure with icosahedral symmetry (each capsid consists of 20
products to recombine or mediate recognition by proteins that prime triangular facets and 12 apices). Influenza, measles and rabies virus
transcription or replication. Retroviral proviral DNA is flanked by form capsids with helical or cylindrical symmetry. The central core is
repeat sequences similar to those of transposable genetic elements. formed by the nucleic acid genome, around which the nucleocapsid
The viral RNA (vRNA) of positive-strand RNA viruses acts directly proteins are arranged like the steps of a spiral staircase (Figure 2-1).
as mRNA for protein synthesis; they resemble eukaroytic RNAs with a More complex virion morphologies also exist. Bacteriophages,
cap at the 5′ end and are polyadenylated (poly-A) at the 3′ end. In viruses that infect bacteria, have complex attachment structures fixed
Examples of virions
Adenovirus HIV-1
Rabies virus
Influenza virus
Figure 2-1 Examples of virions. Adenovirus is an icosahedral DNA virus without an envelope; fibers extend from the 12 points of the icosahedral coat; DNA forms a
ribbon-like molecule. Approximate size 8 nm. HIV-1; glycoprotein (GP) molecules protrude through the lipid membrane; the icosahedral capsid encloses a truncated
conical nucleocapsid in which the diploid RNA is enclosed. Approximate size 100 nm. Influenza virus is an enveloped RNA virus containing nucleocapsid of helical sym-
metry; spikes of hemagglutinin and neuraminidase protrude from the lipid bilayer. Approximate size 100–200 nm (variable). Rabies virus is a helical RNA nucleocapsid
with a bullet-shaped lipoprotein envelope in which approximately 200 GPs are embedded. Approximate size 150 nm. (The diagram is not to relative scale.) (Adapted
from Collier L., Oxford J.: Human virology. Oxford: Oxford University Press; 1990:8 by permission of Oxford University Press.)
to the capsid. The nucleocapsid of orthopoxviruses, such as variola and • Class II viruses have single-stranded DNA genomes used as
vaccinia virus, consists of a network of tubules, sometimes surrounded templates for transcription of viral protein messages needed for
by an envelope, forming a brick-shaped virion. synthesis of complementary DNA. Double-stranded DNA is a
replication intermediate, and DNA replication is dependent on
The Envelope repeats that form structures on one or both ends. The Parvoviri-
Enveloped viruses contain nucleocapsids of either icosahedral (e.g. dae include the B19 erythrovirus that causes erythema infectio-
herpesviruses, togavirus) or helical symmetry (e.g. influenza). The sum (fifth disease) in children and exanthem, arthropathy and
outer envelope is a lipid bilayer derived from host cell membrane in temporarily halts hematopoeisis in adults. This family also
which both viral glycoproteins and some host proteins are embedded. includes the apathogenic adeno-associated dependoviruses
The viral matrix proteins (M proteins) associate with the envelope, (AAV). Parvoviridae have 4.5–5.5 kb ssDNA genomes and only
connecting the capsid to the viral glycoprotein(s) inserted in the lipid two open reading frames, one of which codes for between two
bilayer. Surface glycoproteins are transmembrane proteins that may and four nonstructural proteins and the other coats polypep-
also be coupled to fatty acid moieties, and play a key role in attachment tides. The Circoviridae have circular ssDNA genomes. This
and penetration of virions into the cell. family includes Torque Teno viruses (TTV, TTMV), which cause
Some glycoproteins also have enzymatic activity, such as the influ- widespread human infection without evidence of disease.11
enza virus neuraminidase, which is critical for release of newly formed
viral particles from the host cell membrane. Maturation of protein
• Class I viruses have dsDNA genomes. Replication proceeds to cell

lysis or latency depending on cellular conditions. The lytic phase
structures and transcription steps may occur after release from the host can be subdivided into early and late phases. In the early lytic
cell. For example, the typical conical core of the human immunodefi- phase, viral genes alter cellular conditions to allow efficient viral
ciency virus retrovirus is formed after release as viral protease matures DNA synthesis and transcription, often activating the host cell
the nucleocapsid within the virion.10 and inducing cell division. In the late lytic phase, viral structural
proteins accumulate; virions are assembled and then released
upon death of the cell. In latency, viral gene expression is con-
VIRAL GENE EXPRESSION STRATEGIES fined to functions that prevent replication while maintaining the
In the Baltimore classification, seven major viral replication strategies viral genome within the cell, often for the lifetime of the indi-
are distinguished (see following and Figure 2-2). vidual. When cellular conditions become favorable, the latent
• Class IV viruses contain positive-strand RNA viral genomes that virus can be ‘activated’ into lytic replication.
serve as mRNA. After entry, translation of the genome produces There are many dsDNA viruses of medical importance for
a polyprotein that is processed via enzymatic cleavage, at least in humans, including the herpesvirus family (see Chapter 166) and
part in an autocatalytic fashion. Replication may be regulated by adenoviruses.
the unavailability of functional viral proteases needed to make • Class VI viruses are termed retroviruses: viruses enter the cell
viral structural proteins until later in the replication cycle, as and uncoat, discharging the pre-integration complex, consisting
synthesis of viral complementary RNA and new viral RNA proof the polyadenylated, diploid viral RNA genome together with
ceeds. As viral proteases accumulate, core proteins are efficiently nucleoproteins, the viral reverse transcriptase and the viral inte-
processed, assembled and begin to encapsidate viral RNA. This grase. The two RNA genomes are converted to a single, mostly
strategy is used by picornaviruses and Flaviviridae, including dsDNA copy by reverse transcriptase in a process requiring tem-
hepatitis C viruses. In other (+)ssRNA virus families, including plate switching. The viral integrase then cuts the host genome
Coronaviridae, Caliciviridae and hepatitis E virus, the viral com- and inserts the linearviral DNA into the chromosome as a pro-
plementary RNA is a template for transcription of both full- virus. This process may require cellular activation and/or cell
length vRNA and subgenomic transcripts encoding structural division, though retroviruses can persist for weeks at stages
proteins, allowing regulation of expression. before integration. Integrated virus may become latent, with
• Class V viruses, including Orthomyxoviridae and Bunyaviridae, limited or no transcription by cellular RNA polymerase II, until
have (−)ssRNA genomes. After entry, primary transcription gen- conditions allow virus replication.
erates full-length viral complementary RNA (positive-strand) More complex retroviruses (e.g. spumaviruses, lentiviruses)
which acts both as mRNA for viral protein synthesis and as a first transcribe multiply-spliced mRNAs that direct the synthesis
template for transcription of new viral RNA. Alternatively, the of regulatory proteins. As these accumulate, the processing of
incoming viral RNA may initially be transcribed into mRNA viral transcripts changes and more singly or unspliced mRNAs
messages for individual genes, which must accumulate before coding for viral structural proteins are produced. For example,
transcription of full-length viral complementary RNA and rep- HIV Rev protein, produced from early, multiply-spliced RNA
lication of viral RNA can occur (e.g. Paramyxoviridae, Rhabdo- transcripts, prevents splicing and allows nuclear export of singly-
viridae). The late phases of replication, transcription and viral spliced and unspliced messages. These viruses (and many other
protein synthesis proceed simultaneously. The Arenaviridae and viruses) also co-opt many cellular pathways, including protein
some Bunyaviridae use a more complicated strategy, termed sorting and ubiquitination, to modify the abundance of host
ambisense, wherein both viral RNA and viral complementary proteins that would otherwise target the virus for immune rec-
RNA serve as templates for mRNA transcription by the viral ognition or otherwise interfere with virus replication.12
polymerase. This does not result in the formation of comple- • Class VII hepadnaviruses, including hepatitis B virus, encode

mentary double-stranded (ds) mRNAs, as different portions of genetic information in dsDNA but use reverse transcription
the genome are transcribed from the viral and complementary during infection in the cell to produce the negative strand of viral
RNA strands. DNA, which in turn is used as a template for synthesis of positive-
• Class III viruses, the Reoviridae, have double-stranded, seg- strand viral DNA.
mented RNA genomes. These include Colorado tick fever virus
(Coltivirus) and rotaviruses. Virions have 10–12 dsRNA seg-
ments and replication resembles that of (−)ssRNA viruses in that General Properties and Classification
RNA is not infectious, and transcription of segment-length
mRNAs using the negative strand of the genomic dsRNA must of Bacteria
first occur before genome replication. Both transcription rate Bacteria are small (0.6–4.0 µm) unicellular organisms; 3 × 1012 bacteria
(inverse to segment length) and efficiency of translation (varying weigh in the order of 1 g. A bacterium may divide up to two or three
up to 100-fold) may regulate viral replication. times per hour, implying ~300 g of bacteria could be produced from
Viral ‘lifestyles’
Positive-stranded RNA viruses Negative-stranded

Negative-strandedRNA
RNAviruses
viruses
No subgenomic mRNA With subgenomic mRNA Segmented or nonsegmented Segmented ambisense
ssRNA(+) ssRNA(–)
Early Translation Early Transcription

Early polyprotein Translation
processing, replicase mRNAs,
proteases proteins
ssRNA(–) ssRNA(+) Transcription

Translation
mRNAs,
proteins
ssRNA(+) ssRNA(–)
Late Translation Transcription Late Transcription

Late polyprotein Translation Translation
processing, Polyprotein processing, mRNAs,
structural proteins structural proteins proteins
Progeny virus Progeny virus
DNA viruses Viruses using reverse transcription
Retroviruses Hepatitis B viruses

dsDNA
ssRNA(+)
Reverse
Preliminary
transcription
Transcription
Translation DNA synthesis,
Early
integration
mRNAs,
proteins
Transcription circular Transcription
dsDNA
Translation dsDNA Translation
Early mRNAs, regulatory mRNAs, regulatory and
proteins structural proteins
ssRNA(+) ssRNA(+)
Progeny DNA progeny Reverse
Transcription transcription
Translation
Transcription
Late Translation Late mRNAs, structural
proteins
mRNAs,
dsDNA
proteins ssRNA(+)
progeny
Progeny virus Progeny virus Progeny virus
Figure 2-2 Viral ‘lifestyles’. (Upper left) Single-stranded positive-sense (+ss) RNA viruses can be subdivided into those that produce subgenomic mRNAs (e.g. Togaviri-
dae, Coronaviridae, Calciviridae), allowing additional regulation of transcription, and those that do not (poliovirus, hepatitis A virus, Flaviviridae including hepatitis C
virus). (Upper right) Negative-sense RNA viruses must first transcribe RNA messages from incoming viral RNA (vRNA), as well as making a copy complementary to the
viral genomic DNA (vcRNA) to serve as a template for synthesis of new viral RNA. Some (−)ssRNA viruses use both vRNA and vcRNA as templates for transcription of
mRNA (arenaviruses, some bunyaviruses). (Lower left) Double-stranded DNA viruses have early and late lytic phases of replication, and some (e.g. Epstein–Barr herpes-
virus) also have latent (usually episomal) phases. (Lower right) Viruses using reverse transcription include RNA retroviruses (e.g. HIV), which reverse transcribe a dsDNA
copy from diploid (+)ssRNA vRNA, and hepadnaviruses (e.g. HBV) which reverse transcribe the negative strand of DNA from RNA transcribed from incoming viral DNA.
(Courtesy of Menno Kok and Jean-Claude Pechère.)
a single bacterial cell in one day. Small organisms profit from a favor- for regulatory RNAs.17 E. coli probably contains well over 1500 differ-
able cell surface-to-volume ratio, allowing metabolic fluxes superior ent polypeptides with a variety of functions, including maintenance of
to those attained by larger eukaryotic cells. Bacteria react quickly to membrane structure; transport; respiration; digestion of nutrients;
environmental changes by regulating gene transcription to adapt their synthesis of amino acids, sugars, nucleotides, lipids and vitamins; and
physiology. production of DNA, RNA, proteins and polysaccharides. Naturally
Bacteria were probably the first cells to appear on Earth, more than occurring E. coli isolates can have genomes that differ by up to 1 Mb.
3.5 billion years ago. They have since developed overwhelming diver- Thus the commensal E. coli K12 has a genome of 4.64 Mb, while the
sity, representing the bulk of the world’s biomass today. Although human enteric pathogen E. coli O157:H7 has a genome of 5.53 Mb.
bacteria are not multicellular organisms, they are capable of cell-to-cell Uropathogenic E. coli (UPEC) have genomes varying from 4.94 to
communication.13 By using low molecular weight compounds that 5.23 Mb. The differences in genome sizes are largely due to insertions
they synthesize and secrete, bacteria are able to sense their own density of transposons and/or phages. If the insertions encode virulence
(called quorum sensing), and respond by activating programs such as factors they are referred to as pathogenicity islands. Genomic islands
plasmid conjugation, light production (in certain Vibrio spp.), biofilm in UPEC that are not found in commensal E. coli account for more
formation, or virulence gene expression. Some genera of bacteria do than 10% of the genome, emphasizing the importance of lateral
not make their own signaling compounds but have receptors that gene transfer in the evolution of pathogens. The overall gene order,
respond to signals from other genera. except for the insertions, remains the same in all E. coli and is remark-
Different cell morphologies can be observed with light microscopy ably similar to the gene order in other Enterobacteriaceae such as
(e.g. spherical cocci, rod-shaped bacilli, curved rods and spiral forms). Salmonella enterica.
The rigid cell wall determines the shape of bacteria and resists the
osmotic pressure caused by the large difference in solute concentration Transcription and Translation in Bacteria
between the cytoplasm and the environment. Mycoplasma spp. Gene expression is usually regulated at the level of transcription initia-
lack peptidoglycan and thus have neither a rigid wall nor a defined tion by regulator proteins (and occasionally by small RNA molecules17)
shape. that interact with the ‘promoter DNA’ and with the enzyme RNA
polymerase (see Figure 2-4). Sigma factors recognize specific DNA
BACTERIAL DICHOTOMY REVEALED BY A sequences at promoters and facilitate the binding of RNA polymerase.
SIMPLE STAINING TECHNIQUE The complex opens (‘melts’) the dsDNA to allow synthesis of an RNA
In 1884 the Danish bacteriologist Hans-Christian Gram developed a copy of one of the two DNA strands. Bacterial cells produce multiple
simple staining technique that distinguishes gram-positive from gram- sigma factors, each controlling the expression of a set of genes, and
negative bacteria based on retention of a crystal violet-iodine dye by each expressed under different environmental conditions. Some gene
gram-positives in the presence of an organic solvent such as alcohol or transcription is also regulated by binding of activator proteins upstream
acetone. Those solvents dissolve the dye from gram-negative bacteria of the promoters to sites called enhancers, similar to enhancers in
that are counterstained with a contrasting dye such as safranin. This eukaryotic cells.
dichotomy reflects their distinctive cell wall structures. Gram-positive Four types of RNA are produced: regulatory RNA, transfer (t) RNA,
bacteria characteristically have a thick cell wall made up mainly of large sRNA and messenger RNA (mRNA). tRNAs position the amino acids
molecules of peptidoglycan. Gram-negatives have a thinner peptido- on the ribosomes during protein synthesis and are important struc-
glycan layer surrounded by an asymmetric lipid outer membrane, the tural components of ribosomes. Messenger RNA molecules are gener-
outer layer being composed of lipopolysaccharide (endotoxin) (Figure ally quite unstable but are protected from premature degradation by
2-3). Because gram-negative bacteria have two lipid bilayers, they must the protein synthesis machinery.18 Regulatory RNAs, such as small
use active transport systems and protein channels to import water- RNAs (sRNA) in two component systems, may function similarly to
soluble molecules and nutrients. Export of proteins is accomplished microRNAs in eukaryotes.17 Ribosomes bind mRNA as soon as it
through complex protein structures called secretion systems.14 ‘leaves’ RNA polymerase and start protein synthesis by coupling the
initiator amino acid (formyl-methionine) to the second amino acid in
ORGANIZATION OF THE BACTERIAL CELL the coding sequence and uncoupling it from the tRNA molecule. As
Bacteria have a cell wall, a simple nuclear body without a nuclear mRNA elongation proceeds, more ribosomes bind to the mRNA to
membrane, ribosomes and mesosomes in the cytoplasm, and some- form a ‘polysome’. The polypeptides produced by ribosomes fold into
times granules of reserve material, but no endoplasmic reticulum or native structures either spontaneously or with the help of molecular
organelles such as mitochondria or chloroplasts. They frequently have chaperones. Multiple genes involved in a metabolic pathway are usually
appendages such as flagella that are used for motility, and pili and contiguous in an operon. Bacterial mRNAs generally encode more than
fimbriae that may be used for adhesion or for conjugation. DNA rep- one protein. The bacterial protein synthesis machinery is an important
lication, transcription, protein synthesis, central metabolism and res- target for antibiotics.
piration all take place in the same environment. Complex biochemical
processes may nonetheless be spatially organized.15 The cytoplasmic MOTILITY
membrane contains numerous metabolite transport systems, and is Many bacterial species can detect small variations in concentrations of
also the site of intense enzymatic activity. Like eukaryotic cells, bacteria valuable or harmful substances in the environment, guiding move-
possess efflux systems that allow them to expel unwanted substances ment in a process called chemotaxis.19 Flagella are the effectors of
from the cytoplasm into the environment. Gram-positive bacteria chemotaxis. By changing the direction of flagellar rotation, micro-
express many important enzymes and ligands in their cell wall (e.g. organisms swim towards sites favorable to survival and growth and
Listeria monocytogenes may have 42 different cell wall anchored away from noxious stimuli. Amino acids and sugars are powerful
proteins). chemoattractants. Although many pathogenic species are flagellated, a
Bacteria generally store their genetic information in a single circu- role for motility in virulence has not been established in many cases.
lar chromosome. The Haemophilus influenzae chromosome is 1.83
million base pairs (Mbp) long and encodes 1703 putative proteins.16
The chromosome Bacillus megaterium has 30 Mbp and is more than Pathogenesis of Infectious Disease
500 times the length of the cell. A few organisms, such as Vibrio cholera The key microbial factors involved in the onset and spread of microbial
and Borrelia spp., have multiple chromosomes, and Borrelia genomes infection can be identified by carefully analyzing the interaction of the
are encoded on linear DNA. The advantage of these uncommon micro-organism with its host (Box 2-1). Insight into the intimate
arrangements is not known. relationship between host and pathogen helps us answer the all-
The bacterial chromosome codes for polypeptides and stable RNA important questions of how to eliminate the cause of disease and
molecules such as transfer RNA and ribosomal RNA molecules, and reduce its harmful effects on the human body.
Figure 2-3 Bacterial cell walls. (a) Mycoplasma pneumoniae has a single mem-
brane, made up of phospholipids and membrane proteins. (b) In gram-positive
Bacterial cell walls
organisms the cytoplasmic membrane is covered with a thick layer of peptidogly-
can; chains of lipoteichoic acid anchored in the cell membrane protrude outside.
The single membrane of Mycoplasma pneumoniae Negatively charged teichoic acids are covalently attached to the peptidoglycan.
Cell wall proteins also are covalently attached to the peptidoglycan. There is no
Phospholipids Membrane proteins periplasmic space in gram-positive bacteria. (c) The cell wall of a gram-negative
rod is more complex. The layers are: the cytoplasmic membrane, the periplasmic
space, a layer of peptidoglycan which is thinner than that in gram-positive bacteria
and an asymmetric outer membrane. The inner leaflet of the outer membrane is
made of phospholipids. The outer leaflet has lipopolysaccharides as its principal
lipids; porins, which are channel-forming proteins often organized as trimers, allow
the penetration of hydrophilic molecules through the outer membrane. (d) The
a peptidoglycan of Staphylococcus aureus has polysaccharide chains (‘backbone’)
that are alternating residues of N-acetylglucosamine (GlcNAc) and N-acetylmuramic
The gram-positive bacterial cell wall acid (MurNAc). Tetrapeptides are attached to MurNAc and are linked together
by pentaglycines bridging the L-lysine of each tetrapeptide chain to the D-alanine
Lipoteichoic acid
of the neighboring one. (Courtesy of Menno Kok and Jean-Claude Pechère.)
Phospholipid peptidoglycan
bilayer layer
Transcription and translation in bacteria
b
The gram-negative bacterial cell wall DNA
RNA polymerase
saccharide
Lipopoly-
Porin
membrane
Outer
glycan Phospho-
Ribosome
lipid
Peptido-
Regulator
layer
Periplasmic Inner
protein
space membrane
Phospholipid
bilayer
Protein
c
Structure of peptidoglycan (Staphylococcus aureus)
Repeating disaccharide
Lysozyme split
of backbone
MurNAc -1,4 -1,4 MurNAc

GlcNAc GlcNAc
Lactyl Lactyl
L-Ala L-Ala
Tetra- D-Glu-N D-Glu-N mRNA

peptide L-Lys L-Lys
D-Ala D-Ala Figure 2-4 Transcription and translation in bacteria (Escherichia coli). (Courtesy
GlcNAc -1,4 -1,4 GlcNAc
of Menno Kok and Jean-Claude Pechère.)
GlcNAc GlcNAc
Lactyl Lactyl
L-Ala (Gly)5 L-Ala (Gly)5
D-Glu-N D-Glu-N
Tetra-
peptide L-Lys Cross bridge L-Lys BOX 2-1 IMPORTANT STEPS IN MICROBIAL
D-Ala D-Ala
PATHOGENESIS
(Gly)5 (Gly)5
• Encounter
d • Adherence
• Evasion of host defenses
• Local multiplication or general spread in the body (invasion)
• Cell and tissue damage
• Shedding from the body
The introduction of molecular techniques to make targeted muta- LIFESTYLES AND PATHOGENESIS
tions in pathogenic organisms has led to major advances. Mutants can Each pathogen has its own infection strategy. In the following sections
be tested in appropriate animal or tissue culture models to determine we shall examine the lifestyles of some pathogenic species.
if the loss of a gene affects the virulence of the pathogen without affect-
ing its ability to grow in vitro in standard media. Genes that are identi- Endogenous Infections and Normal Microbial Flora
fied as ‘virulence’ genes are sometimes considered to be ‘accessory’ of the Human Host
genes because they are not required for replication outside the host. A The distinction between parasitism, commensalism and mutualism is
virulence gene can also be cloned into a genetically related nonpatho- not sharp and the condition of the host and the location of the bacteria
genic microbe and tested for its ability to confer new properties on may make a big difference. For instance, UPEC are commensals in the
that organism such as adhesion or hemolysis. colon but cause infections in the urinary tract. Some micro-organisms,
Virulence factors generally fall into two functional categories that referred to as opportunistic pathogens, are commensals in the majority
may overlap. There are purely defensive factors that help the organism of people but can cause disease in an immunocompromised host.
to escape the host’s immune response. Bacterial examples include the Candida albicans is part of the normal oral flora, but in acquired
polysaccharide capsule made by Streptococcus pneumoniae and the immunodeficiency syndrome (AIDS) patients with low numbers of
golden pigment made by Staphylococcus aureus. The former prevents CD4+ T cells, C. albicans causes thrush and esophagitis. Similarly,
complement from effectively opsonizing the bacteria for ingestion and virtually all immunologically normal individuals chronically infected
destruction by neutrophils, while the carotenoid pigment (staphylox- with human cytomegalovirus (CMV) are asymptomatic, but CMV can
anthin) that gives Staph. aureus its name, is an antioxidant that helps cause colitis and pneumonia when the immune system is suppressed.
the bacteria to survive the oxidative damage inflicted by the respiratory It has been suggested that chronic infection with highly prevalent
burst of phagocytes. Conversely, many microbial factors directly viruses, including herpesviruses, may play a protective role against
damage the host. For example, cholera and diphtheria toxins are bacterial infection by boosting innate immunity, implying a complex,
responsible for the manifestations of the diseases they are named for. three-way relationship that defies easy classification.27 Thus, the host
Lipopolysaccharides (LPS) serve both functions; the long polysaccha- and its indigenous microflora maintain a delicately balanced relation-
ride chains divert complement from the inner membrane, rendering ship that, when disrupted, may lead to the development of infectious
gram-negative bacilli resistant to its bactericidal action (defensive), disease.
while the lipid A core stimulates exuberant and damaging inflamma- An inevitable consequence of antibiotic treatment is the elimina-
tion by binding to the Toll-like receptor 4 (TLR4)/MD-2/CD14 tion of susceptible bacteria, which are quickly replaced by antibiotic-
complex expressed on many host cells. resistant species, sometimes leading to deleterious consequences. This
Since expression of virulence genes may carry a large metabolic phenomenon is illustrated by post-antibiotic pseudomembranous
cost, bacteria transcriptionally regulate expression of some virulence colitis caused by toxigenic Clostridium difficile. Probiotics (live micro-
genes in response to environmental signals. Examples include the organisms) may help to restore the natural flora after antibiotic use,
phoP/Q regulon in S. enterica and the agr regulon in Staph. aureus. but their usefulness is still not fully established. For example, Saccha-
The former senses low Mg concentrations and antimicrobial peptides, romyces boulardii or Lactobacillus spp. have been used to prevent
and the latter senses autosecreted peptides via quorum sensing. Acces- relapses of colitis caused by C. difficile (CDI). Two prospective studies
sory gene expression is partially regulated in S. Typhimurium and E. appear to show reduction in incidence of CDI when used prophylacti-
coli by H-NS, a histone-like repressor of horizontally acquired genes. cally.28,29 Fecal transplantation, the introduction of colonic flora from
H-NS silences gene transcription by trapping or excluding RNA poly- healthy individuals into those afflicted with CDI, is an effective tech-
merase from promoter regions and preferentially targets A+T-rich nique in refractory disease.30
DNA, a feature of many horizontally acquired sequences in Entero-
bacteriaceae. However, A+T-richness is a general feature of bacterial Exogenous Infections and the Normal Flora
promoters, and so H-NS is also a global repressor of many regulated Population levels of the different areas of the gastrointestinal tract are
core genes.20 controlled mainly at the level of metabolic competition. Normal flora
Viruses face problems similar to bacteria in the host, but must are well adapted to low oxidation reduction potentials and tightly
solve them using a limited genetic repertoire. Analogous to bacterial adherent to the mucosal epithelium. Pathogens that use the gastroin-
virulence factors, viral genes required for replication and/or pathogen- testinal tract as a portal of entry must find ways of dealing with fierce
esis in the host that are dispensable for replication in tissue culture microbial competition in the colon, or target the less densely populated
are termed accessory genes. For example, simian immunodeficiency small intestine. Small intestinal pathogens have specific adhesins that
virus (SIV) strains lacking the nef gene replicate well in certain cell allow them to remain attached to epithelial cells or to invade those cells
lines but are much less virulent in primate hosts.21 Expression of despite high flow.
both SIV and HIV nef both increases viral infectivity and assists Virulent bacteria have evolved strategies to overcome colonization
in evasion of adaptive host immunity by downregulation of major resistance as well as to out-duel host defenses. For instance, infection
histocompatibility complex (MHC) class I, needed for presentation of epithelial cells by S. enterica stimulates the host cells to produce the
of antigens to allow recognition of infected cells by cytotoxic host-defense protein lipocalin-2, which sequesters enterobactin, the
lymphocytes. siderophore made by most intestinal bacteria. However, Salmonella
RNA viruses have to avoid triggering innate immunity that impairs also make salmochelin, which is not affected by lipocalin-2. Since free
viral replication and modification or destruction of viral RNA by host iron is limiting, this offers a growth advantage to Salmonella. In addi-
restriction factors. Two broad strategies to accomplish this include tion, S. enterica invasion induces production of superoxide by inflam-
masquerading as cellular mRNAs, and inhibiting or degrading host matory cells that can oxidize H2S and thiosulfate into tetrathionate,
factors through the action of viral proteins or decoy RNA.22 For which Salmonella but not E. coli can use as a terminal electron receptor,
example, the HIV vif gene, interacting with proteins in the host ubiqui enabling the former to carry out anaerobic respiration and thus gener-
tin pathway, inactivates APOBEC3G, an innate restriction factor, that ate more ATP than its competitors in the anaerobic intestine.31
otherwise renders viruses uninfectious.23 Similarly, HIV vpu alters Undoubtedly we will discover other strategies used by microbes to deal
protein sorting to prevent cell surface expression of tetherin (BST-2), with competing normal flora.
allowing viral budding to proceed.24 Viruses also produce proteins The skin is much less densely populated by its endogenous flora.
analogous to bacterial toxins, including proteins with superantigen Nevertheless, there are bacteria within skin appendages in all areas of
activity (HIV gp120, Epstein–Barr virus, filovirus)25 and envelope pro- the skin. Surprisingly normal skin also harbors a variety of species of
teins that activate signaling of host tyrosine kinases (e.g. sin nombre the fungus Malassezia and several viruses (papillomavirus, polyoma-
virus).26 virus, circovirus, merkel virus).32 Although intact skin is impermeable
to bacteria, skin disruptions due to lacerations or insect bites can allow even in technologically advanced countries if vaccination efforts are
entry of pathogenic microbes into the body, and abnormal skin such neglected.
as in eczema lacks antimicrobial defensins and has a different bacterial
flora.33 THE INFECTION PROCESS
Attachment to Host Cells
Exogenous Infections
Only a few pathogens can pass directly through the skin. Examples
Exogenous infections occur after direct contamination by microbial
include the cercariae of various Schistosoma species and hookworm
populations in the environment. Humans are continuously in contact
larvae, which can invade the skin with the help of their glandular secre-
with large exogenous microbial populations in the air, soil, food and
tions. Many other pathogens enter the body after insect bites, e.g.
water, which may harbor highly pathogenic bacteria such as Clostrid-
Simulium blackfly bite for Onchocercus volvulus, and anopheles mos-
ium tetani and B. anthracis. Pathogens, such as S. enterica, Staph.
quito bite for malaria. Injection of contaminated medications or blood
aureus, Clostridium perfringens and Clostridium botulinum, and Cam-
can transmit various blood-borne pathogens, such as hepatitis B and
pylobacter jejuni may be present in food and cause food poisoning or
C virus, HIV, West Nile virus, syphilis and malaria, or cause infections
gastroenteritis.
with environmental fungi.34
Live animals represent an important source of exogenous micro-
organisms, producing infections (zoonoses) including cat-scratch Adherence
fever, brucellosis, tularemia, toxoplasmosis, influenza and hantavirus For many microbial and viral pathogens, adherence to the epithelial
pulmonary syndrome. Bats have proven to be a source of several surface of the respiratory, digestive or reproductive mucosa is a com-
viruses, including rabies, Ebola, Marburg, Hendra and Nipah, that pulsory step in pathogenesis. The approach of micro-organisms to an
cause serious infections in different parts of the world. Pathogens can epithelial surface is guided by a balance between attractive and repul-
be transmitted from animals to humans by insect vectors such as flies, sive forces. Initial contact may involve nonspecific interactions, such
mosquitoes and ticks. Plague, Rocky Mountain spotted fever and Lyme as those between exposed hydrophobic structures on the microbial cell
disease are examples of vector-borne zoonotic bacterial infection. envelope and lipophilic areas on the cell membrane, but eventually,
Arboviruses are transmitted by insect vectors and their geographic multiple high-affinity contacts between the microbe and the cellular
range is increasing due to global travel and commerce, and changing surface establish virtually irreversible association. Even for viruses,
climate. Many protozoan pathogens are transmitted by insect bites, attachment may involve multiple adhesins. Interestingly, carbohydrate
malaria being the most important. capsules on respiratory pathogens appear to interfere with epithelial
The most important source of exogenous infections are probably cell adherence and encapsulated bacteria downregulate capsule expres-
humans themselves. Well-known examples of human-to-human sion in order to adhere to or invade epithelial cells.
transmission include sexually transmitted diseases such as AIDS and Specific adherence involves microbial adhesins on the one side and
syphilis, airborne infections such as varicella, rubella, measles and host cell receptors on the other. Specificity of adherence accounts for
tuberculosis, and fecal–oral infections such as amebiasis, shigellosis the early observation that many pathogens infect certain areas or
and typhoid fever. Vertical transmission of infections to the fetus or organs of the body and not others. For instance, the receptors for
newborn is uncommon but may be devastating. Examples include poliovirus, rhinovirus and HIV are expressed only by specific cell types,
toxoplasmosis, CMV, rubella, HIV, listeriosis and syphilis. Cross- restricting virus replication accordingly. Different strains of influenza
infection in hospitals poses enormous problems, especially in intensive virus adhere via the hemagglutinin to different sialic acids, and this
care units, where bacteria are transmitted on fomites or the hands of largely determines not only their host range but also their organ
hospital personnel rather than by direct contact or by droplets. tropism. These and many other examples support the notion that
Certain bacterial respiratory pathogens have no environmental or adhesins can determine the tropism of microbial pathogens. Pathogens
animal hosts, and are passed by droplets from person to person. These such as S. enterica serovar Typhimurium have as many as 12 different
include Streptococcus pyogenes, Strep. pneumoniae and Neisseria men- fimbriae devoted to adhesion, which may explain its broad host range.
ingitidis. If newly colonized individuals do not have protective antibod-
ies they are liable to develop symptomatic infections. Other than Ubiquitous Receptors
pre-existing immunity, why some people become ill after they acquire On the other hand, cell receptors for many organisms are ubiquitous
these organisms and others remain asymptomatic carriers is not well and these organisms have no tissue or even host restriction. Fibrino-
understood. gen, fibronectin, collagen and heparin-related polysaccharides are
A small number of exogenous pathogens are airborne and establish major components of the extracellular matrix (ECM) that coats the
lung infections by direct interactions with alveolar macrophages or mucosal surface of epithelial cells. Members of the integrin family are
mucosal dendritic cells. For this to happen the particles must be ~4 µm involved in the interaction between the ECM and the underlying epi-
in diameter; smaller particles will be exhaled and larger particles will thelium. A number of components of the ECM are used as receptors
be trapped in the nasopharynx. Alveolar macrophages are inherently for microbial adhesins and viral receptor proteins. Staph. aureus has
downregulated for inflammatory responses, which is probably neces- cell wall proteins that recognize nearly all ECM proteins including
sary to prevent lung damage from responses to the many noninfectious fibronectin, elastin, von Willebrand factor, vitronectin and collagen.
particles in the air. However, this makes them ill equipped to kill organ- Attachment to fibronectin is also required for Staph. aureus to
isms that they may ingest. Mycobacterium tuberculosis, primary patho- invade non-phagocytic cells. Fibronectin specifically binds factors on
genic fungi such as Histoplasma capsulatum, Paracoccidioides brasiliensis the cell envelopes of other bacteria including Strep. pyogenes, Trepo-
and Coccidioides immitis, and the environmental bacterium Legionella nema pallidum, Mycobacterium spp. and Orientia tsutsugamushi, the
pneumophila are examples of airborne pathogens. etiologic agent of scrub typhus. Fibrinogen binds groups A, C and G
Exogenous infections, predominant in the past, have dramatically streptococci and a member of the integrin family binds the major
declined in the industrialized world thanks to improved hygiene, vac- invasion factor of Yersinia pseudotuberculosis. Their abundance and
cination programs and infection control programs, but are still preva- structural conservation among mammalian species make ECM com-
lent in areas with limited resources. Pneumococcal pneumonia, ponents ideal targets for bacterial adhesins.
diarrheal diseases from contaminated food and water, malaria, measles,
AIDS and tuberculosis are among the main causes of mortality in low- Bacterial Adhesins
and middle-income countries. In the 1990s, a large diphtheria epi- Close contact between micro-organism and host cell represents
demic occurred in Russia as the result of the collapse of the public an essential step in pathogenesis. It optimizes the interaction of micro-
health infrastructure. Clearly, despite decades of vaccine use, patho- bial virulence factors with the target cell to allow the pathogen to
genic microbes are still in the population and can become epidemic penetrate or cause local cell damage, or both. Other possible functions
Bacterial adherence
Pili-dependent adherence Afimbrial adherence Simple adherence Actual adherence
Pili Nonspecific attractive

forces are
counterbalanced by Specific affinity of
charged repulsion bacterial adhesins to host
cell receptors assures
Bacterium
tight contact
+– –– – – +– – +– – – – + – – + – –– ––+––
– +
+
– – – Bacterium
– + +
– + – +– –– – – +– – +– – – – + – – + – –– ––+– –
+ + +
Host cell – –
+ +
receptor
+– – – +– – – + – – –+ – + – – –+–– +– – – +– – – + – – –+ – + – – –+– –
Host cell
membrane Host Host
Figure 2-5 Bacterial adherence. (Courtesy of Menno Kok and Jean-Claude Pechère.)
of adhesins include modulation of the inflammatory response, adhesin-

directed degranulation from mast cells and adhesin-mediated bacterial Cell wall of Streptococcus pyogenes
phagocytosis by neutrophils. Bacteria use two general strategies to
attach themselves to host cells: fimbrial and afimbrial adhesion (Figure
M protein
2-5).35 NH2
Pili and Fibrillae. Attachment of bacteria to the plasma membrane Hypervariable
can be mediated by filamentous structures protruding from the bacte-
rial surface, called fimbriae or curli. The classification of these coloni-
zation factors is based on morphologic criteria. Fimbriae (or common
pili) are rigid hair-like structures with a regular diameter, whereas curli
are amyloid-like fibers. These structures are distinct from sex pili used
Variable
for bacterial conjugation.

Twenty different colonization factors have been described for E.
coli.36 One of these, the P-pilus, is expressed by uropathogenic E. coli
and mediates adherence to the epithelium of the upper urinary tract.24 ARP/FcR
It recognizes the glycolipid receptor globobiose (α-1–4 linked
di-galactose) on the host cell surface. E. coli can express several differ- Pepsin
ent pili, but not simultaneously. For instance, the mannose-binding Ig binding
pilus is expressed when E. coli are in the bladder and the P-pilus is not. Lipoteichoic
Afimbrial Adhesins. Afimbrial adhesins, such as lectins acid C5a peptidase T antigen
(carbohydrate-binding proteins), also mediate tight binding between Group A
the bacteria and the host cell but, unlike pili, they do not form supra- carbohydrate
molecular structures. Similar adhesins exist in viruses, fungi and pro-
Conserved
tozoa. Afimbrial binding has been extensively studied in S. pyogenes

(Figure 2-6). Two surface components are believed to be critical in the
colonization of an epithelial surface: lipoteichoic acid and fibronectin-
binding protein.
Viral Adhesion
Adhesion is the first step in viral replication. Several viral proteins may
be required to mediate attachment, viral fusion and entry into the cell.
For example, the HIV gp120 protein first attaches to the CD4 molecule
on the cell surface, exposing an area of gp120 that interacts with a
seven-loop transmembrane protein co-receptor, triggering fusion via
a portion of the gp41 transmembrane protein. In rotavirus, too, dif-
COOH
ferent viral proteins interact with membrane carbohydrates, integrins
and a heat shock protein to mediate attachment and entry.37 Figure 2-6 Cell wall of Streptococcus pyogenes. The proposed model of the M
For some viruses (typically enveloped viruses, including measles protein is based on current sequence and structural data. ARP, immunoglobulin
and mumps viruses38), attachment proceeds via direct fusion with the A receptor protein; FcR, receptor for the Fc portions of immunoglobulin. (Adapted
cell plasma membrane. These virions have a transmembrane fusion from Kehoe M.A.: Group A streptococcal antigens and vaccine potential. Vaccine
1991; 9:797–806.)
protein that induces contact between the viral and cellular lipid bilay-
ers. Alternatively, attachment may trigger endocytosis, proceeding
through clathrin-coated pits, frequently involving acidification of the
vesicle to trigger structural changes in viral proteins that result in
escape from the endolysosome into the cytoplasm. This pathway is exceptions. Corynebacterium diphtheriae, which causes pharyngitis,
used by many non-enveloped viruses, including adenovirus, rhinovi- and Bordetella pertussis, which causes whooping cough, produce their
rus and other enteroviruses.39 illnesses via locally released toxins. Some strains of Staph. aureus carry
Cell specificity (‘tropism’) may be relaxed for viruses that use a gene on a mobile genetic element that encodes a super-antigen
ubiquitous receptors or strongly restricted for viruses requiring two or (TSST-1) that can be absorbed from a mucosal surface and precipitate
more cellular receptors. As noted, HIV requires co-expression of CD4 ‘toxic shock’.
and one of several chemokine receptors for efficient infection, and it Some micro-organisms gain access to deeper tissues only after a
principally infects only CD4+ lymphocytes and monocyte/macrophages. physical or chemical injury of the epithelial barrier. This happens after
In contrast, herpes simplex virus type 1 has four envelope glycopro- burns damage the skin epithelial barrier. Invasive micro-organisms
teins that interact with cell surface receptors: gB and gC interact with exhibit the capacity to penetrate the target tissue to which they adhere
heparin sulfate ubiquitously present on cell plasma membranes, while without the need for local disruption of the protective epithelium.
glycoprotein D interacts with nectin-1 or herpesvirus entry mediator Invasive bacteria have developed the capacity to enter host cells that
(HVEM), widely expressed on epithelial cells and some neurons.40 are not naturally phagocytic. Penetration into these ‘nonprofessional’
These different envelope proteins mediate infection of epithelial phagocytes is achieved by either engulfment or zippering. S. enterica
(skin and mucosal) and neural cells, respectively, after passing into and Shigella spp. are examples of bacteria that induce their own engulf-
axon termini of neurons. Tropism is not always restricted by surface ment using type III secretion systems to rearrange the host cell cyto-
binding. The JC polyoma virus receptor, sialyl (α2–6) Gal, has a wide skeleton by injecting proteins that mimic host enzymes through the
distribution in human tissues, while virus replication occurs only in host cell membrane, resulting in actin rearrangement so that the
oligodendrocytes, urothelial cells and possibly B lymphocytes.41 bacteria are carried into the cell (Figure 2-7). The bacteria inject addi-
Viral adherence and invasion can be blocked by neutralizing anti- tional enzymes that restore the cytoskeleton to its original shape and
bodies that specifically bind the active site(s) of the adhesin(s). restore cellular integrity. In contrast, bacteria such as Listeria monocy-
However, many viruses hide these region(s) in protein pockets (or togenes and Yersinia pseudotuberculosis use a ‘zipper’ mechanism to
‘canyons’) or behind attached sugars, making them inaccessible to enter cells that starts with binding to integrins on the cell surface,
neutralizing antibodies, escaping humoral immunity. The relative infi- which leads to cytoskeletal rearrangements. Listeria uses a second
delity of viral polymerases generates mutants during replication which adhesion factor to enter hepatic cells, attaching to the hepatocyte
facilitates escape from host immunity. growth factor receptor, which triggers phosphatidylinositol (PI) 3
kinase activation. Surprisingly, Listeria enters all cells in a clathrin-
Invasion dependent, endocytic manner. The adapter protein Dab2 is required
for the formation of these clathrin-coated pits and for the recruitment
INVASIVE AND NONINVASIVE
of myosin IV, initiating a process that provides a pulling force for
MICRO-ORGANISMS Listeria internalization.
Many micro-organisms, including those of the natural flora, remain In some cases, such as shigellosis, the infection remains confined
at the epithelial surface without invading the underlying tissue (Table to the surface epithelium (see Table 2-4), but in others the micro-
2-4). This type of colonization is usually harmless although there are organisms are transported across the epithelium and released into the
subepithelial space. This process is called transcytosis and involves the
host cell actin network. After transcytosis, the underlying tissues may
be invaded and infection may spread (e.g. N. meningitidis may cross
TABLE Interaction of Micro-organisms with
2-4 the pharyngeal epithelium, enter the blood and cause meningitis).
Epithelial Cells
Some pathogens, such as Strep. pyogenes, usually cause disease on an
Order Micro-organism Disease epithelial surface, but they are also capable of invading epithelial cells
and causing deep tissue infections. For a more detailed analysis of the
GENERALLY CONFINED TO EPITHELIAL SURFACES
mechanisms of invasion, we shall use the example of enteroinvasive
Bacteria Bordetella pertussis Pertussis pathogens.
Chlamydia trachomatis Trachoma, urethritis
Corynebacterium diphtheriae Diphtheria Enteroinvasive Pathogens and the Membranous
Streptococcus pyogenes Uncomplicated pharyngitis
Vibrio cholera Cholera Cell Gateway
Escherichia coli (EPEC) Diarrhea Acute infectious diarrhea spans the clinical spectrum from watery
Viruses Coronaviruses Common cold diarrhea to dysentery (bloody diarrhea). Dysentery occurs when the
Rhinoviruses Common cold pathogen invades the intestinal mucosa and causes structural damage
Rotaviruses Diarrhea to the intestine. The immunologic protection of the intestine is per-
Fungi Candida albicans Thrush formed by epithelial cells themselves and the gut-associated lympho-
Trichophyton spp. Athlete’s foot cytes, which are separated from the intestinal lumen by epithelium.
There are both intraepithelial lymphocytes and localized lymphoid
Protozoa Giardia lamblia Diarrhea
Trichomonas vaginalis Vaginitis follicles that are covered by membranous cells (M cells) that play a
prominent role in intestinal immunity because they are specialized in
ENTER THROUGH THE EPITHELIUM the transport of antigens. Enteroinvasive viruses, protozoa and bacteria
Bacteria Shigella spp. Bacillary dysentery adhere to M cells and exploit their transport functions to invade the
Brucella melitensis Brucellosis host. Infection by poliovirus may proceed by such a route.42
Neisseria meningitidis Meningitis Enteroinvasive bacteria such as Salmonella, Shigella and Yersinia
Salmonella Typhi Typhoid fever
Treponema pallidum Syphilis spp. appear to distinguish between different subsets of M cells. Mem-
Yersinia pestis Plague branous cells produce glycocalyx containing distinctive lectin-binding
sites. Diversity in lectin-binding sites between different locations of
Viruses Measles virus Measles
Rubella virus Rubella the gut may account for the tropism of enteric pathogens, such as the
Varicella Chickenpox preferential colonization of colonic mucosa by Shigella spp., versus the
Poliovirus Poliomyelitis terminal ileum for Salmonella spp. Following adherence, the interac-
Fungi Candida albicans Disseminated candidiasis tions with the M cells vary according to the pathogen (Figure 2-8).
Enteroadherent E. coli are not internalized and hence are not invasive.
Protozoa Toxoplasma gondii Toxoplasmosis
Entamoeba histolytica Liver abscess
V. cholerae is taken up and transported by the M cells but rapidly killed
thereafter.
Triggered uptake into epithelial cells
Yersinia Salmonella Shigella
Actin polymerization
Actin
polymer- Invasin
ization
Cofilin P inositol
metabolism
Rho IpgD
P inositol β1 integrin SipA SipC IpaC
GTPases Vinculin
metabolism
Rho IpaA Actin
Rho GTPase
Rho SopE SptP Actin GTPases VirA
depolymerization
GTPase depolymerization
Kinases SopB
P inositol Microtubule
a b metabolism c Tyrosine kinases depolymerization
Listeria InlA pathway Listeria InlB pathway
Actin polymerization InlA Actin polymerization InlB

gC1qR
Met
Pl3K Ub
E-cadherin Clathrin
Catenins
Cofilin
P inositol
Myosin Rho metabolism
Contractile force GTPase
Rho GTPase Adaptors Actin
d e LimK depolymerization
Figure 2-7 Triggered uptake into epithelial cells. Some invasive bacteria (b and c) express a complex needle-like structure on their cell surface (Type III secretion
system) through which they inject proteins that hijack the adjacent cytoskeleton, triggering membrane ruffling that embraces the adjacent bacterium and internalizes it
in a vacuole. Others have surface receptors for integrins (a, d and e) which trigger a pinocytic-like response leading to uptake.
The Salmonella and Shigella spp. genes involved in invasion of the island, avoiding exposure to cellular bactericidal mechanisms. Although
eukaryotic host cell are homologous and have been remarkably well only some of the cellular targets of the translocated bacterial virulence
conserved with respect to both individual coding sequences and proteins have been identified to date, it is clear that the physiology of
genetic organization.43 Molecular analyses of virulence factors pro- the infected cell is profoundly modified to suit bacterial growth and
duced by enteroinvasive Shigella spp. have revealed that all virulent maintenance.
species harbor a 220 kb plasmid, of which a 31 kb operon, encoding
32 genes, is both necessary and sufficient for invasion of epithelial ACTIN-BASED INTRACELLULAR MOTILITY OF
cells.44 The Salmonella spp. entry functions are clustered in a 35–40 kb MICROBIAL PATHOGENS
pathogenicity island.45 Using type III secretion systems, a needle-like L. monocytogenes, Rickettsia spp., Shigella spp., vaccinia, measles and
molecular complex, invasive bacteria inject effector proteins into the rabies viruses actively modify actin to move about within the cyto-
cytosol and the plasma membrane of the target cell.46,47 Some of these plasm of infected cells and to invade neighboring cells. Microbial prod-
effector proteins specifically modify the activities of cellular small ucts induce the formation of actin cross-linked filaments, which
GTPases (see Figure 2-7), inducing cytoskeleton alterations required assemble in characteristic ‘comet-like tails’ (Figure 2-9).48 Elongation
for bacterial internalization. of the actin filaments generates sufficient force to move the micro-
An important difference between the pathogenic lifestyles of these organisms through the cytoplasm at rates of 2–100 mm/min. Listeria
two bacterial species involves their intracellular fate. Once internalized, penetrates enterocytes using products encoded by the internalin (inl)
both are enclosed by a host cell membrane in an endocytic vesicle, but family of genes, which seem to confer tropism for different cell types.49
Shigella spp. escape from the endosome into the cytoplasm soon after Once inside the cell, L. monocytogenes escapes the phagosome into the
entry, whereas Salmonella spp. have adopted an entirely different strat- cytosol by rapidly lysing the endosomal membrane via the action of
egy. Salmonellae modify the endocytic pathway of the host cell by listeriolysin O, its hemolysin. Actin polymerization is then induced by
means of virulence factors encoded largely by another pathogenicity ActA, localized at one end of the bacterium. Listerial lecithinase and
Enteropathogen–M cell interactions
a Uninfected M cell b Enteroadherent bacteria not internalized c

Negative Transcytosis,
stranded phagocytosis and killing
RNA viruses
Apical side
Microvilli
M cell
Enterocyte
Tight junction
Lymphocyte
M cell
pocket
Nucleus
Basement Macrophage
membrane
Basolateral side
Endocytosis, escape into cytoplasm,
d Transcytosis, replication and dissemination e replication and spread
f Transport across M cell and M cell destruction
Lymphocyte
Figure 2-8 Enteropathogen–M cell interactions. (a) An uninfected M cell, enclosed between two adjacent enterocytes. The basolateral side forms a pocket where
lymphocytes and macrophages are located. (b) Enteroadherent Escherichia coli forms microcolonies at the M cell surface, but is not internalized. (c) Vibrio cholerae
undergoes transcytosis but is efficiently phagocytosed in the submucosa. (d) Campylobacter jejunii and Yersinia spp. undergo transcytosis, replicate in the submucosa
and disseminate. (e) Salmonella spp. are transported across M cells and taken up by interepithelial dendritic cells. (f) Shigella flexneri is endocytosed by M cells, escapes
into the cytoplasm, replicates, is propelled by actin tails and spreads to adjacent enterocytes. (Adapted from Siebers A., Finlay B.B.: M cells and the pathogenesis of
mucosal and systemic infections. Trends Microbiol 1996; 4:22–28.)
phospholipase C facilitate cell-to-cell spread, dissolving the double actively fight the invaders. As a result, draining lymph nodes are often
membranes that separate bacteria from the cytoplasm of neighboring inflamed. If the invading micro-organism is sufficiently virulent or
cells. In this fashion the bacteria spread throughout the body, infecting present in sufficiently large numbers, it may pass into efferent lym-
endothelial cells, Kupffer cells, hepatocytes and placental trophoblasts phatic vessels to be conducted to the bloodstream. The result is primary
while avoiding exposure to humoral and cellular defenses. Intracyto- bacteremia or viremia.
plasmic bacteria do still stimulate cell innate immune responses via Once in the bloodstream, the micro-organisms can circulate as
Nod signaling. either an extracellular or an intracellular species. Pathogens have been
found in polymorphonuclear cells (Anaplasma), lymphocytes (HIV,
EBV), macrophages (M. tuberculosis, H. capsulatum and CMV) and
SUBEPITHELIAL INVASION AND SPREAD even in red blood cells (Plasmodium spp., Bartonella bacilliformis).
THROUGH THE BODY Intracellular transport protects against potent humoral factors in the
Invasion from the epithelium into the deeper tissues can only be plasma, such as complement.
achieved by micro-organisms that effectively resist or subvert the host
defense mechanisms in the subepithelial space, most prominently Infection of Distant Target Organs
phagocytosis. Transported by the bloodstream, invasive micro-organisms reach
Some organisms take advantage of the normal transport of antigens distant organs and create metastatic infection throughout the body.
and are carried by dendritic cells to regional lymph nodes. In the Organs containing macrophages and abundant capillary and sinusoid
lymph nodes, resident macrophages and polymorphonuclear cells networks (e.g. lungs, liver, spleen, kidneys, bone marrow) that are
Actin-based motility in Listeria monocytogenes TABLE Mechanisms of Cell and Tissue Damage
2-5 Produced by Micro-organisms
Actin polymerization is at barbed Mechanism Examples
Actin depolymerization is ends near microbial surface
random throughout tail DIRECT DAMAGE BY MICRO-ORGANISMS
Production of toxins See Table 2-6
Movement Production of enzymes Proteases, coagulase, DNAses

produced by Staphylococcus
aureus
Apoptosis HIV (CD4+ T cells); Shigella spp.

Low filament density Actin filaments Highest filament density (macrophages)
= older filaments are from host and = newest filaments
remain stationary Virus-induced cytopathic effects:
Cell enlargement and lysis Cytomegalovirus
Microbial surface protein, binding site for nucleating factor Formation of syncytium Respiratory syncytial virus
Actin-nucleating factor from host cell Inclusion bodies:
Intracytoplasmic Rabies
Nuclear Herpesviruses
Transformation Human papillomavirus type 16
DAMAGE VIA THE HOST IMMUNE RESPONSE

Cytotoxic T cells and natural killer Production of the measles rash,
lymphocytes hepatitis A
Autoimmunity Acute rheumatic fever,
Streptococcus pyogenes
Immediate hypersensitivity Rashes associated with helminth

infections
Figure 2-9 Actin-based motility in Listeria monocytogenes. The bacterium Cytotoxic hypersensitivity Cell necrosis induced by hepatitis B
moves forwards at the rate of actin-filament growth behind the pathogen. The
electron micrograph shows a section of a CaCo-2 cell infected with L. monocyto- Immune complexes Glomerulonephritis in subacute
genes; the bacterium protrudes into the cytoplasm of an adjacent cell; protrusion endocarditis
is limited by a double membrane (arrowheads). (Adapted from Sanders and Delayed type hypersensitivity Tuberculous granuloma, caseous
Theriot.48) necrosis
exposed directly to circulating blood are especially vulnerable. Slow

blood flow and increased surface area in these sites provide the micro-
organisms enhanced opportunity to adhere and establish infection. CELL AND TISSUE DAMAGE INDUCED BY
The epiphyses of long bones in children are another important target MICRO-ORGANISMS
for certain pathogens such as Staph. aureus and H. influenzae. From Infectious disease is often characterized by cell and tissue damage.
these target organs, the invaders may produce a secondary bacteremia Paralysis in poliomyelitis, exanthem in varicella, gastroduodenal ulcers
or viremia of higher intensity than during primary infections. in Helicobacter pylori infections and bloody diarrhea in shigellosis all
result from damage caused directly or indirectly by micro-organisms.
Viral Invasion: the Example of Measles Virus Cell damage can be generated by a variety of different mechanisms
Inhaled airborne measles virus enters via the membrane co-factor (Table 2-5).
protein (CD46)50 and/or the signaling lymphocyte activation molecule
(SLAM/CD150)46 on the epithelial surface of the respiratory mucosa. BACTERIAL TOXINS
After 2–4 days of local replication in the lining of the trachea and Bacteria produce a large diversity of toxins, which have been classified
bronchi, pulmonary macrophages carry the virus to the regional according to their mode of action (Table 2-6). Historically, exotoxins
lymph nodes, where the infection causes formation of reticuloendo- were defined as soluble substances made by bacteria that have deleteri-
thelial giant cells. Progeny virions enter the bloodstream, and the virus ous effects on the host. As we learn more about the mechanisms of
spreads to the spleen, lymph nodes, the lung, nasopharynx, oral action of exotoxins, the distinction between them and secreted enzymes
mucosa, thymus, liver, skin and the central nervous system, with that play a role in pathogenesis is disappearing. The clostridial neuro-
increasing viremia over the next 4–5 days. Virus shedding from the toxins are good examples of proteases that are exotoxins. These toxins,
nasopharynx begins 12–13 days after infection, before symptoms or which are responsible for tetanus and botulism, are zinc metallopro-
rash develop, increasing transmissibility, so that the attack rate exceeds teases that cleave synaptobrevins so that docking and fusion of synaptic
80% in nonimmune contacts. vesicles are impaired. The localization of the toxins to different nerve
These pathogenic steps correspond to different clinical manifesta- junctions is what determines the different clinical presentations of
tions. During the 10-day incubation period, infection and primary these diseases.
viremia proceed with no symptoms. Fever, malaise, cough and con- Cholera toxin ADP ribosylates Gs protein, locking it into the ‘on’
junctivitis appear during secondary viremia, followed by rash. The position, resulting in unregulated activity of adenyl cyclase and high
characteristic morbilliform exanthem consists of a perivascular mono- intracellular levels of cAMP. The characteristic illness produced by
nuclear infiltrate, including cytotoxic T cells that have migrated to the cholera toxin is not due to the specificity of the toxin binding or its
site of infected endothelial and overlying dermal cells. Virus infection function but rather to the location of the pathogen; V. cholera is an
produces epithelial giant cells, but does not directly destroy infected extracellular mucosal pathogen so only intestinal epithelial cells are
cells in the skin. Leukopenia occurs late in viremia, and immune sup- exposed to the toxin in vivo.
pression can be seen from the time of appearance of symptoms until Traditionally, exotoxins are said to be excreted toxins. However,
2–3 weeks after clinical infection resolves (see Chapter 163). some so-called exotoxins are actually intracellular and are released into
TABLE
2-6 Examples of Bacterial Toxins
Toxin Type Example of Sources Toxin Targets Mechanisms Effects
Endotoxin (LPS, Gram-negative bacteria Lipid A Macrophages, Activation of target cells via Fever, septic shock
lipid A) neutrophils, B TLR4, complement activation;
lymphocytes, release of pro-inflammatory
endothelial cells, cytokines, chemokines, kinins
plasma components
Membrane- Staphylococcus aureus α-Toxin Many cell types Formation of pores Tissue necrosis
disrupting Listeria monocytogenes Listeriolysin Many cell types Formation of pores at acidic pH Escape from the phagosome
toxins Clostridium perfringens Perfringolysin-O Many cell types Phospholipase (removes polar Gas gangrene
head groups from
phospholipids)
A–B type toxins Clostridium tetani Tetanospasmin Synaptic transmission Inhibits release of inhibitory Spastic paralysis
neurotransmitters
Clostridium diphtheriae Diphtheria toxin Many cell types ADP ribosylation of EF-2 Myopathy, polyneuropathy
Vibrio cholerae Cholera toxin Intestinal cells ADP ribosylation of adenylate Profuse watery diarrhea
cyclase, leading to rise in
cyclic AMP
Superantigen Streptococcus pyogenes Streptococcal T cells, macrophages T cell stimulation, release of Fever, rash, toxic shock-like
pyogenic IL-1, IL-2, TNF; possible syndrome
exotoxin enhancement of LPS activities
Staphylococcus aureus Toxic shock T cells, macrophages Same as streptococcal Toxic shock syndrome
toxin pyrogenic toxin
the environment only after cell lysis. The pneumolysin of Strep. pneu- of mechanisms, including proteolysis of IgA, liquefaction of pus,
moniae, for example, is cytoplasmic, the adenylate cyclase of B. pertussis induction of plasma clotting (which may hinder the influx of phago-
is associated with the cytoplasmic membrane, and the heat-labile toxin cytes) and the destruction of extracellular DNA nets produced by
1 (LT-1) from E. coli is periplasmic. Others may be released by local- polymorphonuclear neutrophils (PMNs).
ized disruption of the cell wall, such as the newly described typhoid
toxin.51 Apoptosis
The genetic information that encodes bacterial toxins is frequently Apoptosis is a process in which the cell activates an intrinsic suicide
carried on mobile DNA elements that readily pass from one microbial program. It plays a key role in organ development, tissue repair and
host to another. The toxins that cause diphtheria, cholera, botulism maintenance of the equilibrium of the immune system, processes that
and scarlet fever, and EHEC-associated hemolytic uremic syndrome depend on the addition of new cells and elimination of ‘old’ cells.
are encoded by temperate bacteriophages. Genes for LT-1 and heat- Apoptosis is characterized by reduction of the volume of the cytosol
stable toxin (Sta) of E. coli are carried on plasmids. and nuclear condensation (Figure 2-12). Genomic DNA is cleaved by
an endonuclease that cuts the DNA into multiples of 180–200 bp.52
The Diphtheria Toxin as Example of an A–B Toxin Finally, the remains of the cell are removed by macrophage phagocy-
Diphtheria toxin belongs to the so-called bifunctional A–B toxins tosis, without triggering an accompanying inflammatory response.
(Figure 2-10). Portion A mediates the enzymatic activity responsible Viral infection often triggers apoptosis of infected cells due to inter-
for halting protein synthesis in the target cell while portion B binds to ruption of protein synthesis, transcription or signaling. Apoptosis
a cell receptor and mediates the translocation of the A chain into the seems to contribute to the depletion of CD4+ T cells, both in cell
cytosol. Portion B accounts for the cell and species specificity of the culture and in HIV-infected persons.53 Several different HIV proteins
A–B toxins. The B chain of diphtheria toxin recognizes a heparin- promote or inhibit apoptotic cell death.54 Similarly, lytic infection by
binding precursor of epidermal growth factor, an important hormone EBV and adenoviruses produce apoptosis, while EBV latent membrane
for cell growth and differentiation. Uptake of diphtheria toxin pro- protein 1 (LMP-1) inhibits apoptosis in latency.55 Apoptosis may
ceeds via receptor-mediated endocytosis. Acidification of the endocytic benefit the host, to the extent it eliminates cells before they produce a
vesicle induces a conformational change in the enclosed holotoxin, full complement of progeny virus.
enabling the A subunit to traverse the membrane and reach its cyto- Bacteria can also induce apoptosis. B. pertussis, the agent of whoop-
plasmic target. The A subunit of diphtheria toxin catalyzes ADP ribo- ing cough, triggers macrophage apoptosis by interfering with cellular
sylation of the elongation factor-2 (EF-2), inactivating it. The tox gene regulation at the level of the cytoplasmic second messenger cyclic AMP
is encoded by a phage and is under the control of the repressor protein (cAMP).56 The bacterium induces high levels of cytoplasmic cAMP,
DtxR, which forms an iron complex, DtxR-Fe (Figure 2-11), that binds favoring the induction of apoptosis. Shigella flexneri, a cause of dysen-
DNA and represses tox expression. Thus diphtheria toxin is only syn- tery, can kill macrophages by apoptosis. Cell death is induced by inva-
thesized under low iron conditions, suggesting that it may be produced sion plasmid antigen B (IpaB) encoded by the Shigella virulence
to stimulate iron release from target cells. Interestingly, the Pseudomo- plasmid.57 The Shigella IpaB protein binds to the host cytoplasmic
nas aeruginosa exotoxin A has a very similar structure, but uses a dif- enzyme interleukin IL-1β converting enzyme (caspase-1) and activates
ferent cell receptor: the α-2 macroglobulin low-density lipoprotein it.58 Caspase-1 activates the proinflammatory cytokines IL-1β and
receptor. Like diphtheria toxin, exotoxin A enters the cell via receptor- IL-18 by proteolytic cleavage and initiates one of the pro-apoptotic
mediated endocytosis but the toxin is released only after passage pathways.
through the Golgi system.
Virus-Induced Cytopathic Effect
Hydrolyzing Enzymes Many viruses damage the cells they infect, sometimes inducing visible
Microbial pathogens often secrete hydrolyzing enzymes, such as pro- and distinctive cytopathic effects (Figure 2-13), mediated by virus
teases, hyaluronidases, coagulases and nucleases. These enzymes do replication and/or the host immune response. Poliovirus protease 2A
not harm host cells directly and are therefore not considered to be shuts off host cell protein translation by cleaving eIF4G, needed for
toxins; however, they can facilitate infection by a variety recognition of capped mRNA and cellular protein synthesis59
Diphtheria toxin synthesis and mode of action Iron regulation of diphtheria

toxin synthesis
Toxin synthesis
Diphtheria toxin
25 193 342 gene regulator
(tox)
Op
S–S S–S
Leader peptidase
Dtx R
S–S S–S
Fe
Trypsin-like enzyme
S–S S–S
R-SH
Fe Dtx R
A HS SH B S–S
ADP-ribosyl Membrane Receptor

a transfer insertion binding
Mode of action tox

Dtx R Fe
B chain binds
to receptor
Diphtheria
toxin
Eukaryotic cell Endocytosis Figure 2-11 Iron regulation of diphtheria toxin synthesis. High iron concentra-
tions in the environment repress the synthesis of diphtheria toxin. When bound
to iron, DtxR-Fe binds to the operator (Op) of the tox gene and acts as a tran-
scriptional repressor of the tox gene. (Courtesy of Menno Kok and Jean-Claude
Pechère.)
Endocytosis
NAD
+ EF-2
Acid
Catalysis
Figure 2-12 Apoptosis induced by Sendai virus. Morphologic changes in the

ADP–ribosyl–EF-2 apoptotic Sendai infected cell (right) include the typical condensation of chromo-
+ nicotinamide + H(+) somal DNA. (Courtesy of Menno Kok and Jean-Claude Pechère.)
Death of target cell

and coxsackie B protease 2A cleaves dystrophin in cardiac muscle,
b contributing to myocardititis.60 In contrast, infection with hepatitis A
and hepatitis C viruses produces very little direct killing of hepatocytes,
Figure 2-10 Diphtheria toxin synthesis and mode of action. (a) The 25-residue with most liver damage resulting from the host’s cytotoxic lymphocyte
leader sequence is cleaved off by the bacterial leader peptidase; the A and B
subunits are generated from the precursor protein by a ‘trypsin-like enzyme’. response.
Once in the cytoplasm of a targeted eukaryotic cell, the A chain, responsible for Virus infection may also result in intracellular accumulation or
ADP-ribosyl transfer, is disconnected from the B chain, responsible for receptor release of small molecules, such as reactive oxygen or nitric oxide,
binding and membrane insertion. (b) The B chain binds to a specific receptor on probably via effects on cellular signaling pathways or induction of
the eukaryotic cell. After endocytosis, acidification in the endosome induces inser-
tion of the B chain into the endosomal membrane and translocation of subunit A innate immune responses. These may play important roles in cell
into the cytosol, where it catalyzes the ADP ribosylation of EF-2. As a result, destruction, particularly in macrophages. Rotavirus, CMV and HIV
protein synthesis is inhibited and the targeted cell dies. (Courtesy of Menno Kok infection produce significant increases in intracellular calcium, a
and Jean-Claude Pechère.) common pathway for the development of irreversible cell injury.
lead to cancer. For example Burkitt’s-type lymphoma and craniopha-

Virus-induced cytopathic effects ryngioma are associated with EBV while cervical, oral and anogenital
carcinomas are associated with HPV, Kaposi’s sarcoma-associated her-
Cytoplasmic inclusion Intranuclear inclusion bodies pesvirus produces Kaposi’s sarcoma, and adult T-cell leukemia is
bodies (e.g. rabies virus) (e.g. herpesvirus) caused by human T-cell lymphotropic virus type 1.61
In the case of HPV, persistent infection with ‘high-risk’ strains (e.g.
HPV16 and 18) leads to atypia that progresses to invasive carcinoma.62
When HPV integrates, E2 expression is disrupted, resulting in
unchecked expression of E6 and E7, which knock out important
tumor-suppressor proteins. E7 binds to retinoblastoma protein (Rb)
and cyclins A and E, allowing Rb phosphorylation and release of the
E-2F, promoting G1 to S cell cycle transition and unchecked cellular
proliferation.63 E6 functions as a ubiquitin ligase to degrade the p53
anti-oncogene, which arrests the cell-division cycle when DNA is
Cytoplasmic and intranuclear bodies Areas of rounded and dead/dying cells
damaged, and then activates DNA repair or initiates cell death. Without
(e.g. measles virus) and cell lysis (e.g. enterovirus)
p53, a cell replicates wildly even with damaged DNA. Further chromo-
somal instability and mutations promoted by enhanced viral expres-
sion promote the transformation of infected cells to a malignant
phenotype.
Damage Resulting from Cytotoxic Lymphocytes

Host defense against most viral infections is mediated by the CD8+
cytotoxic T lymphocytes (CTLs) and NK (natural killer) cells. CD8+
lymphocytes recognize, attack and lyse virus-infected cells that present
viral antigens on their surface in the context of MHC class I molecules
Multinucleate giant cells (syncytium; Neoplastic transformation while NK cells attack stressed cells that do not display MHC I. The
e.g. respiratory syncytial virus) (e.g. papillomavirus) cytotoxic reaction contributes to the pathologic and clinical picture of
many viral diseases, including measles and hepatitis A and C as noted
above. Lymphocyte-induced cytotoxicity may also contribute to the
pathology associated with persistent virus infections such as subacute
sclerosing panencephalitis, caused by defective measles virus within
the brain.
HARMFUL IMMUNE RESPONSES

The destructive potential of the immune system is considerable. It can
damage the host in a variety of ways.
Autoimmunity
Autoimmune reactions break the ‘self versus non-self ’ dichotomy
Figure 2-13 Virus-induced cytopathic effects. (Courtesy of Menno Kok and
Jean-Claude Pechère.)
rule. Autoimmune reactions, directed against ‘self-proteins’, may result
from similarity between antigenic determinants of the host and an
infective agent or from alterations of self-components caused by infec-
tion. Acute rheumatic fever (ARF), which occurs after Group A strep-
Viral fusion proteins mediate characteristic formation of multi- tococcal pharyngitis, has been associated with antibodies against
nucleated giant cells (syncytia). Examples include respiratory syncytial antigens found in the cell wall of the streptococcus that also recognize
virus, parainfluenza viruses, measles virus, herpesviruses and some components of the endocardium, synovial membranes, and neurons
retroviruses. Viral infection can also produce eosinophilic or baso- in the brain.64 These are the organs that are affected in ARF. Another
philic inclusion bodies in the cytoplasm or the nucleus, representing example of molecular mimicry is the association between production
aggregates of mature virions, sites of viral replication, viral assembly of anti-ganglioside antibodies, the Miller–Fisher (MFS) variant of the
or degenerative changes. Guillain–Barré syndrome (GBS), and prior C. jejunii infection. This
Infection and Cancer illness is almost certainly due to cross-reacting antibodies against the
sialylated LPS of C. jejunii.
Infection can favor development of cancer by producing chronic
inflammation, impairing immune surveillance and directly altering Hypersensitivity Reactions
cell growth and death, for example: Hypersensitivity reactions occur if the host immune system seemingly
• chronic H. pylori infection is associated with gastric adenocarci- overreacts to microbial infection. Hypersensitivity reactions have been
noma and mucosa-associated lymphoid tissue (MALT) classified by Gell and Coombs into four types.
lymphoma;
• Schistosoma haematobium infestation is associated with bladder Type I or Immediate Hypersensitivity. Type I hypersensitivity
cancer; occurs within minutes of antigen exposure. It results from antigen
• inflammation from HCV and HBV is a cause of hepatocellular binding to mast cell-associated IgE. Vasoactive amines are released and
carcinoma. anaphylactic reactions may develop. Some rashes after helminth infec-
It is possible that different types of infection may act together in pro- tions seem to be due to this Type I hypersensitivity.
moting neoplasia. For example, human papillomavirus (HPV) has Type II or Cytotoxic Hypersensitivity. Type II hypersensitivity
been found to be present in all bladder tumors associated with schis- is a consequence of the binding of specific antibodies to cell surface-
tosomiasis but only the minority without parasitic infestation. Expres- associated antigens. Antibody binding mediates cytotoxicity via
sion of viral oncogenes drives cellular proliferation and impairs complement activation or NK cells. Infected cells bearing foreign anti-
apoptosis, producing disordered growth (transformation) that may gens are then lysed via an antibody-dependent mechanism. This
mechanism may account for liver cell necrosis during hepatitis B TABLE
infection. 2-7 Evasion of Host Defenses
Type III or Immune Complex-Mediated Hypersensitivity. Mechanism Examples
Type III hypersensitivity is induced by classic complement activation,
caused by extracellular antibody–antigen complexes. This causes Surviving the phagocyte and complement attack
inflammation and changes in vascular permeability and attracts neu- Inhibition of chemotaxis C5a peptidase by Streptococcus pyogenes
trophils to tissues where the immune complexes are deposited, includ-
ing the kidneys, joints and small vessels of the skin. Glomerulonephritis Killing the phagocyte before α-Toxin and Panton–Valentine leukocidin
ingestion by Staphylococcus aureus
in chronic malaria and subacute endocarditis are probably due to this
mechanism. Some studies have shown that antibodies to viral proteins, Avoiding ingestion Bacterial capsules (e.g. Streptococcus
including mimivirus viral collagens, which can produce arthritis in pneumoniae)
K (capsule) and O (LPS) antigens in
murine models, are increased in people with rheumatoid arthritis, but gram-negative rods
the role of exposure to viruses in generation of these antibodies
remains unproven. Avoiding complement lysis Coating with IgA antibodies (Neisseria
meningitidis)
Type IV or Delayed-Type Hypersensitivity. Type IV hypersen- Porin binding to factor H and C4 binding
sitivity typically occurs at least 48 hours after exposure to an antigen. protein (Neisseria gonorrhoeae)
It involves activated T cells, which release cytokines and chemokines, Surviving within phagocytes Inhibition of phagolysosome fusion
and macrophages and cytotoxic CD8+ T cells that are attracted by these (Chlamydia trachomatis)
moieties. Delayed-type hypersensitivity and granuloma play a major Escape from phagolysosome (Listeria
monocytogenes)
role in tissue damage observed during infections with slow-growing Inhibit NADPH oxidase fusion with
intracellular organisms, such as M. tuberculosis (tuberculosis), M. phagosome (Salmonella Typhimurium)
leprae (leprosy) and H. capsulatum. Many of the clinical manifestations Inhibition of acidification of phagosome
of chlamydial disease, in particular trachoma, seem to result from a due to exclusion of the vacuolar
H+-ATPase (Mycobacterium tuberculosis)
delayed-type hypersensitivity triggered by chlamydial heat shock pro-
teins. This is not an autoimmune phenomenon directed to heat shock Antigenic variations Shift and drift in influenza A virus, pilin
proteins in general, because the unique rather than the conserved por- variation in N. gonorrhoeae
tions of these proteins seem to be implicated. Tolerance Prenatal infections
Superantigens and Bacterial Components Immunosuppression

Associated with Toxic and Septic Shock Destroying lymphocytes Depletion of CD4+ cells by HIV
Toxic shock and septic shock are impressive syndromes associated with
a variety of infectious diseases. Severe hypotension, multiple organ Avoiding detection HIV and other viruses downregulate MHCI
to avoid recognition by cytotoxic
failure and intravascular disseminated coagulopathy occur in the most lymphocytes
severe cases. Pathogenesis of these syndromes is complex. Various
bacterial components, including LPS, peptidoglycans, lipoteichoic acid Proteolysis of antibodies IgA protease by Haemophilus influenzae
and (in some cases) exotoxins acting as superantigens (see Table 2-6) Presence in inaccessible sites Latent infection in dorsal root ganglia
trigger an intense, potentially lethal host response. Macrophages, neu- (herpes simplex virus)
trophils and/or T cells play important roles in the cascade of events
leading to this condition (see Chapters 11, 176 and 177) by releasing
high levels of inflammatory response mediators, notably tumor necro- phages.65 Organisms like Salmonella require acidification of the phago-
sis factor and IL-1β. some to trigger the PhoP/PhoQ transcriptional regulatory system that
is required for their survival inside macrophages. In contrast, M. tuber-
culosis prevents acidification of the phagosome to varying degrees, and
HOW MICRO-ORGANISMS ESCAPE bacilli residing inside less acidic phagosomes remain metabolically
HOST DEFENSE active.
In spite of the efficacy of host defense mechanisms, microbial patho-
gens can still infect humans and cause disease. This is in part due to Inhibition of Phagocyte Mobilization
the very potent weapons micro-organisms have but it is also due to the Extracellular micro-organisms can avoid phagocytes by inhibiting che-
intricate strategies that micro-organisms use to evade host defenses motaxis or complement activation. Strep. pyogenes and Strep. agalac-
(Table 2-7). tiae make a bacterial enzyme that degrades complement protein C5a,
a main chemoattractant for phagocytes. Pertussis toxin catalyzes ADP
Surviving the Phagocyte ribosylation in neutrophils, which causes a rise in intracellular cAMP
Invaded epithelial cells secrete IL-8, which attracts neutrophils (PMNs) levels that ultimately impairs chemotaxis. Yersinia pestis employs
so that immediately after passage through the epithelial barrier invad- several secreted enzymes (YOPS) to subvert macrophage phagocytosis
ing micro-organisms encounter the most powerful actors of host and ensure the bacteria remain extracellular.
defense: phagocytes. The two main types of phagocyte are PMNs
and macrophages. These ‘professional’ phagocytes can bind micro- Killing the Phagocytes before Being Ingested
organisms with a variety of receptors, some of which specifically inter- Many soluble products excreted by bacteria are potentially toxic
act with bacterial surface structures, or with antibodies or complement for phagocytes entering the foci of infection. Streptolysin-O binds
bound to the microbial surface (opsonized micro-organisms). to cholesterol in cell membranes, resulting in rapid lysis of PMNs,
Ingested bacteria are exposed to a multitude of phagocyte defense including their lysosomes, releasing their toxic contents, which may
mechanisms in the endosomal pathway, including acidification, reac- have additional deleterious effects on neighboring cells. Staph. aureus
tive oxygen species, antimicrobial peptides and hydrolytic enzymes can express two bicomponent pore-forming leukotoxins, Panton-
released after phagosome–lysosome fusion. If the pathogens are killed Valentine and leukotoxin AB, which bind selectively to human leuko-
and degraded in macrophages their microbial antigens may be pre- cytes. Many so-called extra-intestinal pathogenic E. coli are hemolytic
sented via MHC II to lymphocytes. because they produce an RTX membrane toxin that damages PMNs,
Facultative intracellular pathogens have developed strategies to impairing several functions, depending on the local concentration of
avoid, mislead, deregulate, or even profit from residence in macro- the toxin. Several toxins from C. perfringens produce similar effects.
Indeed, pus sampled from lesions of gas gangrene may contain numer-
ous gram-positive rods without any visible PMNs. Phagocytosis and bacterial resistance to killing
‘Professional’ Phagocytes as Vectors or Refuges Ingestion and killing Escape from phagosome
All organisms that have adapted to live inside phagocytic cells have mechanisms and propagation in cytoplasm
developed mechanisms to escape, disarm or survive the onslaught of
Phagocytosis Fusion between
antimicrobial factors. L. pneumophila provokes entry in mononuclear
phagosomes
phagocytes by accumulating the opsonin C3bi on the outer mem- and lysosomes
brane. Macrophages ingest the bacteria via the receptor CR3. Follow-
ing uptake, Legionella remains in phagosomes, which do not fuse with
lysosomes thus providing a refuge for the bacteria. Alveolar macro-
phages are host cells for M. tuberculosis.66 S. enterica are ingested by
intraepithelial dendritic cells and carried into regional lymph nodes
and the systemic circulation by those cells. Many viruses (HIV, dengue
virus, measles, etc.) infect and replicate in monocytes or macrophages.
Infected monocytes may provide HIV with a route through the blood–
Examples: Listeria monocytogenes,
brain barrier into the CNS67 and dendritic cells loaded with infectious Bacteria Reactive oxygen species
Shigella spp.
HIV may activate and infect T cells68 (see Chapter 92). Ehrlichia are killed by Acidification
Lysozyme
small, gram-negative, obligatory intracellular bacteria that enter the
Antimicrobial peptides
cytoplasm of macrophages via caveoli and block lysosomal fusion. Nutrient deprivation
Avoiding Ingestion Inhibition of phagolysosome Resistance to

Numerous pathogenic bacteria are covered with a loose network of fusion lysosome products
polymers, which constitute the bacterial capsule.69 Capsular material
may be very thin, visible only by electron microscopy, as is the case
with the hyaluronate capsule of S. pyogenes. In some species (Strep.
pneumoniae, Klebsiella pneumoniae) capsule material is abundant,
easily visible with a light microscope and responsible for the mucoid
appearance of bacterial colonies. Most of the capsules are composed
of polysaccharides. Some capsule contents mimic host polysaccharides
and are thus recognized as ‘self ’ by the host immune system. Examples
include the capsules of N. meningitidis Group B, which contains sialic
acid, and Strep. pyogenes, which contains hyaluronic acid. Proteins that Example: Legionella pneumophila Examples: Mycobacterium tuberculosis,
and Salmonella spp.
envelop bacteria in S-layers can serve the same function as polysac-
charides, as is seen in Campylobacter fetus and B. anthracis.
Complement components C3b and C3bi are recognized by CR3 on Figure 2-14 Phagocytosis and bacterial resistance to killing. (Courtesy of Menno
Kok and Jean-Claude Pechère.)
phagocytes, and can amplify the opsonic activity of IgG antibodies.
Children who lack C3, the central component of all three complement
pathways, suffer from repeated bacterial infections and often die in necessary for tethering of the ATPase to the phagosome.72 L. pneu-
infancy. Complement may be deposited on bacterial cell walls but mophila accomplishes the same thing by disrupting another host mem-
capsules may mask the opsonins and so protect bacteria from phago- brane protein–protein interaction.
cytosis.70 Encapsulated Strep. pneumoniae resist engulfment by macro-
phages and PMNs and are virulent, while noncapsulated, avirulent Inactivation of Reactive Oxygen Species
mutants are easily ingested and killed by PMN.71 Schistosoma mansoni Reactive oxygen species damage DNA and inhibit bacterial oxidative
employs a different strategy to avoid activation of complement, incor- phosphorylation. Bacteria may escape from the damaging effect of
porating decay accelerating factors in its membrane; these host plasma reactive oxygen species by rapid detoxification of the bactericidal
proteins inhibit deposition of C3 onto host cell membranes. products and by efficient DNA repair. Several bacterial pathogens
M proteins, which form fibrillae (see Figure 2-6), are necessary produce superoxide dismutase (SOD) and catalase, two enzymes that
virulence determinants of Strep. pyogenes. M proteins form stable degrade reactive oxygen species. Bacteria also express Rec-A enzymes
dimers, arranged in an α-helical, coiled coil configuration, with the to repair damaged DNA. In Salmonellae, the RecA pathway is critical,
carboxyl terminal portion closely associated with the cell wall (see as recA mutants are avirulent. The ability of S. enterica to modify the
Figure 2-6). Streptococci that express M proteins on their surface are endocytic pathway of the host cell seems to be the most important
poorly opsonized by the alternative pathway and resist PMN phago- mechanism of resistance to reactive oxygen species. In macrophages,
cytosis. In contrast, streptococci that fail to express M protein are virulent Salmonellae localize in phagosomes devoid of NADPH
readily opsonized and phagocytosed, and are avirulent. The mecha- oxidase, the enzyme that drives the respiratory burst.73
nism of antiphagocytic activity of M proteins remains unsettled.
Resistance to Antimicrobial Peptides
Survival within Phagocytes Several cationic peptides produced within the lysosomal granules of
Once ingested by the phagocyte, the pathogen may survive and grow phagocytes are believed to kill intracellular pathogens by forming
using a variety of strategies (Figure 2-14). Some microbes prevent channels in the bacterial cell wall. Salmonella spp. resist these antimi-
exposure to hydrolytic enzymes by inhibiting fusion of the phagosome crobial peptides by at least two complementary mechanisms, one of
and the lysosome, others survive within the phagolysosome because which, encoded by the sap locus, has been characterized in some detail
they resist enzymatic degradation or neutralize toxic products to which (Figure 2-15). SapA protein forms a complex with the antimicrobial
they are exposed in this compartment. Certain bacteria rapidly escape peptides, reducing the deleterious effect on the bacterial membranes.
from the phagolysosome and propagate in the cytoplasm. Recent Other sap locus proteins (SapB, SapC and SapD) allow the transport
studies suggest that intracellular pathogens, notably M. tuberculosis, of the SapA–peptide complex into the cytosol. Within the cytosol,
may inhibit the acidification of the phagolysosome by excluding vacu- peptidases degrade the bound antimicrobial peptides. Recently it was
olar ATPase using a tyrosine kinase to dephosphorylate a host protein shown that pili make group B streptococci resistant to the mouse
Sap-mediated resistance to antimicrobial peptides Antigenic and phase variations in microbial pathogens
Exchange between pil genes
Antimicrobial peptides
pilS
pilE
A A
A
Cell membrane
B C Not
pilS
expressed
D F
pilE Expressed
Host cell Peptide degradation
a
Figure 2-15 Sap-mediated resistance to antimicrobial peptides by Salmonella Switch mechanism in flagella
spp. Salmonella produces the SapA (A) peptide, which complexes with host cell
antimicrobial peptides. Other proteins encoded by the sap locus (SapB, SapC and
SapD) are required for the transport of the SapA-antimicrobial peptide complex i A BR B
into the cytosol where the antimicrobial peptide is degraded. (Courtesy of Menno
Kok and Jean-Claude Pechère.)
Type A flagella Type B repressor Type B flagella
TABLE
2-8 Examples of Antigenic Variations ii A BR B
Genetic Mechanisms Examples

Type B flagella
Recombination between different Pili in Neisseria gonorrhoeae b
copies of pilin genes
Phase variation – turning expression of Flagella in Salmonella; pili in N. Antigenic shift by gene reassortment
an antigen on or off (‘flip-flop’) gonorrhoeae
Gene reassortment between two strains Influenza virus type A

infecting the same cell
Mutation of surface antigens Influenza virus type A, B and C,

deletion of flagella in Shigella
spp. (avoids TLR5 signaling)
Virus 1
Gene switch leading to surface Trypanosoma brucei
glycoprotein changes
Gene switch leading to production of Yersinia pestis growing at 37 °C;
nonactivating lipopolysaccharides Salmonella enterica growing
inside phagosome (PhoP Gene reassortment
regulated) Host cell in virus 3
c Virus 2
antimicrobial peptide CRAMP and the human homologue, LL-37. M1
protein also protects S. pyogenes from cathelicidin.74 Figure 2-16 Antigenic and phase variations in microbial pathogens. Three
mechanisms are shown. (a) Exchange of DNA between nonexpressed copies of
ANTIGENIC AND PHASE VARIATIONS pilS and the expressed gene pilE in Neisseria gonorrhoeae can change the
Some pathogens can ‘change appearances’, a powerful strategy used to expressed antigen. (b) A switch mechanism is responsible for the (mutually exclu-
sive) production of type A and type B flagella in Salmonella enterica serovar
escape the acquired immune response. Three examples of molecular Typhimurium. Phase variation depends on the orientation of a DNA fragment
mechanisms used to achieve antigenic variation, one each by a bacte- adjacent to the type A flagella gene. When A is expressed (i) from the promoter
rium, a virus and a protozoan, are illustrated in Table 2-8. in the invertible fragment, the repressor for the type B flagella is expressed at the
same time. As a consequence the type B flagella gene is repressed. Inversion of
Antigenic Variation in Neisseria gonorrhoeae the DNA fragment abolishes expression of the A-repressor gene and the
B-repressor gene (ii). In this situation type B flagella are produced. (c) Antigenic
Neisseria gonorrhoeae varies the composition of at least three shift by gene reassortment results from infection of a single cell by two different
major components of its outer membrane: the pili, which mediate virions. (Courtesy of Menno Kok and Jean-Claude Pechère.)
initial attachment to host cells; the membrane protein P.II,
responsible for closer attachment resulting in phagocytosis; and the
lipo-oligosaccharide (LOS). pressure. In addition to this mechanism, pili are subject to phase varia-
Antigenic variations in the major pilin subunit are due to recom- tion (i.e. switches between pil-positive and pil-negative variants) con-
bination between different copies of pil genes scattered over the chro- trolled at the transcriptional level.
mosome (Figure 2-16). Only one or two of these are expressed (pilE, The P.II protein is similarly subject to genetic variation. As a con-
where E denotes ‘expressed’) at any point in time, but numerous strains sequence, the adaptive immune response never quite catches up with
with antigenically distinct pili may arise in response to antibody genetic variation in the bacterial population. The combination of this
mechanism, LOS sialylation and IgA protease production, explains the from a polycistronic transcription unit, in the so-called telomeric
lack of acquired immunity to gonorrhea and makes vaccine develop- expression site adjacent to the telomeric repeats. During chronic infec-
ment very difficult. tion, patients experience successive episodes of parasitemia, each
episode coinciding with expression of a new VSG on the surface of the
Shift and Drift in Influenza A Viruses parasite. With this strategy, trypanosomes avoid complete eradication
Every year, influenza vaccination programs must contend with anti- by the specific immune response, while maintaining the pathogenic
genic variation. Influenza viruses change through drift and shift. Anti- burden at sublethal levels.
genic drift refers to the gradual accumulation of mutations during
circulation of virus as a consequence of the high error rate of RNA- Immunosuppression
dependent RNA polymerase and the selective pressure of immune
responses or antivirals. Influenza A virus mutants with antigenic The most illustrative example of immunosuppression induced by
changes tend to have a selective advantage over the non-mutant viral microbial infection is provided by HIV. Human immunodeficiency
population. Drift can produce raid change, as illustrated by the dra- virus circulating in the bloodstream readily infects CD4+ lymphocytes,
matic increase in amantadine resistance (from 2–12% to >91%) in macrophages and dendritic cells. The destruction of CD4+ T-helper
influenza A/H3N2 strains, from 2005 to 2006, associated with a single cells is particularly detrimental to the host and accounts for the occur-
mutation at position 31 of the M2 protein. As a consequence of anti- rence of a variety of opportunistic infections after the T-cell count
genic drift, the composition of the influenza vaccine must be carefully drops below critical levels. In addition to its general immunosuppres-
evaluated and updated annually to cover those strains likely to be sive effects, HIV-1 preferentially infects HIV-1-specific CD4+ T cells,
circulating. thereby undermining the ability of the host to mount an effective
Antigenic shift refers to the emergence of a novel influenza virus in immune response to the virus.77 HIV infection rapidly causes a pro-
humans, due to direct introduction of an avian strain or to a new strain found depletion of CD4+ T cells in the gut as well as the lymph nodes
produced by recombination and reassortment of two different influ- and peripheral blood. This local immunosuppression is in turn impor-
enza viruses. Antigenic shift results in dramatic changes in the anti- tant in producing continued T-cell activation due to increased bacterial
genic composition of the surface hemagglutinin (which binds the host translocation through the damaged mucosal barrier, further enhanc-
cell receptor) or the neuraminidase (which modifies these receptors) ing susceptibility to HIV infection78 (see Chapter 92).
and can cause devastating worldwide epidemics, or pandemics, in the Other viruses produce immunosuppression in a more subtle
immunologically unprepared population. Recent influenza A pan- fashion. Measles virus infects macrophages and both B and T lympho-
demics occurred in 1957 (the H2N2 ‘Asian Flu’), 1968 (the H3N2 cytes, interfering with the immunocompetence of the host for weeks
‘Hong Kong Flu’) and most recently in 2009, when an unanticipated, after resolution of clinical disease. As a consequence, in areas with a
novel H1N1 influenza A virus originating from circulating seasonal high prevalence of tuberculosis, measles epidemics may be followed by
influenza, avian, and classic and Eurasian swine strains emerged.75 In outbreaks of tuberculosis.
1997, avian influenza A/H5N1 caused 18 human deaths; a different
strain of A/H5N1 has circulated in domestic birds throughout Asia, Conclusion
causing 387 cases and 245 deaths between 2003 and 2008. In the past Throughout evolution, humans, like all mammalian species, have
decade, human infection by H7N2 and H9N2 avian influenza viruses maintained an intimate relationship with the microbial world. We have
had raised concerns, and H7N9 virus caused severe respiratory infec- survived thanks to the efficient defense mechanisms we have developed
tions and death in China in 2013, posing the threat of a future against potentially dangerous micro-organisms. Pathogenic micro-
pandemic. organisms are still here because they have found ways of avoiding
elimination by the host or by the microbial competition. ‘Successful’
Antigenic Variations in Trypanosoma brucei pathogens have developed strategies to enter the body, and reach and
(see Chapter 110) colonize their favorite niche, while defying the powerful human
African trypanosomes (Trypanosoma brucei) are flagellated protozoa, immune system.
transmitted to humans by several species of Glossina (tsetse flies). The In this chapter we have looked into microbial survival strategies.
parasite survives in mammalian body fluids thanks to antigenic varia- Although some of these have been analyzed in ‘molecular detail’, much
tion of the variant surface glycoprotein (VSG), which forms a 15 nm remains to be discovered. Future remedies for infectious diseases are
thick monolayer covering most of the parasite surface.76 Within a likely to be aimed at specific molecular interactions between the patho-
single generation, most or all of the 107 VSG molecules may be replaced gen and its host.
by an unrelated variant, stemming from a repertoire of an estimated
1000 genomic copies of the gene. The VSG gene is invariably expressed References available online at expertconsult.com.
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3
Host Responses to Infection
CARA C. WILSON | ROBERT T. SCHOOLEY
KEY CONCEPTS Innate Immunity

• The host response to infection is composed of diverse, coordi- The innate immune response provides a barrier function, to prevent
nated, highly effective and tightly regulated effector mecha- organisms from invading the body as well as effector mechanisms
nisms that protect the host from a highly diverse array of designed to eliminate microbes that breach the epithelial barriers
microbial entities. through recognition, ingestion and killing by phagocytes. Innate
immunity also alerts the adaptive immune response to microbial inva-
• The innate immune response, consisting of both integumentary
barriers and broadly active immune effector mechanisms, forms sion, stimulates adaptive effector cells and influences the nature of the
the initial level of defense. Innate immunity is designed to form adaptive immune response generated, based on the nature of the
the first ring of defense against microbial invasion and to prime pathogen.
and to amplify subsequent adaptive immune responses.
BARRIER FUNCTIONS OF THE INNATE
• The adaptive immune response includes both cellular and IMMUNE RESPONSE
humoral effectors. Cellular effectors include T lymphocytes that
provide both regulatory and effector functions and immuno- Epithelial barriers form the first line of defense against the microbial
globulins of several classes that are designed to neutralize, world surrounding all multicellular organisms. The skin and mucosal
immobilize or prime pathogens for destruction by cellular surfaces lining the gastrointestinal, respiratory and genitourinary
effectors or by the complement system. tracts provide both a physical barrier to invasion and also play a critical
role in serving as the first geographic location at which interactions
• The immune response is highly regulated and configured to
feature rapid evolution of highly specific responses to new
between pathogens and host occur.1 The critical contribution of an
microbial challenges, downregulation of these responses when intact skin to the prevention of infection is clearly demonstrated by
the microbial threat has been thwarted and memory that the direct relationship between percent of body surface area disrupted
enables a more rapid and effective response should the same in burn injuries and mortality associated with the event. Disruption of
or a related pathogen be encountered in the future. the integrity of the gastrointestinal tract by cytotoxic chemotherapy
compounds the risk of enteric pathogen bacteremia during periods of
• Inherited or acquired disorders of host immune responses
make the host more susceptible to infections against which a
neutropenia during cancer chemotherapy. Additional physical protec-
compromised element of the immune response is directed. tion is provided on mucosal surfaces by the secretion of mucus and
Conversely, dysregulation of the immune response may result immunoglobulins in which bacteria and other pathogens are aggre-
in a number of serious autoimmune processes. gated for clearance by cilia, coughing and/or peristalsis (Figure 3-2).
TABLE
3-1 Innate versus Adaptive Immunity
Overview
The host immune response is complex and largely successful in pre- Innate Adaptive
venting microbial invasion and disease. Organisms have evolved means COMPONENTS
of evading host immune mechanisms. This interplay between patho- Barriers Mucosal epithelia, skin, Antibodies secreted at
gen and host immune response results in a delicate balance, the weight antimicrobial peptides epithelial surfaces,
of which can shift in favor of the pathogen in the setting of immune lymphocytes in epithelia
deficiency states or in favor of the host with vaccination. This chapter Cells Phagocytes (neutrophils, Lymphocytes, antigen-
will broadly address mechanisms that prevent microbial invasion and macrophages, presenting cells
those that rid the body of invading pathogens to eliminate established dendritic cells), (dendritic cells)
infection. Lastly, we will address the consequences to the host of a natural killer cells
strong inflammatory response, a form of ‘friendly fire’ in the body’s Blood proteins Complement Antibodies
war against infection.
Antigen Pattern recognition T-cell receptors, membrane
The immune response can be viewed as consisting of two distinct receptors receptors immunoglobulin
but interconnecting branches, termed innate and adaptive immunity,
that differ in their manner and rapidity of response to pathogens
CHARACTERISTICS
(Figure 3-1). As the first line of defense, the innate system is primarily
composed of cells that serve a barrier function, such as intestinal epi- Specificity For microbial-associated For unique linear and
thelium and skin, and phagocytes that are recruited early to sites of molecular patterns conformational
shared by microbes determinants (epitopes) of
pathogen invasion. Recognition of pathogens by innate immune cells microbial antigens
is mediated by a limited number of germline-encoded pathogen
recognition receptors (PRRs) that recognize conserved microbial com- Diversity Limited, germline- Diverse, receptors
encoded produced by somatic
ponents called microbial-associated molecular patterns (MAMPs). recombination
Conversely, cells of the acquired immune system respond to pathogens
Memory No Yes
at later stages of infection and recognize microbial antigens using
highly specific receptors that require gene rearrangement and clonal From Abbas A.K., Lichtman A.H.: Cellular and molecular immunology, 5th ed.
expansion and persist to provide immunological memory (Table 3-1). Philadelphia, PA: Saunders; 2003. Copyright Elsevier, 2003.
26
Chapter 3 Host Responses to Infection 27
Innate and adaptive immunity
Innate immunity Adaptive immunity
Epithelial barriers B lymphocytes Antibodies
T lymphocytes Effector T cells
Phagocytes
Complement NK cells
Hours Days
1 6 12 1 3 5
Time after infection
Figure 3-1 Innate and adaptive immunity. The mechanisms of innate immunity provide the initial defense against infections. Adaptive immune responses develop later
and consist of activation of lymphocytes. The kinetics of the innate and adaptive immune responses are approximations and may vary in different infections. (From Abbas
A.K., Lichtman A.H.: Cellular and molecular immunology, 5th ed. Philadelphia, PA: Saunders; 2003. Copyright Elsevier, 2003.)
In addition to barrier roles played by the skin and mucosal surfaces, MAMPs, and their binding results in activation of specific signaling
both organs are heavily fortified with both innate and adaptive effector pathways that lead to distinct response patterns. As a result of the
immune mechanisms. Antimicrobial peptides such as defensins, cath conserved nature of MAMPs, a given PRR may recognize multiple
elicidins, lysozyme and lactoferrins are chronically present at integu- organisms that share PAMPs. In turn, a given organism may express
mentary surfaces. Immunoglobulins are both secreted into luminal multiple MAMPs, and thus stimulate multiple PRRs. This specificity,
cavities and affixed to the surface of cells lining these surfaces. Finally, combined with redundancy, ensures an appropriate pathogen-tailored
cellular defense mechanisms abound in and around integumentary innate, and subsequent adaptive, immune response against microbial
surfaces as locations where antigens are processed and presented to the invasion. PRRs in mammalian cells may be divided into two main
immune response for amplification and recruitment, where pathogens classes based on cellular location: (1) membrane-bound receptors,
are physically destroyed by effector cells and where they are actively which include Toll-like receptors (TLRs) and C-type lectin receptors
captured and transported to local lymphoid structures for secondary (CLRs), and (2) cytoplasmic sensors, which include NOD-like recep-
processing and destruction. These integrated immunologic functions tors (NLRs), RIG-I-like receptors (RLRs), pyrin and HIN domain-
of cutaneous and mucosal surfaces play critical roles in determining containing (PYTHIN) family members, and other sensors of cytosolic
downstream immunologic events. nucleic acids.3 Once engaged, PRRs trigger a cascade of intracellular
molecules that link the signal to specific activation pathways (Figure
3-3). These pathways are both complementary and, in some cases,
RECOGNITION AND EFFECTOR FUNCTIONS OF redundant and the ultimate immunologic effect of PRR ligation
THE INNATE IMMUNE RESPONSE depends on downstream integration of the activation pathways.
Innate Immune Recognition by Pattern Toll-like Receptors (TLRs). TLRs are a family of transmembrane
Recognition Receptors PRRs that are evolutionarily conserved from worms to mammals.6,7
As noted above, PRRs recognize MAMPs, and many of these microbial- Ligand recognition is mediated by TLR homodimers, or in some cases,
derived products are shared by both commensal organisms and heterodimers.8,9 Thirteen mammalian TLR family members have been
pathogens (termed pathogen-associated molecular patterns, PAMPs) identified. TLRs have been further divided into subfamilies based on
(reviewed in references 2 and 3). MAMPs are generally highly consequence similarities and recognition of related MAMPs. For instance,
served, essential to micro-organism survival, and may contain carbo- TLRs 7, 8 and 9 recognize nucleic acids, whereas TLRs 1, 2 and 6 re
hydrate, lipid, protein, or nucleic acid components. Examples of cognize lipids. Alternatively, TLR4 recognizes a diverse array of struc-
MAMPs include lipopolysaccharide (LPS) from gram-negative bacte- turally dissimilar ligands.2
ria, peptidoglycan from gram-positive bacteria, flagellin from flagel- TLRs are expressed on both immune and nonimmune cells. On
lated bacteria, fungal mannans, bacterial CpG-DNA, and viral DNA immune cells, TLRs are found on phagocytic and antigen-presenting
or RNA. Although PRRs discriminate between self and non-self, cells (APCs), such as dendritic cells (DCs), macrophages/monocytes,
certain PRRs recognize host self-antigens, such as heat-shock proteins B cells and some subsets of T lymphocytes.10,11 Among nonimmune
and fibrinogen.4,5 PRR recognize a specific MAMP or set of related cells, TLRs are expressed on epithelial cells and fibroblasts. TLR
Innate immune responses in the respiratory tract
Large airways
Cough
Mucociliary Mechanical
Secretory IgA clearance barrier
Ciliated epithelial cell Basal cell Goblet cell
Large and small airways
Inflammatory
mediators
Cytokines
Chemokines
Leukokines
Dendritic cell
Neutrophil
Lymphocyte
Antimicrobial
Alveoli
peptides
Defensins
Cathelicidins Type 1
Lysozyme pneumocyte
Surfactant proteins Alveolar
Lactoferrin macrophage
Type 2
pneumocyte
Secretory IgA
Neutrophil
Airway
macrophage
Blood
capillary Monocyte
Figure 3-2 Innate immune responses in the respiratory tract. (From Sethi S., Murphy T.F.: Infection in the pathogenesis and course of chronic obstructive pulmonary
disease. N Engl J Med 2008; 359: 2355-2365. Copyright 2008, Massachusetts Medical Society.)
expression on intestinal epithelial cells may play an important role in LPS preparations from some non-enteric bacteria serve as TLR2 agon
regulating intestinal inflammation.12 TLRs exhibit differential expres- ists.14 Components of gram-positive bacteria, such as lipoteichoic acid
sion within a cell. TLRs 1, 2, 4, 5 and 6 are expressed on cell surfaces, (LTA) and peptidoglycan (PG), activate immunity primarily by
whereas TLRs 3, 7, 8 and 9 are expressed intracellularly in compart- binding to TLR2. Flagellin, the major component of microbial flagella,
ments such as endosomes. Ligands for extracellular TLRs require inter- is a potent activator of TLR5 and in murine systems also activates
nalization before signaling can take place.2,13 TLR11.15 Flagellins from some pathogenic bacteria have been shown
TLRs recognize components of multiple organisms (Table 3-2). to escape this important host defense mechanism.16 Innate recognition
Several unique cell wall components of bacteria serve as PAMPs. LPS of mycobacteria by TLRs is also an important aspect of the host
(lipopolysaccharide, endotoxin) from enteric gram-negative bacterial response to these intracellular organisms. Mycobacterial cell wall
cell walls binds to CD14, then associates with TLR4 to induce signaling. products stimulate TLRs 2, 4 and 2/1 heterodimers.17,18 Bacterial DNA
PRR response to viral pathogens
TLR2/1
TLR2/6 TLR4
Viral Viral MD2
protein protein
Cell
membrane
Cytoplasm Endosome
MAL MAL TRAM TLR3
MYD88 MYD88 TRIF RIP1 TLR7 TLR9
TLR8
dsRNA Cpg DNA
ssRNA
TR
RAK4 RAK1
IF
RA
TRAF6 TRAF3 8
D8
K1
MY
TRAF6 MYD88
TAK1
IKK TAK1 TAK1
RAK4 RAK1
TAK1/IKK
TRAF6 TRAF3
IKK
IKK IKK
IKK
p p IKK IKK IKK
p IRF3 IRF7
l B
p65 p50 p p
l B
p65 p50 IRF7
p65 p50 p p
p65 p50 IRF3 IRF7 p p
Nucleus Inflammatory cytokines IRF7 IRF7
IFN- and IFN- 1

IFN- and IFN- 2/ 3
Figure 3-3 PRR response to viral pathogens. Recognition of viral PAMPs such as viral proteins, dsRNA, ssRNA and CpG DNA, initiates an antiviral innate immune
response mediated by TLRs. TLR2 and TLR4 are present on the cell surface and recognize viral proteins. TLR3, TLR7, TLR8 and TLR9 are intracellular viral nucleic-acid-
sensing TLRs that are localized in endosomes. Viral dsRNA, ssRNA and unmethylated CpG DNA are recognized by TLR3, TLR7/TLR8 and TLR9, respectively. Upon ligand
recognition, TLR2 along with TLR6 or TLR1 and TLR4 recruits an additional adaptor protein, MAL, to link the TLR domain to MyD88. All TLRs except TLR3 recruit MyD88.
TLR4 also recruits the adapter protein TRIF, as does TLR3. To activate the TRIF-dependent pathway, TLR4 requires the bridging adaptor TRAM and its trafficking into
endosomes. The MyD88-dependent and TRIF-dependent signaling complexes through a cascade of signaling events leading to the activation of several transcription
factors including NF-κB, IRF3 and IRF7. NF-κB transcriptionally regulates the expression of inflammatory cytokines and chemokines while IRF3 and IRF7 control the
transcription of type I and type III IFN genes. Whereas TLR2 signaling only results in NF-κB activation in most cell types, TLR2 can traffic to endosomes in inflammatory
monocytes upon engagement of specific viral ligands such as vaccinia virus or MCMV where it results in IRF3/IRF7 activation and type I IFN induction (not depicted).
(From Lester S.N., Kui L.: Toll-like receptors in antiviral innate immunity. J Mol Biol 2014; 426:1246-1264.)
may also induce an innate immune response by binding of unmethyl- deal of sequence homology (see Figure 3-3). They are expressed in
ated CpG dinucleotides in genomic bacterial DNA (CpG-DNA) to the endosomal membranes, and recognize viral ssRNA.21 Recognition of
endosomally based TLR9. human immunodeficiency virus (HIV)-1 RNA sequences by TLR7/8
TLRs are also critical components of the response to fungi, proto- expressed on APCs such as DCs may contribute to the generalized
zoan parasites and viruses. Several cell wall components of fungi are immune activation associated with HIV disease progression.22–24 TLR9
recognized by TLRs 2 and 4. Different morphologic forms of a fungus plays an important role in innate host recognition of DNA viruses such
(e.g. hyphae versus conidia) may preferentially stimulate one TLR over as herpesviruses, as these viruses contain genomes rich in CpG-DNA
another.19 TLRs function in collaboration with other PRRs, in particu- sequences. TLR9 is expressed on a subpopulation of blood and plas-
lar CLRs, to ward off pathogenic fungal infections. Components of macytoid DCs. TLR9 ligation on these cells stimulates secretion of type
protozoan parasites, including those of Trypanosoma, Plasmodium, I interferons (IFN).25 TLR3, expressed in conventional DCs as well as
Toxoplasma and Leishmania species, activate innate immunity through in epithelial cells and astrocytes in the brain, recognizes dsRNA that
stimulation of TLRs 2, 4, 9, 11 and 12 (reviewed in references 3 and can be generated as a replication intermediate or byproduct during
20). Lastly, nucleotide sequences from numerous RNA and DNA infections with ssRNA or DNA viruses.26 Despite wide expression, the
viruses are recognized by intracellular TLRs, including TLRs 7/8, 9 and role of TLR3 in antiviral immunity remains to be clarified, especially
3. TLR7 and TLR8 are important in viral infections and show a great since TLR3 knock-out mice do not appear to have increased
TABLE Toll-Like Receptor (TLR) Recognition of Dendritic cell (DC) maturation

3-2 Microbial Components
Microbial Immature DC Mature DC T-cell activation
Components Species TLR Usage and proliferation
BACTERIA Microbial Cytokine
Lipopolysaccharides Gram-negative bacteria TLR4 products production
Diacyl lipopeptides Mycoplasma TLR6/TLR2
Triacyl lipopeptides Bacteria and mycobacteria TLR1/TLR2

Cytokines Antigen
Lipoteichoic acid Group B Streptococcus TLR6/TLR2 presentation
Peptidoglycans Gram-positive bacteria TLR2
High endocytosis and High surface MHC
Porins Neisseria TLR2
antigen capture and costimulatory
Lipoarabinomannan Mycobacteria TLR2 Low surface MHC molecule expression
and costimulatory Increased migration
Flagellin Flagellated bacteria TLR5 molecule expression Low endocytosis
CpG DNA Bacteria and mycobacteria TLR9
Figure 3-4 Dendritic cell (DC) maturation.
Flagellin Uropathogenic bacteria TLR11
Salmonella spp.
FUNGI
this chapter; comprehensive reviews can be found in references 9 and
Zymosan Saccharomyces cerevisiae TLR6/TLR2
30. The differences in response patterns mediated by different TLR
Phospholipomannan Candida albicans TLR2 ligands may be in part explained by differential recruitment of adaptor
molecules, although multiple factors are involved, including responder
Mannan Candida albicans TLR4
cell type and additional signals received. For instance, distinct adaptor
Glucuronoxylomannan Cryptococcus neoformans TLR2 and TLR4 molecules mediate the specific signaling pathways that result in the
PARASITES production of type I IFNs versus inflammatory cytokines. This concept
is illustrated for the PRR response to viral pathogens (see Figure 3-3).
tGPI-mutin Trypanosoma TLR2
The specific early response pattern dictated by the sum of pathogen-
Glycoinositol Trypanosoma TLR4 specific TLR signals may profoundly influence whether an effective
phospholipids adaptive response is generated.31 In addition to inducing cytokine and
Hemozoin Plasmodium TLR9 chemokine production, TLR signaling may have other effects. Imma-
ture tissue dendritic cells serve as sentinels to sample the environment.
Profilin-like molecule Toxoplasma gondii TLR11 and Upon appropriate stimulation of DC TLRs, DC maturation is acti-
TLR12
vated, ultimately leading to changes in phagocytic/endocytic capacity,
VIRUSES secretion of cytokines, enhanced processing and presentation of
DNA Viruses TLR9 antigen, upregulation of MHC and costimulatory molecules, and
migration of DCs to T cell areas of draining lymph nodes. Mature DCs
dsRNA Viruses TLR3
are then capable of effectively and efficiently presenting antigen to
ssRNA RNA viruses TLR7 and TLR8 naïve T cells (Figure 3-4).
Envelope proteins RSV, MMTV TLR4 NOD-like Receptors (NLRs). The nucleotide oligomerization
domain (NOD) proteins are another family of germline-encoded PRRs
Hemagglutinin protein Measles virus TLR2
that respond to microbial ‘danger signals’ (reviewed in references 32
Not detected HCMV, HSV1 TLR2 and 33). Unlike TLRs, NLRs sense cytoplasmic MAMPs in response to
viral and intracellular bacterial and pathogens. Occasionally extracel-
HOST
lular pathogens can also be sensed by NLRs, especially if virulence
Heat-shock protein TLR4 factors (such as muropeptides) are transported into the cytoplasm.34,35
60, 70
Upon ligand binding, NLRs oligomerize and recruit several adaptor
Fibrinogen TLR4 proteins to activate a number of signaling pathways that result in
From Akira, S., Uematsu, S., Takeuchi, O.: Pathogen recognition and innate
formation of an ‘inflammasome’ associated with inflammatory cyto-
immunity. Cell 2006; 124:783-801. Copyright © 2006 Elsevier Inc. All kine production, production of antimicrobial peptides and, in some
rights reserved. cases, rapid cell death. One difference between pathogenic and non-
pathogenic microbes is their ability to escape intracellular compart-
ments and either replicate in the cytosol or inject microbial products
susceptibility to viral infections.27 Finally, envelope proteins from into the cytosol for the purpose of manipulating host cellular machin-
several viruses may bind to and activate extracellular TLRs, such ery (reviewed in reference 13). Activation of the NLR pathway may be
as TLRs 2 and 4, resulting in production of inflammatory cytokines seen by the host as a sign of extreme danger, requiring a dramatic
but not antiviral IFNs. This innate cytokine response may contribute response with death of the host cell to prevent the microbe from hiding
to the inflammatory complications associated with certain viral from host defenses within it.36 NLRs play an important role in the host
infections.28 response to organisms such as Listeria monocytogenes,37 Legionella
Upon ligand recognition by TLRs, signaling cascades ultimately pneumophila38 and Helicobacter pylori.35 NLRs are also involved in
result in the activation of transcription factors (such as NF-kB) and driving and directing the pathogen-specific adaptive immune response.
interferon-regulatory factors (IRFs), promoting the production of Numerous other PRRs that sense cytosolic MAMPs have been identi-
inflammatory cytokines and type I interferons (IFNs), respectively.3,29 fied but are beyond the scope of this chapter; excellent reviews are
The topic of TLR signaling is too complex to be adequately covered in available elsewhere (references 3 and 39).
C-type Lectin Receptors (CLRs). The last group of PRRs are the
large family of C-type lectin receptors (CLRs). CLRs are found on Development and differentiation of monocytes and macrophages
phagocytic cells, such as macrophages, DCs and neutrophils, grouped
based on organization of their CLR domains and are diverse in func- Bone marrow Peripheral blood Tissue
tion. They mediate binding, internalization and potentially killing of
micro-organisms, especially fungal pathogens (reviewed in reference Langerhans cells
40). CLRs often recognize carbohydrate MAMPs, such as fungal cell
wall mannans. Examples of CLRs include the mannose receptor
(MR), dectins 1 and 2, DC-SIGN (dendritic cell-specific ICAM-3-
grabbing non-integrin) and collectins. Some of the CLRS, such as
dectin, mediate intracellular signaling,41 whereas others, such as the Blood
MR, lack classic signaling motifs in their cytoplasmic tail.42 Despite monocytes
Antigen
lack of signaling motifs, several studies have reported NF-kB activation
and inflammatory cytokine production following ligation of the
MR.43,44 Dectin-1 binds to B-glucan ligands and recognizes numerous
fungal species, including Candida, Coccidioides, Pneumocystis, Aspergil-
lus and Saccharomyces. Dectin-mediated signaling results in phagocy-
tosis, respiratory burst, activation of phospholipase and cyclooxygenase,
and production of inflammatory cytokines and chemokines that may
influence the adaptive immune response.45 Dectin-2 is a CLR that is
upregulated during inflammation and is important for its recognition
of fungal hyphae.46,47 DC-SIGN is a CLR that internalizes pathogens Mature
and induces signaling, sometimes resulting in production of the dendritic cell
immunosuppressive cytokine, IL-10.48 DC-SIGN is involved in the
innate response against fungal pathogens as well as viruses, such as
human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus Organ-specific differentiation
(HCV).49–51
Collaborative Interactions Between PRRs. It is clear that mul- Lung: Alveolar macrophage
tiple PRRs are capable of recognizing potentially pathogenic microbes, Liver: Kupffer cell
and the overall innate response to a given pathogen likely utilizes Brain: Microglial cell
GI tract: Lamina propria
multiple PRRs from several families simultaneously. There are a
Lymph node: Subcapsular sinus
number of ways in which different PRRs might theoretically interact and medullary macrophages
to benefit the host, and there is some evidence that these coordinated Spleen: Red and white pulp macrophages
interactions, are necessary for an effective response to a microbe.52 Bone marrow: Stromal macrophage Tissue macrophage
Since NLRs recognize cytosolic microbial ligands, they rely on mecha-
nisms that make those ligands available to them. Phagocytosis and Figure 3-5 Development and differentiation of monocytes and macrophages.
killing of bacteria can generate PAMPs that become available to
NLRs.53 Likewise, CLRs such as dectin may collaborate with TLRs by
triggering phagocytosis, phagosome maturation, reactive oxygen pro-
duction and enhancing NF-kB activation.54–56 Thus, it is likely that their anatomical location.66,67 Monocytes originate in bone marrow
innate recognition of many microbes involves surface recognition and and emerge into the peripheral blood as blood monocytes.65 These cells
binding of the organism, via CLRs and surface TLRs (e.g. TLR2, 4, 5), migrate into tissues and differentiate into cells with a wide variety of
followed by internalization and recognition of PAMPs by intracellular morphologies and host defense functions (macrophages and dendritic
TLRs (e.g. TLR7/8 or 9) or NLRs, depending on the ability of the cells), tissue maintenance (glial cells) and structural maintenance
organism itself or its products to escape the endosome and reach the (osteoclasts and osteoblasts) (Figure 3-5).68–70 Macrophages involved
cytosol. Since ligation of many of these PRRs results in induction of in host defense further differentiate into alveolar macrophages in the
signaling cascades, the ultimate response depends on the various lung, Kupffer cells in the liver, Langerhans cells in the skin and other
signals received. Antimicrobial inflammatory responses can be syner- specialized cells depending on their ultimate location. In each of these
gistically activated via ligation of multiple PRRs. For instance, concur- locations, monocytes adapt functions that are particularly suited to
rent ligation of TLR4 by bacterial LPS and TLRs 7, 8, or 9 results in their specific locations. Macrophages also play important housekeep-
the synergistic production of IL-12 p70, a cytokine that has a signifi- ing roles related to removal of cellular debris, immune complexes and
cant impact on directing the adaptive immune response.57–59 Similarly, other cellular and subcellular entities requiring recycling.
concurrent ligation of TLRs and NLRs results in synergistic production Mononuclear cells are resident in tissues on a chronic basis and
of inflammatory cytokines, such as tumor necrosis factor (TNF)-α and also respond to a number of well-characterized growth factors, chemo
IL-1β.60,61 attractants and activators that attract them to sites of inflammation
and activate them to enhance phagocytosis and intracellular killing.
Macrophages interact with these stimuli with several families of surface
Phagocytes receptors that provide specific instructions depending on the stimulus
Phagocytosis is one of the most basic elements of the immune response and the receptor.71 Macrophages are dependent on growth factors
with phylogenetic origins in unicellular organisms. Phagocytosis can including G-CSF and GM-CSF for growth, differentiation and sur-
be undertaken by mononuclear cells, polymorphonuclear cells or NK vival. Chemokines, cytokines and microbial products play important
cells. Although phagocytosis is often thought of as a mechanism by roles in directing migration, secretion and activation. Macrophage
which organisms are merely engulfed and sequestered or destroyed, it functions are further directed by interleukins and interferons produced
also provides a mechanism to break down and process organisms for by lymphocytes and natural killer cells.
presentation as antigens to key elements of the adaptive immune Phagocytes can identify pathogens by cell surface PRRs that recog-
response.62–65 nize PAMPs on the target organism.71,72 Although phagocytes can
Cells of the monocytic lineage are among the most diverse in the engulf micro-organisms and other entities through this PRR–PAMP
immune system and adapt both morphologically and functionally to interaction, the process can also be facilitated by the presence of IgG
or C3b on the surface of targets. IgG1 and IgG3 bind to the FcγR1
receptor constituitively produced by monocytes and produced after Cellular and humoral arms of adaptive immune response
induction on polymorphonuclear cells. These receptors serve as
opsonins to facilitate recognition and tethering of pathogens by the
phagocyte and as activators of the phagocyte oxidative burst through
several intracellular pathways.73,74 Binding other surface molecules
including TLRs, the IL-1 receptor or CD14 can also activate these B cell
intracellular pathways. FcR can either activate or downregulate mac- Antibodies
rophages depending on whether tyrosine-based activation (ITAM) or
inhibitory (ITIM) motifs are formed intracellularly. ITIM motifs and Microbes
other receptors including signal regulatory proteins (SIRP’s) quench Cytokines
CD4 CD8
inflammation to prevent excessive tissue damage as the inflammatory
process develops momentum. In addition to surface molecules, Cytokines Cytokines
a number of intracellular molecules also mediate these functions. CD4
These include nucleotide oligomerization domains (NOD), caspase- Killing
associated recruitment domains (CARD) and leucine-rich repeats. Th1 CTL Infected cell Th2
Once activated, macrophages secrete additional inflammatory and
Cellular arm Humoral arm
chemotactic molecules and are primed to kill engulfed organisms
within the cell. Inflammatory mediators such as IL-6 and IL-1 act
Figure 3-6 Cellular and humoral arms of adaptive immune response. CTL, cyto-
remotely to promote the systemic inflammatory (acute phase) toxic T lymphocyte; DC, dendritic cell; Th, T-helper cell.
response.75,76 Excessive production of these inflammatory cytokines
contributes to the pathogenesis of septic shock and the systemic
inflammatory response syndrome (SIRS). Other macrophage products subsequent exposure (termed an ‘anamnestic response’) to the same
such as collagenase and elastase may produce local tissue destruction pathogen. Thus, the adaptive immune system provides the host with
and participate in deleterious processes, including arthritis and pul- memory for each microbe that is specific, diverse in nature, and quick
monary inflammation. to respond upon re-exposure.
Polymorphonuclear cells are also capable of phagocytosis and Adaptive immunity is comprised of two major types of responses:
intracellular killing. These cells are also ubiquitous and are much cell-mediated and humoral immunity (Figure 3-6). Humoral immu-
shorter-lived than mononuclear cells. Sharing many of the surface nity is mediated by antibodies that are produced by B lymphocytes.
molecules expressed by macrophages, polymorphonuclear cells are Antibodies recognize and bind extracellular microbes and their toxins
particularly efficient at intracellular killing, especially after activation. and neutralize their infectivity. Cell-mediated immunity is primarily
They are less intimately involved in immunoregulation and ‘crosstalk’ mediated by T lymphocytes, with the primary goal of recognizing and
between the innate and adaptive immune systems than monocytes. fighting intracellular pathogens such as viruses and bacteria that can
Phagocytes kill organisms by a number of means, especially after proliferate inside cells, such as phagocytes.
activation. Lysozyme, which is constitutively produced by macro-
phages, can destroy the integrity of the cell walls of gram-positive CELLULAR IMMUNE RESPONSES
organisms or collaborate with complement to damage gram-negative Overview
organisms. Macrophages and polymorphonuclear cells also produce The components of the cellular immune response include several vari-
short peptides termed ‘defensins’ that permeabilize the cell walls of eties of T lymphocytes and APCs, such as dendritic cells and monocyte/
ingested bacteria. The most potent microbicidal functions of phago- macrophages. APCs capture and process exogenous microbes or
cytes are mediated by reactive oxygen molecules formed through process microbes or microbial antigens that are present in the cyto-
peroxidase-dependent and -independent pathways and by nitric oxide plasm (such as intracellular bacteria or viruses). Processed microbial
produced after stimulation by interferon-gamma (IFN-γ) or tumor peptide antigens are expressed in the context of major histocompatibil-
necrosis factor (TNF).77 Genetic or acquired defects in either of these ity complex (MHC) molecules on the surface of APCs and are recog-
pathways greatly increase susceptibility to pathogens traditionally nized by surface receptors on T cells (T-cell receptors, TCRs). There
killed inside the cell, such as Staphylococcus aureus and Salmonella.78,79 are several functionally distinct populations of T cells. Helper T cells
express the CD4 molecule, recognize antigen in the context of MHC
class II molecules, and help to orchestrate the adaptive immune
Adaptive Immunity response through the production of cytokines that provide ‘help’ to B
Whereas innate immunity is an immediate response to conserved cells and CD8+ T cells. Helper T cells also interact directly with APCs,
microbial products that is limited in scope of recognition by a ‘hard- such as DCs, to enhance their ability to present antigen and stimulate
wired’ set of receptors, the adaptive response is more specific and all- effector CD8 T-cell responses (reviewed in reference 81). CD8 T lym-
encompassing in its scope of recognition, but it takes longer to develop. phocytes, often called cytotoxic T lymphocytes or CTL, recognize
Innate and adaptive responses to a particular microbial pathogen are intracellular antigens presented in the context of MHC class I mole-
linked in a complex manner, and the inflammatory responses induced cules. These effector cells often have cytolytic potential and play an
by innate activation are often necessary for appropriate activation and important role in killing infected cells. Another group of T lympho-
direction of the adaptive response. cytes, regulatory T cells, function to inhibit or suppress inflammatory
Adaptive immunity is characterized by several distinctive features adaptive responses (reviewed in reference 82). The complex interplay
that include (1) antigen specificity, (2) diversity of responses, (3) among these different cell types is critical to achieve the ultimate goal
pathogen-specific memory, (4) non-reactivity to self-antigens, and (5) of cell-mediated immunity, which is to eliminate dangerous microbes
response self-limitation (reviewed in reference 80). First, the adaptive without damaging the host through excessive inflammation.
response is characterized by exquisite specificity for distinct molecules,
mediated by a diverse array of surface receptors on B and T lympho- CD4+ T-Cell Responses
cytes. Microbial recognition by the adaptive immune system results in Antigen-specific CD4+ T-cell responses play a central role in the adap-
expansion of clones of B and T lymphocytes that express these ran- tive immune response to microbial pathogens. Naïve CD4+ T cells
domly generated and unique microbe-specific receptors. This specific expand in response to antigenic stimulation and differentiate into
response is generated upon initial exposure to an infectious pathogen, effector T-helper (Th) cells (Figure 3-7). Two distinct Th cell subsets
and the response increases in magnitude and rapidity with each with differing cytokine profiles and effector functions, Th1 and Th2,
infection, then contract into a state of memory. CD4+ T cells play a

T-helper cell subsets critical role in CD8+ T-cell memory development.102 These memory
CD8+ T cells are capable of rapidly expanding upon future re-exposure
Cytokines Functions
to the same pathogen (reviewed in reference 101). Although some
intracellular pathogens are readily cleared by CTL, others, such as
IFN-γ, IL-2 Clear intracellular CMV and EBV, can maintain a state of latency by avoiding such
pathogens clearance.103–105 In these chronic infections, ongoing immune surveil-
Th1 lance by virus-specific CTL results in suppression of overt disease,
unless the host becomes immunocompromised. In contrast, in the case
IL-4, IL-13, IL-25 Clear extracellular of pathogens, such as HIV-1, with a high mutation rate, escape from
pathogens detection by CD8+ CTL is a major mechanism used by the virus to
CD4 Th2 advance its agenda of more active persistence, resulting in chronic
naïve progressive disease.106–108
IL-17, IL-22 Clear certain classes
of extracellular Regulatory T-Cell Responses
Th17 bacteria and fungi Given the inflammatory potential of activated, antigen-specific CD4+
and CD8+ T cells, a number of mechanisms are in place to maintain
Figure 3-7 T-helper cell subsets. (Adapted from Bettelli E., Korn T., Oukka M., the balance between the protective and tissue-damaging effects of the
Kuchroo V.K.: Induction and effector functions of T(H)17 cells. Nature 2008; adaptive immune response. Regulatory T cells, or Treg, are a heteroge-
453(7198):1051-1057.)
neous category of T cells that suppress cytokine secretion and prolif-
eration of effector T cells. This broad category consists of several
were originally described.83,84 Th1 cells are involved in mediating populations of CD4+ Treg, including CD4+CD25high natural Treg cells of
inflammatory responses against intracellular pathogens, such as viruses thymic origin, peripherally-induced, IL-10-producing adaptive type 1
and intracellular bacteria, and produce cytokines such as IFN-γ and regulatory cells (Tr1), and TGF-B-producing T-helper type 3 (Th3)
IL-2. Activated Th1 cells interact with APCs, such as DCs, to enhance cells. In addition, CD8+ and NK regulatory T cells have been described
their ability to prime effector CD8+ T cells that recognize intracellular (reviewed in references 109 and 110). One challenge in characterizing
microbial pathogens.81 They further enhance the expansion of antigen- Treg populations has been the difficulty in finding phenotypic markers
specific effector CD8+ T cells through the production of IL-2. IFN-γ specific to these cells. The most specific marker to date for character-
produced by Th1 cells activates phagocytic cells and enhances their izing natural Treg cells is the transcription factor forkhead box P3
ability to kill ingested organisms. IL-12, a cytokine produced by APCs, (Foxp3). Foxp3 is critical for the development and suppressive func-
is important in the development of Th1 cells (reviewed in reference tion of CD4+CD25high natural Treg cells.111,112 Mutations that render
85). On the other hand, Th2 cells produce IL-4, IL-5, IL-13 and IL-25 Foxp3 dysfunctional result in a severe autoimmune disease in
and play an important role in the clearance of extracellular pathogens humans.113,114 The mechanisms by which regulatory T cells exert their
by providing help to B cells, enabling the production of antibodies. suppressive effects on effector T cells, especially in humans, are not
Thus, they have a central role in orchestrating the humoral immune entirely clear, although both indirect mechanisms such as secretion of
response, as will be described in more detail below. Aberrant or uncon- suppressive cytokines (e.g. IL-10, TGF-B) and direct mechanisms such
trolled Th1 responses may result in inflammatory disorders or autoim- as blocking T-cell activation or degranulation have been implicated
munity, whereas excessive or misdirected Th2 responses may result in (reviewed in reference 109). Also, although antigen-specific Treg cells
atopy and allergy. A number of immune checks and balances such as have been reported in viral infections such as human papillomavi-
the anti-inflammatory cytokines IL-10 (reviewed in reference 86) and rus,115 Treg cell may also suppress pathogen-specific CD4+ and CD8+ T
TGF-B, and regulatory T cells play a role in maintaining a balance cells nonspecifically upon activation. Regulatory T cells modulate the
between effective antimicrobial activity and excessive inflammation. adaptive immune response in both acute and chronic infections limit-
A third subset of T-helper cells, Th17 cells, produce several cyto- ing inflammation and preventing tissue damage.
kines in the IL-17 family,87–90 including IL-17A (IL-17), IL-17F and
IL-22. These cytokines have pro-inflammatory properties and play Antigen-Presenting Cells (APCs)
a role in clearance of certain extracellular bacterial (e.g. Klebsiella Dendritic cells are required in the initiation of the adaptive immune
pneumonia, Mycobacterium tuberculosis) and fungal (e.g. Candida) response because they process exogenous antigens and present them
pathogens.91–94 The expansion and maintenance of Th17 cells is driven in the context of MHC I and II molecules to CD8+ and CD4+ T cells.
in part by IL-23, a pro-inflammatory cytokine in the IL-12 family.87 As the most potent APCs, DCs activate naïve, antigen-specific T cells
Th17 cells play a key role in intestinal defense, through a number of and induce their proliferation and differentiation into T-helper and
mechanisms, including cytokine-enhanced epithelial cell (EC) defen- CTL effector cells. The immunostimulatory capacity of DCs is attribut-
sin production, neutrophil recruitment, and by enhancing epithelia able to high-level expression of MHC and costimulatory molecules,
integrity by fortifying EC tight junctions.95–99 In addition to its role in such as CD40 and CD80. DCs also have a role in stimulating memory
normal host defense, the Th17–IL-23 axis has been implicated in a T cells as well.116
number of autoimmune diseases as well as in inflammatory bowel DCs exist in an immature state in many tissues, where they sample
disease.96,97 the environment by internalizing microbes and microbial antigens. In
many cases, exposure to such antigens results in DC activation, migra-
CD8+ T-Cell Responses tion to local lymphoid tissues and subsequent interactions with T cells.
CD8+ T cells are the primary effector cells responsible for clearing The process of DC activation or ‘maturation’ is complex and involves
intracellular pathogens, such as viruses and intracellular bacteria. changes in phagocytic capacity, upregulation of MHC and costimula-
Naïve CD8+ T cells must interact with mature, antigen-loaded DCs in tory molecules, changes in chemokine receptor expression, and pro-
lymphoid tissue to differentiate into pathogen-specific effector cells. duction of cytokines and chemokines (reviewed in reference 117).
These activated effector CD8+ T cells develop both cytolytic and non- These changes are necessary to induce antigen-specific T cells; in fact,
cytolytic antimicrobial effector functions including MHC I-dependent exposure of T cells to ‘immature’ DCs may result in anergy or toler-
cytolysis of infected target cells and rapid production of beta- ance. The innate response of DCs to microbes and their antigens is
chemokines and cytokines such as IFN-γ and TNF-α (reviewed in critical to DC maturation, and in particular, the recognition of MAMPs
references 100 and 101). Cytolytic T lymphocytes (CTL) proliferate by the many types of PRRs expressed by DCs (such as CLRs and TLRs)
and expand markedly during acute infections, migrate to the sites of regulates each step in the maturation process (reviewed in reference
118). As a result, DCs are considered to bridge innate and adaptive of the two arms of the molecule. These arms are termed the ‘antibody
immunity. The type of DC activated, its tissue location and the microbe binding’ (Fab) regions of the molecule. These two arms of the molecule
that is sensed all determine the nature of the innate response. The type are characterized by major molecular diversity and provide the speci-
of innate response generated, and in particular the cytokine profile of ficity by which each immunoglobulin molecule defines its optimal
the activated DC, then determines the type of adaptive response gener- binding ligand.
ated. For instance, an activated DC that produces IL-12 or IL-23 may
stimulate inflammatory T cells, whereas activated DCs that produce Immunoglobulin Classes
IL-10 may regulate or suppress T-cell inflammation. The adaptive Antibodies are subdivided into isotypes (or classes) and are termed
immune response cannot be fully understood without an understand- IgM, IgG, IgA, IgD and IgE antibodies, based on which of the five
ing of the upstream, innate signals that influence it. different heavy chain molecules are synthesized by the B cell producing
the antibody (Figure 3-9). Humans have two subclasses of IgA (IgA1
HUMORAL IMMUNE RESPONSE and IgA2) and four subclasses of IgG (IgG1, IgG2, IgG3 and IgG4).
The humoral immune response consists of immunological effector The specific range of functions mediated by an antibody is defined
molecules that are present in soluble form in plasma and other bodily by its subclass. Except for a short period of time in B-cell development
fluids. The two major components of this response consist of immu- when a B cell can produce both IgM and IgD, each B cell can make
noglobulins that are produced by specialized cells of the lymphoid only one immunoglobulin subclass at any one time. In addition
lineage (termed B cells) and a family of complement proteins that are to producing heavy and light chains, B cells producing IgM and
primarily synthesized by liver cells. These proteins interact with patho- IgA can produce a joining (or ‘J’) protein that results in antibody
gens alone or in concert to reduce their infectivity or, in some cases, multimerization.
to kill them but they are most effective when they contribute to a IgM antibodies are the first antibodies produced following an anti-
coordinated immune response that includes both cellular and humoral genic challenge and may appear within a week. IgM antibodies are of
components. relatively low affinity but include a joining piece that connects five IgM
molecules to yield ten binding sites as a molecular unit. The enhanced
ANTIBODIES valency increases the effectiveness of IgM antibodies and partially
Immunoglobulins are a family of molecules that combine variable compensates for the relatively low binding affinity of each Fab unit.
regions that provide exquisite specificity for binding to target mole- Because of the high molecular weight of IgM antibodies, they do not
cules with constant structural motifs that allow well-defined interac-
tions with other components of the immune response. The variable
region of the molecule provides the diversity required to identify and
to bind to an essentially limitless range of target molecules while the Comparison of immunoglobulin class stuctures
constant region allows the antibody molecule to channel effector activ-
ities of other components of the immune response that lack the ability
to specifically identify diverse structural targets. IgA dimer
Antibody Structure
Immunogloblin molecules are composed of four protein chains that
are joined by a variable number of disulfide bonds. Each molecule
consists to two identical heavy chain proteins and two identical light
chain proteins (Figure 3-8). These proteins are joined in the shape of Secretory
a ‘Y’ with the heavy chain proteins providing the base of the ‘Y’ and component
part of each of the arms. The base of the ‘Y’ is termed the constant (Fc) IgE, IgE, IgD monomer
region and serves as the portion of the immunoglobulin molecule that J chain
binds to other Fc receptors on the surface of specialized immune cells
and that provides a locus for binding the initial protein of the comple-
ment cascade. Each light chain pairs with a heavy chain to form one
Basic antibody structure
IgM pentamer
Antigen binding sites
Variable region
heavy chain
Fab
(antigen binding)
Variable region region
light chain J chain
Intrachain
disulphide
Light chain bonds
Interchain
disulphide Fc
bonds (constant)
region
Heavy chain
Figure 3-8 Basic antibody structure. Figure 3-9 Comparison of immunoglobulin class structures.
readily leave the vascular space. IgM antibodies primarily function to heavy chain, the cell is termed a B cell, and an analogous process ensues
prevent binding of pathogens to cells or to aggregate pathogens, with the light chain to introduce additional diversity as another re
thereby enhancing physical clearance of the organism. arrangement process develops a DNA segment capable of encoding an
The four subclasses of IgG antibodies are present in the highest intact light chain. Light chains include only the V, J and constant seg-
concentration in the plasma because of their long half-lives (~3 weeks) ments. With the light chain, the B cell can choose one of two different
and high production rates. These antibodies, produced in the second possible constant regions termed kappa or lambda for fusion to the V
wave of response to an antigenic challenge, evolve to much higher and J segments. Once a DNA sequence capable of encoding a light
affinities than observed in IgM antibodies and diffuse much more chain has been assembled, two identical light and two identical heavy
widely throughout the body. Approximately 50% of IgG antibody is chains are synthesized and unite to form a full IgM molecule which is
found outside the vascular space. IgG antibodies are particularly effec- then displayed on the B-cell surface to allow for expansion of those
tive in bringing pathogens into contact with effector cells through with the appropriate specificity and elimination of any B cells with
binding of the Fc portion of the IgG antibody to Fc receptors on these self-specificity.
cells. B cells first express surface IgM while in the bone marrow. Since
IgA antibodies, primarily produced as dimers joined by a J-piece the bone marrow is reasonably sequestered, antigens encountered in
by B cells residing in submucosal locations, are present in the greatest the marrow are most likely host antigens rather than foreign ones. If
concentrations on the mucosal surfaces of the respiratory, gastrointes- a B cell encounters an antigen that binds to its surface IgM molecule
tinal and genitourinary tracts. Greater quantities of IgA antibodies are while still resident in the marrow, it is signaled to either undergo
produced than of all other classes combined.119 IgA dimers are linked apoptosis or to become anergic and not expand further. Thus, B cells
to a secretory component (SC) protein on the internal surface of epi- that recognize self-antigens are prevented from further expansion
thelial membrane cells and then exported into secretions on the apical before leaving the marrow.
side. Once within secretions most of the SC molecule is cleaved and As B cells leave the marrow, long RNA transcripts are produced that
IgA dimers crosslink infectious agents, thereby both blocking their include both the µ and δ segments as well as the previously selected V,
adherence to mucosal surfaces and facilitating physical clearance by D and J segments. Since this messenger RNA can be spliced to produce
cilia and other mechanisms. IgM molecules can also be exported either a heavy chain for an IgM antibody or one for an IgD antibody,
through this pathway. Since most IgA antibodies are secreted through both are produced and B cells express both IgM and IgD simultane-
mucosal surfaces, serum levels of IgA are much lower than those of ously as they emerge from the marrow. If a B cell expressing both IgM
IgG. IgA antibodies do not fix complement or bind to Fc receptors, and IgD encounters cognate antigen, it receives what has been termed
and thus, are relatively poor inducers of inflammatory responses. the ‘first signal’ and is subsequently capable of proliferating when
Because of this property, IgA antibodies can bind and clear potential stimulated by the ‘second signal’, which is delivered by an activated T
food allergens without sensitization.120 Persons who lack IgA antibod- cell. If a B cell does not encounter antigen with which it can bind
ies have a higher incidence of food allergies than the general within a week of leaving the marrow, it becomes anergic and can no
population. longer divide. B cells then express CD40. When specifically bound by
IgE antibodies bind tightly and specifically to mast cells where they a ligand on the surface of activated T cells (CD40 ligand, or CD154),
reside for a prolonged period of time.121 When IgE antibodies bind an the B cell is activated and produces antibody. Additional adhesion
antigen the mast cell releases histamine and other inflammatory medi- molecules are then expressed by T and B cells, resulting in stable
ators resulting in an immediate hypersensitivity response. Although contact between the two cells and a channel between them by which
the specific role for IgE antibodies in host defense against multicellular T cells can secrete specific cytokines and further direct the B cell to
parasites has not been fully delineated, these antibodies seem to be switch its antibody isotype to IgG, IgE or IgA. Once bound by an
integral to the immune response to this group of pathogens.122 activated T cell and appropriately stimulated, B cells can undergo 3–4
IgD antibodies are transiently present on the surface of B cells divisions per day and produce thousands of daughter cells. By this
during B-cell development and play a key role in B-cell maturation and sequence of events, the immune response is capable of randomly creat-
selection. ing immunoglobulin molecules of almost an infinite number of speci-
ficities through recombination in the marrow but while allowing for
Generation of Antibody Diversity and expansion only of those responding to foreign antigens being actively
Isotype Switching encountered as B cells emerge from the marrow.
The mechanisms by which the immune response selects for high- Isotype switching is directed by cytokines produced by T cells in
affinity antibodies, regulates production of the appropriate isotypes close proximity to IgM producing B cells. IL-6, IL-10 and TGF-β signal
during induction of the immune response, and by which antibody B cells to switch to production of IgA antibodies while IL-4 and IL-5
production is downmodulated following an immunologic challenge direct a switch to the IgE isotype. Isotype switching to IgG, IgA and
are among the most elegant regulatory mechanisms in nature. This IgE is accomplished by another DNA rearrangement with ligation of
response features a series of DNA rearrangements that result in cre- the heavy chain V, D and J segments to γ, α or ε segments, respectively.
ation of massive antibody diversity followed by an efficient mechanism Unlike the IgM to IgD isotype switch, which is accomplished by RNA
for selecting for B cells producing antibodies of the highest affinity and splicing, this final isotype switch involves DNA rearrangement and is
eliminating those that produce antibodies that bind to antigens of the a permanent event for the B cell. Progeny of an isotype-switched B cell
host. produce only that isotype from that time forward.
Antibody diversity is created by a series of rearrangements of DNA Ongoing production of specific antibodies is dependent on contin-
as cells mature from pro-B cells to B cells in the bone marrow (Figure ued antigenic stimulation in the face of a regulatory bias to cease
3-10). These rearrangements result in the joining of four segments of production of antibodies of a given specificity and ongoing selection
DNA into the necessary components for the heavy chain of an IgM of antibodies of even higher specificity. As B cells undergo division,
molecule. These components include a constant µ segment as well as they express increasing amounts of a surface molecule known as Fas
three other segments termed V (variable segment), D (diversity and lower levels of Bcl-2. Bcl-2 is required for ongoing division while
segment) and the J (joining segment). These latter segments are ligation of Fas results in death by apoptosis. If a B cell encounters an
selected randomly from 130 possible V segments, 27 possible D seg- antigen that binds its surface immunoglobulin, it produces higher
ments and 6 possible J segments allowing for over 20 000 possible levels of Bcl-XL and survives. As B cells divide, the immunoglobulin
combinations of V, D and J segments with each µ segment. The splicing gene continues to undergo somatic hypermutation and B cells that
mechanisms responsible for this process are themselves ‘sloppy’ and generate immunoglobulin with a higher affinity for the antigens of
allow for the insertion and deletion of bases, thereby greatly increasing interest outcompete other B cells for this antigen and have a selective
potential diversity. Once these arrangements have occurred with the advantage, thereby, further increasing antibody specificity over time.
Generation of antibody diversity
Marrow phase
Pro-B cell B cell
Heavy chain germline DNA

V segments D segments J segments M segments
Options 130 27 6 1 V D J M
Excision and splicing
κ segments κ-chain
Light chain germline DNA
V segments J segments κ or γ chain
γ segments
γ-chain
Excision and splicing
Peripheral phase
T-cell
Encounter IgM
‘Second signal’ recognizable
Anergy or antigen
apoptosis
Isotype switching CD40 ligand/CD154
directed by cytokines CD40
Antigen encountered
IL-6, IL-10, TGF-β
‘first signal’ IgM
IL-4, IL-5 B cell
Ig A
No antigen recognized
Ig E
Anergy; no further division

No antigen
encountered
1 week IgD
Figure 3-10 Generation of antibody diversity.
As antigen density decreases with resolution of an infection, B cells

cease producing antibodies and cells that survive become memory B BOX 3-1 FUNCTIONS OF ANTIBODIES
cells that are capable of rapid expansion if a related antigen is subse- • Cross-linking and physical clearance of pathogens
quently encountered.123 • Neutralization of pathogens
• Initiation and enhancement of complement activity
Antibody Functions • Opsonization of pathogens
• Antibody-dependent cellular cytotoxicity
Antibodies serve in a number of different roles both as freestanding • Modulation of the immune response
molecules and working in concert with other components of the
immune response (Box 3-1).
Neutralization. The most straightforward function of antibodies
involves direct binding to microbes or toxins to block binding to host
cell receptors or to reduce infectivity through a process termed neu- the infectivity of organisms without binding directly to receptor mol-
tralization.124 Microbial pathogens often gain entrance into target cells ecules if they interfere with molecular rearrangements involved in
by binding with specific ligands on the cell surface. Antibodies that infectivity after initial binding has occurred.126
interfere with this interaction reduce the infectivity of organisms by Complement Activation. IgM antibodies and those of the IgG1,
preventing effective interactions with target cells.125 Microbial toxins IgG2 and IgG3 subclasses can activate complement after binding a
also usually bind to specific molecules on the surface of target cells and microbe. IgG1 and IgG3 are usually targeted to protein antigens while
interactions with antibodies that interfere with this interaction can antibodies of the IgG2 subclass usually bind to polysaccharide
markedly reduce the effects of these toxins. Antibodies can also reduce antigens. Individuals with selective IgG2 deficiency exhibit greater
susceptibility to encapsulated organisms.127 As will be described in Classic Pathway. The classic pathway of complement activation can
more detail below, when antibodies activate complement through the be triggered when the first component of the complement cascade, C1,
classic pathway, the first complement component (C1q) binds to the interacts with IgM, IgG1, IgG2 or IgG3 molecules that have undergone
Fc portions of at least two antibody molecules and sets off a series of structural rearrangement following binding to cognate antigen.133 C1
molecular interactions with distal components of the complement circulates as a huge non-covalently linked polyprotein composed of 22
cascade that culminates in the formation of pores in the wall of the protein subunits of five different types and is not activated unless it
microbe leading to osmotic death. Complement can also facilitate the simultaneously encounters Fc regions from at least two immunoglobu-
formation of large soluble complexes of antibodies and pathogens that lin molecules that have bound to an antigenic target. Since IgM circu-
can be eliminated from the host. Red blood cells are coated with recep- lates as a pentamer, a single IgM molecule can activate C1 after binding
tors for complement protein C3b and can transport pathogens to the to a target antigen. IgG-based activation requires that at least two
spleen and liver for ingestion by the reticuloendothelial system. antibody molecules bind in close enough proximity to be bridged by
Opsonization. Antibodies of the IgG1 and IgG3 subclass also target the C1 protein. By requiring both the conformational change following
pathogens for ingestion by phagocytic cells by binding to the pathogen antigen binding and simultaneous interaction with more than one Fc
with the Fab end of the antibody and to a phagocytic cell through Fc region, C1 can freely circulate in its nonactive form and avoid activa-
receptors on the surface of these cells. In addition to providing a bridg- tion by encountering unbound antibody. Once the C1 molecule is
ing mechanism between the microbe and a phagocytic cell and facili- activated, two of its protein subunits, C1r and C1s, are sequentially
tating phagocytosis, the interaction with the Fc receptor activates the activated as proteases. The active C1s serine protease then cleaves
oxidative pathway within the phagocyte and makes it much more effec- another circulating complement protein, C4, to continue the comple-
tive in killing the pathogen within its phagocytic vacuoles. Pathogens ment cascade. C4 is cleaved into a larger component, C4b, that binds
can also be targeted for ingestion by deposition of complement pro- covalent bonds to the pathogen through either an amide or ester bond
teins C3b and C4b on the surface of the pathogen. and a smaller soluble component, C4a, that possesses inflammatory
activity. When C4b is bound to the membrane of a pathogen, it can,
Antibody-Dependent Cellular Cytotoxicity. Antibodies can
in turn, bind complement protein C2 which then becomes a target for
also form bridges between pathogens and NK cells, monocytes or
proteolysis by the C1s protease. The larger fragment of this proteolysis,
granulocytes and activate these cells to secrete microbicidal substances
C2a, then gains proteolytic capability and remains bound to C4b and
including perforins or granzymes that can kill organisms without
forms a protein dimer that can convert C3 to its active form. C4b binds
requiring ingestion. This mechanism is particularly well suited to
to circulating C3 and C2a cleaves one of the two chains of the C3
targets too large for ingestion or for virus-producing cells in which
heterodimer. One of these, C3b, binds either to the C4–C2 dimer and
these antibodies facilitate destruction of the cell before a full comple-
forms a three-component complex known as C5 convertase that is
ment of infectious virus can be produced.128
capable of cleaving C5 and activating the remainder of the comple-
Modulation of the Immune Response. Antibodies are also ment cascade, or that can bind directly to the pathogen surface and
important for modulation of the immune response. When complexed activate the terminal components of the complement cascade through
with antigens as immune complexes, antibodies can downregulate the the alternative pathway.137
humoral immune response – thereby modulating ongoing production
of antibodies as antigen and immune complexes are cleared.
Alternate Pathway. The alternate complement pathway can be acti-
vated as a byproduct of the classic pathway when the C4–C2 dimer
facilitates direct binding of the activated C3 to the pathogen surface as
COMPLEMENT above or when circulating C3 is spontaneously hydrolyzed and acted
The complement system is probably best characterized as a highly on by two proteins (Factors B and D) to form a free C3 convertase
regulated series of proteins that play a key role in interfacing the innate molecule.136 This molecule can, in turn, activate C3b to be deposited
and adaptive immune responses.129,130 The complement system is com- on the pathogen surface where it binds first to Factor B and is then
posed of more than 30 interactive proteins that amplify the effects of trimmed by Factor D to form a surface-bound alternative C3b conver-
antibodies, integrate the cellular and humoral responses, assist in the tase. This molecule forms more activated molecules of C3b and can
clearance of immune complexes, enhance antigen presentation and also be bound by another protein, Properdin, and a second activated
stimulate cellular immunity in the absence of an antibody response. C3b molecule to form an alternative C5 convertase that activates the
These proteins are highly evolved both in their regulation and in their terminal components of the complement cascade.
effector function to provide tightly targeted amplification of the Lectin Pathway. Complement can also be deposited on the surface
immune response, especially in its earliest phases. Complement proof pathogens displaying certain monosaccharides in a process that is
teins are also critical to the cross-linking of antibodies and antigens in initiated when these polysaccharides bind to one of two multimeric
immune complexes and play a critical role in the clearance of immune protein complexes composed of either mannose-binding lectin (MBL)
complexes.131 Complement proteins are primarily synthesized by or C-reactive protein (CRP).134,138 In either case, once one of these
hepatocytes although monocytes and certain epithelial cells can also ligands binds to a monosaccharide on the pathogen surface, proteases
produce complement components. analogous to C1r and C1s (MASP1 and MASP2) in the classic pathway
Initiation of the Complement Cascade are triggered.139 The sequence of events is then the same as in the classic
The complement cascade can be activated by one of three different pathway and results in the deposition of C5 convertase on the surface
types of signals (Figure 3-11). Once activated, the three signaling path- of the pathogen; with CRP the classic pathway is initiated but the
ways converge at an activated protein common to all three pathways, process stops with the formation of C3 convertase allowing opsoniza-
C3b, that catalyzes the remainder of the cascade to produce a mem- tion but not activation of the terminal components of the complement
brane attack complex as well as a family of terminal components with pathway.
immunoregulatory functions.131 The classic complement pathway is Formation of the Membrane Attack Complex. Once the com-
activated by interactions between pathogens and IgM or IgG.132,133 The plement cascade has been initiated by one of these three pathways, the
other two pathways do not require antibody and can evolve very early process converges on cleavage of C5 into an anaphylotoxin (C5a) and
during interactions between pathogen and host. The lectin pathway is C5b which is bound to the wall of the pathogen by the C5 convertase
triggered when one or more circulating mannose-binding ligands bind complex. This process triggers a terminal sequence of binding events
to monosaccharides on the surface of pathogens.134 The alternative for C6 through C9 to form the membrane activation complex.140 The
pathway is activated when C3b is incorporated into an active complex C9 component of this complex forms a pore in the membrane of the
by a circulating protein known as properdin and stabilized on the pathogen and allows ingress of water followed by osmotic lysis of
surface of a pathogen.135,136 the target organism.141
Complement activation and membrane attack complex foundation
Bacterial cell Bacterial cell Bacterial cell
Alternate
Mannose-binding pathway
lectin pathway
Classic
pathway
C3b
C4 Mannose
Factor B
C3b
C4b
Properdin
C1s MASP1 C3b
MASP2 Mannose-binding lectin
C4a
C1r C1q
C3b
Factor D Bb
C4b Ba Bacterial
C2 cell
C3 convertase
C4b C3 convertase
C3
C3b
C2a
C3b
C2b C3a
C3b
Bacterial
cell
C3b
C5 convertase C3b
C5 Bb
C5a
Bacterial
C5b cell
Late steps of complement activation

C5 convertase
C3b C3b C7
C3b C4b C6
C2a C8 Membrane
attack complex
C3b
C3b
Bacterial cell C6 C5b C6 C5b
C7 C7
Proteins or protein complexes with proteolytic capability C8
Proteins with pro-inflammatory properties
H2O ingress and osmotic lysis
Figure 3-11 Complement activation and membrane attack complex foundation. (Adapted from Walport M.J.: Complement (two parts). N Engl J Med. 2001;344:1058-
1066, 1140-1144. Copyright 2001, Massachusetts Medical Society.)
Disorders of the Complement System plement system components that result in inefficient activation of the
The complement system is a self-amplifying pleuripotent system that classic complement pathway may increase the risk for autoimmune
has evolved to play a central role in amplifying both the innate and diseases such as systemic lupus erythematosus.145 Disorders in comple-
adaptive immune responses. From its location in the crossroads of the ment proteins responsible for regulation of C3 activation may increase
immune response, aberrant or inappropriate activation of comple- the risk for membranoproliferative glomerulonephritis or paroxysmal
ment or an absence of any of several of its key components can have nocturnal hemoglobinuria.130,146 The absence of functional C1 inhibi-
very visible clinical manifestations. Deficiencies in the terminal tor is associated with hereditary angioedema.130
components of the complement pathway predispose to disseminated
infection with encapsulated organisms, especially organisms such References available online at expertconsult.com.
as Neisseria meningitidis and N. gonorrhoeae.142–144 Deficiencies of com-
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4
Emerging and Re-emerging
Pathogens and Diseases, and Health
Consequences of a Changing Climate
PHILIP M. POLGREEN | EVELYN L. POLGREEN
KEY CONCEPTS healthcare settings and ultimately community settings. This emergence
of antimicrobial resistance repeated itself many times over in the years
• The pursuit of both natural resources and new sources of food to come, with many other antibiotics and for a wide range of patho-
have put people, wildlife, and disease vectors into close contact gens. At the same time, ambitious programs to eliminate malaria suf-
with each other, increasing the chance for disease spillover. fered setbacks for a variety of reasons in various parts of the world.6
• Risks of emerging infectious disease are especially high where Similarly, some mass vaccination programs failed to meet their origi-
dramatic changes in land use occur. nal goals.
In the last quarter of the 20th century and into the 21st century,
• Changes in global temperatures may directly increase the dis-
several new infections emerged or at least became widely recognized
tribution of populations of disease vectors with regard to both
their latitudes and altitudes. (see Table 4-1). Some of these diseases were not new but had not yet
been appreciated, due to limitations in diagnostic testing. For example,
• Extreme weather events, such as severe flooding, droughts, or the causative agent for Legionnaire’s disease was identified after an
severe storms, increase the probability that infectious disease outbreak in 1976; however, the disease had most likely caused out-
outbreaks occur. breaks of atypical cases of pneumonia for years. Other newly identified
• Geopolitical events such as military conflicts, mass migration pathogens like HIV and hepatitis C were associated with a dramatic
and political unrest can promote conditions that decrease the increase of morbidity and mortality around the world, while other
ability to detect, control and prevent outbreaks of emerging diseases like dengue emerged in new geographic locations. Other
and re-emerging diseases. pathogens have re-emerged after decades of decline. Vaccine-
• Infectious diseases spread rapidly in closed or partially closed preventable diseases like mumps and pertussis have also re-emerged
populations, such as military barracks, college dormitories, and so has tuberculosis. In fact, there may have been more people
prisons, hospitals, nursing homes, and the urban slums of living with tuberculosis in the first decade of the 21st century than at
megacities. any time in history.3 Finally, the increasing resistance of many patho-
gens to antimicrobial agents has hinted that we may enter a post-
• Poverty is associated with several conditions related to the
antibiotic era for some difficult-to-treat infections. This threat was
spread of infectious diseases, e.g. lack of access to clean water,
poor sanitation and lack of access to healthcare. However, highlighted by the recent spread of infections caused by highly resistant
factors connected to economic development may also be gram-negative bacteria capable of producing New Delhi metallo-B-
linked with the emergence of infectious diseases. lactamase (NDM-1) enzyme, such as Escherichia coli and Klebsiella
pneumoniae.7
• New molecular diagnostic platforms, coupled with novel sur- What happened? Travel increased, human behavior changed, and
veillance approaches, will continue to improve the ability to
in some parts of the world people came into closer contact with
identify both new pathogens and outbreaks more quickly.
animals, as human populations moved into new habitats. The way
food was produced and transported also changed. More intensive
animal farming practices made food cheaper but kept more animals
Introduction in smaller spaces. Also, agricultural practices encroached into new
Mass vaccination programs and effective antimicrobials have greatly regions, increasing the chances of spillover of pathogens.8 Now, food
diminished the morbidity and mortality attributable to infectious dis- is often produced hundreds if not thousands of miles from the point
eases.1 However, even before the introduction of antibiotics and vac- of consumption. The resulting product specialization, large-scale
cination programs, the morbidity and mortality caused by infectious farming and production lots and global distribution enable food-based
diseases decreased in a dramatic fashion, in large part due to the wider outbreaks to spread quickly around the globe,9 and also make it dif-
availability of clean water, better sanitation and increased standards ficult to determine the original source of an outbreak.
of living.2,3 These improvements in health were concentrated mostly Pathogens also changed to adapt to new environments. Medical
in higher-income countries, but they occurred in low- and middle- treatments opened new niches for infections (e.g. new implantable
income countries (LMIC) as well.4 Subsequent rapid progress toward medical devices, catheters, new immunosuppressive therapies) and
medical treatments for tuberculosis, successful vaccination programs pathogens also adopted resistance to widely used antimicrobial agents.
against smallpox and polio, and large-scale programs focused on Finally, the concept that problems related to infectious diseases were
malaria, all helped encourage the medical and public health communi- under control may in part have helped lead to the resurgence: the lack
ties to think that the threat posed by infectious diseases was of investment in public health and research may have decreased
diminishing.3 support for surveillance and treatment and thereby may have provided
Yet, infectious diseases never really disappeared as a public health opportunities for infectious diseases to re-emerge.10,11
problem, especially in LMIC, and diseases also continue to emerge and The move to de-emphasize infectious diseases as a major public
evolve in industrialized countries. For example, not long after the health threat may have been in part due to a lack of appreciation
widespread introduction of penicillin, cases of penicillin-resistant of the interplay between infectious diseases, human history and the
Staphylococcus aureus were reported.5 Decades later, resistant strains environment. Thus, the goal of this chapter is to give readers an appre-
would become a major cause of morbidity and mortality both in ciation of why emerging infections were a problem in the past and to
40
Chapter 4 Emerging and Re-emerging Pathogens and Diseases, and Health Consequences of a Changing Climate 41
TABLE Selected Emerging and Re-emerging BOX 4-1 DRIVERS OF EMERGING AND
4-1 Disease-Related Events, 1993–2014 RE-EMERGING INFECTIOUS DISEASES
HUMAN–ECOSYSTEM INTERACTIONS
1993 Hantavirus pulmonary syndrome (USA)
Changes in land use, deforestation, and irrigation
1994 Plague (India) Intensification of farming and agriculture
Specialization of agriculture and foreign trade
1995 Ebola fever (Zaire [Democratic Republic of Congo]) Procurement and sale of bush meat
Crowded and diverse live-animal markets
1996 New variant Creutzfeld–Jakob disease (UK)
Importation of exotic animals
1997 H5N1 influenza (Hong Kong) Construction of dams and roads
1998 Nipah virus encephalitis (Malaysia) CLIMATE, WEATHER, NATURAL DISASTERS

Sea-level rise and flooding of low-lying coastal areas
1999 West Nile encephalitis (USA, Russia) Changes in ocean surface temperatures
Extreme weather and storms
2000 Rift Valley fiver (Kenya, Saudi Arabia, Yemen) Floods
2001 Anthrax (USA) Droughts
Earthquakes
2002 Vancomycin-resistant Staphylococcus aureus (USA) Tsunamis
Displacement of populations
2003 Severe acute respiratory syndrome (China, Hong Kong, Lack of utilities and infrastructure following disasters
Canada)
TRAVEL
2003 Monkey pox (USA) Spread of disease vectors (e.g., mosquitoes) on ships and airplanes
Passengers in confined spaces
2003 Highly virulent strain of Clostridium difficile (Canada,
Rapid transfer of infections to new and susceptible populations
Netherlands, USA, UK)
Return home of ill travelers
2005 Chikungunya (Indian Ocean Islands then spreading to India Delayed diagnosis of returning travelers with infectious diseases
and beyond)
POVERTY
2008 Measles outbreaks associated with low vaccination rates Lack of access to clean water
(European countries, USA) Poor sanitation
Housing with poor ventilation
2008 NDM-1 carrying Enterobacteriaceae (isolated in Sweden in Building materials that house disease vectors
traveler from India) Poor nutrition
Homelessness
2009 Pandemic H1N1 influenza (beginning in Mexico and
Limited access to healthcare
spreading internationally)
Lack of public-health resources
2010 Cholera (Haiti) GOVERNMENTAL AND GEOPOLITICAL FACTORS
2011 E. coli O104:H4-associated hemolytic uremic syndrome Lack of investment in public health
(Germany and European countries) Wars and armed conflict
Mass migration of displaced populations into crowded refugee camps
2012 MERS-CoV (Saudi Arabia) Economic and fiscal crises
2012 Exserohilum rostratum CNS infections from contaminated BEHAVIORAL CHANGES AND EMERGING INFECTIOUS DISEASES
steroid products (USA) Vaccine avoidance and refusal
2013 Chikungunya (Caribbean) Intravenous drug use
Risky sexual activity
2014 Ebola (multiple African countries and isolated cases
internationally) CROWDING, INCREASED POPULATION DENSITY
Colleges and universities
Military populations
Prisons
describe some of the current drivers of emerging infectious diseases Nursing homes and hospitals
today (see Box 4-1), with the hope that such an appreciation will help Megacities
to anticipate future disease threats. Here we consider emerging infec- MEDICAL TECHNOLOGY
tions as either new infections, ones that are increasing in incidence or Widespread use of antimicrobial agents leading to resistance
geographic scope, or infections that are likely to do so. Immunosuppressive medical therapies (e.g., biologics)
Medical devices (e.g., catheters, prosthetic joints)
Transplants and transfusions
A Short History of Emerging
Infectious Diseases
Human settlement and the corresponding development of agriculture
provided ideal conditions for the emergence and spread of infectious Historically, the spread of infectious diseases often followed periods
diseases. Agriculture allowed people to stay in one place, and increased of social upheaval and transitions.14 In some cases, infectious diseases
food production caused the population density to expand far beyond may have played a role in the course of history.13 An epidemic deci-
levels that could be sustained by hunting and gathering alone. This mated the population of ancient Greece, and the ‘Plague of Athens’,
growth in population density provided a critical mass of people to possibly caused by typhus,2 may have determined the outcome of the
sustain and spread contagious infectious diseases.2,12 Also, some agri- Peloponnesian war and the future of the state of Athens. Similarly, the
cultural practices, specifically the domestication of animals, increased ‘Justinian Plague’, believed to have been caused by Yersinia pestis,15
human and animal interactions, as well as interactions between differ- greatly affected the Byzantine Empire and devastated Constantino-
ent animal species. This cross-species mixing provided the ideal condi- ple.14 Centuries later the plague spread to Europe via trade routes and
tions for the evolution of new infectious diseases.2,12 Subsequent resulted in an extraordinarily high mortality rate. The resulting dra-
historical developments involving trade, war and migration created a matic decrease in population in Europe helped increase social mobility
means for spreading disease outbreaks to new populations around and may have helped lead to changes in political and economic
the world.13 structure.16
Exploration and travel also promoted the emergence of new infec- Human–Ecosystem Interactions and
tious diseases into susceptible populations. For example, when the
Spanish reached the Americas, they introduced smallpox and measles. Emerging Infectious Diseases
These diseases had a greater impact on indigenous populations than Humans may have influenced their surroundings ever since Paleolithic
the relatively small armies accompanying Cortez and Pizarro.13 The times. However, the large environmental changes that increased
exchange of emerging infections was heavily one-sided, but not one- the likelihood of humans becoming infected with new pathogens esca-
way. For example, it is likely that Spanish explorers introduced syphilis lated when farmers started domesticating animals and tilling their
to Europe.2,13 fields over 10 000 years ago.12 Even today, in some parts of the world,
During the Industrial Revolution, particularly in Britain, cities, humans are brought very close to animals, as a result of not only
with their rapidly increasing populations, efficiently spread infectious farming approaches, but also processing and selling animals.18 Situa-
diseases. As the population moved from the countryside into the cities tions in which multiple species live in close proximity increase the
to work in the new factories, migrants experienced over-crowding, likelihood that new infections can emerge and spread to humans. In
longer working hours and a poorer diet compared to their contempo- fact, a majority of all emerging and re-emerging infectious diseases are
raries in rural communities. Smallpox, typhus and tuberculosis were zoonotic in nature.19,20 The regions that are at high risk for producing
endemic in cities. Child mortality was high from diseases like measles, emerging infectious diseases feature populations that have more fre-
mumps, pertussis and scarlet fever. Before the widespread introduc- quent interactions between humans and other animals.17,20 Risks of
tion of modern sewage systems in the late 19th century, sewage often disease emergence may be especially high where and when changes in
contaminated water supplies directly. Cleaner water supplies eradi- land use occur, that is when intensified agricultural approaches spread
cated cholera in Britain and the United States, but poor sanitation still into previously uncultivated ecosystems.9 The emergence of Nipah
leads to the spread of cholera in many parts of the world. virus in the 1990s in Malaysia provides an example of an emerging
Over the last several decades, improvements in technology and the infectious disease associated with a change in land use. Pig farms were
standards of living for some have opened new routes for emerging established close to tropical forests, and the virus spread from fruit
infections. The resulting increase in travel now means that infections bats to pigs and then to pig farmers.2,21 Efforts to control this outbreak
can move across continents in a matter of days rather than weeks or resulted in the culling of over a million pigs.21 When forests and other
months. Thus, the closeness between populations and infectious dis- habitats are fragmented by increasing human incursion and changing
eases can no longer be measured in terms of geographic distance, and land use, the amount of area where humans come in contact with
the factors that drive emerging infectious diseases in one part of the wildlife and disease vectors increases due to ‘edge effects’. Habitat
world can affect other parts of the world very quickly. Similarly, the fragmentation has been associated with increased risk for Lyme disease
pursuit of natural resources and sources of food have put people into in the northeastern USA.9 Decreasing levels of wildlife diversity, spe-
close contact with new species, increasing the chance for disease spill- cifically the diversity of bird species, has been associated with increas-
over (Figure 4-1),8,17 which when coupled with the ease with which ing cases of West Nile virus infection among humans. Thus, loss of
both people and diseases can travel, has created an unprecedented biodiversity may also be an important driver of emerging infectious
opportunity for new diseases to emerge and spread.14 diseases.8
Intensified production of domestic animals can also increase the
spread of zoonotic infectious diseases.8 Crowded conditions and lack
of free movement both compromise the health and well-being of the
Human–pathogen interface animals and also make animal-to-animal transmission of diseases
more efficient. Antibiotics are often used to control infections and
promote growth. The widespread use of antibiotics in intensive
farming has introduced antibiotics into the food chain and may lead
Biosphere to antibiotic-resistant bacteria that could affect human health.22
The domestication of animals is not the only food-based risk factor
for emerging infectious diseases. In some regions, the procurement
Wildlife and sale of bush-meat may also be a potential driver of emerging infec-
tious diseases. Indeed, HIV may have emerged in an area in which
non-human primates were used for food.8,17 The sale and widespread
distribution of such foodstuffs may amplify the risk of emerging infec-
tious diseases related to bush-meat or bush-products, especially since
such food products are often smuggled around the world, evading any
Peri-domestic
wildlife sort of inspection systems. Also, some of the animals may be alive at
the time of transport. Crowded and diverse animal markets in South-
ern China may have played an important role in the initial spread of
severe acute respiratory syndrome (SARS).18
The smuggling of animals for pets may also contribute to the pos-
sible spread of infections. Even legal importation of exotic animals has
Humans Livestock been associated with the emergence and spread of infectious diseases
because animals of different species are often kept together in close
spaces during transport and distribution. For example, the outbreak
of monkey pox in the USA was associated with the exotic pet trade.
During this outbreak, over 70 cases were documented. These were
Domestic landscape linked to pet prairie dogs, which most likely acquired the virus from
imported rodents housed in the same distribution center.23
Plant-based agriculture can also help drive the emergence or
re-emergence of infectious diseases. The incursion of farmland into
forested areas increases the likelihood of human interactions with
Figure 4-1 Human–pathogen interface. Pathogen flows between animals and
humans can be direct, indirect, or vector-borne. Flows are dependent upon the
disease vectors. In addition, some farming practices increase the likeli-
duration, frequency and intensity of interactions. (From Jones BA, Grace D, Kock hood of human–insect contact by supporting populations of mosqui-
R, et al. Proc Natl Acad Sci USA 2013; 110(21):8399–8404.) toes. Rice farming, which involves the flooding of fields, and also
irrigation practices can facilitate the growth of mosquito populations.24 vectors. Poor nutrition can also facilitate the acquisition and spread of
Any agricultural practice that generates standing water, including infectious diseases. Furthermore, although poverty, as a risk factor, is
aquaculture, also helps sustain and increase mosquito populations. most commonly measured at a population level (e.g., access to clean
water), poverty can also help drive the spread of infectious diseases at
Travel and Emerging an individual level, even in higher-income countries. For example,
homelessness has been associated with the spread of tuberculosis in
Infectious Diseases several countries. The prevalence of tuberculosis, as well as hepatitis C
Travel is now more accessible than ever before. Over the past several and HIV, may be substantially higher in homeless populations.36
decades, the costs associated with travel have decreased dramatically; Tuberculosis has also been associated with poor neighborhoods, even
at the same time the convenience and speed of travel have increased. in higher-income countries.37
This has created a large network of travelers around the globe, com- People living in poverty often have limited access to healthcare.
posed of more than 25 000 routes by sea and 6000 routes by air (Figure Therefore, in the case of an outbreak, diagnoses can be delayed, and
4-2).25 Thus, travelers provide a way for pathogens to move quickly follow up can be difficult, leading to more opportunities for disease
around the world.26 Even the act of travel itself, with passengers spread. A lack of public health infrastructure and access to medical
cramped in confined spaces (buses, airplanes, trains, ships) increases care may delay the recognition of an emerging infectious disease out-
the potential for diseases, especially those spread by both droplet and break, and thus delay a coordinated public health response. A lack of
airborne routes, to spread from traveler to traveler.27 public health resources can also dilute the effectiveness of a public
The choice of travel destination also places some travelers at extra health response.38
risk. For example, more adventurous travel, especially in rural, tropical Several efforts have been aimed at improving the health of popula-
environments, provides new opportunities to spread emerging infections, using interventions targeted toward improving the standard of
tious diseases, ranging from dengue to malaria and chikungunya.26,28 living or via direct aid to populations living in poverty or with poor
However, even travel to urban environments can put travelers at risk public health. Unfortunately, foreign aid, by itself, is not always associ-
for diseases. For example, dengue fever is becoming more common in ated with a decrease in infectious disease activity or outbreaks for a
many cities around the world.29 Finally, even relatively local travel can variety of reasons. The association between poor nations and infectious
spread diseases. For example, spring-break-associated travel among disease outbreaks involves multiple factors, making interventions dif-
college students helped spread mumps during the largest USA mumps ficult. For example, government corruption may make foreign inter-
outbreak in decades.30 ventions, which are designed to reduce the spread of infections, less
Furthermore, once travelers arrive at their destination or return effective. Specifically, up to 5% of the differences among countries in
home, opportunities to spread travel-acquired diseases are often real- multidrug-resistant tuberculosis could be related to corruption.39 With
ized, as infectious returning travelers come into contact with suscep- corruption, treatments do not necessarily go to those who need them
tible populations. When returning travelers present with travel-acquired most, or even to those with the ability to pay for them, but rather to
diseases, there are often delays associated with a proper diagnosis, those with specific connections. Such factors complicate strategies
treatment and reporting possible cases to public health authorities. designed to reduce both poverty and the spread of infectious diseases
Delays are especially likely to occur if physicians do not have sufficient associated with poverty. When countries attempt to restructure their
experience with emerging infections or do not consider such diseases spending in response to the loan conditions of the International Mon-
in their differential diagnosis. Delays in diagnosing such diseases in etary Fund, the result can be a decrease in spending for public health,
returning travelers can, in some cases, generate additional cases. For treatment, and surveillance.40 For example, the implementation of
example, in 2003 the SARS outbreak spread quickly around the world reform programs of the International Monetary Fund has been associ-
from Hong Kong to Canada and then to other countries, and the ated with increased tuberculosis incidence in post-communist Eastern
spread of SARS was accelerated and facilitated by international air European and former Soviet countries.40 While economic reforms may
travel.31 More recently, international travel has facilitated the interna- ultimately lead to higher standards of living and increased spending in
tional spread of chikungunya. In two neighboring villages in Italy, over public health, economic transitions may help fuel other factors associ-
200 autochthonously transmitted cases of chikungunya were identified ated with emerging infectious diseases. In fact, low- and middle-
and linked to a traveler who had acquired the virus while visiting rela- income countries, in the process of becoming more industrialized, may
tives in India.32 The outbreak’s occurrence demonstrates how easy it engage in more road construction, dam building, mining and other
may be for this disease and others to spread to Europe and beyond. activities, which result in the alteration of land use and deforestation,
Indeed, autochthonously transmitted cases of chikungunya have since and these changes can precipitate environmental changes, which lead
been reported in France33,34 and in the Caribbean. The laboratory- to the emergence of infectious diseases.9,17 Thus, it is possible that
based observation that some mosquitoes in Florida are susceptible to development efforts and aid may in some cases actually help increase
both infection by and dissemination of chikungunya virus raises the the potential of infectious disease outbreaks in low- and middle-income
concern that the disease could spread once introduced in the Southern countries.
USA.35
Finally, human travelers are not the only means by which patho-
gens can travel. Insects, which serve as infectious disease vectors, can Governmental and Geopolitical
also spread diseases when they are accidentally carried from one loca- Factors Associated with Emerging
tion to another. Mosquitoes, for example, can live in the holds or
container vessels of ships or in cargo, such as old tires or bamboo, and Infectious Diseases
then spread around the world, disembarking when the ship’s cargo is Progress in controlling infectious diseases was sometimes followed by
unloaded at a new port.25,33 Airplanes can also transport mosquitoes a shift in public investment away from public health infrastructure to
over extremely long distances. For example, air travel has been impli- other spending priorities. These decisions may have been the result of
cated in the introduction of new species of mosquitoes to Hawaii.25 the optimism that the tide had turned against infectious diseases as a
major future public health threat. However, in other cases, funding
Poverty and Emerging was cut to ease financial pressures. In both situations, the lack of
investment may have prevented future detection and compromised
Infectious Diseases control efforts. For example, during the 1970s, New York City decided
Poverty is associated with several conditions related to the spread of to cut public health funding during a fiscal crisis.41 Unfortunately, in
infectious diseases: a lack of access to clean water, poor sanitation and the following years, tuberculosis re-emerged as an important patho-
housing with poor ventilation or building materials that house disease gen, and now a substantial burden of the disease is associated with
Flight travel paths
Figure 4-2 Flight travel paths. (a) The location of the 3632 airports and (b) the flight routes. (From Huang Z, Das A, Qiu Y, et al. Web-based GIS: the vector-borne
disease airline importation risk (VBD-AIR) tool. Int J Health Geogr 2012; 11:33.)
drug resistance. The lack of public health support may have led to in the 1990s. Following the breakup of the Soviet Union, the previous
decreased diagnosis and treatment and even less efficient administra- public health system became increasingly fragmented, and the result
tion of treatment, and thereby facilitated the emergence of drug- was a re-emergence of several infectious diseases, most notably, diph-
resistant tuberculosis. theria: during the 1990s over 150 000 cases were reported, making it
Another example of how political events and decisions can affect the largest diphtheria epidemic since the 1950s.42 Tuberculosis rates
re-emerging infectious diseases occurred in the former Soviet Union dramatically increased,2 and reported rates of syphilis were also very
high.43 Between 1990 and 1994 all-cause age-adjusted mortality Crowding, Population Density and
increased by more than 30%, and infectious diseases accounted for
approximately 5% of this increase.44 Emerging Infectious Diseases
Wars and other armed conflicts represent another potential driver Many emerging or re-emerging diseases spread rapidly in closed or
of emerging infectious diseases.45 For example, wars can disrupt vac- partially closed populations. The best examples of such populations
cination programs.46 Conflicts can also disrupt disease prevention include military recruits and college students living in dormitories.
efforts, strategies and necessary supplies to protect against or control Prisons are also ideal environments for spreading infections. Not only
for malaria.47 Displaced populations, fleeing from conflicts, often are these populations placed in close contact with one another, by
crowd into refugee camps, and such camps can facilitate the spread of training, working and often sleeping in close quarters (e.g., barracks
re-emerging infectious diseases such as measles.48 and/or dormitories), but also these settings bring people with different
Economic crises can also impact the transmission of communicable levels of immunity together. Historically, especially in the pre-vaccine
diseases and thus the spread of emerging infectious diseases. During era, military recruits were frequently involved in outbreaks of emerg-
recessions, worse infectious disease outcomes have been reported.49 In ing and re-emerging infectious diseases. Although vaccination cover-
Thailand increasing measles, malaria and diarrhea in children, and age is extremely high in most military populations, outbreaks of
dengue in adults were associated with a 30% decrease in gross national emerging infectious diseases still occur. Adenovirus strains have caused
product during the 1997 financial crisis.50 In contrast, the economic severe pneumonia in military populations.58 From a historical perspec-
recession in 2009 in the USA was associated with an unexpected tive, the influenza pandemics of 1968 and especially 1918 were dra-
decline in tuberculosis cases.51 Thus, the relationship between funding matic examples of infectious diseases that spread rapidly in military
and health outcomes is difficult to interpret in the short term by populations, and subsequently military-associated travel may have
examining disease rates in a single country. However, if recessions helped to distribute the disease to civilian populations. Intermittent
exacerbate poverty and undermine public health efforts, such financial meningitis outbreaks have been associated with college campuses.
shocks will hamper efforts to detect and control outbreaks when However, in recent years, college and university students have been
they occur. associated with outbreaks of several re-emerging infections. For
example, mumps outbreaks in several countries have been associated
Behavioral Changes and Emerging with college students.30 As long as people live in close proximity, with
varying levels of immunity and frequent mixing, such settings will
Infectious Diseases continue to be efficient population-based incubators for emerging
While some outbreaks are driven by the choices made by policy infectious diseases around the world.
makers and government officials, others are driven by individual Hospitals and nursing homes are other relatively crowded environ-
choices. Despite the availability of vaccines, in many cases parents are ments ideal for spreading infectious diseases. In fact, SARS was greatly
choosing not to vaccinate their children. These decisions to avoid vac- amplified in hospital settings, spreading both to other patients and
cines have been linked to outbreaks of vaccine-preventable diseases to healthcare workers.59,60 Over the past several decades, the hospital
and in some cases, for example, the re-emergence of measles and environment has created a new ecological niche for the emergence
pertussis.52,53 From a spatial perspective, cases of vaccine-preventable of several antimicrobial-resistant pathogens. Examples include
diseases cluster with areas of lower vaccination and high rates of non- methicillin-resistant Staph. aureus (MRSA)61 and vancomycin-resistant
medical vaccination exemptions.52 At times, vaccination decisions are enterococcus (VRE).62 Although Clostridium difficile is not resistant to
enabled by policy choices that make it easier for parents to refuse vac- antimicrobials per se, it has certainly re-emerged over the past decade,
cination, but in other instances parents go to great lengths to avoid in part due to the widespread use of antimicrobial therapy.63 Cases of
vaccination. Misconceptions about the safety of the vaccines drive C. difficile have also emerged among pediatric populations.64 While
many of the decisions.54 Internationally, misperceptions regarding cases of MRSA first appeared in healthcare settings, they now occur in
vaccine safety are an important public health problem. In fact, during community settings,65 and so too have cases of C. difficile. These cases
the 1980s, concerns about risks in part led to significantly reduced are occurring even in the absence of prior antimicrobial therapy, and
vaccination levels in the Soviet Union, and these lower levels helped without exposure to healthcare environments.63 Finally, one of the
drive a diphtheria outbreak that occurred in both Russia and the newly most alarming developments, with respect to antibiotic resistance, is
independent states.42 the recent emergence and spread of multidrug-resistant gram-negative
Behavioral changes have also been linked to the emergence and bacteria around the world. Many of these have extremely limited treat-
re-emergence of sexually transmitted infections. While syphilis was ment options. Gram-negative bacteria that produce the NMD-1
once a major cause of morbidity, it had been reasonably well con- enzyme are a prime example.7 Although these are thought to have
trolled due to expanded treatment efforts and public health interven- emerged from the Indian subcontinent, cases have occurred around
tions. In fact, syphilis was once pegged as a disease that had the the world, and may be introduced to new healthcare systems from
potential to be eradicated.43 Yet in the past several years the number returning travelers who are seeking medical attention. Once estab-
of cases of syphilis has increased dramatically, and the disease has lished in healthcare settings, these infections could potentially spread
re-emerged.55 Why? Syphilis is straightforward to diagnose and treat. widely.
One reason for the re-emergence of syphilis relates to a behavioral All of the previously mentioned cases of crowding refer to specific
change associated with an emergent technology: the Internet has been examples of institution-based crowding. However, the greatest poten-
used to facilitate sexual encounters. Often these encounters are anony- tial for crowding to support the emergence and spread of new infec-
mous, and thus risky by nature.56 In addition, the specific websites tions is the increasingly dense urbanization that is resulting in the
designed to facilitate these encounters dramatically increase the poten- development of ‘megacities’ in low- and middle-income countries.
tial number and diversity of partners any user can identify. While the These large cities are often composed of over 10 000 000 inhabitants.
Internet has made it easier to find sexual partners, it has complicated Megacities, with their poverty, poor sanitation, lack of infrastructure
the process of contact-tracing for public health officials, a cornerstone and high population densities, are perfect breeding grounds for infec-
of public health interventions for sexually transmitted infections. tious diseases, particularly sewage-related water-borne diseases and
And while syphilis is not resistant to treatment, another sexually diseases that spread person-to-person.3 However, urban environments
transmitted infection, gonorrhea, is now resistant to a number of are also becoming increasingly suited for mosquito-borne illnesses like
antimicrobials,57and as treatment becomes more and more difficult, dengue.29 The populations at greatest risk for acquiring emerging
the infection may re-emerge and become even harder to control than infections are those that live on the edges of these megacities, in the
in past decades, given the increasingly complicated sexual networks in peri-urban areas. People living in these areas are less likely to live in
several communities around the world. homes with concrete floors, have access to clean water, waste removal
and medical services.66 For example, in regions where malaria is

Observed globally averaged combined land and ocean surface
endemic, the urban prevalence of malaria is much lower in central temperature anomaly, 1850–2012
parts of cities than in the surrounding peri-urban areas.67
0.6
Medical Technology and Emerging Annual average
0.4
Infectious Diseases
Over the last several decades, multiple new therapeutic approaches in 0.2
Temperature anomaly (˚C) relative to 1961–1990

organ transplantation, the treatment of autoimmune diseases and also
0.0
cancer have been developed. Many of these therapies lead directly to
a diminution of the patient’s immune response and thus increase the –0.2
risk that a patient will develop a serious infection after their treatment.
Thus, these medical advances have resulted in the emergence and –0.4
re-emergence of new or previously uncommon pathogens. Cytotoxic
therapies used to treat malignancies were not designed to specifically –0.6
suppress the immune system by therapeutic intent. In practice, 0.6
Decadal average
however, they do indeed cause prolonged periods of immunosuppres-
0.4
sion, and as a result many patients have developed a broad range of
unusual infections, and many of the new pathogens are fungal.68 In the 0.2
field of organ transplantation, both for solid organ transplantation and
hematopoietic transplantation, previously rare fungal infections are 0.0
now much more common among patients receiving transplants.69
Often, as a prophylaxis is used to protect against one type of infection, –0.2
a pathogen resistant to the prophylaxis emerges. For example, infec-
tions due to zygomycosis have increased following the widespread use –0.4
of voriconazole administration to treat Aspergillus.70
–0.6
A new of class of drugs often referred to as ‘biologics’ is extremely
effective in treating connective tissue diseases. The most common are 1850 1900 1950 2000
the medications that selectively inhibit tumor necrosis factor-alpha. Year
However, by inhibiting tumor necrosis factor they inhibit granuloma
formation and maintenance, and thus have been associated with a wide Figure 4-3 Observed globally averaged combined land and ocean surface tem-
range of infections, including tuberculosis, herpes zoster and a host of perature anomaly, 1850–2012. Adapted from the IPCC’s Summary Report for
opportunistic infections.71 As these biologics come off patent, their use Policy Makers (2013). Although this temperature rise begins in 1850, at the end of
a naturally cold period in the Earth’s environmental history known as the ‘Little
will become more widespread; cost is currently one of the major limit- Ice Age’, the steepness of the increase in global temperatures is unprecedented
ing factors to their use in many parts of the world. throughout geological time. (From IPCC, www.ipcc.ch/.)
Other therapies also provide opportunities for new pathogens to
emerge and become more common. For example, the increased use of
parenteral nutrition has contributed to bloodstream infections, espe- edented over decades to millennia’.75 However, climate fluctuates over
cially those caused by Candida species.72 The widespread introduction different time scales, from the decadal through the centennial, to the
of venous and urinary catheters created new opportunities for blood- millennial and the million-year spans of geological time. Over the past
stream infections. Indeed, urinary infections associated with catheters several decades, both the atmosphere and the oceans have warmed
are often associated with antimicrobial-resistant pathogens. Catheters (Figure 4-3).75 Temperature ultimately drives many other climate vari-
are certainly not the only medical devices to cause infection. The ables; however, the relationship between climate change and emerging
introduction of almost any new medical device has subsequently infectious diseases is not a simple linear correspondence between
spawned a new type of device-related infection. Thus with the contin- rising temperatures and the increasing incidence of disease. Although
ued growth of implantable devices, new infections will certainly changes in global temperatures may directly shift the distribution of
emerge that previously did not exist. Given that these devices are populations of disease vectors, with regard to their latitudes and alti-
deployed in healthcare settings, they can become infected with emerg- tudes. For example, tick populations, an important driver of some
ing antimicrobial-resistant pathogens. emerging and re-emerging infectious diseases, have readjusted to
The increased sharing of blood and tissues over the past few decades warming temperatures and are now present at higher latitudes in
has also played a large role in the spread of infectious diseases. Prior Sweden; some models predict that the same may happen in Canada
to the identification of the causative agents of both HIV and hepatitis and the USA.76,77
C, transfusions helped spread these diseases.73 In addition, concen- Warming can cause rising sea levels, and consequent flooding of
trated, pooled blood products can facilitate the spread of these emerg- low-lying coastal areas can increase the breeding grounds available for
ing pathogens. The safety of the blood supply has increased dramatically mosquitoes, resulting in a rise in diseases such as malaria, dengue and
since the 1980s, however, pathogens that cannot yet be detected or that yellow fever.78 Flooding can also overwhelm coastal sewage systems,
are not screened for remain a public health threat. Organ transplants causing an outflow of sewage into the surrounding regions. Warming
pose an additional threat of spreading infectious diseases.74 ocean waters may have a direct effect on cholera and other sewage-
related infections because bacterial populations of Vibrio cholera may
Climate, Weather, Natural Disasters increase with rising sea-surface temperatures.79 Evidence from an epi-
demic that started in Peru and spread north along the South American
and Emerging Infectious Diseases coast in 1991, showed that the V. cholera bacteria can attach to plank-
The term ‘climate’ describes long-term trends in temperature, precipi- ton and spread disease, particularly during planktonic blooms, such as
tation, wind strength, humidity, sunshine and cloud cover, and the those that occur during the relatively short-term, periodic El Niño
term ‘weather’ records the same parameters but on a short-term day- climatic events.80 Cholera data from 1980 to 2001 show a close cor-
to-day or a week-to-week basis. According to the Intergovernmental respondence with the increasing intensity of El Niño Southern Oscil-
Panel on Climate Change, ‘Warming of the climate system is unequiv- lation and the associated weather extremes in the Pacific, which are
ocal, and since the 1950s, many of the observed changes are unprec- driven by these events.81
Longer-term climate change may also be increasing the intensity of can cause stagnant pools of water to develop in place of rivers and
more extreme weather events. Recent trends show storms of increasing streams, and these water collections can serve as ideal breeding
severity.82 Unexpected thunderstorms can cause increased rainfall, and ponds for mosquitoes. Storing water in anticipation of drought con
the resulting deluge can overwhelm sewage systems and cause sewage ditions can also provide breeding locations for mosquitoes. Drought-
or contaminated water to pollute drinking water supplies, leading to like conditions helped to drive the emergence of the West Nile virus
outbreaks of water-borne infectious diseases. For example, viral infec- in North America.84 After the introduction of the virus it spread
tions, caused by norovirus and rotavirus, have been reported after quickly across the continent (Figure 4-4). Drought may have been a
storms, as well as bacterial infections caused by Vibrio spp. and Lepto- contributing factor to the explosion of cases of chikungunya in East
spira spp.83 Outbreaks of E. coli O157:H7 can also occur after heavy Africa that subsequently spread to countries around the Indian
rains. In addition, the pools left behind after heavy rains can serve as Ocean.85,86 This outbreak caused hundreds of thousands of cases
breeding sites for mosquitoes. Finally, heavy rainfall can drive rodents around the world and has also generated other outbreaks thousands
from their burrows and into areas where they might come into closer of miles away.
contact with humans. In 1993, early and heavy rains produced a dra- When an environmental disaster such as severe flooding or drought,
matic increase in local rodent populations, which was associated earthquake, tsunami, or severe storm occurs, several disease-spreading
with an outbreak of Hantavirus pulmonary syndrome in the south- events converge: the displacement and migration of victims, the travel
western USA.2 of aid workers, increasing poverty and a lack of utilities and infrastruc-
Even local environmental change, driven by changing seasonal ture (electricity, clean water and sewage disposal facilities). Displaced
weather, can dramatically increase the populations of disease vectors. residents are often weakened as a result of a suspension of their food
In addition to floods, droughts can also cause vector populations supply and healthcare. A lack of access to clean water and disruption
to increase, while also causing food shortages and weakening the in sanitation can increase the chance that, if a pathogen is introduced,
resistance of the local population to disease, particularly in low- it will spread quickly and cause an outbreak. A recent example of such
and middle-income countries. In some cases, drought will reduce an outbreak associated with a natural disaster occurred in 2010, after
the natural predators of rodents, such as owls and hawks, which nor- an earthquake in Haiti. A visitor sponsored by the UN introduced
mally keep rodent populations in check. Even smaller-scale droughts cholera, and it spread quickly across Haiti.87
Approximate geographic distribution of West Nile virus in the Americas, from 1999 to September 2004
2004
1999
2000
2003 2002
2001
2002
2002
Figure 4-4 Approximate geographic distribution of West Nile virus in the Americas, from 1999 to September 2004. Placement of solid lines are based upon serologic
data from dead birds, while the dashed lines are based upon serologic studies of birds and horses. (From Mackenzie JS, Gubler DJ, Petersen LR. Emerging flaviviruses:
the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat Med 2004;10(12 Suppl):S98-109.)
Finally, infectious diseases often have seasonal periodicity; some electronic mail service, ProMED-mail.95 It was the ProMED-mail list-
infections peak during the summer and some during the winter. Many serv which helped provide an alert from a member of the listserv to the
of these diseases are driven by changes in weather, specifically humid- international medical community, regarding the existence of the
ity and temperature.88 Vector-borne diseases usually peak in the disease that would later be identified as SARS. New generations of
summer: particularly mosquito-borne infections in temperate climatic disease-surveillance Web applications, such as Health-Map, EpiSPI-
zones, such as West Nile, St Louis and La Crosse encephalitis, and also DER and BioCaster, combine data from different sources to produce a
tick-borne infections. Other infections that peak in the summer are global view of emerging infectious disease threats as they occur.92,96
skin and soft tissue infections89 and also legionellosis.90 In contrast, These programs mine, filter, aggregate and visualize information about
most viral respiratory diseases peak in the winter months, such as outbreaks in near-real time. Furthermore, new approaches to disease
influenza and respiratory syncytial virus (RSV). In addition, gastroin- surveillance use data harvested from the Internet and social media
testinal viral infections spike during winter months.88 Global climate sources;97,98 these approaches may help supplement traditional forms of
changes may make these seasonal patterns more pronounced and disease surveillance. Finally, the near ubiquity of cell phones around the
result in an associated increase in morbidity and mortality. world may provide a new platform, both to understand how diseases
are spread and also to help coordinate disease control activities.93,99
Detecting Emerging Pathogens
and Outbreaks Conclusion
Although new technologies have provided additional opportunities for Despite the optimism that infectious diseases would be of mostly his-
infectious diseases to emerge and re-emerge, technological advances torical interest, it appears much more likely that emerging and
over this same time period have provided new approaches to identify re-emerging infections will continue to be a part of our future. As the
novel pathogens, detect disease activity and coordinate disease control. historian William H. McNeill wrote in the 1970s, not long after some
For example, diagnostic tests have improved dramatically, allowing us had started to de-emphasize the future importance of infectious dis-
to detect previously unknown pathogens. While it took approximately eases, ‘Ingenuity, knowledge, and organization alter but cannot cancel
2 years to identify the virus that caused acquired immune deficiency humanity’s vulnerability to invasion by parasitic forms of life. Infec-
syndrome (AIDS), the virus responsible for SARS was identified in tious disease which antedated the emergence of humankind will last
approximately 2 weeks. In addition, linking data from different labo- as long as humanity itself, and will surely remain, as it has been hith-
ratories over large geographic distances has dramatically changed the erto, one of the fundamental parameters and determinants of human
way potential food-related outbreaks are detected and traced. For history.’13 Just 10 years after SARS emerged, a new coronavirus also
example, PulseNet USA is a molecular surveillance network that has associated with a respiratory infection in humans, MERS-CoV has
been of assistance in numerous food-borne outbreaks91 and similar appeared.100 While the ultimate impact of this new infection is not
networks exist or are under development in countries around the clear, given that 335 emerging infectious disease-related events
world. New molecular diagnostic platforms, coupled with increased occurred between 1940 and 2004 alone,19 it is most likely that new
surveillance efforts to detect new pathogens in both animals and infections will emerge and that old ones will continue to re-emerge
humans, will continue to improve the ability to identify new pathogens and spread. The Ebola outbreak that began in 2013 in Guinea and
more quickly.92 In addition, the promise of point-of-care testing may spread to other Western African countries in 2014 highlights many
dramatically reduce the time it takes to rule in or rule out specific important drivers of emerging infectious diseases discussed in this
pathogens in the field, without sending specimens to reference labo- chapter.
ratories.93 In 2014 this Ebola outbreak became the largest and most geo-
In response to the threat of emerging infectious diseases, many graphically diverse outbreak to date. Changes in land use and defores-
international cooperative efforts were initiated to build networks to tation increased the probability of spread to humans.101 Extreme
enhance surveillance activities. An example is the World Health Orga- poverty and lack of public health infrastructure, in part due to years
nization’s Global Outbreak Alert and Response Network, which unites of civil conflict and lack of development, facilitated the spread of the
several distinct networks to gather information about diseases in real- disease. Locally relevant cultural issues, such as burial practices con-
time, in order to detect and verify outbreaks around the world.94 Other tributed to intra-family and community spread. In addition, the
transnational networks focus on specific disease threats. For example, disease was introduced to more urban environments where crowding
the European Centre for Disease Prevention and Control’s VBORNTE and poverty further helped spread the disease.101 As travel-related cases
is a network of public health and medical entomologists, which outside of Africa show, human mobility is important in spreading
is dedicated to arthropod vector surveillance within the European infectious disease. Finally, the global public health response to the
Union.33 emerging Ebola crisis was slow and initially ineffectual. Despite a better
Since the 1990s, public health professionals have made several understanding of the drivers of emerging infections, they will continue
attempts to develop international surveillance networks to provide to emerge until we can address the root causes.
health alerts regarding infectious diseases around the world. One
such program, which is not part of any governmental agency, is the References available online at expertconsult.com.
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5
Mathematical Models in Infectious
Disease Epidemiology
PETER J. WHITE
KEY CONCEPTS vaccination policy,8 and planning for and responding to pandemic
influenza,9–11 and bioterrorism,12 planning of intervention trials,13,14
• Mathematical modeling of infectious diseases has a long evaluation of intervention policy (since evaluation of interventions at
history, and is increasingly used to understand transmission close to full-scale is usually impossible),14,15 as well as improving
patterns, better understand natural history, plan studies and understanding of disease natural history, and examining general prin-
public health interventions, evaluate interventions, and plan for
ciples of disease control.16
and respond to outbreaks and epidemics.
Infectious disease epidemiology is inherently multidisciplinary
• Modeling is required to account for the ‘natural dynamics’ because the transmission of infection within a population is affected
arising from the transmission process: the incidence of infection not just by the biologic characteristics of the infectious agent and its
(the rate of new infections arising) depends upon the preva- host, but also by the patterns of contact between hosts (and vectors,
lence (the proportion of the population that is infectious), and where relevant), the environment and, for humans, their use of health
the prevalence depends upon the incidence – there are
services and response to public health interventions, etc. Mathematical
dynamic feedback interactions between population-level prev-
alence of infection and individual-level risk. models are used to characterize the complex interactions between these
factors and to enable information from diverse sources, including
• Population-level transmission-dynamic effects can be benefi- social sciences, to be integrated.
cial: it is not necessary to vaccinate everyone in the population Importantly, models should not be ‘black boxes’, but should be
to prevent an epidemic: if vaccination coverage is sufficiently- clearly described so that non-modelers are able to assess the validity
high then ‘herd immunity’ prevents epidemics occurring, which
of the model and its use of data. Modeling is the process of formalizing
protects those who are not vaccinated.
one’s conception of a system, and the exercise should increase clarity;
• Population-level transmission-dynamic effects can be harmful: nevertheless, infectious disease transmission dynamics are typically
reducing rates of transmission through vaccination can produce inherently complex.
a net increase in disease due to an increase in the average
age at infection unless mitigating action is planned and
implemented.
Dynamics of Infectious Disease
• Multiple interacting factors affect infection-transmission pat-
Transmission
terns, so modeling requires many sources of data, and the The defining characteristic of infectious diseases – that they are trans-
input of professionals from multiple disciplines. missible – means that an individual’s risk of acquiring infection
changes dynamically as levels of infection rise and fall in the
• Economic analysis of infectious disease interventions needs
population.
transmission-dynamic modeling to account for infections
averted, which can be the major health benefit, and can result The fundamental measures in epidemiology are the incidence and
in net cost savings. prevalence. Incidence is the per-capita rate of new cases arising per unit
time, and is usually expressed as x% of the population affected per year
• There is no one ‘correct’ transmission-dynamic model for a or x cases per 1000 per year or x cases per 100 000 per year. Prevalence
disease: different types of models are appropriate for the same is the proportion of the population (usually expressed as a percentage
disease, depending upon the available data, the question
or number per 1000 or per 100 000) that are cases at a point in time.
being addressed, the time-frame of the work and other factors.
For both infectious and noninfectious diseases, prevalence is related to
incidence, since newly arising incident cases become prevalent cases.
For infectious diseases, however, incidence is also related to preva-
The first mathematical model of infectious disease transmission was lence, since it is from prevalent cases that transmission occurs, giving
constructed by Bernoulli in 17601 to determine the impact of variola- rise to incident cases.
tion, a crude form of smallpox vaccination, on life-tables used for The greater the prevalence of infectious individuals the more fre-
actuarial purposes. quently (on average) a person who is susceptible to infection will
Models are tools used throughout science and medicine – they are encounter an infectious individual, providing an opportunity for
used to interpret results, formulate hypotheses and devise experiments transmission to occur.
to test them, derive diagnoses from observed signs and symptoms and Therefore, there is a dynamic feedback process in which incidence
test results, and guide decision-making. Formulating models mathe- depends upon prevalence and prevalence depends upon incidence.
matically facilitates rigorous analysis and allows quantitative predic- This leads to infectious disease epidemics having ‘natural dynamics’,
tions to be made of trends in disease burden and the impact of with incidence typically rising to a peak then declining, in the absence
interventions. of any intervention.
Mathematical models of infectious disease transmission are increas-
ingly being used to guide public health policy. Examples include the A TYPICAL EPIDEMIC
control of an epidemic of foot-and-mouth disease in the UK in 2001,2 In a typical epidemic, without any intervention, prevalence rises
the outbreaks of severe acute respiratory syndrome (SARS)3 and initially as infection spreads. This causes an increase in incidence,
Middle East respiratory syndrome coronavirus (MERS-CoV),4 plan- which in turn causes prevalence to increase even faster – so the epi-
ning control strategies for tuberculosis (TB), human immunodefi- demic accelerates. Consequently, the supply of susceptible individuals
ciency virus (HIV) and sexually transmitted infections (STIs),5-7 becomes depleted (by their becoming infected) and the incidence falls,
49
even though prevalence may continue to rise for a time. Eventually, circumstances it is even possible to observe incidence continue to rise
the fall in incidence leads to a fall in prevalence because infections are despite an effective intervention, due to an increase in prevalence.19
‘lost’ from the population (due to recovery, death or emigration) faster Models can evaluate interventions that have been implemented by
than they are replaced by the spreading of infection. In the longer term, allowing comparison with the ‘counterfactual’ – the modelled scenario
the infectious agent may be able to persist in the population (i.e. of what would have happened in the absence of the intervention.14,15
become endemic) if there is a high-enough rate of resupply of suscep- Crucially, quantitative analysis can determine if a putative cause for
tible individuals due to birth, immigration, recovery from infection (if an observed effect would have been strong enough to cause the effect
there is no lasting immunity) or waning of immunity (if applicable); – e.g. a modeling of the Ugandan HIV epidemic found that several
otherwise the infectious agent will go extinct locally. modes of behavior change (delaying sexual debut, reducing numbers
These population-level effects have important consequences. For of sexual partners, increasing condom use) must have occurred to
example, vaccinating individuals or treating infectious individuals explain the observed decline in prevalence. No single behavior change
benefits not only the individual patient directly but also benefits others was sufficient to account for the observed reduction.15
in the population indirectly by reducing their risk of acquiring infec- Models can help set priorities for empirical research by determining
tion through the reduction in the prevalence of infection in the popu- the importance of different ‘gaps’ in knowledge. This is done by testing
lation. (Quarantine and isolation typically benefit the population the ‘sensitivity’ of a model’s behavior to changes in the values of
more than the affected individuals.) Vaccination against pneumococ- parameters that are poorly estimated by current data to see how much
cus caused the incidence of infection with ‘vaccine’ serotypes to fall they affect predicted levels of disease or the predicted effectiveness of
in those who did not receive the vaccine because they were older different interventions. Typically, some parameters are highly influen-
than the target group for vaccination, as well as in those who were tial, so ideally would be known with high precision, whilst others are
vaccinated.17 less influential.
It is important that economic evaluation of potential interventions
takes account of infections averted, which benefits health and saves Epidemiologic Data
money by averting the need for treatment, by using mathematical
Incidence can be measured directly in longitudinal cohort studies, fol-
models.8,14
lowing a group of subjects through time, or can be calculated from a
series of cross-sectional prevalence surveys.20 Case notifications from
Insights from Transmission-Dynamic surveillance systems are often used as a proxy for incidence (but not
Modeling all infections may be detected and without laboratory confirmation
some cases might be misreported); long-term datasets are available for
Importantly, population-level effects due to infectious disease trans-
a large number of infectious agents due to mandatory (notifiable)
mission dynamics mean there is typically a complex nonlinear rela-
disease surveillance schemes. Analysis of past influenza pandemics has
tionship between the size of an intervention and the outcome.
contributed greatly to preparedness for future pandemics (www.who.int/
Typically, as the scale of an intervention (e.g. vaccination coverage
influenza/preparedness/pandemic/en/).
or provision of treatment) increases from a low level, the benefits –
Serological studies often provide valuable data, particularly when
reductions in levels of disease – accrue ‘faster’ than the costs, until
complemented by clinical investigations (e.g. see http://consise.tghn
disease has been reduced to a low level or even eliminated; further
.org/) – for example in informing on the proportion of infections that
increasing the intervention further produces a diminishing incremen-
are symptomatic, since it is typically only symptomatic infections that
tal benefit. Vaccinating just a small proportion of the population
are detected in surveillance systems.21
mostly benefits only those who receive the vaccine because it does little
to interrupt transmission. Vaccinating a large-enough proportion of
the population to achieve ‘herd immunity’ prevents epidemics, provid- Reproduction Numbers
ing a large ‘indirect’ benefit to those not vaccinated. Another example The key measure of an infectious agent’s ability to spread in a popula-
is in the control of curable infections (e.g. STIs) through treatment: if tion is the reproduction number (sometimes called the net reproduc-
treatment capacity is inadequate then there is a ‘vicious circle’ where tion number or effective reproduction number), R(t), which is the
failing to control transmission in the present results in more infections mean number of new infections caused by a typical infected individual
in the future, maintaining the inadequacy of treatment capacity.6 Con- in the population of interest.22 (Note that ‘(t)’ indicates that the value
versely, making a concerted effort to increase capacity can break this can change with time – see below.) A related quantity is the basic
vicious circle and create a virtuous circle, where promptly treating a reproduction number R0,18 which is defined as the mean number of
large-enough proportion of infections reduces transmission, reducing new infections caused by a typical infected individual in a population
the need for treatment, leading to significant cost savings.6 of wholly susceptible individuals, i.e. R0 is what the value of R(t) would
However, ‘indirect’ population-level effects can also be harmful.18 be if the population were totally-susceptible. It is important to under-
Whilst reducing levels of infection in the population through vaccina- stand that R(t) is specific to the particular infectious agent in the
tion protects those who are not vaccinated as well as those who are particular population at the particular time, and can be changed by
vaccinated by reducing the overall rate of infection, those who do still interventions. R(t) depends upon the average rate of transmission
get infected are older on average when they get infected and this can from an infectious individual and the average duration of infectious-
lead to more severe outcomes for some diseases (e.g. congenital rubella ness. An epidemic requires that R(t)>1, so that the prevalence of infec-
syndrome). Therefore, vaccination can increase the overall rate of tion increases because more than one new infection arises from the
disease – either transiently, until infection is eliminated from the popu- average infected person before that person is ‘lost’ from the infected
lation, if there is high-enough coverage – or indefinitely, if vaccine population. In the typical epidemic described above, depletion of the
coverage is persistently low.18 Mathematical models can help predict ‘supply’ of susceptible individuals causes R(t) to fall, even though R0
these effects and aid the design of strategies to mitigate them, e.g. does not change. In fact, R(t) falls even as incidence rises; the initial
ensuring sufficient vaccination coverage and identifying the at-risk age increase in incidence is driven by the increase in prevalence, with the
range. proportionate increase in prevalence being greater than the propor-
tionate reduction in transmission from the average prevalent case,
Use of Models for Analysis of caused by the reduction in the number who remain susceptible.
Public health interventions aim to reduce and maintain R(t)
Epidemics and Interventions below 1, which may be achieved by reducing the average infectious
Observing a decline in incidence following an intervention is not suf- period (e.g. through treatment or isolation) or the transmission rate
ficient evidence to demonstrate its effectiveness.15 Conversely, in some (e.g. by closing schools and workplaces to combat SARS or influenza,
Chapter 5 Mathematical Models in Infectious Disease Epidemiology 51
or promoting condom use and reductions in numbers of sexual

partners to combat STIs) or using vaccination or prophylaxis to Susceptible–Infected–Recovered (SIR) model
‘remove’ people from the susceptible population. Generally, the higher
the value of R0, the harder an infection will be to control. In a homo-
β γ
geneous population (one where everyone has the same average risk of Susceptible, X(t) Infected, Y(t)
Recovered, Z(t)
acquiring and transmitting infection) the relationship between R0 and (Immune)
R(t) is R(t) = R0×s where s is the proportion of the population that is
susceptible. To prevent an epidemic by vaccination requires that s be
Figure 5-1 Susceptible–infected–recovered (SIR) model. The population is
reduced so that R(t) <1 (i.e. that s be reduced below 1/R0), hence the notionally divided into three compartments according to whether they are Sus-
greater the value of R0 the smaller s must be. The critical vaccination ceptible to infection, Infected (and infectious) or have Recovered from infection
threshold is the proportion of the population that must be successfully and are immune. Individuals who become infected move from the Susceptible
immunized to prevent an epidemic; for childhood infections such as compartment to the Infected compartment; the process of recovery subsequently
moves them from the Infected compartment to the Recovered compartment. The
measles, which have high typical R0 values, this is typically >90% or parameters β and γ affect the rate of transmission of infection and the rate of
even >95%. recovery, respectively.
There are various ways to estimate R0 and R(t), depending upon
the available data.4,18,22,23 It is important to realize that R0 alone does
not provide complete information on the transmission dynamics of an The population can also be stratified by age, sex, co-morbidities, or
infectious agent.3,16 A highly infectious agent that spreads rapidly but other characteristics of interest.
has a short infectious period could have the same R0 as another infec- Representations of contact patterns within populations vary in the
tious agent that is much less infectious but has a longer infectious level of detail used (in part determined by the model structure), from
period – the latter would tend to spread more slowly but for longer. simple homogeneous mixing, to dividing the population into smaller
aggregate groups (e.g. age categories or geographically distinct sub-
Structure of Models of Infectious populations), to having separate households, or even having explicit
networks of contacts between discrete individuals (e.g. sexual-contact
Diseases networks). Models can also represent movement patterns, e.g. com-
All models of infectious disease transmission use a simplified repre- muting to work, or air travel within and between countries.
sentation of the key features of the natural history of the infection, and Models can be deterministic, meaning that they do not explicitly
of the patterns of contact through which transmission occurs.18,22,23 represent randomness arising from the probabilistic nature of trans-
The design of the model used is determined by the question being mission and other events, or stochastic, meaning that they do.22 Deter-
addressed, the availability of data, computing resources available, speed ministic models, which represent expected ‘average’ behavior, are more
of analysis required, and other factors – there is no ‘right’ model for a common because they are simpler and less computationally demand-
particular disease. ing to analyze, but stochastic models are more appropriate to analysis
Important characteristics of the natural history include the incuba- of outbreaks, emergence of novel strains (e.g. with antibiotic resis-
tion period (the time from the point of infection until the appearance tance), or patterns occurring in small populations because they capture
of symptoms) and the latent period (the time from infection to becom- the expected variance due to random events.
ing infectious). These vary greatly (from days to years, depending upon
the infection) and either can be longer than the other. For SARS the EXAMPLE COMPARTMENTAL MODEL
latent period is longer than the incubation period, with people becom- OF INFLUENZA
ing unwell before they become infectious; for HIV the opposite is the For a directly transmitted pathogen such as influenza, where acquired
case (ignoring brief seroconversion symptoms), but for pulmonary TB immunity (to a particular strain) is lifelong, the host population can
they can be the same, with people becoming infectious at the time they be represented by three compartments containing the number of
become unwell. Susceptible, Infected (and infectious) and Recovered (immune, non-
In modeling there is a trade-off between complexity/realism and infectious) individuals. In this example, the latent period is ignored, so
the ability to understand the model’s behavior. Since even simple individuals become infectious as soon as they become infected. This
models can have complex dynamics it is important to make the model so-called ‘Susceptible–Infected–Recovered’ (or ‘SIR’) model approach
as simple as possible, whilst still capturing the essential features of the was first developed by Kermack and McKendrick in 1927,26 elaborated
infection. For example, for genital Chlamydia trachomatis the incuba- upon by Anderson and May,18 and now forms the basis for many
tion period is often omitted from models6 because it is short relative modern-day models of epidemics.
to the infectious period – and so has little effect on the dynamics of A simple SIR-type model (see Figure 5-1), can be applied to data
infection – while HIV’s incubation period is long compared with the from an outbreak of influenza in a boarding school in England.27 Since
symptomatic late-stage period and so it is usually incorporated into the outbreak is short-lived, the population is regarded as ‘closed’: no
models.24 In the case of TB, most people with infection never develop one enters or leaves, and there was no mortality due to infection.
infectious disease (they remain latently infected) and so models dis- (Often, one has to consider immigration, emigration, birth and death
tinguish between these states.25 Modeling of HIV and of TB have – and if the infection being modeled causes mortality then Infected
been reviewed by Johnson and White7, and White and Garnett25, individuals have an additional disease-induced mortality rate to be
respectively. considered.) Additionally, there is only one age group – models of
All models of infectious disease transmission need to represent influenza in the general population typically distinguish age groups,
changes in the infection status of persons in the population, but due to differences in social contact rates, immunity due to past expo-
models vary in how they represent the population and patterns of sure to flu strains, and risk of severe illness if infected.
contact within it. Most commonly, the population is represented in Each compartment has a state variable ‘keeping track’ of the
aggregate, with the population notionally assigned to ‘compartments’ number of individuals in that compartment, which can change through
representing different infection states and the model ‘keeping track’ of time. In this case, the state variables are X(t) for the Susceptible indi-
changes over time in numbers of individuals in each of these different viduals, Y(t) for Infected individuals and Z(t) for Recovered individu-
states (see example below and Figure 5-1). However, other types of als, where ‘(t)’ indicates that the values can change with time. The total
model represent each person in the population as a discrete individual, population size is N(t), where N(t) = X(t) + Y(t) + Z(t). The model
and are able to ‘track’ each individual’s history, as well as individual- consists of a set of differential equations describing the rates that indi-
level variation in different traits – these models are typically very viduals flow between different compartments as they become infected,
computationally demanding. recover, die (not applicable here), etc. The net rate of change in X(t) is
described by the differential equation dX(t)/dt, etc. In this example, susceptible (i.e. when Y(t) = 1 and X(t) = N(t); we ignore the fact that
there are two processes: infection and recovery. really X(t) = N(t) – 1 because one person is infected, because we assume
The number of people becoming infected per day depends upon that N(t) is large) is:
the force of infection (the risk per Susceptible individual of acquiring
β X (t )Y (t ) β N (t ) ⋅1
infection per day) and the number of Susceptible individuals available = =β
to become infected, X(t). The force of infection depends upon the N (t ) N (t )
prevalence of infection, Y(t)/N(t), and the transmission parameter, β, The average infectious period is the reciprocal of the average recovery
which is a combination of the rate of contact between people in the rate (the faster people recover, the shorter their infectious period), i.e.
population and the probability of transmission upon contact between 1/γ. Therefore R0 = β/γ. The estimated values from fitting to data were
an Infected person and a Susceptible person. Therefore, the force of β = 1.97day−1, γ = 0.47day−1 (corresponding to a mean infectious period
infection is βY(t)/N(t) and the transmission rate is X(t)βY(t)/N(t), of 2.12 days), so R0 = 1.97day−1/0.47day−1 = 4.18.
which is conventionally written as β X(t)Y(t)/N(t). Since infection
transfers people from the Susceptible compartment (X(t)) to the
Infected compartment (Y(t)), the term β X(t)Y(t)/N(t) appears nega- Emergency Preparedness and
tively in dX(t)/dt and positively in dY(t)/dt. (Note that the transmis-
sion parameter, β, does not change with time; changes in the daily Response
infection rate are due to changes in Y(t)/N(t) and X(t).) The huge growth in international travel and in population densities in
The number of people recovering per day depends upon the per- many cities offers new challenges in controlling the spread of newly
capita rate of recovery, γ, and the number of people who are Infected, emerging infections. Infectious disease transmission dynamic model-
Y(t), and is γ Y(t). Since recovery transfers people from the Infected ing is now widely used for emergency preparedness and response.
compartment (Y(t)) to the Recovered compartment (Z(t)), the term γ SARS, MERS-CoV and pandemic influenza are used as examples.
Y(t) appears negatively in dY(t)/dt and positively in dZ(t)/dt. (Note
that the per-capita rate of recovery, γ, does not change with time; PANDEMIC INFLUENZA
changes in the daily recovery rate are due to changes in Y(t).) Retrospective modeling, particularly of pandemic influenza, has been
The equations of the model are: used to better understand the behavior of epidemics and the effective-
ness of interventions to inform scenario modeling for planning
dX (t ) − β X (t )Y (t )
= responses to epidemics of novel pathogens, with different characteris-
dt N (t ) tics, and to determine the appropriate size of antiviral stockpiles, and
dY (t ) β X (t )Y (t ) capacity of intensive care facilities.9,10
= − γ Y (t ) In real-time during an epidemic, modeling is used for purposes
dt N (t ) such as:21
dZ (t ) 1. Estimation of severity at the individual level, including what
= γ Y (t ) proportion of infections will be symptomatic cases, and what
dt
proportions of those will be medically attended, hospitalized,
N (t ) = X (t ) + Y (t ) + Z (t ) admitted to intensive care, and what proportion will die.
This model is deterministic, i.e. random (stochastic) events are not These proportions are typically age-dependent, and affected by
considered. This is a common simplification that makes it much easier co-morbidities.
to gain insight into the fundamental dynamics of transmission because 2. Estimation of the expected ultimate size of the epidemic and its
the effects of random chance, which cause fluctuations in the graph, trajectory, based on the initial growth rate and accumulating
are omitted. This model was fitted to data from an outbreak of influ- surveillance data.3,11,28 (Although R0 varies amongst populations,
enza in a boarding school in England27 (Figure 5-2) to estimate values similarities between populations mean that early estimates from
of β and γ. one location can be informative for others.)
R0 is the mathematical product of the transmission rate from a 3. Estimation of the likely impact of different intervention options,
single infected individual in a wholly susceptible population and the and evaluation of interventions that are being implemented.
average infectious period. The algebraic expression for R0 depends
upon the particular model. For this model, the rate of transmission
SEVERE ACUTE RESPIRATORY
from a single infected individual when the population is wholly SYNDROME (SARS)
SARS is caused by a coronavirus (SARS-CoV) normally found in wild
animals such as the palm civet cat and Chinese ferret badger.3,29 Early
cases are thought to have involved zoonotic infection, with subsequent
Example output of Susceptible–Infected–Recovered (SIR) model genetic changes enabling greater human-to-human transmission,
which accounted for the vast majority of cases in the global pandemic
of 2002/3. SARS spread quickly from China to other parts of Asia,
Number 800
Europe, the Americas and elsewhere, infecting >8000 individuals in 29
in each
compartment 600 countries and killing at least 774 people. Transmission was linked to
N(t) close contact with cases, mostly in hospital, affecting healthcare
X(t) workers or patients.3,30
400 Y(t) Models of SARS transmission provided estimates of the key epide-
Z(t) miological parameters and showed how spreading was controlled by
200 Data effective intervention. Reproduction number estimates from before the
WHO global alert, for Hong Kong, Vietnam, Singapore and Canada,
0 respectively, were 3.6, 2.4, 3.1 and 2.7, and after were 0.7, 0.3, 0.7 and
0 5 10 15 1.31 The reduction in the reproductive number in each country reflects
Time (days) the effectiveness of control measures such as quarantine and travel
restrictions in curbing the epidemic.
Figure 5-2 Example output of a Susceptible–Infected–Recovered (SIR) model
Estimating the case-fatality ratio (CFR) of newly emerged patho-
applied to data from an outbreak of influenza. Model parameters were adjusted gens is difficult as defining true cases can be problematic.32 The CFR
to fit the number of Infected individuals, Y(t), to the observed data. may be overestimated if many subclinical infections go uncounted.
Chapter 5 Mathematical Models in Infectious Disease Epidemiology 53
Alternatively, in epidemics where patients are hospitalized for lengthy Future Research
periods before recovering or dying, a naïve real-time CFR estimate,
dividing number of deaths by numbers of cases, will initially underes- There is increasing integration between infectious disease modeling
timate CFR, as patients will be recorded as cases before their outcome and empiric research in the field and laboratory. Models can be used
is known, and then the CFR will apparently rise over time as deaths to help set research priorities by determining which gaps in knowledge
occur and are recorded; in the 2003 SARS epidemic this apparently are most important epidemiologically, and help in the design of trials.13
increasing CFR was wrongly interpreted as indicating an increase in Increases in computing power make it possible to develop increasingly
virulence.3 sophisticated simulation models and to use them in real-time to
Mathematical modeling identifies some key properties that enabled analyze outbreaks to determine whether interventions are working and
SARS to be contained effectively, in contrast to influenza. The genera- to guide policymakers in their response. DNA fingerprinting and now
tion time for influenza (4–6 days) is much shorter than for SARS (8–12 whole-genome sequencing are being used to identify ‘transmission
days),3,16 meaning influenza will spread much quicker. Furthermore, clusters’ of individuals4,33 and the developing field of ‘phylodynamics’34
SARS transmission occurs after the patient becomes symptomatic16 – synthesizes evolution and transmission dynamics. Another area of
making it feasible to use isolation to reduce transmission – whilst research is characterizing contact patterns between individuals in
influenza can be transmitted in the absence of symptoms. more detail35 since this has important consequences for patterns of
transmission.
MIDDLE EAST RESPIRATORY SYNDROME
CORONAVIRUS (MERS-CoV) ACKNOWLEDGMENT
MERS-CoV was first detected in 2012, having apparently arisen from The first version of this chapter, published in the previous edition of
an animal reservoir. To date there has been limited human-to-human this book, was written with Professor Mark Enright.
transmission; modeling4 suggests that medical intervention reduces
transmission and that currently R(t) is most likely <1, although prior References available online at expertconsult.com.
to medical intervention R(t) might be >1, suggesting that the virus
might have pandemic potential if human cases are not detected
efficiently.
KEY REFERENCES
Anderson R.M., May R.M.: Infectious diseases of humans: Fraser C., Riley S., Anderson R.M., et al.: Factors that make full scale implementation. Sex Transm Infect 2007;
dynamics and control. Oxford: Oxford Science Publica- an infectious disease outbreak controllable. Proc Natl 83(Suppl.I):i55-i60.
tions; 1991. Acad Sci USA 2004; 101(16):6146-6151. Mossong J., Hens N., Jit M., et al.: Social contacts and
Brisson M., Edmunds W.J.: Economic evaluation of vacci- Garnett G.P.: Theory is critical in understanding the risks mixing patterns relevant to the spread of infectious dis-
nation programs: the impact of herd-immunity. Med of acquiring HIV. Sex Transm Dis 2007; 34(10):737-738. eases. PLoS Med 2008; 5(3):e74.
Decis Making 2003; 23(1):76-82. Garnett G.P., Cousens S., Hallett T.B., et al.: Mathematical Van Kerkhove M.D., Asikainen T., Becker N., et al.: (The
Donnelly C.A., Fisher M.C., Fraser C., et al.: Epidemiologi- models in the evaluation of health programmes. Lancet WHO Informal Network for Mathematical Modelling for
cal and genetic analysis of severe acute respiratory syn- 2011; 378(9790):515-525. Pandemic Influenza H1N1 2009 [Working Group on
drome. Lancet Infect Dis 2004; 4(11):672-683. Grassly N.C., Fraser C.: Mathematical models of infectious Data Needs]). Studies needed to address public health
Ferguson N.M., Cummings D.A., Fraser C., et al.: Strategies disease transmission. Nat Rev Microbiol 2008; 6:477- challenges of the 2009 H1N1 influenza pandemic:
for mitigating an influenza pandemic. Nature 2006; 487. insights from modeling. PLoS Med 2010; 7(6):e1000275.
442(7101):448-452. Grenfell B.T., Pybus O.G., Gog J.R., et al.: Unifying the epi-
Fraser C., Donnelly C.A., Cauchemez S., et al.: (WHO Rapid demiological and evolutionary dynamics of pathogens.
Pandemic Assessment Collaboration): Pandemic poten- Science 2004; 303(5656):327-332.
tial of a strain of influenza A (H1N1): early findings. Hallett T.B., White P.J., Garnett G.P.: Appropriate evaluation
Science 2009; 324(5934):1557-1561. of HIV prevention interventions: from experiment to
Chapter 5 Mathematical Models in Infectious Disease Epidemiology 53.e1
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1. Bernoulli D.: Essai d’une nouvelle analyse de la mor- cians and epidemiologists. Clin Infect Dis 2003; 23. Keeling M., Rohani P.: Modeling infectious diseases in
talité causée par la petite vérole et des advantages de 36(11):1458-1473. humans and animals. Princeton, NJ: Princeton Univer-
l’inoculation pour la préventir. Mém Math Phys Acad 13. Boily M.C., Abu-Raddad L., Desai K., et al.: Measuring sity Press; 2007.
Roy Sci Paris 1760; 1-45. the public-health impact of candidate HIV vaccines as 24. Garnett G.P.: Theory is critical in understanding the
2. Ferguson N.M., Donnelly C.A., Anderson R.M.: Trans- part of the licensing process. Lancet Infect Dis 2008; risks of acquiring HIV. Sex Transm Dis 2007; 34(10):737-
mission intensity and impact of control policies on the 8(3):200-207. 738.
foot and mouth epidemic in Great Britain. Nature 2001; 14. Garnett G.P., Cousens S., Hallett T.B., et al.: Mathemat- 25. White P.J., Garnett G.P.: Mathematical modeling of the
413(6855):542-548. ical models in the evaluation of health programmes. epidemiology of tuberculosis: modeling parasite transmis-
3. Donnelly C.A., Fisher M.C., Fraser C., et al.: Epidemio- Lancet 2011; 378(9790):515-525. sion and control. Austin, TX: Bioscience/Eurekah;
logical and genetic analysis of severe acute respiratory 15. Hallett T.B., White P.J., Garnett G.P.: Appropriate 2009.
syndrome. Lancet Infect Dis 2004; 4(11):672-683. evaluation of HIV prevention interventions: from 26. Kermack W.O., McKendrick A.G.: A contribution to the
4. Cauchemez S., Fraser C., Van Kerkhove M.D., et al.: experiment to full scale implementation. Sex Transm mathematical theory of epidemics. Proc R Soc Lond
Middle East respiratory syndrome coronavirus: quanti- Infect 2007; 83(Suppl. I):i55-i60. Series A 1927; 115(772):700-721.
fication of the extent of the epidemic, surveillance 16. Fraser C., Riley S., Anderson R.M., et al.: Factors 27. Anonymous: Influenza in a boarding school. Br Med J
biases, and transmissibility. Lancet Infect Dis 2014; that make an infectious disease outbreak controllable. 1978; 1:587.
14(1):50-56. Proc Natl Acad Sci USA 2004; 101(16):6146- 28. Fraser C., Donnelly C.A., Cauchemez S., et al.: (WHO
5. Dye C., Bassili A., Bierrenbach A.L., et al.: Measuring 6151. Rapid Pandemic Assessment Collaboration): Pandemic
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6. White P.J., Ward H., Cassell J.A., et al.: Vicious and vir- older adults in the era of pediatric pneumococcal con- 29. World Health Organization: The WHO response to the
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8. Brisson M., Edmunds W.J.: Economic evaluation of in the UK? An example of analysing patterns of HIV severe acute respiratory syndrome reveal similar
vaccination programs: the impact of herd-immunity. spreading using incidence-to-prevalence ratios. AIDS impacts of control measures. Am J Epidemiol 2004;
Med Decis Making 2003; 23(1):76-82. 2006; 20(14):1898-1901. 160(6):509-516.
9. Ferguson N.M., Cummings D.A., Fraser C., et al.: Strat- 20. Hallett T.B., Zaba B., Todd J., et al.: Estimating inci- 32. Garske T., Legrand J., Donnelly C.A., et al.: Assessing
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2006; 442(7101):448-452. methods and validation. PLoS Med 2008; 5(4):e80. Br Med J 2009; 339:b2840.
10. Halloran M.E., Ferguson N.M., Eubank S., et al.: Mod- 21. Van Kerkhove M.D., Asikainen T., Becker N., et al.: (The 33. Choudhury B., Risley C.L., Ghani A.C., et al.: Identifica-
eling targeted layered containment of an influenza pan- WHO Informal Network for Mathematical Modelling tion of individuals with gonorrhoea within sexual
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2008; 105(12):4639-4644. on Data Needs]). Studies needed to address public 368(9530):139-146.
11. Birrell P.J., Ketsetzis G., Gay N.J., et al.: Bayesian mod- health challenges of the 2009 H1N1 influenza pan- 34. Grenfell B.T., Pybus O.G., Gog J.R., et al.: Unifying the
elling to unmask and predict the influenza A/H1N1pdm demic: insights from modeling. PLoS Med 2010; epidemiological and evolutionary dynamics of patho-
dynamics in London. Proc Natl Acad Sci USA 2011; 7(6):e1000275. gens. Science 2004; 303(5656):327-332.
108(45):18238-18243. 22. Grassly N.C., Fraser C.: Mathematical models of infec- 35. Mossong J., Hens N., Jit M., et al.: Social contacts and
12. Ferguson N.E., Steele L., Crawford C.Y., et al.: Bioter- tious disease transmission. Nat Rev Microbiol 2008; mixing patterns relevant to the spread of infectious dis-
rorism web site resources for infectious disease clini- 6:477-487. eases. PLoS Med 2008; 5(3):e74.
6
Infection Prevention and Control, and
Antimicrobial Stewardship
RANDY A. TAPLITZ | MICHELE L. RITTER | FRANCESCA J. TORRIANI
KEY CONCEPTS direct medical costs to US hospitals of all HAIs among hospital patients
was between 28.4 and 45 billion dollars.
• Infection prevention and control is a discipline in which epide- In addition to the challenges posed by the numbers of HAIs, the
miologic and statistical principles are used to prevent both complexity and the measures required to prevent and track HAIs have
healthcare-associated infections and transmission of infections also increased. Such challenges include:
to patients and healthcare workers.
• controlling antimicrobial resistance and spread of multidrug-
• Healthcare infection surveillance should be a systematic, resistant pathogens;
ongoing risk-stratified process to monitor identifiable events • addressing emerging infections such as severe acute respiratory
(such as surgical site infections) in a defined population. syndrome (SARS), Ebola, novel influenza viruses;
• The process and outcome data generated by hospital epide- • providing constantly updated data for an increasingly sophisti-
miology and other practitioners is relevant to patient safety and cated public, including public reporting;
quality of care at the level of the institution, across institutions • attempting to modernize surveillance and reporting systems,
and extending to credentialing and governmental regulatory often with limited resources available;
boards such as the Joint Commission. • addressing the infectious consequences of ever-more compli-
cated medical procedures, with special populations such as
• One of the most critical functions of the Infection Prevention
Program is to provide education and training for healthcare highly immunosuppressed transplant patients, gene therapy,
providers, including instruction on isolation precautions, aseptic xenotransplantation;
techniques and sterile practices, prevention of blood and body • maintaining a safe workplace in an ever-more complex medical
fluid exposures, and appropriate usage of personal protective system.
equipment and safety devices.
• The goals of an effective antimicrobial stewardship program Organization of Infection Prevention
(ASP) include optimizing clinical outcomes while minimizing and Control
toxicity associated with antimicrobial use and the emergence
of resistance, resulting in a reduction of healthcare costs while Infection prevention and control is a discipline in which epidemiologic
maintaining or improving quality of care. and statistical principles are used in order to prevent or control the
incidence and prevalence of infections. The primary role of an infec-
tion prevention and control program (IPCP) is to reduce the risk of
acquisition of HAI. To ensure the success of an infection control
Introduction program, the appropriate infrastructure and institutional support,
both material and administrative, need to be made available to health-
The concept of infection prevention and control has its roots in the
care epidemiology staff.
pre-germ theory era, when in 1846 Semmelweis introduced hand
The critical functions that often fall under the umbrella of a health-
hygiene with chlorinated lye to physicians, and noted a reduction in
care epidemiology program are listed in Box 6-1.2,7
puerperal sepsis.1 In the USA the hospital discipline of infection
control was established in the 1950s in response to a nationwide epi- MANAGE CRITICAL DATA AND INFORMATION
demic of nosocomial Staphylococcus aureus and the recognition of the
need for nosocomial infection surveillance.2 Since that time, the disci- Develop, Implement and Monitor Surveillance
pline has expanded dramatically, becoming an integral and critical part Based upon an Institution-Specific Risk Assessment
of promoting a safe environment in the healthcare setting. The importance of surveillance and feedback to the clinical users as a
part of hospital infection control programs was established by the 1976
Trends and Complexity of Current Study on the Efficacy of Nosocomial Infection Control (SENIC).
SENIC found that hospitals reduced their nosocomial infection rates
Healthcare in Higher-Income Countries by about 32% if their surveillance and control plan included the fol-
Healthcare-associated infections (HAIs) are a significant cause of mor- lowing components: appropriate emphasis on surveillance activities
bidity and mortality in higher-income countries. It is estimated that and control efforts; appropriate staffing of the infection control
between 4% and 10% of patients admitted to acute care hospitals program; and, for surgical site infections, feedback of wound infection
acquire one or more infections.3,4 Based on a 2011 point prevalence rates to practicing surgeons.8
survey of acute care facilities in the USA, the most common HAIs were Healthcare infection surveillance should be a systematic, ongoing
hospital-acquired pneumonia (HAP) at 21.8%, surgical site infections process to monitor identifiable events (such as surgical site infections)
(SSI) at 21.8%, and Clostridium difficile infections (CDI) at 12.1%. in a defined population. This will initially require a risk stratification
Device-associated infections, i.e. central line-associated bloodstream to determine what the critical targets of surveillance should be. In the
infections (CLABSI), catheter-associated urinary tract infections USA and other higher-income countries, many surveillance activities
(CAUTI) and ventilator-associated pneumonia (VAP) accounted for will be mandated by local or federal authorities and other licensing and
25.6% of HAIs.5 regulatory bodies. Other surveillance activities will vary, based on an
HAIs also result in excess mortality, length of stay (LOS) and understanding of the epidemiology and risk at a particular institution.
increased costs.5,6 In 2007, it was estimated that the overall annual For instance, surveillance for invasive aspergillosis in an institution
54
Chapter 6 Infection Prevention and Control, and Antimicrobial Stewardship 55
5. Appropriate benchmarking should be sought. Increasingly,

BOX 6-1 CRITICAL FUNCTIONS OFTEN MANAGED healthcare systems are being compared and inferences on quality
BY HOSPITAL EPIDEMIOLOGY of care are being made, sometimes with suboptimal risk
• Managing critical data and information adjustment.
• Monitoring and reporting of surveillance results/infection rates to 6. Appropriate risk stratification is essential to identify and priori-
clinical services, administration and regulatory bodies tize which areas should be targeted for performance improve-
• Developing, implementing and monitoring surveillance based upon ment within a given institution. However, differences in hospital
an institution-specific risk assessment
• Developing and implementing policies and procedures to prevent or size, patient mix and risk adjustment introduce complexity
minimize infection risk (e.g. isolation precaution policies, etc.) when comparing rates between smaller community hospitals
• Intervening to prevent disease transmission and tertiary care/specialty hospitals. In 2009, NHSN transi-
• Outbreak investigation and control tioned from reporting rates of HAIs to the standardized infec-
• Education and training
• Collaborating with other programs to achieve common goals tion ratio (SIR).14 The SIR is the ratio of expected over observed
• Occupational and employee health events for a particular HAI. Expected events are based on NHSN
• Post-exposure prophylaxis in the healthcare setting national data collected in the previous years and risk adjusted
• Management of the infected healthcare worker using multivariate regression analysis. Both SIR and rates are
• Environmental health and safety
• Construction infection control currently being used to compare similar healthcare facilities at
• Infectious waste management the state and national level.15
• Environmental cleaning service 7. Reports describing the surveillance activities and findings should
• Air and water handling be prepared (using appropriate statistical analysis) and distrib-
• Respiratory protection
• Disinfection and sterilization uted to the appropriate groups.
• Microbiology laboratory 8. After feedback to the particular service is provided, that service
• Monitoring for isolation of sentinel organisms (generally in conjunction with the IPCP) should develop an
• Monitoring antibiotic resistance profiles action plan for process improvement with measurable outcome
• Pharmacy and therapeutics
• Antimicrobial utilization metrics.
• Safety, quality and public reporting
• Disaster preparedness committee DEVELOP AND IMPLEMENT POLICIES AND
• Bioterrorism preparedness PROCEDURES TO PREVENT OR MINIMIZE
INFECTION RISK
Another critical role for the infection control unit within a healthcare
undergoing new construction and with a large compromised host facility is to develop and implement evidence-based policies and pro-
population might be rated a higher priority than the long-term moni- cedures, such as isolation precaution policies, that are aimed at pre-
toring of Legionella in an institution where Legionella has not been venting HAIs. In general, these policies will be adapted to institutional
identified for years. Each hospital must tailor its surveillance activities needs using resources available from the following:
based on risk assessment of the population as well as the available • relevant published literature
resources within the infection control team and healthcare entity. • professional society guidelines
Such ‘targeted’ surveillance should be defined for each healthcare • professional practice guidelines
environment.9 • state and federal regulatory bodies
A number of components are critical for an effective surveillance • governmental and regulatory agencies.
system. Institutional policies and procedures should be regularly reviewed
1. Clear and uniform definitions of the outcome variables should and updated, and easily accessible to users.
be developed. In the USA, standardized definitions and method
ologies developed by Centers for Disease Control (CDC)/ INTERVENE TO PREVENT DISEASE
National Health and Safety Network (NHSN) have been widely TRANSMISSION
adopted so that comparisons can be made both within the health Outbreak Investigation and Control
system and across institutions.10,11 An outbreak can be defined as an increase in the incidence of a disease/
2. Surveillance should be an active process that includes review of infection above the background rate in a given population. In a health-
microbiologic data, clinical and nursing records, pharmacologic care setting, the ‘background’ rate may be provided by ongoing surveil-
and pathologic data, readmission and reoperation data follow- lance activities as described above. In the healthcare setting, prompt
ing surgery for selected procedures, etc. Automated surveillance identification of an outbreak and intervention on the part of the IPCP
systems utilizing computer-based patient records or other elec- is critical in preventing adverse outcomes and accruing costs. The basic
tronic data may provide a sensitive, specific, time-efficient and components of outbreak investigation are followed, as outlined in Box
cost-effective mechanism in many institutions.12,13 The surveil- 6-2.16 An example would be as follows:
lance methodology should rely on metrics that are objective,
standardized and incorporate meaningful risk adjustment. Hospital X performs a large number of hip joint replacements, and
3. Case adjudication by the practitioners of the procedural area this is a procedure monitored by the IPCP (Figure 6-1).
under evaluation should be avoided; in this setting the process Standardized NHSN criteria are used to define surgical SSIs for hip
may be prone to bias and lose objectivity, especially if financial prosthesis. Hospital X’s surveillance for hip prosthesis involves review
incentives are involved. On the other hand, periodic review of of all microbiology data for all hip replacements done at the
the case definitions and feedback on the surveillance by members institution plus readmission data after hip replacement, as well as
of the practice team may provide insights that can result in cor- antibiotic utilization data for patients with hip replacement. Charts
rective quality improvement actions adapted to that specific are then reviewed to evaluate if a hip infection occurred and at
practice. what level (superficial, deep or organ/space, by NHSN criteria).
4. Whatever the system of surveillance is, both numerator and It is noted that in the third quarter, compared with the previous
denominator data must be available for review. For instance, quarter, there was an increase in the number of hip infections with
central line-associated bloodstream infections (CLABSI) are a standardized infection ratio (SIR) of 4.0. Charts are reviewed to
expressed as number of CLABSI/number of central line days × confirm, and an epidemic curve is generated, suggesting that the
1000. Thus, trends can be tracked and compared within and increase in infection started in mid July. This information is
between institutions. reported back to Orthopedics as well as the Administrative hospital
leadership. Patient data review indicates that the infections are with
BOX 6-2 STEPS IN THE INVESTIGATION AND multiple different organisms, with procedures performed with
CONTROL OF A POTENTIAL OUTBREAK multiple different surgeries in different operating rooms (ORs).
1. Establish case definition(s). It is noted by one of the healthcare workers interviewed that a new
2. Confirm that the cases are ‘real’ (case confirmation). surgical scrub was put into place in late June in the orthopedic ORs,
3. Establish the background rate of disease (in order to confirm and the concern is raised that this may be associated with the
the outbreak and determine the scope of the outbreak increase in infections. A review reveals that the new scrub is not
geographically and temporally). being used per recommendations. A plan to develop and implement
4. Case finding.
an educational module regarding surgical scrub is enacted, and by
5. Examine the descriptive epidemiology of the cases (e.g.
define the age, sex, home/overseas travel, occupation, September the SIR for hip infections has decreased to 1.8.
attendance at events) and plot an ‘epidemic curve’ of time
of onset of disease. The Role of the Microbiology Laboratory
6. Generate a hypothesis regarding the source and route of The microbiology laboratory plays a critical role in both surveillance
exposure. and outbreak investigations. Rapid detection and reporting of key
7. Test the hypothesis by case control, cohort or intervention organisms with high potential to cause outbreaks such as C. difficile or
studies and by epidemiologic typing of representative Mycobacterium tuberculosis are critical components of infection pre-
samples if indicated and if possible.
vention, leading to appropriate implementation of control measures
8. Collect and test potential sources of infection such as envi-
ronmental surfaces, patients, personnel, iv fluids, etc. as and reducing the risk of secondary spread.17
indicated; consider epidemiologic typing to establish an The development of an institutional antibiogram is a critical func-
epidemiologic link to cases. tion that often results from collaboration between different groups, as
9. Devise and implement control measures. will be discussed below.
10. Review results of investigation or report on ongoing inves- Understanding pathogen distribution and relatedness in the hospi-
tigations to administration and staff; consider consultation tal is an important component of both surveillance and outbreak
with local public health officials. investigation. Typing of microbial isolates can help determine whether
11. Follow-up surveillance to evaluate efficacy of control mea- epidemiologically linked pathogens are genetically related and may
sures; generate reports for administration and staff.
help identify the source of an outbreak (environmental, personnel,
etc.). The incorporation of molecular typing methodologies along with
Flow diagram of the detection, evaluation and implementation of interventions to terminate a nosocomial
cluster or outbreak of hip prosthesis infections
Approach Findings Actions

Ongoing surveillance
Routine hip replacement infection surveillance
1. Microbiologic data Increase in readmission rate for
2. Antibiotic utilization data recent hip replacement surgeries
3. Review of readmitted patients
Suspected nosocomial cluster or outbreak

Increased infection rate suspected
Standardized Infection Notify hospital administration
1. Comparison with historical institutional data
Ratio (SIR) increased and orthopedics department
2. Comparison with NHSN standardized data
Case characterization
Increased rate of infection confirmed
1. Chart review using standard case definition Multiple surgeons, multiple
2. Clinical characterization locations, multiple organisms
3. Temporal characterization
Search for contributing factors

Hypothesis generation regarding New scrub materials introduced Scrub procedures reviewed
potential causes of outbreak just prior to SIR increase and modified
Assessment of effectiveness of intervention

Routine hip replacement infection surveillance
1. Microbiologic data Notify hospital administration
SIR declines to baseline
2. Antibiotic utilization data and orthopedics department
3. Review of readmitted patients
Figure 6-1 Flow diagram of the detection, evaluation and implementation of interventions to terminate a nosocomial cluster or outbreak of hip prosthesis
infections.
traditional epidemiologic surveillance has been shown in a number of In general, use of a US Environmental Protection Agency (EPA)-
studies to reduce the number of HAIs and to be cost-effective.18 Typing registered detergent/disinfectant (used according to the manufactur-
can be done using phenotypic methods (e.g. biotyping and serotyping) er’s recommendations for amount, dilution and contact time) is
or genotypic/molecular methods (e.g. pulsed field gel electrophoresis, sufficient to remove pathogens from surfaces of rooms of colonized or
plasmid analysis, southern blotting or PCR). Sequence-based molecu- infected individuals. Certain pathogens (e.g. rotavirus, norovirus, C.
lar epidemiologic analysis includes rapid whole genome sequencing, difficile) may be resistant to some routinely used hospital disinfectants.
which has been used successfully in the evaluation and control of Many investigators have recommended the use of a 1 : 10 dilution of
several important nosocomial outbreaks.19 5.25% sodium hypochlorite (household bleach) and water for routine
environmental disinfection of rooms of patients with C. difficile, noro-
Education and Training virus and rotavirus.
One of the most critical functions of the IPCP is to provide education General and specific recommendations for disinfection and steril-
and training for healthcare providers including instruction on isola- ization may be found in the CDC’s Guidelines for Environmental Infec-
tion precautions, aseptic practice, prevention of blood and body fluid tion Control in Healthcare Facilities.23
exposures, and appropriate usage of personal protective equipment
and safety devices. Disinfection and Sterilization
Numerous reports detailing infection outbreaks secondary to faulty or
COLLABORATE WITH OTHER PROGRAMS TO inadequately disinfected medical instruments highlights the critical
ACHIEVE COMMON GOALS importance of sterilization and disinfection of such items.28 IPCP col-
Occupational and Employee Health laborates with sterile processing to help prevent such problems.
An active employee health service and IPCP collaboration is critical in Medical equipment and instruments/devices must be cleaned and
the protection of healthcare workers and the control of HAIs. Joint maintained according to the manufacturers’ instructions to prevent
objectives generally include: patient-to-patient transmission of infectious agents. Cleaning to
• education of personnel about the principles and importance of remove organic material must always precede high-level disinfection
infection control (a process that eliminates many or all pathogenic organisms except
• prompt diagnosis and appropriate management of transmissible bacterial spores) and sterilization (complete elimination or destruction
diseases in healthcare workers, such as respiratory syncytial virus of all microbial life).
or pertussis Noncritical equipment, such as commodes, intravenous pumps and
• assessment and investigation of potential exposures and out- ventilators, computers used in patient care, etc., must be thoroughly
breaks among personnel cleaned and low-level disinfected before use on another patient. Pro-
• identification and vaccination of workers susceptible to vaccine- viding patients who are on transmission-based precautions with dedi-
preventable diseases cated noncritical medical equipment (e.g. stethoscope, blood pressure
• identification of work-related infection risks and institution of cuff, electronic thermometer) may prevent pathogen transmission. If
preventive measures this is not possible, disinfection after use is recommended. Semi-
• surveillance 20,21
of healthcare workers for diseases such as critical items come in contact with mucous membranes and intact
tuberculosis. skin. This includes respiratory therapy and anesthesia equipment.
The CDC has published extensive guidelines and recommendations High-level disinfection after cleaning is an appropriate standard of
on immunization of healthcare workers, occupational health guide- treatment for heat-sensitive, semi-critical medical instruments (e.g.
lines and protection of healthcare workers from blood-borne patho- flexible, fiberoptic endoscopes).25 This process inactivates all vegetative
gens, including post-exposure prophylaxis guidelines.22 bacteria, mycobacteria, viruses, fungi and some bacterial spores. Criti-
cal items (objects that enter sterile tissue or the vascular system) should
Environmental Health and Safety and either be purchased sterile or undergo heat-based sterilization prior to
Environmental Services patient use. This includes surgical instruments, various catheters,
Environmental Health and Safety and IPCP work together to ensure implants, etc.
environmental safety and prevent exposure of patients and staff to
environmental and airborne pathogens. The combination of infection Pharmacy and Therapeutics, and
control and environmental engineering strategies can help prevent Antimicrobial Stewardship
such occurrences. These control measures include: Infection with antibiotic-resistant bacteria has been associated with
• adherence to ventilation standards for specialized care environ- increased morbidity, mortality and costs of healthcare. The goals of an
ments (e.g. airborne infection isolation rooms, protective envi- effective antimicrobial stewardship program (ASP) include optimizing
ronments or operating rooms) and to water-quality standards, clinical outcomes while minimizing toxicity associated with antimicro-
including for hemodialysis bial use and the emergence of resistance, resulting in a reduction of
• appropriate infectious waste management healthcare costs while maintaining or improving quality of care. It has
• appropriate use of cleaners and disinfectants been shown that the use of an ASP program decreases inappropriate
• appropriate use of precautions during construction. antibiotic use and clinical failure, and significantly increases the rate
In this era of antibiotic-resistant pathogens, the importance of of cure in patients hospitalized with infections.26 The proven benefits
environmental cleaning cannot be overstated. Environmental contami- have now led some jurisdictions to mandate hospitals to establish
nation of floors, beds, tables, faucets, doorknobs, blood pressure cuffs, ASPs.
thermometers, gowns, stethoscopes and computer terminals has all The Infectious Diseases Society of America recommends a multi-
been well documented.23,24 Among other factors associated with trans- disciplinary approach to an ASP, with an infectious disease physician
mission, acquisition of drug-resistant organisms such as vancomycin- and a clinical pharmacist with infectious diseases training as core
resistant Enterococcus (VRE) and methicillin-resistant Staph. aureus members of the ASP team. In order to decrease the occurrence of inap-
(MRSA) may depend on room contamination, and the odds of acquir- propriate antimicrobial use, an ASP often utilizes either formulary
ing antibiotic-resistant bacteria are increased by patient admission to restriction with preauthorization or prospective audit with interven-
a room previously occupied by a patient harboring the resistant tion and feedback. The former requires the hospital to establish a list
organism.24 of restricted antimicrobials and a method by which authorization for
During a suspected or proven outbreak where an environmental use is obtained from an infectious disease physician or clinical phar-
reservoir is suspected, cleaning procedures should be assessed and macists. The latter requires the ASP team to review antimicrobial uti-
adherence should be monitored and reinforced. lization and provide appropriate feedback to prescribing physicians.
Other methods that may be utilized include antimicrobial order forms, sion on Accreditation of Healthcare Organizations (JCAHO) in 2004
guidelines or order sets for the treatment of specific infections, as part of the new National Patient Safety Goal 7A.33
computer-based alerts, and educational programs for hospital staff. A Whenever possible and available, alcohol-based products are
further area of growing importance is the de-escalation of empiric the primary method used for decontaminating hands. In addition,
antimicrobial coverage once culture data have been finalized, thereby hands should be washed with soap and water for 15 seconds if they are
avoiding unnecessary antimicrobial exposure. visibly soiled, or after covering a sneeze, nose blowing or using the
The benefit of an ASP in decreasing the incidence of drug-resistant bathroom.
pathogens has been demonstrated in multiple studies. For example, the Lastly, in the presence of Clostridium spores, alcohol products are
incidence of vancomycin-resistant Enterococcus (VRE), Clostridium discouraged because spores are not killed by alcohol.
difficile and drug-resistant gram-negative bacilli have been shown to In healthcare settings hand hygiene must occur before any direct
decrease in institutions with ASPs.27,28 patient contact and between patients, between tasks/procedures on the
An ASP requires a multidisciplinary approach, with collaboration same patient, before donning gloves and performing an invasive pro-
with a clinical microbiologist, an information systems specialist, an cedure, after contact with intact skin (e.g. taking a pulse/blood pres-
infection control professional and hospital epidemiologist. Because sure), after removing gloves or other personal protective equipment
such ASPs are important patient-safety initiatives, they often function (PPE), after contact with body substances or articles/surfaces contami-
under the umbrella of quality assurance and patient safety, and should nated with body substances, and before preparing or eating food.
receive hospital administrative and fiscal support.29,30 The ASP may Hands should be washed with soap and water after 7–10 applications
also work with microbiology, pharmacy and the IPCP to create an of an alcohol-based product.
institutional and unit-specific antibiogram, which can be accessible to Gloves, Masks, Eye Protection and Face Shields, Aprons,
all antibiotic prescribers in the healthcare system. Gowns and Other Protective Body Equipment. Disposable
Safety, Quality and Public Reporting gloves must be worn for anticipated contact with moist body sub-
stances, mucous membranes, tissue and non-intact skin of all patients,
Healthcare-associated infections are one of the most common prevent-
for contact with surfaces and articles visibly soiled or contaminated by
able complications of hospitalized patients, and therefore are fre-
body substances, during venous blood draws or other vascular access
quently used as indicators of the quality of patient care. Thus, the
procedures (starting a venous line or blood draws) or any other situ-
process and outcome data generated by infection control and other
ation where contamination of hands is anticipated.
practitioners is relevant to patient safety and quality of care at the level
When used, gloves should be donned immediately prior to the task.
of the institution, across institutions and extending to credentialing
Gloves should be removed and disposed of after every task involving
and governmental regulatory boards.31
body substance contact and before leaving the bedside. Gloves should
As of 2014, 37 states (74%) in the USA had enacted legislation
not be worn away from the bedside or laboratory bench, at the nursing
that requires healthcare facilities to publicly report HAIs through
station, to handle charts, when touching clean linen, clean equipment
NHSN. Although there is a wide variation among US states on which
or patient care supplies, or in hallways or elevators. Hands have to be
outcome measures are reported, CLABSI, CAUTI, selected surgical site
washed as soon as possible after glove removal or removal of other
infections, hospital-onset MRSA bloodstream infections and CDI are
protective equipment.
most often reported. In 2013 the CDC Healthcare Infection Control
Masks, in combination with eye protection devices (goggles or
Practices Advisory Committee (HICPAC) published consensus rec-
glasses with side shields) or chin-length face shields, should be worn
ommendations for public reporting10 which emphasize choosing con-
during procedures or other close contacts that are likely to generate
sistent, standardized CDC definitions along with external validation of
droplets, spray or splash of body substances to prevent exposure of
surveillance processes and HAI reporting, discouraging clinician veto
mucous membranes of the mouth, nose and eyes. Nonexhaustive
and adjudication, ensuring feedback to healthcare providers and pro-
examples are surgery, trauma care, newborn delivery, intubation
viding adequate infrastructure support.
and extubation, suctioning, bronchoscopy and endoscopy, emptying
Associated with the widespread adoption of quality improvement
bedpans and suction canisters into a hopper or toilet.
processes, a decrease in HAIs from an estimated 1.7 million HAI in
Plastic aprons or gowns and other protective body clothing are used
2002 to 721 800 HAI in 2011 has been observed.5
during patient care procedures to prevent contamination of clothing
Disaster and Bioterrorism Preparedness and protect the skin of personnel from blood or body fluid exposure.
The anthrax letters mailed within the USA in 2001, the SARS outbreak Additional protective equipment, including surgical caps, hoods
in 2002, the H1N1 (swine flu) pandemic in 2009 and the Ebola out- and shoe covers or boots, may be used in surgical or autopsy areas.
brack in 2014 have heightened the awareness of the importance of All protective body clothing should be removed immediately before
disaster (natural or bioterrorism-related) preparedness. Infection leaving the work area.23,32
control plays an integral role in such an effort, in order to develop
plans to minimize exposure of staff and the potential for nosocomial Transmission-Based Precautions
transmission (see isolation guidelines). Transmission-based precautions are used in addition to standard pre-
cautions in patients with documented or suspected infections or who
Isolation Precautions are colonized with an organism that is transmissible and/or that is of
epidemiologic significance. There are three types of transmission-
STANDARD AND TRANSMISSION-BASED based precautions: contact, droplet and airborne. A sign with the type
PRECAUTIONS of transmission-based precautions should be placed outside the room
Standard Precautions of the patient. In the USA, to comply with the Health Insurance Port
Standard precautions constitute a system of barrier precautions ability and Accountability Act (HIPAA) the name of the infecting
designed to be used by all healthcare personnel on all patients, regard- organisms may not be written on the sign.
less of diagnosis, to reduce the risk of transmission of micro-organisms Waste disposal, spill management, linen and food trays should be
from both recognized and unrecognized sources. These sources include handled in the same way for all patients, regardless of precaution
blood, all body fluids, secretions, excretions, intact and non-intact skin, category. Isolation trays are not required. After patient use, both linen
mucous membranes, equipment and environmental surfaces. and food trays are sent directly for cleaning and disinfection.34
Elements of standard precautions include hand hygiene and the Contact Precautions. Contact precautions are initiated and main-
banning of artificial nails. In 2002, the CDC published guidelines for tained to interrupt the transmission of epidemiologically significant
hand hygiene.32 These guidelines were adopted by the Joint Commis- micro-organisms known to be spread by contact.
Contact precautions are instituted:

• when a patient is colonized or infected with multidrug-resistant BOX 6-3 INFECTIONS REQUIRING DROPLET
organisms or organisms that are not treatable with the usual TRANSMISSION-BASED PRECAUTIONS
antibiotics, i.e. multidrug-resistant organisms • Adenovirus infection
• when a particular organism is identified as being potentially • Anthrax pneumonia
hazardous because of its pathogenicity, virulence, epidemiologic • Coronavirus infection, respiratory
characteristics and that persists in the environment or on hands • Croup (laryngotracheobronchitis)
• Diphtheria
and thus could be easily transmitted, e.g. rotavirus, C. difficile, • Ebola virus infection
Salmonella spp. and Shigella spp. • Herpes simplex
• on a case-by-case basis at the discretion of the IPCP staff, infec- •
•
Influenza
Meningitis
tious diseases staff and/or medical or nursing staff.
• Meningococcal pneumonia
After hand hygiene, the key element of contact precautions is per- • Meningococcemia
sonal protective equipment (PPE). Upon entering the room of a • Mumps (infectious parotitis)
patient placed in contact precautions, disposable gown and gloves • Mycoplasma infections
should be worn. All PPE must be removed before leaving the room and • Parainfluenza
• Parvovirus B19
hand hygiene must be done. Gowns may be worn one time only, and • Pertussis (whooping cough)
then should be disposed of in the regular (nonbiohazardous) waste • Plague
before leaving the room. • Rabies
The patient should be placed in a private room whenever possible. • Respiratory infectious disease, acute (if not covered elsewhere)
• Respiratory syncytial virus (RSV) infection
When a private room is not available, cohorting of patients with the • Rhinovirus infection, respiratory
same confirmed micro-organism (but with no other infection) is • Rubella (German measles)
acceptable after notification of IPCP. Because a negative air pressure • Scarlet fever
room is not required, the door may remain open. When neither a • Streptococcus: Group A
private room is available nor cohorting is achievable, a space separa-
tion of at least 1 meter (3 feet) should be present between the infected
patient and other patients or visitors.
To minimize contamination, equipment should not be shared
(unless it is disinfected properly) between patients. For pediatric BOX 6-4 CONDITIONS REQUIRING AIRBORNE
patients with fecal pathogens such as VRE or rotavirus and who require TRANSMISSION-BASED PRECAUTIONS
weighing, a dedicated scale should be placed in the room. • Hemorrhagic fevers
In critical care units or units where there is a high endemic rate of • Lassa fever
the organism wipe-down of high touch areas should be repeated as • Marburg virus disease
• Mycobacteria, tuberculous
needed and at minimum each shift. Cleaning cloths used in the room • Pneumonia
should not be used to clean other patients’ rooms and equipment. • SARS (coronavirus)
Traffic into the patient’s room should be limited only to essential • Tuberculosis (TB) including multidrug-resistant tuberculosis (MDR-TB)
staff/visitors. All visitors should be instructed in gowning and gloving • Vaccinia
and proper hand hygiene technique. Visitors may be referred to infec-
tion control or given written educational material.
Droplet Precautions. Droplet precautions are required when a
Strict hand hygiene is required before entering the room, after
patient is suspected or known to have an illness transmitted by large
contact with the patient or items contaminated with respiratory
particle droplets or direct contact with respiratory secretions. Droplets
secretions, and upon exiting the room. An OSHA-approved mask for
are often 30–50 µm in size compared to aerosolized droplet nuclei,
tuberculosis, such as the N95 respirator that has been fit-tested or a
which are less than 5 µm in size. They are often generated by a patient
powered air purifying respirator (PAPR), must be worn by healthcare
coughing, sneezing or talking, or during suctioning while in close
personnel.
contact with the patient. Organisms and diseases that require droplet
In the USA, the patient will be placed in a designated private room
precautions are listed in Box 6-3. After hand hygiene, the key element
with monitored negative air pressure in relation to surrounding areas,
of droplet precautions is the use of a surgical mask with eye protection
with a minimum of 12 air exchanges per hour for new construction
for contact within 1 meter (3 feet) of a symptomatic patient. All PPE
and renovation and six air exchanges per hour for existing facilities.
must be removed before leaving the room and hand hygiene must
Air from the room must be discharged directly outdoors or re-circulated
be done.
through high-efficiency particulate air (HEPA) filters before being cir-
The patient should be placed in a private room whenever possible.
culated to other areas in the hospital. The windows and the door to
Because a negative air pressure room is not required, the door may
the patient’s room must remain closed except for entry/exit. The
remain open. When neither a private room is available nor cohorting
patient is confined to the room unless a procedure outside the room
is achievable, a space separation of at least 1 meter (3 feet) should be
is necessary. The patient must wear a tight-fitting surgical mask outside
present between the infected patient and other patients or visitors.
of the room when transported to another department. Patients who
Patient movement should be limited to essential needs outside of
are discharged from the hospital but are still considered contagious
the room. Patients must wear a surgical mask while outside of the
must be instructed about the need to wear a surgical mask. Visitors
room.
should be limited at all times to those strictly necessary and visitors
Visitors should be limited and they must wear a surgical mask with
must wear a surgical mask. Symptomatic household or other contacts
face shield. Nursing staff must instruct family and visitors to wash
of the patient should be instructed not to visit.
hands when entering and exiting the room.
Vacating an Airborne-Precautions Patient Room. If the patient is
Airborne Precautions. Airborne precautions are required when a being evaluated for TB or diagnosed with TB and was in a room
patient is suspected or known to have a disease transmitted by airborne without negative pressure, the room must not be used for 1 hour after
droplet nuclei. The evaporated droplets contain micro-organisms that the patient has been discharged. If the patient is being ruled out for
remain suspended in the air and can be widely dispersed by air currents TB or is diagnosed with TB and was in a negative-pressure room, the
within a room or over a long distance. The diseases or infections room must not be used for 30 minutes after the patient has been
requiring airborne precautions are listed in Box 6-4. discharged.
term use only when rates of infection are high, avoiding routine
BOX 6-5 ORGANISMS REQUIRING AIRBORNE replacement of the line for the purpose of line-infection prevention
NON-ACID-FAST BACILLUS and using standardized process metrics to measure compliance with
TRANSMISSION-BASED PRECAUTIONS these guidelines. However, it was not until the Institute for Healthcare
• Chickenpox (varicella) Improvement (IHI) launched the ‘100 Thousand Lives’ CLABSI pre-
• Herpes zoster (disseminated) vention initiative that these recommendations were widely adopted by
• Herpes zoster (shingles in immunocompromised) healthcare facilities in the USA in the ICU setting.37 Following imple-
• Rubeola (measles) mentation of the IHI campaign, CLABSI rates have seen substantial
and sustained drops not only in the ICU setting but also on acute care
wards.
Airborne precautions are also required for patients with diseases Ventilator-Associated Pneumonia
that are highly communicable by the airborne route. Examples of Ventilator-associated pneumonia (VAP) develops in 9–27% of ICU
diseases that fall into this category of precaution are listed in Box 6-5. patients who require mechanical ventilation.38 To meet the criteria
Nonimmune staff or visitors are not allowed to enter the patient’s for VAP, the pneumonia has to manifest more than 48 hours after
room even to provide care. Nonimmunity means either no history of intubation.
the specific disease or no vaccination against that disease. Respiratory VAP is the leading cause of death among HAIs and is associated
protection is not needed for immune healthcare workers. with a doubling of mortality compared to ventilated patients with
similar characteristics who do not develop VAP.39,40
Healthcare and Device-Associated Infection control/infectious diseases and critical care specialists
have debated for many years on the definitions and methodology to
Infections be used for the diagnosis of VAP.41 Diagnosis of VAP is challenging
Healthcare-associated infections (HAIs) are infections occurring as a because patients requiring mechanical ventilation have underlying
result of treatment and after exposure to the healthcare environment. complex diseases and co-morbidities with similar and confounding
Infections can be acquired in all healthcare settings – ambulatory, symptoms and signs.
inpatient or during emergency room visits. HAIs include those with VAP prevention process measures are now better established and
hospital onset and those with community onset in patients with previ- many are supported by randomized controlled trials. Preventive strate-
ous healthcare encounters. Hospital-onset HAIs manifest 48 hours or gies are aimed at avoiding unnecessary intubation, decreasing the
more after admission to a hospital, within 30 days of discharge from a duration of ventilation, preventing aspiration, and minimizing inocu-
healthcare facility or if a patient visited an outpatient medical facility lation and colonization of the lower respiratory tract with mouth,
within the past 6–12 months.4 Community-associated infections are gastrointestinal and upper respiratory tract flora. When implemented
defined as infections manifesting and diagnosed within 48 hours fully, these measures have resulted in better patient outcomes and are
of admission in patients without any previous encounter with cost-effective.
healthcare. In January 2013, NHSN implemented new surveillance methodolo-
HAIs can be divided into three broad, sometimes overlapping gies and a definition algorithm for ventilator associated events
groups: device-related, non-device-related and procedure-related. (VAE). The algorithm allows for the identification of several tiered
infectious and noninfectious conditions and complications developing
DEVICE-RELATED HAI in mechanically ventilated adults: ventilator-associated condition,
Central Line-Associated Bloodstream Infections infection-related ventilator-associated complication and possible,
Of all device-related HAIs, central line-associated bloodstream infec- probable VAP.42,43
tions (CLABSI) are among the best studied. Vascular access is an essen-
Catheter-Associated Urinary Tract Infections
tial part of care of patients and often extends beyond the inpatient stay
into ambulatory care. Colonization of the device around the insertion Catheter-associated urinary tract infections (CAUTI) are the second
site by bacteria or fungi on the skin is thought to constitute the most most common device-associated infections.5 CAUTI are frequently
frequent first step of a central line infection. However, for invasion into used as a proxy measure for quality. Recommendations for implemen-
the bloodstream to occur, bacteria have to adhere and incorporate into tation, performance measurements and surveillance of CAUTI have
the biofilm,35,36 multiply and then invade. been recently published.44
Bacteremia and sepsis secondary to contamination of the infusate PROCEDURE-RELATED HAI
occur much less frequently but are a recognized source of clusters or
outbreaks of bloodstream infections with gram-negative organisms. SSIs are the most common procedure-related HAI and are associated
Risk factors for CLABSI include host factors (severity of illness, lack with additional hospital days, increased morbidity and increased cost
of skin integrity, type of immunosuppression), factors related to the compared to uncomplicated surgeries.45–48. Implementation of infec-
device (catheter insertion and maintenance processes, type and size of tion prevention bundles such as preoperative chlorhexidine bathing,
catheter, number of lumens, insertion site) and finally factors related glucose control, standardized wound care and antibiotic prophylaxis,
to the function of catheter, and the duration of placement. have been associated with significant reductions in SSI rates.49
CLABSI prevention initiatives and surveillance have been standard- Numerous guidelines and protocols have been developed in recent
ized internationally, have well-established definitions and methodolo- years.44,50
gies and therefore can be easily linked to measurable process and
outcome measures. Unlike other quality and safety measures, surveil- Multidrug-Resistant Organisms
lance of CLABSI has proven very helpful in the objective evaluation of As care has evolved and become more complex, new antimicrobials
the efficacy of performance improvement initiatives.36 have increased antibiotic pressure and thus selection of drug-resistant
In 2002, a working group published guidelines for the prevention mutants. As a result, organisms resistant to multiple classes of drugs
of intravascular device-related bloodstream infections. Among the key have emerged worldwide.51 Infections due to multidrug-resistant
evidence-based recommendations were education and standardization organisms (MDRO) represent a significant proportion of the both the
of insertion and maintenance processes, the use of maximal sterile HAI burden and the day-to-day work of the IPCP.
barrier precautions upon insertion, chlorhexidine skin preparation, Guidelines for metrics to be used to monitor, and processes to
antiseptic/antibiotic-impregnated central venous catheters for short- prevent MDRO in healthcare settings are available.51,52
While resistance definitions for gram-positive organisms are well infection prevention measures and coordinated antimicrobial stew-
established, there is no standard definition for most gram-negative ardship programs.54,55
MDRO.53 For the purpose of this chapter, gram-negative MDRO are
defined as organisms resistant to one or more classes of antimicrobial References available online at expertconsult.com.
agent.
New guidelines for the prevention of MDRO in the healthcare
setting underscore the importance of well-described evidenced-based
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Bolyard E.A., Tablan O.C., Williams W.W., et al.: Guideline care Epidemiology of America guidelines for developing O’Grady N.P., Alexander M., Burns L.A., et al.: Guidelines
for infection control in healthcare personnel, 1998. Hos- an institutional program to enhance antimicrobial stew- for the prevention of intravascular catheter-related infec-
pital Infection Control Practices Advisory Committee. ardship. Clin Infect Dis 2007; 44(2):159-177. tions. Am J Infect Control 2011; 39(4 Suppl.1):S1-S34.
Infect Control Hosp Epidemiol 1998; 19(6):407-463. Kapadia B.H., Johnson A.J., Issa K., et al.: Economic evalu- Perencevich E.N., Stone P.W., Wright S.B., et al.: Raising
Boyce J.M., Pittet D., Healthcare Infection Control Prac- ation of chlorhexidine cloths on healthcare costs due to standards while watching the bottom line: making a busi-
tices Advisory Committee, Society for Healthcare Epide- surgical site infections following total knee arthroplasty. ness case for infection control. Infect Control Hosp Epide-
miology of America, Association for Professionals in J Arthroplasty 2013; 28(7):1061-1065. miol 2007; 28(10):1121-1133.
Infection Control, Infectious Diseases Society of America, Klompas M., Khan Y., Kleinman K., et al.: Multicenter Talbot T.R., Bratzler D.W., Carrico R.M., et al.: Public
Hand Hygiene Task Force: Guideline for hand hygiene in evaluation of a novel surveillance paradigm for complica- reporting of health care-associated surveillance data: re
health-care settings: recommendations of the Healthcare tions of mechanical ventilation. PLoS ONE 2011; commendations from the healthcare infection control
Infection Control Practices Advisory Committee and the 6(3):e18062. practices advisory committee. Ann Intern Med 2013;
HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Koh H.K., Blakey C.R., Roper A.Y.: Healthy people 2020: a 159(9):631-635.
Infect Control Hosp Epidemiol 2002; 23(12 Suppl.): report card on the health of the nation. JAMA 2014; Trick W.E.: Decision making during healthcare-associated
S3-S40. 311(24):2475-2476. infection surveillance: a rationale for automation. Clin
Chitnis A.S., Edwards J.R., Ricks P.M., et al.: Device- Koser C.U., Ellington M.J., Cartwright E.J., et al.: Routine Infect Dis 2013; 57(3):434-440.
associated infection rates, device utilization, and antimi- use of microbial whole genome sequencing in diagnostic
crobial resistance in long-term acute care hospitals
Chapter 6 Infection Prevention and Control, and Antimicrobial Stewardship 61.e1
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2012; 8(8):e1002824. S34.
7
Bacterial Genomes
PIERRE-EDOUARD FOURNIER | DIDIER RAOULT
KEY CONCEPTS Introduction

• With an increased output and lower cost, genomic sequencing The genomic sequencing era may be divided into two periods (Figure
has a clear impact on clinical microbiology. 7-1). In the first decade, from 1995, when the sequencing of the
Haemophilus influenzae genome was performed1 to 2005, sequencing
• More than 49 000 bacterial genomes are currently available, relied on the classic Sanger method, was time- and money-consuming
including those of all major human pathogens.
and was reserved to a limited number of sequencing centers world-
• Clinical applications of bacterial genomics include the design wide. Fewer than 300 bacterial genomes were sequenced during this
of PCR and genotyping assays, the detection of virulence and period (Figure 7-1). Since 2005, the development of new and high-
antibiotic resistance markers, the development of culture throughput sequencing methods,2 together with a steep decrease of the
media, serology assays and vaccines. sequencers’ and reagents’ cost enabling many laboratories to develop
• Real-time genomics may help decipher infectious disease out- their own sequencing projects, led to a striking increase in the number
breaks within a few days. of sequenced genomes, approaching 6000 for the year 2013 alone.
The tremendous source of information provided by genome
• The data analysis capacity and cost remain major drawbacks. sequences revolutionized basic aspects of microbiology. In particular,
genome sizes of bacteria range from 139 kb for Candidatus Tremblaya
princeps to 14 782 kb for Sorangium cellulosum (http://genomesonline
.org/).
Genome analysis, also known as genome mining or in silico analysis,
With more than 49 000 bacterial genome sequences currently available, currently constitutes an irreplaceable research tool for various aspects
including those from all significant human pathogens, genomics has a of microbiology. In particular, the availability of genomes from virtu-
significant impact on clinical microbiology and infectious diseases by ally all bacterial human pathogens has opened perspectives in the fields
enabling the development of improved diagnostic, genotyping, taxo- of diagnosis, epidemiology, pathophysiology and treatment.
nomic, antibiotic and virulence marker detection tools as well as devel- A major advantage of genome sequences over phenotypic methods
opment of new culture media or vaccines. This chapter summarizes is that data can rapidly be shared among scientists worldwide by being
the current achievements in bacterial genomics relevant to medical deposited in online databases and thus are easily comparable among
microbiology. laboratories. The main three databases are the National Center for
Number of sequenced bacterial genomes per year
1000th Escherichia
Number 7000 coli genome
of annually sequenced
bacterial genomes
6000 5836
High throughput Next generation 10 000th

5000 Sanger sequencing genome
sequencing sequencing
4000
3000
Real-time 2735
Introduction genomics
2000
Sequencing of of high 1000th 1562
Haemophilus 100th throughput genome 830
1000 influenzae genome sequencing
226 326
2 2 4 5 4 13 25 29 48 60 77 139 172 177
0
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014*
* For 2014, we indicate the number of genomes sequenced until February 24.
Figure 7-1 Number of sequenced bacterial genomes per year.
62
Chapter 7 Bacterial Genomes 63
Biotechnology Information (NCBI, www.ncbi.nlm.nih.gov/), the DNA and affordable benchtop, or real-time high-throughput sequencers.
Data Bank of Japan (DDBJ, www.ddbj.nig.ac.jp/) and the European These systems enable sequencing bacterial genomes within 1–2 days.3
Bioinformatics Institute (EBI, www.ebi.ac.uk/). In addition to offering Benchtop sequencers were recently and efficiently used for whole
complete microbial genome sequences with links to corresponding genome sequencing (WGS). The GS Junior benchtop sequencer is also
publications, these databases provide online tools for analyzing being extensively used in microbial WGS.4
genome sequences. As of February 24, 2014, 12 272 genome sequences
from 2897 bacterial species are available online (www.genomesonline SINGLE-CELL GENOME SEQUENCING
.org/, https://gold.jgi.doe.gov). For some species, several genomes have Thanks to the development of technologies that rely on sequencing
been sequenced. For 31 species, more than 50 genomes are available, single stretches of DNA molecules rather than using polymerase chain
including 16 species for which more than 100 genomes have been reaction (PCR) amplification of DNA fragments, it is now possible to
sequenced, the species holding the record being Escherichia coli, with access the genomic content of a unique cell. Three single-cell sequenc-
1261 currently available genomes. Sequenced genomes include the ers are currently available, including the Heliscope (Helicos Biosciences
most significant human bacterial pathogens, covering all the phyloge- Corp), the Single Molecule Real Time (SMRT) sequencer (Pacific Bio-
netic domains of bacteria. In addition, more than 27 000 sequencing sciences) and the Oxford Nanopore DNA sequencer (Oxford Nano-
projects are ongoing (www.genomesonline.org/). Moreover, new pore Technologies). These technologies, although different in their
sequencing technologies are making possible the sequencing of random whole-genome amplification method,5 are fast (~200–400 bases/sec.),
community DNA and single cells of bacteria without the need for require minimal sample preparation and produce long read length (up
cloning or cultivation. to 10 000 bp reads). In addition, such a strategy is especially valuable
There are multiple applications for genomics in clinical for micro-organisms that cannot be cultivated. Single-cell sequencing
microbiology: was successfully used for E. coli and Bacillus subtilis. It may also be of
• Real-time genomics may be used to investigate infectious disease particular interest for complex floras, notably when combined with cell
outbreaks. sorting methods like fluorescence-activated cell sorting (FACS) or
• Bacterial genomes may be used as target sources for molecular microfluidic chips.6 The sequence from the genome of a Porphyromo-
detection, identification or genotyping. nas gingivalis strain present in a hospital environmental sample was
• The gene content, obtained by comparison to databases such as obtained by single-cell genomics, demonstrating the ability of this
Clusters of Orthologous Groups (www.ncbi.nlm.nih.gov/COG/) strategy to precisely analyze the genetic variations of micro-organisms
or Kyoto Encyclopedia of Genes and Genomes (www.genome.ad at the strain level.
.jp/kegg/), may be searched for specific phenotypic traits such as
virulence or antibiotic resistance markers, or deficient metabolic
pathways enabling design of improved culture media. Analysis of Genome Sequences
• Antigenic epitopes detected in the deduced proteome may be DATA ANALYSIS
used for serologic applications, development of monoclonal Despite its advantages, high-throughput sequencing is facing new chal-
antibodies or development of vaccines (Figure 7-2). lenges. The huge amounts of produced sequences generated a need for
• Taxonomic description of new bacterial species. high performance computational hardware and expertise. In particu-
lar, the challenge of assembling genomes by combining millions of
Sequencing Strategies reads obtained by various sequencing methods, although theoretically
Since 2005, the introduction of high-throughput sequencing tech- complementary, is not, as yet, solved, in particular when read lengths
niques has revolutionized genomics and metagenomics, and totally are smaller than 100 bp. Another major issue of high throughput
superseded conventional capillary sequencing (Sanger sequencing). genomics is sequence annotation. Both the availability of automated
Over recent years, the landscape of new high-throughput sequencing and high throughput annotation tools and the quality of the annota-
methods, termed ‘next-generation sequencing (NGS)’ has changed, tion produced are also crucial. To date, there is no consensus on anno-
some technologies being progressively abandoned, as is the case for the tation method and standardization of genomic data. Such an effort will
SOLID (Life Technologies), and others emerging, such as single cell be necessary to facilitate future studies.
sequencing (Table 7-1). Currently, two major NGS platforms are used,
including the 454/Roche and Illumina/Solexa platforms (Table 7-1). PANGENOMICS
The pangenome, made of a core genome (genes shared by all strains),
BENCHTOP SEQUENCERS a dispensable genome (genes shared by some, but not all, strains) and
Following the introduction of ultrahigh throughput sequencers, strain-specific genes, represents the complete gene pool of a species.
Roche, Illumina/Solexa and Life Technologies introduced more rapid The pangenome size of bacteria may differ greatly among species and
TABLE
7-1 Currently Available Sequencing Methods
Sanger Di-deoxy
Nucleotide Sequencing Pyrosequencing Sequencing by Synthesis Ligation-Based Sequencing
Platform Capillary sequencers Roche (454) GS-FLX+ Illumina HiSeq 2500 Applied Biosystems SOLID
6
Mb/run 0.44 700 10 3000
Time/run 7 hours 23 hours 6 days 5 days
Read length (bp) 650–800 700 2x125 35

Limits Cost Limited paired-end and targeted sequencing, difficult sequence assembly, especially to disambiguate
repeat regions
Need for high DNA quantity Low sensitivity in homopolymer Specific sequence format
Cloning step sequencing
Misincorporation of excess nucleotides
Beads with mixed templates
Redundancy
Applications of genomics to the clinical microbiology laboratory
From raw sequence to genotype

Identification of
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1
Open reading frame (ORF) annotation
Culture media design
From genotype to phenotype Prediction of

antibiotic resistance
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Start Stop
bla bla
VEB-1 aadB arr-2 cmlA5 OXA-10 aadA1
Prediction of virulence
Gene translation
From genomics to proteomics Identification of

antigenic epitopes
Development of
monoclonal antibodies
Vaccine design
Figure 7-2 Applications of genomics to the clinical microbiology laboratory.

genera, in part because of the frequency of homologous recombination desired objective (genus-, species-, subspecies- or strain-specific).19
and lateral gene transfer. Therefore, one genome per species often Genome sequences may also be used to design multiplex PCR assays
underestimates the genetic complexity at the species level. For E. coli, enabling simultaneous detection and discrimination of various micro-
Streptococcus agalactiae and Strep. pyogenes it was estimated that an organisms, as was the case for members of the M. tuberculosis complex.
average 441, 33 and 27 new genes, respectively, would be unveiled by In addition, the study of genomic sequences enabled the optimiza-
every new sequenced genome. Such intraspecies variations might be tion of the sensitivity of detection, either by selecting a gene or frag-
linked to niche adaptation. Bacteria living in niches with limited access ment of noncoding DNA present as several copies in the genome or
to the global microbial gene pool, such as Bacillus anthracis, Chlamydia by designing nested PCR assays with a reduced risk of contamination,
trachomatis and Mycobacterium tuberculosis, have a much smaller such as ‘suicide PCR’.
intraspecies genomic diversity.7 The most extreme example of genome
homogeneity is Buchnera aphidicola, which experienced neither MOLECULAR GENOTYPING
genome rearrangement nor gene duplication or transfer. Molecular typing methods have largely superseded phenotypic
methods. In a similar fashion as described above, genomic sequences
METAGENOMICS may be a source of genotyping targets. Various genotyping methods,
Deciphering complex floras by identifying the DNAs from the various classified as nonsequence-based and sequence-based, have been
micro-organisms present (termed metagenomics, see Chapter 8) has designed by using genomic sequences.
provided a unique access to the microbial species and genes present in • Nonsequence-based methods rely on the in silico design of
these environments. Similar to genome sequencing, metagenomics has macro-restriction profiles for rare cutter enzymes that may serve
benefited from NGS methods, which enable sequencing of random for restriction fragment length polymorphism-based assays, on
community DNA without the need for cloning or cultivation. By genomic screening for single nucleotide polymorphisms or
analogy, studies of all copies of 16S rDNA in a polymicrobial specimen tandem repeats.20 Such strategies were used for typing Yersinia
have also been named metagenomic studies. Metagenomic studies have pestis, Salmonella typhimurium or Coxiella burnetii isolates.
demonstrated that a great proportion of the biologic diversity in the • Several sequence-based genotyping methods have been designed
bacterial world remains unexplored.8 To date, the metagenomic on the basis of genome sequences, including multilocus sequence
approach has widely been used to study the human microbiome, in typing (MLST) for the study of multidrug resistant E. coli or
particular the oral, skin,9 vaginal and lower intestinal floras,8 the latter Streptococcus pneumoniae, and multispacer typing (MST) for
being by far the most studied. In the gastrointestinal tract, 395 distinct typing Y. pestis, Coxiella burnetii, Bartonella or Rickettsia iso-
bacteria were demonstrated; 62% of these were not previously known lates.21 However, bacterial whole-genome sequencing, by giving
and 80% were uncultivated. In addition, microbial genes outnumbered access to the whole genetic content of a strain, is the most dis-
human genes 100 times, suggesting that the human microbiome criminatory sequence-based genotyping method, as was demon-
may play a major role in human physiology. Unexpectedly, this study strated by the genome-based typing of M. tuberculosis or Staph.
demonstrated great intersubject variability and significant differences aureus clinical isolates.22 However, due to its cost, even if it has
between stool and mucosal community compositions. Metagenomic decreased steeply since 1995, genome sequencing is not, as yet,
studies have also demonstrated that the composition of the human gut a routine tool in most clinical microbiology laboratories.
ecosystem is influenced by several factors, including age, geographic • DNA microarrays are an intermediate between nonsequence-
origin, environment, dietary habits, antibiotics and probiotics.10 In based and sequence-based methods, as they enable detection of
addition, links between microbiota composition imbalance and various subtle strain- or species-specific differences by simultaneous
diseases such as irritable bowel syndrome, cord colitis syndrome,11 comparison of strains at the whole genome level. Such an appli-
Crohn’s disease, necrotizing enterocolitis, polyposis or colorectal cation was used to discriminate among environmental Legionella
cancer, type II diabetes and obesity12 were suggested. In the latter pneumophila strains. Another advantage of microarrays is that
disease, both the gut microbiota richness and its composition might their interpretation may be automated. DNA microarrays may
play a causative role.13 Several human infections have also benefited also be used to detect and identify micro-organisms in complex
from metagenomic studies, notably bacterial vaginosis, brain abscess,14 floras.20
cystic fibrosis, dental infections, diarrhea and pneumonia.
TAXONO-GENOMICS
Using Genome Sequences The current strategy for classifying bacterial isolates is named polypha-
sic taxonomy. It combines phenotypic, chemotaxonomic and geno-
REAL-TIME GENOMICS typic criteria. However, the currently used genotypic criteria, including
The development of NGS benchtop sequencers has made genome DNA–DNA hybridization (DDH), 16S rRNA similarity and genomic
sequencing compatible with the routine clinical microbiology work- G+C content, suffer from several drawbacks, notably a lack of inter-
flow. Such a strategy enables, within a few hours and for a few hundred laboratory and inter-assay reproducibility for DDH, and inter-generic
dollars, exhaustive access to the genotype,16 virulence markers and variations for 16S rRNA similarity and G+C content, which limit
antibiotic resistance repertoire. Real-time genomics has notably been their reliability. By providing the total genetic background of a strain,
used to investigate hospital outbreaks of Acinetobacter baumannii,17 WGS represents a new approach of taxonomy by taking into consid-
Clostridium difficile, E. coli or Staphylococcus aureus infections, a eration the entire genomic content.15 Various approaches to incorpo-
large community-acquired outbreak of E. coli O104:H4 infections in rate genomic data in taxonomy have been described, either based on
Germany, the spread of multiresistant Staph. aureus in cystic fibrosis partial or whole genomic data. An example of use of partial genomic
patients, and to identify the virulence determinants of a Staph. epider- information is the PhyloPhlAn method that uses sequences from 400
midis strain that had caused a native valve endocarditis18 or a chronic proteins. Among the taxonomic tools developed using whole genomic
osteitis-causing Clostridium tetani. These findings demonstrated how data, the determination of the average nucleotide identity (ANI) has
rapid and precise sequencing could transform patient management or been the most used. This parameter was proposed to replace DDH
improve hospital infection control in routine clinical practice. results. ANI was used to characterize new species of Burkholderia,
Geobacter and Vibrio as well as the new genus Sphaerochaeta and the
DESIGN OF MOLECULAR ASSAYS FOR new class Dehalococcoidetes. Another slightly different method is the
DETECTION OF BACTERIAL PATHOGENS determination of the average genomic identity of orthologous gene
By giving access to the complete genetic repertoire of a bacterium, sequences (AGIOS) that was used in a polyphasic strategy together
genomics enabled a rational selection of PCR targets according to the with phenotypic criteria.23,24 The latter method enabled the validation
of Alistipes timonensis sp. nov., Anaerococcus senegalensis sp. nov., Bre- PROTEOME PREDICTION
vibacillus massiliensis sp. nov., Brevibacterium senegalense sp. nov., Development of Serologic Tools
Enterobacter massiliensis sp. nov., Herbaspirillum massiliense sp. nov.
Genome analysis offers the possibility of identifying all putative
and Senegalimassilia anaerobia gen. nov., sp. nov. However, currently,
protein-encoding genes of a given bacterium. This exhaustive approach
there is no consensus on the method that should be used to define a
may be completed by expression of the corresponding proteome,
species.
testing immunoreactive characteristics of selected proteins, and use of
the best antigens for the development of serologic tools. This strategy
Phenotype Prediction allowed the identification of a representative panel of antigens for
DEVELOPMENT OF SPECIFIC CULTURE MEDIA Treponema pallidum and M. leprae. Conversely, the genome may serve
Although cultivation of the causative agent remains a priority during to identify antigens that have been detected within the proteome of a
the diagnosis of bacterial infections, many fastidious species cannot be bacterium by immunoblotting and mass spectrometry. This strategy
isolated in routine laboratory conditions. Thus, genomic sequencing was used for T. whipplei for which 17 proteins specifically reacting with
constitutes a unique approach to identify incomplete metabolic path- patients’ antibodies were identified.
ways as well as the essential nutrients that a bacterium is unable to
produce. It is then theoretically possible to compose specific media by
Vaccine Design
incorporating metabolites that bacteria cannot produce. The first In a similar fashion to the development of serologic assays, a complete
‘noncultivable’ pathogenic bacterium whose genome analysis permit- bacterial genome sequence offers the possibility of rational selection
ted axenic culture was Tropheryma whipplei, the causative agent of of vaccine candidates among its complete antigenic repertoire, notably
Whipple’s disease.25 A similar approach was used for Coxiella burnetii. those that are surface-exposed and conserved among strains.28 This
However, the counter-example of M. leprae that cannot be grown strategy, named reverse vaccinology, may be completed by functional
axenically, despite the identification of many important lacking meta- immunomics for optimal epitope prediction and may result in DNA
bolic activities, highlighted the fact that the genomic identification of vaccines. It has been used successfully to identify potential vaccine
deficient metabolic pathways may not always provide all the clues to targets for B. anthracis, Brucella species, Chlamydia pneumoniae, Lep-
the growth of fastidious bacteria. tospira interrogans, M. tuberculosis, Neisseria meningitidis, Porphyromo-
nas gingivalis, Rickettsia prowazekii, Strep. agalactiae, Strep. pneumoniae
DETECTION OF RESISTANCE TO and Strep. pyogenes. However, the major drawback of reverse vaccinol-
ANTIMICROBIALS ogy for vaccine development is that the strain under investigation does
The rapid increase and spread of multidrug resistant (MDR) bacteria not represent the genetic diversity of its species. This risk has been
have become a major public health problem worldwide. Genome highlighted by the comparison of genome sequences from several
sequencing has the potential to identify the various genetic resistance strains of Strep. agalactiae. In this species, the core genome is consti-
determinants of a given bacterial strain, as was done for an MDR tuted by only approximately 80% of genes, with each new genome
Acinetobacter baumannii that caused a nationwide outbreak of noso- exhibiting ~18% new genes. This finding motivated the design of a
comial infections in France.26 Alternatively, genome sequencing may ‘universal anti-S. agalactiae’ vaccine made up of four antigens, none of
help understand the dynamics of resistance spread in a bacterial which was present in all strains but the combination of which was
species, as was the case for Staph. aureus. However, genome sequencing protective against all strains.29
has demonstrated that genetic resistance determinants, once thought This example, together with accumulating evidence that a single
to have mainly arisen under the pressure of antibiotics, may have genomic sequence may not be sufficient to represent the variability of
emerged from ancient or environmental sources. In addition, genomic bacterial populations within a species, support the use of genome
findings may enable the development of PCR assays specifically target- sequences from multiple strains of a species to identify an efficient
ing resistance-causing genes or mutations that may serve as routine vaccine formulation.
detection tools.
Another situation demonstrating the value of genome sequencing Conclusions and Perspectives
is during identification of resistance mechanisms in fastidious bacteria, In 1995, the outcome of bacterial genome sequencing promised break-
for which phenotypic testing of antibiotic resistance is difficult or throughs in microbiology and infectious disease research. Since then,
impossible, as in T. whipplei where the genome revealed the presence almost 12 300 bacterial genomes have been sequenced. The multiplica-
of mutated gyrA and parC genes, which explains resistance to fluoro- tion of genome sequencing projects, together with extensive metage-
quinolones. Genome sequencing may also allow the identification of nomic studies, will provide a much more complete picture of the
the mechanism of action and target genes of new antimicrobial bacterial world. The potential of this inestimable source of information
compounds. has already allowed scientists to reconsider the fields of bacterial viru-
lence, host–bacteria interactions, microbiologic diagnosis and human
IDENTIFICATION OF VIRULENCE FACTORS microbial ecology. However, despite the many advances permitted by
Virulence genes are potential targets for risk assessment and interven- NGS, we are facing new challenges, including the need to develop
tion strategies. The identification of virulence genes may lead to the improved assembly, annotation and analysis programs able to handle
development of rapid screening tests in order to proceed with effective the huge amounts of sequence data produced by new sequencing tech-
isolation measures in hospitalized patients or delay hospitalization nologies, the continuously growing number of genomic sequences, and
after carriage decontamination. Comparative sequence analyses the complexity of sequences in metagenomic studies. Whether single
provide insight into pathogenic mechanisms of bacteria, allowing cell genomics will help solve some of these issues remains uncertain.
identification of known virulence proteins with conserved sequences Finally, there are not current minimum criteria for genome sequence
or motifs, as well as putative new virulence proteins. However, recent quality, the majority being unfinished, or ‘draft’ or ‘dirty’ genomes,30
studies have suggested that genome reduction, rather than gene gain, and such standards may be useful in order to obtain reliable genome
may also confer virulence, possibly by loss of regulation.27 comparisons.
In addition to allowing a better understanding of bacterial patho-
genesis, identification of virulence factors in genomes may also allow References available online at expertconsult.com.
the design of new potential antimicrobials in addition to allowing the
identification of antimicrobial targets.
KEY REFERENCES
Aagaard K., Petrosino J., Keitel W., et al.: The Human Fleischmann R.D., Adams M.D., White O., et al.: Whole- Li W., Raoult D., Fournier P.E.: Bacterial strain typing in the
Microbiome Project strategy for comprehensive sampling genome random sequençing and assembly of Haemophi- genomic era. FEMS Microbiol Rev 2009; 33(5):892-916.
of the human microbiome and why it matters. FASEB J lus influenzae Rd. Science 1995; 269:496-512. Ramasamy D., Mishra A.K., Lagier J.C., et al.: A polyphasic
2013; 27(3):1012-1022. Lagier J.C., Armougom F., Million M., et al.: Microbial cul- strategy incorporating genomic data for the taxonomic
Blainey P.C.: The future is now: single-cell genomics of bac- turomics: paradigm shift in the human gut microbiome description of novel bacterial species. Int J Syst Evol
teria and archaea. FEMS Microbiol Rev 2013; 37(3): study. Clin Microbiol Infect 2012; 18(12):1185-1193. Microbiol 2014; 64(Pt 2):384-391.
407-427. Ley R.E., Turnbaugh P.J., Klein S., et al.: Microbial ecology:
Didelot X., Bowden R., Wilson D.J., et al.: Transforming human gut microbes associated with obesity. Nature
clinical microbiology with bacterial genome sequencing. 2006; 444(7122):1022-1023.
Nat Rev Genet 2012; 13(9):601-612.
Chapter 7 Bacterial Genomes 67.e1
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Whole-genome random sequençing and assembly of based discovery of Bradyrhizobium enterica in cord Orientalis-like Yersinia pestis, and plague pandemics.
Haemophilus influenzae Rd. Science 1995; 269:496-512. colitis syndrome. N Engl J Med 2013; 369(6):517-528. Emerg Infect Dis 2004; 10:1585-1592.
2. Hall N.: Advanced sequencing technologies and their 12. Ley R.E., Turnbaugh P.J., Klein S., et al.: Microbial 22. Koser C.U., Holden M.T., Ellington M.J., et al.: Rapid
wider impact in microbiology. J Exp Biol 2007; ecology: human gut microbes associated with obesity. whole-genome sequencing for investigation of a neona-
210:1518-1525. Nature 2006; 444(7122):1022-1023. tal MRSA outbreak. N Engl J Med 2012; 366(24):2267-
3. Loman N.J., Misra R.V., Dallman T.J., et al.: Perfor- 13. Le Chatelier E., Nielsen T., Qin J., et al.: Richness of 2275.
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4. Didelot X., Nell S., Yang I., et al.: Genomic evolution expansion of the microbiological spectrum of brain 24. Ramasamy D., Mishra A.K., Lagier J.C., et al.: A poly-
and transmission of Helicobacter pylori in two South abscesses with use of multiple 16S ribosomal DNA phasic strategy incorporating genomic data for the
African families. Proc Natl Acad Sci USA 2013; sequencing. Clin Infect Dis 2009; 48(9):1169-1178. taxonomic description of novel bacterial species. Int J
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5. Blainey P.C.: The future is now: single-cell genomics clinical microbiology with bacterial genome sequenc- 25. Renesto P., Crapoulet N., Ogata H., et al.: Genome-
of bacteria and archaea. FEMS Microbiol Rev 2013; ing. Nat Rev Genet 2012; 13(9):601-612. based design of a cell-free culture medium for Tro-
37(3):407-427. 16. Beres S.B., Carroll R.K., Shea P.R., et al.: Molecular pheryma whipplei. Lancet 2003; 362(9382):447-449.
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7. Mira A., Martin-Cuadrado A.B., D’Auria G., et al.: The 17. Lewis T., Loman N.J., Bingle L., et al.: High-throughput 27. Merhej V., Georgiades K., Raoult D.: Postgenomic anal-
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8
The Microbiome in Infectious
Diseases
MAKEDONKA MITREVA
KEY CONCEPTS viruses (virome: bacteriophages and eukaryotic viruses) and micro-
eukaryotes (meiofauna), which are the least studied components of the
• The micro-organisms that live in or on the human body phylo- human microbiome, and include two major distinct microbial eukary-
gentically represent several kingdoms (prokaryotic and non- otic components of the human microbiome: the fungal (mycobiome)
prokaryotic), defining different types of biomes collectively and nonpathogenic parasites (protozoa and metazoa).
called the microbiome.
Among the numerous benefits that microbial communities bestow
• A ‘healthy’ microbiome contains rich and diverse commensal (including maturation of the immune system,6 the production of new
microbes that enhance metabolism, diminish infection severity blood vessels,7 and the repair of damaged epithelial tissues8), they also
and injurious inflammation, and confer resistance to various protect the host against invading pathogens which may cause infec-
disease states. When infection occurs at a barrier tissue, inter- tions and pathogenesis.9 This protection is enforced by commensal
actions between pathogen(s), commensals and environmental microbes10 that compete for sites of attachment and nutrients, and that
antigens result in a dysbiosis characterizing the infected state.
produce antimicrobial substances, (a process known as ‘colonization
• Metagenomic profiling of the phylogenetic and functional resistance’).10,11 A healthy microbiome has a rich and diverse structure
context of the human microbiome is performed using two that requires microbes that enhance metabolism, diminishes infection
culture-independent sequencing approaches: the conventional severity and injurious inflammation, and confers resistance to various
and less expensive targeted approach (16S and 18S rRNA) and/ disease states. When infection occurs at a barrier tissue, pathogen(s),
or shotgun metagenomic sequencing, which identifies organ- commensals and environmental antigens share the environment,
isms at a lower taxonomic level (e.g. bacterial strains), quanti-
resulting in a dysbiosis that characterizes the infected state. However,
fies the genetic and metabolic potential of the microbiome,
and characterizes components that lack a universal phyloge- when a dense and balanced microbial community is present at the
netic marker (e.g. the virome). exposed surface, it hinders the ability of pathogens to establish a niche.
To understand the dysbiosis associated with infections, one needs to
• The ‘healthy’ microbiome varies by body habitat and between first understand the diversity and structure of the ‘normal’ host-
individuals, but core (shared) habitat-specific microbiome and associated microbial communities that assemble on and in the human
community class groups can be defined and analyzed using
body. In this chapter, we will examine (1) data types and analysis used
taxonomic abundance as well as metagenome-wide variant
studies. to profile the human body-associated microbiota and its functional
capabilities, (2) the microbiome of healthy humans and (3) the micro-
• The human microbiome interacts in very complex ways with biome and infections.
the human immune system and infectious organisms including
bacteria, viruses and micro-eukaryotes (fungi and parasites).
Culture-independent sequencing-based approaches followed
by experimental validations have allowed for analysis of
these complex interactions, showing that the microbiome Micro-organisms represented in the human microbiome
can promote, inhibit or have no effect on pathogen-induced
pathogenesis.
Microbiome
Introduction
The human body is home to an array of micro-organisms collectively
Prokaryotic Non-prokaryotic
called the human microbiota. The human microbiota within a specific
defined habitat (including the molecules that the microbiota produces)
is also known as a human microbiome. The microbiome has been
referred to as a distinct organ because of its production of many
important molecules,1–3 and has even been called our ‘second genome’.4 Bacteria Archaea Viruses Micro-eukaryotes
Indeed, there are an estimated 100 trillion cells in communities of
microbes in and on our bodies, which is 10-fold more than our own
cells. These organisms encode 100-fold more unique genes than the
host genome5 and provide genetic, metabolic and immunologic attri-
butes that lead to normal host development and the promotion of Bacteriophages Eukaryotic viruses
human health. The total genetic composition of all of the micro-
organisms comprising the microbiome is called a metagenome.
The micro-organisms that live in or on the human body phylogen-
tically represent several kingdoms (prokaryotic and non-prokaryotic;
Fungi Protozoa Metazoa
Figure 8-1), defining different types of biomes. The vast majority of
micro-organisms are prokaryotes (bacteriome: bacteria and archaea;
hence the most frequently studied) and the non-prokaryotes include Figure 8-1 Micro-organisms represented in the human microbiome.
68
Chapter 8 The Microbiome in Infectious Diseases 69
Culture-Independent Sequence-Based full-length genes after PCR (with primers amplifying the target gene
from a wide range of micro-organisms), followed by sequencing. The
Taxonomic and Functional Profiling historically used Sanger (capillary-based) sequencing approach has
of the Microbiome been replaced by next-generation sequencing (NGS) technologies.16
The ‘normal’ host-associated human indigenous microbiota has a spe- 16S rRNA Gene
cific phylogenetic and functional context. Thorough identification and 16S rRNA genes have conserved and variable regions (Figure 8-3ai),
characterization of the microbiota is performed by phylogenetic and where conserved areas reflect phylogenetic relationship among species
functional profiling of microbial communities, which requires a multi- (and are used as sites for PCR priming) and highly variable regions
omics approach that includes genomic, transcriptomic, proteomic and reflecting differences between species. Capillary-based sequencing
metabolomic data. All of these approaches are culture-independent, (generating ~750 bp read lengths) requires 2–3 reads to cover the
which is important because it is estimated that 20–60% of the human- entire gene (~1.6 kb). While very accurate (due to the ability to capture
associated microbiome (depending on body site) is unculturable.12–15 the full length of the 16S rRNA gene), this approach is costly, time-
This consideration results in underestimating microbial diversity if consuming, material-inefficient and labor-intensive. NGS platforms
culture-dependent approaches are used. The most routinely used (such as 454/Roche, Ion-Torrent and Illumina) produce much deeper
approach is the metagenomic-based profiling of microbial communi- sampling of the microbial communities while decreasing the cost
ties, which is performed using two culture-independent sequencing- required for data generation. The 400-500 bp read length of the 454/
based approaches: (a) targeted and/or (b) shotgun sequencing (Figure Roche platform has a very low error rate and can also cover up to three
8-2). Fast-evolving DNA sequencing technologies have driven advances of the nine hypervariable regions (e.g. V1 to V3 or V3 to V5). A total
in profiling microbial communities. of 96 samples per region can be profiled, totaling 192 samples per run,
and ~5000 reads per sample. While the sensitivity (in regards to ability
TARGETED METAGENOMIC SEQUENCING to identify taxa to the lowest taxonomic level) of this approach is not
Targeted metagenomic sequencing is DNA sequencing of a specifically as high as full-length 16S rRNA gene sequencing, pyrosequencing has
amplified region of the genome. The 16S rRNA and 18S rRNA genes greatly advanced our understanding of the microbiome. A low-cost,
are the most frequently used targets for bacteria/archaea and eukary- scalable and high-throughput approach to sampling microbial com-
otes, respectively. Based on the diversity of ribosomal RNA sequences, munities is made possible by both the Ion-Torrent sequencers (Ion
one can explore the structure of the microbiome in terms of presence PGMTM Sequencer and Ion Proton™), which can generate up to 400 bp
and relative abundance. The conventional approach involves cloning sequence reads,17,18 and the Illumina MiSeq platform,19 which can
A workflow for analysis of targeted and shotgun metagenomic sequence data
Isolation and
Isolation of
purification of
microbial
DNA from the
community from
microbial
biological sample
community
Targeted metagenomic Shotgun metagenomic

sequencing sequencing
Operational taxonomic Map to sequence Map to microbial Assembly / gene Map to gene sequences
unit (OTU) classification database genome database annotations encoding enzymes
Metagenomic diversity analysis Community structure Genetic profiling Metabolic profiling
α-diversity β-diversity γ-diversity Gene 1 Gene 2 Ribulose-P pathway

(within-sample) (between-sample) (across samples)
# OTUs / 16S / genomes
4.1.2.43 D-Arabino-
Hex-3-ulose-6P
-Xylulose-5P
D-Ribulose-5P
Abundance
5.3.1.27
Diversity
Pentose phosphate D-Fructose-6P

pathway
Xylulose-P pathway
D-Glycer- 2.7.1.11 3.1.3.11
OTU / 16S / genome Sample # Samples aldehyde-3P
2.7.1.29 4.1.2.13
Glycerine-P D-Fructose-1,6-P2
Figure 8-2 A workflow for analyses of targeted and shotgun metagenomic sequence data.
Schematic representation of the targeted and shotgun approach
Targeted metagenomic sequencing Shotgun metagenomic sequencing

i) 16S RNA gene i) Mapping reads to whole genomes
a
Genome
b c
Depth of coverage
V1 V2 V3 V4 V5 V6 V7 V8 V9
Breadth of coverage
ii) 18S, 5.8S and 28S variable regions ii) Mapping reads for genetic analysis
f Gene 1 Gene 2 Gene 3
b c
e
a d
18S ITS15.8S ITS2 28S
a b
Figure 8-3 Schematic representation of the targeted and shotgun approach. (a) Prokaryotic 16S and eukaryotic 18S rRNA gene (or ITS clusters) are used to characterize
metagenome by targeted sequencing. Some primers used in published reports that amplify specific regions of the 16S rRNA gene are: (i) a) 27F and 534R, b) 357F and
926R, c) U968f and 1492r-MP; for the 18S rRNA gene or ITS regions are: (ii) a) 18S_0067a_deg/NSR399, b) ITS1F/ITS2, c) 3271-ITS2F/3271-ITS2R, d) ITS1F/ITS4, e) NL1/
NL4, f) LR0R/LR5-F. (b) Alignment of shotgun metagenomic reads to reference genomes and/or genes.
generate paired 250–300 bp reads. The MiSeq platform is also able to eukaryotes at species and subspecies levels. Co-sequencing of both 18S
sample a single region covered by a single read, or up to three regions, rDNA and ITS (e.g. ITS1-5.8S-ITS2) can provide more comprehensive
which requires assembly of the paired reads. In a single MiSeq run, a classification of the eukaryotic components of the human microbiome.
total of 384 samples can be profiled with ~20 000 reads per sample (on Selection for the amplification of the target region must be performed
average, a total of 7 million assembled reads). It should be noted that carefully because of primer biases (e.g., reference 25).
primers designed to capture certain variable regions (Figure 8-3) can There is no current agreement as to the optimal regions to be
under-represent certain taxonomic clades. In order to quantify and amplified and sequenced. It is often a balance between finding primers
characterize this bias from primer pairs, studies have constructed that best amplify a determinative region, at the risk of losing the ability
so-called ‘mock’ communities where the composition of the bacterial to more broadly characterize a bacterial and fungal/eukaryotic biomass.
species and their representation is known.20 Targeted co-sequencing of the bacterial 16s rRNA and eukaryotic 18S
16S sequence analysis includes analytical processing (trimming, rRNA genes26–28 has been shown to efficiently characterize the micro-
screening and aligning sequences), followed by microbial profiling by biota on different habitats of the human body.
comparisons to 16S rRNA sequences in public databases, or from
operational taxonomic units (OTU) (see Figure 8-2) using the fre- SHOTGUN METAGENOMIC SEQUENCING
quency distribution of sequences found in bins (using an accepted Shotgun metagenomic sequencing is the sequencing of total DNA
threshold of a 3% dissimilarity level for species and 5% for genus). extracted from a whole community, and therefore results in obtaining
The taxonomic depth chosen is frequently situation-dependent. whole genomes (or major portions of the genomes) of the microbes
The ecological parameters that define communities include richness, in the community of interest (metagenome). This is an unbiased
diversity and evenness. Richness considers the number of unique bac- culture-independent approach to profile a microbiota. There are
teria in a community, and diversity reflects richness and relative abun- several applications of metagenomic shotgun approach: (i) Providing
dance of bacteria in the population (e.g. Shannon diversity index), taxonomic profiling of the community at a lower taxonomic level than
which decreases when repartition among species becomes less equal, targeted taxonomic profiling. The 16S rRNA gene can be similar or
with one species predominating over others. Evenness represents com- identical for distantly related members of the same species, so it does
munity equitability and is based on the evaluation of richness and not discriminate lower taxonomic levels. The genomes of strains anno-
diversity (e.g. Shannon equitability index). After determining ecologi- tated as the same species according to 16S rRNA gene sequencing can
cal parameters, comparisons within and between groups (α and β be quite distinct at a whole-genome level, and these differences can be
diversity, respectively) are performed, and the level of saturation quantified with shotgun sequencing (e.g., reference 29). (ii) Obtaining
within the studied cohort per microbiome is determined (γ diversity) the genetic complement of a microbial community, and inferring indi-
(Figure 8-2). vidual gene memberships among the organisms within the commu-
nity. (iii) Functional profiling of communities based on the putative
18S rRNA Gene functions of genes (e.g. enzyme presence and abundance). (iv) Char-
Similar to the bacterial 16S rRNA genes, the eukaryotic 18S rRNA gene acterizing the non-bacterial components of the microbiome (e.g.
has conserved and variable regions. 18S rRNA gene sequences and their viruses). Shotgun metagenomic sequencing is particularly useful in
associated transcribed spacers (internal transcribed spacer; ITS)21,22 are studying viral communities. Because viruses lack a universal phyloge-
used to classify fungi and eukaryotes.23,24 ITS includes ITS1 (located netic marker (e.g. 16S or 18S rRNA genes), the only way to access the
between 18S and 5.8S rDNA) and ITS2 (between 5.8S and 28S rDNA; genetic diversity of viral communities is via shotgun metagenomics
Figure 8-3aii). The variability in ITS1 and ITS2 is greater than 18S (though in clinic multiplex PCR is used, but that approach captures
rDNA gene variability, so it is used to identify fungi and lower only known viruses).
Recently, the increased depth of coverage provided by the NGS- genomes or functional databases and de novo assembly of the reads
based metagenomic shotgun approach has revolutionized human into contigs and calling genes using the resulting assemblies. The align-
virome studies, and provides unbiased characterization of such comment strategy for characterizing microbial communities is database-
munities. However, while shotgun sequencing provides a unique dependent and uses available reference sequences, which is important
opportunity for virome studies, there remain some challenges. First, to successfully define the structure32 or functional inference of the
there is a phylogenetically biased representation of the viral reference microbial community.33 However, this approach depends on the com-
sequences, enabling detection of sequences related to known viruses. pleteness of the reference genomes or the functional databases. For
Second, since the virome represents only a small fraction of the overall example, overall, 58% of the microbial-originated reads (Figure 8-4)
human microbiota (based on the number of virus-originated reads per could be associated with a known genome34 (% reads that align ranged
microbial community), their small genome sizes and low abundance from 33% for anterior nares to 77% for posterior fornix). It is also
challenge the existing primary sequence-based similarity searching possible to perform database-independent analysis of the metage-
tools. A combination of NGS platforms and virome-enrichment nomic shotgun data, by performing de novo assembly of the reads into
approaches can overcome some of the challenges, but if cross-kingdom contigs or assembly-independent comparisons (such as all-vs-all
studies are the focus, then virome-enrichment is not an appropriate sequence comparisons or k-mer-based analyses), but tools for these
approach since the overall microbial community structure could be approaches are still maturing.35
affected. NGS approaches for virome sequence analysis are computa-
tionally very intensive because they involve both (i) nucleotide-based
sequence similarity searches to capture viral sequences homologous to The ‘Healthy Microbiome’
existing viruses and (ii) amino acid-based similarity searches to find The indigenous microbiota of healthy humans has a specific phyloge-
phylogenetically more distant or novel viruses. These computationally netic and functional context. There are global efforts to characterize
intensive approaches have been streamlined by algorithms that increase the human microbiome through large-scale international initiatives,
alignment speed while maintaining sensitivity similar to legacy algo- including the US National Institutes of Health Human Microbiome
rithms such as BLAST (e.g., reference 30). Project (HMP), the European Commission’s Metagenomics of Human
The cost for sequencing is falling, especially on NGS platforms, but Intestinal Tract (MetaHIT) and the Canadian Microbiome Initiative
it remains difficult to know how much sequence data should be gener- (CMI).
ated for any particular community, and designs are often driven by However, while our understanding of the phylogenetic and func-
budgets and semi-empirical and ad hoc heuristic models. Recently, an tional context of the human microbiome is rapidly increasing, it is still
approach based upon a generalization of Stevens’ theorem for ran- based on very few cohorts, resulting in underestimated variations due
domly covering a domain has been proposed.31 This model accounts to parts of the world being understudied and under-represented in the
for the presence of multiple species, and estimates the useful probabili- data. Still, these efforts have provided very rich information about
ties for fully recovering a particular target microbe of interest, as well the basic variations of the microbiomes of healthy humans, the size of
as the average assembly length needed. This method showed improved the core microbiome and the community classes within body habitat-
specificities compared to previous measures, and provides a ‘metage- associated microbiome. For example, the HMP has characterized the
nomic design map’ to enable straightforward analysis and design of microbial communities in and on healthy adults34 as defined by the
future projects. consortium clinical collection sites.36 The five body regions comprise
The other limitation of the metagenomic shotgun approach is that oral, nasal, skin, gastrointestinal and urogenital, and represent the
it is much more costly, particularly for body habitats with high human major ecosystems of the human body. Microbial communities of six
genomic ‘contamination’ (Figure 8-4). Samples with high contamina- of the body habitats (representing four body regions) were character-
tion have less microbial-originated reads, and would therefore require ized using both targeted (16S rRNA gene) and shotgun metagenomic
deeper coverage for phylogenetic and functional profiling of the approaches, and provided a comprehensive view of ‘who’ is there and
microbial community. There are two main approaches for analyzing ‘what’ they might do. There are differences among body habitat in
shotgun data (see Figure 8-2): mapping (alignment) to reference relation to their phylogenetic37,38 and functional complexities33,34
(Table 8-1 and Figure 8-5). The healthy microbiome has been consid-
ered to have higher richness and diversity, so these ecological param-
eters may, in fact, be used as biomarkers of health.
Fraction of sequences that are of human origin in shotgun One of the fundamental questions addressed with large-scale
metagenomic samples obtained from different human habitats
microbiome studies is the existence and size of a ‘core’ microbiome,
defined as a subset of the community that is shared between most
Microbiome Duplicate or low quality Human contamination individuals.41 The human microbiome is highly variable both within a
single subject and between different individuals, resulting in a very
Anterior nares (11 B) small core.37,41 Another fundamental question relates to the overall
composition of the microbiota, and whether the human habitat com-
Buccal mucosa (14 B) mensals could be used to categorize humans in clusters (community
classes) or if the overall microbiota composition is on a gradient. While
Supragingival plaque (15 B) the debate is still on, the MetaHIT project provided evidence for the
Tongue dorsum (16 B)
existence of three robust stool community classes (enterotypes42), indi-
cating that the intestinal microbiota variation is generally stratified,
Posterior fornix (7 B) and not on a gradient. HMP data confirmed these stool community
classes and expanded this observation to nasal, oral, skin and vaginal
Stool (17 B) habitats.39 Overall, two habitat types were identified (type I: low diver-
sity and high silhouette value; and type II: high diversity with median
0% 25% 50% 75% 100% Shannon index and low silhouette value), as well as two to six com-
Proportion of reads munity classes for each of the studied body habitats, which were associ-
ated with host factors such as gender, race, age and geography.
Community class stability is habitat-dependent, with conversion
Figure 8-4 Fraction of sequences that are of human origin in shotgun metage-
nomic samples obtained from different human habitats. The fractions (in billions,
among community classes belonging to type II habitats being more
B) are calculated based on a subset of the HMP data34 obtained from the HMP common than among the type I habitats. While the mechanisms of
DACC site: www.hmpdacc.org. conversion are not known, it is recognized that the switching is more
TABLE
8-1 Taxonomic and Functional Richness Estimated for Each Body Site*
16S rRNA Sequencing Shotgun Metagenomic Sequencing (SMS)
Body Species Functional Metabolic
Region Body Habitat OTUs† Genus‡ Phyla‡ (Genomes)§ Genes§ Modules¶ Pathways¶
Nasal Anterior nares 2264 (1997–2611) 36 (10–83) 5 (3–9) 216 (330) 449 840 198 290
Oral Buccal mucosa 4650 (3212–7076) 44 (16–77) 6 (5–9) 315 (426) 3 264 223 203 291
Supragingival plaque 8254 (7280–9421) 50 (23–86) 6 (5–10) 451 (580) 21 409 084 223 291
Tongue dorsum 7947 (6663–9314) 43 (19–80) 6 (5–8) 402 (580) 21 187 585 217 291
Gut Stool 33 627 (31 147–36 391) 40 (13–82) 4 (2–9) 396 (616) 26 572 444 230 290
Urogenital Posterior fornix 1466 (1228–1786) 11 (2–50) 3 (1–6) 212 (311) 186 169 180 275
*HMP data, healthy adults.

†
16S rRNA – OTUs – based on V1-V3 16S rDNA from 238 subjects including only samples with 1000 or more tags.37
‡
16S rRNA – Genus/phyla based on normalized 1k sequences per sample, based on ~200 subjects (~90 for posterior fornix).39
§
SMS – genomes detected is based on 0.01X depth and 1% breadth of coverage from ~100 individuals (~50 for posterior fornix).40
¶
SMS – module and pathway detection based on HumanN using data from ~100 individuals (~50 for posterior fornix).33
and functional modules with the body mass index, suggesting possible
Distribution of abundances per phyla based on targeted (16S: first pie)
and shotgun metagenomic sequencing (SMS: second pie)
diagnostic potential of microbial markers.42 It has been recognized that
the metagenomic carriage of metabolic pathways is stable among indi-
viduals despite variation in community structure,34 indicating that
Buccal mucosa taxonomic structure is more variable, while the functional capabilities
of the communities are more stable. Nevertheless, both structural and
functional configurations need to be well understood to enable trans-
lational applications of the human microbiome.
Anterior nares 16S SMS Defining the structure, function and diversity of the habitat-specific
Supragingival plaque
microbial communities in healthy subjects is essential to delineate the
basal state of a ‘healthy’ community so that perturbations leading to
dysbiosis state can be recognized and subsequently prevented and/or
16S SMS treated. However, it is worth noting that because of the high geo-
16S SMS graphic and temporal variations between individuals and populations,
Firmicutes
Tongue dorsum
Bacteroidetes a ‘healthy’ microbiota has yet to be defined and it is likely that more
Actinobacteria than one reference microbiome will need to be defined to serve as a
Proteobacteria useful baseline that defines human health state.
Fusobacteria
Other 16S SMS
Microbiome and Infectious Diseases
Posterior fornix Stool The complex ecosystems in the human body experience multifactorial
interactions among the microbiota, the immune system and the infec-
tious organisms. Alterations in one of these components provokes
counter responses in the remaining ones, and the exact mechanisms
16S SMS 16S SMS regarding these interactions are complex and not well understood.
There is a great potential for the clinical application of the human
Figure 8-5 Distribution of abundances per phyla based on targeted (16S: first microbiome, but the kingdom-agnostic approach that is required for
pie) and shotgun metagenomic sequencing (SMS: second pie). The phyla beyond such progress is in its infancy, and better understanding of the complex
the five most abundant phyla are collapsed into a single category called ‘other’. relationship among organisms sharing the same niche in the human
The distributions are calculated based on a subset of the HMP data34 obtained
from the HMP DACC site: www.hmpdacc.org. host still requires the development of new tools and approaches. Nev-
ertheless, it is well accepted that infectious agents should not be viewed
outside of the context and habitat within which they reside/survive.
Associations between pathogens and the microbiome of the shared
frequent among minor community classes, whereas the major ones habitat have a long history, and in recent years have been interrogated
retain dominance over time. in greater depth. Several examples are presented here.
Moving to a much more granular analysis, studies on cross-
continental genomic variations among the HMP and MetaHIT cohorts MICROBIOME AND BACTERIAL INFECTIONS
(total of 207 individuals form Europe and North America) identified Studies have associated changes in the human microbiota as a result
10.3 million single nucleotide polymorphisms (SNPs) in the 101 refer- of both enteric and non-enteric bacterial infections in different body
ence bacterial species represented in both cohorts,43 which is a number habitats. One example is the gut microbiome; it is widely accepted
similar to the SNPs identified in the human genome (14.4 million in that bacterial community diversity in the gastrointestinal (GI) tract
179 human genomes44). The temporal stability of the SNPs has indi- increases in the proximal-to-distal direction, and that the stool is a
cated that an individual is likely to have a unique metagenomic geno- suitable representative for the microbial community in the distal
type, and while it is challenging and may take a long time to identify section of the GI tract. Because it is easy to obtain and represents the
particular variants, SNPs can serve as biomarkers providing useful richest part of the GI tract, stool samples are routinely used to profile
information for human health or disease. For example, analyses at the the distal gut and monitor/define population perturbations. For
gene level were able to identify genes significantly correlated with age, example, based on an analysis of the microbiome in fecal samples from
patients who developed Clostridium difficile infections (CDI) after Recently, the mycobiome of 96 stool samples from healthy subjects70
antibiotic therapy, it has been recognized that the CDI is associated identified 66 fungal genera, with generally mutually exclusive presence
with decreased diversity and richness of the microbiota. Compared to of either the phyla Ascomycota or Basiodiomycota. Individual-specific
patients who did not develop CDI,45 patients with recurrent disease fungal sequence diversity was relatively low compared with prokary-
also have lower diversity than those whose CDI does not recur,46 as do otic diversity, with most subjects having fewer than 10 detectable
patients with primary or recurrent symptomatic CDI, compared to genera and Saccharomyces and Candida being the dominant fungal
patients with asymptomatic colonization.47 The success of fecal micro- taxa. Other studies have focused on the mycobiome of other body
biota transplantation48–50 as a new treatment method has captivated habitats. Based on 20 healthy individuals, 74 cultivable and 11
medical and general audiences. noncultivable fungal genera (total of 101 cultivable species and each
individual carried 9–23 species) have been identified in the oral
MICROBIOME AND VIRAL INFECTIONS cavity,71 and based on 10 healthy individuals, both ascomycetous and
The eukaryotic virome of healthy subjects averages 5–10 viruses per basidiomycetous fungi were identified as normal skin flora in 14 skin
person.51,52 These viruses profoundly affect innate and adaptive immu- sites, and 11 of the 14 skin sites were dominated by fungi of the genus
nity (e.g. references 53–55). Also, prokaryotic viruses are associated Malassezia.28
with changes of the major components of the human microbiome, and A classic example of inter-kingdom interactions that affect human
bacterial phylogenetic and functional structure. Several studies have health is the mucosal Candida infection after antibiotic treatment.
suggested that bacteriophages contribute to or change the metabolic Antibiotics alter bacterial flora, which enables yeast to proliferate. This
capabilities of the bacterial community, with subsequent effects on may be due to competitive exclusion of the yeast by bacterial produc-
host phenotype.56,57 The role of commensal bacteria in viral infections tion of short-chain fatty acids, which may diminish during antibiotic
is not well understood, but it is recognized that they could promote, treatment.72,73 These antibiotic effects can last for months.74 These
inhibit or have no effect on viral replication, transmission and viral- studies highlight the importance of broad assessment of microbial
induced pathogenesis.58 At present, animal data are provocative, but interactions in human health and disease. The oral microbiome and
human data are more limited. mycobiome have also been studied, but mainly in relation to peri-
Inhibition of viral infection and virus-induced pathogenesis by the odontitis. However, periodontitis is not an ‘infection’ according to
host microbiota has been reported for several viruses, including influ- strict definitions, but rather results from complex interactions between
enza59 and human immunodeficiency virus (HIV).60 It has also been oral microbiota, the immune system and the environment. Other
postulated that normal vaginal bacterial populations protect against studies relate to fungi carriage, intensity of carriage and genotype
HIV-1 acquisition, and the lactobacilli that dominate the healthy changes over time. For example, in immunocompromised individuals
vaginal microbiota produce lactic acid which has virucidal properties.61 (such as HIV-infected asymptomatic subjects), oral C. albicans car-
On the contrary, women with lactobacillus-poor flora have an increased riage is higher than in non-HIV-infected individuals and the com-
susceptibility to other sexually transmitted viral infections in addition mensal strains colonizing HIV-infected individuals can undergo strain
to HIV, including human papillomavirus (HPV),62 herpes simplex alterations prior to causing fungal opportunistic infection in the
virus (HSV)63,64 and cytomegalovirus (CMV).65 immunocompromised hosts.75
The microbiota can also promote viral infection and virus-induced
pathogenesis in cases of other viral infections. Using mice, it has Microbiome and Parasite Infections
been demonstrated that the endogenous microbiota directly enhances Many human infections are caused by parasites (protozoan and meta-
replication of some enteric viruses such as poliovirus (Picornaviridae) zoan) that share the human ecosystems with other microbial com-
and reoviruses (Reoviridae).66 This is a result of bacterial products munity members and subsequently metabolize and modify substrates
binding to virus particles, which enhances the viral attachment to interactively.
the epithelial cells, as demonstrated by increased virus infectivity In the case of pathogenic protozoan parasites, studies have shown
in mouse embryonic fibroblasts and human HeLa cell lines by the that normal gut microflora can decrease susceptibility (Cryptosporid-
N-acetylglucosamine-containing surface polysaccharides of gram- ium parvum76) or can stimulate pathogenicity (Giardia duodenalis77).
positive bacteria (peptidoglycan) and gram-negative bacteria (LPS). Intestinal commensal bacteria have also been suggested to increase
Establishment of chronic infection of Mouse Mammary Tumor Virus virulence (Entamoeba histolytica78,79) due to the interaction among
(MMTV; Retroviridae) also requires normal microbiota, as demon- amebae of low pathogenicity and a variety of gram-negative bacteria,
strated by inability of the MMTV to be transmitted to the offspring of or can increase cytopathic effect of E. histolytica, but remains avirulent
germ-free and ABX mice. in case of E. dispar.80 Other body site microbiomes have been studied
with a goal to define possible associations with protozoan pathogens,
MICROBIOME AND MICRO-EUKARYOTIC and to provide a more accurate description of the microbiome/
INFECTIONS pathogen complex interplay. For example, a study of the relationship
The community of all non-prokaryotic lower eukaryotes living in and between vaginal microbiome and Trichomonas vaginalis showed that
on the human body (including fungal and other microbial protozoan T. vaginalis is associated with vaginal microbiota clusters that consist
and metazoan parasites) constitutes the human meiofauna. Similar to of low proportions of lactobacilli and high proportions of Mycoplasma,
studies on prokaryotic community structure, NGS has expanded our Parvimonas, Sneathia and other anaerobes.81
view of meiofauna abundance and diversity, but the diversity and Many metazoan parasites such as parasitic helminths, including
extent of this population is still quite underappreciated. This is unfor- flatworms (cestodes, trematodes) and roundworms (nematodes),
tunate, because meiofauna drive much morbidity, caused by fungi reside in the GI tract, directly modulate the immune system and are
(e.g., Candida, Aspergillus67), unicellular protozoa (e.g., Giardia, Ent- likely to indirectly influence the immune response through their effect
amoeba68) and helminths in low- and middle-income countries (e.g., on the intestinal microbiome. The diversity and richness of the bacte-
Ascaris, hookworm, whipworm69). These meiofauna and their prod- rial communities along the human gut varies among the jejunum,
ucts can affect host cells as well other commensal microbes in shared ileum, caecum and rectum,82 and similarly, different parasitic hel-
niches. minths reside in different locations of the GI tract, and therefore share
a niche with specific body site microbiomes in the GI tract. In case of
Microbiome and Fungal Infections infection with the flatworm Schistosoma mansoni (which is found in
At present, more than 400 species of fungi associated with the human the superior mesenteric veins draining the large intestine), studies have
body have been identified. The majority are difficult or impossible to shown that the host microbiota contributes to the induction of the Th1
culture, therefore culture-independent methods coupled with NGS response82 and that gut microbiota metabolic responses are associated
technology allow better characterization of the human mycobiome. with the helminth infection.83 In another flatworm infection
(Opisthorchis viverrini, small intestine/biliary duct), perturbation of whipworm T. trichiura have provided evidence for an association of
the GI tract microbiome has also been documented,84 and more than the helminth infection with an altered microbiota.86 Similar studies in
60 OTUs detected in the biliary system confirm that bacteriobilia and humans have shown controversial results; one study failed to identify
a microbial community are associated with the parasite. It has been an association87 and another did detect an association resulting in
suggested that the parasites and their microbiota may together drive higher microbiome richness of helminth-infected individuals.88 Studies
the distinctive immune response to this infection (including biliary related to another infection (experimental hookworm infection with
system inflammation which leads to periductal fibrosis, which is a Necator americanus, jejunum) observed a slight (although not signifi-
precursor of cholangiocarcinoma). cant) increase in microbial community richness upon hookworm
Many parasitic roundworms also reside in distinct areas of the infection and also suggests that helminths may restore healthy intesti-
gastrointestinal tract. In the case of the parasitic whipworm Trichuris nal microbiomes.89 How the helminths affect the composition of the
muris (caecum/proximal colon of mice), the intestinal microbiota ben- intestinal microflora in humans, and whether the infections influence
efits this parasite by providing a structural component necessary for immunity to other pathogens through effects on the intestinal micro-
hatching of the parasite’s ova.85 In turn, after hatching, the parasite’s flora, is unknown.90 Several studies have provided evidence that intes-
early larval stages burrow into the intestinal mucosa and allow bacteria tinal helminths benefit the host by preventing allergic responses and
to pass the mucosal barrier and the host immune system. Thus, the controlling autoimmune responses.91 The ‘therapeutic potential’ of
host has to respond in a regulated way to avoid pathological conse- helminths, may be due to their ability to maintain microbial richness,
quences, suggesting that the parasite plays an important role in this and restore microbial homeostasis in the GI tract.
regulation, since during co-evolution it has not only adapted to coexist
but also to utilize this ecosystem for its own reproduction (and hence References available online at expertconsult.com.
survival). Similarly, studies in rhesus macaques with the human
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SECTION 2 Syndromes by Body System: Skin and Soft Tissue
9
Viral Exanthems
ADILIA WARRIS | FRANK P KROON
KEY CONCEPTS the onset of the rash. The incubation period is 11–20 days. The peak
age of infection is between 1 and 8 years.1
• An exanthem in a patient with fever can provide the clinician
with an additional clue to the etiology of the disease. CLINICAL FEATURES
• The kind of efflorescence and distribution of the exanthem may The lesions begin as papules, but progress within hours to clear vesicles
give an indication of the causative agent. surrounded by a variable halo of erythema. Vesicles are often oval, with
the long axis parallel to skin creases, and commonly itch (Figure 9-1).
• A systemic history of immunizations, travel, exposures (e.g. New lesions appear progressively over 5–7 days. The head and upper
insects) and behavior (e.g. sexually transmitted diseases) is trunk are affected first and most densely, the limbs have fewer lesions,
essential.
which appear later. The vesicular fluid opacifies, and in 2–3 days a
• The age, the immune state of the patient, geographic location central dimple appears. A crust then forms from this center outward,
and season will narrow down the broad differential diagnosis. and falls off after about 5 days. Prodromal symptoms of malaise, head-
ache and loss of appetite are mild and more common in adults. Unless
secondary infection of the skin has occurred, scarring is limited to
faint, pale outlines. Indicators of severe disease include confluence of
the rash and multiple mucosal lesions (e.g. oropharynx, genital tract).
Introduction Herpes zoster is heralded by pain in the dermatome served by the
affected sensory root. Groups of papules then appear at the sites where
In this chapter we will focus on the viral diseases frequently accompa- the cutaneous nerves reach the skin. The skin eruption will be restricted
nied by an exanthem. For an extensive review of the clinical presenta- to one dermatome unilaterally in the immunocompetent host; in the
tion, pathogenesis, diagnosis and treatment of the individual infections immunocompromised patient multidermatomal skin eruptions or
the reader is referred to the specific chapters elsewhere in this book. generalization may occur. The papules progress to vesicles, pustules
Viral causes of rash are outlined in Table 9-1. and crustae, but, unlike varicella, lesions may become confluent and
form large, flaccid bullae that rupture to leave weeping bare areas
Classic Viral Exanthems (Figure 9-2). Uncomplicated lesions heal in 4–6 days, but severe rashes
may take 3–5 weeks. Skin depigmentation is often the only sequela.
Scarring is rare.
Varicella (see also Chapter 166)
Varicella zoster virus (VZV), like other herpesviruses, causes a primary COMPLICATIONS
infection (varicella or chickenpox) with seroconversion and subse- Secondary bacterial skin infection (Streptococcus pyogenes, Staphy
quent lifelong latency. Reactivation causes localized neurologic disease lococcus aureus) is the commonest complication of VZV infection and
with an associated skin eruption (herpes zoster or shingles). VZV is occurs in 5–10% of the patients (Figure 9-3). Bacterial infections can
transmitted by droplets and by direct contact with the contents of the lead to abscess formation, cellulitis or erysipelas, and rarely to necro-
vesicles and is highly contagious. Virus shedding starts 2 days before tizing fasciitis. Children are particularly prone to develop toxic shock
TABLE
9-1 Viral Exanthems Categorized by their Efflorescence
Erythematous Maculopapulous Papulovesiculous Vesiculobullous Petechial and Purpuric
Morbillivirus Hepatitis B virus Varicella-zoster virus Cytomegalovirus (congenital)
Rubella Gianotti–Crosti syndrome Herpes simplex virus Rubella (congenital)
Human herpesvirus 6 Asymmetric periflexural exanthem Variola virus Enterovirus
Human herpesvirus 7 Vaccinia virus PPGSS
Parvovirus B19 Monkeypox virus Flaviviruses
Epstein–Barr virus Cowpox virus Viral hemorrhagic fevers
Cytomegalovirus Enteroviruses
Enteroviruses
HIV
Alphaviruses*
Flaviviruses
Menangle virus
PPGSS, Papular–purpuric gloves and socks syndrome.

*Alphaviruses: Chikungunya virus, O’nyong-nyong virus, Sindbis virus, Ross River virus, Mayaro virus.
75
76 SECTION 2 Syndromes by Body System: Skin and Soft Tissue
Figure 9-3 Secondary staphylococcal infection of varicella lesions. Staphylococ-

cal pyrogenic exotoxin has caused a ‘scalded skin’ type of lesion surrounding the
infected spots. (Courtesy of Dr M.G. Brook.)
syndrome. Secondary bacterial infection can also complicate herpes

zoster, especially when severe and in the elderly.
Older patients are at risk of developing postherpetic neuralgia,
defined by persisting pain after an episode of herpes zoster. Average
duration in those aged over 60 years is 60 days, but may persist much
longer.
MANAGEMENT
b Antiviral treatment has minimal impact on mild childhood varicella
and is not recommended. In adolescents and adults, (val)aciclovir
Figure 9-1 The lesions of varicella (chickenpox). At the same time papules, shortens the duration of VZV infections and may reduce the risk of
vesicles and pustules, some of which are beginning to crust from the center, complications. Intravenous aciclovir (10 mg/kg q8h) is the treatment
are seen. of choice for VZV infections in immunocompromised patients or for
severe and complicated VZV infections. The availability of a live atten-
uated VZV vaccine has been shown to have an excellent efficacy to
prevent varicella.2,3
In herpes zoster, antiviral treatment started in the first 48 hours
after the onset of the skin eruption reduces the duration of the rash
and ameliorates zoster-associated pain, but does not prevent posther-
petic neuralgia.4,5 Prevention of herpes zoster and postherpetic neural-
gia in elderly persons has been shown by immunization with the VZV
vaccine.6 Secondary bacterial skin infections should be treated promptly
with antibiotics with activity against Strep. pyogenes and Staph. aureus.
Postherpetic neuralgia responds poorly to analgesics. Amitriptyline or
antiepileptic drugs may give some relief in patients with persistent
postherpetic neuralgia.
Morbilli (see also Chapter 163)

Morbilli is an exanthematic disease caused by the measles virus. In
most populations the majority of adults and children are immune due
to exposure to the measles virus or vaccination. In resource-poor
countries with low vaccination coverage, measles is still a significant
cause of morbidity and mortality. Humans are the only known reser-
voir. The infection is highly contagious and spread is airborne, by
droplets. The incubation period lasts 10–14 days. The prodromal phase
consists of symptoms of malaise, fever, anorexia, followed by conjunc-
tivitis, coryza and cough, and lasts on average for 2–3 days. The period
of contagion ranges from 5 days before to 4 days after the appearance
of the rash. Maximum contagion is probably during the late prodromal
phase, when fever and respiratory symptoms develop.7
CLINICAL FEATURES
Figure 9-2 The rash of herpes zoster. It can be seen that the lesions occur in
groups, with coalescence of lesions in the larger groups. (Courtesy of Barbara A. During the late prodromal phase, patients may develop a pathognomic
Bannister, MD.) enanthem known as Koplik’s spots. Koplik’s spots are 1–3 mm grayish
Chapter 9 Viral Exanthems 77
Figure 9-6 Secondary infections complicating measles. Perioral infection and

paranasal herpes simplex lesion in a 2-year-old girl. (Courtesy of Barbara A. Ban-
nister, MD.)
The differential diagnosis of the measles exanthem includes human

herpesvirus 6 (HHV-6) infection, rubella, infectious mononucleosis,
scarlet fever, Kawasaki disease, toxic shock syndrome, dengue, Rocky
Figure 9-4 The acute rash of measles. Marked conjunctivitis accompanied the Mountain spotted fever and drug allergy. Measles can usually be dis-
maculopapular skin lesion in this unimmunized adult. (Courtesy of Barbara A. tinguished clinically by the intensity of the measles rash, its brownish
Bannister, MD.)
coloration and the combination with other physical findings (e.g.
coryza and conjunctivitis).
COMPLICATIONS
When poor hygiene, crowding or malnourishment exists, severe infec-
tion of macerated perioral or perinasal skin (cancrum oris) may be
caused by pyogenic organisms, often accompanied by herpes simplex
and/or anaerobic mouth flora (Figure 9-6).
MANAGEMENT
After introduction of the live attenuated measles vaccine in the 1960s
this epidemic disease was rapidly controlled. Outbreaks may be seen
in areas with poor compliance to this vaccination. There is no specific
treatment.
Rubella (see also Chapter 163)

Rubella, also known as German measles, is caused by the rubella
virus, and transmitted from person to person by respiratory secretions.
The infectious period starts 7 days before the onset of the rash and
continues for another 2 days. Most shedding of infectious virus occurs
before the onset of the rash. The incubation period is 15–20 days. In
susceptible populations, the peak age of infection is between 5 and
9 years.8
CLINICAL FEATURES
Prodromal symptoms such as malaise are minimal in children,
although the lymph nodes begin to enlarge 3–4 days before the onset
of the rash. Large tender lymph nodes high in the occipital region are
Figure 9-5 The generalized confluent maculopapular rash as seen in measles. typical of rubella. Adults may suffer 3–4 days’ prodrome with low-
grade fever, muscle pains and headache. The rash presents with pink-
red macules and papules on the face and spreads to the chest and
or bluish elevations with an erythematous base, seen on the buccal peripheries over 1–2 days (Figure 9-7). The exanthem begins to fade
mucosa usually opposite the molars or sometimes on the labial mucosa after 1–2 days in order of appearance and disappears completely in 2–3
(see Chapter 163, Figure 163-2). They have been described as ‘salt days. There is often an enanthem with punctate erythematous spots
grains on a red background’. They occur approximately 48 hours before scattered over the hard and soft palate and uvula, called the Forchheim-
the measles exanthem and disappear by the second day of the exan- mer sign. It mimics the rashes of parvovirus infection, echovirus infec-
them. The characteristic rash is maculopapular and blanches, begin- tions and mild scarlet fever or early Kawasaki disease, although it does
ning on the face and spreading to the neck, upper trunk, lower trunk not desquamate on healing.
and extremities (Figures 9-4 and 9-5). The lesions may become conflu- Newborns with congenital rubella syndrome (CRS) show a com-
ent, especially in the face. Palms and soles are rarely involved. The pletely different exanthem. The rash consists of petechial/purpuric-like
cranial-to-caudal progression of the rash is characteristic. The rash lesions scattered over the skin (Figure 9-8). This characteristic exan-
begins to fade 3–4 days after it first appears, and changes to a purplish- them is referred to as ‘blueberry muffin spots’. These spots are thought
brownish color, which is sometimes followed by fine desquamation. to be the consequence of extramedullary dermal erythropoiesis.9,10
Clinical improvement ensues within 48 hours of the appearance of the Congenital cytomegalovirus (CMV) infection should be in the dif-
rash. Atypical mild measles may occur in adolescents and young adults ferential diagnosis when confronted with a neonate with ‘blueberry
who have been vaccinated as a child. muffin spots’.
Figure 9-7 Presenting rash with pink-red macules and papules on the face and
neck as seen in rubella.
Figure 9-9 Parvovirus B19 infections. Characteristic skin abnormalities of the

‘slapped cheeks’, circumoral pallor and a maculopapular exanthem on the trunk.
transmission by the administration of blood or blood products con-

taining parvovirus B19 may occur.11
Figure 9-8 Congenital rubella syndrome. Characteristic rash called ‘blueberry CLINICAL FEATURES
muffin spots’ in a newborn with congenital rubella.
The childhood infection usually manifests itself as erythema infectio-
sum (fifth disease or slapped cheek syndrome), a mild febrile illness
MANAGEMENT with rash. In the first week the viremia is accompanied by a nonspecific
flu-like illness, with fever, malaise, myalgia, headache and pruritus.
The illness is mild and self-limiting; specific treatment is not available. Between 2 and 5 days later (i.e. 1–2 weeks after infection) the ery-
An excellent live attenuated rubella vaccine has been available since thematous malar rash appears (the so-called slapped cheek rash) with
1968 and is used in many parts of the world in childhood immuniza- circumoral pallor (Figure 9-9). This facial rash is often followed by
tion programs and has led to a marked reduction in the prevalence of a maculopapular exanthem on the trunk and extremities, which
rubella and CRS. confluences into a lacy, reticular pattern. In adults, four patterns of
polymorphous skin manifestations have been described including
Erythema Infectiosum papular–purpuric gloves and socks syndrome and asymmetric peri-
Erythema infectiosum is caused by human parvovirus B19, the only flexural exanthem.12 By the time the rash develops, viremia and symp-
member of the Parvoviridae family pathogenic to humans. Cases can toms have resolved. The rash disappears within a week. In adults the
be sporadic or can occur in clustered outbreaks. Most individuals arthralgia may be much more prominent than the rash, and these
become infected during their school years, with over 70% seropreva- complaints may persist for weeks. In such cases, early rheumatoid
lence rates in adults. Approximately 25% of the infections are asymp- arthritis may be suspected clinically.
tomatic, 50% will have nonspecific flu-like symptoms and 25% will
present with the classic symptoms of parvovirus B19 infection includ- COMPLICATIONS
ing rash and/or arthralgia. Parvovirus B19 is transmitted from person Severe outcomes may occur in immunocompromised patients and
to person via respiratory secretions. The incubation period is 4–14 patients with hemoglobinopathies. Infection in these patient groups
days. Furthermore, vertical transmission, resulting in congenital infec- can cause a serious prolonged chronic anemia (pure red cell aplasia)
tion (hydrops foetalis, intrauterine fetal death, miscarriage), and owing to persistent lysis of red blood cell precursors.
MANAGEMENT COMPLICATIONS
Treatment of parvovirus B19 infection is symptomatic. Epstein–Barr virus infections are associated with Stevens–Johnson
syndrome and persistent erythema multiforme.16
Roseola Infantum
Roseola infantum is caused by human herpesvirus 6 (HHV-6).13 MANAGEMENT
Ninety percent of cases occur in children younger than 2 years with Specific treatment is not available.
a peak between 7 and 13 months of age. Seroprevalence rates in
adults range from 70% to 95%. The most common route of HHV-6
transmission appears to be via saliva from mother to child. Perinatal Cytomegalovirus Infection
transmission is also possible; approximately 2% of pregnant women Disease caused by cytomegalovirus is variable, ranging from no disease
shed low levels of virus in genital secretions. The incubation period is in normal hosts to life-threatening infections in immunocompromised
5–15 days. patients.
CLINICAL FEATURES CLINICAL FEATURES
The classic manifestation of HHV-6 infection in children (roseola
Most primary infections are subclinical during childhood, although in
infantum, exanthema subitum, sixth disease) is an abrupt onset of high
young adults a mononucleosis syndrome with fever and lymphade-
fever that lasts for 3–5 days, often accompanied by irritability, although
nopathy can be seen. A maculopapular and rubelliform rash may occur
most children appear well. Furthermore, malaise, palpebral conjunctiv
in CMV mononucleosis.17 The rash may develop after administration
itis, edematous eyelids, uvulo-palatoglossal junctional macules or
of penicillins and is thought to result from immunologic reactions to
ulcers (sometimes called Nagayama spots), mild respiratory and gas-
cellular antigens that are uncovered or expressed in association with
trointestinal symptoms and a bulging fontanel may be present. As fever
acute CMV infection. CMV mononucleosis needs to be differentiated
subsides, a blanching macular or maculopapular nonpruritic rash
from EBV infection and malignancies.
develops, starting on the neck and trunk and spreading to the face
Congenital infections in newborns, mainly due to primary infec-
and proximal extremities. Sometimes this rash is vesicular. The rash
tion in a pregnant woman, can present with a petechial/purpuric rash
usually persists for 1–2 days, but can disappear within several hours.
(‘blueberry muffin spots’), as seen in CRS.9
Acute HHV-6 infection can also present as a febrile illness without a
rash. Cervical, postauricular and/or occipital lymphadenopathy are
COMPLICATIONS
common but appear later during the disease. Primary infection in
adults is rare but might present as a mononucleosis-like syndrome Skin manifestations of acute CMV infections are usually mild but
of varying severity (with or without an exanthem), with prolonged can occasionally be severe, ranging from erythema multiforme to
lymphadenopathy. epidermolysis.18,19
The rash can be easily misdiagnosed as drug allergy. Furthermore,
the differential diagnosis of the exanthem of roseola infantum includes MANAGEMENT
rubella and rubeola, erythema infectiosum and scarlet fever. CMV infections in immunocompetent patients are self-limiting and
specific treatment is not indicated. In contrast, antiviral treatment is
COMPLICATIONS indicated for congenital infections and CMV infections in immuno-
HHV-6 infections have been associated with seizures, either secondary compromised patients (see Chapters 56 and 80).
to the high fever or to the infection itself (encephalitis).
MANAGEMENT Acute HIV Infection (see also Chapter 93)

Most cases are benign and self-limiting. Treatment is supportive. Acute infection with human immunodeficiency virus (HIV) may
present with a skin rash.
HIV is transmitted via unprotected sexual intercourse, vertical
Nonclassic Viral Exanthems transmission and incidents with blood-to-blood contact.
Epstein–Barr Virus Infection CLINICAL FEATURES

Infectious mononucleosis is caused by Epstein–Barr virus (EBV) and The majority of patients with an acute HIV infection appear to be
results from exposure to the oral secretions of seropositive individuals. symptomatic (40–90%).20 The usual time from HIV exposure to the
EBV shares the properties of lifelong latency and persistence with other development of symptoms is 2–4 weeks. Acute HIV infection is char-
members of the herpesvirus family. The incubation period is 2–8 weeks acterized by an abrupt onset of symptoms; the clinical syndrome devel-
in adolescents and young adults but probably shorter in younger ops within 24–48 hours and lasts up to 2 weeks. The most common
children. findings are fever, lymphadenopathy, mild hepatosplenomegaly, sore
throat, painful mucocutaneous ulceration (mouth, esophagus, penis,
CLINICAL FEATURES anus), myalgia/arthralgia, diarrhea, headache, nausea/vomiting, weight
Classic infectious mononucleosis is characterized by fever (mean loss and dry cough. The presence of mucocutaneous ulcers is sugges-
duration of 2 weeks), angina with tonsillitis, malaise and cervical tive of the diagnosis.
lymphadenopathy. In children, primary infection is often asymptom- The exanthem, occurring in 40–80% of symptomatic patients,
atic. A rash, which may be macular, petechial, scarlatiniform, urticarial typically occurs 48–72 hours after the onset of fever and persists for
or erythema multiforme-like, is present in about 10% of cases between 5–8 days.20 The upper thorax and collar region and the face are most
days 4 and 6 of the illness and is localized mainly on the trunk often involved, though the scalp and extremities, including the palms
and upper extremities. The administration of penicillins (especially and soles, may be affected. The lesions are characteristically small
ampicillin and amoxicillin) produces a pruritic maculopapular to (5–10 mm), well-circumscribed, oval or round, pink to deeply red-
morbilliform eruption in 90–100% of patients.14,15 This rash has colored macules or maculopapules (Figure 9-10). Vesicular, pustular
a prolonged duration (up to 10 days). Streptococcal pharyngitis/ and urticarial eruptions have also been reported.
tonsillitis, CMV infection, thrombocytopenic purpura, lupus erythe- The differential diagnosis of acute HIV infection includes, among
matosus and malignancies might give a comparable clinical picture to others, mononucleosis due to EBV or CMV, toxoplasmosis, rubella and
that seen in infectious mononucleosis. syphilis.
Figure 9-11 Hand, foot and mouth disease. Painful ulcerative lesions on the
tongue and buccal mucosa.
mosquitoes have spread to Europe and the Americas. In 2007 a local-

ized outbreak was reported in north-eastern Italy.
CLINICAL FEATURES
The incubation period is 2–3 days (range 1–12 days). The majority of
those infected (>75%) will develop symptoms including an acute onset
Figure 9-10 The lesions in HIV are characteristically small (5–10 mm),
well-circumscribed, oval or round, pink to deeply red-colored macules or
of high fever that typically lasts for two days. The cutaneous manifes
maculopapules. tations occurring in 40–50% of the cases appear 3–5 days after the
onset of the fever, and commonly consists of a macular or maculo-
papular rash of the trunk and limbs which subsides within 4 days.22
The most disabling symptom is polyarthralgia or polyarthritis which
MANAGEMENT usually lasts for 1–2 weeks. Recovery is faster in younger patients. The
joint pains may last as long as 2 years in elderly patients. The rash is
Antiviral therapy is recommended for all persons with HIV infection indistinguishable from other viral infections but additional signs and
and should be offered to those with an early HIV infection. symptoms should give a suspicion of chikungunya.
Viral Hemorrhagic Fevers COMPLICATIONS
Although a number of viral hemorrhagic fevers can give skin rashes, Neurological manifestations like encephalopathy, acute flaccid paraly-
only the exanthem caused by dengue is discussed in this chapter. The sis and Guillain-Barré syndrome are rare.
viral hemorrhagic fevers are discussed in more detail in Chapter 132.
Dengue (see also Chapter 133) is caused by a flavivirus most com- MANAGEMENT
monly transmitted by Aedes aegypti. The A. aegypti and dengue viruses Currently there is no specific therapy.
are endemic in every continent except Europe and Antarctica. Epi-
demic dengue hemorrhagic fever occurs predominantly in Asia and the Hand, Foot and Mouth Disease
Americas. Hand, foot and mouth disease (HFMD) is caused by enteroviruses and
is most commonly associated with coxsackievirus A6 and A16 and/or
CLINICAL FEATURES
enterovirus 71.23 The epidemics observed in individual countries seem
The manifestations of the disease range from a relatively mild illness to be associated with the warmer seasons (summer and early fall).
(dengue fever), characterized by fever, rash, headache, muscle and HFMD is highly contagious and is spread by oral–oral and fecal–
joint ache, to the serious manifestation of dengue hemorrhagic fever. oral routes. Fecal shedding may last for 4–6 weeks but its relevance in
The macular or maculopapular rash, usually at the face, thorax and transmission is unknown. It typically affects children under 10 years
flexor surfaces, with islands of normal skin, usually appears 3–7 days of age. The incubation period is 3–6 days.
after onset of the fever and lasts for 2–4 days.21 The rash resembles
those observed in measles, Kawasaki disease and scarlet fever. CLINICAL FEATURES
A 12–36-hour prodrome of low-grade fever, malaise, cough, anorexia,
COMPLICATIONS
abdominal pain and sore mouth occurs. Patients may present with
Dengue hemorrhagic fever is the most serious manifestation of dengue either exanthem or enanthem but most manifest both. Painful ulcer-
with plasma leakage syndrome, thrombocytopenia and life-threatening ative lesions in the oral cavity are most commonly found on the hard
bleeding problems. palate, tongue and buccal mucosa. The enanthem begins as 2–8 mm
MANAGEMENT erythematous macules and papules, which progress through a short
vesicular stage to form a yellow-gray ulcer with an erythematous halo.
Treatment consists of supportive care. Lesions may coalesce, and the tongue may become red and edematous
(Figure 9-11). Pain may interfere with oral intake. The oral lesions
Chikungunya (see also Chapter 133) resolve spontaneously in 5–7 days.
Chikungunya is caused by an alphavirus and can be transmitted by The skin rash is characterized by 2–3 mm erythematous macules
both Aedes aegypti and A. albopictus mosquitoes. The disease occurs in or papules with a central gray vesicle; these usually appear shortly after
Africa, Asia and the Indian subcontinent. In the past decades Aedes the oral lesions, with the hands more commonly involved than the feet
Figure 9-14 Acropapulovesicular syndrome. Generalized monomorphic exan-

them consisting of erythematous papules and papulovesicles distributed
symmetrically.
TABLE Viral and Bacterial Infections and

9-2 Immunizations Associated with the
Gianotti–Crosti Syndrome
Figure 9-12 Hand, foot and mouth disease. The skin rash is characterized by
Viral infections Hepatitis A, B and C virus, Epstein–Barr virus,
erythematous macules or papules, with the hands more commonly involved than
cytomegalovirus, human herpesvirus 6,
the feet.
coxsackievirus (A16, B4, B5), echovirus,
rotavirus, parvovirus B19, respiratory
syncytial virus, parainfluenza virus, mumps
virus, HIV
Bacterial infections Group A streptococci, Mycoplasma

pneumoniae, Bartonella hensalae, Borrelia
burgdorferi
Immunizations Measles–mumps–rubella, polio, influenza,
diphtheria, pertussis, hepatitis B
This syndrome is also named Gianotti–Crosti syndrome (GCS). Ini-

tially, this syndrome was diagnosed in association with anicteric hepa-
titis B infection. It is well known that several viruses and some bacteria
can cause it, and the literature suggests that it is also associated with
Figure 9-13 Hand, foot and mouth disease. Typical vesicles are seen on the foot immunizations (Table 9-2).25–28 The pathogenesis is unclear. It mainly
of a 3-year-old child. (Courtesy of Barbara A. Bannister, MD.) affects children between 2 and 6 years of age, but there are numerous
reports of GCS in adults, mainly women, suggesting hormonal factors
play a role.29
(Figures 9-12 and 9-13). The sides of the fingers and dorsal surfaces
are more often involved than the palms and soles. Most children will CLINICAL FEATURES
develop lesions at other sites next to the hands, feet and mouth, and The rash is characterized by a monomorphic exanthem consisting of
widespread vesicular exanthema is not uncommon.24 Lesions appear skin colored to erythematous papules and papulovesicles with a diam-
elliptical, with the long axis parallel to skin lines, and may be asymp- eter of 2–4 mm distributed symmetrically on the cheeks, nares and
tomatic or painful. They crust and gradually disappear over 5–10 days the extensor side of the limbs (Figures 9-14 and 9-15). Larger plaques
without scarring. of confluent papules can be seen on the elbows and knees. The non-
Stomatitis caused by herpes simplex virus is clinically indistin- itching exanthem develops within a week and disappears in 2–4 weeks;
guishable from the oral lesions seen in HFMD, although the former is however, cases have been described in which the skin abnormalities
not followed by an exanthem. Other differential diagnostic consider- lasted for 4 months. Malaise, lymphadenopathy, hepatosplenomegaly
ations are herpangina, infections caused by EBV, HSV and VZV, and low-grade fever may accompany the rash.30
Behçet’s disease and syphilis in adults. Henoch–Schönlein purpura, erythema multiforme, HFMD, pity-
MANAGEMENT riasis lichenoides and asymmetric periflexural exanthem of childhood
may mimic the Gianotti–Crosti syndrome. Papular urticaria can also
The illness is mild and self-limiting. Symptomatic treatment with give a comparable exanthem.
simple analgesics may be indicated.
MANAGEMENT
Acropapulovesicular Syndrome Specific treatment is not indicated. Due to the association (although
Papular acrodermatitis of childhood or acropapulovesicular syndrome sporadic) with hepatitis B virus infections, it is recommended to
is a papular or papulovesicular skin eruption localized on the limbs. perform serology to exclude hepatitis B virus infection.
Unilateral Laterothoracic Exanthem CLINICAL FEATURES

of Childhood Symmetric erythema and edema of the hands and feet progress to
petechial and purpuric macules and papules that are followed by des-
31
In 1962 a new localized exanthem was reported and in 1992 was quamation (Figure 9-16). A sharp demarcation is seen at the wrists and
described as laterothoracic exanthem.32 Because this exanthem is not ankles. Very seldom the rash extends to nonacral sites. Occasionally,
only laterothoracically located, the term asymmetric periflexural exan- complaints of pruritus or pain may accompany the skin eruption.
them is preferred. It is most likely caused by a virus, with a human Fever and lymphadenopathy may accompany the rash but is not
herpesvirus considered to be the most likely cause. The peak age of seen in the juvenile variant.38 A polymorphous enanthem, including
infection is 2 years.
CLINICAL FEATURES
The rash consists of an erythematous papular, sometimes vesicular or
squamous exanthem with a mild pruritus, localized around a skin fold
such as the axilla or groin. The skin fold itself is not affected. The
exanthem consists of 1 mm erythematous papules that are often sur-
rounded by a pale halo, followed by eczematous patches separated by
normal skin. Centrifugal progression of the lesions can be seen for
8–15 days, with spontaneous recovery within 4 weeks. A mild upper
respiratory illness or prodrome is often associated with the rash.
Lymphadenopathy can be found but is not obligatory.33
The exanthem has to be differentiated from allergic contact eczema,
miliaria, scarlet fever, pityriasis rosea (affecting mainly adolescents)
and GCS.
MANAGEMENT
Symptomatic treatment for the pruritus may be necessary.
Papular–Purpuric Gloves and

Socks Syndrome
It has been suggested that papular–purpuric gloves and socks syn-
drome (PPGSS) is a manifestation of an underlying immunologic
mechanism that may be induced by viral or drug-related antigens.
Reported etiologies include parvovirus B19 (more than half of the
cases),34,35 measles virus, EBV, CMV, HHV-6, coxsackievirus B6 and
hepatitis B. PPGSS occurs most commonly in young adults during the
spring and summer.35,36 A juvenile variant has been described in chil- Figure 9-15 Gianotti–Crosti syndrome. Mild papulovesicular rash on the lower
dren <5 years of age showing different clinical features and seems not extremities in a young boy. (Illustration kindly provided by the Department of
to be associated with parvovirus B19 infection.37 Dermatology, Radboud University Nijmegen Medical Center, The Netherlands.)
a b
Figure 9-16 Papular–purpuric gloves and socks syndrome. Symmetric erythema and edema of the hands and feet progress to petechial and purpuric macules and
papules.
hyperemia, aphthae, petechiae and erosions on the palate, pharynx and MANAGEMENT
tongue, are seen in the majority of adult patients, being less common Symptomatic treatment with moisturizers and antihistamines may be
in infants and children. indicated.
The differential diagnosis includes erythema multiforme, HFMD,
GCS, Kawasaki disease and Rocky Mountain spotted fever, although References available online at expertconsult.com.
the defined acral distribution generally allows differentiation from
other exanthems.
COMPLICATIONS
The rash resolves spontaneously in 1–2 weeks without any known
sequelae.
KEY REFERENCES
Banatvala J.E., Brown D.W.G.: Rubella. Lancet 2004; Hubiche T., Schuffenecker I., Boralevi F., et al.: Dermato- primary infection in adults. J Am Acad Dermatol 2014;
363:1127-1137. logical spectrum of hand, foot and mouth disease from 71(1):62-69.
Borge Nelson J.S., Seabury Stone M.: Update on selected classical to generalized exanthema. Pediatr Infect Dis J Mendoza N., Diamantis M., Arora A., et al.: Mucocutaneous
viral exanthems. Curr Opin Pediatr 2000; 12:359-364. 2014; 33:e92-e98. manifestations of Epstein–Barr virus infection. Am J Clin
Brandt O., Abeck D., Gianotti R., et al.: Gianotti–Crosti syn- Kahn J.O., Walker B.D.: Acute human immunodeficiency Dermatol 2008; 9:295-305.
drome. J Am Acad Dermatol 2006; 54:136-145. virus type 1 infection. N Engl J Med 1998; 339: Moss J.M., Griffin D.E.: Measles. Lancet 2012; 379:
Cohen J.I.: Herpes zoster. N Engl J Med 2013; 369: 33-39. 153-164.
255-263. Liu W., Wu S., Xiong Y., et al.: Co-circulation and genomic Prymula R., Bergsaker M.R., Esposito S., et al.: Protection
Fretzayas A., Douros K., Moustaki M., et al.: Papular– recombination of coxsackievirus A16 and enterovirus 71 against varicella with two doses of combined measles–
purpuric gloves and socks syndrome in children and during a large outbreak of hand, foot, and mouth disease mumps–rubella-varicella vaccine versus one dose of
adolescents. Pediatr Infect Dis J 2009; 28:250-252. in Central China. PLoS ONE 2014; 9:e96051. monovalent varicella vaccine: a multicenter, observer-
Heininger U., Seward J.F.: Varicella. Lancet 2006; Mage V., Lipsker D., Barbarot S., et al.: Different pattern of blind, randomized, controlled trial. Lancet 2014;
368:1365-1376. skin manifestations associated with parvovirus B19 383:1313-1324.
Chapter 9 Viral Exanthems 83.e1
REFERENCES
1. Heininger U., Seward J.F.: Varicella. Lancet 2006; 15. Patel B.M.: Skin rashes with infectious mononucleosis 28. Hofmann B., Schuppe H.C., Adams O., et al.: Gianotti–
368:1365-1376. and ampicillin. Pediatrics 1967; 40:910-911. Crosti syndrome associated with Epstein–Barr virus
2. Marin M., Meissner H.C., Seward J.F.: Varicella preven- 16. Mendoza N., Diamantis M., Arora A., et al.: Mucocuta- infection. Pediatr Dermatol 1997; 14:273-277.
tion in the United States: a review of successes and neous manifestations of Epstein–Barr virus infection. 29. Brandt O., Abeck D., Gianotti R., et al.: Gianotti–
challenges. Pediatrics 2008; 122:e744-e751. Am J Clin Dermatol 2008; 9:295-305. Crosti syndrome. J Am Acad Dermatol 2006; 54:136-
3. Prymula R., Bergsaker M.R., Esposito S., et al.: Protec- 17. Drago F., Aragone M.G., Lugani C., et al.: Cytomegalo- 145.
tion against varicella with two doses of combined virus infection in normal and immunocompromised 30. Borge Nelson J.S., Seabury Stone M.: Update on
measles–mumps–rubella–varicella vaccine versus one humans: a review. Dermatology 2000; 200:189-195. selected viral exanthems. Curr Opin Pediatr 2000;
dose of monovalent varicella vaccine: a multicenter, 18. Wanner M., Pol-Rodriguez M., Hinds G., et al.: Persis- 12:359-364.
observer-blind, randomized, controlled trial. Lancet tent erythema multiforme and CMV infection. J Drugs 31. Brunner M.J., Rubin L., Dunlap F.: A new papular
2014; 383:1313-1324. Dermatol 2007; 6:333-336. erythema of childhood. Arch Dermatol 1962; 85:539-
4. Cohen J.I.: Herpes zoster. N Engl J Med 2013; 369:255- 19. Seishima M., Oyama Z., Yamamura M.: Erythema mul- 540.
263. tiforme associated with cytomegalovirus infection in 32. Bodemer C., Prost Y.: Unilateral laterothoracic exan-
5. Dworkin R.H., Schmader K.E.: Recommendations for nonimmunosuppressed patients. Dermatology 2001; them in children: a new disease? J Am Acad Dermatol
the management of herpes zoster. Clin Infect Dis 2007; 203:299-302. 1992; 27:693-776.
34:S1-S26. 20. Kahn J.O., Walker B.D.: Acute human immunodefi- 33. Coustou D., Leaute-Labreze C., Bioulac-Sage P., et al.:
6. Oxman M.N., Levin M.J., Johnson G.R., et al.: A vaccine ciency virus type 1 infection. N Engl J Med 1998; 339:33- Asymmetric periflexural exanthem of childhood. Arch
to prevent herpes zoster and postherpetic neuralgia in 39. Dermatol 1999; 135:799-803.
older adults. N Engl J Med 2005; 352:2271-2284. 21. Kenzaka T., Kumabe A.: Skin rash from dengue fever. 34. Grilli R., Izquierdo M.J., Farina M.C., et al.: Papular–
7. Moss J.M., Griffin D.E.: Measles. Lancet 2012; 379:153- BMJ Case Rep 2013; doi: 10.1136/bcr-2013-201598. purpuric ‘gloves and socks’ syndrome: polymerase
164. 22. Bandyopadhyay D., Ghosh S.K.: Mucocutaneous mani- chain reaction demonstration of parvovirus B19 DNA
8. Banatvala J.E., Brown D.W.G.: Rubella. Lancet 2004; festations of chikungunya fever. Indian J Dermatol 2010; in cutaneous lesions and sera. J Am Acad Dermatol 1999;
363:1127-1137. 55:64-67. 41:793-886.
9. Brough A.J., Jones D., Page R.H., et al.: Dermal eryth- 23. Liu W., Wu S., Xiong Y., et al.: Co-circulation and 35. Feldmann R., Harms M., Saurat J.H.: Papular–purpuric
ropoiesis in neonatal infants: a manifestation of intra- genomic recombination of Coxsackievirus A16 and ‘gloves and socks’ syndrome: not only parvovirus B19.
uterine viral disease. Pediatrics 1967; 40:627-635. enterovirus 71 during a large outbreak of hand, foot, Dermatology 1994; 188:85-87.
10. de Mol A.C., Vrancken S., Eggink A.J., et al.: The first and mouth disease in Central China. PLoS ONE 2014; 36. Fretzayas A., Douros K., Moustaki M., et al.: Papular–
newborn with congenital rubella syndrome during the 9:e96051. purpuric gloves and socks syndrome in children and
rubella epidemic in the Netherlands. Ned Tijdschr 24. Hubiche T., Schuffenecker I., Boralevi F., et al.: Derma- adolescents. Pediatr Infect Dis J 2009; 28:250-252.
Geneeskd 2006; 150:741-746. tological spectrum of hand, foot and mouth disease 37. Hsieh M.Y., Huang P.H.: The juvenile variant of
11. Young N.S., Brown K.E.: Parvovirus B19. N Engl J Med from classical to generalized exanthema. Pediatr Infect papular–purpuric gloves and socks syndrome and its
2004; 350:586-597. Dis J 2014; 33:e92-e98. association with viral infections. Br J Dermatol 2004;
12. Mage V., Lipsker D., Barbarot S., et al.: Different pattern 25. Cajuto R., Gelmetti C., Ermacora E., et al.: Gianotti– 151:201-206.
of skin manifestations associated with parvovirus B19 Crosti syndrome: a retrospective analysis of 308 cases. 38. Gutermuth J., Nadas K., Zirbs M., et al.: Papular–
primary infection in adults. J Am Acad Dermatol 2014; J Am Acad Dermatol 1982; 6:862-866. purpuric gloves and socks syndrome. Lancet 2011;
71(1):62-69. 26. Taieb A., Plantin P., du Pasquier P., et al.: Gianotti– 378:98.
13. Dockrell D.H.: Human herpesvirus 6: molecular Crosti syndrome: a study of 26 cases. Br J Dermatol
biology and clinical features. J Med Microbiol 2003; 1986; 115:49-59.
52:5-18. 27. Yoshida M., Tsuda N., Morihata T., et al.: Five patients
14. Pullen H., Wright N., Murdock J.M.: Hypersensitivity with localized facial eruptions associated with Gianotti–
reactions to antibacterial drugs in infectious mononu- Crosti syndrome caused by primary Epstein–Barr virus
cleosis. Lancet 1967; 2:1176-1178. infection. J Pediatr 2004; 145:843-894.
10
Cellulitis, Pyoderma,
Abscesses, and Other Skin and
Subcutaneous Infections
DENNIS L. STEVENS
KEY CONCEPTS • historic clues such as contact with insects or animals, especially
involving bites, travel to specific geographic areas, occupation or
• Skin and subcutaneous infections (SSIs) can be caused by a
wide variety of bacteria, viruses, fungi, myocobacteria and use of a hot tub
parasites. • the immune status of the host
• chronicity
• The astute clinician must evaluate the clinical signs and symp-
toms, and perform a detailed history, to include travel, insect
• anatomic distribution.
If the diagnosis cannot be established based upon the history, symp-
bites, animal bites, human bites and trauma, to develop a dif-
toms and signs, then needle aspiration, biopsy or surgical exploration
ferential diagnosis.
may be necessary to obtain specimens for appropriate staining and
• SSIs can vary in severity from mild to life-threatening and clini- culture.
cians must use acute diagnostic techniques, radiology and sur- As the antimicrobial susceptibility of these microbes varies greatly,
gical consultation to arrive at a timely diagnosis, particularly for treatment (particularly for severe infections) should be based upon the
those patients with severe signs of infection. results of microscopy, Gram stain and culture whenever possible.
• Purulent infections are most commonly caused by Staphylococ-
cus aureus and are designated as abscesses, folliculitis, furun- Epidemiology
cules and carbuncles. The area of erythema surrounding a
These infections are among the most common in all age groups. Some
purulent focus is not cellulitis.
are age-related, e.g., impetigo is more common in children, erysipelas
• Non-purulent SSIs are reddish-pink, diffuse and are caused is more common in older adults.
most commonly by group A streptococcus, but also groups B, SSIs can be caused by bacteria (including rickettsiae), fungi, viruses,
C and G. parasites and spirochetes. Although there are hundreds of possible
• Predisposing conditions for recurrent cellulitis include chronic etiologic agents (Tables 10-1 to 10-4), Staphylococcus aureus and Strep-
venous insufficiency, lymphatic obstruction and saphenous vein tococcus pyogenes are the predominant causes. SSIs caused by newly
donor site. recognized or previously rarely encountered microbes are described in
immunocompromised patients, especially patients with acquired
• Predisposing conditions for purulent Staph. aureus infection
immune deficiency syndrome (AIDS).
include nasal colonization, eczema and most likely certain
strains of MRSA containing the gene for PVL. Several noninfectious diseases can mimic infection of the soft
tissues. For example, patients who have contact dermatitis, pyoderma
• Some conditions such as septic arthritis or olecranon bursitis gangrenosum, gout, psoriatic arthritis with distal dactylitis, Reiter’s
can be associated with reddened, tender skin and pain, and syndrome, relapsing polychondritis or mixed cryoglobulinemia sec-
mimic cellulitis. ondary to immune complex disease from chronic hepatitis C or B virus
• In addition to the clinical signs of infection of the skin itself, the infection may present with erythematous rashes, with or without fever.
astute clinician must be cognizant of systemic signs of infection
to determine if more severe infection such as necrotizing fas- Pathogenesis
ciitis, gas gangrene or toxic shock syndrome is developing.
The integument is an organ that reacts to noxious, infectious, external
and internal stimuli in a limited number of ways. It is therefore not
surprising that infection can be mimicked by noninfectious condi-
tions. The rich plexus of capillaries beneath the dermal papillae pro-
Introduction vides nutrition to the stratum germinativum and the dermatocytes,
Infections of the skin and/or subcutaneous tissues are highly diverse which are bound together by tight junctions and form the barrier to
in respect to etiologic organisms, incidence, clinical manifestations, microbial invasion. Once microbes have penetrated this barrier
severity and complications. They may occur as single or recurrent through a hair follicle, cut or bite, the plexus of capillaries delivers the
episodes. Many cases are mild or self-limited, but some progress to components of the host’s defense – oxygen, complement, immuno-
cause scarring, loss of digits or limbs, or even death. globulins, granulocytes, macrophages and lymphocytes – to the site of
The terminology can be confusing because several different names infection.
may be used to describe the same condition (see Table 10-1 for Perhaps the first signal to the immune system of the presence of
nomenclature). foreign material is provided by the organisms themselves. Virtually all
When a patient presents with soft tissue infection, the clinician bacteria are comprised of proteins with an N-formyl-methionine
faces the challenge of establishing a specific diagnosis and prescribing group, which are chemoattractive to granulocytes and monocytes.
definitive treatment. Important points in diagnosis are: Other microbial cell wall components such as zymosan of yeast, endo-
• the patient’s symptoms toxins of gram-negative bacteria and peptidoglycans of gram-positive
• the general appearance of the infected site bacteria activate the alternative complement pathway,1 yielding
84
Chapter 10 Cellulitis, Pyoderma, Abscesses, and Other Skin and Subcutaneous Infections 85
TABLE
10-1 Nomenclature, Location and Etiology of Some Common Skin and Subcutaneous Infections
Terminology Subgroups Location Etiology
Pyoderma Impetigo (impetigo contagiosa) Skin Streptococcus pyogenes,

Staphylococcus aureus
Bullous impetigo Skin Staph. aureus with group II phage
Folliculitis (pustulosis) Skin, hair follicles Staph. aureus
Folliculitis (sycosis) barbae Skin, hair follicles of the beard Strep. pyogenes, Staph. aureus
Hot tub folliculitis Skin Pseudomonas aeruginosa
Abscesses Furuncle (boil, subcutaneous abscess) Subcutaneous tissue Staph. aureus

Hydradenitis suppurativa Multiple furuncles in sweat glands: axilla, Staph. aureus and other bacteria, including
groins gram-negative bacilli and anaerobes
Carbuncle Dense group of furuncles in areas of thick Staph. aureus
skin: back of neck, shoulders, buttocks
Cellulitis Skin and subcutaneous tissue Staph. aureus, Strep. pyogenes, group C and
G streptococci, P. aeruginosa, Haemophilus
influenzae or gram-negative bacilli; fungi can
cause cellulitis in immunocompromised hosts
Erysipelas Skin Strep. pyogenes
Ecthyma Skin and subcutaneous tissue Strep. pyogenes, Staph aureus or both; other
bacteria
Ecthyma gangrenosum Skin and subcutaneous tissue in P. aeruginosa
neutropenic patients
TABLE
TABLE Probable Etiology of Soft Tissue Infections 10-3 Differential Diagnosis of Bullous Skin Lesions
10-2 Associated with Some Specific Risk Factor
or Setting Clinical Condition Etiology
Bullous impetigo Staphylococcus aureus carrying group II

Risk Factor or Setting Likely Etiologic Agent phage
Cat bite Pasteurella multocida Erysipelas Streptococcus pyogenes
Dog bite P. multocida, Capnocytophaga Staphylococcal scalded skin Staph. aureus producing exfoliative toxin
canimorsus (DF-2), syndrome
Staphylococcus intermedius
Necrotizing fasciitis Type I: mixed aerobic and anaerobic
Tick bite followed by erythema Borrelia burgdorferi bacteria
chronicum migrans rash Type II: Strep. pyogenes
Hot tub exposure Pseudomonas aeruginosa Gas gangrene Clostridium perfringens, C. septicum
Diabetes mellitus or peripheral Group B streptococci Halophilic vibrio sepsis Vibrio vulnificus
vascular disease
Pemphigoid Immune-mediated
Periorbital cellulitis (children) Haemophilus influenzae
Toxic epidermal necrolysis Drug-induced
Saphenous vein donor site cellulitis Groups C and G streptococci
Fresh water laceration Aeromonas hydrophila
Sea water exposure, cirrhosis, raw Vibrio vulnificus

oysters
Cellulitis associated with stasis Groups A, C and G streptococci

dermatitis
TABLE
Lymphedema Groups A, C and G streptococci 10-4 Differential Diagnosis of Crusted Skin Lesions
Cat scratch Bartonella henselae, B. quintana Clinical Condition Etiology
HIV-positive patient with bacillary B. henselae, B. quintana Impetigo Staphylococcus aureus,

angiomatosis Streptococcus pyogenes or
both
Fishmongering, bone rendering Erysipelothrix rhusiopathiae
Ringworm Dermatophytic fungi (e.g. Tinea
Fish tank exposure Mycobacterium marinum rubrum)
Compromised host with ecthyma P. aeruginosa Systemic fungal infections Histoplasma capsulatum
gangrenosum Coccidioides immitis
Blastomyces dermatitidis
Agammaglobulinemic patient with Campylobacter jejuni
‘erysipelas’ Cutaneous mycobacterial infection Mycobacterium tuberculosis
Human bite Eikenella corrodens, Fusobacterium M. marinum
spp., Prevotella spp., Cutaneous leishmaniasis Leishmania tropica
Porphyromonas spp.,
Streptococcus pyogenes Nocardiosis Nocardia asteroides
serum-derived chemotactic factors. Chemotactic factors are therefore beard area (sycosis barbae). Prompt cleansing, debridement and dis-
promptly produced at the site of infection by multiple mechanisms. infection of such lesions are important for preventing infection, par-
The diapedesis of phagocytes through endothelial cell junctions is ticularly in the case of bite wounds. Treatment of eczema reduces the
dependent upon the sequential expression of adherence molecules on risk of secondary bacterial infection.
the surface of the polymorphonuclear leukocyte (PMNL)2,3 such as Prevention of recurrent folliculitis or furunculosis is difficult, but
l-selectin and CD11b/CD18 in association with counter-receptors there has been some success using intranasal bacitracin or mupirocin
(adhesins) on the endothelium.4 Surface expression of these molecules ointment. Chlorhexidine scrub may eliminate or reduce staphylococ-
results first in ‘rolling’ of PMNLs along the endothelium, followed by cal carriage in adults.7 Prophylaxis with systemic antibiotics is of
tethering, and finally firm adhesion of the PMNLs onto the endothelial doubtful efficacy and can result in emergence of resistant strains; it
surface. Phagocytes leave the capillary through endothelial cell inter- should be tried only for severe cases (see below).
stices bound by endothelial cell adherence molecules, which are found Recurrent bacterial cellulitis of the lower extremities can often be
only at these junctional sites. prevented by topical antifungal treatment for dermatophyte infections,
The PMNL follows the gradient of chemotactic factors derived such as tinea pedis, because even inapparent superficial fungal infec-
from the bacteria and serum to the site of active infection. Activated tion can serve as a portal of entry for gram-positive cocci.
endothelial cells also produce chemotactic cytokines, such as interleu-
kin (IL)-8. Finally, activated granulocytes synthesize the chemoattrac- Clinical Features, Diagnosis and
tant leukotriene B4 from arachidonic acid.
Production of proinflammatory cytokines such as IL-1, IL-6 and
Management of Specific Soft
tumor necrosis factor (TNF) enhance the immune functions: they Tissue Infections
induce fever, prime neutrophils, and increase antibody production FOLLICULITIS, FURUNCLES AND CARBUNCLES
and the synthesis of acute phase reactants, such as C-reactive protein.5,6 Pustules or abscesses develop when organisms permanently or tran-
Cytokine-driven stimulation of endothelial cells results in the genera- siently resident on the skin surfaces are introduced into deeper tissues
tion of nitric oxide and prostaglandins, both of which cause vasodilata- (Figure 10-1). Pathogens can also seed the skin from hematogenous
tion and lead to greater blood flow to the tissue. These processes result sources such as bacteremias, associated with staphylococcal endocar-
in the cardinal manifestations of inflammation: heat, swelling, ery- ditis (Figure 10-2) or by contiguous spread from infectious foci in the
thema and tenderness or pain. lung or gastrointestinal tract. Most commonly, small focal abscesses
At some locations, factors such as pressure, thrombosis or drugs develop in the superficial layers of the skin, where hair follicles serve
may reduce or stop blood flow, resulting in inadequate oxygenation. as the portal of entry. Such lesions are called folliculitis. Staph. aureus
Corticosteroids, which inhibit phospholipase A2 activity (necessary for
releasing arachidonic acid from cell membranes), and nonsteroidal
anti-inflammatory agents, which inhibit cyclo-oxygenase (the enzyme
necessary for the synthesis of prostaglandins), reduce local blood flow
to tissues. These drugs are therefore useful in the treatment of nonin-
fectious inflammation because they reduce pain and swelling. However,
in undiagnosed bacterial infection, these drugs may lead to more
severe infection or mask clinical signs, so delaying the correct
diagnosis.
If tissue perfusion is moderately attenuated, tissues may remain
viable, but the threshold for progression of infection may be lowered.
Predisposing conditions in this category include:
• peripheral vascular disease affecting large arteries
• diabetes mellitus causing microvascular disease
• chronic venous stasis causing postcapillary obstruction. Figure 10-1 Cutaneous infection at the previous insertion site of an intravenous
Necrosis of the skin and deeper tissue may occur if there is severe catheter. Organisms from the skin were likely introduced into the dermis and
hypoxia. Two examples are: subcutaneous tissue at the time of catheter insertion. Many of these infections
• pressure necrosis resulting in decubitus ulcers; and remain superficial, but in this patient suppurative thrombophlebitis with bactere-
mia ensued.
• compartment syndromes resulting in hypoxia and then necrosis
in muscles confined within tight fascial bundles.
In the normal host, only pathogens such as Staph. aureus and group
A streptococci are able to cause disease by virtue of their potent viru-
lence factors, such as toxins, capsules or dermonecrotic enzymes,
which attenuate host defenses and induce clinical disease. In fact,
normal skin, although constantly exposed to many indigenous and
exogenous microbes, rarely becomes infected.
In contrast, patients with compromised skin integrity (e.g. patients
with burns), vascular defects (e.g. in diabetes mellitus or pressure
ulceration) or immunologic deficits may become infected with either
virulent organisms (e.g. staphylococci or streptococci) or microbes
that are usually saprophytic, such as Pseudomonas aeruginosa, Esche-
richia coli, enterococci or Fusarium spp. Defects such as neutropenia
attenuate the host response and once the invading pathogen has
breached the skin could predispose to worse outcomes.
Prevention
Avoidance of cuts, scratches and other forms of trauma that disrupt
the natural barrier function of the skin helps to prevent SSIs. For Figure 10-2 Diffuse skin involvement. Petechial lesions in a patient with Staphy-
example, cessation of shaving may prevent recurrent folliculitis in the lococcus aureus bacteremia, endocarditis and acute aortic insufficiency.
accounts for most of these infections, but many different bacterial Administration of intranasal mupirocin or bacitracin ointment for
species can occasionally cause folliculitis. the first 5 days of each month has been shown to decrease colonization
Folliculitis can progress to form subcutaneous abscesses, called and reduce the frequency of recurrent infection by about 50%.8 Treat-
furuncles or boils, which usually drain and resolve spontaneously, but ment of recurrent furunculosis may also require surgical incision and
may progress to form a large, exquisitely painful group of contiguous drainage as well as antistaphylococcal antibiotics such as oral dicloxa-
furuncles, called a carbuncle (Figure 10-3). Carbuncles require surgical cillin or parenteral nafcillin. In general, surgical drainage alone is suc-
drainage as well as antibiotic treatment.6 cessful, unless the patient has fever, leukocytosis or the lesions are
greater than 5 cm in diameter. Community-acquired methicillin-
RECURRENT FURUNCULOSIS resistant Staph. aureus (CA-MRSA) which harbors Panton–Valentine
Certain individuals are predisposed to recurrent Staph. aureus skin leukocidin (PVL) has been associated with epidemics of these types of
infections (recurrent furunculosis). Although it has been suggested infection among prisoners, athletes and children in daycare centers.
that diabetic patients are especially prone to boils and carbuncles, few Interestingly, PVL may be more of a marker than a true virulence
data support this concept. Patients with hyper IgE-Job’s syndrome, factor.
who have often a congenital defect of the STAT3 gene, are strongly
predisposed to focal Staph. aureus infections. However, most patients Predisposing Factors
do not have immunologic or metabolic abnormalities, and the greatest Superficial dermal trauma such as insect bites or abrasions can also
predisposing factor is colonization of the anterior nares with Staph. result in cutaneous abscesses. Eczema may also serve as a portal of
aureus (Figure 10-4). Thus, touching the nose or nasal secretions and entry. Superinfected eczema may be difficult to distinguish from
then rubbing or scratching the skin results in autoinoculation and eczema itself because both result in crusted lesions, exudation and
abscess formation. Breaking the cycle can be useful to prevent recur- cutaneous erythema. The presence of lymphangitis, pustules or fever
rences; however, it is important to document nasal colonization by suggests infection. Because Staph. aureus is the most common cause
appropriate techniques. of infected eczema, treatment with an oral antistaphylococcal antibi-
otic such as dicloxacillin or trimethoprim–sulfamethoxazole (TMP–
SMX) (for CA-MRSA) is warranted.
Sebaceous glands empty into hair follicles; if the ducts become
blocked they form sebaceous cysts, which may resemble a staphylococ-
cal abscesses or become secondarily infected. Chronic folliculitis is
uncommon except in acne vulgaris in which normal flora (e.g. Propi-
onibacterium acnes) may play a role.
Recurrent folliculitis is most common in black males and associ-
ated with trauma from shaving (folliculitis barbae). Hidradenitis sup-
purativa occurs in either acute or chronic forms and can lead to
recurrent axillary, periareolar, perineal or pudendal abscesses.
Although the exact pathogenesis of recurrent hidradenitis is not
understood, it is considered to be due to abnormal apocrine sweat
glands and recent studies demonstrate dramatic resolution with anti-
TNF strategies.
DIFFUSE FOLLICULITIS
Diffuse folliculitis occurs in two distinct settings. The first –‘hot tub
folliculitis’– is associated with water maintained at a temperature
Figure 10-3 Carbuncle of the buttock caused by Staphylococcus aureus. This
large carbuncle developed over the course of 7–10 days and required surgical between 37 and 40 °C (98.6 and 104 °F) that is insufficiently chlori-
drainage plus treatment with antibiotics. The patient had previously experienced nated and is caused by P. aeruginosa. The infection is usually self-
numerous episodes of Staph. aureus cutaneous abscesses. He carried the staphy- limited, although serious complications of bacteremia and shock have
lococci in his anterior nares. occasionally been reported.
The second form of diffuse folliculitis – swimmer’s itch (Figure
10-5) – occurs when the skin is exposed to water infected with avian
freshwater schistosomes. Warm water temperatures and alkaline pH
are suitable for molluscs, which are the intermediate host between
birds and humans. Free-swimming cercariae readily penetrate human
hair follicles or pores, but quickly die. This triggers a brisk allergic
reaction, causing intense itching and erythema. The infestation is self-
limited, secondary infection is uncommon and antipruritics and
topical corticosteroid cream promptly relieve the symptoms.
STAPHYLOCOCCAL SCALDED SKIN SYNDROME

Staphylococcal scalded skin syndrome (SSSS) has been described in
all age groups, but it is usually seen in children <5 years of age, includ-
ing neonates.9 The characteristic features are a faint erythematous rash
with the formation of flaccid bullae (Figure 10-6). Staph. aureus of
phage group II is the causative organism. Its toxin exfoliatin affects the
cell junctions of young dermal cells, leading to intraepidermal cleavage
in the stratum corneum. A classic feature is Nikolsky’s sign, in which
Figure 10-4 Staphylococcal nasal carriage. This patient had a small staphylococ- lateral pressure on the skin results in shearing off of the top layer of
cal abscess beneath the mucosa of the nose, illustrating how Staphylococcus
aureus, which colonizes the nares, can infect skin and submucosa. Intact mucosa
skin (Figure 10-7). The mortality of SSSS is low, and fluid loss from
is highly resistant to infection; such infections usually occur as a result of defects the skin is minimal. Appropriate antibiotic therapy is the main com-
in the mucosal membranes or via hair follicles inside the nose. ponent of treatment.
Figure 10-7 Toxic epidermal necrolysis. This picture shows a skin slough (Nikol-
sky’s sign), which resulted when lateral pressure was applied by the thumb in a
plane parallel to the skin surface. This disorder is more common in adults, has a
high mortality rate and is usually caused by medications.
Figure 10-5 Swimmer’s itch of the forearm caused by duck schistosomes.
Diffuse folliculitis can be caused by Pseudomonas aeruginosa (hot tub folliculitis),
schistosomes (swimmer’s itch) or Staphylococcus aureus (folliculitis). This young
man had been fishing in an alkaline lake in the western part of the USA. He had are caused by Staph. aureus, including CA-MRSA.9 Staphylococci and
been fishing from a ‘float tube’ and had exposed only his hands and arms to the group A streptococci can often be co-isolated from impetiginous
water. The rash was associated with severe itching. Although his white blood count
was not elevated, 35% of the white cells were eosinophils. lesions. Group A streptococci alone currently cause less than half the
cases. Staphylococcal impetigo tends to occur sporadically, whereas
epidemics of streptococcal impetigo have been well described. Epi-
demics occur throughout the year in tropical areas or during the
summer months in temperate climates. Streptococcal impetigo is
sometimes complicated by poststreptococcal glomerulonephritis. This
complication is more likely to occur during epidemics of impetigo
caused by certain M types such as M type 49 (see Chapter 177).
Impetigo is characterized by thick-crusted lesions with rounded or
irregular margins (Figure 10-8a), often on the face.10 Streptococcal
impetigo frequently has a golden brown or honey color, resembling a
plaque of dried serum. Children between 2 and 10 years are most
commonly infected, with a strong association with poor socioeco-
nomic conditions and poor hygiene.
Initially, colonization of unbroken skin occurs either exogenously
from other infected persons (hence the term impetigo contagiosa) or
endogenously by contamination of the skin with organisms carried in
the anterior nares or oropharynx. The development of impetiginous
lesions takes 10–14 days and likely is initiated through intradermal
inoculation (such as by minor abrasions and insect bites). Initially,
impetigo may appear as vesicular lesions, which become crusts (Figure
10-8b).
Patients with streptococcal impetigo should receive penicillin treat-
ment, particularly when numerous sites of the skin are involved,
although treatment may not prevent poststreptococcal glomerulo
nephritis. Topical treatment, such as bacitracin or mupirocin, is also
effective.
Figure 10-6 Staphylococcal scalded skin syndrome. Flaccid bullae occur as BULLOUS IMPETIGO
single or multiple lesions. Examination of a frozen tissue section reveals that the
cleavage plane is at the stratum corneum. This disease must be distinguished from Bullous impetigo is caused by strains of Staph. aureus harboring a
toxic epidermal necrolysis (see Figure 10-7). group II bacteriophage that contains genetic elements coding for a
toxin, which causes separation of the cellular planes in the stratum
corneum and hence characteristic superficial flaccid bullae. These
SSSS must be distinguished from toxic epidermal necrolysis, which lesions may coalesce and form large reddish plaques, usually involving
is more common in adults and usually a drug reaction; it has a high the neck, face or chin. The flaccid bullae easily rupture and may not
mortality rate (see Figure 10-7). Frozen section examination of a be apparent when the patient is first seen. Because of the superficial
punch biopsy readily distinguishes these two entities: SSSS shows a nature, scarring does not occur. Appropriate treatment is an anti-
cleavage at the level of the stratum corneum, whereas toxic epidermal staphylococcal antibiotic, which may be given orally.
necrolysis shows deeper cleavage at the stratum germinativum.
ECTHYMA, PARONYCHIA AND BLISTERING
IMPETIGO DISTAL DACTYLITIS
Impetigo contagiosa is a form of superficial pyoderma caused by strep- Ecthyma, like impetigo, is characterized by dry crusted lesions of the
tococci and/or staphylococci. Currently, about half of impetigo cases skin and may be caused by Staph. aureus, group A streptococcus or
Figure 10-9 Erysipelas. This form of cellulitis is caused by Streptococcus pyo-

genes and is most common in the elderly. Unique characteristics include a fiery
red or salmon color, well-demarcated edges, desquamation after 5–7 days and
location on the face or lower extremities. This picture was taken 48 hours after
treatment with penicillin when the brilliant red salmon color had evolved to a
reddish blue color. On the second day of treatment patients usually have less pain
and fever subsides, but swelling may be more extensive.
fold, rapid progression and intense pain (Figure 10-9). Flaccid super-
ficial bullae may develop during the second to third day of the illness,
but extension to deeper soft tissues is rare. Since it is a toxic reaction,
cultures of skin biopsies are generally negative, though throat cultures
may be positive.
Surgical debridement is rarely necessary, and treatment with peni-
cillin is effective. Swelling may progress for a time despite appropriate
treatment, even while fever, pain and the intense red color are dimin-
b ishing. Desquamation of the involved skin occurs after 5–10 days.
Erysipelas is most common in elderly adults, and the severity of
Figure 10-8 Impetigo. (a) Impetigo in a homeless man. Both Staphylococcus systemic toxicity can vary geographically and over time, likely due to
aureus and group A streptococci were cultured from these lesions. (b) Impetigo,
with initial vesicles changing to crusts.
strain differences. Lymphedema (e.g. after mastectomy) predisposes to
recurrent erysipelas. A rare form of erysipelas is caused by Campylo-
bacter jejuni and Campylobacter fetus, especially in patients with agam-
maglobulinemia and occasionally in patients with AIDS.
both. Unlike impetigo, this lesion extends into the dermis and may
therefore lead to post-treatment scarring.9 CELLULITIS
Paronychia, an infection between the nail plate of a digit and the The term ‘cellulitis’ is commonly used by physicians, but is not well
cuticle, is associated with sucking of the fingers or following prolonged defined. It is a localized area of soft tissue inflammation characterized
immersion of the hands in water. Herpetic whitlow (see below) may by leukocytic infiltration of the dermis, capillary dilatation and prolif-
resemble paronychia but is associated with intense pain. Paronychia eration of bacteria. Clinically cellulitis is an acute inflammatory condi-
may occur in immunocompromised patients. Staphylococci are the tion of the skin with localized pain, erythema, swelling and heat.6 The
most common etiologic agents, although oral anaerobes and strepto- erythema is paler than the flaming red of erysipelas, and has indistinct
cocci may also be isolated. Candida albicans and fungi such as Fusar- margins (Figure 10-10).
ium spp. may be isolated from paronychias in immunocompromised Cellulitis is caused most commonly by indigenous bacteria such as
patients. Drainage is best accomplished between the nail plate and the Strep. pyogenes, but also group C and group G streptococci, and group
cuticle. Antimicrobial agents are rarely needed in otherwise healthy B streptococcus in diabetic adults.
individuals. Bacteria may gain access to the epidermis through cracks in the
Blistering distal dactylitis, characterized by painful blisters on the skin, abrasions, cuts, burns, insect bites, surgical incisions and intra-
fingerpads of digits, is most common in children. Strep. pyogenes is the venous catheters.
most common cause, although Staph. aureus can cause a similar lesion. Erythema of the skin surrounding a central localized infection such
Incision and drainage may be useful, in conjunction with an antibiotic as an abscess (Figures 10-11 and 10-12), folliculitis or foreign body
appropriate for Staph. aureus or Strep. pyogenes. (e.g. a sliver, prosthetic device or intravascular catheter) may be con-
fused with cellulitis, and is referred to as purulent skin and soft tissue
ERYSIPELAS infection.
Erysipelas is a cellulitis caused by a toxin of Strep. pyogenes and occa- In contrast, cellulitis due to Strep. pyogenes is a more rapidly
sionally by streptococci of groups B, C and D.11,12 It is characterized by spreading diffuse process that may be associated with lymphangitis
an abrupt onset of fiery red swelling of the face or extremities. Distinc- (Figure 10-13) and fever.13 The correct term is non-purulent skin and
tive features are well-defined margins, particularly along the nasolabial soft tissue infection or cellulitis.
Figure 10-12 Staphylococcus aureus cellulitis of the nose. The focal lesion
began in a hair follicle inside the nose, with redness, swelling and pain. Rarely,
such lesions on the nose are complicated by extension into the cavernous sinus
via veins draining the central part of the face.
Figure 10-10 Cellulitis. In contrast to erysipelas, cellulitis is a pink color rather

than brilliant red and has indistinct margins. Staphylococcus aureus and group A,
C and G streptococci are the most common etiologies. Many other bacteria may
cause cellulitis (see Table 10-1).
Figure 10-13 Lymphangitis. Cellulitis caused by group A streptococci began

below the knee and rapidly spread; about 4 hours later lymphangitis had spread
up the inner aspect of the thigh.
Recurrent Cellulitis
Recurrent streptococcal cellulitis of the lower extremities may be
caused by group A, C or G streptococci in association with skin lesions
such as chronic venous stasis (Figure 10-14), saphenous venectomy for
coronary artery bypass surgery14 or healed burns, especially if the skin
is colonized by dermatophyte fungi. Streptococci also cause recurrent
cellulitis/erysipelas among patients with chronic lymphedema.
Cellulitis Associated with Predisposing Conditions
a
A number of other conditions predispose to infection by endogenous
or exogenous pathogens (see Table 10-2). For example:
• Strep. agalactiae cellulitis occurs in patients who have diabetes
mellitus.15
• Haemophilus influenzae causes periorbital cellulitis in children
with sinusitis, otitis media or epiglottitis and is is less common
due to H. influenzae b vaccination.
Cellulitis Associated with Bites (see also
Chapter 73 and Practice Point 25)
Many species of bacteria can cause cellulitis. These often occur in
special settings, and the history can provide useful clues to the diag-
nosis (see Table 10-2). Bites of various types may introduce specific
organisms into the deeper tissues, resulting in soft tissue infections.
For example, cellulitis associated with cat bites and, to a lesser degree,
dog bites is commonly caused by Pasteurella multocida, although in
the latter case Staphylococcus intermedius and Capnocytophaga cani-
b morsus must also be considered. Cellulitis and abscesses following dog
and human bites also contain a variety of anaerobes.16P. multocida is
Figure 10-11 Cellulitis. (a) This case was caused by Staphylococcus aureus and resistant to dicloxacillin and nafcillin, but sensitive to all other β-lactam
is spreading centripetally from a central localized focus of infection. The redness
and swelling characteristic of cellulitis are apparent over the upper eyelid. (b) The
antimicrobials as well as quinolones, tetracycline and erythromycin.
cellulitis has developed from a localized staphylococcal abscess formed in a Ampicillin–clavulanate, ampicillin–sulbactam or cefoxitin are good
meibomian gland (chalazion). choices for treating animal or human bite infections.
TABLE Differential Diagnosis of Ulcerative

10-5 Skin Lesions
Clinical Condition Etiology
Anthrax Bacillus anthracis
Cutaneous diphtheria Corynebacterium diphtheriae
Ulceroglandular tularemia Francisella tularensis
Bubonic plague Yersinia pestis
Buruli ulcer Mycobacterium ulcerans
Primary syphilis Treponema pallidum
Chancroid Haemophilus ducreyi
Lucio’s phenomenon Mycobacterium leprae
Decubitus (pressure) ulcer Mixed aerobic and anaerobic bacteria
Leishmaniasis Leishmania tropica
Ecthyma gangrenosum Pseudomonas aeruginosa

Tropical ulcer Idiopathic and nonspecific; mixed
bacterial species
Figure 10-14 Cellulitis of the lower leg associated with chronic venous insuffi-
ciency. Streptococci of groups A, B, C and G are the most common isolates.
Group B streptococci seldom cause cellulitis in previously healthy hosts, but
should be considered in people who have peripheral vascular disease or diabetes In the last of these, P. aeruginosa is often introduced into the deep
mellitus. tissues by stepping on a nail, a scenario referred to as the ‘sweaty tennis
shoe syndrome’.
Treatment includes surgical inspection and drainage, particularly
Soft tissue infections may result from the bites of mosquitoes, horse
if the injury also involves bone or joint capsule. Choices for empiric
flies and spiders; usually they cause only local allergic reactions with
treatment pending antimicrobial susceptibility include aminoglyco-
itching, swelling and erythema. Similarly, brown recluse spider bites
sides, third-generation cephalosporins, semisynthetic penicillins such
may resemble acute infection at first, but later there is primary tissue
as piperacillin, or fluoroquinolones.
destruction and central necrosis due to the action of dermonecrotic
Cellulitis caused by gram-negative bacilli, including P. aeruginosa,
toxins. These infections may resemble pyoderma gangrenosum or may
is most common in hospitalized immunocompromised hosts. Recently,
become secondarily infected with skin organisms. Mosquito bites may
Stenotrophomonas maltophilia has emerged as an important cause of
serve as portals of entry for skin organisms such as Staph. aureus or
nosocomial cellulitis in cancer patients.17 It has been isolated from
Strep. pyogenes. Given the number of individuals bitten by insects,
incubators, nebulizers, humidifiers and tap water in hospitals. The
these infections are relatively rare.
cellulitis may be related to intravenous catheters and may be metastatic
Cellulitis Associated with Water Exposure and via the bloodstream.
Exposure to Fish TMP–SMX, or ticarcillin–clavulanic acid, with or without cipro-
Aeromonas hydrophila causes a highly aggressive form of cellulitis floxacin, are reasonable treatment choices; cultures and sensitivities
in tissues surrounding lacerations that were sustained in fresh are necessary.
water lakes, rivers and streams. This organism is sensitive to amino- Other Causes of Cellulitis
glycosides, fluoroquinolones, chloramphenicol, TMP–SMX (co- The gram-positive aerobic rod Erysipelothrix rhusiopathiae, which
trimoxazole) and third-generation cephalosporins, but is resistant to causes erysipeloid, a type of cellulitis found typically in bone renderers
ampicillin. and fishmongers, remains susceptible to erythromycin, clindamycin,
Vibrio vulnificus can cause cellulitis or necrotizing fasciitis and is tetracycline and cephalosporins, but is resistant to sulfonamides and
associated with swimming in the Gulf of Mexico, South Atlantic chloramphenicol.
Ocean, and other sites including water off the coasts of Taiwan and
South Africa. In addition, patients who have cirrhosis of the liver may Differential Diagnosis
develop severe soft tissue infection after ingestion of oysters from these The etiology of cellulitis can be suspected on the basis of the epidemio-
areas. logic data supplied above. If there is drainage, an open wound or an
Streptococcus iniae is a cause of cellulitis among workers handling obvious portal of entry, Gram stain and culture can often provide a
tilapia fish. definitive diagnosis (Table 10-5). In the absence of these findings, the
Fish food containing the water fleas Daphnia can be contaminated bacterial etiology of cellulitis may be difficult to establish. Even with
with Mycobacterium marinum, which may cause cellulitis or granulo- needle aspiration from the leading edge or punch biopsy of the cel-
mas of skin exposed to the water in aquariums or following injuries in lulitis itself, cultures are positive in only 20% of cases.18 This suggests
swimming pools. Rifampin (rifampicin) plus ethambutol has been an that relatively low numbers of bacteria may cause cellulitis and that
effective treatment for some, although no comprehensive studies have the expanding area of erythema within the skin may be the direct result
been carried out. Some strains of M. marinum are susceptible to tet- of extracellular toxins or the soluble mediators of inflammation elic-
racycline or TMP–SMX. ited by the host.
There are four types of cellulitis caused by P. aeruginosa and other
gram-negative bacteria: Antibiotic Treatment
• ecthyma gangrenosum in neutropenic patients Because many different microbes can cause cellulitis, the choice of
• hot tub folliculitis initial empiric antibiotic therapy depends upon the clinical features
• burn wound sepsis described above. Once cultures and sensitivities are available, the
• cellulitis following penetrating injury. choice is easier and more specific. The physician must first decide
whether the patient’s illness is severe enough to require parenteral

treatment, either in hospital or on an outpatient basis. Because of the
virtual epidemic of MRSA infections worldwide, severe soft tissue
infections should be treated with agents that have high level activity
against these strains. Local antibiograms are thus crucial for rational
treatment.
Presumed Streptococcal or Staphylococcal Cellulitis. For
presumed streptococcal or staphylococcal cellulitis, nafcillin, cephalo-
thin, cefuroxime, vancomycin and erythromycin are good choices.
Cefazolin and ceftriaxone have less activity against Staph. aureus than
cephalothin, although clinical trials have shown a high degree of effi-
cacy. Ceftriaxone is a useful choice for outpatient treatment because
it can be given once daily. Similarly, teicoplanin, like vancomycin, has Figure 10-15 Cutaneous anthrax lesion on the thumb of a 23-year-old Turkish
excellent activity against Strep. pyogenes and Staph. aureus and may be woman. The lesion developed after wounding herself on the teeth of a slaugh-
tered sheep. Microbiologic tests yielded Bacillus anthracis. She recovered after
given once daily by intravenous or intramuscular injection. Because treatment with penicillin. (Courtesy of IC Gyssens and D Weyns.)
MRSA has recently increased in prevalence throughout much of the
world, vancomycin, daptomycin, televancin, ceftaroline or linezolid
should be used empirically in patients with severe soft tissue infections
who are toxic or in those who have recently been hospitalized or Cutaneous Diphtheria
received antibiotics.19 Since 1980 cutaneous diphtheria has been recognized in homeless
For patients being treated with oral antibiotics, dicloxacillin, cefu- individuals who present with chronic nonhealing ulcers with an over-
roxime axetil, cefpodoxime, erythromycin, clarithromycin and lying dirty gray membrane. These lesions may mimic those of psoria-
azithromycin are all effective treatments. For proven MRSA infections sis, eczema or impetigo, but have a deeper base. Appropriate cultures
linezolid, TMP–SMX or doxycycline are reasonable choices though of the ulcer are mandatory because organisms growing from routine
choices should be guided by local antibiograms or cultures and cultures may be misidentified as diphtheroids.26
sensitivities. Cutaneous Tularemia (Ulceroglandular Tularemia)
For known group A, B, C or G streptococcal infections, penicillin (see also Chapter 127)
or macrolides should be used orally or parenterally. For serious group
A streptococcal infections such as necrotizing fasciitis or streptococcal Cutaneous tularemia occurs following a tick bite or handling of
toxic shock syndrome, clindamycin is more efficacious than penicil- infected rodents or lagomorphs (rabbits). It most commonly presents
lin.20 This is probably because in this type of infection where there are with regional lymphadenopathy associated with suppuration and
large numbers of bacteria, streptococci are in a stationary growth phase fever, although pneumonic, oculoglandular, oropharyngeal and
and do not express a full complement of penicillin-binding proteins.21 typhoidal forms have also been described. The characteristic lesion is
In contrast, the activity of clindamycin is not affected by inoculum size a small ulceration with an eschar, which develops 2–10 days after
or growth phase. In addition, clindamycin suppresses the synthesis of exposure. Treatment with streptomycin or gentamicin has been suc-
many streptococcal exotoxins and surface proteins.22,23 cessful, and doxycycline, chloramphenicol or a fluoroquinolone are
alternatives.
Other Types of Cellulitis. For cellulitis-associated dog or cat
bites caused by Eikenella corrodens useful antibiotics are penicillin, Buruli Ulcer (see also Chapter 185)
ceftriaxone, TMP–SMX, tetracyclines and fluoroquinolones. Interest- Buruli ulcer is caused by Mycobacterium ulcerans. It presents as a
ingly, this organism is resistant to oxacillin, cefazolin, clindamycin and shallow ulcer, which slowly expands centripetally. It is uncommon in
erythromycin. the USA and Europe, but is endemic in tropical climates, particularly
Cellulitis associated with cat bites may fail to respond to treatment Africa. Diagnosis is easily established by biopsy, acid-fast staining or
with oral cephalosporins, erythromycins and dicloxacillin. Reasons for culture. The organism is susceptible to isoniazid, rifampin and para-
failure include resistance of P. multocida to oxacillin and dicloxacillin aminosalicylic acid (PAS). Oral treatment with isoniazid and rifampin
and the inadequate serum and tissue levels attained with older oral for 2–3 months is usually successful.
cephalosporins and erythromycins. Amoxicillin clavulanate orally, or
ampicillin–sulbactam intravenously are the best treatments. Leishmaniasis (see also Chapter 123)
Erysipelas-like skin lesions caused by Campylobacter spp. in patients Leishmaniasis also presents as shallow ulcers with an expanding
with agammaglobulinemia may not respond to antibiotics alone; sup- margin (Figure 10-16). Diagnosis should be suspected in patients
plementation with IgM (by infusion of fresh plasma) may be necessary residing in or returning from Central or South America. A biopsy from
to obtain bactericidal serum.24 the raised edge stained with Giemsa or Wright’s stain demonstrates
the amastigote stage of Leishmania tropica. Treatment with antimony
compounds is effective, but requires prolonged administration over
CUTANEOUS ULCERS 4–6 months.
Infectious ulceration of the skin results from either:
• direct destruction of dermal cells by bacterial products; or Other Causes of Cutaneous Ulcers
• an intense inflammatory reaction. The differential diagnosis of cutaneous ulcers in genital areas should
include:
Cutaneous Anthrax • syphilis
This is an example of direct destruction of dermal cells by toxins pro- • chancroid
duced by Bacillus anthracis (see Table 10-5). This disease is tradition- • lymphogranuloma venereum
ally contracted by direct inoculation of the skin of animal handlers, • herpes simplex virus infection.
especially goat and sheep herders or hide processors,25 but recent cases Noninfectious causes of cutaneous ulceration include:
have occurred as the result of deliberate bioterrorism (see Chapter 75). • Behçet’s syndrome
The lesion begins as a papule, which evolves into a bulla and then • cutaneous vasculitis, including lupus erythematosus
ulcerates (Figure 10-15). Sepsis may occur. The diagnosis is established • toxic epidermal necrolysis
by aspiration of the leading edge of the lesion, Gram stain and culture. • pressure necrosis
Penicillin is appropriate therapy (see also Chapter 134). • brown recluse spider bites.
Figure 10-17 Gram stain of purulent material demonstrating Staphylococcus

aureus. The microbial etiology of cellulitis may be suspected based upon signs,
symptoms and history; however, definitive diagnosis requires Gram stain and
Figure 10-16 Leishmaniasis. Typical crusted edge with central necrosis suggest- culture. If there is no portal of entry, aspiration or even punch biopsy of cellulitic
ing leishmaniasis. A history of travel to Central or South America or Iraq should skin yields a positive culture in only 20% of cases.
be ascertained. Biopsy of the ulcer crater with Giemsa staining revealed amasti-
gotes of Leishmania tropica. (Courtesy of M Keuter.)
Solitary shallow ulcers of skin and mucous membranes have also been
described in disseminated histoplasmosis.
Herpes simplex can cause primary or recurrent cutaneous infec-
tions of the digits (herpetic whitlow) or head and neck. This viral
infection is often misdiagnosed and mistreated as a bacterial condition,
and occurs in those who are exposed to inoculation of the skin from
oral secretions, such as dentists, dental hygienists, nurses, anesthesi-
ologists and wrestlers.
A variety of animal pox viruses can cause cutaneous infection in
humans. Orf is caused by a DNA virus similar to smallpox and causes a
shallow ulcers (in general only one lesion) on the digits of animal
handlers working with sheep or goats that harbor open mucous mem-
brane lesions.25
Bacillary Angiomatosis (see also Chapter 98)
Bacillary angiomatosis is a primary infection of endothelial cells that
has important cutaneous manifestations.27 The lesions may appear as
purple nodules resembling Kaposi’s sarcoma. They may also appear as
scaly or ulcerated lesions or as superficial pink papules or plaques in
black people. This disease usually occurs in HIV-infected people and
is caused by Bartonella henselae or B. quintana. The organisms can be
acquired from cat bites and scratches or from cat fleas. The course and
extent of infection is highly variable and depends upon the host’s
immune status.
Histopathology reveals capillary proliferation. The organisms can
be visualized using Warthin–Starry silver stain or electron microscopy. b
Bacteriologic identification requires a special culture technique: lysed
blood centrifugate or digested tissue is plated onto chocolate or Figure 10-18 Cellulitis at the elbow associated with olecranon bursitis. (a) Pale
Columbia agar and incubated for 10–14 days at 35 °C (95 °F) in 5–7% pink erythema on the inner aspect of the elbow. (b) Careful inspection demon-
carbon dioxide. Small, dry, adherent oxidase-negative colonies of strates a focal infection over the point of the elbow. Fluid aspirated from the
gram-negative curved rods with twitching motility can be identified as olecranon bursa yielded a pure culture of Staphylococcus aureus.
Bartonella spp. by fluorescent antibody, gas–liquid chromatography or
biochemical tests.28
Resistance to penicillin, cephalosporins, sulfonamides and vanco-
mycin has been described. The recommended therapy is erythromycin (Figure 10-18), septic arthritis, osteomyelitis, staphylococcal parotitis
500 mg q6h.23 and other deep infections of the head and neck, such as anaerobic
infections, actinomycosis and tooth abscesses (Figure 10-19).
CUTANEOUS MANIFESTATIONS OF Further information regarding the diagnosis and treatment of
INFECTIONS OF DEEP SOFT TISSUES common and uncommon skin and soft tissue infections, including
Staphylococcal infections of deeper tissues may also cause superficial those in compromised hosts, can be found in reference 29.
redness, warmth and swelling of the skin, even though the skin itself
is not infected (Figure 10-17). Examples include olecranon bursitis References available online at expertconsult.com.
a b
Figure 10-19 Erythema and swelling of the face due to a tooth abscess. (a) Swelling of the face, on inspection resembling periorbital cellulitis. (b) Further inspection
reveals a gingival abscess above the patient’s left upper canine tooth.
KEY REFERENCES
Baddour L.M., Bisno A.L.: Non-group A beta-hemolytic Hirschmann J.: Staphylococcal soft tissue infections. In: Norrby A., Eriksson B., Norgren M., et al.: Virulence prop-
streptococcal cellulitis: association with venous and Stevens D.L., ed. Atlas of infectious diseases. Philadelphia, erties of erysipelas-associated group A streptococci. Eur J
lymphatic compromise. Am J Med 1985; 79:155-159. PA: Churchill Livingstone; 1995:2-10. Clin Microbiol Infect Dis 1992; 11:1136-1143.
Bisno A.L., Stevens D.L.: Streptococcal infections in skin Kerstens P.J., Endtz H.P., Meis J.F., et al.: Erysipelas-like Stevens D.L., Bisno A.L., Chambers H.F., et al.: Practice
and soft tissues. N Engl J Med 1996; 334:240-245. skin lesions associated with Campylobacter jejunii septi- guidelines for the diagnosis and management of skin and
Doebbeling B.N., Reagan D.R., Pfaller M.A., et al.: Long- cemia in patients with hypogammaglobulinemia. Eur J soft-tissue infections. Clin Infect Dis 2014; 59(2):e10-e52.
term efficacy of intranasal mupirocin ointment: a pro- Clin Microbiol Infect Dis 1992; 11:842-847. Stevens D.L., Herr D., Lampiris H., et al.: Linezolid versus
spective cohort study of Staphylococcus aureus carriage. Megarbane B., Carbon C.: Unusual presentations of bacte- vancomycin for the treatment of methicillin-resistant
Arch Intern Med 1994; 154:1505-1508. rial skin and soft-tissue infections and their treatment. Staphylococcus aureus infections. Clin Infect Dis 2002;
Goldstein E.J.C.: Bite wounds and infection. Clin Infect Dis Curr Opin Infect Dis 1996; 9:58-62. 341:1481-1490.
1992; 14:633-640.
Chapter 10 Cellulitis, Pyoderma, Abscesses, and Other Skin and Subcutaneous Infections 94.e1
REFERENCES
1. Greenblatt J., Boackle R.J., Schwab H.J.: Activation of 11. Bernard P., Bedane C., Mounier M., et al.: Streptococ- nation for the inoculum effect. J Infect Dis 1993;
the alternate complement pathway by peptidoglycan cal cause of erysipelas and cellulitis in adults. Arch Der- 167:1401-1405.
from streptococcal cell wall. Infect Immun 1978; 19:296- matol 1989; 125:779-782. 22. Gemmell C.G., Peterson P.K., Schmeling D., et al.:
303. 12. Norrby A., Eriksson B., Norgren M., et al.: Virulence Potentiation of opsonization and phagocytosis of Strep-
2. Zimmerman G.A., McIntyre T.M.: Neutrophil properties of erysipelas-associated group A strepto- tococcus pyogenes following growth in the presence of
adherence to human endothelium in vitro occurs by cocci. Eur J Clin Microbiol Infect Dis 1992; 11:1136- clindamycin. J Clin Invest 1981; 67:1249-1256.
CDw18 (Mo1, Mac–1/LFA–1, GP150,95) glycoprotein- 1143. 23. Sriskandan S., McKee A., Hall L., et al.: Comparative
dependent and independent mechanisms. J Clin Invest 13. Bisno A.L., Stevens D.L.: Streptococcal infections in effects of clindamycin and ampicillin on superantigenic
1988; 81:531-537. skin and soft tissues. N Engl J Med 1996; 334:240-245. activity of Streptococcus pyogenes. J Antimicrob Che-
3. Carlos T.M., Harlan J.M.: Membrane proteins involved 14. Baddour L.M., Bisno A.L.: Non-group A beta-hemolytic mother 1997; 40:275-337.
in phagocyte adherence to endothelium. Immunol Rev streptococcal cellulitis: association with venous and 24. Kerstens P.J., Endtz H.P., Meis J.F., et al.: Erysipelas-
1990; 114:5-28. lymphatic compromise. Am J Med 1985; 79:155-159. like skin lesions associated with Campylobacter jejunii
4. Bevilacqua M.P.: Endothelial-leukocyte adhesion mol- 15. Stevens D.L., Haburchak D., McNitt T.R., et al.: Group septicemia in patients with hypogammaglobulinemia.
ecules. Ann Rev Immunol 1993; 11:767-804. B streptococcal osteomyelitis in adults. South Med J Eur J Clin Microbiol Infect Dis 1992; 11:842-847.
5. Stevens D.L.: Cytokines; an updated compendium. 1978; 71:1450-1451. 25. Everett E.D.: Infections associated with animal contact.
Curr Opin Infect Dis 1995; 8:175-180. 16. Goldstein E.J.C.: Bite wounds and infection. Clin Infect In: Stevens D.L., ed. Atlas of infectious diseases, 5. Phila-
6. Stevens D.L.: Soft tissue infections. In: Isselbacher K.J., Dis 1992; 14:633-640. delphia, PA: Churchill Livingstone; 1995:2-8.
Braunwald E., Wilson J.D., et al., eds. Harrison’s text- 17. Vartavarian S.E., Papakadis K.A., Palacios J.A., et al.: 26. Megarbane B., Carbon C.: Unusual presentations of
book of medicine. 13th ed. New York: McGraw–Hill; Mucocutaneous and soft tissue infections causes by bacterial skin and soft-tissue infections and their treat-
1994:561-563. Xanthomonas maltophilia: a new spectrum. Ann Intern ment. Curr Opin Infect Dis 1996; 9:58-62.
7. Doebbeling B.N., Reagan D.R., Pfaller M.A., et al.: Med 1994; 121:969-973. 27. Cockerell C.J., LeBoit P.E.: Bacillary angiomatosis: a
Long-term efficacy of intranasal mupirocin ointment: 18. Duvanel T., Auckenthaler R., Rohner P., et al.: Quanti- newly characterized, pseudoneoplastic, infectious,
a prospective cohort study of Staphylococcus aureus car- tative cultures of biopsy specimens from cutaneous cel- cutaneous vascular disorder. J Am Acad Dermatol 1990;
riage. Arch Intern Med 1994; 154:1505-1508. lulitis. Arch Intern Med 1989; 149:293-336. 22:501-512.
8. Raz R., Miron D., Colodner R., et al.: A 1 year trial of 19. Stevens D.L., Herr D., Lampiris H., et al.: Linezolid 28. Welch D.F., Hensel D.M., Pickett D.A., et al.: Bactere-
nasal mupirocin in the prevention of recurrent staphy- versus vancomycin for the treatment of methicillin- mia due to Rochalimaea henselae in a child: practical
lococcal nasal colonization and skin infection. Arch resistant Staphylococcus aureus infections. Clin Infect identification of isolates in the clinical laboratory. J Clin
Intern Med 1996; 156:1109-1112. Dis 2002; 341:1481-1490. Microbiol 1993; 31:2381-2386.
9. Hirschmann J.: Staphylococcal soft tissue infections. In: 20. Stevens D.L., Bryant A.E., Yan S.: Invasive group A 29. Stevens D.L., Bisno A.L., Chambers H.F., et al.: Practice
Stevens D.L., ed. Atlas of infectious diseases. Philadel- streptococcal infection: new concepts in antibiotic guidelines for the diagnosis and management of skin
phia, PA: Churchill Livingstone; 1995:2-10. treatment. Int J Antimicrob Agents 1994; 4:297-301. and soft-tissue infections. Clin Infect Dis 2014;
10. Dillon H.C.: Impetigo contagiosa: suppurative and 21. Stevens D.L., Yan S., Bryant A.E.: Penicillin binding 59(2):e10-e52.
nonsuppurative complications. Clinical, bacteriologic protein expression at different growth stages deter-
and epidemiologic characteristics of impetigo. Am J Dis mines penicillin efficacy in vitro and in vivo: an expla-
Child 1968; 115:530-541.
11
Necrotizing Fasciitis, Gas Gangrene,
Myositis and Myonecrosis
DENNIS L. STEVENS | MICHAEL J. ALDAPE | AMY E. BRYANT
KEY CONCEPTS apparent portal of entry1 and the only physical signs of infection may
be fever and localized pain; in some cases localized infection may not
• Gas gangrene caused by Clostridium perfringens remains as a become apparent until systemic signs such as hypotension or organ
severe life-theatening infection. failure develop.
• Clostridium sordellii infection is associated with hemoconcen- Early in the course of type II necrotizing fasciitis with a defined
tration, leukemoid reaction and absence of fever and has been portal of entry, there is generally evidence of localized inflammation
associated with childbirth, medical abortion and skin-popping (swelling, redness, warmth and tenderness). At that point the process
black tar heroin. may resemble simple cellulitis (see Chapter 10). In type I necrotizing
fasciitis there is generally gas in the tissue, like in gas gangrene. Where
• Necrotizing fasciitis and gas gangrene require aggressive diag-
nostic procedures and rapid surgical debridement.
• Toxins from group A streptococcus and Clostridium perfrin-
gens cause vascular occlusion leading to rapid tissue Differential diagnosis of infections involving muscle and fascia
destruction.
• Antibiotics that suppress toxin production, such as clindamycin
are more efficacious than β-lactam antibiotics in severe group Necrotizing Necrotizing Myositis due
A streptococcal and clostridial infections. Clinical fasciitis fasciitis Gas to viruses or
feature type I type II gangrene Pyomyositis parasites
Fever
Introduction
Note 1
The spectrum of infections of the deep soft tissues ranges from local- Diffuse
ized bacterial, viral and parasitic lesions to rapidly spreading, tissue- pain
destructive infections such as necrotizing fasciitis and myonecrosis.
Note 2
For example, pyomyositis, which is common in the tropics but rare in Localized
temperate zones, is a focal infection of skeletal muscle that is usually pain
caused by Staphylococcus aureus; it generally remains localized and
rarely causes systemic complications. In contrast, necrotizing fasciitis Systemic
and myonecrosis may be caused by single or multiple pathogens and toxicity
often give rise to extensive tissue loss, bacteremia, organ failure, shock
and death. Even the experienced clinician may have difficulty distin- Gas in
guishing between the different forms of deep soft tissue infection tissue
during the early stages. Finally, despite early diagnosis and appropriate
treatment, some patients will lose tissue, even limbs, whereas others Obvious Note 3 Note 4
will succumb to systemic complications. This chapter emphasizes the portal of
entry
clinical clues that help to make early, specific diagnoses.
Diabetes
Clinical Clues and Differential mellitus
Diagnosis Note 1: Pain with influenza is diffuse myalgia. Pleurodynia may be associated
Pain, either generalized or localized, is the most common reason with severe localized pain (i.e. devil’s grip). Pain with trichinosis may be severe
patients with deep-seated infection seek medical care (Figure 11-1). and localized.
Early in the course of necrotizing fasciitis caused by group A strepto- Note 2: Severe pain is present in necrotizing fasciitis associated with group A
streptococcal necrotizing fasciitis. Necrotizing fasciitis type I is commonly seen in
coccus (GAS), patients may have a viral-like prodrome with nausea, people who have diabetes mellitus who have peripheral neuropathy; hence the
vomiting, diarrhea and fever; however, later in the course of the pain may not be severe.
disease, patients present with increasingly severe localized pain with Note 3: Fifty percent of patients who have necrotizing fasciitis caused by group A
continuing fever. streptococci may not have an obvious portal of entry.
A portal of entry can be defined in the majority of cases of deep Note 4: Gas gangrene associated with trauma may be caused by Clostridium
perfringens, Clostridium septicum and Clostridium histolyticum and there is
bacterial soft tissue infections. In type I necrotizing fasciitis, infection
always an obvious portal of entry. Spontaneous gas gangrene caused by
begins at the site of a surgical incision, at a mucosal tear or at sites of Clostridium septicum is usually not associated with an obvious portal of entry.
skin breakdown in patients who have diabetes mellitus or peripheral Organisms lodge in tissue as a result of bacteremia originating from a bowel
vascular disease. Similarly, traumatic gas gangrene occurs at the site of portal of entry.
major trauma such as crush or penetrating injuries severe enough
to cause arterial damage. In contrast, patients who have either type Figure 11-1 Differential diagnosis of infections involving muscle and fascia. Red,
II necrotizing fasciitis or spontaneous gas gangrene may have no severe; orange, moderate; yellow, mild-to-moderate; blue, mild; white, none.
95
Figure 11-3 Ludwig’s angina. Infection begins with a break in the mucosal lining
in the oropharynx; oral bacterial flora invade the soft tissues at the base of the
tongue and penetrate through the floor of the mouth and into soft tissue of the
Figure 11-2 Histopathologic examination of tissue from a patient who has nec- neck. The floor of the mouth is elevated and patients talk as though they have a
rotizing fasciitis with extension into the underlying musculature. Note the absence ‘hot potato’ in their mouth. Potential airway obstruction is a major concern.
of acute inflammatory cells in the area of muscle necrosis. When present, infiltrat- Although patients usually respond to penicillin, surgical consultation should be
ing granulocytes can be seen at the interface between normal and necrotic tissue obtained and CT or MRI scans are useful for determining whether a necrotizing
and are often massed within small postcapillary venules. process is present.
there is no apparent portal of entry, the leading diagnoses to be con-

sidered are infection with GAS (type II necrotizing fasciitis), Clos-
tridium septicum (spontaneous gangrene) or Vibrio vulnificus. Gas in
the tissue favors clostridial infection. Gas may be detected by physical
examination (crepitus) or by imaging (radiography, magnetic reso-
nance imaging [MRI] or computed tomography [CT] scan). GAS
should be suspected if there is fever and severe pain and a history of
blunt trauma or muscle strain. V. vulnificus should be suspected in a
patient with cirrhosis, a history of ingestion of raw oysters or exposure
to seawater.2 Later, erythema is superseded by violaceous bullous
lesions, massive local swelling becomes apparent and signs of systemic
toxicity develop rapidly (see Chapter 182). Aeromonas hydrophila
infection is associated with a traumatic breach in the skin and con-
tamination by fresh water.
Necrotizing Infections
NECROTIZING FASCIITIS
Necrotizing fasciitis is a deep-seated infection of the subcutaneous
tissue that results in progressive destruction of fascia and fat, although
it may spare the skin.3 Two clinical types exist.
Type I Necrotizing Fasciitis Figure 11-4 CT scan of a soft tissue infection of the neck. This infection is caused
by group A streptococci, which invaded as a rare complication of a previous ‘strep
Type I necrotizing fasciitis is a mixed infection (polymicrobic) caused throat’. Surgical drainage yielded a pure culture of group A streptococci and
by aerobic and anaerobic bacteria. It occurs most commonly after established a diagnosis. The patient was treated with intravenous penicillin for 10
surgical procedures, in diabetic patients or in those who have periph- days and made a good recovery.
eral vascular disease (see Figure 11-2). Nonclostridial anaerobic cel-
lulitis and synergistic necrotizing cellulitis are both variants of the
same syndrome. This distinction is not considered important any suppurative thrombophlebitis and occlusion of the jugular vein
more. (Lemierre’s syndrome).
Clinical Features. These infections most commonly occur on or Diagnostic Tests. The first goal is to determine the depth and
about the feet, with rapid extension along the fascia into the leg. extent of the infection. MRI or CT scans are invaluable to determine
Although cellulitis is common in diabetic patients, necrotizing fasciitis whether the infection is localized or spreading along fascial planes. The
should be considered when cellulitis and systemic signs of infection second goal is to determine whether surgery is necessary. Because of
such as tachycardia, leukocytosis, acidosis or marked hyperglycemia the proximity to vital structures of the neck, surgical consultation is of
are present. In addition to its spontaneous occurrence in diabetic major importance because exploration, drainage and debridement
patients, type I necrotizing fasciitis may also be a result of a breach in may be necessary to prevent airway obstruction, to determine the level
the integrity of mucous membranes from surgery or instrumentation. of soft tissue involvement and to establish which bacteria are involved.
In the head and neck region, bacterial penetration into the fascial Treatment. Both Ludwig’s angina and necrotizing fasciitis of the
compartments can result in a related syndrome known as Ludwig’s head and neck are usually caused by mouth anaerobes such as Fuso-
angina (Figure 11-3) (see also Chapter 35) or it may develop into bacterium spp., anaerobic streptococci, Bacteroides spp. and spiro-
necrotizing fasciitis. Group A streptococci (but also anaerobes such chetes. Either penicillin or clindamycin is effective treatment, largely
as Fusobacterium necrophorum) may cause necrotizing fasciitis or a because the oropharyngeal gram-positive aerobic cocci and anaerobes
peritonsillar abscess, which can extend into the deep structures of are generally susceptible to both. In contrast, type I necrotizing fasciitis
the neck (Figure 11-4). Infection with F. necrophorum can also cause below the diaphragm requires ampicillin plus clindamycin and a
Chapter 11 Necrotizing Fasciitis, Gas Gangrene, Myositis and Myonecrosis 97
fluoroquinolone to cover the Bacteroides spp. and Enterobacteriaceae.

In Europe, other choices could be ampicillin/sulbactam and metroni-
dazole given intravenously, or for less severe infection or as stepdown
therapy, amoxicillin/clavulanic acid and metronidazole given orally.
Type II Necrotizing Fasciitis

Type II necrotizing fasciitis is mono-microbial; since the mid-1980s
there has been an increase in the frequency of necrotizing fasciitis
caused by GAS in all parts of the world and since it is reportable, the
current annual incidence is 3–3.5 cases per 100 000.4 Type II necrotiz-
ing fasciitis can also be caused by V. vulnificus in association with
seawater and pre-existing cirrhosis or A. hydrophila and related to
freshwater injuries, although both are far less common.
Type II necrotizing fasciitis caused by GAS (previously called strep-
tococcal gangrene)5 may occur in any age group and among patients
without complicated medical illnesses. Predisposing factors include: a
• a history of blunt trauma;
• muscle strain;
• childbirth;
• chickenpox;
• nonsteroidal anti-inflammatory agents;6
• intravenous drug abuse; or
• penetrating injury such as caused by a laceration or a surgical
procedure.
In penetrating injuries, the skin serves as the portal of entry for the
streptococci. In contrast, among patients without a defined portal of
entry, hematogenous translocation of GAS from the throat (asymp-
tomatic or symptomatic pharyngitis) to the site of blunt trauma or
muscle strain probably occurs.7
GAS have caused epidemics of pharyngitis and scarlet fever in
schools, rheumatic fever in military recruits and surgical wound infec-
tions in hospitalized patients. Thus, close contacts of a patient who has
type II necrotizing fasciitis have a high likelihood of becoming colo- b
nized with a virulent strain. Clearly, the risk of developing a secondary
case of fulminant necrotizing fasciitis is very low, but it is probably Figure 11-5 Type II necrotizing fasciitis caused by group A streptococci. (a) This
50-fold higher than it is in the general population. The risk to family patient was a 60-year-old man who had type 2 diabetes mellitus and who had a
members and hospital workers is dependent upon the degree of expo- 3-day history of malaise, diffuse myalgia and low-grade fever. Over the course of
2–3 hours the pain became excruciating and was localized to the calf. During this
sure and the susceptibility of the host. Contacts with conditions such time the calf swelled. Note that the skin over the anterior shin looks relatively
as open wounds or chickenpox, as well as family members and health- normal, but that two small purple bullae are present. (b) Extensive necrotizing
care workers with frequent or continuous contact with a case of nec- fasciitis was present on surgical exploration. In addition, myonecrosis was present
rotizing streptococcal infection, should be treated with an agent to beneath the fascia. The patient developed profound hypotension, acute respira-
tory distress syndrome and renal failure. He died despite aggressive surgical and
which the strain is sensitive (e.g. penicillin). medical management. There was no definable portal of entry, yet group A strep-
Pathogenesis. Pyrogenic exotoxins can bind simultaneously to tococci were grown from deep cultures and from blood.
the major histocompatibility complex (MHC) class II of antigen-
presenting cells, and certain Vβ segments of the T-cell receptor in the
absence of classic antigen processing.8 Thus, they are superantigens
that cause rapid proliferation of T cells bearing these Vβ repertoires Conversely, erythema may be absent and the characteristic bullae may
(see Chapter 3). This is associated with production of cytokines (tumor develop in skin of normal appearance. The bullae are initially filled
necrosis factor (TNF), interleukin (IL)-1, IL-6, IL-2, and interferon- with clear fluid and rapidly take on a blue or maroon appearance
gamma).9 Production of these cytokines contributes to shock, organ (Figure 11-5). When the bullous stage is observed, there is already
failure and tissue destruction.10 extensive necrotizing fasciitis (Figure 11-5) and patients usually exhibit
Clinical Features. Necrotizing fasciitis can remarkably rapidly fever and systemic toxicity.
progress from an inapparent process to extensive destruction of tissue, Although many different M-types of GAS have been associated with
systemic toxicity, loss of limb or death.1,7,11 Unexplained pain that necrotizing fasciitis in the past, M types 1 and 3 have been most com-
increases rapidly may be the first manifestation.1,7 The early signs of monly isolated from patients.7 These strains can produce the pyrogenic
infection may not be apparent, particularly in patients with postsurgi- exotoxins A, B and C.1,12 Necrotizing fasciitis caused by these strains is
cal infection, wounds, or diabetes. In patients with diabetes, the frequently complicated by ‘streptococcal toxic-shock syndrome’ with
absence of pain may be due to neuropathy. In surgical, trauma and early onset of shock and multiple organ failure1 (see also Chapter 177).
postpartum patients, the increasing pain may be assumed as part of Diagnosis. Serum creatine phosphokinase, aspartate aminotransfer-
the normal convalescence rather than to acute infection. Such a delay ase and creatinine are usually elevated, and, together with leukocytosis
in diagnosis may allow the disease to progress before appropriate anti- with left shift, these findings should prompt surgical exploration.1
biotics and surgical invention are initiated. There may also be fever, Punch biopsy and frozen section to establish the diagnosis have been
malaise, myalgias, diarrhea and anorexia during the first 24 hours; advocated, but may be false-negative if the deep tissue is not ade-
erythema, diffuse or local, may also be present. In most patients excru- quately sampled. Soft tissue radiographs, MRI and CT scans show soft
ciating pain without any cutaneous findings may be the only clue of tissue swelling.13 Gas is not present and abscess formation is not appar-
infection. Within 24–48 hours, erythema may develop or darken to a ent. These radiographic abnormalities are not unusual in uninfected
reddish-purple color, frequently with associated blisters and bullae. patients who have trauma or in postsurgical or postpartum patients
a
Figure 11-6 Postpartum sepsis due to group A streptococci. The patient was a
24-year-old woman who delivered a normal child. Thirty-six hours after delivery
she developed fever, leukocytosis with marked left shift and increasing low
abdominal pain. This MRI demonstrates swelling of the uterus, although not out
of proportion for a recent delivery. There was no gas in the tissue. An emergency
laparotomy revealed necrosis of the mucosa of the uterus, necrotizing fasciitis and
myonecrosis of the uterus.
(Figure 11-6). Surgeons may not be interested in surgical exploration

with such imaging findings, yet a toxic patient with the above labora-
tory abnormalities should provide the impetus to at least inspect the
deep tissue. Direct surgical exploration will usually demonstrate nec-
rotizing fasciitis, prompt debridement of necrotic tissue and provide
material for Gram stain and culture.
Management. The three main themes in treatment are surgical
debridement, appropriate antibiotics and intensive care. Some patients
require mechanical ventilation and others need hemodialysis. Because
of intractable hypotension and diffuse capillary leak, massive amounts b
of intravenous fluids (10–20 L per day) are often necessary, although
Figure 11-7 Type I necrotizing fasciitis. A 24-year-old man had been in good
anasarca is a common complication. In some patients hypotension health but was awakened with severe perineal pain. (a) This photograph was taken
improves with intravenous fluid alone. Pressors such as dopamine may 3 hours later. Note the massive swelling of the scrotum. (b) Soft tissue radiograph
be useful, but there is little evidence in this specific infection. Although shows gas in the tissues of the thigh, buttocks, scrotum and anterior abdominal
potent vasoconstrictors such as epinephrine may improve blood pres- wall. Surgical inspection revealed brownish fluid in the scrotum, with gray, dull-
colored, friable fascia but normal underlying musculature. Cultures grew Entero-
sure, symmetrical gangrene may ensue due to reduced perfusion. coccus faecalis, Bacteroides fragilis, Escherichia coli and anaerobic streptococci.
Antibiotic selection is difficult in patients who have rapidly pro- The patient was treated with ampicillin, clindamycin and gentamicin for 3 weeks
gressing infection. Studies suggest that clindamycin is superior to peni- and surgical drains were placed in the scrotum, buttocks, thigh and anterior
cillin for treatment of experimental necrotizing fasciitis or myonecrosis abdominal wall. There was an excellent clinical response. In some cases, surgery
of a more radical nature may be necessary.
caused by GAS.14 Penicillin failure may be due to reduced expression
of critical penicillin-binding proteins during the bacterial stationary
phase.15 Clindamycin may be more efficacious because it is not affected
by inoculum size or stage of growth, it suppresses toxin production, it
facilitates phagocytosis of GAS by inhibiting M-protein synthesis, it
suppresses the production of regulatory elements that control cell wall FOURNIER’S GANGRENE
synthesis and it has a long post-antibiotic effect.16 In the perineal area, penetration of the gastrointestinal or urethral
Neutralization of circulating streptococcal toxins is a desirable mucosa by bacteria may cause ‘Fournier’s gangrene’, an aggressive
therapeutic goal and is advocated by some experts.17–20 Some batches infection caused by aerobic gram-negative bacteria, enterococci and
of intravenous immunoglobulin contain neutralizing antibodies anaerobic bacteria such as Bacteroides spp. and peptostreptococci.
against some streptococcal toxins.19 On the basis of two case reports,17,18 These infections begin abruptly with severe pain and may spread
a nonrandomized clinical trial20 and a small randomized trial in rapidly to the anterior abdominal wall and the gluteal muscles;
Europe,19 there is a suggestion that this treatment may affect the mor- in males, infection frequently extends to the scrotum and penis
tality and morbidity. Although acknowledging the limited data, the (Figure 11-7).
high mortality of this condition has resulted in wide use of IVIG in Surgical inspection and appropriate debridement are necessary for
Europe; the UK government panel on IVIG, for instance, permits use both diagnosis and treatment. Antibiotic treatment should be based
of a single dose of 2 g/kg body weight in severe GAS necrotizing fas- on Gram stain, culture and sensitivity information when available. An
ciitis. The mortality of GAS necrotizing fasciitis in the pre-antibiotic appropriate empiric regimen would be either ampicillin or ampicillin
era was about 25% when treated with surgery (such as ‘bear claw’ and sulbactam combined with either clindamycin or metronidazole. If
fasciotomies) alone.21 Mortality due to GAS necrotizing fasciitis has the patient has had prior hospitalization or recently used antibiotics,
not decreased and still ranges from 30% to 70% despite antibiotics, broader gram-negative coverage is advisable (substituting ticarcillin–
appropriate surgical debridement and intensive care, suggesting that clavulanic acid or piperacillin–tazobactam for ampicillin or adding a
more virulent strains have emerged. fluorinated quinolone or an aminoglycoside).
MELENEY’S SYNERGISTIC GANGRENE The second type, anaerobic cellulitis, occurs when there is devital-
This rare lesion in postsurgical patients is a slowly expanding, indolent ized tissue in a wound, sufficient for growth of C. perfringens or other
ulceration confined to the superficial fascia. It results from synergy strains. Although gas is produced locally and extends along fascial
between Staph. aureus and microaerophilic streptococci. As in other planes, bacteremia and invasion of healthy tissue do not occur. Appro-
necrotizing infections, antibiotics and debridement are the mainstays priate medical and surgical management, including prompt removal
of treatment. of the devitalized tissue, is all that is necessary for cure, and mortality
is generally nil.22
NONCLOSTRIDIAL ANAEROBIC CELLULITIS The third type is clostridial gas gangrene or myonecrosis. This is
Nonclostridial anaerobic cellulitis is due to mixed anaerobic and defined as an acute invasion of healthy muscle that is undamaged by
aerobic organisms that produce gas in tissues. Unlike clostridial cel- trauma or ischemia.25 It is divided into three different subtypes:
lulitis, it is usually associated with diabetes mellitus and often produces • traumatic gas gangrene;
a foul odor. Surgical exploration is required to distinguish this condi- • spontaneous or nontraumatic gas gangrene;
tion from necrotizing cellulitis, myonecrosis and necrotizing fasciitis • recurrent gas gangrene caused by C. perfringens.
by Clostridium spp. Traumatic gas gangrene is the most common. It develops when a
deep, penetrating injury that compromises the blood supply (e.g. knife
CLOSTRIDIAL CELLULITIS or gunshot wounds, crush injury) creates an anaerobic environment
Clostridial cellulitis is usually preceded by local trauma or recent that is ideal for clostridial proliferation. This type of trauma accounts
surgery. C. perfringens is the most common causative species. Gas is for about 70% of cases of gas gangrene. C. perfringens is found in about
invariably found in the skin; the fascia and deep muscle are spared. 80% of such infections;22 the remainder are caused by C. septicum, C.
Although clostridial cellulitis differs from clostridial myonecrosis in novyi, C. histolyticum, C. bifermentans, C. tertium and C. fallax. Other
that there is less systemic toxicity, thorough surgical exploration and conditions associated with traumatic gas gangrene are bowel and
debridement is needed to distinguish these entities. MRI or CT scans biliary tract surgery, intramuscular injection of adrenaline, illegal
as well as a serum creatinine phosphokinase are useful to determine abortion, retained placenta, prolonged rupture of the membranes and
whether muscle is involved. Treatment is discussed below under gas intrauterine fetal demise or missed abortion in postpartum patients.
gangrene. Spontaneous or nontraumatic gas gangrene is less common and
often caused by the more aerotolerant species, C. septicum. Most of
Clostridial Gas Gangrene these cases occur in patients who have an intestinal portal of entry such
as adenocarcinoma.
EPIDEMIOLOGY Third, and least common, is recurrent gas gangrene caused by C.
Until the middle of the 20th century, wartime injuries were commonly perfringens. This has been described in people with nonpenetrating
complicated by gas gangrene caused by Clostridium spp. During the injuries at sites of previous gas gangrene; residual clostridial spores
Civil War in the USA, nearly 50% of soldiers who sustained gunshot may remain quiescent in tissue up to 20 years, and then germinate
wounds developed infection and many of them developed gas gan- when minor trauma provides anaerobic conditions suitable for
grene. Clostridial gangrene is typically a sporadic infection but during growth.26
the Civil War epidemics of ‘hospital gangrene’ were described. Con-
tributing factors included severe trauma, grossly contaminated
wounds, crowded and dirty conditions, application of soiled dressings TRAUMATIC GAS GANGRENE
and primitive surgical techniques. Group A streptococci (GAS) and C. Pathogenesis
perfringens were the major pathogens. The initiating trauma introduces organisms (either vegetative forms
Gas gangrene was also common during World War I, where the or spores) into the deep tissues and produces an anaerobic niche with
soil was rich with animal feces full of vegetative spores of clostridia. In a sufficiently low redox potential and acid pH for optimal clostridial
contrast, in North Africa during World War II cases of gangrene were growth.22,25 Necrosis progresses within hours. At the junction of
far less common, presumably because the desert sand contained few necrotic and normal tissues few polymorphonuclear leukocytes
clostridial spores.22 Gas gangrene has become uncommon in modern (PMNLs) are present, yet pavementing of these cells along the endo-
warfare because wounded soldiers are evacuated rapidly to well- thelium is apparent within capillaries and in small arterioles and post-
equipped hospitals for surgical intervention, arterial reconstruction capillary venules.27,28 Later in the course there is leukostasis within
and antibiotic treatment. larger vessels. Thus, the histopathology of clostridial gas gangrene is
In modern times sporadic cases in the population are associated opposite to that seen in soft tissue infections caused by pyogenic
with complications of penetrating trauma, compound fractures or organisms such as Staph. aureus, in which an early luxuriant influx of
septic abortions. Gas gangrene is also seen with natural disasters such PMNLs localizes the infection without adjacent tissue or vascular
as earthquakes, with victims sustaining massive trauma and delays in destruction. Recent studies suggest that θ-toxin (Figure 11-8) at the
appropriate medical care. For the first time in history, spontaneous gas site of infection destroys host tissues and inflammatory cells.29 As
gangrene caused by C. septicum may be more common than trauma- the toxin diffuses into surrounding tissues or enters the systemic cir-
associated gas gangrene caused by C. perfringens, C. histolyticum or culation, it promotes dysregulated adhesion between PMNLs and
other Clostridium spp. (see Chapter 184). Recently, severe soft tissue endothelial cells, and primes leukocytes for increased respiratory burst
infections caused by C. perfringens, C. sordellii and C. novyi have been activity.29
described among intradermal (‘skin popping’) and intravenous drug α-toxin (see Figure 11-8), a phospholipase C, directly suppresses
users.23,24 myocardial contractility ex vivo30 and may contribute to profound
Three types of clostridial soft tissue infections have been hypotension via a sudden reduction in cardiac output.31 Experimen-
defined:22 tally, α-toxin induces a profound and irreversible defect in perfusion
• simple wound contamination or colonization; as measured by laser Doppler blood flow.32,33 Simultaneously, there is
• anaerobic cellulitis; and rapid appearance of circulating aggregates of platelets and neutrophils
• clostridial gas gangrene. bound together by the platelet surface receptor GPIIb/IIIa.32 These
Simple wound contamination or colonization does not progress to actions lead to vascular leukostasis, endothelial cell injury and regional
true infection for various reasons (e.g. insufficient devitalized tissue to tissue hypoxia that expand the anaerobic environment and contribute
promote infection, effective host responses or effective medical and to the rapidly advancing margins of tissue destruction that are charac-
surgical management). Contamination is very common; 30–80% of teristic of clostridial gangrene.22 In experimental models, θ-toxin (a
open traumatic wounds contain clostridial species.25 cholesterol-binding cytolysin) causes ‘warm shock’, defined as
Figure 11-9 Extensive gas gangrene of the arm due to Clostridium perfringens.
A 35-year-old man sustained a knife wound to the forearm. He did not seek
medical care, but 36 hours later experienced severe pain in the upper arm and
came to the emergency room. There was extreme tenderness of the arm and
crepitus was easily demonstrated. A radiograph also demonstrated gas in the
deep soft tissues. Surgical debridement and antibiotics were instituted, but later
Figure 11-8 Colonies of Clostridium perfringens growing on an anaerobic blood amputation at the level of the shoulder was necessary. A pure culture of C. per-
agar plate. θ-toxin causes the clear zone of hemolysis closest to the colony. A fringens was grown from the deep tissues.
second area of partial hemolysis is caused by α-toxin, an enzyme with phospho-
lipase C activity.
a markedly reduced systemic vascular resistance combined with a packed red blood cells. Both α- and θ-toxins contribute to this intra-
markedly increased cardiac output.30,31 θ-toxin accomplishes this by vascular hemolysis. Not all cases of C. perfringens bacteremia have been
inducing endogenous mediators that cause relaxation of blood vessel associated with gas gangrene36 but 90% of C. perfringens and 100% of
wall tension (such as the lipid autacoids prostacyclin or platelet- C. septicum isolates from blood were associated with clinically signifi-
activating factor).34 Reduced vascular tone develops rapidly and, in cant infection.37
order to maintain adequate tissue perfusion, a compensatory host Additional complications of clostridial myonecrosis include jaun-
response is required; this either increases cardiac output or rapidly dice, renal failure, hypotension and liver necrosis. Renal failure is
expands the intravascular blood volume. Patients with gram-negative largely due to hemoglobinuria and myoglobinuria, but it may be a
sepsis compensate for hypotension by markedly increasing cardiac result of acute tubular necrosis caused by hypotension.
output; however, this adaptive mechanism may not be possible in
shock induced by C. perfringens due to direct suppression of myocar- Diagnosis
dial contractility by α-toxin.30 The role of other endogenous mediators Increasing pain at a site of previous injury or surgery, together with
such as cytokines as well as the potent endogenous vasodilator brady- signs of systemic toxicity and gas in the tissues, support the diagnosis.
kinin have not been elucidated. Definitive diagnosis rests on demonstrating large, gram-variable rods
at the affected site (Figure 11-10). Note that although clostridia stain
Prevention gram-positive when obtained from bacteriologic media, from infected
Aggressive debridement of devitalized tissue and repair of compro- tissues they often appear both gram-positive and gram-negative. In
mised vascular supply greatly reduce the risk of gas gangrene in fresh specimens they may appear to be encapsulated.38,39
contaminated deep wounds. Intramuscular adrenaline, prolonged Affected muscles appear edematous, and reddish-blue to black and
application of tourniquets and surgical closure of traumatic wounds do not bleed or contract when stimulated. Some degree of necrotizing
should be avoided. Patients with compound fractures are at particular fasciitis and cutaneous necrosis is also present. Microscopic evaluation
risk of gas gangrene if the wound is surgically closed. Patients with of biopsy material (see Figure 11-10) demonstrates organisms among
contaminated wounds should receive prophylactic antibiotics. degenerating muscle bundles and, characteristically, an absence of
PMNLs.25,40
Clinical Findings
The first symptom is the sudden onset of severe pain at the site of Morbidity and Mortality
recent surgery or trauma.19,23 The mean incubation period is less than Before the availability of antibiotics, gas gangrene was usually
24 hours, but ranges from 6 hours to days, probably depending on the fatal. Since then, mortality rates from gas gangrene caused by C.
degree of soil or fecal contamination and the extent of vascular perfringens have improved, owing to antibiotic therapy, aggressive
compromise. surgical debridement, vascular reconstructive surgery and, possibly,
The skin may initially appear pale, but it quickly changes to bronze hyperbaric oxygen therapy. The role of each of these modalities will be
then purplish red, becoming tense and exquisitely tender (Figure discussed below.
11-9). Bullae develop; they may be clear, red, blue or purple.
Gas in tissue may be obvious from physical examination, soft Management
tissue radiographs, CT scan or MRI. None of these radiographic pro- Penicillin, clindamycin, tetracycline, chloramphenicol, metronidazole
cedures is more specific or more sensitive than the physical finding of and a number of cephalosporins have excellent in vitro activity against
crepitus in the soft tissue.3 However, radiographic procedures are par- C. perfringens and other clostridia. No controlled clinical trials have
ticularly helpful for demonstrating gas in deeper tissue such as the been conducted to compare the efficacy of these agents in humans.
uterus. Based on in vitro susceptibility data, most textbooks state that penicil-
Signs of systemic toxicity develop rapidly; these include tachycar- lin is the drug of choice.41,42 However, experimental studies in mice
dia, fever and diaphoresis, followed by shock and multiple organ suggest that clindamycin has the greatest efficacy and penicillin the
failure. Shock is present in 50% of patients at the time they present to least.43,44 Other agents with greater efficacy than penicillin include
the hospital.35 Bacteremia occurs in 15% of patients and may be associ- erythromycin, rifampin (rifampicin), tetracycline, chloramphenicol
ated with brisk hemolysis. In one patient the hematocrit fell from 37% and metronidazole.43,44 Slightly greater survival was observed in
to 0% over a 24-hour period despite transfusion with 10 units of animals receiving both clindamycin and penicillin; in contrast,
molecules such that toxin-induced vascular leukostasis and resultant

tissue injury are attenuated.
Prognosis
Patients presenting with gas gangrene of an extremity have a better
prognosis than those with truncal or intra-abdominal gas gangrene,
largely because it is difficult to debride such lesions adequately.41,42,53
Hyperbaric oxygen could be useful in such patients. In addition to
truncal gangrene, patients who have associated bacteremia and intra-
vascular hemolysis have the greatest likelihood of progressing to shock
and death. In one study of patients who developed shock at some point
in their hospitalization, 40% died, compared with 20% in the group
as a whole.35 In another study, patients in shock at the time of diagnosis
had the highest mortality.53
a
SPONTANEOUS, NONTRAUMATIC GAS
GANGRENE DUE TO C. SEPTICUM
Pathogenesis
Predisposing factors include:53–55
• colonic carcinoma;
• diverticulitis;
• gastrointestinal surgery;
• leukemia;
• lymphoproliferative disorders;
• cancer chemotherapy;
• radiation therapy; and
• AIDS.
Cyclic or other forms of neutropenia are also associated with spon-
taneous gas gangrene due to C. septicum and in such cases necrotizing
enterocolitis, cecitis or distal ileitis are commonly found. These intes-
b tinal pathologies permit bacterial access to the bloodstream; conse-
quently, the aerotolerant C. septicum can become established in normal
Figure 11-10 Clostridium perfringens in a patient who has extensive gas gan- tissues.22
grene. (a) Gram stain of tissue removed from the arm of the patient described in C. septicum produces four toxins: α-toxin (lethal, hemolytic, nec-
Figure 11-9. Note that the bacteria are rod-shaped but gram-variable. Note also rotizing activity); β-toxin (deoxyribonuclease); γ-toxin (hyaluroni-
that there are few if any acute inflammatory cells at the site of infection. (b) Trans-
mission electron micrograph of C. perfringens. Note the endospores.
dase); and δ-toxin (septicolysin, an oxygen-labile hemolysin).
C. septicum also produces a protease and a neuraminidase.22 The C.
septicum α-toxin does not possess phospholipase activity and is thus
antagonism was observed with penicillin plus metronidazole.44 Because distinct from the α-toxin of C. perfringens. Active immunization
2–5% of strains are resistant to clindamycin, a combination of penicil- against α-toxin significantly protects against challenge with viable C.
lin and clindamycin is warranted. Based on his experiments and his septicum.56 The mechanism by which α-toxin contributes to C. septi-
vast clinical experience with gas gangrene, the late Dr William Alte- cum pathogenesis is unknown (see Chapter 184).
meier recommended tetracycline and penicillin.45 Thus, given an Clinical Features
absence of efficacy data from clinical trials in humans, the best treat- The onset of disease is abrupt, often with excruciating pain, heaviness
ment would appear to be clindamycin or tetracycline combined with or numbness.22,27,53–55 The first symptom may be confusion or malaise.
penicillin. The failure of penicillin in experimental clostridial myone- Swelling advances and bullae appear filled with clear, cloudy, or pur-
crosis may be due to continued toxin production and filament forma- plish fluid. The skin around such bullae has a purple hue (Figure
tion rather than lysis.46 In contrast, the efficacy of clindamycin and 11-11), perhaps reflecting vascular compromise resulting from bacte-
tetracycline may be due to their rapid inhibition of toxin synthesis.46 rial toxins diffusing into surrounding tissues.53 Histopathology of
Aggressive and thorough surgical debridement is mandatory to muscle and connective tissue includes cell lysis and gas formation;
improve survival, preserve limbs and prevent complications.41,42 The inflammatory cells are notably absent.53
use of hyperbaric oxygen (HBO) is controversial, although some non-
randomized studies have reported good results with HBO therapy Diagnosis
when combined with antibiotics and surgical debridement.35,47,48 Unlike in traumatic gas gangrene, bacteremia precedes cutaneous
Experimental studies in animals have demonstrated that HBO alone manifestations by several hours. In the absence of the usual cutaneous
can be effective treatment if the inoculum is small and treatment is manifestations of gas gangrene, other causes of fever and extremity
begun immediately.49 Other studies have demonstrated that HBO was pain such as deep vein thrombophlebitis or cellulitis are considered
only of slight benefit when combined with penicillin.50 However, sur- first, delaying appropriate diagnosis and treatment, and, as a conse-
vival was better with clindamycin alone than with either HBO alone, quence, increasing mortality.
penicillin alone or HBO plus penicillin together.50 The benefit of HBO,
at least theoretically, is to inhibit bacterial growth,51 to preserve mar- Management
ginally perfused tissue and to inhibit toxin production.52 Altemeier did No trials have evaluated the efficacy of antibiotics or HBO for treating
not use HBO and was able to realize a mortality rate of less than 15% spontaneous gas gangrene. In vitro data indicate that C. septicum is
using surgical debridement and antibiotics (tetracycline plus penicil- uniformly susceptible to penicillin, tetracycline, erythromycin, clinda-
lin) alone.45 mycin, chloramphenicol and metronidazole. The aerotolerance of C.
Specific antitoxin antibodies for adjunctive treatment are no longer septicum may reduce the likelihood that HBO therapy would be
available. Future strategies may target endogenous pro-adhesive effective.51
Figure 11-11 Spontaneous necrotizing fasciitis due to Clostridium septicum.

This patient developed sudden onset of severe pain in the forearm. Swelling
rapidly ensued and he sought medical treatment. Crepitus was present on physi-
cal examination and gas in the soft tissue was verified with routine radiographs.
Immediate surgical debridement revealed necrotizing fasciitis but sparing of the
muscle. Note the purple-violaceous appearance of the skin. See also Figure 11-12.
Figure 11-13 MRI scan showing high-signal STIR sequence (consistent with
marked edema) in the adductor muscles of the left leg in a patient with Staphy-
lococcus aureus bacteremia (arrow). At operation, necrotic and infected muscle
was decompressed and debrided. This represents the ‘woody’ stage, prior to
muscle liquefaction and the formation of frank abscesses.
England. Patients have severe soft tissue infections with shock with a
case fatality rate of 20–30%.24 The mortality rate of women who
acquire postpartum C. sordelli has been 100%.59
Unlike C. perfringens and C. septicum infections, pain may not be
a prominent feature of C. sordellii infections. The absence of fever and
the paucity of signs and symptoms of local infection make early diag-
nosis difficult.42 The mechanisms of diffuse capillary leak, massive
edema and hemoconcentration are clearly related to elaboration of a
potent toxin or toxins. A crude toxin preparation has been shown to
cause leakiness of endothelial cells in vitro.60 Hematocrits of 75–80%
have been described and leukocytosis of 50–100 x109 cells/L with a left
shift is common.40,57 A neuroaminidase of C. sordellii appears to lead
to proliferation of bone marrow progenitor cells that likely contributes
to the leukemoid reaction.59
Figure 11-12 Colonic carcinoma in a patient who has spontaneous gas gan-
grene caused by Clostridium septicum. The patient described in Figure 11-11 was
found to have a mass in the colon. Surgical resection revealed an adenocarci- C. TERTIUM INFECTIONS
noma, which probably served as a portal of entry for the C. septicum bacillus. C. tertium has been associated with spontaneous myonecrosis; however,
Hematogenous seeding of the forearm resulted in spontaneous gas gangrene. it more commonly causes bacteremia in compromised hosts who have
received long courses of antibiotics. Bacteremia probably arises from
Prognosis the bowel, and the presence of the organism in the bowel may be partly
The mortality of spontaneous clinical gangrene ranges from 67% to related to antimicrobial suppression of normal flora and its relative
100%, with the majority of deaths occurring within 24 hours of onset. resistance to penicillin, cephalosporins and clindamycin. C. tertium is,
Unfavorable factors include underlying malignancy and compromised however, usually quite sensitive to chloramphenicol, vancomycin and
immune status. All patients who survive bacteremia or spontaneous metronidazole. Because this organism can grow aerobically, it may be
gangrene caused by C. septicum should have diagnostic studies of the mistakenly disregarded as a contaminant such as a diphtheroid or a
gastrointestinal tract (Figure 11-12). Occasionally, this has led to Bacillus sp.41,42
detection and cure of an unsuspected malignancy.53
Pyomyositis
C. SORDELLII INFECTIONS Most cases of pyomyositis occur in tropical areas; however, recent
Patients with C. sordellii infection present with unique clinical features reports indicate a large increase in incidence in temperate climates
including edema, absence of fever, leukemoid reaction, hemoconcen- caused by methicillin-resistant Staph. aureus (MRSA).60 Local trauma,
tration and later shock and multiple organ failure.43 Often C. sordellii muscle strain and overuse are predisposing factors. Initially, seeding
infections develop after childbirth or after gynecologic procedures57,58 of traumatized muscle occurs and physical findings are not usually
and most represent endometrial infection. Rarely, cases have occurred helpful. Within 10–20 days, fever, chills, muscle pain and tenderness
at sites of minor trauma such as lacerations of the soft tissues of an are manifest (see Figure 11-1). Most patients seek medical care at this
extremity. Outbreaks of C. sordellii and C. novyi infections have been stage and a diagnosis can be established by appropriate imaging studies
described among intravenous drug users in Scotland, Ireland and (Figure 11-13), needle aspiration or exploration. Patients in whom a
diagnosis has not been made may progress to shock and organ failure. treatments since most cases are caused by Staph. aureus. Definitive
Staph. aureus is the most common cause of pyomyositis in tropical and treatment can then be established based on cultures and sensitivities.
nontropical areas, and among HIV-positive patients. Hospitalized Due to an increase in the prevalence of MRSA, it may be necessary to
immunocompromised patients who are HIV-negative occasionally use vancomycin or linezolid empirically pending sensitivity results.61
develop pyomyositis caused by gram-negative bacteria.
Surgical drainage of the abscess and empiric administration of par- References available online at expertconsult.com.
enteral antibiotics such as nafcillin or cephalosporins are reasonable
KEY REFERENCES
Aldape M.J., Bryant A.E., Ma Y., et al.: The leukemoid reac- Bryant A.E., Chen R.Y.Z., Nagata Y., et al.: Clostridial gas and penicillin in the treatment of streptococcal myositis.
tion in Clostridium sordellii infection: neuraminidase gangrene II: phospholipase C-induced activation of J Infect Dis 1988; 158:23-28.
induction of promyelocytic cell proliferation. J Infect Dis platelet GPIIb/IIIa mediates vascular occlusion and myo- Stevens D.L., Herr D., Lampiris H., et al.: Linezolid versus
2007; 195(12):1838-1845. necrosis in C. perfringens gas gangrene. J Infect Dis 2000; vancomycin for the treatment of methicillin-resistant
Aldape M.J., Bryant A.E., Stevens D.L.: Clostridium sordellii 182(3):808-815. Staphylococcus aureus infections. Clin Infect Dis 2002;
infection: epidemiology, clinical findings, and current Centers for Disease Control: Soft tissue infections among 341:1481-1490.
perspectives on diagnosis and treatment. Clin Infect Dis injection drug users – San Francisco, California, 1996– Stevens D.L., Maier K.A., Laine B.M., et al.: Comparison of
2006; 43(11):1436-1446. 2000. MMWR Morb Mortal Wkly Rep 2001; 50:381-384. clindamycin, rifampin, tetracycline, metronidazole and
Anonymous: Vibrio vulnificus infections associated with Darenberg J., Ihendyane N., Sjolin J., et al., Streptig Study: penicillin for efficacy in prevention of experimental gas
eating raw oysters – Los Angeles, 1996. MMWR Morb Intravenous immunoglobulin G therapy in streptococcal gangrene due to Clostridium perfringens. J Infect Dis 1987;
Mortal Wkly Rep 1996; 45:621-624. toxic shock syndrome. A European randomized, double 155:220-228.
Ballard J., Bryant A., Stevens D., et al.: Purification and blind, placebo-controlled trial. Clin Infect Dis 2003; Stevens D.L., Musher D.M., Watson D.A., et al.: Spontane-
characterization of the lethal toxin (alpha-toxin) of Clos- 37(3):333-340. ous, nontraumatic gangrene due to Clostridium septicum.
tridium septicum. Infect Immun 1992; 60:784-790. Pannaraj P.S., Hulten K.G., Gonzalez B.E., et al.: Infective Rev Infect Dis 1990; 12:286-296.
Bisno A.L., Stevens D.L.: Streptococcal infections in skin pyomyositis and myositis in children in the era of Stevens D.L., Tanner M.H., Winship J., et al.: Reappearance
and soft tissues. N Engl J Med 1996; 334:240-245. community-acquired, methicillin-resistant Staphylococ- of scarlet fever toxin A among streptococci in the Rocky
Bryant A.E., Chen R.Y.Z., Nagata Y., et al.: Clostridial gas cus aureus infection. Clin Infect Dis 2006; 43(8): Mountain West: severe group A streptococcal infections
gangrene I: cellular and molecular mechanisms of micro- 953-960. associated with a toxic shock-like syndrome. N Engl J
vascular dysfunction induced by exotoxins of C. perfrin- Stevens D.L., Gibbons A.E., Bergstrom R., et al.: The Eagle Med 1989; 321:1-7.
gens. J Infect Dis 2000; 182(3):799-807. effect revisited: efficacy of clindamycin, erythromycin,
Chapter 11 Necrotizing Fasciitis, Gas Gangrene, Myositis and Myonecrosis 103.e1
REFERENCES
1. Stevens D.L., Tanner M.H., Winship J., et al.: Reap- 22. Smith L.D.S.: Clostridial wound infections. In: Smith diseases. New York: Churchill Livingstone; 1990:1851-
pearance of scarlet fever toxin A among streptococci in L.D.S., ed. The pathogenic anaerobic bacteria. Spring- 1860.
the Rocky Mountain West: severe group A streptococ- field, Ill.: CC Thomas; 1975:321-324. 43. Stevens D.L., Maier K.A., Laine B.M., et al.: Compari-
cal infections associated with a toxic shock-like syn- 23. Centers for Disease Control: Soft tissue infections son of clindamycin, rifampin, tetracycline, metronida-
drome. N Engl J Med 1989; 321:1-7. among injection drug users – San Francisco, California, zole and penicillin for efficacy in prevention of
2. Anonymous: Vibrio vulnificus infections associated with 1996–2000. MMWR Morb Mortal Wkly Rep 2001; experimental gas gangrene due to Clostridium perfrin-
eating raw oysters – Los Angeles, 1996. MMWR Morb 50:381-384. gens. J Infect Dis 1987; 155:220-228.
Mortal Wkly Rep 1996; 45:621-624. 24. Centers for Disease Control: Update: Clostridium novyi 44. Stevens D.L., Laine B.M., Mitten J.E.: Comparison of
3. Gozal D., Ziser A., Shupak A., et al.: Necrotizing fasci- and unexplained illness among injecting-drug users – single and combination antimicrobial agents for pre-
itis. Arch Surg 1986; 121:233-235. Scotland, Ireland, England, April–June 2000. MMWR vention of experimental gas gangrene caused by Clos-
4. Schwartz B., Facklam R.R., Brieman R.F.: Changing Morb Mortal Wkly Rep 2000; 49:543-545. tridium perfringens. Antimicrob Agents Chemother 1987;
epidemiology of group A streptococcal infection in the 25. MacLennan J.D.: The histotoxic clostridial infections of 31:312-316.
USA. Lancet 1990; 336:1167-1171. man. Bacteriol Rev 1962; 26:177-276. 45. Altemeier W.A., Fullen W.D.: Prevention and treat-
5. Stevens D.L.: Clostridial myonecrosis and other clos- 26. Stevens D.L., Laposky L.L., Montgomery P., et al.: ment of gas gangrene. JAMA 1971; 217:806-813.
tridial diseases. In: Bennett J.C., Plum F., eds. Cecil Recurrent gas gangrene at a site of remote injury: local- 46. Stevens D.L., Maier K.A., Mitten J.E.: Effect of antibiot-
textbook of medicine, 20th ed. Philadelphia: WB Saun- ization due to circulating antitoxin. West J Med 1988; ics on toxin production and viability of Clostridium
ders; 1996:2090-2093. 148:204-205. perfringens. Antimicrob Agents Chemother 1987; 31:213-
6. Stevens D.L.: Could nonsteroidal anti-inflammatory 27. McNee J.W., Dunn J.S.: The method of spread of gas 218.
drugs (NSAIDs) enhance the progression of bacterial gangrene into living muscle. Br Med J 1917; 1:727-729. 47. Heimbach R.D., Boerema I., Brummelkamp W.H.,
infections to toxic shock syndrome? Clin Infect Dis 28. Robb-Smith A.H.T.: Tissue changes induced by C. et al.: Current therapy of gas gangrene. In: Davis J.C.,
1995; 21:977-980. welchii type a filtrates. Lancet 1945; 2:362-368. Hunt T.K., eds. Hyperbaric oxygen therapy. Bethesda,
7. Stevens D.: Streptococcal toxic shock syndrome: spec- 29. Bryant A.E., Bergstrom R., Zimmerman G.A., et al.: MD: Undersea Medical Society; 1977:153-176.
trum of disease, pathogenesis and new concepts in Clostridium perfringens invasiveness is enhanced by 48. Bakker D.J.: Clostridial myonecrosis. In: Davis J.C.,
treatment. Emerg Infect Dis 1995; 1:69-78. effects of theta toxin upon PMNL structure and func- Hunt T.K., eds. Problem wounds: the role of oxygen. New
8. Marrack P., Kappler J.W.: The staphylococcal entero- tion: the roles of leukocytotoxicity and expression of York: Elsevier; 1988:153-172.
toxins and their relatives. Science 1990; 248:705-711. CD11/CD18 adherence-glycoprotein. FEMS Immunol 49. Hill G.B., Osterhout S.: Experimental effects of hyper-
9. Hackett S.P., Stevens D.L.: Superantigens associated Med Microbiol 1993; 7:321-326. baric oxygen on selected clostridial species: II. In vivo
with staphylococcal and streptococcal toxic shock syn- 30. Stevens D.L., Troyer B.E., Merrick D.T., et al.: Lethal studies on mice. J Infect Dis 1972; 125:26-35.
dromes are potent inducers of tumor necrosis factor effects and cardiovascular effects of purified alpha- and 50. Stevens D.L., Bryant A.E., Adams K., et al.: Evaluation
beta synthesis. J Infect Dis 1993; 168:232-235. theta-toxins from Clostridium perfringens. J Infect Dis of hyperbaric oxygen therapy for treatment of experi-
10. Stevens D.L., Bryant A.E., Hackett S.P., et al.: Group A 1988; 157:272-279. mental Clostridium perfringens infection. Clin Infect Dis
streptococcal bacteremia: the role of tumor necrosis 31. Asmuth D.A., Olson R.D., Hackett S.P., et al.: Effects of 1993; 17:231-237.
factor in shock and organ failure. J Infect Dis 1996; Clostridium perfringens recombinant and crude phos- 51. Hill G.B., Osterhout S.: Experimental effects of hyper-
173:619-626. pholipase C and theta toxins on rabbit hemodynamic baric oxygen on selected clostridial species: I. In vitro
11. Chelson J., Halstensen A., Haga T., et al.: Necrotising parameters. J Infect Dis 1995; 172:1317-1323. studies. J Infect Dis 1972; 125:17-25.
fasciitis due to group A streptococci in western Norway: 32. Bryant A.E., Chen R.Y.Z., Nagata Y., et al.: Clostridial 52. van Unnik A.J.M.: Inhibition of toxin production in
incidence and clinical features. Lancet 1994; 344:1111- gas gangrene I: cellular and molecular mechanisms of Clostridium perfringens in vitro by hyperbaric oxygen.
1115. microvascular dysfunction induced by exotoxins of C. Antonie Van Leeuwenhoek 1965; 31:181-186.
12. Hauser A.R., Stevens D.L., Kaplan E.L., et al.: Molecu- perfringens. J Infect Dis 2000; 182(3):799-807. 53. Stevens D.L., Musher D.M., Watson D.A., et al.: Spon-
lar analysis of pyrogenic exotoxins from Streptococcus 33. Bryant A.E., Chen R.Y.Z., Nagata Y., et al.: Clostridial taneous, nontraumatic gangrene due to Clostridium
pyogenes isolates associated with toxic shock-like syn- gas gangrene II: phospholipase C-induced activation of septicum. Rev Infect Dis 1990; 12:286-296.
drome. J Clin Microbiol 1991; 29:1562-1567. platelet GPIIb/IIIa mediates vascular occlusion and 54. Johnson S., Driks M.R., Tweten R.K., et al.: Clinical
13. Bisno A.L., Stevens D.L.: Streptococcal infections in myonecrosis in C. perfringens gas gangrene. J Infect Dis courses of seven survivors of Clostridium septicum
skin and soft tissues. N Engl J Med 1996; 334:240-245. 2000; 182(3):808-815. infection and their immunologic responses to a toxin.
14. Stevens D.L., Gibbons A.E., Bergstrom R., et al.: The 34. Whatley R.E., Zimmerman G.A., Stevens D.L., et al.: Clin Infect Dis 1994; 19:761-764.
Eagle effect revisited: efficacy of clindamycin, erythro- The regulation of platelet activating factor synthesis in 55. Alpern R.J., Dowell V.R. Jr: Clostridium septicum infec-
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15. Stevens D.L., Yan S., Bryant A.E.: Penicillin binding 35. Hart G.B., Lamb R.C., Strauss M.B.: Gas gangrene: I. A characterization of the lethal toxin (alpha-toxin) of
protein expression at different growth stages deter- collective review. J Trauma 1983; 23:991-1000. Clostridium septicum. Infect Immun 1992; 60:784-790.
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16. Stevens D.L., Bryant A.E., Yan S.: Invasive group A 37. Brook I.: Anaerobic bacterial bacteremia: 12-year expe- 58. Aldape M.J., Bryant A.E., Stevens D.L.: Clostridium sor-
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JAMA 1992; 267:3315-3316. Med J Aust 1943; 2:224-226. reaction in Clostridium sordellii infection: neuramini-
18. Yong J.M.: Letter. Lancet 1994; 343:1427. 39. Keppie J., Robertson M.: The in vitro toxigenicity and dase induction of promyelocytic cell proliferation.
19. Darenberg J., Ihendyane N., Sjolin J., et al., Streptig other characters of strains of Cl. welchii type A from J Infect Dis 2007; 195(12):1838-1845.
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streptococcal toxic shock syndrome. A European ran- 40. Stevens D.L.: Clostridial infections. In: Stevens D.L., tive pyomyositis and myositis in children in the era of
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21. Meleney F.L.: Hemolytic streptococcus gangrene. Arch associated diseases). In: Mandell G.L., Douglas R.G.,
Surg 1924; 9:317-364. Bennett J.E., eds. Principles and practice of infectious
12
Arthropod Vectors of
Medical Importance
JEAN-MICHEL BERENGER | PHILIPPE PAROLA
KEY CONCEPTS such as ticks (Ixodes spp.) or sand flies and thereby the distribution of
their associated diseases (such as Lyme disease and leishmanioses,
• Many hematophagous arthropods are vectors of pathogens respectively). In France, another species of tick, Rhipicephalus sanguin-
(bacteria, viruses and parasites) responsible for human eus, has increased its distribution area. It was initially based in the
diseases. south, but has extended north since 1960.3 Deforestation in South
• Climate change, human activities and population growth are America promotes contact with Triatominae. International trade in old
factors promoting emerging and reemerging vectors, nui- car tires has promoted the spread of Aedes albopictus. Tourism acceler-
sances and diseases. ated reemergence of bed bugs around the world. It also has increased
world distribution of diseases such as dengue, chickungunya and Zika.
• Over the last decade and currently, several arboviruses have
broadened their global distribution (dengue, chikungunya, This chapter gives a short description of the main vectors and
Zika). arthropods that are a major nuisance.
• Hard ticks and soft ticks are the main vectors for pathogenic
bacteria (Rickettsia spp., Borrelia spp. etc.).
Arachnida
IXODIDA – IXODIDAE (HARD TICKS)
• Mosquitoes are the main vectors for arboviruses (dengue,
yellow fever, chikungunya) and parasites (Plasmodium spp.,
This family comprises 14 genera and some 700 species.4 Hard ticks are
Filariasis spp. etc.) and contribute to their global expansion. found in all zoogeographic regions of the world.5 The main genera of
medical interest are Rhipicephalus, Ixodes, Dermacentor, Amblyomma,
• Bed bugs and scabies are nuisances currently reemerging in Haemophysalis and Hyalomma.
the world. The biological cycle of ticks includes four stages of life: the eggs,
the larvae with six legs, the nymph and adult with eight legs. All stages
are hematophagous (‘blood eating’); a blood meal is necessary for
reaching the next stage or for maturation of eggs in the female. The
Introduction body of the tick is oval when unfed, and becomes rounded when
Arthropods (‘articulate legs’) are the major phylum of invertebrates. female ticks are engorged. In the latter situation, a female can reach
Among them, arachnids (eight legs) and insects (six legs) play an a length of 25 mm. The mouthparts (capitulum) are located at the
important role in human health by the use of defensive or preying front of the head and are visible on dorsal view. Males are generally
mechanisms (venom) or by the transmission of pathogens: parasites, smaller than females and show a scutum covering the entire abdomen
viruses or bacteria. In the latter case, the arthropod is named a vector. (Figure 12-1); in the female (Figure 12-2) the scutum is small and
A vector is a blood-feeding arthropod that provides active transmis- located just behind the head, an important characteristic which allows
sion of a pathogen from one vertebrate to another vertebrate. Mosqui- the abdomen to bloat during the blood meal. The first step before the
toes, ticks, fleas and lice are examples of vectors. This transmission can taking of the blood meal is the fixation on the host, which requires
be ‘mechanical’ if the insect carries a pathogen derived from a con- some hours. After that, the blood meal can start and takes longer in a
taminated source (food, crockery, mucous membrane) to a vertebrate hard tick for the female, up to a number of days. The hosts of hard
host. This is the case for flies or cockroaches; it is also the case if the ticks are mammals, birds, reptiles and amphibians. Usually ticks are
pathogen stays just at the level of the mouthparts, as in stable flies or host-specific. Hard ticks transmit many pathogens.6–10 This transmis-
horse flies (Tabanidae). sion may be carried out by salivary injection or by infected feces – see
These vectorial systems are composed of three elements: host, Table 12-1.
vector and pathogen. They can be responsible for a million deaths
every year, as in the case of dengue and malaria. Diseases induced by ARGASIDA – ARGASIDAE (SOFT TICKS)
pathogens transmitted via mosquitoes (yellow fever, West Nile fever, This family comprises five genera and 193 species distributed over all
chikungunya), ticks (Lyme disease, rickettsioses, tick encephalitis), continents.4 The main genera of medical interest are Argas and Orni-
Assassin Bugs Triatominae (Chagas disease) or lice (epidemic typhus, thodoros (Figure 12-3). The biological cycle includes eggs, larval stage
trench fever) may cause additional significant morbidity. and many nymphal stages (four to seven, depending on species) and
Over the last decade, medical entomology has been growing in adults. Adults are 8–13 mm long and have an oval body. As indicated
importance for human health. There is an increase worldwide of by their name (soft ticks), the body has no scutum and is covered with
arthropod-borne diseases, emergence or reemergence in some cases.1 many small tubercles. The usual color is grey. The mouthparts of
Factors such as human population growth and associated deforestation Argasidae are situated on the ventral part of the face, not visible on
contribute to this situation. These factors have strongly enhanced the dorsal view. Lack of scutum and the position of the mouthparts are
risk of contact with wild arthropods (e.g., leading to many more cases the main differences with Ixodidae. All stages need a blood meal for
of Chagas disease). Tourism, international trade (mosquitoes), popula- development and females need it for egg maturation. Argasidae are
tion migration (driven by war, water, work etc.), climate change and endophilic and spend their life near their host (under stones, nest,
pesticide resistance also play a role. house, etc.). During the day they are hidden, helped by their flattened
These factors modify the biology and distribution of vectors. For bodies, and they can stay there a long time. Their blood meal takes
example, we know that high temperature increases risk for some tick 15–20 minutes. The hosts of Argasidae are mammals, birds and rep-
bites on humans.2 Temperature also influences distribution of vectors tiles, with generally a narrow association.
104
Chapter 12 Arthropod Vectors of Medical Importance 105
Figure 12-3 Adult Ornithodoros sonrai with eggs.
Figure 12-1 Amblyomma variegatum, male. Note the scutum covers the entire
abdomen.
The longevity of this species is astounding: they live more than 10
years, and when they are infected the pathogen is conserved for all
their lifetime, making them efficient vectors. They are good vectors for
Borrelia spp. and some arboviruses.11–13 For more information, see
Table 12-1.
ACARINA – MITES
With an estimate of more than half a million species, this is the
largest group of Arachnida. The diversity inside the group (morphol-
ogy, diet, biology etc.) is also very significant. Many species living in
our environment are responsible for allergy (e.g. asthma) or contact
dermatitis.14
Trombiculid Mites (Lymphophagous)
Among the more than 2000 species belonging to the Trombiculidae,
around 20 species have human health importance. Two main genera
are responsible for scrub itch (trombidiosis): Eutrombicula in Europe
and Neotrombicula in the New World. One genus, Leptotrombidium,
is significant in medical terms.
The biological cycle comprises eggs, larvae, nymphs and adults.
Nymphs and adults (male and female) have no human health interest
but they are predaceous of small arthropods. Adults are very small, 1
or 2 mm, and reddish in color. Larvae are very small, with six legs and
not visible to the naked eye when unfed (0.15–0.3 mm). Larvae are
lymphophagous, feeding on mammals or birds and humans. After
feeding, they fall on the ground. Only larvae bite humans. Leptotrom-
bidium spp. are a vector of a pathogenic bacteria, Orientia tsutsugamu-
shi, responsible for scrub typhus in the Asia–Pacific area.
Hematophagous Mites
Hematophagous mites belong to the superfamily Mesostigmata. These
mites live in direct contact with their hosts – in the nests of birds,
mammals or reptiles. They generally take the blood meal on the young
in the nest, and after feeding, reach the litter. With a high reproduction
Figure 12-2 Amblyomma variegatum, female. Note the reduced scutum behind
rate, the number of mites increases quickly and can cause severe
the head. anemia of the host. If the host (bird, mammal) is nesting near people,
the problem begins when the young leave the nest, when the nest
inhabitants die or when the population of mites becomes significant;
then the mites can enter dwellings and bite humans. The biological
TABLE
12-1 Main Arthropod Vectors and Pathogens Associated
Arthropod Vectors Main Vector Genera Pathogen Transmitted Disease
Hard ticks (Ixodidae) All Rickettsia spp. Various tick-borne spotted fever group
Ixodes spp. Borrelia burgdorferi Lyme disease
Dermacentor andersoni Coltivirus Colorado tick fever
Hyalomma spp. Nairovirus Crimean-Congo hemorrhagic fever
Haemaphysalis spp. Flavivirus Kyasanur forest disease
Dermacentor reticulatus Flavivirus Omsk hemorrhagic fever
Ixodes spp. Flavivirus Tick-borne encephalitis
Rhipicephalus sanguineus Rickettsia conorii Mediterranean spotted fever
Amblyomma spp. Rickettsia africae African tick-bite fever
Dermacentor spp., Amblyomma spp., Rickettsia rickettsii Rocky Mountain spotted fever
Rhipicephalus spp.
Ixodes spp., Amblyomma spp., Francisella tularensis Tularemia
Dermacentor spp.
Dermacentor spp., Ixodes spp. Babesia spp. Babesiosis
Amblyomma spp., Ixodes spp. Ehrlichia chaffeensis Human ehrlichiosis and anaplasmosis
Anaplasma phagocytophilum
Soft ticks (Argasidae) Ornithodoros spp. Borrelia spp. Tick-borne relapsing fever
Argas spp. Arboviruses Kyasanur forest disease, Quaranfil,
Colorado tick fever, Alkhurma
hemorrhagic fever viruses
Chiggers mites Leptotrombidium spp. Orientia tsutsugamushi Scrub typhus

(Trombiculidae)
Haematophagous mites Dermanyssus spp. Bartonella quintana Trench fever

Flavivirus St Louis encephalitis
Liponyssoides sanguineus Rickettsia akari Rickettsial pox
Lice (Anoploura) Pediculus humanus corporis Rickettsia prowazeki Epidemic typhus

Bartonella quintana Trench fever
Borrelia recurrentis Louse-borne relapsing fever
Yersinia pestis Plague
Bugs – Reduviidae Panstrongylus spp. Trypanosoma cruzi Chagas disease

Triatominae (Hemiptera) Triatoma spp.
Rhodnius spp.
Cimicidae – Bed bugs and Cimex lectularius Bartonella quintana? Rickettsia parkeri?
‘wild bugs’ C. hemipterus
Stricticimex parvus and Cimex insuetus Orthobunyaviruses Kaeng Khoi virus
Fleas (Siphonaptera) Numerous species, main Pulicidae Bartonella quintana Trench fever
Rickettsia typhi Murine typhus
Rickettsia felis Flea-borne spotted fever
Bartonella henselae Cat scratch disease
Yersinia pestis Plague
Tunga penetrans Tungiasis
Flies (Diptera)
Mosquitoes Anopheles spp. Plasmodium spp. Malaria

Anopheles, Culex, Aedes spp. Wuchereria bancrofti Lymphatic filariasis
Anopheles, Mansonia, Aedes spp. Brugia spp. Lymphatic filariasis
Anopheles, Culex, Aedes spp. Arboviruses Arboviruses
Aedes aegypti, A. albopictus Flavivirus Dengue, Zika, chikungunya
Alphavirus
Aedes aegypti Flavivirus Yellow fever
Culex spp. Flavivirus West Nile fever, Japanese encephalitis
Biting midges Culicoides spp. Mansonella perstans and Mansonella Mansonelliasis

(Ceratopogonidae) Forcipomyia spp. ozzardi
Culicoides spp. Arbovirus Oropouche virus
Tsetse flies Glossina spp. Trypanosoma brucei gabiense and T. b. African trypanosomiasis
rhodesiense (African sleeping sickness)
Sand flies (Psychodidae) Phlebotomus spp. Leishmania spp. Visceral and cutaneous leishmaniasis
Phlebovirus (Bunyaviridae) Sand fly fever
Lutzomyia spp. Leishmania spp. Visceral and cutaneous leishmaniasis
Bartonella bacilliformis Carrion’s disease (Oroyo fever)
Horse flies and Deer flies Tabanus spp. Francisella tularensis Tularemia
(Tabanidae) Chrysops spp. Bacillus anthracis Anthrax
Loa loa Filariasis
Black flies (Simuliidae) Simulium spp. Onchocerca volvulus Onchocerciasis (river blindness)
Mansonella ozzardi Mansonelliasis
Figure 12-4 Ornithonyssus bacoti mite. Note the long hairs on the body.
cycle includes egg, larva, protonymph, deutonymph and adult. All

these stages are hematophagous. Adults are very small, around 0.6 to Figure 12-5 Female Pediculus humanus capitis. Note the bifid apex of the
little more than 1 mm, and they increase after a blood meal. The body abdomen.
is generally oval, with few or many setae, a dorsal (scutum) and three
ventral (sternal, genital-ventral and anal) plates. The hosts are
mammals, reptiles, birds and arthropods.
Among Mesostigmata, two families are of medical interest: the
Macronyssidae and the Dermanyssidae. In the Macronyssidae, the
genus Ornithonyssus is the most important for human health. Ornitho-
nyssus bacoti (Figure 12-4) are ectoparasites of rats, mice and other
small mammals, but rarely of birds. They are distributed around the
world, especially in the area of ports. Many pathogens have been found
in this mite – Bartonella spp., Rickettsia typhi, Rickettsia akari, Coxiella
burneti, Western equine encephalitis virus, St Louis encephalitis virus
– but its true role as a vector is not proven.15
In Dermanyssidae, the genus Dermanyssus is of medical importance
and is generally associated with birds. It is a vector of St Louis encepha-
litis virus and can also transmit Bartonella quintana.16,17
Liponyssoides sanguineus, associated with rodents, is a vector of
rickettsial pox (Rickettsia akari). This disease first emerged in New York
City in 1946 and now has spread worldwide.18 Figure 12-6 Female Pediculus humanus corporis with nits laid on tissue.
Skin Ectoparasites: Scabies

Scabies19,20 is an infestation due to an ectoparasite mite, Sarcoptes
scabiei variety hominis, belonging to the family Sarcoptidae. According
to the World Health Organization, around 300 million people are
Insecta
infested in the world. The biological cycle comprises eggs, larvae, ANOPLOURA – LICE
nymphs and adults. Adults are very small, 0.4 mm for the female, less In the suborder Anoploura, the sucking lice are found exclusively on
for the male. The female creates burrows under the skin and lays three mammals.21 Three species are of human health interest: the head louse
to five eggs per day. The mites are transmitted by contact, skin to skin (Pediculus humanus capitis) (Figure 12-5), the body louse (Pediculus
or with contaminated clothes. People on all continents may be infested. humanus corporis) (Figure 12-6) and the pubic louse (Phthirus pubis).
Because of the high degree of contagion, major outbreaks occur in All three species feed on human blood but the body louse is the only
social habitats, when people have close contacts. The signs and symp- species that can transmit pathogen bacteria.
toms are erythematous papules and intensive pruritus, often at night, The biological cycle comprises the eggs or ‘nit’ (Figure 12-7)
with conspicuous skin lesions, generally on hands (interdigital spaces), attached to the hair for head louse and pubic louse or on the clothes
feet, belt line, back and genitalia. Sarcoptes are not vectors but this for body louse. There are three young stages which are similar to the
nuisance has been increasing since the last decade. adult, although with reduced size. The female is a little bigger than the
Elimination of scabies involves the washing of clothes and bed male and possesses an abdomen with a bifid apex. The male shows
sheets at >50 °C, cleaning furniture and rooms, and also topical and 10–11 longitudinal black strips on the abdomen. The duration of the
systemic treatment for all the family and relatives. biological cycle (egg to adult) is 20–26 days in good conditions.
Figure 12-7 A nit of Pediculus humanus capitis fixed on a hair. Note the con-
spicuous operculum.
Human lice take many little blood meals during the day. If not,
when there is no human host, the louse dies in a few days. For the body
louse, for example, good hygiene and frequent changes of clothes
makes the population disappear.
Body lice are vectors of Rickettsia prowazekii, responsible for epi-
demic typhus. The Rickettsia are found in the feces and the hemo-
lymph of the louse and the contamination occurs when people scratch, Figure 12-8 Female Xenopsylla cheopis.
by contact with mucous membranes or by inhalation of the dry feces.
Two other bacteria are transmitted by body lice: Borrelia recurrentis,
agent of relapsing fever, and Bartonella quintana, responsible for
trench fever, which occurred among soldiers during the First and in the skin, generally in the feet. Treatment consists of incision and
Second World Wars. Currently, the latter disease is reappearing in withdrawing the flea mechanically, afterwards disinfecting the hole.
homeless populations. Recent studies have shown that body lice are The control of flea infestation needs two insecticide treatments
potential vectors of Yersinia pestis, agent of plague.22,23 separated by 10 days because the cocoons are resistant. Use of a vacuum
cleaner is also important for eradication of larvae.
SIPHONAPTERA – FLEAS
The order Siphonaptera is divided into eight families, including more HETEROPTERA
than 200 genera and 2500 species. The most important genera in Heteroptera is a wide suborder of predaceous and phytophagous bugs,
human health terms are Ctenocephalides, Pulex and Xenopsylla. Fleas including only two families (of which only Polyctenidae is not of
are distributed worldwide, some species following domestic animals human health interest) with hematophagous species: Cimicidae and
(dog, cat) as Ctenocephalides. Reduviidae Triatominae. The main characteristic of Heteroptera is the
They are small insects, 1–5 mm; the body is flattened laterally, mouthparts, composed of a rostrum with stylets forming a salivary
generally light brown to dark brown, with modified posterior legs for duct (injection of saliva) and an alimentary duct (aspiration of prey
jumping, no wings and reduced antennae. digested, plant fluid or blood). They are biting/sucking insects.
The biological cycle comprises the eggs, white and deposited on the
ground, the vermiform larvae eating organic debris, a pupa enclosed Cimicidae
in a cocoon made with a mix of flea silk and dust, and finally adults. This family is divided into six subfamilies comprising around 100
In the absence of a host, the pupa can survive a long period (>1year) species. The Cimicidae are ectoparasites of bats, birds and humans.
in the cocoon, and can emerge suddenly when the presence of a host Bites on other mammals or reptiles may occur but are accidental. Two
is detected. Fleas usually bite at night during the host’s sleep; the bites species are of human health importance: Cimex lectularius (Figure
are characteristic, with three or more bites aligned. Fleas are generally 12-9), occurring in Palearctic and Nearctic regions, and C. hemipterus,
associated with a specific host (mammals or birds), but if absent, they distributed in tropical areas. As indicated by their common name, ‘bed
can easily change to another host species. bugs’, they live closely related to humans; they are found in beds or
The main pathogen transmitted by fleas is the bacterium Yersinia just around. Exclusively associated with humans, this insect moves
pestis, the agent causing plague. Historically, this disease was respon- with us, in luggage, modes of transport, from apartment to apartment,
sible for millions of deaths. Foci of sylvatic plague exist in the world, and in second-hand material (furniture, books etc.).
associated with animals such as rodents and lagomorphs. The best Bed bugs are small insects, 5–7 mm for adults, oval body, brown
well known association is rats with Xenopsylla cheopis (Figure 12-8). (unfed) or dark brown/reddish brown (after feeding), with a flattened
Fleas are also a vector of Rickettsia typhi, responsible for murine body and no wings. The biological cycle is composed of eggs, five
typhus, and Rickettsia felis.24,25 Bartonella henselae is another bacterium immature stages and adults. They are nocturnal, solenophagous and
transmitted by fleas, and a recent study has shown the potential trans- the saliva contains anesthetic components, which allows taking of a
mission of Bartonella quintana.26 short blood meal (5–15 minutes) during the host’s sleep. After feeding,
Tunga penetrans is an uncommon flea found in tropical areas. This they reach a hiding place for digestion and egg production. The feces
species is not a vector of disease but it is an important nuisance in are deposited outside this hiding place as black spots (digested blood),
these countries, also for tourists. The female of Tunga penetrans embeds and these constitute a good sign for finding and eradicating bed bugs.
Figure 12-11 Female Rhodnius prolixus. Note the elongated head.
clean, with two insecticide treatments separated by 7 days, because eggs

Figure 12-9 Female Cimex lectularius, the ‘bed bug’, after a meal. are resistant to insecticides. The use of two or three different classes of
insecticide is recommended, because many bed bug populations are
now resistant.34
Triatominae35
Among the predaceous bugs Reduviidae (Assassin Bugs), one subfam-
ily, the Triatominae, has evolved to hematophagy. Triatominae are
composed of 14 genera and 140 species, inhabiting the Americas from
southern Argentina to the Mid-USA.36 One genus, Linshcosteus, is dis-
tributed in India and one species, Triatoma rubrofasciata, associated
with rats, migrates with ships and is now distributed to all main tropi-
cal ports. Three genera in particular are of medical importance: Tri-
atoma, Rhodnius and Panstrongylus. Triatoma infestans, Rhodnius
prolixus (Figure 12-11) and Panstrongylus megistus are domesticated
species; they live in houses with people and accomplish their complete
biological cycle in this environment.
Triatominae present a diversity of body size from 5 to 40 mm but
the main species are around 20 mm. The head is elongated, with a long
and straight rostrum folded under the head. They possess wings, and
are black and brown in color; sometimes they show bright colors (red,
yellow). The biological cycle comprises eggs, oval or rounded (Figure
12-12), five young stages similar to adult but without wings, and adults
(with females larger than males). They bite people during sleep and
Figure 12-10 Skin reactions to bed bug bites. take a blood meal.
Triatominae can transmit a protozoan, Trypanosoma cruzi, the
agent of Chagas disease. The trypanosomes live in the gut of Triato-
Since the end of the Second World War, the use of DDT seems to minae and they are evacuated with the feces on the skin of humans.
have mainly eradicated bed bugs, but its banning in 1972 and the Indirect transmission occurs when people scratch the skin, introducing
increase of tourism and international trade, and the use of non- feces into the bite wound. Other ways of inoculation are via the mucous
remnant pesticides, has enabled bed bugs to make a comeback. membranes (eyes, for example), blood transfusion, organ donation
Since the end of the 1990s, bed bugs have become a major problem and food contamination.37 The reservoirs of the parasite are mammals.
in the USA, Canada, Europe, Asia and Australia, with an increasing Trypanosoma cruzi is responsible for Chagas disease (see Chapter
number of infestation cases, especially in houses, hotels, apartment 124).38 Infection can stay in a chronic phase without symptoms for a
buildings and means of transportation. long time, and in this case humans may also act as reservoirs. In 2008,
Bed bugs have a great psychological impact on people,27,28 and some the World Health Organization estimated that there were >25 million
people can develop a more or less severe allergic reaction against the people exposed to Chagas disease in South and Central America.
bite (Figure 12-10).29 All countries of South and Central America have begun programs
For now, bed bugs are not considered as vectors for infectious to fight Triatominae and Chagas disease (Southern Cone Initiative)
agents relevant for humans,30 but care may be taken because recent since the 1990s. This program comprises use of insecticides in villages,
studies tend to indicate a role in the transmission of bacteria (Barton- education to increase the knowledge of the problem in the population
ella, Rickettsia) to humans31,32 and wild Cimicidae (Stricticimex parvus and detection in blood donors.
and Cimex insuetus), associated with bats in Asian caves, may be
vectors of Kaeng Koi virus to humans.33 DIPTERA
Successful control of bed bugs needs serious organization. It is The main characteristic of this wide order is that they have two wings
important to associate a mechanical fight with vacuum cleaning, (diptera). The order regroups flies, including mosquitoes, and shows a
washing sheets and clothes at 60 °C and freezing all objects possibly great diversity in feeding. It has colonized all environments, from sea
infested at −20 °C for 72 hours, with a chemical fight once the place is level to the snow of mountains. The order contains the major species
Figure 12-12 Eggs of Triatoma infestans. Note the pink colour of some eggs
indicating they are near hatching.
important for health of humans and animals, as they can be vectors of

viruses, bacteria and parasites.
Figure 12-13 Larvae of Aedes albopictus.
Culicidae – Mosquitoes
Among the three subfamilies of Culicidae, two are of medical interest:
the Anophelinae, with the most important genus, Anopheles; and the
Culicinae, with principally the genera Aedes, and Culex. Other genera,
Mansonia, Haemagogous, and Sabethes, are of less interest.
Mosquitoes are distributed worldwide; some species are invasive,
turning human activities (tourism, international trade) to their advan-
tage. A mosquito possesses two wings, which are immaculate or some-
times with brownish spots, long and fragile legs, and a body that is
brown to black in color, sometimes with white stripes (on thorax or
legs) and a characteristic long proboscis (mouthparts). They are sole-
nophagous, the mouthparts include stylets that can reach the blood
vessels directly. The saliva contains mainly hemostatic and anesthetic
components and can induce an acute reaction in certain individuals.
The life cycle includes eggs deposited alone (Anopheles) or in clus-
ters (as in Culex and Aedes) on the surface of water, four larval instars
living in water but equipped with a respiratory siphon and eating
organic matter (Figure 12-13), a nymph that does not eat, and adults.
Both adults feed on sugar juice but females need blood meals for pro-
duction of eggs. Biting activity is generally nocturnal or crepuscular
(Anopheles spp., Culex spp.), but some species are diurnal (Aedes spp.). Figure 12-14 Female Aedes albopictus. Note the conspicuous white stripes.
Anophelinae. The genus Anopheles includes more than 450 spp.39
Anopheles is the only genus able to transmit Plasmodium.40–42 The main
vectors of Plasmodium parasites in Africa are Anopheles gambiae and
An. funestus. Many species occur in other countries and some of them international trade, etc.). They exhibit a great plasticity, which permits
are competent vectors of Plasmodium. In addition to Plasmodium them adaptation to novel environments, as is the case with, e.g., Aedes
parasites, Anopheles can transmit filarial worms and some arboviruses, albopictus (Figure 12-14).
but Anopheles seems not to be an important vector for the latter. Control. The only effective vaccine currently available against
Culicinae. This subfamily contains more than 40 genera.39 Genera mosquito-borne diseases is yellow fever vaccine. For malaria, there is
Aedes, Culex and Mansonia are distributed worldwide; Haemagogus good chemoprophylaxis but some Plasmodium spp. have developed
and Sabethes are restricted to the New World. Culex is an important resistance (see Chapter 117).
vector for filariasis in tropical areas of the world, Aedes and Mansonia It is important to control larval instars because they are confined
particularly in Asia. All these genera are also vectors of arboviruses, as in water and it is easier at this stage to combat them with a biocide
shown in Table 12-1.43,44 such as Bacillus thuringiensis (Bti). Use of repellents (DEET, IR 3535),
Aedes aegypti, Aedes albopictus and Aedes japonicus are examples of wearing long clothes and sleeping under bed nets are also recom-
species with an expanded distribution due to human activities (tourism, mended in tropical areas.
Figure 12-16 Conspicuous eyes of a tabanid.
Tabanids are medium-size to bigger-size flies (6–25 mm), with a

large head and conspicuous eyes, eyes generally with beautiful stripes
(Figure 12-16); the body color is generally yellowish, grey to dark, the
wings sometimes exhibit brownish spots or stripes (Chrysops, Haema-
topota). The biological cycle includes eggs deposited en masse (>100
eggs), larva with 6 to 13 instars, a pupa and adults. Adults feed on plant
nectar, but females need a blood meal for production of eggs. Tabanids
are pool feeders (telmophagous) and biting activity takes place during
Figure 12-15 Female of the sand fly Phlebotomus perniciosus. Note the hairy daytime; bites are painful. It is difficult to catch these flies because they
wings and body. are very fast fliers. Tabanids take short blood meals by bite and repeat-
edly bite to obtain a complete meal. This makes them good carriers of
disease.
Psychodidae – Sand Flies45 They are mechanical vectors of some bacteria, in particular Fran-
The subfamily Phlebotominae, belonging to Psychodidae, is composed cisella tularensis and Bacillus anthracis. They are biological vectors of
of six genera and more than 1000 species. Among them, two genera filarial nematodes, such as Loa loa in Africa.
are of medical interest: Phlebotomus and Lutzomyia. Phlebotomus
(Figure 12-15) occurs in the Old World whereas Lutzomyia are distrib- Simuliidae – Black Flies
uted in the New World. Black flies include more than 1200 species, occurring in all continents
The biological cycle includes eggs, deposited on the ground, larvae and in particular in the Palearctic region. The main genus and the most
with four instars each eating on organic matter, a pupa and adults. important in medical entomology is the genus Simulium (>1000 spp.).
Adults feed on plant nectar but the female needs additional blood for The biological cycle includes eggs, larval instars (six to nine), pupae
egg maturation. Adults are very small in size, 1.5–4 mm, light in color, and adults. Males and females are very small in size, 1.5–4 mm, and
body densely covered with hair, wings acute at their apex, and with a only females take a blood meal. The general color of the body is black
hunchback appearance. with big compound eyes and a hunchback thorax. The larval develop-
Sand flies are pool feeders (telmophagous) with short mouthparts, ment takes place in running water, where the larvae are fixed under
explaining why they can only bite through unprotected skin and not stones or vegetable matter using the abdomen apex. Biting activity
through clothes. They are nocturnal and hosts belong to mammals, occurs during the day outdoors. Because of their short mouthparts
birds and reptiles. they cannot bite through clothing. Black flies are pool feeders (tel-
Sand flies are vectors of protozoan Leishmania species responsible mophagous) and the bite is painful. The bite is followed by a severe
for leishmaniasis in tropical areas (see Chapter 123). Leishmania infan- acute reaction, due to components of saliva such as histamine (which
tum is the only worldwide species. Reservoirs of this parasite are is a vasodilator).
mammals, mainly humans, rodents, dogs, and marsupials depending The most important role of Simuliidae as a vector is the transmis-
on species and geographical area. sion of a filarial nematode, Onchocerca volvulus. This nematode is often
Sand flies can also transmit bacteria in South America, Bartonella located in the eye and is responsible for blindness in some countries.
bacilliformis, and arboviruses in Europe, Asia and Africa belonging to Some areas near rivers in Africa are deserted by people because of this
Phlebovirus: Sandfly fever Naples virus (Naples-like virus and Toscana disease (‘river blindness’).48,49
virus), Salehabad virus and two relative species, Sicilian and Corfou
viruses.46 Glossinidae – Tsetse Flies
Control. It is recommended, in particular in tropical areas, to use This family, which has more than 30 species, includes just one genus,
repellents (DEET, IR 3535), wear long clothes and sleep under bed nets Glossina. These species are distributed in Central Africa, from east to
with a small mesh because of the size of sand flies. west coast. Tsetse flies are medium sized, between 6 and 15 mm, and
have a characteristic proboscis directed forward (Figure 12-17). The
Tabanidae – Horse Flies47 body color is yellowish to brown, sometimes with black stripes. The
This family comprises 144 genera and about 4400 species. They are biological cycle is original in Glossina as in other pupipare: the larva
distributed worldwide, in particular in areas with large animals such accomplishes its development within the female abdomen, with the
as deer and cattle. They are an important nuisance for livestock and help of lactiferous glands; when the larval development is achieved, the
humans and their economic impact is serious. female directly lays the pupa.
Biting activity occurs during daytime. Both males and females bite
mammals, including humans. Glossina are the vectors of African try-
panosomiasis (sleeping sickness), due to the protozoan, Trypanosoma
brucei. T. brucei is divided into two subspecies, T. brucei gambiense
(95% of sleeping sickness cases) and T. brucei rhodesiense. In this case,
Trypanosoma reaches the salivary glands of Glossina and the transmis-
sion of Trypanosoma is direct.50,51
Control. There is no insecticide resistance in tsetse flies and treat-
ment with pyrethroids gives good results.
Ceratopogonidae – Biting Midges
Ceratopogonidae is a large family with 78 genera and subgenera and
approximately 4000 species. The genus Culicoides is the most impor-
tant in medical and veterinary entomology.52 The biological cycle com-
prises eggs – deposited in decaying vegetable material representing
food for the future larvae – larvae (vermiform), pupae and adults.
Males and females are very small (1.5–5 mm) and characterized by
brownish and whitish spots on the wings. Only females take blood
meals; males eat sugar meals, such as flower nectar. These species are
pool feeders (telmophagous). Biting activity takes place at daybreak/
twilight, and for some species at night. The bites are painful despite
their small size.
Biting midges are found across the entire world and are resistant
to cold, which allows them to colonize high altitude areas (4000 m).
Biting midges represent a major nuisance in some countries; their
Figure 12-17 Female tsetse fly, Glossina morsistans. Note the proboscis
vector role occurs in South America where they transmit the Oro-
directed forward. (Courtesy of Jeremy Bouyer.) pouche virus (Amazonian area) and filariae53 (for more information
see Table 12-1).
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of some dermanyssoid mites (Acari, Mesostigmata, vectors of Chagas’ disease. Bull Am Mus Nat Hist 1979; midges: their role as arbovirus vectors. Annu Rev
Dermanyssoidea). Parasite 2005; 12(2):99-109. 163:123-520. Entomol 2000; 45:307-340.
13
Dermatologic Manifestations of
Systemic Infections
CHANTAL P. BLEEKER-ROVERS | HENRY J.C. DE VRIES
KEY CONCEPTS are solitary or several in number, but rarely may appear in a dissemi-
nated version.
• Dermatologic manifestations of systemic infections can be
either pathogen-related (i.e. result from direct harm by the
Verruga Peruana. In the acute phase (Oroya fever), B. bacilliformis
infectious agent) or host-related (i.e. result from an inflamma- causes fever, hemolytic anemia, headache, myalgia and arthralgia. The
tory reaction against the infectious agent). second phase occurs between two weeks and several years later and is
characterized by the eruption of crops of nodular and/or verruginous
• Pathogen-related skin lesions result from an infection residing skin lesions, predominantly on the head and distal extremities (Peru-
in the skin itself or via toxins produced by an infectious agent vian warts).2 The disease is endemic in Peru, but also in Colombia and
at a distance, reaching the skin via the circulation.
Ecuador. The chronic phase, frequently accompanied by mild systemic
• Host-related skin lesions are typically characterized by a symptoms, may present without any history of an acute illness. Lesions
cutaneous inflammatory reaction triggered by an infection vary in size and number and may appear as red or purple papules a
elsewhere. few millimeters in diameter to pedunculated, sessile, or plaque-like
• Most pathogen-related skin lesions are pathogen-specific, lesions several centimeters across. New lesions may arise for up to 6
whereas most host-related skin lesions are non-specific and can months in untreated patients. The angiomatous nodules are prone to
be caused by different pathogens. bleeding. Verruga peruana normally heal spontaneously, although the
course is often prolonged.
Brucellosis
Brucellosis is a common zoonotic infection with worldwide occur-
Introduction rence caused by Brucella abortus and B. melitensis (see Chapter 129).
Skin lesions sometimes occur in disseminated infection. The cutaneous
The skin can be affected by systemic infections in several ways:
manifestations of brucellosis can be multiple and are due to direct
• Pathogen-related dermatologic manifestations: inoculation, hypersensitivity phenomena, deposition of immune com-
• via direct harm by the infectious agent located in the skin plexes and direct invasion by the organism reaching the skin hematog-
• via indirect harm, for example via a toxin produced by the enously.3 Four clinical patterns of brucellar skin lesions have been
infectious agent at a distance, reaching the skin via the
described: (1) disseminated papulonodular eruptions (most common);
circulation.
(2) erythema nodosum-like eruptions; (3) extensive purpura; and (4)
• Host-related dermatologic manifestations: diffuse maculopapular rash.4 Brucellosis-induced skin lesions may
• via an inflammatory cutaneous reaction against an infectious appear in both the initial episode and during relapses. Urticarial reac-
agent located in the skin
tions (erythema brucellum) have been found in veterinarians and
• via an inflammatory cutaneous reaction triggered by an infec- animal handlers.
tion at a distance.
In many situations it is difficult to decide whether the pathogen- Pseudomonas aeruginosa
related dermatologic manifestations result from the infectious agent Ecthyma gangrenosum is classically associated with P. aeruginosa bac-
residing in the skin directly or indirectly by an inflammatory response, teremia in immunocompromised patients. Most infections occur via
so these groups will be discussed together. In Table 13-1 an overview
of pathogen-related specific dermatologic manifestations is given with
references to chapters in which some of these manifestations are
described in detail. To preclude redundancy, those manifestations
described elsewhere are not included in this chapter, including viral
exanthems, sexually transmitted infections and helminthic disease.
Dermatologic Manifestations Caused

by Specific Pathogens
BACTERIAL INFECTIONS
Bartonellosis
Bacillary Angiomatosis. Bartonella henselae can cause a transient
self-limiting lymphangitis in immunocompetent individuals (cat-
scratch disease). B. quintana historically caused ‘trench fever’, but has
more recently been associated with bacteremia and endocarditis.
During immunosuppression, as in acquired immunodeficiency syn-
drome (AIDS), these pathogens can cause a more persistent skin infec-
tion called bacillary angiomatosis. Typically first small red-to-purple
Figure 13-1 Bacillary angiomatosis: violaceous nodule caused by Bartonella
papules (Figure 13-1) develop that may gradually expand into large henselae in the scapular region of a patient with late-stage human immunodefi-
pedunculated lesions or nodules. The lesions usually have a livid ciency virus (HIV) infection. (Department of Dermatology, Academic Medical
appearance and may bleed profusely with trauma.1 Most often, lesions Centre, University of Amsterdam, Amsterdam, The Netherlands.)
113
TABLE
13-1 Dermatologic Manifestations Caused by Specific Pathogens
Infection Micro-organism Dermatologic Manifestation Chapter
Bartonellosis B. henselae Bacillary angiomatosis

B. quintana
B. bacilliformis Verruga peruana: crops of nodular or ferruginous skin
lesions
Borreliosis (Lyme) B. burgdorferi Erythema migrans Chapter 46

B. afzelii
B. garinii
B. burgdorferi Lymphocytoma Chapter 46
B. afzelii
B. garinii
B. afzelii Acrodermatitis chronica atrophicans Chapter 46
Brucellosis B. abortus Chronic ulceration Also Chapter 129

B. melitensis
B. abortus Cutaneous and subcutaneous abscesses Also Chapter 129
B. melitensis
B. abortus Disseminated erythematoviolaceous papulonodular Also Chapter 129
B. melitensis lesions
Gonococcal infection Neisseria gonorrhoeae Primary cutaneous gonorrhea Chapters 65 and 179
Neisseria gonorrhoeae Disseminated gonococcal infection Chapters 65 and 179
Leprosy M. leprae Macular hypopigmented or erythematous anesthetic Chapter 108

lesions in tuberculoid leprosy
M. leprae Sharply defined macules, sometimes appearing as Chapter 108
‘target’ lesions in borderline tuberculoid
M. leprae Erythematous macules, papules and/or nodules, skin Chapter 108
thickening in lepromatous leprosy
Melioidosis Burkholderia pseudomallei Skin ulcers, abscesses and cellulitis Chapter 125
Pseudomoniasis P. aeruginosa Ecthyma gangrenosum Also Chapter 181
Rickettsiosis Rickettsia spp. Eschar Chapter 187

Rickettsia spp. Rash Chapter 187
Staphylococcal infection Staph. aureus Staphylococcal scalded skin syndrome Also Chapter 176
Staph. aureus Toxic shock syndrome Also Chapter 176
Streptococcal infection Group A streptococci Rheumatic fever Also Chapter 177

Group A streptococci Scarlet fever Also Chapter 177
Group A streptococci Streptococcal toxic shock syndrome Also Chapter 177
Syphilis T. pallidum Ulcer in primary syphilis Chapter 61

Rash in secondary syphilis Chapter 61
Gummas in tertiary syphilis Chapter 61
Tuberculosis M. tuberculosis Primary inoculation tuberculosis Also Chapter 31

Tuberculosis verrucosa cutis Also Chapter 31
Scrofuloderma Also Chapter 31
Tuberculosis cutis orificalis Also Chapter 31
Lupus vulgaris Also Chapter 31
Acute miliary tuberculosis Also Chapter 31
Metastatic tuberculous abscess Also Chapter 31
Endemic Treponematoses
Bejel T. pallidum subsp. endemecium Oral or nasopharyngeal papules or ulcers in primary Chapter 109
bejel
Oral or nasopharyngeal mucous patches or Chapter 109
condylomata lata in secondary bejel
Gummas in tertiary bejel Chapter 109
Pinta T. pallidum subsp. carateum Papules or erythematous macules coalescing into a Chapter 109
scaling plaque in primary pinta
Erythematous, scaling papules expand, coalescing into Chapter 109
psoriasiform plaques (pintids) in secondary pinta
Pigmentary abnormalities in tertiary pinta Chapter 109
Yaws T. pallidum subsp. pertenue Papule (mother yaw) or papilloma (framboesia) in Chapter 109
primary yaws
Multiple smaller papules or discoid lesions in Chapter 109
secondary yaws
Gummatous lesions in tertiary yaws Chapter 109
VIRAL INFECTIONS
Chikungunya fever Chikungunya virus Erythematous maculopapulous rash Chapter 133
Cow pox Cow pox virus Vesiculobullous rash Chapter 170
Cytomegalovirus infection Cytomegalovirus Erythematous maculopapulous rash Chapter 9

Chapter 13 Dermatologic Manifestations of Systemic Infections 115
TABLE
13-1 Dermatologic Manifestations Caused by Specific Pathogens (Continued)
Infection Micro-organism Dermatologic Manifestation Chapter
Dengue virus infection Dengue virus Erythematous maculopapulous rash Chapter 133
Enterovirus infection Enteroviruses Erythematous maculopapulous or vesiculobullous rash Chapters 9 and 164
Epstein–Barr virus infection Epstein–Barr virus Erythematous maculopapulous rash Chapter 9
Flavivirus infection Flaviviruses Erythematous maculopapulous or petechial and Chapter 175

purpuric rash
Hepatitis B Hepatitis B virus Papulovesiculous rash Chapters 10 and 165
Herpes simplex Herpes simplex virus Vesiculobullous rash Chapter 9
HIV/AIDS Human immunodeficiency virus Erythematous maculopapulous rash Chapters 9, 93 and 98
Roseola infantum, exanthema subitum Human herpesvirus 6 Erythematous maculopapulous rash Chapter 9
Human herpesvirus 7 infection Human herpesvirus 7 Erythematous maculopapulous rash Chapter 9
Monkeypox Monkeypox virus Vesiculobullous rash Chapter 170
Measles Measles virus Erythematous maculopapulous rash Chapters 9 and 163
Erythema infectiosum Parvovirus B19 Erythematous maculopapulous rash Chapters 9 and 169
Rubella Rubella virus Erythematous maculopapulous rash Chapters 9 and 163
Eczema vaccinatum Vacciniavirus Vesiculobullous rash Chapter 9
Chickenpox Varicella zoster virus Vesiculobullous rash Chapter 9

Herpes zoster
Smallpox Variolavirus Vesiculobullous rash Chapter 9
FUNGAL INFECTIONS
Blastomycosis B. dermatitidis Verrucous lesion or subcutaneous nodules Also Chapter 189
Candidemia Candida spp. Painless pustules or nodules Also Chapter 189
Coccidioidomycosis C. immitis Papules, nodules, gummas, acneiform pustular lesions, Also Chapter 189
C. posadasii ulcerated and verrucous plaques, scar-like lesions,
abscesses, fistulas
Cryptococcosis C. neoformans Tubercle, nodule or abscess in primary lesion Also Chapter 189
C. gatti
C. neoformans Painless papules, ulcers or plaques in disseminated Also Chapter 189
C. gatti disease
Histoplasmosis H. capsulatum Nodules, papules, plaques, ulcers, vesicles, pustules, Also Chapter 189
abscesses, generalized dermatitis, exfoliative
erythroderma, necrotizing vasculitis, cellulitis,
panniculitis, petechiae, purpura and ecchymoses
Paracoccidioidomycosis P. brasiliensis Mucous membranes: painful ulcers Also Chapter 189

Skin: papules, nodules, plaques, verrucous lesions,
ulcers
PROTOZOAL INFECTIONS
Leishmaniasis (visceral) L. donovani Kala-azar Also Chapter 123

L. infantum
(L. mexicana)
(L. tropica)
L. donovani Post-kala-azar dermatitis Also Chapter 123
Trypanosomiasis T. brucei gambiense African trypanosomiasis: chancre, erythematous, Also Chapter 110
T. brucei rhodesiense urticarial or macular rash
T. cruzi Acute Chagas: red indurated swelling (chagoma), Also Chapter 124
morbilliform eruption (schizotrypanides)
Reactivation: erythematous nodules or plaques
HELMINTHIC INFECTIONS
Cysticercosis Taenia solium Subcutaneous nodules Chapter 195
Gnathostomiasis Gnathostoma spinigerum Localized, intermittent, migratory erythematous (sub) Chapter 195
cutaneous swellings
Fascioliasis F. hepatica Tender migrating erythematous itchy nodules, Chapter 195

F. gigantica abscesses
Loiasis Loa loa Subcutaneous swellings (Calabar) Chapter 121
Mansonella infection M. perstans Subcutaneous swellings (Calabar), urticaria, pruritus, Chapter 121
M. ozzardi dermal thickening, nonanesthetic hypopigmented
M. streptocerca macules
Toxocariasis T. canis Chronic pruritus/prurigo, chronic urticaria, eczema Chapter 195
T. cati
Figure 13-2 Ecthyma gangrenosum in the setting of Pseudomonas aeruginosa

sepsis. (Courtesy of J.W.M. van der Meer.)
contact with contaminated water (hot tubs, saunas, tropical swimming

pools). The lesions of ecthyma gangrenosum commonly begin as pain-
less red macules, which rapidly evolve into areas of induration that Figure 13-3 Extensive desquamation and erosions on the buttocks and upper
thighs of a young girl with Staphylococcal scalded skin syndrome (SSSS). (Depart-
develop into pustules and/or bullae (Figure 13-2). Ultimately, these ment of Dermatology, Academic Medical Centre, University of Amsterdam,
become gangrenous ulcers. Ecthyma lesions typically progress rapidly Amsterdam, The Netherlands.)
within 12–18 hours. The lesions may involve the skin or mucous
membranes and may be single or multiple. Most patients have fever,
but ecthyma gangrenosum can occur in the absence of constitutional
and extremities. The face is almost never involved. The erythema is
signs.
transient and migratory and is neither pruritic nor indurated. Subcu-
Staphylococci taneous nodules, varying between a few millimeters to 2 cm, over the
Staphylococcal Scalded Skin Syndrome. Newborns are espe- joints, scalp and spinous processes of the thoracic or lumbar vertebrae
cially susceptible to the staphylococcal scalded skin syndrome (SSSS occur rarely, but they are most often seen in patients with carditis.6
or Ritter disease).5 Two major exfoliative toxin serotypes (ETA and Scarlet Fever. Scarlet fever, also known as ‘scarlatina’, is a diffuse
ETB) have been identified. Affected infants are febrile with diffuse erythematous eruption that generally occurs in association with phar-
blanching erythema often beginning around the mouth. Flaccid blis- yngitis. Development of the rash requires prior exposure to Streptococ-
ters (Figure 13-3) appear 1–2 days later, especially in areas of mechani- cus pyogenes (group A streptococcus) and occurs as a result of
cal stress. Gentle pressure applied to the skin results in separation of delayed-type skin reactivity to pyrogenic exotoxin. The rash of scarlet
the upper epidermis and wrinkling of the skin (Nikolsky’s sign). fever is a diffuse erythema that blanches with pressure, with numerous
Within an hour, histopathologic examination of a snap-frozen blister small (1–2 mm) papular elevations, giving a ‘sandpaper’ quality to the
roof can help to differentiate between SSSS and other acute bullous skin (Figure 13-4a). It usually starts on the head and neck and is
skin diseases that can occur in newborns. In SSSS, the entire upper accompanied by perioral pallor and a strawberry tongue (Figure
epidermis may be shed. Flaky desquamation occurs as the lesions heal 13-4b). Subsequently, the rash expands rapidly to cover the trunk,
without scarring. When SSSS occurs in adults, it is usually in those followed by the extremities and, ultimately, desquamates. It often
with a pre-existing medical condition, such as immunosuppression. exhibits a linear petechial character in the antecubital fossae and axil-
Toxic Shock Syndrome. Toxic shock syndrome (TSS) results from lary folds, known as Pastia’s lines. Scarlet fever can predispose to acute
infection or colonization with a strain of Staphylococcus aureus that rheumatic fever.
produces toxic shock syndrome toxin-1.5 The key features of TSS are Streptococcal Toxic Shock Syndrome. In approximately 10%
a widespread macular blanching erythroderma, resembling sunburn of group A streptococcal infections, production of superantigen
occurring in association with profound hypotension and multiple toxins leads to streptococcal toxic shock syndrome (STSS). STSS is
organ dysfunction. If the rash develops within a few hours, TSS should characterized by fever and rash, with rapid progression to shock and
be ruled out. As morbidity and mortality from TSS are high, early multi-organ failure. The typical ‘sunburn’ type rash is widespread,
recognition combined with intensive supportive management is criti- erythematous, macular and blanching. Characteristically, there is sub-
cal. Desquamation occurs 1–2 weeks after onset. sequent desquamation about 2 weeks after the initial illness. Given the
rapid clinical progression, effective management of invasive group A
Streptococci streptococcal infections highly depends on early recognition of the
Rheumatic Fever. Acute rheumatic fever is an inflammatory sequel disease and prompt initiation of supportive care together with anti-
of group A streptococcal pharyngitis. The incidence of acute rheumatic bacterial therapy. In cases of toxic shock syndrome, it is often difficult
fever had been declining even before the use of antibiotics became to distinguish between streptococcal and staphylococcal infection
widespread, but the disease remains a significant cause of morbidity before cultures become available and so the antibacterial choice must
and mortality in children in low- and middle-income countries (see include coverage of both organisms. In addition, clindamycin is an
Chapter 52). The onset of rheumatic fever usually occurs 2–3 weeks important adjunctive antibacterial because of its antitoxin effects and
following the initial pharyngitis, although in some cases it can present excellent tissue penetration. Early institution of intravenous immuno-
months later. The disease can manifest itself in a variety of presenta- globulin therapy should be considered in cases of STSS.7
tions, including carditis, arthritis, chorea, subcutaneous nodules and
a distinctive rash known as erythema marginatum, which is a macular, Tuberculosis
serpiginous, blanching, erythematous rash with sharply demarcated Cutaneous lesions are relatively uncommon manifestations of tuber-
borders. The lesions vary in size and commonly appear on the trunk culosis, occurring in only 1–2% of infected patients. The pathway of
Figure 13-5 Scrofuloderma in a 60-year-old patient. A biopsy confirmed tuber-

culoid granulation tissue and the patient responded to antituberculous therapy.
process is relatively common. Scrofuloderma most commonly devel-

ops in children, adolescents and elderly individuals. Early lesions are
firm, painless, subcutaneous, red–brown nodules that overlie foci of
tuberculous infection. The neck, axillae and groin are often involved,
with the cervical lymph nodes as the most common source of infec-
tion.8 The suppurative nodules gradually enlarge, and eventually form
ulcers and sinus tracts that drain watery, purulent or caseous mate-
rial.10 Lesions may be single or multiple. Spontaneous healing may
occur, but it may be years before lesions are completely replaced by
b scar tissue.
Tuberculosis Cutis Orificalis. Tuberculosis cutis orificialis is a
Figure 13-4 (a) Erythematous monomorphic rash on the inner thighs and pubic rare manifestation of tuberculosis that most frequently occurs among
region of a young boy with scarlet fever. (b) Strawberry tongue with pronounced
papules, typical for scarlet fever. (Department of Dermatology, Academic Medical
middle-aged and elderly adults. It develops in individuals with both
Centre, University of Amsterdam, Amsterdam, The Netherlands.) advanced tuberculosis of the gastrointestinal tract, lungs, or genitouri-
nary tract and impaired cell-mediated immunity. The skin lesions
result from the autoinoculation of the mucocutaneous tissues near
bacterial entry into the skin, the host’s immune status and the presence body orifices by the draining sites of visceral infection.11 A typical
or absence of host sensitization to M. tuberculosis influence the pre- lesion appears as a red–yellow nodule that rapidly breaks down to form
sentation of tuberculosis in the skin. a painful, circular or irregularly shaped, ‘punched-out’ and friable
Primary Inoculation. Primary inoculation tuberculosis, also 1–3 cm ulcer with a pseudomembranous fibrinous base.9 Tuberculosis
known as tuberculous chancre and primary tuberculous complex, is a cutis orificalis heralds a poor overall prognosis, as patients tend to have
rare form of cutaneous tuberculosis that results from the direct entry severe internal organ disease. Without successful treatment, the lesions
of the organism into the skin or mucosa of a nonsensitized individual. progress and may eventually contribute to the development of fatal
It primarily occurs in children within one month after inoculation.8 miliary tuberculosis. Although resolution within two months after the
The lesion begins as a nondescript red–brown papule or nodule that initiation of treatment has been reported, other cases may be unre-
evolves into a painless, shallow and undermined ulcer with a granulo- sponsive to treatment.
matous base, most commonly affecting the face or extremities. Lesions Lupus Vulgaris. Lupus vulgaris, the most common form of cutane-
are usually 1 cm or less in diameter, but occasionally exceed 5 cm.8 ous tuberculosis in Europe, is a chronic and progressive form of cuta-
Slowly progressive and painless regional lymphadenopathy frequently neous tuberculosis that represents a reactivation of infection in people
becomes apparent 3–8 weeks later. Left untreated, primary inoculation with moderate to high immunity against the bacillus.8 Lupus vulgaris
tuberculosis may persist for up to one year.8 A scar typically remains may occur either as a result of direct extension from an underlying
after resolution. focus or via lymphatic or hematogenous spread. Lupus vulgaris occurs
Tuberculosis Verrucosa Cutis. Tuberculosis verrucosa cutis is a in individuals of all ages and women are two to three times more likely
form of cutaneous tuberculosis that occurs after direct inoculation of than men to be affected. Lupus vulgaris usually begins as a collection
the mycobacteria into the skin of a previously sensitized host with of discrete, red-brown papules that subsequently coalesce to form an
moderate to high immunity against the bacillus.9 It is much more indolent, asymptomatic plaque (Figure 13-6). The plaque gradually
common than the primary inoculation variant. In adults, it most fre- reaches a size of 0.5–10 cm and develops central clearing and atrophy.
quently develops on the acral extremities while the ankles or buttocks The borders may acquire a serpiginous or verrucous quality. Hyper-
are more frequently affected in children. The skin lesions are usually trophic, ulcerative and vegetative forms of lupus vulgaris may also
solitary and manifest as painless, violaceous or brown–red, indurated occur.11 In Western countries, lesions often develop on the head and
warty plaques that range from 1 to 5 cm in diameter. Although ulcer- neck, while in (sub)tropical areas, lesions are commonly found on the
ation is uncommon, fissures that exude purulent drainage or kerati- lower extremities or buttocks. Without therapy, lesions of lupus vul-
nous material may occur.8 Skin lesions may persist for years if left garis persist. Over the course of years, the plaques may grow to enor-
untreated, although spontaneous resolution is also possible.9 mous sizes. In addition, ulceration and destruction of underlying
Scrofuloderma. Scrofuloderma results from the direct extension of tissues may occur, causing severe disfigurement.8
the infection from a deep structure (e.g., lymph node or bone, Figure Acute Miliary Tuberculosis. Acute miliary tuberculosis is a rare
13-5) into the overlying skin.10 Coexistence with an active pulmonary form of tuberculosis that results from hematogenous dissemination.
the fourth decade of life and is more common in men. Most cases are
acquired through the respiratory tract by inhalation. Symptoms are
usually severe, starting with an infection resembling pneumonia that
later disseminates to the skin, bones and central nervous system. Cuta-
neous blastomycosis is the most frequent extrapulmonary form.13
Primary cutaneous forms are produced by traumatic inoculation of
the skin and are characterized by the presence of papules that may
progress to pustules with regional lymphadenopathy that generally
resolve spontaneously in weeks to months without treatment. Second-
ary cutaneous forms are more frequent. Skin lesions can have an ulcer-
ated or warty appearance of various sizes and may extend with
progression of the disease over the years. Some may even display an
eschar that can mimic squamous cell carcinoma, pyoderma gangreno-
sum, or keratoacanthoma.13
Candidemia and Invasive Candidiasis

Invasive candidiasis is defined by hematogenous spread to multiple
Figure 13-6 Lupus vulgaris: a perioral annular plaque with a papulomatous organs. Although Candida albicans is the most common cause of can-
border and signs of central clearing in a male patient with pulmonary tuberculosis.
(From the collection of Jan and Titia Warndorff.) didemia, isolation of non-albicans species has increased in recent years.
Immunocompromised or ICU patients are most at risk for the devel-
opment of candidemia. Clusters of painless pustules or bullae on an
The disorder typically occurs in infants or individuals with impaired erythematous base occur on any area of the body. In severely neutro-
cell-mediated immunity.11 Most patients with acute miliary tubercu- penic patients, the lesions may be macular rather than pustular.
losis do not exhibit cutaneous lesions; pinpoint red–blue or purpuric
papules with overlying tiny vesicles that subsequently become umbili- Coccidioidomycosis
cated and crusted can be seen. Individual lesions heal over the course Coccidioidomycosis is a systemic fungal infection caused by Coccidi-
of 1–4 weeks, and often resolve with hypopigmented depressed scars.11 oides immitis and C. posadasii spp., which are predominant in the
Metastatic Tuberculous Abscesses. Metastatic tuberculous Americas. Acute lesions involve the lung parenchyma. When the
abscesses, also known as tuberculous gummas, usually arise as a con- disease spreads, the skin is one of the most affected organs. Cutaneous
sequence of hematogenous spread to the subcutaneous tissue during coccidioidomycosis can present as papules, nodules, gummas, acne-
a state of reduced cell-mediated immunity.11 Patients with metastatic iform pustular lesions, ulcerated and verrucous plaques, scar like
tuberculous abscesses present with single or multiple, non-tender, lesions, abscesses and fistulae.14 The spectrum of skin manifestations
fluctuant, subcutaneous nodules. The nodules eventually reach the also includes nonspecific skin disease, such as erythema nodosum,
skin, resulting in the formation of ulcers and draining sinuses.8 Lesions erythema multiforme and, rarely, Sweet’s syndrome.
may occur at any skin site but frequently develop on the extremities.
Although lesions in immunocompetent individuals may persist for Cryptococcosis
years if untreated, spontaneous resolution can eventually occur.8 Cryptococcosis is a systemic fungal infection, caused by Cryptococcus
neoformans or C. gatti. The former has a universal geographic distribu-
Tuberculids. Tuberculids are cutaneous lesions that arise as a reac-
tion, whereas C. gatti is prevalent in tropical and subtropical areas.
tion to hematogenous spread of M. tuberculosis. The pathogenesis of
Clinical manifestations vary from asymptomatic pulmonary coloniza-
these reactive manifestations is not well understood. Typical for tuber-
tion to disseminated disease. Meningoencephalitis is the main clinical
culids are evidence of manifest or past tuberculosis and lesions that
manifestation and a cause of high mortality.15 Primary cutaneous
respond well to treatment with tuberculostatic drugs. There are three
infection is rare.16 Skin lesions are observed in 6% of AIDS-associated
main clinical manifestations of tuberculids: erythema induratum of
disseminated cryptococcosis and in 10–15% of otherwise immuno-
Bazin, lichen scrophulosorum and papulonecrotic tuberculids. In
compromised patients.15 Initially painless umbilicated papules occur,
some cases multiple forms of cutaneous tuberculids can coexist. Ery-
which eventually ulcerate (Figure 13-7). Papules in patients with severe
thema induratum of Bazin is the most common form, occurring
immunodeficiency may be complicated by vasculitis appearing in the
mostly in women around menopause or during adolescence. The clini-
form of palpable purpura. Subcutaneous nodules are more common
cal picture consists of tender nodules on the lower extremities some-
in patients receiving high doses of corticosteroids; some evolve to
times surrounded by pitting edema. The lesions evolve into deep
destructive gummas.15
irregular ulcers. Lichen scrofulosorum is predominantly seen in ado-
lescents and children. The eruption consists of small (0.5–3.0 mm),
skin-coloured, closely grouped papules located on chest, back, Histoplasmosis
abdomen and proximal limbs, mostly without subjective symptoms. Histoplasmosis is a granulomatous infection caused by Histoplasma
In some instances small crusts or pustules are attached to the papules.12 capsulatum, which is distributed worldwide, especially in North
Papulonecrotic tuberculids mainly affect children and young adults12 and Central America. Histoplasmosis has been described in three
and consist of recurring, fibrotic, red papulopustules or papules, different forms: acute pulmonary, chronic cavitary and disseminated.
widely distributed in a symmetric pattern. Central ulceration can Pulmonary involvement is the most common clinical presentation.
occur. The lesions can be found initially on the extensor surface of the Cutaneous manifestations are reported to occur in 10–25% of AIDS
extremities and on the buttocks, although they can eventually become patients with disseminated histoplasmosis.17 The primary cutaneous
widespread. While without treatment new lesions arise, individual lesion is rare. It may appear as an ulcer or a painless chancre with
lesions heal spontaneously in a few weeks, often with scar formation. regional lymphadenopathy and usually disappears within weeks or
months. Disseminated skin lesions are polymorphic, ranging from
macules (molluscum contagiosum-like umbilicated) papules, kera-
FUNGAL INFECTIONS totic plaques, pustules, nodules, ulcers, erosions, or acneiform erup-
Blastomycosis tions (Figure 13-8). The oral mucosa may be affected in 75% of
Blastomycosis is a systemic mycosis with a high prevalence in the patients. Rapid initiation of treatment is indicated due to the high
Midwest of the USA. The disease most commonly occurs in adults in mortality risk of disseminated disease.
is typical. Orofacial disease is often associated with massive cervical

and submandibular lymphadenopathy, which may develop fistulae and
draining sinuses. Immunocompromised patients are at risk of severe
disseminated infection and skin involvement is more common.18
PROTOZOAL INFECTIONS
Visceral Leishmaniasis
Cutaneous and mucocutaneous leishmaniasis are discussed in Chapter
123. Visceral leishmaniasis is primarily caused by the Old World species
Leishmania donovani and L. infantum. New World species are usually
associated with (muco)cutaneous disease, and rarely cause visceral
disease.
Kala-azar. The most important clinical manifestation of visceral
leishmaniasis is kala-azar. The incubation period is usually 2–6 months
but can range from weeks to several years. Onset of symptoms is
usually insidious, with slow progression of malaise, fever, weight loss
and splenomegaly over a period of months. Kala-azar (‘black fever’)
refers to darkening of the skin, which is a common symptom in South
Asia but not elsewhere.19 Visceral leishmaniasis is nearly always lethal
Figure 13-7 Cutaneous cryptococcosis in a renal transplant patient. The lesions without treatment. Even with treatment, fatality rates can be 10% or
started as nodules that then rapidly ulcerated. CT scan of the brain showed no higher.
abnormality, but Cryptococcus neoformans was isolated from the cerebrospinal
fluid. Post Kala-azar Dermatitis. Post kala-azar dermal leishmaniasis
caused by L. donovani generally develops after apparent successful cure
from visceral leishmaniasis. Post kala-azar dermatitis is confined to
South Asia and East Africa.20 In the South Asian variant, polymorphic
lesions consisting of macules/patches along with papulonodules are
prevalent, whereas the Sudanese variant has papular or nodular lesions.
The age distribution in South Asia and Sudan also differs, as in the
former, young adults are more affected whereas in the latter, children
are more affected. A lag period ranging from 2 to 10 years exists
between cure from visceral leishmaniasis and onset of post kala-azar
dermatitis.20
Trypanosomiasis
African Trypanosomiasis. African trypanosomiasis, caused by
Trypanosoma brucei gambiense or T. b. rhodesiense, is characterized by
an early stage during which trypanosomes circulate in the blood or
lymphatics, and a late stage, in which there is involvement of the
central nervous system. T. b. gambiense causes a slowly progressive
infection, and an oligosymptomatic phase can last for months or years.
In contrast, T. b. rhodesiense presents as a rapidly progressive infection,
often with signs of sepsis. Both infections are considered fatal without
treatment. The trypanosomal chancre typically appears approximately
one week after the bite of an infected tsetse fly. It is a well-circumscribed,
rubbery, painful, indurated, red lesion 2–5 cm in diameter, sometimes
with a black necrotic center (eschar). It is seen more frequently with
infection due to T. b. rhodesiense than T. b. gambiense. The chancre
usually resolves spontaneously after several weeks. Six to eight weeks
after infection, a transient, erythematous, urticarial, or macular rash
Figure 13-8 Histoplasmosis: disseminated livid macules in a patient with late may be observed.21 Lesions may be poorly defined, centrally pale, eva-
stage HIV infection. The marker lines demarcate the enlarged liver and spleen. nescent, annular, or blotchy erythematous macules on the trunk.
(Department of Dermatology, Academic Medical Centre, University of Amster-
dam, Amsterdam, The Netherlands.) Chagas Disease. Chagas disease is caused by T. cruzi and is endemic
in large parts of Latin America (see also Chapter 124). Both acute
natural infection and recrudescence of infection observed in immuno-
Paracoccidioidomycosis compromised individuals may present with cutaneous lesions. In acute
Paracoccidioidomycosis is the most prevalent systemic mycosis in infection, a minority of patients will experience a nonspecific febrile
Latin America. It is a chronic, granulomatous mycosis caused by Para- illness after an incubation period of 1–2 weeks. There are several well-
coccidioides brasiliensis. There are two forms: the acute juvenile and described dermatological manifestations of acute Chagas disease.22 A
chronic adult forms. The juvenile form represents only 3–5% of all chagoma is a red, indurated swelling at the site of inoculation, which
cases. Infection involves mainly the mononuclear phagocyte system. develops in the weeks after the initial bite and persists for weeks after-
Skin lesions are often present but the mucous membranes and the ward. Romaña’s sign is a unilateral painless periorbital swelling caused
lungs are rarely involved. In contrast, the more common adult form, by trypomastigotes that are transferred to the conjunctiva by rubbing
which almost exclusively affects men, is slowly progressive and causes in the eye. The patient subsequently develops eyelid edema and con-
predominantly pulmonary and mucocutaneous disease. Ulcerative junctivitis, which may be associated with lymphadenitis or even cel-
painful oral lesions are present in the majority of cases. Cutaneous lulitis. A small minority of patients will develop a diffuse morbilliform
lesions are polymorphic, consisting of papules, plaques and nodules, eruption in the weeks after acute inoculation, which is called schizo-
which may become verrucous or ulcerative. Centrofacial localization trypanides.22
a b
Figure 13-10 Skin lesions (Janeway spots) on the foot (a) and septic emboli of
the retina (b), the results of peripheral emboli in acute endocarditis caused by
Staphylococcus aureus.
Figure 13-9 Target lesions in a male patient with erythema multiforme. The
inflammatory cutaneous reaction was attributed to recurrent herpes simplex infec-
tions. (Department of Dermatology, Academic Medical Centre, University of
Amsterdam, Amsterdam, The Netherlands.)
Nonspecific Host-Related
Dermatologic Manifestations
ENDOCARDITIS STIGMATA
Peripheral cutaneous or mucocutaneous lesions of infectious endocar-
ditis include petechiae, splinter hemorrhages, Janeway lesions, Osler’s
nodes, and Roth spots (Chapter 51).23 Petechiae are the most common
skin manifestation. They may be present on the skin or on mucous
membranes. Splinter hemorrhages are also nonspecific; they are non-
blanching, linear, reddish-brown lesions found under the nail bed.
Janeway lesions, Osler’s nodes and Roth spots are more specific find-
ings of infectious endocarditis, which occur most frequently in the Figure 13-11 Osler node on the thumb during subacute endocarditis. This was
a rounded, tender, inflamed mass about 5 mm in diameter.
setting of protracted bacteremia. Janeway lesions are macular, non-
painful, erythematous lesions on the palms and soles (Figure 13-10a).
Osler’s nodes are painful, violaceous nodules found in the pulp of
fingers and toes (Figure 13-11). Roth spots are exudative, edematous
hemorrhagic lesions of the retina (Figure 13-10b). Most of these TABLE Nonspecific Host-Related Dermatologic
lesions arise from deposition of immune complexes. 13-2 Manifestations: Infections and Vaccines
Associated with Erythema Multiforme
ERYTHEMA MULTIFORME
Erythema multiforme (EM) is an acute, immune-mediated condition
characterized by the appearance of distinctive target-like lesions on the Mycoplasma pneumoniae
skin. Initial lesions may begin as round erythematous papules that Treponema pallidum
Legionella spp.
evolve into classic target lesions (Figure 13-9).24 Typical target lesions
Mycobacterium tuberculosis
consist of three components: a dusky central area or blister, a dark red Rickettsia spp.
inflammatory zone surrounded by a pale ring of edema, and an ery-
thematous halo on the extreme periphery of the lesion.24 Cutaneous VIRAL INFECTIONS
lesions most commonly appear in a symmetrical distribution on the Adenovirus
extensor surfaces of the acral extremities, and subsequently spread in Coxsackievirus
a centripetal manner. The face, neck, palms, soles, flexural surfaces of Cytomegalovirus
Epstein–Barr virus
the extremities, and/or trunk may also be involved. A variety of factors Herpes simplex virus
have been implicated in the pathogenesis of EM. The disorder is most Human immunodeficiency virus (HIV)
commonly induced by infection (Table 13-2), with herpes simplex Hepatitis B virus
virus being the most frequent precipitator. The clinical course of EM Hepatitis C virus
is usually self-limited, resolving within weeks. In a minority of cases, Poliomyelitis virus
Poxviruses (including orf, milker’s nodules)
the disease recurs frequently over the course of years. Varicella-zoster virus
ERYTHEMA NODOSUM FUNGAL INFECTIONS

Erythema nodosum is presumed to represent a delayed hypersensitiv- Histoplasma capsulatum
ity reaction to antigens associated with various infectious agents (Table Coccidioides immitis
13-3), drugs and other diseases. Streptococcal infections are the most Dermatophytes
common infectious cause in both adults and children while tubercu- VACCINES
losis and leprosy (erythema nodosum leprosum) are still common
causes in endemic areas. Erythema nodosum is characterized by red Diphtheria–tetanus–pertussis
Hepatitis B
or violet subcutaneous nodules that usually develop in a pretibial Smallpox
location that resolve without scarring over a 2- to 8-week period
Figure 13-13 Purpura fulminans associated with Capnocytophaga canimorsis

infection. (Courtesy of J.W.M. van der Meer.)
TABLE Nonspecific Host-Related Dermatologic

13-3 Manifestations: Infections Associated with
Erythema Nodosum
Bartonella spp.
Campylobacter spp.
Chlamydia spp.
Franciscella tularensis
Leptospira spp.
Figure 13-12 Painful subcutaneous nodules on the lower extremities of a patient Mycobacterium leprae
with systemic sarcoidosis. The inflammatory cutaneous reaction is indistinctive Mycobacterium tuberculosis
from erythema nodosum triggered by a systemic infection. (Department of Der- Mycoplasma pneumoniae
matology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Neisseria gonorrhoea
Netherlands.)
Rickettsia spp.
Salmonella spp.
Streptococci
(Figure 13-12).25 Lesions can also appear on the thighs, trunk and Treponema pallidum
Yersinia spp.
upper extremities, but absence of nodules on the legs is atypical.
Postinflammatory hypo- or hyperpigmentation does occur. VIRAL INFECTIONS
Epstein–Barr virus
PURPURA FULMINANS Hepatitis B virus
Purpura fulminans is a rapidly progressive thrombotic disorder in Hepatitis C virus
which there is hemorrhagic infarction of skin and disseminated intra- Herpes simplex virus
vascular coagulation. It is often accompanied by multiorgan failure Human immunodeficiency virus (HIV)
Parvovirus B19
and therefore associated with high mortality and long-term morbidity
in survivors. It may be a presenting feature of severe sepsis and is a FUNGAL INFECTIONS
cardinal feature of meningococcal sepsis, which is complicated by Blastomyces dermatitidis
purpura fulminans in 10–20% of cases. Less commonly, purpura ful- Coccidioides immitis
minans complicates sepsis caused by Streptococcus pneumoniae, group Histoplasma capsulatum
A and B streptococci, Capnocytophaga canimorsis (Figure 13-13), Hae-
PARASITIC INFECTIONS
mophilus influenzae and Staph. aureus, and infection with Plasmodium
falciparum, particularly in asplenic patients.26 Purpura fulminans may Entamoeba histolytica
occur as an autoimmune phenomenon after otherwise benign infec- Giardia lamblia
tions such as Varicella. The initial appearance of lesions is of well-
demarcated erythematous macules that progress rapidly to develop
irregular central areas of blue–black hemorrhagic necrosis. A thin may be reversible, established lesions often progress within 24–48
border of erythema that fades into adjacent uninvolved skin typically hours to full-thickness skin necrosis or more extensive soft-tissue
surrounds advancing areas of central necrosis. Hemorrhage into the necrosis that may require surgical debridement or amputation.
necrotic dermis causes lesions to become painful, dark and raised,
sometimes with vesicle or bulla formation.26 Although early lesions References available online at expertconsult.com.
KEY REFERENCES
Ameen M., Talhari C., Talhari S.: Advances in paracoccidi- Hemmige V., Tanowitz H., Sethi A.: Trypanosoma cruzi Murray R.J.: Recognition and management of Staphylococ-
oidomycosis. Clin Exp Dermatol 2010; 35(6):576-580. infection: a review with emphasis on cutaneous cus aureus toxin-mediated disease. Intern Med J 2005;
Barbagallo J., Tager P., Ingleton R., et al.: Cutaneous tuber- manifestations. Int J Dermatol 2012; 51(5):501- 35(Suppl. 2):S106-S119.
culosis: diagnosis and treatment. Am J Clin Dermatol 508. Negroni R.: Cryptococcosis. Clin Dermatol 2012; 30(6):599-
2002; 3(5):319-328. Huff J.C.: Erythema multiforme. Dermatol Clin 1985; 609.
Chalmers E., Cooper P., Forman K., et al.: Purpura fulmi- 3(1):141-152. Steer A.C., Lamagni T., Curtis N., et al.: Invasive group A
nans: recognition, diagnosis and management. Arch Dis Lopez-Martinez R., Mendez-Tovar L.J.: Blastomycosis. Clin streptococcal disease: epidemiology, pathogenesis and
Child 2011; 96(11):1066-1071. Dermatol 2012; 30(6):565-572. management. Drugs 2012; 72(9):1213-1227.
Chang P., Rodas C.: Skin lesions in histoplasmosis. Clin Maguina C., Guerra H., Ventosilla P.: Bartonellosis. Clin Uslan D.Z., Jacobson K.M., Kumar N., et al.: A woman with
Dermatol 2012; 30(6):592-598. Dermatol 2009; 27(3):271-280. fever and rash after African safari. Clin Infect Dis 2006;
Cribier B., Caille A., Heid E., et al.: Erythema nodosum and Mukhopadhyay D., Dalton J.E., Kaye P.M., et al.: Post kala- 43(5):609, 661-662.
associated diseases: a study of 129 cases. Int J Dermatol azar dermal leishmaniasis: an unresolved mystery. Trends Welsh O., Vera-Cabrera L., Rendon A., et al.: Coccidioido-
1998; 37(9):667-672. Parasitol 2014; 30(2):65-74. mycosis. Clin Dermatol 2012; 30(6):573-591.
Chapter 13 Dermatologic Manifestations of Systemic Infections 121.e1
REFERENCES
1. Koehler J.E., Tappero J.W.: Bacillary angiomatosis and 10. Sehgal V.N.: Cutaneous tuberculosis. Dermatol Clin 20. Mukhopadhyay D., Dalton J.E., Kaye P.M., et al.: Post
bacillary peliosis in patients infected with human 1994; 12(4):645-653. kala-azar dermal leishmaniasis: an unresolved mystery.
immunodeficiency virus. Clin Infect Dis 1993; 17(4): 11. Barbagallo J., Tager P., Ingleton R., et al.: Cutaneous Trends Parasitol 2014; 30(2):65-74.
612-624. tuberculosis: diagnosis and treatment. Am J Clin Der- 21. Uslan D.Z., Jacobson K.M., Kumar N., et al.: A woman
2. Maguina C., Guerra H., Ventosilla P.: Bartonellosis. Clin matol 2002; 3(5):319-328. with fever and rash after African safari. Clin Infect Dis
Dermatol 2009; 27(3):271-280. 12. Frankel A., Penrose C., Emer J.: Cutaneous tuberculosis: 2006; 43(5):609, 661-662.
3. Karaali Z., Baysal B., Poturoglu S., et al.: Cutaneous a practical case report and review for the dermatologist. 22. Hemmige V., Tanowitz H., Sethi A.: Trypanosoma cruzi
manifestations in brucellosis. Indian J Dermatol 2011; J Clin Aesthet Dermatol 2009; 2(10):19-27. infection: a review with emphasis on cutaneous mani-
56(3):339-340. 13. Lopez-Martinez R., Mendez-Tovar L.J.: Blastomycosis. festations. Int J Dermatol 2012; 51(5):501-508.
4. Milionis H., Christou L., Elisaf M.: Cutaneous manifes- Clin Dermatol 2012; 30(6):565-572. 23. Murdoch D.R., Corey G.R., Hoen B., et al.: Clinical pre-
tations in brucellosis: case report and review of the 14. Welsh O., Vera-Cabrera L., Rendon A., et al.: Coccidioi- sentation, etiology, and outcome of infective endocar-
literature. Infection 2000; 28(2):124-126. domycosis. Clin Dermatol 2012; 30(6):573-591. ditis in the 21st century: the International Collaboration
5. Murray R.J.: Recognition and management of Staphy- 15. Negroni R.: Cryptococcosis. Clin Dermatol 2012; on Endocarditis-Prospective Cohort Study. Arch Intern
lococcus aureus toxin-mediated disease. Intern Med J 30(6):599-609. Med 2009; 169(5):463-473.
2005; 35(Suppl. 2):S106-S119. 16. Chayakulkeeree M., Perfect J.R.: Cryptococcosis. Infect 24. Huff J.C.: Erythema multiforme. Dermatol Clin 1985;
6. Burke R.J., Chang C.: Diagnostic criteria of acute rheu- Dis Clin North Am 2006; 20(3):507-544, v-vi. 3(1):141-152.
matic fever. Autoimmun Rev 2014; 13(4-5):503-507. 17. Chang P., Rodas C.: Skin lesions in histoplasmosis. Clin 25. Cribier B., Caille A., Heid E., et al.: Erythema nodosum
7. Steer A.C., Lamagni T., Curtis N., et al.: Invasive group Dermatol 2012; 30(6):592-598. and associated diseases: a study of 129 cases. Int J Der-
A streptococcal disease: epidemiology, pathogenesis 18. Ameen M., Talhari C., Talhari S.: Advances in paracoc- matol 1998; 37(9):667-672.
and management. Drugs 2012; 72(9):1213-1227. cidioidomycosis. Clin Exp Dermatol 2010; 35(6):576- 26. Chalmers E., Cooper P., Forman K., et al.: Purpura ful-
8. MacGregor R.R.: Cutaneous tuberculosis. Clin Derma- 580. minans: recognition, diagnosis and management. Arch
tol 1995; 13(3):245-255. 19. Bern C., Joshi A.B., Jha S.N., et al.: Factors associated Dis Child 2011; 96(11):1066-1071.
9. Handog E.B., Gabriel T.G., Pineda R.T.: Management of with visceral leishmaniasis in Nepal: bed-net use is
cutaneous tuberculosis. Dermatol Ther 2008; 21(3): strongly protective. Am J Trop Med Hyg 2000; 63(3-
154-161. 4):184-188.
14
Superficial Fungal Infections
DAVID W. WARNOCK | TOM M. CHILLER
KEY CONCEPTS Members of all three groups can cause human infections, but their
natural reservoirs have important implications for acquisition, site and
• The principal fungal infections of the skin are dermatophytosis, spread of the disease. Infections originating from the soil are the least
candidiasis and pityriasis versicolor. Their prevalence varies common. Infections with animal origins are more frequent and par-
from one part of the world to another, but in the tropics they ticular species are often associated with particular animal hosts.
are among the most common causes of skin disease.
Anthropophilic dermatophytes account for most human infections;
• With the exception of dermatophytosis, superficial fungal infec- these species are contagious and readily transmitted from person to
tions are rarely transmitted from person to person. person.
Tinea capitis (dermatophytosis of the scalp) is predominantly a
• In the temperate, higher-income countries, tinea pedis (foot
infection) is the most common form of dermatophytosis. disease of childhood. The etiologic agents differ per continent. The
By contrast, in the tropics, tinea capitis and tinea corporis anthropophilic species Trichophyton tonsurans has replaced Microspo-
(infection of the scalp, and trunk and limbs) are the most rum audouinii as the principal cause in urban populations in North,
prevalent. Central and South America.4 Infections with this organism have also
become much more common in the UK, particularly among black
• In addition to pityriasis versicolor, Malassezia spp. are also
African or black Caribbean school children. The cause of this rise is
associated with two other common skin disorders, folliculitis
and seborrhoeic dermatitis. possibly associated with increased migration. In France, and in par-
ticular Paris, the main anthropophilic dermatophytes causing tinea
• Fungal infections of nails are usually caused by dermatophytes. capitis originate from Africa, particularly T. soudanense. Favus, a der-
Less frequently, they may be caused by Candida species and matophytosis of the scalp caused by T. schoenleinii, is now rare in the
a number of molds, including Scopulariopsis brevicaulis, Asper- UK and Western Europe, being largely confined to Eastern Europe and
gillus spp. and Fusarium spp.
Asia. Other less common causes of tinea capitis include the animal
• Superficial fungal infections often present with characteristic species M. canis and T. verrucosum. Tinea pedis (dermatophytosis of
lesions but where this is not the case, material should be col- the feet) is easily spread from person to person. The predominant agent
lected for microscopic examination and culture. The latter is the anthropophilic species T. rubrum, but it can also be caused by T.
permits the pathogen involved to be determined, and may aid mentagrophytes var. interdigitale. The main spread occurs in communal
the selection of the best treatment. baths and showers.5
• Many topical and systemic agents are available for treatment Cutaneous candidiasis is less common than dermatophytosis.
of these infections. The choice of treatment and its duration Candida albicans, the predominant organism, is a commensal of the
depends on the etiological agent, the site of infection and the mouth and gastrointestinal tract. It is seldom recovered from normal
extent of the disease. skin, being much less prevalent than C. parapsilosis, but it is a frequent
colonizer of moist or damaged skin and nails.
Malassezia spp. are common commensal yeasts of the skin of the
Introduction head and trunk during late childhood.6 In hot humid climatic condi-
tions, these lipophilic organisms produce pityriasis versicolor. In the
The most common superficial fungal diseases are dermatophytosis, tropics, up to 50% of the population may be affected. Malassezia spp.
candidiasis and pityriasis versicolor. Less frequent infections of the skin can be transmitted from person to person, either through direct
and hair include tinea nigra and piedra. In addition, a number of contact or through contaminated clothing or bedding. In most cases,
nondermatophytic molds can cause nail disease (onychomycosis). The however, infection is endogenous and spread between individuals is
prevalence of these infections varies worldwide, but in many tropical uncommon.
countries they are among the most common skin diseases. Moreover, Tinea nigra is a chronic infection of the palms and soles. It is rare,
superficial fungal infections, such as dermatophytosis and onychomy- with a worldwide distribution, being more common in the (sub)
cosis, are an important problem in individuals positive for human tropics. The etiologic agent, Hortaea werneckii, is a saprophytic mold
immunodeficiency virus (HIV), transplant recipients and other immu- found in soil and decomposing vegetation. Human infection is thought
nocompromised patients. Prompt diagnosis is important to prevent to follow traumatic inoculation.
more severe complications; however, this can be difficult because of Black piedra is an uncommon hair infection that occurs in humid
atypical clinical manifestations. In such patients, skin and nail infec- tropical regions. The natural habitat of the etiologic agent, Piedraia
tions can be difficult to treat because the disease is often more extensive hortae, is unknown. There are reports of familial infection. White
and severe. piedra is even less common. It is found worldwide, but more prevalent
in the (sub)tropics. The etiologic agents, Trichosporon spp., are yeasts
Epidemiology with a widespread natural distribution and are sometimes found on
Dermatophytoses are caused by molds of the genera Trichophyton, normal skin.
Microsporum and Epidermophyton.1,2 Many of approximately 40 known Onychomycosis is a nonspecific term for fungal disease of the
species are worldwide in distribution, but others are confined to par- nails; tinea unguium is a more specific term to describe dermatophyte
ticular regions.3 About 10 species are common human pathogens. The nail infection. At least 80% of fungal nail infections and 90% of
dermatophytes invade the stratum corneum of the skin and other toenail infections are due to dermatophytes, in particular T. rubrum;7
keratinized tissues, such as nails and hair. There are three ecologic 5–10% of nail infections are due to Candida species and the remainder
groups depending on their natural habitat: soil (geophilic species), are attributable to non-dermatophytic molds. Most prominent
animals (zoophilic species) or humans (anthropophilic species). among these are Scopulariopsis brevicaulis, Neoscytalidium dimidiatum
122
Chapter 14 Superficial Fungal Infections 123
(Hendersonula toruloidea), Acremonium and Sarocladium spp., Asper- the animal source. M. canis infection of cats and dogs can often be
gillus spp. and Fusarium spp.7 These molds are not contagious. Ony- detected with Wood’s light. The subsequent course of action will
chomycosis is more prevalent in older people and men are more depend upon the value placed on the infected animal. It is more dif-
commonly affected than women. Toenails are more frequently involved ficult to detect and eliminate T. verrucosum infection in cattle, because
than fingernails. infected hairs are not fluorescent and because the fungus can survive
for long periods on hairs and scales that have been deposited on the
walls of buildings and gates. Fungicidal washes have sometimes been
Pathogenesis and Pathology effective in controlling this infection.
Tinea pedis easily spreads from person to person. Transfer within
The dermatophytes are keratinophilic fungi normally found growing households has been reported, but the main spread occurs in com-
in the dead keratinized tissue of the stratum corneum, within and munal baths and showers.5 Educating infected people not to expose
around hair shafts, and in the nail-plate and keratinized nail-bed. The others to their infection by covering their feet while walking barefoot
clinical appearances of these infections are the result of tissue damage on the floors of communal changing rooms and by avoiding public
by the fungus (mainly in hair and nail infections) and of the host baths and showers can help to reduce the spread. Frequent hosing of
immune response. The tissue damage is due to mechanical forces and the floors of public baths and antifungal foot dips near communal
enzyme activities. Dermatophytes produce keratinolytic proteinases baths are helpful preventive measures. Prompt treatment of tinea pedis
that function best at acidic pH and these are important virulence and the use of separate towels are sensible measures to prevent tinea
factors.1 cruris, tinea manuum and tinea unguium.
The immune response to dermatophytes has been studied in Intertriginous candidiasis of the fingernails is often seen in people
human infections and in animal models.8 The humoral response does whose occupation necessitates frequent wetting of the hands. Protec-
not help to eliminate infection; the highest antibody levels are often tive gloves can help to prevent this infection. This condition is also seen
found in patients with chronic dermatophytosis. The cell-mediated in diabetic patients and good glucose control is important in preven-
response is important in ridding the stratum corneum of the infection and control.
tion.9 Dermatophytes vary in their host interactions. Zoophilic species, Good personal hygiene is important in preventing the spread of
such as T. verrucosum, often elicit intense inflammation in humans, piedra. Infected people should not share hair brushes or combs with
leading to enhanced epidermal proliferation and sometimes spontane- others.
ous cure.10 Anthropophilic species such as T. rubrum often produce
chronic or recurrent lesions. Chronic dermatophytosis in healthy
people may be mediated by fungal cell wall components, such as
Clinical Features
mannan, that diminish the local immune response.11 The dermatophytes are the predominant causes of fungal disease of
Except for neonatal infections, most cases of superficial candidiasis the scalp, toe clefts, soles, palms and nails. In the temperate, higher-
result from infection with the host’s own commensal flora. This shift income countries, tinea pedis is the most common dermatophytosis.
in the host–fungus relationship results from a number of influences, In the tropics, tinea capitis and tinea corporis are the most prevalent.
of which host factors appear to be the most important. Local tissue
damage is a critical factor in the pathogenesis of cutaneous candidiasis; TINEA CAPITIS
most infections occur in moist, occluded sites and follow maceration The clinical manifestations of tinea capitis vary and depend on the
of the tissue. The term chronic mucocutaneous candidiasis (CMC) is dermatophyte species and the degree of host response (Table 14-1).
used to describe a group of rare infections of the skin, mucous mem- The lesions can range from mild scaling and hair loss with minimal
branes, hair and nails that are due to inherited abnormalities of the inflammation to severe inflammation with kerion formation. Infection
cell-mediated immune response. Mutations in the CC domain of may also be associated with painful regional lymphadenopathy, par-
STAT1 underlie autosomal dominant CMC and lead to defective ticularly in those with inflammatory lesions. A generalized eruption of
responses of Th1 and Th17 helper T cells.12 This may explain the itchy papules, particularly around the ear, may occur as a reactive
increased susceptibility to fungal infection. Around 50% of CMC cases phenomenon (an ‘id’ response). This may coincide with the start of
also have a severe endocrine disorder. antifungal treatment and may be mistaken for a drug reaction.15
Malassezia spp. are present on the normal skin from late childhood. In M. audouinii infection the lesions consist of well-demarcated
Hot, humid environmental conditions predispose for pityriasis versi- patches of partial alopecia. Inflammation is minimal, but fine scaling
color. The infection may occur in otherwise healthy individuals and in
some immunocompromised patients such as those receiving long-
term systemic corticosteroids. Malassezia spp. also play a role in sebor- TABLE Some Characteristics of Common
14-1 Dermatophytes Causing Scalp Infection
rhoeic dermatitis and dandruff, two closely related conditions with a
localized inflammatory response against yeasts on the skin. The patho-
Fluorescence
genetic mechanisms involved remain unclear.13 Arthrospore Arthrospore Under
Organism Size Arrangement Wood’s Light
Prevention Microsporum Small (2–3 µm) Ectothrix Yes
Prevention of dermatophytosis must take into account the site of the audouinii
infection, the etiologic agent and the source of the infection. Anthro- Microsporum canis Ectothrix Yes
Small (2–3 µm)
pophilic tinea capitis is a common infection in children. It easily
spreads from child to child, both at home and at school. To prevent Trichophyton Small (3–5 µm) Ectothrix No
this, contacts of children infected with Microsporum audouinii can be mentagrophytes
examined for infected fluorescent hairs with Wood’s light (ultraviolet Trichophyton Large (4–8 µm) Endothrix No
light filtered through nickel oxide glass). In the more common non- soudanense
fluorescent infection with T. tonsurans, detection is more difficult, but Trichophyton Large (4–8 µm) Endothrix No
the scalp brush sampling method is often helpful in detecting subclini- tonsurans
cal disease.14 Those found infected must be treated and good personal
Trichophyton Large (5–10 µm) Ectothrix No
hygiene should be stressed. Children are allowed to return to school verrucosum
once they are on appropriate antifungal treatment.15
Trichophyton Large (4–8 µm) Endothrix No
In the case of tinea capitis and tinea corporis caused by zoophilic violaceum
species, such as M. canis and T. verrucosum, it is important to locate
is characteristic. Most of the hairs in these lesions are broken off near TINEA CORPORIS
the surface of the scalp. In M. canis infection the picture is similar, but The clinical manifestations of tinea corporis are varied and often
usually with more inflammation. In both these infections the hair depend on the infective species. The disease often follows contact with
surface is coated with small arthrospores (ectothrix infection) and infected animals, but occasionally results from contact with contami-
show green fluorescence under Wood’s light. nated soil. M. canis is a frequent cause of human infection and T.
In T. tonsurans and violaceum infections the lesions are often incon- verrucosum infection is common in rural districts. Infections with
spicuous and inflammation may be minimal. The typical lesions are anthropophilic species, such as T. rubrum, often follow spread from
irregular patches of scaling. The affected hairs often break off at the another site, such as the feet. Infections with T. tonsurans are some-
surface of the scalp, giving a ‘black-dot’ appearance. The hairs are filled times seen in children with tinea capitis.
with arthrospores (endothrix infection) and do not fluoresce under The characteristic lesion is an annular scaling plaque with a raised
Wood’s light. erythematous border and central clearing. In their most florid form
The most florid form of tinea capitis is a kerion. This is a painful the lesions can become indurated and pustular (Figure 14-2). This is
inflammatory mass in which the hairs that remain are loose. Thick more common in infections with zoophilic organisms. The differential
crusting with matting of adjacent hairs is common. Pus may be dis- diagnosis includes discoid eczema, impetigo, psoriasis and discoid
charged from one or more points. A kerion may be limited in extent, lupus erythematosus. Perifollicular pustules (Majocchi’s granuloma)
but a large confluent lesion may develop (a severe form of kerion) that are indicative of deep-seated follicular involvement and require sys-
involves most of the scalp. In most cases this violent reaction results temic therapy.
from infection with an animal dermatophyte such as T. verrucosum or
T. mentagrophytes var. mentagrophytes. However, geophilic or anthro- TINEA CRURIS
pophilic organisms are sometimes involved. In T. verrucosum infec- Infection of the groin and the perianal and perineal regions is more
tions the hairs are covered with chains of large arthrospores but they common in men. The predominant causes are the anthropophilic
do not fluoresce under Wood’s light. species T. rubrum and Epidermophyton floccosum. The infection often
Favus is a fungal scalp infection, caused by T. schoenleinii, an follows spread from another site in the same person (e.g. feet or nails),
anthropophilic dermatophyte noted for its persistence. Favus presents but person-to-person spread (e.g., through contaminated clothing) is
with hair loss and the formation of cup-shaped crusts known as not uncommon.
scutula. These give off a fetid odor and can amalgamate to form dense In color, the lesions are erythematous to brown. They have raised
mats on part or all of the scalp. Longstanding favus can lead to per- scaling margins and radiate from the groin down the inner border of
manent patches of cicatricial alopecia. Infected hairs give off a dull the thigh. Patients often have intense pruritus. The differential diagno-
green fluorescence under Wood’s light. sis includes intertriginous Candida infection, bacterial intertrigo, pso-
Tinea capitis must be distinguished from seborrheic dermatitis, riasis and seborrheic dermatitis.
psoriasis, bacterial folliculitis and cicatricial alopecia.
TINEA IMBRICATA
TINEA BARBAE This is a chronic infection that is characterized by the development of
The animal species T. verrucosum and T. mentagrophytes var. mentag- homogeneous sheets or concentric rings of scaling that can spread to
rophytes are the principal causes of dermatophyte infection of the cover large parts of the affected person. Most reports of tinea imbricata
beard and mustache areas of the face. M. canis is a less common cause. have come from the Pacific Islands and Melanesia with occasional
The characteristic appearance is of a highly inflammatory pustular reports from South East Asia and Central and South America. The
folliculitis (Figure 14-1). Some infections are less severe and consist of etiologic agent is the anthropophilic species T. concentricum.
circular, erythematous, scaling lesions.
TINEA FACIEI
The more common causes of dermatophyte infection of the face are T.
rubrum and T. mentagrophytes var. mentagrophytes, but many other
species may be involved, including T. tonsurans and M. canis. The
typical annular lesions are erythematous, but scaling is often absent.
The lesions are often pruritic and exacerbation after exposure to the
sun is common.
Figure 14-2 Tinea corporis due to Trichophyton mentagrophytes var.

Figure 14-1 Tinea barbae due to Trichophyton verrucosum. mentagrophytes.
Figure 14-3 Moccasin tinea pedis due to Trichophyton rubrum. Figure 14-4 Total dystrophic onychomycosis due to Trichophyton rubrum.
TINEA PEDIS other molds, such as Acremonium and Fusarium spp., are also encoun-
Infection of the feet is the most common form of dermatophytosis in tered. Concurrent tinea pedis is not as frequent as in distal lateral
the UK and North America. The main organisms involved are the subungual onychomycosis.
anthropophilic species T. rubrum and, less commonly, T. mentagro- Proximal subungual onychomycosis is the least common pre
phytes var. interdigitale. The most common clinical presentation is sentation of dermatophyte nail infection. In the USA T. rubrum
interdigital maceration, peeling and fissuring, mostly in the spaces is the principal cause. Immunocompromised individuals, especially
between the fourth and fifth toes. Itching is a common symptom. those who are HIV-positive, may present with this type; conditions
Another common presentation associated with T. rubrum is hyper- such as peripheral vascular disease and diabetes mellitus may also
keratosis of the soles, heels and sides of the feet. The affected sites are present in this way.
pink and covered with fine, white scales. This is often chronic and Unlike dermatophytosis, Candida infections of the nails often begin
resistant to treatment. With extensive involvement of the foot, the term in the proximal nail-plate and are associated with nail-fold infection.
‘moccasin tinea pedis’ is often applied (Figure 14-3). This is frequently
associated with nail infection. CANDIDIASIS
A third form of tinea pedis, associated with T. mentagrophytes Cutaneous candidiasis (intertrigo) tends to develop in warm, moist
var. interdigitale, is an acute vesicular infection of the soles. This sites such as the skin folds under the breasts and the groin, especially
severe form may resolve without treatment, but exacerbations tend in overweight or diabetic people. The initial lesions are papules or
to occur under hot humid conditions. There is often associated vesicopustules that enlarge and become confluent. Larger lesions are
hyperhidrosis. erythematous with an irregular margin. Smaller, satellite lesions are
Tinea pedis can be difficult to distinguish from other infectious common. Soreness and itching are usual. The differential diagnosis
causes of toe web infection, such as Candida intertrigo and erythrasma. includes dermatophytosis, seborrheic dermatitis, bacterial intertrigo
Noninfectious conditions that mimic tinea pedis of the soles include and psoriasis.
psoriasis and contact dermatitis. Infection of the skin between the fingers or toes also occurs. Infec-
tion of the webs of the fingers presents as a macerated, erythematous
TINEA MANUUM lesion (Figure 14-5). It is often uncomfortable and may be painful. It
Tinea manuum is usually unilateral, the right hand being more com- is usually seen in people whose occupations necessitate frequent
monly affected than the left. Lesions on the dorsum of the hand appear immersion of the hands in water. Infection of the webs of the toes
similar to those of tinea corporis, with a distinct border and central mimics tinea pedis and many cases do occur in conjunction with this
clearing. Infection of the palms is more common. This presents as a form of dermatophytosis.
diffuse scaling hyperkeratosis, with accentuation of the fissuring in the Chronic mucocutaneous candidiasis (CMC) is a rare condition that
palmar creases. T. rubrum is the most common cause of tinea manuum. affects people with underlying endocrinologic and/or immunologic
The differential diagnosis includes contact dermatitis, eczema and disorders. The disease often develops during the first 3 years of life.
psoriasis. The mouth is usually the first site to be affected, but lesions then appear
on the scalp, hands, feet and nails. In some patients, severely disfiguring
TINEA UNGUIUM hyperkeratotic lesions develop.
The most common causes of dermatophyte infection of the nails are Three forms of Candida nail infection are recognized: infection of
T. rubrum and T. mentagrophytes var. interdigitale, but many other the nail-folds (paronychia), distal nail infection and total dystrophic
species may be involved. Three clinical forms are recognized. Distal (or onychomycosis. The last is a manifestation of CMC. Infection of the
lateral) subungual disease is most common. This usually begins as a nail-folds is more common in women than in men. The periungual
discoloration and thickening of the nail, often at the lateral edges skin is raised and painful and a prominent gap develops between the
initially, which then spreads proximally along the nail-bed resulting in fold and the nail-plate. White pus may be discharged. The infection
subungual hyperkeratosis and onycholysis. It may be confined to one usually starts in the proximal nail-fold, but the lateral margins are
side of the nail or spread sideways to involve the whole nail-bed. It can sometimes the first site to be affected. The nail-plate may be invaded.
result in destruction of the entire nail-plate and separation of the nail Distal Candida nail infection presents as onycholysis and subungual
from the nail-bed (Figure 14-4). hyperkeratosis. It is uncommon and usually associated with some
In superficial white onychomycosis, crumbling white lesions are underlying vascular problem, such as Raynaud’s phenomenon. It is
evident on the nail surface, particularly the toenails. This condition is often difficult to distinguish from dermatophytosis, but Candida ony-
most commonly caused by T. mentagrophytes var. interdigitale, but chomycosis tends to affect the fingernails rather than the toenails, and
Figure 14-6 Pityriasis versicolor showing depigmented lesions.
first, expand and become confluent. The disease is asymptomatic and

may long remain undiagnosed. It must be distinguished from malig-
nant melanoma and chemical stains.
PIEDRA
Figure 14-5 Interdigital candidiasis. Black piedra is most often seen on the scalp hair. Small, brown or black
hard nodules, which are difficult to remove, are formed on the distal
hair shafts. White piedra is similar, but the nodules are softer and pale
there is typically less subungual hyperkeratosis. In patients with CMC, in color. It affects the hairs of the beard and mustache. Less commonly,
the nail-plate is invaded from the outset, causing gross thickening and it involves the scalp or pubic hair.
hyperkeratosis.
ONYCHOMYCOSIS
PITYRIASIS VERSICOLOR Up to 5% of cases of onychomycosis are due to nondermatophyte
Pityriasis versicolor is a disfiguring but otherwise harmless condition molds, such as Aspergillus, Fusarium and Acremonium spp., and
in which the organisms, usually Malassezia globosa, develop filaments Scopulariopsis brevicaulis. With the exception of Neoscytalidium dimid-
and cause damage in the stratum corneum through tissue invasion, iatum, these molds usually affect nails that have previously been dis-
dyspigmentation and minor inflammation. The characteristic lesions eased or damaged. This may explain why these infections often affect
consist of patches of fine brown scaling that are found particularly on only one nail. The clinical appearance of the lesions is nonspecific
the upper trunk, neck, upper arms and abdomen. In light-skinned (Figure 14-7). Distal subungual hyperkeratosis with onycholysis of
people the affected skin may appear darker than normal. The lesions the distal nail plate is common. Superficial white lesions are another
are light pink in color but grow darker, turning a pale brown shade. In presentation.
dark-skinned or tanned people, the affected skin becomes depig-
mented (Figure 14-6). SUPERFICIAL FUNGAL INFECTIONS IN
Hyperpigmented lesions must be distinguished from erythrasma, IMMUNOCOMPROMISED PATIENTS
seborrheic dermatitis, pityriasis rosea and tinea corporis. Hypopig- In general, fungal infections, such as dermatophytosis and onychomy-
mented lesions can be confused with pityriasis alba and vitiligo. cosis, are no more common in immunocompromised persons than in
immunocompetent individuals.16,17 The clinical manifestations of der-
MALASSEZIA FOLLICULITIS matophytosis are often also similar. However, the presentation can be
In addition to pityriasis versicolor, Malassezia spp. are also associated atypical, particularly in patients with T-cell defects, such as transplant
with folliculitis and seborrhoeic dermatitis. There are two main forms recipients and patients with acquired immunodeficiency syndrome
of Malassezia folliculitis. The first, most common in young adults, (AIDS). Patients treated with TNF blockers may be at increased risk
consists of small, scattered, itching and erythematous follicular papules for superficial fungal infections.18 The major features in these groups
that develop on the back, chest or upper arms, and slowly enlarge to are loss of obvious lesions, minimal scaling and the presence of follicu-
become pustular. These often appear after sun exposure or antibiotic lar papules or pustules. In addition, the lesions can be more extensive
or immunosuppressive treatment. These patients do not usually have than normal. Tinea pedis has been described in both transplant recipi-
seborrhoeic dermatitis. It is often overlooked and may easily be con- ents and AIDS patients. The lesions are often indistinguishable from
fused with common acne. those in normal individuals but can be extensive, with involvement of
The second form is seen in some patients with seborrhoeic derma- the dorsum of the foot. In tinea corporis and tinea cruris, the lesions
titis; there are numerous small follicular papules scattered over the can be extensive but the inflammation is mild and the margin is indis-
upper and lower chest and back. The rash is more florid and particu- tinct. Facial dermatophytosis has been noted in AIDS, where it can be
larly marked on the back. A third form of Malassezia folliculitis is seen confused with seborrheic dermatitis. This is because the rash is diffuse
in persons with HIV infection (see below). and can spread across both cheeks.
Although proximal subungual onychomycosis is the most infre-
TINEA NIGRA quent form of fungal nail disease in the general population, it is
Tinea nigra lesions, which are found on the palm or sole, consist of common in AIDS patients and is considered a useful clinical marker
one or more flat, dark brown or black, nonscaling patches with a well- of HIV infection.19 Infection of the toenails is much more frequent
defined edge. Inflammation is absent. The lesions, which are small at than of the fingernails. T. rubrum is the usual cause. In AIDS patients,
Direct microscopic examination of skin and nail material is

often sufficient for the diagnosis of dermatophytosis, but it gives no
indication about the species. With hair specimens, size and disposition
of the arthrospores can give an indication as to the etiologic agent (see
Table 14-1).
Culture is more reliable for diagnosis than microscopy. It permits
the species of dermatophyte to be determined and this can aid the
selection of the most appropriate treatment. If possible, both micros-
copy and culture should be performed on all specimens. If there is
insufficient material for both, microscopy should be performed.
Numerous nucleic acid amplification methods have been described
for the direct detection of fungal DNA in skin and nail specimens,22
but these have seldom been validated against microscopy and/or
culture.
Cutaneous candidiasis is often difficult to diagnose if the lesions
are atypical. Isolation of Candida albicans from scrapings is of
doubtful significance because the organism is a common colonizer of
cutaneous lesions in moist sites. Microscopic demonstration of the
organism in scrapings is much more significant. Isolation of C. albicans
from nails is seldom significant unless the organism is seen on direct
microscopy.
Microscopy of scrapings from lesions will permit the diagnosis of
pityriasis versicolor if there are clusters of round or oval cells together
with short broad filaments (which are seldom branched). Because this
appearance is pathognomonic for pityriasis versicolor, and because
Malassezia spp. are part of the normal skin flora, culture is not helpful.
Figure 14-7 Onychomycosis due to Neoscytalidium dimidiatum (Hendersonula Direct microscopy and culture of scrapings or epilated hairs will
toruloidea).
permit the diagnosis of tinea nigra and piedra.
It is not unusual to culture molds other than dermatophytes from
abnormal nails on media from which cycloheximide has been omitted.
it can spread rapidly from the proximal margin and superior surface Often, these molds are casual, transient contaminants and direct
of the nail to produce gross white discoloration of the plate without microscopy is negative. However, if filaments are seen on microscopic
obvious thickening. examination but no dermatophyte is isolated, the mold may be the
Malassezia infections of the skin can take a number of different cause of the infection.
clinical forms in immunocompromised persons, including pityriasis
versicolor, Malassezia folliculitis and seborrheic dermatitis.16,17 The
clinical manifestations of pityriasis versicolor in immunocompro- Management
mised persons are similar to those seen in normal individuals. However, There is a good selection of topical and systemic agents for the treat-
the lesions are usually more erythematous and may appear raised. In ment of superficial fungal infections. The choice of treatment and its
immunosuppressed individuals, Malassezia spp. can also cause follicu- duration depends on the causative organism, the site of infection and
litis, characterized by multiple itching follicular papules and pustules the extent of the disease, as well as on other factors for each individual
on the trunk and face, and often associated with severe seborrhoeic patient, such as concurrent disease and medication. Topical agents can
dermatitis. be used for localized skin infections, but they are seldom successful for
Seborrheic dermatitis is a chronic relapsing skin disease. The lesions sites with a thick keratin layer or when follicular structures are involved.
take the form of an erythematous scaling rash on the scalp, in the The palms and soles and certainly the nails and hair often require
nasolabial folds, eyebrows, behind the ears and on the chest. Seborrheic systemic antifungal treatment. Although they respond well to many
dermatitis may appear in any individual, but it is particularly common topical and systemic antifungal agents, AIDS patients often suffer from
and troublesome in immunocompromised persons, estimated to occur recurrent episodes of superficial fungal infections. If the disease is
in 30% of HIV-positive individuals20 and 10% of renal transplant chronic and extensive, systemic treatment is required.
recipients.21 In AIDS, the onset may be sudden and the rash more
extensive than in others. TINEA CAPITIS
Topical treatment is ineffective on its own, but may reduce the risk of
Diagnosis transmission to others in the early stages of systemic treatment.15 Sele-
Superficial fungal infections often present with characteristic lesions nium sulfide and povidone iodine shampoos, used twice weekly,
but where this is not the case, mycologic investigation can assist in reduce the carriage of viable spores.
diagnosis. Material should be collected from cutaneous lesions by A systematic review of 21 clinical trials suggested that newer treat-
scraping outward from the margin. Cleansing the site with 70% alcohol ments, including terbinafine, itraconazole and fluconazole, may be as
before sampling will increase the likelihood of detecting fungus by effective as griseofulvin in children with tinea capitis caused by Tricho-
direct microscopy. Nail specimens should be taken from discolored or phyton spp.23 There was insufficient evidence on the use of systemic
dystrophic parts and should include the full thickness of the nail. If treatments in children with Microsporum infections. The oral granule
distal subungual lesions are present, debris should be collected from formulation of terbinafine is licensed in some countries for use in
underneath the nail. With superficial nail-plate involvement, the scrap- children ≥4 years and it appears to be safe and effective in this group.24
ings should be taken from the nail surface. Specimens from the scalp Dosage ranges from 250 mg/day in children >35 kg, to 187.5 mg in
should include hair roots and skin scales. As an alternative to scraping, those weighing 25–35 kg, and 125 mg in those weighing <25 kg.
the affected area can be brushed with a sterile, single-use, plastic tooth- In other countries, the older drug griseofulvin must still be used in
brush, which can be sent for culture. Wood’s light is sometimes useful children. The recommended dose is 20–25 mg/kg/day for at least 6–8
for the selection of sites of active infection, especially if the lesions are weeks. A confirmatory culture is often done at 5–6 weeks to determine
inconspicuous or atypical. if longer courses are needed.
TINEA CORPORIS AND TINEA CRURIS may be required in patients with extensive or recalcitrant lesions. To
The choice of topical or systemic treatment in these conditions depends prevent relapse, maintenance treatment may be given once or twice
on the extent of the disease. Localized lesions can be treated with per week.
topical antifungals. Numerous imidazole and allylamine formulations
are available. These should be applied morning and evening for 4–6 SEBORRHEIC DERMATITIS
weeks. To prevent relapse, treatment should be continued for at least This is a difficult condition to treat in AIDS patients. Milder forms can
1 week after the lesions have cleared. often be managed with topical ketoconazole 2% cream with or without
If the disease is widespread or follicular structures are involved (i.e., a topical corticosteroid. Terbinafine cream may also be effective.
pustules), or the patient fails to respond to topical preparations, oral Patients with inflamed lesions often benefit from topical application
treatment is usually indicated. Terbinafine 250 mg/day for 2–4 weeks of combined hydrocortisone 1% and antifungal drugs. However,
and itraconazole 100 mg/day for 2 weeks are more effective than gris- relapse is common.
eofulvin 10–20 mg/kg/day for 4–6 weeks. Unlike itraconazole, oral
terbinafine has a low potential for drug interactions, making it a useful
agent for the treatment of dermatophytosis in AIDS patients and other TINEA NIGRA
immunocompromised individuals. Terbinafine has been reported to Benzoic acid compound ointment or 10% thiabendazole solution can
be a safe and effective drug for tinea corporis and cruris in these patient be applied morning and evening for 3–4 weeks. Topical imidazoles are
groups.25,26 also effective.
TINEA PEDIS PIEDRA

Tinea pedis seldom clears if left untreated. Infection of the webs of the Black piedra can be treated with a topical salicylic acid preparation
toes will often respond to topical terbinafine, applied morning and or an imidazole cream. Relapse is common. Shaving or clipping
evening for 1–2 weeks. Topical imidazoles can also be used, but they the affected hairs is often sufficient to clear white piedra. To prevent
are less effective and must be applied for at least 4 weeks.27 The recur- recurrence, an imidazole lotion can be applied to the scalp after
rence rate following topical treatment is quite high and it is not shampooing.
uncommon for chronic infection to persist.
If the disease involves the soles or if there is acute inflammation,
oral treatment should be given. Terbinafine 250 mg/day for 2 weeks ONYCHOMYCOSIS
has been shown to be effective in tinea pedis. Itraconazole 100 mg/day Systemic treatment is almost always more successful than topical treat-
is an alternative, but it must be given for 4 weeks.28 A recent systematic ment, which should only be used in superficial white onychomycosis,
review suggested that terbinafine is more effective than griseofulvin; possibly in very early distal lateral subungual infection, or when sys-
no significant difference was detected between terbinafine and itracon- temic treatment is contraindicated.32 Topical applications of tiocon-
azole, or between fluconazole and itraconazole, although the trials were azole, amorolfine or ciclopirox solution should be continued for at
small.29 Chronic tinea pedis is often associated with nail infection. least 6 months for fingernails and 12 months or longer for toenails.
Inadequate treatment of onychomycosis may result in reinfection of Once daily topical treatment for 48 weeks with efinaconazole 10%
the feet. Terbinafine has been reported to be a safe and effective drug solution may be useful for the management of distal lateral subungual
for tinea pedis in AIDS.25,26 onychomycosis.33 Oral terbinafine is the treatment of choice for proven
dermatophyte infections of the nail (tinea unguium).34 However, it is
TINEA MANUUM not appropriate for Candida infections, nondermatophytic mold infec-
Local treatment with an imidazole or an allylamine will often suffice tions or mixed infections.35 Pulsed treatment with terbinafine (250 mg
to clear tinea manuum. In cases that fail on topical preparations, oral twice daily for 1 week each month for 3–4 months) is at least as effec-
treatment is indicated. Infections of the palms are difficult to clear with tive as continuous treatment while offering potential improvements in
griseofulvin, but oral terbinafine 250 mg/day for 2–6 weeks is highly patient compliance and cost-effectiveness.36,37 The dose for continuous
effective.30 Itraconazole 100 mg/day for 4 weeks is an alternative. treatment is 250 mg/day for a period of 6–12 weeks for fingernails and
3–6 months for toenails. Oral terbinafine will also clear any associated
CANDIDIASIS skin infection without the need for additional topical treatment. Ter-
Most patients with cutaneous candidiasis will respond to topical treat- binafine 250 mg/day for 3 months is effective in the treatment of
ment with terbinafine or an imidazole such as clotrimazole or micon- dermatophyte infections of the nail in AIDS patients. No drug interac-
azole, applied for 2–4 weeks. However, relapse is common if any tions or significant adverse effects related to the drug have been
underlying problem is not controlled. If the infection is associated with reported.38
an underlying skin disease, such as flexural eczema or diaper derma- Itraconazole is licensed for the oral treatment of nail infections at
titis, treatment with a combination preparation containing an azole a dose of 200 mg/day for 3–6 months. Pulsed treatment with itracon-
agent together with hydrocortisone is often helpful. azole is as effective as continuous treatment. Itraconazole has a broader
Long-term treatment with itraconazole or fluconazole has helped spectrum than terbinafine and is more appropriate in nondermato-
many patients with chronic mucocutaneous candidiasis. However, pro- phyte or mixed nail infections.35 However, itraconazole interacts with
tracted treatment has led to the development of azole-resistant strains a number of other drugs (e.g., protease inhibitors in AIDS) and this
of C. albicans.31 can limit its usefulness.
Oral griseofulvin is only effective in dermatophytosis. It is no longer
PITYRIASIS VERSICOLOR a first-line choice for toenail infections, but it works quite well in fin-
If left untreated, pityriasis versicolor will persist for long periods. Most gernail infections if given over 6–9 months. It must be taken until the
patients respond to topical treatment with terbinafine, azole agents or affected nail has fully grown out. It has a number of side effects and
selenium sulfide shampoo, but more than half relapse within 12 can interact with other medications.
months. Oral treatment with itraconazole 200 mg/day for 1 week is Most Candida nail infections will respond to topical treatment,
indicated for extensive or recalcitrant lesions. Oral terbinafine and particularly those associated with paronychia. An imidazole lotion
griseofulvin are ineffective. alternating with an antibacterial lotion is usually effective.32 Itracon-
azole 400 mg/day once daily for 1 week each month for 2 months is
MALASSEZIA FOLLICULITIS the most effective agent for treatment of candidiasis of the fingernails.
Treatment with a topical imidazole or selenium sulfide is often effec- Fluconazole is not licensed for fungal nail disease, but it is sometimes
tive, but oral treatment with itraconazole 200 mg/day for 1–2 weeks useful in severe Candida nail infections.
Other interventions include chemical dissolution of the nail using Oral antifungal treatment of onychomycosis can be followed with
40% urea paste and, in rare instances, surgical removal of the nail. topical terbinafine or ciclopirox nail solution in an attempt to prevent
Surgical removal is a painful and disfiguring procedure that should be recurrence.
reserved for cases where there are either contraindications to the use
of systemic antifungal agents or a drug-resistant fungus is present. References available online at expertconsult.com.
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controlled trials. J Am Acad Dermatol 2008; 59:41-54. 25:126-134. versus continuous terbinafine for onychomycosis: a ran-
Fuller L.C., Barton R.C., Mohd Mustapa M.F., et al.: British Roberts D.T., Taylor W.D., Boyle J.: Guidelines for treatment domized, double-blind, controlled trial. J Am Acad Der-
Association of Dermatologists’ guidelines for the man- of onychomycosis. Br J Dermatol 2003; 148:402-410. matol 2005; 53:578-584.
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8. 26. Elewski B., Smith S.: The safety and efficacy of terbin- ciency syndrome: treatment with terbinafine. Br J
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Mod Med 1971; 10:758-761. 27. Evans E.G.V., Dodman B., Williamson D.M., et al.:
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British Association of Dermatologists’ guidelines for the tinea pedis. Br Med J 1993; 307:645-647.
PRACTICE
POINT
1 Management of Infected Diabetic

Foot Ulcers
EDGAR J.G. PETERS | BENJAMIN A. LIPSKY
Introduction are unreliable. Specimens of deep tissue, obtained after cleaning and
debridement and by curettage or biopsy, provide more accurate culture
The estimated incidence of developing a foot infection in persons with results. An aspiration of purulent secretions is also reliable. In osteo-
diabetes ranges from an overall lifetime risk of 4% (in Dutch family myelitis a specimen of bone, obtained by percutaneous biopsy (but not
practices) to 7% yearly (in high-risk American patients). The usual through the wound base) or by surgical excision, is more reliable than
point of entry for pathogens is a wound, especially a neuropathic or that of soft tissue. Several studies have shown that results of superficial
neuroischemic ulcer. Unless promptly and appropriately treated, infec- swab cultures do not correlate well with those of bone specimens. The
tion can spread contiguously to underlying tissues, including bone. probe-to-bone test (palpating for bone with a blunt, sterile metal
Diabetic foot infections are the leading cause of diabetes-related hos- probe) suggests osteomyelitis when positive in a patient with high pre-
pitalization and account for about 60% of lower-extremity amputa- test probability and usually rules out osteomyelitis when negative in a
tions in higher-income countries. Risk factors for a diabetic foot patient with low pretest probability. Both the sensitivity and specificity
infection include: >30-day duration of foot ulceration; history of of plain radiographs for diagnosing osteomyelitis are <75%. Among
recurrent foot ulcers; wound caused by trauma; previous lower extrem- imaging tests, magnetic resonance imaging (MRI) is the most useful
ity amputation; peripheral sensory neuropathy; renal insufficiency; for detecting soft tissue or bone infection, with sensitivity and specific-
and walking barefoot. ity of ~90%. Nuclear medicine (especially bone) scans are much less
specific than MRI. High-resolution ultrasonography may be helpful
Clinical Features of Diabetic for detecting soft tissue abscesses or sinus tract formation.
Foot Infection
The presence of infection in a diabetic foot wound is diagnosed by Microbiology
clinical parameters, i.e., classic signs and symptoms of inflammation, Mild infections in patients who have not recently been treated with
not microbiological tests. Unfortunately, foot ischemia, peripheral antibiotics are often caused by single organisms, usually aerobic gram-
neuropathy and diminished leukocyte function are often present in positive cocci, i.e. Staphylococcus aureus and/or β-hemolytic strepto-
diabetes and may alter or obscure the clinical and laboratory findings. cocci. In moderate and severe infections, especially those previously
A simple, but validated classification scheme for severity of infection treated, the presence of additional pathogens cannot be safely excluded.
(Table PP1-1) helps to predict need for hospitalization and clinical These infections, especially when chronic, are usually polymicrobial,
outcome and to guide therapeutic interventions. including gram-positive cocci, enterobacteriaceae, sometimes nonfer-
mentative gram-negative rods (Pseudomonas spp.) and, especially in
DIAGNOSTIC TESTS those with gangrene or ischemia, obligate anaerobes. Consider
Determining the causative pathogens and their antibiotic sensitivities methicillin-resistant Staph. aureus (MRSA) or extended spectrum
is essential for guiding antimicrobial therapy. Because open wounds β-lactamase producing gram-negative rods when there is a high local
may be colonized by nonpathogens, results of a superficial swab culture incidence of these organisms. Pseudomonas species are more often
TABLE
PP1-1 Infectious Diseases Society of America (IDSA) and PEDIS Classification on Diabetic Foot Infection
PEDIS* IDSA Infection
Clinical Manifestation of Infection Grade Severity
No symptoms or signs of infection 1 Uninfected
Infection involving the skin and the subcutaneous tissue only (without involvement of deeper tissues and without systemic 2 Mild
signs as described below). At least two of the following items are present:
Local swelling or induration
Erythema >0.5–2 cm around the ulcer
Local tenderness or pain
Local warmth
Purulent discharge (thick, opaque to white, or sanguineous secretion)
Other causes of an inflammatory response of the skin are excluded (e.g., trauma, gout, acute Charcot neuro-osteoarthropathy,
fracture, thrombosis, venous stasis)
Erythema >2 cm plus one of the items described above (swelling, tenderness, warmth, discharge) or 3 Moderate
Infection involving structures deeper than skin and subcutaneous tissues such as abscess, osteomyelitis, septic arthritis, fasciitis
No systemic inflammatory response signs, as described below
Any foot infection with the following signs of a systemic inflammatory response syndrome. This response is manifested by two 4 Severe
or more of the following conditions:
Temperature >38 °C or <36 °C
Heart rate >90 beats/min
Respiratory rate >20 breaths/min or PaCO2 <32 mm Hg
White blood cell count >12 000 or < 4.0 x 109/L or 10% immature (band) forms
*PEDIS = perfusion, extent (size), depth (tissue loss), infection and sensation (neuropathy).
From Peters E.J., Lipsky B.A.: Med Clin North Am 2013; 97(5):911–946
130
Practice Point 1 Management of Infected Diabetic Foot Ulcers 131
pathogens in patients from hot climates or who have frequent expo- biomechanical pressure offloading (preferably with a total contact cast
sure of their feet to water. or other irremovable offloading device), often one or more surgical
procedures (e.g., necrotectomy, abscess drainage, bone excision) and
Therapy sometimes revascularization (by percutaneous intravascular tech-
Clinically uninfected diabetic foot wounds do not require antimicro- niques or open arterial bypass surgery).
bial therapy; available evidence does not support treatment to either The choice of an empiric antibiotic regimen must take into
improve healing or prevent infection. Unwanted effects of this antibio account the likely causative pathogen(s), patient-specific issues (e.g.,
tic overtreatment include higher treatment costs, development of allergies, renal impairment) and published evidence of efficacy, but is
antimicrobial resistance, and complications such as Clostridium largely based on infection severity. Suggested empirical regimens,
difficile-associated diarrhea and allergic reactions. Antimicrobial partly based on a systematic review of therapeutic options, are shown
therapy is necessary, albeit not sufficient, to cure most infections. in Table PP1-2. No single antimicrobial regimen has been found
Treatment typically also requires appropriate sharp debridement, to be most effective. Therapy should be culture-based and as
TABLE
PP1-2 Suggested Empiric Antibiotic Regimens Based on Clinical Severity for Diabetic Foot Infections
Infection Severity Likely Pathogen Antimicrobial Agent Comment
Mild (Usually Staphylococcus aureus Dicloxacillin or flucloxacillin QID dosing, narrow spectrum, inexpensive
Treated with Oral (MSSA), Streptococcus
Antibiotics) spp. Clindamycin Usually active against community-acquired MRSA, consider
ordering a D-test before using for MRSA. Inhibits protein
synthesis of some toxins
Cephalexin QID dosing, inexpensive
Levofloxacin Once-daily dosing, suboptimal against Staph. aureus
Amoxicillin/clavulanate Relatively broad-spectrum oral agent, includes anaerobic coverage
MRSA Doxycycline or minocycline Active against many MRSA and some gram-negative organisms,
uncertain against Streptococcus spp.
Trimethoprim-sulfamethoxazole Active against MRSA and some gram-negatives. Uncertain activity
against Streptococcus spp.
Moderate (Oral or MSSA, Streptococcus spp., Levofloxacin Once-daily dosing, suboptimal against Staph. aureus
Initial Parenteral Enterobacteriaceae,
Antibiotics) or obligate anaerobes Cefoxitin Second-generation cephalosporin with anaerobic coverage
Severe (Usually
Ceftriaxone Once-daily dosing, third-generation cephalosporin
Treated with
Parenteral Ampicillin/sulbactam or Adequate if low suspicion of Pseudomonas aeruginosa
Antibiotics) amoxicillin/clavulanate
Moxifloxacin Once-daily oral dosing. Relatively broad-spectrum, including most

obligate anaerobic organisms
Ertapenem Once-daily dosing. Relatively broad-spectrum including

anaerobes, but not active against P. aeruginosa
Levofloxacin or ciprofloxacin Limited evidence supporting clindamycin for severe Staph. aureus
with clindamycin infections; po and iv formulations for both drugs
Imipenem–cilastatin Very broad-spectrum (but not against MRSA); use only when this
is required. Consider when ESBL-producing pathogens
suspected
MRSA Linezolid Expensive; increased risk of toxicities when used >2 wk
Daptomycin Once-daily dosing. Requires serial monitoring of CPK
Vancomycin Vancomycin MICs for MRSA are gradually increasing
Pseudomonas aeruginosa Piperacillin–tazobactam TID/QID dosing. Useful for broad-spectrum coverage. P.

aeruginosa is an uncommon pathogen in diabetic foot infections
except in special circumstances
MRSA, Enterobacteriaceae, Vancomycin,* ceftazidime, Very broad-spectrum coverage. Usually only used for empiric
Pseudomonas spp., and cefepime, piperacillin/ therapy of severe infection. Consider addition of obligate
obligate anaerobes tazobactam, aztreonam, or a anaerobe coverage if ceftazidime, cefepime, or aztreonam
carbapenem selected
Narrow-spectrum agents (e.g., vancomycin, linezolid, daptomycin) should be combined with other agents (e.g., a fluoroquinolone) if a polymicrobial infection
(especially moderate or severe) is suspected.
Use an agent active against MRSA for patients who have a severe infection, evidence of infection or colonization with this organism elsewhere, or epidemiological risk
factors for MRSA infection.
Select definitive regimens after considering the results of culture and susceptibility tests from wound specimens, as well as the clinical response to the empiric
regimen.
Similar agents of the same drug class can probably be substituted for suggested agents.
D-test = double disk diffusion assay for inducible clindamycin resistance.
Some of these regimens do not have FDA approval for complicated skin and skin structure infections.
*Daptomycin or linezolid may be substituted for vancomycin.
Abbreviations: CPK, creatine phosphokinase; ESBL, extended-spectrum β-lactamase; FDA, US Food and Drug Administration; iv, intravenous; MIC, minimum
inhibitory concentration; MRSA, methicillin-resistant Staph. aureus; MSSA, methicillin-sensitive Staph. aureus; po, oral; QID, 4 times a day; TID, 3 times a day.
Based on IDSA Guideline, from Lipsky B.A., et al.: Clin Infect Dis 2012; 54(12):e132–173
narrow-spectrum and short-duration as possible. Duration of treat- no studies of the optimal route (i.e., oral or parenteral) of treatment
ment for soft tissue infections is usually 1–2 weeks for mild infections for soft tissue or bone infections. While there are no studies on the
and 2–4 weeks for severe infections. Mild infections are usually need for hospitalization, we suggest it is usually appropriate for those
treated with oral agents, severe infections typically require parenteral patients who have a severe foot infection, who are clinically unstable
treatment, at least initially, followed by oral treatment. Duration of or who, for social or medical reasons, require close supervision (e.g.,
treatment for osteomyelitis depends on the degree of resection of blind or disabled patients or those with a poor family or social
infected bone: 2–5 days when all infected bone has been resected; 1–3 network). Hospitalized patients can be discharged when their clinical
weeks when there is residual soft tissue but not bone infection; 4–6 situation improves and any further treatment can be done on an
weeks in case of infected, but viable bone; and up to 3 months when ambulatory basis.
there is residual necrotic bone. These suggested durations are pre-
dominantly based on expert opinion, as there are few published Further reading available online at expertconsult.com.
studies. A recent systematic review of diabetic foot infections found
Practice Point 1 Management of Infected Diabetic Foot Ulcers 132.e1
FURTHER READING
Dinh M.T., Abad C.L., Safdar N.: Diagnostic accuracy of the Lipsky B.A., Aragón-Sánchez J., Diggle M., et al.: Interna- in diabetes: a systematic review. Diabetes Metab Res Rev
physical examination and imaging tests for osteomyelitis tional Working Group on the Diabetic Foot (IWGDF). 2016; 32(Suppl. 1):145-153.
underlying diabetic foot ulcers: meta-analysis. Clin Infect IWGDF guidance on the diagnosis and management of Senneville E., Melliez H., Beltrand E., et al.: Culture of per-
Dis 2008; 47(4):519-527. foot infections in persons with diabetes. Diabetes Metab cutaneous bone biopsy specimens for diagnosis of dia-
Lipsky B.A., Berendt A.R., Cornia P.B., et al.: Infectious Dis- Res Rev 2016; 32(Suppl. 1):45-74. betic foot osteomyelitis: concordance with ulcer swab
eases Society of America Clinical Practice Guideline for Peters E.J., Lipsky B.A., Aragón-Sánchez J., et al.: Interna- cultures. Clin Infect Dis 2006; 42(1):57-62.
the Diagnosis and Treatment of Diabetic Foot Infections. tional Working Group on the Diabetic Foot (IWGDF).
Clin Infect Dis 2012; 54(12):e132-e173. Interventions in the management of infection in the foot
PRACTICE
POINT
2 Managing the Patient with Recurring

Skin Infections
THUSHAN I. DE SILVA | STEPHEN T. GREEN
Background sites, such as the vulva and perianal region (sometimes in association
with Enterobius vermicularis), can also be problematic.
Skin infections come in many forms. Most commonly, troublesome To make matters more complex, cellulitis of the lower extremities
skin infection is synonymous with cellulitis, an entity that illustrates is more likely to be complicated by thrombophlebitis in elderly patients,
the cardinal signs of inflammation. Cellulitis is an acute, usually non- which in turn can encourage recurrence of cellulitis.
contagious, inflammation of the connective tissue of the skin, resulting A number of clinical scenarios and risk activities render patients
from bacterial infection and characterized by localized warmth, ery- particularly vulnerable to recurrent episodes of cellulitis. These include:
thema, pain and tenderness, swelling and reluctance to mobilize the
affected area (Figure PP2-1). When such a problem is recurrent, this
• tinea pedis or onychomycosis;
can become extremely tiresome and even disabling.
• fissures between toes;
Cellulitis is usually consequent upon a break developing in the skin
• diabetes mellitus – there may be a family history;
surface or its appendages, such as a laceration, cut, fissure, puncture
• peripheral vascular (arterial) disease – there may be a history of
smoking, angina pectoris and/or hypertension;
wound, insect bite, animal or human bite, scratch, abrasion, blisters or
friction burn, such as might occur with shoes that are too tight. Organ-
• ischemic or venous ulceration of the skin (including sickle cell
disease);
isms normally confined to the skin surface are admitted to the dermis
where they proliferate and lead to cellulitis.
• post-deep venous thrombosis;
• eczema and dermatitis;
Recurrent Cellulitis • immunodeficiency states, for example patients with HIV infec-
tion, neutropenia (granulocytopenia), Job’s syndrome (hyper IgE
Recurrent cellulitis may occur due to factors facilitating the recurrent syndrome with recurrent staphylococcal cellulitis) or use of
entry of organisms into the dermis or, less commonly, impaired immunosuppressive or corticosteroid drugs – always establish
host immunity. Effective management of recurrent cellulitis involves the medication history;
identifying these factors and, if possible, remedying them. Recurrent • lymphatic obstruction, for example post-radiotherapy (e.g. post-
cellulitis may cause local persistent lymphedema, resulting in perma- mastectomy), post-block dissection of lymph nodes for cancer
nent hypertrophic fibrosis, as well as further increasing the risk of (Figure PP2-2), elephantiasis (e.g. due to infections by Wucher-
recurrences. eria bancroftii, Brugia malayi, Onchocerca volvulus) or Milroy’s
Most often the lower limbs are involved in recurrent cellulitis. The disease;
site may be the arm if, for example, the patient has received radio- • scar cellulitis (e.g. previous burn or skin graft sites and in areas
therapy to the axillary area as part of breast cancer treatment. Other from which veins were harvested for coronary artery bypass
grafting);
• trauma related, for example cosmetic piercings (studs, rings),
intravenous drug users, recurrent localized trauma, self-harm or
Munchausen’s syndrome;
• nasal carriage of staphylococci;
• lepromatous leprosy;
• underlying occult osteomyelitis;
• very poor personal hygiene (e.g. associated with alcoholism);
and
• morbid obesity – largely associated with recurrent lower limb
cellulitis (see Figure PP2-1).
Microbiology
In immunocompetent individuals, cellulitis is most often the result of
gram-positive aerobic cocci, particularly Staphylococcus aureus and
Streptococcus pyogenes, or sometimes a combination of both. It can be
clinically difficult to decide which of them is the causative organism.
Non-group A streptococci, particularly groups B, C and G, are some-
times implicated.
Some Staph. aureus strains may produce the Panton–Valentine leu-
kocidin toxin (PVL), a cytotoxin that causes leukocyte destruction and
tissue necrosis. Outbreaks of recurrent cellulitis, boils and abscesses
have been reported within families by this strain. In particular, epi
demics of PVL-producing community-acquired methicillin-resistant
Staph. aureus (MRSA) have occurred. Awareness of the high transmis-
sibility and virulence of the PVL-producing strain is crucial in avoiding
recurrence, eradicating reservoirs and preventing severe complications
Figure PP2-1 Severe recurrent cellulitis associated with obesity. such as necrotizing pneumonia.
133
Figure PP2-3 Mixed Aspergillus and Prototheca cellulitis in a neutropenic

patient.
Figure PP2-2 Severe recurrent cellulitis in a lymphedematous leg following

radical surgery for rhabdomyosarcoma.
Recurrent cellulitis due to streptococci may be seen in association

with chronic lymphedema (e.g. from lymph node dissection, post-
irradiation, Milroy’s disease, or elephantiasis).
Neutropenic patients may develop cellulitis due to other organ-
isms, such as gram-negative bacilli (e.g. Proteus, Serratia, Enterobacter
spp.) and fungi. Rarely, the infection can be mixed with fungal and
algal species (e.g. Aspergillus and Prototheca spp., Figure PP2-3). Cam-
pylobacter species may cause both sepsis and cellulitis in hypogam-
maglobulinemic patients. The organism is often isolated from tissue
biopsies and blood cultures.
Other organisms may be involved as part of a mixed picture,
depending upon the source of the organisms. Incontinent patients
may contaminate their lower limbs with urine and feces while intra-
venous drug users can inoculate their own tissues (Figure PP2-4) with
a variety of organisms from contaminated needles. Patients whose
cellulitis is the result of deliberate self-harm may also yield multiple
organisms on culture. This is an extremely difficult diagnosis to make
and requires the highest levels of clinical acumen. For example, self-
inoculation with milk has been reported as the cause of recurrent
cellulitis.
Is It Really Cellulitis?
Sometimes the apparent recurrent cellulitis problem may not in fact
be cellulitis, and the following should be considered:
• acute gout can resemble recurrent cellulitis and certain diuretics
may predispose to gout;
• recurrent deep venous thrombosis; Figure PP2-4 Intravenous drug user with severe recurrent cellulitis of the left
arm.
• migratory necrolytic erythema associated with underlying neo-
plasia, particularly glucagonoma of the pancreas;
• inflammatory carcinoma of the breast, which produces a picture • palmoplantar pustulosis and pyoderma gangrenosum, such as
of localized cellulitis unresponsive to antibiotics; that associated with inflammatory bowel disease, can be mis-
• herpes zoster, which can cause recurrent rash that may be com- taken for cellulitis;
plicated by superinfection; • scurvy and pellagra; and
• erythema nodosum, especially if it recurs; • fixed drug eruptions.
Practice Point 2 Managing the Patient with Recurring Skin Infections 135
Assessment and Diagnosis • where allergy to β-lactam drugs is an issue – macrolides, clinda-
mycin, levofloxacin or moxifloxacin;
Unless pus has formed or an open wound is present, it is often difficult
to isolate the responsible organism from a case of cellulitis. Aspiration
• where outpatient parenteral antibiotic therapy (OPAT) is an
option – ceftriaxone, daptomycin and telavancin offer once daily
of material from the advancing edge of the lesion, skin biopsy and dosing and dalbavancin is dosed once weekly;
blood cultures yield potential pathogens in only about 25% of cases.
The etiology of most cases of cellulitis will usually be Staph. aureus
• where MRSA is an issue – oral options include linezolid or
tedizolid, doxycycline or minocycline, and rifampin (rifampicin)
and/or Strep. pyogenes. or co-trimoxazole depending on sensitivities; several intravenous
In unusual circumstances, such as patients who are immunocom- options are now available including vancomycin, daptomycin,
promised or those not responding to empiric therapy, or indeed when- ceftaraline, telavancin, dalvabancin, tigecycline and quinupristin–
ever the clinical history points toward other infective or noninfective dalfopristin;
diagnostic options, further investigations may be warranted. This may
become particularly important where the patient is suffering recurrent
• where anaerobes are an issue – metronidazole, clindamycin, line-
zolid or quinupristin–dalfopristin; and
attacks. For example, among those with peripheral vascular disease or
diabetes mellitus, minor injuries or cracked skin in the feet or toes can
• where Campylobacter spp. are an issue – macrolides, quinolones
or carbapenems, with treatment according to sensitivities.
serve as an entry point for recurrent infection. Surgical care includes debridement of devitalized tissue. Incision
Attention should accordingly be directed toward establishing the and drainage may be indicated if suppuration occurs. Treat local effects
presence or absence of factors that might be supporting the develop- of cellulitis by elevating the affected limb.
ment of recurrent cellulitis and might be amenable to correction.
The following range of tests can be applied selectively according to PREVENTION OF RECURRENCES
circumstances: Adequate patient education and training are essential.
• microbiologic – swabs from areas of abscess or bullae formation, Skin and foot care for tinea pedis and onychomycosis includes:
needle aspiration of the advancing edge of cellulitis or full skin
biopsy for culture, interdigital skin and/or nail scrapings (espe-
• patient training regarding proper skin hygiene and suitable
footwear;
cially where tinea pedis is present), blood culture (positive in
only a few patients), nasal swabs (especially for Staph. aureus
• treating affected toe webs or feet with topical antifungals;
carriage, including methicillin-resistant Staph. aureus (MRSA)),
• consideration of oral antifungals such as terbinafine for severe
chronic tinea pedis or onychomycoses; and
perianal cellophane tape (for Enterobius ova), throat swab (for
Strep. pyogenes in those with erythema nodosum) and bullous
• expert podiatry – cuts and fissures should be washed and kept
clean while healing.
fluid (including polymerase chain reaction for herpes simplex For cases caused by edema, treat any underlying cause (e.g. cardiac
and varicella-zoster viruses); failure, filariasis) and relieve edema using support stockings, special-
• imaging – tissue scanning (plain radiographs, ultrasound, com- ized bandaging and nocturnal elevation of the affected area. Diuretics
puted tomography, magnetic resonance imaging) may identify may have a role.
collections of pus meriting drainage, foreign bodies or underly- Immunocompromised patients will remain vulnerable to recurrent
ing osteomyelitis (if gas is seen in the tissues, the differential infections and therefore may need prolonged antibiotics until their
diagnosis includes gangrene and fasciitis, which are generally immune status improves.
considered to be surgical emergencies), Doppler scans (which Both a meta-analysis and a randomized controlled trial of antibi-
may assist in identifying deep venous thrombosis or peripheral otic prophylaxis in patients with recurrent episodes of cellulitis suggest
arterial disease); a benefit, which may also be a cost-effective strategy. Oral penicillin V
• hematologic and immunologic – blood films (macrocytosis asso- may be an appropriate option, although the protective effect may
ciated with alcohol excess and microfilaria in suspected filariasis), diminish once prophylaxis is stopped and may also be less effective in
differential white cell count (to identify neutropenia, eosino- those with a high body mass index, multiple previous episodes or
philia, e.g. in filariasis), hemoglobin electrophoresis in sickle cell lymphedema. Early institution of antibiotics may represent an alterna-
disease, immunoglobulin levels and subsets, complement levels, tive strategy. The patient must be trained to spot the early signs of
T-cell subsets; recurrence, and given a supply of antibiotics (such as amoxicillin or
• serology – HIV-1 and HIV-2, antistreptolysin and anti-DNAse B flucloxacillin) to take. They should be advised to seek medical advice
titers, hepatitis C, hepatitis B (may point toward occult intrave- as soon as possible.
nous drug abuse), filariasis, onchocerciasis if the patient is at risk; Decolonization of Staph. aureus carriage can be attempted with a
• biochemistry – blood glucose, urate levels, liver function tests; and regimen such as intranasal mupirocin and chlorhexidine body washes
• skin biopsy – may help with rarer causes of cellulitis. if it is thought to be associated with recurrent disease.
Management Conclusion
MANAGING THE ACUTE PHASE Recurrent cellulitis is responsible for much morbidity. Diagnosis is
OF RECURRENCES not always straightforward and it presents a significant management
Elevation of the affected limb is important. Tissue penetration sufficient challenge.
to achieve adequate local antibiotic concentrations can be problematic.
For acute exacerbations, intravenous therapy may therefore be neces- Further reading available online at expertconsult.com.
sary. A useful agent is flucloxacillin.
Other antibiotics may be indicated, depending upon the clinical
scenario:
Practice Point 2 Managing the Patient with Recurring Skin Infections 135.e1
FURTHER READING
Adler A., Temper V., Block C.S., et al.: Panton–Valentine Green S.T.: Infections and tropical diseases: Oxford handbook Mattia A.R.: Perianal mass and recurrent cellulitis due to
leukocidin-producing Staphylococcus aureus. Emerg Infect of clinical and laboratory investigation. Oxford: Oxford Enterobius vermicularis. Am J Trop Med Hyg 1992;
Dis 2006; 12:1789-1790. University Press; 2002:257-302. 47:811-815.
Baddour L.M.: Recent considerations in recurrent cellulitis. Hook E.W. 3rd, Hooton T.M., Horton C.A., et al.: Microbio- Oh C.C., Ko H.C., Lee H.Y., et al.: Antibiotic prophylaxis for
Curr Infect Dis Rep 2001; 3:461-555. logical evaluation of cutaneous cellulitis in adults. Arch preventing recurrent cellulitis: a systematic review and
Baddour L.M., Bisno A.L.: Recurrent cellulitis after saphe- Intern Med 1986; 146:295-337. meta-analysis. J Infect 2014; 69(1):26-34.
nous venectomy for coronary bypass surgery. Ann Intern Kerstens P.J., Endtz H.P., Meis J.F., et al.: Erysipelas-like Thomas K.S., Crook A.M., Nunn A.J., et al.: Penicillin to
Med 1982; 97:493-556. skin lesions associated with Campylobacter jejuni septi- prevent recurrent leg cellulitis. N Engl J Med 2013;
Buckley D.A., Barnes L.: Vulvar lymphangiectasia due to caemia in patients with hypogammaglobulinaemia. Eur J 368(18):1695-1703.
recurrent cellulitis. Clin Exp Dermatol 1996; 21:215-216. Clin Microbiol Infect Dis 1992; 11(9):842-847.
SECTION 2 Syndromes by Body System: The Lymphatic System
15
Lymphadenopathy
ETHAN RUBINSTEIN† | YOAV KEYNAN
KEY CONCEPTS • the paracortical region, underneath the cortex, which is com-
posed mainly of T lymphocytes and dendritic cells; and
• An enlarged lymph node should lead to a detailed history and
physical examination of all palpable lymph node stations.
• the medulla, the innermost region, containing fewer lympho-
cytes than the other two regions but more plasma cells that
• Localized lymphadenopathy should trigger a search for etiol- secrete immunoglobulins.
ogy in the catchment area of the affected node. Afferent lymphatic vessels empty the lymph drained from the tissues
into the subcapsular sinus; from there the lymph flows through the
• The location of an enlarged node may provide diagnostic clues cortex, paracortex and medulla, allowing phagocytic and dendritic
as to the etiology.
cells to trap any foreign material. The efferent lymphatic vessels carry
• Generalized adenopathy (involving three or more lymph node lymph rich in lymphocytes and antibodies into the circulatory system.
groups) should always be investigated with imaging, to assess The lymph node has two functions:
lymph nodes that are not within reach, and with further specific • it acts as a defensive barrier; and
tests. • it serves as a factory for lymphocyte maturation and differentia-
• Localized lymphadenopathy, persisting for more than a month, tion and as an antibody production site during antigenic
in the presence of constitutional symptoms should be consid- challenge.
ered for biopsy.
LYMPHADENITIS
• Localized or generalized lymphadenopathy of unknown cause Lymphadenitis is an inflammation of the lymph node. The initial
requires HIV testing as part of the diagnostic investigations.
phase of an acute inflammation consists of swelling and hyperplasia
The human lymphatic system

Introduction
The body has approximately 600 lymph nodes, but only those in the
cervical, submandibular, axillary or inguinal regions are normally pal-
pable in healthy people. Lymphadenopathy is a change in the size and/
Preauricular
or consistency of a lymph node or lymph node group (regional lymph-
adenopathy), or may be generalized involving multiple sites and mul- Postauricular
tiple lymph node groups. The lymph node system is the major
component of the body’s surveillance system against foreign invaders Submental Suboccipital
and functions as the hub where antigen-presenting cells interact with
lymphoid cells to generate an adaptive immune response against Submandibular
Supraclavicular
myriad foreign antigens including microbial pathogens, tumor cells, Cervical
immune complexes and foreign material.
The lymphoid system grows rapidly during childhood and achieves
twice the adult size in early adolescence. Thereafter it starts regressing,
reaching adult maturity at about the age of 20–25 years. Lymphade- Axillary nodes
nopathy, particularly peripheral, is thus a common finding in child-
hood, adolescence and young adulthood.1 Lymphadenopathy may
be divided into acute and chronic lymphadenitis, i.e. inflammatory
lymphadenopathy, lymphadenopathy that accompanies lymphoprolif-
erative disease, infiltrative lymphadenopathy secondary to malignant
disease and reactive lymphadenopathy that may be infectious or Mesenteric
noninfectious. Table 15-1 summarizes the differential diagnosis of
lymphadenopathy.
Lumbar nodes
Pathogenesis and Pathology
THE NORMAL LYMPH NODE Rectosacral nodes
Lymph nodes are widely distributed throughout the human body,
particularly at potential portals (Figure 15-1). The normal lymph node
is an oval, encapsulated, soft structure, 1–2 cm in diameter with an
average weight of approximately 1 g. Inguinal nodes
Histologically the lymph node can be divided into three regions
(Figure 15-2):2
• the cortex, the outermost layer, which is composed mainly of B
lymphocytes and macrophages arranged in primary follicles;
†
Deceased Figure 15-1 The human lymphatic system.
136
Chapter 15 Lymphadenopathy 137
TABLE
15-1 Differential Diagnosis of Lymphadenopathy
Etiology Regional Generalized Suppurative/Caseating
INFECTIOUS LYMPHADENOPATHY
Bacterial (Acute)
Streptococcal + +
Scarlet fever + +
Staphylococcal + +
Diphtheria +
Ludwig’s angina +
Tuberculosis + + +
Syphilis + +
Chancroid +
Plague + +
Tularemia + +
Rat-bite fever +*
Anthrax +
Melioidosis +
Glanders + +
Cat-scratch disease + + +
Typhoid fever +
Rickettsial
Boutonneuse fever +*
Scrub typhus +
Rickettsial pox +
Chlamydial
Lymphogranuloma venereum + +
Viral
Measles +
Rubella +
Infectious mononucleosis +
HIV/AIDS +
Cytomegalovirus infection +
Dengue +
West Nile fever +
Lassa fever +
Genital herpes + +
Epidemic keratoconjunctivitis (adenovirus) + +
Pharyngoconjuctival fever (adenovirus) +
Mycotic
Histoplasmosis + +
Coccidioidomycosis +
Paracoccidioidomycosis +
Cryptococcosis + +
Protozoan
Visceral leishmaniasis +
Leishmaniasis + +
Continued on following page

138 SECTION 2 Syndromes by Body System: The Lymphatic System
TABLE
15-1 Differential Diagnosis of Lymphadenopathy (Continued)
Etiology Regional Generalized Suppurative/Caseating
African trypanosomiasis + +
Chagas disease +
Toxoplasmosis + +
Helminthic
Loa loa + + (Bubo)
Onchocerciasis + + (Bubo)
Filariasis +
NONINFECTIOUS LYMPHADENOPATHY
Sarcoidosis +
Connective tissue disorders +
Kawasaki disease + +
Rosai–Dorfman disease + +
Kikuchi’s disease + +
Castleman’s disease + +
Drug hypersensitivity +
Silicone breast implant +
Infiltrative Malignant
Metastatic carcinoma + +
Metastatic melanoma +
Leukemia +
Infiltrative nonmalignant
Lipid storage disease +
Amyloid +
Primary Lymphoproliferative
Lymphoma + +
Angioimmunoblastic lymphadenopathy +
Lymphomatoid granulomatosis +
Malignant histiocytosis +
Drug Induced
Allopurinol, atenolol, captopril, carbamazepine, cephalosporins, gold hydralazine, penicillin, +

phenytoin, primidone, pyrimethamine, quinidine, sulfonamides, sulindac
*Ulceroglandular
of the sinusoidal lining cells and infiltration by leukocytes and edema. infectious in origin. In contrast, lymphadenopathy in adults more
This leads to distention of the node’s capsule which causes local pain. often reflects serious disease. One study revealed a 0.6% annual
The process may progress to abscess formation causing the node to incidence of unexplained lymphadenopathy in the general population.
become fluctuant depending on the causative micro-organism and the Of 2556 patients with unexplained lymphadenopathy, 3.2% required
host response. The node may break into the skin and produce a drain- a biopsy but only 1.1% had a malignancy. The probability of a neo-
ing sinus. Following the infection the node resumes its normal archi- plasm affecting enlarged peripheral lymph nodes increases steadily
tecture or, if severely damaged, may obliterate completely. Acutely with age; in those older than 50 years who are referred for biopsy
inflamed lymph nodes are most commonly caused by entrapped because of longstanding enlarged lymph nodes, more than 60% of
microbes. cases of lymphadenopathy are due to a malignancy.2,3 In contrast, in
Chronic lymphadenitis is typically a proliferative process with primary care settings, patients 40 years of age and older with unex-
either follicular hyperplasia or paracortical lymphoid hyperplasia plained lymphadenopathy have about a 4% risk of cancer versus a
depending on the cause of the inflammation; such nodes are 0.4% risk in patients younger than age 40.4 In tropical and subtropical
nontender. regions leading causes may include parasitic diseases as well as
infections.
Lymphadenopathy is defined as generalized whenever three or
Epidemiology more anatomically discrete groups of lymph nodes are involved. The
In children the cause of lymphadenopathy is apparent in most cases. different infectious etiologies of generalized lymphadenopathy are
In approximately 80% of the cases it is benign, mainly reactive– shown in Table 15-1. Occasionally lymph nodes that are not palpable
may be involved, as is the case with lymph node involvement in tions of the face or neck and, uncommonly, it may be a complication
anthrax or typhoid (abdominal), sarcoidosis and tuberculosis of streptococcal pharyngitis.5 In adults, anaerobic bacteria, of which
(mediastinal). the predominant species are Prevotella spp., Peptostreptococcus spp.,
Viral diseases are the major cause of generalized lymphadenopathy. Propionibacterium acnes and Fusobacterium spp., are recovered in 30%
The bacterial diseases that may cause generalized lymphadenopathy of cervical lymphadenitis cases, 13% are anaerobes alone and 17% are
include tuberculosis, typhoid fever, brucellosis, syphilis and leptospi- mixed anaerobic–aerobic bacteria.6
rosis. In the differential diagnosis of generalized lymphadenopathy Acute pyogenic cervical lymphadenitis is unilateral. In contrast,
important parameters are the age of the patient, epidemiologic factors, acute bilateral cervical lymphadenitis is commonly due to viral upper
relevant traveling, contact with sick individuals, accompanying signs respiratory infection, infectious mononucleosis, streptococcal pharyn-
and symptoms (rash, splenomegaly), and laboratory findings. gitis or localized periodontal infections. Acute suppurative axillary
lymphadenitis is a severe infection with prominent systemic manifesta-
Clinical Features tions and axillary pain that radiates to the shoulder and down to the
REGIONAL LYMPHADENOPATHY arm. The axilla, arm, shoulder and supraclavicular and pectoral areas
are markedly edematous, but there are no signs of skin infection or
AND LYMPHADENITIS lymphangitis. The portal of entry of the infecting bacteria (group A
Acute Suppurative Lymphadenitis streptococci or Staph. aureus) is often a traumatic lesion of the arm.7
Acute suppurative lymphadenitis is commonly caused by pyogenic Rapidly enlarging lymph nodes may be accompanied by systemic
infections, arising from draining of the organisms causing the initial manifestations, including toxic shock syndrome, without obvious
focus of infection (especially Staphylococcus aureus or group A strep- genital or skin lesions.8,9
tococci). The most commonly involved sites are the submandibular, Patients who have chronic granulomatous disease experience recur-
cervical, inguinal and axillary lymph node groups. rent pyogenic infections, of which the most common manifestations
The affected lymph node is extremely tender and firm, although it are lower respiratory tract infections, suppurative lymphadenitis, sub-
may be fluctuant, and the overlying skin may be red and warm. There cutaneous abscesses and hepatic abscesses.10 The infecting pathogens
are usually systemic manifestations. Acute cervical lymphadenitis due are catalase-positive organisms such as Staph. aureus, Serratia marce-
to a pyogenic infection is more common in children than adults. In scens, Burkholderia (Pseudomonas) cepacia and Aspergillus spp. The
both children and adults it is commonly due to staphylococcal infec- histologic appearance of the lymph node is one of inflammation with
granuloma formation and necrosis.10,11
Cat-Scratch Disease
The lymph node Cat-scratch disease typically manifests after a cat scratch or bite
as regional lymphadenopathy distal to the involved lymph node.
The mode of transmission is presumably direct contact with the caus-
Afferent ative agent, primarily Bartonella henselae. The disease occurs world-
lymphatic wide, with healthy children and adolescents being most frequently
vessels
affected.12 A history of a trivial cat scratch or a bite by a kitten can
Germinal be elicited in most cases.13 Occasionally, typical cat-scratch disease
center Postcapillary
venule cases can be caused by other pathogenic Bartonella sp. (i.e. Bartonella
clarridgeiae).14
Primary Tender lymphadenopathy develops within 1–3 weeks after inocula-
lymphoid tion. Commonly, an erythematous papule at the site of inoculation
follicle precedes the development of lymphadenopathy and may last for
several weeks. Regional lymph node enlargement is the sole manifesta-
Cortex tion in one-half of the patients. Most commonly the cervical, axillary
Cross-section of or epitrochlear lymph nodes are involved, but any peripheral nodes at
a post-capillary multiple sites may be enlarged. In one-third of the patients, low-grade
Paracortex fever is present, and about 15% have systemic manifestations such as
venule
malaise, headache, splenomegaly and sore throat. Unusual clinical
Medulla
manifestations occur in 10% of patients; the most frequent of these is
Capsule the oculoglandular syndrome of Parinaud,13,15 which is conjunctivitis
Mantle of cells
Lymphatic artery
with ipsilateral preauricular lymphadenitis (Table 15-2). The adenopa-
Efferent lymphatic vessel thy subsides spontaneously within several months. Occasionally, aspi-
Lymphatic vein ration of a suppurative lymph node is needed to relieve pain.
The diagnosis is based on epidemiologic exposure and can be con-
Figure 15-2 The lymph node. firmed by detection of serum antibody to B. henselae.13 Occasional
TABLE
15-2 Oculoglandular Syndromes
Disease Infecting Organism Features
Cat-scratch disease Bartonella henselae Parinaud’s sign in 3%, conjunctivitis in 6%
Tularemia Francisella tularensis Parinaud’s sign in 5%
Lymphogranuloma venereum Chlamydia trachomatis Parinaud’s sign in <1%
Pharyngoconjunctival fever Adenovirus 3,7 Common in children
Epidemic keratoconjunctivitis Adenovirus 8, 19, 37 Occasionally seen in adults

Chagas disease Trypanosoma cruzi Romaña’s sign
Figure 15-3 Tuberculous lymphadenitis of the axilla. Figure 15-4 Bubonic plague, axillary bubo and accompanying edema.
cat-scratch disease cases caused by other pathogenic Bartonella may,

however, be serologically negative.14 TABLE Differential Diagnosis of Infectious Inguinal
In atypical presentations or whenever a neoplastic or mycobacterial 15-3 Lymphadenopathy
process is suspected, a lymph node biopsy or aspirate may be needed.
Sexually Transmitted Diseases Other Diseases
Mycobacterial Lymphadenitis Syphilis Pyogenic infections
This is the most common form of extrapulmonary tuberculosis in the
Lymphogranuloma venereum Cellulitis
Western world.16 Tuberculous cervical lymphadenitis is caused by
spread of Mycobacterium tuberculosis from a lung infection. Scrofula Chancroid Plague
often presents as a one-sided red, painless mass, located along the Genital herpes Filariasis
upper border of the sternocleidomastoid muscle or in the supracla-
vicular area or axilla. In areas in which both tuberculosis and HIV are Granuloma inguinale Onchocerciasis
prevalent, tuberculous lymphadenitis may be the presenting sign in
50% of young children and is often associated with intrathoracic
disease17 (Figure 15-3). Currently most tuberculous lymphadenitis is the discrete lymph nodes become matted together to form the charac-
caused by M. tuberculosis and atypical mycobacteria, particularly M. teristic bubo with extensive surrounding edema (Figure 15-4). The
scrofulosum and M. avium complex (MAC).18 The process is indolent matted lymph nodes are exquisitely tender. Isolation of Y. pestis from
and slowly progressive and is not accompanied by systemic symptoms. an aspirated bubo, blood, bone marrow and multiple organs is possible
If systemic signs appear, or the process is outside the cervical lesion, but bacterial growth is slow; rapid identification can be accomplished
miliary tuberculosis should be suspected. With M. bovis infection the by a characteristic Gram or Wayson stain. Such patients should be
primary focus is usually the tonsil or the pharynx. immediately isolated, reported and treated.22
The diagnosis of mycobacterial lymphadenitis is confirmed micro- Tularemia (see Chapter 127) occurs only in the northern hemi-
biologically and with histology of the afflicted lymph node. Fine needle sphere. Over 80% of infections are acquired by handling infected
aspiration frequently reveals the presence of granuloma but only rarely animals or by tick or deer fly bites. In the Western world most cases
yields smears that are positive or material that is culture positive.18 are sporadic, whereas in other parts of the world large water-borne,
Microbiologic and histologic examinations are complementary as M. arthropod-borne and airborne outbreaks have been reported. Infec-
tuberculosis has been isolated from lymph nodes not showing granu- tion commonly manifests as an ulceroglandular or oculoglandular
loma, and granulomata have occasionally grown atypical mycobacte- syndrome.21 The most common portals of entry are the skin and the
ria. Acid-fast bacilli are only rarely seen in smears except in HIV conjunctiva, with an ulcer or a pustule, or in the case of the conjunctiva
co-infected patients. New diagnostic techniques such as DNA hybrid- or eyelid, conjunctivitis, a papule or an ulcer, developing 1–10 days
ization, polymerase chain reaction (PCR) and blotting techniques hold after exposure. Regional lymphadenopathy follows and the enlarged
promise for more accurate and rapid diagnosis19 (see Chapter 185). lymph nodes may suppurate. Systemic manifestations are common
Lymphadenopathy may occur after initiation of antiretroviral therapy, but systemic toxicity and prostration is absent. Presumptive diagnosis
as a result of immune reconstitution. is made on epidemiologic grounds and confirmed by specific serologic
tests.23
Plague and Tularemia
Both these infections are zoonoses that produce rather similar mani- INGUINAL LYMPHADENOPATHY
festations, mostly fever and regional lymphadenitis.20 Plague and tula- Sexually transmitted diseases (STDs) and metastatic genital neoplastic
remia may be used as bioterrorism agents as they are highly infectious disease are the most common causes of inguinal lymphadenopathy.
when dispersed by the airborne route.21,22 The differential diagnosis of infectious inguinal lymphadenopathy is
Plague is caused by Yersinia pestis (see Chapter 126). Most human shown in Table 15-3.
cases are in the bubonic form transmitted by the bite of infected fleas.
After an incubation period of 2–8 days patients develop sudden fever, Chancroid
chills, malaise and headache. Usually by the same time or within a few Chancroid is caused by Haemophilus ducreyi and in some parts of the
hours, a painfully swollen regional lymph node appears in the draining world (e.g. Thailand) it is one of the most common causes of genital
region of the inoculation site, commonly in the axilla, neck or groin. ulcer with inguinal lymphadenopathy (see Chapter 64). The chancroid
The primary lesion is occasionally found at the bite site and may ulcer is a painful, nonindurated lesion that appears 1 day to several
develop into an area of cellulitis or an abscess. Over the next few days, weeks after inoculation. Inguinal lymphadenitis occurs in between
patient only one chancre appears but in the immunocompromised

patient, especially in patients who have AIDS, multiple chancres may
be seen. In women and homosexual men, the chancre may be located
in the perianal region or in the anal canal. Regional painless lymph-
adenopathy is characteristic at this stage of disease. The chancre usually
heals and disappears after 3–6 weeks, but the lymphadenopathy may
persist for longer. The symptoms of secondary syphilis appear 2–8
weeks after the chancre has healed, with generalized lymphadenopathy
and various skin lesions in the majority of patients. Chancre and sec-
ondary syphilis manifestations may coexist in HIV-infected individu-
als. Epitrochlear lymphadenopathy suggests the diagnosis.26
Genital Herpes
The typical vesicles associated with inguinal lymphadenopathy usually
suggest the correct diagnosis. Rarely, lymph node enlargement may
appear before the rash develops.27
The lymphadenopathy associated with primary herpes is either
unilateral or bilateral; in severe cases generalized lymphadenopathy
may also occur. Genital lesions and lymphadenopathy are common in
genital herpes in the immunocompetent host; however, massive
lymphadenitis is frequently seen in the immunocompromised patient.
The diagnosis is based on isolation of herpes simplex virus from a skin
lesion, preferably from a vesicle28 (see also Chapter 62).
Figure 15-5 Groove sign of lymphogranuloma venereum. There is cleavage of

Granuloma Inguinale
extensive lymphadenopathy by the inguinal ligament. Granuloma inguinale (donovanosis) is caused by Calymmatobacterium
granulomatis. The disease is rare in the Western world but is a major
cause of genital ulcer in south-east India, Brazil and some parts of
Africa. The penile papules of granuloma inguinale appear within days
one-third and one-half of untreated cases. The lymph nodes are of inoculation and rapidly ulcerate to form a red, granulomatous,
enlarged, painful and tender. The process is most commonly unilateral painless ulcer with a characteristic surface that bleeds easily on contact.
and, without treatment, can progress to suppuration with periadenitis Subcutaneous spread into the inguinal region results in swellings
and involvement of the overlying skin (bubo). (pseudobuboes) that are not a true adenitis. Lymphedema and ele-
Culture provides the definitive diagnosis; however, H. ducreyi is a phantiasis occasionally result from scarring and blockage of the lym-
fastidious organism and immediate direct inoculation into specific phatics. Granuloma inguinale should be differentiated from other
culture media is required for bacterial growth and isolation. Chemo- genital ulcerative lesions with inguinal lymphadenopathy. The diagno-
therapy is sufficient in most uncomplicated cases but abscesses that are sis is established through the demonstration of the typical intracellular
more than 5 cm in diameter may need surgical drainage24 (see also Donovan bodies in stained smears obtained from the lesions29 (see
Chapter 64). Chapter 64).
Lymphogranuloma Venereum PARASITIC LYMPHADENOPATHY

Lymphogranuloma venereum is a rare STD caused by C. trachomatis Toxoplasmosis
serovars L1, L2 and L3. The typical vesicular lesions appear 1–2 weeks Lymphadenopathy is an important clinical sign of acquired primary
after inoculation but the incubation period varies between 5 and 20 toxoplasmosis in the immunocompetent and occurs in up to 84%
days. The lesions often go unnoticed by the patient. Inguinal lymph- (mean 64%) of cases in different studies. Lymphadenopathy is typically
adenopathy appears 1–6 weeks after the vesicles disappear. The lymph- found in the neck, most commonly in the posterior and anterior cervi-
adenopathy is most commonly unilateral but is bilateral in 30–40% of cal regions, followed by the suboccipital region, the axillae and then
patients. The nodes are painful and the groove sign (cleavage of the the groins. It is usually found at single sites in adults (in 90%), but
enlarged nodes by the inguinal ligament) is seen in 25% of patients multiple sites are more common in children. Retroperitoneal or mes-
(Figure 15-5). The involved lymph nodes frequently coalesce to form enteric lymphadenopathy occur occasionally and cause abdominal
a bubo. If untreated, the nodes may rupture and a nonhealing fistula pain. Toxoplasmic lymphadenopathy has been described in unusual
is formed. sites such as the lung hilus, the mammary gland, parotid gland and
The anorectal syndrome, which occurs mainly in women and chest wall.30 Lymphadenopathy may be the only symptom of toxoplas-
homosexual men, results from involvement of the pelvic lymph nodes. mosis but generally there are additional symptoms – often fever and
In the male, abscess formation may occur in the dorsal lymphatic of rarely splenomegaly and/or hepatomegaly. In approximately 15%
the penis and cause tissue destruction and elephantiasis of the penis. of cases, Toxoplasma lymphadenopathy is associated with fever,
Chlamydia trachomatis can be isolated from both blood and aspirates headache, myalgia and sore throat that may mimic infectious
of lymph nodes in approximately 30% of cases. Incision of the bubo mononucleosis.
is not warranted for diagnosis and positive serologic tests or nucleic On palpation, the lymph nodes are usually discrete, of varying
acid amplification based assays in the appropriate clinical setting are firmness, and may or may not be tender; they rarely suppurate or
highly sensitive and specific for the diagnosis25 (see Chapter 64). ulcerate. A chronic lymphadenopathy fluctuating in size over several
months has also been described.30 The histologic appearance should
Syphilis be differentiated from lymphoma, cat-scratch disease and Kikuchi’s
The lymphadenopathy of primary syphilis is easily differentiated from lymphadenitis.
chancroid and lymphogranuloma venereum because nodes involved Enlarged glands will usually resolve within 1–2 months in 60% of
in syphilis are firm, only moderately enlarged, nonsuppurative and patients. However, 25% of patients take 2–4 months to return to
painless. The classic primary chancre appears 14–30 days after inocula- normal, 8% take 4–6 months and in 6% the enlarged lymph nodes do
tion and is a nonexudative, painless ulcer. In the immunocompetent not return to normal until much later.
The diagnosis of toxoplasmosis cannot be made solely on clinical

grounds. Histologic features in lymph node biopsies are suggestive of
toxoplasmosis but are not diagnostic.30
Antibodies to Toxoplasma gondii are usually detectable within 2
weeks of infection and reach a peak within 2 months. Toxoplasma
lymphadenopathy in immunocompetent patients normally resolves
without treatment.
Acute infection by Toxoplasma gondii is common worldwide. The
prevalence of seropositivity by the fourth decade of life in North
America is 30–50% and higher than 90% in certain European
countries.31
Toxoplasmosis has been estimated to cause between 3% and 7% of
clinically significant lymphadenopathy. The differential diagnosis of
Toxoplasma from lymphoma may, on occasion, save unnecessary inva-
sive diagnostic workup.
Leishmaniasis (see Chapter 123)

Enlarged lymph nodes occur in the majority (77%) of people with
confirmed cutaneous leishmaniasis in South America and in patients
who have Leishmania major and L. tropica acquired in equatorial Africa Figure 15-6 Winterbottom’s sign: lymph node enlargement in the posterior
and the Middle East.32,33 Lymphadenopathy may precede the cutaneous neck, a sign of African trypanosomiasis.
lesion by some 2 weeks in two-thirds of the cases. Cultures of the
lymph nodes obtained by aspiration or biopsy are more frequently
positive (86%) than cultures obtained from the skin lesions. In Brazil somes. Commercial antibody tests for East African trypanosomiasis
lymphadenopathy (whether localized or generalized) may often be the are not available. For early- and late-stage disease, treatment usually
first, and sometimes the only, symptom of cutaneous leishmaniasis.34,35 results in resolution of symptoms and rapid clearance of parasitemia
Lymph node histology may show necrotizing or suppurative granulo- on repeat blood smears. Most patients experience full recovery follow-
mas, sometimes with discharging sinuses. Patients who have leishman- ing treatment.36,37
ial lymphadenopathy often have fever, hepatomegaly, splenomegaly,
intense skin reaction and lymphocyte proliferation when exposed to American Trypanosomiasis (Chagas Disease)38
suitable antigenic stimulation. In an endemic area, therefore, an unex- (see Chapter 124)
plained lymphadenopathy should prompt an investigation for
Lymphadenopathy appears in around two out of three patients with
leishmaniasis.
the acute disease; additional signs and symptoms also occur. An
African Trypanosomiasis (see Chapter 110) enlarged liver and spleen are mainly observed in children, whereas
generalized lymphadenopathy is observed in 60% of all patients. Sub-
Human African trypanosomiasis, or sleeping sickness, is an illness
cutaneous edema, either generalized or localized to the face and/or
endemic to sub-Saharan Africa, caused by the flagellate protozoan,
lower extremities, is observed in 30–50% of cases.
Trypanosoma brucei, which exists in two morphologically identical
subspecies: Trypanosoma brucei rhodesiense (East African or Rhodesian
African trypanosomiasis) and Trypanosoma brucei gambiense (West Filariasis39 (see Chapter 121)
African or Gambian African trypanosomiasis). Both of these parasites The most common symptoms of filarial lymphatic disease include
are transmitted to human hosts by bites of infected tsetse flies (Glossina fever, inguinal or axillary lymphadenopathy, distinctive lymphangitis
species), which are found only in Africa. Humans are infected follow- spreading retrogradely from the lymph node where the filaria reside to
ing a fly bite, which occasionally causes a skin chancre at the site. These the periphery, testicular and/or inguinal pain, skin exfoliation, and
injected trypomastigotes further mature and divide in the blood and limb or genital swelling. Such attacks last for 3–7 days and recur
lymphatic system, causing symptoms of malaise, intermittent fever, between 6 and 12 times per year. Attacks subside spontaneously
rash and wasting. Eventually, the parasitic invasion reaches the central without specific therapy. Affected lymph nodes are enlarged and
nervous system (CNS), causing behavioral and neurologic changes, painful, and the surrounding lymph vessels also appear inflamed and
such as encephalitis and coma. indurated. With the continuation of lymphangitis and lymphadenitis,
In the first stage of the disease the major findings are painless skin pitting edema of the skin appears; this is transformed into brawny
chancre that appears about 5–15 days after the bite, intermittent fever edema of the involved area causing thickening of the subcutaneous
(refractory to antimalarials), general malaise, myalgia, and headache tissue and hyperkeratosis. Coarsening of the skin ensues with deep
usually 3 weeks after the tsetse fly bite, accompanied by generalized fissuring and nodular and papillomatous hyperplastic skin changes.
lymphadenopathy, pruritus, urticaria and facial edema (minority of Occasionally local lymphedema appears causing penile, testicular,
patients). Axillary and inguinal lymphadenopathy is noted more often labial or limb enlargement. In some patients passage of cloudy milk-
in patients with the East African form; cervical lymphadenopathy is like urine may denote chyluria. Occasionally local thrombophlebitis
more commonly observed in patients with the West African form. The may complicate the clinical picture. Infection by Brugia malayi may
classic Winterbottom’s sign is clearly visible (i.e. enlarged, nontender, result in an abscess of the local lymphatic apparatus leaving character-
mobile posterior cervical lymph node) (Figure 15-6). Fevers, tachycar- istic scars.
dia, irregular rash, edema and weight loss ensue. Lymphadenopathy
has to be differentiated from tuberculosis lymphadenitis, HIV and Onchocerciasis40
cancer. A definitive diagnosis of infection requires detection of try- The major manifestations of the disease are dermatitis, onchocercoma,
panosomes in blood, lymph nodes, cerebrospinal fluid, skin chancre lymphadenitis and visual impairment or blindness. Mild to moderate
aspirates or bone marrow. lymphadenopathy is common, particularly in the inguinal and femoral
The standard serologic assay to diagnose West African trypanoso- areas. Involved nodes are characteristically firm and nontender;
miasis is the card agglutination test for trypanosomiasis (CATT), at times they may reach gigantic proportion and be associated
results of which are available in only 10 minutes. It is highly sensitive with lymphedema causing elephantiasis (hanging groins). Itching
(96%) but less specific because of cross-reactivity with animal trypano- skin and chronic papular onchodermatitis with depigmentation are
bothersome, sometimes accompanied by lymphadenopathy in con- particularly constitutional symptoms such as fever, sweats, fatigue and
junction with secondarily infected skin lesions. unintentional weight loss. In addition, the patient should be asked
about travel history, country of origin, disease exposures (e.g. tuber-
Wuchereria bancrofti Infection41 culosis) and risk behaviors (e.g. sexual activity). A comprehensive
Lymphadenopathy is the striking feature of infection with Wuchereria physical examination should be done with emphasis on lymph node
bancrofti. Filaria are frequently found in the enlarged lymph node. distribution, size, mobility and consistency. The size and consistency
While the peripheral blood smear and involved organs are character- of the spleen and liver should also be examined. In patients with a CD4
ized by intense eosinophilia, the histology of the lymph node may not cell count >200 cells/µL, a tuberculin skin test should be done. Labora-
reveal eosinophilic infiltration. At times, the genitalia may be involved tory studies should include complete blood count, including a careful
with funiculitis, epididymitis, scrotal pain and skin changes and dis- evaluation of the peripheral blood smear. CD4 cell count should be
figuration of the penis. Scrotal lymphedema, hydrocele and elephan- done as early as possible since the whole differential diagnosis will
tiasis may be present. In addition, characteristic gigantic swelling of depend on this number. Evaluation of hepatic biochemistry, renal
the leg below the knee and of the arm below the elbow, described as function and urine analysis are useful to identify underlying systemic
elephantiasis, may develop as a result of lymphatic involvement. Occa- disorders that may be associated with lymphadenopathy. Additional
sionally obstruction of the retroperitoneal lymphatics occurs, leading studies, such as lactate dehydrogenase (LDH), uric acid, calcium and
to rupture of lymphatic vessels into the kidney and appearance of phosphate, may be indicated if malignancy is suspected. Tests for
chyluria. specific organisms (e.g. Bartonella henselae) should be done according
to clinical assessment.
VIRAL LYMPHADENOPATHY Imaging studies should include chest X-ray and, when appropriate,
HIV tomography. Mediastinal or hilar lymphadenopathy is not a part of the
persistent generalized lymphadenopathy (PGL) syndrome and when-
Lymphadenopathy is very common in HIV-infected individuals
ever isolated intrathoracic lymphadenopathy is detected, a thorough
and may occur at any stage of HIV infection. Generalized lymphade-
investigation for mycobacterial disease is recommended. In such cases
nopathy was one of the characteristic manifestations of the AIDS epi-
tuberculosis is found in more than half of the patients.47
demic, even before its etiology was recognized.42 In the San Francisco
Fine needle aspiration biopsy (FNA-B) is a worthwhile procedure
Men’s Health Cohort Study marked lymphadenopathy was present in
and may allow a rapid diagnosis, obviating the need for surgery and
29% of seropositive men43 and 29.2% among 1616 HIV-positive
enabling swift treatment to be undertaken in both adults and chil-
persons in India.44 Acute retroviral syndrome is often associated with
dren.48,49 If FNA-B is nondiagnostic (false-negative results are relatively
generalized lymph node enlargement (see Chapter 93). In the majority
common), an open biopsy for definitive evaluation should be done.
of cases it usually appears during the second week of the illness. The
Biopsy specimens should be sent for (myco)bacterial and fungal cul-
lymphadenopathy commonly involves the cervical, axillary and ingui-
tures, acid-fast staining for mycobacteria and cytologic examination.
nal regions.45 In the early stage of the infection the lymph nodes are
Most patients with PGL will not require any treatment. In most
characterized histopathologically by pronounced follicular hyperplasia
patients highly active antiretroviral therapy (HAART) will reduce viral
that, with progression of the disease, evolves into a pattern of follicular
load and lymphadenopathy will subside. When a specific diagnosis is
involution.46
made, specific therapy should be instituted.
Lymph node enlargement in patients with HIV, especially with
immunosuppression, may indicate a serious local or systemic condi- Human T-lymphocyte Leukemia Virus 1 (HTLV 1)50
tion, and should be evaluated carefully. Rapid enlargement of a previ- Generalized lymph node enlargement is the most common manifesta-
ously stable lymph node or a group of nodes requires evaluation to tion of HTLV-1 infection. Additional characteristic findings include
identify the cause and to determine whether treatment is needed. Simi- skin lesions, hepatosplenomegaly, hypercalcemia, lymphocytosis with
larly, nodes that are abnormal in consistency, tender to palpation, abnormal circulating lymphocytes and hyperimmunoglobulinemia.
fluctuant, asymmetrical, adherent to surrounding tissues or accompa- Geographic-dependent findings are tropical spastic paraparesis and
nied by other symptoms should be evaluated promptly. myelopathy in some tropical areas. Untreated, the disease undergoes
A multitude of opportunistic infections and malignancies can cause rapid clinical deterioration.
lymphadenopathy in patients with HIV (see Chapter 94). The likely
causes of lymphadenopathy, and thus the diagnostic workup, will Infectious Mononucleosis
depend in part on the patient’s degree of immunosuppression (Table Infectious mononucleosis is a disease of teenagers and young adults.
15-4). Sudden enlargement, pain or tenderness of a lymph node war- It is classically characterized by fever, tonsillopharyngitis, lymphade-
rants further diagnostic procedures. nopathy, splenomegaly and atypical lymphocytes on peripheral blood
In the evaluation of patients with HIV with lymph node enlarge- smear. Epstein–Barr virus (EBV) is the cause in 80–90% of cases, fol-
ment, the history should include accompanying symptoms, lowed by cytomegalovirus (CMV; 8–16%) and toxoplasmosis (1–2%).51
TABLE
15-4 Causes of Lymphadenopathy in HIV-positive Patients
Generalized Lymphadenopathy Localized Lymphadenopathy
HIV (acute or persistent generalized lymphadenopathy) Local infection
Viral diseases (Epstein-Barr virus, cytomegalovirus, hepatitis B virus, hepatitis C virus) Tuberculosis
Tuberculosis Fungal disease (histoplasmosis, coccidioidomycosis, etc.)
Syphilis (secondary) Lymphogranuloma venereum, chancroid
Bartonella henselae Lymphoma or other malignancy
IRIS (immune reconstitution syndrome) Castleman’s disease
Drugs (e.g. abacavir) Kaposi’s sarcoma

Multicentric Castleman’s disease
It is usually a benign and self-limiting process. Patients exhibit general- DISEASE PROGRESSION
ized lymphadenopathy and localized lymph node enlargement with or Lymphadenopathy of long duration (>1 month) mandates a thorough
without systemic manifestations. Lymphadenopathy is observed in the investigation. While lymphadenopathy caused by the agent of cat-
vast majority of children and young adults with infectious mononu- scratch disease, Bartonella henselae, and by Toxoplasma gondii can
cleosis but only in approximately 45% of patients older than 40 years.52 persist for several months, the presumed etiology may be in doubt if
Lymph nodes are usually moderately enlarged and not very tender; the enlarged lymph nodes persist for more than 6 months; in such cases
they can be found at the posterior cervical, axillary, epitrochlear, sub- a biopsy of the lymph node is indicated. Fine needle aspiration has
mandibular, submental and groin regions. Lymph node histology replaced the previously often used open surgical biopsy, and is suitable
demonstrates paracortical immunoblastic proliferation as seen in for most diagnostic purposes (except for the diagnosis of lymphoma).
many viral infections.53 The average rate of diagnosis of a biopsied lymph node is 50–60%.
Serious complications of infectious mononucleosis include menin- Among patients in whom a diagnosis cannot be established through a
goencephalitis with seizures, myelitis, peripheral neuropathy, splenic lymph node biopsy, 25% will develop a lymphoma within 1 year.
rupture, upper airway obstruction, interstitial pneumonitis and severe Therefore patients who undergo a nondiagnostic lymph node biopsy
hepatitis with liver failure. Death is rather rare. need to be followed up.
Management THE ROLE OF AGE

Lymphadenopathy may be the presenting sign in many diseases. The Lymphadenopathy is exceedingly common in the pediatric age group
physical examination of a patient needs to include a description and represents a benign process in approximately 80% of cases. As
of the most important lymph node groups (cervical, clavicular, such, a trial of antibiotics is justified prior to an extensive workup. In
axillary, inguinal) and a search for lymph node enlargement of uncon- adults, particularly if over 50 years of age, lymphadenopathy (regional
ventional sites (suboccipital, scalenal, epitrochlear, popliteal, etc.) or generalized) that persists for several weeks requires a thorough
when indicated. evaluation and consideration for biopsy.
In adults, small lymph nodes, the size of a small olive, can be
normally palpated in the inguinal region and in children in the suboc-
cipital and submental regions. Enlarged and certainly persistent supra- PHYSICAL CHARACTERISTICS OF
clavicular, scalenal, axillary and epitrochlear lymph nodes will usually THE ENLARGED LYMPH NODE
require investigation, including aspiration or a biopsy of the node. The size, consistency and relation to surrounding and underlying
tissues are important clues to the diagnosis of enlarged lymph nodes.
MODE OF PRESENTATION Lymph nodes involved by an infective process tend to be large, soft and
In acutely ill patients who have a tender enlarged lymph node, bacterial tender. Signs of local inflammation may be present and draining
etiology is most likely, frequently but not always caused by gram- sinuses may be seen in tuberculous cervical lymphadenitis; inguinal
positive cocci. A thorough ear, nose and throat examination is manda- draining sinuses are occasionally seen in lymphogranuloma venereum
tory in lymphadenitis or lymphadenopathy of the cervical, submental and chancroid. Nodes involved by lymphoma are characterized as
and head regions. In endemic regions, plague, anthrax and tularemia rubbery, matted together and usually nontender. Metastatic lymph
should be suspected. An acutely ill patient found to have generalized nodes due to carcinoma are usually firm, nontender and fixed to the
lymphadenopathy (more than three sites) should be evaluated for sys- surrounding tissues.
temic infections including infectious mononucleosis, typhoid fever,
rickettsiosis, leptospirosis, miliary tuberculosis and tularemia, as well
as disseminated streptococcal and staphylococcal infections. In mildly LOCATION
symptomatic younger individuals and in symptomatic transplant Specific locations of enlarged lymph nodes are frequently associated
patients with generalized lymphadenopathy the most likely etiologies with specific etiologies (Table 15-5). As intrathoracic and intra-
will be EBV, CMV and HIV; all of these require special laboratory abdominal lymph nodes are usually not palpable, appropriate imaging
investigations.54 studies are necessary (ultrasound, CT).
TABLE
15-5 Location of Enlarged Lymph Node and Associated Disease
Site of Enlarged Lymph Node Associated Disease or Condition
Occipital Scalp infections, insect bites, head lice, allergy to hair shampoo
Posterior auricular Rubella, infected ear piercing, otitis externa, HIV infection
Anterior auricular Eye and conjunctival infection, tularemia
Posterior cervical Toxoplasmosis
Submental Dental and oral cavity infections
Anterior cervical and submandibular Oral cavity infections, infectious mononucleosis, cytomegalovirus, HIV, tuberculosis
Supraclavicular Neoplasia
Mediastinal Sarcoidosis, tuberculosis, histoplasmosis, blastomycosis, anthrax, neoplasia (lymphoma, metastasis)
Axillary Cat-scratch disease, pyogenic infections of the arm, neoplasia
Epitrochlear Viral diseases, cat-scratch disease, tularemia, hand infections, secondary syphilis
Abdominal/retroperitoneal Tuberculosis, yersiniosis, neoplasia

Inguinal Genital herpes, syphilis, lymphogranuloma venereum, granuloma inguinale, filariasis, pediculosis pubis, neoplasia
Head and Neck Lymphadenopathy tuberculin test is usually positive in tuberculosis; however, if negative,
The oropharyngeal cavity (including the teeth) is the most common it should be repeated in 14 days. If still negative a lymph node biopsy
cause for head and neck lymphadenopathy, followed by the nasal is indicated. Occasionally disseminated atypical mycobacterial infec-
cavity and the skin covering the head and neck. In children and young tion (e.g. M. cheloni, M. avium complex) may also manifest as thoracic
adults enlarged lymph nodes must be differentiated from epidermoid or generalized lymphadenopathy.
cysts, thyroglossal cysts, branchial cysts and parotid and submental In adults, unilateral mediastinal and hilar lymphadenopathy
enlarged glands. Symmetric lymph node enlargement is usually benign without any other symptoms or signs suggests a neoplastic etiology
and of viral etiology in most instances; unilateral lymph node enlarge- and a biopsy to confirm the diagnosis is required. An exception may
ment raises a wider differential diagnosis list including viral etiology. be the patient with HIV, or a person who arrives from an area endemic
The most common causes of unilateral enlargement include inflam- for tuberculosis or endemic fungal infection (such as histoplasmosis
mation of a draining lymph node as a consequence of a local (bacte- and coccidioidomycosis). Bilateral hilar lymphadenopathy in the
rial) infection, cat-scratch disease, toxoplasmosis and neoplasia. If asymptomatic young adult is commonly caused by sarcoidosis. In
asymmetrical cervical lymph node enlargement persists beyond a few patients who have parenchymal involvement in addition to the hilar
weeks and serologic tests for toxoplasmosis and cat-scratch disease are lymphadenopathy, a search for tuberculosis needs to be undertaken
negative, a biopsy, usually with a fine needle, is indicated. An abnormal with sputum investigations (smear and culture) and, if necessary,
chest radiograph with associated unilateral cervical lymph node bronchoscopy. Bronchoscopy increases the yield for M. tuberculosis in
enlargement is highly suspicious (in 80% of patients) of neoplastic sputum-negative patients by 50–75%. The presence of an ulcerating
etiology or granulomatous disease, and in such instances a lymph node granuloma on bronchoscopy will augment the positive rate even
surgical biopsy may be more accurate than fine needle aspiration. further.
Supraclavicular adenopathy, particularly in adults, is most likely to be
neoplastic, frequently secondary to gastric cancer. Rare situations that Abdominal Lymphadenopathy
may cause cervical lymphadenopathy include Kimura disease (eosino- Infectious etiologies of abdominal lymphadenopathy are few and
philic hyperplastic lymphogranuloma) and Gianotti–Crosti syndrome include mesenteric and intestinal tuberculosis, Yersinia enterocolitica
(hepatitis B-associated lymphadenopathy in children) (see Chapter 9). infection, Whipple’s disease and intestinal anthrax; occasionally
Crohn’s disease will be accompanied by enlarged mesenteric lymph
Axillary Lymphadenopathy nodes. More commonly enlarged abdominal lymph nodes are of neo-
Infections causing unilateral axillary lymphadenopathy include local plastic etiology. Occasionally abdominal lymph node enlargement can
infectious processes of the arm and hand, hidradenitis suppurativa, be seen during attacks of familial Mediterranean fever (FMF) and
cat-scratch disease, HIV, toxoplasmosis and tularemia, streptococcal similar disorders, such as Muckle–Wells syndrome, chronic infantile
and staphylococcal lymphadenitis and sleeping sickness. Postvaccina- neurologic cutaneous articular syndrome (CINCA/NOMID), tumor
tional lymphadenopathy was regularly seen following smallpox vac- necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS)
cination and occurs occasionally following anthrax vaccination. It is and hyperimmunoglobulinemia D with periodic fever syndrome
also seen post measles vaccination where characteristic Warthin– (HIDS).55
Finkeldey multinucleated giant cells are seen on biopsy. Bacille
Calmette–Guérin (BCG) vaccination is also occasionally accompanied Inguinal Lymphadenopathy
by an enlarged local lymph node from which M. bovis may be isolated. Inguinal lymph node enlargement is very common in a variety of
Asymptomatic unilateral axillary lymph node enlargement is suspi- STDs, namely syphilis, chancroid, lymphogranuloma venereum, gran-
cious of being of neoplastic etiology. Bilateral axillary lymph node uloma inguinale, genital herpes, pediculosis pubis and HIV. In Women
enlargement can be practically caused by all etiologies: viral, bacterial, unguinal node enlargement can be secondary to inflammation of the
protozoal, neoplastic, allergic and noninfectious inflammatory Bartholin or Skene glands of the labia. Other causes include cat-scratch
diseases. disease, purulent infections of the upper and lower leg (streptococcal
and staphylococcal), Kikuchi’s disease and toxoplasmosis. In endemic
Thoracic Lymphadenopathy areas or in travelers or immigrants returning from endemic areas the
Major etiologies causing thoracic lymphadenopathy include neoplasia, differential diagnosis should include filariasis, Bancroftian filariasis,
tuberculosis, sarcoidosis, endemic mycosis and anthrax. In children, onchocerciasis and human plague.
mediastinal lymphadenopathy, uni- or bilateral with or without visible
lung X-ray findings, is characteristic for primary tuberculosis; malig- References available online at expertconsult.com.
nant lymphoma, however, may also present in this manner. The
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92:1282-1287. Acta Trop 2005; 93:303-310. 1995; 12:284-287.
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ficial lymph nodes. Br J Dis Chest 1980; 74:369-373. nopathy as the first sign of human cutaneous infection periodic fever syndromes or hereditary autoinflamma-
17. Bem C., Patil P.S., Bharucha H., et al.: Importance of by Leishmania braziliensis. Am J Trop Med Hyg 1995; tory syndromes. Am J Physiol Regul Integr Comp Physiol
human immunodeficiency virus-associated lymphade- 53:256-259. 2007; 292:R86-R98.
nopathy and tuberculous lymphadenitis in patients 36. Courtin F., Jamonneau V., Duvallet G., et al.: Sleeping
undergoing lymph node biopsy in Zambia. Br J Surg sickness in West Africa (1906–2006): changes in spatial
1996; 83:75-78. repartition and lessons from the past. Trop Med Int
18. Wolinsky E.: Mycobacterial lymphadenitis in children: Health 2008; 13:334-344.
a prospective study of 105 nontuberculous cases with 37. Maudlin I.: African trypanosomiasis. Ann Trop Med
long-term follow-up. Clin Infect Dis 1995; 20:954-963. Parasitol 2006; 100:679-701.
SECTION 2 Syndromes by Body System: The Lymphatic System
PRACTICE
POINT
3 Evaluation and Management of the

Solitary Enlarged Lymph Node
YOAV KEYNAN | ETHAN RUBINSTEIN†
Introduction Kikuchi’s disease affects younger women and may be accompanied

by constitutional symptoms suggesting lymphoma or systemic infec-
Enlargement of lymph nodes has been reviewed in Chapter 15. Lymph tion. Biopsy reveals infiltration by plasmocytoid cells and histiocytes
node enlargement should first be differentiated from other masses and coagulative necrosis (Figure PP3-1). Histology, as well as nonspe-
originating from nonlymphoid tissue. The differential diagnosis of cific symptoms, make it difficult to distinguish from lymphoma and
solitary and generalized lymph node enlargement is similar although systemic lupus erythematosus (SLE). Kikuchi’s disease is usually self-
viral and protozoal causes are fewer in the former. The causes vary limiting with a favorable prognosis.
according to patient’s age, the anatomic location, geographic region; Noninfectious causes of an enlarged lymph node can be divided
in histologic studies in the literature malignant causes are over- into two broad categories, inflammatory and infiltrative, with further
represented, but these are uncommon in primary care practice. Overall, subdivision into immunologic and lymphoproliferative in the former
staphylococcal and streptococcal infections are the most common and metastatic and storage in the latter (see Table PP3-1).
causes of localized lymphadenopathy, especially when with cervical or The infectious causes of solitary lymph node enlargement include
axillary nodes. In 17% to over 40%, the etiology of solitary lymph node viruses, bacteria, rickettsia, fungi and protozoa (Table PP3-2). Immune
enlargement is not established; this is probably an underestimate since reconstitution after initiation of antiretroviral therapy may present as
these figures are based on biopsied cases. solitary adenopathy (Figure PP3-2). Many agents are capable of causing
In general, a lymph node will enlarge in response to several pro- generalized as well as localized lymphadenopathy.
cesses, the most frequent being:
• infiltration by malignant cells; Clinical Manifestations
• infiltration by inflammatory cells in response to an infectious
agent: either residing within the node or being filtered from Enlarged lymph node(s) may lead the patient to seek medical care or
afferent lymphatics or blood; and may be an incidental finding. Not every palpable lymph node has an
• proliferation of lymphocytes in response to antigenic stimuli. underlying defined pathologic process – inguinal lymph nodes <2 cm
Most enlarged lymph nodes demonstrate nonspecific inflamma- in diameter are considered normal for adults and axillary lymph nodes
tion, only a minority shows a distinctive histology. Caseating necrosis are commonly palpable in laborers. Enlarged cervical and subman-
suggests mycobacterial or fungal etiology, and granulomatous inflam- dibular lymph nodes are common in infants and children.
mation without necrosis is typical for several infectious and non Evaluation of the enlarged lymph node includes a detailed history:
infectious processes, such as cat-scratch disease, Kikuchi’s disease, the duration of the lymphadenopathy; presence of pain, drainage, skin
sarcoidosis, tularemia and lymphogranuloma venereum. or mucosal lesions; and any associated local infections. Presence of
a b
Figure PP3-1 Kikuchi’s disease. (a) Section of a lymph node with extensive paracortical area of coagulative necrosis (H & E). (b) Lesion with infiltration of histiocytes
intermingled with small lymphocytes, immunoblasts, apoptotic bodies and foamy macrophage (arrow) (H & E). (Courtesy of Doron Rimar and Yaaov Schendler.)
†
Deceased
146
Practice Point 3 Evaluation and Management of the Solitary Enlarged Lymph Node 147
TABLE
PP3-1 Noninfectious Causes of Lymphadenopathy
Inflammatory Immunologic Rheumatoid arthritis
Systemic lupus erythematosus
At the site of vaccination
Sarcoidosis
Drugs (anticonvulsants)
Immune reconstitution inflammatory syndrome (IRIS)
Local allergic reactions
Lymphomyeloproliferative Leukemia
Lymphoma
Castleman’s disease
Sinus histiocytosis with massive lymphadenopathy (Rosai–Dorfman disease)
Kikuchi’s disease
Infiltrative Metastatic malignancy Skin, melanoma, head and neck, breast, sarcoma
Storage Gaucher’s disease
Niemann–Pick disease
TABLE
PP3-2 Infectious Etiologies of Solitary Lymph Node Enlargement
Generalized
Infectious Agent Example Site Adenopathy Comments
Bacteria Group A streptococci Cervical +
Pyogenic
Staphylococcus aureus Regional
Corynebacterium diphtheriae Regional
Mycobacteria Mycobacterium tuberculosis Regional +
Mycobacterium scrofulaceum Cervical
Nontuberculous mycobacteria Regional
Treponema Syphilis Regional +
Endemic treponema, yaws Regional
Other Francisella tularensis Regional +
Bacillus anthracis Regional
Yersinia pestis Regional
Burkholderia pseudomallei, B. mallei Regional
Bartonella Regional
Streptobacillus moniliformis, Spirillum minus Regional
Haemophilus ducreyi Regional
Rickettsia/ Rickettsia tsutsugamushi Regional +

Chlamydophila
Rickettsia akari Regional
Rickettsia africae, R. sibirica, R. australis, R. honei Regional
Rickettsia slovaca Cervical
Rickettsia mongolotimonae Regional Lymphangitis-associated rickettsiosis
Chlamydia trachomatis (lymphogranuloma venereum) Regional +
Fungi Histoplasma capsulatum Regional
Coccidioides immitis Regional
Paracoccidioides brasiliensis Regional

TABLE
PP3-2 Infectious Etiologies of Solitary Lymph Node Enlargement (Continued)
Generalized
Infectious Agent Example Site Adenopathy Comments
Protozoa Toxoplasma gondii Cervical
Trypanosoma brucei Cervical
Leishmania spp. (cutaneous) + L. braziliensis regional lymphadenopathy

may precede skin lesions
Helminths Filariasis +
Loa loa
Onchocerca volvulus
Viruses Herpes simplex virus type 2 Inguinal + Mucocutaneous lesion may be absent
Human herpesvirus 8 Cervical, Kaposi’s sarcoma

preauricular
Adenoviruses Especially types 3 and 7

pharyngoconjunctival fever
HIV Usually generalized; localized
lymphadenopathy may be the presenting
symptom of immune reconstitution
200um 100um
a b
Figure PP3-2 Immune reconstitution, enlarged inguinal lymph node

approximately 1 month after antiretroviral therapy was initiated. (a) Section
of inguinal node, showing granulomatous inflammation with necrosis.
(b) Granulomatous inflammation. (c) Acid-fast bacilli seen in lymph nodes,
50um
c subsequently identified as Mycobacterium avium. (Courtesy of Dr Anamarija
Perry.)
Practice Point 3 Evaluation and Management of the Solitary Enlarged Lymph Node 149
systemic symptoms, history of travel, sexual behavior, occupation, in children, is often due to mononucleosis caused by Epstein–Barr
exposure to animals, previous vaccinations and tattooing may guide virus (EBV), cytomegalovirus (CMV), Toxoplasma and neck infection.
the diagnostic approach. Posterior cervical lymphadenopathy is seen in tuberculosis, toxoplas-
The physical examination should assess the size, texture, adherence mosis, cat-scratch disease, Kikuchi’s disease and both cancers of the
to surrounding tissues, tenderness, discharge and fluctuance. Careful head and neck, and lymphomas. Hard lymph node in the neck of an
examination of the skin, mucous membranes and genitalia is of elderly subject suggests cancer and needs exploration.
extreme importance in patients with regional adenopathy. All major Right supraclavicular lymphadenopathy is usually due to malig-
lymph node groups should be palpated including assessment of the nancy in the mediastinum, lung and esophagus while left supraclavicu-
size of liver and spleen. lar lymphadenopathy (Virchow’s node) arises from abdominal
malignancy and prostatic, testicular and ovarian malignancy.
Investigations Axillary lymphadenopathy is associated with a cat-scratch disease,
History and physical examination guide the diagnostic and therapeutic breast cancer or remote malignancy. Silicone breast implants can cause
approach. A history of skin breakdown and a fluctuant lymph node axillary isolated inflammatory lymphadenopathy.
make staphylococcal infection the most likely diagnosis; in other cases Epitrochlear lymphadenopathy suggests a purulent infection in the
the etiology may not be apparent. Basic tests include complete blood dorsum of the hand, syphilis, tularemia, sarcoidosis and lymphoma.
count, swabs from skin lesions, ulcers and pharynx in case of cervical Inguinal lymphadenopathy implies that cancer of the genital tract
adenopathy. A fluctuant node should be aspirated and stained with in females, the lower extremity, rectum, and penis in males should be
Gram, acid-fast stain, silver stain and potassium hydroxide (KOH). considered.
Specimens should be cultured for (myco)bacteria and fungi. Blood
cultures should be obtained from febrile patients. Serologic tests assist Management
the diagnosis of some bacteria, rickettsia and protozoa. Images of the Management is guided by the identification of the causative organism
chest, abdomen and pelvis are indicated when a systemic cause of or other etiology. For suppurative lymphadenopathy accompanied by
lymphadenopathy is suspected. Histology with specific staining for lymphangitis, or when a skin infection is considered as portal of entry,
mycobacteria, fungi and cat-scratch disease is indicated when culture staphylococcal and streptococcal infections are most likely and
is negative or empiric therapy unsuccessful. penicillinase-resistant penicillin is an appropriate choice. A node of
Excisional biopsy is usually preferred to needle aspiration and is <1 cm in a person <40 years of age with no features of malignancy
the mainstay of diagnosis for entities such as nontuberculous lymph- (hard, fixed node) can be observed for a few weeks; often spontaneous
adenopathy. The application of 16S rRNA amplification and detection resolution will occur. If the cause does not become apparent, the node
with polymerase chain reaction (PCR) are superior diagnostic methods is >2 cm, enlarges during the observation period, or fails to respond
for Bartonella, Coxiella burnetii and Tropheryma whipplei. Proteomics to empiric therapy, a biopsy is indicated.
and metagenomic platforms are expected to further facilitate the diag-
nosis of lymphadenopathy. Further reading available online at expertconsult.com.
Another way to assess enlarged solitary nodes is according to their
location. In the anterior cervical region, lymphadenopathy, especially
Practice Point 3 Evaluation and Management of the Solitary Enlarged Lymph Node 149.e1
FURTHER READING
Bazemore A.W., Smucker D.R.: Lymphadenopathy and Rolain J.M., Lepidi H., Zanaret M., et al.: Lymph node Song J.Y., Cheong H.J., Kee S.Y., et al.: Disease spectrum of
malignancy. Am Fam Physician 2002; 66:2103-2110. biopsy specimens and diagnosis of cat-scratch disease. cervical lymphadenitis: analysis based on ultrasound-
Fournier P.E., Gouriet F., Brouqui P., et al.: Lymphangitis- Emerg Infect Dis 2006; 12(9):1338-1344. guided core-needle gun biopsy. J Infect 2007; 55(4):
associated rickettsiosis, a new rickettsiosis caused by Rick- Safont M., Angelakis E., Richet H., et al.: Bacterial lymph- 310-316.
ettsia sibirica mongolotimonae: seven new cases and review adenitis at a major referral hospital in France from 2008 Zumla A., James D.G.: Granulomatous infections: etiology
of the literature. Clin Infect Dis 2005; 40(10):1435-1444. to 2012. J Clin Microbiol 2014; 52(4):1161-1167. and classification. Clin Infect Dis 1996; 23:146-158.
Kelly C.S., Kelly R.E.: Lymphadenopathy in children. Pediatr
Clin North Am 1998; 45:875-888.
SECTION 2 Syndromes by Body System: The Eye
16
Conjunctivitis, Keratitis and Infections
of Periorbital Structures
MICHEL DRANCOURT | MARIE BOULZE PANKERT | LOUIS HOFFART
KEY CONCEPTS Presentation of Community-Acquired

• Viral conjunctivitis is the most common cause of conjunctivitis, Infectious Conjunctivitis
accounting for up to 80% of all cases; the majority of cases are CONJUNCTIVITIS IN NEONATES
caused by adenovirus.
In neonates, infectious conjunctivitis is named ophthalmia neonato-
• The most common causes of bacterial conjunctivitis are Staphy- rum in the first three weeks of life. Its occurs worldwide, but is uncom-
lococcus aureus, Streptococcus pneumoniae and Haemophilus mon where there is adequate infant eye prophylaxis. The most serious
species. cause is Neisseria gonorrhoeae (gonococcal conjunctivitis), while more
• Blindness due to trachoma, a consequence of recurrent child- common causes are Chlamydia trachomatis,6 chemical irritation and
hood infection with Chlamydia trachomatis, remains an impor- HSV. Globally gonococcal ophthalmia neonatorum is an important
tant problem in resource-poor countries. cause of blindness. The risk of ophthalmia neonatorum for a child
born to an infected mother is 30–50% for gonorrhea7 and 15–35% for
• Herpes simplex virus (HSV) and varicella-zoster virus (VZV) are
major causes of keratitis.
chlamydial infection.8 Transmission usually occurs in the birth canal.
Gonococcal conjunctivitis presents as a hyperacute conjunctivitis with
• Wider use of contact lenses has led to increased prevalence of preauricular lymphadenopathy 24–48 hours after birth and earlier
keratitis with opportunistic pathogens such as Pseudomonas after premature rupture of membranes. Lid edema, chemosis and
spp., nontuberculous mycobacteria, Fusarium and free-living profuse purulent secretion rapidly progress to corneal opacities; ulcer-
Acanthamoeba amebae. ation with high risk of perforation, and endophthalmitis may occur.
Chlamydial conjunctivitis presents 5–12 days after birth with a watery
discharge, which becomes purulent more slowly. Follicles are absent
because the conjunctival lymphoid tissue in infants is immature.
Untreated the condition usually resolves in 3–4 weeks, but can take 1
year. Rarely membranes and micropannus form, resulting in signifi-
cant stromal scarring in later life. Pneumonitis, rhinitis, vaginitis and
Conjunctivitis otitis can follow the conjunctivitis.
Conjunctivitis is inflammation of the conjunctiva, with bacterial con- CONJUNCTIVITIS IN CHILDREN

junctivitis being the eye disease that is most commonly seen by general Bacteria are belived to account for 50–70% of acute conjunctivitis in
practitioners.1 The incidence of infectious conjunctivitis presenting to children. The most common pathogens include Staphylococcus aureus,
general practitioners in the Netherlands was measured to be 13.9 per Staph. epidermidis, Streptococcus pneumoniae and Moraxella catarrha-
1000 person-years.2 Bacterial conjunctivitis has an excellent prognosis lis.9 Typical symptoms of bacterial conjunctivitis are unilateral or bilat-
with high frequency of spontaneous remission. Infectious conjuncti- eral conjunctival hyperemia with mild to moderate discharge and early
vitis must be differentiated from noninfectious conjunctivitis due to morning crusting. Chlamydial conjunctivitis manifests as two forms:
dry eye, or allergic conjunctivitis which can affect 15-40% of the popu- trachoma and inclusion conjunctivitis. Chlamydial serotypes A–C
lation,3 or acute and chronic inflammatory conditions of the conjunc- cause trachoma characterized by a severe follicular reaction of the
tiva such as Stevens–Johnson syndrome or mucous membrane superior tarsal conjunctiva, which may develop into scarring known
pemphigoid. Exogenous causes include pollution and medication as Arlt’s line or cause limbal follicles which later form Herbert pits.
(conjunctivitis medicamentosa). Rarely conjunctival or eyelid tumors These patients may present with vision loss due to the development of
can cause conjunctivitis (masquerade syndrome). Molluscum conta- corneal cicatrization. Chlamydial serotypes D–K cause inclusion con-
giosum lesions near the eye can shed viral particles into the eye and junctivitis, which is unilateral followed by chronic follicular conjunc-
cause a reactive follicular conjunctivitis, without evidence of conjunctivitis with mucopurulent discharge that is generally seen in sexually
tival infection. Large crops of molluscum lesions with a distribution active adolescents. Brazilian purpuric fever is caused by a rare invasive
in the chin strap region and perioculum can be seen in patients with clone of Haemophilus influenzae biogroup aegyptius. Genome analysis
AIDS.4 The distinction between noninfective and infectious causes is found a unique suite of novel adhesins.10 Systemic disease occurs in
usually clear from the history. Clues include a history of initial children 1–3 weeks after an episode of conjunctivitis. It is seen over a
improvement on starting a new type of eye drop followed by worsen- widespread area in Brazil and there is a case mortality of 70%. The
ing and complaints that the eye drops sting. Thorough history taking clinical picture is similar to that of meningococcal sepsis. The Brazilian
is necessary because patients may not recall all the different eye drops purpuric fever clone of H. influenzae biogroup aegyptius is resistant to
that they have been using during an episode of conjunctivitis. With- trimethoprim but is sensitive to chloramphenicol and ampicillin.
drawal of all topical medication and reassessment 2 or 3 days later is During epidemics systemic rifampin (rifampicin) (20 mg/kg/day for 2
helpful. In allergic conjunctivitis there is often a history of atopy and days) may be used as prophylaxis against Brazilian purpuric fever for
chronic mucus discharge, and giant papillae are seen.5 Except for chla- children who have conjunctivitis.
mydial conjunctivitis, infectious conjunctivitis rarely lasts longer than
3 weeks, beginning to resolve after 10 days. Conjunctivitis medicamen- BACTERIAL CONJUNCTIVITIS IN ADULTS
tosa can be a difficult condition to diagnose and may follow an infec- Bacterial conjunctivitis is ubiquitous and is more common in warmer
tious conjunctivitis. months and regions. Bacterial conjunctivitis is the second most
150
Chapter 16 Conjunctivitis, Keratitis and Infections of Periorbital Structures 151
common infectious etiology of conjunctivitis in adults. It is transmit- polio-like radiculopathy follows AHC. HSV causes unilateral follicular
ted by contact with ocular or upper respiratory tract discharge of conjunctivitis, which is associated with ipsilateral vesicular facial rash.
people who have the infection, fomites, medical equipment or shared Molluscum contagiosum is caused by a human-specific double
cosmetics. In some areas insect vectors are involved. Tearing, irritation stranded DNA poxvirus which typically affects otherwise healthy chil-
and sticky discharge without preauricular lymphadenopathy are early dren, with a peak incidence between 2 and 4 years. It presents as a
clinical features. The conjunctiva is pink (not red). The lids may be unilateral follicular conjunctivitis with associated unilateral lesion of
stuck together by a mucopurulent exudate on awakening. In adults the the eyelid margin.
most common pathogens identified are Staph. aureus followed by
Strep. pneumoniae and Haemophilus species.11 Bacterial conjunctivitis
(especially with Staph. aureus) may result from the superinfection of Diagnosis of Infectious
viral conjunctivitis, in the case of Staph. aureus for example. Conjunctivitis
Trachoma is a scarring condition of the conjunctiva and cornea in Microbiologic investigation is necessary only in neonatal, hyperacute,
adults caused by recurrent childhood infection with C. trachomatis. severe, unusual or chronic cases. Microscopy of conjunctival smears
Trachoma occurs worldwide and is endemic in rural areas of low- and can be useful, and conjunctival swabs on blood agar and (especially in
middle-income countries (LMIC). Blindness due to trachoma is still children) chocolate agar are used. H. influenzae biogroup aegyptius
common in parts of the Middle East, northern and sub-Saharan Africa, and Strep. pneumoniae are common causes. H. influenzae type b and
parts of the Indian subcontinent, South East Asia and China. There are Moraxella and Branhamella spp., Neisseria meningitidis and Corynebac-
pockets of infection in South America, among Australian Aborigines, terium diphtheriae are also involved.15,16 The diagnosis of trachoma is
in the Pacific islands and in native American reservations in the south- made on clinical grounds in endemic areas. Expressed follicles have a
west USA. characteristic microscopic appearance involving macrophages (Leber’s
Acute chlamydial conjunctivitis is characterized by a diffuse cells), plasma cells and lymphoblasts. C. trachomatis types A–C are
follicular reaction in the conjunctiva of the superior tarsal plate and at involved. Secondary bacterial superinfection is common and causes
the limbus with soft follicles. Papillary hypertrophy is a nonspecific severe disease. A point-of-care (POC) test was developed for the rapid
sign. With resolution of the follicles there is subconjunctival scarring diagnosis of trachoma17 yet instability to heat and dryness limited its
and a loss of conjunctival mucin-producing goblet cells. Blinding field performances in Africa.18 The diagnosis of adenovirus can be
complications result from chronic re-infection,12 severe dry eyes and done as a POC detection of antigen19 and real-time polymerase chain
entropion leading to corneal scarring, bacterial superinfection and reaction (PCR).20 Recently a second generation device, the AdenoPlus
ulceration. (RPS ADP, Rapid Pathogen Screening Inc.) was FDA-approved with
Adult inclusion conjunctivitis is an acute condition associated with the added benefit of detection of all 55 adenoviral serotypes.21 Most
sexually transmitted chlamydial infection: it presents with a mucopu- epidemics of viral conjunctivitis are caused by adenoviruses, com-
rulent discharge after a 4- to 12-day incubation period. It is often monly serotypes 8, 19 and 37 for EKC, and types 3 and 8 for PCF.
monocular and develops into a chronic follicular conjunctivitis, often Picornaviruses such as enterovirus type 70 and coxsackievirus type A24
with epithelial keratitis and limbal follicles. Tender preauricular cause AHC. Conjunctivitis can be a feature of many other viral dis-
lymphadenopathy is common. Untreated the disease has a chronic eases, including influenza, rubella, rubeola, chickenpox and glandular
course and may progress to keratitis and possibly iritis. fever.
VIRAL CONJUNCTIVITIS
Viral conjunctivitis is common, accounting for up to 80% of all cases Prevention of Infectious
of conjunctivitis and occurs worldwide. Between 65% and 90% of
cases of viral conjunctivitis are caused by adenovirus.13 Epidemics
Conjunctivitis
frequently occur and may be propagated in eye clinics. Transmission IN NEONATES
is by direct or indirect contact with ocular or upper respiratory tract Topical prophylaxis was described in 1881 by Credé. His silver nitrate
secretions. Airborne transmission occurs. Viral particles can remain eye drops substantially reduced the incidence of gonococcal conjunc-
infectious on surfaces for more than 1 month. The incubation period tivitis; however, they are inactive against Chlamydia and may be toxic.
is from 2 days to 2 weeks, and infected people remain contagious for Recently, 2.5% aqueous povidone–iodine has been shown to be safer,
up to 2 weeks after the symptoms begin. cheaper and more effective.22,23 Maternal treatment before birth is the
The main patterns of viral conjunctivitis are: best prevention.
• epidemic keratoconjunctivitis (EKC), associated with adenovi-
rus serotypes 8, 19 and 37; IN CHILDREN AND ADULTS
• pharyngoconjunctival fever (PCF), usually due to adenovirus The most important step in management of adenoviral conjunctivitis
serotype 3 but serotypes 1, 4, 5, 6, 7 and 14 have also been impli- is prevention of transmission. Control of epidemics associated with
cated;14 and eye clinics involves setting up a triage system for those suspected of
• acute hemorrhagic conjunctivitis (AHC). viral conjunctivitis.24 These patients are seen in a separate room with
The symptoms and signs of these patterns of infection are similar, dedicated personnel. The use of gloves and noncontact examination
but vary in degree. All of these patterns present as an acute follicular techniques are strongly recommended. Staff infected with viral con-
conjunctivitis, with watering, grittiness, redness, ecchymosis and lid junctivitis should be furloughed until 2 weeks after the start of symp-
edema, often with flu-like symptoms. Preauricular lymphadenopathy toms, by which time they are considered to be no longer contagious.
and bilateral involvement are common. It is recommended that personnel remain away from the workplace
In EKC most patients have some focal epitheliopathy and photo- for the duration of symptoms, specifically as long as eyes are red and
phobia by 2 weeks. Subepithelial opacities appear after 2 weeks in 50% tearing. Additionally, as a standard practice, close attention to hand-
of patients and occasionally impair vision. These lesions cause occa- washing and limiting contact is emphasized to each patient.
sional recurrences of grittiness. The natural history is of slow resolu- Trachoma is transmitted by contact with ocular or nasopharyngeal
tion, which can take more than 1 year. secretions, either directly through fomites or insect vectors (the flies
In PCF there is a similar ophthalmic picture, but the systemic fea- Musca sorbens in Africa and the Middle East and Hippelates spp. in
tures are more pronounced. the Americas). Untreated active lesions can be infectious for years.
In AHC ecchymosis is more prominent and the onset of symptoms Prevention of transmission is the most important public health
more rapid. AHC is generally caused by enterovirus 70 or coxsackievi- measure.25 Education about personal hygiene and regular washing of
rus A2, although it has been described with adenovirus 11. Rarely, a the face is very important, and these hygiene measures require only
152 SECTION 2 Syndromes by Body System: The Eye
a tiny amount of water. There has been mass treatment of the popula-
tion with topical azythromycin twice a day for three days in hyperen-
demic areas.
Managment of Infectious
Conjunctivitis
The management of viral conjunctivitis is supportive, with warm or
cold compresses reducing symptoms of itch, plus lubrication and
cycloplegics if there is an element of keratitis (see below). Antibacterial
prophylaxis is probably unnecessary and can cause an allergic or toxic
conjunctivitis. Steroids are typically withheld in the acute phase unless Figure 16-1 Typical microbial keratitis. Note accumulation of inflammatory cells
there are substantial corneal, subepithelial infiltrates with reduced at the dependent part of the anterior chamber of the eye (hypopyon) and mid-
vision and/or conjunctival adhesive membranes. corneal defect. Courtesy of Myron Yanoff.
Mild bacterial conjunctivitis is usually self-limited in the otherwise
healthy subject and it is reasonable to simply observe these patients
and use supportive care including physiological serum eye washing
and refrigerated artificial tears. If used in the first 2–5 days, topical systemic immunosuppression, injury or chronic disease). Algorithms
antibiotics can hasten resolution of symptoms in culture positive for the initial division of keratitis into the main clinical situations are
disease.26 If administered after 5 days of initial symptoms, the effect of shown in Figure 16-2. Microbial keratitis is responsible for 30% of
treatment will be minimal. However, no antibiotic has been identified cases of blindness in some LMIC. In hot climates fungal infection is
in the literature as superior to any other. more frequent, although bacterial keratitis still accounts for 60% of
Topical broad-spectrum antibiotic drops are used twice a day until cases.28
the symptoms subside, which should occur rapidly. In Europe, chlor- Surgery, particularly corneal grafts and corneal sutures, and con-
amphenicol is historically used and azythromycin is increasingly pre- comitant use of topical corticosteroids increase the risk of infection.
scribed due to short duration of therapy (3 days versus 5 days in classic Other than vitamin A deficiency, systemic predisposing conditions are
prescription). In the USA, neomycin, polymyxin and bacitracin are relatively unimportant clinically. Vitamin A deficiency is particularly
used. Gentamicin and tobramycin are useful against gram-negative important in children who are malnourished and who have a concomi-
organisms, but cause a higher rate of local toxic reactions. Erythromy- tant infection, especially measles, in which keratomalacia (corneal
cin or the quinolones may also be used. However, polymyxin β- melting) can occur suddenly. Staphylococcus spp., Streptococcus and
trimethoprim ophthalmic solution performed as well as moxifloxacin Pseudomonas spp. and the Enterobacteriaceae (Citrobacter, Klebsiella,
and was cost-saving in treating acute conjunctivitis in children.27 Enterobacter, Serratia and Proteus spp.) accounted for 87% of cases of
Treatment of chlamydial ophthalmia neonatorum comprises 2 bacterial keratitis in one series.29
weeks of erythromycin 10 mg/kg q12h for the first week and q8h for Pseudomonas infection is recognized for its swift suppurative course
the second week of life. to perforation secondary to proteolytic enzyme release. It is particu-
The Brazilian purpuric fever clone of H. influenzae biogroup aegyp- larly common in soft contact lens wearers. Serratia marcescens corneal
tius is resistant to trimethoprim but is sensitive to chloramphenicol ulcers have been associated with the wearing of contact lenses and with
and ampicillin. During epidemics systemic rifampin (rifampicin) contaminated eye drops. N. gonorrhoeae, C. diphtheriae and Haemophi-
(20 mg/kg/day for 2 days) may be used as prophylaxis against Brazilian lus and Listeria spp. are capable of penetrating an intact corneal epi-
purpuric fever for children who have conjunctivitis. thelium. Other bacteria and fungi produce disease only after a loss of
The drug of choice for treating N. gonorrhoeae and N. meningitidis corneal epithelial integrity. Mycobacterium tuberculosis is a rare cause
is an extended-spectrum cephalosporin such as ceftriaxone 1 g (25– of keratitis in the course of tuberculous scleritis.30 Also, Nocardia spp.
40 mg/kg) every 12 hours for 3 days (see Chapter 65). Repeated irriga- can cause keratitis.31
tion of the conjunctival sac is recommended to reduce inflammatory If the clinical picture progresses after 2 days of treatment the patient
microbial mediators in the cornea. Treatment of chlamydial conjunc- should be admitted to hospital for supervised treatment. If after the
tivitis is with doxycycline 100 mg q 12 h or erythromycin stearate first week there is no response to therapy, consider stopping therapy
500 mg q 6 h. Topical treatment is relatively ineffective. and reculturing or switching to a different antibiotic, guided by anti-
biotic sensitivity testing or consider coinfection, in particular with
fungi.
Keratitis
BACTERIAL KERATITIS
Infectious keratitis can be caused by bacteria, viruses, fungi or parasites Management
and can be suspected in various clinical situations, herein classified Either gentamicin 1.5% with cefuroxime 5% or the fluoroquinolones
as community-acquired keratitis, contact lens-related keratitis, and ofloxacin 0.3% or ciprofloxacin 0.3% are effective against 90% of
healthcare-associated. Infectious keratitis is a medical emergency of expected isolates in most clinical settings.32,33
which improper management can lead to loss of vision. Noninfectious Aminoglycosides are toxic to the epithelium in moderate doses and
keratitis is most common but infectious cases must be quickly identi- quinolones are preferred as monotherapy. In cases in which strepto-
fied or eliminated before considering other management. Sometimes cocci are likely (e.g. chronic ocular surface disease, children) there may
noninfectious keratitis, such as corneal infiltrates associated with be quinolone resistance, and combination with cefuroxime 5% is re
blepharitis, must be considered. commended. There are increasing reports of quinolone resistance in
some settings.34
Community-Acquired Keratitis Initial treatment is with drops every hour, day and night for 2 days,
Typical acute microbial keratitis is the major syndrome. Patients followed by review.35 If the clinical picture has improved or not wors-
present with a corneal epithelial defect, a stromal infiltrate (Figure ened, treatment is then reduced to drops every hour by day for 3 days.
16-1) and various levels of intraocular inflammation with anterior After this time the ulcer should be sterile. Treatment is reduced to
chamber reaction and hypopyon. The other main clinical problems prophylactic levels q6h until the epithelium has healed. One trap for
are herpesvirus infections, with recurrent inflammation leading to the inexperienced is that intensive treatment with ciprofloxacin 0.3%
scarring, and infection in a ‘compromised’ cornea (i.e. after local or can cause a white ciprofloxacin precipitate to form in the corneal
Diagnosis of keratitis
Infiltrate within No stromal infiltrate

the corneal stroma
Epithelial defect and No epithelial defect or No epithelial defect or Dendritic

fluorescein staining only mild staining only mild staining, staining pattern
but disordered
epithelial appearance
Diameter of Diameter of Previous similar Gray–white,

infiltrate infiltrate episodes, possible ring Pain out of History of Previous No history of
<1 mm, little >1 mm, peripheral infiltrate, proportion to previous (may history of trauma
or no anterior anterior location at the pain a clinical signs, be remote) trauma
chamber chamber margins of the predominant history of trauma,
activity, history activity, palpebral fissure, feature contact lens exposure to
of contact lens central blepharitis or use or chemicals,
use location meibomitis, little environmental cleansers,
anterior exposure eyebaths
chamber activity
Contact Typical acute Marginal Late Early Recurrent Possible Herpes

lens-related microbial keratitis Acanthamoeba Acanthamoeba erosions or healing keratitis
sterile infiltrate keratitis keratitis keratitis toxic keratitis abrasion
Treat without Urgent Treat without Prompt Prompt Withhold Wait 1 day Treat without
further investigation further investigation investigation treatment and and reassess further
investigations and treatment investigations and treatment and treatment observe investigations
by a corneal by a corneal closely
specialist specialist
Figure 16-2 Diagnosis of keratitis.
stroma adjacent to an epithelial defect. This may be confused with Recurrence occurs in around 10% of cases at 1 year and 50% by 20
progression of the infection. years. Triggers include fever, trauma, surgery and ultraviolet light.
After 5 days of antibiotic treatment, if the epithelium is closed and Recurrence is a consequence of latency.40 Typical presentation is
the infection controlled, topical corticosteroid can be introduced to central corneal dendritic ulcers without infiltration easily seen with
limit inflammation and stromal scar.36 fluoresceine test. Spread from eye to eye is uncommon except in atopic
patients in whom delayed-type hypersensitivity is impaired. These
VIRAL KERATITIS: HERPES SIMPLEX patients are at risk of bilateral disease, larger geographic ulcers and
VIRUS TYPE 1 OR 2 disseminated infection.
Epidemiology With each recurrence, corneal scarring increases, and it is thought
Herpes simplex keratitis has an annual incidence of new cases of that viral particles remaining within the cornea cause the continuing
8/10 000. The incidence peaks at ages 5–10 years and 35–40 years. inflammation and edema seen in disciform keratitis.
Males are affected twice as often as females. Approximately 50% of
patients have a history of herpes labialis. Primary ocular infection
Management
occurs in 5%.37
Corneal infection is usually with HSV type 1 (in 98% of cases), Untreated herpes simplex keratitis usually resolves within 1–2 weeks,
except in neonatal herpes infection, when 80% of cases are due to HSV but it can progress, resulting in the development of geographic ulcers.
type 2. Resolution is more rapid if the dendritic ulcer is debrided. Antiviral
treatment also speeds up resolution, and no benefit has been shown
Pathogenesis and Pathology for a combination of debridement and antiviral agents when compared
The pattern of dendritic ulcers is caused by direct infection of corneal with the use of antiviral agents alone. The choice of antiviral agent
epithelium. It is thought that delayed-type hypersensitivity to viral depends on availability. In Europe aciclovir 3% ophthalmic ointment
antigens causes the inflammation that leads to disciform keratitis.38 five times a day is almost universally preferred because it is effective
Recurrent HSV keratitis has been described in the course of Alport and has a low incidence of toxicity.41 In the USA, trifluridine 1%
syndrome.39 2-hourly is used.
Oral aciclovir or famciclovir is effective but comparatively expen-
Clinical Features sive. It may be useful when there is a desire to reduce corneal exposure
Primary ocular infection is usually asymptomatic, although a vesicular to topical agents.
reaction may be seen. Occasionally there is a follicular conjunctivitis. Prophylactic treatment with oral aciclovir 400 mg q12h reduces the
Corneal damage is caused by recurrent disease. recurrence rate of stromal (severe) disease from 28% to 14%.42
Figure 16-3 Herpes zoster ophthalmicus. Inflamed right periorbital skin, with Figure 16-4 Fungal keratitis. The corneal surface looks rough, and there are
conjunctivitis and a lesion on the nose. Courtesy of Myron Yanoff. several satellite lesions best seen here at the periphery on the left side of the
cornea. Courtesy of Myron Yanoff.
The management of the chronic sequelae of herpes simplex kera- otherwise healthy eyes. In temperate climates infection most often
titis may require topical corticosteroid therapy under close ophthalmic occurs in association with chronic ocular surface disease or prolonged
supervision. Topical antiviral treatment reduces recurrence rates in corticosteroid use. The septate filamentous fungal species, especially
these patients.43 Fusarium and Aspergillus spp., are the most common cause of fungal
keratitis. With increasing distance from the equator the relative inci-
VIRAL KERATITIS: HERPES ZOSTER dence of candidal infection increases. Dematiaceous filamentous fungi
OPHTHALMICUS such as Curvularia spp. are of low virulence and cause indolent
Epidemiology infections.
VZV is a herpesvirus that causes chickenpox as a primary infection Clinical Features
and shingles on recurrence. Around 90% of adults are seropositive for
Fungal keratitis usually presents as a typical microbial keratitis. It is
VZV. The rate of recurrence increases with age, and second recurrences
not possible to diagnose the type of infection on clinical grounds.
can occur in those who have impaired immunity.
Clinical context is the most important guide to appropriate investiga-
Pathogenesis and Pathology tion and therapy. In filamentous fungal keratitis the corneal surface is
Reactivated virus replicates in the nerve root ganglion, producing local gray or dull. Satellite lesions are common in the surrounding stroma
inflammation and premonitory pain before it travels down peripheral and may be seen with an intact epithelium (Figure 16-4). Candidal
nerves to the skin or eye. A perineuritis and vasculitis occurs, and lesions appear in corneas that are already abnormal. They are often
in the eye a disciform keratitis, iritis and cyclitis are common quite localized at first with a collar-button configuration.
manifestations.
Management
Clinical Features Historic data are the best guide to selecting antifungal therapy.29 The
The clinical appearance is typical. Symptoms of eye involvement greatest experience in the use of antifungals for keratitis comes from
include photophobia and decreased vision. Hutchinson’s sign, a India. However, this experience may not apply to situations where
rash on the side of the nose, is associated with ocular inflammation there is a local or systemic disorder of immunity.
(Figure 16-3). No currently available antifungal agent has a favorable profile of
activity and toxicity. Response to antifungal treatment is poor com-
Management pared with that to antibacterial treatment. Surgical management
Oral aciclovir 800 mg five times a day for 7 days accelerates skin (corneal transplant) may be necessary.
healing and reduces the incidence of episcleritis, keratitis, iritis, Combined topical and systemic therapy is often used and is usually
postherpetic neuralgia and probably acute pain.44 The newer antivirals prolonged. Corneal drug penetration is helped by daily scraping of the
famciclovir and valaciclovir have improved bioavailability and are epithelium and necrotic stroma.
increasingly used instead of aciclovir (see Chapter 153). There is little The choice of antifungal agent is often dictated by availability. Most
role for topical antivirals. Systemic corticosteroids used with antiviral topical antifungal agents must be made locally from tablets or intra-
therapy have some benefit in shortening the clinical syndrome, but venous preparations.
they do not reduce the incidence of postherpetic neuralgia.45 Among the polyenes, amphotericin B is fungicidal, but is toxic to
Disciform keratitis, iritis and cyclitis respond to conventional the eye in high concentrations. It is used diluted in sterile water at
topical corticosteroid treatment, but prolonged therapy, sometimes for 0.1–0.15% two to four times every hour for the first 1–2 days. Nata-
years, is required. mycin 5% has poor corneal penetration, but is useful for superficial
filamentous fungal infections.
AIDS: VARICELLA-ZOSTER Among the pyrimidines, flucytosine 1% can be prepared from a
EPITHELIAL KERATITIS commercially available intravenous or tablet form and is used in com-
A chronic, painful epithelial keratitis has been described in patients bination only (early resistance occurs) with amphotericin B for candi-
with AIDS and severe immunodeficiency. Clinically characterized by a dal keratitis. Concomitant systemic use may be helpful.
variable dendrite-like keratitis, the associated severe, burning pain is Among the imidazoles, miconazole 10 mg/mL in polyethoxylated
the most dramatic feature. Response to treatment is variable; some castor oil (intravenous preparation) was effective in more than 60%
patients have responded to oral or topical aciclovir, but such patients of cases in a prospective trial in India47 when used topically every 2
tend to relapse when treatment stops.46 hours. Ketoconazole 2% is prepared as an aqueous solution from
tablets and is probably effective against Aspergillus flavus, but not
FUNGAL KERATITIS Aspergillus fumigatus or Fusarium spp. Systemic and topical adminis-
Fungal infections are seen in two distinct clinical settings. In hotter tration are often combined. Econazole 1% is used topically in combi-
climates the cornea is inoculated with infected vegetable matter as a nation with systemic itraconazole, and clotrimazole 1% vaginal cream
result of agricultural or other trauma. Infection can then occur in has also been used. Fluconazole is given systemically or as a 0.2–0.5%
topical aqueous solution. The newer oral azoles have variable activity In early epithelial disease there may be punctate keratopathy, pseu-
against different fungal species (see Chapter 156) and may be useful dodendrites, epithelial wrinkling, diffuse or focal subepithelial infil-
in some circumstances. trates and radial perineural infiltrates. Ring infiltrates and corneal
Silver sulfadiazine 1% is used for antibiotic prophylaxis in patients ulceration may present later.57,61 Pain out of proportion to the clinical
who have burns. It has moderate antifungal activity in vitro, but has signs is common, but not constant. The clinical picture may resemble
been widely used in LMIC as a topical antifungal with good rates of herpetic or fungal keratitis, and a high index of suspicion is warranted
success, particularly against Fusarium spp. in contact lens wearers who have apparent herpetic disease. Bacterial
Chlorhexidine gluconate 0.2% solution is at least as effective as coinfection or superinfection in late disease occurs in around 10% of
natamycin in treating fungal infections and is suggested as an inexpen- cases and causes an atypical presentation.
sive agent for use in LMIC.32 The clinical course of Acanthamoeba keratitis is prolonged. Early
Initial treatment for fungal keratitis depends upon local experience. diagnosis is important, but treatment started before proper diagnostic
Topical econazole 1% (or amphotericin B 0.15% or 0.3%) can be used tests are carried out only confuses the clinical picture. Unlike bacterial
hourly for 48 hours, then 2-hourly for 72 hours and then at a reduced keratitis there is no justification for starting therapy without investiga-
dosage depending upon the initial response. Long-term treatment is tion. A delay of 1–2 days while a patient is referred for expert opinion
required. Systemic treatment is used as an adjunct. If surgical debride- and investigation is less harmful than early inappropriate therapy. The
ment is performed, a 2 mm clear margin is advised. The inflammatory grave prognosis of Acanthamoeba keratitis in the past was due to the
reaction results from live organisms and fungal debris. Because slow inexorable progression of disease rather than fulminant corneal
most antifungal agents are fungistatic, reduction of inflammation also destruction.
depresses local immunity so that the organisms are not killed. Con- For microbiologic analysis, specimens can be plated on non-
comitant corticosteroid use is therefore not recommended for fungal nutrient agar, which is later overlain with Escherichia coli in the labora-
keratitis. tory. Tracks of bacterial clearing show where the amebae have been
grazing. Bacterial and fungal cultures should also be obtained.
Microscopy techniques vary. Fluorescent microscopy can be carried
Contact Lens-Related Keratitis out using calcofluor white, which stains the walls of cysts, with acridine
The wide use of contact lenses has led to increased prevalence of spe- orange or with an immunofluorescent antibody. An immunoperoxi-
cific opportunistic pathogens including Pseudomonas spp., nontuber- dase test is used in some laboratories. Confocal microscopy of a wet
culous mycobacteria such as Mycobacterium chelonae,48 fungi such as preparation can be used to identify motile trophozoites, which have a
Fusarium,49 and free-living Acanthamoeba amebae.50 The wearing of large karyosome and a contractile vacuole.
contact lenses increases the risk of developing bacterial keratitis.51 The Biopsy specimens should also be stained with hematoxylin and
annual incidence is 5/10 000 for daily wear of soft lenses and 20/10 000 eosin, periodic acid–Schiff and methenamine silver to demonstrate
for overnight wear of soft lenses, although estimates 10-fold higher Acanthamoeba cysts.
than this have been made. It has been estimated that over 65% of all Sensitivity testing, although useful in screening for amebicides, is
new cases of keratitis in London, UK are due to the wearing of contact less useful in the management of individual cases,60,62 perhaps because
lenses.52 The largest risk factor is the overnight wearing of soft lenses. Acanthamoeba encysts in infected tissues.
This increases the risk fivefold compared with the daytime wearing of
lenses and 20-fold compared with the wearing of rigid lenses.35 One Management
particular situation is microbial keratitis associated with orthokeratol- The diamidines, propamidine isethionate 0.1% and hexamidine 0.1%
ogy, with Pseudomonas aeruginosa and Acanthamoeba spp. being the and the cationic antiseptics, polyhexamethyl biguanide (PHMB)
leading causes; cases have been mostly reported in East Asian patients.53 0.02% and chlorhexidine 0.02%, are probably the most effective medi-
The incidence of fungal keratitis associated with contact lenses steadily cations,54, 63 although availability can be a problem. Local manufacture
increased up to >50 % in Florida.54 Higher incidence has been noted of chlorhexidine or PHMB may be possible from 20% disinfectant
in the 2004–2006 multicountry Fusarium keratitis epidemic,55 which preparations. The azoles (clotrimazole, fluconazole, ketoconazole and
has been associated with the use of particular soft contact lenses miconazole) have also been suggested for use as a third agent.
and contact lens solution. Fusarium keratitis evolves towards corneal Initial treatment starts immediately after the epithelium is debrided
ulceration.56 using a cationic antiseptic and a diamidine, each hour day and night
for 48 hours, then hourly by day for 3 days. Dosage is then reduced to
ACANTHAMOEBA KERATITIS 3-hourly to reduce local toxicity. If toxicity is suspected the frequency
Clinical Features of the diamidine should be reduced. It may take 2 weeks to achieve a
Acanthamoeba keratitis is a painful vision-threatening infection, which response to treatment. Pain relief with systemic nonsteroidal anti-
can lead to ulceration of the cornea, loss of visual acuity and eventually inflammatory agents and cycloplegia is very important. The use of
blindness and enucleation. Acanthamoeba keratitis is associated with corticosteroids in controlling inflammation is controversial. Some
trauma to the cornea and contact lens wear, and use of contaminated authorities say that they are contraindicated at any stage. Others advo-
saline solution is the major risk factor. Indeed, Acanthamoeba amebae cate the use of a weak topical corticosteroid to control inflammation
live in soil and water, including swimming pools, water storage tanks after at least 2 weeks of anti-amebic therapy, emphasizing the impor-
and contact lens cases (see Chapter 193).57 Approximately 10–15% of tance of continued anti-amebic therapy until several weeks after the
cases are associated with agricultural and other trauma, but most are corticosteroid is stopped.
associated with contact lens use and the occurrence of Acanthamoeba
keratitis is increasing in the USA.58 Poor lens hygiene by soft contact DIAGNOSIS OF INFECTIOUS KERATITIS
lens wearers and the use of homemade saline- or chlorine-based dis- In some parts of the world broad-spectrum therapy is used without
infection systems are risk factors. Disposable lens wearers have a par- initial investigation and it has been suggested that this practice could
ticularly high risk, although this may be related to care systems used be extended.64 If microbiologic services are not available there is little
with the lenses.59 The use of tank-stored water by contact lens wearers choice. However, the current high success rates of this treatment may
to rinse lenses or lens cases may have introduced amebae into their not continue and in some areas antibiotic resistance is developing.
lens care systems.60 The free-living protozoa have been seen grazing on Corneal scraping also debrides the ulcer, allows antibiotics to enter the
bacterial slime on the bottom of contact lens cases. base of the ulcer and provides microbiologic data (provided that anti-
A 360° or paracentral stromal ring infiltration is a characteristic of microbial therapy has not been given within the previous 24 hours).
Acanthamoeba keratitis, and a nonhealing corneal ulcer is often the The cornea is anesthetized with one drop of oxybuprocaine. Using a
first clue. slit-lamp, necrotic material is removed from the center of the ulcer
using a blade. A 23-gauge needle tip is scraped parallel to the cornea PREVENTION
to remove infected tissue. A fresh needle is used for each specimen. If Good lens hygiene, the use of hydrogen peroxide 3% for at least 3
a slit-lamp is not available scraping with a scalpel blade is safer than hours62 and avoidance of tap water in contact lens care are important
using a needle. The diagnostic yield is greater from the sides of the preventive measures.53 The role of mechanical rubbing is still debated.74
ulcer than from necrotic areas. Slides should be made for Gram stain The main cause of fungal keratitis worldwide is trauma. In higher-
and Giesma stain, and appropriate bacterial cultures (and fungal cul- income countries risk factors include protracted epithelial ulceration,
tures if suspected) should be prepared directly from the needle. therapeutic wearing of soft contact lenses, corneal transplant and
Bending the tip of the needle before use facilitates this. The sharp side topical corticosteroid therapy. Patients who have exposure keratitis
is used to scrape the cornea and the smooth surface used to plate out and a history of previous herpes simplex or herpes zoster keratitis are
the specimen without penetrating the surface of the agar. at risk.
Diagnosis is by microscopy and culture of a corneal scrape. In
contact lens wearers the lenses and the lens case should be cultured. Keratitis Following Ocular Surgery
As for bacterial keratitis, microscopic examination of Gram-stained
Penetrating keratoplasty has been complicated by Gemella haemolysans
corneal smears or biopsy may reveal bacteria.65 Acid fast bacteria may
keratopathy75 diagnosed by corneal biopsy. Laser in situ keratomileusis
be observed in cases of Mycobacterium spp. and Nocardia spp. kerati-
(LASIK) may be complicated by infectious keratitis. A three-patient
tis.65 Diagnosis of Acanthamoeba keratitis is made by microbiologic
cluster of Nocardia asteroides keratitis was traced to inappropriate use
and histopathologic examination of tissue specimens. The epithelium
of the same blade and microkeratome in all patients.65 Propionibacte-
is removed for examination by epithelial biopsy. In cases in which only
rium acnes has been recovered in one case.76 Notably, several nontu-
the stroma appears to be involved, corneal biopsy (described above)
berculous, rapidly growing mycobacteria including Mycobacterium
is necessary. If culture is negative, tear fluid PCR has been suggested
chelonae caused post-LASIK keratitis.77
as an adjunctive investigation.66
Methicillin-resistant Staph. aureus keratitis has been described fol-
For viral keratitis viral culture or immunofluorescence67 can be
lowing refractive surgery.78 Staph. aureus and Strep. pneumoniae in
used to confirm infection, but in practice the diagnosis is clinical. In
LMIC, and Staph. epidermidis in higher-income countries are respon-
epithelial disease there is a characteristic dendritic ulcer (Figure 16-5).
sible for infectious keratitis following keratoplasty.79
Corneal sensation is often impaired, and there is usually a history of
similar attacks in the past.
Diagnosis is by culture of corneal scrapes. In indolent cases corneal Infections of Periorbital Structures
biopsy is indicated. Laboratory diagnosis of infectious keratitis relies
on culture-based and OCR-based detection of the pathogen in suitable Periorbital Cellulitis
ocular specimen. A ‘keratitis kit’ can been developed in order to stan- The orbit is the bony structure surrounding the eye. Infection of
dardize both the clinical specimens and laboratory tests. the contents of the bony orbit is called orbital cellulitis. Orbital infec-
Definitive diagnosis of Acanthamoeba keratitis is made by micro- tion commonly occurs as a result of contiguous spread from adjacent
scopic observation of amebal trophozoites and cysts in corneal scrap- structures. Periorbital cellulitis is divided into preseptal or postseptal
ings or biopsy, or on their cultivation from infected tissues. Confocal (orbital) depending on the site of infection. Orbital cellulitis is sight-
microscopy has been used as an aid in the diagnosis.68 Also, PCR-based threatening and occasionally life-threatening.
molecular tests applied to corneal specimens and tear fluid allow one Preseptal cellulitis is 5–10 times more common than orbital cellu-
to identify and genotype Acanthamoeba by 18S rDNA sequencing.69 litis in infants and toddlers and is not sight-threatening or life-
Sequence analysis of the internal transcribed spacer 1 and microsatel- threatening, but it can, rarely, spread to become orbital cellulitis. It is
lites analysis may allow further genotyping.70 MALDI-TOF mass spec- commonly caused by H. influenzae or Streptococcus spp. and follows
trometry is a promising rapid method, not only for the identification an upper respiratory tract infection. In adults it is most often seen after
of isolates, but also the detection/identification of amebae in corneal minor trauma such as an infected bite or scratch.
specimens.71 A real-time PCR assay72 and a multiplex real-time PCR The source and agents of infection causing orbital cellulitis vary
assay73 have also been developed for the rapid detection of most, but with age. The paranasal sinuses (the ethmoid, maxillary and frontal
not all, the Acanthomoeba spp. genotypes involved in keratitis. sinuses) are the main sources. In older children and adults dental
abscesses and trauma become important causes. Endogenous orbital
cellulitis is rare.
CLINICAL FEATURES
In adults there is frequently a history of sinusitis, headache or recent
tooth extraction or abscess.
Preseptal cellulitis is characterized by eyelid swelling and edema,
which is usually unilateral and mainly involves the upper lids. Lower
lid swelling occurs when the cellulitis is secondary to dacryocystitis.
Edematous conjunctiva can prolapse between the lids.
In orbital cellulitis features of preseptal cellulitis are variably
present, but there is also proptosis, decreased ocular mobility and even
decreased vision or a relative afferent pupil defect. These signs are
caused by increased intraorbital pressure due to edema or abscess. If a
subperiosteal abscess forms there may be nonaxial displacement of the
globe and a palpable fluctuant mass in the orbit. Headache, fever and
leukocytosis are common.
DIAGNOSIS
a b Blood and local cultures are mandatory. A computed tomography
(CT) scan can distinguish between preseptal and orbital cellulitis and
Figure 16-5 Herpes simplex virus dendritic keratitis, showing branching epithe-
lial lesions seen (a) without staining and (b) with rose bengal staining. Rose
show the site of an orbital or subperiosteal abscess:
bengal stains the devitalized cells at the edges of the dendritic lesions. Courtesy • preseptal cellulitis produces edema of the lids and tissues ante-
of Myron Yanoff. rior to the orbital septum; and
• orbital cellulitis produces edema of the orbital tissues and Management

proptosis. Treatment is generally symptomatic. Corticosteroids can help speed up
Orbital cellulitis is often associated with signs of primary or sec- resolution. It can be difficult to distinguish dacryoadenitis from idio-
ondary sinus disease. pathic lacrimal gland inflammation (pseudotumor), although the
Staphylococcus and Streptococcus spp. and, in those under four years presence of enlarged preauricular lymph nodes makes a viral diagnosis
of age, H. influenzae are the main pathogens that cause preseptal and more likely.
orbital cellulitis in children. In subperiosteal abscesses in children over
nine years of age and adults there is often a mixed infection of aerobes CANALICULITIS
and anaerobes from extending sinus or dental infections. There are chronic and acute forms. Acute dacryoadenitis may be
caused by herpes simplex or herpes zoster and is often unrecognized
MANAGEMENT except as a conjunctivitis and by its sequelae: scarred closed canaliculi
Preseptal cellulitis responds well to systemic antibiotics. One or more and a punctum.
broad-spectrum agents that cover Staphylococcus and Streptococcus spp. Chronic canaliculitis is usually unilateral and is characterized by
and H. influenzae should be used. A response is usual within 24 hours. pain or tenderness at the inner canthus. A chronic conjunctivitis may
Orbital cellulitis requires prompt diagnosis and inpatient treatment mask the more specific signs. The lacrimal punctum may pout and
with intravenous antibiotics. Monitoring of vision, pupillary reaction, ‘sulfur granules’ may be expressed. These sulfur granules are patho
extraocular movements and central nervous system function should gnomonic of infection with Actinomyces israelii, an anaerobic gram-
be carried out during the first 1–2 days until the infection begins to positive branching filamentous bacterium. Less common causes are
resolve. If a subperiosteal abscess or sinusitis is identified and the clini- Aspergillus and Candida spp.
cal picture is not improving after 24 hours, surgical management is Treatment is by incision of the infected canaliculus and wash-out
required. Orbital or brain abscesses are less common and should be of all ‘sulfur’ material, usually with a penicillin-containing irrigation
drained immediately. fluid.
Lacrimal System Infections DACRYOCYSTITIS

DACRYOADENITIS Pathogenesis and Pathology
Dacryoadenitis is usually due to a viral infection of the lacrimal gland. This condition occurs in chronic and acute forms.
Patients present with adenopathy, fever, malaise and leukocytosis. The In adults an acquired blockage of the lacrimal drainage system can
causes include infectious mononucleosis, herpes zoster, mumps, tra- cause an acute or chronic infection. An acute infection can be precipi-
choma, syphilis, tuberculosis and sarcoidosis. Dacryoadenitis occa- tated by instrumentation for investigation of a suspected blocked lac-
sionally occurs in dehydrated patients as an ascending staphylococcal rimal duct. For this reason, mucoceles or chronic dacryocystitis should
infection associated with a purulent discharge. On CT scanning there not be probed or syringed. Acute dacrocystitis presents with a painful
is diffuse lacrimal gland swelling without bony defects. swelling over the lacrimal sac.
Treatment is with warm compresses and systemic antibiotics. A
Diagnosis large abscess should be drained by a stab through the skin or inferior
The condition is usually self-limiting. Investigation other than CT fornix conjunctiva. A dacryocystorhinostomy will prevent recurrence.
scanning is reserved for chronic dacryoadenitis, and such patients
should be referred for specialist investigation to exclude neoplasia. References available online at expertconsult.com.
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Chapter 16 Conjunctivitis, Keratitis and Infections of Periorbital Structures 157.e1
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practitioners adhere to the guideline on infectious acute conjunctivitis in children. J Pediatr 2013; 162:857- other risk factors in microbial keratitis. Lancet 1991;
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Survey of General Practice. BMC Fam Pract 2007; 28. Liesegang T.J., Forster R.K.: Spectrum of microbial 53. Watt K.G., Swarbrick H.A.: Trends in microbial keratitis
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3. Bielory B.P., O’Brien T.P., Bielory L.: Management of 90:38-47. 33(6 Pt 2):373-377, discussion 382.
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4. Kanski J., Bowling B.: Clinical ophthalmology: a system- 30. Tabbara K.F.: Tuberculosis. Curr Opin Ophthalmol nemesis on the block? Eye Contact Lens 2007; 33(6 Pt
atic appraoch, 7th ed, Edinburgh: Elsevier; 2012. 2007; 18:493-501. 2):415-417, discussion 424-425.
5. de Groot H., Brand P.L., Fokkens W.F., et al.: Allergic 31. Lalitha P., Srinivasan M., Rajaraman R., et al.: Nocardia 55. Gorscak J.J., Ayres B.D., Bhagat N., et al.: An outbreak
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985-988. Am J Ophthalmol 2012; 154:934-939. the northeastern United States. Cornea 2007; 26:1187-
6. Wright H.R., Turner A., Taylor H.R.: Trachoma. Lancet 32. Parks D.J., Abrams D.A., Sarfarazi F.A., et al.: Compari- 1194.
2008; 371:1945-1954. son of topical ciprofloxacin to conventional antibiotic 56. Hu S., Fan V.C., Koonapareddy C., et al.: Contact lens-
7. Laga M., Meheus A., Piot P.: Epidemiology and control therapy in the treatment of ulcerative keratitis. Am J related Fusarium infection: case series experience in
of gonococcal ophthalmia neonatorum. Bull World Ophthalmol 1993; 115:471-477. New York City and review of fungal keratitis. Eye
Health Organ 1989; 67:471-477. 33. Hyndiuk R.A., Eiferman R.A., Caldwell D.R., et al.: Contact Lens 2007; 33(6 Pt 1):322-328.
8. Talley A.R., Garcia-Ferrer F., Laycock K.A., et al.: Com- Comparison of ciprofloxacin ophthalmic solution 0.3% 57. Martinez A.J., Visvesvara G.S.: Free-living, amphizoic
parative diagnosis of neonatal chlamydial conjunctivitis to fortified tobramycin–cefazolin in treating bacterial and opportunistic amebas. Brain Pathol 1997; 7:583-
by polymerase chain reaction and McCoy cell culture. corneal ulcers. Ciprofloxacin Bacterial Keratitis Study 598.
Am J Ophthalmol 1994; 117:50-57. Group. Ophthalmology 1996; 103:1854-1862. 58. Foulks G.N.: Acanthamoeba keratitis and contact lens
9. LaMattina K., Thompson L.: Pediatric conjunctivitis. 34. Goldstein M.H., Kowalski R.P., Gordon J.: Emerging wear: static or increasing problem? Eye Contact Lens
Dis Mon 2014; 60(6):231-238. fluoroquinolone resistance in bacterial keratitis. A 2007; 33(6 Pt 2):412-414, discussion 424-425.
10. Strouts F.R., Power P., Croucher N.J., et al.: Lineage- 5-year review. Ophthalmology 1999; 106:1313-1318. 59. Radford C.F., Bacon A.S., Dart J.K., et al.: Risk
specific virulence determinants of Haemophilus influen- 35. Dart J.K.: The epidemiology of contact lens related factors for Acanthamoeba keratitis in contact lens
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11. Azari A.A., Barney N.P.: Conjunctivitis: a systematic 36. McGhee C.N., Dean S., Danesh-Meyer H.: Locally 60. Seal D., Stapleton F., Dart J.: Possible environmental
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12. Beatty W.L., Byrne G.I., Morrison R.P.: Repeated and 37. Norn M.S.: Dendritic (herpetic) keratitis. I. Incidence 61. Rahman M.R., Johnson G.J., Husain R., et al.: Ran-
persistent infection with chlamydia and the develop- – seasonal variations – recurrence rate – visual impair- domised trial of 0.2% chlorhexidine gluconate and
ment of chronic inflammation and disease. Trends ment – therapy. Acta Ophthalmol (Copenh) 1970; 48:91- 2.5% natamycin for fungal keratitis in Bangladesh. Br J
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13. O’Brien T.P., Jeng B.H., McDonald M., et al.: Acute 38. Pepose J.S.: Herpes simplex keratitis: role of viral infec- 62. Moore M.B.: Acanthamoeba keratitis and contact lens
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Opin 2009; 25:1953-1961. 35:345-352. 33-35.
14. Newman H., Gooding C.: Viral ocular manifestation: a 39. Chung P.C., Lin K.K., Song H.S., et al.: Alport syndrome 63. Bacon A.S., Frazer D.G., Dart J.K., et al.: A review of 72
broad overview. Rev Med Virol 2013; 23:281-294. with recurrent herpes simplex virus keratitis. Cornea consecutive cases of Acanthamoeba keratitis, 1984–
15. Liesegang T.J.: Bacterial keratitis. Infect Dis Clin N Am 2007; 26:1279-1281. 1992. Eye 1993; 7:719-725.
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rial conjunctivitis. Am J Ophthalmol 1991; 112:2-9. 151. 65. Garg P., Sharma S., Vemuganti G.K., et al.: A cluster of
17. Michel C.E., Solomon A.W., Magbanua J.P., et al.: Field 41. Elder M.J., Kilvington S., Dart J.K.: A clinicopathologic Nocardia keratitis after LASIK. J Refract Surg 2007;
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antibiotic treatment for trachoma control: a compara- keratitis. Invest Ophthalmol Vis Sci 1994; 35:1059-1064. 66. Lehmann O.J., Green S.M., Morlet N., et al.: Polymerase
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18. Harding-Esch E.M., Holland M.J., Schémann J.F., et al.: simplex virus eye disease. Herpetic Eye Disease Study samples in the diagnosis of Acanthamoeba keratitis.
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tions in The Gambia and Senegal. PLoS Negl Trop Dis factors for herpes simplex virus epithelial keratitis vitro evaluation of antimicrobial compounds for cysti-
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ness of a point-of-care test for adenoviral conjunctivitis. thalmol 1996; 80:969-972. 68. Parmar D.N., Awwad S.T., Petroll W.M., et al.: Tandem
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20. Malamos P., Georgalas I., Rallis K., et al.: Evaluation of herpes zoster ophthalmicus by oral acyclovir. Am J Med of suspected Acanthamoeba keratitis. Ophthalmology
direct immunofluorescence assay and cytological exam- 1988; 85:90-93. 2006; 113:538-547.
ination in comparison to polymerase chain reaction of 45. Wood M.J., Johnson R.W., McKendrick M.J., et al.: A 69. Visvesvara G.S., Moura H., Schuster F.L.: Pathogenic
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21. Kam K.Y., Ong H.S., Bunce C., et al.: Sensitivity and zoster. N Engl J Med 1994; 330:896-900. Sappinia diploidea. FEMS Immunol Med Microbiol 2007;
specificity of the AdenoPlus point-of-care system in 46. Chern K.C., Conrad D., Holland G.N., et al.: Chronic 50:1-26.
detecting adenovirus in conjunctivitis patients at an varicella-zoster virus epithelial keratitis in patients with 70. Köhsler M., Leitner B., Blaschitz M., et al.: ITS1
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22. Isenberg S.J., Apt L., Yoshimori R., et al.: Povidone– 47. McLeod S.D., Kolahdouz-Isfahani A., Rostamian K., zoa). Parasitol Res 2006; 98:86-93.
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23. Isenberg S.J., Apt L., Wood M.: A controlled trial of keratitis. Ophthalmology 1996; 103:23-28. mass spectrometry. J Eukaryot Microbiol 2003; 50:156-
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neonatorum. N Engl J Med 1995; 332:562-566. tis: elucidation of diagnosis through evaluation of 72. Rivière D., Szczebara F.M., Berjeaud J.M., et al.: Devel-
24. Haller E.M., Auer-Grumbach P., Stuenzner D., et al.: smears of fluid from patient’s contact lens care system. opment of a real-time PCR assay for quantification
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25. Munoz B., West S.: Trachoma: the forgotten cause of outcomes of Fusarium keratitis associated with contact 73. Qvarnstrom Y., Visvesvara G.S., Sriram R., et al.: Mul-
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26. Sheikh A., Hurwitz B.: Antibiotics versus placebo for 50. Keay L., Edwards K., Naduvilath T., et al.: Microbial of Acanthamoeba spp., Balamuthia mandrillaris, and
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116.
17
Endophthalmitis
MICHEL DRANCOURT | FRÉDÉRIC MATONTI
is contaminated with vegetable matter.8 The leading organisms in this

KEY CONCEPTS
setting are staphylococci, especially Staph. aureus, and Bacillus spp.
• Endophthalmitis is fortunately an uncommon condition; how Endogenous bacterial and fungal endophthalmitis are the least
ever, it may result in severe visual impairment or loss of an eye. common forms, accounting for less than 2–8% of cases; they usually
• Causes include postsurgical, post-traumatic and endogenous follow bloodstream spread of organisms and are commonly associated
endophthalmitis with a number of chronic medical conditions, such as diabetes melli-
tus, chronic renal failure, chronic immunosuppression, invasive
• Fungal endophthalmitis may occur as exogenous or endoge medical procedures (including urinary catheterization and intravascu-
nous infection; molds are usually associated with exogenous
lar central lines) and intravenous drug abuse.
infection, with Candida species the most common cause of
endogenous fungal endophthalmitis.
• Early diagnosis of endophthalmitis requires a high index of
suspicion as classic features of infection may be absent. Although a broad range of organisms can cause endophthalmitis, the
most common causative infectious agents are bacteria. Virtually any
• Early institution of antimicrobial therapy is essential to optimal bacterium, including those usually accepted as saprophytes, can cause
outcome in the management of infective endophthalmitis. infection, although members of the normal ocular microflora are the
Intravitreal injection of antibiotics is the most effective way of most commonly implicated.
rapidly achieving high intraocular antibiotic levels; however,
long-term use of intravitreal injections may produce significant ACUTE AND DELAYED-ONSET POSTOPERATIVE
retinal toxicity.
ENDOPHTHALMITIS
• The primary complication of endophthalmitis is retinal detach Infecting organisms are usually introduced into the eye via incisions
ment that may occur at any time before, during or after at the time of surgery. Nosocomial outbreaks of endophthalmitis
treatment. caused by contaminated irrigation fluids, intraocular lenses and donor
corneas have been recognized. A contaminated phacoemulsification
probe was demonstrated as a source of nosocomial endophthalmitis
following phacoemulsification cataract extraction surgery.9 Infiltration
Epidemiology of pathogens in the immediate postoperative period may be associated
DEFINITION AND NOMENCLATURE
Endophthalmitis is an infection within the vitreous and may involve
the cornea and, in severe cases, the sclera (panophthalmitis). A number
TABLE
of classifications of this condition have been published but from a Microbial Etiology of Endophthalmitis
17-1
practical point of view, categorization by the clinical setting, taking
into account such factors as the events preceding infection and the time Category of Endophthalmitis Common Causative Organisms
to diagnosis, is most appropriate. Categories include postoperative
Postoperative Acute Coagulase-negative staphylococci
endophthalmitis (acute within 2 weeks of operation or delayed onset, Staphylococcus aureus
more than 2 weeks after operation), associated with conjunctival filter- Streptococcus spp.
ing blebs seen in treatment of glaucoma, post-traumatic endophthal- Gram-negative bacilli
mitis and endogenous endophthalmitis. Each of these subtypes may Pseudomonas spp.
Delayed Staphylococcus epidermidis
have characteristic clinical features and a spectrum of common caus- Propionibacterium acnes
ative pathogens (Table 17-1). This classification fits with the clinical Candida spp.
classification of uveitis.1 Filtering Streptococcus spp.
bleb Haemophilus influenzae
INCIDENCE AND PREVALENCE OF Staphylococcus aureus
ENDOPHTHALMITIS Post-traumatic Bacterial Staphylococcus aureus; other
Although recent eye surgery is the most common cause of endophthal- Staph. spp.
Bacillus spp.
mitis, accounting for more than 70% of cases, the incidence of infec- Pseudomonas spp.
tion after cataract extraction, the most commonly performed eye Other gram-negative bacilli; anaerobes;
surgery, is very low, at 0.07–0.13%.2,3 Endophthalmitis may occur after corynebacteria; streptococci
any other form of ocular surgery, but appears to be more common Fungal Penicillium spp.; Fusarium spp.;
Acremonium spp.; other filamentous
after glaucoma filtering procedures. Non-tuberculous mycobacteria fungi
are emerging agents in this situation.4 It has been estimated that the
Endogenous Bacterial Enteric gram-negative bacilli
rate of endophthalmitis is between 0.36% and 0.053% of the intravit- Streptococcus spp.
real injections.5,6,7 Fungal Yeasts (Candida albicans, Cryptococcus
Endophthalmitis after penetrating ocular trauma is common, rep- spp.)
resenting 7–30% of all endophthalmitis cases; 3–26% of penetrating Filamentous fungi (Aspergillus spp.,
Acremonium spp., Fusarium spp.,
eye injuries develop infection. It is more common when trauma is Paecilomyces spp.)
associated with a retained intraocular foreign body or when the injury
158
Chapter 17 Endophthalmitis 159
with inadequately buried sutures, suture removal or the presence of mised patients.26 Direct intravenous inoculation as a result of narcotic
vitreous wicks. abuse or contaminated infusion solutions has also been reported.
In over 70% of cases, the pathogenic organism is a gram-positive Other fungi less commonly implicated in endogenous fungal end
bacterium. Staph. epidermidis and other coagulase-negative staphylo- ophthalmitis include Cryptococcus neoformans, Aspergillus spp. and
cocci are now the most frequently isolated bacteria from postsurgical Paecilomyces spp.
endophthalmitis, representing 50–55% of all culture-positive cases.10
Staph. aureus and Streptococcus spp. are cultured from 10–30% of
postoperative infections, whereas gram-negative organisms, including Prevention
Pseudomonas spp., Proteus spp. and Citrobacter spp., are implicated in The prevention of endophthalmitis is based on identification and pre-
only 7–20%. The change in prevalence of Staph. epidermidis probably treatment of high-risk patients, and reduction in the conjunctival com-
represents, at least in part, a past failure to recognize coagulase- mensal flora.
negative staphylococci as potential ocular pathogens. Delayed-onset
endophthalmitis is often caused by Staph. epidermidis, Corynebacte- PREOPERATIVE PRECAUTIONS
rium spp. and Candida spp. A specific syndrome of chronic localized High-Risk Patients
infection may occur with Propionibacterium acnes. Filtering bleb endo- Host factors that lower resistance to infection, such as chronic immu-
phthalmitis is frequently caused by streptococci (60%) and Haemophi- nosuppression or diabetes mellitus, have been reported as significant
lus influenzae (20%), although Staph. aureus remains a prominent risk factors for postoperative endophthalmitis. Reduction in immuno-
pathogen.11,12 Fungal endophthalmitis is usually observed as clusters of suppressive medications, when possible, and optimal control of blood
cases caused by the use of contaminated irrigating solution,13 intraocu- glucose are essential in such groups. Pre-existing infection of external
lar lens,14 ventilation system15 and hospital construction activity16 but ocular tissue, for example chronic blepharitis, conjunctivitis and lacri-
sporadic cases have also been observed.17 Postoperative fungal infec- mal outflow obstruction, should be identified and treated with appro-
tion is very rare. A 27-case series has been observed over a 5-year priate topical antibiotics.
period of time;17 in this series, endophthalmitis was caused mainly by
Aspergillus spp. with a median 10.5-day latent period.17 Antimicrobial Prophylaxis
The aim of preventive treatment is to reduce eyelid and ocular surface
POST-TRAUMATIC ENDOPHTHALMITIS microflora; this may be achieved by using topical antibiotics, topical
Post-traumatic infection may be polymicrobial (10–40%); it can be antiseptic agents or subconjunctival antibiotics at the time of surgery.
caused by anaerobic organisms, especially Clostridium species. Staph.
Topical Antibiotics. Although there is no consensus as to the
aureus remains a common agent, although saprophytes, such as Bacil-
optimal use of preoperative topical antibiotics in intraocular surgery,
lus spp., especially associated with intraocular foreign bodies, may
several studies have demonstrated significant falls in bacterial coloni-
induce fulminating endophthalmitis.18 Spread of organisms through
zation of the conjunctiva with the application of topical antibiotics and
corneal abrasions and penetrating corneal ulcers, particularly those
have thus suggested a reduction in the incidence of postoperative
involving fungi, Staph. aureus or Pseudomonas aeruginosa, may lead to
endophthalmitis with the use of such antibiotics preoperatively. Topical
endophthalmitis.19
antibiotics have been reported to be most effective in decreasing con-
ENDOGENOUS ENDOPHTHALMITIS junctival bacterial colony counts when administered 2 hours before
surgery.27 Until the early 1980s, gentamicin (3 mg/mL) was consis-
Endogenous infection may be associated with a recognizable infective
tently found to be the most effective antibiotic in this situation com-
focus elsewhere in the body and this may provide an indication as to
pared with other agents such as chloramphenicol (5 mg/mL), bacitracin
the likely causative organism. Ocular involvement, however, may also
(10 mg/mL), neomycin (5 mg/mL) and polymixin (2.5 mg/mL).28
be the first and only manifestation of systemic infection particularly
However, the increase in gentamicin resistance among Staph. epider-
in the course of endocarditis. The diagnosis of endogenous end
midis, now the most common cause of postoperative endophthalmitis,
ophthalmitis should prompt explorations (three blood cultures, serol-
suggests that it may no longer be the optimal agent for prophylaxis.29
ogy for fastidious bacteria and echocardiography) to eliminate
Vancomycin, when used prophylactically, has been shown to be active
endocarditis.20,21 More recently, Streptococcus spp. other than Strep.
against staphylococci, but the potential risk of emerging resistance in
pneumoniae, Staph. aureus and Enterobacteriaceae from gastrointesti-
enterococci and to a lesser extent in methicillin-resistant Staph. aureus
nal sources have become more prominent.22 Intravenous drug use may
has led some authorities to discourage this practice. Although no spe-
be associated with infection with Candida spp., Aspergillus spp. and
cific recommendations have been developed for ophthalmology, it
Bacillus cereus, although more common pathogens, including Staph.
seems appropriate to restrict the use of vancomycin to the treatment
aureus, may be involved. Exceptionally, late-onset endophthalmitis
of, for example, serious keratitis, endophthalmitis or orbital cellulitis
may develop after Bacille Calmette–Guérin (BCG) immunotherapy for
caused by β-lactam resistant gram-positive organisms or alternatively
bladder carcinoma.23 Other mycobacterial causes of endophthalmitis
to the treatment of enterococci and Staph. aureus in patients unable to
are also exceptional including Mycobacterium haemophilium.24
tolerate β-lactam antibiotics. More recently, fluoroquinolones (all
FUNGAL ENDOPHTHALMITIS compounded at a concentration of 3 mg/mL), have been shown to be
very effective in reducing conjunctival and eyelid bacterial flora when
Fungal endophthalmitis may occur as exogenous or endogenous used preoperatively.30
infection. After trauma, fungal endophthalmitis may represent up to
10% of cases, particularly if penetration with vegetable matter has Subconjunctival Antimicrobials. Subconjunctival antibiotics
occurred.25 Extension of a fungal corneal ulcer may also lead to end can be administered after intraocular surgery based on the rationale
ophthalmitis. In this situation, the use of topical steroids is a major that, at the completion of the ocular procedure, it is appropriate to
risk factor.19 inhibit growth of any bacteria that may have gained entry into the eye
Fungi most commonly identified in this situation are usually sap- during surgery. During routine cataract surgery, aqueous fluid samples
rophytic and may include Aspergillus spp., Fusarium spp., Acremonium have been demonstrated to be culture positive in up to 43% of cases.31
spp. and Paecilomyces spp. Endogenous fungal endophthalmitis has Conflicting results as to the value of this modality have been reported
been seen with increasing frequency over the past two decades, concur- and penetration into the vitreous is relatively poor.
rent with an increased recognition of systemic fungal infections. Topical Antiseptics. Application of 5% aqueous povidone–iodine
Candida albicans is the most frequently reported causative agent after solution alone has been shown to be nontoxic and to decrease periop-
hematogenous dissemination from other infected body sites, particu- erative conjunctival bacterial colony counts and reduce the incidence
larly infected central venous catheters, and often in immunocompro- of postoperative endophthalmitis significantly. In combination with
Figure 17-1 Corneal edema and fibrinous anterior chamber exudate in a trau-
Figure 17-2 B-scan ultrasound of the eye showing total vitreous opacity of a
matic foreign body-induced endophthalmitis. Any posterior vitreal or retinal view
severe endophthalmitis in patient seen in Figure 17-1. This horizontal ‘cut’ through
is obscured by the anterior corneal and aqueous haze.
the eye shows the normally ‘transparent’ vitreous cavity to be filled with inflam-
matory debris, but there is no obvious retinal detachment.
topical antibiotics, povidone–iodine has been found to sterilize the

conjunctiva in more than 80% of treated patients.32
INTRAOPERATIVE PRECAUTIONS
Although the judicious use of preoperative antibiotics can reduce
infection rates considerably, they do not replace meticulous aseptic
technique in intraocular procedures. An appropriate operating room
environment, with efficient ventilation to reduce bacterial contamina-
tion, is essential; surgical techniques should be modified to minimize
entry of ocular surface microbes into the eye during the surgical pro-
cedure, and adhesive-backed plastic drapes to isolate the eyelids and
lashes from the operative field are recommended.
Implantation of intraocular lenses with prolene haptics appears to Figure 17-3 A dense vitreous abscess in advanced endophthalmitis. This
increase the risk of endophthalmitis, probably because coagulase- partially-treated postoperative endophthalmitis has vitreous cellular and protein
negative staphylococci bind well to this particular plastic. Binding to deposits obscuring the retinal view.
polymethylmethacrylate material is less, and therefore its use may
reduce risk.33 Care must be taken to minimize contact with the external
eye during insertion of an intraocular lens to prevent contamination
with conjunctival flora. A foldable lens insertion device has been devel-
oped to facilitate this. There is always the threat of infection from
personnel and equipment in the operating room, and from contami-
nated irrigation solutions.
In recent years, the intraoperative use of cefuroxime (1 mg/0.1 mL)
injected in the anterior chamber has substantially reduced the rate of
endophthalmitis after cataract surgery from a risk of 0.3% to a risk
between 0.029% and 0.043%.34,35
Clinical Features
Figure 17-4 The typical posterior capsular opacities seen in a late-onset Staphy-
Clinical signs of endophthalmitis vary greatly depending on the pre- lococcus epidermidis endophthalmitis. These deposits are actual coccal colonies,
ceding events, the nature of the infecting organism, the degree of tissue which are frequently removed at subsequent vitrectomy surgery to open up the
inflammation and the duration of disease. Early diagnosis requires the capsular bag to intraocular antibiotics.
maintenance of a high index of suspicion as classic features of infection
may be absent.
DELAYED-ONSET POSTOPERATIVE
ACUTE POSTOPERATIVE ENDOPHTHALMITIS ENDOPHTHALMITIS
Acute postoperative endophthalmitis usually occurs within 2 weeks of Delayed-onset endophthalmitis has a more insidious course and
surgery, whereas the presentation of infection after penetrating trauma frequently overlaps with acute postoperative endophthalmitis if less
will often be more rapid. As a general principle, the more rapid the virulent organisms are implicated. Symptoms may not manifest
onset of symptoms, the more virulent the organism, with Staph. until weeks or even months after surgery, although early mild clinical
aureus, Streptococcus pyogenes, Bacillus spp. and gram-negative bacilli features with progressive worsening over time are not uncommon
being implicated in very rapid onset of infection within 24–72 hours (Figure 17-4). When delayed-onset endophthalmitis is caused by P.
of surgery. This presentation is characterized by marked anterior acnes, it usually develops months after cataract extraction; patients
chamber inflammation, by the rapid development of a fibrinous ante- will often have a history of corticosteroid-responsive postoperative
rior chamber exudate with hypopyon (which produces severe pain, inflammation with a fluctuating course over many months. The most
more prominent than general postoperative discomfort) and by a pro- common clinical signs are posterior capsular deposits and chronic
gressive decrease in visual acuity. A marked vitreous inflammatory iridocyclitis.37
reaction, often obscuring visualization of the retina, frequently follows Fungal infection may also have a delayed clinical onset. Anterior
(Figures 17-1 to 17-3). Associated features may include marked con- chamber reaction is seen with progressive white infiltrates often adher-
junctival, lid and corneal edema, but systemic features are virtually ent to the iris and posterior corneal surface (Figures 17-5 and 17-6).
never seen. It is important to note that peripheral retinal hemorrhages Fluffy white fungal ball infiltrates (‘string of pearls’) occurring in the
are an early sign of acute endophthalmitis.36 vitreous are characteristic (Figure 17-7). Patients who have chronic
Figure 17-5 A ‘quiet’ endogenous fungal endophthalmitis with small hypopyon.

This eye is relatively quiet with little chemosis, injection and pain, but has a small
hypopyon and some small fungal ‘balls’ on the temporal iris.
Figure 17-8 Horizontal computed tomography scan section of eye seen in

Figures 17-1 and 17-2 revealing metallic intraocular foreign body in vitreous cavity
(arrow). This CT scan demonstrates that the vitreous opacity seen by ultrasound
is ‘invisible’ to this investigation.
are commonly seen, ultimately in association with typical signs of

endophthalmitis. Viridans streptococci, H. influenzae, Staph. aureus
and Moraxella spp.38 are commonly implicated.
POST-TRAUMATIC ENDOPHTHALMITIS
Presentation will vary depending on the nature and severity of the
ocular trauma or the type of retained foreign body, for example steel
or vegetable matter, and the virulence and concentration of the organ-
ism initially deposited into the intraocular tissues (Figure 17-8). The
Figure 17-6 The degraded ophthalmoscopic retinal view obtained in patient
seen in Figure 17-5. The corneal edema and anterior chamber activity make vitre- more virulent this organism, including Staph. aureus and B. cereus, the
ous and retinal observation difficult. more rapid the onset of pain and associated ophthalmic features of
infection. B. cereus, fungi and, to a lesser extent, Nocardia spp. and
atypical mycobacteria should be considered when injury to the eye is
related to plant or vegetable matter.39
ENDOGENOUS ENDOPHTHALMITIS
Endogenous endophthalmitis usually has an insidious onset with a
slow decrease in visual acuity caused by vitritis and localized areas of
chorioretinitis. It may be suspected when other systemic symptoms of
infection are present or in certain groups of patients, including those
in whom bacteremia or fungemia is common, such as those with infec-
tive endocarditis and those with intravascular or urinary catheters, or
patients who abuse intravenous drugs. Rarely, a fungal endophthalmi-
tis, with a predilection for Paecilomyces infection, may occur in other-
wise healthy individuals with no antecedent trauma.40
Figure 17-7 Fungal ‘fluff balls’ on the iris seen in a fungal endophthalmitis. DIFFERENTIAL DIAGNOSIS
Although these are not pathognomonic, their appearance raises the real possibil- The differential diagnosis of postoperative inflammation includes
ity that the infection is of fungal origin.
sterile uveitis related to retained lens cortex; operative complications
such as vitreous loss, hemorrhage and iris trauma; pre-existing uveitis;
and toxicity of foreign material such as irrigation solutions introduced
postoperative endophthalmitis caused by coagulase-negative staphylo- during surgery. These presentations are often difficult to distinguish
cocci may present with a hypopyon and diffuse vitritis, which occa- from similar symptoms caused by infective endophthalmitis and
sionally obscures the view of the fundus. Visual loss is usually more careful sequential monitoring of such eyes or intraocular sampling for
severe than that in endophthalmitis caused by P. acnes or fungi. culture is appropriate to facilitate early diagnosis and treatment.
FILTERING BLEB ENDOPHTHALMITIS
A conjunctival filtering bleb is a collection of fluid under the conjunc-
Diagnosis
tiva resulting from the formation of a fistula at operation through the MICROBIOLOGIC INVESTIGATIONS
sclera from the anterior chamber in an endeavor to reduce pressure in IN ENDOPHTHALMITIS
the anterior chamber. Endophthalmitis associated with a conjunctival Confirmation of the diagnosis of infective endophthalmitis is essential
filtering bleb is actually an acute presentation of endophthalmitis, but to rational management. Because most postoperative infections are
may occur months to years after the operation with rapid development caused by normal ocular flora, there is some correlation between the
of symptoms. Intraocular spread occurs from an initial bacterial pen- results of external swabs of the eyelid margins and conjunctivae with
etration through the mucosa of the bleb, often in association with intraocular isolates.41 These should not be used to determine causative
bacterial conjunctivitis. Infection is often associated with late bleb pathogens; routine preoperative cultures have a low predictive value
leakage and is facilitated by antimetabolites (e.g. 5-FU or mitomycin) and are not recommended. The optimal specimen for laboratory pro-
used to ensure bleb survival.8 A purulent discharge and an injected bleb cessing in endophthalmitis is an intraocular aspirate; aqueous and
vitreous specimens should be obtained, although the latter appears the β-lactam antibiotics for up to 4 hours; however, vitreous concentra-
most reliable, as some 30–55% of concomitant aqueous specimens are tions are generally poor. Subconjunctival injections are an irritant
negative in the presence of positive vitreous isolates.42 In the case of and are painful, thus limiting duration of this form of therapy to a
late endophthalmitis, aqueous vitreous and some capsule material few days.
should also be cultured. Foreign bodies should be processed in trau-
matic endophthalmitis, whereas a swab of the bleb may assist in bleb- Topical Antibiotic Therapy
associated infections. The efficacy of topical antibacterial applications in endophthalmitis is
Because specimen volumes are often very limited, the traditional not well studied, although significant concentrations of antibiotics in
approach of direct inoculation onto culture media for aerobic and the anterior segment can be obtained with frequent administration of
anaerobic bacteria, and fungi, remains important. Rapid results by highly concentrated (fortified) solutions. A combination of vancomy-
microscopy of Gram stains are useful, with positive results occurring cin and fortified gentamicin, e.g. 1.5%, provides a broad-spectrum
in some 50–70% of well-collected vitreous aspirates.43 An appropriate cover, but solutions must be prepared by a qualified pharmacist as they
clinical history should accompany specimens to the laboratory so that are not commercially available. Third-generation cephalosporins, such
culture can be prolonged for fastidious organisms and so that skin as cefotaxime and ceftazidime, and fluoroquinolones, such as cipro-
commensals such as P. acnes are not routinely discarded as contami- floxacin, may be used to replace gentamicin to provide appropriate
nants. Polymerase chain reaction (PCR)-based detection of the 16S gram-negative cover. The use of collagen shields to produce frequent
rRNA gene for detection of bacteria and of the 18S rRNA gene for the topical application of antibiotic solutions has been explored, but is
detection of fungi greatly helps in the diagnosis of endophthalmitis.44-47 limited by potential corneal toxicity. Iontophoresis also increases ante-
These techniques are particularly helpful when the patient received rior chamber concentrations, but its efficacy remains unproved.
intraocular antibiotic/antifungal treatment prior to intraocular sam-
pling.48 Because of high risk of contamination, nested-PCR44 should be Systemic Antibiotics
replaced by real-time PCR targeting specific pathogens such as Neis- In humans, intraocular penetration of systemically administered
seria meningitidis.49 antibiotics is generally poor. However, intravenous antibiotics are a
common adjunctive therapy in endophthalmitis, justified in that they
may enhance concentrations of antibiotics achieved with intravitreal
Management agents and extend the duration of therapeutic activity. Intraocular
ANTIBIOTIC CHEMOTHERAPY inflammation and/or performance of a vitrectomy may alter the
Early institution of antimicrobial therapy is essential to optimal blood–retina barrier to allow improved intraocular penetration.
outcome in the management of infective endophthalmitis. Contro- Posterior chamber concentrations of newer and broad-spectrum
versy continues as to the best therapeutic approach. agents, including ceftazidime, imipenem and ciprofloxacin, appear
improved, particularly in terms of efficacy against gram-negative
Intravitreal Antibiotics bacilli such as Pseudomonas spp. However, none is reliably active
Intravitreal injection of antibiotics is the most effective way of rapidly against Staph. epidermidis, the most common cause of postoperative
achieving high intraocular antibiotic levels. Direct intravitreal injec- endophthalmitis, and resistance may develop rapidly.
tions of nonpreserved (i.e. intravenous) formulations of antibiotics are A multicenter randomized trial, the Endophthalmitis Vitrectomy
now the recommended route of administration in endophthalmitis Study (EVS), sponsored by the National Eye Institute of the National
treatment. The rationale of such therapy is that, although antibiotics Institutes of Health, followed a cohort of 420 patients who had clinical
when administered topically, subconjunctivally or systemically may evidence of endophthalmitis within 6 weeks after cataract surgery or
attain therapeutic concentrations in the anterior chamber, concentra- secondary intraocular lens implantation.28 Patients were randomly
tions in the vitreous are much lower. Intravitreal injections may assigned to therapy, with or without pars plana vitrectomy and with
produce significant retinal toxicity, although single injections have or without systemic antibiotics (ceftazidime and amikacin), but each
been shown to be safe and effective. patient underwent intravitreal injection of vancomycin and amikacin.
The optimal combination of antibiotics in empiric therapy nor- When outcome was assessed 9–12 months after the operation, no dif-
mally covers gram-positive and gram-negative organisms. Over recent ference in final visual acuity or media clouding between groups with
years, vancomycin has replaced first-generation cephalosporins for and without systemic antibiotics could be determined. Well conducted
gram-positive activity because of the increasing incidence of Staph. as this study was, a number of questions remain unanswered, particu-
epidermidis infection resistant to methicillin and other β-lactam drugs. larly in relation to generalization of the results. Do the results, for
Reports of retinal toxicity caused by gentamicin led to the use of ami- example, extrapolate to gram-negative infection or to other categories
kacin to cover gram-negative organisms, as this later antibiotic was of ocular surgery? Moreover, a significant percentage of coagulase-
believed to be less toxic. Amikacin has now been used widely in con- negative staphylococci and Streptococcus spp., the most common gram-
trolled and uncontrolled clinical situations. However, more recently, positive pathogens, are resistant to ceftazidime and amikacin, although
gentamicin and amikacin have been associated with macular infarc- vancomycin was active against all.
tion50 and this has led to increased use of other broad-spectrum gram- Duration of therapy is very variable. In spite of the presence of an
negative antimicrobial agents, particularly ceftazidime. An initial single ocular foreign body such as an intraocular lens, endophthalmitis
injection of 0.2 mg vancomycin maintains therapeutic concentration caused by Staph. epidermidis will settle rapidly with appropriate man-
for at least 3 days and a repeat injection at that time for at least 4 days.51 agement. Length of therapy can be assessed by a reduction in cellular
Repeat injections of aminoglycosides should be avoided, except in activity in both the anterior and posterior chambers and by improve-
severe cases. Intravitreal amphotericin B injections (1–5µg) can be ment in visual acuity.
utilized in fungal endophthalmitis, with a single repeat inoculation Guidelines have been published for the treatment of fungal end
after 72–96 hours in progressive infection; again, however, toxicity ophthalmitis.46 They incorporated itraconazole, a lipophilic antifungal
limits longer duration of therapy. imidazole, shown to be efficacious in Aspergillus endophthalmitis. Flu-
conazole, a hydrophilic imidazole, achieves useful concentrations in
Subconjunctival Antibiotics intraocular tissue and has also proved successful in Candida end
The data regarding subconjunctival antibiotic penetration is conflict- ophthalmitis. Voriconazole, a newer broad-spectrum antifungal with
ing, possibly because of varying degrees of inflammation in the eye or intraocular penetration, has been used successfully.52,53 Amphotericin
poor and variable sampling techniques. Penetration is affected by the B, often the only available therapy in filamentous fungal infections
transcleral and transcorneal permeability of the agent, but high other than those caused by Aspergillus spp., does not achieve significant
aqueous levels can be achieved with vancomycin, gentamicin and concentrations in intraocular tissue. Nevertheless, it is widely used in
TABLE
17-2 Initial Empiric Recommendations for Antimicrobial Therapy of Endophthalmitis
ANTIMICROBIAL THERAPY
Category of Endophthalmitis Topical Intravitreal Systemic
Postoperative Acute Cefazolin (5 mg/mL) + gentamicin Cefazolin (2.25 mg) + Cefazolin (2 g q8h) + gentamicin
(8–15 mg/mL) or amikacin amikacin (400 µg) (4–5 mg/kg q24h)* or amikacin
(25–50 mg/mL) Vancomycin (1 mg) + (15 mg/kg q24h)*
Vancomycin (50 mg/mL) + gentamicin amikacin or ceftazidime Vancomycin + gentamicin or amikacin
or amikacin or ceftazidime (5 mg/mL) (2.25 mg) or ceftazidime (2 g q8h) or
or ciprofloxacin (3 mg/mL) ciprofloxacin (400 mg q12h)
Delayed Vancomycin + gentamicin or amikacin Vancomycin + amikacin or Vancomycin + gentamicin or amikacin
or ceftazidime or ciprofloxacin ceftazidime or cefotaxime (2 g q6h) or
ceftazidime or ciprofloxacin
Filtering bleb Vancomycin + ceftazidime or Vancomycin + ceftazidime Vancomycin +/or cefotaxime,
ciprofloxacin ceftazidime, ciprofloxacin
Post-traumatic Vancomycin + gentamicin or amikacin Vancomycin + amikacin or Vancomycin + gentamicin or amikacin
or ceftazidime or ciprofloxacin ceftazidime or ceftazidime or ciprofloxacin
Dosages given in brackets apply to all citations of each specific drug within the relevant column.
*Dosages must be adjusted to reflect the patient’s age, body weight and renal function.
both conventional and liposomal formulations, in fungal endophthal- An early injection seems to be more effective on the final
mitis with some evidence of success. prognosis.57
Specific Recommendations Management of Intraocular Lens
Endophthalmitis may cause irreparable visual loss within 24–48 hours. In most cases of acute postoperative pseudophakic endophthalmitis,
Initial therapy must frequently be empiric, because of the low sensitiv- removal of the intraocular lens is not necessary and does not influence
ity of Gram stain film and the 24–48 hour delay until culture results outcome. In fact, it may be hazardous and predispose to anterior
become available. Antibiotic therapy should be chosen to cover the segment hemorrhage and retinal detachment. Exceptions may occur
spectrum of pathogens likely to be implicated. In this situation clas- when the pathogen is a fungus and in cases of late-onset endophthal-
sification of endophthalmitis by clinical setting provides useful infor- mitis caused by P. acnes when conservative treatment with intravitreal
mation. Suggested initial antibiotic therapy for acute postoperative, vancomycin and corticosteroids is unsuccessful. In such cases, com-
filtering bleb and post-traumatic endophthalmitis is illustrated in plete capsulectomy and lensectomy may be necessary to provide cure.
Table 17-2.
Localized bleb infection without endophthalmitis can usually ini- Outcome
tially be managed with topical therapy. Because of the increased preva- Up to 50% of patients who have endophthalmitis suffer major
lence of H. influenzae in this infection, a combination of antibiotics visual loss within 24–48 hours of onset, emphasizing the essential need
that covers this pathogen and provides broad-spectrum activity against for early diagnosis and prompt treatment.56 Approximately 30% of
gram-positive and gram-negative organisms should be chosen. New patients in recent studies of endophthalmitis achieved a final visual
combinations have been recently reviewed.54 acuity of 20/60 or better after treatment.58,59 Certain factors are highly
ADJUNCTIVE THERAPY correlated with poor visual outcome; these include severity of infec-
tion, delay in time to diagnosis and institution of treatment, virulence
Vitrectomy of infecting organisms and intraocular complications such as vitreous
The place of pars plana vitrectomy remains a controversial issue in the hemorrhage and retinal detachment. Poor vision at the time of diag-
management of endophthalmitis. The theoretic rationale for such a nosis correlates with either a virulent organism, such as Bacillus
procedure is that it offers a reduction in organism load, a reduction in spp., Streptococcus spp. or gram-negative bacilli or fungi, or a delay in
traction effect on the retina with less potential for detachment, collec- diagnosis even with a low-virulence organism. Normally, however,
tion of adequate culture material and possibly improved distribution Staph. epidermidis endophthalmitis has an excellent outcome, although
of intravitreal antibiotics. Evidence for its efficacy has been conflicting, even in this situation some 10% of patients develop blindness.60
often as a result of poorly controlled studies. The EVS was designed to Culture-negative cases of endophthalmitis generally have a better
determine definitively the value of vitrectomy in the presence of intra- visual outcome than do culture-positive groups, which may relate to
vitreal antibiotics. The final conclusions of this study were that visual the lower virulence of more fastidious organisms or to the veracity of
acuity was improved significantly in patients treated with vitrectomy diagnosis.
only if the initial vision was light perception, but not if initial vision The outcome of post-traumatic endophthalmitis and endophthal-
was hand movements or better; that is, the most severe cases on pre- mitis related to a conjunctival filtering bleb is poor, probably because
sentation benefited most from vitrectomy.55 of the intrinsic virulence of organisms implicated; however, for con-
Corticosteroids verse reasons, prognosis in delayed ophthalmitis, including that caused
by P. acnes, is usually more favorable.
The use of corticosteroids to reduce the inflammatory response to The primary complication of endophthalmitis is retinal detach-
infection and thus preserve ocular tissue is widely practiced with ment that may occur at any time before, during or after treatment.
administration by several routes, including intraocular, periocular, Prognosis in this situation is poor, although surgical repair can salvage
topical and systemic, but its place in therapy remains contentious. useful vision in a substantial number of patients.
Experimental animal studies demonstrate superior outcomes utilizing
corticosteroids with antibiotics even in endophthalmitis caused by References available online at expertconsult.com.
pseudomonads and fungi. In general, clinical studies do not report
deterioration in outcomes if corticosteroids are used in combination
with antibiotics, at least at the ocular level.56
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Chapter 17 Endophthalmitis 164.e1
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15. Fridkin S.K., Kremer F.B., Bland L.A., et al.: Acremo- Swedish National Study. J Cataract Refract Surg 2013; use of intravitreal dexamethasone in presumed bacte-
nium kiliense endophthalmitis that occurred after cata- 39:15-21. rial endophthalmitis: a randomized trial. Br J Ophthal-
ract extraction in an ambulatory surgical center and 36. Godley B.F., Folk J.C.: Retinal hemorrhages as an early mol 2011; 95:1385-1388.
was traced to an environmental reservoir. Clin Infect Dis sign of acute bacterial endophthalmitis. Am J Ophthal- 57. Bohigian G.M., Olk R.J.: Factors associated with a poor
1996; 22:222-227. mol 1993; 116:247-249. visual result in endophthalmitis. Am J Ophthalmol 1986;
16. Tabbara K.F., al Jabarti A.L.: Hospital construction- 37. Winward K.E., Pflugfelder S.C., Flynn H.W. Jr, et al.: 101:332-341.
associated outbreak of ocular aspergillosis after cataract Postoperative Proprionibacterium endophthalmitis. 58. Ormorod L.D., Ho D.D., Beeker L.E., et al.: Endo-
surgery. Ophthalmology 1998; 105:522-526. Treatment strategies and long term results. Ophthalmol- phthalmitis caused by coagulase negative staphylococci.
17. Narang S., Gupta A., Gupta V., et al.: Fungal endo- ogy 1993; 100:447-451. I: disease spectrum and outcome. Ophthalmology 1993;
phthalmitis following cataract surgery: clinical presen- 38. Cornut P.L., Chiquet C., Bron A., et al.: Microbiologic 100:715.
tation, microbiological spectrum, and outcome. Am J identification of bleb-related delayed-onset endo- 59. Kattan H.M., Flynn H.W., Pflugfelder S.C., et al.: Noso-
Ophthalmol 2001; 132:609-617. phthalmitis caused by Moraxella species. J Glaucoma comial endophthalmitis surgery: current incidence of
18. Schemmer G.B., Driebe W.T. Jr: Post-traumatic Bacillus 2008; 17:541-545. infection after intraocular surgery. Ophthalmology
cereus endophthalmitis. Arch Ophthalmol 1987; 39. Kangas T.A., Greenfield D.S., Flynn H.W., et al.: 1991; 98:227-238.
105:342-344. Delayed-onset endophthalmitis associated with con- 60. Doft B.M., Kelsey S.F., Wisniewski S.R.: Retinal detach-
19. Henry C.R., Flynn H.W. Jr, Miller D., et al.: Infectious junctival filtering blebs. Ophthalmology 1997; 104:746- ment in the Endophthalmitis Vitrectomy Study. Arch
keratitis progressing to endophthalmitis: a 15-year 752. Ophthalmol 2000; 118:1661-1665.
study of microbiology, associated factors, and clinical 40. Hirst L.W., Sebban A., Whitby M., et al.: Non-traumatic
outcomes. Ophthalmology 2012; 119:2443-2449. mycotic keratitis. Eye 1992; 6:391-395.
20. Rana M., Fahad B., Abid Q.: Embolic Aspergillus endo- 41. Bannerman T.L., Rohden D.L., McAllister S.K., et al.:
phthalmitis in an immunocompetent patient from The source of coagulase negative staphylococci. Endo-
18
Infectious Retinitis and Uveitis
MICHEL DRANCOURT
KEY CONCEPTS likely causes of uveitis (Table 18-1).1 Intermediate uveitis centers about
the equator of the eye between the anterior and posterior parts of the
• Uveitis may result from the direct invasion of the intraocular uveal tract, whereas anterior uveitis involves the anterior chamber and
structures by a pathogen, from inflammation in the course of posterior uveitis involves the posterior segment of the eye.
infection, or both. There are many known causes of uveitis, including infections, auto-
• Anatomical classification is routinely used for diagnosis immune disorders, various other systemic diseases and trauma. Using
purposes. strict diagnostic criteria, about 80% of uveitis cases remains of uncer-
tain origin despite extensive investigation. In trying to determine the
• Uveitis kits ease standardizing clinical sampling and laboratory
cause of any particular case of uveitis, the ophthalmologist considers
workflow for the accurate diagnosis of infectious uveitis.
a number of features, including the distribution and morphologic
• Diagnosis of infectious uveitis relies on both serological testing characteristics of the lesions, the chronicity of the disorder and the
and, in selected cases, investigation of the intraocular fluid for presence of underlying systemic diseases. In select cases, invasive diag-
direct diagnosis. nostic testing in the form of anterior chamber paracentesis, vitreous
• Despite extensive microbiological investigations, a majority of biopsy or even retinal biopsy may be necessary to rule out an infectious
uveitis cases remain undiagnosed. etiology. A ‘uveitis kit’ can be used to standardize both the clinical
specimens and the laboratory investigations and to ease and speed
• Fastidious bacteria are the leading causes of documented the workflow for nurses, doctors and clinical microbiologists
uveitis.
(Figure 18-2).2
This chapter describes the major manifestations of uveitis and reti-
nitis, with an emphasis on the infectious causes of these syndromes.
Uveitis and retinitis in immunosuppressed patients and neonates are
Introduction considered separately because the causative agents differ from those in
Uveitis is an inflammation of any etiology in one or more parts of immunocompetent and adult patients. Only the infectious aspects
the uveal tract of the eye which includes the choroid, the iris and the pertinent to the eye will be discussed.
ciliary body. In this chapter, uveitis will be considered as any inflam-
mation of the internal structure of the eye. It includes inflammation Epidemiology
of the iris (iritis) or ciliary body (cyclitis) called anterior uveitis; Uveitis and retinitis are uncommon in clinical practice. In Minnesota,
inflammation of the vitreous (vitritis), retina (retinitis) or choroid USA, the annual incidence of new cases of uveitis has been found to
(choroiditis) called posterior uveitis; and inflammation of the entire be 17/100 000 population,3 though it has been estimated that in the
globe called panuveitis (Figure 18-1). Endophthalmitis, although Western world uveitis accounts for approximately 10% of the visual
overlapping with uveitis and retinitis, is considered separately (see handicap.4 Anterior uveitis accounts for 50–60% of all uveitis cases in
Chapter 16). a tertiary care center and 90% in primary care settings.5 The putative
The location, distribution and ophthalmoscopic appearance of association of uveitis due to gram-negative bacteria including Barton-
inflammatory lesions is useful to the ophthalmologist in suggesting ella spp. with HLA-B27, is controversial.6
Clinical classification of uveitis
Anterior Intermediate Posterior

uveitis uveitis uveitis
Panuveitis
Figure 18-2 The ‘uveitis kit’ facilitates the laboratory investigation of uveitis
Figure 18-1 Clinical classification of uveitis relies on the anatomy. suspected to be of infectious origin.
165
TABLE
18-1 Anterior, Intermediate and Posterior Uveitis: Definitions and Common Symptoms
Anterior Uveitis Intermediate Uveitis Posterior Uveitis
Ophthalmoscopic signs that Inflammatory cells in the anterior chamber Inflammatory cells more highly Inflammation of retina,
define the type of uveitis with or without keratic precipitates or iris concentrated in anterior vitreous choroid, retinal vessels,
lesions than in anterior chamber posterior vitreous humor,
or a combination of these
Additional clinical signs Ciliary flush (perilimbal injection of the sclera) Macular edema Retinal vasculitis
Posterior synechiae Inflammatory exudate on pars plana Optic disk edema
Macular edema
Symptoms Pain ‘Floaters’ ‘Floaters’

Redness Blurred vision
Photophobia
Figure 18-4 Hypopyon. The finding of a hypopyon (layered inflammatory cells

in the anterior chamber of the eye) usually denotes a severe anterior uveitis.
so much intraocular inflammation that a cloudy media results. Ocular

ultrasonography should be performed in such cases.
The characteristic causes and clinical presentations of uveitis seen
Figure 18-3 A retroillumination view through the dilated pupil highlights the in a general community-based ophthalmologic practice and in a ter-
inflammatory cells suspended in the vitreous.
tiary referral center have been found to differ (Table 18-2). In the
community ophthalmic practice, about 90% of uveitis was anterior
and most cases of anterior uveitis were acute. By contrast, in the ter-
Infectious uveitis or retinitis in neonates is almost always the result tiary referral center only 50–60% of uveitis was anterior, with posterior
of congenital infection – toxoplasmosis, rubella, cytomegalovirus uveitis and panuveitis significantly more prevalent.5 An infectious
(CMV), and herpesvirus (i.e. the TORCH syndrome, see Chapter 56). cause was documented in 21% of the referred patients and 14% of the
Each of the TORCH agents can involve the uvea or retina. community-based patients. The uveitis was attributed to a systemic
disease, usually rheumatologic, in a smaller number of patients.
Clinical Features Among the most common causes of uveitis in both settings, three were
Common symptoms of intraocular inflammation, irrespective of the infectious (cytomegalovirus, herpesviruses and Toxoplasma gondii).
cause, are ocular pain, photophobia, ‘floaters’ (specks that appear to Anterior uveitis is much more common than posterior uveitis, and the
float in the visual field) and impaired vision (see Table 18-1). Both specific cause is more likely to be identifiable.
eyes may be affected simultaneously, but unilateral involvement does
not rule out a systemic cause. Anyone with these symptoms should Pathogenesis and Pathology
have an ophthalmologic evaluation with pharmacologic dilatation of Most of the infectious agents discussed in this chapter gain access to
the pupil and examination by slit lamp and indirect ophthalmoscopy. the ocular structures via hematogenous spread of micro-organisms
The findings allow the process to be characterized as anterior, inter- from other sites. The uveal tract is highly vascular, offering a ready
mediate or posterior uveitis, or panuveitis (see Table 18-1). target for seeding by blood-borne microbes. Some organisms (e.g.
Additional clinical signs include conjunctival injection, anterior herpesviruses, T. gondii) have a propensity for the retina itself. In some
segment cells and ‘flare’ (protein floating in aqueous fluid, seen on slit types of infectious uveitis (e.g. tuberculous and possibly spirochetal
lamp examination), keratic precipitates (white cells adherent to the uveitis), the inflammation may be produced by a combination of
posterior cornea), iris nodules (granulomas), posterior synechiae, pos- microbial invasion and immunologic mechanisms. Q fever (Coxiella
terior segment cells (Figure 18-3), optic disk edema, retinal vasculitis, burnetii) uveitis is due to intraocular inflammation without any direct
retinitis and choroiditis. A hypopyon refers to layered inflammatory microbial invasion.7,8 Occasionally, uveitis occurs as a ‘sympathetic’
cells that settle gravitationally in the inferior aspect of the anterior reaction to an adjacent infection (e.g. anterior uveitis in patients with
chamber (Figure 18-4). In cases of severe acute uveitis, there may be HSV keratitis). It is hypothesized that other infections gain access to
Chapter 18 Infectious Retinitis and Uveitis 167
TABLE
18-2 Uveitis in Community-Based and Tertiary Ophthalmology Centers
Patients in Community-Based
Characteristics Ophthalmology Practice Patients in Tertiary Referral Center
Mean age of patients (y) 46 45
Males (%) 49 52
Percentage with:
Anterior uveitis 91 60
Intermediate uveitis 1 12
Posterior uveitis 5 15
Panuveitis and other 3 13
Percentage of cases of anterior uveitis that are chronic 9 63
Percentage in which specific diagnosis was made 47 58
Percentage attributable to infection 14 21
Percentage associated with systemic disease (including infections) 13 9
Most common causes of uveitis HLA-B27-associated anterior uveitis (15%) CMV retinitis (33%)
CMV retinitis (7%) HLA-B27-associated anterior uveitis (8%)
Traumatic uveitis (5%) Pars planitis syndrome (6%)
VZV uveitis (4%) HSV-associated uveitis (5%)
Toxoplasma retinochoroiditis (4%) Toxoplasma retinochoroiditis (4%)
Most common causes of posterior uveitis CMV retinitis CMV retinitis

Toxoplasma retinochoroiditis Toxoplasma retinochoroiditis
The figures for the proportion of cases in which a specific diagnosis was made are based on data gathered, or requested, at the first visit; cases of CMV retinitis and
‘masquerade’ syndrome are omitted. The figures for the proportion of cases associated with systemic disease include cases due to varicella, candidiasis,
coccidioidomycosis and syphilis.
the eye by spreading along nerves, such as the acute retinal necrosis Management
(ARN) syndrome associated with VZV.
The eye is unique among organs in showing a neovascular response There are two major principles of therapy for intraocular infections.
to prolonged inflammation. Newly formed, acquired vessels them- The first is to treat the infection. Drugs for the treatment of ocular
selves can cause severe loss of vision. Together with specific treatment diseases may be given by topical administration, periocular injection,
of the underlying cause, laser photocoagulation, corticosteroids or systemic administration (orally or intravenously, or both) and intra-
intravitreal injection with anti-VEGF agents may be needed to treat vitreal injection.
ocular neovascularization.9 The second principle is to suppress intraocular inflammation, lest
there be persisting damage to the retina and other crucial structures.
This is usually accomplished by using corticosteroids, which may be
Laboratory Diagnostics given by similar topical, oral, periocular or intravitreal routes. Rarely
Specimens including serum and an intraocular specimen (either ante- systemic immunosuppression is employed.
rior chamber puncture or vitrectomy fluid) can be collected as parts
of a ‘Uveitis kit’.2 Laboratory tests must be interpreted in the presence
UVEITIS IN IMMUNOCOMPETENT ADULTS
of an adequate control group:2 laboratory diagnosis includes indirect AND CHILDREN
diagnosis by serology and direct diagnosis which mainly relies upon Viral Causes of Uveitis
the real-time polymerase chain reaction (PCR) detection of specific Uveitis, especially anterior uveitis, may occur in the course of many
pathogen sequences and rarely on the immunostaining and culture of viral infections, most commonly those caused by rubeola virus and the
a few pathogens. Serology using either enzyme-linked immunosorbant herpesvirus family (Table 18-3). The uveitis is generally self-limiting
assay (ELISA) or indirect immunofluorescence assay (IFI) is used to and does not require treatment. Measles often causes conjunctivitis
diagnose fastidious pathogens including Rickettsia spp., C. burnetii,7,8 and keratitis; the keratitis rarely leads to bacterial ulceration and per-
Bartonella spp.,6,10 syphilis2 and borreliosis including Lyme disease foration of the cornea. Other rare complications are chorioretinitis or
uveitis.11 Direct detection of the nucleic acids of the pathogen by PCR neuroretinitis; these may occur, together with measles encephalitis,
must rely on real-time PCR rather than poorly sensitive ‘universal’ 1–2 weeks after the onset of the rash.
PCRs. Real-time PCR of intraocular fluids can detect herpesvirus, The ocular lesions of rubeola are generally self-limiting and no
fungi, mycobacteria, protozoal eye disease and infectious bacterial specific treatment is available. Involvement of the optic disk (optic
endophthalmitis.12 Obviously, the small volume of the intraocular neuritis) may cause severe visual loss, but this may improve spontane-
specimen limits the number of real-time PCRs which can be done. ously over subsequent months. There may be residual pigmentary
Immunodetection has been successful in the diagnosis of Bartonella retinopathy with salt-and-pepper appearance (Figure 18-5).
spp. uveitis6 and in the diagnosis of Tropheryma whipplei uveitis.13 The Subacute sclerosing panencephalitis (SSPE), which results from
latter pathogen has been cultured once from an intraocular speci- measles infection in very early life, commonly causes chorioretinitis,
men.13 Targeting the 16S ribosomal DNA can be used to detect and usually about the time that the neurologic signs of the disease become
identify bacteria in vitreous samples; yet the sensitivity of the method evident. The chorioretinitis is often focal, involving the macula,
is low and this approach should be used to diagnose endophthalmitis.14 and there is mild vitritis (Figure 18-6). Cortical blindness may occur.
Internal transcribed spacer DNA can be used to diagnose fungal The prognosis of the ocular lesions is poor. There is no specific
endophthalmitis.15 treatment.
TABLE
18-3 Viral Causes of Retinitis and Uveitis*
Viral Infection Systemic Infection Features of Retinitis or Uveitis Other Ocular Disease
Measles Uveitis occurs 1–2 weeks after onset of Common: anterior uveitis Common: conjunctivitis, keratitis
rash Rare: chorioretinitis or neuroretinitis Rare: optic neuritis
SSPE Uveitis occurs some years after infection Chorioretinitis involves macula Papillitis; motility disturbances
Herpes simplex virus Primary infection; lids and conjunctiva Common: anterior uveitis Dendritic corneal ulcer common
Rare: posterior uveitis, retinitis, ARN
Varicella-zoster virus Convalescence from varicella or Common: mild, anterior uveitis, Granulomatous keratic precipitates;
trigeminal zoster (often with self-limited; rarely, chorioretinitis or ARN synechiae; glaucoma, cataract
nasociliary branch involved)
Epstein–Barr virus Infectious mononucleosis Rare: mild anterior uveitis or chorioretinitis Common: follicular conjunctivitis
Influenza, adenovirus, Systemic infection usually evident Rare: bilateral, mild, self-limited, anterior None
mumps uveitis
Rare: neuroretinitis or optic neuritis
*These ocular problems are seen in immunocompetent adults and children. ARN, acute retinal necrosis; SSPE, subacute sclerosing panencephalitis.
Figure 18-6 Macular retinitis. This patient has subacute sclerosing

panencephalitis.
Figure 18-5 Salt-and-pepper fundus. The pigment alterations in the macula give
a ‘dirty’ appearance to the retina. The lesion occurred following congenital rubella
infection. The vertical black line across the fovea is a focusing stick.
Herpes simplex virus infection of the eye in children and adults Bacterial Causes of Uveitis
usually presents as recurrent keratitis with characteristic dendrites (see Many bacterial species are associated with ocular infections (Table
Chapter 166). There may be an associated or isolated anterior uveitis 18-4) but in practice, fastidious bacteria and chiefly Bartonella species
and it has been estimated that 9% of anterior uveitis is attributable to are documented as responsible for uveitis.
HSV.16 Rarely, HSV keratitis may spread along the axons to produce Both Bartonella henselae and Bartonella quintana have been shown
retinitis and posterior uveitis (see below). to cause uveitis; a few patients have been diagnosed with other Bar-
Varicella, especially in the convalescent stage, may cause a mild, tonella species. Bartonella species cause stellate neuroretinitis, also
self-limited anterior uveitis. A more serious lesion, keratitis, may known as macular star (Figure 18-7). Bartonella infection should be
develop in patients who have trigeminal zoster, especially during con- suspected in any patient with optic disk edema and intraocular inflam-
valescence from zoster that has involved the nasociliary branch of the mation, especially if retinal lesions are seen. Diagnosis relies on serol-
trigeminal nerve. It may be accompanied by anterior uveitis which may ogy and western immunoblotting can be used to distinguish between
be treated with 1% trifluridine ophthalmic drops or oral aciclovir or the various Bartonella species. Direct diagnosis can be done by real-
valaciclovir. Rarely, trigeminal zoster may lead to chorioretinitis and time PCR detection and immunhistochemistry detection of the caus-
a form of necrotizing herpetic retinitis referred to as the ARN syn- ative Bartonella.
drome (see below). Cases have been reported with primary varicella Among spirochetes, the agent of syphilis Treponema pallidum is a
infection of childhood (chickenpox).17 cause of uveitis. Over the last 10 years, syphilitic uveitis has been diag-
Recently, Ebola virus has been detected in the ocular fluid of con- nosed mainly in male patients who have sex with males, regardless of
valescent patients with uveitis.18 a human immunodeficiency virus (HIV) co-infection (see Chapter
TABLE
18-4 Bacterial Causes of Retinitis and Uveitis*
Bacterial Infection Systemic Infection Features of Retinitis or Uveitis Other Ocular Disease
Borrelia burgdorferi Features of extraocular Lyme disease Nonspecific anterior or posterior uveitis Conjunctivitis
Treponema pallidum Uveitis usually during secondary Common: bilateral anterior uveitis Acute bilateral interstitial keratitis
syphilis; interstitial keratitis is Rare: choroiditis (large while lesions), (age 5–10 years, after congenital
delayed manifestation of retinal vasculitis, papillitis infection)
congenital syphilis
Bartonella spp. Nonspecific systemic symptoms Bilateral papillitis: optic disk edema, white None
antedate ocular symptoms retinal lesions, vitritis
Metastatic endophthalmitis Often extraocular source is evident Often bilateral: focal or diffuse uveitis or None
retinitis
*These ocular problems are seen in immunocompetent adults and children.
iridocyclitis, retinal vasculitis, exudative retinal detachment, vitritis

and optic disk edema. Orbital pseudotumor and orbital myositis have
also been described.25 The diagnosis relies on serology including
western-immunoblotting confirmation and speciation. The treatment
is with systemic antibiotics appropriate for the stage of the disease (see
Chapter 46).
The infectious agent of Whipple’s disease, Tropheryma whipplei, is
associated with a multisystem disorder, which can include panuveitis,
retinitis and choroiditis. The diagnosis can be made by real-time PCR
detection of specific repeated sequences and immunochemistry detec-
tion of the pathogen on intraocular fluid smear.13,26
A new form, as postoperative T. whipplei uveitis, has been described
in patients who recently underwent cataract surgery; it is putatively
due to local reactivation of this pathogen with local corticosteroid
therapy.27
Rickettsiae targeting the endothelial cells, may rarely cause retinitis
and uveitis. In particular, Rickettsia conorii and Rickettsia rickettsii have
been demonstrated in this situation.28,29
Mycobacterium tuberculosis infection can cause anterior uveitis,
posterior uveitis or isolated choroiditis. However, this clinically sus-
pected diagnosis is never confirmed in high-income countries whereas
reports from low- and middle-income countries may rely on PCR-
Figure 18-7 Neuroretinitis with a macular star associated with Bartonella infec-
tion. Note the swelling of the optic disk with hard exudate in the macula in the based techniques such as the nested-PCR, which are limited by false
so-called ‘stellate’ pattern. positives. Data from the USA suggest a tubercular etiology in less than
0.5% of patients managed in a tertiary care uveitis service.30
Tuberculosis-associated uveitis usually improves within 2 weeks of the
61).2,19 Intraocular infection may occur during the early stage of infec- start of specific antituberculous treatment.
tion and can be directly diagnosed by real-time PCR. Later in the Bacterial endophthalmitis is considered in detail in Chapter 17.
evolution, patients may develop a bilateral (though occasionally asym-
metric) anterior uveitis, sometimes with iris nodules (granulomas). Fungal Causes of Uveitis
Less common is a choroiditis with large, white, ‘geographic’ lesions. The most common fungal species that cause metastatic endophthal-
There may also be retinal vasculitis, vitritis and papillitis.20 Conjunc- mitis are Candida spp. (Table 18-5), especially C. albicans. The hall-
tivitis, scleritis and episcleritis have also been reported.21Uveitis mark lesion is a yellow-white, fluffy patch of retinitis with indistinct
remains the most common ocular finding in tertiary syphilis, affecting borders (Figure 18-8), almost always associated with vitritis. Some
2.5–5% of patients.22 In addition to the Argyll Robertson pupil that cases of Candida endophthalmitis have an indolent course and some
may be present, other ophthalmic findings include papillitis, periphle- even improve spontaneously. Treatment of Candida infections is dis-
bitis, vitritis and serous retinal detachment. One recent evaluation of cussed in detail in Chapter 49.
the clinical findings in tertiary syphilis described a group of patients Whereas metastatic Candida infection usually occurs in a setting of
with an acute syphilitic posterior placoid chorioretinits.23 In the setting active fungemia, Histoplasma ocular infection usually occurs without
of HIV, early syphilis tends to be associated with a florid uveitis and evident extraocular infection (see Table 18-5). The lesions arise from
non-treponemal antibody test-positive syphilitic meningitis. Late previous hematogenous spread to the choroid, producing a granuloma
syphilis produces a chronic posterior uveitis with associated subclinical that usually becomes an inactive scar. Disk edema with optic neuritis
neurosyphilis;24 this transition to the tertiary stage is often accelerated can occur acutely. As a late complication, choroidal neovascular mem-
in those with HIV. Syphilis should be considered in the differential branes can emanate from old choroidal scars, leading to retinal edema,
diagnosis of any posterior segment inflammation or any bilateral ante- hemorrhage and permanently decreased central vision.
rior segment inflammation. The diagnosis is made serologically and A diagnosis of ocular histoplasmosis is suspected by finding the
confirmed by western immunoblotting. Treatment is according to the characteristic choroidal lesions (Figure 18-9) in a patient who has
stage of the syphilis (see Chapter 61). resided in an area endemic for the fungal infection. Serologic or skin
Borrelia burgdorferi infection may cause a wide variety of ocular tests for histoplasmosis are usually positive but do not prove the diag-
problems. Conjunctivitis and keratitis occur commonly in the early nosis. The primary visual risks are associated with late neovascular
stages of infection. In the later stages of Lyme disease there may be vessel growth from the chorioretinal scars. Laser photocoagulation and
TABLE
18-5 Fungal Causes of Retinitis and Uveitis*
Fungal Infection Systemic Infection Features of Retinitis or Uveitis Other Ocular Disease
Candida spp. Risk factors for candidemia Whitish fluffy patch of retinitis Anterior segment cells with hypopyon;
and some vitritis corneal abscess
Histoplasma capsulatum History of residence in an endemic Choroidal granulomas, scars; No anterior segment inflammation
area; no extraocular infection optic neuritis; no vitritis
evident
Figure 18-10 A Nocardia chorioretinal abscess. This abscess is in the macula of

a patient on systemic immunosuppression following heart transplant.
Figure 18-8 A focal area of superficial retinitis and vitritis. This occurred second-
ary to Candida albicans. intravitreal administration of anti-VEGF agents are the primary treat-
ment modalities. There is no indication for antifungal treatment.
Rarely, other fungi such as Coccidioides, Blastomyces and Aspergillus
spp. and Cryptococcus neoformans may cause chorioretinitis by hema-
togenous spread. Nocardia spp. (Figure 18-10) also occasionally cause
chorioretinitis.
Parasitic Causes of Uveitis
Toxoplasma gondii infection is a common cause of posterior segment
infection in children and adults (Table 18-6). It has been estimated to
afflict 1.26 million individuals in the USA alone.31 In the immunocom-
petent, it represents the most common cause of infectious posterior
uveitis worldwide. In many countries, most cases of ocular toxoplas-
mosis are thought to represent reactivations following primary intra-
uterine infection (see Chapter 56). However, in some countries, such
as Brazil, postnatally acquired infection is the more common anteced-
ent of ocular toxoplasmosis. Postnatally acquired toxoplasmosis is fol-
lowed by ocular toxoplasmosis in fewer than 5% of cases.
The lesions of ocular toxoplasmosis are found preferentially in the
nerve fiber layer of the retina, but can affect any layer including the
choroid.32 Healed lesions of congenital toxoplasmosis are flat, atro-
phic, variably pigmented chorioretinal scars that have a propensity for
the macular area of the fundus (Figure 18-11). There may be recurrent
bouts of uveitis, caused by the rupture of cysts, releasing trophozoites.
Most patients have their first reactivation before 30 years of age and it
Figure 18-9 The classic ocular findings of previous histoplasmosis. Note the
peripapillary atrophy and punched-out yellowish chorioretinal scars. An old cho-
has been estimated that recurrence occurs in 79% of patients.33
roidal neovascular membrane is present in the center of the histoplasmosis scar Ophthalmoscopic examination shows vitritis and one or more
temporal to the macula. white retinal lesions that are usually round or oval and up to 5 mm in
diameter. There may be many such lesions surrounding an old scar
(Figure 18-12). Aggregates of vitreous cells over the active lesions are
the rule. The appearance of the vitreous haze and white granuloma has
TABLE
18-6 Parasitic Causes of Retinitis and Uveitis*
Parasitic Infection Systemic Infection Features of Retinitis or Uveitis Other Ocular Disease
Toxocara canis Children 6 months to 4 years of Usually unilateral; pale granulomatous mass or No anterior segment inflammation
age; no extraocular infection focal retinitis; traction bands; vitritis
Toxoplasma gondii Usually acquired in utero but not Recurrent self-limiting attacks of chorioretinitis May be keratic precipitates (granulomatous
evident systemically and vitritis (‘headlight in the fog’) reaction) in anterior chamber
TABLE
18-7 Characteristics of Some Infections Causing Posterior Uveitis/Retinitis without Extraocular Manifestations
Infection Usual Number of Lesions Appearance of Lesions Distribution of Lesions Accompanying Vitritis
Toxoplasma gondii One to a few ‘Headlight in fog’ Random, but heavier in Almost always
macular area
Toxocara canis One Granuloma Macula, optic disk or Always

periphery
Histoplasma capsulatum Multiple Choroidal granulomas Various Almost never
Treponema pallidum Diffuse retinochoroiditis Bilateral anterior uveitis; large white Random Always
geographic choroidal lesions
Borrelia burgdorferi Focal or diffuse Anterior uveitis, retinal vasculitis, Random Usually
exudative retinal detachment
Mycobacterium tuberculosis One or a few Retinitis or chorioretinitis Random Usually
Figure 18-12 A reactivated area of retinal toxoplasmosis. The lesion is the area
of whitening in the macula of the right eye. Overlying vitritis creates the classic
Figure 18-11 An old, inactive congenital macular toxoplasmosis scar. The
appearance of a ‘headlight in the fog’.
patient’s vision was 20/400.
been likened to a ‘headlight in the fog’. There may be retinal hemor- lesions need to be treated. The highest priority for treatment is for
rhages, sheathing of arterioles and venules, and papillitis. In the ante- lesions that threaten the fovea, the optic nerve or large areas of the
rior segment, there may be a granulomatous reaction in the anterior nerve fiber layer, as well as those that produce enough vitritis to impair
chamber with keratic precipitates and conjunctival injection. vision. Once the fovea is directly involved, visual acuity is usually
A diagnosis of ocular toxoplasmosis is based on the characteristic permanently compromised. Severe vision loss (visual acuity ≤20/200)
appearance of the lesions together with a positive serum antibody test in at least one eye has been described in up to 24% of ocular toxoplas-
for T. gondii (see Chapter 194). PCR of vitreous aspirates has also been mosis patients.33
utilized (see above). Other possible causes of localized necrotizing There is no consensus among uveitis specialists on treatment
retinitis with vitritis, such as syphilis or tuberculosis, should be con- because evidence is sparse. Typically, treatment is the same as for other
sidered (Table 18-7). systemic forms of toxoplasmosis – pyrimethamine, sulfadiazine and
In otherwise healthy persons, flare-ups of ocular toxoplasmosis clindamycin (see Chapter 157), though the use of antiparasitics does
tend to be self-limiting over a period of weeks to months. Not all active not affect visual outcome.33 Others have advocated the use of
trimethoprim–sulfamethoxazole alone and in combination with

clindamycin and suggested similar efficacy.34 Corticosteroids are often
used concomitantly, but not without the anti-infective drugs. Laser
photocoagulation may be used for active lesions unresponsive to medi-
cation and pars plana vitrectomy may be used to clear vitreous
opacities.
Ocular infection by Toxocara canis, the dog roundworm, occurs in
young children, especially boys, aged from 6 months to 4 years (see
Table 18-6). Toxocara cati, the cat roundworm, has also been impli-
cated, but the organisms have never been positively identified in
the human eye. The typical presenting complaint is decreased vision,
strabismus or leukocoria (a whitish lesion in the pupil). Toxocara
infection is acquired by the ingestion of soil contaminated with
embryonated eggs (see Chapter 195). The larvae are believed to reach
the eye by hematogenous spread. The ocular findings are generally
unilateral.
The major differential diagnoses of ocular toxocariasis are nonin-
fectious diseases such as retinoblastoma and Coats’ disease, a congeni-
tal vascular disorder. Retinoblastoma should always be considered and
ruled out. Peripheral blood eosinophilia is rare in ocular toxocariasis.
A serum ELISA antibody titer to the parasite of 1 to 8 or more supports
the diagnosis. A positive ELISA titer of the intraocular fluid, which
may be found even if the serum titer is negative, is highly indicative of
the infection. Treatment is directed toward stemming the intraocular Figure 18-13 Typical appearance of the retina in acute retinal necrosis syn-
inflammation, clearing any media opacity and preventing permanent drome. There is dense peripheral retinal whitening with a geographic border.
distortion in the retinal architecture. Corticosteroids, usually applied Satellite lesions are common. The view is hazy owing to vitritis.
locally in the eye, and cataract and/or vitrectomy surgery are the main-
stays of treatment.
Diffuse unilateral subacute neuroretinitis has been attributed to
two nematodes which invade the subretinal space and induce inflam- Diagnosis is typically based on the characteristic clinical presentation
mation, Ancylostoma caninum (definitive host is dog, found in the though PCR of intraocular aspirates may be helpful.
southeast USA) and Baylisascaris procyonis (definitive host is raccoon, Retinal detachment follows in up to 75% of patients. The detach-
found in the northwest USA). Early in the clinical course, vitritis, ments are notoriously difficult to repair. Previous prophylactic laser
grayish outer retinal lesions and optic disk edema are noted. Later in treatment of healthy retina posterior to the areas of necrosis reduces
the course of the disease the retina takes on a ‘retinitis pigmentosa’-like the incidence of retinal detachment.
appearance with pigment epithelial changes, arteriolar attenuation and The mainstay of treatment for ARN is aciclovir, given in high
optic nerve atrophy. In 25% of cases, a worm is visualized on clinical dosage intravenously (e.g. 12–15 mg/kg q8h for 7–14 days). Oral aci-
examination. The condition is treated by applying laser photocoagula- clovir or one of its prodrugs should be continued for at least 2–3
tion directly to the visualized nematode, which if achieved early may months to lessen the risk of fellow eye involvement. Systemic cortico-
arrest the severe vision loss that results. steroids are employed to decrease inflammation, but never prior to the
Rarely, uveitis occurs in other parasitic infections such as cysticer- institution of antiviral therapy. Retinal detachments require complex
cosis, myiasis and onchocerciasis. vitreoretinal surgery for successful repair, often with silicone oil place-
ment. It has been suggested that patients who have AIDS and who
ACUTE RETINAL NECROSIS (ARN) SYNDROME develop ophthalmic zoster should be given long-term oral prophylaxis
The ARN (acute necrotizing herpetic retinitis) syndrome is a recently with aciclovir, but there is no proof of benefit from this approach.36
described, rare syndrome of vaso-obliterative retinal and choroidal
vasculitis, diffuse retinal necrosis and vitritis. It typically affects healthy UVEITIS AND RETINITIS IN
immunocompetent people and has no predilection for race or sex. IMMUNOSUPPRESSED PATIENTS
ARN is bilateral in one-third of patients (BARN), although the two Because of the AIDS pandemic, ophthalmologists encounter a variety
eyes need not be affected simultaneously and involvement in the fellow of intraocular infections that were previously either unknown or
eye may occur years later. Although reported in children as young as extraordinarily rare.
8 years of age, it occurs most often in adults with a bimodal age dis-
tribution with peaks at 20 and 50 years of age. Conclusive evidence Cytomegalovirus Retinitis (see also Chapter 94)
now exists that VZV is the primary cause; HSV is less common.35 The most common ocular infection in HIV-positive adult patients is
Patients infected with HIV who develop herpes zoster of the first divi- CMV retinitis. In higher-income countries prior to 1996, CMV retini-
sion of the trigeminal nerve appear to have a high risk of subsequent tis occurred in about 35% of adult patients who had AIDS. Since
ARN, often bilateral, over the next few weeks to months.36 antiretroviral therapy has become widely available in high-income
Recent immunologic research suggests that specific human leuko- countries, the incidence of CMV retinitis has dropped dramatically.
cyte antigens (HLAs) may predispose to ARN. Some 55% of Caucasian CMV retinitis rarely occurs in patients who have CD4+ lymphocyte
ARN patients were found to have the HLA-DQw7 antigen versus 19% counts over 50 cells/µL.38 Pediatric patients with AIDS have a much
of controls. More aggressive and fulminant disease has been associated lower incidence of CMV retinitis than adults.
with HLA-DR9.37 ‘Floaters’ and blurred vision are the most common complaints, if
ARN causes diffuse arteritis and phlebitis with sheathing of the any. Often, an active infection is noted incidentally on routine oph-
retinal vessels and striking white areas of full thickness retinal necrosis thalmologic screening examination. In 40% of patients with CMV
(Figure 18-13). Broad areas of the peripheral retina are involved early retinitis, the lesions are bilateral at presentation. Nearly 75% of patients
and the macula is usually spared initially. There is often mild inflam- present to the ophthalmologist with disease that is considered imme-
mation of the anterior segment. As the disease progresses there is diately sight-threatening. Pain, redness or more than a mild anterior
increasing vitritis. Optic neuropathy with disk edema may appear. uveitis are unusual with CMV retinitis.
Figure 18-15 HIV retinopathy. There are multiple superficial white patches in
Figure 18-14 Cytomegalovirus infection with granular retinal whitening along the retina (cotton-wool spots). These do not affect vision and typically wax and
the major blood vessels with mild hemorrhage. The view is clear because there is wane over time.
only mild vitritis.
The hallmark lesion of CMV retinitis is a necrotizing, full-thickness with HSV and VZV. Whereas toxoplasmosis in immunocompetent
retinitis resulting in retinal cell death (Figure 18-14). Retinal tissue patients produces a slowly progressive, focal, relapsing chorioretinitis,
adjacent to major retinal blood vessels or the optic disk is often affected in immunocompromised patients it can produce a severe diffuse retin
initially. The areas of active retinitis have a granular appearance and itis. Serologic testing may be helpful. Nearly one-third of patients who
are dirty-white in color. Hemorrhage is common, owing to damage to have AIDS and Toxoplasma retinitis have concurrent toxoplasmosis of
vascular endothelial cells. The appearance has been likened to a ‘brush the central nervous system. Ocular syphilis can also mimic CMV reti-
fire’ and to ‘ketchup and cottage cheese’. The retinitis spreads contigu- nitis, but the lesions of secondary syphilis are usually a choroiditis,
ously as well as by producing satellite lesions. It is common to see areas rather than a retinitis.
of healed retinitis alongside areas of active necrosis. Areas of burned-
out necrosis show an absence of retinal tissue while the underlying Acute Retinal Necrosis Syndrome
retinal pigment epithelium assumes a salt-and-pepper appearance. The ARN syndrome (see above) occurs in both healthy and immuno-
Loss of vision occurs because of both the death of retinal cells and suppressed people, including those with AIDS. Acute retinal necrosis
retinal detachment. About 10–20% of eyes with CMV retinitis can be differs from CMV retinitis in that the lesions of ARN are typically
expected to suffer a detached retina. The risk is time dependent; after peripheral and the course is much more rapid. In addition, significant
1 year the risk approaches 50%. Although vitreous surgery to repair vitreous cells are a prominent feature of ARN, but not of CMV retini-
the detached retinas is anatomically successful in more than 90% of tis. Patients who have HIV infection and who develop zoster of the
instances, visual results are often limited by the underlying disease first division of the trigeminal nerve appear to have a high risk of
process. subsequent ARN, which is often bilateral, over the next few weeks to
Treatment of HIV-associated CMV retinitis is discussed in detail months.36 Therefore, when a rash of ophthalmic zoster appears,
in Chapter 94. Immunologic improvement with antiretroviral therapy patients who have AIDS should be followed carefully for signs of ARN.
may result in an immune recovery uveitis in patients with prior A specific type of rapidly progressive ARN is progressive outer
or undiagnosed CMV disease (see Chapter 95). It has been hypothe- retinal necrosis (PORN). PORN is secondary to VZV infection and has
sized to be secondary to a reaction to CMV antigens typically occurring been described in patients who have AIDS and a low CD4+ lymphocyte
2–16 weeks (median 4 weeks) following an increased CD4 count. count.42 Without aggressive therapy, PORN results in bilateral loss of
Treatment with corticosteroids has not been shown to reactivate CMV vision within days to weeks. The recommended treatment is a combi-
retinitis.39,40 nation of foscarnet and either ganciclovir or aciclovir, given intrave-
nously or via intravitreal injection.
Other Causes of Uveitis and Retinitis Perhaps the most common cause of noninfectious anterior uveitis
About 75% of patients with HIV-1 infection have a non-sight-threat- in HIV-positive patients is a dose-related reaction to rifabutin. Patients
ening retinopathy that may be caused by the HIV-1 itself.41 The lesions receiving rifabutin for prophylaxis against Mycobacterium avium-
consist of multiple, bilateral, cotton-wool spots and scattered retinal intracellulare in conjunction with another agent that interferes with
hemorrhages (Figure 18-15). If there is concern that such lesions may the metabolism of rifabutin (such as clarithromycin or ritonavir) and
be due to CMV, close observation over a period of days to weeks with patients weighing less than 65 kg who are receiving 600 mg of rifabutin
documentation by photographs is recommended. are at particular risk. The incidence of rifabutin-induced uveitis is 20%
Opportunistic infections with Pneumocystis jirovecii, Histoplasma among AIDS patients taking the medication, but it has been reported
capsulatum, Cryptococcus neoformans and atypical mycobacteria may in HIV-negative patients as well. Treatment with corticosteroids and
produce multifocal choroiditis in patients who have AIDS. These discontinuation of the medication usually results in prompt reversal
infections are rarely sight-threatening, but they should alert the clini- of the inflammation. Systemic cidofovir has also been reported to
cian to the presence of a systemic infection. Unfortunately, it is gener- cause uveitis in patients who have AIDS.
ally not possible for the ophthalmologist to distinguish between these
possible opportunistic infections on the basis of the eye examination References available online at expertconsult.com.
alone.41
Other important posterior segment infections that can occur in
HIV-positive patients include toxoplasmosis, syphilis and infection
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Drancourt M., Berger P., Terrada C., et al.: High prevalence Soheilian M., Sadoughi M.M., Gharjarnia M., Nomenclature for reporting clinical data. Results of the
of fastidious bacteria in 1520 cases of uveitis of unknown et al.: Prospective randomized trial of trimethoprim/ first international workshop. Am J Ophthalmol 2005;
etiology. Medicine (Baltimore) 2008; 87:167-176. sulfamethoxazole versus pyrimethamine and sulfadiazine 140:509-516.
Duker J.S., Blumenkranz M.S.: Diagnosis and management in the treatment of ocular toxoplasmosis. Ophthalmology Varkey J.B., Shantha J.G., Crozier I., et al.: Persistence of
of the acute retinal necrosis (ARN) syndrome. Surv Oph- 2005; 112:1876-1882. Ebola virus in ocular fluid during convalescence. N Engl
thalmol 1991; 35:327-343. Sorbin L., Foster C.S.: Cytomegalovirus retinitis after J Med 2015; 372:2423-2427.
Goldberg D.E., Smithen L.M., Angelilli A., et al.: HIV- one decade of HAART. Int Ophthalmol Clin 2007;
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25:633-649. Teasley L.A., Foster C.S.: Syphilis: an ophthalmologic
Holland G.N.: Ocular toxoplasmosis: a global reassessment. update. Int Ophthalmol Clin 2007; 47:133-144.
Part I: epidemiology and course of disease. Am J Ophthal- The Standardisation of Uveitis Nomenclature (SUN)
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Tropheryma whippelii from the vitreous fluid of a Infect Dis 2009; 15:825-827. tions of acquired immune deficiency syndrome. Oph-
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Med 2003; 139:1046-1047. ranean spotted fever in Marseille: descriptive epidemi- 42. Forster D.J., Dugel P.U., Frangieh G.T., et al.: Rapidly
14. Knox C.M., Cevallos V., Margolis T.P., et al.: Identifica- ology and the influence of climatic factors. Eur J progressive outer retinal necrosis in the acquired
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1999; 128:511-512. acute unilateral vision loss with cystoid macular edema
PRACTICE
POINT
4 Management of Red Eye

MICHEL DRANCOURT | LOUIS HOFFART
Introduction Conjunctivitis is the major clinical manifestation of active trachoma,

a disorder that is largely limited to endemic areas in low- and middle-
Red eye is a common sign of ocular infections (etiologies are income countries. Adult inclusion conjunctivitis is a chronic (weeks
presented in Chapters 16 to 18) and noninfectious conditions, some to months), indolent follicular conjunctivitis caused by certain sero-
of them being vision-threatening etiologies requiring same-day refer- types of sexually transmitted Chlamydia trachomatis. Concurrent
ral to an ophthalmologist. asymptomatic urogenital infection is typically present.
When to Refer the Patient to the KERATITIS
Ophthalmologist? Keratitis is responsible for red eye along with photophobia and foreign
Clinical interview and examination can determine the affected eye body sensation. In addition, herpes simplex keratitis produces watery
segment and select situations requiring same-day referral to an oph- discharge. There may be a faint branching grey opacity on penlight
thalmologist (Box PP4-1). Such situations include a history of trauma exam best visualized with application of fluorescein. Epidemic kerato-
and contact lens wear, severe ocular pain, impaired vision, foreign body conjunctivitis is a particularly fulminant cause of keratitis due to
sensation, corneal opacity or infiltrate at penlight examination and adenovirus types 8, 19, and 37. Multiple corneal infiltrates are barely
hypopyon (layer of white cells in the anterior chamber). Also, unilat- visible with a penlight to the skilled observer but fluorescein staining
eral red eye associated with nausea and vomiting, suggestive of acute reveals multiple punctate staining lesions. Overnight wear of contact
angle-closure glaucoma, and masquerade syndromes due to malignant lenses is associated with a higher incidence of bacterial keratitis char-
etiologies including B cell lymphoma and metastases of cancer such as acterized by a corneal opacity or infiltrate (typically a round white
breast cancer should be referred (Table PP4-1). spot) seen with a penlight in association with red eye, photophobia,
and foreign body sensation. Mucopurulent discharge is typically
present. Fulminant cases may present with an associated hypopyon
Which Ocular Segment is Affected? (layer of white cells in the anterior chamber). Amebal keratitis is also
CONJUNCTIVITIS associated with contact lens wearing.
Conjunctivitis is usually a benign, self-limited condition and probably
the most common cause of red eye in the community setting. Con- ANTERIOR UVEITIS (OR IRITIS)
junctivitis is responsible for diffuse or localized redness (episcleritis) Anterior uveitis (or iritis) may be responsible for red eye (Figure
in one or both eyes. Patients complain of morning crusting and PP4-1). Patients with iritis may present in a similar fashion to those
daytime redness and discharge. Morning watery discharge of viral with an active corneal process but there is no foreign body sensation
conjunctivitis contrasts with daylong purulent discharge in the course per se. The cardinal sign of iritis is ciliary flush: injection that gives the
of bacterial conjunctivitis. Viral conjunctivitis, a self-limiting infection, appearance of a red ring around the iris. Typically, there is no discharge
most often bilateral, typically caused by adenovirus, may be part of a and only minimal tearing. Patients with iritis should be referred to an
viral prodrome followed by adenopathy, fever, pharyngitis and upper ophthalmologist within a matter of days. Toxoplasmosis is a surpris-
respiratory tract infection, or the eye infection may be the only mani- ingly common cause of uveitis in the normal host, suspected on the
festation of the disease. Neisseria gonorrhoeae causes a hyperacute bac- basis of a very typical chorioretinal lesion. Most chorioretinal scarring
terial conjunctivitis that is severe and sight-threatening, requiring
immediate ophthalmologic referral. The eye infection is characterized
by a profuse purulent discharge with redness, irritation and tenderness TABLE Major Groups of Conditions Responsible for
with chemosis, lid swelling and tender preauricular adenopathy. PP4-1 the Differential Diagnosis of Red Eye
Etiology Associated Clinical Signs/Symptoms
BOX PP4-1 CLINICAL SIGNS AND SYMPTOMS Acute angle-closure glaucoma Nausea, vomiting
INDICATING SAME-DAY REFERRAL TO Conjunctivitis
AN OPHTHALMOLOGIST IN PATIENTS Viral Morning – watery discharge
WITH RED EYE Bacterial Fever, pharyngitis
Allergic Daylong purulent discharge
MEDICAL HISTORY Watery discharge
• Contact lens wearing Photophobia
• Ocular surgery Impaired vision
• Ocular trauma Foreign body sensation
SYMPTOMS Keratitis
• Nausea, vomiting Viral Corneal infiltrate
• Severe ocular pain Bacterial Corneal opacity
• Impaired vision Amebal Hypopyon
• Foreign body sensation Anterior uveitis
SIGNS Viral Red eye
Bacterial Ciliary flush
• Corneal opacity Parasite
• Corneal infiltrate Masquerade syndromes
• Hypopyon (white cells in the anterior chamber) Mycoses
175
virus keratoconjunctivitis can closely mimic the appearance of ocular

adenovirus infection. Herpetic infections require specialist advice
regarding antiviral therapy. Bacterial conjunctivitis also is likely to be
self-limited in most patients, although treatment probably shortens
the clinical course and reduces person-to-person spread of this highly
contagious condition. Appropriate choices for bacterial conjunctivitis
include erythromycin ophthalmic ointment, sulfa ophthalmic drops,
or polymyxin/trimethoprim drops. Other alternatives include tetracy-
cline ointment, or chloramphenicol eye drops. These are still widely
used in the UK and elsewhere, despite the fact that very rare instances
of chloramphenicol-induced aplastic anaemia have been described.
These agents cover the most common pathogens responsible for bacte-
rial conjunctivitis, and patients should respond to this treatment
within 1 to 2 days. Patients who do not respond should be referred to
an ophthalmologist. The fluoroquinolones are effective and well-
tolerated; they are the treatment of choice for corneal ulcers and are
Figure PP4-1 Red eye in a patient diagnosed with Whipple’s disease uveitis. extremely effective against Pseudomonas spp. However, fluoroquino-
lones are not first-line therapy for routine cases of bacterial conjunc-
from toxoplasmosis is due to infection during gestation, but scarring tivitis because of concerns regarding emerging resistance and cost. The
is increasingly being recognized as a result of primary infections exception is conjunctivitis in a contact lens wearer; once keratitis has
as well. Other etiologies recognized after extensive investigations been ruled out, it is reasonable to treat these individuals with a fluo-
include viruses and fastidious bacteria such as, Borrelia and Bartonella roquinolone due to the high incidence of Pseudomonas infection.
spp. Contact lens wearers with a red eye should discontinue contact lens
wear. If the diagnosis is conjunctivitis, contact lens wear can resume
When to Perform Microbiologic when the eye is white and has no discharge for 24 hours after the
completion of antibiotic therapy. The lens case should be discarded
Sampling? and the lenses subjected to overnight disinfection or replaced if dispos-
Questions arise of when, how and which specimen to obtain? Cultures able. Systemic therapy with doxycycline, tetracycline, erythromycin or
are not necessary for the initial diagnosis and therapy of conjunctivitis azithromycin is required to eradicate adult inclusion conjunctivitis.
except for patients with symptoms of hyperacute conjunctivitis in
whom Giemsa and Gram stains may be helpful to identify gram- RECURRENCE
negative diplococci suggestive of Neisseria gonorrhoeae. A point-of- Duration of symptoms in patients with herpes simplex keratitis is
care rapid test for adenoviral conjunctivitis has been favourably reduced with treatment with topical or oral antiviral agents. Immuno-
evaluated by modelled cost effectiveness analysis. The diagnosis of compromised patients may require topical and systemic treatment, and
adult inclusion conjunctivitis can be confirmed with Giemsa or direct longer duration of therapy. A small percentage of patients develop
fluorescent antibody-staining of conjunctival smears or by culture or chronic or recurrent inflammation, or recurrent viral keratitis, both of
polymerase chain reaction (PCR) of swabbed specimens. which are treated with prophylactic oral antiviral agents. Some patients
Keratitis lesions are sampled for microbiologic diagnosis based on also benefit from treatment with topical corticosteroid agents, used in
culture and PCR-based detection of major pathogens including her- conjunction with antiviral prophylaxis. Fortified topical antibiotics
pesvirus, bacteria and amebae. and fluoroquinolones are still the mainstay of bacterial keratitis
Patients with uveitis of unknown etiology which is bilateral, recur- therapy. Voriconazole may be useful for treating amebal keratitis.
rent, sight-threatening or non-responsive to therapy will require exten- Specific anti-infectious treatment should be prescribed in addition
sive evaluation for etiology. Vitreous humor should be sampled to to steroids in case of uveitis, in collaboration with the ophthalmologist
exclude ocular lymphoma by cytology and interleukin 10 measure- and the infectious disease specialist.
ments, and to search for selected pathogens (see below).
Further reading available online at expertconsult.com.
When to Provide Anti-infectious
Treatment?
Viral conjunctivitis is a highly contagious, self-limited process for
which there is no specific antiviral agent. Herpes simplex
Practice Point 4 Management of Red Eye 176.e1
FURTHER READING
Anger C., Lally J.M.: Acanthamoeba: a review of its Drancourt M., Berger P., Terrada C., et al.: High prevalence Thomas P.A., Geraldine P.: Infectious keratitis. Curr Opin
potential to cause keratitis, current lens care solution of fastidious bacteria in 1520 cases of uveitis of unknown Infect Dis 2007; 20:129-141.
disinfection standards and methodologies, and strategies etiology. Medicine (Baltimore) 2008; 87:167-176. Udeh B.L., Schneider J.E., Ohsfeldt R.L.: Cost effectiveness
to reduce patient risk. Eye Contact Lens 2008; 34:247- Miller J.: Metastatic ocular tumors of the anterior segment. of a point-of-care test for adenoviral conjunctivitis. Am J
253. Optometry 2008; 79:189-192. Med Sci 2008; 336:254-264.
SECTION 2 Syndromes by Body System:
The Central Nervous System
19
Acute and Chronic Meningitis
MATTHIJS C. BROUWER | DIEDERIK VAN DE BEEK
KEY CONCEPTS vaccines into vaccination programs in several countries further reduced
the disease burden of bacterial meningitis in high- and medium-
• The epidemiology of bacterial meningitis has changed income countries.3
following implementation of vaccines against Haemophilus Streptococcus pneumoniae affects all ages and causes the most severe
influenzae type B, Streptococcus pneumoniae and Neisseria disease in the very young and the very old.2 Of the more than 90
meningitidis.
pneumococcal serotypes, a few dominate as the causes of meningitis.
• Lumbar puncture should be performed in all patients with sus- The increase of drug-resistant strains of S. pneumoniae is an emerging
pected (bacterial or viral) meningitis. problem worldwide.5 The prevalence of antibiotic-resistant strains in
some parts of the USA is as high as 50–70% with important conse-
• Empiric treatment for bacterial meningitis consisting of antibi-
otics and adjunctive dexamethasone must be started before quences for treatment.6
cranial imaging is performed. Neisseria meningitidis is mainly responsible for bacterial meningitis
in young adults; it causes sporadic cases and epidemics.2,7 Its incidence
• Despite adequate treatment a high proportion of patients with shows a peak in winter and early spring and varies greatly around the
bacterial meningitis develop neurologic and systemic world. Small outbreaks typically occur in young adults living in close
complications.
quarters, such as dormitories of military camps or schools. Major
• Viral meningitis is usually self-limiting and often does not epidemics have occurred periodically in sub-Saharan Africa (the
require antiviral treatment. so-called ‘meningitis belt’), Europe, Asia and South America. During
these epidemics, attack rates can reach several hundred per 100 000,
• The differential diagnosis of chronic meningitis depends on
age, exposure to animals, travel and immune status of the with devastating consequences.
patient. The group B streptococcus (Strep. agalactiae) is a pathogen of neo-
nates and often causes a devastating sepsis and meningitis.2 It colonizes
the maternal birth canal and is transmitted to the child. The colonized
newborn can develop group B streptococcal disease of early onset
(developing at less than 7 days of age; median 1 day) or late onset
Introduction (developing later than 7 days of age). Screening for colonization and
Meningitis is an infection of the meninges and subarachnoid space, subsequent eradication treatment of pregnant women has resulted in
but can also involve the cortex and brain parenchyma (meningoen- an 80% reduction in early-onset group B streptococcal disease.8
cephalitis) because of the close anatomic relation between the cerebro- Listeria monocytogenes causes meningitis preferentially in neonates,
spinal fluid (CSF) and the brain. Inflammatory involvement of the in adults with immunosuppression or iron overload, in the elderly,
subarachnoid space with meningeal irritation leads to the classic triad and in pregnant women.9 Presentation is similar to pneumococcal and
of headache, fever and meningism, and to a pleocytosis in the CSF. meningococcal meningitis, although the duration of symptoms before
Involvement of the brain cortex and parenchyma may result in behav- presentation is longer. Haemophilus influenzae causes meningitis in
ioral changes, focal neurologic abnormalities and impairment of con- young children. In countries with routine vaccination against H. influ-
sciousness. Although these latter signs are classically considered to be enzae type b it has become a rare disease.3
encephalitis, meningitis and encephalitis should rather be seen as a Bacterial meningitis also occurs in hospitalized patients (‘nosoco-
continuum. Thus, although somewhat artificial, this chapter will be mial meningitis’). In a large city hospital, almost 40% of cases may
limited to those infections in which the meninges are inflamed. For a be nosocomial.10 Most cases occur in patients undergoing neurosurgi-
discussion of encephalitis the reader is referred to Chapter 20. cal procedures, including implanting of neurosurgical devices, and
in patients with severe neurotrauma. The organisms causing nosoco-
mial meningitis differ markedly from those causing community-
Acute Bacterial Meningitis acquired meningitis and include gram-negative rods (Escherichia coli,
Klebsiella spp., Pseudomonas aeruginosa, Acinetobacter spp., Enterobac-
Epidemiology ter spp. and others), staphylococci and streptococci other than Strep.
The incidence of acute bacterial meningitis is 1.4–2.6/100 000 persons pneumoniae.11
per year in high-income countries, resulting in 5000 cases in the USA
annually.1,2 Vaccination strategies have substantially changed the epi- Pathophysiology and Pathology
demiology of community-acquired bacterial meningitis during the Specific bacterial virulence factors for meningeal pathogens include
past two decades.3 The routine vaccination of children against Hae- specialized surface components that are crucial for adherence to the
mophilus influenzae type b has virtually eradicated H. influenzae men- nasopharyngeal epithelium, the evasion of local host defense mecha-
ingitis in the industrialized world.3 As a consequence, Streptococcus nisms and subsequent invasion of the bloodstream (Figure 19-1).12 In
pneumoniae has become the most common pathogen beyond the neo- pneumococcal disease, presence of the polymeric immunoglobulin A
natal period and bacterial meningitis has become a disease predomi- receptor on human mucosa, which binds to a major pneumococcal
nantly of adults.2 The introduction of conjugate vaccines against seven adhesin, CbpA, correlates with the ability of pneumococci to invade
serotypes of Strep. pneumoniae that are among the most prevalent in the mucosal barrier. Viral infection of the respiratory tract may also
children aged 6 months to 2 years has reduced the rate of invasive promote invasive disease.12 From the nasopharyngeal surface, encap-
pneumococcal infections in young children and in older persons.4 The sulated organisms cross the epithelial cell layer and invade the small
integration of the meningococcal protein–polysaccharide conjugate subepithelial blood vessels. Binding of bacteria to upregulated
177
178 SECTION 2 Syndromes by Body System: The Central Nervous System
Pathogenic steps in pneumococcal meningitis
Pneumococcus
IgA1-protease
IgA
Polysaccharide
capsule
Cell wall Streptococcus pneumoniae A. Nasopharynx
Mucous layer
Epithelial lining
CbpA ChoP PsaA NanA
PAFr Interstitium
plgR GlcNac endothelial lining
Hyaluronate
lyase degrades Pneumolysin binds to IgA
Transcytosis hyaluronan
Epithelial cell Polysaccharide capsule and

B. Circulation
Cbps interfere with complement
activation and phagocytosis
Autolysis
Release of bacterial components C. Subarachnoid
Antibiotics space
Figure 19-1 Pathogenic steps in pneumococcal meningitis. Neuraminidase (NanA) decreases viscosity of the mucus and exposes N-acetyl-glucosamine (GlcNAc)-
receptors on epithelial cells, which interact with pneumococcal surface-associated proteins (such as PsaA). IgA1 proteases cleave opsonizing host IgA. Cytokines stimulate
cell-surface expression of platelet-activating-factor receptors (PAFr). Binding to PAFr via cell-wall phosphocholine (ChoP) induces internalization and migration (trans-
cytosis) of pneumococci through the epithelial barrier, which is facilitated by binding of choline-binding protein A (CbpA) to the polymeric Ig-receptor (pIgR). After
penetrating the mucosal epithelium, hyaluronate lyase facilitates bacterial spreading by degrading hyaluronan, an important component of the interstitial matrix. Once
in the bloodstream the polysaccharide capsule and choline-binding proteins (Cbps) enhance intravascular survival by interfering with activation of the complement
cascades and phagocytosis. Pneumolysin reduces serum opsonic activity by binding to IgG. By changing the composition of surface components (phase variation)
pneumococci adapt to the host environmental conditions and migration through the blood–brain barrier. Attachment to endothelial cells occurs to several glycoconju-
gates. Activated endothelial cells upregulate PAFr and thereby enable pneumococci (mainly transparent phase variants) to invade the subarachnoid space via transcytosis.
The poor local host defenses in the subarachnoid space facilitate multiplication of bacteria, which undergo autolysis (mediated by autolysins or antibiotics) and release
bacterial compounds. (Reproduced with permission from Weisfelt et al.79)
receptors (e.g. platelet activating-factor receptors) promotes migration tion of C3b on the bacterial surface, thereby facilitating opsonization,
through the respiratory epithelium and vascular endothelium, result- phagocytosis and intravascular clearance of the organism.13 Genetic
ing in invasive disease. variations leading to functional deficiencies of several components
In the bloodstream, bacteria must survive host defenses, including involved in the activation and function of complement-mediated
circulating antibodies, complement-mediated bactericidal mecha- defenses have been identified (i.e. mannose-binding lectin, properdin,
nisms and neutrophil phagocytosis. Possession of a polysaccharide lack of terminal complement components), which increase the suscep-
capsule is a shared feature of the principal hematogenous meningeal tibility for invasive meningococcal and pneumococcal infections.14
pathogens. To survive the various host conditions they encounter The blood–brain barrier is formed by endothelial cells, which
during infection, pneumococci undergo spontaneous and reversible restrict blood-borne pathogen invasion. Cerebral capillaries, as
phase variation, which involves changes in the amount of important opposed to other systemic capillaries, have adjacent endothelial cells
surface components.12 The polysaccharide capsule is instrumental in fused together by tight junctions that prevent intercellular transport.15
inhibiting neutrophil phagocytosis and complement-mediated bacte- Bacteria are thought to invade the subarachnoid space via transcytosis.
ricidal activity. Several defense mechanisms counteract the antiphago- Non-hematogenous invasion of the CSF by bacteria occurs in situa-
cytic activity of the bacterial capsule. Activation of the alternative tions of compromised integrity of the barriers surrounding the brain,
complement pathway results in cleavage of C3 with subsequent deposi- e.g. in patients with mastoiditis or sinusitis. Direct communication
Chapter 19 Acute and Chronic Meningitis 179
between the subarachnoid space and the skin or mucosal surfaces as a ases, zinc-dependent enzymes produced as part of the immune
result of malformation or trauma may also result in meningeal infec- response to bacteria that degrade extracellular matrix proteins, also
tion. Furthermore, bacteria can also reach the CSF as a complication contribute to the increased permeability of the blood–brain barrier.12
of neurosurgery, spinal anesthesia or placement of a ventricular CSF The major element leading to increased intracranial pressure in
catheter. bacterial meningitis is the development of cerebral edema, which may
Physiologically, concentrations of leukocytes, antibodies and com- be vasogenic, cytotoxic or interstitial in origin. Vasogenic cerebral
plement components in the subarachnoid space are low, which facili- edema is a consequence of increased blood–brain barrier permeabil-
tates multiplication of bacteria. Pneumococcal cell-wall components, ity.17 Cytotoxic edema results from an increase in intracellular water
pneumolysin and bacterial DNA induce a severe inflammatory following alterations of the cell membrane and loss of cellular homeo-
response via binding to Toll-like receptor (TLR)-2.12 Once engaged, stasis. Cytotoxic mechanisms include ischemia and the effect of excit-
this signaling receptor transmits the activating signal into the cell, atory amino acids. Secretion of antidiuretic hormone also contributes
which initiates the induction of inflammatory cytokines. Endotoxin is to cytotoxic edema by making the extracellular fluid hypotonic and
a major component of the outer membrane of the meningococcus and increasing the permeability of the brain to water. Interstitial edema
is crucial in the pathogenesis of sepsis and meningitis.7 The host occurs by an increase in CSF volume, either through increased CSF
responds to bacterial endotoxin with proinflammatory gene expres- production via increased blood flow in the choroid plexus, or decreased
sion and activation of coagulation pathways.12 resorption secondary to increased CSF outflow resistance.
The subarachnoid inflammatory response is accompanied by pro- The exact mechanisms that lead to permanent brain injury are
duction of multiple mediators in the central nervous system (CNS). incompletely understood. Cerebral ischemic necrosis probably con-
Tumor necrosis factor (TNF), interleukin 1β and interleukin 6 are tributes to damage to the cerebral cortex (see Figure 19-2). Cerebro-
regarded as the major early response cytokines that trigger the inflam- vascular complications occur in 22–25% of patients with bacterial
matory cascade, which induces various pathophysiologic alterations meningitis.18,19 Other abnormalities include subdural effusion or
implicated in pneumococcal meningitis (Figure 19-2).12,16 TNF and empyema, septic sinus thrombosis, subarachnoid hematomas, brain
interleukin 1β stimulate the expression of chemokines and adhesion abscess, hydrocephalus and herniation of the temporal lobes or
molecules, which play an important part in the influx of leukocytes cerebellum.19-21
from the circulation to the CSF. Upon stimulation with bacterial com- There is diffuse acute inflammation of the pia-arachnoid, with
ponents, macrophages and granulocytes release a broad range of migration of neutrophil leukocytes and exudation of fibrin into the
potentially tissue-destructive agents, which contribute to vasospasm CSF. Pus accumulates over the surface of the brain, especially around
and vasculitis, including oxidants (e.g. peroxynitrite) and proteolytic its base and the emerging cranial nerves, and around the spinal
enzymes such as matrix metalloproteinases. Matrix metalloprotein- cord. The meningeal vessels are dilated and congested and may be
a b c
d e f
Figure 19-2 Multiple complications in a patient with pneumococcal meningitis. (a) T2-proton-density-weighted MRI of the brain shows a transverse view of a hyperin-
tense signal (arrows) in the basal ganglia that indicates bilateral edema. (b) A post-mortem view of the brain of the same patient shows yellowish-colored meninges as
a result of extensive inflammation. (c) Confirmation of the bilateral infarction of the basal ganglia (arrows). The microscopic substrate in the same patient shows a men-
ingeal artery with (d) lymphocytic infiltration in and around the vessel wall, (e) extensive subpial necrotizing cortical inflammation, and (f) edema in the white matter.
(Reproduced with permission from van de Beek et al.17)
surrounded by pus. Pus and fibrin are found in the ventricles and there antimicrobial therapy should be initiated when CSF analysis (e.g.
is ventriculitis, with loss of ependymal lining and subependymal Gram stain, leukocyte count) confirms the diagnosis.
gliosis. Infection may block CSF circulation, causing obstructive
hydrocephalus or spinal block. In many cases death may be attribut- CSF ANALYSIS
able to related sepsis, although bilateral adrenal hemorrhage (Water- When CSF analysis shows increased white blood cell counts, confirm-
house–Friderichsen syndrome) may well be a terminal phenomenon ing a diagnosis of meningitis, many clinicians would like to determine
rather than a cause of fatal adrenal insufficiency, as was once imagined. who has life-threatening bacterial meningitis and who has the less
Patients with meningococcal sepsis may develop acute pulmonary concerning viral meningitis. The CSF abnormalities of bacterial men-
edema. ingitis include raised opening pressure, polymorphonuclear leukocy-
tosis, decreased glucose concentration and increased protein
Clinical Features concentration.29 In bacterial meningitis, the white blood cell count is
typically >1000 cells/µL, while in viral meningitis it is <300 cells/µL,
The clinical presentation of a patient with bacterial meningitis may
although there is considerable overlap. The neutrophil count is higher
vary depending on age, underlying conditions and severity of illness.22
in bacterial than in viral meningitis. More than 90% of cases present
Clinical findings of meningitis in young children are often minimal,
with CSF white cell counts of >100/µL.25 In immunocompromised
and in childhood bacterial meningitis and in elderly patients classic
patients, CSF white blood cell counts may be lower, although acellular
symptoms such as headache, fever, nuchal rigidity and altered mental
CSF is probably rare, except in patients with tuberculous meningitis.30
status may be less common than in younger and middle-aged adults.23
The normal CSF glucose concentration is between 2.5 and 4.4 mmol/L
Infants may become irritable or lethargic, stop feeding, and are found
which is approximately 65% of the serum glucose. In bacterial menin-
to have a bulging fontanelle, separation of the cranial sutures, menin-
gitis the glucose concentration is usually <2.5 mmol/L or <40% of the
gism and opisthotonos, and they may develop convulsions.
serum glucose. The CSF protein in bacterial meningitis is usually
A meta-analysis of 845 patients aged over 30 years showed poor
>50 mg/dL.2,25
sensitivity and specificity for symptoms predicting community-
Gram stain is positive in identifying the organism in 50–90% of
acquired bacterial meningitis such as headache, nausea and vomiting.24
cases and CSF culture is positive in 80% of untreated patients.2 The
A prospective study of 696 adults with community-acquired bacterial
yield of Gram staining of CSF decreases slightly if the patients are
meningitis found an incidence of 44% for the classic triad of fever,
already on antibiotic treatment. CSF Gram staining has a high specific-
neck stiffness and change in mental status (Glasgow Coma Scale
ity (>97%) for identifying the causative organism, but sensitivity is
≤14).25 However, 95% of patients with culture-proven bacterial men-
considerably lower (~60%), especially in L. monocytogenes (10–30%).2,27
ingitis presented with at least two signs or symptoms of headache,
Latex particle agglutination tests that detect antigens of N. meningiti-
fever, neck stiffness and alterations in mental status. Purpuric rash is
dis, Strep. pneumoniae, H. influenzae and Strep. agalactiae have been
one of the hallmarks of meningococcal disease, but can be subtle and
used to provide diagnostic confirmation but do not provide an incre-
is absent in half of meningococcal meningitis patients.26
mental yield compared to CSF Gram staining. In recent years PCR has
At physical examination, Kernig’s sign, Brudzinski’s sign and
proven to have incremental value in addition to CSF culture and Gram
meningismus lack adequate sensitivity to be used in isolation to
stain, especially in patients treated with antibiotics before the lumbar
exclude bacterial meningitis.22 In a meta-analysis of studies in adults,
puncture.2,22 Broad-range PCR is used increasingly to detect the most
Kernig’s sign and Brudzinski’s sign showed poor sensitivity (9–11%)
common bacteria in a single test, with good sensitivity (80–100%) and
with high specificity (95%) in predicting meningitis.22 Neck stiffness
specificity (95–100%).2,22
had a sensitivity of 31% with specificity of 71%. Naturally, physicians
do not rely on a single test for diagnosis and combine a number SKIN BIOPSY
of historical and physical examination findings to form a clinical
Microbiologic examination of skin lesions can be of additional value
impression.
in patients with suspected meningococcal infection with negative CSF
Gram stain or culture.2 The results are not affected by previous anti-
Diagnosis and Management biotic treatment and isolation of the meningococcus from skin biopsy
Given the high mortality of acute bacterial meningitis, starting treat- facilitates determination of antibiotic susceptibility patterns.
ment and completing the diagnostic process should be carried out
simultaneously in most cases.27 The first step is to evaluate vital func- ANTIBIOTIC TREATMENT
tions, obtain blood cultures, and start antimicrobial therapy and Empiric antibiotic treatment should be based on the most common
adjunctive dexamethasone when indicated (Figure 19-3). At the same bacterial species that cause the disease according to the patient’s age
time, the level of suspicion for the presence of bacterial meningitis or clinical setting and on antibiotic susceptibility patterns of the
should be determined. pathogens. Neonatal meningitis is largely caused by group B strepto-
Retrospective studies suggest a link between delay in the adminis- cocci, E. coli, and L. monocytogenes.2 Initial treatment, therefore,
tration of antimicrobial therapy and adverse outcome.22 In a prospec- should consist of ampicillin plus a third-generation cephalosporin
tive study involving 156 patients with pneumococcal meningitis (cefotaxime or ceftriaxone), or ampicillin and an aminoglycoside
who were admitted to the intensive care unit, a delay of more than (Table 19-1).2
3 hours after presentation to the hospital before the initiation of Due to the emergence of multidrug-resistant strains of Strep. pneu-
antimicrobial therapy was associated with an increased 3-month moniae, vancomycin is often added to the initial empiric antimicrobial
mortality.28 regimen in adult patients. Although intermediate penicillin resistance
In patients with suspected bacterial meningitis in whom lumbar is common in some countries, the clinical importance of penicillin
puncture is postponed because of coagulation disorders (e.g. dissemi- resistance in the meningococcus has yet to be established. In countries
nated intravascular coagulation) or severe septic shock, or in whom with low rates of pneumococcal penicillin resistance (such as The
cranial imaging is indicated before lumbar puncture, blood cultures Netherlands), first-line treatment consists of a third-generation cepha-
should be drawn and antimicrobial therapy should be initiated without losporin (ceftriaxone or cefotaxime) combined with ampicillin to
delay (see Figure 19-3).22 In patients who have not undergone prior cover for L. monocytogenes.2 In the UK, the addition of vancomycin is
imaging and in whom disease progression is apparent, therapy should also not considered necessary and is not recommended unless the
be started directly after lumbar puncture, as well as in all patients with patient presents from one of the geographic regions associated with
cloudy CSF (suggestive of bacterial meningitis). In patients without high-level ceftriaxone resistance, such as Spain, southern Africa and
apparent progress of disease and no cloudy CSF on lumbar puncture, the USA.
Management of patients with suspected community-acquired bacterial meningitis
Suspicion for bacterial meningitis

Typical signs may be absent, prior antibiotics may mask severity of illness
Assess severity Start investigations

Ventilation Blood cultures
Circulation Blood gases
Neurologic examination Serum laboratory investigations
Chest X-ray
Rash: skin biopsy
Shock and/or coagulopathy?

Anticoagulant use
Disseminated intravascular coagulation
Yes No
Shock: low-dose steroids Indications for imaging before lumbar puncture?

No shock: DXM
Empiric antimicrobial therapy
Yes No
Stabilization and/or correction coagulant DXM and empiric antimicrobial therapy Lumbar puncture
Indications for imaging before lumbar puncture? Yes CT/MRI scan brain Cloudy CSF or apparent progress of disease?
No Significant space-occupying lesion? Yes No
Lumbar puncture Yes DXM and empiric antimicrobial therapy
CSF consistent with bacterial meningitis? CSF consistent with bacterial meningitis?
No Yes Yes No
Bacterial meningitis: Bacterial meningitis:

DXM and empiric therapy No lumbar puncture DXM and empiric therapy
Reconsider diagnosis
Figure 19-3 Algorithm for the management of patients with suspected community-acquired bacterial meningitis. CSF, cerebrospinal fluid; DXM, dexamethasone. (This
material was previously published by van de Beek et al.27 as part of an online supplementary appendix. ©2006 Massachusetts Medical Society. All rights reserved.)
Recommendations directed at common specific organisms in with meningococcal meningitis treated with monotherapy of penicillin
adults are described below and general recommendations based on the or ampicillin should also receive chemoprophylaxis, since these drugs
isolated micro-organism are listed in Table 19-2. do not reliably eradicate carriage. Recommendations for prophylactic
therapy are listed in Table 19-2.
ANTIBIOTIC PROPHYLAXIS
Prophylaxis is indicated for intimate contacts of patients with menin- ADJUNCTIVE DEXAMETHASONE TREATMENT
gococcal meningitis, which covers those eating and sleeping in the Animal models of bacterial meningitis showed that bacterial lysis,
same dwelling as well as those having close social and kissing contacts, induced by antibiotics, leads to subarachnoid inflammation.12 The
or healthcare workers who perform mouth-to-mouth resuscitation, severity can be attenuated by treatment with steroids. Several trials
endotracheal intubation or endotracheal tube management.2,27 Patients were done to assess adjunctive steroids in bacterial meningitis.
TABLE
19-1 Recommendations for Empiric Antimicrobial Therapy in Suspected Community-Acquired Bacterial Meningitis
Predisposing Factor Common Bacterial Pathogens Initial Intravenous Antibiotic Therapy
AGE
<1 month Streptococcus agalactiae, Ampicillin plus cefotaxime or an aminoglycoside

Escherichia coli,
Listeria monocytogenes
1–3 months Streptococcus pneumoniae, Ampicillin plus vancomycin plus ceftriaxone or cefotaxime*
Neisseria meningitidis,
Strep. agalactiae, Haemophilus influenzae, E. coli, L. monocytogenes
3–23 months Strep. pneumoniae, Vancomycin plus ceftriaxone or cefotaxime*

N. meningitidis,
Strep. agalactiae, H. influenzae,
E. coli
2–50 years N. meningitidis, Vancomycin plus ceftriaxone or cefotaxime*

Strep. pneumoniae
>50 years N. meningitidis, Vancomycin plus ceftriaxone or cefotaxime plus ampicillin†

Strep. pneumoniae,
L. monocytogenes,
Aerobic Gram-negative bacilli
With risk factor Strep. pneumoniae, Vancomycin plus ceftriaxone or cefotaxime plus ampicillin†
present‡ L. monocytogenes,
H. influenzae
*In areas with very low penicillin-resistance rates monotherapy third-generation cephalosporin may be considered.
†
In areas with very low penicillin-resistance and cephalosporin-resistance rates, combination therapy of amoxicillin and third-generation cephalosporin may be
considered.
‡
Alcoholism, altered immune status.
This material was published previously as part of an online supplementary appendix to van de Beek D., de Gans J., Tunkel A.R., Wijdicks E.F.: Community-acquired
bacterial meningitis in adults. N Engl J Med 2006; 354:44-53. Copyright 2006 Massachusetts Medical Society. All rights reserved.
Dexamethasone is a glucocorticosteroid with excellent penetration in in mortality (7 to 4%) or hearing loss (8 to 3%) after the introduction
the CSF. In a meta-analysis of randomized trials dexamethasone of dexamethasone, while a significant decline in autoimmune arthritis
reduced meningitis-associated hearing loss in children with H. influ- from 12 to 5% was observed.26 Both studies showed no evidence of
enza meningitis.31 harm. For L. monocytogenes meningitis, a sharp increase in unfavorable
Most available studies on dexamethasone therapy in adults with outcome rate was seen after the implementation of dexamethasone.9
bacterial meningitis suffered from methodological flaws. In 2002, a In a multivariate analysis however, dexamethasone was not signifi-
European randomized controlled trial showed that dexamethasone, cantly associated with outcome and the strongest factor influencing
given before or with the first dose of antibiotics, resulted in a reduction prognosis was infection with an emerging virulent L. monocytogenes
in the relative risk of an unfavorable outcome (0.59) and in death strain (sequence type 6).
(0.48) in adults with bacterial meningitis. This effect was most The use of dexamethasone in bacterial meningitis remains contro-
apparent in pneumococcal meningitis, in which mortality was versial in certain patient groups. First, there seems to be no benefit in
decreased from 34% to 14%.32 Follow-up studies of this trial showed patients in low-income countries. Explanations for this could be a
the treatment benefit of dexamethasone was not decreased by an delayed presentation, increased clinical severity, underlying anemia,
increase in neuropsychological deficits and that the survival benefit malnutrition, human immunodeficiency virus (HIV) infection and
persisted for over 13 years.33,34 A subsequent review in adults, which other unidentified differences between populations.31 Furthermore, by
included five clinical trials, confirmed the corticosteroid-associated reducing permeability of the blood–brain barrier, steroids can impede
reduction in mortality and neurologic sequelae.35 The reduction in case penetration of antibiotics into the CSF, as was shown for vancomycin
fatality in patients with pneumococcal meningitis was 21%. In menin- in animal studies, and lead to treatment failures, especially in drug-
gococcal meningitis, mortality and neurologic sequelae were not sig- resistant pneumococcal meningitis. However, an observational study
nificantly altered. Adverse events were equally divided between the in suspected pneumococcal meningitis showed appropriate concentra-
treatment and placebo groups. Based on these results, dexamethasone tions of vancomycin in CSF when steroids were used.37
has become routine therapy in adults with suspected bacterial
meningitis. INTENSIVE CARE MANAGEMENT
An updated Cochrane analysis including 4121 patients showed that Monitoring in an ICU is recommended to recognize changes in con-
corticosteroids were associated with a non-significant reduction in case sciousness and the development of new neurologic signs, monitor for
fatality (RR 0.74), reduced severe hearing loss (RR 0.67) and long-term subtle seizures and treat severe agitation. Bacterial meningitis may be
neurologic sequelae (RR 0.83). Corticosteroids reduced mortality in associated with septic shock, which is an important predictor of
adults with pneumococcal meningitis (RR 0.84).31 The beneficial effect outcome. Furthermore, patients with bacterial meningitis are at risk
of dexamethasone was only observed in high-income countries. of hyponatremia, although this is often mild.38 Hyponatremia may be
The implementation of dexamethasone in the treatment of bacte- a result of cerebral salt wasting, the syndrome of inappropriate antidi-
rial meningitis was studied in two studies from a large Dutch observa- uretic hormone secretion, or aggressive fluid resuscitation. A Cochrane
tion cohort. These showed dexamethasone was given according to meta-analysis showed some evidence in support of maintaining intra-
guidelines (10 mg QID, 4 days) in 84% of patients with pneumococcal venous fluids rather than restricting them.39 Hypernatremia is predic-
meningitis and following the implementation of dexamethasone mor- tive of unfavorable outcome and mortality.40 Several treatment options
tality decreased from 30 to 20%.36 The rate of hearing loss declined such as hypothermia and intracranial pressure (ICP) management
from 22% before the implementation of dexamethasone to 12% after. with CSF catheters have been suggested to improve outcome in
In meningococcal meningitis patients there were no significant changes patients with severe bacterial meningitis. Animal studies suggested a
TABLE Specific Antimicrobial Therapy in Community-Acquired Bacterial Meningitis Based on CSF Culture Results
19-2 and In-Vitro Susceptibility Testing
Micro-Organism, Susceptibility Standard Therapy Alternative Therapies
Streptococcus pneumonia
Penicillin MIC
<0.1 mg/L Penicillin G or ampicillin Cefotaxime or ceftriaxone, chloramphenicol
0.1–1.0 mg/L Cefotaxime or ceftriaxone Cefepime, meropenem
>2.0 mg/L Vancomycin plus cefotaxime or ceftriaxone* Fluoroquinolone†
Cefotaxime or ceftriaxone MIC

>1.0 mg/L Vancomycin plus cefotaxime or ceftriaxone‡ Fluoroquinolone†
Neisseria meningitidis
Penicillin MIC
<0.1 mg/L Penicillin G or ampicillin Cefotaxime or ceftriaxone, chloramphenicol
0.1–1.0 mg/L Cefotaxime or ceftriaxone Chloramphenicol, fluoroquinolone, meropenem
Listeria monocytogenes Penicillin G or ampicillin¶ Trimethoprim–sulfamethoxazole, meropenem

¶
Group B streptococcus Penicillin G or ampicillin Cefotaxime or ceftriaxone
Escherichia coli and other Cefotaxime or ceftriaxone¶ Aztreonam.¶ fluoroquinolone, meropenem,¶ trimethoprim–
Enterobacteriaceae sulfamethoxazole, ampicillin¶
Pseudomonas aeruginosa Ceftazidime¶ or cefepime¶ Aztreonam,¶ ciprofloxacin,¶ meropenem¶
Haemophilus influenzae
β-Lactamase negative Ampicillin Cefotaxime or ceftriaxone, cefepime, chloramphenicol, fluoroquinolone
β-Lactamase positive Cefotaxime or ceftriaxone Cefepime, chloramphenicol, fluoroquinolone
Chemoprophylaxis§
Neisseria meningitidis Rifampin (rifampicin), ceftriaxone,
ciprofloxacin, azithromycin
CSF, cerebrospinal fluid; MIC, minimum inhibitory concentration.

*Consider addition of rifampin (rifampicin) if dexamethasone is given.
†
Gatifloxacin or moxifloxacin; no clinical data on use in patients with bacterial meningitis.
‡
Consider addition of rifampin (rifampicin) if the MIC of ceftriaxone is >2  mg/L.
¶
Consider addition of an aminoglycoside.
§
Prophylaxis is indicated for close contacts who are defined as those with intimate contact, which covers those eating and sleeping in the same dwelling as well as
those having close social and kissing contacts; or healthcare workers who perform mouth-to-mouth resuscitation, endotracheal intubation or endotracheal tube
management.
General recommendations for intravenous empiric antibiotic treatment have included penicillin, 2 MU q4h; amoxicillin or ampicillin, 2 g q4h; vancomycin, 15 mg/kg
q8h; third-generation cephalosporin: ceftriaxone, 2 g q12h, or cefotaxime, 2 g q4–6h; cefepime, 2 g q8h; ceftazidime, 2 g q8h; meropenem, 2 g q8h;
chloramphenicol, 1–1.5 g q6h; fluoroquinolone: gatifloxacin, 400 mg q24h, or moxifloxacin, 400 mg q24h, although no data on optimal dose needed in patients
with bacterial meningitis; trimethoprim–sulfamethoxazole, 5 mg/kg q6–12h; aztreonam, 2 g q6–8h; ciprofloxacin, 400 mg q8–12h; rifampicin (rifampin) 600 mg
q12–24h; aminoglycoside: gentamicin, 1.7 mg/kg q8h. The preferred dose for chemoprophylaxis: rifampin (rifampicin), 600  mg po q12h for 2 days; ceftriaxone, 250 
mg im; ciprofloxacin, 500 mg po; azithromycin, 500 mg po.
This material was published previously as part of an online supplementary appendix to van de Beek D., de Gans J., Tunkel A.R., Wijdicks E.F.: Community-acquired
bacterial meningitis in adults. N Engl J Med 2006; 354:44-53. Copyright 2006 Massachusetts Medical Society. All rights reserved.
favorable effect of therapeutic hypothermia on outcome of bacterial Seizures occur in about 20% of patients with bacterial meningitis.44
meningitis. A randomized controlled trial, however, showed that mod- These patients tend to be older, are more likely to have focal abnormali-
erate hypothermia did not improve outcome in patients and was sug- ties on brain CT and to have Strep. pneumoniae as the causative micro-
gestive of being harmful.41 Case-control studies reported on ICP organism, and they have a higher mortality. If a patient with a decreased
management in patients with severe bacterial meningitis have been level of consciousness has a normal brain CT and normal serum elec-
published, but results are difficult to interpret because of confounding trolytes, an electroencephalogram (EEG) should be performed to look
variables and bias.42 for seizure activity. A low threshold for starting antiepileptic therapy
in those with clinical suspicion of seizures should be kept.
DECLINE IN CONSCIOUSNESS Following the introduction of dexamethasone, a novel complica-
In patients with a decline in consciousness or failure to improve upon tion has been identified. Patients made an excellent initial recovery, but
antimicrobial therapy, brain imaging is indicated to detect intracranial deteriorated after 1–2 weeks with focal neurologic deficits, decreased
complications such as cerebral infarction, hydrocephalus, cerebral level of consciousness and multiple areas of cerebral infarction on
hemorrhage, empyema and brain abscess.20,21,43 A decline in conscious- cranial imaging.45 This was found to occur in 2% of the population
ness in bacterial meningitis is compatible with meningoencephalitis and pathology examination showed diffuse thrombosis in the cerebral
(Figure 19-4). On neuroimaging, early signs of brain edema are the vessels leading to infarction. It has been hypothesized that the inflam-
disappearance of Sylvian fissures and a narrowing of ventricular size. matory response is reactivated after the effect of dexamethasone wanes.
In an advanced stage of brain edema and raised intracranial pressure, Potentially, treatment with high-dose steroids upon deterioration may
basal cisterns and sulci may become obliterated. If a communicating improve outcome in these patients.
hydrocephalus is identified, lumbar punctures can be performed or the
temporary insertion of a lumbar drain should be considered. In FOCAL NEUROLOGIC ABNORMALITIES
patients with mild enlargement of the ventricular system without clini- In meningitis, focal cerebral abnormalities (hemiparesis, monoparesis
cal deterioration, spontaneous resolution may occur and ‘watchful or aphasia) are most commonly caused by stroke or seizures, or a
waiting’ may be justified. Acute obstructive hydrocephalus requires combination of the two.18,44 Activation of inflammation and coagula-
ventricular drainage.21 tion are closely related and interdependent.12 In a patient with rapid
a b
c d
Figure 19-4 Neuroimaging of cerebrovascular complications of bacterial meningitis. (a) MRI showing bilateral infarction (arrow) in the basal ganglia causing decline in
consciousness. (b) MRI showing a focal zone of signal abnormality in the right dorsal aspect of the medulla oblongata (arrow) which has restricted diffusion, suggestive
of cerebral infarction. (c) CT showing bilateral occipital brain edema indication infarction (arrow). (d) CT showing hypodense areas in the left basal ganglia (right arrow)
and cerebellum (left arrow) consistent with infarction.
deterioration, subdural empyema should be considered. Clues to the WHEN TO REPEAT A LUMBAR PUNCTURE
diagnosis are the presence of sinusitis and mastoiditis (and recent The yield of a second lumbar puncture was studied in a retrospective
surgery for either of these disorders).20 Abnormalities of the cranial French ICU cohort study.47 CSF cultures from the repeated lumbar
nerves are caused by the meningeal inflammatory process or by an puncture were sterile in all patients, therefore the authors conclude
increase in CSF pressure. The most frequent cranial nerve abnormality their data do not support routine repetition of lumbar puncture.
is the involvement of the eighth cranial nerve, which is reflected in a In general, a repeat CSF analysis is only advised in patients whose
hearing loss in 14% of patients. condition has not improved after 48 hours of appropriate antimicro-
bial and adjunctive dexamethasone treatment. It is specifically war-
RECURRENT BACTERIAL MENINGITIS ranted when pneumococcal meningitis caused by penicillin-resistant
Recurrent bacterial meningitis occurs in 5% of community-acquired or cephalosporin-resistant strains is suspected.48 Gram staining and
bacterial meningitis cases; predisposing conditions are head injury and culture of the CSF should be negative after 24 hours of appropriate
CSF leak, and occasionally humoral immundeficiency.46 The high antimicrobial therapy.
prevalence of remote head injury and CSF leakage justifies an active
search for anatomic defects and CSF leakage. Detection of β-2 transfer-
rin in nasal discharge is a sensitive and specific method to confirm a Outcome
CSF leak and thin-slice CT of the skull base is best to detect small bone Community-acquired bacterial meningitis in adults is a severe
defects. The detection of a small bone defect does not prove CSF disease with high fatality and morbidity rates. Meningitis caused by S.
leakage. Surgical repair has a high success rate. pneumoniae has the highest case fatality rates, reported from 19% to
37%.2,36 Whereas neurologic complications are the leading cause of Patients with herpes simplex virus (HSV) meningitis are usually
death in younger patients, elderly patients die predominantly from infected with HSV type 2 and present with a rather benign disease.
systemic complications.49 Of those who survive, up to 50% develop This is in contrast with herpes simplex encephalitis (HSE) caused by
neurologic sequelae, including cognitive impairment.50 For meningo- HSV type 1, which is a serious illness with significant risks of morbidity
coccal meningitis, mortality is around 5%. The strongest risk factors and death (Chapter 166). Patients with herpes meningitis by HSV type
for an unfavorable outcome in bacterial meningitis are impaired con- 2 typically have recurrent episodes so-called Mollaret’s meningitis.
sciousness, low CSF white cell count and infection with Strep. Other less common causes are EBV, cytomegalovirus and mumps.56
pneumoniae.25
Laboratory Findings
Post-traumatic Bacterial Meningitis Initial CSF samples, while frequently suggestive of the diagnosis, are
This is often indistinguishable clinically from spontaneous meningitis. neither sensitive nor specific enough to differentiate viral from bacte-
However, in obtunded or unconscious patients with a recent or previ- rial meningitis.22 The CSF in patients with viral meningitis typically
ous head injury, few clinical signs may be present.51 Fever and deterio- exhibits pleocytosis with 10–500 leukocytes and a slightly elevated
ration in the level of consciousness or loss of vital functions may be protein level (>100 mg/dL). The glucose level in the CSF is typically
the only signs of meningitis. The rare finding of a CSF leak supports greater than 40% of a simultaneously drawn serum sample.
the possibility of meningitis. The range of bacteria causing meningitis Cultures of specimens of body fluids other than CSF may be useful
in these patients is broad and consideration should be given to in establishing the etiologic diagnosis in selected patients with menin-
broad-spectrum antibiotics including metronidazole for anaerobic goencephalitis.53 Specific clinical findings should also direct other sites
pathogens.51 for culture (e.g. stool, skin, sputum).
Molecular techniques have advanced identification of viral agents.
PCR provides a rapid and reliable test for verifying the etiology of
Viral Meningitis certain types of meningitis. These techniques provide results within
24–36 hours and therefore may limit the duration of hospitalization,
Epidemiology antibiotic use and excessive diagnostic procedures (for further discus-
sion, see Practice Point 5). Diagnostic serologic assays have simplified
Acute viral meningitis and meningoencephalitis represent the majority the diagnosis of viral infections of the CNS. The ELISA assay that
of viral CNS infections and frequently occur in epidemics with a sea- detects IgM antibodies in the CSF from patients with presumed Japa-
sonal distribution.52 Enteroviruses cause an estimated 90% of cases in nese encephalitis (JE) is both sensitive and specific, as most patients
countries that immunize against mumps, while arboviruses constitute have antibodies at the time of hospitalization and virtually all acquire
the majority of the remaining reported cases in the USA.53 Most cases them by the third day of illness.57 Unlike herpesviruses, which are
occur from late spring to autumn, reflecting the increased incidence of ubiquitous agents with generally high basal seroprevalence levels in the
enteroviral and arboviral infections during these seasons. general population, seroprevalence levels for individual arboviruses are
generally low.
Pathophysiology and Pathology
The pathogenesis of meningitis and meningoencephalitis are similar Antiviral Treatment
and requires that viruses reach the CNS by hematogenous or neuronal Antiviral therapy exists for HSV-1, HSV-2, varicella-zoster virus
spread. Viruses most frequently access the CNS after a high-titer (VZV), cytomegalovirus (CMV) and HIV.53 The introduction of aci-
secondary viremia and cell-free or cell-associated CNS entry. Other clovir has resulted in a sharp decline in mortality and morbidity from
than direct entry via cerebral vessels, virus can initially infect the HSE.58 Most authors recommend the use of intravenous aciclovir for
meninges and then enter the parenchyma across either ependymal cells HSV meningitis, although no definitive clinical trials have been con-
or the pial linings. Viruses exhibit differences in neurotropism and ducted. There are no data on benefit of antiviral treatment or on sup-
neurovirulence. pressive therapy for recurrent HSV meningitis.
In the normal host, viral meningitis is a relatively benign self-
Clinical Features limited disease. A prospective study in children less than 2 years of age,
Clinical manifestations of patients presenting with viral meningitis for example, found that even in the 9% of children who develop evi-
vary with age, immune status and viral etiology. The clinical examina- dence of acute neurologic disease (complex seizures, increased intra-
tion of a patient with suspected meningitis has been described previ- cerebral pressure or coma) long-term prognosis is excellent. During
ously in this chapter. follow-up (42 months), children with acute CNS complications per-
Epidemiologic features such as the season of the year, prevalent formed neurodevelopmental tasks and achieved developmental mile-
diseases within the community, travel, recreational activities (e.g. stones as well as did children with an uncomplicated course.59,60
caving or hiking), occupational exposures and animal contacts (e.g. In case reports, immunoglobulin preparations, given systemically
insect, tick or animal bite) may provide helpful clues to the diagnosis.53 or intrathecally, decreased mortality and morbidity in agammaglobu-
Late summer and early fall are seasons when enteroviral infections are linemia patients with (persistent) enteroviral meningitis. Enteroviral
encountered in temperate climates. Similarly, during warm summer infections in neonates frequently produce overwhelming viremia and
months, mosquito propagation may enhance the likelihood of trans- CNS disease. A blind, randomized controlled trial did not demonstrate
mission of arthropod-borne viruses. clinical benefit for enterovirus-infected neonates with severe life-
Patients with enteroviral meningitis often present with nonspecific threatening disease who received intravenous immunoglobulin.61
symptoms such as fever of 3–5 days’ duration, malaise and headache.54 Pleconaril, an inhibitor of enterovirus replication, was tested in two
Nuchal rigidity and photophobia are the hallmark signs and symptoms placebo-controlled clinical trials. Of 607 randomized patients in a
for meningitis, but 33% of patients with viral meningitis have no multicenter, double-blind, placebo-controlled study, 240 patients were
evidence of meningismus.55 Children may present with seizures sec- confirmed to have enterovirus infection.62 Resolution of headache in
ondary to fever, electrolyte disturbances or the infection itself. In the patients with concomitant moderate to severe nausea at baseline
immunocompromised host, enteroviral infection is both a diagnostic occurred at a median of 9.5 days in the absence of therapy and was
quandary and a potentially life-threatening disease. While physical reduced to 7.0 days for pleconaril recipients (p = 0.009). Over 50% of
examination of the patient usually does not suggest an etiologic diag- untreated-patients had a persistent headache that was greater than 1
nosis, a few considerations are essential. week in duration. Pleconaril shortened the course of illness compared
to placebo recipients, especially in the early disease course. However, from the rupture of a tubercle into the subarachnoid space. It is the
the benefit was achieved only modestly in a subgroup analysis of most important cause of chronic meningitis. In low- and middle-
patients with more severe disease after adjusting for confounding income countries (LMIC) TBM remains a common cause of bacterial
variables. meningitis, particularly in populations with a high prevalence of HIV
infection.30
Supportive Therapy Most patients with TBM have progressive headache and signs of
After establishing a presumptive diagnosis and instituting therapy, the meningeal irritation, followed by cranial nerve involvement, other
clinician must also vigilantly anticipate and treat complications associ- neurologic deficits and progressive mental status changes over a period
ated with the viral CNS disease or the therapeutic interventions,53 as of weeks.30,63 These prodromal symptoms can last from 2 to 8 weeks
described in this chapter for patients with bacterial meningitis. Sei- until the classic features of meningitis become more apparent. Patients
zures secondary to direct viral CNS damage, inflammatory vasculitis commonly present to hospital, when the infection is well established.
and electrolyte changes require anticonvulsant therapy. They will usually complain of headache and vomiting; many will
present confused or comatose. Examination reveals neck stiffness in
most, although rarely as marked as in pyogenic meningitis. Cranial
nerve palsies (especially third, sixth and seventh nerves) are found in
Chronic Meningitis 25% of patients. Ten percent of patients will present with a mono- or
hemiparesis. Rarely, TBM presents as an acute meningoencephalitis
Clinical Features that can be difficult to distinguish from pyogenic bacterial or viral
meningitis.63 Seizures are rare in adults with TBM, but more common
Chronic meningitis is defined by symptoms of meningeal inflamma- in children. HIV infection does not appear to alter the clinical presen-
tion with CSF pleocytosis that persist for more than 4 weeks. Symp- tation of TBM, although other extrapulmonary disease is more likely
toms and signs of chronic meningitis evolve over several days to weeks. in HIV-infected patients.
Patients complain of headaches, often associated with signs of infec- Tuberculous meningitis may be a consequence of either primary
tion (fever, anorexia). Nuchal rigidity may be subtle or absent. Many infection or reactivation of disease. The diagnosis can be confirmed by
forms of chronic meningitis involve the base of the brain and can lead a positive CSF culture; however, M. tuberculosis is recovered from the
to cranial nerve palsies, often affecting eye movements and facial mus- CSF in only 38–88% of cases.30 A moderate lymphocytic pleocytosis is
culature. As the syndrome progresses, signs of brain involvement with most common. The glucose can be very low; the protein is often very
seizures, mental status changes, confusion or hallucinations, and focal high. CSF smears for acid-fast bacilli are positive in only a minority of
neurologic deficits develop. Hydrocephalus and increased intracranial cases (10–20%). Tuberculin skin tests are frequently negative in TBM.
pressure may accompany the syndrome. Interferon-gamma release assays in CSF have a reasonable specificity
(70–90%) when sufficient volumes of CSF are used (5–10 mL), but
Tuberculous Meningitis low sensitivity (50–70%).30
One of the most common causes of chronic meningitis is Mycobacte- The treatment of TBM follows the model of short course chemo-
rium tuberculosis (Table 19-3). Tuberculous meningitis (TBM) results therapy of pulmonary tuberculosis (Table 19-4): an ‘intensive phase’
TABLE
19-3 Microbial Causes of Chronic Meningitis
Predominant Type of CSF Predisposition and Risk
Pathogen Pleocytosis Factors Associated Clinical Manifestations
Bacteria Actinomyces spp. Neutrophils Mouth and ear lesions CNS lesions, endophthalmitis
Borrelia burgdorferi (Lyme Lymphocytes Tick bite Cranial nerve palsy (VII nerve)
disease)
Brucella spp. Lymphocytes, neutrophils Unpasteurized dairy products Undulant fever, hepatomegaly
Leptospira spp. Neutrophils Exposure to urine of infected Hepatomegaly, hepatitis, thrombocytopenia
animals
Mycobacterium tuberculosis Neutrophils, monocytes, Immunodeficiency, high Cranial nerve palsy (VI nerve)
lymphocytes endemic prevalence
Nocardia spp. Neutrophils Immunodeficiency Abscesses
Treponema pallidum Eosinophils, lymphocytes Sexually transmitted diseases Cranial nerve palsy (VII and VIII nerves)
Tropheryma whipplei Neutrophil Gastrointestinal Whipple Cognitive decline, gait ataxia, supranuclear
disease gaze palsy
Viruses Cytomegalovirus Lymphocytes; neutrophils Immunodeficiency Fever, retinitis

(in HIV)
Echovirus Lymphocytes Agammaglobulinemia Dermatomyositis
Lymphocytic choriomeningitis Lymphocytes Exposure to rodents Orchitis, leukocytopenia, thrombocytopenia
virus
Mumps virus Neutrophils No vaccination Parotitis, orchitis, oophoritis
HIV Lymphocytes HIV risk factors Mononucleosis-like illness
Fungi Aspergillus spp. Lymphocytes or neutrophils Immunodeficiency, surgery Lung involvement

Candida spp. Neutrophils Antibiotics, surgery, Disseminated disease
immunodeficiency
Coccidioides spp. Lymphocytes Endemic areas Lung involvement
Cryptococcus spp. Lymphocytes Immunodeficiency Encephalitis, headache
Histoplasma spp. Lymphocytes Endemic areas, Fever, oral lesions, hepatosplenomegaly
immunodeficiency
Pseudallescheria spp. Neutrophils Immunodeficiency Skin lesions, endophthalmitis
Sporothrix spp. Neutrophils Immunodeficiency Skin lesions, endophthalmitis
Parasites Taenia solium Eosinophils Endemic areas Elevated intracranial pressure, calcified
lesions on cranial imaging
Angiostrongylus spp. Eosinophils Raw seafood Fever
TABLE
19-4 Treatment Recommendations for Common Treatable Causes of Chronic Infectious Meningitis
Agent Therapy Dose Route
Herpesviruses Aciclovir 10 mg/kg q8h iv
Mycobacterium tuberculosis Isoniazid 10 mg/kg/q24h (up to 300 mg/q24h) po or iv

Rifampin (rifampicin) 10 mg/kg/q24h (up to 600 mg/q24h) po or iv
Ethambutol 25 mg/kg/q24h po or iv
Pyrazinamide 25 mg/kg/q24h (up to 2.5 g/q24h) po or iv
Brucella spp. (>8 years) Doxycycline plus gentamicin 100 mg q12h po

1.7–2 mg/kg q8h iv
Brucella spp. (<8 years) Trimethoprim–sulfamethoxazole plus gentamicin 5 mg/kg trimethoprim q12h po
25 mg/kg sulfamethoxazole q12h po
2 mg/kg q8h iv
Treponema pallidum Penicillin G 2 g q4h iv
Borrelia spp. Ceftriaxone 2–3 g q24h iv
Cryptococcus spp. Amphotericin B plus flucytosine 0.5–0.8 mg/kg/q24h iv

37.5 mg/kg q6h po
Coccidioides spp. Fluconazole 400–600 mg/q24h po
of treatment with four drugs, followed by a prolonged ‘continuation Other Infectious Causes of
phase’ with two drugs. When there is no suspicion of multidrug resis-
tance, the first 2 months of treatment should be with isoniazid, Chronic Meningitis
rifampin, pyrazinamide and either streptomycin, ethambutol or ethi- Secondary syphilis may cause chronic meningitis. The disease is slowly
onamide.30 An open-label phase 2 trial showed high-dose rifampin has progressive, and generally symptoms have been present for more than
superior plasma and CSF concentrations, and resulted in a substantial 1 month before presentation. Cranial nerve palsies are common; the
reduction in mortality in patients with severe disease.64 Further trials facial and acoustic nerves are the most frequently affected. Diagnosis
on optimal rifampin use in tuberculous meningitis are currently is based on a positive non-treponemal antibody test in CSF. Treatment
ongoing. British and American guidelines suggest between 9 and 12 consists of high-dose penicillin (see Table 19-4).69
months total antituberculosis treatment for TBM, although a recent The diagnosis of meningitis associated with Lyme disease, caused
systematic review concluded that 6 months might be sufficient pro- by Borrelia burgdorferi, should be considered in patients who live or
vided the likelihood of drug resistance is low. have traveled through endemic regions, particularly those with a
The use of steroids in the treatment of TBM was first reported in history of a tick bite or erythema chronicum migrans.70 Meningitis
the early 1950s.65 Continued research supports the use of steroids while may persist for weeks and may be associated with cranial nerve palsies
adequately treating with multiple antimycobacterial drugs in TBM. A and peripheral neuropathies. Syphilis, other spirochetal diseases and
meta-analysis of 595 patients found that the use of adjunctive steroids collagen vascular diseases may result in a false-positive Lyme serology.
led to fewer deaths and reduced incidences of death and disability.66 A Treatment consists of high-dose ceftriaxone, although a clinical trial
randomized, double-blind, placebo-controlled trial of 545 patients showed oral doxycycline to be equally effective in European adults
found that patients receiving dexamethasone had a reduced risk of with mild neuroborreliosis.70,71
death (RR 0.69) that was consistent across subgroups of differing clini- Whipple’s disease is a rare, systemic infectious disease caused by
cal severity.67 Although there were significantly fewer serious adverse the bacterium Tropheryma whipplei.72 Neurologic manifestations
events in the patients receiving dexamethasone, this study did not occur in three situations: neurologic relapse of previously treated
report an associated reduction in the proportion of patients who devel- Whipple’s disease, neurologic involvement in classic Whipple’s disease,
oped severe disabilities. A long-term follow-up study showed dexa- and isolated neurologic symptoms due to T. whipplei without evidence
methasone improved survival in the first 2 years after disease, but of intestinal involvement. Many patients have systemic symptoms,
afterwards a beneficial effect was not observed.68 such as fever, weight loss, peripheral lymphadenopathy and arthralgia.
The largest randomized study recommends a stratified dexametha- The predominant symptoms include cognitive impairment, ophthal-
sone treatment regimen in patients with TBM.67 Under this protocol, moplegia, ataxia and upper motor neuron disorder. A review sum-
patients with a Glasgow Coma Scale score of less than 15 or who have marized outcomes for 30 patients described in the literature: 18 (60%)
a focal neurologic deficit are treated with intravenous dexamethasone had improvement and 10 died (33%); in 1 patient, the disease stabi-
for 4 weeks (0.4 mg/kg per day in week 1, 0.3 mg/kg per day in week lized. Treatment consisted of high-dose ceftriaxone, followed by main-
2, 0.2 mg/kg per day in week 3, and 0.1 mg/kg per day in week 4), tenance therapy with co-trimoxazole or hydroxychloroquine in
followed by a taper of oral dexamethasone (4 mg/day, 3 mg/day, 2 mg/ combination with doxycycline.73
day and 1 mg/day, each for a period of 1 week). Patients with a normal Presentations of chronic meningitis caused by Cryptococcus neofor-
mental status and no neurologic findings receive intravenous dexa- mans or Cryptococcus gatii range from a subacute meningoencephalitis
methasone for 2 weeks (0.2 mg/kg per day in week 1, then 0.1 mg/kg to fever of unknown origin.74 People at highest risk are those with
per day in week 2), followed by the same oral taper as described above. defects in cellular immunity such as occurs in AIDS, hematologic
It is recommended that the steroid treatment should start as soon as malignancies and prolonged use of high-dose corticosteroids. CSF
possible after initiation of first-line antituberculous drugs. shows moderate lymphocytic pleocytosis; however, in patients who
Tuberculous meningitis leads to severe CNS inflammatory pro- have AIDS, inflammation may be virtually absent. Cryptococcal
cesses with secondary damage; mortality of up to 50% has been antigen latex agglutination is positive in more than 90% of cases,
reported.30 whereas microscopy of India ink preparations to visualize the yeast in
CSF is less sensitive (but may be more readily available). Treatment solium.77 Seizures are the most common manifestation. Intraventricu-
recommendations are provided in Table 19-4 (see also Chapters 94 lar and basilar cysts (racemose cysticercosis) may present with signs of
and 189). obstructive hydrocephalus. The CSF shows a lymphocytic pleocytosis
Coccidioides immitis grows in the dry sandy soils of the south-west with eosinophils. CT scans of the head show multiple calcified lesions.
USA, and Central and South America.75 Acute infection is acquired by Serology of blood and CSF may provide support for the diagnosis.
inhalation of the spores, and meningitis develops within a few months. Treatment should be tailored according to the type of neurocysticer-
There are few distinguishing features of the disease; some patients who cosis and may consist of albendazole, steroids, analgesics, antiepileptic
have generalized disease have erythema nodosum; hydrocephalus is a drugs, surgical resection of lesions and placement of ventricular shunts
common complication. CSF eosinophilia in patients who have lived or (see Chapter 119).
traveled through endemic regions should alert the clinician to the pos- Angiostrongylus cantonensis, the rat lung worm, is most prevalent
sibility of Coccidioides meningitis. Complement-fixing antibodies are in Asia and the Pacific Islands and is acquired by the ingestion of raw
present in the CSF in 75–95% of cases and CSF cultures are positive or inadequately cooked shellfish or snails.78 Symptoms are typical of
in more than 50%. Treatment is usually with an azole or amphotericin chronic meningitis, and rash with pruritus is also common. Infection
B, depending on the clinical manifestations and the immune status of results in peripheral eosinophilia and chronic eosinophilic meningitis,
the host (see also Chapters 33 and 189). which resolves spontaneously within 2 months. There is no effective
Histoplasma meningitis is a rare complication of histoplasmosis.76 therapy.
The diagnosis should be considered in patients who live or have trav- Other even less common causes of infectious chronic meningitis
eled through endemic regions – the Ohio River Valley of the USA, the are organisms that usually cause abscesses, which may leak into the
Caribbean and South America. CSF cultures are positive in 27–65% of subarachnoid space to cause chronic meningitis. These conditions
cases. Blood should be cultured and a buffy coat of the blood should include blastomycosis, paracoccidioidomycosis, phaeohyphomycosis,
be examined for the presence of the fungus. Histoplasma polysaccha- mucormycosis, actinomycosis, nocardiosis and toxoplasmosis. Less
ride antigen is found in the urine, blood or CSF in 61% of patients common fungi causing this syndrome include Sporothrix schenckii,
and in an even higher proportion of patients who have AIDS. Adequate chromoblastomycosis and Aspergillus spp.
and prolonged antifungal therapy is indicated in all cases of CNS his-
toplasmosis (see also Chapters 33 and 189). References available online at expertconsult.com.
Neurocysticercosis is endemic in Mexico, South America and Asia.
Infection is acquired by eating food contaminated with eggs of Taenia
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vaccines on bacterial meningitis worldwide. Lancet 2012; Clin Microbiol Rev 2008; 21:519-537.
380:1703-1711.
Chapter 19 Acute and Chronic Meningitis 188.e1
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20
Encephalitis and Myelitis
KAREN C. BLOCH | CAROL A. GLASER | ALLAN R. TUNKEL
KEY CONCEPTS Epidemiology

• The epidemiology of encephalitis is evolving due to the devel- In the USA, encephalitis accounts for >20 000 hospitalizations per year,
opment of effective vaccines against previously common with costs estimated at 2 billion dollars annually.8 The case fatality rate
pathogens (e.g. measles virus), emerging pathogens (e.g. among patients with encephalitis varies from 3.8% to 7.4% and is
West Nile virus), and newly discovered organisms (e.g. Nipah significantly higher in patients also infected with human immunode-
virus). ficiency virus (HIV).9,10 In some infections, such as those caused by
• Encephalitis and myelitis are diagnostically challenging infec- rabies virus or Naegleria fowleri, the mortality rate is almost 100%.
tions due to the inability to easily sample the involved tissues Additionally, these estimates of disease burden do not take into
and the large number of organisms that have been associated account the significant morbidity among survivors of encephalitis,
with these syndromes. with the resultant loss of productivity and need for prolonged reha-
bilitation or skilled nursing care.
• The microbiology of encephalitis and myelitis includes rela-
US hospital discharge survey data between 1998 and 2010 point to
tively common organisms that have tropism for the central
nervous system (CNS) (e.g. herpes simplex virus 1 (HSV-1)), an average annual age-adjusted rate of 6.9 encephalitis hospitalizations
relatively uncommon organisms that are strongly associated per 100 000 US population.8 Outside of the USA, there are important
with CNS infections (e.g. rabies virus), common organisms that viruses, such as measles, rabies and Japanese encephalitis virus (JEV),
uncommonly infect the CNS (e.g. varicella-zoster virus), and which contribute significantly to the disease burden (Figure 20-1). For
organisms that have been linked to encephalitis but in which instance, JEV causes 20 000 cases each year worldwide; 20–30% of
causality is uncertain (e.g. Mycoplasma). these result in death, and over 50% of survivors have neurologic
• Noninfectious etiologies, particularly autoimmune syndromes sequelae.11
such as anti-N-methyl-D-aspartate receptor (NMDAR) enceph- Rates of encephalitis are highest at the lower and upper age ranges.
alitis, are increasingly recognized as presenting identically to One study reported a rate of encephalitis in children <1 year of age of
infectious encephalitis. 18.4/100 000 child-years, almost double that seen in older children.12
Adults age >65 years have a relative risk of hospitalization for encepha-
• All patients with encephalitis and myelitis should have diagnos-
litis 2.2 times that of persons younger than 65 years.8 While encepha-
tic testing (typically polymerase chain reaction (PCR) of CSF)
for the most common viral pathogens, including HSV, varicella- litis hospitalizations among patients with HIV infection or organ
zoster virus (VZV) and the enteroviruses. transplantation are similar to those reported in the general population,
they are at risk for infection from a broader array of pathogens. Expo-
• An individualized diagnostic approach based on consideration sures or risk factors associated with specific infectious causes of
of immune status, seasonality, geography, animal and arthro- encephalitis, and myelitis, are listed in Table 20-1.
pod exposures, clinical findings, and radiographic abnormali-
ties is also indicated.
Microbiology
• Empiric antimicrobial therapy should be given until diagnostic
Infectious causes of encephalitis and myelitis include viruses, bacteria,
testing returns negative; this includes aciclovir and antibiotics
directed against bacterial etiologies of meningitis or rickettsial fungi and parasites. The spectrum of causative agents has shifted in
diseases, as appropriate. If no infectious etiology is identified, recent years, primarily due to a decrease in vaccine-preventable condi-
consideration should be given to starting immunosuppression tions such as measles, mumps, rubella and varicella.12,13 Infectious
for an autoimmune cause of encephalitis. agents that predominate in one region may be uncommon elsewhere.14-16
Examples of emerging causes of encephalitis and myelitis worldwide
include Nipah virus,17,18 Balamuthia mandrillaris,19,20 Chandipura
virus,21 Hendra virus,22 Powassan virus,23 and enterovirus 71.6
A useful paradigm for organizing the vast number of causative
Introduction agents is to categorize them based on the strength of association with
Encephalitis is defined by the presence of inflammation in the brain, encephalitis and myelitis. The first group includes the most commonly
associated with clinical evidence of neurologic dysfunction.1 It is one identified etiologies in the USA such as herpes simplex virus 1 (HSV-
of the most challenging syndromes for clinicians to diagnose and 1), West Nile virus (WNV) and the enteroviruses, followed by other
manage, particularly because a specific pathogen is identified in fewer herpesviruses (Table 20-2). Some studies have found that VZV vascu-
than 50% of cases.2 Diagnostic difficulties in establishing an etiology lopathy or encephalitis is relatively common in adults with an inci-
include the vast number of infectious causes of encephalitis, the many dence rivaling that of HSV.14,24 Other agents may be highly endemic
noninfectious etiologies that may cause encephalitis, and mispercep- regionally (e.g. La Crosse virus) or internationally (e.g. rabies virus,
tions about molecular versus serologic testing. Guidelines for the diag- JEV). Bacterial agents, including Ehrlichia spp. and Rickettsia rickettsii,
nosis and management of encephalitis have recently been published are potentially treatable causes of encephalitis and myelitis.25,26
and address many of these issues.3-5 The second category includes less commonly identified agents,
Myelitis refers to inflammation of the spinal cord, as a result of a which are neurotropic and well-associated causes of sporadic encepha-
direct infectious process or through postinfectious or other mecha- litis and myelitis (Table 20-3). They fall into two categories:
nisms;6,7 in association with encephalitis, this syndrome is often • uncommon pathogens with prominent CNS symptoms (e.g.
referred to as encephalomyelitis. This chapter will focus on the syn- Eastern equine encephalitis and Venezuelan equine encephalitis
dromes of encephalitis and myelitis in immunocompetent hosts, with viruses); and
a more detailed discussion of pathogen-specific infections in the chap- • relatively common pathogens (e.g. Borrelia burgdorferi, Coxiella
ters dedicated to those microbes. burnetii) that rarely cause CNS infections.
189
Worldwide distribution of major arboviral encephalitides
SLE TBE
EEE
LAC TBE WN
POW
WN WN JE
WN
JE JE
EEE: Eastern equine encephalitis VEE

JE: Japanese encephalitis EEE JE
LAC: La Crosse encephalitis WEE
MVE: Murray Valley encephalitis SLE
POW: Powassan encephalitis MVE
SLE: St. Louis encephalitis
TBE: Tick-borne encephalitis
WEE: Western equine encephalitis
WN: West Nile encephalitis
VEE: Venezuelan equine encephalitis
Figure 20-1 Worldwide distribution of major arboviral encephalitides. Courtesy of the Centers for Disease Control and Prevention.
Most problematic is the third category of agents: those anecdotally CNS. Encephalitis can present with purely parenchymal findings, but
associated with encephalitis and myelitis but with minimal neurotro- more commonly has associated meningeal inflammation, representing
pism and inconclusive laboratory data confirming direct CNS invasion an overlap syndrome meningoencephalitis. The signs and symptoms
(Table 20-4). For instance, Mycoplasma pneumoniae is the most of encephalitis are determined by the brain area involved and by the
common agent identified in several large pediatric case series of severity of infection. Some organisms show tropism for particular
encephalitis and myelitis.27-29 However, causality is difficult to estab- anatomic sites; for example, HSV-1 infection almost universally
lish, particularly if the only laboratory test is positive Mycoplasma involves one or both temporal lobes and can present as focal temporal
serology.28 Other organisms associated with encephalitis but with lobe seizures.37
similar ambiguity include influenza virus,30 rotavirus,31 human herpes- Fever and headache frequently precede the onset of altered mental
virus 6,32 parvovirus B1933 and others listed in Table 20-4. status, which can range from mild confusion to obtundation. Rarely,
Perhaps the most challenging aspect of encephalitis for patients, patients with inflammation localized to extracerebral portions of the
families and clinicians is that, despite the multitude of causal organ- CNS may have intact cognition; primary varicella infection is associ-
isms, no pathogen is identified in the majority of cases. Studies con- ated with cerebellar inflammation, with findings of ataxia and nystag-
ducted in geographically distant sites on disparate populations mus but no cognitive deficits.38 Other neurologic manifestations may
consistently report that 50–70% of cases remain unexplained.2,8,34 In a include behavioral changes (such as psychosis), focal paresis or paraly-
prospective study testing 1570 well-defined cases over a 7-year period sis, cranial nerve palsies, or movement disorders such as chorea.16 The
using a standardized diagnostic algorithm including extensive molecu- frequency of seizures varies based on the pathogen; generalized sei-
lar testing, no etiologic cause was identified in 63%.16 Approximately zures are common with Bartonella (cat scratch) encephalopathy39 but
10% of patients initially thought to have an infectious cause of enceph- are noted in <10% of cases of WNV encephalitis.40
alitis were ultimately diagnosed with a noninfectious condition. In this Rabies deserves special mention because of the severity of illness
cohort, among patients <30 years of age, an autoimmune syndrome and worldwide importance. Rabies virus infection, with very few
termed anti-NMDAR encephalitis accounted for >4 times as many exceptions, is almost invariably fatal, and the time to progression from
cases as WNV, HSV-1 and VZV combined.35 Although ovarian tera- onset of symptoms to death is typically less than 2 weeks.41 Symptoms
toma is the most common trigger for anti-NMDAR encephalitis, HSV initially are nonspecific, but may include fever, headache, pharyngitis
encephalitis may also be a trigger for subsequent development of anti- and weakness. The diagnosis should be considered in any patient with
NMDAR encephalitis.36 a rapid progression of illness, particularly if hydrophobia, autonomic
instability or extreme agitation is present. Paresthesia at the inocula-
tion site is a unique feature of rabies.
Clinical Features Myelitis may occur in patients with or without encephalitis. Myeli-
Encephalitis is infrequently confirmed by pathology. Therefore, signs tis is characterized by motor weakness, ascending sensory deficit and
and symptoms of neurologic dysfunction are used as surrogate markers early bowel and bladder involvement.6,42,43 Motor weakness may be of
for brain inflammation. Encephalopathy, defined as disruption of the upper motor neuron type (manifested as spasticity, hyperreflexia
brain function without direct brain inflammation, may mimic enceph- and extensor plantar reflexes) or the lower motor neuron type (mani-
alitis, although fever is less common and there is usually minimal CSF fested as flaccid weakness and decreased or absent deep tendon
pleocytosis.4 Causes of encephalopathy include metabolic distur- reflexes). Acute flaccid paralysis is seen in a number of viral causes of
bances, hypoxia, ischemia, intoxications, organ dysfunction, paraneo- myelitis, including infection caused by enteroviruses (e.g. poliovirus
plastic syndromes or systemic infections not directly involving the and enterovirus 71) and flaviviruses (e.g. WNV, JEV and tick-borne
Chapter 20 Encephalitis and Myelitis 191
TABLE
20-1 Exposures Associated with Agents Causing Encephalitis and Myelitis
Risk factor/Exposure Agent
ARTHROPODS
Mosquito bite* Alphaviruses (Western equine encephalitis virus, Eastern equine encephalitis virus, Venezuelan
equine encephalitis virus)
Flaviviruses (West Nile virus, Japanese encephalitis virus, St Louis encephalitis virus)
Bunyaviruses (California/La Crosse virus)
Tick bite Powassan virus, Anaplasma phagocytophilum, Ehrlichia spp., rickettsial species, tick-borne
encephalitis virus, Borrelia burgdorferi
Sandflies Bartonella bacilliformis, Chandipura virus (India)
Tsetse flies Trypanosoma brucei gambiense, Trypanosoma brucei rhodesiense (Africa)
WILD/DOMESTIC ANIMALS
Bats Rabies virus, Nipah virus, Histoplasma capsulatum

Dogs Rabies virus
Cats Bartonella henselae, Toxoplasma gondii, rabies virus
Rodents* Lymphocytic choriomeningitis virus, Leptospira spp.
Raccoon Baylisascaris procyonis, rabies virus
Sheep/goats Coxiella burnetii
Birds* Cryptococcus neoformans, Chlamydia psittaci
Old-world monkeys B virus
Horses* Hendra virus (Australia)
Swine Nipah virus (South East Asia)
Skunks Rabies virus
Parturient animals (especially farm animals) Coxiella burnetii
Fresh water Naegleria fowleri, Leptospira spp.
Soil (aerosolized or ingested) Balamuthia mandrillaris, Baylisascaris procyonis, endemic fungi
Undercooked freshwater fish, chicken or pork Gnathostoma spp. (South East Asia, Mexico)
Raw or undercooked fresh water prawns, crabs or frogs, or Angiostrongylus cantonensis (South East Asia, Pacific Islands, Caribbean)
unwashed produce (with snails/slugs)
Unpasteurized milk Coxiella burnetii, tick-borne encephalitis virus, Listeria monocytogenes
SEASON
Fall Enteroviruses, arthropod-borne pathogens (see above)

Winter Influenza virus
Spring Enteroviruses, arthropod-borne pathogens (see above)
Summer Enteroviruses, arthropod-borne pathogens (see above)
RECREATION
Camping/hunting Arthropod-borne pathogens (see above)

Spelunking Rabies virus, Histoplasma capsulatum
Sexual activity HIV, syphilis, herpes simplex virus 2
*Rodents, birds and horses may serve as reservoir hosts for arboviruses, but transmission to humans is generally from an arthropod vector.
encephalitis virus).3,40,42 Subacute myelitis is often caused by retrovi- retention. Transverse myelitis may be produced by direct invasion of
ruses;6,42 human T-cell lymphotrophic virus 1 (HTLV-1) causes disease the spinal cord with organisms such as Borrelia burgdorferi; vasculitis
primarily in the thoracic spinal cord with resultant progressive spastic of the anterior spinal artery caused by VZV, tuberculosis and syphilis
paraparesis, and HIV may cause spastic paraparesis and sensory ataxia. may also lead to transverse myelitis.
When both halves of the spinal cord are affected, the entity is Evidence of inflammation or infection at sites distant from the CNS
referred to as transverse myelitis.6,42 Patients with transverse myelitis may be useful in making a microbiologic diagnosis in patients with
present with a syndrome mimicking transection of the spinal cord encephalitis and myelitis. For instance, rickettsial diseases, VZV and
with involvement of the motor, sensory and autonomic pathways; WNV can often have associated skin manifestations. Stomatitis and
virtually all patients have paresthesias, numbness or radicular dyses- ulcerative lesions in the mouth or an exanthem in a peripheral distri-
thesias with an associated sensory level. Autonomic symptoms can bution might suggest enterovirus infection. Patients with tuberculous
include constipation, bowel or bladder incontinence and urinary and fungal meningoencephalitis may have suggestive pulmonary
TABLE
20-2 Relatively Common Causes of Encephalitis and Myelitis in Immunocompetent Patients
Etiology Epidemiology Clinical Features Diagnosis
VIRUSES
Enteroviruses (includes Peak incidence in late summer and Range from aseptic meningitis (most CSF PCR or culture. Stool or throat
coxsackie viruses, early fall; enterovirus 71 a cause of common) to encephalitis; enterovirus 71 swab PCR or culture suggestive, but
echoviruses and large outbreaks in Asia, with causes rhombencephalitis not diagnostic, of CNS involvement
enterovirus 71) children primarily affected
Epstein–Barr virus Either during acute infection or Infectious mononucleosis symptoms CSF PCR (may be falsely positive
reactivation, primary CNS during acute infection, cerebellar ataxia, through detection of latently
lymphoma sensory distortion (‘Alice-in- infected macrophages), serology
Wonderland’ syndrome) (IgM positive in acute infection)
HSV-1 and -2 HSV-1 accounts for 5–10% of Temporal lobe seizures (apraxia, lip CSF PCR
encephalitis, typically reactivation smacking), behavioral abnormalities
disease; HSV-2 seen in neonates
Japanese encephalitis Mosquito-borne, most common Seizures, Parkinsonian features, acute CSF IgM, CSF antigen, serology
virus (JEV) worldwide cause of encephalitis, flaccid paralysis variably seen. MRI (cross-reacts with other flaviviruses)
endemic throughout Asia; vaccine classically with thalamic and basal
preventable ganglia involvement
La Crosse virus Mosquito-borne, endemic in Varies from subclinical illness to seizures Serology
midwestern and eastern USA; peak and coma
incidence in school-aged children
Rabies virus Vaccine preventable; most common Often with numbness or neuropathic pain Antibodies (serum, CSF), PCR of saliva
vector is bat, and bites often at site of bite, progressing to or CSF, IFA of nuchal biopsy or CNS
unrecognized; dogs important in hydrophobia (with drooling), agitation, tissue; coordinate testing with local
LMIC; worldwide distribution delirium, autonomic instability, coma; health department
paralytic form with ascending paralysis
in 30%
St Louis encephalitis Mosquito-borne, endemic to western Tremors, seizures, paresis, urinary Serology (cross-reacts with other
virus (SLE) USA, with periodic outbreaks in symptoms, SIADH variably present flaviviruses)
central/eastern USA; peak
incidence in adults >50 years
Tick-borne Transmitted via tick or ingestion of Weakness ranging from mild paresis to Serology
encephalitis virus unpasteurized milk; endemic to acute flaccid paralysis
eastern and central Europe, Far
East
Varicella-zoster virus Acute infection (chickenpox) or Vesicular rash (disseminated or DFA or PCR of skin lesions, CSF PCR,
reactivation (shingles) dermatomal), cerebellar ataxia, large serum IgM (acute infection)
vessel vasculitis, vasculopathy may
mimic stroke symptoms
West Nile virus (WNV) Mosquito-borne, emerging cause of Weakness and acute flaccid paralysis, CSF IgM, paired serology (cross-
epidemic encephalitis throughout tremors, myoclonus, Parkinsonian reactivity with WNV and SLE),
USA, Europe; endemic in Middle features, MRI with basal ganglia and CSF PCR in severely
East; peak incidence adults >50 thalamic lesions immunocompromised patients
years
BACTERIA
Bartonella henselae Typically follows scratch or bite from Encephalopathy with seizures (often status Serology (acute usually diagnostic),
(and other cat or kitten; highest incidence in epilepticus), with rapid recovery; PCR of lymph node, CSF PCR rarely
Bartonella spp.) children peripheral lymphadenopathy variably positive
noted; CSF usually paucicellular
Mycobacterium Most common in LMIC; disease Subacute basilar meningitis, lacunar CSF AFB smear, culture, PCR;
tuberculosis in extremes of age or infarcts, hydrocephalus; CSF formula respiratory cultures highly suggestive
immunocompromised often with low glucose, high protein;
often have associated pulmonary
findings
Ehrlichia/Anaplasma Tick-borne bacteria causing human Acute onset of fever and headache; rash Morulae in WBCs, PCR of whole blood,
monocytic and human granulocytic seen in <30% of cases of Ehrlichia in serology (seroconversion may occur
ehrlichiosis, respectively; former adults; leukopenia, thrombocytopenia several weeks after symptoms)
endemic to southern and central and elevated serum transaminases
USA, latter to northeast USA and frequent manifestations
the Midwest
Rickettsia rickettsii Tick-borne infection found Acute onset of fever and headache; Serology (seroconversion may occur
throughout North America, with petechial rash in 85% of cases several weeks after symptoms), PCR
peak incidence in southeast and beginning 3 days after onset of or IHC staining of skin biopsy of rash
south central USA symptoms
AFB, acid-fast bacilli; CSF, cerebrospinal fluid; DFA, direct fluorescent antibody; IFA, indirect fluorescent antibody; IHC, immunohistochemical; LFTs, liver function
tests; LMIC, low- and middle-income countries; PCR, polymerase chain reaction; SIADH, syndrome of inappropriate antidiuretic hormone secretion.
TABLE
20-3 Less Common Established Causes of Encephalitis and Myelitis in Immunocompetent Patients
VIRUSES
B virus Transmitted by bite of old-world macaque Vesicular eruption at site of bite Culture and PCR of vesicles and CSF
followed by neurologic symptoms,
including transverse myelitis
Eastern equine Coastal states (Atlantic and Gulf); children Ranges from subclinical to fulminant; Serology
encephalitis virus and elderly disproportionately affected mortality 50–70%
Hendra virus Endemic in Australia; associated with Nonspecific Contact local health department or
horse exposure Special Pathogens Branch at CDC
Lymphocytic Peak incidence in fall and winter Orchitis, parotitis Serology

choriomeningitis virus
Measles virus Vaccine-preventable illness; measles Measles encephalitis nonspecific; SSPE CSF antibodies, brain tissue PCR;
inclusion body encephalitis onset 1–6 has a subacute onset with EEG changes often diagnostic
months after infection; subacute progressive dementia, myoclonus,
sclerosing panencephalitis (SSPE) a late seizures and ultimately death
manifestation (>5 years after infection)
Mumps virus Vaccine-preventable illness Parotitis, orchitis; hearing loss frequent Serology, throat swab PCR, CSF
culture or PCR
Murray Valley encephalitis Peak incidence in aboriginal children; Nonspecific presentation; case fatality Serology (may cross-react with other
virus indigenous to Australia and New 15–30% flaviviruses)
Guinea
Nipah virus Epidemics in South East Asia Myoclonus, dystonia, pneumonitis Serology (Special Pathogens Branch,
CDC)
Powassan virus Tick-borne; endemic in New England Nonspecific Serology (cross reacts with other
states and Canada bunyaviruses)
Rubella virus Vaccine-preventable illness Neurologic findings typically occur at Serology, CSF antibodies
same time as rash and fever
Vaccinia Infection or vaccination as precipitating Vaccinia rash (localized or CSF antibodies, serum IgM (natural
event; thought to be autoimmune disseminated) infection)
phenomenon
Venezuelan equine Central/South America; rarely in border Myalgias, pharyngitis, upper Serology, viral cultures (blood,
encephalitis virus states of USA (Texas, Arizona) respiratory symptoms variably oropharynx), CSF antibody
present
Western equine Summer and early fall onset; Western USA Nonspecific Serology
encephalitis virus and Canada, Central and South America
BACTERIA
Borrelia burgdorferi Tick-borne infection, with encephalitis in Facial nerve palsy (often bilateral), Serology (serial EIA and Western
early disseminated Lyme disease, meningitis, radiculitis; may be blot), CSF antibody index, CSF
encephalopathy in late disease associated with or follow erythema PCR
migrans rash
Coxiella burnetii Animal exposures (particularly placenta Nonspecific Serology

and amniotic fluid)
Treponema pallidum Sexually transmitted disease, with Protean manifestations including VDRL Serum non-treponemal
meningoencephalitis seen in early temporal lobe focality (mimics antibody test with confirmatory
disseminated disease and progressive herpes simplex virus), general FTA-ABS. If high clinical suspicion
dementia in late disease paresis, psychosis, dementia and based on positive serum
testing, obtain CSF VDRL (specific,
but not sensitive); if CSF VDRL
non-reactive, consider CSF
FTA-ABS (sensitive, but not
specific)
Tropheryma whipplei – Progressive subacute encephalopathy; CSF PCR, PAS-positive cells in CSF,
oculomasticatory myorhythmia small bowel biopsy
pathognomonic; variably
enteropathy, uveitis
PROTOZOA
Balamuthia mandrillaris Central America (natives and immigrants), Subacute progressive disease Serology (research laboratories),
southern and western USA characterized by space-enhancing brain histopathology
lesions, often with cranial nerve
palsies and hydrocephalus (similar to
tuberculosis)
Naegleria fowleri Summer months; children and adolescent Anosmia, progressive obtundation; Motile trophozoites on wet mount of
boys at highest risk; swimming in fresh typically a neutrophilic pleocytosis warm CSF, brain histopathology
water, and particularly water sports, a
risk factor

TABLE
20-3 Less Common Established Causes of Encephalitis and Myelitis in Immunocompetent Patients (Continued)
HELMINTHS
Baylisascaris procyonis Pica, particularly near raccoon latrine Obtundation, coma; typically with CSF and serum antibodies (Perdue
significant CSF and peripheral Department of Veterinary
eosinophilia Pathology)
Schistosomiasis Worldwide; depends on species (see Myelopathy (usually S. mansoni), Serology; direct microscopy of stool/
Chapter 118) flaccid paraplegic NS changes urine
(S. japonicum); delirium
CSF, cerebrospinal fluid; EIA, enzyme immunoassay; FTA-ABS, fluorescent treponemal antibody absorption; PAS, periodic acid-Schiff; PCR, polymerase chain reaction.
TABLE Selected Pathogens of Unknown Neurotropic Potential that are Anecdotally Associated with Encephalitis
20-4 and Myelitis
Etiology Epidemiologic and Clinical Features Diagnosis
VIRUSES
Adenovirus Sporadic cases; children and immunocompromised at greatest Viral culture or PCR from respiratory site, CSF, or
risk; variably associated respiratory symptoms brain tissue
Human herpesvirus 6 Most commonly reported in immunocompromised, particularly CSF PCR

hematopoietic stem cell transplant recipients; latent infection
of neural tissues making significance of detection in brain
tissue difficult to determine
Hepatitis C Hepatitis C seropositive patient CSF PCR
Human metapneumovirus Newly described pathogen almost exclusively in children Respiratory tract PCR
Influenza virus Sporadic disease in children, with most reports from Japan and Respiratory tract culture, PCR or rapid antigen;
South East Asia; upper respiratory symptoms; acellular CSF, CSF and brain PCR infrequently positive
10% with bilateral thalamic necrosis; high mortality
Parvovirus B19 Sporadic cases, variably associated with skin rash IgM antibody, CSF PCR
Rotavirus Typically children, winter months, usually with diarrhea Stool antigen, CSF PCR (CDC)
BACTERIA
Chlamydia spp. Anecdotal reports with C. psittaci and C. pneumoniae Nasopharyngeal swab; respiratory or CSF PCR
Mycoplasma pneumoniae In some pediatric series, the most common cause of PCR of nasopharyngeal swab or respiratory culture;
encephalitis; respiratory symptoms variably present, but serum IgM, CSF PCR rarely positive
pneumonia rare; often with white matter involvement
consistent with ADEM
ADEM, acute disseminated encephalomyelitis; CSF, cerebrospinal fluid; PCR, polymerase chain reaction.
findings. Regional lymphadenopathy is typically present in patients

with Bartonella encephalopathy. Diarrhea may be seen with enterovi- Pathology and Pathogenesis
rus, adenovirus or rotavirus infections. Most infectious agents that cause encephalitis and myelitis gain access
A syndrome frequently misclassified as encephalomyelitis, based on to the CNS via the hematogenous route, causing diffuse neurologic
the similar clinical presentation, is postinflammatory encephalomyeli- dysfunction. Following local infection, a viremia follows, leading to
tis, occurring days to weeks after an infectious illness or immuniza- invasion and replication within the CNS.48 Why certain viruses are
tion.44,45 Most widely cited is acute disseminated encephalomyelitis more neurotropic than others is unknown, although it has been pos-
(ADEM), seen primarily in children and adolescents and characterized tulated that the small size of the arboviruses allows them to escape
by poorly defined white matter lesions on MRI that enhance following clearance by the mononuclear phagocyte system; arboviruses likely
gadolinium administration (Figure 20-2).46,4 Postinflammatory en enter the CNS via cerebral capillaries, with endothelial cell infection
cephalomyelitis is presumed to be an immunologic response to an preceding infection of the neural parenchyma.49 Studies have identified
antecedent antigenic stimulus, with up to 90% of patients reporting hypertension as a risk factor for the development of WNV neuroinva-
an infectious illness, or receipt of an immunization, in the weeks before sive disease, suggesting that defects in the blood–brain barrier may be
onset of ADEM.47 Viral infections associated with ADEM include a risk factor.50
measles, mumps, rubella, varicella-zoster, Epstein–Barr, cytomegalovi- Another mechanism that organisms such as rabies virus and polio-
rus, herpes simplex virus 1 and 2, hepatitis A virus and enteroviruses. viruses use to gain access to the CNS is retrograde spread through
Immunizations associated with ADEM include vaccines for JEV, yellow neuronal networks. After introduction through the skin, usually via a
fever, measles, influenza, smallpox, anthrax and rabies virus; however, bite, rabies virus replicates in the skeletal muscle and travels to the CNS
a causal association with these vaccines is difficult to establish. ADEM via the peripheral nerves. In cases of prolonged incubation periods,
generally begins between 2 days and 4 weeks following the antigenic rabies virus likely remains close to the site of viral entry.51
stimulus, with rapid onset of encephalopathy, with or without menin- A third mechanism that organisms use to gain entry into the CNS
geal signs;47 neurologic presentation depends upon the location of the is exemplified by amebae such as Naegleria fowleri. These organisms
lesions. are most commonly found in water. When water in introduced
transnasally, such as occurs when diving under water, organisms pass and anterior horn cells of the spinal cord.57 The white matter is primar-
through the cribriform plate and invade the frontal lobes of the brain.52 ily affected in postinfectious encephalitis (i.e. as in ADEM) where there
The pathogenesis of herpes simplex encephalitis (HSE) is incom- is perivenular mononuclear inflammation, edema and demyelination
pletely understood.53,54 Serologic studies suggest that one-third of cases of brain tissue with a relative sparing of the axons.47
represent primary infection and two-thirds are a result of reactiva-
tion.55 For primary HSE, theorized routes of entry into the CNS Diagnosis
include hematogenous dissemination, migration from the nasopha- Although many cases of encephalitis and myelitis remain undiagnosed,
ryngeal mucosa through the cribriform plate, or retrograde spread and many causes are not treatable, a thorough diagnostic evaluation is
from viral-infected ganglion to the brain tissue.56 In cases of HSV important. Identification of a specific causative agent may allow for the
reactivation, the virus that replicates in the trigeminal ganglion might discontinuation of potentially toxic antimicrobial therapy and may be
spread to the frontal and temporal lobes via the tentorial nerves.53 useful for prognosis and counseling of patients and families.3 Epide-
In acute viral encephalitis, the classic histopathologic findings miologic clues may guide specific diagnostic testing (see Table 20-1).
include perivascular mononuclear cell inflammation, neuronal Specific clinical findings should direct testing from other sites for
destruction, neuronophagia and microglial nodules. Certain infectious culture or other diagnostic tests.
agents have a predilection for specific brain regions; e.g. the neuroin- Initial laboratory testing should include a complete blood count,
vasive flaviviruses (such as WNV and JEV) localize in regions impor- tests of renal and hepatic function, and coagulation studies. Results of
tant for motor control such as the thalamus, basal ganglia, brainstem these may suggest a particular etiology; a low white blood cell count,
low platelet count and elevated liver transaminases might suggest
Ehrlichia or Anaplasma infection. A chest radiograph should be
obtained, as a focal infiltrate would prompt further diagnostic studies
such as sputum induction or bronchoscopy.
Neuroimaging is important in all patients with encephalitis. MRI
is more sensitive than CT, and is preferred3; diffusion-weighted MRI
is superior to conventional MRI for detection of abnormalities caused
by HSV, enterovirus 71 and WNV. In addition, some neuroimaging
patterns may suggest infection caused by certain organisms (Table
20-5). In patients with HSE, there may be edema and hemorrhage in
the temporal lobes (see Figure 20-3). Patients with flavivirus encepha-
litis may display characteristic patterns of mixed intensity or hypodense
lesions on T1-weighted images in the thalamus, basal ganglia and
midbrain (Figure 20-4). In patients with ADEM, MRI generally reveals
multiple focal or confluent areas of signal abnormality in the subcorti-
cal white matter (Figure 20-2). MRI of the spine is abnormal in about
90% of patients with transverse myelitis,6 commonly manifested as an
area of T2-weighted hyperintensity in the central region of the spinal
cord occupying two-thirds or more of the cross-sectional area; swelling
of the spinal cord is seen in about 50% of patients.
Electroencephalography (EEG) should also be performed in
patients with encephalitis. Although EEG findings are rarely specific
Figure 20-2 Brain MRI of a 3 year old with new onset seizures showing increased
for a given pathogen, results can help in identifying the degree of
T2 signal affecting the white matter in diffuse regions of the cerebral cortex con- cerebral dysfunction, detecting subclinical seizure activity, and identi-
sistent with acute disseminated encephalomyelitis. fying the area of the brain involved.
TABLE
20-5 Possible Etiologic Agents of Encephalitis Based on Neuroimaging Findings
Neuroimaging Finding Possible Infectious Agents
Arteritis and infarctions Varicella-zoster virus (VZV), Nipah virus, Rickettsia rickettsii, Treponema pallidum
Calcifications Cytomegalovirus (cortical), Toxoplasma gondii (periventricular), Taenia solium
Cerebellar lesions VZV, Epstein–Barr virus, Mycoplasma pneumoniae
Focal lesions in basal ganglia, thalamus and/or Epstein–Barr virus, Eastern equine encephalitis virus, Murray Valley encephalitis virus, St Louis
brain stem encephalitis virus, Japanese encephalitis virus, West Nile virus (WNV), enterovirus 71, influenzae virus
(acute necrotizing encephalopathy), human transmissible spongiform encephalopathies, Tropheryma
whipplei, Listeria monocytogenes
Hydrocephalus Mycobacterium tuberculosis, Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum,

Balamuthia mandrillaris
Space-occupying lesions Toxoplasma gondii, Balamuthia mandrillaris, Acanthamoeba spp., Taenia solium
Subependymal enhancement Cytomegalovirus
Temporal and/or frontal lobe involvement Herpes simplex virus, VZV, human herpesvirus 6, WNV, enteroviruses, Treponema pallidum (medial
lobes)
White matter abnormalities VZV, cytomegalovirus, Epstein–Barr virus, human herpesvirus 6, HIV, Nipah virus, JC virus, measles virus
(subacute sclerosing panencephalitis), Baylisascaris procyonis, acute disseminated encephalomyelitis
This is not meant to be a comprehensive list to detail all etiologic agents based on neuroimaging findings, but to suggest that certain etiologies have been
associated with findings on neuroimaging studies.
Figure 20-3 Brain MRI in a patient with herpes simplex encephalitis (HSE). FLAIR demonstrates hypersignal and swelling in the right insula, superior temporal, parahip-
pocampal and orbitofrontal gyri. (Courtesy of Glenn A. Tung MD, Warren Alpert Medical School of Brown University.)
a b
Figure 20-4 Brain MRI in a patient with West Nile virus encephalitis. FLAIR (a) and trace diffusion-weighted (b) MR imaging demonstrates symmetric hypersignal and
swelling involving the bilateral inferior parietal and insular cortices and both thalami (arrows). (Courtesy of Glenn A. Tung MD, Warren Alpert Medical School of Brown
University.)
Lumbar puncture with CSF analysis (cell count and differential, diagnostic; in rabies, Negri bodies are a distinctive histopathologic
glucose and protein) and a measurement of the opening pressure feature. Pathologic examination of the brain may also be very helpful
should routinely be performed unless there is a specific contraindica- to diagnose Balamuthia mandrillaris and other free-living amebic
tion.3 Most patients with viral encephalitis have mononuclear cell infections. Brain biopsy may have a role in diagnosis of both infectious
pleocytosis with cell counts ranging from 10 to 1000/microliter. Early and noninfectious etiologies, particularly when there are focal lesions
in the disease process, CSF pleocytosis may be absent or there may be on neuroimaging.59
an elevation in neutrophils. The CSF protein concentration is typically More in-depth discussion of diagnostic testing is provided in the
elevated, but usually less than 100–200 mg/dL, while the CSF glucose agent-specific chapters; however, some pathogens should be routinely
concentration is normal. Neutrophilic pleocytosis (particularly with a considered in all patients with encephalitis. An HSV PCR should be
white blood cell (WBC) count >1000/microliter), CSF protein performed on the CSF of all patients with encephalitis. False-negative
>200 mg/dL or CSF glucose less than two-thirds of serum glucose PCR can occur within the first 72 hours of onset; if HSE is strongly
suggests a bacterial, mycobacterial, fungal, parasitic or noninfectious suspected (e.g. because of temporal lobe involvement), a repeat HSV
etiology. CSF viral cultures are of limited value in patients because of PCR on a later sample of CSF is recommended.60,61 Enterovirus
low sensitivity and are generally not recommended.58 CSF cultures for and varicella PCR should be done on CSF since these are also
bacteria, fungi and mycobacteria should be performed as identification common causes of encephalitis,16 although the sensitivity of CSF PCR
of a pathogen has significant implications for treatment. for VZV is low (~30%) and CSF serology is a more sensitive test for
Brain biopsy, previously considered instrumental in the etiologic VZV vasculopathy.62 Testing for M. pneumoniae deserves special
diagnosis of encephalitis, has largely been replaced by CSF molecular mention since it is one of the leading agents identified serologically
tests.3 However, for certain types of infection, brain biopsy may be among children with encephalitis;27,28 diagnostic testing should include
immunoglobulin M (IgM) on acute serum and immunoglobulin G patients with suspected HSV encephalitis and continued until infec-
(IgG) on paired samples, with attempts to amplify the bacteria from tion with HSV and VZV has been excluded. Empiric therapy for bacte-
CSF and nasopharyngeal swabs in suggestive cases. rial meningitis should be initiated when clinical and laboratory testing
Testing for less common agents should be based on the patient’s is compatible with bacterial infection.57 If rickettsial or ehrlichial infec-
exposures, risk factors, and clinical and laboratory characteristics (see tions are suspected, doxycycline should also be used.
Tables 20-1 and 20-4). Many infections require acute and convalescent In patients suspected to have postinfectious encephalomyelitis
(i.e. paired) serum samples to determine a diagnosis.3 Ideally, a serum (i.e. ADEM), steroids or other immunotherapies are often recom-
specimen from the acute phase of the illness should be stored and mended.3 High-dose intravenous corticosteroids (methylprednisolone
tested in parallel with the convalescent sample. Since arboviruses are 1 g intravenous daily for at least 3–5 days, followed by an oral taper
a leading cause of encephalitis, testing for geographically relevant for 3–6 weeks) are generally recommended for ADEM; plasma
viruses should be considered during the appropriate season. IgM and exchange should be considered in patients who respond poorly to
IgG ELISAs have become useful and widely available for the diagnosis corticosteroids. Although there is no clear evidence of effective therapy
of arboviral encephalitis.63 For WNV, detection of intrathecal IgM for transverse myelitis, intravenous methylprednisolone (followed by
antibody is both specific and sensitive for diagnosis.64 There is substan- oral prednisone) may shorten the duration of illness and improve
tial cross-reactivity among the flaviviruses (e.g. WNV, SLE and JEV) outcome6; one study, however, did not confirm this benefit.65 Some
and plaque-reduction neutralization assays may be helpful in distin- patients may also receive clinical benefit from plasma exchange or
guishing which flavivirus is involved in the event of elevated titers. cyclophosphamide,66 although more studies are needed. Treatment of
Serologic testing for Rickettsia, Ehrlichia and Anaplasma spp. autoimmune encephalitis (e.g. anti-NMDAR encephalitis) is based on
should be performed in all encephalitis patients during the appropriate use of immunosuppressive regimens (corticosteroids, intravenous
season and with travel to, or residence in, endemic areas. Empiric immunoglobulin, plasma exchange)67 in female patients, evaluation
therapy should not be withheld in patients with a compatible clinical for an underlying ovarian teratoma (and removal, if present) is also
presentation, however, since antibodies are frequently absent early in indicated.
the illness.26 Detection of antibodies against free-living amebae (e.g. In addition to directed therapy, aggressive supportive care is criti-
Balamuthia) in patients with compatible clinical and laboratory find- cal, and minimizing secondary brain injury is a high priority. Compli-
ings is suggestive of amebic meningoencephalitis.19 cations of encephalitis include elevated intracranial pressure,
hydrocephalus, stroke and seizures; these should be managed expec-
tantly, often in an ICU setting.68 Rehabilitation guidelines for encepha-
Management litis survivors are not yet developed, but physical therapy and cognitive
Specific antiviral therapy is limited to infections caused by herpesvi- therapy should be considered.
ruses (especially HSV-1 and VZV) and HIV.3 Aciclovir (10 mg/kg
intravenous q8h in children and adults with normal renal function; References available online at expertconsult.com.
20 mg/kg intravenous q8h in neonates) should be initiated in all
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Med Virol 2008; 80:118-124.
21
Brain Abscess and Other Focal
Pyogenic Infections of the
Central Nervous System
ITZHAK BROOK
KEY CONCEPTS frontal, temporal, frontal-parietal, parietal, cerebellar and occipital

lobes.1 The diagnosis and management of BA have changed during the
• Focal pyogenic infections of the central nervous system (CNS) past years resulting from the availability of noninvasive radiographic
include brain abscess (BA), spinal cord abscess, subdural diagnostic techniques, antimicrobials that penetrate the blood–
empyema, epidural abscess and suppurative intracranial brain barrier and into abscesses, and minimally invasive surgical
phlebitis.
procedures.
• The most frequent intracranial locations (in descending order
of frequency) are: frontal, temporal, frontal-parietal, parietal,
cerebellar and occipital lobes.
• The major predisposing factors for BAs are: an associated con- Relationships between potential sources of infection
tiguous focus of infection, trauma, hematogenous spread from and sites at which CNS infections may occur
a distant focus and cryptogenic (no recognized focus).
• The microbial etiology depends on the patient’s age, site of Dura mater
primary infection, the patient’s underlying condition and Parietal Arachnoid
immune status, and the geographic locale. lobe mater
Frontal
• The organisms most commonly isolated are anaerobic bacteria,
lobe
aerobic and microaerophilic streptococci, Enterobacteriaceae,
and Staphylococcus aureus. Superior Ethmoidal
sagittal air cells
• The most common symptoms are headache, altered mental sinus
status, focal neurologic findings, fever, nausea and vomiting, Frontal
and seizures. sinus
• Specimens obtained during surgery or stereotactic CT-guided Cavernous
aspiration should be sent for aerobic, anaerobic, mycobacterial sinus
and fungal culture and, when indicated, for protozoa.
• Before abscess encapsulation and localization, antimicrobial
therapy, accompanied by measures to control increasing intra-
cranial pressure, are essential. Occipital
lobe Sphenoidal
• Once an abscess has formed, surgical excision or drainage sinus
combined with prolonged antibiotics (usually 4–8 weeks) Cerebellum
remains the treatment of choice.
Superior sagittal sinus
Body of lateral
ventricle
Introduction Frontal lobe Third
ventricle
Focal pyogenic infections of the central nervous system (CNS) include Falx cerebri
brain abscess (BA), spinal cord abscess (SCA), subdural empyema (SE), Dura
epidural abscess (EA) and suppurative intracranial phlebitis (SIP). mater
These conditions are characterized by the presence of one or more Thalamus
Temporal
localized and well-defined collections of purulent material within the lobe
cranial vault or the paraspinal space. They exert their effects largely by Tentorium
direct involvement and destruction or encroachment of the brain or cerebelli Apex of
petrous
spinal cord parenchyma, by elevation of intracranial pressure or by Petrous part part of
interference with flow of blood or cerebrospinal fluid (CSF). of temporal temporal
Infections in contiguous structures generally lead to infections bone bone
relating to their anatomy (Figure 21-1) as will be discussed in detail Tympanic External
below. The focal nature of these infections often manifests by focal membrane auditory
neurologic deficits, rather than global CNS dysfunction. canal
Mastoid
CN IV
Brain Abscess Pons CN V
BA is a focal suppurative process of the brain parenchyma. The most Figure 21-1 Anatomic relationships between potential contiguous sources of
frequent intracranial locations (in descending order of frequency) are: infection and sites at which focal pyogenic CNS infections may occur.
198
Chapter 21 Brain Abscess and Other Focal Pyogenic Infections of the Central Nervous System 199
Epidemiology Hematogenous abscesses are often multiple; approximately 10–15%

of patients with BAs have multiple abscesses. They tend to occur in the
BA is uncommon; the lifetime incidence is 1.3/100 000 person-years, distribution of the middle cerebral artery at the junction of the gray
although the overall incidence decreased from 2.7/100 000 person- and white matter, where microcirculatory flow is poorest. The most
years in 1935–44 to 0.9/100 000 person-years in 1965–81. The highest commonly affected lobes are the fontal, temporal, parietal, cerebellar
rates were in children 5–9 years old and adults >60 (2.5/100 000 and occipital.13 Cyanotic congenital heart disease and chronic pyogenic
person-years each).2 BAs account for approximately 1 in 10 000 hospi- lung diseases (e.g. lung abscess, bronchiectasis) are common predis-
tal admissions in the USA.3 posing factors. Hereditary hemorrhagic telangiectasia (Osler–Weber–
The patients’ ages vary with the predisposing factors; BAs following Rendu disease) is also associated with BA; possibly because pulmonary
otitis media are most common among young children and older arteriovenous malformations allow septic microemboli to bypass the
adults, while those due to paranasal sinusitis are common among older pulmonary filter and reach the cerebral circulation. Abscesses can
children and young adults.3–5 BAs are approximately 2–3 times more follow dental extractions and other manipulations, dilatation of esoph-
frequent among males.3 ageal strictures and endoscopic sclerosis of esophageal varices.
The major predisposing factors are:
• an associated contiguous focus of infection (e.g. sinusitis, sub-
acute or chronic otitis media and mastoiditis) (40–50% of cases); Pathophysiology
• trauma (e.g. penetrating head injury, post-neurosurgery) (10%); The main pathogenetic factors are a source of virulent organisms and
• hematogenous spread from a distant focus (e.g. in association the presence of ischemic or devitalized brain tissue. The vulnerability
with pulmonary, skin, abdominal and pelvic infections, endo- of compromised tissue to BA is evidenced by their occurrence after
carditis, injected drug use, neutropenia, transplantation, cya- trauma or cerebrovascular accident, in association with cyanotic heart
notic heart disease and esophageal dilatation or sclerosis of or lung disease and in areas of poor local perfusion such as the junction
varices) (25%); of gray and white matter. The early stage of the infection (first 7–14
• cryptogenic (no recognized focus) (15%). days) is called cerebritis and is associated with edema. Necrosis and
BA associated with a contiguous focus usually causes a single BA. liquefaction occur after 2–3 weeks, and the lesion becomes gradually
The commonest underlying conditions in low- and middle-income surrounded by a fibrotic capsule.14
countries are subacute and chronic otitis media and mastoiditis.4 There are two main postulated mechanisms by which BA may occur
However, their role has declined with early antimicrobial therapy for in association with a contiguous focus of infection: 1) direct extension
ear infections. The current risk of BA in otitis media is < 0.5%.6 BA is through infected bone; and 2) hematogenous spread through emissary
also associated with cerebrovascular accidents, immunosuppression, or diploic veins or spread through local lymphatics.
HIV,7 cyanotic heart disease, trauma,8 and head and neck infections Otogenic infections may also spread through the internal auditory
(sinus, paranasal, dental).9 Bacterial meningitis was the most common canal, between suture lines or through cochlear aqueducts. Abscesses
predisposing factor in Turkish children.10 developing after trauma or neurosurgery may follow deep wound
BAs associated with otitis media and mastoiditis are most common injury with direct inoculation into the brain parenchyma or may result
in the inferior temporal lobe and cerebellum (Table 21-1). BAs associ- from extension of a superficial infection through compromised
ated with sinusitis occur primarily in the frontal or the temporal lobes. tissue.15,16
The frontal lobe is also most commonly affected following mandibular The sites most commonly involved by solitary BA are the frontal
dental infections. and temporal lobes, followed by the frontoparietal region, the parietal,
Abscess can occur following neurosurgery. Post-traumatic abscesses cerebellar and occipital lobes.17 These areas are those most likely to be
usually occur with a penetrating wound, but also occur in closed head associated with a contiguous focus or hematogenous seeding. Rarely,
injuries such as facial trauma. Bullet and shrapnel wounds to the brain abscesses may occur in other areas, such as the pituitary gland, thala-
can result in necrotic tissue leaving metal fragments. Injuries include mus, basal ganglia and brain stem, and be associated with specific
penetrating pencil tip and lawn dart injuries. Abscess presentation can predisposing conditions. For example, pituitary abscesses are often
occur months to years after the precipitating event. In one study, the associated with pituitary adenomas and with sphenoidal sinusitis.
median time to development of BA was 113 days.11 BAs can occur up Experimental animal data, surgery and autopsy findings and radio-
to 52 years after war-related penetrating head injuries.12 graphic examinations indicate that BAs develop in four stages:18 an
early and late cerebritis (days 1–3 and 4–9, respectively) and an early
and late capsule formation (days 10–13 and day 14+, respectively).
These represent a continuum rather than discrete steps. The evolution
is dependent upon the causative organism(s), local factors, host immu-
TABLE Site of Brain Abscess Based on Predisposing nologic status and antimicrobial therapy.
21-1 Condition The microbial etiology depends on the patient’s age, site of primary
Predisposing Condition Site
infection, the patient’s underlying condition, and immune status,
and the geography (Table 21-2).19–26 The organisms most commonly
Otitis media or mastoiditis Temporal lobe isolated are anaerobes, streptococci, the Enterobacteriaceae, Staphylo-
Cerebellum
coccus aureus (including methicillin-resistant)27 and fungi; 30–60%
Paranasal sinusitis Frontal lobe are polymicrobial. The predominant anaerobes are generally members
Temporal lobe of the oropharyngeal flora associated with otorhinolaryngeal infec-
Dental infection/manipulation Frontal lobe tions. However, anaerobes of gastrointestinal and female genital origin
can also hematogenously cause BA. The anaerobes most commonly
Trauma/neurosurgery Related to wound isolated include anaerobic streptococci, gram-negative bacilli (Pre-
Meningitis Cerebellum votella, Porphyromonas and Bacteroides fragilis group), Clostridium,
Frontal lobe Propionibacterium, Fusobacterium, Eubacterium, Veillonella and
Cyanotic heart disease Actinomyces spp.
Pyogenic lung disease The aerobic pathogens include aerobic and microaerophilic strep-
Bacterial endocarditis Middle cerebral artery distribution tococci such as Streptococcus anginosus or milleri group (Strep. angino-
Gastrointestinal source sus, Strep. constellatus and Strep. intermedius), alpha-hemolytic
T-cell deficiency
Neutropenia
streptococci, and Strep. pneumoniae. Aerobic gram-negative rods are
common following neurosurgery or trauma and common ones are
TABLE
21-2 Likely Pathogens and Suggested Empiric Therapy for Brain Abscess Based on Predisposing Condition
Predisposing Condition Likely Pathogens Empiric Therapy
Otitis media or mastoiditis Aerobic, anaerobic and microaerophilic streptococci Third-generation cephalosporin + metronidazole ±
Anaerobic gram-negative bacilli (i.e. Prevotella spp., antistaphylococcal penicillin or a penicillin
Bacteroides spp.)
Enterobacteriaceae
Pseudomonas aeruginosa
Actinomyces, Nocardia
Sinusitis and dental infections Aerobic, anaerobic and microaerophilic streptococci Penicillin or third-generation cephalosporin +
Anaerobic gram-negative bacilli (i.e. Prevotella, Bacteroides metronidazole
spp., Fusobacterium spp.)
Enterobacteriaceae
Haemophilus spp.
Trauma or post-neurosurgery Staphylococcus aureus Vancomycin + third- or fourth-generation

Coagulase-negative staphylococci cephalosporin ± metronidazole
Enterobacteriaceae
Streptococcus spp.
Clostridium spp.
Congenital heart disease Aerobic and microaerophilic streptococci Third-generation cephalosporin + vancomycin
Haemophilus spp.
Pyogenic lung disease Aerobic and anaerobic streptococci Penicillin or third-generation cephalosporin plus
Nocardia asteroides metronidazole
Actinomyces spp. Trimethoprim–sulfamethoxazole
Fusobacterium spp. Vancomycin + ampicillin and gentamicin +
Anaerobic gram-negative bacilli (i.e. Prevotella spp., antistaphylococcal penicillin
Bacteroides spp.)
Nocardia spp.
Alpha-hemolytic streptococci
Enterococcus spp.
Haemophilus spp.
Gastrointestinal source Enterobacteriaceae Third- or fourth-generation cephalosporin +

Bacteroides fragilis metronidazole
Liver abscess or diabetes mellitus Klebsiella pneumoniae Third- or fourth-generation cephalosporin, meropenem
Urinary tract Pseudomonas, Enterobacteriaceae, Enterobacter Third- or fourth-generation cephalosporin, meropenem
Transplantation Aspergillus, Candida, Cryptococcus, Mucorales, Nocardia, Variable

Toxoplasma gondii
T-cell deficiency and Aerobic gram-negative bacilli Variable

immunocompromised Toxoplasma gondii
Nocardia spp.
Mycobacterium spp.
Cryptococcus neoformans
Aspergillus spp.
Coccidioides immitis
Candida spp.
Mucorales
Neutropenia Enterobacteriaceae Third- or fourth-generation cephalosporin, meropenem

Pseudomonas aeruginosa Amphotericin B
Fungi, especially Aspergillus, Mucor and Candida
HIV infection Toxoplasma gondii Variable

Mycobacterium
Cryptococcus
Nocardia
Living, visiting or immigrating Taenia solium Variable
from an endemic area Schistosoma japonicum
Entamoeba histolytica
Paragonimus spp.
Klebsiella pneumoniae, Escherichia coli, Pseudomonas spp. and Proteus in immunocompromised patients; Aspergillus spp. are common in
species. Staph. aureus is also common after trauma.17–26 transplant patients.30 Patients with T-cell defects (including AIDS) are
High frequency of BA due to K. pneumoniae is mainly seen in South predisposed to infections with intracellular organisms such as Toxo-
East Asia.28 It is found with or without meningitis and as a metastatic plasma gondii, Nocardia spp., Cryptococcus neoformans, Mycobacterium
infection associated with community-acquired primary liver abscess. spp. and fungi (e.g. Aspergillus, Candida, Cryptococcus, Mucorales, Coc-
Fungi were common in a report from Saudi Arabia29 and particularly cidioides, Histoplasma capsulatum).20
Parasites and helminths that can cause BA include Taenia solium

(cysticercosis), Entamoeba histolytica, Schistosoma japonicum and Par-
agonimus spp.31
Prevention
The appropriate use of antibiotics in patients with predisposing infec-
tions, such as otitis media and mastoiditis, is the primary means of
prevention. Other measures include surgical correction of cyanotic
heart disease, dental hygiene, management of pyogenic lung infections
and proper sterile techniques during neurosurgical procedures. In
patients with T-cell defects, measures to prevent exposure to T. gondii
are recommended.22
Clinical Features
The clinical manifestations are largely those of a space-occupying
lesion.17,32 Most common are headache (75% of patients), usually
hemicranial, altered mental status, focal neurologic findings (especially
hemiparesis) (>60%), fever (50%), nausea and vomiting (25–50%) and
seizures (usually generalized) (30%). Nuchal rigidity may occur with
abscesses near the meninges. Vomiting often develops with increased
intracranial pressure.
Other signs and symptoms vary with the abscess stage, size and Figure 21-2 Contrast-enhanced CT scan of the head in the coronal projection
of a 43-year-old man with an atrial septal defect that persisted after attempts at
anatomic location: surgical repair. The patient presented with seizures after undergoing dental work
• abscesses of the frontal lobe: headache, drowsiness, global mental for which he did not receive antimicrobial prophylaxis. Note the ring-enhancing
status changes, inattention, hemiparesis with unilateral motor lesion in the right frontoparietal region with edema and mass effect.
signs and expressive speech disturbances;
• temporal lobe abscesses: ipsilateral headache and aphasia (if the
abscess involves the dominant hemisphere) and a visual field
defect; and follow-up care. It is used to confirm the diagnosis, to localize the
lesion, and to monitor the progression. However, the results can lag
• cerebellar abscesses: vomiting, ataxia, nystagmus and dysmetria; behind clinical findings. The characteristic appearance of BA on CT
• brain stem abscesses: headache, facial weakness, hemiparesis, scan varies with the stage of disease.34 During the cerebritis stage,
vomiting and dysphagia.
Papilledema is present in older children and adults, and bulging cerebral edema is prominent without abnormalities. As capsule is
fontanelles in infants. Rapid deterioration with nuchal rigidity suggests formed, the abscess appears as a lesion with a hypodense center of
abscess rupture into the intraventricular or subarachnoid space. A necrotic debris surrounded by ring enhancement, which may be sur-
ruptured abscess may produce purulent meningitis with signs of neu- rounded by hypodense cerebral edema (Figure 21-2). Although highly
rologic damage. sensitive, CT scanning is not specific. These findings are also seen in
Laboratory findings may include a leukocytosis and a left shift, but cerebral neoplasms, cerebrovascular accidents or granulomas.
~40% of patients have normal leukocyte concentrations. Serum Many consider MRI as the diagnostic method permitting accurate
sodium levels may be lowered due to inappropriate antidiuretic diagnosis and follow-up because of superior sensitivity and specificity.
hormone production. The erythrocyte sedimentation rate (ESR) is Compared with CT, it offers better detection of cerebritis, cerebral
often elevated. An elevated C-reactive protein is sensitive (77–90%) edema, and early detection of satellite lesions and spread into the
and specific (77–100%) when used to distinguish BA from cerebral ventricles and subarachnoid spaces. MRI is more sensitive than CT in
neoplasms. early cerebritis (slightly low intensity on T1-weighted images and very
The differential diagnosis of BA includes infective and noninfective low intensity on T2-weighted images) and may be more sensitive for
conditions. Infective ones include: SE, EA, bacterial meningitis, cryp- posterior fossa lesions due to the absence of bone artifact14,33 (Figure
tococcosis, cysticercosis, cranial osteomyelitis, septic cerebral emboli, 21-3). It may distinguish abscess fluid from CSF, which is important if
septic dural sinus thrombosis, mycotic aneurysm, suppurative throm- intraventricular rupture is suspected. Enhancement with gadolinium-
bophlebitis, and encephalitis. Noninfective conditions include: hemor- DTPA allows evaluation of disruption of the blood–brain barrier and
rhage, cerebral neoplasm (primary or metastatic), venous sinus permits greater distinction of the radiographic appearance of the
thrombosis, cerebrovascular infarct or hemorrhage, headache and central abscess, capsule and surrounding edema. Examination by 1H
migraine. magnetic resonance spectroscopic imaging has been proposed as a
means of distinguishing BA from other focal cerebral parenchymal
lesions.
Diagnosis Edema and contrast enhancement on CT and MRI may be dimin-
Radiographic imaging with contrast-enhanced CT or MRI has contrib- ished or absent in immunocompromised patients, possibly due to poor
uted greatly to diagnosis and management of BA.14,33 CT is not as sensi- host inflammatory response. Electroencephalography revealing a focus
tive as MRI but is easier to perform. Plain skull radiographs are of high voltage with slow activity is nonspecific and rarely of value.
insensitive but the presence of air indicates further evaluation. 99mTech- Lumbar puncture should be avoided in patients with known or
netium (99mTc) brain scanning is very sensitive and the procedure of suspected BA. The yield of CSF culture is low (< 10%) and the risk of
choice if CT or MRI is unavailable; 99mTc scanning may be more sensi- herniation is considerable (15–30%). The leukocyte count is generally
tive than CT in early cerebritis. 99mTc-HMPAO labeled leukocyte single elevated. It reaches ≥100 000/µL with a rupture of BA into the CSF.
photon emission CT (SPECT) is a potential means of distinguishing Many red blood cells are generally observed then, with a CSF lactic
BA from other focal parenchymal lesions, such as neoplasms. Ultraso- acid level >500 mg/L.
nography may be used if other techniques are unavailable. In patients in whom rupture is considered, blood cultures should
CT scanning, preferably with contrast, rapidly detects the size, the be obtained and appropriate antibiotic therapy should be initiated,
number and the location of abscesses, and is the mainstay of diagnosis before performing an imaging procedure. Lumbar puncture may be
a b
Figure 21-3 Contrast-enhanced CT and MRI scans of the head in the coronal projection of a 43-year-old woman with headaches after a recent fall on her head. (a) CT
scan image reveals a cystic ring-enhancing lesion in the left cerebellum. Note the prominent bone artifact. (b) T1-weighted MRI scan image reveals an enhancing cystic
lesion in the left cerebellum with significant surrounding edema. Bone artifact is absent. Both CT and MRI scans were felt to be most consistent with a primary or meta-
static neoplasm, but culture of material obtained at stereotactically-guided aspiration grew Staphylococcus aureus.
performed if there is no evidence of a mass lesion (confirmed by CT repeated aspirations are preferred. High-dose antimicrobial(s) for an
or MRI) or signs of raised intracranial pressure (focal neurologic extended period may be an alternative approach in these patients.
finding or papilledema). In patients with HIV infection, PCR examina- A number of factors should be considered when choosing the
tion of CSF may be useful in diagnosing toxoplasmosis or tuberculous appropriate therapeutic approach. Recovery of the etiologic agent(s)
abscesses.7,20 from blood, CSF, abscess or other normally sterile sites allows for the
Serological tests (e.g. antibodies) can aid in the diagnosis of toxo- appropriate selection of antimicrobials.
plasmosis or neurocysticercosis. The duration of the symptoms before diagnosis is an important
Specimens obtained during surgery or stereotactic CT-guided factor. Early antimicrobial therapy, before an expanding mass exists,
aspiration should be sent for aerobic, anaerobic, mycobacterial and may prevent progress from cerebritis to abscess. Patients who have
fungal cultures and, when indicated, for protozoa. In one study, symptoms for <1 week have a more favorable response to medical
Gram stain revealed organisms in 82% of cases and culture was posi- therapy than those with symptoms persisting >1 week.
tive in 88%.14 Gram stain and special stains should be performed, Under certain circumstances BA may be treated without surgical
which include fungal stains (e.g. methenamine silver, mucicarmine), drainage. Small abscesses (<2.5 cm) and cerebritis may respond to
an acid-fast stain for mycobacteria and a modified acid-fast stain antimicrobials alone. Medical therapy alone may also be indicated in
for Nocardia species. Several studies utilizing 16S ribosomal DNA poor surgical candidates where prolonged parenteral antimicrobial
polymerase chain reaction amplification increased the number of therapy (at least 8 weeks) and close monitoring with sequential CT or
bacterial species recovered from BAs as compared with standard MRI scans are necessary. Patients treated with medical therapy alone
culture.35 usually improve clinically before changes in the CT scan are observed.
CT scanning and MRI should eventually show a decrease in the size of
the lesion and edema, and a lessening of the enhancement ring.
Management Improvement on CT scans is generally observed within 1–4 weeks
Before abscess encapsulation and localization, antimicrobials, accom- (average 2.5 weeks) and complete resolution in 1–11 months (average
panied by measures to control increasing intracranial pressure, are 3.5 months). Radiographic abnormalities may persist for months after
essential.36 Once an abscess has formed, surgical excision or drainage successful therapy (Figure 21-4).
combined with prolonged antimicrobial therapy (usually 4–8 weeks) Patients with cerebritis can be treated with a shorter course (4–6
remains the treatment of choice. Some advocate complete evacuation weeks). However, those with an encapsulated abscess, tissue necrosis,
of the abscess, while others advocate repeated aspirations as indi- undrained abscess(es), multiloculated abscess(es), lesions in vital loca-
cated.37 The procedures used are aspiration through a burr hole and tions and the immunocompromised need 6 to 8 weeks or longer,
complete excision after craniotomy. Drainage permits microbiologic depending on initial size, causative pathogen(s) and treatment
evaluation of abscess material, which guides antimicrobial therapy. response.39 The long course is needed for brain tissue to repair and
Since aspiration is generally as effective as excision and is less invasive, close abscess space. The initial course is intravenously, often followed
it became the procedure of choice. Stereotactic CT-guided aspiration by 2–6 months of oral therapy. A shorter course (3–4 weeks) may be
permits accurate access even to areas that had been difficult to reach adequate in patients who had surgical drainage. Because of the poor
by aspiration, such as the brain stem, cerebellum and thalamus,38 and penetration of various antimicrobials through the blood–brain barrier,
multiple abscesses may be drained. Neuroendoscopic aspiration has antimicrobial choice is restricted and maximal doses are often
also been used with success. necessary.
Emergency surgery should be performed for a single abscess. Initial empiric antimicrobial therapy should be based on the
Abscesses >2.5 cm are excised or aspirated, while those <2.5 cm or expected etiologic agents based on the likely predisposing conditions,
which are at the cerebritis stage are aspirated for diagnostic purposes the primary infection source and the presumed pathogenesis. Antibiot-
only. In cases of multiple abscesses or in abscesses in essential areas, ics should be parenteral, active against likely pathogens, penetrate into
a b
Figure 21-4 Contrast-enhanced CT scans of the head in the coronal projection of a 66-year-old woman with a group B streptococcal brain abscess demonstrating
evolution of the abscess during and after surgical and antimicrobial therapy. (a) The original scan demonstrates a hypodense necrotic center surrounded by an enhancing
capsule and hypodense edema. (b) 7 weeks later, after stereotactically-guided aspiration and a full course of antimicrobial therapy, the central cavity can no longer be
seen, although the enhancement and surrounding edema persist to a small degree.
abscess fluid (and the site of any underlying infection) in adequate Epidemiology
concentrations and be bactericidal.40 The combination of penicillin
or a third-generation cephalosporin (cefotaxime or ceftriaxone) plus SE in adults is most often a complication of acute or chronic bacterial
metronidazole is effective empiric therapy in most cases (see Table sinusitis, otitis media or mastoiditis.9,42 It is the most common intra-
21-2). An antistaphylococcal penicillin (e.g. flucloxacillin, nafcillin or cranial complication of sinusitis, accounting for ~60% of such cases.43
oxacillin) should be used if susceptible staphylococci are identified. The frontal and ethmoidal sinuses are the foci in over half of the cases.
Vancomycin should be used if methicillin-resistant Staph. aureus Hematogenous spread from a distant source may also occur. In chil-
(MRSA) is suspected or identified, or if the patient is allergic to dren the most common predisposing condition is bacterial meningitis.
β-lactams. Cefepime or ceftazidime are administered to treat Pseudo- Other predisposing conditions include trauma, neurosurgery, infected
monas aeruginosa. Those with HIV infection may require therapy for subdural hematoma, ethmoidectomy, polypectomy and nasal surgery.
toxoplasmosis (see Chapter 94).7,20 Hematogenous spread from a distant location (mainly the lung) is
Open craniotomy, debridement, intraventricular lavage and intra- uncommon. There is a male predominance in SE and EA.44,45
ventricular as well as intravenous antimicrobial(s) are recommended Most EAs in the past were due to sinusitis (particularly frontal),
after intraventricular rupture of BA. Changes in therapy should be otitis media, mastoiditis or cranial trauma. Currently many cases
guided by microbiological results and clinical and radiographic follow neurosurgery.45
progress.
Corticosteroids, mannitol and hyperventilation may be indicated Pathogenesis and Pathophysiology
where there is increased intracranial pressure. Corticosteroids are con- As with BAs, the infection spreads into the epidural or subdural space
troversial. Steroids can retard encapsulation, increase necrosis, reduce from a contiguous focus through infected bone or hematogenously
antibiotic penetration into the abscess, alter CT scans and can produce through emissary veins. EA is generally associated with SE and overly-
a rebound effect when discontinued. If used to reduce cerebral edema, ing osteomyelitis, and usually consists of a localized lesion with a
therapy should be of short duration. The appropriate dosage and central collection of pus surrounded by a wall of inflammation that
timing are unknown. Routine use of corticosteroids in the absence of may calcify. These abscesses rarely spread downwards into the spinal
increased intracranial pressure is not recommended. canal because the dura is very tightly attached around the foramen
Prognosis has improved considerably, since the introduction of CT magnum. The infection can spread rapidly through the subdural space
scanning. Mortality is now 5–15%. Long-term sequelae occur in about until it is limited by its natural boundaries. These include the falx
one-third of patients and include mental retardation, seizures and focal cerebri, tentorium cerebelli, brain base, foramen magnum posteriorly
neurologic deficits. Poor prognostic factors include delayed or missed and the anterior spinal canal. Within the compartments defined by
diagnosis, multiple lesions, deep-seated lesions, intraventricular these boundaries, the progressing infection behaves as an expanding
rupture, severe impairment of mental or neurologic status (including mass lesion.
coma), fungal etiology and extremes of age. The frequency of neuro- As the lesion expands, intracranial pressure increases and the cere-
logical sequelae in survivors is 20–79% and relates to how quickly bral parenchyma is compromised. Interference with flow of blood or
diagnosis is made and antimicrobials administered.41 CSF may cause cerebral edema and hydrocephalus. Septic thrombosis
of veins within the affected subdural or epidural space may lead to
cavernous sinus thrombosis or cortical veins, leading to brain tissue
infarction.
Subdural Empyema and Organisms commonly isolated from adults with SE and EA include
Intracranial EA anaerobes, aerobic streptococci, staphylococci, Strep. pneumoniae,
Haemophilus influenzae and aerobic gram-negative bacilli. Polymicro-
SE and EA are focal collections of pus between the dura and arachnoid bial infections are common; in one study >50% of infections were
maters, and outside the dura mater, respectively. SE accounts for polymicrobial.44,46 Infections caused by Mycobacterium and Candida
~15–20% of all focal intracranial infections. spp. have been reported.47 In children, the commonest agents are those
Figure 21-6 Contrast-enhanced CT scan of the head in the coronal projection

Figure 21-5 Contrast-enhanced CT scan of the head in the coronal projection
of a 19-year-old man with otitis media who presented with sinus congestion 1
of a 23-year-old man with fever and headache. There is a small isodense extra-axial
week earlier. Plain films of the sinuses revealed opacification of the right maxillary
fluid collection in the subdural space on the right, with significant mass effect
and ethmoidal sinuses and an intracranial air–fluid level. Note the intracranial gas
shown by right-to-left midline shift and effacement of the right lateral ventricle.
in the right frontal region abutting a hypodense region in the epidural space with
There was also opacification of the frontal and ethmoid sinuses, suggesting sinus-
ring enhancement and surrounding edema, representing an intracranial EA.
itis as the source of this subdural empyema.
of the underlying meningitis. In the past, this has been H. influenzae Management
in children outside the neonatal age; however, as the frequency of H.
influenzae meningitis declined, its role in SE diminished. Anaerobes Treatment requires a combination of drainage and antimicrobial
were identified in children in association with sinusitis.48 therapy. Surgical evacuation is needed in most patients. It provides
Organisms commonly recovered from intracranial EA associated immediate decompression and specimens for microbiology and should
with sinusitis or otitis are microaerophilic or anaerobic streptococci, be done by craniotomy or through burr holes. Although the optimal
Propionibacterium, Peptostreptococcus and Prevotella spp. The com- procedure is not known, in one study of 699 patients, limited proce-
monest organisms associated with neurosurgery are staphylococci, dures such as burr holes were associated with a worse prognosis than
Propionibacterium spp., and aerobic gram-negative bacteria. The infec- more extensive ones.51 It may also be necessary to debride the primary
tion can also spread inward from osteomyelitis of the skull or be infection. Samples should be submitted for Gram stain and aerobic
introduced by fetal monitoring probes.49 and anaerobic cultures. Antimicrobials alone may be used for a limited
number of patients with very small fluid collections.44,45
The choice of empiric antimicrobial therapy depends on the
Clinical Features patient’s age, predisposing conditions and the primary infection site
The signs and symptoms result from the infection and the slowly (Table 21-3). Antimicrobial choice should be adapted when results of
expanding intracranial mass. The early symptoms are fever and head- Gram stain of aspirated material and cultures are available. In adults,
ache. The headache is often focal but may become generalized. These the wide variety of possible pathogens and the potential for polymi-
symptoms are usually followed by papilledema and focal neurologic crobial infection dictate broad-spectrum therapy. In children, therapy
defects. Abscesses near the petrous portion of the temporal bone may should be directed against the likely causes of meningitis. Parenteral
be associated with palsies of cranial nerves V and VI, causing unilateral therapy should be continued for 3–6 weeks, with close monitoring of
facial pain and lateral rectus muscle weakness. Periorbital edema and clinical status and radiographic appearance.
subgaleal abscess (Pott’s puffy tumor) may be found in up to one-third
of patients. Signs of increased intracranial pressure (vomiting, gait
disturbances and mental status changes) and meningeal irritation may Suppurative Intracranial Phlebitis
follow and may be accompanied by seizures, hemiparesis and hemi-
sensory defects.44 EA complicating sinusitis can cause purulent nose or SIP is inflammation of the blood vessels within the cranium resulting
ear drainage.50 from infection.52
Diagnosis Epidemiology, Pathogenesis

CT and MRI scanning are the diagnostic procedures of choice. Imaging and Pathophysiology
reveals a hypodense lesion with displacement of the arachnoid mater SIP usually follows infections of the sinuses, middle ear, mastoids, face,
in both entities, with accompanying displacement of the dura mater oropharynx and, in particular, the nasal furuncle. It may be associated
noted in patients who have SE. Mass effect is more common with SE with SE, EA or bacterial meningitis. Conditions associated with
than with EA (Figure 21-5). Capsule formation with contrast enhance- increased blood viscosity or hypercoagulability (i.e. inflammatory
ment occurs in either condition, but is more common with EA (Figure bowel disease) increase the risk of nonsuppurative thrombosis of the
21-6). Cranial osteomyelitis may be noted in patients with underlying intracranial venous sinuses as well as of SIP.
contiguous foci of infection. Gadolinium-enhanced MRI may detect Spread generally occurs along emissary veins. The venous sinuses
lesions not noted on CT (because they are isodense with the cerebral most commonly involved are the cavernous sinus, lateral sinus and
tissue on CT). As with BA, lumbar puncture is contraindicated in superior sagittal sinus. If there is sufficient involvement of the vascu-
patients with known or suspected SE or EA.44,45 lature, cerebral edema and hemorrhagic infarction may result. The
The differential diagnosis of EA includes metastatic tumors, disc infarcts tend to occur in venous watershed regions. Involvement of the
and bony disease (including vertebral discitis and osteomyelitis), men- superior sagittal sinus or of the lateral sinuses may block CSF reabsorp-
ingitis and early stage of herpes zoster. tion and lead to hydrocephalus and increased intracranial pressure.
TABLE Pathogens and Suggested Empiric Antibiotic Regimens for Subdural Empyema and Intracranial Epidural
21-3 Abscess Based on Underlying Condition
Predisposing Condition Likely Pathogens Empiric Therapy
Sinusitis Aerobic, anaerobic and microaerophilic streptococci Third-generation cephalosporin + metronidazole

Anaerobic gram-negative bacilli (i.e. Prevotella spp., Bacteroides spp.) ± antistaphylococcal penicillin or a penicillin
Enterobacteriaceae
Streptococcus pneumonia
Otitis media or mastoiditis Aerobic, anaerobic and microaerophilic streptococci Third-generation cephalosporin + metronidazole
Anaerobic gram-negative bacilli (i.e. Prevotella spp., Bacteroides spp.) ± antistaphylococcal penicillin or a penicillin
Enterobacteriaceae
Trauma Staphylococcus aureus Vancomycin + third- or fourth-generation

Coagulase-negative staphylococci cephalosporin
Enterobacteriaceae
Dental infection Aerobic, anaerobic and microaerophilic streptococci Penicillin or third-generation cephalosporin +
Fusobacterium spp. metronidazole
Anaerobic gram-negative bacilli (i.e. Prevotella spp., Bacteroides spp.)
Neonate Enterobacteriaceae Third-generation cephalosporin + ampicillin

Group B streptococci
Infant or child Streptococcus pneumoniae Third-generation cephalosporin ± vancomycin
Neisseria meningitidis
Involvement of contiguous structures can lead to BA, SE, EA or men-

ingitis, or distant seeding and infection of the lungs and other organs.
The microbiology of SIP is similar to that of SE and intracranial
EA, with Staph. aureus, streptococci and anaerobes being most com-
monly identified organisms.
Clinical Features
Clinical manifestations vary with the location of the involved venous
sinuses or cortical veins.
Cavernous sinus thrombosis is associated with palsies of cranial
nerves III, IV, V and VI, producing loss of corneal reflexes, ophthal-
moplegia and hypesthesia over the upper part of the face. Papilledema
and visual loss may result from obstruction of retinal venous return.
Lateral sinus thrombosis involves cranial nerves V and VI, resulting
in altered facial sensation and lateral rectus muscle weakness. Obstruc-
tion of venous CSF resorption may cause communicating hydrocepha-
lus and increased intracranial pressure. Cranial nerves IX, X and XI
may also be affected.
Superior sagittal sinus involvement may also diminish CSF resorp-
tion. Additionally, venous drainage obstruction from the motor cortex
region of the cerebral hemispheres may lead to leg weakness.
Figure 21-7 Contrast-enhanced MRI scan of the head in the sagittal projection
Cortical vein thrombosis may be neurologically silent or produce of a 29-year-old man with sinus congestion and headache. There is non-uniform
only transient defects if collateral venous drainage compensates for signal intensity of the cavernous venous sinuses, indicating cavernous sinus throm-
thrombosis. If collateral flow is inadequate, the lesion can cause pro- bosis. The sphenoid, ethmoidal and maxillary paranasal sinuses also demon-
gressive neurologic defects depending on the involved vein’s location. strated abnormal signal intensity.
Unilateral or bilateral extremity weakness, hemiparesis, aphasia, sei-
zures and mental status changes may be seen.
Management
Diagnosis Empiric antimicrobial therapy is similar to SE and intracranial EA (see
MRI is more sensitive than CT and is the diagnostic procedure of Table 21-2). Control of increased intracranial pressure may be neces-
choice. MRI shows increased signal within the involved vessel (Figure sary with corticosteroids, hyperosmolar agents and hyperventilation.
21-7). Its sensitivity can be enhanced by the use of MRI angiography. Anticoagulant therapy has been used with some success, but risks
CT may be used when MRI is unavailable. If CT or MRI is unremark- hemorrhagic infarction. Surgery may be required for drainage of asso-
able and SIP is still suspected, angiography should be performed. ciated abscesses.
Spinal Epidural Abscess

Spinal epidural abscess (SEA) is a focal infection of the paraspinal
epidural space. It requires prompt recognition and appropriate man-
agement to avoid potentially serious complications.
Epidemiology
SEA is rare occurring in 2–25 patients per 100 000 admitted to hospi-
tal.53 The increased sensitivity and accuracy of laboratory and radio-
logical methodologies, aided by the use of MRI, has increased its rate
of diagnosis.54 The incidence is similar in both genders and the median
age of onset is ~50 years.
Pathogenesis and Pathophysiology

SEA may be secondary to direct inoculation into the spinal canal
during spinal or epidural anesthetic procedures, surgery or epidural
catheter placement (risk of 0.5–3%)55 and contiguous source of infec-
tion, such as vertebral osteomyelitis, infected psoas muscle, pyogenic
infectious discitis, penetrating trauma or decubitus ulcers, or may arise
by hematogenous spread from a distant source.42,54–57 The use of face
masks when epidural catheters are placed has been recommended as
a means to reduce spinal abscesses. Figure 21-8 Contrast-enhanced MRI scan of the spine in the coronal projection
of a 28-year-old man with a 1-week history of headache, fever and sweats. Physical
Past back trauma, spinal and paraspinal procedures, diabetes mel- examination demonstrated meningismus but no focal neurologic deficits. Scans
litus, alcoholism, intravenous drug use, HIV infection, tattooing, acu- in the sagittal section demonstrated a substance nearly isointense with the spinal
puncture, local spinal injections and contiguous bony or soft tissue cord and running nearly the length of the cord. This scan clearly demonstrates
infection are common risk factors.56 Possible sources for hematoge- impingement and anterior displacement of the cord by the spinal EA.
nous seeding of the spinal epidural include pulmonary infections,
endocarditis, bacteremia, cutaneous, intra-abdominal, pelvic and geni- admission was 5 and 9 days, respectively, and the median number of
tourinary infections. Spread from these sources occurs via the paraver- emergency room visits before admission was two (1–8).61 Sedimenta-
tebral venous plexus. In about one-third of patients no identifiable tion rate is usually elevated and the leukocyte count may be elevated
infection source can be found. or normal.60
The abscess can extend longitudinally in the epidural space, damag- Plain radiographs may reveal osteomyelitis or discitis. Gadolinium-
ing the spinal cord by direct compression, interruption of the arterial enhanced MRI has supplanted CT and myelography as the diagnostic
blood supply and local vasculitis, thrombosis and thrombophlebitis of procedure of choice for SEA61,62 (Figure 21-8). MRI is highly sensitive
nearby veins, and by bacterial toxins and inflammatory mediators. (91%) and can identify osteomyelitis and intramedullary spinal cord
Longitudinal extension is common in infection arising in the epidural lesions. It also enables early detection of an abscess while it is still small
space. The average extent is 3–5 spinal cord segments, but the whole prior to spinal cord compression. If MRI is not available, myelography
length of the spinal column may be affected. The abscess may contain should be performed.
granulation tissue after 2 weeks. In most adult cases, the thoracic spine Recovery of etiologic organisms from blood, abscess contents
is involved, while cervical and lumbar involvement is more common or CSF is important. CSF may show high protein and pleocytosis.
in children. There is a male predominance.57 Gram stain is usually negative and cultures are positive in <25% of
Staph. aureus accounts for three-quarters of isolates.57 The rate of specimens.56
MRSA infection is steadily rising, reaching 40% of all Staph. aureus.56 The differential diagnosis includes other conditions that cause back
Other staphylococci, aerobic and anaerobic streptococci, E. coli and P. pain and neurologic deficits, including disc and bony disease, discitis,
aeruginosa are also common.57 Polymicrobial infections are rare causes. osteomyelitis, meningitis, malignancy and early herpes zoster.
Mycobacterium tuberculosis, Candida and Nocardia spp. can also cause
an abscess.58
Management
Clinical Features Urgent decompression and surgical drainage or aspiration plus paren-
teral antimicrobial therapy are indicated.62,63 These are ordinarily
There are four clinical stages: achieved by laminectomy, but CT-guided aspiration may be performed
• fever and focal back pain; in selected patients. The outcome in patients on medical therapy only
• nerve root compression with nerve root pain; is similar to those who have surgery.64,65 Early surgery improves neu-
• spinal cord compression with accompanying deficits in motor, rologic outcomes compared with surgical treatment delayed by a trial
sensory, and bowel and bladder sphincter function; of medical management.66 A nonsurgical approach is rarely used but
• paralysis. may be tried in those with significant surgical risk and an identified
Respiratory compromise may be present if the cervical cord is pathogen. Close neurologic monitoring and follow-up MRI to dem-
involved.59 Progression tends to be rapid with direct hematogenous onstrate reduction and resolution of the abscess are needed in these
spread, and may be very painful. Progression to stage 2 tends to occur cases. If there is neurologic deterioration, surgery should be performed
slowly in those with abscesses secondary to vertebral osteomyelitis, but without delay.
may accelerate later. Headache, meningismus and focal tenderness are An antistaphylococcal penicillin should be instituted as empiric
common.59 therapy; vancomycin may be used in those allergic to penicillin and
those with MRSA. Antimicrobials effective against gram-negative
Diagnosis organisms (i.e. third-generation cephalosporins) and anaerobes (i.e.
Clinical suspicion is essential, as the presentation may be atypical. A metronidazole) should be added in patients whose underlying source
study of 63 patients showed that the mean duration of symptoms might have been an intra-abdominal, pelvic or genitourinary infection.
between onset of symptoms and the first emergency room visit or The duration of parenteral therapy should be ≥3–4 weeks; if
osteomyelitis is present, it should be continued for 8 weeks. Therapy pathogens are aerobic and anaerobic bacteria as well as Nocardia spp.
length can be adjusted according to resolution of the abscess on MRI. The aerobic and facultatives include Staph. aureus; aerobic, anaerobic
Follow-up MRI is generally performed at about 4 weeks if the patient and microaerophilic streptococci spp.; E. coli; Listeria monocytogenes
is improving, or earlier if clinical deterioration occurs. and Burkholderia cepacia. The anaerobes include Bacteroides and Pre-
votella spp., Actinomyces spp. and Propionibacterium acnes.67,68 Symp-
Spinal Cord Abscess toms mimic those of SEA. Diagnosis may be made by CT, MRI or
myelography. Treatment consists of surgical debridement and pro-
This is a rare condition defined as a focal suppurative process of the longed antimicrobial therapy. Antimicrobials should be directed
spinal cord parenchyma. It usually involves the thoracic segment of the against the potential pathogens and be guided by appropriate
spinal cord and is generally hematogenous in origin. The lungs are cultures.
usually the source of infection and it can occur in intravenous drug
users and secondary to congenital dermal sinuses. The major References available online at expertconsult.com.
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12. Marquardt G., Schick U., Moller-Hartmann W.: Brain in the diagnosis and follow-up of brain abscess. Radiol- abscess: a meta-analysis of 915 patients. Neurosurg Rev
abscess decades after a penetrating shrapnel injury. Br J ogy 1980; 135:663-671. 2000; 23:175-204.
Neurosurg 2000; 14:246-248. 35. Al Masalma M., Lonjon M., Richet H., et al.: Metage- 58. Metta H., Corti M., Redini L., et al.: Spinal epidural
13. Carpenter J., Stapleton S., Holliman R.: Retrospective nomic analysis of brain abscesses identifies specific abscess due to Mycobacterium tuberculosis in a patient
analysis of 49 cases of brain abscess and review of the bacterial associations. Clin Infect Dis 2012; 54:202-210. with AIDS: case report and review of the literature. Braz
literature. Eur J Clin Microbiol Infect Dis 2007; 26:1-11. 36. Yogev R., Bar-Meir M.: Management of brain abscesses J Infect Dis 2006; 10:146-148.
14. Rath T.J., Hughes M., Arabi M., et al.: Imaging of cere- in children. Pediatr Infect Dis J 2004; 23:157-159. 59. Hawkins M., Bolton M.: Pediatric spinal epidural
britis, encephalitis, and brain abscess. Neuroimaging 37. Ratnaike T.E., Das S., Gregson B.A., et al.: A review of abscess: a 9-year institutional review and review of the
Clin N Am 2012; 22:585-607. brain abscess surgical treatment–78 years: aspiration literature. Pediatrics 2013; 132:e1680-e1685.
15. Glickstein J.S., Chandra R.K., Thompson J.W.: Intracra- versus excision. World Neurosurg 2011; 76:431-436. 60. Davis D.P., Wold R.M., Patel R.J., et al.: The clinical
nial complications of pediatric sinusitis. Otolaryngol 38. Kocherry X.G., Hegde T., Sastry K.V., et al.: Efficacy of presentation and impact of diagnostic delays on emer-
Head Neck Surg 2006; 134:733-736. stereotactic aspiration in deep-seated and eloquent- gency department patients with spinal epidural abscess.
16. Migirov L., Duvdevani S., Kronenberg J.: Otogenic region intracranial pyogenic abscesses. Neurosurg Focus J Emerg Med 2004; 26:285-291.
intracranial complications: a review of 28 cases. Acta 2008; 24:E13. 61. Adogwa O., Karikari I.O., Carr K.R., et al.: Spontaneous
Otolaryngol 2005; 125:819-822. 39. Infection in Neurosurgery Working Party of the British spinal epidural abscess in patients 50 years of age and
17. Nielsen H., Glydensted C., Harmsen A.: Cerebral Society for Antimicrobial Chemotherapy: The rational older: a 15-year institutional perspective and review of
abscess: aetiology and pathogenesis, symptoms, diagno- use of antibiotics in the treatment of brain abscess. Br the literature. J Neurosurg Spine 2014; 20(3):344-
sis, and treatment. Acta Neurol Scand 1982; 65:609-622. J Neurosurg 2000; 14:525-530. 349.
18. Britt R., Enzmann D., Yeager A.: Neuropathological and 40. Lonsdale D.O., Udy A.A., Roberts J.A., et al.: Antibacte- 62. Tompkins M., Panuncialman I., Lucas P., et al.: Spinal
computed tomographic findings in experimental brain rial therapeutic drug monitoring in cerebrospinal fluid: epidural abscess. J Emerg Med 2010; 39:384-390.
abscess. J Neurosurg 1981; 55:590-603. difficulty in achieving adequate drug concentrations. 63. Bluman E.M.1., Palumbo M.A., Lucas P.R.: Spinal epi-
19. Brook I.: Microbiology of intracranial abscesses and J Neurosurg 2013; 118:297-301. dural abscess in adults. J Am Acad Orthop Surg 2004;
their associated sinusitis. Arch Otolaryngol Head Neck 41. Tseng J.H., Tseng M.Y.: Brain abscess in 142 patients: 12:155-163.
Surg 2005; 131:1017-1019. factors influencing outcome and mortality. Surg Neurol 64. Siddiq F., Chowfin A., Tight R., et al.: Medical vs surgi-
20. Moulignier A.: HIV and the central nervous system. Rev 2006; 65:557-562. cal management of spinal epidural abscess. Arch Intern
Neurol (Paris) 2006; 162(1):22-42. 42. Osborn M.K., Steinberg J.P.: Subdural empyema and Med 2004; 164:2409-2412.
21. Brook I.: Microbiology of intracranial abscesses associ- other suppurative complications of paranasal sinusitis. 65. Wheeler D., Keiser P., Rigamonti D., et al.: Medical
ated with sinusitis of odontogenic origin. Ann Otol Lancet Infect Dis 2007; 7:62-67. management of spinal epidural abscesses: case report
Rhinol Laryngol 2006; 115:917-920. 43. Singh B., van Dellen J., Ramjettan S., et al.: Sinogenic and review. Clin Infect Dis 1992; 15:28-29.
22. Singh N., Husain S.: Infections of the central nervous intracranial complications. J Laryngol Otol 1995; 66. Patel A.R., Alton T.B., Bransford R.J., et al.: Spinal epi-
system in transplant recipients. Transpl Infect Dis 2000; 109:945-950. dural abscesses: risk factors, medical versus surgical
2:101-111. 44. Nathoo N., Nadvi S.S., van Dellen J.R., et al.: Intracra- management, a retrospective review of 128 cases. Spine
23. Tunkel A.R., Pradhan S.K.: Central nervous system nial subdural empyemas in the era of computed tomog- J 2014; 14:326-330.
infections in injection drug users. Infect Dis Clin North raphy: a review of 699 cases. Neurosurgery 1999; 67. Kurita N.1., Sakurai Y., Taniguchi M., et al.: Intramed-
Am 2002; 16:589-605. 44:529-535. ullary spinal cord abscess treated with antibiotic
24. Le Moal G., Landron C., Grollier G., et al.: Characteris- 45. Nathoo N., Nadvi S.S., van Dellen J.R.: Cranial extradu- therapy–case report and review. Neurol Med Chir
tics of brain abscess with isolation of anaerobic bacteria. ral empyema in the era of computed tomography: a (Tokyo) 2009; 49:262-268.
Scand J Infect Dis 2003; 35:318-321. review of 82 cases. Neurosurgery 1999; 44:748-753. 68. Bartels R., Gonera E., van der Spek J., et al.: Intramedul-
25. Tsou T.P., Lee P.I., Lu C.Y., et al.: Microbiology and epi- 46. Al Masalma M., Armougom F., Scheld W.M., et al.: The lary spinal cord abscess: a case report. Spine 1995;
demiology of brain abscess and subdural empyema in expansion of the microbiological spectrum of brain 20:1199-1204.
22
Tetanus and Botulism
AIMEE C. HODOWANEC | THOMAS P. BLECK

Tetanus: TETANUS
Tetanus is still common in low- and middle-income tropical countries,
• Tetanus remains an important cause of death in low- and
middle-income countries (LMIC), particularly among neonates.
where it is an important cause of death, particularly in neonates. The
World Health Organization estimated that in 2011 about 61 000 new-
• Tetanus is caused by tetanospasmin, a neural toxin that pre- borns died worldwide from tetanus.3 In higher-income countries,
dominantly interferes with the inhibition of spinal cord reflexes, however, owing to active immunization, better hygiene, wound care
and is produced by the bacterium Clostridium tetani. and management of childbirth, the disease is now rare. The annual
• Tetanus causes muscle rigidity and spasms; it may be localized, incidence of tetanus has fallen from nearly 4 to 0.06 per million popu-
cephalic or generalized (most common). lation in the USA since 1947 (Figure 22-2); mortality has dropped even
more, with a case-fatality rate of only 13.2%.4 In England and Wales
• Active immunization with tetanus toxoid is extremely effective there were 175 cases of tetanus (and 19 deaths) in the period from 1984
in preventing tetanus.
to 2000.5
• Treatment of tetanus involves administration of human tetanus Neonatal tetanus usually occurs within 3–14 days of birth in infants
immune globulin (HTIG), the antibiotic metronidazole, wound delivered under nonsterile conditions to non-immunized women. The
debridement and sedation. umbilical cord stump is the usual portal of entry, particularly if cul-
Botulism: tural practices dictate the application of animal dung to the stump. At
other ages acute wounds are the portal of entry for C. tetani in about
• Botulism is caused by one of several (types A–G) neurotoxins 80% of cases, with the remainder associated with chronic decubitus
produced by C. botulinum. ulcers, gangrene, abscesses or parenteral drug abuse.
• There are three forms of botulism: food-borne botulism from
ingestion of preformed toxin; wound botulism; and botulism BOTULISM
from intestinal colonization, usually seen in infants. There are three forms of botulism: food-borne botulism from inges-
tion of preformed toxin; wound botulism; and botulism from intesti-
• Botulism causes disturbances of vision, difficulties in swallowing
nal colonization, usually seen in infants. All three forms of botulism
and speech, and weakness of the muscles of the trunk and
extremities. occur throughout the world. Accurate data about the incidence of
botulism are difficult to obtain but it is estimated that in the USA there
• Adequate processing and storage of food to destroy spores
and prevent their germination and toxin production can
prevent food-borne botulism.
Botulinum toxin in its derivative and activated forms
• Treatment of botulism involves supportive care and the admin-
istration of an equine heptavalent antitoxin to adults and chil-
dren and human botulinum immune globulin (BabyBIG) to Derivative botulinum toxin Activated botulinum toxin
infants below 1 year of age. (150 kDa) (150 kDa)
Light chain Heavy chain

s s (50 kDa) (150 kDa)
s s
Introduction
Tetanus and botulism are preventable diseases that nevertheless con-
tinue to cause serious morbidity and mortality, especially in the low- Figure 22-1 Botulinum toxin in its derivative and activated forms. Clostridial
and middle-income countries. Both are caused by members of the toxins as produced by the bacteria (left) and after nicking to produce light and
genus Clostridium; in both cases, disease is caused by exotoxins that heavy chains, linked by a disulfide bond.
conform to an A–B model, each being composed of an enzymatic (A)
portion and a binding (B) portion. The biologic activity resides in the
A portion, whereas the B subunits may bind to target cells but are TABLE Characteristics of Groups of C. botulinum and
biologically inactive. Common to both toxins, A and B are domains of 22-1 the Toxins that Produce Human Disease
a single protein that is cleaved by proteolytic activity of the bacterium
(Figure 22-1). Tetanus is caused by tetanospasmin (TS), a neural toxin Heat
that predominantly interferes with the inhibition of spinal cord Toxins Resistance Disease
reflexes, and is produced by the obligate anaerobic bacterium C. tetani. Group Produced Proteolysis of Spores Severity
Botulism is caused by one of several (types A–G) neurotoxins pro- Group I A, B, F Yes High Severe
duced by C. botulinum (Table 22-1). Types A, B and E and, less com- Group II B, E, F No Low Less severe
monly, F are associated with human disease.1,2
208
Chapter 22 Tetanus and Botulism 209
Annual rate* of tetanus cases and tetanus deaths in the USA
Rate 4.5
Cases 0.18
4.0 Deaths 0.16
0.14
3.5 0.12
0.10
3.0 0.08
0.06
2.5
0.04
0.02
2.0
0
2000 2001 2002 2003 2004 2005 2006 2007 2008
1.5
1.0
0.5
0
1947 1952 1957 1962 1967 1972 1977 1982 1987 1992 1997 2002 2007
Year
*Per 1 million population.
Figure 22-2 Annual rate (*per 1 million population) of tetanus cases and tetanus deaths. From the US Centers for Disease Control and Prevention.
were 474 outbreaks (a large proportion from Alaska) involving nearly encoded gene and is synthesized as a 151 kDa polypeptide. As with
1050 persons between 1950 and 1990. In the UK the incidence is much botulinum toxins, this polypeptide is then split by clostridial proteo-
lower than in Europe or the USA, with only nine outbreaks between lytic cleavage into the light (L) chain (approximately 50 kDa and con-
1922 and 1988. taining the enzymatic (A) domain) and the heavy (H) chain
Most cases of food-borne botulism are associated with home- (approximately 100 kDa and containing the binding (B) domain).
preserved meats, fish and vegetables, but the vehicles are often idiosyn- Most of the tetanus toxin gets into the bloodstream, and then enters
cratic to a country or culture.6 In the USA (apart from Alaska), Spain, the central nervous system (CNS) via neurons to exert its toxicity
Italy and China, most cases follow consumption of home-preserved (Figure 22-3). The effect of each toxin is via a three-stage process:
vegetables contaminated with type A C. botulinum. In Alaska, Japan, binding, internalization and induction of paralysis.8 The H chain inter-
Canada and Scandinavia cases are usually due to type E toxin and acts with the ganglioside GT1 of neurons at neuromuscular junctions,
follow the consumption of fermented foods or preserved fish products; both locally and distally (via the bloodstream), and enables the L chain
in central continental Europe cases typically arise from home-cured to enter the cytoplasm of the neuron. The TS is then transported intra-
meats and are caused by nonproteolytic strains of type B C. botulinum. axonally in a retrograde manner to the cell body in the ventral horns
Commercially prepared foods are rarely implicated. of the spinal cord and the motor nuclei of cranial nerves and then, via
Nearly 1000 cases of infant botulism were reported in the USA trans-synaptic spread, to other neurons within the CNS. Within the
between 1976 and 1990. Cases occur most frequently in the second neurons, TS acts as a zinc-dependent protease that cleaves synapto-
month of life and 95% of cases are in infants less than 6 months old.1 brevin, a protein component of synaptic vesicles,9 and prevents release
There is a significant association between infant botulism and inges- of neurotransmitters at the presynaptic membrane. Inhibitory inter-
tion of honey. However, despite widespread campaigns against infant neurons in the spinal cord (using glycine as a transmitter) and descend-
consumption of honey, US rates of infant botulism have been stable at ing inhibitory projection neurons from the brain stem (using γ-amino
approximately 100 cases per year, suggesting additional food sources butyric acid; GABA) are most severely affected, but cells of the auto-
of botulinum spores. nomic nervous system are also involved.
Occasionally, botulism follows wound infections with C. botulinum.
The wounds are often compound fractures or penetrating wounds. In BOTULISM
more recent years, cases have been reported among drug users who Food-borne botulism follows ingestion of preformed toxin. In other
inject black tar heroin or snort cocaine that is contaminated with C. forms of the disease, toxin is produced in vivo and released when veg-
botulinum organisms or spores.7 etative cells lyse. The toxin is not released from spores. Botulinum
toxins are the most poisonous substances known, and are synthesized
Pathogenesis and Pathology as a polypeptide of molecular weight 150–165 kDa, which is then
broken into a heavy chain of about 100 kDa and a light chain joined
TETANUS by a disulfide bond. The mechanism of action is similar to that of TS,
The clostridia are gram-positive, anaerobic, spore-forming bacilli. In resulting in cleavage of synaptobrevin and inhibition of release of
tetanus, spores of C. tetani contaminate a wound and germinate under acetylcholine at peripheral cholinergic synapses. The heavy chain binds
anaerobic conditions. The proliferating organisms elaborate the rapidly to the membrane of the presynaptic α motor neuron and then
tetanus toxin TS, one of the most potent of the known poisons, with some of the toxin molecule translocates through the membrane.
an estimated lethal dose of 2.5 ng/kg. It is produced by a plasmid- Finally, there is a slow paralytic step that may depend upon
Sites of action of tetanospasmin
Clostridium
tetani Diffuses out
of cell Excitatory
TS synapse
TS
α motor
neuron Presynaptic excitatory
TS + neuron
TS +
TS TS + TS TS TS
TS
TS
Retrograde +
TS – Inhibitory
transport + –
TS – TS synapse
TS
Neuromuscular TS
junction TS
Muscle
fibers Presynaptic inhibitory
neuron
Figure 22-3 Sites of action of tetanospasmin (TS). TS is produced by Clostridium tetani at the site of the wound and binds and internalizes at the neuromuscular junc-
tion into the α motor neuron. It then travels by retrograde axonal flow to the cell body and diffuses out into the synapses and extracellular space of the CNS. It enters
other neurons and travels further into the CNS. Its major effect is to inhibit transmitter release from the glycinergic presynaptic inhibitory neuron but it can also inhibit
release of transmitters at the excitatory synapses and of acetylcholine at the neuromuscular junction.
TABLE
22-2 Recommendations for Use of Tetanus Prophylaxis in Wound Management
CLEAN MINOR WOUNDS ALL OTHER WOUNDS
History of tetanus toxoid
administration Tetanus toxoid* Immunoglobulin Tetanus toxoid* Immunoglobulin
Unknown or less than Yes and proceed with immunization No Yes and proceed with immunization Yes (250 IU HTIG)
three doses
Three or more doses No, unless >10 years since last dose No No, unless >5 years since last dose No
*Vaccine preparation depends on age and vaccination status of patient.
temperature and activity of the neuron. The process is slowly reversible booster immunization.13 Neonatal tetanus can be prevented by ensur-
and the synapse is inactivated for a long time. Initial recovery of func- ing that all pregnant women are immune.
tion depends upon the budding and growth of new presynaptic end- The need for both active and passive immunization against tetanus,
plates, but the original synapse eventually can regain activity. with toxoid and specific human tetanus immunoglobulin (HTIG),
Infant botulism results from colonization of the infant’s gastroin- should be reviewed after any injury that brings an individual to medical
testinal tract with as many as 108 proteolytic C. botulinum organisms attention (Table 22-2).14 Clean minor wounds do not need any special
per gram of feces.10 The mechanisms that relate to colonization and treatment. All other wounds, including frostbite, burns and others,
toxin absorption from the infant gut are unclear, and both the organ- should be considered to render the patient prone to tetanus. Foreign
ism and toxin may continue to be excreted in the feces for several bodies and ischemic tissue should be removed. If the patient has not
months after the illness has resolved. Wound botulism typically results received a primary series, then the age-appropriate tetanus vaccine and
from soil contamination of severe wounds or follows the subcutaneous HTIG (250 IU intramuscularly) should be given. If the patient com-
injection of contaminated material. pleted a primary vaccine series but has not had a booster within 5 years,
Death results from respiratory paralysis; there are no specific a tetanus toxoid-containing vaccine alone should be given.
pathologic findings on gross or histologic examination in any of the
forms of botulism. BOTULISM
The key to preventing botulism is adequate processing and storage of
Prevention food to destroy spores and prevent their germination and toxin pro-
duction. Spores are not killed by boiling at 212°F (100°C) but are
TETANUS destroyed by heating at 250°F (121°C) for 2.5 minutes. Once toxin is
Tetanus is a completely preventable disease. Generally, concentrations formed, it can be inactivated by boiling or heating at 176°F (80°C) for
of antibody to TS as low as 0.01 IU/mL are regarded as protective 30 minutes.
against clinical tetanus, although cases have occurred in patients who Toxin production by strains of C. botulinum is inhibited at a pH
have antibody concentrations at least 10-fold higher than this. Active below 4.6, in saline, and at low temperatures (below 38°F (3.3°C)); the
immunization with tetanus toxoid is extremely effective.11 A primary respective values differ somewhat for different strains. Commercial
series of five doses of diphtheria, tetanus and acellular pertussis (DTaP) canneries pay particular attention to less acidic (pH >4.6) fruit and
vaccine given in childhood, followed by a tetanus, reduced diphtheria, vegetables; the canning and curing of meats relies on a reduced heat
DTaP vaccine between age 11 and 18, then a tetanus toxoid and reduced treatment to kill vegetative bacteria and sodium chloride and nitrite to
diphtheria toxoid (Td) booster every 10 years is recommended.12 inhibit spore growth. Honey has been associated with infant botulism
Immunity wanes in the elderly, who should be specially targeted for and is not recommended for infants less than 1 year old.
TABLE Rating Scale for Severity and Prognosis of

22-3 Tetanus
Score 1 Point for Each of the Following
• Incubation period <7 days
• Period of onset <48 hours
• Acquired from burns, surgical wound, compound fracture, septic abortion
• Narcotic addiction
• Generalized tetanus
• Pyrexia >104°F (40°C)
• Tachycardia >120 beats/min (>150 beats/min in neonates)
Total Score Provides Indication of Severity and Prognosis
Score Severity Mortality

0–1 Mild <10%
2–3 Moderate 10–20%
4 Severe 20–40%
Figure 22-4 Facial spasm and risus sardonicus in a Filipino patient who has
tetanus. 5–6 Very severe >50%
Note: Cephalic tetanus is always scored as severe or very severe, and neonatal
tetanus as very severe.
Clinical Features
TETANUS
The incubation period ranges from 1 day to several months, but most complications are those related to general debility and prolonged
cases start between 3 and 21 days after an acute injury. There is a cor- intensive care.
relation between the distance of the injury from the CNS and the
duration of the incubation period. The time between the first symptom BOTULISM
and the first reflex spasm is termed the period of onset. There are four Food-borne botulism usually develops 12–36 hours after ingestion
clinical forms of tetanus – neonatal, localized, cephalic and generalized of the toxin, although the interval may be as short as 6 hours or as
– depending on the predominant site of toxin action.15 long as 10 days. Patients who have type E toxin-mediated disease tend
Localized tetanus consists of fixed muscle rigidity and painful to have shorter incubation periods than those with type B. Wound
spasms, sometimes lasting weeks or months, confined to an area close botulism occurs at a mean of 7.5 days (range 4–18 days) after the
to the site of the injury. It is rare and generally mild but may herald injury.16
generalized tetanus. Cephalic tetanus is a form of localized tetanus Typically, botulism first affects the muscles supplied by the cranial
associated with wounds to the head or face or with chronic otitis nerves with disturbances of vision and difficulties in swallowing and
media, and manifested by atonic palsies involving the motor cranial speech, followed by descending weakness of muscles of the trunk and
nerves. The incubation period is often only 1–2 days and generalized extremities that is bilateral but not necessarily symmetric. Cardiovas-
tetanus may follow. cular, gastrointestinal and urinary autonomic dysfunction may follow.
Generalized tetanus (by far the most common form) typically starts The presentation may be related to the type of toxin: autonomic symp-
with rigidity and spasm of the masseter muscles, causing trismus or toms occur earlier and are more prominent in intoxication with type
lockjaw and the characteristic risus sardonicus – a grimace through B and E toxins.
clenched teeth and closed mouth with wrinkled forehead and raised Common presenting symptoms are diplopia, dysphagia, dysarthria,
eyebrows (Figure 22-4). Other muscles, first in the neck, then the dry mouth and fatigue (Table 22-4).17 Ptosis and ophthalmoplegia are
thorax, back and extremities, become rigid and go into spasms, pro- common physical signs, together with facial weakness and a decreased
ducing opisthotonos, abdominal rigidity and apnea. Tetanic spasms are gag reflex. The pupils are dilated or fixed in less than 50% of cases.
intermittent, irregular and unpredictable, although they are often trig- Frequently, there is weakness of the extremities, although deep tendon
gered by external stimuli, sometimes very trivial such as a sudden noise reflexes are usually normal. Patients are usually afebrile and have no
or puff of cold air, or even the internal stimulus of a distended bladder sensory deficits. Patients who have wound botulism have a similar
or bowel. Each spasm is sudden, painful and generalized, resulting in presentation but acute gastrointestinal symptoms are lacking.
opisthotonos, leg extension and arm flexion; pharyngeal spasm causes Constipation is the first sign of infant botulism, with neurologic
dysphagia and spasm of the glottis may cause immediate asphyxiation signs developing either concurrently or up to several weeks later.
and death. Cognitive functions are not affected. Severe tetanus is Hypotonia of the neck and extremities is a prominent manifestation
accompanied by abnormalities of the autonomic nervous system, of infant botulism. The neurologic signs progress in a similar fashion
including hypo- or hypertension, arrhythmias and flushing. to those in other forms of botulism but they may be overlooked by the
Neonatal tetanus typically starts with poor sucking and irritability, parents, who merely note the infant is irritable, lethargic or unable to
followed by trismus and tetanospasms. It has a higher mortality than suck. There is a wide range of clinical illness associated with infant
tetanus at other ages. botulism; 50% of cases develop ventilatory failure.
With intensive care, the death rate from tetanus (which is due to
respiratory dysfunction or autonomic cardiovascular instability) may
be as low as 10–20%, with higher rates in infants and in the elderly. A
Diagnosis
rating scale for the severity and prognosis of tetanus may be used TETANUS
(Table 22-3). In general, the more rapid the evolution of symptoms The diagnosis of tetanus depends upon clinical features, and epide-
and signs, the worse the prognosis but the belief that a short incubation miologic history and laboratory tests are usually unhelpful. There is
period leads to a worse prognosis has been challenged.15 often a moderate leukocytosis, but the cerebro-spinal fluid (CSF) is
Complications related to spasms include vertebral and long bone normal, except for increased intracranial pressure associated with
fractures, glottic obstruction and asphyxia, and intramuscular hema- increased muscle tone (raising intrathoracic pressure, which is then
tomas. Rhabdomyolysis is common in generalized tetanus. Other transmitted). Neither electroencephalography nor electromyography
includes prominent ataxia. Myasthenias lack autonomic dysfunction

TABLE Frequency of Symptoms in Types A, B and E and are less fulminant than botulism.
22-4 Food-borne Botulism17
Type A Disease Type B Type E Management
Symptoms (% Of Cases) Disease (%) Disease (%)
TETANUS
Dysphagia 25–96 77–100 63–90 A detailed guide to the management of the patient with tetanus is
Dry mouth 26–83 96–100 55–88 available.15 HTIG, 500 IU as a single intramuscular injection, should
be given at the time of diagnosis in order to prevent further circulating
Diplopia 50–90 57–100 85
toxin from reaching the CNS.14,18 The use of intrathecal HTIG to neu-
Dysarthria 25–100 69–100 50 tralize toxin that has entered but is not yet fixed to nervous tissue19 has
Fatigue 8–92 69–100 Not known
not been consistently beneficial and is not routinely recommended;
injections are potent stimuli for tetanic spasms.
Weakness of arm 16–86 64–86 Not known The source of toxin should be removed by wound debridement and
Constipation 73 17–100 25–38 removal of foreign bodies. Only vegetative forms of C. tetani will be
susceptible to antibiotics. Therapy with metronidazole should be used
Weakness of leg 16–76 64–86 Not known to eradicate C. tetani.20 Penicillin is less suitable as it is a central GABA
Dyspnea 35–91 34 88 antagonist.
A benzodiazepine should be used to produce sedation, decrease
Vomiting 70 50–100 88–100
rigidity and control spasms. Airway protection during spasms is para-
Dizziness 8–86 30–100 63 mount. If ventilation is compromised, the patient should be sedated,
Diarrhea 35 8–14 10
intubated, provided with a soft nasal feeding tube and transferred to a
quiet and darkened area. A tracheostomy is often advisable as the
Paresthesiae 20 12–14 Not known patient may require much higher doses of sedation to tolerate an
endotracheal tube than a tracheostomy tube. If benzodiazepines do not
adequately control the spasms the patient will need long-term neuro-
muscular blockade.
The management over the next few weeks is that of any ventilated
is helpful. Occasionally, characteristic gram-positive bacilli with ter- patient plus specific therapy for autonomic nervous system complica-
minal or subterminal spores may be visualized in aspirates from a tions and control of spasms.21 Sympathetic hyperactivity is treated with
wound but anaerobic cultures are rarely positive and the organism combined α- and β-blockade or morphine. Intrathecal baclofen has
may be grown from wounds in the absence of disease. Therefore, been shown to be effective in controlling muscle rigidity.19 Epidural
neither stains nor cultures of wounds are diagnostically useful. blockade with local anesthetics may be needed. Parasympathetic over-
activity is rare, but if bradycardia is sustained then a pacemaker may
BOTULISM be needed.
Routine laboratory tests are not helpful in the diagnosis of botulism. Clinical tetanus does not induce immunity against future attacks
The diagnosis is best confirmed by assay of botulism toxin in the of the disease and all patients should be fully immunized with tetanus
patient’s blood, gastric washings or feces by means of toxin neutraliza- toxoid during convalescence.
tion tests in mice. Toxin may also be demonstrated in the incriminated
BOTULISM
food. This test takes up to 96 hours to perform and the initial diagnosis
must therefore be based on clinical findings. Clostridium botulinum Elimination of any unabsorbed toxin from the gastrointestinal tract
may be cultured or the toxin detected by an enzyme-linked immuno- should be encouraged in patients who have suspected botulism.
sorbent assay in the patient’s feces, particularly in infant botulism and Administration of an emetic or gastric lavage is recommended if inges-
other cases resulting from intestinal colonization. tion of the suspect food has occurred within the preceding few hours
Electrophysiologic studies show normal nerve conduction veloci- and (unless there is a paralytic ileus) purgation or high enemas should
ties, but the electromyogram is often abnormal with facilitation (an be administered even several days after food ingestion.
incremental increase) of the amplitude evoked in the muscle when The mainstay of therapy for botulism is meticulous supportive care.
high-frequency (20–50 per second) repetitive stimuli are applied to the Patients should be admitted to an intensive care unit and their respira-
relevant nerve. tory function monitored by repeat vital capacity measurements. Intu-
bation should be performed if vital capacity falls below 12 mL/kg.
Differential Diagnosis Equine heptavalent antitoxin, containing antibodies to types A–G
toxin, is available through public health services in many countries.
TETANUS There are few data concerning its use in humans but it is clearly effec-
Strychnine poisoning is the only true mimic of tetanus, although there tive in experimental animals. It should be given as early as possible in
are several other diseases that may overlap to some extent. Strychnine the course of the illness but its use needs careful consideration in view
poisoning develops more rapidly than tetanus and there is usually no of the risk of serious anaphylaxis or serum sickness. A test dose may
muscle rigidity between spasms; serum analysis for strychnine should be administered into the skin. If there is no hypersensitivity, then treat-
be performed in suspect cases. Other causes of trismus include dys- ment may proceed with one vial given intravenously for an average
tonic reactions to phenothiazines and dental abscesses. Tetany from adult. Human botulinum immune globulin (BabyBIG) is available for
hypocalcemia or alkalosis tends to affect the extremities rather than infants through the California Department of Public Health (http://
the axial muscles and there is no trismus. www.infantbotulism.org). Antibiotics do not help except as part of
meticulous debridement of the wound in wound botulism.
BOTULISM The relevant public health authorities should be notified promptly
The diseases most often confused with botulism are Guillain–Barré of a suspected case of botulism so that the necessary investigation may
syndrome (particularly the Miller–Fisher variant, predominantly be conducted.
affecting the cranial nerves), myasthenia gravis and the Eaton–Lambert The severity and duration of food-borne botulism are related to the
myasthenic syndrome, and tick paralysis. Guillain–Barré syndrome amount of toxin ingested. Respiratory failure occurs in 20–35% of
frequently has sensory components and the Miller–Fisher syndrome patients; the mean duration of respiratory support is 7 weeks for those
requiring mechanical ventilation. Recovery from botulism is usually during 1980–89. The prognosis for infants hospitalized with botulism
complete but persistent dysphagia, diplopia and prolonged weakness and given meticulous supportive care is very good, with less than 1.3%
are rare complications of severe cases.22 case-fatality rate and most achieving full recovery.
There has been a steady decline in mortality associated with botu-
lism over the past century; from 70% in the period 1910–19 to 9% References available online at expertconsult.com.
KEY REFERENCES
Bleck T.P.: Clostridium botulinum. In: Mandell G.M., Passaro D.J., Werner S.B., McGee J.: Wound botulism asso- Tetanus surveillance – United States, 2001-2008. MMWR
Bennett J.E., Dolin R., eds. Principles and practice of infec- ciated with black tar heroin among injecting drug users. Morb Mortal Wkly Rep 2011; 60(12):365-369.
tious diseases. 7th ed. New York: Churchill Livingstone; JAMA 1998; 279:859-863. Updated recommendations for use of tetanus toxoid,
2009:3097-3102. Schiavo G., Benfenati F., Poulain B., et al.: Tetanus and reduced diphtheria toxoid and acellular pertussis (Tdap)
Merson M.H., Dowell V.R.: Epidemiologic, clinical, and botulinum-B neurotoxins block neurotransmitter release vaccine from the Advisory Committee on Immunization
laboratory aspects of wound botulism. N Engl J Med by proteolytic cleavage of synaptobrevin. Nature 1992; Practices, 2010. MMWR Morb Mortal Wkly Rep 2011;
1973; 289:1105-1110. 359:832-835. 60(1):13.
Morgan J.C., Bleck T.P.: Clinical aspects of tetanus. In: Brin Schreiner M.S., Field E., Ruddy R.: Infant botulism: a review
M.F., Hallett M., Jankovic J., eds. Scientific and therapeutic of 12 years’ experience at the Children’s Hospital of
aspects of botulinum toxin. Philadelphia: Lippincott Wil- Philadelphia. Pediatrics 1991; 87:159-165.
liams and Wilkins; 2002:151-164.
Chapter 22 Tetanus and Botulism 213.e1
REFERENCES
1. Arnon S.S.: Infant botulism: anticipating the second 9. Schiavo G., Benfenati F., Poulain B., et al.: Tetanus and 16. Merson M.H., Dowell V.R.: Epidemiologic, clinical,
decade. J Infect Dis 1986; 154:201-206. botulinum-B neurotoxins block neurotransmitter and laboratory aspects of wound botulism. N Engl J
2. Bartlett J.C.: Infant botulism in adults. N Engl J Med release by proteolytic cleavage of synaptobrevin. Nature Med 1973; 289:1105-1110.
1986; 315:254-335. 1992; 359:832-835. 17. Woodruff B.A., Griffin P.M., McCroskey L.M., et al.:
3. World Health Organization. Immunization surveil- 10. Schreiner M.S., Field E., Ruddy R.: Infant botulism: a Clinical and laboratory comparison of botulism from
lance, assessment and monitoring. Maternal and Neo- review of 12 years’ experience at the Children’s Hospital toxin types A, B, and E in the United States 1975–1988.
natal Tetanus (MNT) elimination. Available: http:// of Philadelphia. Pediatrics 1991; 87:159-165. J Infect Dis 1992; 166:1281-1286.
www.who.int/immunization_monitoring/diseases/ 11. Amanna I.J., Carlson N.E., Slifka M.K.: Duration of 18. Brauner J.S., Rios Vieira S.R., Bleck T.P.: Changes in
MNTE_initiative/en/index.html. humoral immunity to common viral and vaccine anti- severe accidental tetanus mortality in ICU during two
4. Tetanus surveillance – United States, 2001-2008. gens. N Engl J Med 2007; 357:1903-1915. decades in Brazil. Intensive Care Med 2002; 28:930-935.
MMWR 2011; 60(12):365-369. 12. Updated recommendations for use of tetanus toxoid, 19. Engrand N., Guerot E., Rouamba A., et al.: The efficacy
5. Rushdy A.A., White J.M., Ramsay M.E., et al.: Tetanus reduced diphtheria toxoid and acellular pertussis of intrathecal baclofen in severe tetanus. Anesthesiology
in England and Wales, 1984–2000. Epidemiol Infect (Tdap) vaccine from the Advisory Committee on 1999; 90:1773-1776.
2003; 130:71-77. Immunization Practices, 2010. MMWR 2011; 60(1):13. 20. Ahmadsyah I., Salim A.: Treatment of tetanus: an open
6. Bleck T.P.: Clostridium botulinum. In: Mandell G.M., 13. Gergen P.J., McQuillan G.M., Kiely M., et al.: A popu- study to compare the efficacy of procaine penicillin and
Bennett J.E., Dolin R., eds. Principles and practice of lation-based serologic survey of immunity to tetanus in metronidazole. Br Med J 1985; 291:648-650.
infectious diseases. 7th ed. New York: Churchill Living- the United States. N Engl J Med 1995; 332:761-786. 21. Wright D.K., Lalloo U.G., Nayiager S., et al.: Autonomic
stone; 2009:3097-3102. 14. Keller M.A., Stiehm E.R.: Passive immunity in preven- nervous system dysfunction in severe tetanus: current
7. Passaro D.J., Werner S.B., McGee J.: Wound botulism tion and treatment of infectious diseases. Clin Microbiol perspectives. Crit Care Med 1989; 17:371-445.
associated with black tar heroin among injecting drug Rev 2000; 13:602-614. 22. Wilcox P., Andolfatto G., Fairbarn M.S., et al.: Long-
users. JAMA 1998; 279:859-863. 15. Bleck T.P., Brauner J.S.: Tetanus. In: Scheld W.M., term follow-up of symptoms, pulmonary function,
8. Morgan J.C., Bleck T.P.: Clinical aspects of tetanus. In: Whitley R.J., Marra C.M., eds. Infections of the central respiratory muscle strength, and exercise performance
Brin M.F., Hallett M., Jankovic J., eds. Scientific and nervous system. 3rd ed. New York: Lippincott Williams after botulism. Am Rev Resp Dis 1989; 139:157-163.
therapeutic aspects of botulinum toxin. Philadelphia: Lip- and Wilkins; 2004:625-648.
pincott Williams and Wilkins; 2002:151-164.
23
Transmissible Spongiform
Encephalopathies of
Humans and Animals
SIMON MEAD | JOHN COLLINGE | SARAH J. TABRIZI
KEY CONCEPTS detergents (Figure 23-1). The disease-associated isoform, PrPSc, is

found only in infected brains as aggregated material, is partially resis-
• Prion diseases are transmissible neurodegenerative disorders tant to proteases and insoluble in detergents and has a high content of
of mammalian species. β-sheet secondary structure.
• Highly specific diagnostic imaging and cerebrospinal fluid anal The precise atomic structure of the prion is still undetermined but
yses are available. considerable evidence argues that prions are composed of an abnormal
isoform of PrP. According to the protein-only hypothesis of prion
• Inherited prion diseases are remarkably heterogeneous and replication, PrPSc recruits PrPC into the infectivity-associated isoform,
prion protein gene testing should be considered in any un
an event that is central to prion propagation.
diagnosed dementia or ataxia.
• Prion diseases can be transmitted by surgical instruments, Epidemiology
therefore precautions should be considered in patients and
at-risk individuals. ANIMAL PRION DISEASES
Scrapie, the prototypic prion disease (Table 23-1), has been recognized
• It is increasingly recognized that most of the late-onset neuro as an enzootic disease of sheep and goats for >250 years. Present in
degenerative disorders share fundamental features with prion
diseases, and are termed ‘prion-like’ in their mechanisms
Structure of human prion protein
Introduction
The prion diseases or transmissible spongiform encephalopathies
(TSE) are a group of closely related transmissible neurodegenerative
conditions of humans and animals. In recent years prion diseases have
captured the public attention with the evolving epidemic of bovine
spongiform encephalopathy (BSE) epidemic in Europe, and the sub-
sequent appearance of a novel phenotype of Creutzfeldt–Jakob disease Carbohydrate
(CJD), variant CJD (vCJD) in humans, which is experimentally linked
to dietary exposure to BSE. Recently, the secondary transmission of
vCJD by blood transfusion has generated concern.
The nature of the transmissible agent in TSE has been a subject of Disulfide bond
intense controversy. The initial assumption that the agent must be
some form of virus was challenged by the failure to directly demon-
strate a virus (or an immunological response to it), and by the remark-
able resistance of the transmissible agent to treatment inactivating α-helix
nucleic acids (ultraviolet light or nucleases). Already in 1966, Alper
and others suggested that the transmissible agent is devoid of nucleic
acid,1 and led Griffith to suggest in 1967 that it might be a protein.2
Progressive enrichment of brain homogenates for infectivity resulted
in the isolation of a protease-resistant sialoglycoprotein, designated the
prion protein (PrP) by Prusiner and co-workers in 1982.3 PrP was the
major constituent of infective fractions and was found to accumulate
in affected brains and sometimes to form amyloid deposits. Prusiner
proposed the term prion (proteinaceous infectious particle)3 to distin- GPI anchor
guish the infectious pathogen from viruses or viroids. Prions were
defined as ‘small proteinaceous infectious particles that resist inactiva-
tion by procedures which modify nucleic acids’.
The unifying hallmark is the aberrant metabolism of PrP, which
exists in at least two different physicochemical, conformational states.
The normal form, PrPC, is a highly conserved cell surface protein
attached via a glycophosphatidylinositol anchor (Fig 23-1). It is
Figure 23-1 The structure of PrPC showing three alpha helices, a single disul-
expressed in a wide range of cell types, particularly neuronal cells. PrPC phide bond, up to two carbohydrate moieties and attachment to the cell surface
is a 33–35 kDa sialoglycoprotein with a high content of α-helical sec- via a glycophosphatidylinositol anchor. An N-terminal region containing octapep-
ondary structure that is sensitive to protease treatment and soluble in tide repeats appears to be unstructured and is not shown.
214
Chapter 23 Transmissible Spongiform Encephalopathies of Humans and Animals 215
TABLE
23-1 Animal Prion Diseases
Disease Host Etiology
Scrapie Sheep and goats Thought to involve both horizontal and vertical transmission
Transmissible mink encephalopathy Captive mink Probably food-borne, although the origin of infectious prions
is uncertain
Chronic wasting disease Captive and free-ranging mule deer Origin unknown. There is evidence for horizontal transmission
and Rocky Mountain elk
Bovine spongiform encephalopathy (BSE) Cattle Food-borne in the form of contaminated meat and bone meal
Feline spongiform encephalopathy Domestic and zoo cats Feed contaminated with BSE prions
Exotic ungulate encephalopathy Captive Bovidae Feed contaminated with BSE prions
TABLE
23-2 Human Prion Diseases
Age of Onset or Incubation Period
Disease Incidence Etiology and Duration of Illness
Sporadic Creutzfeldt–Jakob 1 case per 1 million population Unknown but hypotheses include Age of onset is usually 45–75 years; age
disease (CJD) somatic mutation or spontaneous of peak onset is 60–65 years; 70% of
conversions of PrPC into PrPSc cases die in under 6 months
Inherited prion disease (GSS, FFI, 10–20% of cases of human Autosomal dominant PRNP mutation Onset tends to be earlier in familial
CJD, PrP systemic amyloidosis) prion disease CJD compared to sporadic CJD. Can
be wide phenotypic variability
between and within families
Kuru >2500 cases among the Fore Infection through ritualistic Incubation period 5–>40 years; duration
people in Papua New Guinea cannibalism of illness 12 months
Iatrogenic Creutzfeldt–Jakob About 500 cases to date Infections from contaminated human Incubation periods of cases from human
disease growth hormone, human growth hormone 4–>40 years;
gonadotropin, depth electrodes, duration of illness 6–18 months
corneal transplants, dura mater
grafts, neurosurgical procedures
Variant Creutzfeldt–Jakob disease Over 220 cases in UK and rest Infection by BSE-like prions Mean age of onset 26 years; mean
of world* duration of illness 14 months
*To October 2015.

FFI, fatal familial insomnia; GSS, Gerstmann–Sträussler–Scheinker syndrome; PRNP, prion protein gene; PrPC, normal form of prion protein; PrPSc, disease-associated
isoform of prion protein.
many countries, its prevalence in the UK has been estimated as 0.5–1% is widespread in peripheral cervid tissues, excreta and secretions, offer-
of the sheep. It is clear that natural scrapie is an infectious disease,4 for ing a mechanism for horizontal transmission through environmental
which susceptibility is genetically modulated by the host. contamination by carcasses.11 Several polymorphisms of the cervid PrP
Following its discovery in 1985, BSE reached epidemic proportions, gene are known to influence susceptibility to CWD.10 Although CWD
with >180 000 confirmed cases in UK cattle, and much smaller numbers will have been consumed by humans, no atypical prion strains have
in many other European countries. Numbers declined since feeding been detected in hunters or local populations,12 and transgenic studies
ruminant protein to ruminants was banned and reinforced in 1996, with ‘humanized’ mice support the existence of a strong barrier to
although a few cases in cattle born after this date are still occurring. transmission between cervid and human.13
Over 2 million cattle were infected with BSE in the UK.5 Smaller epi-
demics have been described in Switzerland, Ireland, Portugal and
France; and cases have been reported in Japan, Canada and the USA. Human Prion Diseases
Epidemiologic studies point to contaminated offal used in the manu- The human prion diseases (HPD) are unique in biology in that they
facture of meat and bone meal and fed to cattle as the source of prions.6 manifest as sporadic, genetic and infectious diseases (Table 23-2). The
Because the UK has a relatively large sheep population in which scrapie majority of cases of human prion disease occurs sporadically as
is endemic, it was hypothesized that scrapie-contaminated sheep offal Creutzfeldt–Jakob disease (sCJD) at roughly 1 per 106 population
was the initial source of BSE. An alternative view is that BSE prions across the world, with equal incidence in men and women. The aetiol-
originated spontaneously in cattle and that infection was amplified by ogy of sCJD is unknown, although hypotheses include somatic muta-
recycling of infected cattle with subclinical disease. The host range of tion of the PrP gene (referred to as PRNP), and spontaneous conversion
BSE is unusually wide, affecting many other species (Table 23-1). Rare of PrPC into PrPSc as a rare stochastic event. There is a common coding
atypical forms of BSE were first identified in 2004 in Italy and France polymorphism at codon 129 of PRNP encoding either methionine or
on the basis of an apparently higher (BSE-H) or lower (BSE-L) molec- valine (Figure 23-2). Homozygosity at this position (denoted 129MM
ular mass of partially protease digested PrPSc compared with typical or 129VV) predisposes to the development of sporadic and iatrogenic
BSE.7,8 The pathogenicity of atypical BSE in humans is predicted by CJD.14–17
transgenic studies.9 Approximately 15% of HPD are inherited with autosomal domi-
Prion disease of wild and captive cervids, known as chronic wasting nant inheritance. Inherited HPD have been shown to associate with
disease (CWD), has been increasingly documented in the USA and more than 60 different missense and insertion mutations in the coding
Canada, principally in Colorado and Wyoming.10 Deposition of PrPSc sequence of PRNP (see Figure 23-2).18 Although the HPD are
Prion protein gene
Pathogenic mutations F198S

E196K
T193I E200K
T188A
T188K D202N
T188R
V203I
H187R R208C
R208H
T183A V210I
P105L
P105T S132I V180I Y226X
Y145X
P102L G114V D178N E211Q Q227X
R148H Q212P M232T
2-OPRD OPRI A117V
Q160X
G131V Y163X Q217R P238S
D167N
1 22 51 91 112 135 231 253aa
A117A E219K
P39P G54S G124G M129V V161V R228R
1-OPRI
1-OPRD Y128Y N171S S230S
G142S
Polymorphic variants G127V Y150Y H177H Q212Q M232R
Figure 23-2 Prion protein gene. Proposed causal mutations (above) and polymorphic variants which are benign or confer resistance changes (below) in the prion
protein (PrP) gene are shown. The central bar illustrates the secondary structural features of the PrP (purple = alpha helix).
experimentally transmissible, the acquired forms have, until recently, properties of PrPSc from the brains of BSE-infected cattle and patients
been confined to rare and unusual situations. For example, kuru was who have CJD, has demonstrated that vCJD is different from sporadic
caused by cannibalism among the Fore linguistic group in Papua New CJD but similar to BSE.27,28 Moreover, the incubation times and profile
Guinea.19 The disease originated at the beginning of the 20th century of neuropathologic lesions of vCJD and BSE prions are indistinguish-
and was the leading cause of death in this population by the middle of able in inbred lines of mice.29 These data argue that BSE and vCJD are
the century, killing >2500 people in a population of 30 000. Mainly the same strain. All autopsy-proven cases of vCJD have been 129MM,
adult women and children of both sexes were affected, with an annual a genotype shared by ~40% of the White British population; a single
disease-specific mortality of ~3%. The roughly seven-fold higher inci- patient with genotype 129MV was thought to have vCJD based on
dence of disease in adult women than adult men was the result of clinical, imaging and spinal fluid tests but did not have post-mortem
higher exposure of women to infectious brain material. Since the ces- confirmation.30
sation of cannibalistic practices around 1956, the disease has all but Polymorphisms in the human PRNP gene are not the sole genetic
died out, with only a handful of cases currently occurring in older influence on disease susceptibility and incubation time. Studies with
people who were presumably exposed to kuru as young children, indi- inbred mice show that large differences occur even with the same
cating an incubation time in these cases of >50 years.20 In kuru all amino acid sequence of the PrP, suggesting that other genes contribute
codon 129 genotypes were affected as the epidemic evolved, with to the observed variation. Studies of quantitative trait loci (QTL)
codon heterozygotes (129MV) having the longest mean incubation linked to prion disease incubation periods in mice have identified
time.21,22 Elderly women survivors of the epidemic of kuru are over- susceptibility loci on chromosomes 2, 4, 8, 11, 12 and 15.31,32 These
whelmingly codon 129MV, supporting the concept that kuru imposed QTL studies provide strong evidence that loci other than the coding
strong balancing selection on the Fore.23 Recently a novel missense region of PRNP have a major influence on scrapie incubation time.
variant of PRNP was found strongly protective against kuru, and Iatrogenic secondary transmission of vCJD has now occurred by
selected for in the Fore population of the Eastern Highlands of Papua blood transfusion from preclinical vCJD.33–35 Three patients have been
New Guineau.24 identified from a cohort of 23 who have survived more than 5 years
Other examples of acquired HPD have resulted from iatrogenic after receiving vCJD-implicated blood. In 2004 a 62-year old patient
transmission of CJD during corneal transplantation, contaminated was diagnosed with vCJD post-mortem, 6.5 years after transfusion of
electroencephalographic electrode implantation and surgical opera- a single unit of red cells;34 later in 2004 an elderly patient who died of
tions using contaminated instruments or apparatus. In addition, iat- an unrelated cause 5 years after transfusion of a single unit of red cells
rogenic CJD has occurred after implantation of dura mater grafts and was found to have PrPSc deposition in lymphoreticular tissues consis-
treatment with growth hormone or gonadotropin derived from pitu- tent with vCJD infection.33 In 2006 a patient was confirmed to have
itary glands of human cadavers.25 vCJD at autopsy having received a unit of vCJD-implicated red cells 6
The appearance of CJD in teenagers and young adults in the UK years earlier.35 This patient was diagnosed whilst alive and had PrPSc
during the mid-1990s prompted concern that they acquired the illness deposition in tonsillar tissue. Early in his disease, MRI was negative for
as a result of exposure to BSE. By March 1996, it became clear that the the pulvinar sign. Both clinically affected patients were genotype
unusual clinical presentation and neuropathology was remarkably 129MM, but the subclinically-infected patient was 129MV, indicating
consistent in these cases.26 Up until December 2014 there have been the potential of individuals with this genotype to replicate vCJD
177 deaths from probable or pathologically confirmed vCJD in the UK: prions. The fact than no PrPSc was detectable in the tonsil of this
predominantly teenagers and young adults, and over 200 deaths patient may reflect the selection of a novel strain in 129MV or alter-
worldwide. Molecular strain typing, which focuses on the biochemical natively relate to the amount and distribution of PrPSc seen early in
infection. With an average of ~6 years, the shortest incubation times features; dementia occurs much later in the course, which is longer
of secondary vCJD are, as expected, considerably shorter than the than that of classic CJD. Fatal familial insomnia (FFI) is characterized
shortest incubation times of primary vCJD of ~12 years. 6000 patients by progressive untreatable insomnia, dysautonomia and dementia,
have been notified of their exposure to vCJD-implicated blood selective thalamic degeneration and is most commonly associated with
products. a missense mutation at codon 178 of PRNP.51 The FFI phenotype also
Estimates of the prevalence of the carrier state have relied on occurs sporadically with no causative mutation in PRNP identified.52
screening of surgical lymphoreticular tissue.36,37 The largest study, con- The early clinical presentation of vCJD resembles kuru more than
ducted on 32 441 anonymized appendectomy specimens, identified 16 classic CJD and consists of behavioral and psychiatric disturbances,
positives, resulting in an estimated prevalence of vCJD infection of peripheral sensory disturbance and cerebellar ataxia. Common early
493/million (CI 282–801).38 All three genotypes at codon 129 were psychiatric features include dysphoria, withdrawal, anxiety, insomnia
associated with abnormal PrP deposition.39 and apathy. Neurological symptoms precede psychiatric symptoms in
15% of cases studied, and were present in combination with psychiat-
ric symptoms in 22% of cases from the onset of disease. No common
Clinical Features early neurological features were noted, but paresthesia and/or pain in
The HPD can be divided etiologically into inherited, sporadic and the limbs is seen in around half of the cases. However, a significant
acquired forms with CJD, Gertsmann–Sträussler–Scheinker syndrome proportion of patients exhibited neurological symptoms within 4
(GSS) and kuru now seen as clinicopathological syndromes rather than months of clinical onset, and these included poor memory, pain,
individual disease entities. The identification of one of the pathogenic sensory symptoms, unsteadiness of gait and dysarthria. Disorientation,
PRNP mutations in a patient with neurodegenerative disease allows hallucinations, paranoid ideation, confabulation, impaired self care,
the diagnosis of an inherited HPD and sub-classification according to and the commonest neurological features (cerebellar signs, chorea,
mutation.40 Pathogenic mutations have been described in two groups:1 dystonia, myoclonus, upper motor neuron signs and visual symptoms)
point mutations resulting in amino acid substitutions in PrP or pro- developed late.53 The duration of disease is longer in vCJD with mean
duction of a stop codon resulting in expression of a truncated PrP;2 survival times of ~13 months, compared with ~4 months for classic
alteration of integral copies of an octapeptide repeat present in a CJD. Moreover, whereas classic CJD is predominantly a late-onset
tandem array of five copies in the normal protein (see Figure 23-2). disease with a peak onset between 60 and 65 years, the median onset
They are all autosomal dominantly inherited conditions. Kindreds of vCJD is 26 years.53 The EEG is not helpful in the diagnosis of vCJD,
with inherited prion disease have been described with phenotypes of whilst generalized slowing is usually present, the characteristic periodic
classical CJD, GSS, and also with a range of other neurodegenerative changes associated with classic CJD are not. The CSF 14-3-3 protein
disease phenotypes. Some families show remarkable phenotypic vari- is less helpful, and is often negative. MRI, however, is useful in the
ability which can encompass both CJD- and GSS-like cases as well as diagnosis of vCJD; in the majority, high signal is noted in the posterior
cases which do not conform to either CJD or GSS.41 Such atypical HPD thalamus (pulvinar) bilaterally on dual echo (T2 or proton density-
may lack the histological features of a spongiform encephalopathy weighted) MRI (Figure 23-3).54 Other common MRI features of vCJD
entirely although PrP immunohistochemistry is usually positive.42 are medial thalamic and periaqueductal gray matter high signal, and
Progressive dementia, cerebellar ataxia, pyramidal signs, chorea, the notable absence of cerebral atrophy. In 2011 a prototype blood-
myoclonus, extrapyramidal features, pseudobulbar signs, seizures and based assay for vCJD was reported which relies on the presumed
amyotrophic features are seen in variable combinations. PRNP analysis capture of abnormal PrP by steel beads followed by immunodetec-
is also used for presymptomatic genetic testing in affected families.43 tion55 with a sensitivity of 71%, and very high specificity.56 vCJD can
Recently a new prion disease, PrP systemic amyloidosis, was described be diagnosed by detection of PrPSc immunostaining on tonsil biopsy.
in association with the 163X mutation of PRNP. These patients present Importantly, PrPSc is only detectable in tonsil and other lymphoreticu-
with diarrhea, and symptoms associated with a sensory and autonomic lar tissues in vCJD, and not other forms of HPD, indicating that it has
neuropathy in their third–sixth decade.44 a distinctive pathogenesis.57,58 The PrPSc type detected on Western blot
Classic CJD is a rapidly progressive dementia accompanied by in vCJD tonsil has a characteristic pattern designated type 4, by the
myoclonus. Decline to akinetic mutism and death is rapid, often occur- London classification. Tonsil is the tissue of choice for biopsy in pos-
ring within 3–4 months. Cerebellar ataxia, extrapyramidal and pyra- sible vCJD. Tonsil biopsy is well tolerated, and has shown 100% sen-
midal features and cortical blindness are also frequent. The EEG may sitivity and specificity.57 If the tonsil biopsy is positive with the specific
show characteristic pseudo-periodic sharp wave activity which is vCJD banding pattern (Figure 23-4), a brain biopsy is unnecessary.
helpful in diagnosis but present only in up to 70% of cases. Cerebro-
spinal fluid (CSF) immunoassay for the neuron-specific 14-3-3 protein
may be helpful.45,46 A raised 14-3-3 protein is not specific for classic
CJD and is raised in viral encephalitis or recent stroke; it is a marker MOLECULAR STRAIN TYPING
of rapid neuronal injury and loss. More concerning, with respect to The marked clinical heterogeneity observed in sporadic CJD is unex-
the differential diagnosis, is that it may also be raised in rapidly pro- plained. Distinct isolates, or strains of prions can be propagated in the
gressive forms of Alzheimer’s disease, which may be confused with same host and these are biologically recognized by distinctive clinical
CJD. Technologies which test patient biofluids, typically CSF, for and pathological features in experimental animals (for review see refer-
seeding the misfolding of recombinant PrP in vitro (termed quaking ence 59). It is therefore likely that a proportion of the clinicopathologi-
induced conversion, QUIC) are increasingly entering clinical use.47 cal heterogeneity in CJD, and other HPD, relates to the propagation
MRI scanning, particularly diffusion-weighted sequences, is highly of distinct human prion strains. The identification of these prion
sensitive in classic CJD. Caudate and putamen hyperintensity is well strains would allow an etiology-based classification of CJD by typing
known, but cortical ribbon hyperintensity and thalamic high signal in of the infectious agent itself.
129MV patients is increasingly recognized.48 Atypical cases of classic The existence of prion strains has been difficult to accommodate
CJD can still present diagnostic difficulties.49 within the protein-only model of prion propagation. As they can be
The clinical features of kuru consist of a progressive cerebellar serially propagated in inbred mice with the same PRNP genotype, they
ataxia accompanied by dementia in the later stages and death, usually cannot be encoded by differences in PrP primary structure. Further-
occurring within 12 months.50 Iatrogenic HPD arising from intracere- more, strains can be re-isolated in mice after passage in intermediate
bral or optic inoculation usually manifests as classic CJD, whilst those species with different PrP primary structures. Conventionally, distinct
arising from a peripheral inoculation, such as pituitary growth strains of conventional pathogens are explained by differences in their
hormone commonly present like kuru with a progressive ataxia. GSS nucleic acid genome. However, in the absence of such a scrapie genome,
commonly presents as a chronic cerebellar ataxia with pyramidal alternative possibilities must be considered. Experimental evidence
a b c d
Figure 23-3 (a) Diffusion-weighted imaging (DWI) showing cortical ribbon in sCJD. (b) FLAIR images and (c) DWI showing high signal in the caudate, putamen, and
less so from the thalamus, in sCJD. (d) FLAIR images in iCJD showing cortical, caudate, putamen and thalamic high signal.
a b c
d e f
Figure 23-4 Examples of prion pathology. (a) Spongiform change in sCJD (H&E). (b) Gliosis and spongiform change in sCJD (GFAP). (c) Perineuronal PrP staining in
sCJD (ICSM35). (d) Perivacuolar PrP staining in sCJD (ICSM35). (e) Synaptic PrP staining in sCJD (ICSM35). (f) Kuru-like plaques in sCJD (ICSM35). (Courtesy of Professor
Sebastian Brandner, UCL Institute of Neurology.)
now suggests that PrPSc itself may encode strain-specific phenotypic the ratios of the three PrP glycoforms maintained on passage in trans-
properties. Different sub-types of PrPSc were associated initially with genic mice expressing human PrP.27 Furthermore, transmission of
two strains of transmissible mink encephalopathy in hamsters.60 human prions and bovine prions to wild type mice results in murine
Several human PrPSc types have been identified which are associated PrPSc with fragment sizes and glycoform ratios which correspond to
with different phenotypes of CJD.27,61,62 The different fragment sizes the original inoculum.27 Variant CJD is associated with PrPSc glyco-
seen on Western blots, following treatment with proteinase K, suggests form ratios, which are distinct from those seen in classic CJD. Similar
that there are several different human PrPSc conformations, referred ratios are seen in BSE, and BSE when transmitted to several other
to as ‘molecular strain types’. These types can be further classified by species.27
the ratio of the three PrP bands seen after protease digestion, repre- BSE and vCJD has now been propagated in Prnp-null transgenic
senting di-, mono- and unglycosylated fragments of PrPSc. By the mice expressing the human prion protein modelling three different
London classification system, sporadic CJD is associated with PrPSc codon 129 genotypes.63–66 Transgenic mice for human 129MM propa-
type 1–3, while type 4 human PrPSc is uniquely associated with vCJD gate either type 2 or 4 PrPSc with respective neuropathologies consis-
and characterized by glycoform ratios which are distinct from those tent with human sporadic CJD or vCJD, whereas transgenic mice
observed in classic CJD.27,61 Importantly, these biochemical changes in homozygous for human 129VV either propagate novel type 5 PrPSc and
PrPSc are transmissible to the PrP in a host. This has been demon- a distinct pattern of neuropathology or develop clinical prion disease
strated in studies with CJD isolates, with both PrPSc fragment sizes and in the absence of detectable PrPSc. Transmissions to human 129MV
mice were complex, with four distinct phenotypes, including the Codon 129
propagation of type 4 PrPSc in the absence of florid plaques. These
findings argue that primary BSE prion infection, as well as secondary MM MM MM
infection by iatrogenic routes, may not be restricted to a single disease MV MV
phenotype including extensive transmission as a subclinical carrier VV VV
state. Further, these studies raise the possibility that some humans sCJD vCJD
infected with BSE prions may develop a clinical disease indistinguish-
able from classic CJD associated with type 2 PrPSc. All these data kDa
strongly support the ‘protein only’ hypothesis of infectivity and suggest
that strain variation is encoded by a combination of PrP conformation 36
and glycosylation pattern.
PATHOLOGY 30
The animal and HPDs share a number of characteristic features, the
most consistent being the neuropathological changes that accompany
disease in the central nervous system (CNS). The neuropathological
similarities between scrapie and kuru strongly suggested that the two
diseases might be closely related, and that kuru, like scrapie, might also 16
be transmissible by inoculation.67 Subsequently, brain extracts from
patients with kuru produced a progressive neurodegenerative condi-
tion in inoculated chimpanzees after an incubation period of 18–21 1 2 3 4
months.68 The neuropathologic similarities between kuru and CJD
prompted similar transmission experiments from CJD patients.69 London PrPSc type
Although the brains of patients or animals who have prion disease Figure 23-5 Western blot of four patient brain samples prepared by homogeni-
frequently show no macroscopically recognizable abnormalities, zation in phosphate buffered saline, partial protease digestion using proteinase
microscopic examination typically reveals characteristic histopatho- K, and immunoblotting. Three PrP immunoreactive bands are seen related to
three glycosylation states (un-, mono-, and diglycosylated). Types 1–3 are seen in
logic changes, consisting of neuronal vacuolation and degeneration, sCJD with restriction to certain codon 129 genotypes (above) and can be distin-
which gives the gray matter a microvacuolated or ‘spongiform’ appear- guished by apparent molecular weight. Type 4 is different from sporadic types by
ance (Figure 23-4a), and a reactive proliferation of astroglial cells the predominance of the diglycosylated (top) band and is exclusively seen in
(Figure 23-4b), often out of all proportion to the degree of nerve cell vCJD.
loss. Although spongiform degeneration is frequently detected, it is not
an obligatory feature of prion disease; astrocytic gliosis, although not PrP, analogous to the oligomers implicated as the prime cause of
specific to prion diseases, is more constantly seen. The lack of inflam- disease in other neurodegenerative conditions such as Alzheimer’s
mation is also an important characteristic. Although it is by no means disease and Parkinson’s disease.79 However, more precise characteriza-
a constant feature, some examples of prion disease show deposition of tion of the infectious and toxic entity of prion disease is going to
amyloid plaques composed of insoluble aggregates of PrP. Amyloid require the synthesis of prion from recombinant substrates. Although
plaques are a notable feature of kuru and GSS but they are infrequent there has been some success,80 synthetic prions have only been gener-
in the brains of patients with classic CJD. ated in such low concentrations that analysis of molecular structure is
Although there is wide variation in the neuropathologic profiles of impossible.81,82
different forms of HPD, the histopathologic features of vCJD are The essential role of host PrPC for prion propagation and patho-
remarkably consistent and distinguish it from other HPD. Large genesis is demonstrated by the fact that mice in which the PrP gene
numbers of PrP-positive amyloid plaques are a consistent feature of has been disrupted (referred to as Prnp0/0) are resistant to scrapie,74,83
vCJD but they differ from the plaques seen in kuru and GSS in that and that reintroduction of the murine PrPC transgene restores suscep-
the surrounding tissue takes on a microvacuolated appearance, giving tibility to infection.84 Gene-targeted Prnp0/0 mice have also been studied
the plaques a florid appearance (Figure 23-4).26 vCJD is clearly very to probe the normal function of PrPC. Two independently generated
different in its pathogenesis from other HPD, and this is reflected in lines of gene-targeted Prnp0/0 mice developed normally and had no
the tissue distribution of PrPSc in vCJD. As mentioned, it is readily gross phenotypic abnormalities.83,85 The relative normality of these
detectable in lymphoreticular tissue, and using highly sensitive immu- Prnp0/0 mice was thought to result from effective adaptive changes
noassays, PrPSc has been found in retina, optic nerve, rectum, adrenal during development. However, data from Prnp-conditional knockout
gland and thymus post-mortem.58,70 mice suggest this is not the case;86 these mice undergo ablation of
neuronal PrP expression at 9 weeks of age. The mice remain healthy
PATHOGENESIS without evidence of neurodegeneration or an overt clinical phenotype
Detection of PrPSc in brain material by immunohistochemical or demonstrating that acute loss of neuronal PrP in adulthood is toler-
immunoblotting techniques is considered to be diagnostic of prion ated, and that the pathophysiology of prion diseases is not due to loss
disease (Figure 23-5). However, certain examples of natural and of normal PrP function.86 The normal function of PrP is not known
experimental prion disease occur without accumulation of detectable but PrP knockout mice show defects in neurophysiological and bio-
protease-resistant PrPSc,71–73 and the time course of neurodegeneration chemical function. Electrophysiological studies have demonstrated
is not equivalent to the time course of PrPSc accumulation in mice that fast inhibition and long-term potentiation mediated by δ-
expressing lower than normal levels of PrPC.74 Moreover, PrPSc is not aminobutyric acid receptors were impaired in hippocampal slices from
toxic to cells that do not express PrPC,75,76 and mice expressing PrP Prnp0/0 mice87,88 and that calcium-activated potassium currents were
without a glycophosphatidylinositol anchor to the cell membrane may disrupted.86,89 These abnormalities of synaptic inhibition are reminis-
be infected with prions but do not develop neurodegeneration.77 Addi- cent of the neurophysiological defects seen in patients with CJD and
tional evidence that PrPSc may not be the neurotoxic species has been in scrapie-infected mice,87 and suggest a direct role for PrP in the
demonstrated in mice inoculated with Sc237 hamster prions. These modulation of neuronal excitability. Normal PrP is able to bind copper
mice replicate prions to high levels in their brains but do not develop ions,90,91 with femtomolar affinity,92 and a role for PrP in copper metab-
any signs of clinical disease during their normal lifespan.78 Recently, olism or transport has been suggested. Other suggested functions
PrPSc fractionation experiments suggest that the most infectious entity include as a nerve growth factor,93 self-renewal of hemopoietic stem
of prion disease is an oligomer (about 14–28-mer) of misfolded cells,94 or in the maintenance of myelin sheaths in peripheral nerves.95
It appears that neither accumulation of PrPSc nor loss of normal PrP followed this strategy. The UK National Blood Transfusion Service
function is the cause of the neurodegeneration in prion diseases. It is now imports all plasma and plasma derivatives from BSE-free coun-
possible that a toxic intermediate is produced in the conversion of PrPC tries, and blood donors are screened to exclude anyone with a blood
to PrPSc, and that the steady state level of such an intermediate could relative with classic CJD or vCJD. Several countries have instituted
then determine the rate of neurodegeneration.78 policies of deferral of blood donors who have resided in the UK for a
cumulative period of 6 months or more from 1980 until the end of
Prevention 1996. In view of the potential exposure to the vCJD agent in other
Because there are currently no treatments for these invariably fatal European countries in addition to the UK, the Food and Drug Admin-
diseases, prevention is particularly important. A most effective example istration in the USA has a blood donation deferral policy of a cumula-
of prevention was the cessation of cannibalistic practices among the tive 10-year residence in France, Portugal and Ireland. The American
Fore people of Papua New Guinea in the 1950s, which resulted in Blood Banks have adopted a deferral policy of 3 months residence in
the disappearance of kuru. The replacement of growth hormone the UK and 6 months residence in any other European country. The
derived from the pituitary glands of human cadavers with recombinant efficacy of these risk reduction procedures is not known, and a screen-
growth hormone was implemented to avoid iatrogenic transmission of ing test for blood infectivity is urgently needed.
CJD to young children with growth hormone deficiency. Similarly, Transmission of classic CJD has occurred via surgical instruments
because CJD has resulted from the use of prion-contaminated surgical as prion infectivity resists conventional sterilization.97 Surgery may be
instruments or apparatus after neurosurgical or ophthalmic proce- an epidemiological risk factor for classic CJD.98,99 The presence of vCJD
dures, it is advised that surgical instruments be incinerated in cases in peripheral tissues commonly involved in routine surgery has raised
where CJD is confirmed so as to avoid future iatrogenic transmission concerns about this mechanism of secondary transmission. A three-
of prion disease. Current policy in the UK is to quarantine surgical stage detergent/enzymic procedure has been demonstrated to be effec-
instruments until a suspected diagnosis is confirmed (see https:// tive at decontamination of prions.100
www.gov.uk/government/publications/guidance-from-the-acdp-tse-
risk-management-subgroup-formerly-tse-working-group). Recent ex Development of Therapies
periments have confirmed that prions adhere to metal following a Curative therapies for prion infection are conceivable, but, if devel-
contact time with infected brain of as little as 5 minutes.96 oped, will not be available for some years.101 Such approaches are likely
When it was realized that BSE was caused by feeding prion- to target PrP.101 However, the development of neuroprotective agents,
contaminated foodstuffs to cattle, a number of preventive measures and pre- and postexposure prophylaxis is also important. In addition,
were introduced in the UK. In July 1988 a ban on feeding ruminant- early firm diagnosis will be crucial to allow such treatments to be initi-
derived protein to other ruminants was introduced to break the cycle ated before extensive brain damage occurrs. A number of compounds
of infection via feed. A ban on specified bovine offal was introduced have been shown to be effective at clearing PrPSc in cell cultures. These
in the UK in 1989 to prevent inclusion in the human food chain of include the acridine and phenothiazine derivatives quinacrine and
bovine tissues thought to contain the highest titer of prions; these chlorpromazine, Congo red, sulphated polyanions and anti-PrP anti-
included lymphoreticular tissues and the CNS. The European Union bodies (reviewed in reference 102). A few compounds have been
imposed a worldwide ban on the export of British cattle, products shown to prolong survival in animal models after intraperitoneal
derived from them (with the exception of products for technical uses) inoculation with prions. These include pentosan polysulphate,103 cyclic
and mammalian meat and bonemeal in March 1996 after the announce- tetrapyrroles,104 and CpG oligodeoxynucleotides.105 Treatment of mice
ment that BSE and vCJD might be linked. Since then, >1.35 million with anti-prion monoclonal antibodies results in delay of clinical onset
cattle over 30 months old have been culled in the UK in a further beyond 300 days (versus controls ~190 days) after intraperitoneal
attempt to limit human exposure to BSE. The ‘Over Thirty Month’ administration of mouse prions.106 However, clinical duration was not
(OTM) rule is one of the UK BSE controls to prevent further BSE- prolonged when treatment was started after neurological onset, and
infected cattle from entering the human food chain, because cattle >30 there was no effect if prions were administered intracerebrally. The
months are more likely to develop BSE than younger animals. There- PRION-1 trial of quinacrine in the UK, and a further study in the US
fore, since 1996 there has been a ban on selling meat in the UK from have been completed and were negative. Pentosan polysulphate has
slaughtered cattle >30 months old. The cost of tackling BSE to British been used in a small number of patients with various HPDs, in many
and European taxpayers has been >£7000 million. These measures cases with direct intracerebral delivery. Given the very small sample
appear to have been effective in reducing the incidence of BSE in the size, adverse events and lack of placebo group, it is very difficult to
UK and the number of newly identified BSE cases has declined sharply. conclude whether this treatment has any benefit (see http://
The EU-imposed ban on British beef exports was lifted in late 1999 www.cjd.ed.ac.uk/bone.pdf for details). Currently a huge international
after the EU was satisfied that appropriate measures had been taken to research effort is underway to develop therapies aimed at both pre- and
counteract the likelihood of BSE-infected animals getting into the postexposure prophylaxis, in addition to neuroprotective agents that
human food chain. may slow down disease progression.
Prior to the realization of blood transmission of vCJD, the UK
government decided in 1998 that all blood donations should be leu- References available online at expertconsult.com.
kodepleted. Since then the majority of European countries have
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24
Infections in Hydrocephalus Shunts
ROGER BAYSTON | IVAN PELEGRIN
KEY CONCEPTS Pathogenesis and Pathology

• The incidence of shunt infection is higher (up to 25%) in pre- The source of the organisms is almost invariably the patient’s skin,
mature and term infants than in older children and adults from which they gain access to the device during its insertion.5,6 Even
(3–8%). after thorough skin preparation, resident bacteria in follicles remain
and it is therefore not unusual to find staphylococci in the incision
• Most shunt infections are caused by coagulase-negative staph-
during the procedure and they are highly likely to adhere to and colo-
ylococci (e.g. Staphylococcus epidermidis).
nize the inner surfaces of the shunt. After adhering to the shunt mate-
• Propionibacterium acnes is also important: anaerobic, may take rial, they multiply and produce copious amounts of exopolysaccharide
up to 10 days to grow on culture, easily missed or dismissed (‘slime’), enabling the formation of a biofilm. Growth is very slow and
as a contaminant. this accounts for the often long periods between surgery and clinical
• Most shunt pathogens originate on the patient’s skin or mucous presentation of infection. The majority of shunt infections are caused
membranes and gain access to the shunt during surgery. by coagulase-negative staphylococci (CoNS), with fewer caused by
Staphylococcus aureus (5–18%) and Propionibacterium acnes (9%).
• Once inside the shunt tubing, bacteria grow as biofilms. Infections due to P. acnes are often unrecognized because the bacte-
• Symptoms in ventriculoatrial (VA) shunt infections differ from rium is a slow-growing anaerobe. Infections in primary shunts where
ventriculoperitoneal (VP): VA mainly bacteramic, later immune a previous extraventricular drain (EVD) has not been used are more
complex disease; VP mainly intra-abdominal, cysts and obstruc- likely to be due to CoNS, whereas rates from studies where no distinc-
tion. Both usually show ventriculitis. tion is made show lower rates of CoNS (~40%). Polymicrobial shunt
• Incidence can be reduced by adoption of written rigorously infection rates range between 12% and 15% and gram-negative bacilli
applied surgical protocols. between 4% and 7%.7,8
The clinical presentation of infection in VA shunts differs from that
• Evidence for the role of prophylactic antibiotics is weak despite in VP shunts (Table 24-1). In the former, bacteria from the shunt enter
large numbers of trials. the bloodstream directly to cause intermittent fever which, in infec-
• Antimicrobial-impregnated catheters have reduced infection tions caused by Staph. epidermidis, propionibacteria or coryneforms,
rates in trials but no randomized controlled trial (RCT) evidence
exists. Silver-processed catheters have shown benefit in one
RCT. A national RCT comparing the two types of catheter
(BASICS trial) is underway in the UK.
Routes of drainage of VP and VA shunts
• Treatment of shunt infection is complicated by biofilm in
the tubing, which is not eradicated by antibiotics; and by the
poor cerebrospinal fluid (CSF) penetration of intravenous
antibiotics.
• Treatment should include shunt removal, and external ventricu-
lar drainage with intraventricular antibiotics.
• An important exception is community-acquired meningitis
(Haemophilus, meningococcus, pneumococcus). This is not a
shunt infection. The shunt should not be removed, and the
meningitis treated conventionally.
Hydrocephalus shunts drain excess cerebrospinal fluid (CSF) from the

cerebral ventricles, usually to the peritoneal cavity (ventriculoperito-
neal, VP) or less commonly to the right cardiac atrium (ventricu-
loatrial, VA) (Figure 24-1).
Epidemiology
The incidence of infection varies according to the age at which the
shunt is inserted. Up to 25% of operations in premature infants with
hydrocephalus after periventricular hemorrhage result in infection, Figure 24-1 Routes of drainage of ventriculoperitoneal and ventriculoatrial
whereas in older children the incidence is 3–8%.1 Although the inci- shunts. Ventriculoperitoneal shunts drain CSF from the cerebral ventricles to the
peritoneal cavity via catheter tubing implanted superficially over the rib cage. The
dence of shunt infections has generally fallen, it is still unacceptably lower end of the peritoneal catheter lies free in the abdomen. Ventriculoatrial
high, as a recent study from 30 different countries has reported.2 Some shunts drain CSF via a convenient neck vein such as the jugular and the superior
rare centers report rates of infection near to zero3,4 vena cava to the right atrium.
221
TABLE
24-1 Clinical Features of Ventriculoatrial (VA) and Ventriculoperitoneal (VP) Shunt Infections of Surgical Origin
Clinical Feature VA Shunts VP Shunts
Time from surgery to presentation Weeks, months, several years <9 months
Intermittent fever 75% <50%
Anorexia, lassitude, poor sleep pattern >80% >50%
Shunt obstruction <1% ≥75%

Other features Chills, rigors: 20% Abdominal pain, bloating: ≈75%
Arthralgia: 50% [late onset cases (1–15 years)] Swelling, erythema over shunt tubing: ≈60%
Rash: 70% [late onset cases (1–15 years)] Headache, vomiting, etc. (i.e. recurrence of
Nephritis: 30% [late onset cases (1–15 years)] hydrocephalus): ≥75%
Percentages indicate the approximate proportion of cases in which features are present. It is important to realize that each case is different and that many of these
features may be absent or modified.
Figure 24-3 External shunt infection in a premature infant with poor nutritional
status. The infection can be caused by organisms introduced at surgery or they
Figure 24-2 Cystic obstruction of a ventriculoperitoneal shunt caused by shunt may gain access through minor skin abrasions and pressure necrosis. Differing
infection with Staphylococcus epidermidis. Bacteria and bacterial products enter- from the more common internal shunt infections, they are usually caused by
ing the peritoneal cavity via the shunt catheter evoke an inflammatory response Staphylococcus aureus and constitute a wound infection enhanced by a foreign
involving the greater omentum, which seals off the catheter outlet. The resulting material.
cyst fills with CSF, giving rise to recurrence of the hydrocephalus. Cystic obstruc-
tion can occur from noninfective causes but unlike those cases caused by infec-
tion, which present within 6–9 months of surgery, they can arise at any time.
Prevention
Expertise with shunt infections and surgical experience are very
important and shunt surgery should be carried out only by experi-
enced personnel or by fully supervised trainees. The use of standard-
may continue for months or years with little other evidence of infec- ized protocols can reduce shunt infection rates.12 Povidone–iodine or
tion. However, antibody to bacterial components is produced in large chlorhexidine, both alcohol based, should be used for skin preparation.
quantities and immune complex disease may ensue, with deposits of Assiduous surgical aseptic technique is extremely important, with
C3, C4, IgG and IgM on the synovial and glomerular basement mem- attention to ‘no touch’ techniques and glove changing. The use of
branes. Hypertension, renal failure (shunt nephritis) and arthropathy intravenous prophylactic antibiotics appears to be reasonable and are
may result.9 In contrast, in VP and lumboperitoneal (LP) shunt infec- recommended by guidelines, but they have not been found to have a
tions, the bacteria are discharged into the peritoneal cavity, provoking statistically significant beneficial effect in properly designed trials
the greater omentum to seal off the distal catheter. This and associated unless the infection rate exceeds 15%.13 Most centers worldwide use a
adhesions give rise to shunt obstruction and raised CSF pressure dose of a 1st or 2nd generation cephalosporin intravenously at induc-
(Figure 24-2). With repeated infections the absorptive capacity of the tion of anesthesia.14 Use of vancomycin as a prophylactic agent should
peritoneum may be lost. In both VP and VA shunts ventriculitis is seen be considered in the context of high prevalence of methicillin-resistant
in most cases, although the inflammatory response is usually feeble. Staphylococcus aureus (MRSA).15 One group has found benefit from
A few shunt infections are due to causes other than surgery. In the intraventricular use of 10 mg vancomycin and 3 mg gentamicin in
undernourished babies or adults, erosion of the skin over the shunt 1–2 mL sterile water for injection as soon as the ventricular catheter is
can lead to secondary infection with Staph. aureus or gram-negative inserted.16
bacteria (Figure 24-3). Another unusual cause of VP shunt infection is To reduce the infection rate further, an innovative process (Bac-
visceral perforation by the distal catheter, which results in polymicro- tiseal, Codman & Shurtleff Inc.) has been developed. In preclinical tests
bial infection of the cerebral ventricles.10 As a result of the increasing high-level protection of all shunt surfaces, undiminished by high CSF
use of VP shunts in the elderly with normal pressure hydrocephalus, protein levels, has been demonstrated for approximately 2 months.17
mixed enteric infections arising from diverticulitis may be seen. While the 12 clinical trials so far vary considerably in design and
Cerebrospinal fluid shunts, including VA, appear to be unusually quality, all except one (without randomization and definition for infec-
free from becoming infected hematogenously, and no cases have been tion) show a reduction in infection rate.18,19 A silver-processed shunt
documented from such sources as dental surgery. The risk of VP shunt (Silverline, Spiegelberg) is currently being investigated against Bac-
infection during continuous ambulatory peritoneal dialysis is low.11 tiseal and plain.20
Chapter 24 Infections in Hydrocephalus Shunts 223
Clinical Features raised with no other cause, shunt infection is likely and should be
confirmed by CSF aspiration.
The clinical features of VA, VP and LP shunt infections differ consider-
ably (Table 24-1). In VA shunts symptoms considered serious enough
to warrant specialist medical attention may not appear for months or
Management
years.9 Many patients, but not all, have intermittent low-grade fever. Three factors are important in the antimicrobial therapy of shunt
Some report chills and occasionally rigors. Transient rashes, sore throat infections. The first is the mode of growth of the organisms in the
and muscular and joint pains are common. Anemia is often found and shunt lumen. The concentration of antimicrobials required to kill
there is increasing lassitude, anorexia, irritability and poor sleep, and biofilm organisms is often several logs higher than the conventional
later, arthralgia. These features are nonspecific and often mistaken for minimum inhibitory concentration.29
other conditions. As the disease progresses, nephritis and vasculitis The second is the multiresistance of many strains of CoNS. Almost
may appear. Endocarditis is rare. all are resistant to penicillin and at least 50% are resistant to methicillin
In contrast, infections in VP and LP shunts almost always present and cephalosporins. Resistance to aminoglycosides is also common.
within 6–9 months after surgery.21,22 Fever is present in fewer than 50% The incidence of resistance to rifampin and clindamycin is low in most
of cases and is usually intermittent and mild. Chills and rigors are rare. centers.
There may be failure of the abdominal wound to heal, with CSF leak The third factor is the lack of a vigorous inflammatory response in
and sometimes catheter protrusion. Abdominal discomfort, bloating, the central nervous system (CNS), so that most antimicrobials fail to
pain or tenderness may occur. In LP shunts there is often spinal pain. penetrate the CSF, like aminoglycosides, β-lactams and glycopeptides.
However, the most constant symptoms are those of hydrocephalus Of the few drugs that give acceptable CSF concentrations, chloram-
caused by obstruction at the distal end and the differential diagnosis phenicol is bacteriostatic and ineffective in treating shunt infections;
is between infective and noninfective shunt obstruction. In the former rifampin is highly active against most organisms causing shunt infec-
there is often erythema and tenderness over the lower shunt track, tions but cannot be given alone because of rapid development of
whereas these features are absent in noninfectious obstruction. Distal resistance; trimethoprim is active against fewer gram-positive bacteria
VP shunt obstruction more than 9 months after shunt surgery is very than rifampin. However, linezolid is active against bacteria commonly
unlikely to be infectious.22,23 A very small number of cases present as found in shunt infection, including those that are methicillin resistant,
acute abdomen, with fever, abdominal pain and tenderness suggesting and has good CSF penetration in the absence of meningeal inflamma-
appendicitis or peritonitis.24 This may present at any time and may lead tion;30 it eradicates staphylococcal biofilms under simulated in vitro
to unnecessary laparotomy. conditions.31 Experience with linezolid treatment without shunt
VP shunt infections can also present after perforation of the bowel, removal is currently lacking.
vagina or other organ.25 The distal catheter often protrudes from the These factors explain the generally disappointing results of treat-
anus or vagina and CSF leaks from these sites. Presentation is usually ment of shunt infections without shunt removal. The shunt should
as meningitis rather than shunt obstruction or peritonitis, with few therefore be removed early and an EVD inserted to control CSF pres-
abdominal features. Considering the large numbers of bacteria seen in sure (Box 24-1). This two-stage shunt replacement is supported by
the CSF, the patients are not usually severely ill and recovery is often many reports, clearly indicating that shunt retention is associated with
uneventful after shunt removal, without need for laparotomy. a greater chance of relapse, longer hospital stay and greater risk of
death. A one-stage shunt replacement after externalization of the distal
Diagnosis shunt catheter and CSF sterilization with intravenous/intrashunt anti-
biotics has shown worse results than the two-stage shunt proce-
Blood cultures should be done if shunt infection is suspected. However, dure.32,33,34 However, one report has claimed success in Staph.
in infected VP and LP shunts, fewer than 5% are culture positive, epidermidis shunt infections using intraventricular vancomycin and
except where Staph. aureus or gram-negative bacilli are involved. In intravenous or oral rifampin without shunt removal.35 The success of
VA infections the positivity rate is much higher. In longstanding infec- the regimen appears to depend on early diagnosis, elective placement
tions blood cultures may remain negative, possibly because of high of a contralateral reservoir for antibiotic therapy, and Staph. epidermi-
antibody and opsonin titers and blood should be drawn for culture on dis as the cause. No prospective randomized studies of antimicrobial
several occasions. Attempts should be made to compare consecutive treatment have been performed in the last 20 years.36
isolates, by antibiograms and by molecular typing techniques. Dif Antimicrobials should be begun as soon as the diagnosis is con-
ferentiation between contaminants and pathogens remains a problem. firmed. Vancomycin is recommended for CoNS, Staph. aureus, coryne-
Aspiration of CSF from the shunt reservoir carries little risk of forms and for susceptible enterococci. As the drug does not give
introducing infection. A portion of the sample should be centrifuged adequate CSF concentrations when given intravenously,37 it should be
for Gram stain and culture, whatever the cell count, because bacteria given intraventricularly unless the CSF cell count and protein concen-
are not infrequently found without a significant cellular response. As tration indicate a vigorous inflammatory response. Intraventricular
with blood cultures, isolates should be kept and identified, although vancomycin should be administered via a reservoir or through the
the isolation of an organism from a shunt aspirate, particularly if it is clamped EVD. Alternatively, an Ommaya reservoir can be inserted
also seen on Gram stain, is diagnostic of shunt infection. No isolate
should be disregarded. CSF cultures obtained from shunts should be
incubated for at least 10 days because growth of P. acnes might take
longer.26 BOX 24-1 TREATMENT OF SHUNT INFECTIONS
The shunt might be infected only distal to the reservoir and in such CAUSED BY STAPHYLOCOCCUS
cases reservoir aspiration may yield normal CSF that is culture nega- EPIDERMIDIS, OTHER COAGULASE-
tive. With symptoms and a suggestive history, negative blood and CSF NEGATIVE STAPHYLOCOCCI AND
cultures cannot rule out shunt infection completely. OTHER SUSCEPTIBLE GRAM-POSITIVE
In view of the difficulties of laboratory and clinical diagnosis in VA BACTERIA
shunt infections, serologic tests have been developed. A whole-cell • Shunt removal, insertion of external drain with ≥5 cm tunnel
agglutination test using Staph. epidermidis has proved useful and its • Intraventricular vancomycin 20 mg q24h plus intravenous/oral rifampin
use has been associated with fewer cases of nephritis.9 The test is not (rifampicin) 15 mg/kg q24h (pediatric) or 600 mg q24h (adults), both
useful in VP or LP shunt infections. Plasma C-reactive protein (CRP) in two divided doses
• After 7–10 days of treatment, if clinical response and if CSF cultures
can be helpful in distinguishing between infective and noninfective negative, re-shunt if necessary. Stop both antibiotics on day of
distal VP shunt obstruction.27,28 For VP shunts, if symptoms of obstruc- re-shunting.
tion appear within 6–9 months of surgery, and the plasma CRP is
contralaterally.35 The standard dose of intraventricular vancomycin is be monitored to avoid subtherapeutic or toxic levels; for CNS infec-
20 mg daily, although this should be reduced to 10 mg daily for those tions blood levels should be maintained between 15 and 20 mg/L.
with small ventricles. The dose depends on ventricular volume rather Using this regimen, CoNS should no longer be detectable in the
than on age or body weight. The vancomycin should be diluted in CSF on microscopy or culture by day 4 and any fever should have
1–2 mL sterile water for injection. In addition to vancomycin, rifampin resolved. A new shunt, if needed, can be inserted by day 7–10, the last
should be given intravenously in a total dose of 15 mg/kg per day dose of antibiotics being given on that day. It is unwise to wait for a
(q12h) for children or 300 mg q12h for adults along with intravenous few days after stopping treatment, as this is the period of greatest risk
or intramuscular flucloxacillin (250–500 mg q6h or 60–125 mg q6h for secondary infection from the EVD. Using this regimen for CoNS,
for children) or oxacillin (500 mg q6h; for children >40 kg body Staph. aureus, coryneforms and propionibacteria, successful eradica-
weight, use adult dose, <40 kg 25–50 mg/kg q4h). The drugs can be tion and re-shunting within 10 days without relapse can be expected
given orally in most cases after a few days. Alternatively, trimethoprim in almost all cases.38
can be given intravenously, 3 mg/kg q8h for children and 250 mg q12h For shunt infections caused by gram-negative bacilli, the shunt
for adults. Teicoplanin offers no obvious advantage over vancomycin. should again be removed and the treatment for gram-negative menin-
Intraventricular vancomycin given in the doses recommended gitis (Chapter 19) instituted.
above leads to CSF concentrations that commonly reach 5–10 times A notable exception to the rule of shunt removal is community-
the expected plasma concentrations, but no toxicity has been encoun- acquired bacterial meningitis in shunted persons. Such patients should
tered. Attempts should not be made to titrate the dose to keep the CSF be treated in the same way as those without shunts and can be expected
concentrations below the toxic plasma levels. There is no indication to respond at least as well. On no account should these patients be
for the use of intravenous vancomycin in addition to that given by the subjected to shunt removal.39
intraventricular route except in the case of Staph. aureus shunt infec-
tions: intravenous vancomycin should be given in a dose of 30–60 mg/ Full reference list available online at expertconsult.com.
kg q6h for children and 30 mg/kg every q8–12h for adults. It should
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4. Chocksey M.S., Malik I.A.: Zero tolerance to shunt 2006; 105:242-247. 30. Boak L.M., Li J., Spelman D., et al.: Successful treatment
infections: can it be achieved? J Neurol Neurosurg Psy- 17. Bayston R., Lambert E.: Duration of activity of cerebro- and cerebrospinal fluid penetration of oral linezolid in
chiatry 2004; 75:87-91. spinal fluid shunt catheters impregnated with antimi- a patient with coagulase-negative Staphylococcus ven-
5. Bayston R., Lari J.: A study of the sources of infection crobials to prevent bacterial catheter-related infection. triculitis. Ann Pharmacother 2006; 40:1451-1455.
in colonised shunts. Dev Med Child Neurol 1974; J Neurosurg 1997; 87:247-251. 31. Bayston R., Ullas G., Ashraf W.: Action of linezolid or
16(Suppl. 32):16-22. 18. Farber S.H., Parker S.L., Adogwa O., et al.: Effect of vancomycin on biofilms in ventriculoperitoneal shunts
6. Shapiro S., Boaz J., Kleiman M., et al.: Origins of organ- antibiotic-impregnated shunts on infection rate in in vitro. Antimicrob Agents Chemother 2012; 56:2842-
isms infecting ventricular shunts. Neurosurgery 1988; adult hydrocephalus: a single institution’s experience. 2845.
22:868-872. Neurosurgery 2011; 69:625-629. 32. James H.E., Walsh J.W., Wilson H.D., et al.: Prospective
7. Conen A., Walti L.N., Merlo A., et al.: Characteristics 19. Pattavilakom A., Xenos C., Bradfield O., et al.: Reduc- randomized study of therapy in cerebrospinal fluid
and treatment outcome of cerebrospinal fluid shunt- tion in shunt infection using antibiotic impregnated shunt infection. Neurosurgery 1980; 7:459-463.
associated infections in adults:a retrospective analysis CSF shunt catheters: an Australian prospective study. J 33. Yogev R.: Cerebrospinal fluid shunt infections: a per-
over an 11-year period. Clin Infect Dis 2008; 47:73-82. Neurosci 2007; 14:526-531. sonal view. Pediatr Infect Dis 1985; 4:113-118.
8. von der Brelie C., Simon A., Gröner A., et al.: Evaluation 20. Jenkinson M.D., Gamble C., Hartley J.C., et al.: The 34. Schreffler R.T., Schreffler A.J., Wittler R.R.: Treatment
of an institutional guideline for the treatment of cere- British antibiotic and silver-impregnated catheters for of cerebrospinal fluid shunt infections: a decision anal-
brospinal fluid shunt-associated infections. Acta Neuro- ventriculoperitoneal shunts multi-centre randomised ysis. Pediatr Infect Dis J 2002; 21:632-636.
chir 2012; 154:1691-1697. controlled trial (the BASICS trial): study protocol. 35. Brown E.M., Edwards R.J., Pople I.K.: Conservative
9. Bayston R., Swinden J.: The aetiology and prevention of Trials 2014; 15:4. management of patients with cerebrospinal fluid shunt
shunt nephritis. Z Kinderchir Grenzgeb 1979; 28:377- 21. Piatt J.H.: Cerebrospinal fluid shunt failure: late is dif- infections. Neurosurgery 2006; 58:657-665.
384. ferent from early. Pediatr Neurosurg 1995; 23:133-139. 36. Drew R.J., Cole T.S., Lee M.K., et al.: Antimicrobial
10. Ghritlaharey R.K., Budhwani K.S., Shrivastava D.K., 22. Ronan A., Hogg G.G., Klug G.L.: Cerebrospinal fluid treatment options for neurosurgical ventricular shunt
et al.: Trans-anal protrusion of ventriculo-peritoneal shunt infections in children. Pediatr Infect Dis J 1995; infections in children from 1993 to 2012: a systematic
shunt catheter with silent bowel perforation: report of 14:782-786. review. Childs Nerv Syst 2014; 30:841-850.
ten cases in children. Pediatr Surg Int 2007; 23:575-580. 23. Bayston R., Spitz L.: Infective and cystic causes of mal- 37. Arnell K., Enblad P., Wester T., et al.: Treatment of cere-
11. Dolan N.M., Borzych-Duzalka D., Suarez A., et al.: Ven- function of ventriculoperitoneal shunts for hydroceph- brospinal fluid shunt infections in children using sys-
triculoperitoneal shunts in children on peritoneal alus. Zeit Kinderchir Grenzgeb 1977; 22:419-424. temic and intraventricular antibiotic therapy in
dialysis: A survey of the International Pediatric Perito- 24. Worley G., Wiener J.S., George T.M., et al.: Acute combination with externalization of the ventricular
neal Dialysis Network. Pediatr Nephrol 2013; 28:315- abdominal symptoms and signs in children and young catheter: efficacy in 34 consecutively treated infections.
319. adults with spina bifida: ten years’ experience. J Pediatr Neurosurgery 2007; 107(Suppl. 3):213-219.
12. Kestle J., Riva-Cambrin J., Wellons J.C., et al.: A stan- Surg 2001; 36:1381-1386. 38. Bayston R., de Louvois J., Brown E.M., et al.: Treatment
dardized protocol to reduce cerebrospinal fluid shunt 25. Akcora B., Serasian Y., Sangun O.: Bowel perforation of infections associated with shunting for hydrocepha-
infection: The HCRN Quality Improvement Initiative. and transanal protrusion of a ventriculoperitoneal lus. British Society for Antimicrobial Chemotherapy
J Neurosurg Pediatr 2011; 8:22-29. shunt catheter. Pediatr Neurosurg 2006; 42:129-131. Working Party Report on Use of Antibiotics in Neuro-
13. Brown E.M., de Louvois J., Bayston R., et al.: Antimi- 26. Desai A., Lollis S.S., Missios S., et al.: How long should surgery. Br J Hosp Med 1995; 53:368-373.
crobial prophylaxis in neurosurgery and after head cerebrospinal fluid cultures be held to detect shunt 39. Bayston R.: Hydrocephalus shunt infections. London:
injury. British Society for Antimicrobial Chemotherapy infections? J Neurosurg Pediatr 2009; 4:184-189. Chapman and Hall Medical; 1989.
Working Party Report on the Use of Antibiotics in Neu-
rosurgery. Lancet 1994; 344:1547-1551.
PRACTICE The Central Nervous System
POINT
5 Role of Rapid Viral Detection in

Meningitis
REMI N. CHARREL
Introduction For a long time, virus isolation in cell culture was the most sensitive
and reliable method for detecting viruses in clinical specimens. A cyto-
In meningitis, clinical signs and symptoms are mostly nonspecific, pathic effect in these cultures was usually observed after 4–5 days,
particularly in infants and young children. Also, the laboratory find- sometimes longer. For enteroviruses, the isolation rates varied between
ings may vary widely, and thus are poor indicators of the etiology. Viral 35 and 70%.
meningitis often mimics bacterial sepsis or bacterial meningitis. When For HSV, the shell vial centrifugation method, combining cell
bacterial meningitis is misdiagnosed as viral meningitis, the conse- culture and staining, detects HSV between 16 and 48 hours after
quences may be devastating. One approach is to hospitalize every inoculation.
patient suspected of meningitis and initiate intravenous antibiotics No rapid diagnostic methods are available for arboviral meningitis.
until bacterial diagnosis is excluded or viral diagnosis is confirmed. In addition, in many cases the virus is no longer present in CSF or blood
Although this practice is very popular, it is very costly. In addition, it when central nervous system (CNS) signs occur, thus combined direct
may lead to complications of parenteral fluid therapy and of antibiot- and indirect diagnosis is required.
ics, to nosocomial infections and loss of work productivity. Thus, Therefore, enteroviruses and HSV were prioritized targets in
detection of the causative agent is pivotal to optimize management, research and development programs of commercial diagnostic com-
i.e., hospitalization, antibiotic or antiviral therapy. Clearly, rapid con- panies. Significant progress has been made during the last 7 years.
firmation of the viral etiology will greatly benefit these patients. Techniques based on the detection of virus antigens have been out-
stripped by molecular methods such as polymerase chain reaction
Viruses Causing Viral Meningitis (PCR), and more recently by real-time molecular methods that are
Numerous types of virus can cause meningitis. Among these, entero- much less prone to laboratory contamination. Presently, real-time
viruses (Picornavirales) are by far the most common, comprising >100 PCR detection of viruses is considered the gold standard for the diag-
distinct viruses. They have a worldwide distribution, with greater nosis of viral meningitis.
prevalence in temperate climates during the warm months of the year.
Enterovirus meningitis is common among young children, but clini- DEFINITION OF ‘RAPID DIAGNOSIS’
cally it is very difficult to distinguish it from bacterial meningitis or During the last 20 years the concept of rapid diagnosis has changed.
meningitis due to other viruses. Thus, patients suspected of enterovi- Currently, rapid detection of viruses causing CNS infections means
rus meningitis are often treated empirically. that a result must be obtained within 24 hours, which is truly achiev-
Meningitis caused by herpes simplex virus (HSV) and varicella- able by using direct detection based on real-time molecular methods.
zoster virus (VZV) are treatable with aciclovir. However, to have a practical impact on patient management, the delay
Worldwide, mumps is a leading cause of aseptic meningitis, between admission to the emergency room and the virological result
although its incidence has decreased strongly in countries where should be even shorter, i.e., within 3–6 hours (including transportation
mumps immunization has been implemented. of the specimens from the clinical ward to the laboratory). To shorten
Other viruses that can cause meningitis are Epstein–Barr virus, the time lag between test results and the actual treatment decision,
human herpesvirus type 6, alphaviruses (Eastern/Western/Venezuelan there is an increasing interest in full automation of real-time molecular
equine encephalitis), flaviviruses (West Nile, St Louis encephalitis, methods to be implemented in point-of-care (POC) tests. Because the
Murray valley encephalitis, tick-borne encephalitis, dengue viruses), result has a direct impact on the decisions of the physician in charge
phleboviruses (Toscana virus), Bunyaviruses (La Crosse virus, Califor- of the patient, the performance of the laboratory tests must be of very
nia encephalitis), lymphocytic choriomeningitis virus, measles, rubella high quality, i.e. ≥95% for both sensitivity and specificity. In addition,
and human influenza viruses. The epidemiology of these viruses ‘express’ diagnostics for enteroviruses and HSV/VZV should be acces-
largely depends on geography. sible round the clock, 7 days a week. Depending on the local organiza-
There are two options, which can be combined for optimal diag- tion, different approaches can be considered to speed up the diagnostic
nosis of meningitis: process.
• to detect enteroviruses, which are the most frequently encoun- When the laboratory is in the close vicinity of the clinical wards
tered viruses in meningitis, do not necessitate specific treatment where patients suspected to have meningitis are admitted, the organi-
and generally have an excellent prognosis; and zation of day and night shifts may provide capacity for rapid diagnosis.
• to detect HSV and VZV, for which aciclovir administration is When the laboratory and the clinical wards are distant, solutions have
indicated. to be more inventive. For instance, POC laboratories can be placed
If both results are negative, antibiotic therapy should be continued close to the relevant clinical wards, such as the emergency room, and
until the causing agent has been identified. operated by laboratory personnel. The latest tests can be performed by
personnel with limited laboratory training.
Laboratory Techniques for DEVELOPMENT AND EXPANSION
Documentation of Viral Meningitis OF TECHNIQUES
Laboratory documentation of viruses causing meningitis is a challenge, In 2007, the Food and Drug Administration validated the Xpert Flu
1) because the viral load in cerebrospinal fluid (CSF) is usually low, Enterovirus test onto the GeneXpert system. Briefly, it is a fully auto-
and hence the method needs to have excellent sensitivity; and 2) mated random access process that reduces handling time to minutes.
because rapid results are needed for the management of the patient. The CSF sample is deposited in a cartridge that is loaded onto the
225
equipment, where nucleic acid extraction, real-time RT-PCR, valida- that ranks as third in the causes of meningitis in Spain, southern
tion and interpretation are done in an integrated manner. The result France and Italy) would be important candidates to be included in the
is obtained in 150 minutes. panel. Since tests consisting of such dedicated panels are not envi-
To date, this system cannot detect HSV, VZV or other viruses sioned to be commercially available in the near future, in-house devel-
causing meningitis. However, it has stimulated the field, and newcom- opment of tests must be considered.
ers have recently proposed tests that can detect different meningitis
viruses with very limited handling. Such novel assays for rapid detec- Conclusions
tion in CSF of viruses causing meningitis will be brought to the market There is no specific treatment for viral meningitis except meningitis
soon. caused by HSV and VZV. Evidence that meningitis is caused by entero-
ADAPTATION TO LOCAL EPIDEMIOLOGY viruses will, however, have the following consequences: early with-
drawal of antibiotics; early hospital discharge; avoidance of intravenous
When designing tests for rapid detection of viral meningitis, one must therapy; avoidance of unnecessary tests. Access to rapid detection of
consider the local epidemiology when listing the viruses that merit viral meningitis has proven to attain a 75% reduction of the length of
inclusion in the rapid panel of meningitis. For instance, in Mediter- hospital stay within the 10-year period between 2000 and 2010.
ranean countries, emerging viruses (such as West Nile virus) or
neglected viruses (such as Toscana virus, a sand fly-borne Phlebovirus Further reading available online at expertconsult.com.
Practice Point 5 Role of Rapid Viral Detection in Meningitis 226.e1
FURTHER READING
Chonmaitree T., Baldwin C.D., Lucia H.L.: Role of the virol- Marlowe E.M., Novak S.M., Dunn J.J., et al.: Performance Nolte F.S., Rogers B.B., Tang Y.W., et al.: Evaluation of a
ogy laboratory in diagnosis and management of patients of the GeneXpert enterovirus assay for detection of rapid and completely automated real-time reverse tran-
with central nervous system disease. Clin Microbiol Rev enteroviral RNA in cerebrospinal fluid. J Clin Virol 2008; scriptase PCR assay for diagnosis of enteroviral meningi-
1989; 2(1):1-14. 43(1):110-113. tis. J Clin Microbiol 2011; 49(2):528-533.
Cohen-Bacrie S., Ninove L., Nougairède A., et al.: Revolu- Ninove L., Nougairede A., Gazin C., et al.: Comparative Patel S.R., Weir F., Dailey P., et al.: Democratizing molecular
tionizing clinical microbiology laboratory organization detection of enterovirus RNA in cerebrospinal fluid: Gen- diagnostics: the GeneXpert® enterovirus assay. Expert
in hospitals with in situ point-of-care. PLoS ONE 2011; eXpert system vs. real-time RT-PCR assay. Clin Microbiol Opin Med Diagn 2009; 3(1):91-97.
6(7):e22403. Infect 2011; 17(12):1890-1894.
PRACTICE The Central Nervous System
POINT
6 Investigation of Psychiatric
Manifestations of Encephalitis
DAVID B. CLIFFORD
Psychiatric Manifestations with HIV-associated dementia (HAD), termed AIDS dementia complex
in the early part of the epidemic. Behavioral changes were recognized
of Encephalitis as an occasional manifestation of HAD. Subacute changes ranging from
Psychiatric diseases are common and can be very serious. They may apathy and social withdrawal to frank psychotic behavior sometimes
present insidiously, or have fulminant onset. Most dramatic are psy- associated with visual hallucinations are seen. Since HIV affects more
chotic disorders where perception of the world is distorted and thought than 30 million people worldwide, and still is frequently unrecognized
processes may become illogical. Such symptoms develop in younger until advanced immunodeficiency develops, this is a widespread poten-
people commonly in association with schizophrenia, but also may be tial cause of psychiatric presentations that are driven by viral brain
part of the spectrum of manic manifestations of bipolar affective disinfection. Symptoms respond to appropriate psychiatric symptomatic
order. When symptoms are initiated by these relatively common psy- therapy and eventually antiretroviral therapy contributes to blunting
chiatric diseases, use of specific therapies can control symptoms and these symptoms. The complex socio-demographic associations of HIV
abnormal behavior, but curative therapy is not yet possible. Long-term may result in unique psychiatric stress, making this chronic encephalitis
disability often results. Increasingly it is recognized that these psychi- more likely to be associated with depressive symptoms and complica-
atric disorders are symptoms of complex brain disorders with strong tions. Interestingly some recent evidence even favors clinical depression
biological bases including genetic associations. However, similar as in a risk for CSF HIV RNA detection.
behavior and symptoms can at times be triggered by encephalitis that
may be infectious or autoimmune. In these cases, missed diagnoses LIMBIC ENCEPHALITIS
commonly lead to permanent disability or death while early initiation Subacute encephalitis where no infectious cause is identified has long
of appropriate therapy may be curative. Consequently, it is important been described. In some patients this entity occurs in conjunction with
for emergency medicine physicians, internists, psychiatrists, neurolo- tumors or precedes tumor development by months to years and,
gists and infectious disease specialists to consider infectious or inflam- increasingly, cross-reacting antibodies to brain targets are found that
matory diseases in early evaluation of new psychiatric disorders. mediate these entities. Specific antibodies recognizing distinct CNS
Focal or multifocal encephalitic conditions can generate psychiatric proteins, including the excitatory amino acid receptor, N-methyl-D-
symptoms through a number of mechanisms. Brain lesions in speech aspartate (NMDA), voltage-gated potassium channels (VGKC) and
systems may lead to language disorders that can mimic psychiatric several other proteins are commonly identified. It has become apparent
disease. Speech may become illogical or hard to follow, and under- that in many cases no tumor is ever identified when antibodies develop,
standing of language may be lost. Alternatively, non-convulsive ictal although it is important to carefully search for tumors in these patients.
disorders most commonly originating in the temporal lobes can result Series of more than 500 cases have now been assembled, documenting
in lapses of normal attention and interaction suggesting psychiatric
conditions. Destructive lesions in frontal lobes that may give few sen-
sorimotor findings can result in marked behavioral changes that vary
from disinhibition to blunted affect with alteration of attention.
HERPES SIMPLEX ENCEPHALITIS

The most common sporadic serious viral encephalitis is caused by
herpes simplex virus 1 (HSV-1). This virus most typically invades
temporal and frontal lobes, resulting in a presentation including psy-
chiatric behavior. It is often a severe and aggressive encephalitis, and
within days results in progressive mental status decline, fevers and
epileptic seizures. However, since personality and behavioral changes
may be the first sign of this condition, and early diagnosis and therapy
are key to optimal outcome, it is critical that clinicians consider this
treatable etiology of psychiatric symptoms in such cases, and aggres-
sively pursue the diagnosis. The keys to rapid diagnosis include obtain-
ing cerebrospinal fluid (CSF), in which HSV-1 DNA is detectable by
polymerase chain reaction (PCR) and brain imaging studies, prefera-
bly MRI studies, in which temporal lobe involvement is typically
detected (Figure PP6-1). Prompt recognition of this entity with early
aciclovir therapy greatly enhances the otherwise grim prognosis.
HUMAN IMMUNODEFICIENCY VIRUS

Human immunodeficiency virus (HIV-1), like several other retrovi-
ruses, invades the central nervous system early in infection, and is
associated with a variety of neurological and psychiatric conditions. In Figure PP6-1 Magnetic resonance scan showing early changes of herpes
advanced HIV disease, when the cellular immune system is severely simplex encephalitis in the left medial temporal lobe (arrow). This localization is
compromised, independent replication of HIV in the brain is associated typical and results in behavioral changes as well as seizures in many patients.
227
the value of early diagnosis and aggressive immunotherapy with the

potential for improved outcomes. These entities not uncommonly TABLE Infective Causes of Encephalitis Occasionally
present with behavioral and neuropsychiatric symptoms which are PP6-1 Associated with Neuropsychiatric
attributed to psychiatric disease. Delay in diagnosis may result in Manifestations
serious disability or death. The prior term of ‘limbic encephalitis’
denotes the common involvement of the temporal lobe, which notori- Rabies Tick-borne encephalitis*
ously is the source of neuropsychiatric ictal behaviors. These condi- Epstein–Bar virus Dengue*
tions are common in childhood and young adult life but may occur at
any age. Regions of inflammatory change are often detected on MRI Borna virus Brucella*
brain scans and antibodies are detectable. Diagnosing and treating West Nile virus Typhoid
these patients, who often require heroic support, can be worthwhile
Eastern equine encephalitis* St Louis encephalitis*
since the disorders can be reversed with combinations of immuno-
therapy, often including plasma exchange, immunoglobulin therapy *Case reports only.
and immunomodulatory therapy.
A fascinating recent observation is that HSV encephalitis may lead
to development of NMDA receptor antibodies in as many as 30% of precipitate persistent immune responses through ‘inoculation’ with
cases. They have been associated with symptomatic relapsing post- critical neuronal proteins, subsequently triggering autoimmune
HSV encephalitis that may respond to immunotherapy rather than behavioral syndromes. This fascinating insight should lead astute clini-
antiviral therapy. cians to consider immune-mediated disease when atypical and chronic
Finally, a large number of infections that may cause encephalitis inflammatory brain disorders are encountered following infectious
have been linked to occasional neuropsychiatric presentations (Table illnesses. This consideration also serves to remind clinicians that psy-
PP6-1). The evidence that this is a causal association is often weak, or chiatric disorders are truly physiological brain disorders. While they
based on single case reports. may be more complicated and difficult to study than most medical
disorders, they share critical biological bases that, when understood,
Summary can offer valuable insights to therapy. Early brain imaging, CSF evalu-
Psychiatric presentations of infectious disorders are important. A ations and thoughtful evaluation may be life saving for individuals
variety of pathophysiologic processes can drive the changes including with psychiatric manifestations of inflammatory brain disorders.
seizures and metabolic stress precipitated by infection. Emerging evi-
dence also supports the concept that infectious encephalitis may Further reading available online at expertconsult.com.
Practice Point 6 Investigation of Psychiatric Manifestations of Encephalitis 228.e1
FURTHER READING
Armangue T., Leypoldt F., Malaga I., et al.: Herpes simplex Kennedy P.G., Steiner I.: Recent issues in herpes simplex Pruss H., Finke C., Holtje M., et al.: N-methyl-D-aspartate
virus encephalitis is a trigger of brain autoimmunity. Ann encephalitis. J Neurovirol 2013; 19:346-350. receptor antibodies in herpes simplex encephalitis. Ann
Neurol 2014; 75:317-323. Lakeman F.D., Whitley R.J.: Diagnosis of herpes simplex Neurol 2012; 72:902-911.
Armangue T., Titulaer M.J., Malaga I., et al.: Pediatric anti-N- encephalitis: Application of polymerase chain reaction to Titulaer M.J., Hoftberger R., Iizuki T., et al.: Overlapping
methyl-D-aspartate receptor encephalitis-clinical analysis cerebrospinal fluid from brain-biopsied patients and cor- demyelinating syndromes and anti-N-D-aspartate recep-
and novel findings in a series of 20 patients. J Pediatr 2013; relation with disease. National Institute of Allergy and tor encephalitis. Ann Neurol 2014; 75:411-428.
162:850-856 e2. Infectious Diseases Collaborative Antiviral Study Group. Titulaer M.J., McCracken L., Gabilondo I., et al.: Treatment
Clifford D.B., Ances B.M.: HIV-associated neurocognitive J Infect Dis 1995; 171:857-863. and prognostic factors for long-term outcome in patients
disorder. Lancet Infect Dis 2013; 13:976-986. Leypoldt F., Titulaer M.J., Aguilar E., et al.: Herpes simplex with anti-NMDA receptor encephalitis: an observational
Dalmau J., Rosenfeld M.R.: Paraneoplastic syndromes of virus-1 encephalitis can trigger anti-NMDA receptor cohort study. Lancet Neurol 2013; 12:157-165.
the CNS. Lancet Neurol 2008; 7:327-340. encephalitis: case report. Neurology 2013; 81:1637- Watkins C.C., Treisman G.J.: Neuropsychiatric complica-
Hammond E.R., Crum R.M., Treisman G.J., et al.: The 1639. tions of aging with HIV. J Neurovirol 2012; 18:277-
cerebrospinal fluid HIV risk score for assessing central Navia B.A., Jordan B.D., Price R.W.: The AIDS dementia 290.
nervous system activity in persons with HIV. Am J Epi- complex: I. Clinical features. Ann Neurol 1986; 19:517- Whitley R.J.: Herpes simplex virus infections of the central
demiol 2014; 180(3):297-307. 524. nervous system. Drugs 1991; 42:406-427.
The Respiratory System
25
Laryngitis, Epiglottitis and Pharyngitis
LUU-LY PHAM | RAFIK BOURAYOU | VALÉRIE MAGHRAOUI-SLIM |
ISABELLE KONÉ-PAUT
KEY CONCEPTS cause of consultation in a emergency department. Fewer than 5% of

children with croup are admitted to hospital and less than 1–3% of
• Croup is the most common cause of stridor in children, caused those who are admitted, have been intubated. The generalization
by acute viral infection in most cases (parainfluenza) and mainly of treatment with oral corticosteroids and nebulized adrenaline
affects young children between 6 months and 3 years old. reduced the rate of hospitalization and complications. Mortality is now
• Treatment with oral corticosteroids and nebulized adrenaline very rare and the mortality rate is estimated at about 1 in 30 000 cases.1
reduced the rate of hospitalization and complications.
• The diagnoses of bacterial epiglottitis and viral laryngotracheo-
Physiopathology
bronchitis (croup) in infants and children may be confused. Upper airway obstruction is caused by an acute viral infection, in most
cases parainfluenza types 1 and 3.5 Other pathogens implicated include
• Epiglottitis is an acute inflammation of the epiglottis or supra-
influenza virus A and B, human rhinovirus, respiratory syncytial virus,
glottis that may lead to the rapid onset of life-threatening
airway obstruction caused by Haemophilus influenzae type b adenovirus, coronavirus,6 metapneumovirus and, rarely, measles virus
(Hib) and is an otolaryngologic emergency. Since the wide- and herpes simplex virus. When croup is caused by influenza viruses,
spread implementation of a conjugate vaccine for Hib, the the clinical picture is usually more severe than the clinical course
incidence of epiglottitis significantly declined in children and caused by parainfluenza viruses.7 Laryngeal diphtheria and croup asso-
there was a consequent shift in disease from young children to ciated with measles are now very rare in immunized children but cases
adults. and outbreaks have been reported in nonimmunized regions.
• The management of epiglottitis includes securing the airways Although respiratory viruses represent the majority of cases of
and appropriate antibiotics (ceftriaxone). croup in children, some bacterial pathogens, such as Moraxella catarrh-
alis, Haemophilus influenzae and Streptococcus pneumoniae, have been
• Group A streptococcus is a frequent cause of pharyngitis that frequently isolated from the nasopharynx in adults with acute
can be diagnosed by rapid antigen-detection test. Antibiotic laryngitis.
treatment reduces the risk of complications, including rheu-
Infection with a recognized pathogen leads to generalized airway
matic fever and acute glomerulonephritis.
inflammation and edema of the upper airway mucosa, including the
larynx, trachea and bronchi. The subglottic region becomes narrowed
and results in a barky cough, turbulent airflow and stridor, and chest-
wall indrawing. Hypoxia, hypercapnia and respiratory failure may be
Laryngitis present in severe croup.
Croup is a common childhood disease and one of the most frequent The peak incidence of croup at the age of 2 years could be
causes of acute respiratory distress in young children. It is character- attributable to increased exposure to viral pathogens combined with
ized by varying degrees of inspiratory stridor, barking cough and the toddler’s smaller subglottic space, with a greater risk or airway
hoarse voice, resulting from upper airway obstruction usually caused narrowing.1
by an acute viral infection. It mainly affects children between 6 months Airways anomalies are common in children with recurrent croup8
and 3 years old, with a peak annual incidence in the second year of or in infants aged under 6 months. Laryngobronchoscopy may allow
life.1,2 Corticosteroids are the mainstay of treatment and nebulized identification of the cause of croup in those particular groups and
epinephrine in children with severe croup has reduced the need for enable a more accurate prognosis.
intubation or tracheotomy. Nowadays, mortality from croup has
become a rarity in higher-income countries. Most children can be Prevention
managed in the primary care setting. Prevention of disease depends mainly on good handwashing and pre-
venting the spread of oral secretions. Vaccines are available to prevent
Epidemiology some of these diseases. Vaccine against diphtheria had a major impact
Croup is the most common cause of stridor in children and accounts in reducing the numbers of laryngeal diphtheria worldwide. The ability
for up to 15% of emergency department and primary care visits for of influenza vaccine to prevent laryngitis has not been studied.
respiratory infections in the USA.3 It mainly affects young children
between 6 months and 3 years old but croup can rarely occur in babies Clinical Features
<6 months, in adolescents and also in adults. Boys are more susceptible Croup usually begins with nonspecific respiratory symptoms, includ-
than girls (male:female preponderance of 1.4:1).2 Croup season peaks ing rhinorrhea, sore throat and cough. Fever is generally low grade but
in late autumn (September to December), which closely correlates can exceed 40 °C. Most children have mild short-lived symptoms,
with the prevalence of parainfluenza virus infection in the community, which are resolved by 2 days.9 Only a few children continue to have
and also occurs in winter, with a strong seasonality pattern.4 There is symptoms for up to 1 week. Symptoms nearly always become worse
often a smaller spring peak. Episodes are usually self-limiting and are during night-time hours, with the appearance of a very characteristic
influenced by weather conditions. and distinctive barky cough. Stridor, hoarse voice and respiratory dis-
Due to the sudden onset of croup symptoms during the night and tress are seen frequently. Children with typical viral croup should not
even though most children have mild croup, this disease is a frequent drool nor appear toxic.
229
230 SECTION 2 Syndromes by Body System: The Respiratory System
TABLE
25-1 Westley Croup Score
Symptom Descriptor Score
Stridor None 0
When agitated 1
At rest 2
Retractions None 0
Mild 1
Moderate 2
Severe 3
Air entry Normal 0

Decreased 1
Markedly decreased 2
Cyanosis in room air None 0

With agitation 4
At rest 5
Level of consciousness Normal 0

Disoriented 5
Total score 0–17
Mild croup: scores 1–2; moderate croup: scores 3–8; severe croup: scores >8.
From Westley C.R., Cotton E.K., Brooks J.G.: Nebulized racemic epinephrine by Figure 25-1 Anteroposterior neck film demonstrating steeple sign (arrows) in a
IPPB for the treatment of croup: a double-blind study. Am J Dis Child 1978; case of croup.
132(5):484–7
Determination of disease severity relies on clinical assessment. BOX 25-1 DIAGNOSES TO BE CONSIDERED IN
Symptoms may range from minimal inspiratory stridor to severe CHILDREN WITH STRIDOR AND
failure secondary to airway obstruction. In mild cases, respiratory RESPIRATORY DISTRESS
sounds at rest are normal; mild expiratory wheezing may be heard.
• Croup
Children with severe croup have inspiratory and expiratory stridor • Epiglottitis
with suprasternal, intercostal and subcostal retractions. Air entry may • Bacterial tracheitis
be poor. Lethargy and agitation may be a result of hypoxemia. Warning • Laryngeal diphtheria
signs of severe respiratory disease include tachypnea, tachycardia and • Tracheal foreign-body aspiration
• Retropharyngeal abscess
late cyanosis. • Peritonsillar abscess
Various methods and scores for objective assessment of respiratory • Angioneurotic edema
distress in children with croup are used but none of them has been • Allergic reaction and anaphylaxis
shown to enhance routine clinical care. One of the most commonly
used scoring systems has been that of Westley et al. (Table 25-1), which
evaluates the severity of croup by assessing five factors: level of con-
sciousness, cyanosis, stridor, air entry and retractions.10
Management and Treatment
Diagnosis The use of corticosteroids and the effectiveness of nebulized adrenaline
(epinephrine) in severe cases have improved the management of croup
The diagnosis of croup should be made clinically. No tests are needed and led to diminution of the rate of hospitalization, intubation and
in uncomplicated laryngitis. mortality.
Direct examination with a flexible nasolaryngoscope usually reveals First, primary care consists in making children with croup as com-
secretion, erythema and edema of the vocal folds but is mainly indi- fortable as possible, because agitation can cause substantial worsening
cated in children with recurrent croup or in infants under 6 months of symptoms. Oxygen is the immediate treatment in severe presenta-
of age to identify anatomical airway abnormalities, such as subglottic tion with considerable upper airway obstruction and significant
stenosis or associated gastroesophageal reflux disease that could be hypoxemia (SaO2 <90%).
treated. Treatment with humidified air (mist therapy) has been the corner-
Laboratory tests are not needed to confirm the diagnosis in a child stone of the management of croup, but the effectiveness of mist
presenting with the typical clinical features of croup. Rapid antigen therapy has been questioned.12 A Cochrane review of data concluded
tests and viral cultures do not aid in the routine acute management of that there was no evidence that inhalation of humidified air in children
a child with croup and, similarly, radiologic studies are not recom- with mild-to-moderate croup resulted in a substantial improvement
mended in a child who has a typical history of croup and who responds in the croup score.13
appropriately to treatment. Plain films of the airway and a chest radio- Corticosteroid therapy is now routinely recommended by all
graph may be obtained to rule out findings suggestive of another etiol- experts. Meta-analyses of randomized trials have consistently demon-
ogy. Anteroposterior films may demonstrate symmetric subglottic strated significant improvement in patients treated with corticoste-
narrowing (‘steeple sign’) (Figure 25-1),11 although this may be absent roids as compared with controls. Trials of corticosteroids in croup have
in up to 50% of cases and may be present in the absence of croup. involved a variety of drugs, dosages and routes of administration. The
regimens studied most frequently have been oral single-dose dexa-
Differential Diagnosis methasone (0.6 mg/kg) and nebulized budesonide (2 mg). Dexameth-
Clinicians must remain watchful to distinguish viral laryngitis with asone and budesonide are effective in relieving the symptoms of croup
differential diagnoses of diseases that can present with stridor and as early as 6 hours after treatment.14
respiratory distress (Box 25-1). Bacterial causes should be suspected in The oral or intramuscular route is either equivalent or supe
children with severe respiratory distress and toxic appearance. rior to inhalation.1 The addition of inhaled budesonide to oral
Chapter 25 Laryngitis, Epiglottitis and Pharyngitis 231
dexamethasone in children admitted with croup did not confer any Antibiotics are not recommended in the treatment of laryngitis,
additional advantage.15 neither in children nor in adults, except if a bacterial pathogen
Nebulized adrenaline (epinephrine) has been extensively studied is suspected, as in laryngeal diphtheria, where serotherapy is
for the treatment of croup. Controlled trials demonstrated that the recommended.
administration of nebulized epinephrine is associated with clinically The Alberta Medical Association clinical pathway committee has
and statistically significant transient reduction of symptoms of croup developed and implemented the management algorithm outlined in
30 minutes post-treatment. Evidence does not favor racemic epineph- Figure 25-2.
rine or L-epinephrine,16 or intermittent positive-pressure breathing
over simple nebulization.17
In severe croup, repeated nebulizations with adrenaline (epineph- Epiglottitis
rine) have been used and have decreased the need for intubation.
Intubation in severe croup is required in less than 1–3% of Epiglottitis is an acute inflammation of the epiglottis or supraglottis
children. that may lead to the rapid onset of life-threatening airway obstruction
The Alberta Medical Association guideline for the diagnosis and management of croup
Mild Moderate Severe
(without stridor or significant (stridor and chest-wall indrawing (stridor and indrawing of the sternum associated with
chest-wall indrawing at rest) at rest without agitation) agitation and lethargy)
Give oral dexamethasone Minimize intervention Minimize intervention (as for moderate croup)
(0.6 mg/kg of body weight) • Place children on parent’s lap Provide ‘blow-by’ oxygen (optional unless cyanosis is
Educate parents • Provide position of comfort present)
• Anticipated course of illness
• Signs of respiratory distress
• When to seek medical attention Give oral dexamethasone Nebulize epinephrine
(0.6 mg/kg of body weight) • Racemic epinephrine 2.25% (0.5 ml in 2.5 ml saline)
or L-epinephrine 1:1000 (5 ml)
May discharge home without Give oral dexamethasone (0.6 mg/kg of body weight),
further observation Observe for improvement may repeat once
If vomiting, consider administering
budesonide (2 mg) nebulized with epinephrine
If too distressed to take oral medication, consider
administering budesonide (2 mg) nebulized with
Patient improves as evidenced by no longer having: No or minimal epinephrine
• chest-wall indrawing improvement
• stridor at rest by 4 hours
Educate parents (as for mild croup) Consider admission
Discharge home (see below)
Good response to nebulized epinephrine Poor response to nebulized epinephrine
Observe for 2 hours Repeat nebulized epinephrine
Contact pediatric intensive care unit

for further management
Persistent mild symptoms Recurrence of severe respiratory distress
No recurrence of: Repeat nebulized epinephrine
• chest-wall indrawing If good response continue to observe
• stridor at rest
Provide education (as for mild croup)
Consider admission (general ward) if:
received steroid ≥4 hours ago
Discharge home continued moderate respiratory distress (without agitation or lethargy):
• stridor at rest
• chest-wall indrawing
(If the patient has recurrent severe episodes of agitation
or lethargy, contact pediatric intensive care unit)
Figure 25-2 The Alberta Medical Association guideline for the diagnosis and management of croup. (From Bjornson C.L., Johnson D.W.: Croup. Lancet 2008;
371(9609):329–339.)
and is an otolaryngologic emergency. Since the widespread implemen-

tation of a conjugate vaccine for Haemophilus influenzae type b (Hib)
nearly two decades ago, the incidence of epiglottitis has significantly
declined in children. Securing the airway and antibiotic treatment
should be accomplished immediately in a controlled setting.
Epidemiology
Traditionally, epiglottitis was most commonly caused by Hib and pri-
marily reported in children aged 2–7 years. The introduction of the
Hib conjugate vaccine in the 1990s into national immunization in
industrialized countries has led to rapid and sustained declines in a
invasive Hib disease incidence across all age groups and dramatically
changed the epidemiology of acute epiglottitis.
Invasive Hib disease in England and Wales has been declining since
2002, reaching its lowest incidence of 0.02 per 100 000 (14 cases) in
2012. In children aged <5 years of age, Hib incidence was 0.06 per
100 000 (2 cases), compared with 35.5 per 100 000 prior to routine Hib
vaccination.18–20 Between 2009 and 2012, only 19 cases of epiglottitis
were reported, it was 17.9% of all cases of invasive Hib infections
reported in the UK, and 68% (13/19) of culture-confirmed epiglottitis
cases occurred in patients aged >45 years (median age 49.2 years).18
Mortality rates have decreased considerably since the introduction
of the Hib vaccine and the consequent shift in disease from young
b
children to adults. Death rates are now less than 1% for children but
approach 7% for adults. When deaths have occurred, a large percentage
Figure 25-3 Acute epiglottitis with views of the cherry red epiglottis on direct
transpired due to delay in diagnosis or shortly after arrival at a medical laryngoscopy.
facility for appropriate care.21
A large 8-year national retrospective review in the USA revealed
that the typical patient admitted with epiglottitis was a mid-40-year-
old, Caucasian, urban, male, with co-morbidities and the majority of Clinical Features
mortalities were adults. The mean number of cases of epiglottitis over Clinical features of acute epiglottitis include stridor, dyspnea, hoarse-
the study period was 4062 cases/year. This series identified two newly ness, fever, sore throat, odynophagia, dysphagia, drooling and cervical
recognised vulnerable populations for epiglottitis: infants <1 year and lymphadenopathy. General malaise often precedes presentation. Acute
the elderly age group.22 epiglottitis may progress rapidly into life-threatening upper airway
obstruction. The abrupt onset of edema and inflammation of the
Physiopathology epiglottis and surrounding tissues can progress to total airway obstruc-
tion. Signs of respiratory distress or sepsis can lead to death.
Haemophilus influenzae type b (Hib) can colonize the pharyn of oth- Affected children are anxious and lean forward to open their airway.
erwise healthy children through respiratory transmission from inti- The diagnosis is easily made by viewing the epiglottis, which is swollen
mate contact. These bacteria may penetrate the mucosal barrier, and red (Figure 25-3). Intubation is often required but can be avoided
invading the bloodstream and causing bacteremia, and seeding of the in some cases with quick administration of antibiotic treatment.
epiglottis and surrounding tissues. Presentation in adults may be with a slower onset. The airway
Prior to routine vaccination, Hib was also a major cause of sepsis, obstruction occurs because of a progressive cellulitis of the supraglottic
pneumonia, as well as skin, soft tissue, bone and joint infections. area. Thus at presentation, antibiotic treatment and intubation at the
Hib infection of the epiglottis leads to acute onset of inflammatory first sign of increasing respiratory compromise may avert the need for
edema, beginning on the lingual surface of the epiglottis where the tracheotomy.
submucosa is loosely attached. Swelling significantly reduces the airway
aperture. Edema rapidly progresses to involve the aryepiglottic folds,
the arytenoids and the entire supraglottic larynx. The tightly bound
Diagnosis
epithelium on the vocal cords halts edema spread at this level. Aspira- Visualization of the posterior pharynx is the best way to confirm the
tion of oropharyngeal secretions or mucous plugging can cause respi- diagnosis of epiglottitis. Because airway obstruction is the most feared
ratory arrest. complication of this disease, this examination should be done in a
An individual case of bacterial epiglottitis may be due to Hib vac- manner and place where immediate intubation can be performed if
cination failure, lack of vaccination, infections with bacterial species necessary. The larynx can be safely and accurately visualized with flex-
other than Hib or an underlying immunological illness. ible laryngoscopy (Figure 25-3).
A wide variety of species of bacteria other than Hib may cause A complete blood cell count with differential, blood cultures and
epiglottitis, including non-type b Haemophilus strains, groups A, B epiglottic cultures are obtained after the airway is secure and the
and C streptococci, Staphylococcus aureus, Strep. pneumoniae, and patient is stable. Elevated white blood cell counts are frequently present,
Pasteurella multocida. but positive blood culture results are extremely variable (6–15%).
Culturing swabs from the epiglottis in children almost always
obtains Hib. In adults, others pathogens may be obtained.
Prevention Lateral neck radiographs may demonstrate the classic thumb sign
The incidence of epiglottitis has decreased markedly since the advent (Figure 25-4). It is actually a rounded mass shadow of the normal
of the routine Hib vaccination and the reduction was noted among leaf-like epiglottis resulting from the thickening and edema of the
young children.23 Following the introduction of the different Hib inflamed epiglottic tissue. Another radiologic feature of acute epiglot-
immunization strategies over the past decade, cases in all age groups titis is the ‘vallecula sign’, which is the result of partial or complete
have continued to decline rapidly and have now become extremely obliteration of a well-defined air pocket bounding the base of tongue
rare in children and occur mainly in older adults with co-morbidities. and the epiglottis. The poor sensitivity (38%) and specificity (78%) of
Intubation is needed for less than 24 hours in most cases. Most

children can be successfully extubated after 24 hours of antibiotic
therapy. The duration of hospital treatment averages 3 days.
Family members and daycare contacts should receive rifampin pro-
phylaxis for 2 days to avoid secondary infection.
Mortality has become rare with the advent of Hib vaccination and
with rapid appropriate diagnosis and management.
Conclusion
In conclusion, epiglottitis has become rare in industrialized countries
with the advent of universal vaccinations against Hib, with the conse-
quent shift in disease from young children to adults. It still remains
potentially life-threatening, however, and can be rapidly fatal if not
promptly recognized and appropriately managed.
Pharyngitis
Pharyngitis is a very common inflammatory condition of the pharynx
accompanied by a sore throat and difficulty in swallowing. It is usually
viral but may be caused by bacterial or fungal infection.
Group A streptococcus is a frequent cause of pharyngitis that is easy
and important to diagnose because complications include rheumatic
fever and acute glomerulonephritis, which can be prevented by appro-
Figure 25-4 Lateral neck film demonstrating thumb sign with edema of the
epiglottis. priate antibiotic treatment. Serious complications of pharyngitis may
also include peritonsillar or retropharyngeal abscess.
Epidemiology
Acute pharyngitis accounts for 1.3% of outpatient visits to care provid-
plain films limits their utility, whereas the larynx can be safely and ers in the USA.
accurately visualized with flexible laryngoscopy.24 Group A streptococcus (Streptococcus pyogenes) is responsible for
5–15% of cases of pharyngitis in adults and 20–30% of cases in chil-
Differential Diagnosis dren.26,27 Streptococcal pharyngitis occurs most commonly among
The diagnoses of bacterial epiglottitis and viral laryngotracheobron- children between 5 and 15 years of age. In temperate climates, the
chitis (croup) in infants and children may be confused. In the early incidence is highest in winter and early spring.
phases of illnesses, some symptoms and signs are shared but their Bacterial causes of upper respiratory infections are led by group A
subsequent clinical courses and necessary treatments are very different. β-hemolytic streptococci (GAS) but can also be caused by H. influen-
Early recognition of epiglottitis is vital to avoid misdiagnosis and life- zae, Bordetella pertussis, Chlamydia pneumoniae, Arcanobacterium hae-
threatening acute airway obstruction and peripheral circulatory failure. molyticum, Mycoplasma pneumoniae and Yersinia enterocolitica, among
A study illustrated the difficulty in differentiating epiglottitis and others.
croup in the early phases of illness.23 The signs of upper airway obstruc- Many viruses are responsible for acute pharyngitis. Adenoviruses,
tion without coughing, along with drooling, reliably differentiate epi- rhinoviruses, coronaviruses, enteroviruses, parainfluenza and influ-
glottitis from croup. Additional but less reliable hallmarks of epiglottitis enza viruses most frequently cause self-limiting viral infections. Other
are preference to assume a sitting position, refusal of food or drink, viral infections, such as respiratory syncytial virus (RSV) and Epstein–
inability to swallow, a complaint of sore throat and vomiting. An Barr virus (EBV), still frequently occur. Herpes simplex virus (HSV)
altered voice is not discriminating. Fever in epiglottitis is usually above and coxsackieviruses are also implicated in acute pharyngitis, often
38 °C. associated with gingivitis.
If a stridulous child has a cough and is not drooling, the diagnosis Viral upper respiratory infections frequently occur in mini-
is likely to be a croup, but in a child who is drooling and not coughing, epidemics. They are more common in the winter except for those
the diagnosis is likely to be epiglottitis rather than croup. caused by enteroviruses, which are more common in the summer.
If the index of suspicion is high for epiglottitis, direct inspection Some viral infections occur year round, with non-seasonal pattern
should be performed only under anesthesia with the intention of intu- (adenoviruses). GAS infections are more common in the winter. Some
bation. If the suspicion is very low and the intention is to exclude the bacterial infections appear to be linked to preceding viral infections
condition, direct inspection is not totally contraindicated but should and hence occur more commonly in the winter. Pharyngeal coloniza-
be done only where facilities and personnel are on hand to intubate, tion may occur throughout the year.
should sudden obstruction be precipitated. Although acute pharyngitis is one of the most frequent illnesses for
which pediatricians and other primary care physicians are consulted,
Management with an estimated 15 million visits per year in the United States,27 only
Securing the airways is the initial step in the management of epiglot- a relatively small percentage of patients have GAS pharyngitis.28
titis. A combination of predictive factors such as stridor, hoarseness,
respiratory distress, dyspnea, chest wall retractions and upright posi- Physiopathology
tion have been associated with the need for airway intervention.25 Adenovirus, RSV and other viruses directly invade the pharyngeal cells
Appropriate antibiotics include ceftriaxone, cefotaxime and cefu- and produce an inflammatory response. This leads to the well-described
roxime. Ampicillin should not be used due to high frequency of ‘red, sore throat’. Additionally, adenovirus and EBV often produce lym-
ampicillin-resistant strains of Hib. Steroids are commonly employed phoid hyperplasia and tonsillar exudation. Herpes simplex virus
to decrease mucosal edema of the epiglottis, but no evidence of any (HSV) and coxsackievirus infections frequently lead to ulcerations of
benefit from their use has been yet established. the oral mucosa. HSV ulcers are more common in the anterior part of
the mouth and coxsackievirus ulcers occur more frequently in the common. Throat pain may be severe, and it is often worse on one side.
posterior part of the pharynx. HSV often produces a significant gingi- Cough, coryza and conjunctivitis are not typical symptoms of strep-
vitis as well. tococcal pharyngitis, and, if present, can suggest a viral cause.
Streptococcal pharyngitis often involves the posterior pharynx, Some patients who have a streptococcal sore throat have a charac-
with petechiae on the uvula and soft palate.29 When one sees this clini- teristic red ‘scarlet fever’ rash that begins in the groin and axillary areas
cal sign, GAS is often isolated by throat culture. A confusing factor is and spreads over the body. The rash is sandpaper-like and may itch.
that up to 10% of patients who have EBV infections will have a second- A strawberry tongue is also often present. Other patients have a char-
ary group A β-hemolytic streptococcal pharyngitis during their illness. acteristic rash on the face.
Corynebacterium diphtheriae can also cause pharyngitis, producing a Without treatment, the illness usually resolves within 3–5 days, but
characteristic gray membrane across the structures of the posterior complications may happen, including the post-infectious syndromes
pharynx. This is seldom seen today except in a few geographic areas of post-streptococcal glomerulonephritis and acute rheumatic fever.
where diphtheria outbreaks have occurred in recent times, such as Rheumatic fever is now rare in higher-income countries,32,33 but it
Russia. remains the leading cause of acquired heart disease among children in
There are also noninfectious causes of pharyngitis, such as Behçet’s many resource-poor areas (see Chapter 52).
syndrome, Kawasaki disease, Marshall’s syndrome or periodic fever Severe unilateral pain or inability to swallow that arises or pro-
(characterized by recurrent febrile episodes associated with aphthous gresses several days into the illness may raise concern about a local
stomatitis, pharyngitis, and cervical adenitis).30 suppurative complication such as peritonsillar or retropharyngeal
abscess. This is usually easily diagnosed by an asymmetry of the tonsil-
Prevention lar pillars. The affected side is asymmetrically enlarged and protrudes
Prevention of pharyngitis depends mainly on good handwashing and anteriorly into the mouth. Many other agents may be indistinguishable
preventing the spread of oral secretions. Contamination by aerosolized clinically from streptococcal pharyngitis (Box 25-2). Coxsackieviruses
oral secretions, hand-to-mouth contact with multiple individuals and often cause ulcers in the posterior pharynx along with a sore throat.
the use of common utensils can be limited to reduce the spread of viral Measles can cause a severe pharyngitis, but the associated symptoms
pharyngitis, but some viruses are known to be particularly resilient. of conjunctivitis, rash and Koplik’s spots make the disease easily diag-
RSV has been cultured from tabletops hours after being inoculated;31 nosable. Parainfluenza and influenza viruses can give a painful phar-
measles has been known to be contracted from the air in a physician’s yngitis, with frequently associated symptoms of cough and laryngitis.
waiting room. Transmission of streptococcal pharyngitis seems to EBV, adenovirus, cytomegalovirus and HSV can produce significant
require closer contact than for most viruses. pharyngitis. They also tend to last longer than the other viral causes of
There are vaccines available to prevent some of the diseases. Measles pharyngitis. These viruses produce other upper respiratory symptoms
has dramatically decreased in most countries since the advent of such as nontender cervical adenopathy, or in the case of HSV, tongue
measles vaccines. Influenza vaccines are recommended in groups and mouth ulcers. HSV pharyngitis has been described as a disease in
at risk. which ‘the gums swell up and swallow the teeth’ (Figure 25-6). Acute
HIV infection (‘seroconversion illness’) may cause symptoms in up to
Clinical Features 50% of patients. It is a mononucleosis-like illness in which pharyngitis
is a prominent feature (see Chapter 93). Corynebacterium diphtheriae
Pharyngitis is a ubiquitous infection. A ‘sore throat’ affects most people causes diphtheria, which is easily diagnosed because of the gray pseu-
at least once every year. Most cases of viral pharyngitis are associated domembrane in the posterior pharynx along with pharyngitis (Figure
with an upper respiratory infection (nasopharyngitis). Generally naso- 25-7). Arcanobacterium haemolyticum is a common cause of pharyn-
pharyngitis has a prodrome that may include malaise, diaphoresis, gitis and can also cause a scarlatiniform rash. It is a cause of many
fever, headache and general aches and/or pains. Coryza and sore throat non-GAS throat infections.34 Neisseria gonorrhoeae is an important
then begin. Many infections will progress to produce a cough and/or cause of pharyngitis in sexually active individuals. The appearance of
laryngitis. Some viral infections produce predominantly coryza, others
more pharyngitis, and others more cough or laryngitis.
Pharyngitis caused by GAS is the most common infection causing
significant pharyngeal edema, frequently with petechiae on the soft BOX 25-2 INFECTIOUS CAUSES OF ACUTE
palate and uvula (Figure 25-5). Tender cervical nodes are common. PHARYNGITIS
Small children may complain of abdominal pain, which may be due to BACTERIA
mesenteritic adenitis. Headache and raised temperature are also • Group A, C and G streptococci
• Mixed anaerobes
• Fusobacterium necrophorum
• Arcanabacterium haemolyticum
• Neisseria gonorrhoeae
• Treponema pallidum
• Francisella tularensis
• Corynebacterium diphtheriae
• Yersinia enterolitica
• Yersinia pestis
• Mycoplasma pneumoniae
• Chlamydophila pneumoniae
• Chlamydophila psitacci
VIRUS
• Rhinovirus
• Coronavirus
• Adenovirus
• Influenza virus
• Parainfluenza virus
• Coxsackievirus
• Herpes simplex virus
• Epstein–Barr virus
• Cytomegalovirus
• Human immunodeficiency virus
Figure 25-5 GAS tonsillitis.
test to detect the presence of the bacteria: a throat culture or a rapid

antigen-detection test of a throat swab specimen.
The rapid antigen-detection test (RADT) detects the presence of
GAS within a few minutes and has high sensitivity and specificity. It
allows the practitioner to treat only those cases with GAS, thus avoid-
ing prescribing antibiotics for viral infections. Only group A strepto-
coccus leads to rheumatic fever, so the antibiotic treatment is not only
necessary to eliminate the pharyngitis but also to prevent the subse-
quent rheumatic disease.
Clinical guidelines state that negative RADTs do not require con-
firmation by a back-up method in adults but RADTs fail to detect a
substantial number of adult patients with clinically significant pharyn-
gitis and so culture can still be useful, notably in diagnosis of other
bacterial pharyngitis. In children with symptoms and signs highly sug-
gestive of streptococcal pharyngitis, even if the RADT is negative, a
throat culture should be performed. If the RADT is positive, a throat
culture is not needed for diagnosis.
Certain persons are asymptomatic carriers of Strep. pyogenes and
carriage can persist for weeks or months. In the absence of suggestive
clinical findings, a positive culture or RADT is likely to reflect inciden-
Figure 25-6 Primary infection of HSV-1
tal carriage of Strep. pyogenes.
Measurement of serum antibodies to streptolysin O or DNase B can
be useful to provide support for the diagnosis of acute rheumatic fever
or post-streptococcal glomerulonephritis, but is not helpful in the
management of pharyngitis, since titers increase until 7–14 days after
the onset of infection, reaching a peak in 3–4 weeks.37
Management
Most cases of pharyngitis are caused by viruses and do not need any
antibiotic treatment. Studies have shown that antibiotic treatment in
streptococcal pharyngitis reduces the duration of the symptoms,
reduces the risk of suppurative complications of streptococcal infec-
tions and reduces also the risk of subsequent development of acute
rheumatic fever. A Cochrane review of randomized, placebo-controlled
trials showed that antibiotic therapy significantly reduced the risks of
acute otitis media and peritonsillar abscess.38 For group A streptococ-
cal pharyngitis, recommended therapy in the USA is 10 days of oral
penicillin or amoxicillin (6 days in France). Azithromycin and clinda-
Figure 25-7 Diphtheria pharyngitis with gray pseudomembranes in the poste- mycin are acceptable alternatives for patients with penicillin allergy.28
rior pharynx.
Without treatment, streptococcal pharyngitis is associated with persis-
tence of positive throat cultures for up 6 weeks in 50% of patients. In
patients with recurrent pharyngitis, regardless of the etiology of the
the pharyngitis is nondiagnostic, so a heightened awareness is required episodes, the benefit of tonsillectomy may be discussed.
to make this diagnosis35 (see Chapter 65). Chlamydia pneumoniae and A 2012 update by the Infectious Diseases Society of America IDSA28
Mycoplasma pneumoniae can cause pharyngitis, but generally will gave clinical practice guideline for the diagnosis and management of
progress to cough also, often with wheezing and pneumonia.36 Candida group A streptococcal pharyngitis.
albicans can cause pharyngitis but normally only in the immunocom-
promised host. The pharyngitis is hyperemic, with white plaques on Conclusion
the buccal mucosa. In conclusion, acute pharyngitis is an ubiquitous infection. Group A
streptococcus is one of common causes of pharyngitis that should be
Diagnosis diagnosed and treated to prevent post-streptococcal complications.
Presentation of acute pharyngitis may be nonspecific. The diagnosis of
streptococcal pharyngitis should be based on the results of a specific References available online at expertconsult.com.
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Chapter 25 Laryngitis, Epiglottitis and Pharyngitis 235.e1
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sonality patterns in croup presentations to emergency L-epinephrine and racemic epinephrine aerosols in the 30. Thomas K.T., Feder H.M. Jr, Lawton A.R., et al.: Peri-
departments in Alberta, Canada: a time series analysis. treatment of laryngotracheitis (croup). Pediatrics 1992; odic fever syndrome in children. J Pediatr 1999;
Pediatr Emerg Care 2011; 27(4):256-260. 89(2):302-306. 135(1):15-21.
5. Marx A., Török T.J., Holman R.C., et al.: Pediatric hos- 17. Bjornson C., Russell K., Vandermeer B., et al.: Nebu- 31. Hall C.B., Douglas R.G. Jr: Modes of transmission of
pitalizations for croup (laryngotracheobronchitis): lized epinephrine for croup in children. Cochrane Data- respiratory syncytial virus. J Pediatr 1981; 99(1):100-
biennial increases associated with human parainfluenza base Syst Rev 2013; (10):CD006619. 103.
virus 1 epidemics. J Infect Dis 1997; 176(6):1423- 18. Collins S., Ramsay M., Campbell H., et al.: Invasive 32. Zimmerman R.A., Siegel A.C.: A follow-up report on a
1427. Haemophilus influenzae type b disease in England and streptococcal and rheumatic fever epidemic: data con-
6. Miller E.K., Gebretsadik T., Carroll K.N., et al.: Viral Wales: who is at risk after 2 decades of routine child- firming the epidemicity of the 1961 Dickinson, North
etiologies of infant bronchiolitis, croup and upper hood vaccination? Clin Infect Dis 2013; 57(12):1715- Dakota, episode. Pediatrics 1966; 38(4):578-584.
respiratory illness during 4 consecutive years. Pediatr 1721. 33. Denny F.W., Wannamaker L.W., Brink W.R., et al.:
Infect Dis J 2013; 32(9):950-955. 19. Hargreaves R.M., Slack M.P., Howard A.J., et al.: Chang- Prevention of rheumatic fever; treatment of the preced-
7. Peltola V., Heikkinen T., Ruuskanen O.: Clinical courses ing patterns of invasive Haemophilus influenzae disease ing streptococcic infection. JAMA 1950; 143(2):
of croup caused by influenza and parainfluenza viruses. in England and Wales after introduction of the Hib 151-153.
Pediatr Infect Dis J 2002; 21(1):76-78. vaccination programme. BMJ 1996; 312(7024):160-161. 34. Miller R.A., Brancato F., Holmes K.K.: Corynebacterium
8. Rankin I., Wang S.M., Waters A., et al.: The manage- 20. Ladhani S.N.: Two decades of experience with the Hae- hemolyticum as a cause of pharyngitis and scarlatini-
ment of recurrent croup in children. J Laryngol Otol mophilus influenzae serotype b conjugate vaccine in the form rash in young adults. Ann Intern Med 1986;
2013; 127(5):494-500. United Kingdom. Clin Ther 2012; 34(2):385-399. 105(6):867-872.
9. Thompson M., Vodicka T.A., Blair P.S., et al.: Duration 21. Carey M.J.: Epiglottitis in adults. Am J Emerg Med 1996; 35. Hutt D.M., Judson F.N.: Epidemiology and treatment of
of symptoms of respiratory tract infections in children: 14(4):421-424. oropharyngeal gonorrhea. Ann Intern Med 1986;
systematic review. BMJ 2013; 347:f7027. 22. Shah R.K., Stocks C.: Epiglottitis in the United States: 104(5):655-658.
10. Westley C.R., Cotton E.K., Brooks J.G.: Nebulized national trends, variances, prognosis, and management. 36. Grayston J.T.: Infections caused by Chlamydia pneu-
racemic epinephrine by IPPB for the treatment of Laryngoscope 2010; 120(6):1256-1262. moniae strain TWAR. Clin Infect Dis 1992; 15(5):757-
croup: a double-blind study. Am J Dis Child 1978; 23. Tibballs J., Watson T.: Symptoms and signs differentiat- 761.
132(5):484-487. ing croup and epiglottitis. J Paediatr Child Health 2011; 37. Wessels M.R.: Clinical practice: Streptococcal pharyn-
11. Stroud R.H., Friedman N.R.: An update on inflamma- 47(3):77-82. gitis. N Engl J Med 2011; 364(7):648-655.
tory disorders of the pediatric airway: epiglottitis, 24. Stankiewicz J.A., Bowes A.K.: Croup and epiglottitis: a 38. Del Mar C.B., Glasziou P.P., Spinks A.B.: Antibiotics for
croup, and tracheitis. Am J Otolaryngol 2001; 22(4): radiologic study. Laryngoscope 1985; 95(10):1159-1160. sore throat. Cochrane Database Syst Rev 2006; (4):
268-275. 25. Crosby E., Reid D.: Acute epiglottitis in the adult: is CD000023.
12. Scolnik D., Coates A.L., Stephens D., et al.: Controlled intubation mandatory? Can J Anaesth/J Can Anesth
delivery of high vs low humidity vs mist therapy for 1991; 38(7):914-918.
croup in emergency departments: a randomized con- 26. Bisno A.L.: Acute pharyngitis: etiology and diagnosis.
trolled trial. JAMA 2006; 295(11):1274-1280. Pediatrics 1996; 97(6 Pt 2):949-954.
13. Moore M., Little P.: WITHDRAWN: Humidified air 27. Ebell M.H., Smith M.A., Barry H.C., et al.: The rational
inhalation for treating croup. Cochrane Database Syst clinical examination: does this patient have strep
Rev 2011; (6):CD002870. throat? JAMA 2000; 284(22):2912-2918.
26
Otitis, Sinusitis and Related
Conditions
LUU-LY PHAM | RAFIK BOURAYOU | VALÉRIE MAGHRAOUI-SLIM |
ISABELLE KONÉ-PAUT
KEY CONCEPTS Between 50% and 85% of children will have at least one episode of
AOM by 3 years of age4 and worldwide there are 709 million estimated
Otitis new cases of AOM annually, with 51% of these occurring in children
• Otitis is one of the most frequent diseases in early childhood
under 5 years of age.5 OME is the commonest cause of hearing impair-
and one of the reasons for first prescription of antibiotics. ment in children and can affect as many as 80% of children at some
stage,6 with 2.2 million new cases of OME annually in the USA.7 OM
• Streptococcus pneumoniae (SP) is the most frequent pathogen remains the most common condition for which antibacterial agents
identified and increasing resistance may influence antibiotic are prescribed for children in the United States8 and the percentage of
treatment. OM visits resulting in antibiotic prescriptions remained relatively
• High-dose amoxicillin is recommended as the first-line anti stable (80% in 1995–1996; 76% in 2005–2006).9
biotic in most patients. Although OM has a high morbidity, mortality rates are generally
low. Complications such as acute mastoiditis usually occur in children
• The occurrence of complications such as mastoiditis should be
monitored, even if they have become less frequent since the
under 2 years of age and the incidence is 1.2–6.0 in 100 000.10
advent of antibiotic treatment.
Physiopathology
• The arrival of the pneumococcal conjugate vaccine (7-valent
then 13-valent) had a strong impact on SP nasopharyngeal Pathogenesis of OM is complex and multifactorial. The middle ear and
carriage and is involved in modifications of the bacterial rhinopharynx are covered by a ciliated respiratory mucous membrane.
ecology, with consequences that are still under study The middle ear communicates with the pharynx by the Eustachian
tube, which allows physiologic drainage of the mucus secreted by the
Sinusitis middle ear. Viral aggression against the respiratory epithelium, so
• Sinusitis may be severe in children. frequent in early childhood, decreases ciliary movement, favoring bac-
terial adhesion. At the same time, the inflammation provokes Eusta-
• Purulent acute ethmoiditis represents a real pediatric emer- chian tube obstruction. Together, these mechanisms facilitate bacterial
gency, and this diagnosis must be considered in a child pre- proliferation in the middle ear, with the formation of pus.
senting with edema of the superior eyelid associated with
swelling of the internal corner of the eye and nose root.
Acute otitis media develops in two phases:
• first, the congestive phase (red eardrums);
• Ethmoiditis requires parenteral empiric antibiotic therapy that • and second, the purulent phase (tympanic inflammation and
must target Haemophilus influenzae (HI) and Staphylococcus effusion behind the eardrum).
aureus. The principal causative pathogens are Streptococcus pneumoniae (SP)
• Since the era of pneumococcal vaccination, and with the arrival that is associated with a more frequent risk of complications, Hae-
of PCV13 vaccine, a continuing decrease in isolates of SP and mophilus influenzae (HI), Moraxella catarrhalis (MC) and also Staphy-
an increase in β-lactamase-producing HI are observed. lococcus aureus.
In most cases, AOM is self-limiting. The natural history of otitis
media is very favourable. In a systematic review of literature, AOM
symptoms improved within 24 hours without antibiotics in 61% of
Otitis children, rising to 80% by 2–3 days.11
In contrast to AOM, OM with effusion (OME) is a chronic inflam-
Otitis media (OM) is a group of infective and inflammatory conditions matory condition that typically affects children between 3 and 7 years
affecting the middle ear, that is frequent in early childhood and a old. It is characterized by the presence of an effusion – glue-like fluid
leading cause of healthcare visits worldwide.1 It is the first reason for behind an intact tympanic membrane in the absence of signs and
prescription of antibiotics in pediatric practice, although OM resolves symptoms of acute inflammation. The commonest reported symptom
spontaneously within 48 hours. Overuse of antibiotics may favor the is hearing loss, which may lead to speech delay or educational
development of multidrug-resistant pathogens. Appropriate prescrip- problems.
tion of antibiotics for OM is based on clinical findings, patient’s age OME after untreated AOM had 74% resolution by 3 months. In
and bacterial ecology. contrast, chronic OME had only 26% resolution by 6 months and 33%
resolution by 1 year.11
Epidemiology
Acute otitis media (AOM) and otitis media with effusion (OME) are Bacteriology
common in young children and are associated with upper respiratory Micro-organisms detected in the middle ear during AOM include
tract infection.2 The immaturity of the immune system plays a major pathogenic bacteria, as well as respiratory viruses. Bacteria are retrieved
role in their development but other risk factors – such as male sex, in 50–90% of cases of AOM. The principal pathogens identified by
lower age (peak age of incidence is between 6 and 15 months3), family aspiration and culture of middle ear fluid are SP (the most frequent,
history and early entry into day care – are well known. 20–35%), HI, MC and Streptococcus pyogenes (group A). Staph. aureus
236
Chapter 26 Otitis, Sinusitis and Related Conditions 237
(less than 5%) and Pseudomonas aeruginosa, retrieved in a few cases,

may also cause chronic OM.
Since the use of the conjugated 7-valent vaccine (PCV7), the rate
of vaccine-type-associated AOM has been reduced by 57%,12 but the
frequency of HI AOM has increased.13
Strep. pyogenes is more frequent in Europe than in the USA, espe-
cially in children more than 2 years old. Respiratory viruses (RSV and
influenza mostly, but also enterovirus and rhinovirus) are also found
alone or in association with bacteria in the auricular liquid.
Modification of the bacterial ecology over the past few years, as well
as increasing resistance, may influence antibiotic treatment. Antibiotic
susceptibility of major AOM bacterial pathogens continues to change.
Current US data indicate that approximately 83% and 87% of isolates
of SP from all age groups are susceptible to regular and high-dose
amoxicillin, respectively. A high percentage of multidrug-resistant SP
were mostly isolated from recurrent and persistent AOM cases, and
were most frequently nonvaccine serotypes.14 Between 58 and 82% of
HI isolates are susceptible to regular and high-doses of amoxicillin.15,16
These current data represent a significant decrease in β-lactamase-
producing HI, compared with data reported in the 2004 American Figure 26-1 Acute otitis media compared with normal tympanic membrane.
AOM guideline. One hundred percent of MC are β-lactamase-positive
but remain susceptible to amoxicillin-clavulanate.17
Congestive otitis and purulent otitis are separate conditions:
• Congestive otitis (CO) is an acute inflammation of the middle
Prevention ear. Eardrums are congested but contours are normal and there
VACCINATION is no tympanic convexity. CO is mostly caused by viral infection.
Secondary bacterial infection is possible and justifies medical
The pneumococcal conjugate vaccine was primarily developed against
follow-up.
the invasive forms of pneumococcal disease. Vaccination by the con-
jugated 7-valent (PCV7) has modest beneficial effects in healthy • Purulent or suppurative otitis (PO) (Figure 26-1) is an inflam-
mation of the tympanic membrane associated with a retrotym-
infants with a low baseline risk of AOM.18 Administering PCV7 in
panic effusion and presence of pus in the middle ear, which can
high-risk infants, after early infancy and in older children with a
sometimes be exteriorized by otorrhea. Common symptoms are
history of AOM, appears to have no benefit in preventing further
severe ear pain (expressed in a young child by irritability, tears
episodes. Immunized children had fewer episodes of AOM caused by
and sleeplessness), fever, asthenia and anorexia. Ear pain arising
the seven serotypes contained in the vaccine but had more episodes of
at night and fever are frequent but not mandatory. The ear drum
AOM caused by the other serotypes. The use of PCV7 had a strong
perforates in approximately 5% of cases and the perforation
impact on penicillin nonsusceptible SP carriage in children with
usually heals spontaneously. Associated nonspecific signs include
AOM.19 Unfortunately, since the introduction of PCV7, a multiresis-
gastrointestinal disorders, cough and rhinorrhea in the context
tant serotype 19A SP has emerged in the USA.14
of associated viral infection.
The advent of pneumococcal conjugated 13-valent (PCV13) has
Some clinical associations indicate a diagnosis of bacterial otitis
further reduced rates of invasive pneumococcal disease (IPD) com-
media – for example, otitis with conjunctivitis may indicate HI; high
pared with PCV7 but its impact on SP nasopharyngeal carriage and its
fever with ear pain may indicate SP.
contribution to reduce otitis media and pneumonia, as well as the
External otitis must be distinguished from AOM with otorrhea, in
prevalence of resistant pneumococcal strains, are still being studied.20
which there is no perforation of the tympanic membrane and pain
The antibiotic susceptibility pattern is expected to evolve with the use
persists in spite of drainage of secretions.
of PCV13. The widespread use of PCV13 could potentially reduce
OME is a chronic inflammatory condition that may occur as a
diseases caused by multidrug-resistant pneumococcal serotypes and
residual effect of AOM, or there may be no preceding history. It is
diminish the need for the use of higher doses of amoxicillin for AOM.
characterized by an accumulation of fluid in the middle ear behind an
TYMPANOSTOMY TUBES AND intact tympanic membrane, without the symptoms or signs of acute
ADENOIDECTOMY infection. Clinical features include a history of hearing difficulties,
poor attention, behavioral problems, and delayed speech and language
The efficacy of these procedures in the prevention of AOM has not development.4 Diagnosis is made by otoscopy with variable clinical
been demonstrated but they do avoid hearing disorders due to repeated findings (abnormal colour, retracted/concave tympanic membrane,
episodes of AOM.8 Insertion of tympanostomy tubes seems to prevent and air–fluid levels). Audiogram may be performed and typically
one attack of AOM or keep one child in three free from AOM in 6 shows a mild conductive hearing loss.24
months.21 They may be beneficial in chronic otitis media with
effusion.7,22
Complications
Some 60–80% of cases of uncomplicated AOM resolve within 24–48
Diagnosis hours without antibiotic treatment.
AOM usually affects children aged under 2 years, and presents with The occurrence of mastoiditis, labyrinthitis, brain abscesses, facial
acute onset symptoms and signs of otalgia and fever. According to the nerve palsy and septic thrombophlebitis has become rare, since the
severity of symptoms and associated systemic signs, the child may (or advent of antibiotic treatment.25
may not) receive antibiotic treatment initially. Otoscopic examination Mastoiditis particularly affects children younger than 2 years. Sys-
allows the diagnosis of AOM. However, the technique can be prob- temic signs are associated with local inflammatory signs in front of
lematic due to issues that may arise during examination (e.g. small the mastoid (Figures 26-2 and 26-3). Virulent pathogens such as group
auditory canals, cerumen obstruction, child restlessness).23 Rhino- A streptococcus, SP and type b HI in non-immunized subjects are
pharyngitis and/or child screams during examination induce conges- commonly found. Staph. aureus and Enterobacteriaceae cause sub-
tion and hypervascularization of the eardrum. acute mastoiditis.
Figure 26-2 Mastoiditis: local inflammatory signs in front of the mastoid. Figure 26-3 CT scan of mastoiditis.
TABLE
26-1 Recommended Antibiotic Treatment in Otitis Media
ANTIBIOTIC TREATMENT AFTER 48–72 H OF FAILURE OF INITIAL
INITIAL IMMEDIATE OR DELAYED ANTIBIOTIC TREATMENT ANTIBIOTIC TREATMENT
Recommended First-Line Alternative Treatment Recommended First-Line
Treatment (if Penicillin Allergy) Treatment Alternative Treatment
Amoxicillin (80–90 mg/ kg per day Cefdinir (14 mg/kg per day Amoxicillin-clavulanate* Ceftriaxone, 3 days
in two divided doses) in one or two doses) (90 mg/kg per day of Clindamycin (30–40 mg/kg per day in three divided
amoxicillin, with 6.4 mg/kg doses), with or without third-generation
per day of clavulanate in cephalosporin
two divided doses)
or Cefuroxime (30 mg/kg per or Failure of second antibiotic

day in two divided doses)
Amoxicillin-clavulanate* (90 mg/kg Cefpodoxime (10 mg/kg per Ceftriaxone (50 mg im or iv Clindamycin (30–40 mg/kg per day in three divided
per day of amoxicillin, with day in two divided doses) for 3 days) doses) plus third-generation cephalosporin
6.4 mg/kg per day of Tympanocentesis†
clavulanate [amoxicillin to Ceftriaxone (50 mg im or iv Consult specialist†
clavulanate ratio, 14 : 1] in two per day for 1 or 3 days)
divided doses)
*May be considered in patients who have received amoxicillin in the previous 30 days or who have the otitis–conjunctivitis syndrome.
†
Perform tympanocentesis/drainage if skilled in the procedure, or seek a consultation from an otolaryngologist for tympanocentesis/drainage. If the tympanocentesis
reveals multidrug-resistant bacteria, seek an infectious disease specialist consultation.
Reproduced from Lieberthal AS, et al. Pediatrics 2013;131(3):e964–999.
Mastoiditis may progress to cerebral abscess, central venous throm- PCV7 and updated data on the in vitro susceptibility of bacterial patho-
bosis, osteomyelitis and hydrocephaly. Labyrinthitis is caused by dis- gens most likely to cause AOM, the recommendations for the first-line
semination of infection in the inner ear. Vestibular syndrome is the antibiotic remains unchanged from 2004.
key feature. Benign facial nerve palsy may also occur; this has a favor- Prescription of antibiotics depends essentially on two factors: the
able outcome with antibiotic and corticosteroid treatment. age of the child (younger or older than 2 years) and the severity of
systemic signs. For children younger than 2 years, initial antibiotic
treatment is recommended. For children older than 2 years with few
Treatment or no symptoms, symptomatic treatment only is recommended, with
The rationale for antibiotic therapy in children with AOM is based on patient re-evaluation after 48–72 hours. This attitude is justified
a high prevalence of bacteria in the accompanying middle ear effusion. because immediate treatment has only a modest effect on the course
Antibiotic treatment leads to a statistically significant reduction of of AOM.28
children with AOM experiencing pain at 2–7 days compared with High-dose amoxicillin is recommended as the first-line treatment
placebo, even though most children (82%) settle spontaneously. It in most patients (Table 26-1). The justification for the use of amoxicil-
appears to be most useful in children under 2 years of age with bilateral lin relates to its effectiveness against common AOM bacterial patho-
AOM, or with both AOM and otorrhea. For most other children with gens as well as its safety, low cost, acceptable taste and narrow
mild disease, an expectant observational approach seems justified.26 microbiologic spectrum. In children who have taken amoxicillin in the
In 2004, the American Academy of Pediatrics (AAP) proposed previous 30 days, those with concurrent conjunctivitis, or those for
guidelines for treatment of AOM27 and a revision was proposed in whom coverage for β-lactamase-positive HI and MC is desired, therapy
2013.9 It provided recommendations to primary care clinicians for the should be initiated with high-dose amoxicillin–clavulanate (90 mg/kg/
management of children from 6 months through 12 years of age with day of amoxicillin, with 6.4 mg/kg/day of clavulanate). Alternative
uncomplicated AOM (Box 26-1). Despite new data on the effect of initial antibiotics include cefdinir (14 mg/kg per day in one or two
BOX 26-1 2013 GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF ACUTE OTITIS MEDIA FROM THE
AMERICAN ACADEMY OF PEDIATRICS
1A: Clinicians should diagnose acute otitis media (AOM) in children who [102.2 °F]). When observation is used, a mechanism must be in place to
present with moderate to severe bulging of the tympanic membrane (TM) ensure follow-up and begin antibiotic therapy if the child worsens or fails
or new onset of otorrhea not due to acute otitis externa. Evidence Quality: to improve within 48–72 hours of onset of symptoms. Evidence Quality:
Grade B; Strength: Recommendation. Grade B. Strength: Recommendation.
1B: Clinicians should diagnose AOM in children who present with mild bulging 4A: Clinicians should prescribe amoxicillin for AOM when a decision to treat
of the TM and recent (less than 48 hours) onset of ear pain (holding, with antibiotics has been made and the child has not received amoxicillin
tugging, rubbing of the ear in a nonverbal child) or intense erythema of in the past 30 days or the child does not have concurrent purulent con-
the TM. Evidence Quality: Grade C. Strength: Recommendation. junctivitis or the child is not allergic to penicillin. Evidence Quality: Grade
1C: Clinicians should not diagnose AOM in children who do not have middle B. Strength: Recommendation.
ear effusion (MEE) (based on pneumatic otoscopy and/or tympanometry). 4B: Clinicians should prescribe an antibiotic with additional β-lactamase cover-
Evidence Quality: Grade B. Strength: Recommendation. age for AOM when a decision to treat with antibiotics has been made,
2: The management of AOM should include an assessment of pain. If pain and the child has received amoxicillin in the last 30 days or has concurrent
is present, the clinician should recommend treatment to reduce pain. purulent conjunctivitis, or has a history of recurrent AOM unresponsive to
Evidence Quality: Grade B. Strength: Strong Recommendation. amoxicillin. Evidence Quality: Grade C. Strength: Recommendation.
3A: Severe AOM: The clinician should prescribe antibiotic therapy for AOM 4C: Clinicians should reassess the patient if the caregiver reports that the
(bilateral or unilateral) in children 6 months and older with severe signs or child’s symptoms have worsened or failed to respond to the initial
symptoms (i.e. moderate or severe otalgia or otalgia for at least 48 hours antibiotic treatment within 48–72 hours and determine whether a
or temperature 39 °C [102.2 °F] or higher). Evidence Quality: Grade B. change in therapy is needed. Evidence Quality: Grade B. Strength:
Strength: Strong Recommendation. Recommendation.
3B: Nonsevere bilateral AOM in young children: The clinician should prescribe 5A: Clinicians should not prescribe prophylactic antibiotics to reduce the fre-
antibiotic therapy for bilateral AOM in children 6 months through 23 quency of episodes of AOM in children with recurrent AOM. Evidence
months of age without severe signs or symptoms (i.e., mild otalgia for less Quality: Grade B. Strength: Recommendation.
than 48 hours and temperature less than 39 °C [102.2 °F]). Evidence 5B: Clinicians may offer tympanostomy tubes for recurrent AOM (three epi-
Quality: Grade B. Strength: Recommendation. sodes in 6 months or four episodes in 1 year with one episode in the
3C: Nonsevere unilateral AOM in young children: The clinician should either preceding 6 months). Evidence Quality: Grade B. Strength: Option.
prescribe antibiotic therapy or offer observation with close follow-up 6A: Clinicians should recommend pneumococcal conjugate vaccine to all chil-
based on joint decision-making with the parent(s)/caregiver for unilateral dren according to the schedule of the Advisory Committee on Immuniza-
AOM in children 6 months to 23 months of age without severe signs or tion Practices of the Centers for Disease Control and Prevention, American
symptoms (i.e., mild otalgia for less than 48 hours and temperature less Academy of Pediatrics (AAP), and American Academy of Family Physicians
than 39 °C [102.2 °F]). When observation is used, a mechanism must be in (AAFP). Evidence Quality: Grade B. Strength: Strong Recommendation.
place to ensure follow-up and begin antibiotic therapy if the child worsens 6B: Clinicians should recommend annual influenza vaccine to all children
or fails to improve within 48–72 hours of onset of symptoms. Evidence according to the schedule of the Advisory Committee on Immunization
Quality: Grade B. Strength: Recommendation. Practices, AAP and AAFP. Evidence Quality: Grade B. Strength:
3D: Nonsevere AOM in older children: The clinician should either prescribe Recommendation.
antibiotic therapy or offer observation with close follow-up based on joint 6C: Clinicians should encourage exclusive breastfeeding for at least 6 months.
decision-making with the parent(s)/caregiver for AOM (bilateral or unilat- Evidence Quality: Grade B. Strength: Recommendation.
eral) in children 24 months or older without severe signs or symptoms (i.e., 6D: Clinicians should encourage avoidance of tobacco smoke exposure. Evi-
mild otalgia for less than 48 hours and temperature less than 39 °C dence Quality: Grade C. Strength: Recommendation.
Reproduced from Lieberthal AS, et al. Pediatrics 2013;131(3):e964–999.
doses), cefuroxime (30 mg/kg per day in two divided doses), cefpo- respiratory symptoms.29 In the USA antibiotics are prescribed for 82%
doxime (10 mg/kg per day in two divided doses), or ceftriaxone of children with acute sinusitis.30
(50 mg/kg, administered intramuscularly).
A 10-day course of treatment is recommended for children under
2 years of age or with severe symptoms; a 7-day course is effective in
Pathogenesis
children 2–5 years of age with mild or moderate AOM and a 5–7-day Most cases of sinusitis are caused by bacterial or viral infections but
course is acceptable for children 6 years and older with mild or moder- may also be related to allergy. Bacterial sinusitis usually starts with a
ate AOM. Parenteral antibiotic treatment is mandatory for complica- viral disease or an allergic rhinitis with secondary bacterial infection.
tions such as mastoiditis. Persistent obstruction of the sinus ostium by inflammatory edema
Since most cases of OME will resolve spontaneously, only children causes secondary bacterial colonization. In addition, there is a diminu-
with persistent middle ear effusion and associated hearing loss poten- tion of mucociliary transport which may impair the normal secretion
tially require treatment. A recent review did not support the routine flow, creating an optimal environment for bacterial multiplication.31
use of antibiotics for children up to 18 years with otitis media with The American Academy of Pediatrics (AAP) defines acute bacterial
effusion.6 sinusitis as a bacterial infection of the paranasal sinuses lasting less
than 30 days in which symptoms resolve completely.32
The most common infectious agents are SP (30–50%), non typable
Sinusitis HI (20–30%) and Moraxella catarrhalis (MC) (12–28%). Since the
introduction of these vaccines for SP and HI, a significant decrease in
Sinusitis is an inflammation of the lining of the paranasal sinuses the frequency of SP has been observed and the bacterial data have
(infectious or noninfectious; bacterial or viral). Symptoms of acute changed, with predominance of non-b HI (41%), SP (25%), MC
sinusitis last less than 4 weeks, but subacute sinusitis or chronic sinus- (14%), Strep. pyogenes (12%) and Staph. aureus (8%). There is also a
itis can occur. Sinusitis can be further classified according to the ana- decrease of SP resistant to penicillin from 44% in 1997 to 27% in 2005
tomic site (maxillary, ethmoidal, frontal and sphenoidal). Most and an increase of HI with β-lactamase (37% versus 44%), although
frequent causative bacteria are Streptococcus pneumoniae (SP) and these differences are not statistically significant.33
Haemophilus influenzae (HI). Rare cases of sinusitis of dental origin must be considered in
patients with pain following recent dental procedures. In most cases,
Epidemiology anaerobic bacteria of the oropharynx colonize necrotic dental tissue
Acute bacterial sinusitis is a common complication of viral upper and then colonize the sinuses. Treatment with antibiotic therapy is
respiratory infection (URI) or allergic inflammation that has been essential.34 Chronic sinusitis can also be a complication of gastro-
observed in between 6% and 7% of children seeking care for esophageal reflux.35
Fungal sinusitis can affect immunocompromised hosts, such as

patients with neutropenia, diabetes mellitus and AIDS. There is also
an allergic fungal sinusitis believed to be an allergic reaction to aerosol-
ized environmental fungi, including Aspergillus and dematiaceous
species, in immunocompetent hosts.
Prevention
Prevention is primarily based on vaccination. Influenza vaccine should
be administered annually, and PCV13 should be administered at the
recommended ages for all children. Since the introduction of the pneu-
mococcal conjugate vaccines, there is an increasing prevalence of HI
as a cause of sinusitis and an increasing prevalence of β-lactamase
production among these strains.
Clinical Features
Sinusitis can cause different symptoms in children at varying ages.
Younger children often present with persistent rhinorrhea (often
purulent), cough and foul-smelling breath; fever is generally low grade.
Facial pain and headaches are rare. The differential diagnosis with a
viral upper respiratory tract infection (URTI) is difficult to establish a
and no single sign or symptom has strong diagnostic value. However,
sinusitis should be considered in patients who present with symptoms
of a viral URTI of more than 10 days’ duration.
In older children and adults, signs are more localized and the most
frequent symptoms are facial pain, headaches, fever, nasal congestion
or obstruction and daytime cough. Clinical examination may reveal
facial tenderness or swelling over the maxillary or frontal sinuses.
In chronic sinusitis (signs present for at least 12 weeks), cough is
prominent. This cough is usually present throughout the day and
occasionally precipitates emesis, especially after wakening. Chronic
headache may also be present: the pain is often dull in nature and
radiates to the top of the head or in temporal regions. Purulent or
mucopurulent nasal discharge often completes this cluster of signs.
The localization of sinusitis varies according to age because of the
chronology of development of the sinuses: patients between 6 months
and 5 years develop ethmoidal sinusitis; those older than 3 years
develop maxillary sinusitis and those older than 10 years develop
frontal sinusitis. Sphenoid sinusitis is exceptional among children.
Maxillary sinusitis is common in children older than 3 years and
resolves spontaneously in most cases. Two clinical pictures can be
distinguished:
b
• acute purulent maxillary sinusitis with fever >39 °C lasting more
than 3 days, headaches, purulent rhinorrhea and sometimes
Figure 26-4 Acute ethmoiditis. (a) Swelling of the internal corner of the eye and
periorbital edema; and nose root. (b) Edema of superior eyelid.
• subacute maxillary sinusitis with cough, purulent rhinorrhea
and nasal obstruction, which may last more than 10 days without
amelioration.
Headaches, prolonged fever associated with morning cough and common viral rhinopharyngitis, with a high fever in the presence of
purulent sputum are clear signs of bacterial sinusitis. Frontal sinusitis general signs. The etiologic agents are Staph. aureus and HI b. Staph.
is rare. It particularly affects children older than 10 years and teenagers. aureus is suspected if there is a suggestion of facial trauma or cellulitis
The pain is located above the eye socket, is unilateral and throbbing of the face. Complications are serious because of the nearness of the
in nature, and is increased by anteflexion of the head. Complications brain and its venous channels, i.e. vascular complications (thrombosis
can be serious (eyes, osteomyelitis of the cranial bones). of the cavernous sinus) and neuromeningeal complications (purulent
meningitis, brain abscess and cerebral empyema). Cerebral computed
Complications tomography (CT) must be ordered if any neurologic sign is present
Complications of sinusitis are caused by bacterial spread to nearby (Figure 26-5). Visual involvement may include loss of vision or loss of
structures such as the orbit, bone or central nervous system via the eye-globe mobility. Intracranial complications are more common in
venous system. Although extremely rare, bacterial spread by hemato older children and adults (e.g. cerebral abscess of the frontal lobe or
genous dissemination can cause distant infection. Orbital cellulitis is subdural abscess). These patients present with fever, neck rigidity and
the most common complication, especially in ethmoidal sinusitis. neurologic abnormalities. Osteomyelitis of the frontal bone may be
Purulent acute ethmoiditis (exteriorization of ethmoiditis in the observed in maxillary sinusitis.
orbit wall which is very tenuous) represents a real pediatric emergency,
which can occur in children aged more than 1 year. This diagnosis Diagnosis
must be considered in a child presenting with edema of the superior The diagnosis of sinusitis is clinical, but there are no reliable diagnostic
eyelid associated with swelling of the internal corner of the eye and criteria to distinguish between patients with acute viral and bacterial
nose root (Figure 26-4). It is a severe complication of an apparently sinusitis. Microbiologic diagnosis of sinusitis is difficult and requires
Figure 26-6 CT scan of acute maxillary sinusitis. Note the opaqueness of the
right maxillary sinus.
a
BOX 26-2 2013 GUIDELINES FOR THE DIAGNOSIS

AND MANAGEMENT OF ACUTE
BACTERIAL SINUSITIS IN CHILDREN
AGED 1–18 YEARS FROM THE
AMERICAN ACADEMY OF
PEDIATRICS
1: Clinicians should make a presumptive diagnosis of acute bacterial sinus-
itis when a child with an acute URI presents with the following:
• Persistent illness, i.e. nasal discharge (of any quality) or daytime cough
or both lasting more than 10 days without improvement; or
• Worsening course, i.e. worsening or new onset of nasal discharge,
daytime cough, or fever after initial improvement; or
• Severe onset, i.e. concurrent fever (temperature ≥39 °C/102.2 °F) and
purulent nasal discharge for at least three consecutive days (Evidence
Quality: B. Strength: Recommendation).
2A: Clinicians should not obtain imaging studies (plain films, contrast-
enhanced CT, MRI, or ultrasonography) to distinguish acute bacterial
sinusitis from viral URI (Evidence Quality: B. Strength: Strong Recom-
b mendation).
2B: Clinicians should obtain a contrast-enhanced CT scan of the paranasal
sinuses and/or an MRI with contrast whenever a child is suspected of
Figure 26-5 (a, b) CT scans of left acute ethmoiditis. having orbital or central nervous system complications of acute bacterial
sinusitis (Evidence Quality: B. Strength: Strong Recommendation).
3A: The clinician should prescribe antibiotic therapy for acute bacterial sinus-
a sample of sinus secretions not contaminated by the resident bacterial itis in children with severe onset or worsening course (signs, symptoms,
or both) (Evidence Quality: B. Strength: Strong Recommendation).
flora of the nose. This sample may be obtained by a needle puncture 3B: The clinician should either prescribe antibiotic therapy or offer additional
of the sinus. This is an invasive procedure, which may explain the lack outpatient observation for 3 days to children with persistent illness
of data concerning bacterial pathogenic agents of sinusitis. (nasal discharge of any quality or cough or both for at least 10 days
Plain film radiographs may help when diagnosis is difficult. The without evidence of improvement) (Evidence Quality: B. Strength: Re
commendation).
radiograph shows an opaqueness of the sinus, which may be unilateral 4: Clinicians should prescribe amoxicillin with or without clavulanate as
or the sinus shape is asymmetrical, and thickening of the mucous first-line treatment when a decision has been made to initiate antibiotic
membrane is greater than 4 mm; fluid levels are exceptional. Radio- treatment of acute bacterial sinusitis (Evidence Quality: B. Strength:
graphs must be interpreted according to age. In young children, only Recommendation).
5: Clinicians should reassess initial management if there is either a care-
maxillary and ethmoidal sinuses are aerated. However, opacification giver report of worsening (progression of initial signs/symptoms or
of the sinus or a mucous thickening may be present even if the patient appearance of new signs/symptoms) or failure to improve (lack of reduc-
is asymptomatic. CT scan is used in cases of sphenoidal sinusitis (not tion in all presenting signs/symptoms) within 72 hours of initial manage-
seen on standard radiography), ethmoiditis and complicated maxillary ment (Evidence Quality: C. Strength: Recommendation).
sinusitis (Figure 26-6).
Reproduced from Wald ER, et al. Pediatrics 2013;132(1):e262–280.
Management
Antibiotic treatment is indicated in cases of purulent sinusitis 36 and
hospitalization may be required in severe forms of ethmoiditis. Most with or without clavulanate is the first-line treatment of acute bacterial
cases of mild maxillary sinusitis will resolve spontaneously without sinusitis.
antibiotics. High-dose amoxicillin therapy is adequate to overcome the resis-
In 2013, the American Adademy of Pediatrics updated clinical tance to penicillin of SP but since the era of anti-pneumococcal
practice guidelines regarding the management of acute bacterial sinus- vaccination and with the advent of PCV13 conjugate vaccine, a con-
itis in children and adolescents37 (Box 26-2). Antibiotic therapy for tinuing decrease in isolates of SP (including a decrease in isolates of
acute bacterial sinusitis is indicated in children with severe onset or nonsusceptible SP) and an increase in β-lactamase-producing HI are
worsening course. Either antibiotic therapy or additional observation observed, thus standard-dose amoxicillin–clavulanate may be most
is recommended for 3 days to children with stable illness. Amoxicillin appropriate.
TABLE
26-2 Initial Management or in Case of Worsening or Lack of Improvement at 72 Hours of Acute Sinusitis
Initial Management Worse in 72 Hours Lack of Improvement in 72 Hours
Observation Initiate amoxicillin with or without clavulanate Additional observation or initiate antibiotic based on shared
decision-making
Amoxicillin High-dose amoxicillin–clavulanate Additional observation or high-dose amoxicillin–clavulanate based

on shared decision-making
High-dose amoxicillin–clavulanate Clindamycin* and cefixime or linezolid and Continued high-dose amoxicillin-clavulanate or clindamycin* and
cefixime or levofloxacin cefixime or linezolid and cefixime or levofloxacin
*Clindamycin is recommended to cover penicillin-resistant Streptococcus pneumoniae. Some communities have high levels of clindamycin-resistant Strep.
pneumoniae. In these communities, linezolid is preferred.
Reproduced from Wald ER, et al. Pediatrics 2013;132(1):e262–280.
Clinicians should reassess initial management if there is either Haemophilus and methicillin-sensitive staphylococci. Penetration and
worsening (progression of initial signs/symptoms or appearance of meningeal distribution are adequate. Duration of treatment is 10 days
new signs/symptoms) or failure to improve within 72 hours of initial in a hospital setting. In anaerobic infection, an antibiotic of the imid-
management. If the diagnosis of acute bacterial sinusitis is confirmed azole family will be added in first intention (e.g. metronidazole). Surgi-
with worsening symptoms or failure to improve, then clinicians may cal intervention can be considered according to the efficacy of
change the antibiotic therapy for patients initially managed with anti- antibiotics, ophthalmologic involvement and CT data.
biotics or initiate antibiotic treatment of patients initially managed Regarding the potential adjuvant therapy for acute sinusitis, a
with observation (Table 26-2).37 recent Cochrane Review on decongestants, antihistamines and nasal
Patients allergic to amoxicillin can be treated with cefdinir, cefu- irrigation found no appropriately designed studies to determine the
roxime, or cefpodoxime. The duration of antibiotic therapy varies effectiveness of these interventions.38
from 10 to 28 days of treatment. A single 50 mg/kg dose of ceftriaxone,
given intravenously or intramuscularly, can be used for children who FUNGAL SINUSITIS
are vomiting, unable to tolerate oral medication, or unlikely to be Fungal sinusitis is typically seen in immunodeficient patients. The
adherent to the initial doses of antibiotic. If clinical improvement is most common organisms are Aspergillus species, although zygomyces
observed at 24 hours, an oral antibiotic can be substituted to complete are also seen, especially in patients with uncontrolled diabetes mellitus.
the course of therapy. Children who are still significantly febrile or Progression can be extremely rapid, and management should include
symptomatic at 24 hours may require additional parenteral doses intravenous antifungal therapy and aggressive surgical debridement39
before switching to oral therapy. (see also Chapter 189). Allergic fungal sinusitis is a result of an inflam-
Ethmoiditis requires parenteral empiric antibiotic therapy in a hos- matory response of the sinus mucosa to colonizing fungi (usually
pital setting. Nose pus swabs and hemocultures may guide the antibi- molds).40 Management includes steroid therapy and surgical debride-
otic choice. The antibiotic must target HI and Staph. aureus. An ment. The value of antifungal therapy is unclear.
intravenous third-generation cephalosporin, such as cefotaxime or
ceftriaxone associated with an aminoglycoside, is active against References available online at expertconsult.com.
KEY REFERENCES
American Academy of Pediatrics Subcommittee on Man- otic use on nasopharyngeal carriage of nonsusceptible Shapiro D.J., Gonzales R., Cabana M.D., et al.: National
agement of Acute Otitis Media: Diagnosis and manage- pneumococci in children with acute otitis media. Pediatr trends in visit rates and antibiotic prescribing for chil-
ment of acute otitis media. Pediatrics 2004; 113(5): Infect Dis J 2006; 25(11):1001-1007. dren with acute sinusitis. Pediatrics 2011; 127(1):28-34.
1451-1465. Fortanier A.C., Venekamp R.P., Boonacker C.W.B., et al.: Venekamp R.P., Sanders S., Glasziou P.P., et al.: Antibiotics
American Academy of Pediatrics Subcommittee on Man- Pneumococcal conjugate vaccines for preventing otitis for acute otitis media in children. Cochrane Database Syst
agement of Sinusitis and Committee on Quality Improve- media. Cochrane Database Syst Rev 2014; (4):CD001480. Rev 2013; (1):CD000219.
ment: Clinical practice guideline: management of Grijalva C.G., Poehling K.A., Nuorti J.P., et al.: National Wald E.R., Applegate K.E., Bordley C., et al.: Clinical prac-
sinusitis. Pediatrics 2001; 108(3):798-808. impact of universal childhood immunization with pneu- tice guideline for the diagnosis and management of acute
Azzari C., Martinón-Torres F., Schmitt H.-J., et al.: Evolv- mococcal conjugate vaccine on outpatient medical care bacterial sinusitis in children aged 1 to 18 years. Pediatrics
ing role of 13-valent pneumococcal conjugate vaccine in visits in the United States. Pediatrics 2006; 118(3): 2013; 132(1):e262-e280.
clinical practice. Pediatr Infect Dis J 2014; 33(8): 865-873.
858-864. Lieberthal A.S., Carroll A.E., Chonmaitree T., et al.: The
Cohen R., Levy C., de La Rocque F., et al.: Impact of pneu- diagnosis and management of acute otitis media. Pediat-
mococcal conjugate vaccine and of reduction of antibi- rics 2013; 131(3):e964-e999.
Chapter 26 Otitis, Sinusitis and Related Conditions 242.e1
REFERENCES
1. Klein J.O.: The burden of otitis media. Vaccine 2000; 16. Harrison C.J., Woods C., Stout G., et al.: Susceptibili- 27. American Academy of Pediatrics Subcommittee on
19(Suppl.1):S2-S8. ties of Haemophilus influenzae, Streptococcus pneu- Management of Acute Otitis Media: Diagnosis and
2. Revai K., Dobbs L.A., Nair S., et al.: Incidence of acute moniae, including serotype 19A, and Moraxella management of acute otitis media. Pediatrics 2004;
otitis media and sinusitis complicating upper respira- catarrhalis paediatric isolates from 2005 to 2007 to 113(5):1451-1465.
tory tract infection: the effect of age. Pediatrics 2007; commonly used antibiotics. J Antimicrob Chemother 28. McCormick D.P., Chonmaitree T., Pittman C., et al.:
119(6):e1408-e1412. 2009; 63(3):511-519. Nonsevere acute otitis media: a clinical trial comparing
3. Klein J.O.: Epidemiology of otitis media. Pediatr Infect 17. Hoban D.J., Doern G.V., Fluit A.C., et al.: Worldwide outcomes of watchful waiting versus immediate antibi-
Dis J 1989; 8(Suppl. 1):S9. prevalence of antimicrobial resistance in Streptococcus otic treatment. Pediatrics 2005; 115(6):1455-1465.
4. Qureishi A., Lee Y., Belfield K., et al.: Update on otitis pneumoniae, Haemophilus influenzae, and Moraxella 29. Kakish K.S., Mahafza T., Batieha A., et al.: Clinical
media – prevention and treatment. Infect Drug Resist catarrhalis in the SENTRY Antimicrobial Surveillance sinusitis in children attending primary care centers.
2014; 7:15-24. Program, 1997–1999. Clin Infect Dis 2001; 32(Suppl. 2): Pediatr Infect Dis J 2000; 19(11):1071-1074.
5. Monasta L., Ronfani L., Marchetti F., et al.: Burden of S81-S93. 30. Shapiro D.J., Gonzales R., Cabana M.D., et al.: National
disease caused by otitis media: systematic review and 18. Fortanier A.C., Venekamp R.P., Boonacker C.W.B., trends in visit rates and antibiotic prescribing for chil-
global estimates. PLoS ONE 2012; 7(4):e36226. et al.: Pneumococcal conjugate vaccines for preventing dren with acute sinusitis. Pediatrics 2011; 127(1):28-34.
6. Van Zon A., van der Heijden G.J., van Dongen T.M.A., otitis media. Cochrane Database Syst Rev 2014; 31. Steele R.W.: Chronic sinusitis in children. Clin Pediatr
et al.: Antibiotics for otitis media with effusion in chil- (4):CD001480. (Phila) 2005; 44(6):465-471.
dren. Cochrane Database Syst Rev 2012; (9):CD009163. 19. Cohen R., Levy C., de La Rocque F., et al.: Impact 32. American Academy of Pediatrics Subcommittee on
7. Rosenfeld R.M., Culpepper L., Doyle K.J., et al.: Clini- of pneumococcal conjugate vaccine and of reduction Management of Sinusitis and Committee on Quality
cal practice guideline: otitis media with effusion. Oto- of antibiotic use on nasopharyngeal carriage of nonsus- Improvement: Clinical practice guideline: management
laryngol Head Neck Surg 2004; 130(5 Suppl.):S95-S118. ceptible pneumococci in children with acute otitis of sinusitis. Pediatrics 2001; 108(3):798-808.
8. Grijalva C.G., Nuorti J.P., Griffin M.R.: Antibiotic pre- media. Pediatr Infect Dis J 2006; 25(11):1001- 33. Brook I., Foote P.A., Hausfeld J.N.: Frequency of recov-
scription rates for acute respiratory tract infections in 1007. ery of pathogens causing acute maxillary sinusitis in
US ambulatory settings. JAMA 2009; 302(7):758- 20. Azzari C., Martinón-Torres F., Schmitt H.-J., et al.: adults before and after introduction of vaccination of
766. Evolving role of 13-valent pneumococcal conjugate children with the 7-valent pneumococcal vaccine.
9. Lieberthal A.S., Carroll A.E., Chonmaitree T., et al.: vaccine in clinical practice. Pediatr Infect Dis J 2014; J Med Microbiol 2006; 55(Pt 7):943-946.
The diagnosis and management of acute otitis media. 33(8):858-864. 34. Brook I.: The role of anaerobic bacteria in sinusitis.
Pediatrics 2013; 131(3):e964-e999. 21. Lous J., Ryborg C.T., Thomsen J.L.: A systematic review Anaerobe 2006; 12(1):5-12.
10. Chesney J., Black A., Choo D.: What is the best practice of the effect of tympanostomy tubes in children with 35. Rudolph C.D.: Supraesophageal complications of gas-
for acute mastoiditis in children? Laryngoscope 2014; recurrent acute otitis media. Int J Pediatr Otorhinolar- troesophageal reflux in children: challenges in diagnosis
124(5):1057-1058. yngol 2011; 75(9):1058-1061. and treatment. Am J Med 2003; 115(Suppl. 3A):150S-
11. Rosenfeld R.M., Kay D.: Natural history of untreated 22. Giebink G.S.: Otitis media prevention: non-vaccine 156S.
otitis media. Laryngoscope 2003; 113(10):1645-1657. prophylaxis. Vaccine 2000; 19(Suppl.1):S129-S133. 36. Smith M.J.: Evidence for the diagnosis and treatment
12. Eskola J., Kilpi T., Palmu A., et al.: Efficacy of a pneu- 23. Roddey O.F. Jr, Hoover H.A., Earle R. Jr: Physical of acute uncomplicated sinusitis in children: a system-
mococcal conjugate vaccine against acute otitis media. examination for otitis media. Pediatr Infect Dis J 2003; atic review. Pediatrics 2013; 132(1):e284-e296.
N Engl J Med 2001; 344(6):403-409. 22(7):673. 37. Wald E.R., Applegate K.E., Bordley C., et al.: Clinical
13. Grijalva C.G., Poehling K.A., Nuorti J.P., et al.: National 24. American Academy of Family Physicians, American practice guideline for the diagnosis and management of
impact of universal childhood immunization with Academy of Otolaryngology-Head and Neck Surgery, acute bacterial sinusitis in children aged 1 to 18 years.
pneumococcal conjugate vaccine on outpatient medical American Academy of Pediatrics Subcommittee on Pediatrics 2013; 132(1):e262-e280.
care visits in the United States. Pediatrics 2006; Otitis Media With Effusion: Otitis media with effusion. 38. Shaikh N., Wald E.R., Pi M.: Decongestants, antihista-
118(3):865-873. Pediatrics 2004; 113(5):1412-1429. mines and nasal irrigation for acute sinusitis in chil-
14. Pichichero M.E., Casey J.R.: Emergence of a multiresis- 25. Nussinovitch M., Yoeli R., Elishkevitz K., et al.: Acute dren. Cochrane Database Syst Rev 2010; (12):CD007909.
tant serotype 19A pneumococcal strain not included in mastoiditis in children: epidemiologic, clinical, micro- 39. Schubert M.S.: Allergic fungal sinusitis: pathophysiol-
the 7-valent conjugate vaccine as an otopathogen in biologic, and therapeutic aspects over past years. Clin ogy, diagnosis and management. Med Mycol 2009;
children. JAMA 2007; 298(15):1772-1778. Pediatr (Phila) 2004; 43(3):261-267. 47(Suppl.1):S324-S330.
15. Tristram S., Jacobs M.R., Appelbaum P.C.: Antimicro- 26. Venekamp R.P., Sanders S., Glasziou P.P., et al.: Anti- 40. Epstein V.A., Kern R.C.: Invasive fungal sinusitis and
bial resistance in Haemophilus influenzae. Clin Micro- biotics for acute otitis media in children. Cochrane complications of rhinosinusitis. Otolaryngol Clin North
biol Rev 2007; 20(2):368-389. Database Syst Rev 2013; (1):CD000219. Am 2008; 41:497-524.
27
Bronchitis, Bronchiectasis
MARCUS W. BUTLER | MICHAEL P. KEANE

• Acute bronchitis is a very common, usual viral, infection lasting In the USA, approximately 5% of adults self-report that they experi-
no more than 3 weeks, which usually requires no testing or ence an attack of acute bronchitis in a given year, and about 90% of
antimicrobial therapy. Nonetheless, inappropriate overpre- such persons seek medical attention for it.5 US physicians have reported
scription of antibiotics for acute bronchitis remains a global acute bronchitis as the ninth most common illness among outpa-
concern. tients.6 A comparable 5% annual incidence rate among previously well
• Bronchiectasis is an increasingly recognized, etiologically het- adults has been demonstrated in a United Kingdom prospective study.7
erogeneous and potentially serious form of chronic suppurative
lung infection with a tendency to have recurrent infective exac- Pathophysiology
erbations and decline in health status over time. The majority of pathogens implicated in causing acute bronchitis are
• Bronchiectatic lungs exhibit diverse polymicrobial communities viruses, with pathogens documented in only a minority of patients
during phases of clinical stability and during exacerbations that studied (16–29%).8,9 To date, only a handful of viruses and even fewer
interact with defects in host defense, impaired drainage and/ bacteria have been recognized to cause acute bronchitis (Table 27-1).
or obstruction to perpetuate lung inflammation via activation Despite laboratory isolation of the typical community-acquired pneu-
of immune, proteolytic and oxidative processes. monia bacteria such as Streptococcus pneumoniae, Haemophilus influ-
• Therapy of stable bronchiectasis is centered on airway secre- enzae and Moraxella catarrhalis in 26% of investigated cases of acute
tion clearance strategies and approaches designed to prevent bronchitis in one study,7 there is no convincing causation data to show
acute exacerbations (mainly antibiotic- and immunization- bronchial wall invasion by such typical bacteria. In contrast, influenza
based and targeting identified pathogens). A viral infection of large airways results in rapid cytopathologic change,
with a lymphocytic inflammatory infiltrate and associated denuding
• A growing body of research activity is focusing on non-cystic
fibrosis bronchiectasis interventions including an emphasis on of the airway epithelial barrier.19 Human parainfluenza viruses, which
accurate etiologic diagnosis, use of clinical prediction tools, in immunocompetent subjects only causes self-limiting respiratory
inhalational antibiotics, and long-term macrolides to favorably disease, exhibit a tropism towards superficial ciliated cells, with
influence disease outcomes. budding of virions directed to apical epithelial surfaces. Human para-
influenza virus infection also leads to inhibition of ciliary motility,
which plausibly contributes to impaired clearance of mucus and cel-
lular debris.10,20 Respiratory syncytial virus resembles parainfluenza
virus in having limited cytopathic potential in human airway epithe-
lium, and targeting the superficial ciliated cells with resultant impaired
Bronchitis ciliary beating.21,22 Minimal discernible epithelial necrosis or sloughing
Bronchitis, in its broadest sense, refers to any inflammatory process occurs in human rhinovirus-mediated acute bronchitis, and the symp-
involving the bronchi, or large conducting airways of the lungs distal toms are thought to reflect activation of host defense and inflamma-
to the trachea and proximal to the smaller airways or bronchioles, the tory responses, as with the other less cytopathic respiratory viruses.23
latter characterized histologically by their lack of hyaline cartilage, Interestingly, there is some in vitro evidence to suggest greater suscep-
goblet cells or submucosal glands.1 Bronchitis can be classified as acute tibility to rhinovirus infection of bronchial rather than nasal epithe-
or chronic: chronic bronchitis, a frequent feature of chronic obstruc- lium, though rhinovirus is a more prevalent cause of upper respiratory
tive pulmonary disease (COPD), is conventionally defined as the pro- than lower respiratory tract infections.24 The bacterial pathogen best
duction of excessive sputum on most days for at least 3 months, and described to cause acute bronchitis symptoms is Bordetella pertussis,
for at least 2 consecutive years.2 Unlike acute bronchitis, the principal which adheres to ciliated respiratory epithelial cells and induces local
causative insult in chronic bronchitis is felt to be an aberrant response tissue damage via tracheal cytotoxin, dermonecrotic toxin or adenylate
to noxious stimuli, principally tobacco smoke, and to a much lesser cyclase, among other biologically active substances and virulence
extent other air pollutants and occupational exposures. A variety of factors.25 Another causative bacteria, Mycoplasma pneumoniae, pro-
mainly viral but also bacterial pathogens can be responsible for acute duces adherence proteins that have a particular affinity for respiratory
exacerbations of chronic bronchitis/COPD. Noninfective events can tract epithelium, and subsequent to attachment, the bacteria release
also give rise to exacerbations of COPD, including pulmonary hydrogen peroxide, superoxide and a vacuolating cytotoxin that are
thromboembolism. COPD and the role of antimicrobial therapy is toxic to ciliated epithelial cells.26,27
discussed elsewhere in this textbook (see Practice Point 10).
Acute bronchitis constitutes one of the most widely encountered Approach to Diagnosis
conditions seen by clinicians. In the typical case of acute bronchitis, The cardinal symptom of acute bronchitis is acute cough, present
the tracheobronchial tree is inflamed due to a lower respiratory tract between 5 to 21 days, and usually associated with purulent sputum,
infection which is not as severe as pneumonia, with the infectious often with associated wheeze or chest heaviness. By definition, acute
agent being viral in origin in the great majority of cases. The condition bronchitis is a primary diagnosis, and not secondary to an underlying
presents as a cough with or without accompanying sputum produc- chronic pulmonary disease such as asthma. Any fever is generally low-
tion, and which fails to settle by 5 days, distinguishing it from overlap grade. Severe paroxysmal cough, with or without cough-induced
with the common cold.3 The symptoms of acute bronchitis do not emesis and a more prolonged course, should prompt consideration of
persist beyond 3 weeks, after which time other diagnoses should be pertussis infection, and requires a high index of suspicion to make the
considered.4 diagnosis.
243
TABLE
27-1 Known Infectious Causes of Acute Bronchitis
Etiologic Agent Observations
VIRUSES
Influenza virus, types A and B Fever, myalgia and headache often accompany the cough. Therapy: oseltamivir or zanamivir for 5 days
Parainfluenza virus Often association of contact with croup case. No vaccine or antiviral drug licensed10
Respiratory syncytial virus Adult re-infection is the norm. Wheeze is common. Inhaled ribavirin used if severely immunocompromised.
No vaccine available11
Rhinovirus (HRV) Mild disease, but HRV strains A and C have been linked to more severe illness12
Human metapneumovirus More prevalent in young children and the elderly: in the latter, causes influenza-like illness and colds13
Adenovirus Causes influenza-like illness
Corona viruses Newer identified members include NL63, HKU1. Occur in winter, with short incubation time. No specific
therapy or vaccine. SARS and MERS cause more serious viral pneumonia14,15
Human bocavirus 1 (HBoV1) Due to virus persistence, acute HBoV1 diagnosis should be based on serology or serum PCR16
BACTERIA
Mycoplasma pneumoniae Causes more upper than lower respiratory tract symptoms. Gradual symptom onset (2–3 days). Causes <1%
of acute cough cases17
Chlamydophila (Chlamydia) pneumoniae Hoarseness may precede cough. No strong evidence to support use of macrolides and tetracycline therapy
in uncomplicated bronchitis linked to mycoplasma or chlamydophila
Bordetella pertussis, B. parapertussis B. pertussis accounts for 1% of acute bronchitis in the USA.18 Macrolides are first-line therapy
It is not necessary to perform any diagnostic testing when the clini- of acute and chronic cough such as pneumonia, upper airway cough
cal suspicion is acute bronchitis. Some erroneously assume that the syndrome, gastroesophageal reflux and initial presentations of asthma
presence of purulent sputum indicates serious infection, though fewer and COPD.
than 5% of patients with discolored sputum have evidence of pneu-
monia.28 The practical diagnostic difficulties provide the rationale to Principles of Management
find a tool that may predict bacterial rather than viral infection, such In general, cases of acute bronchitis are managed conservatively with
as procalcitonin (PCT), a peptide pre-hormone of calcitonin, normally symptomatic support and advice from a knowledgeable healthcare
secreted by C cells of the thyroid in response to hypercalcemia, with professional. As the vast majority of cases of acute bronchitis are not
low levels in serum (<0.5 ng/mL), but also elaborated in inflammatory bacterial in origin and are self-limiting, there are well-founded con-
states, being produced by liver hepatocytes, peripheral blood mono- cerns that over-prescription of antibiotics for acute bronchitis could
nuclear cells and modulated by lipopolysaccharides and sepsis-related lead to an excess of adverse drug reactions, costs and antimicrobial
chemokine signals.29–31 Its upregulation appears to be abrogated by resistance.28,35 In the most recent Cochrane systematic review of anti-
interferon-gamma-mediated inhibition in the setting of viral infection, biotic therapy in data from randomized controlled trials involving
rendering PCT more specific for bacterial infection. A recent meta- more than 3000 instances of acute respiratory tract infection, the treat-
analysis of 14 randomized trials (4221 participants, mainly in Europe), ment strategy resulting in least antibiotic use and comparable patient-
examining whether or not procalcitonin levels could be used to safely related outcomes was to avoid prescribing antibiotics and advise the
guide therapy decisions in settings varying from primary care to ICU, patient to return if symptoms did not resolve.35 It has been suggested
concluded that the strategy was not associated with higher mortality that anti-inflammatory therapy might reduce the cough symptom in
rates or treatment failure, and significantly reduced antibiotic con- acute bronchitis.3,36 A recent Spanish primary care study of 416 sub-
sumption across all clinical settings and types of acute respiratory tract jects randomized to receive the nonsteroidal anti-inflammatory drug
infection.32 A significant minority studied had acute bronchitis. A ibuprofen, amoxicillin–clavulanic acid or placebo for uncomplicated
recent multinational real-life observational study showed that those acute bronchitis and discolored sputum showed no significant differ-
with acute bronchitis (253 patients) had the highest compliance with ences in the number of days with cough (ibuprofen: 9 days, 95% CI
a PCT-guided antibiotic-treatment algorithm for lower respiratory 8–10; amoxicillin–clavulanic: 11 days, 95% CI 10–12; placebo: 11 days,
tract infections (81%, vs 70.1% for acute exacerbations of COPD and 95% CI 8–14).37
vs 63.7% for community-acquired pneumonia; p < 0.001). Overall, in Appropriate symptomatic treatment for acute bronchitis includes
this study that encouraged the use of highly sensitive immunoassays consideration of a short-acting beta-2 agonist if there is prominent
for PCT measurement, it was found that antibiotic therapy duration wheeze or dyspnea on exertion, although there are conflicting and
was shorter if the PCT algorithm was complied with.33 While the data limited data on this approach. Experts have differed on whether anti-
are encouraging, the use of PCT in routine care awaits further valida- tussive agents such as short-term codeine or preparations containing
tion in large trials. hydrocodone should be used for persistent cough.3,38,39 Greater con-
For influenza-like illnesses, a rapid influenza diagnosis test is avail- sensus surrounds the recommendation for macrolide therapy when B.
able and can be used seasonally. The US Centers for Disease Control pertussis is the cause, and for oseltamivir or zanamivir when influenza
(CDC) has issued guidance on the use of such tests in clinical prac- A is identified early in the course of illness.
tice.34 Bacterial cultures of sputum are not recommended in patients
with acute bronchitis. Pertussis can be diagnosed by a nasopharyngeal
swab or aspirate taken from the posterior nasopharynx and sent for Bronchiectasis
culture, supplemented by rapid polymerase chain reaction (PCR)
testing, where available, given the rapidity and sensitivity of the latter Ectasia or dilatation of the bronchi, referred to as bronchiectasis, is
test. The differential diagnosis of acute bronchitis includes other causes an uncommon suppurative lung disease state typically characterized
Chapter 27 Bronchitis, Bronchiectasis 245
by a cough productive of purulent sputum and predisposition to 100 000.44 There appears to be an elevated mortality rate observed in
recurrent and often refractory acute infective exacerbations. There is prospective studies of bronchiectasis sufferers. In a study that enrolled
often associated progressive dyspnea with accelerated decline in lung and followed 91 patients with bronchiectasis for a period of 13 years,
function, episodic hemoptysis and impaired quality of life. Different a mortality rate of 29.7% was observed.45 A more recent bronchiectasis
morphologic patterns of ectatic airways have been described, including cohort of 608 patients had a mortality rate of 10.2% over a 4-year
cylindrical, varicoid (visually resembling venous varicosities), saccular period.46
and cystic varieties, with the latter two signifying more severe, destruc-
tive disease typically. Though an uncommon disease, bronchiectasis
appears to be increasingly recognized, based on recent Medicare Pathophysiology
Part B outpatient data, in which the average annual prevalence rate A variety of factors are usually involved in the development of bron-
was 138/100 000 people.40 A previous study showed an estimated chiectasis. There is typically a defect in host defense, or some form of
prevalence of adult bronchiectasis in the USA of 52/100 000.41 Data impaired drainage and/or obstruction within the airway walls that
suggest a higher prevalence is found in Asian populations, among combines with a perpetuating infectious process that begets inflamma-
women and with advancing age.40 The annual associated cost of care tion, and activates immune responses, proteolytic and oxidative pro-
in the USA was estimated at $630 million in 2005.41 In Germany, a cesses. A diverse array of conditions is associated with the development
steadily increasing prevalence of bronchiectasis-associated hospitaliza- of bronchiectasis to a varying extent and severity (see Table 27-2). An
tions has been recently observed, highest in the elderly and in females, example of a recognized etiology is shown in Figure 27-1. However,
with the average annual age-adjusted rate for bronchiectasis as any despite an exhaustive work-up, there may be no cause found in half of
(primary or other) diagnosis being 9.4 hospitalizations per 100 000.42 all cases.47 It is envisaged that important advances in our understand-
Asian data suggest even higher rates of annual age-adjusted hospital- ing of the pathobiology of non-cystic fibrosis (CF) bronchiectasis will
ization for any diagnosis of bronchiectasis, at 16.4 per 100 000,43 similar result from collaborations in the form of patient registries, as have been
to the US rate for the period from 1993 to 2006, which was 16.5 per established.48
TABLE
27-2 Recognized Etiologies of Bronchiectasis, and their Associated Diagnostic Tests
Etiologic Type Diagnosis Diagnostic Testing
Post-infective Childhood bacterial infections (Streptococcus pneumoniae, Usually a prior clinical diagnosis. Bacterial sputum cultures
Haemophilus influenzae, Pseudomonas aeruginosa, Bordetella
pertussis)
Viral (adenovirus, measles, influenza) Usually a prior clinical diagnosis
Allergic bronchopulmonary aspergillosis Clinical, imaging and immunologic criteria
Immune deficiency Immunoglobulin deficiency (common variable immune deficiency, Serum total immunoglobulins, IgG subclasses,
X-linked agammaglobulinemia, IgG subclass deficiencies, pneumococcal vaccine titers, dihydrorhodamine 123
selective IgA deficiency, Nezelof’s syndrome etc.), chronic oxidation test, nitroblue tetrazolium test, genetic testing
granulomatous disease
HIV HIV testing
Chronic lymphocytic leukemia CBC, peripheral blood smear, flow cytometry
Immune modulation (post transplant) Clinical diagnosis
Hyperimmunoglobulin E (Job’s) syndrome IgE levels, Th17 cell count
CFTR gene dysfunction Cystic fibrosis Positive sweat chloride tests, two CFTR mutations,
abnormal nasal potential difference
Ciliary disease Primary ciliary dyskinesia (including Kartagener syndrome) Situs abnormalities on imaging, nasal nitric oxide, electron
microscopy, genetic testing (over 20 causative genes
identified)
Post-obstructive Benign/malignant tumors Image-guided biopsy

Tuberculous lymphadenitis (Mycobacterium tuberculosis), also Mycobacterial and fungal sputum evaluation,
post-infective bronchoscopy (including endobronchial ultrasound-
Other lymphadenopathy (granulomatous, histoplasmosis) guided transbronchial needle aspirates). Also for TB:
Mantoux test, interferon-gamma release assay. Also for
histoplasmosis: blood/urine antigen testing, serology
Airway injury Inhalational injury (chlorine, ammonia, smoke etc.) Usually a clinical diagnosis. Endoscopic inspection
Aspiration (oropharyngeal, gastroesophageal) EGD, barium swallow, 24 hour esophageal pH probe
Rheumatology-related Rheumatoid arthritis Clinical diagnosis, rheumatoid factor, anti-CCP

Systemic lupus erythematosus Clinical diagnosis, ANA, anti-dsDNA
Sjögren’s syndrome Sicca complex, anti-Ro/SSA, anti-La/SSB, MR of salivary
gland, salivary gland biopsy
Relapsing polychondritis Cartilage biopsy in correct clinical setting
Inherited cartilage Mounier–Kuhn syndrome (tracheobronchomegaly) High-resolution CT of chest

disorder Williams–Campbell syndrome (cartilage deficiency) High-resolution CT of chest
Inflammatory bowel Ulcerative colitis (more often associated with bronchiectasis) Clinical diagnosis, bowel imaging studies, colonoscopic
disease Crohn’s disease (less often associated with bronchiectasis) biopsies
Others Alpha-1 antitrypsin deficiency Serum A1AT levels and phenotype/genotype
Yellow nail syndrome Clinical diagnosis: lymphedema, dystrophic yellow nails
and pleural effusions. Usually sporadic
Diagnostic test abbreviations: ANA, antinuclear antibody; CBC, complete blood count; CCP, cyclic citrullinated peptide; EGD, esophagogastroduodenoscopy; MR,
magnetic resonance; CT, computed tomography.
likely reflecting less overgrowth by pathogens such as P. aeruginosa.

The same group also showed that bacterial community composition
similarity correlated significantly with neutrophil inflammation,
cough-specific symptoms and lung function.53 Recently, Purcell et al.
from the UK evaluated sputa from 70 non-CF bronchiectasis outpa-
tients with culture and pyrosequencing and found no relationship of
bacterial community diversity with lung function, antibiotic therapy
or gender, though they found that P. aeruginosa and H. influenzae
exerted a significant effect on the diversity of the bacterial community
in the lungs of their patients.54 A larger number of taxa (27), including
Pasteurellaceae, Streptococcaceae, Xanthomonadaceae, Burkholderia-
les, Prevotellaceae and Veillonellaceae, were associated with acute
exacerbations, whereas a smaller number of taxa (11), including Pseu-
domonas spp., correlated with stable states, suggesting that the bacterial
community in the lungs of exacerbating patients has a more dynamic
community composition than that seen in stable patients, somewhat
at odds with the earlier findings of Tunney et al. using similar pyrose-
quencing technologies.52 This more recent study did not evaluate the
stability of this signal over differing timepoints, however.54 Nontuber-
culous mycobacteria (NTM) appear to be uncommonly identified in
non-CF bronchiectasis, detected in 2% of 100 patients in one cohort,
with a predilection towards Mycobacterium avium complex (MAC).55
a Another large cohort study of 98 adult-onset bronchiectasis patients
identified 10% with NTM.56
A key factor in the high frequency of colonization by P. aeruginosa
in both CF and non-CF bronchiectasis is its ability to form biofilms,
which protect the bacterial colony from the innate host response and
the effects of antibacterial therapies. Many bacteria that can cause
bronchiectasis (e.g. Pseudomonas aeruginosa) can form biofilms.
Clinical Findings
Bronchiectasis may be present when a patient presents with chronic
cough and sputum expectoration. There is usually a history of frequent
attacks of chest infections requiring repeated courses of antibiotics.
Less commonly, the cough may be nonproductive. Other frequently
reported symptoms include dyspnea, pleuritic chest pain, wheeze and
symptoms of rhinosinusitis. The patient may also have episodic
b hemoptysis, fatigue and, in women, stress urinary incontinence.57,58
Other suspect presentations include the patient with an ostensible
Figure 27-1 (a) Cystic bronchiectasis post-tuberculosis and thoracoplasty. This diagnosis of COPD who lacks a convincing risk factor such as smoking,
is the frontal chest radiograph from an 85-year-old woman who developed pul- a patient with difficult to control asthma despite optimal management,
monary tuberculosis in her early twenties and who failed pneumothorax and or the finding of Pseudomonas or NTM in sputum.
plombage interventions before undergoing a right thoracoplasty procedure at the
age of 25. Since then, she had chronic sputum production with infective exacerba-
tions. (b) Her cross-sectional imaging reveals severe cystic bronchiectasis in the Approach to Diagnosis
atelectatic right upper lobe.
Once the suspicion for bronchiectasis arises, diagnostic testing is con-
ducted, firstly to confirm the finding of bronchiectasis radiologically,
and then to assess for reversible etiologic factors. Finally, physiologic
assessments are appropriate as a baseline indication of the functional
Bacteriology capacity of the patient, with a view to follow-up. The optimal test with
Airway infection is a prominent feature of bronchiectasis, but the which to make the diagnosis is high resolution computed tomography
relationship between infection and disease progression is imperfectly (CT) scan imaging, preferably using helical high-resolution multi
understood.49–51 Where traditional culture techniques have long iden- detector technology that is usually available, looking for evidence of
tified aerobic pathogens such as H. influenzae, Pseudomonas aeruginosa airway dilation and mucus plugging. The dilated airways are suggested
and Strep. pneumoniae, work by Tunney and colleagues using addi- by the lack of bronchial tapering (see Figure 27-2), the presence of ring
tional anaerobic culturing and high-throughput pyrosequencing with shadows (sometimes accompanied by mucus/secretions) and the
sputum samples has demonstrated diverse polymicrobial communities signet ring sign (cross-sectional luminal airway diameter greater than
in bronchiectatic lungs during clinical stability and during exacerba- the diameter of the adjacent vessel, see Figure 27-3). Dilated airways
tions, with an unexpected degree of stability observed in both micro- are reproducibly suggestive of bronchiectasis when the lumen is at least
bial load and community composition. The study authors contended 1.5 times the diameter of the accompanying vessel.59 Mucus plugging
that changes in microbiota composition do not account for exacerba- involves large and/or small airways, with the latter site resulting in
tions of bronchiectasis, while conceding that potential pathobiological appearances known as tree-in-bud (see Figures 27-2 and 27-4).
interactions among microbes or alterations in microbial genetic factors Other studies frequently undertaken in the evaluation of bronchi-
remain unexplored as potential mechanisms of exacerbation.52 Others ectasis patients include a complete blood count (which may show
have shown clinical measures of bronchiectatic disease activity can be anemia, suggestive of ulcerative colitis or Crohn’s disease; or may
related to the lower airway microbiota. Rogers and co-workers showed suggest eosinophilic states), bacterial, mycobacterial and fungal sputum
that the more diverse the lower airway microbiota in non-CF bronchi- stains/cultures, serum immunoglobulins A, E, G, M and IgG subclasses,
ectasis, the higher the forced expiratory volume in 1 second (FEV1), pneumococcal vaccine titers (looking for impaired response), serum
Figure 27-2 Lack of tapering of peripheral airway walls. In this 57-year-old man
of European ancestry with idiopathic bronchiectasis there are a number of areas
demonstrating the ‘tram tracks’ sign, or lack of tapering of opposing airway walls
when viewed in longitudinal cross-section (arrows). In addition, there is evidence
of bronchiolar filling defects, referred to as ‘tree-in-bud’ appearance (arrowhead). Figure 27-4 Mucus plugging, cystic bronchiectasis. This 75-year-old man with
The patient has been chronically colonized with Mycobacterium abscessus. non-CF bronchiectasis who was a former smoker underwent a left lower lobe
segmentectomy 50 years previously to remove a focus of very severe bronchiec-
tasis. He now has evidence of severe cystic bronchiectasis in his right lower lobe,
with extensive mucoid filling (an example is pointed to by the arrow). His smaller
left lung volume is evident.
Principles of Management
Though multiple causes exist for bronchiectasis, management of the
disease in the office setting is largely centered on the principles of
airway clearance strategies (which include exercise-based interven-
tions) and approaches designed to prevent acute exacerbations (mainly
antibiotic-based and targeting identified pathogens; also immuniza-
tions), with less clear roles for bronchodilator or additional anti-
inflammatory therapies at present. The therapeutic interventions are
intended to enhance quality of life, preserve pulmonary function
and minimize healthcare utilization. Such is the inherent difficulty in
producing robust evidence of therapeutic efficacy and safety in this
diverse patient population that, as of yet, no pharmaceutical agent has
received approval from the US Food and Drug Administration for the
treatment of non-CF bronchiectasis. Significant progress has been
Figure 27-3 Ring shadows, ‘signet ring’ sign. Both upper lobes of this 38-year- made, however, and the condition is attracting greater attention now
old woman with idiopathic bronchiectasis, colonized by Pseudomonas aerugi- than in the past. It is important to direct therapy against the underlying
nosa, show evidence of ring shadows, with thickened and dilated airway walls cause of bronchiectasis where known, as appropriate. Acute manage-
(black arrows). In addition, she exhibits the ‘signet ring’ sign, with the dilated
airway diameter greater than 1.5 times that of its accompanying vessel (white
ment is based on identifying those in need of inpatient therapy and
arrow). Finally, the arrowhead points to a cylindrical bronchiectatic airway partially refining antibiotic selection to reflect isolated pathogens and local
filled by mucus. resistance patterns, with augmented airway clearance techniques and
dealing with specific situations including hemoptysis. The need for
surgical interventions such as lung transplantation or surgery to
remove severely damaged segments or lobes that perpetuate infection
electrophoresis, sweat chloride measured on two separate occasions, or hemorrhage, should continue to recede with earlier identification
CFTR genetic testing, alpha1-antitrypsin level and phenotype or geno- and better medical management. Over recent years, some data have
type, serology tests for antinuclear antibody, rheumatoid factor, anti- begun to accrue that specifically address non-CF bronchiectasis man-
cyclic citrullinated peptide, SSA/Ro and SSB/La antibodies. Less agement, with important lessons learnt, for example the potential
frequently requested tests reserved for more specific situations include danger of CF therapies being indiscriminately extrapolated to non-
those outlined in Table 27-2. CF patients, as with aerosolized recombinant deoxyribonuclease
Spirometry is used in the assessment of all airways diseases, (dornase-alpha).61
however the forced expiratory volume of air in 1 second (FEV1) has
limitations as a decision-making tool in bronchiectasis: there is a poor Prevention of Exacerbations
correlation of CT imaging with expiratory airflow limitation, and Exacerbations of bronchiectasis can be more difficult to identify than
dynamic changes in FEV1 in response to therapy are modest.60 The in COPD or asthma, as bronchiectasis patients will often feel tired,
severity of bronchiectasis may now be better assessed using the Bron- prone to breathlessness and describe having discolored sputum at
chiectasis Severity Index (BSI), a prospectively validated multidimen- baseline. Though there is no universally agreed definition of a bron-
sional clinical prediction tool.60 chiectasis exacerbation, high-quality clinical trials that have utilized
exacerbations in the preceding year. Erythromycin was shown to mod-

TABLE Definition of an Exacerbation of Bronchiectasis estly reduce protocol-defined pulmonary exacerbations (mean events
27-3 That Has Been Used in Clinical Trials61,62 1.29 vs 1.97 per patient per year, p = 0.003), reduce sputum production
and attenuate the decline in lung function (mean difference in FEV1
Symptom Requirement to
Meet Protocol Definition
of 2.2% of predicted, p = 0.04), at a cost of increased macrolide-
Symptom of Exacerbation61,62 resistant oropharyngeal streptococci (median change 27.7% vs 0.04%
in placebo subjects, p < 0.001).70 Pseudomonas-colonized patients also
Change in sputum production* At least four of the listed
Increased dyspnea† symptoms, signs or gained from having fewer such exacerbations in the active treatment
Increased cough laboratory findings must arm.70 A recent multicenter randomized trial emanating from the
Fever greater than 38 °C be present Netherlands, the BAT trial, evaluated 12 months of daily azithromycin
Increased wheezing (250 mg) versus placebo in 83 bronchiectasis patients having had at
Decreased exercise tolerance, malaise,
fatigue or lethargy
least three lower respiratory tract infections in the previous year. While
Fall in pulmonary function measures‡ macrolide resistance was again noted (88% with azithromycin, 26%
Radiographic changes indicative of a new with placebo), the active therapy group experienced fewer exacerba-
pulmonary process tions (p < 0.001), with at least one exacerbation occurring in 46% of
Changes in chest sounds azithromycin-treated subjects versus 80% of those on placebo (hazard
*This includes sputum consistency, color, volume, or hemoptysis. ratio 0.29 [95% CI 0.16–0.51]).62 The EMBRACE trial, which enrolled
†
This includes chest congestion or shortness of breath. those with at least one exacerbation of bronchiectasis in the previous
‡
In the trials by O’Donnell et al.61 and by Altenburg et al.,62 this was a fall of at year, found that 6 months of three-times-a-week azithromycin
least 10% in either the forced expiratory volume in 1 second (FEV1) or the
forced vital capacity (FVC) from a previously recorded value.
(500 mg) reduced the exacerbation frequency rate compared to
placebo (relative reduction 0.38 [95% CI 0.26–0.54]), though without
a benefit in terms of lung function or quality of life in this shorter
study.64
exacerbation frequency as a primary outcome show similarities in the Consensus may be slowly emerging with regards to the benefit of
definition of exacerbation used (see Table 27-3).61,62 Other studies have macrolide therapy in patients who are experiencing frequent exacerba-
described symptom-based exacerbations as an increase in or new onset tions of non-CF bronchiectasis, though many questions remain,
of more than one of the three Anthonisen criteria that have been used including the frequency of dosing, selection of the most appropriate
to describe a COPD exacerbation: an increase in sputum volume, patients and the import of macrolide resistance and cardiovascular
sputum purulence, or dyspnea.63,64 The British Thoracic Society has toxicity in this patient population should more widespread macrolide
recently recommended that antibiotics be given for non-CF bronchi- use occur.71,72 Other toxicities of macrolides also require consideration
ectasis exacerbations that present with an acute deterioration, typically in weighing up decisions to commence long-term macrolide therapy
over the course of a number of days, with worsening pulmonary symp- or not, including hearing loss, diarrhea, abdominal discomfort, nausea
toms and/or systemic upset. The pulmonary symptoms are cough, and hepatotoxicity. Therapy with long-term macrolides should perhaps
increased sputum volume or change of viscosity, increased sputum be reconsidered in those who are managing reasonably well with other
purulence with or without increasing wheeze, breathlessness or aspects of bronchiectasis management, including airway clearance,
hemoptysis.65 prompt use of antibiotics for exacerbation and who show no evidence
It is intuitively attractive to aim to suppress the bacterial burden of progression of disease or lack severe baseline impairments in lung
for symptomatic patients with bronchiectasis who have failed measures function.73
to have a pathogenic organism eradicated. Where P. aeruginosa is first A number of clinical trials over the years, some of which were
identified in sputum, it is recommended that eradication be attempted randomized and controlled, have evaluated prolonged treatment with
with a 2-week course of an oral antipseudomonal agent such as cipro- various nebulized antibiotics in non-CF bronchiectasis, including
floxacin 750 mg BD, with further regimens a consideration for those amoxicillin, ceftazidime, aztreonam, colistin, ciprofloxacin and amino-
who fail to clear the organism, such as intravenous and inhaled anti glycoside agents, chiefly gentamicin and tobramycin.74–78 All trials thus
pseudomonals.66 Patients who continue to have copious sputum and far have suffered, to varying degrees, from being underpowered or
frequent infective episodes can be considered for more prolonged anti- from other study design limitations including an insufficiently long
biotic therapy. In support of such an approach, there is a clear propor- duration on active therapy, and the reproducibility limitations often
tional relationship between airway bacterial load on the one hand and observed in disease populations characterized by phenotypic hetero-
measures of systemic and airway inflammation, exacerbations and geneity, a factor in non-CF bronchiectasis. There are promising indica-
health-related quality of life on the other. The inflammation will lessen tors nonetheless. Inhaled gentamicin has been used off-label in non-CF
with short- and long-term antibiotic interventions.67 Long-term oral bronchiectasis by reconstituting 80 mg of the intravenous preparation
antibiotics have been in clinical use and studied as an intervention for in 0.9% saline to the 5 mL volume employed in commonly used nebu-
bronchiectasis patients for decades. A systematic Cochrane review in lizer systems, and given as a twice-daily regimen. Such therapy has been
2007 of nine eligible trials concluded there was a small benefit to the shown over 3 days to reduce microbial load, sputum myeloperoxidase
use of prolonged antibiotics in treating purulent bronchiectasis in (as a surrogate of neutrophil quantity) and sputum volume, improve
children and adults.68 Where non-macrolide oral antibiotics are con- peak expiratory flow rates and improve exercise capacity as assessed by
cerned (such as amoxicillin or doxycycline), it would seem reasonable Borg breathlessness scores and 6-minute walk test distance.79 A more
to consider a prolonged suppressive regimen for patients who are suf- recent single-masked study randomized 65 patients to a year of either
fering from at least three exacerbations a year and who cannot be nebulized gentamicin or nebulized normal saline and found that gen-
considered for long-term macrolide regimens, provided they are not tamicin therapy led to a reduction in sputum bacterial density, with
colonized with P. aeruginosa.66 Nontuberculous mycobacteria are prob- the secondary endpoint of exacerbation frequency also favoring gen-
lematic pathogens when present and should not be treated with mac- tamicin over placebo (0 [IQR 0–1] vs 1.5 [IGR 1–2], p<0.0001), though
rolide monotherapy, but rather in accordance with American Thoracic all outcome measures reverted to baseline at 3-month follow-up,
Society/Infectious Diseases Society of America guidelines.69 attesting to the lack of durable response off therapy.77
Macrolide antibiotics continue to attract increasing attention as a Regarding inhaled tobramycin solution (TSI), a 28-day study of
preventative intervention in bronchiectasis. The Australian BLESS trial aerosolized tobramycin (300 mg BD) vs placebo equivalent in a popu-
randomized 117 non-CF bronchiectasis patients to receive either twice lation of 74 patients colonized with pseudomonas reported a 10 000-
daily erythromycin ethylsuccinate (400 mg BD per os) or placebo for fold reduction in pseudomonal density, with no treatment effect seen
one year, at a single center. Patients had to have had two or more on lung function.76 There has been concern about the toxicity of
inhaled tobramycin, and in a small uncontrolled pilot study where 41 who should not receive further doses. Inhaled beta-2 agonist medica-
patients were given TSI for 2 weeks on, 2 weeks off, for 12 weeks in tions can be simultaneously used in those patients with lesser extent
total, 10 patients experienced therapy-limiting side effects of cough, of bronchospasm and who would otherwise benefit from inhaled
wheeze and worsened dyspnea.80 A higher rate of wheeze (50% of 26 antibiotics.
TSI-treated subjects vs 15% in aerosolized quinine–sulphate placebo
arm) was seen in another trial of 14 days of TSI added to oral cipro- Treatment of Acute Exacerbations
floxacin for acute exacerbations of P. aeruginosa infection in non-CF
When a patient with bronchiectasis experiences the symptoms of an
bronchiectasis, despite favorable effects of tobramycin on microbio-
acute exacerbation (see Table 27-3), sputum should be sent for bacte-
logical parameters.81
rial and mycobacterial stains and culture, with antibiotic therapy initi-
Nebulized colistin has been widely used in Europe to treat non-CF
ated pending the results of these samples, and based on the patient’s
bronchiectasis, with some data to support its use. A small Australian
prior sputum results where known. When there is no available prior
observational study of nebulized colistin 30 mg daily in 2 mL of solu-
bacteriologic information on a patient’s sputum, empiric therapy
tion added to usual care of 18 patients, over 75% of whom had P.
should be directed against Pseudomonas but be cognizant of other
aeruginosa, showed a slower decline in FEV1 (44 mL/year vs 104 mL/
frequently isolated pathogens, including H. influenzae, M. catarrhalis
year, p = 0.035), with improved quality of life.82 Recently, a multina-
and Staphylococcus aureus. The quinolones levofloxacin or moxifloxa-
tional double-blind randomized controlled trial evaluated the I-neb
cin would be appropriate choices, given the broader spectrum of activ-
adaptive aerosol delivery device (Philips Respironics, Chichester, UK)
ity of such quinolones compared to ciprofloxacin, provided patients
in 144 non-CF bronchiectasis patients colonized by P. aeruginosa (73
are counseled regarding the risk for quinolone-associated tendinopa-
treated with colistin 1 million IU vs 71 with 0.45% saline placebo). The
thy, especially in older, renally impaired patients or those on concomi-
primary endpoint, time to first exacerbation, was not met in this
tant steroids.87 Clostridium difficile colitis is another concern, as with
6-month study. Median time (25% quartile) to exacerbation was 165
many other antibiotics, especially in the elderly. A chest radiograph
(42) vs 111 (52) days in the colistin and placebo groups respectively
helps rule out other noninfective causes of exacerbation such as pneu-
(p = 0.11). Secondary endpoints were all more encouraging, with
monia or less commonly, a pneumothorax. The majority of patients
improved time to exacerbation in adherent patients (adherence quar-
experiencing an exacerbation can be treated in the outpatient setting.
tiles 2–4), reduced P. aeruginosa density and improved quality of life
When sputum results are known, therapy can be tailored to reflect
scores, with 7% treatment-induced wheeze rate in colistin-treated sub-
sensitivity results, aiming for the optimum balance among efficacy and
jects versus 1.4% in controls. Other adverse events were not signifi-
toxicity. As many patients with bronchiectasis can have resistant
cantly different. Notably, fewer than 10% of the patients were receiving
strains of bacteria such as P. aeruginosa, which have no orally active
azithromycin therapy, highlighting the gap in knowledge regarding the
form of therapy, intravenous therapy is required, which may be pro-
role of inhaled antibiotics in chronic macrolide users.83
vided on an inpatient or outpatient basis (the latter if the patient satis-
The monobactam aztreonam has unacceptable airway side effects
fies local service criteria), but admission to hospital is advised if
if used in its pure form. Airway inflammatory changes from aztreonam
the patient displays significant tachypnea, hypotension, confusion,
inhalation have resulted in the development of a lyophilized formula-
hypoxemia or fever. The British Thoracic Society guidelines make an
tion using lysine as an excipient, and has been used to treat
expert recommendation of combination antibiotics in the setting
pseudomonas-colonized cystic fibrosis patients.84 Recent preliminary
of resistant Pseudomonas, while acknowledging the issue as controver-
data from two phase III trials, in which a combined total of 270 patients
sial. Some may prefer to decide on single versus combination therapy
were assigned to aztreonam lysine for inhalation (AZLI) for 28 days,
based on overall initial severity at presentation, though firm data for
demonstrated failure to meet the primary endpoint of improvement
either approach are lacking. Where aminoglycosides are used, they
in quality of life scores, with more adverse events noted in the active
should only be in addition to another agent, not as monotherapy, and
drug arms of both trials, though the trial with the less favorable treat-
require protocols for monitoring with pharmacy involvement, aiming
ment effect had an excess of ever-smokers among the AZLI-treated
for a peak concentration of 7–10 mg/L and a trough concentration of
group (47% vs 30%), a possible confounding influence.85
<2 mg/L.56 The presence of renal impairment, advanced patient age
A long-acting formulation of ciprofloxacin, containing a mixture
and the typically lengthy 14-day duration of antibiotics given for bron-
of free drug and liposomal ciprofloxacin, has been developed in an
chiectasis exacerbations highlight the need for particular vigilance to
attempt to reduce the all-pervasive side effect of bronchospasm. In a
toxicity in those receiving aminoglycosides.
phase II multicenter trial, where 42 non-CF bronchiectasis patients
were randomized to either dual-release ciprofloxacin for inhalation
(DRCFI) or control liposomes in saline and treated over 24 weeks in Summary
a ‘28 days on/28 days off ’ manner, DRCFI resulted in a significant Acute bronchitis and non-cystic fibrosis bronchiectasis reflect oppos-
reduction in Pseudomonas density, a delayed time to first exacerbation ing ends of the spectra of chronicity, incidence and severity of infec-
(median 134 vs 58 days, p = 0.057 modified intention to treat analysis, tious airway diseases and both have traditionally suffered from a dearth
p = 0.046 per protocol analysis), and fewer pulmonary adverse effects of research focus. Acute bronchitis, generally virally mediated, repre-
versus placebo.78 In relation to inhaled antibiotics for nontuberculous sents an opportunity for the healthcare professions to make a favorable
mycobacteria complicating bronchiectasis, a retrospective analysis of impact on the emerging epidemic of antimicrobial resistance, though
20 patients (18 with non-CF bronchiectasis, 2 with CF) who had influenza needs to be carefully considered. Of late there is heightened
inhaled amikacin added to their failing regimen for NTM found that interest in non-cystic fibrosis bronchiectasis in particular, stemming
symptom scores either improved (45%) or stabilized (35%) in the from an increased rate of detection, better understanding of the under-
majority of subjects, though 55% had worsening of their CT appear- lying pathobiology and the unmet clinical need for proven licensed
ances in the median 19 months of follow-up. Fifteen patients were therapies. As the disease is characterized by pulmonary infective epi-
culture-positive for Mycobacterium abscessus and the remaining 5 had sodes, the role of the innate and adaptive immune responses and the
MAC. Thirty-five per cent of the cohort had to stop amikacin due to interaction of host immunity with the local microbiome will continue
toxicities of therapy.86 to be a major focus of interest, utilising newer research technologies
Irrespective of the choice of inhaled antibiotic for non-CF bronchi- analogous to recent research directions for other complex disorders.
ectasis patients, in view of the potential for drug-induced wheeze, the Research priorities for bronchiectasis have recently been articulated
initial treatment is best administered in a clinical setting with spirom- by a newly formed bronchiectasis network in the UK and are centered
etry performed pre- and (15–30 minutes) post-dose, in order to detect on the need for better epidemiologic data, enhanced efforts to help
those patients whose FEV1 measurement drops significantly in response identify the cause of bronchiectasis for the ~50% of patients for
to the inhaled antibiotic (i.e. a 15% drop in FEV1, or >200 mL) and whom no (potentially reversible) causative factor is identified, and the
requirement for adequately powered and designed randomized clinical more hopeful for those now living with bronchiectasis than in any
trials to address the deficit in robust positive studies of therapeutic period in the past.
interventions for the disease.80 Given the uncommon nature of the
disorder, patient registries are highly desirable and are now in recent References available online at expertconsult.com.
existence to help further these goals.88,89 The future is therefore much
KEY REFERENCES
Altenburg J., de Graaff C.S., Stienstra Y., et al.: Effect of fibrosis bronchiectasis. Am J Respir Crit Care Med 2011; bronchiectasis: the BLESS randomized controlled trial.
azithromycin maintenance treatment on infectious exac- 183(4):491-499. JAMA 2013; 309(12):1260-1267.
erbations among patients with non-cystic fibrosis bron- O’Donnell A.E., Barker A.F., Ilowite J.S., et al.: Treatment of Tunney M.M., Einarsson G.G., Wei L., et al.: Lung micro-
chiectasis: the BAT randomized controlled trial. JAMA idiopathic bronchiectasis with aerosolized recombinant biota and bacterial abundance in patients with bronchi-
2013; 309(12):1251-1259. human DNase I. rhDNase Study Group. Chest 1998; ectasis when clinically stable and during exacerbation.
Chalmers J.D., Goeminne P., Aliberti S., et al.: The bronchi- 113(5):1329-1334. Am J Respir Crit Care Med 2013; 187(10):1118-1126.
ectasis severity index: an international derivation and Pasteur M.C., Bilton D., Hill A.T.: British Thoracic Society Wenzel R.P., Fowler A.A. 3rd.: Clinical practice: acute bron-
validation study. Am J Respir Crit Care Med 2014; 189(5): guideline for non-CF bronchiectasis. Thorax 2010; chitis. N Engl J Med 2006; 355(20):2125-2130.
576-585. 65(7):577. Wong C., Jayaram L., Karalus N., et al.: Azithromycin for
Gonzales R., Bartlett J.G., Besser R.E., et al.: Principles of Rogers G.B., van der Gast C.J., Cuthbertson L., et al.: Clini- prevention of exacerbations in non-cystic fibrosis bron-
appropriate antibiotic use for treatment of uncompli- cal measures of disease in adult non-CF bronchiectasis chiectasis (EMBRACE): a randomised, double-blind,
cated acute bronchitis: background. Ann Intern Med correlate with airway microbiota composition. Thorax placebo-controlled trial. Lancet 2012; 380(9842):
2001; 134(6):521-529. 2013; 68(8):731-737. 660-667.
Haworth C.S., Foweraker J.E., Wilkinson P., et al.: Inhaled Seitz A.E., Olivier K.N., Adjemian J., et al.: Trends in bron-
colistin in patients with bronchiectasis and chronic Pseu- chiectasis among medicare beneficiaries in the United
domonas aeruginosa infection. Am J Respir Crit Care Med States, 2000 to 2007. Chest 2012; 142(2):432-439.
2014; 189(8):975-982. Serisier D.J., Martin M.L., McGuckin M.A., et al.: Effect of
Murray M.P., Govan J.R., Doherty C.J., et al.: A randomized long-term, low-dose erythromycin on pulmonary exac-
controlled trial of nebulized gentamicin in non-cystic erbations among patients with non-cystic fibrosis
Chapter 27 Bronchitis, Bronchiectasis 250.e1
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28
Community-Acquired Pneumonia
RICHARD G. WUNDERINK
KEY CONCEPTS a beneficial effect of herd immunity on adults,8 and more extensive
management of adults according to guideline-recommended antibiotic
• Community-acquired pneumonia (CAP) is the most common therapy.9
cause of admission of adults in the USA.
• Diagnosis of community-acquired pneumonia is relatively easy Diagnosis
in previously healthy patients but may be challenging in those Diagnosis of classic CAP is not difficult in patients without underlying
with underlying cardiopulmonary disease or in the elderly. cardiopulmonary disease. A triad of (1) evidence of infection (fever or
• The highest yield for diagnostic testing for CAP etiology is in chills, leukocytosis) with (2) signs or symptoms localizing to the respi-
the critically ill and those with risk factors for drug-resistant ratory system (cough, increased sputum production, shortness of
pathogens. breath, chest pain, abnormal pulmonary exam with crackles, signs of
consolidation, or finding of a pleural effusion), accompanied by (3) a
• The majority of hospitalized CAP patients can be treated with
either a respiratory fluoroquinolone or cephalosporin/macrolide new or changed radiographic infiltrate, usually accurately defines a
combination. patient with CAP. In patients with lung cancer, pulmonary fibrosis or
other chronic infiltrative lung diseases, and congestive heart failure
• Alternative antibiotic treatment should be based on presence (CHF),10 the diagnosis of CAP can be very difficult. Atypical presenta-
of multiple risk factors for drug-resistant pathogens (i.e. tions also complicate diagnosis. Confusion may be the only presenting
healthcare-associated pneumonia), specific risks (e.g. travel or
symptom in the elderly, leading to delay in diagnosis.11
zoonotic risks), or unique syndromes (e.g. toxin-mediated
community-acquired MRSA syndrome). The differential diagnosis of CAP (Table 28-1) results from either
noninfectious inflammatory disorders that also cause radiographic
• Decisions regarding initial placement in an intensive care unit infiltrates or concurrent non-lower respiratory tract infection with
(ICU) of tenuous CAP patients should be based on the number other causes of infiltrate. Viral upper respiratory tract infection (URI)
of minor physiologic factors and laboratory abnormalities asso- in association with worse CHF is probably the most common pneu-
ciated with risk of subsequent deterioration.
monia mimic, given the frequency of both disorders.
• Number of deaths by pneumonia is decreasing in the world
linked to child vaccination of pneumococcus and large-scale RADIOLOGY
use of antibiotics in India/China. Radiographic infiltrates may also be subtle: an individual radiologist
may miss infiltrates in up to 15% of cases and two radiologists reading
the same chest radiograph disagree in 10% of cases.12 Computed
tomography (CT) detects alveolar infiltrates in a not inconsequential
Introduction number of patients with manifestations of CAP but normal chest
Captain of the men of death … radiographs.13 The inflammatory reaction caused by antibiotic-
Sir William Osler MD induced bacterial lysis and aggressive fluid resuscitation will often
Community-acquired pneumonia (CAP) is one of the most under unmask these otherwise radiographically occult infiltrates on a subse-
appreciated medical illnesses in the USA. The combination of pneu- quent chest radiograph.
monia and influenza is the ninth leading cause of death overall and The most difficult radiographic challenge is detection of acute
the most common cause of infectious death in the USA, causing an pneumonia in the setting of chronic lung disease, such as pulmonary
estimated 50 000 deaths in 2010.1 This number is likely an underesti- fibrosis, pneumoconioses, bronchiectasis, cystic fibrosis and even
mate because many deaths caused directly by CAP are coded as sepsis,
for which pneumonia is the most common source,2 or attributed to
an underlying condition (such as cancer and Alzheimer’s disease), for
which pneumonia is the terminal event. For example, the proximate TABLE Differential Diagnosis of Community-Acquired
cause of death in >40% of patients with dementia is pneumonia.3 28-1 Pneumonia
Lower respiratory tract infection remains the leading cause of infec-
tious death in the world as well, exceeding deaths from tuberculosis, Abnormal CXR Normal CXR
human immunodeficiency virus (HIV) and malaria combined.4 Congestive heart failure* Acute exacerbation of COPD
CAP is the most common reason for hospital admission of adults
Aspiration pneumonitis Influenza
in the USA.5 It is a common cause of severe complications, including
septic shock,2 acute respiratory distress syndrome (ARDS) and acute Pulmonary infarction Acute bronchitis
renal failure. Even in survivors, hospital admission for CAP has been Acute exacerbation of pulmonary fibrosis Pertussis
associated with increased subsequent mortality and with accelerated
cognitive decline. Acute exacerbation of bronchiectasis Asthma*
Acute eosinophilic pneumonia
CAP is also costly, with the estimated annual cost of CAP in the Hypersensitivity pneumonitis
USA being $10.8 billion.6,7 Indirect costs are also substantial: CAP is a Pulmonary vasculitis
major cause of work days and days of school lost to illness. Cocaine-induced (‘crack lung’)
The mortality rate from CAP has changed very little until the last CXR, chest radiograph.
decade. Two factors likely have contributed to this recent decrease: *Fever or other signs of infection due to concomitant upper respiratory
widespread use of conjugate pneumococcal vaccines in children, with infection.
251
increased secretions and airway narrowing due to RSV airway infection

leading to a radiographic infiltrate from atelectasis. Conversely, infec-
tion can progress through the entire respiratory tract, such as influenza
URI followed by cough and wheezing from tracheobronchitis, culmi-
nating in hypoxemia and infiltrates from influenza pneumonia.
Classically, pneumonia is thought to result from introduction of
pathogens into the lower respiratory tract through four pathways.
Aspiration from the oropharynx is likely the most common for bacte-
rial pneumonia. Small-volume aspiration occurs frequently during
sleep (especially in the elderly) and in patients with decreased levels of
consciousness. Viruses and tuberculosis are inhaled as contaminated
droplets. Rarely, pneumonia occurs via hematogenous spread (e.g.,
from tricuspid endocarditis) or by contiguous extension from an
infected pleural or mediastinal space.
Recognition that a normal flora exists at the alveolar level of the
lung, rather than the distal lung being sterile, raises an alternative
mechanism for development of bacterial pneumonia. The normal lung
microbiome is similar to that of the normal oropharynx, predomi-
nantly streptococci (including the pneumococcus) but also including
Figure 28-1 Cavitary pneumonia in an otherwise healthy young adult caused by Haemophilus, Mycoplasma and other CAP pathogens, but at signifi-
methicillin-resistant Staphylococcus aureus (MRSA). cantly lower concentrations.15,16 CAP may therefore result from a per-
turbation in the normal balance, for example a viral URI, resulting in
disruption of the balance and outgrowth of a specific species. This
TABLE Differential Diagnosis of Cavitary/Necrotizing hypothesis is very consistent with the frequent association between
28-2 CAP in Non-immunocompromised Patients antecedent or concomitant viral infection and bacterial CAP.
• Toxigenic Staphylococcus aureus, including MRSA HOST DEFENSES

• Anaerobic aspiration syndrome For pneumonia to occur, lung host defenses must be overcome. The
• Klebsiella spp.
• Streptococcus milleri normal lung host defenses are formidable, given that the lung repre-
• Right-sided endocarditis sents the greatest amount of surface area in contact with the external
• Coccidioidoidomycoses environment and is therefore routinely exposed to infectious micro-
• Blastomycoses organisms. As a result, the lungs and entire respiratory tract have
• Tuberculosis
• Nontuberculous mycobacteria effective and redundant host defense mechanisms in order to respond
to this infectious challenge.
Mechanical factors are critically important for inhaled pathogens;
the hairs and turbinates of the nares and the branching architecture of
emphysema or CHF. Comparison to chest radiographs at a time of the tracheobronchial tree trap microbes on the airway lining, where
clinical stability is very important for these cases. If not available, other mucociliary clearance and local antibacterial factors either clear or kill
clinical manifestations, including use of biomarkers,10 may be required potential pathogens. The gag reflex and cough play major roles in
to avoid excessive antibiotic therapy. protection from aspiration challenges.
The pattern of radiographic infiltrates is occasionally helpful in the By adhering to mucosal cells of the oropharynx, normal flora
differential diagnosis of etiology. Cavitary CAP (Figure 28-1) has a prevent attachment of pathogenic bacteria and thereby decrease risk
limited differential diagnosis (Table 28-2), although it varies somewhat of aspirating these more virulent bacteria. Disruption of the normal
by geographic location. Conversely, even though viral or atypical bac- microbiome of both oropharynx and lung by antibiotics, viruses, or
terial pneumonia more commonly cause diffuse interstitial infiltrates, other factors not only leads to increased risk of pneumonia but also
this pattern is not distinctive enough to guide antibiotic therapy. predisposes to more antibiotic-resistant pathogens.
Radiographic pattern is also associated with prognosis. Initial pres- When these mechanical barriers are overcome or when the
ence of bilateral infiltrates is consistently associated with greater mor- micro-organisms are small enough to be directly inhaled to the alveolar
tality and need for ICU care.9 A rapid increase in radiographic level, resident alveolar macrophages are extremely efficient at clearing
infiltrates, whether due to uncontrolled infection or development of and killing pathogens. Macrophages are assisted by the alveolar epithe-
ARDS, in the initial 24–48 hours, is also associated with antibiotic lial cells, which produce proteins (e.g., surfactant proteins A and D)
failure and need for ICU care.14 Conversely, presence of a pleural effu- with opsonic properties or direct antibacterial or antiviral activity.
sion has been associated with better prognosis. Once engulfed by the macrophage, the pathogens – even if they are not
killed – are eliminated via either the mucociliary elevator or the
Pathophysiology lymphatics.
Pneumonia results from the proliferation of microbial pathogens, most Only when the capacity of the alveolar macrophages to ingest or
commonly bacteria, but occasionally by viruses, fungi, parasites and kill the micro-organisms is exceeded does clinical pneumonia become
other infectious agents, in the alveoli and the host’s response to those manifest. In that situation, the alveolar macrophages initiate the
pathogens. The latter is critically important since recent data have inflammatory response to bolster lower respiratory tract defenses.
demonstrated the presence of a normal bacterial microbiome in the Localizing infection to the alveolar space is an important but
alveoli. underappreciated component of host immunity. Factors preventing
bacteremia and defending the vascular space are poorly understood.
BACTERIAL INVASION Even the presence of bacterial DNA in peripheral blood appears to
Infection of the lower respiratory tract can occur at each level, with a correlate with mortality and organ dysfunction.17 Clearly, preformed
varying proportion of viral and bacterial etiologies at each level, and antibody is important, since the most incontrovertible evidence of
can be confused with pneumonia. Respiratory bronchiolitis due to pneumococcal vaccine efficacy is prevention of invasive disease, includ-
respiratory syncytial virus (RSV) in children is a classic example of ing bacteremia.18 Ability to opsonize bacteria is also important since
confusion between CAP and more proximal level infection, with the deficiencies in mannose-binding lectin and complement are also
Chapter 28 Community-Acquired Pneumonia 253
associated with increased bacteremia and invasive pneumococcal Epidemiology

disease.19,20 Splenic clearance of opsonized bacteria is also important
for the pneumococcus and other encapsulated bacteria. CAP occurs in every ecological niche in the world from the Arctic
regions to deserts to jungle, although the most frequent pathogens may
CLINICAL MANIFESTATIONS vary. Table 28-4 lists geographic and zoonotic considerations for etiol-
The host inflammatory response, rather than simply proliferation of ogy. A general seasonal pattern occurs, with higher rates in the winter/
micro-organisms, triggers the clinical syndrome of pneumonia. Release rainy season, tracking most closely with respiratory viruses such as
of inflammatory mediators, such as interleukin (IL)-1 and tumor influenza and RSV.
necrosis factor (TNF), results in fever. Chemokines, such as IL-8 and CAP occurs in all ages but incidence and mortality are greatest in
granulocyte colony-stimulating factor, stimulate bone marrow release the extremes of age.23 In infants, lack of humoral immunity to common
of neutrophils and homing to the lung, producing both peripheral pathogens such as influenza, RSV and Streptococcus pneumoniae is the
leukocytosis and increased purulent secretions. Erythrocytes crossing major factor. In the elderly, a senescent host immune system and high
the alveolar–capillary membrane in the stage of red hepatization result frequency of co-morbid illnesses play the greatest role. Females are
in hemoptysis. Inflammatory mediators released by macrophages and slightly more likely to develop CAP while males are more likely to die
the newly recruited neutrophils cause an alveolar capillary leak equiva- from CAP.
lent to that demonstrated for ARDS, although initially localized in In the USA, 80% of CAP patients are treated as outpatients.
pneumonia. Radiographic infiltrates and rales detectable on ausculta- Of hospitalized patients, 15–20% require ICU monitoring or
tion are a direct result of the alveolar–capillary leak syndrome. Hypox- interventions.
emia results from alveolar filling but may be exacerbated by paralysis
of the hypoxemic vasoconstriction that would normally occur with Etiology
fluid-filled alveoli by some bacterial pathogens. Increased respiratory The major etiologies of CAP are listed in Table 28-5. By far, the most
drive as part of the systemic inflammatory response syndrome leads to common bacterial etiology is Strep. pneumoniae. The actual proportion
respiratory alkalosis. Decreased compliance due to capillary leak, caused by viruses is difficult to determine since the majority of detec-
hypoxemia, increased respiratory drive, increased secretions and occa- tions are from the upper respiratory tract, and it is unclear whether
sionally infection-related bronchospasm all lead to dyspnea and, if the virus present in the oropharynx is causing the pneumonia, predis-
severe enough, respiratory failure. posed to a superinfection bacterial pneumonia, or is simply an inno-
cent bystander. This dilemma is most obvious for human rhinovirus
IMMUNOCOMPROMISE detection in adults.
People with no recognizable defect in any component of host defense
can develop CAP. However, the more severe the manifestations and the
less virulent the pathogen, the more likely some component of the host
defense is deficient. Genetic deficiencies in every component of host TABLE Pathologic Phases of Classic Lobar
28-3 Pneumonia
defense have been described and the list of primary immunodeficiency
syndromes increases yearly.21 Extrinsic factors such as cigarette smoke,
alcohol intoxication and particulate matter inhalation can contribute. Exudative
However, the most important risks are age and co-morbid illnesses, • Proteinaceous fluid-filling alveolus
• Bacteria present
such as diabetes mellitus, CHF, emphysema, cirrhosis and liver failure.22 • Macrophages but few neutrophils
Even in cases of overt immunocompromise, such as neutropenia from
chemotherapy, leukemia and HIV disease, the usual CAP pathogens Red Hepatization
are still important although the differential of etiologies becomes • Extravasated erythrocytes
much larger. • Fewer bacteria
• Minimal neutrophils
Pathology Gray Hepatization

The series of pathologic changes seen in classic lobar bacterial pneu- • Many neutrophils
monia is described in Table 28-3. The gray hepatization phase corre- • No bacteria
• No additional erythrocytes
sponds with successful containment of the infection and improvement • Abundant fibrin
in gas exchange, with restoration of the normal hypoxic vasoconstric-
tor response. This classic pattern does not apply to pneumonia of all Resolution
etiologies, especially viral or Pneumocystis pneumonia. If microaspira- • Macrophages again predominate
• Necrotic neutrophils, cellular ghosts
tion is the underlying mechanism, a bronchopneumonia pattern is • Debris of bacteria, fibrin
seen and the corresponding phases may not occur.
TABLE
28-4 Zoonoses and Geographic Considerations
Travel Pathogen(s) Exposure Pathogen(s)
Ohio/Mississippi/St Lawrence river valleys Histoplasma capsulatum Bird or bat dung Histoplasma capsulatum
Southwestern USA Coccidioides spp. Pet birds Chlamydophila psittaci

Hantavirus
Yersinia pestis
Upper Midwest USA woods Blastomyces Rabbits Francisella tularensis
South East Asia Burkholderia pseudomalleoli Exposure to sheep, goats, parturient cats Coxiella burnetii
Avian influenza
Acinetobacter spp.
Hotel or cruise ship stay in last 2 weeks Legionella spp. Sick dogs Blastomyces
TABLE
28-5 Common Etiologies of CAP* TABLE Criteria for Healthcare-Associated Pneumonia
28-8 (HCAP)
BACTERIAL VIRAL
• Streptococcus pneumoniae • Rhinovirus† Original Criteria9 Pneumonia-Specific Criteria26
• Staphylococcus aureus • Influenza
• Mycoplasma pneumoniae • Respiratory syncytial virus Hospitalization for ≥2 days in previous Hospitalization for ≥2 days in
• Chlamydophila pneumoniae • Human metapneumovirus 90 days previous 90 days
• Legionella spp. • Coronaviruses
• Other streptococci • SARS Nursing home or extended care facility Antibiotics in previous 90 days
Strep. mitis • MERS residents
Strep. agalactia • Adenovirus
Chronic home infusion therapy Non-ambulatory status
Strep. viridans • Parainfluenza virus
Strep. sanguis • Varicella Chronic dialysis within 30 days Tube feedings
• Haemophilus spp.
• Pseudomonas aeruginosa FUNGAL Home wound care Immunocompromise
• Enterobacteriaceae • Pneumocystis jirovecii
Escherichia coli Family member with MDR pathogen Gastric acid suppressive
Klebsiella spp. agents
Acinetobacter spp. Immunosuppressive disease/therapy*
Branhamella sp.
*Not included in original criteria but frequently included in many HCAP studies.
SARS, severe acute respiratory syndrome; MERS, Middle East respiratory
syndrome.
*Roughly order of frequency.
settings such as nursing homes and chronic dialysis units. An episode
†
Association with CAP but unclear causality. of aspiration weeks prior to presentation without intervening medical
attention is the classic predisposition for anaerobic pneumonia, often
complicated by empyema as well. Otherwise, anaerobes play a minor
role in usual CAP.
TABLE Chronic Pulmonary Infections that May HCAP was proposed as a discrete entity with the goal of identifying
28-6 Present as Acute Pneumonia those patients who were more likely to receive initially inappropriate
• Endemic fungi antibiotic therapy, and have an associated higher mortality risk.27,28
Histoplasmosis While early observational studies of culture-positive cases suggest
Blastomycosis improved outcome from broad-spectrum antibiotic therapy in persons
Coccidioidomycosis
• Actinomycosis
with HCAP risk factors,27,28 prospective studies using the same
• Nocardia definition find lower rates of antibiotic-resistant pathogens and many
• Mycobacterial infection culture-negative cases.26,29,30 Even more concerning were reports of
Tuberculosis adverse outcomes among persons with HCAP risk factors treated with
Nontuberculous mycobacteria
• Melioidosis (Burkholderia pseudomallei )
broad-spectrum antibiotic therapy.26,31
Rather than using the original definition derived from healthcare-
associated bacteremia, a prospective multicenter study identified six
independent risk factors (Table 28-8) for pneumonia caused by patho-
TABLE Community-Onset Pneumonia Syndromes in gens resistant to the usual inpatient antibiotic regimens recommended
28-7 Special Populations by Infectious Diseases Society of America (IDSA)/ American Thoracic
Society (ATS) guidelines.26 While the risk factors were similar to the
Syndrome Examples original, the incidence of drug-resistant pathogens was not signifi-
Hospital-acquired Recent discharge, long-term weaning facilities, cantly increased until three or more risk factors are present. A separate
rehabilitation institutes analysis specifically for MRSA found that presence of one MRSA-
specific risk factor (prior MRSA infection/colonization, chronic hemo-
Healthcare-associated Nursing homes, chronic hemodialysis
dialysis, or heart failure) and another pneumonia-specific risk factor
Immunocompromised Chemotherapy, HIV disease, transplant, acute may warrant MRSA coverage (but not dual anti-pseudomonal antibi-
leukemia/lymphoma otics). Importantly, this new definition would result in significantly
Aspiration Severe alcoholism, seizure disorder, stroke fewer patients receiving broad-spectrum antibiotics than the original
HCAP definition.9
Less common etiologies are usually associated with specific geo- COMMUNITY-ACQUIRED MRSA CAP
graphic areas or exposure to specific zoonoses (see Table 28-4). Occa- The MRSA identified in patients with HCAP risk factors is likely a
sionally, more chronic pulmonary infections can masquerade as acute hospital-acquired strain. However, in the USA a specific USA300 strain
CAP (Table 28-6) and should be considered in endemic areas and if of MRSA causes CAP in previously healthy patients, specifically
the time course is more indolent.24 without HCAP or other risk factors for MDR pathogens.32,33 Many of
the characteristic presenting features of this MRSA strain (Table 28-9),
HEALTHCARE-ASSOCIATED as well as the methicillin-sensitive variant, are a result of exotoxin
PNEUMONIA (HCAP) production.32 The Panton–Valentine Leukocidin (PVL) gene is an effi-
Concern has been raised about community-onset pneumonia caused cient marker of toxigenic strains but is not the main exotoxin involved
by pathogens usually associated with hospital-acquired pneumonia or in the increased lethality.33 The USA300 strain is increasingly being
even ventilator-associated pneumonia, including methicillin-resistant found in hospital-acquired MRSA infections, blurring some of the
Staphylococcus aureus (MRSA) and multidrug resistant (MDR) gram- epidemiologic distinctions.
negative pathogens.9,25–27 Several community-onset pneumonia syn-
dromes at risk for more drug-resistant pathogens can be defined (Table DETERMINATION OF ETIOLOGY
28-7). In the USA, transfer of hospitalized patients to long-term While the diagnosis of CAP is relatively straightforward, determination
ventilator-weaning facilities or acute rehabilitation institutes, rather of etiology is very difficult.9 Even with aggressive use of currently avail-
than completing their recovery in an acute care hospital, does not able diagnostic tests, the etiology remains unknown in >50% of cases.
decrease their risk of the typical hospital-acquired pathogens. These A complete history of travel, pets and hobbies is critical for suspi-
patients have previously been lumped together with those in lower-risk cion of the less common pathogens (see Table 28-4), as well as CAP
TABLE Clinical Features Suggesting Community- TABLE IDSA/ATS Recommended Empirical Antibiotic
28-9 Acquired MRSA Pneumonia 28-11 Therapy9
Cavitary infiltrate or necrosis Neutropenia Disposition Recommended Class Typical Examples
Rapidly increasing pleural effusion Erythematous skin rash Outpatient Macrolide Azithromycin 500 mg po
once, then 250 mg q day
Gross hemoptysis (not just blood- Skin pustules
streaked) Doxycycline Clarithromycin 500 mg po BD
Concurrent influenza Young, previously healthy Recent oral Change antibiotic class
Severe CAP in summer months antibiotics Consider:
Fluoroquinolone
Amoxicillin ±
clavulanate
TABLE Indications for More Aggressive Diagnostic Non-ICU Respiratory Moxifloxacin 400 mg q day or
28-10 Testing in Cap9 inpatient fluoroquinolone Levofloxacin 750 mg po q day
or Ceftriaxone 1–2 g q day or
ICU admission Cirrhosis/severe chronic liver disease* β-lactam and macrolide Ampicillin–sulbactam 2 g iv
q8h plus
26
HCAP risk factors Severe chronic obstructive lung Azithromycin 500 mg q day
disease†
ICU patient Ceftriaxone
Failure of outpatient antibiotic Asplenia (anatomic and functional)* plus
therapy Azithromycin or
Respiratory
Cavitary infiltrates on presentation Recent travel (within 2 weeks)‡ fluoroquinolone
Leukopenia Positive Legionella or pneumococcal
urinary antigen test†
Active alcohol abuse Pleural effusion Since outpatient treatment failure is rare and the guideline-
compliant therapy covers 90% of etiologies in hospitalized patients,
*Mainly blood cultures. deviation from these guidelines should have appropriate justification.
†
Mainly respiratory sample.
‡
Legionella urinary antigen. Presence of risk factors for MDR (see Table 28-8) or zoonotic/
geographic-specific pathogens (see Table 28-4) may justify alternative
empirical coverage but should be accompanied by aggressive attempts
mimics (see Table 28-1). Unfortunately, diagnosis of many of these at diagnosis, in order to appropriately de-escalate broader-spectrum
pathogens requires acute and convalescent serology or tests sent to a antibiotic therapy.26,40 Quality improvement projects consistently show
reference laboratory, making most treatment empirical. that as compliance with IDSA/ATS guideline antibiotics increases,
In general, the greater the likelihood of unusual bacterial patho- mortality rates and length of stay decrease.41,42 Conversely, continuing
gens, the greater the yield of diagnostic tests. Patients with severe CAP broad-spectrum antibiotics for CAP patients without documented
requiring ICU admission34 and/or HCAP risk factors26 started on MDR pathogens is associated with excess mortality.26,31
broad-spectrum antibiotics have the clearest indication for extensive Macrolides appear to have beneficial effects in excess of their
diagnostic testing, including attempts at obtaining sputum culture. coverage of atypical pathogens, especially in the more severely ill
The yield of testing is higher in the critically ill CAP patient, possibly patient.43,44 These benefits may be due to immunomodulatory effects
because endotracheal intubation allows direct sampling of the lower on the host, less cell lysis-induced cytokine release, or inhibition of
respiratory tract. Other indications and the corresponding appropriate bacterial virulence factors, such as biofilms, quorum sensing and toxin
tests are listed in Table 28-10.9 production.
Biomarkers have been used in an attempt to differentiate viral from CA-MRSA would require specific coverage since the regimens in
bacterial pneumonia. The best validated is procalcitonin (PCT).10,35 Table 28-11 have inadequate MRSA coverage. For patients with HCAP-
This pro-hormone is elevated in uncontrolled bacterial infections and MRSA risk factors, linezolid has a 15% better clinical response rate
actively suppressed by the interferon response induced in many viral than vancomycin.45 Because manifestations of the USA300 strain of
pneumonias. However, PCT may be low in atypical pathogen CAP as CA-MRSA CAP are disproportionately exotoxin-mediated (see Table
well and is clearly elevated in severe viral CAP, such as seen in the 28-7),32 treatment with antibiotics that suppress toxin production,
2009–2010 influenza A pandemic, with or without evidence of super- such as linezolid or clindamycin (added to vancomycin), are preferred
imposed bacterial pneumonia. C-reactive protein (CRP) is more non- and have been associated with lower mortality.33 Ceftaroline, the only
specific than PCT in CAP but may be a better predictor of treatment antibiotic approved for CAP recently, has MRSA activity as well.
failure.14 One of the most critical elements of treatment is early initiation of
appropriate antibiotic therapy after the diagnosis of CAP has been
Treatment made. The first dose should be given in the emergency department
Almost every antibiotic approved by the US Food and Drug Adminis- (ED) to allow closer monitoring of the initial response and to assure
tration in the past four decades has an indication for CAP. In general, that the initial dose is given promptly.9 Timing of the first dose is even
keys to appropriate therapy are adequate coverage of Strep. pneumoniae more important when the patient presents with septic shock; the goal
and the atypical bacterial pathogens (Mycoplasma, Chlamydophila, should be initial antibiotic within the first hour.46
Legionella). The recommended regimens from the IDSA/ATS guideline For uncomplicated bacterial CAP, the usual duration of treatment
are listed in Table 28-11.9 European guidelines differ in that β-lactam should be 5–7 days. Certain pathogens, such as Legionella, may require
antibiotics (typically amoxicillin) remain the recommended agent for up to 2 weeks of therapy. Conversion to an equivalent oral agent is
mild–moderate CAP.36,37 A recent study from the Netherlands suggests appropriate whenever the patient is clinically improving and able to
that a strategy of empirical treatment for moderately severe CAP with tolerate food.
β-lactam monotherapy is noninferior to either β-lactam–macrolide
combination therapy or fluoroquinolone monotherapy.38 The primary INFLUENZA TREATMENT
factors to discriminate among the antibiotic options, therefore, should Treatment of influenza pneumonia has not been prospectively studied
be local resistance patterns in community organisms, recent antibiotic specifically. Experience during the 2009–10 pandemic and retrospec-
use, which increases the risk of class resistance,39 and cost. tive analysis47 suggest that antivirals should be used if a patient has a
radiographic infiltrate, no matter the duration of symptoms. The resulted in decreased mortality (23.4% to 5.7%) and fewer floors to
potential for oseltamivir-resistant strains should be monitored from ICU transfers (32.0% to 14.8%) without significantly increasing direct
CDC and local health department information as each influenza ICU admissions.49
season progresses. The major issue is whether antibiotics are always
needed for influenza CAP, with no clear data or consensus. For a full PLEURAL EFFUSION
description of the use of antiviral therapy, see Chapter 154. A new pleural effusion in a patient admitted with CAP should always
prompt concern for empyema or complicated parapneumonic effusion
Other Management (generally pleural fluid pH <7.2). Early diagnosis by thoracentesis,
placement of a chest tube and use of tissue plasminogen activator
DISPOSITION combined with DNAase can prevent the need for surgical intervention
The major determinant of the cost of CAP care is the physician’s deci- in the majority of cases.56 Management of pleural effusions in patients
sion to hospitalize. Of CAP patients who present to the ED, 40–60% with CHF and intermittent pleural effusions is less straightforward but
are admitted,22,48,49 with considerable variability in admission for thoracentesis in all unclear situations is warranted.
patients with similar clinical characteristics. Use of scoring systems,
such as the Pneumonia Severity Index (PSI)22 and the CURB-65 Score50 ADJUNCTIVE TREATMENT
that were developed specifically to guide admission decisions, result in Some patients benefit from aerosolized β-agonist bronchodilators for
fewer admissions of low acuity patients with no increase in adverse wheezing or other bronchial hygiene maneuvers for difficult expecto-
outcomes.48 PSI is a complex score, requiring formal scoring or elec- ration. Patients with viral lower respiratory tract infections occasion-
tronic decision support whereas CURB-65 (confusion, uremia, respira- ally require anticholinergic aerosols to control nonproductive cough.
tory rate, blood pressure, age >65 years) is both easy to remember and Use of systemic corticosteroids in CAP patients who have no other
calculate, although not as well validated as PSI. Both scores are valid indication, e.g. asthma or COPD exacerbation associated with pneu-
for analysis of groups of CAP admissions, but admission of low score monia, remains controversial. In moderate disease, a potential benefit
patients is legitimate, for both objective reasons (e.g. low arterial satu- of shortening hospitalization is counterbalanced by an increased risk
rations) and subjective (e.g. unreliable home support, concern regard- of superinfection.57 In severe viral pneumonia, either SARS or the
ing compliance). 2009–2010 influenza pandemic,58 steroid use was associated with worse
Decisions regarding initial ICU placement of tenuous CAP patients outcomes.
probably have the greatest potential impact on mortality. Patients
transferred to the ICU within 48 hours of initial admission to a general EXACERBATION OF CO-MORBID ILLNESSES
medical service have higher mortality than those with an obvious need As mentioned, CAP can exacerbate underlying chronic illnesses such
for ICU care (mechanical ventilation or hypotension requiring vaso- as asthma and COPD, diabetes mellitus and CHF. Up to 15–20% of
pressors) at the time of admission.49,51,52 The fraction of hospitalized patients admitted with pneumococcal CAP can have a new cardiovas-
pneumonia patients admitted to the ICU also varies widely (5–20%) cular diagnosis during the acute hospitalization, including acute myo-
depending on hospital and health system characteristics.49,53–55 cardial infarction, atrial fibrillation and other arrhythmias, or CHF.59
The IDSA/ATS guidelines suggest that presence of >3 of a group of Destabilization of co-morbid illness is more likely to cause hospital
nine minor criteria (Table 28-12) warrant consideration for ICU readmission than complications of CAP or its treatment.
admission.9 Other scores to predict clinical deterioration with similar
parameters have also been developed and validated.53–55 For each, the Prevention
probability of need for invasive ventilatory or vasopressor therapy
The main CAP preventive measures are vaccination and smoking ces-
increases with increasing number of criteria or points, with a threshold
sation.9 Even among patients without obstructive lung disease, smokers
score around three to consider ICU admission. All these ICU admis-
are at increased risk of pneumococcal CAP.
sion scores are overly sensitive, resulting in substantially more ICU
admissions if followed rigidly.9,49 The most appropriate use of these INFLUENZA VACCINATION
scores may be to focus attention on patients with high scores while still Two forms of influenza vaccine are available – intramuscular inacti-
in the ED. A quality-improvement study demonstrated that increased vated influenza vaccine and intranasal live-attenuated cold-adapted
attention in the ED to patients with >3 IDSA/ATS minor criteria influenza vaccine. The latter is contraindicated in immunocompro-
mised patients. Specific vaccine components are reassessed yearly
based on the main circulating strains in the opposite hemisphere. In
the event of an influenza outbreak, unprotected patients at risk from
TABLE Minor Criteria for Consideration of ICU complications should be vaccinated immediately and given chemopro-
28-12 Admission for Severe CAP phylaxis with oseltamivir for 2 weeks, at which time vaccine-induced
antibody levels should be sufficiently protective.
IDSA/ATS Criteria9 Other Criteria53–55
PNEUMOCOCCAL VACCINE
Confusion Lactic acidosis
A pneumococcal polysaccharide vaccine (PPV23) and a protein con-
Uremia (BUN >20 mg/dL) pH <7.30–7.35 jugate vaccine (PCV13) are both available in the USA. The vaccine
Tachypnea (RR >30/min) Low albumin efficacy of PPV23 has been questionable, particularly in the elderly and
other at-risk populations. Administration of the protein conjugate
Bilateral radiographic infiltrates Hyponatremia (<130 mEq/L) vaccine to children has led to an overall decrease in the prevalence of
Severe hypoxemia (P/F <250) Leukocytosis >20 x109/L antimicrobial-resistant pneumococci and in the incidence of invasive
pneumococcal disease among both children and adults.18,60 However,
Thrombocytopenia Hypoglycemia
vaccination may result in replacement of vaccine serotypes with non-
Hypotension requiring aggressive fluid vaccine serotypes, as was seen with serotypes 19A and 35B after intro-
resuscitation duction of the original 7-valent conjugate vaccine.61 The 13-valent
Hypothermia conjugate vaccine is now also recommended for the elderly and for
younger immunocompromised patients (see also Chapter 177).
Leukopenia
BUN, blood urea nitrogen; RR, respiratory rate; P/F, PaO2/FiO2ratio. References available online at expertconsult.com.
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29
Hospital-Acquired, Healthcare-
Associated and Ventilator-Associated
Pneumonia
ANTOINE ROCH | GUILLEMETTE THOMAS | SAMI HRAIECH |
LAURENT PAPAZIAN | WILLIAM G. POWDERLY
KEY CONCEPTS infection in the intensive care unit (ICU). Nevertheless, a decreasing
trend in incidence has been highlighted during the last years, with a
• Healthcare-associated pneumonia (HCAP) is the leading cause reported reduction in incidence from 15% to 8% of patients from 2004
of death among hospital infections. Excess mortality attribut- to 2009 likely due to better prevention and to surveillance programs.2
able to ventilator-associated pneumonia (VAP) is limited but There is a decreasing risk of acquiring VAP during ICU stay. This risk
pneumonia contributes to a higher morbidity with longer inten-
was reported to be of 3% per day until day 5, decreasing to 2% per day
sive care unit (ICU) stay, duration of mechanical ventilation and
greater costs. until day 10 and 1% at day 15.3 The mortality rate of VAP ranges from
0% to 65% depending on studies.4 This disparity is in large part linked
• Multidrug-resistant (MDR) gram-negative bacilli are an impor- to the types of patient studied (medical, surgical, trauma) and to the
tant cause of hospital-acquired pneumonia (HAP), HCAP and heterogeneity of the diagnostic criteria employed. Although the excess
VAP. mortality attributable to VAP is probably limited,5,6 VAP contributes
• HAP is suspected based on clinical signs and should be to a higher morbidity with longer ICU stay, duration of mechanical
confirmed if possible using tracheal or alveolar sampling ventilation and greater costs.7,8
techniques. A large number of micro-organisms have been implicated in HAP
and VAP (Table 29-1). The most common pathogens are aerobic
• Antimicrobial therapy should be started as soon as diagnosis
is suspected and sampling performed. Seven to eight days gram-negative bacilli (Escherichia coli, Klebsiella pneumoniae, Entero-
of antimicrobial therapy is usually sufficient for most cases of bacter spp., Pseudomonas aeruginosa, Acinetobacter spp.) and Staphy-
uncomplicated HAP, HCAP or VAP. lococcus aureus. Many infections are polymicrobial. Besides bacteria,
viruses such as cytomegalovirus (CMV) and herpes simplex virus
• Validated prevention measures include: avoidance of mechani- (HSV) could be significant agents of late VAP occurring in patients
cal ventilation if possible; hygiene compliance with alcohol-
presenting with viral reactivation.9 Recently, CMV reactivation has
based hand sanitizer; mouth decontamination with 0.12%
chlorhexidine at least four times a day; keeping patients in the been shown to be associated with an increased mortality in critically
semirecumbent position (30°–45°); an endotracheal tube cuff ill patients.10
pressure >20 cmH2O; and the use of prevention programs The micro-organisms associated with HCAP are more similar to
in ICUs. HAP than community-acquired pneumonia (Chapter 28). However,
Streptococcus pneumonia and Haemophilus species may be seen more
frequently than in typical HAP.11,12,13
An additional feature of HAP, HCAP and VAP is that infection
may be caused by multidrug-resistant (MDR) pathogens. The risk
Hospital-acquired pneumonia (HAP) is defined as pneumonia occur- factors for infection associated with MDR pathogens are shown in
ring at least 48 hours after hospital admission, excluding any infection Box 29-1.
incubating at the time of admission.1 Ventilator-associated pneumonia
(VAP) is defined as a pneumonia occurring in patients under mechani- Pathophysiology
cal ventilation for at least 48 hours and characterized by the presence HAP and VAP are usually caused by the aspiration into the lungs of
of a new or progressive infiltrate, signs of systemic infection (tempera- bacteria that colonize the upper respiratory tract. The oropharynx of
ture, blood cell count), changes in sputum characteristics and wors- a hospitalized or ventilated patient becomes colonized rapidly by
ened lung function.1 Healthcare-associated pneumonia (HCAP) is enteric gram-negative bacteria, usually acquired from the hospital
defined as pneumonia that occurs in a nonhospitalized patient with environment. These bacteria are not normally present in the upper
extensive healthcare contact, as defined by one or more of the respiratory tract and the frequency of colonization increases with the
following: increasing severity of the underlying illness, the use of antibiotics and
• Intravenous therapy, wound care, or intravenous chemotherapy the duration of ventilation. The presence of the endotracheal tube
within the prior 30 days (ETT) allows for a direct communication between the oral–supraglottic
• Residence in a nursing home or other long-term care facility space and the lower respiratory tract. Although the ETT cuff can
• Hospitalization in an acute care hospital for two or more days prevent macroscopic aspiration, it does not assure a perfect seal. Sub-
within the prior 90 days sequently, oropharyngeal secretions pool upon the cuff and leak
• Attendance at a hospital or hemodialysis clinic within the prior through.14 Moreover, the presence of the ETT creates a mechanical
30 days. obstacle to mucus clearance15 and mucus accumulates into distal bron-
chial airways. The other mechanism involved in VAP is bacterial colo-
Epidemiology nization of the ETT forming a biofilm. The biofilm constitutes a
HAP is the second most common infection acquired in hospital after protective environment from host defenses and antimicrobial agents.16
urinary tract infection and is a leading cause of death among all The same pathogens are usually found in the biofilm and in distal
hospital-acquired infections. VAP is the major cause of nosocomial samplings in patients presenting withVAP.17
258
Chapter 29 Hospital-Acquired, Healthcare-Associated and Ventilator-Associated Pneumonia 259
TABLE
TABLE Micro-organisms Responsible for Ventilator- 29-2 Clinical Pulmonary Infection Score
29-1 Acquired Pneumonia
Temperature ≥36.5 °C and ≤38.4 °C: 0 points
Agent Organism ≥38.5 °C and ≤38 °C: 1 point
≤36 °C or ≥39 °C: 2 points
Gram-positive cocci Staphylococcus aureus
Streptococcus pneumoniae White blood cells ≥ 4g/L and ≤ 11g/L: 0 points
Coagulase-negative staphylococcus <4g/L or >11g/L: 1 point
If ≥0.5 g/L immature forms: + 1 point
Gram-positive bacilli Corynebacterium spp.
Listeria monocytogenes Tracheal aspirations* <14+: 0 points
Nocardia spp. ≥ 14+: 1 point
If purulence: + 1 point
Gram-negative bacilli (lactose Haemophilus influenzae
positive) Escherichia coli PaO2/FiO2 ratio >240 or ARDS: 0 points
Klebsiella spp. ≤240 without ARDS: 2 points
Enterobacter spp.
Proteus spp. Chest radiograph Absence of infiltrate: 0 points
Diffuse infiltrate: 1 point
Gram-negative bacilli (lactose Pseudomonas aeruginosa Localized infiltrate: 2 points
negative) Burkholderia cepacia
Acinetobacter spp. Semiquantitative culture of tracheal Pathogenic bacteria ≤1+: 0 points
Stenotrophomonas maltophilia secretions (0, 1, 2 or 3+) Pathogenic bacteria >1+: 1 point
Same bacteria as the Gram: + 1 point
Gram-negative cocci Neisseria spp.
Moraxella spp. ARDS, acute respiratory distress syndrome.
*For each aspiration, the nurses estimate the quantity of tracheal secretions
Anaerobes (cocci) Peptostreptococcus spp. harvested and assign a semi-quantitative score (increasing from 0 to 4+). The
Veillonella spp. total estimation is obtained by adding up all of the pulses noted for 24 hours.
The total score ranges from 0 to 12. A score >6 is in favor of a ventilator-
Anaerobes (bacilli) Bacteroides spp. associated pneumonia with a sensitivity of 93% and a specificity of 100%
Fusobacterium spp. compared with bronchoalveolar lavage, and a sensitivity of 72% and a
Prevotella spp. specificity of 85% compared with lung histologic assessment.
Actinomyces spp. Reproduced from Pugin J., et al.: Diagnosis of ventilator-associated pneumonia
by bacteriologic analysis of bronchoscopic and nonbronchoscopic ‘blind’
Intracellular micro-organisms Legionella spp.
bronchoalveolar lavage fluid. Am Rev Respir Dis 1991; 143:1121-1129.
Chlamydia pneumoniae
Mycoplasma pneumoniae
Fungi Candida spp.

Aspergillus spp. spread of infection to the lungs from a distant focus and inhalation of
pathogens aerosolized either from contaminated respiratory equip-
Viruses Influenza, parainfluenza, adenovirus
Respiratory syncytial virus
ment (e.g. ventilator or nebulizer equipment) or from the hospital
Herpes simplex virus environment (e.g. showers and water systems colonized with Legionella
Cytomegalovirus bacteria).
Other agents Pneumocystis jirovecii
Mycobacterium tuberculosis Diagnosis
Strongyloides stercoralis
CLINICAL DIAGNOSIS
Reproduced from Park DR: The microbiology of ventilator-associated The clinical diagnosis of HAP, HCAP and VAP is based on the associa-
pneumonia. Respir Care 2005; 50: 742–765. tion of an infectious syndrome (fever or hypothermia/leukopenia or
hyperleukocytosis), a lung infiltrate seen on chest radiography (appear-
ance or modification), purulent bronchorrhea and worsened gas
BOX 29-1 RISK FACTORS ASSOCIATED WITH AN exchange. The clinical pulmonary infection score (CPIS)19 is based on
INCREASED INCIDENCE OF six clinical and laboratory variables: temperature, leukocyte count,
MULTIDRUG-RESISTANT BACTERIA volume and purulence of tracheal secretions, oxygenation, chest radio-
graphic findings, and presence or absence of positive sputum cultures.
• Antimicrobial therapy in preceding 90 days
• Current hospitalization of 5 days or more
Its sensitivity and specificity for a threshold at 6 are acceptable (Table
• High frequency of antibiotic resistance in the community or in the 29-2). The original score includes culture results, which are not typi-
specific hospital unit cally available when initially assessing a patient who has suspected
• Hospitalization for 2 days or more in the preceding 90 days VAP. Subsequent studies demonstrated that modified versions of the
• Residence in a nursing home or extended care facility
• Home infusion therapy (including antibiotics)
CPIS excluding culture results have quite low sensitivity and specificity
• Chronic dialysis within 30 days for the diagnosis of VAP.20
• Home wound care Most clinicians would start empiric antimicrobial therapy if there
• Family member with multidrug-resistant pathogen is a new or changing infiltrate on radiography, plus at least two other
• Immunosuppressive disease and/or therapy
clinical features. However, this approach may lead to overdiagnosis
and treatment for pneumonia as there are many other causes of chang-
ing pulmonary infiltrates, hypoxemia and leukocytosis in hospitalized
VAP is histologically characterized by polymorphonuclear neutro- patients.
phils present in the bronchioles and adjacent alveoli. A grading system
of four successive stages based on histologic analysis of the lungs of 83 NONRESPIRATORY MICROBIOLOGIC SAMPLES
patients who were invasively ventilated and who died in the ICU has Blood cultures are insufficient but are nevertheless always recom-
been proposed.18 Owing to repeated seeding of the lower airways, these mended before administering antimicrobial therapy.1 Antigenuria
lesions are very heterogeneous and present at different histologic stages enables the detection of Streptococcus pneumoniae and Legionella pneu-
at the same time. It should be noted that the lesions are predominant mophila serogroup 1 antigens, usually performed on urinary strip (or
in the right lung and in dependent lung segments. Less commonly, even in the alveolar liquid) within the framework of community-
other mechanisms may be involved, including the hematogenous acquired pneumonia and can be useful with VAP. CMV antigenemia
BOX 29-2 MICROBIOLOGIC DIAGNOSTIC TOOLS TABLE Empiric Antimicrobial Therapy of

AND THRESHOLDS OF SIGNIFICANCE 29-3 HAP/HCAP/VAP
• Blind tracheal aspirate ≥105 or 106 cfu/mL
Empiric antimicrobial therapy in Ampicillin–sulbactam
• Blind mini-bronchoalveolar lavage or blind protected double catheter
case of early-onset HAP (<5th Ceftriaxone
brushing ≥ 103 cfu/mL
day) and in the absence of Levofloxacin or moxifloxacin
• Protected specimen brush under fibroscopy ≥103 cfu/mL
multidrug-resistant bacterium Ertapenem
• Bronchoalveolar lavage under fibroscopy ≥104 cfu/mL
risk factors
Empiric antimicrobial therapy in Cefepime or ceftazidime

case of late-onset HAP/VAP or imipenem or meropenem
(≥ 5th day) and/or the presence or piperacillin–tazobactam
of multidrug-resistant plus
or CMV polymerase chain reaction (PCR) amplification on blood can bacterium risk factors Ciprofloxacin or levofloxacin
detect CMV as a possible VAP agent within the framework of late VAP or gentamicin or tobramycin
(at least 5 days of mechanical ventilation). or amikacin
plus
NONDIRECTED RESPIRATORY SAMPLES (Box 29-2) Linezolid or vancomycin*
Thanks to the contribution of quantitative cultures, tracheal aspirate *If suspicion or risk factors of methicillin-resistant Staphylococcus aureus
(TA) has found its place among diagnostic methods. The predomi- (corticotherapy, recent antimicrobial therapy, mechanical ventilation >6 days).
Adapted from the ASLD/IDSA guidelines: Guidelines for the management of
nance of the right side and the fact that one is dealing with broncho- adults with hospital-acquired, ventilator-associated, and healthcare-associated
pneumonia with a bronchial component undoubtedly explains the pneumonia. Am J Respir Crit Care Med 2005; 171:388-416.
interest of this technique in the diagnosis of VAP. When TA at a
threshold of 105 cfu/mL was compared with protected specimen brush
(PSB) or bronchoalveolar lavage (BAL), the sensitivity and specificity
to prescribe adequate antibiotic therapy (while waiting for BAL culture
were 92.8% and 80%, respectively. A protected double catheter
results) in 95% of the patients in whom a VAP is ultimately diagnosed
(double-plugged catheter), protected by a glycol polyethylene plug,
by BAL culture.25
makes it possible to perform ‘blind aspiration brushing’ through an
In clinical practice, a probable bacterial VAP could be defined as a
internal catheter or mini-BAL in which 20 mL of liquid are instilled
modified CPIS of 5 or greater, 20 combined with BAL cultures with
and whose semiquantitative culture has revealed a sensitivity of 80%
greater than 104 colony-forming units (cfu)/mL for at least one organ-
and a specificity of 66%.
ism, PTC cultures with greater than 103 cfu/mL for at least one organ-
DIRECTED RESPIRATORY SAMPLES (Box 29-2) ism, or endotracheal aspirate culture with greater than 105 cfu/mL for
BAL is performed by instilling and recovering sterile saline solution at least one organism. A modified CPIS of 5 or greater without the
through the internal channel of the fiberscope which is positioned above defined criteria would define a possible VAP.26
in a third- or fourth-generation bronchus where only distal bronchi-
oles and alveoli are sampled. No consensus has been established on Treatment
the quantity to administer by aliquot, on the number of aliquots or Since the great majority of HAP, HCAP and VAP are due to bacteria,
on preserving or eliminating the first aliquot representing the bron- empiric antimicrobial therapy is indicated if there are strong clinical
chial fraction of BAL. A meta-analysis of 23 studies revealed the indications for the diagnosis. The consensus from the American Tho-
sensitivity of BAL at 73 ± 18% and its specificity at 82 ± 19% when racic Society and the Infectious Diseases Society of America1 proposes
VAP was diagnosed.21 The interest in BAL is also based on the possibil- broad-spectrum empiric double antimicrobial therapy in cases where
ity of examining for other pathogens, such as intracellular pathogens infection when multidrug-resistant bacteria is suspected and double
and their nucleic acid, thanks to PCR amplification which appears or even mono narrow-spectrum antimicrobial therapy in other cases
to be more effective than cultures that are difficult to perform. A viral (Table 29-3). This antimicrobial therapy must begin promptly after
diagnosis (HSV, CMV) can also benefit from PCR amplification performing an initial series of cultures and obtaining respiratory
techniques. samples (tracheal aspirate, PSB, BAL, etc.) where possible. Antibiotics
Protected specimen brush (PSB) is a double catheter sealed by a should be given intravenously initially, and when the response to treat-
glycol polyethylene plug that enables brushing of the distal bronchial ment is satisfactory, switched to oral or enteral administration if pos-
mucosa following insertion of an endoscope. The low volume of secre- sible. The key decision in initial empiric therapy is whether the patient
tions harvested explains a certain number of false-negatives as well as has risk factors for MDR organisms (Box 29-1). Dosing of antibiotics
the difficulty in performing a direct examination and culturing on the for empiric therapy for MDR pathogens is summarized in Table 29-4.
same brush. This technique22 provides a sensitivity ranging from 33% In patients with suspected VAP, initial treatment is also influenced
to 100%. by whether it is early-onset or late-onset VAP (time between initiation
of mechanical ventilation and VAP onset is less or more than 5 days).
SAMPLING STRATEGY IN CLINICAL PRACTICE Empiric therapeutic choices are also influenced by the local microbio-
The literature supports the view that PSB, BAL and TA specimens logic ecology and by any available microbial data (e.g. from TA, BAL,
cultured quantitatively can provide useful and reliable information mini-BAL).
about the likely presence and cause of VAP. Their value is considerably Several observational studies have shown that appropriate antimi-
diminished if the patient is already receiving antibiotics, which is the crobial therapy administered as soon as possible was associated with a
usual situation. There is controversy as to whether these tests improve reduction in the mortality of patients with suspected VAP.27 The
patient management and outcome in routine clinical practice. One choice of therapy must also take into account recent antimicrobial
study has shown that the use of a directed sampling strategy including therapy received by the patient so that a different class of antibiotic is
BAL23 decreased mortality, decreased antibiotic use and decreased the used to initiate treatment. For patients with suspected VAP, an alterna-
rate of inappropriate treatment. More recently, a study has random- tive approach to initial antimicrobial therapy is to administer antimi-
ized 740 patients suspected of VAP to specimens obtained via BAL or crobial therapy as soon as BAL has been performed by making use of
TA. This study showed no difference in any clinical outcome.24 the tracheal aspirate results available in patients who are receiving
However, patients known to be colonized by multidrug-resistant invasive mechanical ventilation. A study has shown that this method
micro-organisms were excluded in this latter study. It has also been improves the appropriateness of treatment compared with the use of
suggested that routine TA performed twice a week makes it possible the recommended guidelines.25
Chapter 29 Hospital-Acquired, Healthcare-Associated and Ventilator-Associated Pneumonia 261
ing co-morbidities, infection with MDR pathogens and delay in

Initial Intravenous Adult Doses of Antibiotics initiation of effective antibacterial therapy.1,27,40–42
TABLE for Empiric Therapy of VAP in Patients with
29-4 Late-Onset Disease or Risk Factors for
Multidrug-Resistant Pathogens Prevention
GENERAL MEASURES
Antibiotic Dosage
Preferential use of noninvasive ventilation compared with first-
Ceftazidime 2 g q8h intention invasive mechanical ventilation when possible reduces the
Cefepime 1–2 g q8–12h
incidence of nosocomial pneumonia.43 The use of sedation and
weaning protocols with noninvasive ventilation makes it possible to
Imipenem 500 mg q6h or 1 g q8h reduce the duration of invasive mechanical ventilation and therefore
Meropenem 1 g q8h to reduce the incidence of VAP. Effective infection control measures
include staff education, compliance with alcohol-based hand disinfec-
Piperacillin–tazobactam 4.5 g q6h
tion, and isolation to reduce cross-infection with MDR pathogens.1
Gentamicin 7 mg/kg q24h
Tobramycin 7 mg/kg q24h ORAL DECONTAMINATION, SELECTIVE

DIGESTIVE DECONTAMINATION,
Amikacin 20 mg/kg q24h
ANTIBIOTIC PROPHYLAXIS
Levofloxacin 750 mg q24h Daily local oropharyngeal decontamination by chlorhexhidine
Ciprofloxacin 400 mg q8h appears to be effective in the prevention of VAP and is strongly
recommended.1
Vancomycin 15 mg/kg q12h Selective digestive decontamination (SDD), given the coexistence
Linezolid 600 mg q12h of an oropharyngeal and a gastric colonization source, has long been
proposed as a means to prevent VAP.44 It is generally made up of a
combination of three anti-infectious agents with no or low systemic
diffusion (amphotericin B, polymyxin, aminoglycoside), applied on
In any case, rapid deterioration or the absence of improvement the buccal mucosa and administered in the digestive tract by nasogas-
after 72 hours of empiric treatment imposes systematic re-evaluation. tric tube associated with short parenteral systemic antibiotic prophy-
It should be noted that the absence of response to empiric treatment laxis. Numerous studies have reported a reduction in the incidence of
can be linked to a nonbacterial infection, particularly viral, or to an VAP but in practice it would appear that this method is little used and
extrapulmonary infection, or to the absence of an infectious problem. not formally recommended in the latest international consensus con-
Short antimicrobial therapy (8 days) can be recommended in early- as ferences.1,45 Certain problems that are inherent in the use of SDD have
well in late-onset VAP28,29 except in cases of Pseudomonas aeruginosa been advanced. The aspiration of antibiotics in the lower respiratory
or VAP related to non-fermentative gram-negative bacteria, where at tract accounts for a great number of sterile cultures or cultures that
least 15 days of antibiotic therapy appear to be necessary with dual are inferior to the recommended thresholds, given the partial but
therapy maintained for the first 5 days.28 insufficient activity on these pathogens by antibiotics administered
The administration of antiviral treatment (ganciclovir for CMV, orally and the theoretic impact that the extensive use of SDD could
aciclovir for herpes simplex virus) should be considered in patients have on the ecology of ICUs and the emergence of MDR bacteria.
with late VAP associated with positive PCR amplifications on respira- However, a randomized prospective study on a large population
tory or blood samples. However, further interventional studies are reported a reduction in the incidence of VAP and a reduction in mor-
needed to evaluate whether this treatment can improve prognosis. tality in the group benefiting from SDD with, in addition, a reduction
Serum procalcitonin (PCT) level has been proposed as a diagnostic in gram-negative bacteria46 while another randomized study showed a
marker of VAP. Five studies reported good specificities but sensitivities decrease in mortality with the systematic use of SDD in critically ill
of 41% to 100%. Taken together, these studies suggest that serum PCT patients suggesting, that physicians reluctance to use SDD is increas-
is not a good biomarker for diagnosis of VAP.30–34 Nevertheless, several ingly difficult to sustain, based on available data.47
controlled trials showed that a PCT-guided strategy (with antibiotic Systemic antibiotic prophylaxis used alone without local decon-
stop guided by PCT level kinetics) reduced the duration of antibiotic tamination increases the risk of the development of MDR bacteria
therapy without harmful effects when compared with standard therapy and the data regarding its efficacy in the prevention of VAP are
in patients with nosocomial infections.35–37 Limiting exposure to anti- contradictory.
biotics decreases costs and the risk of the emergence of resistant bac-
teria. Thus, following serial PCT levels in patients with known VAP STRESS-ULCER PROPHYLAXIS
may allow earlier cessation of antibiotic therapy. The use of gastric protectors that increase the gastric pH (anti-H2,
Aerosolization of antibiotics has the advantage of high local con- anti-acids) expose the patient to the risk of gastric microbial develop-
centrations and fast clearance, which in turn may yield improved ment. A large randomized study comparing sucralfate with ranitidine
efficacy and decreased risk of microbial resistance. To date, aerosolized reported that the latter is more effective in the prevention of gastric
antibiotics (notably amikacin and colistin) are considered suitable bleeding and, in addition, did not increase the incidence of VAP.48
as adjuncts to systemic antibiotic therapy, especially in patients with
MDR pathogens or nonresponding VAP.38 Specially engineered ENTERAL NUTRITION
systems are currently in development to improve lung deposition of Early enteral nutrition is the standard of care in critically ill patients
antibiotics. receiving invasive mechanical ventilation49 but its use has been sug-
gested to increase the risk of VAP. However, the role for the stomach
Prognosis as a reservoir of VAP-causing micro-organisms is controversial. In
Although the absolute mortality rates in patents with HAP are high theory, gastric overdistension due to frequently observed gastroparesis
(33–50%),1 attributable mortality (that due to the pneumonia alone) may lead to regurgitation and aspiration, but there is no evidence of a
is considerably less and ranges from 3% to 17%.39 Factors associated sequence leading over time from gastric colonization to VAP.50
with an increased mortality include serious illness at the time of diag- Recently, a protocol of enteral nutrition management without residual
nosis (respiratory failure, coma, ARDS), bacteremia, serious underly- gastric volume monitoring was shown not to be inferior to a similar
protocol including residual gastric volume monitoring in terms of in VAP sampling are frequently identical.59 Silver-coated ETTs have
protection against VAP.51 been proposed to reduce biofilm formation.60 Silver has a very effective
broad-spectrum antimicrobial activity and blocks biofilm formation
PATIENT POSTURE in animal models. No convincing evidence is yet available to date on
The semirecumbent position makes it possible to limit inhalation in its influence on VAP.
patients receiving enteral nutrition. The only randomized study evalu-
ating the role of the position of the patient on the development of VAP BUNDLES AND PREVENTION PROGRAMS
has shown the protective effect of the semirecumbent position at 45°.52 ‘Bundles’ are a grouping of a small and simple set of practices – gener-
It should be noted that no benefit in terms of mortality was demon- ally three to five – which are well-established practices. When used
strated between the two groups. In all, the principal measurement and individually, they are found to be effective to improve patients’ out-
the only one currently recommended is a positioning of patients in the comes and when performed collectively and reliably they are expected
semirecumbent position between 30° and 45°, especially when enteral to result in a better outcome than when implemented individually. A
nutrition is administered. four-element ventilator-associated pneumonia prevention bundle,
consisting of head-of-bed elevation, oral chlorhexidine gel, limiting
AIRWAY DEVICES the use of sedation and the use a ventilator weaning protocol has
Microaspiration of contaminated subglottic respiratory secretions shown to decrease VAP incidence.61 A multifaceted behavioral
around the endotracheal tube (ETT) cuff plays a very important role program, which combined an educational session to encourage care-
in the occurrence of VAP. In this sense, efforts have been made to givers to adopt eight recommended practices, regular reminders and
attempt to prevent bacteria from entering around the ETT. It must be performance assessment feedback to reinforce changes, and technical
stressed that studies evaluating the effectiveness of these techniques improvements to facilitate compliance with the less feasible measures,
demonstrated conflicting results, and that clear recommendations are has also shown a dramatic decrease in the rate of VAP.62 The eight
weak to date. measures included:
The subglottic secretion drainage (SSD) was designed to evacuate • hygiene compliance with alcohol-based hand sanitizer;
the secretions that accumulate on top of the cuff. The results of the • use of gloves and gowns, both of which are able to limit
use of SSD on VAP prevention are mixed. Nevertheless, the benefit of cross-infection;
SSD has been reported in two meta-analyses53,54 and additional ran- • keeping patients in the semirecumbent position (30–45°) rather
domized studies are required to define its effectiveness. than the supine position to prevent aspiration;
The use of closed tracheal suction systems may limit the entry of • an endotracheal tube cuff pressure >20 cm H2O, which lowers
bacteria in airways and may reduce cross-contamination between the risk of leakage of bacterial pathogens around the cuff into
patients. Again, conflicting results have been reported and a meta- the lower respiratory tract;
analysis of randomized controlled trials found no difference in the • orogastric tubes, rather than nasogastric tubes, to reduce the
incidence of VAP between patients managed with closed or open tra- frequency of sinusitis and possibly VAP;
cheal suction systems.55 • avoiding gastric overdistension, which might increase the risk of
A constant cuff pressure below 20 cm H2O during the first 8 days aspiration;
of intubation has been reported as an independent risk factor for the • mouth decontamination with 0.12% chlorhexidine at least four
development of VAP.56 In this sense, continuous cuff pressure moni- times/day;
toring has been associated with a decreased rate of VAP.57 • the elimination of nonessential tracheal suction was introduced
New cuff materials and shapes attempt to prevent microchannel as a preventive measure, because avoiding ventilator-circuit dis-
formation around the cuff, thus limiting aspiration of secretions. A connection might contribute to lowering cross-infection.
cuff made of polyurethane material that has an ultrathin cuff mem- To date, no study has yet demonstrated the effectiveness of this meth-
brane may prevent the formation of folds within the ETT cuff.58 odology on patients’ outcomes.
Finally, the biofilm constitutes a protective environment from host
defenses and antimicrobial agents. Pathogens found in the biofilm and References available online at expertconsult.com.
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Bouadma L., Luyt C.E., Tubach F., et al.: Use of procalcito- Fagon J., Chastre J., Wolff M., et al.: Invasive and noninva- tion of the clinical pulmonary infection score as an early
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intensive care units (PRORATA trial): a multicentre- associated pneumonia: a randomized trial. Ann Intern 31:676-682.
randomised controlled trial. Lancet 2010; 375:463-474. Med 2000; 132:621-630. Pugin J., Auckenthaler R., Mili N., et al.: Diagnosis of
Canadian Critical Care Trials Group: A randomized trial of Guidelines for the management of adults with hospital- ventilator-associated pneumonia by bacteriologic analy-
diagnostic techniques for ventilator-associated pneumo- acquired, ventilator-associated, and healthcare-associated sis of bronchoscopic and nonbronchoscopic ‘blind’
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Chastre J., Wolff M., Fagon J.Y., et al.: Comparison of 8 vs 388-416. 143:1121-1129.
15 days of antibiotic therapy for ventilator-associated Kollef M.H.: Inadequate antimicrobial treatment: an Schuetz P., Christ-Crain M., Thomann R., et al.: Effect of
pneumonia in adults: a randomized trial. JAMA 2003; important determinant of outcome for hospitalized procalcitonin-based guidelines vs standard guidelines on
290:2588-2598. patients. Clin Infect Dis 2000; 31:S131-S138. antibiotic use in lower respiratory tract infections: the
Chiche L., Forel J.M., Papazian L.: The role of viruses in Kollef M.H., Hamilton C.W., Montgomery A.B.: Aerosol- ProHOSP randomized controlled trial. JAMA 2009;
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de Smet A.M., Kluytmans J.A., Cooper B.S., et al.: Decon- Kristoffersen K., Søgaard O., Wejse C., et al.: Antibiotic
tamination of the digestive tract and oropharynx in ICU treatment interruption of suspected lower respiratory
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562. 2361-2367.
30
Lung Abscesses and Pleural
Abscesses
CHRISTINA LISCYNESKY | JULIE E. MANGINO
KEY CONCEPTS Over the past five to six decades, the incidence of bacterial lung
abscess in the USA has diminished considerably and the mortality rate
• Lung abscesses are visible on radiographs as an air–fluid level. has decreased from 30–40% to 5–10%. Factors associated with a worse
• Lung abscesses are often a result of aspiration pneumonia, and prognosis include advanced age, prolonged symptoms, concomitant
as such anaerobes play a dominant role. disease, nosocomial infection and (according to some studies) larger
cavity size.5 In the past, tuberculosis was responsible for a higher pro
• Lung abscess treatment should be prolonged until radiographic portion of lung abscesses. In recent years, more lung abscesses have
resolution or stability/scarring of the abscess cavity. been associated with pulmonary malignancies or other underlying
• Augmentin or clindamycin are excellent choices for treatment conditions.6–8
of community-acquired lung abscess.
EMPYEMA
• Pleural effusions greater than 1 cm in a febrile patient should A pleural effusion associated with pneumonia, lung abscess or bron
be aspirated and analyzed for exudative properties.
chiectasis is referred to as a parapneumonic effusion. These effusions
• Therapy for pleural effusions is directed to the specific patho- occur in up to 40% of people who have bacterial pneumonia and are
gens identified. the most common cause of exudative pleural effusions in the USA.9
• Empyemas need to be drained via catheter, chest tube or
Empyema, or pleural pus, is an infected parapneumonic effusion with
surgery. characteristic changes in the composition of the pleural fluid. Mortal
ity ranges from approximately 2% to 50%, with the lowest rates in
young, healthy people and the highest rates in the elderly and immuno
compromised. The prognosis is poorer when pathogens are resistant
to antimicrobial drugs or when appropriate treatment is delayed.9–11
Introduction
Lower respiratory tract infections (LRTIs) are a major indication Pathogenesis and Pathology
for antimicrobial therapy in high-income countries. Although many Micro-organisms gain access to the lower respiratory tract by a variety
LRTIs are self-limiting, those caused by necrotizing organisms are of routes, such as inhalation of aerosolized particles, aspiration of
invariably serious; they may lead to abscess formation in the lung and oropharyngeal secretions and hematogenous spread from distant sites
can spread to the pleural space. (Figure 30-1). Less frequently, infection occurs by direct extension
from a contiguous site. Lung abscess is caused only by organisms that
Epidemiology cause necrosis, but empyema can result from infection by any pathogen
The etiologies of lung abscess and pleural abscess, or empyema, vary that reaches the pleural space.
in different parts of the world. The common denominator is usually
aspiration pneumonia, acquired either in the community or in the LUNG ABSCESS
hospital. Aspiration pneumonia leading to a necrotizing pneumonia Of the inhaled respiratory pathogens, only the mycobacteria (see
or lung abscess, with or without an empyema, is a continuum; any or Chapters 31 and 32) and the dimorphic fungi (see Chapter 33) com
all stages may be encountered. Underlying diseases, associated trauma monly cause lung abscesses. Bacterial abscesses are usually caused by
or surgery and the timeliness of appropriate therapy are the major aspiration of oropharyngeal secretions3 or, occasionally, by hemato
factors determining the clinical presentation and prognosis. genous seeding.1 Aspiration of small quantities of oropharyngeal secre
tions occurs commonly and intermittently, particularly during sleep.
LUNG ABSCESS Despite the frequency of aspiration, the airways below the level of the
A lung abscess is arbitrarily defined as a localized area of pulmonary larynx are normally sterile. Highly efficient clearing mechanisms are
necrosis caused by infection, with a solitary or dominant cavity mea in place; these include; cough, a mucociliary system that carries par
suring at least 2 cm in diameter. When cavities are multiple and smaller ticles cephalad to be swallowed, phagocytosis by alveolar macrophages
than 2 cm, the infection is usually referred to as a necrotizing pneu and neutrophils aided by opsonizing antibodies and complement, and
monia.1,2 Most abscesses are suppurative bacterial infections caused by lymphatic trapping with sequestration in regional lymph nodes. Risk
aspiration.3 factors for pneumonia after aspiration include conditions that increase:
Primary lung abscesses typically present in patients who have no the inoculum of pathogens in aspirated secretions, the likelihood of
predisposing disease other than a predilection to aspirate or poor aspiration and volume of the aspirate (Table 30-1). Under these cir
dental hygiene with gingivitis; they are more common in males than cumstances, aspirated oropharyngeal secretions are more likely to
in females. Secondary lung abscesses occur in patients who have an cause chemical irritation and infection. If an anaerobic pleuropulmo
underlying condition such as a partial bronchial obstruction or lung nary infection occurs in an edentulous patient, the diagnosis of bron
infarct, or in those who are otherwise immunocompromised because chogenic carcinoma should be considered.1,2,4,12
of chemotherapy, malignancy, organ transplantation or HIV infection. The composition of oropharyngeal flora at the time of aspiration
Lung abscesses may be termed nonspecific or putrid, referring, respec determines the potential etiologic agents for LRTIs. Although the
tively, to the often unclear etiology and the offensive odor of the classic non-necrotizing respiratory pathogens Streptococcus pneu-
sputum.3,4 moniae and Haemophilus influenzae can cause disease by this
263
Causes of lower respiratory tract infections in adults
Aspiration
Community- Hospital-
Organisms Inhalation acquired acquired Hematogenous
Streptococcus pneumoniae
Oropharyngeal streptococci and anaerobes
Enterobacteriaceae
Legionellaceae
Chlamydia pneumoniae
Viruses
Histoplasma capsulatum
Blastomyces dermatitidis
Mycobacteria
Common cause of infection Less common cause of infection
Figure 30-1 Causes of lower respiratory tract infections in adults. Oropharyngeal streptococci and anaerobes, Staphylococcus aureus, Enterobacteriaceae, Pseudo-
monas aeruginosa, the dimorphic fungi (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis) and mycobacteria frequently cause necrosis and
subsequent abscess formation.
TABLE Risk Factors for Aspiration Pneumonia and TABLE Anaerobic Bacteria Associated with
30-1 Lung Abscess 30-2 Pleuropulmonary Infections
Increased bacterial Periodontal disease, gingivitis, tonsillar or dental Gram-negative Bacteria Gram-positive Bacteria
inoculum abscess, drugs that decrease gastric acidity
Bacilli Bacteroides fragilis group Actinomyces spp.
Impairment of Drugs, alcohol, general anesthesia, metabolic Fusobacterium nucleatum Bifidobacterium spp.
consciousness encephalopathy, coma, shock, cerebrovascular Fusobacterium necrophorum Clostridium spp.
accident, cardiopulmonary arrest, seizures, Porphyromonas spp.* Eubacterium spp.
surgery, trauma Prevotella spp.† Lactobacillus spp.
Propionibacterium spp.
Impaired cough and Vocal cord paralysis, intratracheal anesthesia,
gag reflexes endotracheal tube, tracheostomy, myopathy, Cocci Veillonella spp. Gemella morbillorum‡
myelopathy, other neurologic disorders Peptostreptococcus
spp.¶
Impairment of Diverticula, achalasia, strictures, disorders of Streptococcus spp.
esophageal gastrointestinal motility, neoplasm,
function tracheoesophageal fistula, pseudobulbar palsy *Porphyromonas spp. include organisms previously named Bacteroides
melaninogenicus subsp. asaccharolyticus, B. endodontalis and B. gingivalis.
Emesis Nasogastric tube, gastric dilation, ileus, intestinal †
Prevotella spp. include organisms previously named B. melaninogenicus
obstruction subspp. melaninogenicus and intermedius, B. oralis and B. denticola.
‡
Gemella morbillorum was previously named Streptococcus morbillorum.
¶
Peptostreptococcus spp. are now divided into four genera – Anaerococcus,
Finegoldia, Gallicola and Peptoniphilus.
mechanism, normal oropharyngeal secretions contain many more retrospective evaluation of 90 adults with lung abscesses in Taiwan
streptococci of various species and more anaerobes (approximately revealed that gram-negative bacilli caused 36% of cases, whereas anaer
108 organisms/mL) than aerobes (approximately 107 organisms/mL). obes accounted for 34% of cases. Twenty-five percent of the patients
Some streptococcal species are microaerophilic (i.e. they require sup in this study had received antibiotics prior to culture, which could have
plemental carbon dioxide to grow on artificial media).13,14 The pneu made recovery of anaerobes even less likely.18 Post-influenza Staph.
monia that follows aspiration, with or without abscess formation, aureus pneumonia can cavitate to form lung abscesses. In the 2003–
is typically polymicrobial with between two and four bacterial 2004 influenza season, 25% of 16 patients with post-influenza staphy
species present in large numbers. In general, 50% or more of these lococcal pneumonia had cavitation or necrosis on radiograph.19
infections are caused by purely anaerobic bacteria, 25% are caused The anaerobes associated with pleuropulmonary infection, using
by mixed aerobes and anaerobes, and 25% or fewer are caused by current nomenclature,20,21 are shown in Table 30-2. The primary
aerobes only. Among hospitalized patients, progressive colonization pathogens are Streptococcus spp., Peptostreptococcus spp. (now divided
with Staphylococcus aureus, Enterobacteriaceae and Pseudomonas into four genera – Anaerococcus, Finegoldia, Gallicola and Peptoniphi-
aeruginosa occurs. These aerobic organisms are frequent causes of lus), Fusobacterium nucleatum and Prevotella spp. Additionally, Porphy-
healthcare-associated aspiration pneumonia and lung abscess.13,15–17 A romonas spp. are commonly associated with periodontal disease and
Chapter 30 Lung Abscesses and Pleural Abscesses 265
may also be isolated. Although not consistently part of the normal TABLE
oropharyngeal flora, members of the Bacteroides fragilis group of 30-3 Causes of Empyema
organisms are isolated from approximately 15% of patients.2,12–14,16,20
Pulmonary infection Skeletal infection
A variety of virulence factors associated with oropharyngeal strep • Pneumonia • Paravertebral abscess
tococci and anaerobes have been identified. Properties that facilitate • Lung abscess • Vertebral osteomyelitis
attachment include capsular polysaccharides, fimbriae, hemagglutinin • Bronchiectasis Direct inoculation
and lectin. Tissue breakdown and the metabolic activity of organisms Mediastinal disease • Trauma
• Tracheal fistula • Thoracentesis
provide reducing substances and a low redox potential; these factors • Esophageal perforation Postoperative
facilitate bacterial proliferation. Volatile fatty acids, sulfur compounds, • Subdiaphragmatic infection • Hemothorax (infected)
indoles, amines and hydrolytic enzymes (hyaluronidase, chondroitin • Subphrenic abscess • Pneumothorax (infected)
sulfatase and heparinase) produced by damaged tissue lead to subse • Hepatic abscess • Bronchopleural fistula
quent abscess formation.22
The pathology of aspiration pneumonia is characterized by alveolar
edema and infiltration with inflammatory cells. Foci of aspiration
pneumonia most commonly develop in the subpleural regions of the rare causes of lung abscesses. Cryptococcus, Aspergillus and Rhizopus
gravity-dependent segments of the lungs, particularly the superior spp. occasionally cause disease in normal hosts, but are more com
segments of the lower lobes and the posterior segments of the upper monly opportunistic pathogens. Patients with acquired immunodefi
lobes. The right lung is the more frequent location, presumably because ciency syndrome (AIDS) may have cavitary lesions caused by atypical
of the less acute angle in the take-off of the right main stem bronchus. mycobacteria, particularly Mycobacterium kansasii, Mycobacterium
In general, the right upper and lower lobes are most commonly avium complex (MAC) and other organisms such as Rhodococcus equi
involved, followed by the left lower lobe and right middle lobe.1,4,23,24 and Nocardia asteroides.25 Burkholderia pseudomallei is endemic to
The degree and rate of progression of aspiration pneumonia varies South East Asia, particularly Thailand, and typically causes upper lobe
considerably. These infections may be acute, subacute or chronic, cavities. In endemic areas, the parasites Paragonimus westermani and
depending on the cause, size of inoculum and host factors. If the Entamoeba histolytica may cause abscess by contiguous extension.
process is indolent, fibrosis limits the spread of infection. Abscesses
EMPYEMA
typically communicate with a bronchus, producing the familiar air-
filled cavity seen on radiographs 1–2 weeks later (Figure 30-2).6 The pleural space is normally sterile. It is most commonly contami
Infective endocarditis (predominantly right-sided), intravenous nated by direct extension from a contiguous focus of infection, pneu
drug injection and indwelling right atrial catheters placed for vascular monia or esophageal perforation, or by direct inoculation from trauma
access are commonly associated with septic pulmonary emboli, which or surgery (Table 30-3).9,26,27 The pleural space may also become
hematogenously seed the lung. There may be a solitary infiltrate or involved through hematogenous seeding from a distant focus of infec
cavity or, more often, multiple bilateral lesions. The most common tion, particularly in the presence of abnormal tissue such as hemotho
etiologic agents are the healthcare-associated pathogens Staph. aureus rax or pleural malignancy.
and aerobic gram-negative bacilli (see Figure 30-1). Any organism that The initial stage in the pathogenesis of empyema associated with
is part of the skin flora or contaminants in injected material may be pneumonia is the development of a sterile parapneumonic effusion
responsible. (Table 30-4).9,28 The effusion is initially transudative but rapidly
Some uncommon causes of lung abscess should be considered in becomes exudative with an influx of leukocytes and increasing perme
appropriate circumstances. Inhaled micro-organisms such as Legio- ability of the visceral pleura. Neutrophils, lactate dehydrogenase (LDH)
nella spp., Chlamydia spp., Mycoplasma pneumoniae and viruses are and protein increase, and glucose and pH decrease. Fibrin is deposited
on the pleural surfaces and loculations may occur. With time, a final
organizing stage occurs in which pleural fibroblasts produce an inelas
tic membrane or pleural peel that encases the lung and restricts infla
tion. Invasion with bacteria accelerates the fibropurulent reaction.
Empyema fluid is relatively deficient in opsonins and complement and
it becomes progressively more acidic as the infection ensues. An
empyema may spontaneously drain through necrotic lung tissue into
a bronchus (bronchopleural fistula) or can communicate through the
chest wall (empyema necessitans).9,11,27
Overall, the relative frequencies of various organisms causing
empyema have changed over time. Prior to the antibiotic era, most
empyemas were caused by Strep. pneumoniae and, to a lesser extent, by
Staph. aureus and Strep. pyogenes. In the early 1970s, anaerobic empy
emas were recognized more frequently, coinciding with a surge of
interest in anaerobic infections (Table 30-5).29,30 About 50% of empy
emas were caused by aerobes then, with gram-positive cocci being
more common than gram-negative bacilli. About 25% were caused by
anaerobes and about 25% were mixed aerobic–anaerobic infections.
Strep. pneumoniae was frequent in young ambulatory patients, anaer
obes were most frequent after aspiration, and Staph. aureus and aerobic
gram-negative bacilli were most frequent after thoracotomy.10,13,31,32
Because one-quarter of all empyemas are now associated with trauma
or surgery, there has been a relative increase in the proportion of
staphylococcal infections and a decrease in anaerobic infections.9
Prevention
Minimizing the risks of aspiration in those who are unconscious,
undergoing anesthesia or subject to seizures will reduce the incidence
Figure 30-2 Cross-section of a lung abscess. of pneumonia with subsequent abscess formation or empyema. If
TABLE
30-4 Characteristics* of Pleural Fluid Associated with Bacterial Lower Respiratory Tract Infection
EXUDATE
Uncomplicated Complicated
Pleural Fluid Characteristic Transudate Parapneumonic Effusion Parapneumonic Effusion Empyema
Appearance Clear Variable Variable Pus
White blood cell count (cells/mL) <1000 Variable Variable >15 000
Differential cell count Variable Neutrophils Neutrophils Neutrophils
Protein (g/dL) <3.0 >3.0 >3.0 >3.0
Glucose (mg/dL) Same as serum >60 40–60 <40
pH Greater than serum >7.2 7.0–7.2 <7.0
Lactate dehydrogenase (units/mL) <200 <1000 >1000 >1000

Bacteria Absent Absent Absent Absent
*The values may overlap. Complicated pleural effusions are those with fluid characteristics that indicate the potential need for tube drainage. When the glucose is
40–60 mg/dL or the pH is 7.0–7.2, repeat thoracentesis may be helpful. When the glucose is <40 mg/dL or the pH is less than 7.0, a chest tube is indicated even if
bacteria are not present by smear or culture.
Data from Light9 and Sokolowski et al.28
leukocyte count of more than 15 x109/L.4,32 True rigors are uncommon.

TABLE Frequency of Organisms Isolated from Among community-acquired cases, conditions predisposing to aspira
30-5 Bacterial Empyemas tion are alcoholism, seizures and drug overdose. Among healthcare-
acquired cases, patients tend to have neurologic disorders, such as
% OF ISOLATES cerebrovascular accidents and brain tumors, or metabolic disorders
1971–1973 29
1969–197810 1973–198530 that result in stupor or coma. Only a minority of patients who have
Organism (n = 214) (n = 93) (n = 343) aspiration pneumonia have putrid sputum, which, if present, develops
Haemophilus <1 0 3 1–2 weeks into the course when an abscess has formed.13,15,16,32
influenzae Lung abscesses may also present in a more indolent fashion with
weeks to months of productive cough, malaise, weight loss, low-grade
Streptococcus 2 7 20
pneumoniae
fever, night sweats, leukocytosis and anemia. The patient may become
debilitated. Lung abscess must be distinguished from a necrotic neo
Other streptococci 13 22 8 plasm. Patients with neoplasms often lack risk factors for aspiration,
(including
microaerophiles)
symptoms of respiratory infection, fever and leukocytosis. The possi
bility of tuberculosis or a noninfectious cause of a lung cavity (neo
Staphylococcus 8 8 17 plasm, infarct or vasculitis) should be suspected in a patient treated
aureus
for presumed lung abscess who does not respond to appropriate anti
Enterobacteriaceae 9 10 11 microbial therapy.
Pseudomonas spp. 5 9 3
In the pre-antibiotic era, lung abscess characteristically ran a
chronic course with the potential for sudden, severe complications.
Other aerobes 5 2 2 These included brain abscess, massive hemoptysis, endobronchial
Bacteroides spp. 11 14 8 spread to other portions of the lung, and rupture into the pleural space
with the development of a bronchopleural fistula and pyopneumotho
Anaerobic cocci 15 9 10 rax. With modern antimicrobial therapy, these complications are rare.
Fusobacterium spp. 7 8 6
EMPYEMA
Prevotella spp. 6 4 6
Symptoms of empyema include fever, chills, cough, dyspnea and chest
Other anaerobes 19 7 6 pain associated with a recent pulmonary or contiguous infection in the
oropharynx, mediastinum or subdiaphragmatic area. The occurrence
of persistent fever and leukocytosis with a pleural effusion despite
appropriate antibiotics should suggest the presence of empyema. There
pneumonia does occur, timely administration of appropriate antibiot may also be severe constitutional manifestations such as shock, tachy
ics reduces the likelihood of progression. Pleural effusions should be pnea, altered consciousness and respiratory failure. Typical findings on
aspirated and analyzed for diagnosis and drained, if indicated, to abort physical examination include diminished breath sounds, dullness to
progressive suppurative complications. percussion and a pleural friction rub. Patients with an empyema sec
ondary to an aerobic pneumonia tend to present with an acute illness,
Clinical Features whereas those who have an anaerobic pneumonia have a subacute
clinical syndrome with findings such as putrid sputum.1,6,32
LUNG ABSCESS
Aspiration is usually subtle and unrecognized but may lead to pneu
monia and lung abscess. If overt, it may be followed by symptoms and
Diagnosis
signs such as choking, cough, wheezing, cyanosis or asphyxia, due to RADIOGRAPHY
the particulate, liquid and chemical nature of the material aspirated. Both lung abscess and empyema may be suspected from clinical symp
Within hours, there may be fever, tachypnea, diffuse rales and hypox toms but the chest radiograph is the primary tool for diagnosing these
emia.12,32 If pneumonia develops, patients usually present within a infections. Radiographs obtained soon after aspiration usually demon
week with a productive cough, temperature over 38.9 °C (102 °F) and strate localized or diffuse alveolar infiltrates within 1–2 days. There is
Chapter 30 Lung Abscesses and Pleural Abscesses 267
Figure 30-5 CT scan of a lung abscess showing an air–fluid level.
Figure 30-3 A lung abscess showing an air–fluid level.
Figure 30-6 Gram stain of lower respiratory tract secretions. The patient had a
lung abscess caused by oropharyngeal streptococci and anaerobes.
Figure 30-4 A lung abscess associated with a multinodular bronchogenic

carcinoma. abscesses that are not apparent on plain radiographs and can distin
guish between parenchymal and pleural disease (Figure 30-5). Locu
lated empyema with a bronchopleural fistula may resemble a lung
nothing distinctive about the appearance of aspiration pneumonia abscess. Features on CT that tend to favor lung abscess are the presence
except that infiltrates are usually in dependent segments of the lung. of thick walls and lesions that are round or oblong, whereas empyemas
Multilobar involvement may suggest impairment of the host immune have thinner walls with a smooth luminal margin and exterior.36 Both
system.33 ultrasound and CT may be used to guide aspiration of fluid from
The characteristic appearance of a lung abscess is that of a density abscesses or the pleural space.
or mass with a cavity, frequently with an air–fluid level indicating
communication with the tracheobronchial tree (Figure 30-3). The time INVESTIGATIONS
required for cavitation after a known episode of aspiration is about The first step in determining the specific etiology of any LRTI is the
1–2 weeks. With necrotizing pneumonia, multiple small lucencies in evaluation of lower respiratory tract secretions by Gram stain. These
circumscribed areas of opacification may develop more rapidly.1,6,34 are most useful if they are obtained before antimicrobial treatment.
Abscesses due to tuberculosis are less likely to have an air–fluid level If stains of expectorated specimens show neutrophils and alveolar
and are more likely to have a dense fibronodular infiltrate that sur macrophages, without squamous epithelial cells (indicative of con
rounds the cavities.24 Those associated with a malignancy may be more tamination with saliva), they are useful for defining the offending
sharply defined or have an eccentric-shaped cavity with a thick, irregu pathogen(s). In aerobic pneumonia there is usually a single predomi
lar wall (Figure 30-4). nant organism; in aspiration pneumonia there is usually a mixed flora,
A pleural effusion, visible on posterior-anterior and lateral upright representing the diverse morphotypes of the oropharyngeal flora.
chest radiographs, suggests the possibility of empyema. On a decubitus Typically, there are various sizes of gram-positive cocci and pleomor
film, with the suspect side down, free pleural fluid can be visualized phic gram-negative coccobacilli and bacilli, which may be tapered and
between the chest wall and the dependent lung. If the layer of pleural are generally smaller and poorer-staining than the Enterobacteriaceae
fluid is greater than 1 cm thick, it should be aspirated for diagnostic (Figure 30-6).1,2,12,14,37
studies. A decubitus film with the suspect side up is also useful because Invasive procedures, such as endotracheal aspiration and bronchos
it permits assessment of any underlying parenchymal infiltrate, less copy, may be useful to obtain lower respiratory secretions for evalua
obscured by the effusion.9,27 tion. Tracheal aspiration through the nose or the mouth is of limited
Ultrasound and computed tomography (CT) are helpful in defin use because these specimens are often contaminated with oropharyn
ing pleuropulmonary lesions.35 Ultrasound can define small, loculated geal flora. Bronchoscopy with bronchoalveolar lavage is useful because
collections of pleural fluid. The portability of the machine allows large samples can be obtained with relatively little contamination.
bedside evaluation and drainage for critically ill patients. CT can define The bronchoscopic techniques of protected catheter aspiration and
protected specimen brushing reduce contamination considerably, but producers and resistant to penicillin. In a study of 449 isolates, which
they provide relatively scanty specimens and rely on quantitative cul included Bacteroides spp. other than B. fragilis, Fusobacterium spp.,
tures to help distinguish the significance of cultures. In general, counts Prevotella spp. and Porphyromonas spp. from 28 US medical centers,
of more than 105 cfu/mL of respiratory secretions for an appropriate 57.9% of isolates were β-lactamase producers.40
organism (see Figure 30-1, Table 30-2) are indicative of infection.1,6,17,26 Today, transtracheal aspiration and other invasive procedures are
Specimens of lower respiratory tract secretions that have passed rarely performed to determine the microbiologic etiology of aspiration
through the mouth should be cultured for aerobes but not for anaer pneumonia and lung abscesses in non-immunocompromised patients.
obes. The absence of aerobic pathogens in specimens from untreated Treatment is usually empiric and largely effective.15 Clinical outcome
patients should indicate the possibility of anaerobic infection. When for most anaerobic infections seems to correlate with in vitro data as
specimens are contaminated by saliva, the streptococci and anaerobes broadly applied, and detailed study of individual cases does not seem
comprising normal oropharyngeal flora will always grow in culture, to be necessary. Monitoring trends in susceptibility patterns and
whether or not infection is present, and they provide no insight into detailed study in problematic individual cases suffices.32
the pathogenicity of the organisms isolated. The in vitro spectrum and clinical utility of antimicrobials for the
The problem of contamination of respiratory tract secretions by treatment of lower respiratory tract bacterial infections is summarized
saliva can be avoided if specimens of lower respiratory secretions are in Figure 30-7. For community-acquired infections that result from
obtained by transtracheal aspiration. A catheter is passed through the aspiration, and where oropharyngeal streptococci and anaerobes are
cricothyroid membrane and specimens are collected by suction.1,13,16 the likely pathogens, penicillin G (or ampicillin or amoxicillin) remains
Although never used today, this technique established the role of an excellent foundation for treatment, but the addition of a β-lactamase
anaerobes in suppurative pleuropulmonary infections in the early inhibitor or metronidazole is advisable owing to the frequency of
1970s. Another method for obtaining uncontaminated material for β-lactamase production among gram-negative anaerobes.32,40,41 Clinda
culture is percutaneous transthoracic needle aspiration (percutaneous mycin is also a primary therapeutic agent, despite in vitro resistance
abscess drainage). Today, this procedure is more frequently performed among some Bacteroides and Fusobacterium spp. Resistance rates vary
under fluoroscopic or CT guidance for the diagnosis of malignancy significantly in different geographic regions, so surveillance of resis
than to obtain material for culture. It can be used, however, to aspirate tance is important in assessing the utility in a given area.7,15,37,41,42 Met
peripheral abscesses, particularly if bronchoscopy does not provide an ronidazole alone is not effective because of its inactivity against the
adequate specimen for microbiologic diagnosis. aerobic and microaerophilic streptococci.15,41,43
If appropriate specimens from the lower respiratory tract are For healthcare-acquired infections, where Staph. aureus and aerobic
obtained for culturing anaerobes, they should be expeditiously trans gram-negative bacilli are common components of the oropharyngeal
ported to the laboratory, with minimal exposure to air, for proper flora, piperacillin or ticarcillin (rather than penicillin or ampicillin)
processing. If tuberculosis or fungal infection is in the differential with a β-lactamase inhibitor provide better coverage of likely patho
diagnosis, appropriate smears and cultures should be requested. If a gens. Appropriate alternatives are imipenem alone, clindamycin plus
malignancy is suspected, cytologic stains should be performed. An an aminoglycoside or ciprofloxacin, or an expanded spectrum cepha
amplified Mycobacterium tuberculosis direct test (MTD) can be useful losporin such as cefotaxime, ceftizoxime or ceftriaxone plus metroni
for detection of smear-negative pulmonary tuberculosis cases. dazole. In healthcare settings with a high incidence of methicillin-resistant
In addition to lower respiratory tract secretions, blood and pleural Staph. aureus (MRSA) pulmonary infection, intravenous vancomycin
fluid, if present, should also be sent to the laboratory for microbiologic or linezolid should be considered. Many cephalosporins, for example
evaluation. In anaerobic lung infections, blood cultures are rarely posi ceftazidime, have little or no activity against anaerobes and should not
tive. If pleural fluid is present, it should be analyzed for protein, LDH, be used unless the etiology has been defined and involves aerobic
glucose, WBC and determination of pH, as well as microbiologic eval gram-negative bacilli.15,11,43
uation. Serum protein and LDH should be simultaneously measured For most community-acquired infections, amoxicillin-clavulanate
in order to apply Light’s criteria.38 or clindamycin are excellent oral drugs that can be used for continued
treatment after initial parenteral therapy.3 A less costly oral alternative
Management is penicillin V plus metronidazole. If aerobic gram-negative bacilli are
present, oral treatment is more problematic and must be based on the
LUNG ABSCESS results of susceptibility tests. Levofloxacin plus clindamycin or cipro
In the past, penicillin G was the preferred drug for treating aspiration floxacin plus a penicillin or clindamycin may be appropriate. Moxi
pneumonia and lung abscesses, as well as all anaerobic infections above floxacin has greater activity than ciprofloxacin or levofloxacin against
the diaphragm caused by oropharyngeal flora. In a study of more than oropharyngeal streptococci and anaerobes.44,45 In the treatment of
70 patients hospitalized with lung abscesses in the 1960s, nearly all aspiration-associated pulmonary infections, moxifloxacin appears to
responded to intravenous penicillin G. be clinically as effective and as safe as ampicillin-sulbactam.46 Tetracy
In the 1970s, when transtracheal aspiration defined the microbiol clines are no longer recommended for treatment because of high rates
ogy of pneumonia and lung abscesses, concern over the use of penicil of anaerobic resistance. The macrolides and azalides have inconsistent
lin was raised because of occasional therapeutic failures and the in vitro activity against oropharyngeal anaerobes.47 Ertapenem, a once-
isolation of penicillin-resistant B. fragilis from some patients.1,16 daily carbapenem, can be used if the oral route is precluded and if the
However, in one study that compared clindamycin, a drug that is active infection does not include P. aeruginosa.48 Other agents that have sub
against B. fragilis, with penicillin G for treatment of aspiration pneu optimal or no activity against oropharyngeal streptococci and anaer
monia and primary lung abscess, there was no difference in rates of obes include aztreonam and trimethoprim-sulfamethoxazole. The
defervescence, radiographic clearing or ultimate outcome. Notably, anti-staphylococcal penicillins, vancomycin or linezolid should be
seven patients from whom B. fragilis was isolated responded to reserved for documented staphylococcal infections. Ceftaroline has not
penicillin.34 been specifically studied for lung abscess, but is effective for MRSA
In a 1990 study of 37 patients who had lung abscess or necrotizing pneumonia.5 Daptomycin is ineffective as it is inactivated by pulmo
pneumonia,39 only 1/19 patients failed to respond to clindamycin, nary surfactant.
whereas 8/18 failed with penicillin G. In this study, patients underwent The duration of antimicrobial therapy necessary to treat pleuropul
transtracheal aspiration or protected specimen brushing to culture for monary infections is variable: 1–2 weeks may suffice for simple aspira
anaerobes; 9/10 of the penicillin-G-resistant strains were β-lactamase tion pneumonia but necrotizing pneumonia and lung abscesses may
producers. It is now recognized that there has been a change in require 3–24 weeks. Parenteral therapy is generally employed until the
the susceptibilities of the oropharyngeal gram-negative anaerobes patient is afebrile (most are afebrile in 7 days) and able to have a con
since the 1970s. Many, in addition to B. fragilis, are now β-lactamase sistent enteral intake.32 Prolonged therapy is advisable, with treatment

Antimicrobials for bacterial lung abscesses and empyemas
Aerobes Anaerobes
ae
s
s
riace
iae
e
sa
acte
t
t
i
d
b
h
h
e
is
mon
gino
enza
us
o
rob
Cocc
Haem
Strep
Strep
Stap
Pseu
Fuso
Porp
Bact
Prev
aeru omonas
spp. acterium
spp. yromona
fragil roides
influ ophilus
pneu ococcus
spp. ococcus
aure ylococcu
Ente
spp. tella
Antimicrobial
Penicillin G, ampicillin, amoxicillin
Ampicillin–sulbactam, amoxicillin–clavulanate
Piperacillin, ticarcillin
Piperacillin–tazobactam, ticarcillin–clavulanate
Nafcillin, dicloxacillin
Cefazolin, cephalexin
Cefuroxime, cefpodoxime
Cefoxitin, cefotetan
Cefotaxime, ceftriaxone, ceftizoxime
Ceftazidime
Cefepime
Ertapenem
Imipenem
Erythromycin
Azithromycin
Clarithromycin
Clindamycin
Tetracyclines
Ciprofloxacin, ofloxacin
Moxifloxacin
Trimethoprim–sulfamethoxazole
Metronidazole
Chloramphenicol
Aminoglycosides
Vancomycin *
Linezolid *
Ceftaroline
Susceptible in vitro and preferred clinically Susceptible in vitro, but Inconsistent or borderline activity Inactive in vitro
(expanded spectrum antimicrobials are other drugs preferred in vitro and/or suboptimal clinical and clinically
Chapter 30 Lung Abscesses and Pleural Abscesses
necessary only if infections are polymicrobial) (or efficacy not established) efficacy (not recommended) ineffective
* Only cover gram-positive cocci
Figure 30-7 Antimicrobials for bacterial lung abscesses and empyemas. Information for Streptococcus pneumoniae is for penicillin-susceptible strains – selected cephalosporins or vancomycin
269
should be used for resistant strains. Information for Staphylococcus aureus is for methicillin-susceptible strains – vancomycin should be used for resistant strains. Vancomycin is the drug of choice
for β-lactam-resistant gram-positive organisms.
defined etiology are more common, facilitating antibiotic choice. Anti

Duration of therapy for lung abscess biotics should be administered in full doses for 2–4 weeks. Therapy
may be prolonged further, particularly if drainage is not optimal. Anti
Cases 100
biotic levels in pleural fluid are comparable to those in serum, so
(%) standard systemic doses provide adequate pleural fluid levels.27
90 The proper assessment and management of parapneumonic effu
80 sions associated with LRTIs is critical for a successful outcome. Most
70
small effusions clear with antimicrobial treatment and need not be
Radiographic drained. However, if fluid persists more than a few days or layers to
60 more than 1 cm on a decubitus radiograph with the involved side
clearing
50 dependent, it should be aspirated and analyzed. The characteristics of
the fluid are used to determine the need for tube drainage (see Table
40
Cavity 30-4). See Practice Point 7 for further discussion.
30 closure Chest tube drainage of complicated parapneumonic effusions is
20 successful in most patients. It should not be delayed, because effusions
Fever
progress from free-flowing to loculated fluid rapidly. When the fluid
10
is loculated, drainage by repeated thoracentesis or tube insertion may
0 not be adequate. The presence of loculated infected fluid should be
0 1 2 3 4 6 8 10 15 24 suspected if the patient remains ill, febrile or has a persistent leukocy
Weeks tosis. After appropriate evaluation by ultrasound or CT, options for
Penicillin G Clindamycin management include image-guided percutaneous drainage,52 followed
by instillation of fibrinolytic agents, as needed.35,53 If administered
Figure 30-8 Duration of therapy for lung abscess. Response of patients who had before fibrosis occurs, these agents attack the fibrin membranes causing
lung abscess to penicillin G (17 patients) and clindamycin (16 patients). the loculations. Successful therapy leads to an increase in the amount
of drainage from the pleural space and can be administered for up to
2 weeks. Thoracoscopy to mechanically lyze adhesions and inspect the
continued until the cavity is gone or until serial radiographs show pleural cavity has also been used to assist in management.9 If patients
considerable improvement or a small stable residual scar (Figure 30-8). do not respond to the above measures, open drainage, evacuation of
The time to cavity closure depends largely on the size of the cavity all infected material and decortication of the pleura should be consid
when treatment is initiated and on the condition of the patient. ered (see Practice Point 7).
Surgical drainage of lung abscesses is rarely indicated because A serious complication of an empyema is a bronchopleural fistula
drainage occurs naturally via the tracheobronchial tree. If spontaneous (BPF). The presence of a peripheral air–fluid level radiographically
drainage is not adequate, even with the aid of postural drainage and suggests the presence of a BPF, although such an air–fluid level may
percussion, CT-guided percutaneous abscess drainage may then be occasionally be due to the presence of gas-forming bacteria. Adequate
beneficial.49 The drainage catheter can be left in place until there is tube drainage is mandatory to minimize the spread of infection to
clinical improvement and drainage has diminished, usually within other portions of the lungs. Empyema with a BPF after pneumonec
several days to 1 week. Endoscopic drainage can also be useful for tomy is a disastrous surgical complication. The fistula often does not
patients who are considered to be poor surgical candidates.50 Other close with antibiotics, tube drainage and irrigation, and complex surgi
indications for drainage include large abscess cavity (>6 cm), abscess cal procedures are usually necessary.9
caused by resistant organisms, obstructing neoplasm impeding drain
age and failure of medical treatment. In these situations, a lobectomy References available online at expertconsult.com.
or pneumonectomy may be required.51
EMPYEMA
Antimicrobial treatment of empyema is similar to that of aspiration
pneumonia and lung abscess but single-organism infections with a
KEY REFERENCES
Bartlett J.G.: Anaerobic bacterial infections of the lung. Finegold S.M.: Overview of clinically important anaerobes. Pohlson E.C., McNamara J.J., Char C., et al.: Lung abscess:
Chest 1987; 91:901-909. Clin Infect Dis 1995; 20(Suppl. 2):205-207. a changing pattern of the disease. Am J Surg 1985;
Bartlett J.G.: Antibiotics in lung abscess. Semin Respir Infect Light R.W.: Parapneumonic effusions and empyema. In: 150:97-101.
1991; 6:103-111. Retford D.C., ed. Pleural diseases. Baltimore, MD: Wil Yu H.: Management of pleural effusion, empyema, and lung
Bartlett J.G.: How important are anaerobic bacteria in aspi liams and Wilkins; 1995:129-153. abscess. Semin Intervent Radiol 2011; 28(1):75-86.
ration pneumonia: when should they be treated and what Mansharamani N., Balachandran D., Delaney D., et al.:
is optimal therapy? Infect Dis Clin North Am 2013; Lung abscess in adults: clinical comparison of immuno
27(1):149-154. compromised to non-immunocompromised patients.
Bartlett J.G., Finegold S.M.: Anaerobic infections of the lung Respir Med 2002; 96:178-185.
and pleural space. Am Rev Respir Dis 1974; 110:56-77. Ott S.R., Allewelt M., Lorenz J., et al.: German Lung Abscess
Bartlett J.G., Gorbach S.L., Tally F.P., et al.: Bacteriology and Study Group: Moxifloxacin vs ampicillin/sulbactam in
treatment of primary lung abscess. Am Rev Respir Dis aspiration pneumonia and primary lung abscess. Infec-
1974; 109:510-518. tion 2008; 36(1):23-30.
Chapter 30 Lung Abscesses and Pleural Abscesses 270.e1
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77. 20. Finegold S.M.: Overview of clinically important anaer 40. Appelbaum P.C., Spangler S.K., Jacobs M.R.:
2. Bartlett J.G., Gorbach S.L., Tally F.P., et al.: Bacteriology obes. Clin Infect Dis 1995; 20(Suppl. 2):205-207. β-Lactamase production and susceptibilities to amoxi
and treatment of primary lung abscess. Am Rev Respir 21. Summanen P.: Microbiology terminology update: clin cillin, amoxicillin-clavulanate, ticarcillin, ticarcillin-
Dis 1974; 109:510-518. ically significant anaerobic gram-positive and gram- clavulanate, cefoxitin, imipenem and metronidazole of
3. Bartlett J.G.: How important are anaerobic bacteria in negative bacteria (excluding spirochetes). Clin Infect Dis 320 non-Bacteroides fragilis Bacteroides isolates and 129
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4. Pohlson E.C., McNamara J.J., Char C., et al.: Lung 23. Cameron J.L., Mitchell W.H., Zuidema G.D.: Aspiration for anaerobic infections. Clin Infect Dis 1996;
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331. lung abscess and empyema: radiography and computed tions: factors for predicting clinical outcome of lung
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19. Hageman J.C., Uveki T.M., Francis J.S., et al.: Severe penicillin for anaerobic lung infections: high rate of thoracic empyemas. Ann Thorac Surg 1994; 57:803-
community-acquired pneumonia due to Staphylococcus penicillin failures associated with penicillin-resistant 814.
31
Tuberculosis
REINOUT VAN CREVEL | PHILIP C. HILL
KEY CONCEPTS notification data and incidence rate estimates across the world are
shown in Figure 31-1 and show the predominance of the disease in
• Tuberculosis, caused by Mycobacterium tuberculosis spread by LMIC.
aerosols, kills more people than any other infectious disease. In wealthier nations, rates of tuberculosis have been falling since at
• After exposure to tuberculosis, only around 5–10% of individu- least as early as 1900, initially mainly due to social improvements and
als will develop active disease, up until decades afterwards. development, with likely contributions from BCG vaccination and the
Risk factors for tuberculosis include HIV, diabetes and use of use of sanatoria. This was followed by an accelerated decline since
immunosuppressive drugs. 1950, probably due to the introduction of effective chemotherapy for
M. tuberculosis infection and disease. However, tuberculosis persists in
• Screening exposed individuals for latent tuberculosis with
the tuberculin skin test (TST) or interferon gamma release many wealthy nations, especially in particular population groups such
assays (IGRAs), followed by prophylaxis can prevent active as poorer communities, migrants, homeless populations, intravenous
tuberculosis. drug users and prisoners.2. The worldwide prevalence of diabetes mel-
litus is increasing and increases the risk of tuberculosis, threatening TB
• Tuberculosis can occur anywhere in the body, but typically control in areas where both diseases predominate.3 Other specific risk
presents as subacute pulmonary disease with cough, weight
factors are heavy alcohol consumption, smoking, low body mass index,
loss (40–75%), fever (30–60%) and night sweats (40–60%).
biomass fuel consumption, outdoor air pollution and a range of
• Diagnosis depends on microbiological testing of sputum, alve- medical conditions with immunocompromise.4
olar lavage or tissue biopsies; pulmonary cavities on X-ray and
necrotizing granulomata in biopsies are strongly suggestive of The Impact of HIV
tuberculosis. The WHO estimate that there were 1.1 million new cases of tubercu-
• Tuberculosis requires at least 6 months of treatment with a losis associated with HIV in 2012 and 320 000 TB deaths were in HIV-
4-drug regimen including rifampin and isoniazid; drug-resistant positive people.1 HIV-seropositive patients are more susceptible to
tuberculosis is a clinical and public health challenge. infection by M. tuberculosis. Reactivation of tuberculosis occurs at least
10 times more frequently than in age-matched controls. The majority
of people coinfected with tuberculosis and HIV live in sub-Saharan
Africa (approximately 75%), the Indian subcontinent and South East
Tuberculosis is the most important mycobacterial infection and is the Asia (Figure 31-2). Patients tend to be sicker and in greater need of
subject of this chapter. The other mycobacterial infections except for hospitalization. The relationship between HIV and tuberculosis is such
leprosy are covered in Chapter 32; leprosy in Chapter 108. Details of that all tuberculosis patients should be offered HIV screening. Diag-
antimycobacterial drugs are to be found in Chapter 148. Tuberculosis nosis of dual infection may be difficult since HIV predisposes to atypi-
and HIV coinfection is also covered separately in Chapter 96. The cal, nodal and extrapulmonary disease. The subject of HIV–tuberculosis
clinical microbiology of mycobacterial infections is discussed in coinfection is explored in depth in Chapter 96 and is not considered
Chapter 185. further here.
SPREAD OF INFECTION
Tuberculosis Spread of infection is dependent on inhalation of aerosols from indi-
Tuberculosis, a disease identified in skeletons more than 6000 years viduals with pulmonary disease. Proximity to and duration of associa-
old, remains one of the most prevalent infectious diseases in the world. tion with an index case are critical factors. Approximately 25–60% of
This chapter focuses on current understanding of pathophysiology, household contacts of an index case may acquire infection although
epidemiology and clinical aspects of tuberculosis. the extent to which individual genetic predisposition or immunologic
impairment contribute to this is uncertain. Although contributory, the
Epidemiology exact role of factors such as vitamin D deficiency and iron overload in
the spread of tuberculosis is unknown. Development of disease occurs
WORLDWIDE INCIDENCE AND PREVALENCE in up to 10% of infected persons and is significantly affected by
Mycobacterium tuberculosis is estimated to infect approximately one- impaired cell-mediated immunity.
third of the world’s population, over 2 billion people worldwide. The
global burden of tuberculosis probably peaked in 2010 and the number Transmission in Closed Institutions
of new cases per year is now declining slowly; the World Health Orga- Overcrowding contributes to the spread of tuberculosis. Close proxim-
nization (WHO) reported that there were approximately 8.6 million ity to infected individuals is a significant issue in any closed institution
new cases and 1.3 million deaths from tuberculosis in 2012.1 While the and for healthcare workers. Many countries have specific guidelines
TB death rate has dropped dramatically since 1990, over 95% of TB for tuberculosis control in institutions. In prisons, the situation is
deaths occur in low- and middle-income countries (LMIC). Tubercu- complicated by the fact that inmates have an increased incidence of
losis notification rates are adjusted to provide incidence estimates in HIV, are frequently moved to other prisons or back into the commu-
LMIC. For this, available data from prevalence surveys and a variety nity with little warning and may be poorly managed in terms of health
of different sources, including expert opinion, are used. Historical services. Since release of prisoners is often into poor circumstances and
incidence rates are continually revised through application of the most crowded hostels, the consequence of undetected or inadequately
recent methodologies and can change significantly, by as much as 50%. treated tuberculosis may be rapid spread of disease. Mass incarceration
Therefore they should be interpreted with caution. Recent tuberculosis can lead to an increase in cases of tuberculosis and a rise in
271
Estimated tuberculosis incidence rates worldwide in 2012
Estimated new TB
cases (all forms) per
100,000 population
per year
0–9.9
10–19
20–49
50–124
125–299
300–499
≥500
No data
Not applicable
Figure 31-1 Estimated tuberculosis incidence rates worldwide in 2012. (Reproduced with permission from the World Health Organization, 2013.)
drug-resistant disease.5 An effective public health program with an bacillus and host–defense mechanisms.6,7 M. tuberculosis may be
active community care component can overcome such problems. destroyed by alveolar macrophages or neutrophils. If it is not imme-
Genetic techniques using restriction fragment length polymor- diately killed, a primary complex consisting of a small infiltrate and
phism (RFLP) analysis (often of the insertion sequence IS6110) or draining lymph nodes develops. Small calcifications may be seen on
variable number tandem repeat (VNTR) technology which character- radiographic examination, and the PPD (purified protein derivative of
izes the number of tandem repeats in 24 different loci have proven tuberculin) skin test, as a marker of an M. tuberculosis-specific T-cell
useful in documenting outbreaks or clustering of tuberculosis. Whole response, becomes positive several weeks after infection. In a minority
genome sequencing is likely to overtake all other tools, providing of cases active disease develops (progressive primary tuberculosis),
improved strain differentiation, and revealing greater genetic diversity either in the lungs or anywhere else after hematogenous dissemination
than has been previously recognized. of M. tuberculosis. In the remainder, infection is stabilized, but may
reactivate months or years later, usually under conditions of failing
Pathogenesis and Pathology immune surveillance.
THE PATHOGEN Innate Host Response to M. tuberculosis
Mycobacteria can be divided into two main groups – slow and rapid Alveolar macrophages are the first cells to encounter and phagocytose
growers. Some mycobacteria, including M. tuberculosis complex and M. tuberculosis. Phagocytosis and immune recognition by Toll-like
M. leprae are obligate pathogens, while many other species live freely receptors (TLRs) and other pattern recognition receptors (PRRs)8 may
in the environment (including some that are able to cause disease in lead to control of mycobacterial growth, either through acidification
humans, as described in Chapter 32). of phagolysosomes, oxidative stress from reactive nitrogen intermedi-
M. tuberculosis, discovered by Robert Koch in 1882, is characterized ates, activity of antimycobacterial peptides such as cathelicidin,
by a complex and lipid-rich outer cell wall which is responsible for its or autophagy (a process in which cytoplasmatic cargo is targeted
slow growth, staining properties and some of its pathogenic features. for degradation in specialized structures termed autophagosomes).
Mycobacteria are often termed acid-fast bacilli (AFB), as they retain Immune recognition induces cytokines and chemokine production
the color of arylmethane dyes when treated with diluted acid. and an inflammatory response, with influx and activation of mono-
cytes and neutrophils. Neutrophils contribute to phagocytosis, myco-
HOST RESPONSE TO M. TUBERCULOSIS bacterial killing and stimulation of adaptive immunity, but can also
After inhalation of M. tuberculosis droplet nuclei, different scenarios have a detrimental role through induction of a damaging inflamma-
may follow (see Figure 31-3), reflecting the balance between the tory response.9
Chapter 31 Tuberculosis 273
Estimated HIV prevalence in new TB cases worldwide in 2012
HIV prevalence in
new TB cases,
all ages (%)
0–4
5–19
20–49
≥50
No data
Not applicable
Figure 31-2 Estimated HIV prevalence in new tuberculosis cases worldwide in 2012. (Reproduced with permission from the World Health Organization, 2013.)
Second Stage – Adaptive Immunity to Tuberculosis create a peripheral fibrotic capsule (see Figure 31-4). Classic for tuber-
The HIV epidemic has dramatically demonstrated the importance of culosis granulomas is the presence of a necrotic caseous core. Granu-
CD4+ T cells for control of mycobacterial growth. CD4+ T cells exert lomas are believed to benefit the host by containing growth and
their protective effect by the production of cytokines, primarily dissemination of M. tuberculosis, although there are accumulating data
interferon-gamma (IFN-γ). This T-cell response increases macrophage that challenge this dogma.6
activation and is the basis for diagnosis of latent tuberculosis infection TNF-α plays a critical role in maintenance of tissue granulomas, as
(LTBI) (see under: Diagnosis). There is a considerable delay in the was illustrated by the increased rate of reactivation of latent tubercu-
onset of detectable T-cell responses when compared with other lung losis in subjects who received anti-TNF therapy for rheumatoid arthri-
infections, possibly as a result of increased activity of regulatory T cells. tis.10 From animal models and genetic studies it appears also that the
CD8+ T cells also contribute to anti-M. tuberculosis immunity, by interleukin (IL)-12/IFN-γ axis is needed for effective granuloma for-
secreting IFN-γ and products that can directly kill the M. tuberculosis mation.7 Granuloma formation is compromised in individuals suffer-
bacilli. M. tuberculosis lipid antigens can also be processed and pre- ing from HIV infection or other types of reduced T-cell immunity.
sented to unconventional T cells such as γδ T cells and natural killer Immunopathogenesis
(NK) T cells.6,7 It is important to realize that vaccine-induced T-cell
responses correlate poorly with protective immunity, and that natu- A strong and prolonged inflammatory response may contribute to
rally acquired T-cell immunity in tuberculosis patients does not tissue damage and necrosis, such as is found in typical pulmonary
prevent exogenous re-infection with M. tuberculosis. Clearly, our cavities. The host response also leads to the paradoxical worsening of
understanding of the correlates of protection in tuberculosis is disease, which can occur during tuberculosis treatment, especially
incomplete. among HIV-coinfected patients starting antiretroviral treatment.
Virulent mycobacteria counter host defense mechanisms through These immunopathologic reactions are probably caused by restoration
inhibition of phagolysosomal fusion, and phagosome maturation and of T-cell responses and have been termed ‘immune reconstitution
acidification. M. tuberculosis also induces relatively reduced apoptosis inflammatory syndrome’ (IRIS; see also Chapter 95).
of macrophages and neutrophils, and higher levels of type I interferons
and other cytokines that counter effective host defense. Prevention
Granulomas, Hallmark of Tuberculosis PUBLIC HEALTH MEASURES
The host response to M. tuberculosis leads to formation of a granu- Many countries have a system, often legally enforced, of infectious
loma, composed of a central mass of infected macrophages, stimulated patient notification to a central body which traces infected contacts of
macrophages that have differentiated into multinucleated giant cells, index cases. In addition, high-risk patients or communities such as
epithelioid cells and neutrophils. This accumulation of cells is sur- intravenous drug users may be screened in order to institute definitive
rounded by lymphocytes, largely CD4+ T cells, and fibroblasts that or prophylactic therapy. In its simplest form, case finding involves
Sequence of events after exposure to a patient

with active tuberculosis
Inhalation of
M. tuberculosis
Immediate Primary
killing of MTB complex
(PPD/IGRA neg) (PPD/IGRA pos)
Stabilization Localized disease Dissemination

(latency) (primary TB) of MTB
Acute disease
Stabilization
(meningitis,
(latency)
miliary TB)
a
Reactivation
(post-primary TB)
Figure 31-3 Sequence of events after exposure to a patient with active tuber-
culosis. IGRA = interferon gamma release assay; MTB, Mycobacterium tuberculo-
sis bacillus; neg = negative; PPD, purified protein derivative of tuberculin.
examining sputum smears, although radiologic examination may be a

useful adjunct. However, sputum smear microscopy will miss about
50% of culture-positive patients who are infectious. Routine screening
for latent infection in countries with low rates of infection is appropri-
ate in individuals particularly likely to reactivate disease such as those
who are immunosuppressed, including renal dialysis patients and
those about to receive immunosuppressive therapy.11
Patients with suspected or confirmed pulmonary TB disease should
b
be isolated until either tuberculosis disease has been ruled out or effec-
tive treatment established. In high-income nations, laminar airflow Figure 31-4 Granuloma in cynomolgus macaques, a non-human primate, reca-
and negative-pressure ventilation rooms are used for known or sus- pitulate the morphology and architecture of lesions seen in human TB. These
pected tuberculosis, particularly in patients with multidrug-resistant lesions can include epithelioid macrophage-dense non-necrotic granulomas (a)
(MDR) disease. The use of an efficient personal protective mask is key and necrotic granulomas (b) where a mass of caseous necrosis is surrounded by
epithelioid macrophages, foamy macrophages and a T-cell-dense lymphocyte
but not always available in many tuberculosis endemic parts of the cuff. (Images courtesy of Dr Joshua Mattila, University of Pittsburgh.)
world. In many instances, basic patient isolation and possibly specified,
ventilated rooms for procedures that generate aerosols is all that is
feasible. Shortwave ultraviolet illuminators to kill organisms in clinics than 5 mm diameter following a standard injection of 5 units PPD is
and shelters are potentially useful. Appropriate control measures regarded as negative and greater than 10 mm diameter as positive.
should be defined in advance in high-risk procedure rooms (e.g. bron- PPD may have a booster effect on immunologic memory, which can
choscopy suites), during patient transport and in all at-risk institu- cause confusion if re-testing occurs after a few months.
tions, which range from healthcare facilities through to shelters for the In the USA, induration greater than 5 mm is taken as positive in
homeless. patients with HIV, a close contact with tuberculosis or a fibrotic chest
radiograph; induration at or above 10 mm is positive in any other
TESTING FOR EXPOSURE at-risk groups. Patients who are immunosuppressed such as those with
The Tuberculin Skin Test (TST) HIV (particularly if the CD4+ T-cell count is below 0.4 x109/L) or who
The TST, or Mantoux test, is the commonest test used to screen for have viral infections such as measles, have a strong tendency to anergy.
latent tuberculosis infection and depends on the intradermal injection Systemic illnesses, including miliary tuberculosis, are also associated
of a specified quantity of an internationally standardized purified with anergy. False-negative tests occur at the extremes of age, and fol-
protein derivative (PPD) of tuberculin. Tuberculin positivity manifests lowing use of inadequately stored tuberculin or due to poor injection
as induration at the site of testing after 48 hours. Induration less technique. BCG vaccination, especially when given in early
adolescence as opposed to at birth, may give a positive TST, although recipients is established. Chemoprophylaxis should be deferred in
this effect wanes over time. Large indurations are unlikely to be caused pregnant women, a group more prone to isoniazid hepatitis (see also
by BCG. Practice Point 9).
Interferon-Gamma Release Assays VACCINES
(see also Chapter 185) The live-attenuated BCG vaccine was first used in 1921. Vaccination
There are two main types of IFN-γ release assay (IGRA) in use: leads to a local immune response and scar formation. Adverse reac-
a whole-blood enzyme-linked immunosorbent assay (ELISA)-based tions other than local irritation are uncommon and anaphylaxis
system and an enzyme-linked immunospot (ELISpot)-based detection extremely rare. Adenitis, sometimes suppurative, is the most impor-
of IFN-γ.12 They use the relatively M. tuberculosis-specific RD-1 anti- tant complication, lupoid reactions, infected osteitis and disseminated
gens, early secreted antigen target (ESAT)-6 and culture filtrate protein BCG disease are very rare, the latter two necessitating therapy with
(CFP)-10. The main advantages of IGRAs are that they are not affected rifampin (rifampicin) and isoniazid.
by previous BCG vaccination, are not confounded by boosting and do BCG vaccination is more efficacious further from the Equator, and
not require a second visit for reading at 48 hours. They are, however, against tuberculosis meningitis or disseminated tuberculosis in chil-
relatively expensive compared to the TST. dren rather than adult pulmonary disease.19 There is a poor correlation
IGRAs have now been incorporated into national testing guide between tuberculin reactivity after vaccination and protection against
lines for screening and prevention of tuberculosis in a number of disease. There a number of approaches to developing new tuberculosis
different countries including the USA.11,12 It is generally advised that vaccines, including genetic modification of BCG and development of
they can be used in the same situations where the TST is used. They new live attenuated vaccines. The first human efficacy trial of a new
may offer some advantages with respect to sensitivity in immunosup- vaccine, based upon M. tuberculosis antigen 85 as a booster to a BCG,
pressed patients, although both the TST and IGRAs have impaired has been disappointing.20
performance in these individuals. There is a theoretic advantage in
algorithms that only conduct IGRA testing in those already positive by
TST, although this still requires two clinic visits and can suffer from Clinical Features
combining the suboptimal sensitivity of both tests.13 IGRAs have use In this section, the diverse clinical presentations of primary,
in excluding diagnosis of tuberculosis in children and in the context pulmonary and miliary tuberculosis are reviewed, together with the
of occupational health screening, where the boosting effect places the characteristic changes found on radiologic examination. In addition,
TST at a disadvantage. A negative test in a healthy patient helps exclude the principal extrapulmonary manifestations of tuberculosis are
M. tuberculosis infection. However, as with other diagnostic tests, the considered.
predictive value depends on the prevalence of M. tuberculosis in the
population that is being tested. There is some evidence that the quan- PRIMARY AND CHILDHOOD INFECTION
titative IGRA test readout reflects M. tuberculosis load, although this Primary tuberculosis is usually acquired by inhalation of infected par-
property has not proven to be useful as a treatment efficacy readout.14 ticles. Inhaled bacilli pass into the lung, where damage is usually but
not always confined to one segment with concurrent involvement of
CHEMOPROPHYLAXIS draining, frequently hilar, lymph nodes. This gives rise to the primary
Chemoprophylaxis is an increasingly important component of tuber- (Ghon) complex. Clinical disease develops in up to 10% of people who
culosis control programs. The combined effect of treatment of disease establish an infection with M. tuberculosis. After initial infection, the
and infection is synergistic at the population level.15 Indeed, prophy- only sequela may be scar tissue, which is often calcified and later iden-
laxis is already recommended for all under-5-year-old contacts of TB tified on routine chest radiography.
cases in LMICs, once they have been cleared of having TB disease.16 Symptomatic patients present with cough with variable amounts of
Prophylaxis is practiced most commonly and successfully in tubercu- sputum and hemoptysis together with localized pleuritic chest pain
losis control programs in higher-income countries. The various and dyspnea. In addition, systemic features such as fever, night sweats,
options for treatment regimens are summarized in Table 31-1. Isonia- anorexia and weight loss occur. Primary tuberculosis manifests as hilar
zid for 9 months is most commonly used, while shorter alternative adenopathy (often asymmetric) and associated consolidation on chest
regimens of 3 or 4 months with at least equivalent efficacy, improved radiograph. In children, lymphadenopathy without consolidation is
adherence and acceptable side effect profiles are increasingly used.17 A common. Less typical chest radiographs of primary infection include
combination of short-course rifampin and pyrazinamide has unac- those that appear normal or have widespread disease, lobar consolida-
ceptable levels of hepatotoxicity. Chemoprophylaxis is advocated in tion and pleural effusions. An unusual complication of primary tuber-
HIV-seropositive patients because of the increased incidence of clinical culosis is bronchial obstruction due to pressure of a node on a main
disease in patients exposed to M. tuberculosis and those in tuberculosis bronchus. This phenomenon, sometimes called epituberculosis, may
endemic areas,18 regardless of the results of tests for infection. Chemo- lead to secondary bronchiectasis. Untreated primary disease may prog-
prophylaxis should also be considered in patients with latent infection ress to involve the entire lung and disseminate, at which stage those
prior to the initiation of TNF inhibitors and all such patients should affected may have a continuous cough and sputum production, severe
be screened. Use of chemoprophylaxis in potential transplant dyspnea, high fevers, drenching sweats and cachexia. Chest radiograph
TABLE
31-1 Possible Regimens for Treating Latent Tuberculosis Infection
Drug Dose Duration Interval Side Effects
Isoniazid (INH) 300 mg daily or 9 months Daily or twice weekly Hepatotoxicity, rash, peripheral neuropathy
900 mg twice weekly
Rifampin 600 mg 4 months Daily Hepatotoxicity, leukopenia, thrombocytopenia, drug interactions
Rifampin + INH 600 mg + 300 mg 3 months Daily Combined
Rifapentin + INH 900 mg + 300 mg 3 months Weekly Hepatotoxicity, hypersensitivity
Rifampin + pyrazinamide No longer recommended because of unacceptable hepatotoxicity

reveals widespread patchy consolidation with areas of collapse and

cavitation.
Endobronchial tuberculosis is usually a complication of primary
infection although it may occur during reactivation. It may follow
adhesion of inflamed lung parenchyma or lymph nodes to bronchi or
may arise via lymphatic or hematogenous spread of infection and even
from direct seeding of inhaled bacilli. Endobronchial tuberculosis
probably frequently goes undiagnosed. The classic clinical presenta-
tion is with a barking cough and wheeze but onset may be gradual,
mimicking other respiratory diseases ranging from asthma to cancer.
Sputum production may be exacerbated when the mucosa is breached
and caseous material extruded. Parasternal pain, dyspnea, symptoms
due to collapse and consolidation of distal lung tissue and systemic
manifestations of tuberculosis may be found. The most important late
complication of endobronchial infection is bronchiectasis.
PULMONARY INFECTION
Risk Factors for Reactivation
Reactivation of tuberculosis mostly occurs in the absence of any known
risk factors, but is strongly associated with HIV-infection or use of
immunosuppressive medication (e.g. TNF-inhibitors or corticoste-
roids) for autoimmune diseases or organ transplantation, and to a
lesser extent with milder immunosuppressive states such as diabetes,
‘immunosenescence’ in old age, kidney failure, use of inhalation cor-
ticosteroids, malnutrition or vitamin D deficiency. Co-morbid disease
may mimic tuberculosis symptoms, while immunodeficiency or use of
immunosuppressive drugs can mask symptoms and delay diagnosis. Figure 31-5 Typical chest radiograph from a patient with tuberculosis showing
Especially in low-incidence areas or in the absence of typical chest upper lobe shadowing and elevation of hilar lymph nodes. (Courtesy of Prof. Dr
Christoph Lange, University of Lübeck, Germany.)
radiograph findings, other diagnoses should be considered: lung
cancer in elderly (smoking) individuals, lung abscess and infection
with nontuberculous mycobacteria, Burkholderia pseudomallei (in
South East Asia and Australia), Nocardia, Rhodococcus etc.
Clinical Presentation
The classic presentation of reactivation tuberculosis is characterized by
weeks to months of chronic cough; other symptoms include weight
loss (40–75%), fatigue (60–80%), fever (30–60%) and night sweats
(40–60%). Initially, the cough is usually mild and non-productive,
only occurring in the morning as a result of accumulation of secretions
during sleeping, similar to and often confused with a smoker’s cough.
During disease progression the cough may become more continuous
throughout the day and productive of yellow, yellow–green or blood-
streaked sputum. Hemoptysis may be massive from either enlarged
bronchial arteries around tuberculous cavities (Rasmussen’s aneu-
rysms) or more frequently from erosions involving other bronchial or
pulmonary arteries. Dyspnea suggests extensive disease and is a late
symptom. Pleuritic chest pain indicates inflammation in and possibly
infection of adjacent pleura.
Clinical examination may be misleading in the early stages of
disease when radiologically apparent changes of consolidation and
cavitation are hard to detect. Noninfectious complications of tubercu-
losis may be present (see below). Conversely, along with the infre-
quency of dyspnea, a distinguishing feature from other bacterial
pneumonias is the relative lack of auscultatory signs in TB cases, even
in the presence of extensive changes seen on the chest radiograph. A
small minority of patients with rapidly progressive disease present in Figure 31-6 Chest radiograph of a patient with bilateral infiltration and cavities.
acute respiratory failure and may develop the adult respiratory distress (Courtesy of Prof. Dr Christoph Lange, University of Lübeck, Germany.)
syndrome (ARDS).
Chest radiography shows disease localized to apical and posterior
segments of the upper lobes of the lung in more than 85% of cases described, such as more subtle infiltration (Figure 31-7). It can be dif-
with other sites often secondarily affected. The apical segment of the ficult to distinguish early reactivation from chronic healed lesions
lower lobe is also frequently involved. Infiltration and cavitation sec- without follow-up. Computed tomography (CT) scan findings include
ondary to caseous necrosis may be associated with air–fluid levels. On cavitation with scarring as well as characteristic nodules and branching
treatment, most cavities heal completely leaving residual scarring, linear structures, sometimes referred to as a tree-in-bud pattern
often calcific. Tuberculous chest radiographs frequently show bilateral (Figure 31-8).
shadowing with upper zone predominance and fibrotic changes, lobar Laboratory investigations in pulmonary tuberculosis may reveal
atelectasis, elevation of hilar nodes and deviation of the trachea leukocytosis and a monocytosis, but more commonly the leukocyte
(Figures 31-5 and 31-6). A wide range of less common findings are count is normal and, more rarely, it is leukopenic. Anemia, generally
significant years later and is best defined by high-resolution CT scan-

ning. Tissue destruction may be so great as to cause respiratory failure.
Patients with a history of tuberculosis are also at increased risk of a
second episode of tuberculosis and probably also to infection with
nontuberculous mycobacteria, as a result of reduced pulmonary or
systemic host defense.
PLEURAL TUBERCULOSIS
Pleural tuberculosis classically occurs 6–12 weeks after primary disease
but onset may be delayed and pleuritis may be the first sign of reactiva-
tion. Chest radiograph usually demonstrates a unilateral effusion, with
or without pulmonary involvement. Bilateral effusions occur in
approximately 10% of patients, especially in patients with miliary
tuberculosis. Ultrasound or CT scan may reveal loculated effusions to
aid diagnostic and therapeutic aspirations. Effusions are usually straw-
colored but may be bloodstained and occasionally frankly bloody.
Pleural aspirates typically show elevated protein (>30 g/L), glucose
values below serum glucose concentration, a moderately reduced pH
(~7.3), and a leukocyte count between 0.5 and 5 x109/L with a pre-
dominance of lymphocytes. In the majority of cases, pleural tubercu-
losis develops as a result of an immunologic response to tubercle bacilli
that reach the pleural space from a subpleural granuloma. As a result,
Figure 31-7 Less typical radiograph: retrocostal infiltrate right upper lobe. microscopic examination for mycobacteria is rarely (<15%) positive,
(Courtesy of Prof. Dr Christoph Lange, University of Lübeck, Germany.) and even culture and molecular testing (PCR) of pleural fluid are often
negative. Elevated IFN-γ has a particularly high sensitivity and specific-
ity for diagnosing pleural tuberculosis, while IGRAs on pleural fluid
has no clear added value.22 Two other biochemical tests, pleural fluid
lysozyme and adenosine deaminase (ADA), have also proven useful. A
pleural biopsy may be needed to make a final diagnosis.
Rare cases are caused by a true empyema, in which case frank pus
from a ruptured pulmonary cavity or adjacent parenchymal focus is
found in the pleural compartment, with large numbers of mycobacte-
ria and neutrophils present. Pleural exudates can also be caused by
malignancy (characterized by the presence of malignant cells on cyto-
logic examination), connective tissue diseases like SLE, while especially
in HIV-infected patients there may be a wider differential diagnosis,
including Kaposi’s sarcoma (classically with bloody pleural fluid) and
primary effusion lymphoma (PEL).
MILIARY TUBERCULOSIS
Disseminated or miliary tuberculosis is a severe form of tuberculosis
which results from hematogenous spread of tubercle bacilli which may
occur if they reach the circulation via the lymphatics. In 1700 John
Jacob Manget likened the innumerable tubercles he found in visceral
sites like liver, spleen, bone marrow, brain and lungs, to millet seeds
(miliarius in Latin) and introduced the term miliary tuberculosis.
Figure 31-8 CT scan of pulmonary tuberculosis showing tree-in-bud pattern. Nowadays, the term is restricted to disseminated tuberculosis with
(Courtesy of Prof. Dr Christoph Lange, University of Lübeck, Germany.) miliary shadows on chest radiography (Figure 31-9). It was tradition-
ally thought to occur mostly during progressive primary infection,
especially in young children, but it is also found in reactivation tuber-
normochromic and normocytic, is typical. An acute-phase response is culosis and in adults, often in the context of decreased cellular immu-
almost invariably present with moderately elevated C-reactive protein nity such as in HIV/AIDS, malnutrition, or organ transplantation.
(CRP) concentrations in plasma, raised erythrocyte sedimentation rate Disseminated infection may also follow BCG when given into the
(ESR) and in more chronic cases, decreased serum albumin. Hypona- bladder in patients with bladder cancer.
tremia occurs in >10% of patients due to antidiuretic hormone-like Patients may present with an acute sepsis-like syndrome with
activity (SIADH) although it may be a manifestation of concurrent severe respiratory symptoms, or with a more chronic presentation with
extrapulmonary infection. A small number of patients have hypercal- cachexia, fever and and night sweats.23 Hepatomegaly is often present,
cemia, probably due to abnormal vitamin D processing or production and dyspnea, neurologic symptoms, cardiac complaints or signs of
of PTH-related peptide by granuloma macrophages.21 adrenal insufficiency may develop depending on the localization and
burden of granulomas. Widespread macular and papular skin lesions
Complications (tuberculosis miliaris disseminata) are suggestive of miliary infection.
The principal acute complications of pulmonary tuberculosis are Choroidal tubercles 0.5–3.0 mm in diameter are essentially diagnostic
hemoptysis (discussed above) and pneumothorax. Bronchopleural fis- of miliary disease (Figure 31-10). The chest radiograph of miliary
tulae may heal spontaneously or require tube drainage and, rarely, tuberculosis has well-defined nodules less than 5 mm in diameter
surgery. Chronic complications of lung tuberculosis relate to paren- throughout both lung fields (Figure 31-9). Radiographic changes may
chymal damage and scarring. Aspergillomas may develop within only develop after a patient has been admitted to hospital, so patients
healed cavitating lesions; patients typically present with hemoptysis. must be reassessed frequently. Larger nodules and a pulmonary focus
Localized bronchiectasis (see Chapter 27) may only become clinically occur in approximately one-third of patients. CT or magnetic
Figure 31-9 Chest radiograph of miliary tuberculosis, showing characteristic

mottled shadowing throughout both lung fields. (Courtesy of Prof. Dr Christoph
Lange, University of Lübeck, Germany.) Figure 31-11 MRI scan of cervical tuberculosis with massive paravertebral
abscess which extends through the left C7 to T1 neural exit foramen causing an
extradural collection compressing the spinal cord. (Courtesy of Dr J Jackson,
Imperial College Healthcare NHS Trust, London, UK.)
EXTRAPULMONARY TUBERCULOSIS
This section reviews extrapulmonary tuberculosis not considered in
detail elsewhere and refers readers to other relevant chapters. Up to
40% of all cases of tuberculosis diagnosed in northern Europe and the
USA are extrapulmonary. It is very likely that in resource-poor areas
of the world, where the focus is on diagnosis of people who are poten-
tially infectious, a large amount of extrapulmonary disease goes
undetected.
Lymph Node Disease (see also Chapter 15)
Lymphadenitis is the most common extrapulmonary presentation of
tuberculosis. Mycobacterial lymphadenitis may be casued by M. bovis
in settings where bovine tuberculosis is not well controlled and milk
is not pasteurized, while nontuberculous mycobacteria, especially M.
avium, are the primary cause in countries with low tuberculosis trans-
mission. The most commonly involved nodes are those in the cervical
region (called scrofula in the historical literature), sometimes in asso-
ciation with axillary, inguinal or hilar lymphadenopathy. Patients
usually present with painless lymphadenopathy along the upper border
of the sternocleidomastoid muscle, systemic symptoms are mostly
mild. If left untreated, lymph nodes may liquify, rupture and cause
Figure 31-10 Choroidal tuberculosis. Choroidal disease is a manifestation of TB sinus formation. Diagnosis is made by fine-needle aspiration; incision
which is highly suggestive of miliary disease. (With permission from James DG,
Studdy PR. A color atlas of respiratory diseases, 2nd ed. London: Mosby; 1992.) biospies should be avoided as they may result in sinus formation.
Isolated mediastinal lymphadenopathy, classically a feature of
primary tuberculosis, is often found in HIV-infected individuals. Mes-
resonance imaging (MRI) scanning may show smaller nodules not enteric lymphadenitis in the absence of peritoneal or intestinal tuber-
apparent on radiography. Abdominal ultrasound scanning may show culosis is rare.
increased echogenicity and focal lesions in the liver. Laboratory tests
are often abnormal with anemia, thrombocytopenia, leukopenia or Musculoskeletal Infection
leukocytosis; elevated liver function tests and ESR, low albumin, signs Spinal tuberculosis (Pott’s disease) accounts for 50% of tuberculous
of SIADH of sterile pyuria. Sputum examination, bronchoscopy and osteomyelitis (Figure 31-11). The thoracic spine is most frequently
bone marrow or liver biopsy may help confirm the diagnosis. involved, followed by lumbar and then cervical regions. Presentation
is usually with back or neck pain, and systemic symptoms tend to be Central Nervous System and Eye Disease
less marked than in pulmonary disease. External pressure on the spinal Tuberculous meningoencephalitis and central nervous system tuber-
cord or penetration of the dura leads to neurologic symptoms like culomas are extremely important, carrying high morbidity and mor-
paraplegia in about a third of cases. Some patients have an associated tality rates. These topics are considered further in Chapter 19.
flank mass or other evidence of extraspinal tuberculosis. In more Ocular tuberculosis is relatively uncommon but important since, if
chronic cases, vertebral body collapse and gibbus formation lead to overlooked, may result in blindness. The commonest manifestation is
kyphosis of the spine. Typically, infection begins in the vertebral choroidal disease (Figure 31-10) secondary to hematogenous spread
metaphysis and erodes into the vertebral end-plate with relative in the context of miliary tuberculosis which may rarely spread to the
sparing of the intervertebral disc as seen on plain radiographs. CT or retina.
ideally MRI scanning is needed for proper evaluation of the spinal
cord, and visualization of paraspinal (e.g. psoas) abscesses (Figure Tuberculosis of the Head and Neck
31-11). Diagnosis is confirmed by vertebral biopsy or aspiration of Aside from cervical node disease, tuberculosis of the head and neck is
paraspinal abscess. Neurologic symptoms often disappear with medical relatively uncommon and usually arises secondarily to pulmonary
treatment only, but surgery is probably indicated for marked or wors- infection. Laryngeal tuberculosis may present with hoarseness, pain on
ening neurologic deficits, vertebral instability and draining of large speaking or swallowing, hemoptysis and respiratory obstruction.
abscesses. Osteomyelitis is otherwise most frequently found in the Cough may reflect lung disease or involvement of the superior laryn-
metaphyses of long bones, sometimes accompanied by sinus tracts or geal nerve. Untreated, widespread local tissue destruction may occur
soft tissue masses. Diagnosis may be difficult since lesions can appear with secondary laryngeal stenosis.
osteolytic or sclerotic on radiography and malignancy may be sus- Tuberculosis in the oral cavity generally presents as a solitary, often
pected at first. inflamed ulcer with irregular borders. There may be secondary infec-
Tuberculous arthritis most frequently presents in the hips and tion of salivary glands.
other weight-bearing joints although any joint may be involved. Poly-
articular disease occurs in less than 20% of patients but evidence of Dermatologic Disease
tuberculosis elsewhere, generally the lung, is present in about 50% of Dermatologic manifestations of primary and miliary infection are to
cases. Synovial fluid has a high leukocyte count, but microscopy and be found in Chapter 13.
culture are often negative. Ideally a synovial biopsy should be exam-
ined histologically and microbiologically. Rare cases of prosthetic joint CLINICAL MANIFESTATIONS IN HIV-POSITIVE
infection have been described. Tenosynovitis is rare. PATIENTS
Tuberculous abscesses may form in most soft tissues including The clinical manifestations of tuberculosis in HIV-seropositive and
muscle and may be multiple. The classic abscess site is in the psoas -seronegative patients are often similar and are reviewed in Chapter
muscle, which can present with or without localizing signs. 96. Initiation of HIV therapy may lead to ‘unmasking’ of tuberculosis,
either pulmonary or extrapulomary, due to a restoration of T-cell
Abdominal Infection immunity (Chapter 95).
In the absence of HIV infection the abdomen is only rarely affected.
Disease is usually secondary to hematogenous spread of mycobacteria NONINFECTIOUS COMPLICATIONS
but can be secondary to local invasion or ingestion of organisms. In Erythema nodosum is the most common noninfectious complication
the gut, tuberculosis most frequently affects the ileocecal region, then of primary tuberculosis although it may occur in other granulomatous
the small bowel and then the colon; involvement of the duodenum, diseases (e.g. leprosy, sarcoid). It is particularly associated with
stomach and esophagus is extremely rare. Approximately one-third primary disease. Other rare noninfectious manifestations of tubercu-
of patients have evidence of tuberculosis elsewhere, usually in the losis include reactive (poly)arthritis, cutaneous vasculitis, interstitial
lung. nephritis, retinal vasculitis and hypertrophic pulmonary osteoarthro
Symptoms reflect the site of involvement but may be nonspecific pathy. The syndrome of inappropriate antidiuretic hormone secretion
with fever, weight loss, chronic abdominal pain, nausea and anorexia. (SIADH) may lead to hyponatremia. Hypercalcemia may occur as a
Ileocecal tuberculosis may present as an acute abdomen secondary to result of tuberculous granulomas secreting vitamin D or PTH-like
either obstruction of the bowel lumen or appendix or following bowel peptides.21
perforation. Any tuberculous lesion, particularly those in the colon,
may present with massive gastrointestinal bleeding but this is rare.
Unusual sites of intra-abdominal tuberculosis include the pancreas
Diagnosis
and the adrenal glands, where disease presents very rarely as an adrenal CLINICAL APPROACH
crisis but more commonly with an insidious onset. Tuberculous peri- The definitive diagnosis of tuberculosis requires identification of the
tonitis is an important manifestation of disease and is discussed in pathogen in a patient’s secretions or tissues. Empiric therapy is often
Chapter 41. Tuberculosis of the urogenital tract is specifically explored initiated before a definitive diagnosis has been made but this should
in Practice Point 18. always be pursued to determine the drug susceptibility of the organism
which guides individual treatment regimens. Sputum microscopy
Pericardial Infection (see Chapter 50) and culture has a high diagnostic yield, identifies the majority of infec-
The onset is often insidious although acute pericarditis may occur. tious patients and is cheap to perform. Sputum should be collected on
Common symptoms include breathlessness, chest pain and nonspe- at least two separate occasions. Although induced sputum obtained in
cific changes such as fever and weight loss. Signs of cardiac tamponade properly ventilated and isolated areas can be useful, bronchoscopy
such as raised jugular venous pressure, hepatomegaly, ascites and with alveolar lavage has the best diagnostic yield. M. tuberculosis
edema may be present, and in a minority of cases develops acutely, is infrequently seen on aspiration of pleural fluid and cultured in
requiring urgent pericardiocentesis. ECG may show low voltage or ST less than 50% of cases. Pleural biopsy reveals granuloma or results
elevation consistent with acute pericarditis. An effusion may be seen in culture of the pathogen in more than 90% of cases. Thoracoscopy,
on chest radiography but is better characterized by echocardiography in exceptional circumstances, may be indicated since it allows for
or CT scanning. Pericardial calcification occurs late and in less than visually guided biopsy of lesions. 2-Fluorodeoxyglucose positron
25% of cases, although data are limited. Diagnosis may be extremely emission tomography combined with CT (FDG PET–CT) can localize
difficult; failure to identify the organism and to detect granuloma on and grade tuberculosis-associated inflammation. It is expensive and
biopsy specimens does not rule out infection. Constrictive pericarditis cannot always distinguish tuberculosis from malignancy, bacterial
may develop after active infection has resolved or been treated. infections or other inflammatory processes, but PET–CT may have a
Figure 31-13 Ziehl–Neelsen-stained sputum specimens containing Mycobacte-

a rium tuberculosis. (Courtesy of Dr J van Ingen, Radboud University Medical
Center, Nijmegen, The Netherlands.)
move from the diagnostic trial to full therapy. A diagnostic trial of

therapy should last a minimum of 2–4 weeks.
MICROBIOLOGIC DIAGNOSIS
The standard method for staining clinical specimens for M. tuberculo-
sis is that of Ziehl–Neelsen (Figures 31-13 and 31-14). Diagnostic
microscopy is most successful in patients with extensive disease and
cavitation on chest radiography but only diagnoses about 50–70% of
b cases positive by culture. Culture of the organism with subsequent
testing for drug sensitivity from clinical specimens is the cornerstone
Figure 31-12 2-Fluorodeoxyglucose–positron emission tomography (FDG PET) of diagnosis and ultimate treatment; this is particularly important with
scan in untreated bilateral pulmonary tuberculosis: (a) three-dimensional rendered
image and (b) transverse image at the level of the carina. (Courtesy of Dr S. Mal- the emergence of drug-resistant TB, as ‘blind’ therapy in the absence
herbe, Stellenbosch University, South Africa.) of sensitivity testing may increase the risk of multidrug resistance. The
clinical microbiology and further diagnostic testing for tuberculosis is
reviewed in detail in Chapter 185.
role in diagnosis of extrapulmonary (e.g. spinal) tuberculosis, and
in evaluating extent of pulmonary disease and treatment response Management
(Figure 31-12).24 FIRST-LINE ANTIMYCOBACTERIAL DRUGS AND
In extrapulmonary or miliary infection, appropriate body fluids THEIR TOXICITIES
and/or tissues must be obtained for microbiologic and histologic This and the next section briefly outline the principal characteristics
examination, with the aid of ultrasound, CT or MRI scanning if of the most important antituberculous drugs. These drugs are fre-
available. Liver biopsy and bone marrow aspiration are useful investi- quently used in fixed-dose regimens in various combination tablets in
gations in disseminated or occult disease.25 For tuberculous lymphad- order to simplify regimens and improve patient compliance. More
enitis, fine needle aspiration (FNA) is the initial investigation of detail as to mechanisms, dosage regimens and complications are to be
choice since it is easy to perform and has a high specificity and sensitiv- found in Chapter 148.
ity when both microbiologic and cytologic specimens are collected.
FNA does not preclude subsequent lymph node biopsy. In pericardial Isoniazid
tuberculosis, aspiration of pericardial fluid may recover the pathogen Isoniazid (INH) is a bactericidal drug that is well absorbed, minimally
but is frequently nondiagnostic and pericardial biopsy is often bound to plasma proteins, has a half-life of 1–3 hours depending on
indicated. patient acetylator status and is excreted in urine. Concentrations
Specimens from potentially infected patients are normally analyzed achieved in most tissues are similar to those in serum.
in local laboratories but drug sensitivity testing and more specialized The most important, potentially fatal side effect of isoniazid is
facilities are ideally concentrated in centralized laboratories. hepatotoxicity which is more common in patients older than 60 years,
If no diagnostic results are forthcoming in patients in whom tuber- in the presence of coexisting liver disease and possibly in pregnancy
culosis is a possibility, the clinician may reasonably resort to a trial of (see Practice Point 9). Asymptomatic, usually transient rises in trans-
therapy. Improvement of symptoms and a decrease in the acute phase aminases occur in about 20% of patients. A greater than threefold
response (monitored by ESR, CRP, etc.) are sufficient indications to increase in enzyme levels above the normal range is an indication to
TABLE
31-2 Drug Interactions with Rifampin*
Drug Category Example
Antibacterials Chloramphenicol
Antifungals Fluconazole
Antimalarials Mefloquine
HIV treatment Most anti-HIV drugs, especially protease

inhibitors†
Corticosteroids Prednisolone
Anticoagulants Warfarin
Analgesics Methadone
Immunosuppressive therapy Ciclosporin
Ulcer-healing drugs Cimetidine
Respiratory drugs Theophylline
Cardiac drugs
Beta-blockers Propranolol
Calcium-channel blockers Diltiazem
Cardiac glycosides Digitoxin (only member of class affected)
Antiarrhythmics Disopyramide
Lipid-lowering drugs Fluvastatin
CNS drugs
Antiepileptics Phenytoin
Anxiolytics Diazepam
Antidepressants Tricyclic compounds
Antipsychotics Haloperidol
Figure 31-14 Mycobacterium tuberculosis in sputum detected by auramine Endocrine drugs

staining. (Courtesy of Dr J van Ingen, Radboud University Medical Center, Nijme-
Antidiabetics All antidiabetic drugs except metformin
gen, The Netherlands.)
and insulin
Estrogens and progesterones Combined and progesterone-only

discontinue therapy. In practice, it is often impossible to separate contraceptive pill
isoniazid hepatotoxicity from that due to rifampin or pyrazinamide Thyroid replacement Thyroxine
but interestingly, re-introduction of these drugs singly rather than in
combination usually avoids a second episode of hepatotoxicity. The *These are the principal classes of drugs for which metabolism is increased
other major side effect is a peripheral and rarely optic neuritis due to (plasma concentration decreased) when taken with rifampin (rifampicin). The
examples are not exhaustive and clinicians should check interactions with
interference with niacin metabolism. This is prevented by concomitant related drugs in appropriate formularies.
administration of vitamin B6 (pyridoxine 10 mg daily). †
Discussed separately in Chapter 103.
Rifampin
Rifampin is a bactericidal drug that undergoes first-pass metabolism used at standard doses (15 mg/kg). Patients can be assessed by an
in the liver where it is deacylated, excreted into bile and then into ophthalmologist prior to starting treatment but lack of this facility
the gut where there is a minor degree of enterohepatic circulation. should not prevent use of ethambutol. Patients should be warned to
Rifampin is a potent inducer of hepatic enzymes and therefore has report symptoms of visual change immediately and ethambutol should
many clinically significant interactions with other drugs (Table 31-2). generally be avoided in children.
Patients should be warned that rifampin turns all body secretions,
including urine and tears, orange. This is a useful side effect in terms
Streptomycin
of monitoring compliance. Streptomycin, is an aminoglycoside that has to be given intramuscu-
larly. Resistance mutations arise readily in response to isolated strep-
Pyrazinamide tomycin therapy and lead to drug resistance. The principal side effects
Pyrazinamide, a structural analog of nicotinamide, is a bactericidal of aminoglycosides are ototoxicity and nephrotoxicity.
drug which is well absorbed via the gut and distributed widely includ-
ing in the central nervous system (CNS). Serum half-life is about 10 SECOND-LINE DRUGS
hours and excretion is urinary. Second-line agents are becoming increasingly important with the rise
Hepatotoxicity ranging from elevation of liver transaminases to in drug-resistant organisms. Basic information about such drugs is
frank jaundice and liver failure is the principal side effect of provided in Table 31-3 and discussed in detail in Chapter 148. Quino-
pyrazinamide. lones such as levofloxacin and moxifloxacin are being investigated as
agents that may reduce the duration of therapy required for treatment
Ethambutol of drug-sensitive disease. In a recent randomized controlled trial
Ethambutol is a bactericidal drug that is rapidly and well absorbed in (RCT), linezolid, when added to an optimal background regimen
the gut, with peak serum levels occurring 2 hours after a dose. It is greatly increased treatment success in patients with extensively drug-
then rapidly excreted in urine. resistant (XDR) TB.26 Limitations of linezolid include its cost and
The most important complication of ethambutol therapy is retro- toxicity (myelosuppression and neuropathy). Clofazimine, used in
bulbar neuritis manifested by impaired visual acuity, color blindness treatment of M. leprae, is a rediscovered compound, with proven effi-
and restricted visual fields. Except in patients with pre-existing oph- cacy.27 Other drugs not normally considered as useful treatment for
thalmic disease, optic neuritis is extremely rare when ethambutol is tuberculosis include meropenem and clavulanic acid.28
TABLE
31-3 Second-Line Therapy in Tuberculosis (see also text and Chapter 148)
Modification of
Usual Initial Adult Dose Drug Dose in
Drug Mechanism of Action Toxicity (70 kg) Route Renal Impairment
GROUP II
Amikacin Binds 30S ribosome Ototoxicity, nephrotoxicity 7.5 mg/kg q12h* im or iv Yes (TDM)
Capreomycin Binds 30S and 50S 1 g q24h im or iv Yes
ribosomes
Kanamycin Binds 30S ribosome 15 mg q12h* im or iv Yes
GROUP III
Moxifloxacin Inhibits topoisomerase II GI disturbances, tendinitis, 400 mg q24h po or iv No
insomnia, QT prolongation
Levofloxacin Inhibits topoisomerase II GI disturbances, tendinitis, insomnia 500 mg q12h po or iv Yes
GROUP IV
Para-aminosalicylic Competes with Gastrointestinal intolerance, 12 g q24h (divided po or iv No
acid (PAS) mycobacterial hypersensitivity, hypothyroidism, doses)
dihydropteroate crystalluria
synthetase
May decrease
proinflammatory
immune responses
Ethionamide Inhibits cell wall mycolic Gastrointestinal intolerance, 750 mg q24h (or divided po No
(prothionamide) acid synthesis hepatitis, hypersensitivity, in two doses)
convulsions, depression, alopecia
Cycloserine Competitive D-alanine Seizures, psychoses, various CNS 750 mg q24h po Yes
analog effects
GROUP V
Amoxicillin/clavulanic Inhibits cell wall Hypersensitivity (penicillin allergy), 1200 mg q12h po or iv Yes
acid synthesis GI disturbances
Clofazimine Skin discoloration, GI disturbances 100 mg q24h po No
Meropenem Hypersensitivity, neurotoxicity 1000 mg q8/q12h iv Yes
Imipenem 500 mg q8/q12h iv Yes
Linezolid Anemia, thrombocytopenia, 600 mg q24h po or iv No

peripheral neuropathy,
hypersensitivity
NEW COMPOUNDS
Delamanid Blocks mycolic acid QT prolongation 100 mg q12h po No
synthesis
Bedaquiline Inhibits mycobacterial QT prolongation, hepatotoxicity 400 mg q24h po No
ATP synthase
*Peak drug levels should be less than 3 mg/dL (30 mg/L) and trough less than 1 mg/dL (10 mg/L).
Several newly developed agents clearly hold big promise for MDR- The standard treatment protocol is given in Table 31-4. For sensi-
and XDR-TB. Bedaquiline is the first new tuberculosis drug released tive organisms, drug therapy in compliant patients is very efficacious,
in 40 years. It is a diarylquinolone targeting mycobacterial ATP syn- with cure rates approaching 100%. However, it may be 2 weeks before
thase, with promising activity against both drug-sensitive and drug- clinical improvement becomes apparent, which is important in both
resistant tuberculosis. However, concern is still present regarding the empiric trials of therapy and for appropriate patient expectations.
safety of the drug.29 Delamanid, which blocks mycolic acid production, Radiologic improvement lags further behind and it may take 3–5
is another promising compound, improving MDR-TB treatment and months before all that remains is residual scarring seen on the chest
reducing mortality.30 radiograph. Drug therapy must be linked with the public health mea-
sures discussed above.
TREATMENT REGIMENS The standard dose of rifampin (~10 mg/kg) is currently debated.
The aim of multidrug therapeutic regimens is to kill actively growing Higher doses of rifampin are generally well tolerated and not more
and semi-dormant M. tuberculosis bacilli, and prevent the emergence toxic. High-dose rifampin significantly lowered mortality in an RCT
of drug-resistant mutants. The potent antituberculous drugs isoniazid in tuberculous meningitis,31 and shorter regimens using high-dose
and rifampin should be used throughout a 6-month course, with pyra- rifampin are being evaluated for pulmonary TB. For isoniazid, a higher
zinamide during the first 2 months. As a fourth drug ethambutol is dose of 10 mg/kg (versus standard 5 mg/kg) has been advocated in
now routinely added for the first 2 months; streptomycin is a less children and in adults who are rapid metabolizers of INH.
acceptable alternative, largely because of its higher resistance rates and The necessary duration of treatment for extrapulmonary tubercu-
parenteral administration. losis is debated. Limited trials in osteomyelitis, regarded as a difficult
TABLE
31-4 Standard Treatment Regimen and Necessary Dose Modifications in Renal Impairment
Drug Adult Dose (Orally) Duration of Treatment Modification of Drug Dose in Renal Impairment
(1) Isoniazid* 5 mg/kg (maximum 300 mg) 6 months No
(2) Rifampin (rifampicin)* 10 mg/kg (maximum 600 mg) 6 months No
(3) Pyrazinamide* 30 mg/kg (maximum 2.0 g) 2 months ↓ dose or ↑ dosage interval
(4) Ethambutol 15 mg/kg †

2 month ↓ dose or ↑ dosage interval
or
Streptomycin 15 mg/kg im (maximum 1.0 g) 2 months ↓↓ dose or ↑↑ dosage interval
*Isoniazid and rifampin (rifampicin) are marketed as a single combination tablet ± pyrazinamide which may facilitate compliance.
†
Some authorities use ethambutol at 25 mg/kg for 2 months only (longer courses should be at 15 mg/kg).
Estimated proportion of multidrug-resistant tuberculosis among newly diagnosed cases worldwide in 2012
Percentage
of cases
0–2.9
3–5.9
6–11.9
12–17.9
≥18
No data
Subnational data only
Not applicable
Figure 31-15 Estimated proportion of multidrug-resistant tuberculosis among newly diagnosed cases worldwide in 2012. Figures are based on the most recent year
for which data have been reported, which varies among countries. (Reproduced with permission from the World Health Organization, 2013.)
site to treat, indicate that 9 months of therapy is effective providing 300 000 incident cases (Figure 31-15). An estimated 10% of MDR-TB
both isoniazid and rifampin are used. In miliary disease, the 6-month cases are extensively drug-resistant (XDR), defined as also resistant to
regimens have been very successful. Intermittent regimens adminis- second-line injectable drugs and fluorquinolones, and a total of 92
tered three times weekly are used, but it is generally recommended to countries had reported at least one XDR-TB case by mid-2013.1
use daily treatment throughout to reduce the risk of emerging drug MDR-TB and XDR-TB are the results of mismanagement including
resistance, failure and relapse.32 intermittent or interrupted use of TB drugs, errors in prescription,
poor compliance, and low quality of drugs. Failure to detect and initi-
Treating Multidrug- and Extensively ate timely treatment of MDR-TB increases transmission, often within
Drug-Resistant Organisms health facilities; in some areas between 5 and 10% of primary TB is
Multidrug resistance (MDR) is defined as resistance to at least isonia- MDR-TB. Treatment success of MDR-TB varies between 50% and
zid and rifampin and has become a major international problem. In 80%, and the prognosis of patients with XDR-TB often approaches
2012, the estimated global burden of MDR-TB was 450 000, including that of patients in the pre-antibiotic era.33,34
Treatment protocols for MDR and XDR disease must be designed safe. The presence of antituberculous drugs in breast milk is seldom a
for the individual but the aim is to use as many of the first-line drugs problem unless both mother and child are on treatment, in which case
as possible before adding in second-line drugs. Dependent on resis- up to 20% more isoniazid than indicated may be received by the child
tance testing, the first-line drugs pyrazinamide (PZA) and ethambutol, and bottle-feeding is preferable. Breast-feeding children of mothers
WHO group 2 (the ‘injectables’) and group 3 (fluoroquinolones) taking isoniazid require pyridoxine supplementation.
should be core drugs (see Table 31-3), with accompanying drugs from
groups 4 and 5 to prevent further resistance formation.35 The newer SURGERY FOR TUBERCULOSIS
compounds delamanid and bedaquilin are both very promising. Treat- Surgical techniques such as artificial pneumothoraces, phrenic nerve
ment duration beyond 18 months, and use of directly observed and paralysis, plombage and thoracoplasty, are part of the history of tuber-
individualized treatment regimens, probably increase treatment culosis before the era of chemotherapy, but have not been evaluated
success.33,35 with randomized trials. Now surgeons are most often involved in
diagnostic rather than therapeutic procedures. Resection of tissue may
The Use of Steroids (see also Practice Point 8) be very useful in patients with MDR or XDR tuberculosis and circum-
Adjunctive steroids have been shown to reduce mortality associated scribed disease.41 Other indications include massive hemoptysis (after
with tuberculous meningitis, although neurologic disability is proba- embolization has failed) and tuberculous empyema and bronchopleu-
bly not affected. The effect of adjuvant corticosteroids may be depen- ral fistulae. Surgery has been widely used in the treatment of spinal
dent on the inflammatory status of the affected meningitis patient; tuberculosis but is only indicated in the presence of progressive neu-
patient survival in a landmark trial on corticosteroids in Vietnam36 was rologic abnormality and spinal instability and to drain large paraver-
associated with a functional single nucleotide polymorphism (SNP) in tebral abscesses where CT-guided drainage is not possible. Surgery
the promoter region of the Leukotriene A4 Hydrolase (LTA4H) gene, may be required following destructive tuberculosis involving weight-
which determines the balance between pro-inflammatory leukotriene bearing joints, and in nodal tuberculosis if a fluctuant mass persists.
B4 (LTB4) and anti-inflammatory lipoxin A4 (LXA4).37 The role of In pericardial disease, a pericardial window removes the need for
steroid therapy for pericardial tuberculosis is unclear; a recent large repeated drainage. Pericardectomy may be required in constrictive
randomized trial suggested that adjunctive steroids do not reduce the pericarditis; success rates are probably greater if surgery is performed
risk of tamponade or death.38 Steroids may have a role in pleural before extensive calcification develops.
disease, and a very mild effect on pulmonary tuberculosis, although
this is generally not recommended.39 Corticosteroids are effective in IMMUNOTHERAPY AND THE FUTURE
treating the immune-reconstitution inflammatory syndrome (IRIS) in Use of new drugs such as delaminid and bedaquiline, or new drug
HIV-associated tuberculosis.40 In all cases, steroid metabolism is combinations including higher dose rifampin will lead to more effec-
increased by rifampin. tive and hopefully shorter treatment regimens. Evaluation of newer
regimens is still hampered by inadequate biomarkers of disease and
PREGNANCY treatment response. Increasing understanding of immune and inflam-
Tuberculosis treatment during pregnancy should not be deferred. Iso- matory responses including the processes that drive tissue damage and
niazid, rifampin and ethambutol are not teratogenic but few data exist development of cavitation may allow the development of novel thera-
on pyrazinamide. Streptomycin is associated with fetal hearing loss pies or treatment vaccines.
and should be avoided. Little is known about second-line drugs in
pregnancy except para-aminosalicylic acid (PAS), which appears to be References available online at expertconsult.com.
KEY REFERENCES
Diacon A.H., Donald P.R., Pym A., et al.: Randomized pilot outcome in 109 treated adults. Am J Med 1990; 89(3): Ruslami R., Ganiem A.R., Dian S., et al.: Intensified regimen
trial of eight weeks of bedaquiline (TMC207) treatment 291-296. containing rifampicin and moxifloxacin for tuberculous
for multidrug-resistant tuberculosis: long-term outcome, O’Garra A., Redford P.S., McNab F.W., et al.: The immune meningitis: an open-label, randomised controlled phase
tolerability, and effect on emergence of drug resistance. response in tuberculosis. Annu Rev Immunol 2013; 2 trial. Lancet Infect Dis 2013; 13(1):27-35.
Antimicrob Agents Chemother 2012; 56(6):3271-3276. 31:475-527. Skripconoka V., Danilovits M., Pehme L., et al.: Delamanid
Graham S.M.: Treatment of paediatric TB: revised WHO Pai M., Denkinger C.M., Kik S.V., et al.: Gamma interferon improves outcomes and reduces mortality in multidrug-
guidelines. Paediatr Respir Rev 2011; 12(1):22-26. release assays for detection of Mycobacterium tuberculosis resistant tuberculosis. Eur Respir J 2013; 41(6):1393-
Keane J., Gershon S., Wise R.P., et al.: Tuberculosis associ- infection. Clin Microbiol Rev 2014; 27(1):3-20. 1400.
ated with infliximab, a tumor necrosis factor alpha- Rangaka M.X., Wilkinson R.J., Boulle A., et al.: Isoniazid Xu H.-B., Jiang R.-H., Li L.: Pulmonary resection for
neutralizing agent. N Engl J Med 2001; 345(15):1098-1104. plus antiretroviral therapy to prevent tuberculosis: a ran- patients with multidrug-resistant tuberculosis: system-
Lange C., Abubakar I., Alffenaar J.-W.C., et al.: Manage- domised double-blind, placebo-controlled trial. Lancet atic review and meta-analysis. J Antimicrob Chemother
ment of patients with multidrug-resistant/extensively 2014; 384:682-690. 2011; 66(8):1687-1695.
drug-resistant tuberculosis in Europe: a TBNET consen- Riza A.L., Pearson F., Ugarte-Gil C., et al.: Clinical manage-
sus statement. Eur Respir J 2014; 44(1):23-63. ment of concurrent diabetes and tuberculosis and the
Maartens G., Willcox P.A., Benatar S.R.: Miliary tuberculo- implications for patient services. Lancet Diabetes Endocri-
sis: rapid diagnosis, hematologic abnormalities, and nol 2014; 2(9):740-753.
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34:271-286. treatment for multidrug-resistant tuberculosis: long-
32
Nontuberculous Mycobacterial
Diseases
JAKKO VAN INGEN
KEY CONCEPTS Lymphadenitis is the second most common disease manifestation and
can present as swelling of a single or group of lymph nodes in the
• Diseases caused by nontuberculous mycobacteria are increas- cervicofacial region of immunocompetent children or as generalized
ing in incidence and prevalence, mainly in areas where tuber- lymphadenopathy in disseminated disease in the severely immuno-
culosis prevalence is in decline. compromised. Skin disease is the third most common presentation and
• Chronic pulmonary infections are the most frequent disease again includes localized disease (mostly caused by M. marinum, or by
manifestation. M. ulcerans in endemic areas) in immunocompetent hosts exposed
through minor skin abrasions or disseminated disease (mostly caused
• Three distinct pulmonary nontuberculous mycobacterial
by rapid growers such as M. abscessus) in the severely immunocom-
disease manifestations exist: fibrocavitary (tuberculosis-like),
nodular-bronchiectatic and hypersensitivity pneumonitis. promised. Disseminated disease, bone, joint and soft tissue infections
and genitourinary tract infections are all very rare. These distinct
• Nontuberculous mycobacteria cause cervicofacial lymphadeni- disease manifestations and their treatment are discussed in separate
tis in immunocompetent children. paragraphs.
• Other extrapulmonary and disseminated nontuberculous Increasing prevalences of pulmonary NTM disease have been
mycobacterial diseases affect the severely immunocompro- reported from many geographic areas, mainly those where tuberculo-
mised. sis prevalence has fallen. Across Europe, incidence rates of 1–3 per
100 000 persons per year have been reported. In Ontario, Canada, the
• Treatment is long and often involves prolonged intravenous
estimated NTM disease incidence amounted to 3/100 000 in 1997 and
therapy; expert consultation and guidance is advised.
rose to 4.7/100 000 in 2003. In Queensland, Australia, where NTM
• The role of drug susceptibility testing for treatment guidance disease is a reportable condition, the incidence of notified cases of
is limited, but evident. clinically significant disease rose from 2.2/100 000 in 1999 to 3.2/100 000
in 2005. In the USA, the mean annual prevalence of NTM pulmonary
disease was 5.5/100 000, ranging from 1.7/100 000 in Southern Colo-
Introduction rado to 6.7/100 000 in Southern California. An annual increase in
prevalence of 2.6% was noted in this study.3
All members of the genus Mycobacterium other than the Mycobacte- Different forces drive the changing epidemiology in different areas:
rium tuberculosis complex and M. leprae are collectively labeled as in the Netherlands, the increasing incidence is largely explained by
environmental mycobacteria or nontuberculous mycobacteria (NTM). increased isolation of M. avium from pulmonary specimens in males
The presence of these mycobacteria in water and soil was discovered >40 years of age and mirrors the increasing prevalence of chronic
immediately after the discovery of the tubercle bacillus by Koch, but it obstructive pulmonary disease (COPD); in Queensland, Australia, the
took several decades before these NTM were first associated with rising incidence mainly results from an increased incidence of nodular-
human disease. By now, we know that these mycobacteria are ubiqui- bronchiectatic M. intracellulare disease in elderly female patients.
tous in soil, dust, amebae, on plants and in natural as well as treated Patients with cystic fibrosis (CF) form a distinct category of patients
water systems and that some cause disease in animals.1,2 The NTM are susceptible to NTM lung disease. Epidemiological studies have mea-
a grouping of over 150 species, with hundreds if not thousands of sured NTM isolation prevalences of 6.6% (France), 13.0% (USA) and
species still awaiting discovery. Most currently known species have
been isolated from clinical samples, but only a small subset of some 20
species is encountered on a more or less regular basis in clinical prac-
tice;3 the top 10 of clinically most important species is presented in TABLE Ten Most Frequently Isolated NTM and Their
Table 32-1. 32-1 Sites of Infection
Epidemiology Growth Rate Species Main Site of Infection
The environment is the source of human infections and human trans- Slow M. avium complex (M. avium, Pulmonary, lymph node,
mission is thought to be exceedingly rare,1,2 though possible transmis- M. intracellulare, minor disseminated
sion events have recently been reported from cystic fibrosis clinics. As species)
M. kansasii Pulmonary, disseminated
a result, these diseases receive little public health attention and there is M. xenopi Pulmonary
a lack of good data on their epidemiology, particularly in Europe. The M. malmoense (northwestern Pulmonary, lymph node
isolation frequencies of the different species differ strongly by region Europe)
and are likely related to factors of climate and geography. The M. avium M. simiae Pulmonary
M. ulcerans Skin
complex (MAC, which consists of M. avium, M. intracellulare, M.
chimaera and a number of uncommon species) bacteria are the most Intermediate M. marinum Skin
frequently isolated environmental mycobacteria worldwide, a position Rapid M. abscessus Pulmonary, skin, soft
they have taken over from M. kansasii in many regions.1,2 The back- tissues
ground of this shift away from M. kansasii is not fully understood. M. chelonae Skin, soft tissues
M. fortuitum Skin, soft tissues,
Pulmonary infections are the most frequent disease type caused by pulmonary
NTM and often occur in patients with pre-existent pulmonary disease.
285
22.6% (Israel) in CF patients, but the predominant species differ by percentages may vary considerably between different geographic areas.
site; MAC seems most frequent in the USA, whereas M. abscessus The observed differences in clinical relevance between NTM species
predominates in Europe and M. simiae in Israel. In most studies, the suggest a role of bacterial virulence factors, but these remain largely
NTM isolation prevalence in patients with CF increases with age.4 unknown.
Of the extrapulmonary diseases, sound epidemiological data are
available only for NTM lymphadenitis. In a nationwide study in Clinical Features
Germany during the 2003–2005 period, a similar annual incidence rate
PULMONARY DISEASE
of 1.3/100 000 children was calculated; the incidence was highest in
children under 4 years of age.5 In most settings, the incidence of other NTM can cause three distinct types of pulmonary disease: fibrocavi-
extrapulmonary NTM diseases is low and stable. tary disease, nodular-bronchiectatic disease and hypersensitivity pneu-
monitis. When NTM lung disease first gained interest in the late 1950s,
it was mainly a disease of miners and smokers, thus men; their upper
Pathogenesis and Pathology lobe cavitary disease was difficult to distinguish from pulmonary
Granuloma formation is the main host response to NTM. The extent tuberculosis (Figure 32-1). In sanatoria, these men stood out for their
of granuloma formation and the structure of the granulomas largely old age compared to tuberculosis patients, history of smoking and
depend on the immune status of the patient. Central caseous necrosis, chronic lung disease and limited response to drug therapy. During the
considered typical of M. tuberculosis infection, is infrequently seen; 1980s, the nodular-bronchiectatic lung disease was first acknowledged
non-caseating granulomas are the norm, but in severely immunocom- in mainly female patients without a history of chronic lung disease,
promised patients ill-formed granulomas occur, that can even resem- defined radiologically by bronchiectasis and nodular lesions, and pre-
ble spindle cell tumors. dominantly affecting the middle lobe and lingula (Figure 32-2). This
The emergence of NTM diseases in patients with (acquired) immu-
nodeficiencies has given clues to the importance of distinct cells and
pathways in the immune control of NTM. NTM infection, particularly
by the M. avium complex (MAC), is most common in HIV-infected
patients when the CD4+ T-cell count falls below 50/µL, thus showing
the importance of T lymphocytes in protection against NTM.6 The
importance of IFN-γ and IL-12 signaling pathways is evident from the
observation that patients with defects in the IFN-γ and IL-12 receptors
or downstream signaling processors develop disseminated NTM infec-
tions very early in life, often as the first sign of their immune defect.
Tumor necrosis factor (TNF-)α is also involved in the killing of NTM
by macrophages and NTM disease is a well-established complication
of anti-TNF therapies.7
Genetic mutations associated with increased host susceptibility to
NTM lung disease have also been identified, but all seem very rare.
They include mutations in the cystic fibrosis transmembrane con
ductance regulator (CFTR) gene, the natural resistance-associated
macrophage protein 1 gene (Nramp1; synonym: slc11A1) and the
alpha-1-antitrypsin gene. The roles of mutations in the Toll-like recep-
tor 2 and vitamin D receptor remain controversial. The lung tissue
damage inferred by pre-existent pulmonary diseases, such as COPD,
Figure 32-1 Cavitary Mycobacterium szulgai pulmonary disease. Cavitary
is likely more important in the development of cavitary lung disease. lesions in both upper lobes, with signs of emphysema.
The nodular-bronchiectatic disease tends to affect postmenopausal
women, who are taller and leaner than controls and sometimes have
a distinct body habitus with scoliosis, pectus excavatum and mitral
valve prolapse, but the genetic background of this habitus remains to
be studied. Also, high prevalences of gastro-esophageal reflux disease,
26–44%, have been described in patients with mostly nodular bron-
chiectatic NTM lung disease. For both disease types, the exact patho-
genesis remains largely unknown.8
To date, no immunodeficiencies have been specifically associated
with NTM lymphadenitis in children. Bacille Calmette-Guérin (BCG)
vaccination seems to infer cross-protection to NTM lymphadenitis.
Countries that halted childhood BCG vaccination subsequently
noticed an increase in the incidence of pediatric cervicofacial lymph-
adenitis caused by NTM.
The role of bacterial virulence factors is least understood. A definite
diagnosis of NTM lung disease is based on the combination of pulmo-
nary symptoms (e.g. chronic cough, fatigue, dyspnea), radiologic
abnormalities (e.g. cavities or nodular lesions with bronchiectasis) and
repeated isolation of the same NTM species from pulmonary speci-
mens (see below). Yet the percentage of patients that meets all these
criteria differs per species isolated. In the Netherlands, patients from
whom M. kansasii or M. malmoense are isolated from pulmonary
specimens generally meet these criteria. For MAC, M. abscessus and M.
xenopi, 40–60% of patients with a pulmonary isolate ultimately meet Figure 32-2 Nodular-bronchiectatic Mycobacterium intracellulare pulmonary
these diagnostic criteria, but for species like M. chelonae, M. gordonae disease. Bronchiectasis, nodular lesions and a ‘tree in bud’ appearance suggestive
or M. fortuitum, this percentage drops to well below 20%.9 These of bronchiolitis are seen.
Chapter 32 Nontuberculous Mycobacterial Diseases 287
can detect the more fastidious NTM, e.g. M. haemophilum and ‘M.
tilburgii’.
LOCALIZED NTM SKIN DISEASE

Localized NTM skin disease can be divided into three main disease
phenotypes; two of them are named diseases. The first and foremost
is Buruli ulcer disease, a severe skin disease caused by M. ulcerans that
progresses from nodular skin lesions into large ulcers. This disease is
endemic to parts of West Africa and Australia (its former name was
Bairnsdale ulcer disease), but is also seen in specific foci in Latin
America and East Asia, mainly China.11
The second is the so-called fish tank granuloma (previously also
called swimming pool granuloma) caused by infection of existing skin
abrasions by M. marinum, acquired during fish tank cleaning or other
fish- or water-related activities. This usually leads to a single papulo-
nodular, verrucous, or ulcerated granulomatous lesion, 1–3 cm in
diameter, mostly on the hand or lower arm. The skin disease caused
by M. marinum may progress to form multiple lesions in a typical
sporotrichoid pattern, if left untreated. Taking a proper history is
important to obtain evidence for contact with potential sources of M.
Figure 32-3 Hypersensitivity pneumonitis caused by Mycobacterium avium after
hot tub exposure. Focal areas of ground glass opacity are seen, in combination
marinum. In immunocompromised patients, the infection can spread
with nodular lesions and a ‘tree in bud’ appearance suggestive of bronchiolitis. to underlying bony structures, joints and regional lymph nodes. True
disseminated M. marinum disease is very rare and limited to the
severely immunocompromised.12
The last recognized localized NTM skin disease is a grouping of
syndrome was labeled the ‘Lady Windermere syndrome’ after the main wound or injection site infections. These usually follow medical pro-
character in the eponymous play by Oscar Wilde and was suggested to cedures, tattooing or cosmetic therapies that involve incisions in or
result from voluntary cough suppression. The cough suppression injections into skin or subcutaneous fat and inoculation of contami-
hypothesis has been largely disproven. A decade later, hypersensitivity nated products. Outbreaks have also been noted in beauty salons where
pneumonitis was reported, often related to exposure to aerosols gener- foot baths were heavily contaminated with NTM, which were aerosol-
ated by indoor hot tubs or metalworking fluid.1,2 ized and infected small wounds of the legs that had occurred after
Patients with cavitary or nodular-bronchiectatic disease generally shaving, causing furunculosis. Rapidly growing mycobacteria (RGM,
present with a longstanding, often productive, cough, accompanied by e.g. M. fortuitum, M. chelonae, M. abscessus) are the most frequent
slowly progressive fatigue, malaise and weight loss. Fever, night sweats causative agents of these diseases, although M. haemophilum has also
and hemoptysis are rare and signify severe disease. The clinical course been observed as a causative agent of skin infection after inoculation
of disease is slow (slower than tuberculosis), but the cavitary disease of contaminated tattoo ink.13
usually progresses faster than the nodular-bronchiectatic disease.2,9
Discerning NTM disease from progression of the underlying lung EXTRAPULMONARY AND
disease, both clinically and radiologically, can be difficult. DISSEMINATED DISEASE
The hypersensitivity pneumonitis has a subacute presentation with Disseminated NTM disease gained prominence during the early phase
dyspnea and sometimes fever. Radiological features include nodular of the human immunodeficiency virus (HIV) pandemic, before the
lesions and a ‘ground glass’ appearance in high-resolution computed advent of highly active antiretroviral treatment (HAART), though it
tomography (CT) scans (Figure 32-3). Given its subacute presentation, had been reported decades before.1 Disseminated disease in HIV
the link with a specific NTM exposure event (hot tub, metalworking patients is mainly caused by M. avium, although less common species
fluid or other) may not be immediately clear.2 such as M. genavense and M. simiae have been implicated;2 the RGM
Not all NTM cause all three pulmonary disease types. Mycobacte- are remarkably absent as causative agents of HIV-associated dissemi-
rium kansasii, M. malmoense and M. xenopi frequently cause fibrocavi- nated NTM disease. Most patients present with fever, abdominal pain
tary disease, but rarely nodular-bronchiectatic disease; MAC and M. or diarrhea, weight loss and lymph node swelling, hepatomegaly or
abscessus can cause both types of disease; and MAC and M. immuno- splenomegaly observed on physical examination. Given that many
genum (a contaminant of metal-working fluid) are known to cause patients excrete large numbers of M. avium bacilli in feces and common
hypersensitivity pneumonitis. involvement of the bowel, the gastrointestinal tract is commonly
The clinical relevance of isolation of NTM from pulmonary speci- regarded as the primary source of disseminated M. avium disease. Dis-
mens differs strongly by species. To determine whether a patient has seminated M. avium disease was frequently caused by a specific subset
true pulmonary NTM disease, diagnostic criteria have been published of M. avium bacteria, identified as the Mav-B sequevar by 16S-23S
by the American Thoracic Society.2 internal transcribed spacer sequencing. With the advent of HAART,
these disseminated NTM diseases have become relatively rare again,
LYMPHADENITIS affecting those with late diagnoses of HIV infection with low (typically
Lymphadenitis caused by NTM usually affects lymph nodes in a single <50/µL) CD4 counts or patients failing HAART treatment6 (see also
site. The submandibular and cervical lymph nodes are most frequently Chapter 94). Yet, this same disease is now observed in iatrogenic
affected, although axillar and inguinal lymphadenitis have been immunocompromised patients, e.g. after solid organ transplant or
observed. Patients are typically (though not exclusively) children, during anti-TNF-α treatment.2,7
under the age of 8 years. This disease is relatively benign and most Disseminated NTM disease is an entity distinct from the immune
patients present with an enlarged lymph node without constitutional reconstitution inflammatory syndrome that can also present with
symptoms; in more advanced disease, fluctuating masses with viola- newly diagnosed NTM diseases in HIV-infected patients who have
ceous overlying skin are seen. Even if multiple nodes are involved, recently started HAART. This syndrome usually involves fever and
disease is usually unilateral.2,10 If a biopsy specimen is available for lymph node enlargement in one or more sites (see Chapter 95).
microbiological diagnosis, molecular tools are likely more sensitive The RGM also cause disseminated disease in severely immunocom-
than culture in these paucibacillary infections, in part because these promised patients, mainly in those with hematological malignancies
Figure 32-4 Skin lesions of disseminated Mycobacterium haemophilum disease. Figure 32-6 Tenosynovitis of the wrist caused by Mycobacterium abscessus after
Skin induration, erythema as well as nodular, pustular and ulcerative lesions. skin trauma. A subtle swelling of the ulnar side of the wrist is visible.
BOX 32-1 SUMMARY OF THE AMERICAN

THORACIC SOCIETY DIAGNOSTIC
CRITERIA FOR NONTUBERCULOUS
MYCOBACTERIAL LUNG DISEASE
CLINICAL
(All Three Need to be Fulfilled)
1. Pulmonary symptoms.
2. Nodular or cavitary opacities on chest radiograph, or a high-
resolution CT scan that shows multifocal bronchiectasis with
multiple small nodules.
and
3. Appropriate exclusion of other diagnoses.
MICROBIOLOGIC
1. Positive culture results from at least two separate expecto-
Figure 32-5 A draining sinus associated with Mycobacterium fortuitum arthritis
of the shoulder after trauma. rated sputum samples. (If the results from the initial sputum
samples are nondiagnostic, consider repeat sputum acid-fast
bacilli (AFB) smears and cultures.)
or
and solid organ transplant recipients. This disease is very different 2. Positive culture results from at least one bronchial wash or
from the HIV-related disseminated MAC disease, as it presents with lavage.
fever and (sub)cutaneous nodular or ulcerative lesions (Figure 32-4). or
The M. fortuitum complex, M. chelonae, M abscessus as well as the 3. Transbronchial or other lung biopsy with mycobacterial his-
slow-growing M. haemophilum have been described as causative agents topathologic features (granulomatous inflammation or AFB)
and positive culture for NTM or biopsy showing mycobacte-
of these disseminated skin diseases, in which bones and joints may also rial histopathologic features (granulomatous inflammation or
be involved. AFB) and one or more sputum or bronchial washings that are
Most focal extrapulmonary infections, like the skin infections, culture-positive for NTM.
result from direct inoculation of NTM during or after trauma. These
can lead to arthritis (Figure 32-5) or osteomyelitis. One specific extra- Notes:
pulmonary disease manifestation that merits attention is the tenosy- At least three consecutive respiratory samples are needed to apply these
criteria.
novitis of the wrist. This condition tends to affect immunocompromised Expert consultation should be obtained when NTM are recovered that are
patients or gardeners or plant handlers who sustain repetitive skin either infrequently encountered or that usually represent environmental
abrasions and cuts. This disease manifestation can be caused by contamination.
common NTM pathogens such as MAC, M. kansasii, M. malmoense Patients who are suspected of having NTM lung disease but who do not meet
the diagnostic criteria should be followed until the diagnosis is firmly estab-
and M. abscessus, but has also been repeatedly associated with the lished or excluded.
generally apathogenic slow growers in the M. terrae–M. nonchromo- Making the diagnosis of NTM lung disease does not, per se, necessitate the
genicum group (Figure 32-6).14 institution of therapy, which is a decision based on potential risks and ben-
efits of therapy for individual patients.
Diagnosis
Because of their omnipresence in our environment,2 isolation of NTM
from non-sterile body sites does not imply true infection or disease, diagnostic criteria to aid clinicians. A summary of these criteria is
per se. This mainly applies to isolation of NTM from the respiratory presented in Box 32-1.2
tract. Repetitive isolation, signs of clinical disease, radiological abnor- Isolation of NTM from normally sterile sites, preferably backed up
malities, the exact species isolated and predisposing conditions of the by histological evidence of granulomatous inflammation, suffices for
patient involved all are helpful in determining whether the isolated the diagnosis of extrapulmonary/disseminated NTM disease.2
mycobacteria are to be considered the causative agents of the patient’s The clinical signs and symptoms recorded above are nonspecific,
disease. The American Thoracic Society has published a set of so diagnosis strongly relies on radiology (for pulmonary disease) and
culture. The radiological features of cavitary NTM lung disease resem-

ble those of tuberculosis, but the differential diagnosis can include TABLE Treatment Regimens for Pulmonary Disease
32-2 by the Most Prominent NTM Species
fungal infection, malignancy and sarcoidosis, depending on local epi-
demiology and patient characteristics. For the nodular–bronchiectatic
NTM Species Recommended Regimen
disease manifestation, the differential diagnosis can include nocardio-
sis, fungal disease, viral infection or diseases such as sarcoidosis and MAC Macrolide, rifamycin, ethambutol daily
cystic fibrosis. or TIW ± streptomycin/amikacin
three times a week
Microbiological diagnosis of NTM disease has seen tremendous
change over the past two decades (see Chapter 185). It has moved to M. kansasii Rifampin, ethambutol, isoniazid daily
rapid and highly sensitive automated liquid culture systems and rapid or rifampin, macrolide, ethambutol
identification by simple yet sophisticated molecular tools.1,2,15 The daily or three times a week
sample processing and culture techniques are identical to those used M. szulgai, M. malmoense, See MAC above (less reliable data)
for tuberculosis. Direct microscopy of clinical samples relies on aura- M. xenopi
mine staining and fluorescence microscopy or classic Ziehl–Neelsen M. simiae No regimen with good clinical data
staining, both of which perform equally for M. tuberculosis and NTM. on efficacy
For samples from nonsterile sites, decontamination is required before
M. abscessus subsp. abscessus Three or four of the following:
inoculation on culture media. The 1% n-acetyl-l-cysteine and sodium M. abscessus subsp. bolletii amikacin, cefoxitin, imipenem,
peroxide (NALC-NaOH) method, frequently applied in tuberculosis (former ‘M. bolletii’) tigecycline, linezolid, macrolide
diagnostics, performs well for NTM too. In specific patient categories, (macrolides may be inactive if erm
mainly those with bronchiectasis and colonization by Pseudomonas gene is functional)
aeruginosa, contamination of cultures may be a significant problem. M. abscessus subsp. bolletii Macrolide plus two of the following:
For these samples, alternative decontamination methods have been (former ‘M. massiliense’) amikacin, cefoxitin, imipenem,
linezolid
suggested. One option is to decontaminate with chlorhexidine instead
of NALC-NaOH; this does increase the yield of cultures, but this
method in incompatible with widely used automated liquid culture
systems. The other option is to perform NALC-NaOH with a second
decontamination step with oxalic acid.15
The sensitivity of culture-based diagnosis can be significantly rifampin and ethambutol, with adjunctive streptomycin twice weekly
enhanced if cultures are performed in liquid as well as solid media, and in the first 3 months. Of 40 patients treated, all initially converted to
if samples are incubated at 30 as well as 37 degrees Celsius. The latter negative cultures; one relapse (2.5%) was noted after completion of
aspect, incubation temperature, pertains particularly to skin and treatment.16 The BTS later performed a trial of a shorter and simpler
lymph node samples, as the NTM that cause infection at these sites regimen, 9 months of rifampin and ethambutol. This trial recorded
typically grow better at low temperatures (M. marinum, M. haemophi- one case of failure during treatment of 173 patients; after 5 years of
lum, RGM).12–14 This aspect may, in fact, explain the skin/cold body follow-up, the total relapse rate was 10%. More recently, a case series
site tropism of these NTM species. in Israel studied the efficacy of a regimen of rifampin, ethambutol
and clarithromycin, which was given for 12 months after culture con-
Management version (mean 21 months). This long, intensive regimen led to 100%
culture conversion, but no long-term follow-up data have been
TREATMENT OF PULMONARY DISEASE published.17
In contrast to tuberculosis, diagnosis of NTM lung disease does not
necessarily require specific treatment. The decision to treat needs to be MAC
individualized, depending on the causative Mycobacterium species, The outcome of treatment for pulmonary MAC disease is less predict-
achievable treatment goals (reduction of symptoms or sputum conver- able and less favorable than for M. kansasii. The role of macrolides still
sion) and patient acceptance, tolerance and adherence. Treatment can has not been fully resolved. Case series from the USA and Japan showed
vary from observation with best pulmonary care, to oral antibiotics efficacy of macrolide-based regimens, typically rifampin, ethambutol
three times a week or daily, additional intravenous therapy in the first and clarithromycin. After 6 months of this triple-drug regimen, culture
months or surgical resection of affected lung tissue combined with conversion was attained in 36 out of 39 patients in the USA (92%) and
antibiotic therapy.2 28 out of 39 patients in Japan (72%). Long-term outcomes were poorer
Current treatment recommendations have a limited evidence base. in both studies, with prolonged culture conversion in 32 of 39 patients
Other than the trials performed by the British Thoracic Society (BTS) (82%) in the USA and 22 of 39 patients (56%) in the study in Japan.18
and the aminoglycoside trial in Japan, most evidence is constructed These figures are similar to the outcomes of the two BTS trials that
from case series with divergent treatment regimens and expert opinion. assessed the efficacy of 24 months of isoniazid–rifampin–ethambutol
The goal of therapy is 12 months of sputum culture negativity while versus rifampin–ethambutol and later rifampin–ethambutol–
on therapy. Treatment should always consist of multidrug regimens. clarithromycin versus rifampin–ethambutol–ciprofloxacin. The
For MAC and other slow growers, the combined use of rifampin and former trial reported failure rates of 46% in 37 patients receiving
ethambutol is advocated because of in vitro synergy between the two rifampin and ethambutol, versus 16% in 38 receiving isoniazid–
drugs; ethambutol destabilizes the mycobacterial cell wall and then rifampin–ethambutol, although the isoniazid regimen led to a higher
allows entry of rifampin, which normally fails to reach its intracellular mycobacterial disease-associated death rate. The latter trial observed
target, the RNA polymerase, in sufficient concentrations. The use of treatment failure of 13% in 83 patients receiving the rifampin–
these companion drugs also prevents the emergence of macrolide resis- ethambutol–clarithromycin regimen, versus 23% in 87 patients receiv-
tance, at least in MAC, which is associated with very poor outcomes ing the rifampin–ethambutol–ciprofloxacin regimen. The percentage
of therapy.2 Currently recommended treatment regimens for selected of patients alive and cured after 5 years of follow-up was low in
NTM respiratory pathogens are presented in Table 32-2. all arms of both trials (23–34%), much lower than in the case series
from the USA and Japan.19 The vast differences in study set-up,
M. kansasii exact regimens and study populations hamper solid comparisons
Among the pulmonary NTM diseases, M. kansasii disease stands out between the BTS trials data and the case series of macrolide-based
for its high cure rates, even after relatively short treatment. An early regimens. Despite conflicting trial data, the use of macrolide-based
cohort study in the USA tested a regimen of 12 months isoniazid, regimens is now widespread and these regimens are recommended
by the American Thoracic Society.2 These regimens are mostly given is responsible for inducible macrolide resistance in many mycobacte-
daily, but can be given thrice-weekly in patients with limited disease ria, including M. abscessus. Thus, for M. abscessus disease, macrolides
(Table 32-2). should probably be used only for isolates that lack inducible erm gene
The efficacy of adjunctive streptomycin administration during the activity, i.e. part of the M. abscessus subsp. bolletii strains, former ‘M.
first 3 months of treatment was assessed in a separate trial in Japan. massiliense’.20
The addition of streptomycin to the rifampin–ethambutol–clarithro-
mycin regimen led to a faster conversion to negative cultures, but had The Role of Surgery
no impact on relapse or failure rates. Its use is now mostly restricted Adjunctive surgical resection is effective in a subset of patients with
to cases of severe cavitary disease.2 pulmonary NTM disease. The problem is that this subset has not been
While positive cultures during or after treatment suggest treatment well defined. The most critical issues in the decision on this interven-
failure, in nodular bronchiectatic disease these can also represent ‘re tion are the selection of patients eligible for surgery and its exact
infection’ with a new MAC genotype than disease ‘relapse’ with isola- timing. Timing is essential to prevent disease progression into a stage
tion of the pretreatment MAC genotype. The clinical relevance of where safe and effective surgery is no longer possible. Development of
reinfection MAC isolates must be individually determined. additional (cavitary) lesions in multiple lobes, deterioration of patient
condition and acquisition of further drug resistance may render
M. xenopi adjunctive surgery and postoperative chemotherapy ineffective. The
The two BTS trials have also addressed treatment of pulmonary M. possible role of surgery should be considered, in communication with
xenopi disease. These trials assessed the efficacy of 24 months of a specialized center, for every patient who is about to start multidrug
isoniazid–rifampin–ethambutol versus rifampin–ethambutol and later therapy. Surgical treatment should be performed only in a center that
rifampin–ethambutol–clarithromycin versus rifampin–ethambutol– has thoracic surgeons, infectious disease specialists and pulmonary
ciprofloxacin. Despite a treatment failure and relapse rate of 24%, physicians with experience in NTM disease as well as general pulmo-
the rifampin–ethambutol clarithromycin regimen is favored by the nary surgery and capable of providing long-term follow-up.2,23
researchers, as it yields the lowest death rates, both due to mycobacte-
rial disease and all-cause.19 The very low number of patients per arm Unresolved Issues in NTM Pulmonary Disease
(17–20) limits the applicability of its findings. Mycobacterium xenopi
For species that rarely cause pulmonary disease, no evidence-based
tends to affect a specific patient category with a very poor prognosis.
treatment regimens exist. For RGM, treatment regimens should be
In one cohort study, 70% of patients died during 3 years of follow-up
based on results of in vitro drug susceptibility testing. For many slow-
after the diagnosis of M. xenopi lung disease; the median survival was
growing NTM species, treatment can be extrapolated from MAC, M.
16 months.
malmoense and M. xenopi treatment. For M. simiae, these rifampin–
M. malmoense ethambutol-based regimens are known to yield very limited results.
This may result, in part, from a lack of synergy between rifampin and
The last NTM species covered in the BTS trials is M. malmoense, a
ethambutol for this species. Here, a completely new treatment regimen
species for which other data on treatment and outcome are scarce,
needs to be designed; a combination of clofazimine and amikacin has
partly because this species is mostly restricted to northwestern Europe.
been proposed as a backbone for such a regimen, as well as combina-
Outcome of treatment for M. malmoense disease is usually more favor-
tions of macrolides and fluoroquinolones.
able than that for MAC or M. xenopi pulmonary disease. The BTS trials
The multidrug regimens lead to significant pharmacokinetic inter-
revealed that the relapse/failure rate was equal for the rifampin–
actions. Particularly, rifampin lowers the serum levels of macrolides
ethambutol (12%; n=52 patients), isoniazid–rifampin–ethambutol
and – to a lesser extent – moxifloxacin in patients with pulmonary
(9%; n=54) and rifampin–ethambutol–clarithromycin (5%; n=86)
NTM disease. Given the high levels of natural resistance of NTM to
regimens. The addition of clarithromycin did lead to an increase in
antimicrobial drugs, serum concentrations of all key drugs are gener-
reported side effects.19 These data have been confirmed in smaller case
ally too low to overcome the minimum inhibitory concentrations and
series.
meet pharmacodynamic targets for the drug. The clinical implications
M. abscessus of these low serum levels remain unknown but these may partly
explain the poor outcomes of drug treatment.24
For M. abscessus no reliably and predictably effective treatment exists.
Although the cavitary and nodular-bronchiectatic disease manifes-
Treatment usually consists of an intensive phase with multiple intra-
tations are different disease types affecting distinct patient groups,
venous antibiotics (amikacin, cefoxitin/imipenem and/or tigecycline)
treatment is often identical. The differential efficacy of currently rec-
with oral macrolides, all based on in vitro drug susceptibility testing,
ommended and new regimens against these different disease manifes-
followed by a continuation phase of mostly oral or inhaled drugs,
tations should be a subject of future studies.
where the role of drug susceptibility testing is less prominent.20 A
recent case series applied individualized regimens that included mac-
rolides, amikacin, cefoxitin, imipenem and tigecycline, based on in TREATMENT OF EXTRAPULMONARY AND
vitro drug susceptibility testing results; 33 out of 69 patients (48%) DISSEMINATED DISEASE
showed prolonged conversion to negative cultures and this percentage Treatment of cervicofacial lymphadenitis caused by NTM can range
was highest for those who underwent adjunctive surgical resection from observation (as disease can be self-limiting) to antibiotic
of affected lung tissue (57% vs 28% conversions in patients who treatment or surgical resection. A comparative trial revealed that surgi-
received drug treatment only). These outcomes strengthened the exist- cal excision was more effective than antibiotic therapy (96% cure rate,
ing treatment recommendations, which stress the importance of surgi- versus 66% for a 3-month regimen of rifabutin–clarithromycin).10 In
cal resection when possible and backed up by multidrug treatment patients with advanced disease, the outcomes of antibiotic treatment
regimens selected on basis of in vitro drug susceptibility testing equal those of a wait-and-see approach.
results.21 Another recent study has shown that treatment outcome is The skin disease caused by M. marinum is treated based on its
most favorable in patients with disease caused by the former ‘M. mas- severity. For a single small lesion, freezing may suffice, or monotherapy
siliense’ (which is now part of M. abscessus subsp. bolletii). The propor- with a macrolide, tetracycline or trimethoprim–sulfamethoxazole.
tion of patients with sputum conversion and maintenance of negative Most experts favor multidrug regimens, mostly rifampin–ethambutol
sputum cultures was higher in 64 patients with ‘M. massiliense’ infec- or ethambutol–clarithromycin, as these have proven highly efficacious
tion (88%) than in 81 patients with M. abscessus infection (25%), after in case series. In advanced disease, multidrug treatment is the norm
treatment with a clarithromycin-containing regimen in combination and the triple-drug regimen of rifampin, ethambutol and a macrolide
with an initial 4-week course of cefoxitin and amikacin.22 This particu- is used; adjunctive surgical debridement is recommended in cases of
lar subspecies of M. abscessus has a deletion in its erm gene. This gene bone and joint involvement.2,12
Treatment for M. ulcerans skin disease has changed dramatically the USA and Japan have assessed the efficacy of triple-drug regimens
over the past decade, from primarily surgical treatment, to antibiotic of rifampin, ethambutol and a macrolide in MAC lung disease. In
treatment with rifampin and streptomycin for 8 weeks, to now com- these series, treatment outcome was significantly worse in patients
pletely oral 8-week regimens of rifampin with either clarithromycin or with macrolide-resistant MAC bacteria, either at baseline or acquired
quinolones.11,25 during therapy. Tanaka and colleagues revealed that culture conver-
Treatment of tenosynovitis of the wrist caused by NTM is depen- sion rates of the triple-drug regimens of rifampin, ethambutol and a
dent on causative species and its susceptibilities, but should also macrolide with adjunctive aminoglycosides during the first 6 months
include evacuation of pus from the affected tendons, if needed even in of therapy were 71.8% overall, but only 25% in patients whose initial
multiple procedures during the treatment period. The optimal dura- isolates were resistant to macrolides.18 In the British Thoracic Society
tion of drug treatment is not known.2 trial of regimens of rifampin and ethambutol with or without isonia-
For the disseminated diseases, usually presenting with multiple zid for MAC, M. xenopi and M. malmoense lung disease, no relation
skin and subcutaneous abscesses, and other extrapulmonary diseases between susceptibility to isoniazid, rifampin and ethambutol tested
caused by RGM, no evidence-based treatment regimens are available. alone and treatment outcome could be established, but in these trials
Treatment is based on surgical debridement where possible, with 4 a deviant susceptibility test method was applied.19 Similarly, trials of
months of two-drug antibiotic treatment based on in vitro susceptibil- monotherapy with rifampin, ethambutol, clofazimine or clarithromy-
ity test results.26 For M. fortuitum complex infections, regimens can cin for HIV-associated disseminated M. avium disease established that
include a combination of quinolones, co-trimoxazole, tobramycin, only susceptibility test results for clarithromycin predicted outcome
doxycycline and imipenem; for M. chelonae, two-drug combinations of treatment: in a clarithromycin monotherapy dose-finding trial,
of tobramycin, imipenem, macrolides and linezolid are usually effec- 99% of all pre-treatment isolates were susceptible to 4 µg/mL of clar-
tive. One trial of 6 months’ clarithromycin monotherapy for dissemi- ithromycin in broth macrodilution; 46% developed minimum inhibi-
nated M. chelonae skin disease showed a 92% cure rate and one relapse tory concentrations (MICs) >32 µg/mL during treatment and
with a clarithromycin-resistant isolate. Few drugs are active against M. follow-up and these increased MICs were associated with recrudes-
abscessus, where regimens usually are combinations of amikacin, imi- cence of symptoms and increases in bacterial load in blood
penem, cefoxitin, linezolid and macrolides; the latter probably only cultures.28
work for strains with no functional erm gene (former ‘M. massiliense’). Rifampin and ethambutol show clear synergistic effect in vitro; in
The role of tigecycline in these RGM infections remains unknown, a series of just five patients, treatment failure of rifampin–ethambutol-
although it is being used in M. abscessus disease. If underlying bone based regimens for MAC lung disease was associated with acquired
and joints are involved, surgery has a more prominent role and treat- resistance to these drugs, when tested in combination. Nonetheless, the
ment is prolonged to 6 months.2 Where possible, underlying immu- true clinical relevance of susceptibility testing to rifampin and etham-
nodeficiencies should be treated, or immunosuppressive treatment butol in combination has not been established.29 Hence, for MAC, only
should be halted or decreased in dose or frequency. susceptibility testing of macrolides (i.e. clarithromycin) is currently
In contrast to the lack of trial data in all other forms of NTM recommended.
disease, disseminated MAC disease is treated based on the evidence For M. kansasii, rifampin-resistant isolates have been observed in
gathered in several trials in HIV-infected patients. The currently patients who failed treatment with rifampin-based regimens; thus,
recommended regimen is clarithromycin 500 mg twice-daily and eth- initial testing should include only rifampin.28
ambutol 15 mg/kg once-daily with or without rifabutin 300 mg once- For the rapid growers, relations between MICs and outcomes have
daily27 (see Chapter 94 for further discussion). Identical regimens are been studied for several drugs (e.g. tobramycin, co-trimoxazole, cefox-
applied in disseminated disease by other slow-growing NTM (M. itin, doxycycline) albeit mostly in extrapulmonary disease and key
genavense, M. simiae), but limited data on efficacy are available. drugs including amikacin and macrolides were not included. This
study has largely shaped the current recommendations on drug sus-
THE ROLE OF DRUG SUSCEPTIBILITY TESTING ceptibility testing of aminoglycosides, tetracyclines, sulphonamides,
The role of drug susceptibility testing in the choice of agents for anti- cefoxitin and macrolides.26,28 Minimum inhibitory concentrations of
microbial treatment of NTM disease, mainly that of slow growers, any other drug should be interpreted with caution; seeking expert
remains a subject of debate. Important discrepancies between drug consultation before applying non-standard drugs in regimens is
susceptibility measured in vitro and the activity of the drug observed recommended.
in vivo have been noted, both in pulmonary and disseminated disease. For M. marinum, routine drug susceptibility testing is not recom-
In addition, the currently recommended technique, broth microdilu- mended for primary isolates, since susceptibility to all first-line drugs
tion in cation-adjusted Mueller–Hinton medium, is little used outside is the norm and the outcomes of treatment are generally good.28 For
the USA. Yet, all in vitro–in vivo correlations discussed here are based M. ulcerans, the difficulties in culturing the organism hamper attempts
on this microdilution method and results of other methods cannot at clinically meaningful drug susceptibility testing; drug susceptibility
easily be extrapolated.28 testing is only performed in research settings.
In lung disease caused by MAC, the macrolide antibiotic clarithro-
mycin was the first drug for which a relationship between in vitro References available online at expertconsult.com.
activity and in vivo efficacy could be demonstrated. Case series from
KEY REFERENCES
Griffith D.E., Aksamit T.R.: Therapy of refractory nontuber- Research Committee of the British Thoracic Society: Clar- nontuberculous mycobacteria. Drug Resist Updat 2012;
culous mycobacterial lung disease. Curr Opin Infect Dis ithromycin vs ciprofloxacin as adjuncts to rifampicin and 15:149-161.
2012; 25:218-227. ethambutol in treating opportunist mycobacterial lung van Ingen J., Egelund E.F., Levin A., et al.: The pharmaco-
Griffith D.E., Aksamit T., Brown-Elliot B.A., et al.: An offi- diseases and an assessment of Mycobacterium vaccae kinetics and pharmacodynamics of pulmonary Mycobac-
cial ATS/IDSA statement: diagnosis, treatment, and pre- immunotherapy. Thorax 2008; 63:627-634. terium avium complex disease treatment. Am J Respir Crit
vention of nontuberculous mycobacterial diseases. Am J Uslan D.Z., Kowalski T.J., Wengenack N.L., et al.: Skin and Care Med 2012; 186:559-565.
Respir Crit Care Med 2007; 175:367-416. soft tissue infections due to rapidly growing mycobacte- Winthrop K.L., Yamashita S., Beekmann S.E., et al.: Myco-
Jarand J., Levin A., Zhang L., et al.: Clinical and microbio- ria: comparison of clinical features, treatment, and sus- bacterial and other serious infections in patients receiv-
logic outcomes in patients receiving treatment for Myco- ceptibility. Arch Dermatol 2006; 142:1287-1292. ing anti-tumor necrosis factor and other newly approved
bacterium abscessus pulmonary disease. Clin Infect Dis van Ingen J., Bendien S.A., de Lange W.C.M., et al.: Clinical biologic therapies: case finding through the Emerging
2011; 52:565-571. relevance of nontuberculous mycobacteria isolated in Infections Network. Clin Infect Dis 2008; 46:1738-1740.
Karakousis P.C., Moore R.D., Chaisson R.E.: Mycobacte- the Nijmegen–Arnhem region, the Netherlands. Thorax
rium avium complex in patients with HIV infection in 2009; 64:502-506.
the era of highly active antiretroviral therapy. Lancet van Ingen J., Boeree M., van Soolingen D., et al.: Resistance
Infect Dis 2004; 4:557-565. mechanisms and drug susceptibility testing of
Chapter 32 Nontuberculous Mycobacterial Diseases 291.e1
REFERENCES
1. Wolinsky E.: Nontuberculous mycobacteria and associ- cial lymphadenitis in children: a multicenter, random- Mycobacterium abscessus pulmonary disease. Clin Infect
ated diseases. Am Rev Respir Dis 1979; 119:107-159. ized, controlled trial. Clin Infect Dis 2007; 44:1057-1064. Dis 2011; 52:565-571.
2. Griffith D.E., Aksamit T., Brown-Elliot B.A., et al.: An 11. Portaels F., Silva M.T., Meyers W.M.: Buruli ulcer. Clin 22. Koh W.J., Jeon K., Lee N.Y., et al.: Clinical significance
official ATS/IDSA statement: diagnosis, treatment, and Dermatol 2009; 27:291-305. of differentiation of Mycobacterium massiliense from
prevention of nontuberculous mycobacterial diseases. 12. Petrini B.: Mycobacterium marinum: ubiquitous agent Mycobacterium abscessus. Am J Respir Crit Care Med
Am J Respir Crit Care Med 2007; 175:367-416. of waterborne granulomatous skin infections. Eur J Clin 2011; 183:405-410.
3. Prevots D.R., Shaw P.A., Strickland D., et al.: Nontuber- Microbiol Infect Dis 2006; 25:609-613. 23. Mitchell J.D., Bishop A., Cafaro A., et al.: Anatomic lung
culous mycobacterial lung disease prevalence at four 13. Uslan D.Z., Kowalski T.J., Wengenack N.L., et al.: Skin resection for nontuberculous mycobacterial disease.
integrated health care delivery systems. Am J Respir Crit and soft tissue infections due to rapidly growing myco- Ann Thorac Surg 2008; 85:1887-1893.
Care Med 2010; 182:970-976. bacteria: comparison of clinical features, treatment, and 24. van Ingen J., Egelund E.F., Levin A., et al.: The pharma-
4. Roux A.L., Catherinot E., Ripoll F., et al.: Multicenter susceptibility. Arch Dermatol 2006; 142:1287-1292. cokinetics and pharmacodynamics of pulmonary
study of prevalence of nontuberculous mycobacteria in 14. van Ingen J.: Diagnosis of nontuberculous mycobacte- Mycobacterium avium complex disease treatment. Am J
patients with cystic fibrosis in France. J Clin Microbiol rial disease. Semin Respir Crit Care Med 2013; 34:103- Respir Crit Care Med 2012; 186:559-565.
2009; 47:4124-4128. 109. 25. Chauty A., Ardant M.F., Marsollier L., et al.: Oral treat-
5. Reuss A.M., Wiese-Posselt M., Weissmann B., et al.: 15. Olsen R.J., Cernoch P.L., Land G.A.: Mycobacterial ment for Mycobacterium ulcerans infection: results from
Incidence rate of nontuberculous mycobacterial disease synovitis caused by slow-growing nonchromogenic a pilot study in Benin. Clin Infect Dis 2011; 52:94-96.
in immunocompetent children: a prospective nation- species: eighteen cases and a review of the literature. 26. Wallace R.J., Swenson J.M., Silcox V.A., et al.: Treatment
wide surveillance study in Germany. Pediatr Infect Dis J Arch Pathol Lab Med 2006; 130:783-791. of nonpulmonary infections due to Mycobacterium for-
2009; 28:642-644. 16. Ahn C.H., Lowell J.R., Ahn S.S., et al.: Short-course tuitum and Mycobacterium chelonei on the basis of in
6. Karakousis P.C., Moore R.D., Chaisson R.E.: Mycobac- chemotherapy for pulmonary disease caused by Myco- vitro susceptibilities. J Infect Dis 1985; 152:500-514.
terium avium complex in patients with HIV infection bacterium kansasii. Am Rev Respir Dis 1983; 128:1048- 27. Gordin F.M., Sullam P.M., Shafran S.D., et al.: A ran-
in the era of highly active antiretroviral therapy. Lancet 1050. domized, placebo-controlled study of rifabutin added
Infect Dis 2004; 4:557-565. 17. Shitrit D., Baum G.L., Priess R., et al.: Pulmonary Myco- to a regimen of clarithromycin and ethambutol for
7. Winthrop K.L., Yamashita S., Beekmann S.E., et al.: bacterium kansasii infection in Israel, 1999–2004: clini- treatment of disseminated infection with Mycobacte-
Mycobacterial and other serious infections in patients cal features, drug susceptibility, and outcome. Chest rium avium complex. Clin Infect Dis 1999; 28:1080-
receiving anti-tumor necrosis factor and other newly 2006; 129:771-776. 1085.
approved biologic therapies: case finding through the 18. Tanaka E., Kimoto T., Tsuyuguchi K., et al.: Effect of 28. van Ingen J., Boeree M., van Soolingen D., et al.: Resis-
Emerging Infections Network. Clin Infect Dis 2008; clarithromycin regimen for Mycobacterium avium tance mechanisms and drug susceptibility testing of
46:1738-1740. complex pulmonary disease. Am J Respir Crit Care Med nontuberculous mycobacteria. Drug Resist Updat 2012;
8. Kim R.D., Greenberg D.E., Ehrmantraut M.E., et al.: 1999; 160:866-872. 15:149-161.
Pulmonary nontuberculous mycobacterial disease: pro- 19. Research Committee of the British Thoracic Society: 29. Hoffner S.E., Heurlin N., Petrini B., et al.: Mycobacte-
spective study of a distinct preexisting syndrome. Am J Clarithromycin vs ciprofloxacin as adjuncts to rifampi- rium avium complex develop resistance to synergisti-
Respir Crit Care Med 2008; 178:1066-1074. cin and ethambutol in treating opportunist mycobacte- cally active drug combinations during infection. Eur
9. van Ingen J., Bendien S.A., de Lange W.C.M., et al.: rial lung diseases and an assessment of Mycobacterium Respir J 1994; 7:247-250.
Clinical relevance of nontuberculous mycobacteria iso- vaccae immunotherapy. Thorax 2008; 63:627-634.
lated in the Nijmegen–Arnhem region, the Netherlands. 20. Griffith D.E., Aksamit T.R.: Therapy of refractory non-
Thorax 2009; 64:502-506. tuberculous mycobacterial lung disease. Curr Opin
10. Lindeboom J.A., Kuijper E.J., Bruijnesteijn van Cop- Infect Dis 2012; 25:218-227.
penraet E.S., et al.: Surgical excision versus antibiotic 21. Jarand J., Levin A., Zhang L., et al.: Clinical and micro-
treatment for nontuberculous mycobacterial cervicofa- biologic outcomes in patients receiving treatment for
33
Fungal Pneumonias
CAROL A. KAUFFMAN
KEY CONCEPTS and areas under trees that serve as bird and bat roosts and caves with
high bat populations are especially likely to have high concentrations
• Most acute infections with Histoplasma capsulatum are asymp- of H. capsulatum. In the endemic areas, exposure to H. capsulatum is
tomatic or cause mild pulmonary symptoms and do not require common and it is estimated that hundreds of thousands of persons are
antifungal therapy. infected yearly. Most infections are sporadic, acquired during the
• Most acute infections with Blastomyces dermatitidis are asymp- course of daily living, but dramatic outbreaks have been documented,
tomatic or cause mild pulmonary symptoms. Even if the patient including the large outbreak in Indianapolis that infected over a
is improving, antifungal therapy should be given. hundred thousand persons. Many smaller outbreaks have been traced
back to spelunking (potholing), demolition of buildings or other activ-
• Exposure to a large inoculum of H. capsulatum or B. dermatiti-
dis can lead to severe pneumonia and acute respiratory distress ities that disrupt contaminated soil.1
syndrome, even in healthy hosts.
• Immunosuppressed persons, such a those with AIDS and those
treated with tumor necrosis factor antagonists, can develop Infection begins when the microconidia of H. capsulatum are inhaled
severe pneumonia and/or disseminated infection after expo- into the alveoli. Neutrophils and macrophages phagocytize the organ-
sure to endemic fungi. ism, which triggers conversion to the yeast phase. The organism sur-
vives within macrophages, is spread to the hilar and mediastinal lymph
• Most patients with coccidioidomycosis have mild pneumonia
nodes, and subsequently disseminates hematogenously. Asymptomatic
and do not need antifungal therapy.
hematogenous dissemination likely occurs in most patients who are
• Pulmonary complications, including persistent thin-walled cavi- infected. Specific cell-mediated immunity against H. capsulatum devel-
ties and chronic progressive pneumonia, occur in 5–10% of ops in a few weeks, leading to macrophage activation and, ultimately,
patients with coccidioidomycosis. killing of the organism. Cell-mediated immunity is crucial for control
• Paracoccidioidomycosis in older men causes chronic cavitary of the infection. It is thought that organisms can remain in a dormant
lesions and fibrosis mostly in middle and lower lung fields. The state, similar to that which occurs with Mycobacterium tuberculosis, and
less common juvenile or acute form of paracoccidioidomycosis then reactivate years later should cellular immunity wane.
occurs in immunosuppressed younger individuals and is char- The extent of disease is determined both by the inoculum of conidia
acterized by diffuse pulmonary infiltrates. inhaled and the immune response of the host. A small inoculum can
• Pulmonary infection associated with sporotrichosis is uncom- cause severe infection in markedly immunosuppressed hosts, especially
mon and occurs mostly in older men who have chronic obstruc- those who have AIDS or have been treated with antitumor necrosis
tive pulmonary disease. factor (TNF) agents.2,3 Conversely, healthy individuals can develop
life-threatening infection when exposed to a large inoculum of fungi.
Clinical Features
It is important to emphasize that most patients who become infected
Introduction with H. capsulatum remain asymptomatic or at most have a self-
This chapter will focus on the pulmonary aspects of the endemic limited ‘flu-like’ illness. In those patients who do have acute pneumo-
mycoses, those fungi that are geographically restricted and that have nia, symptoms are usually fever, fatigue, dyspnea, cough, mild chest
the capability to cause infection in healthy hosts. Most infections with discomfort, arthralgias and myalgias. The chest radiograph reveals a
these fungi are initiated with inhalation of the conidia from the mold patchy lobar or multilobar infiltrate; hilar lymphadenopathy, when
phase, which exists in the environment, and thus the lungs play a major present, is a clue to the possibility of a fungal pneumonia.4 The initial
role in the pathogenesis and clinical presentation of these infections. diagnosis in almost all patients is that of an atypical bacterial pneu-
Infections with the endemic mycoses in immunosuppressed individu- monia, and almost all have received antibiotics to no avail before the
als are usually more severe and are more likely to be disseminated. possibility of histoplasmosis is entertained. If several patients who were
involved with a particular outdoor activity have the same symptoms
and see the same physician, then fungal pneumonia assumes a more
Histoplasmosis prominent position in the differential diagnosis.
A small minority of patients with acute pulmonary histoplasmosis
Mycology and Epidemiology develop severe pneumonia that can progress to acute respiratory dis-
The causative agent of histoplasmosis is Histoplasma capsulatum, a tress syndrome (ARDS). This occurs most often in patients who are
dimorphic fungus that exists as a mold in the environment but con- immunosuppressed or in those who had an overwhelming exposure
verts to a yeast form in tissues at 37 °C. There are two human patho- to the organism. Diffuse infiltrates that often have a nodular compo-
gens, H. capsulatum var. capsulatum and H. capsulatum var. duboisii. nent are noted on chest radiograph (Figure 33-1). In immunosup-
The latter organism is endemic in Africa and will not be discussed pressed patients, severe diffuse pulmonary involvement is often one
further. H. capsulatum is found primarily in North America in the component of widespread disseminated infection.
Ohio and Mississippi River valleys and in many countries in Central Chronic cavitary pulmonary histoplasmosis almost always occurs
America; localized foci exist in countries surrounding the Mediterra- in older adults who have underlying emphysema and clinically mimics
nean Sea and in South East Asia. reactivation tuberculosis. Symptoms include fever, fatigue, anorexia,
The environmental niche for H. capsulatum is soil that is enriched weight loss, cough productive of purulent sputum and hemoptysis.
by the nitrogen contained in bird and bat guano. Abandoned buildings Chest radiographs show unilateral or bilateral upper lobe infiltrates
292
Chapter 33 Fungal Pneumonias 293
Figure 33-3 Typical 2–4 µm yeast forms of Histoplasma capsulatum seen on a

biopsy taken from an enlarged necrotic adrenal gland. The tissue is stained with
Gomori methenamine silver stain.
Figure 33-1 Diffuse pulmonary infiltrates in a 40-year-old woman who had
received a renal transplant 2 years before and who developed acute pulmonary
histoplasmosis. dyspnea, cough, wheezing and hemoptysis. CT scan reveals the extent
of the fibrosis and angiographic studies pinpoint those vessels that are
stenotic. When vessels to both lungs are involved, the disease is almost
always fatal.
Many patients with disseminated histoplasmosis will have pulmo-
nary manifestations. These may be subtle, as often occurs in older
patients with chronic progressive histoplasmosis, but the pulmonary
component may also be life-threatening, which is noted most often in
immunosuppressed patients.
Diagnosis
Histoplasmosis is definitively diagnosed by growth of the organism
from samples taken from the infected site.6 Sputum, bronchoalveolar
lavage (BAL) fluid, lung tissue or mediastinal lymph nodes are accept-
able samples. H. capsulatum may take as long as 4–6 weeks to grow on
Sabouraud’s agar at room temperature in the mold form. Tentative
identification can be made on seeing the characteristic tuberculate
macroconidia; definitive identification is made with the use of a com-
mercially available DNA probe that is highly specific for H.
capsulatum.
Identification of the organism in tissue or fluid samples allows an
early diagnosis while awaiting culture results.7 The organisms appear
as uniform, 2–4 µm oval budding yeasts, most easily seen on tissue
Figure 33-2 Chronic cavitary pulmonary histoplasmosis in an elderly man who stained with methenamine silver or periodic acid–Schiff (PAS) stains
had severe underlying emphysema. or in smears or touch preparations stained with Giemsa stain (Figure
33-3). For patients who have disseminated disease in addition to pul-
monary manifestations, biopsy samples taken from bone marrow,
and thick-walled cavities, and fibrosis is seen in the lower lung fields4 lymph nodes or lesions on the mucous membranes or skin may reveal
(Figure 33-2). the organisms and avoid the need for bronchoscopy.
There are several complications of pulmonary histoplasmosis that Serology plays an important role in the diagnosis of pulmonary
can occur months to years after the initial infection. Mediastinal gran- histoplasmosis, especially chronic cavitary histoplasmosis and acute
uloma is characterized by persistent mediastinal and/or hilar lymph- pulmonary histoplasmosis.6 Both complement fixation (CF) and
adenopathy.5 Many patients are asymptomatic and the problem is immunodiffusion (ID) tests are available and should be ordered. For
discovered when a chest radiograph is performed for another reason. patients with acute pneumonia, the initial studies may be negative but
Others have symptoms of dysphagia, chest pain, dyspnea or nonpro- will show a fourfold rise over the subsequent few weeks. Antibody titers
ductive cough when the enlarged lymph nodes impinge on adjacent are almost always positive in patients with chronic cavitary histoplas-
structures. CT scan usually reveals a confluence of lymph nodes that mosis. Serology is not as useful in immunosuppressed patients who
are surrounded by a fibrous capsule and that have central necrosis. often cannot mount an antibody response.
Most patients have resolution of the lymphadenopathy, but fistula Antigen detection, using an enzyme immunoassay that measures a
formation and compression of adjacent structures may require inter- cell wall polysaccharide antigen of H. capsulatum in urine and serum,
vention. This syndrome does not progress to mediastinal fibrosis. is useful in patients with acute pulmonary histoplasmosis, especially
Mediastinal fibrosis is a rare complication of pulmonary histoplas- those with diffuse pneumonia, but is usually not helpful for chronic
mosis in which the host responds to histoplasmosis with excessive cavitary histoplasmosis or mediastinal syndromes.7,8 In those patients
fibrosis that ultimately encases the great vessels and/or bronchi.5 who have dissemination in addition to pulmonary involvement, the
Obstruction of the superior vena cava and/or the vessels to one lung antigen assay has proved to be extremely useful. Cross-reactivity occurs
is most common. The disease is progressive and the symptoms include with other endemic fungi, especially Blastomyces dermatitidis.
Management and both neutrophils and cell-mediated immunity are important in

the response to infection.14 It is likely that hematogenous dissemina-
The Infectious Diseases Society of America has developed guidelines tion occurs early in most patients, but is usually asymptomatic. Weeks
for the management of histoplasmosis.9 In general, patients with severe to months later, often after the pulmonary lesion has healed, patients
pulmonary histoplasmosis should be treated initially with an ampho- can present with cutaneous or other organ involvement. It should be
tericin B formulation. Lipid formulations are associated with fewer presumed that all extrapulmonary lesions represent hematogenous
adverse effects and may be more effective.10 For most patients, after a dissemination. Blastomycosis tends to be more severe in those with
few weeks of amphotericin B therapy, step-down therapy to itracon- cell-mediated immune dysfunction.15 Reactivation of prior infection
azole is recommended. with B. dermatitidis has been noted, but appears to be less common
Patients who have mild to moderate pulmonary histoplasmosis than noted with H. capsulatum.
should be treated with itraconazole.9 Fluconazole is less effective. Vori-
conazole and posaconazole can be used for patients who are intolerant
of itraconazole, but there are only a limited number of reports on the
Clinical Features
use of these agents for histoplasmosis.11 The echinocandins do not have Most patients with acute pulmonary infection with B. dermatitidis
activity against H. capsulatum and should not be used. remain asymptomatic or have a mild ‘flu-like’ illness that is never
Most patients with acute pulmonary histoplasmosis have self- diagnosed as blastomycosis. Those who have acute pneumonia mani-
limited infection and do not need to be treated with an antifungal fest fever, cough, mild dyspnea, myalgias and arthralgias, and are noted
agent. However, some patients remain symptomatic for weeks, and in to have a localized pulmonary infiltrate on chest radiograph. Most
these patients a short course of itraconazole 200 mg daily for 6–12 patients are given a diagnosis of an atypical bacterial pneumonia and
weeks is recommended.9 Severe acute pulmonary histoplasmosis are treated with antibiotics. Only when the infection does not respond
should be treated preferably with lipid formulation amphotericin B, to this therapy is a fungal infection considered and further diagnostic
3–5 mg/kg daily; amphotericin B deoxycholate, 0.7–1.0 mg/kg daily studies undertaken.
also can be used. After the patient improves, step-down therapy to A small proportion of patients with acute blastomycosis develop
itraconazole, 200 mg twice daily, can be initiated. Therapy should con- overwhelming pulmonary infection with ARDS16 (Figure 33-4). This
tinue until all infiltrates have resolved. Many clinicians use intravenous occurs more often in immunocompromised patients, but is also
methylprednisolone in addition to amphotericin B during the first 1–2 reported in previously healthy adults. The presumption in the latter
weeks in patients who are severely hypoxemic.9 group is that they inhaled a large number of conidia that overwhelmed
Most patients who have chronic cavitary pulmonary histoplasmosis their immune response. The mortality rate is extremely high in this
can be treated with itraconazole, 200 mg twice daily. Treatment should rapidly progressive form of pulmonary blastomycosis.
continue for at least a year, but outcomes are still poor in many patients Pulmonary blastomycosis can present as a mass-like lesion that is
because of the degree of fibrosis that has occurred. indistinguishable from lung cancer or with upper lobe cavitary lesions
Patients with mediastinal granuloma do not require therapy with that resemble tuberculosis or histoplasmosis13 (Figure 33-5). Fever,
an antifungal agent. However, in symptomatic patients, many clini- night sweats, weight loss, fatigue, dyspnea and cough with purulent
cians give a 6- to 12-week course of 200 mg itraconazole once or twice sputum and hemoptysis are often present for weeks before the patient
daily although there are no data proving that this is effective.9 Surgical seeks medical attention.
resection of the granulomatous mass can be helpful in relieving com- Cutaneous lesions are the most common manifestation of extra-
pressive symptoms caused by encroachment on vital structures. pulmonary blastomycosis; their appearance in a patient who has a
Mediastinal fibrosis should not be treated with an antifungal agent nonresolving pneumonia should lead to the consideration of
or with corticosteroids. Placement of stents in obstructed great vessels blastomycosis.
by an interventionalist who is experienced in the treatment of this rare
disease has proved extremely useful in providing symptomatic relief.12 Diagnosis
Patients who have pulmonary involvement as one manifestation of Blastomycosis is definitively diagnosed when the organism is grown in
disseminated disease should always receive antifungal therapy. Patients the laboratory.14 For pulmonary blastomycosis, sputum, BAL fluid and
who have mild to moderate symptoms can be treated with itracon- lung tissue are acceptable samples. B. dermatitidis takes several weeks
azole, 200 mg twice daily for a year. Patients who have severe symptoms to grow at room temperature in the mold form. Once growth occurs,
should be treated initially with lipid formulation amphotericin B, identification can be made quickly with the use of a commercially
3–5 mg/kg daily. available DNA probe that is highly specific for B. dermatitidis.
Prior to the growth of the organism, a preliminary diagnosis of
Blastomycosis pulmonary blastomycosis can often be made by examining sputum or
BAL fluid treated with potassium hydroxide or calcofluor white or a
cytologic preparation stained with Papanicolaou stain.17 The
Mycology and Epidemiology
The causative agent of blastomycosis is Blastomyces dermatitidis, a
dimorphic fungus that exists as a mold in the environment but con-
verts to a yeast form in tissues at 37 °C. The organism is found in North
America, Africa and the Middle East. Most cases are reported from
states that border the Mississippi River basin, the Canadian provinces
of Ontario and Manitoba, and areas bordering the St Lawrence Seaway.
There are occasional reports of cases that are associated with small
microfoci that exist outside the typical endemic areas.
The environmental niche for this organism appears to be soil and
decaying wood, especially along waterways. Outbreaks have been
traced back to outdoor activities, such as canoeing, camping and clear-
ing vegetation.13

Blastomycosis begins with inhalation of the conidia of B. dermatitidis Figure 33-4 Severe diffuse pneumonia with ARDS due to Blastomyces derma-
into the alveoli. The mold form converts to the yeast form in the lungs, titidis in a 56-year-old patient with no underlying illnesses.
Management
The Infectious Diseases Society of America guidelines for the manage-
ment of blastomycosis note that all patients with symptomatic pulmo-
nary blastomycosis should be treated with an antifungal agent.19 Even
those who have acute pulmonary blastomycosis that appears to be
resolving should be treated in order to decrease the risk for subsequent
extrapulmonary infection. Mild-to-moderate blastomycosis can be
treated with an azole agent; severe infection should be treated with an
amphotericin B formulation as initial therapy.
Most cases of pulmonary blastomycosis are treated with itracon-
azole, 200 mg once or twice daily.19 Second-line agents that can be used
for patients who do not tolerate itraconazole include high-dose fluco-
nazole, voriconazole and posaconazole.11,15 Fluconazole is not as effec-
tive as itraconazole for blastomycosis. Voriconazole is increasingly used
for patients who are intolerant of itraconazole; presumably posacon-
azole also could be used in those patients, but few data are available.
The echinocandins have no activity against B. dermatitidis and should
not be used.
Amphotericin B is reserved for those patients who have severe
pneumonia with B. dermatitidis. A lipid amphotericin B formulation,
3–5 mg/kg daily, is preferred, but amphotericin B deoxycholate,
0.7–1 mg/kg daily, can be used.19 Some physicians use adjunctive meth-
ylprednisolone for patients who have severe pulmonary infection and
ARDS.20 After several weeks, if the patient’s condition has improved,
step-down therapy to oral itraconazole, 200 mg twice daily, is recom-
mended. Most patients who have pulmonary blastomycosis should be
Figure 33-5 Mass-like lesion in a 47-year-old man who was thought to have lung
cancer until the biopsy revealed many granulomas and culture yielded Blastomy- treated for 6–12 months.
ces dermatitidis.
Coccidioidomycosis
Mycology and Epidemiology
Coccidioides is a dimorphic fungus that exists as a mold in the environ-
ment and as a spherule in vivo. It differs from the other dimorphic
fungi in that the dimorphism is not regulated by temperature. There
are two species: C. immitis refers to isolates from California and C.
posadasii to isolates from all other areas. Coccidioides species are gener-
ally found in the Lower Sonoran life zone, which is a desert environ-
ment that occurs in certain areas of South America, Central America
and the Southwestern United States.21
Most inhabitants of the endemic area are infected before they reach
adulthood. An increasing number of infections are reported in older
adults who move to these warm climates at retirement never having
been exposed to this organism previously. Catastrophic events, such as
earthquakes, have led to the occurrence of coccidioidomycosis in areas
beyond those normally seen, and environmental cycles of rain and
Figure 33-6 Lung biopsy from a 54-year-old man who had a left upper lobe drought in the desert are important in the natural history of Coccidi-
pulmonary infiltrate. Thick-walled, broad-based, budding yeasts are seen with the oides spp.21
periodic acid–Schiff stain.

organisms are large (8–10 µm), thick-walled yeasts that have a single The mold form of Coccidioides develops arthroconidia that are easily
broad-based bud; this specific morphology distinguishes B. dermatiti- dispersed and inhaled into the alveoli where the organism transforms
dis from most other yeasts (Figure 33-6). into the spherule form. Spherules are large (20–80 µm), thick-walled
If skin lesions are present in a patient with pulmonary infiltrates, structures that contain hundreds of endospores. The spherule ruptures
biopsy should be performed and may yield a diagnosis of blastomyco- when filled and releases many endospores, each of which is able to
sis without having to perform bronchoscopy. The yeasts can be visual- spread to form a new spherule.
ized in tissues with methenamine silver or PAS stains. The primary host defense against Coccidioides appears to be cell-
CF and ID antibody assays are neither sensitive nor specific for mediated immunity. Neutrophils are present in most lesions, but they
blastomycosis and are of little use for diagnosis. An enzyme immuno- cannot eliminate spherules. It is likely that many patients experience
assay that detects a polysaccharide cell wall antigen of B. dermatitidis silent hematogenous dissemination. Coccidioides species have the
in urine and serum is commercially available and is especially useful potential to reactivate years after the primary infection with the organ-
in patients who have severe pulmonary infection.18 There is a high ism. For still unexplained reasons, dark-skinned races, especially
degree of cross-reactivity between the antigen tests for H. capsulatum African Americans and Filipinos, are at higher risk for dissemination
and B. dermatitidis. and severe infection than light-skinned persons.21
Figure 33-7 CT scan of a previously healthy 42-year-old African American man

who developed cavitary pulmonary coccidioidomycosis following a brief visit to
Bakersfield, California several months before.
Figure 33-8 Lung biopsy obtained from a patient with HIV infection who devel-
Clinical Features oped fever, hypoxemia and diffuse pulmonary infiltrates. Several Coccidioides
spherules containing endospores are noted.
Most persons infected with Coccidioides species have no symptoms or
have mild symptoms suggesting a ‘flu-like’ illness.22 Patients with acute
coccidioidal pneumonia have fever, fatigue, myalgias, arthralgias, dry
cough, anterior chest pain and dyspnea. Erythema nodosum frequently
occurs, especially in women, and should raise the possibility of coc- Management
cidioidomycosis. Chest radiographs show patchy pneumonitis, with or The Infectious Diseases Society of America has developed guidelines
without hilar lymphadenopathy.23 In highly endemic areas, coccidioi- for the management of coccidioidomycosis.27 Most patients are treated
domycosis has been found to cause 20–25% of cases of community- with either fluconazole or itraconazole.28 There are few reports on the
acquired pneumonia.24 use of voriconazole and posaconazole, but increasingly these agents are
In patients who are immunocompromised, especially those with used in patients who are intolerant of or who have failed therapy with
AIDS, transplant recipients and those treated with anti-TNF agents, itraconazole or fluconazole.29 The echinocandins have no activity
and in those who had exposure to a large number of arthroconidia, against Coccidioides species and should not be used to treat
severe pneumonia with diffuse reticulonodular infiltrates and progres- coccidioidomycosis.
sion to ARDS can occur.21,25 Most patients with acute pulmonary coccidioidomycosis have a
Approximately 5–10% of patients have pulmonary complications benign course and do not require therapy with an antifungal agent.
following acute coccidioidal pneumonia. These include benign coc- However, patients who continue to have symptoms for 3–4 weeks with
cidioidomas, which are persistent asymptomatic pulmonary nodules, no improvement should be treated either with fluconazole, 400 mg
and solitary, thin-walled cavities that can persist for months to years. daily, or itraconazole, 200 mg twice daily, for 3–6 months.22 Patients
Although many cavities will resolve, hemoptysis or cavity rupture into who have underlying immunosuppression and patients who are
the pleural space, leading to development of a bronchopleural fistula African American or Filipino should be treated because of the high
can occur in some patients.22 Chronic progressive pneumonia is char- risk for dissemination in these groups.
acterized by thick-walled cavity formation, fibrosis, purulent sputum, Severe coccidioidal pneumonia should be treated initially with a
hemoptysis and dyspnea. This form of coccidioidomycosis occurs lipid formulation of amphotericin B, 3–5 mg/kg daily, but amphoteri-
mostly in those who are older and have chronic obstructive pulmonary cin B deoxycholate, 0.7–1.0 mg/kg daily, also could be used. After the
disease and/or diabetes mellitus (Figure 33-7). patient has had a clinical response, therapy can be stepped down to
Fewer than 1% of patients with symptomatic coccidioidomycosis itraconazole or fluconazole given for 1–2 years.
will develop symptoms of disseminated infection. Almost always, these Persisting thin-walled cavities can be observed, but surgical removal
patients are either dark-skinned or immunosuppressed. is reasonable for those that are adjacent to the pleura or that are noted
to enlarge.27 Chronic pulmonary coccidioidomycosis should be treated
Diagnosis with itraconazole, 200 mg twice daily, or fluconazole, 400 mg daily, for
Coccidioidomycosis is definitively diagnosed when the organism is 1–2 years. Persistent cavitary lesions that remain after adequate therapy
grown in culture from involved tissues or body fluids. Coccidioides should be evaluated for the feasibility of surgical removal.21
species grow as a white mold within a few days on most standard
media. It is important to warn laboratory personnel if coccidioidomy-
cosis is a possibility as the mold form is highly infectious. Coccidioides
Paracoccidioidomycosis
is classified as a bioterrorism agent and must be handled using bio-
safety level 3 precautions, which are not present in most laboratories. Mycology and Epidemiology
The large spherules are readily identified using KOH or calcofluor Paracoccidioidomycosis is caused by Paracoccidioides brasiliensis, a
white preparations on sputum or BAL fluid. Smears from skin lesions thermally dimorphic fungus that in the environment is a mold, and at
show the spherules as do standard hematoxylin and eosin-stained 37 °C it becomes a yeast with multiple buds. P. brasiliensis is endemic
tissue sections (Figure 33-8). This is extremely helpful in establishing in humid areas in several countries in Central and South America;
an early diagnosis while awaiting culture reports from a reference most cases are reported from Brazil.30 The environmental niche is
laboratory. presumably soil, and the disease is most often seen in middle-aged to
Serology is helpful in the diagnosis of coccidioidomycosis, espe- elderly men who live in rural areas. Paracoccidioidomycosis is unique
cially if a reference laboratory experienced in testing for coccidioido- among the endemic fungi in that there is a strong sexual preference
mycosis performs the tests.26 Acute coccidioidomycosis can be (male to female ratio 13 : 1). This imbalance can be partly explained by
diagnosed by finding IgM antibodies that are measured by an ID assay; environmental exposure, but may also possibly be related to inhibitory
IgG antibodies measured by CF appear later and persist longer. effects of estrogens on the growth of the organism.31
Figure 33-10 Smear from a lymph node aspirate showing the typical captain’s
wheel configuration of budding daughter cells on the mother cell of Paracoccidi-
oides brasiliensis. (Reproduced with permission from Kauffman, C.A.: Atlas of
fungal infections, 2nd ed. New York: Springer; 2007.)
Figure 33-9 Chest radiograph of an older man who had chronic paracoccidioi-
domycosis. (Reproduced with permission from Kauffman CA.: Atlas of fungal A presumptive diagnosis of paracoccidioidomycosis can be made if
infections, 2nd ed. New York: Springer; 2007.) the organism can be visualized in smears with calcofluor white or KOH
or in tissue sections stained with methenamine silver or PAS stains.
The yeast cells are large (10–30 µm) and thick-walled, and the budding
daughter cells have a narrow base and remain attached around the
Pathogenesis and Pathology circumference of the mother cell, creating a distinctive picture likened
to a ship’s steering wheel (Figure 33-10).
Paracoccidioidomycosis is acquired by inhalation of conidia of P. Serology is less useful than culture techniques. Several different
brasiliensis into the alveoli where they are phagocytized by macro- assays, including ID, counterimmunoelectrophoresis and CF, have
phages and convert to the yeast phase. It is likely that silent hematog- been used, but none is commercially available and the sensitivity and
enous dissemination occurs during most infections. Patients who have specificity of each test has not been firmly established.
deficient cellular immunity, especially those who have AIDS, have
widespread disseminated infection.32 Well-documented cases have Management
occurred years after patients have left the endemic area. Many authors
consider early childhood exposure the initial event and subsequent Azole agents have assumed the primary role for the treatment of para-
reactivation to be the cause of most cases of the chronic adult form of coccidioidomycosis. Itraconazole, 100 mg daily, for 6–12 months, is
paracoccidioidomycosis. recommended most often.34 Ketoconazole, 200–400 mg daily for 1
year, is still used because it is much less expensive than itraconazole;
Clinical Features however, it is not as efficacious and has more adverse effects than
itraconazole. Voriconazole appears to be efficacious and achieves supe-
Most cases of paracoccidioidomycosis occur in older men, are slowly rior levels in the CNS in those patients with disseminated infection.35
progressive and are characterized as the chronic or adult form of the Sulfonamides had been the treatment of choice for years, but are less
disease.30 Pulmonary involvement is prominent; symptoms include effective than the azoles and are used less frequently now.
fever, cough productive of purulent sputum, hemoptysis and dyspnea. For immunosuppressed patients who have widely disseminated P.
Chest radiographs reveal nodular, interstitial or cavitary lesions that brasiliensis infection, amphotericin B deoxycholate, 0.7–1.0 mg/kg
are more often in the middle and lower lung fields rather than the daily is recommended; there is little experience with lipid formulations
apices32 (Figure 33-9). Progressive fibrosis is frequently seen, and is a of amphotericin B. After a clinical response is achieved, step-down
major cause of death.33 Many patients with this form of paracoccidi- therapy with itraconazole is appropriate.
oidomycosis have ulcerative or nodular mucous membrane lesions,
primarily in the anterior nares and oral cavity, and papular, nodular,
or ulcerative skin lesions. Sporotrichosis
A less common form of paracoccidioidomycosis, the acute or juve-
nile form, also involves the lungs.32 The hallmark of this form of Mycology and Epidemiology
paracoccidioidomycosis is widespread involvement of liver, spleen, Sporothrix schenckii is a dimorphic fungus that is found throughout
lymph nodes, bone marrow, skin and lungs. Patients younger than 30 the world and that is a mold in the environment and a yeast at 37 °C.
years of age, as well as immunosuppressed patients, especially those S. schenckii encompasses a complex of at least six phylogenetically dif-
with AIDS, typically show this manifestation of paracoccidioidomyco- ferent species that vary in regard to geography and virulence.36 The
sis. The disease can progress rapidly and culminate with ARDS. organism is found in soil, decaying wood and sphagnum moss, and
outbreaks are described in association with exposure to contaminated
Diagnosis moss or timbers. Most cases are sporadic and related to exposure
Growing P. brasiliensis from samples taken from infected sites, such as during activities, such as landscaping, farming and gardening. The
sputum, BAL fluid or lung tissue from those with pulmonary infection, organism can also be acquired from animals, with most cases being
establishes the diagnosis. The organism grows slowly in the mold phase linked to infected cats. An outbreak in Rio de Janeiro associated with
at room temperature on Sabouraud’s agar, and conversion to the yeast transmission from infected cats has been ongoing since 1998 and has
phase is necessary for firm identification.30 infected over 2000 persons and many thousands of cats.37
However, pulmonary sporotrichosis is sufficiently rare that one must

be sure that the pulmonary infiltrate is not due to another etiology;
for this reason, most patients have sputum or BAL fluid cultures per-
formed as well.
Serology has not proved useful and is currently not available. Poly-
merase chain reaction (PCR) has been used for tissue specimens, but
is available only from reference laboratories.
Management
Most patients who have pulmonary sporotrichosis should be treated
initially with amphotericin B, preferably a lipid formulation, 3–5 mg/
kg daily, but amphotericin B deoxycholate, 0.7–1.0 mg/kg daily, can be
used.40,41 After improvement is noted, step-down therapy to itracon-
azole, 200 mg twice daily, for at least 1 year is recommended. If the
patient is not seriously ill, itraconazole, 200 mg twice daily is recom-
mended as initial therapy. Surgical removal of a single cavitary lesion
should be considered.40 Unfortunately, many patients have severe
underlying pulmonary disease and surgery is not an option.
Fluconazole failure rates for pulmonary sporotrichosis are high,
voriconazole has no activity and should not be used, and posaconazole,
although active in vitro, has been used rarely to treat sporotrichosis.
Drugs that are used for lymphocutaneous sporotrichosis, such as
potassium iodide and terbinafine, are ineffective and should not be
used for pulmonary sporotrichosis.
Figure 33-11 Chronic cavitary pulmonary sporotrichosis in a 54-year-old man

who had emphysema.
Penicilliosis
Pathogenesis and Pathology Mycology and Epidemiology
In contrast to the other dimorphic fungi, in which inhalation is the Talaromyces is a mold in the environment and a yeast in the tissues at
primary mode of acquisition, S. schenckii causes disease in almost all 37 °C. The yeast divides by septation and not budding in contrast to
cases by inoculation of the conidia through scratches or punctures most other dimorphic fungi. Talaromyces is endemic in rural areas in
from thorns, wood splinters or other sharp objects. Pulmonary sporo- most South Eastern Asian countries, including Thailand, Vietnam,
trichosis is uncommon and likely occurs when conidia are inhaled. The Laos and southern China. The environmental niche is presumably soil.
immune response to S. schenckii is a mixture of neutrophils and cell- Bamboo rats in these same areas are also frequently infected, but there
mediated immunity. Patients with cellular immune deficiencies, such is no evidence of transmission from rats to humans.42
as AIDS, or those treated with immunosuppressive drugs are at risk of
developing widespread dissemination, including pulmonary disease, Pathogenesis and Pathology
when infected with S. schenckii.38,39 Talaromyces is presumed to cause infection after the conidia are
inhaled into the alveoli. Pulmonary manifestations are usually silent
Clinical Features and hematogenous dissemination is the rule. The most important host
Sporotrichosis is primarily a localized lymphocutaneous infection and defense against this organism is cellular immunity. Healthy individuals
is discussed elsewhere (see Chapter 189). Pulmonary sporotrichosis is rarely have symptoms, but those who have deficient cellular immunity,
rare and almost always occurs in patients with underlying chronic especially persons with AIDS, develop disseminated infection.43
obstructive pulmonary disease (COPD) and often alcoholism.40 The
clinical picture is similar to tuberculosis or chronic cavitary histoplas- Clinical Features
mosis. Fever, night sweats, fatigue, cough with purulent sputum, Pulmonary manifestations of infection with Talaromyces are seen
hemoptysis and increasing dyspnea are noted in most patients. Chest almost entirely in patients who have widespread disseminated infec-
radiographs show apical infiltrates with thick-walled cavities (Figure tion. Fever, weight loss, lymphadenopathy, hepatosplenomegaly and
33-11). Rare cases of disseminated sporotrichosis in markedly immu- skin lesions are common presenting symptoms. Pulmonary symptoms
nosuppressed patients have diffuse pulmonary infiltrates associated other than dyspnea are uncommon. The chest radiograph usually
with dyspnea and hypoxemia. shows diffuse infiltrates.
Diagnosis Diagnosis
The diagnosis of sporotrichosis is based on growth of the organism The diagnosis of penicilliosis is established by growing the organism
from samples taken from involved tissues. The organism grows in days from a tissue sample or body fluids. Most patients will have a biopsy
to weeks on Sabouraud’s agar at room temperature as a mold with taken from a skin lesion, a lymph node or bone marrow, and not
conidia arranged in a distinctive bouquet pattern on thin hyphae. samples from the respiratory tract. The organism grows as a mold at
Seeing this allows for presumptive identification, but definitive identi- room temperature after a few weeks; production of red pigment on
fication requires conversion to the yeast phase at 35–37 °C. The yeasts Sabouraud’s agar allows a presumptive diagnosis before conversion to
are rarely seen in sputum or BAL fluid. They can be found in tissue the yeast phase is accomplished to confirm identification.
using methenamine silver or PAS stains, but are often difficult to Smears of body fluids or from a bone marrow aspirate can establish
visualize. an early diagnosis if the characteristic yeast form of Talaromyces is
If a patient has cutaneous lesions in addition to pulmonary disease, identified. The yeasts are oval to sausage-shaped and have a central
sampling a skin lesion is a simple way in which to make the diagnosis. septum, unlike other small yeasts, such as H. capsulatum.
Management mild-to-moderate illness, therapy can be initiated with itraconazole,

200 mg twice daily.44
Amphotericin B is recommended for those patients who have severe
illness; following a clinical response, step-down therapy with itracon-
azole, 200 mg twice daily, is appropriate.44 For patients who have References available online at expertconsult.com.
KEY REFERENCES
Aung A.K., Teh M.B., McGrath C., et al.: Pulmonary sporo- Kauffman C.A., Bustamante B., Chapman S.W., et al.: Clini- Vanittanakom N., Cooper C.R. Jr, Fisher M.C., et al.: Peni-
trichosis: case series and systematic analysis of literature cal practice guidelines for the management of sporotri- cillium marneffei infection and recent advances in the
on clinic-radiological patterns and management out- chosis: 2007 update by the Infectious Diseases Society of epidemiology and molecular biology aspects. Clin Micro-
comes. Med Mycol 2013; 51:534-544. America. Clin Infect Dis 2007; 45:1255-1265. biol Rev 2006; 19:95-110.
Barros M.B., Paes R., Schubach A.O.: Sporothrix schenckii Nguyen C., Barker B.M., Hoover S., et al.: Recent advances Wheat L.J., Conces D., Allen S.D., et al.: Pulmonary histo-
and sporotrichosis. Clin Microbiol Rev 2011; 24:633-654. in our understanding of the environmental, epidemio- plasmosis syndromes: recognition, diagnosis, and man-
Chapman S.W., Dismukes W.E., Proia L.A., et al.: Clinical logical, immunological, and clinical dimensions of coc- agement. Semin Respir Crit Care Med 2004; 25:129-144.
practice guidelines for the management of blastomycosis: cidioidomycosis. Clin Microbiol Rev 2013; 26:505-525. Wheat L.J., Freifeld A.G., Kleiman M.B., et al.: Clinical prac-
2008 update by the Infectious Diseases Society of Queiroz-Telles F., Escuissato D.L.: Pulmonary paracoccidi- tice guidelines for the management of patients with his-
America. Clin Infect Dis 2008; 46:1801-1812. oidomycosis. Semin Respir Crit Care Med 2011; toplasmosis: 2007 update by the Infectious Diseases
Galgiani J.N., Ampel N.M., Blair J.E., et al.: Coccidioidomy- 32:764-774. Society of America. Clin Infect Dis 2007; 45:807-825.
cosis. Clin Infect Dis 2005; 41:1217-1223. Saccente M., Woods G.L.: Clinical and laboratory update on
Hage C.A., Ribes J.A., Wengenack N.L., et al.: A multicenter blastomycosis. Clin Microbiol Rev 2010; 23:367-381.
evaluation of tests for diagnosis of histoplasmosis. Clin Smith J.A., Kauffman C.A.: Blastomycosis. Proc Am Thorac
Infect Dis 2011; 53:448-454. Soc 2010; 7:173-180.
Chapter 33 Fungal Pneumonias 299.e1
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3. Hage C.A., Bowyer S., Tarvin S.E., et al.: Recognition, 19. Chapman S.W., Dismukes W.E., Proia L.A., et al.: Clin- 35. Queiroz-Telles F., Goldani L.Z., Schlamm H.T., et al.:
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34
Management of the Infected Cystic
Fibrosis Patient
HEATHER STRAH | DANIEL ROSENBLUTH
KEY CONCEPTS testing will usually detect a significant decline from the patient’s base-
line measurements.
• An acute decline in lung function in persons with cystic fibrosis
generally represents a potentially reversible acute exacerbation
and should be treated aggressively.
Diagnosis
Diagnosis of a pulmonary exacerbation is usually made when a patient
• Antibiotic selection should be based upon sputum culture presents with a combination of some or all of the above-mentioned
results. signs and symptoms, in association with a decrease in their forced vital
• In patients who are chronically infected with Pseudomonas capacity (FVC) and/or forced expiratory volume in 1 second (FEV1).
aeruginosa two antipseudomonal antibiotics should be used to Spirometry is the best objective measure of a patient’s status and,
treat an exacerbation requiring parenteral therapy. during exacerbations, will usually demonstrate worsening airway
obstruction and a decline of at least 10%. A significant decline in FEV1
• As an infection control precaution, healthcare personnel should
assume all cystic fibrosis (CF) patients carry organisms that are even in the absence of worsening symptoms should result in intensified
transmissible and potentially harmful to other CF patients. therapy.
• Chronic inhaled antibiotic therapy may reduce exacerbation
and hospitalization rates, and improve lung function in individu-
Management Options
als with CF. Optimal management of the infected patient with CF requires the
identification of specific, often multiple, pathogens that infect the indi-
• Airway clearance methods, including bronchodilators, chest vidual patient. Early in life, infection with Staph. aureus and Hae-
physiotherapy, dornase alfa and hypertonic saline, are essential
mophilus influenzae is common. While oxacillin-sensitive and resistant
therapies for patients with CF.
Staph. aureus may persist, as patients age infections are predominantly
caused by gram-negative organisms, such as P. aeruginosa, Achromo-
bacter spp., Stenotrophomonas maltophilia and Burkholderia cepacia
complex. Infections with B. cepacia complex can be especially difficult
to treat, associated with an accelerated decline in lung function in some
Definition of the Problem patients, and with epidemic outbreaks at some CF centers. As this
The airways of persons with cystic fibrosis (CF) are chronically infected organism may not grow readily in culture, all respiratory samples from
with bacteria, usually Staphylococcus aureus and mucoid strains of patients with CF should be cultured on media specific for this organ-
Pseudomonas aeruginosa. Persistent infection and chronic inflamma- ism, in addition to the other organisms mentioned above. When
tion result in mucus hypersecretion, obstruction of airways and bron- applied to lower respiratory tract secretions, culture-independent
chiectasis which manifest clinically as cough, sputum production and methods may identify pathogens including anaerobes that are not
dyspnea. While symptoms progress slowly, patients may have an accel- typically associated with airway infection in CF. A loss in lower airway
erated, often reversible, decline associated with increased bacterial microbiome diversity is associated with increasing age and decreasing
burden in the airways. These episodes and their associated symptoms lung function.1 The significance of the wide diversity of these patho-
are referred to as a pulmonary exacerbation. Optimal management of gens, and their role in CF disease, remains to be determined.2
the infected CF patient necessitates strategies to combat both chronic
airways infection and exacerbations.
Typical Case BOX 34-1 SIGNS AND SYMPTOMS OF ACUTE

EXACERBATIONS OF CF-RELATED
Individuals with cystic fibrosis-related lung disease typically exhibit LUNG DISEASE
symptoms of chronic cough, sputum production and dyspnea. Pulmo-
nary exacerbations are usually characterized by increased cough and • Increase in cough and sputum production
sputum production, a change in the color or character of the sputum, • Change in the color or character of sputum
• Dyspnea and worsening exercise tolerance
dyspnea and worsening exercise tolerance. These exacerbations may be • Fatigue
accompanied by generalized fatigue, fevers, decreased appetite, weight • Fevers
loss and worsening glycemic control. Exacerbations may be highlighted • Decreased appetite
by massive hemoptysis, a true medical emergency (Box 34-1). • Weight loss
• Worsening glycemic control
Physical examination may demonstrate wheezes or crackles, acces- • Massive hemoptysis
sory muscle use, tachycardia, cyanosis and decreased oxyhemoglobin • New wheezes or crackles
saturation. Chest radiographs may be unchanged, or reveal new infil- • Use of accessory muscles of respiration
trates or evidence of increased mucus plugging on a background of • Tachycardia
• Cyanosis
chronic bronchiectatic changes. The onset of an exacerbation can be • New radiographic infiltrate
insidious and patients may not fully appreciate the magnitude of their • Decrease in FEV1
decline until questioned carefully. In these cases pulmonary function
300
Chapter 34 Management of the Infected Cystic Fibrosis Patient 301
with CF. This may be accomplished via traditional chest percussion

BOX 34-2 MANAGEMENT OF ACUTE and postural drainage or with the assistance of various devices such as
EXACERBATIONS OF CF-RELATED percussors, pneumatic compression vests, or handheld devices that
LUNG DISEASE provide oscillatory positive expiratory pressure to the airways.9
• Parenteral antimicrobial therapy based on respiratory culture results Dornase alfa (Pulmozyme®) degrades extracellular DNA which is
(typically two antipseudomonal agents) present in airway secretions of patients with CF. Daily inhalation of
• Enhanced airway clearance dornase alfa decreases the viscoelasticity of the CF sputum and has
• Bronchodilators been shown to improve lung function and decrease the need for par-
• Mucolytics
• Nutritional support enteral antibiotics.10 Additionally, inhalation of hypertonic (7%) saline
improves lung function and decreases exacerbation rates by restora-
tion of the airway surface liquid volume and increasing cough-
When treating acute exacerbations (Box 34-2), selection of specific mediated airway clearance. Other adjunctive therapies for the infected
antimicrobials should be guided by results of sputum culture. Though CF patient include regular exercise and aggressive nutritional support
routinely performed, results of susceptibility tests for P. aeruginosa do to address increased metabolic needs exhibited by many patients.
not correlate with clinical response. Synergy testing, even for multiply When administered to patients with CF who are chronically
resistant oraganisms, has no added benefit and is not recommended.3 infected with P. aeruginosa, azithromycin has been shown to improve
Mild exacerbations may sometimes be treated with oral and/or inhaled lung function and decrease exacerbations when compared to placebo.
antibiotics. Response to oral therapy should be closely monitored and In CF patients without a history of Pseudomonas, use of macrolide
if ineffective, a switch should be made to parenteral therapy. Severe antibiotics may still result in fewer pulmonary exacerbations but does
exacerbations should be treated parenterally, generally with two antip- not improve lung function.5,11 Routine screening for nontuberculous
seudomonal agents: usually a third- or fourth-generation cephalospo- mycobacteria (NTM) should be performed in patients on a chronic
rin or antipseudomonal penicillin, along with an aminoglycoside. macrolide antibiotic to avoid single-drug therapy for NTM and emer-
Therapy should be modified based on culture results. The antipseudo- gence of macrolide-resistant organisms. Between 13% and 23% of CF
monal penicillins or carbapenems may be more active against Achro- patients are infected with NTM, most commonly Mycobacterium
mobacter spp., and carbapenems may have increased activity against B. avium complex and M. abscessus.12 M. abscessus may be associated with
cepacia. Infections with Stenotrophomonas maltophilia are sometimes transmission between patients.13,14 Some patients acquire NTM
best treated with trimethoprim–sulfamethoxazole, minocycline or without a clear effect on clinical status, determining the need for treat-
ticarcillin–clavulanate. Since patients with CF often exhibit high ment may be problematic, as treatment can be difficult and eradication
volumes of distribution and increased antimicrobial drug clearance, may not be possible. Patients who are repeatedly culture-positive, do
higher doses of antibiotics should be utilized. Aminoglycosides admin- not respond to courses of routine antibacterial therapy, have evidence
istered on a once-daily dosing schedule demonstrate efficacy equal to of new cavitary disease on imaging, or changes on computed tomog-
three-times daily dosing with reduced drug toxicity. Peak and trough raphy (CT) scan compatible with mycobacterial infection, should be
drug levels should be monitored.3 Typically, 2–3 weeks of parenteral considered for specific therapy.
therapy is required. Optimal management of infected CF patients requires an effective
Therapy of the chronically infected CF patient may include inhaled infection control strategy to prevent patient-to-patient transmission of
suppressive antibiotic therapy. In clinical trials, cycled (28 days on fol- virulent organisms. This strategy should include both the inpatient
lowed by 28 days off medication) twice-daily administration of a and outpatient settings and conform to local infection control guide-
preservative-free formulation of tobramycin (TOBI®) was shown to lines. Frequent handwashing by patients and providers is extremely
improve lung function and decrease hospitalizations in patients colo- important. In the outpatient setting, rooms and high-touch areas
nized with P. aeruginosa.4,5 Inhaled aztreonam lysine (Cayston®) has should be cleaned frequently. All patients should be treated equally and
been shown to have equivalent long-term results as tobramycin.7 as though respiratory secretions contain organisms that are potentially
Because declines in lung function or worsened symptoms are observed infectious to other CF patients. Healthcare personnel should imple-
during months off medication, some CF centers choose to alternate ment contact precautions for all CF patients in the inpatient and out-
between tobramycin and aztreonam in 28-day cycles. Patients are often patient setting. Pulmonary function labs should take special precautions
treated with other inhaled antibiotics such as colistin; however, the use to avoid transmission of infectious agents by installing HEPA filters or
of these agents is less well studied. A study of oral cephalexin prophy- allowing 30 minutes between patients with cystic fibrosis.15
laxis in infants and young children with cystic fibrosis failed to dem-
onstrate a clinical benefit. Inhaled antipseudomonal antibiotics are Conclusion
effective when used to eradicate new onset Pseudomonas infection. A Management of the infected patient with cystic fibrosis requires strate-
study comparing four treatment regimens using inhaled tobramycin gies to address both the chronic infection and acute exacerbations of
with or without ciprofloxacin administered in either a cycled schedule infection. This necessitates routine symptomatic and physiologic eval-
or in response to sputum cultures, found that eradication rates and uation of patients, along with frequent microbiologic surveillance of
pulmonary exacerbation-free periods were similar for the four groups.8 airway secretions. These should guide aggressive but appropriate use
Inhaled aztreonam has also been shown to be effective for eradication of oral, inhaled and parenteral antibiotics, along with adjunctive thera-
of new Pseudomonas infection. More recently, CFTR modulators iva- pies such as bronchodilators, mucolytics, airway clearance, pulmonary
caftor and, possibly, ivacaftor/lumicaftor have been shown to delay rehabilitation and nutritional support. Finally, an effective infection
acquisition of P. aeruginosa and in some cases, may help to eradicate control policy should be in place to prevent patient-to-patient trans-
the infection in patients treated with these new medications.6 mission of potentially harmful organisms.
In addition to antimicrobial therapy, airway clearance is an essen-
tial component in the management of the infected airways of patients References available online at expertconsult.com.
KEY REFERENCES
Assael B.M., Pressler T., Bilton D., et al.: Inhaled aztreonam Binder A.M., Adjemian J., Olivier K.N., et al.: Epidemiology Clement A., Tamalet A., Leroux E., et al.: Long term
lysine vs. inhaled tobramycin in cystic fibrosis: a com- of nontuberculous mycobacterial infections and associ- effects of azithromycin in patients with cystic fibrosis: a
parative efficacy trial. J Cystic Fibrosis 2013; 12(2): ated chronic macrolide use among persons with cystic double-blind, placebo controlled trial. Thorax 2006;
130-134. fibrosis. Am J Respir Crit Care Med 2013; 188(7):807-812. 61(10):895-902.
Cox M.J., Allgaier M., Taylor B., et al.: Airway microbiota Mogayzel P.J. Jr, Naureckas E.T., Robinson K.A., et al.: Update. Infect Control Hosp Epidemiol 2014; 35(Suppl
and pathogen abundance in age-stratified cystic fibrosis Cystic fibrosis pulmonary guidelines. Chronic medica- 1):S1-S67.
patients. PLoS ONE 2010; 5(6):e11044. tions for maintenance of lung health. Am J Respir Crit Surette M.G.: The cystic fibrosis lung microbiome. Ann Am
Flume P.A., Mogayzel P.J. Jr, Robinson K.A., et al.: Cystic Care Med 2013; 187(7):680-689. Thorac Soc 2014; (Suppl. 1):S61-S65.
fibrosis pulmonary guidelines: treatment of pulmonary Quan J.M., Tiddens H.A., Sy J.P., et al.: A two-year ran-
exacerbations. Am J Resp Crit Care Med 2009; 180(9):802- domized, placebo-controlled trial of dornase alfa in
808. young patients with cystic fibrosis with mild lung func-
Flume P.A., Robinson K.A., O’Sullivan B.P., et al.: tion abnormalities. J Pediatrics 2001; 139(6):813-820.
Cystic fibrosis pulmonary guidelines: airway clearance Saiman L.M.D., Siegel J.D., LiPuma J.J., et al.: Infection
therapies. Respir Care 2009; 54(4):522-537. prevention and control guideline for cystic fibrosis: 2013
Chapter 34 Management of the Infected Cystic Fibrosis Patient 302.e1
REFERENCES
1. Cox M.J., Allgaier M., Taylor B., et al.: Airway micro- 7. Assael B.M., Pressler T., Bilton D., et al.: Inhaled aztreo- 12. Binder A.M., Adjemian J., Olivier K.N., et al.: Epidemi-
biota and pathogen abundance in age-stratified cystic nam lysine vs. inhaled tobramycin in cystic fibrosis: a ology of nontuberculous mycobacterial infections and
fibrosis patients. PLoS ONE 2010; 5(6):e11044. comparative efficacy trial. J Cystic Fibrosis 2013; associated chronic macrolide use among persons with
2. Surette M.G.: The cystic fibrosis lung microbiome. Ann 12(2):130-134. cystic fibrosis. Am J Respir Crit Care Med 2013;
Am Thorac Soc 2014; 11(Suppl. 1):S61-S65. 8. Treggiari M.M., Retsch-Bogart G., Mayer-Hamblett N., 188(7):807-812.
3. Flume P.A., Mogayzel P.J. Jr, Robinson K.A., et al.: et al.: Comparative efficacy and safety of 4 randomized 13. Aitken M.L., Limaye A., Pottinger P., et al.: Respiratory
Cystic fibrosis pulmonary guidelines: treatment of pul- regimens to treat early Pseudomonas aeruginosa infec- outbreak of Mycobacterium abscessus subspecies mas-
monary exacerbations. Am J Resp Crit Care Med 2009; tion in children with cystic fibrosis. Arch Pediatr Adolesc siliense in a lung transplant and cystic fibrosis center.
180(9):802-808. Med 2011; 165(9):847-856. Am J Respir Crit Care Med 2012; 185(2):231-232.
4. Flume P.A., O’Sullivan B.P., Robinson K.A., et al.: Cystic 9. Flume P.A., Robinson K.A., O’Sullivan B.P., et al.: 14. Bryant J.M., Harris S.R., Parkhill J., et al.: Whole-
fibrosis pulmonary guidelines: chronic medications for Cystic fibrosis pulmonary guidelines: airway clearance genome sequencing to establish relapse or re-infection
maintenance of lung health. Am J Resp Crit Care Med therapies. Respir Care 2009; 54(4):522-537. with Mycobacterium tuberculosis: a retrospective obser-
2007; 176(10):957-969. 10. Quan J.M., Tiddens H.A., Sy J.P., et al.: A two-year ran- vational study. Lancet Resp Med 2013; 1(10):786-792.
5. Mogayzel P.J. Jr, Naureckas E.T., Robinson K.A., et al.: domized, placebo-controlled trial of dornase alfa 15. Saiman L.M.D., Siegel J.D., LiPuma J.J., et al.: Infection
Cystic fibrosis pulmonary guidelines. Chronic medica- in young patients with cystic fibrosis with mild lung prevention and control guideline for cystic fibrosis:
tions for maintenance of lung health. Am J Respir Crit function abnormalities. J Pediatrics 2001; 139(6):813- 2013 Update. Infect Control Hosp Epidemiol 2014;
Care Med 2013; 187(7):680-689. 820. 35(Suppl. 1):S1-S67.
6. Heltshe S.L., Mayer-Hamblett N., et al.: Pseudomonas 11. Clement A., Tamalet A., Leroux E., et al.: Long term
aeruginosa in Cystic Fibrosis Patients with G551D- effects of azithromycin in patients with cystic fibrosis:
CFTR Treated With Ivacaftor. Clin Infect Dis 2015; a double-blind, placebo controlled trial. Thorax 2006;
60(5):703-712. 61(10):895-902.
PRACTICE The Respiratory System
POINT
7 Investigation of Pleural
Discharge/Fluid
SAMI HRAIECH | BENOIT D’JOURNO | LAURENT PAPAZIAN
Introduction precisely. Ultrasonography can also detect loculated effusions. Ultra-

sound guidance reduces the incidence of iatrogenic pneumothorax
Parapneumonic effusion (PPE) complicates approximately 40% of following thoracocentesis. Computed tomography (CT) scanning is
bacterial pneumonias with an increasing incidence. Early antimicro- recommended if the diagnosis is doubtful, to detect abnormalities
bial therapy usually permits effective treatment of small uncompli- associated with or causing the effusion or to differentiate between
cated PPE. However, in a few cases of patients late in the course of their an empyema and a parenchymal abscess. CT scanning is also useful
pneumonia or when receiving inadequate antimicrobial therapy, the to help management decisions about drainage (Figures PP7-1 and
persistent spread of bacteria into the pleural space leads to complicated PP7-2).
PPE including thoracic empyema, in which mortality can reach 20%.
Fluid investigation and imaging are crucial to guide the treatment of
such a disease and avoid complications.
Pleural Fluid Analysis
Pleural fluid sampling is recommended in all patients with a pleural
Pathophysiology effusion >10 mm depth on ultrasound when associated with a pneu-
monia. Thoracocentesis is the simplest procedure to collect pleural
The development of empyema associated with pneumonia is a progres- fluid. The procedure should be performed under sterile conditions and
sive process and has been classified into three stages on the basis of the the site of puncture can be localized by percussion or ultrasonography
natural course of the disease. and usually corresponds to the intersection between the midaxillary
In the early exudative stage (uncomplicated PPE – UPPE), there is line and the 6th to 7th intercostal space. Local anesthesia should be
fluid movement into the pleural space due to increased capillary vas-
cular permeability and production of inflammatory mediators facili-
tating fluid entry into the pleural cavity. At this stage, pleural fluid
contains proteins and neutrophils and is free of bacteria. This exudate
usually disappears with pneumonia treatment and does not lead to
pleural sequelae.
If appropriate treatment is not initiated, UPPE evolves towards
complicated PPE which is a fibrinopurulent stage with increasing fluid
accumulation and bacterial invasion across the damaged endothelium.
Neutrophil recruitment and lysis in the pleural space increase the
lactate dehydrogenase (LDH) concentration and promote the anaero-
bic metabolism of glucose with local acidosis. Fibrin deposition pro-
motes the formation of membranes within the fluid.
The third stage corresponds to empyema and is defined by the
presence of pus in the pleural fluid. Bacteria may be observed on a
Gram stain but a positive culture is not required for the diagnosis. A
solid fibrous pleural peel begins to form which can wrap the lung
preventing re-expansion, impairing lung function and creating a per-
sistent pleural space favoring the infectious process.
a
Microbiology
Streptococcal species and Staphylococcus aureus are the most frequently
encountered bacteria in community-acquired PPE. Enterobacteriaceae
are often seen in patients with co-morbidities. Anaerobes are increas-
ingly identified especially because of development of DNA-based
identification techniques. The causative pathogens of empyema are
aerobes in about 40% of cases, anaerobes in up to 30% and multiple
organisms in around 30%. In hospital-acquired PPE, Staph. aureus
infections, including methicillin-resistant strains, are preponderant.
Gram-negative such as Escherichia coli, Enterobacter spp. and Pseudo-
monas aeruginosa are responsible for the remainder as well as anaer-
obes and polymicrobial infections.
Imaging
b
Posteroanterior and lateral chest radiographs are generally sufficient
to diagnose PPE. Chest radiographs may detect a pleural abnormality Figure PP7-1 Nosocomial pneumonia complicated by left lung abscess and
when pleural fluid exceeds 50 mL. However, ultrasonography is used empyema in an immunocompromised patient. (a) Chest radiography; (b) CT scan.
to confirm and estimate the amount of liquid in pleural space more White arrow indicates empyema.
303
Loculated
pleural effusion
Rib
Lung Needle tip
Pleural
effusion
Lung Liver
Diaphragm
a b
Figure PP7-2 Ultrasound contribution in (a) thoracocentesis/drainage guidance; (b) diagnosis of loculated PPE.
<3.4 mmol/L are also accurate markers to indicate the need for chest
TABLE Pleural Fluid Analyses at Different Stages of drain insertion.
PP7-1 Parapneumonic Effusion Small uncomplicated PPE could be treated with antibiotics alone.
Poor clinical progress with antibiotics alone should lead to repeat
Parapneumonic Parapneumonic
pleural fluid sampling and chest tube drainage. An algorithm for the
Characteristics Effusion Effusion Empyema management of PPE is proposed in Figure PP7-3.
Appearance Slightly turbid Cloudy Pus CHEST TUBE DRAINAGE
pH ≥7.2 <7.2 NA Traditionally, chest tube drainage is performed using large bore (>28
F) tubes however small bore catheters (10–14 F) may be as efficient
Glucose, mmol/L >3.4 <3.4 NA
and more comfortable for the patient but require regular flushing to
LDH, IU/L <700 >1000 NA avoid catheter blockage. The safe zone for puncture corresponds to the
Ratio pleural : serum >0.6 >0.6 NA intersection between the mammary and midaxillary line at the 4th to
LDH 5th intercostal space. The chest tube is introduced within the pleural
space and directed posteriorly towards the lower lobes. Aspiration of
Ratio pleural : serum >0.5 >0.5 NA
protein pleural fluid with a closed suction system is recommended at a depres-
sion range from −30 to −100 cmH2O. Complications of chest tube
PMN leukocyte <15 000 >25 000 NA insertion include pain, pneumothorax and hemorrhage. Ultrasound
count, cells/µL
(or CT scan) guided insertion may decrease such complications and
Gram stain and Negative May be positive May be improve the efficacy of drainage.
culture positive
LDH, lactate dehydrogenase; NA, not applicable; PMN, polymorphonuclear. PLEURAL FIBRINOLYTICS
There is no evidence to support the routine use of fibrinolytics for all
PPE. Fibrinolytic therapy may be considered in patients with loculated
administered to the upper side of the lower rib of the intercostal space pleural effusions or ineffective effusion drainage because it may prevent
until aspiration of pleural fluid into the syringe. the need for surgical intervention. Treatments such as DNAse mole-
Appearance, biochemical analysis (including pH, LDH, glucose, cules are under investigation.
proteins), bacteriology and cytology should be systematically per-
formed. Pleural fluid may be inoculated directly into bottle culture THORACIC SURGERY
medium for aerobic and anaerobic bacteria, and on demand for myco- In the setting of inappropriate pleural drainage, persistent pleural
bacteria, fungi and viruses. Pleural fluid for pH analysis should be sepsis, multiple loculations or empyema, surgical options should be
collected anaerobically in a heparinized blood gas syringe and then considered promptly. This includes thoracoscopy, video-assisted tho-
measured using a blood gas analyzer. racic surgery (VATS) and thoracotomy. VATS is increasingly used as
Depending on the appearance, pH, glucose, LDH and bacteriologic first-line therapy. If VATS is unable to provide adequate pleural inves-
findings, the pleural effusion can be classified into three stages, as sum- tigation, thoracotomy will be required. Decortication is the optimal
marized in Table PP7-1. treatment, but this requires major surgery and cannot be performed
in the most debilitated patients. It consists of stripping the visceral
Management of Pleural Effusion pleura allowing the lung to fully re-expand into the parietal pleura. It
Empiric antibiotic treatment should include agents active against is indicated in uncontrolled pleural sepsis, or sometimes in restrictive
anaerobic organisms. Penicillins, cephalosporins and metronidazole ventilatory failure.
penetrate well into the pleural space; aminoglycosides may be inacti-
vated due to the acidity of pleural fluid. Conclusion
Frankly purulent fluid should receive prompt pleural drainage. The Early diagnosis and management of pleural infections associated with
presence of organisms identified on direct examination or culture pneumonia remains the key to successful treatment. All patients with
should also lead to pleural fluid evacuation. Patients with a loculated pneumonia should be screened to detect the presence of pleural effu-
pleural collection or with an air–fluid level or pleural thickening sion. Observation is usually adequate for small unseptated free effu-
should receive early chest drainage. A pH <7.2 is a strong indication sions. If a complicated PPE is suspected or if sepsis persists,
for pleural drainage. Pleural fluid LDH >1000 UI/L and glucose level thoracocentesis should be performed and the analysis of pleural fluid
Practice Point 7 Investigation of Pleural Discharge/Fluid 305
may guide the therapeutic approach. Imaging such as ultrasound or

Practical management of pleural effusion with timing for pleural
examination in patients presenting with pneumonia CT scanning may be useful to facilitate the diagnosis of doubtful forms
or to guide sampling or chest tube drainage. Surgical options should
be proposed in the presence of empyema or in ineffective pleural
Pleural effusion associated with pneumonia drainage. Decortication is a more invasive procedure which should be
performed only in patients with uncontrolled pleural sepsis or unex-
pandable lung disease.
Chest X-ray, ultrasound
Minimal, Non-minimal or
uncomplicated PPE loculated effusion
Antibiotics, observation
Non-resolving
Resolution
sepsis
Thoracocentesis (ultrasound-guided)
Appearance, bacteriology, biochemistry,

cytology
Small to medium
Pus (empyema) Complicated PPE
uncomplicated PPE
Chest tube drainage • Large bore ?

• Small bore ?
• Fibrinolytics ?
• DNAse ?
96 hours improvement
Yes No
Surgery: CT scanning:
Remove tube ?
VATS ? Tube position ?
Thoracotomy ? Residual collection ?
Figure PP7-3 Practical management of pleural effusion with timing for pleural
examination in patients presenting with pneumonia. PPE, parapneumonic effu-
sion; VATS, video-assisted thoracic surgery.
Practice Point 7 Investigation of Pleural Discharge/Fluid 305.e1
FURTHER READING
Davies H.E., Davies R.J., Davies C.W., BTS Pleural Disease Janda S., Swiston J.: Intrapleural fibrinolytic therapy for ment of pleural fluid pH and glucose. Am J Respir Crit
Guideline Group: Management of pleural infection in treatment of adult parapneumonic effusions and empy- Care Med 2008; 178(5):483-490.
adults: British Thoracic Society Pleural Disease Guideline emas: a systematic review and meta-analysis. Chest 2012; Sahn A.: Diagnosis and management of parapneumonic
2010. Thorax 2010; 65(2):41-53. 142(2):401-411. effusions and empyema. Clin Infect Dis 2007; 45(11):
Horsley A., Jones L., White J., et al.: Efficacy and complica- Rahman N.M., Mishra E.K., Davies H.E., et al.: Clinically 1480-1486.
tions of small-bore, wire-guided chest drains. Chest 2006; important factors influencing the diagnostic measure-
130(6):1857-1863.
POINT
8 When to Use Corticosteroids

in Noncentral Nervous
System Tuberculosis
GUY THWAITES
Introduction of cervical or inguinal tuberculous lymphadenitis, despite painful node

enlargement occurring in one-third of patients after the start of treat-
The use of corticosteroids in the management of noncentral nervous ment. Extrapolation of the effect of corticosteroids on mediastinal
system tuberculosis is supported by much anecdote but few controlled adenopathy suggests they might be of benefit, and many physicians use
trial data. It has long been observed that the symptoms of tuberculosis them in patients with painful, swollen nodes that are threatening to
often worsen after the start of treatment, a phenomenon believed to rupture.
be caused by an exaggerated inflammatory response to dead or dying A summary of the evidence and treatment recommendations for
mycobacteria. It is hypothesized that corticosteroids suppress this all forms of noncentral nervous system tuberculosis are presented in
response and thereby improve outcome. This hypothesis has never Table PP8-1. Data from a large, well-conducted study published in
been confirmed in any form of the disease, but remains sufficiently 1983 strike an important note of caution: patients with bacteria resis-
attractive to induce many physicians to start adjunctive corticoste- tant to two or more drugs who received prednisolone responded to
roids, particularly for the most severe forms of tuberculosis. treatment less well than those in the control group and bacteria could
be cultured from the sputum for longer. Therefore, the risk of drug
Evidence of Efficacy resistance should be carefully assessed before adjunctive corticoste-
The best evidence for a beneficial effect of corticosteroids in noncentral roids are considered for any form of tuberculosis.
nervous system disease exists for pericardial tuberculosis and is derived
from two trials performed 25 years ago in South Africa. Use of Adjunctive Corticosteroids in
• The first trial compared prednisolone with placebo in the treat- Tuberculosis and HIV Infection
ment of 143 patients with active constrictive tuberculous peri-
carditis and showed that prednisolone increased the rate of The safety and efficacy of adjunctive corticosteroids in patients with
clinical improvement, reduced the risk of death, and reduced the tuberculosis and HIV infection are unproven. HIV-infected adults with
need for pericardectomy. pericardial tuberculosis probably should receive prednisolone, but for
• The second trial studied 243 patients with tuberculous pericar- all other forms of HIV-associated tuberculosis (with the exception of
cerebral tuberculosis) there are no grounds to recommend their
dial effusion and compared open complete surgical drainage
with percutaneous pericardiocentesis as required; in addition, routine use.
patients were randomized to receive either prednisolone or A randomized controlled trial of prednisolone for HIV-infected
placebo. Prednisolone reduced the risk of death from pericarditis adults with pleural tuberculosis in Uganda suggested the prednisolone-
and the need for repeat pericardiocentesis, but did not reduce treated group recovered faster but suffered from a significantly
the incidence of constrictive pericarditis. After 10 years of increased incidence of Kaposi’s sarcoma. Peripheral blood CD4+ T-cell
follow-up, prednisolone was associated with a significant reduc- counts and viral loads increased in both treatment arms, but without
tion in the risk of death from pericarditis of either form. any significant difference between them. Another study from the same
Treatment guidelines published in the UK and the USA recommend center of the immunoadjuvant properties of prednisolone in HIV-
adjunctive prednisolone for the treatment of HIV-uninfected patients infected adults with pulmonary tuberculosis again observed a transient
with pericardial tuberculosis. There is less certainty for HIV-infected rise in peripheral blood HIV viral load in the prednisolone group that
patients, although a small trial in HIV-infected adults from Zimbabwe fell when the drug was discontinued. Unlike the previous study, there
suggested that 6 weeks of adjunctive prednisolone reduced the risk of was no observed increase in Kaposi’s sarcoma or other opportunistic
death from effusive tuberculous pericarditis. infections in those treated with prednisolone, although they suffered
There is little convincing evidence that adjunctive corticosteroids more fluid retention, hypertension and hyperglycemia than the con-
benefit patients with other forms of noncentral nervous system tuber- trols. The study was not powered to detect a difference in clinical
culosis, although a recent systematic review and meta-analysis of outcome and few data regarding clinical and radiographic progress are
trials performed in all disease types found corticosteroids reduced given. However, the authors report a faster time to sputum sterility in
mortality by 17% – a consistent effect across all tuberculosis types, the prednisolone group, an intriguing observation that replicates the
including pulmonary disease. Advocates of corticosteroids will also findings of studies performed 40 years previously in HIV-uninfected
point out that there is little evidence they do harm and appear to speed patients with pulmonary tuberculosis.
symptom resolution. There is evidence that corticosteroids speed early One controlled trial of corticosteroids in HIV-positive patients with
symptom resolution in primary tuberculosis and tuberculous pleuritis TB who were on antiretroviral therapy and developed paradoxical
and peritonitis, although they do not appear to reduce the fibrotic immune reconstitution inflammatory syndrome (IRIS) showed
complications of these diseases. Corticosteroids may also reduce improvement in symptoms and reduction in need for hospitalization
mediastinal lymph node enlargement in primary tuberculosis and in the steroid-treated group (see also Chapters 95 and 96).
decrease the local obstructive complications. Unfortunately, there have
been no controlled trials of the use of corticosteroids in the treatment Further reading available online at expertconsult.com.
306
Practice Point 8 When to Use Corticosteroids in Noncentral Nervous System Tuberculosis 307
TABLE Summary of Treatment Recommendations and Evidence for Adjunctive Corticosteroids in Noncentral
PP8-1 Nervous System Tuberculosis
Corticosteroids
Recommended by
Corticosteroids the Infectious Suggested
Type of Recommended by Diseases Society Corticosteroid
Tuberculosis NICE UK (2016)* of America (2003)† Regimens Summary of the Evidence from RCTs
Pulmonary No No Twelve RCTs of variable size and quality suggest

corticosteroids may speed resolution of symptoms and
chest radiograph changes, but have no beneficial effect
on long-term fibrotic complications or death. May be
indicated in those with severe lung disease
Pericardial Yes Yes Prednisolone Three RCTs (one involving HIV-infected adults) observed
60 mg weeks 1–4 prednisolone was associated with faster resolution of
30 mg weeks 5–8 effusions and lower mortality. Progression to constrictive
15 mg weeks 9–10 disease not affected
5 mg week 11. Then stop
Pleural No No Four RCTs suggest prednisolone resulted in faster resolution

of symptoms and effusion, but no impact on development
of fibrosis, restrictive lung disease or death
Primary No No Two RCTs suggest prednisolone may reduce mass effects of

mediastinal lymphadenopathy, although one trial used
very high doses (5 mg/kg) to achieve the effect
Lymph node No No No evidence from controlled trials
Bone and joint No No No evidence from controlled trials
Peritoneal No No One RCT of 47 patients, using prednisolone 30 mg q24 h for

3 months, reported no difference in symptom resolution
between groups and a nonsignificant reduction in chronic
fibrotic complications in the prednisolone group
Genitourinary No No No evidence from controlled trials

Miliary No No One RCT from China involving 55 patients (14 of whom also
had meningeal disease) reported fewer deaths in the
prednisolone group (not statistically significant)
*Internal Clinical Guidelines Team (UK): Tuberculosis: Prevention, Diagnosis, Management and Service Organisation. National Institute for Health and Care Excellence
(UK); 2016. Available: http://www.ncbi.nlm.nih.gov/pubmed/26820019.
†
Infectious Diseases Society of America, et al.: Treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167(4):603–662.
RCT, Randomized controlled trial.
Practice Point 8 When to Use Corticosteroids in Noncentral Nervous System Tuberculosis 307.e1
FURTHER READING
American Thoracic Society/Centers for Disease Control and Elliott A.M., Luzze H., Quigley M.A., et al.: A randomised, tuberculosis-associated immune reconstitution inflam-
Prevention/Infectious Diseases Society of America: Treat- double blind, placebo controlled trial of the use of pred- matory syndrome. AIDS 2010; 24:2381-2390.
ment of tuberculosis. Am J Respir Crit Care Med 2003; nisolone as an adjunct to treatment in HIV-1 associated Internal Clinical Guidelines Team (UK): Tuberculosis: Pre-
167(4):603-662. pleural tuberculosis. J Infect Dis 2004; 190(5):869- vention, Diagnosis, Management and Service Organisation.
Critchley J.A., Young F., Orton L., et al.: Corticosteroids for 878. National Institute for Health and Care Excellence (UK);
prevention of mortality in people with tuberculosis: a Majanja-Kizza H., Jones-Lopez E., Okwera A., et al.: Immu- 2016. Available: http://www.ncbi.nlm.nih.gov/pubmed/
systematic review and meta-analysis. Lancet Infect Dis noadjuvant prednisolone therapy for HIV-associated 26820019.
2013; 3:223-237. tuberculosis: a phase 2 clinical trial in Uganda. J Infect Dis Strang J.I.G., Nunn A.J., Johnson D.A., et al.: Management
Dooley D.P., Carpenter J.L., Rademacher S.: Adjunctive cor- 2005; 191(6):856-865. of tuberculous constrictive pericarditis and tuberculous
ticosteroid therapy for tuberculosis: a critical appraisal of Meintjes G., Wilkinson R.J., Morroni C., et al.: Randomized pericardial effusion in Transkei: results at 10 years
the literature. Clin Infect Dis 1997; 25:872-887. placebo-controlled trial of prednisone for paradoxical follow-up. Q J Med 2004; 97:525-535.
POINT
9 How to Manage a Patient

on Anti-TB Therapy with
Abnormal Liver Enzymes
L. PETER ORMEROD | THOMAS C. BAILEY
Introduction normal with symptoms of hepatotoxicity or five times normal in

the absence of symptoms, then the medications should be stopped.
The incidence of toxic hepatitis due to antituberculosis drugs depends Such patients are best managed in consultation with an expert experi-
on the drug itself, and risk factors such as age, underlying liver disease enced in the treatment of TB patients. Immediate management
and other medical comorbidities, concomitant administration of other depends on the severity of the patient’s illness (Figure PP9-2). If the
hepatotoxic drugs and daily use of alcohol. Hepatic reactions to anti- patient is not unwell and had a form of tuberculosis that is noninfec-
tuberculosis drugs were reported in 4% of cases treated with isoniazid/ tious, no treatment is needed until liver enzymes reach pre-treatment
rifampin with or without pyrazinamide in a UK trial, and in 3% in a level. If the patient is unwell or the sputum is smear-positive within 2
large clinical series. The overall rate of adverse reactions increases with weeks of commencing a rifampin/isoniazid-based regimen, some form
age. Liver tests, particularly serum bilirubin and transaminases – aspar- of drug treatment needs to be given until liver function returns to
tate aminotransferase (AST) and alanine aminotransferase (ALT) – pre-treatment levels. In such cases a regimen of a fluoroquinolone
should be checked before treatment. Pre-treatment liver function (moxifloxacin or levofloxacin), ethambutol, and an injectable agent
testing is not advised for children receiving isoniazid or rifampin for (amikacin, streptomycin, or capreomycin) with appropriate renal, ves-
treatment of latent infection because of the very low incidence of tibular and visual checks is advised unless there are clinical contrain-
reactions. dications, or drug resistance to these agents is known or suspected.
Once liver tests return to pre-treatment level, rifampin 600 mg/day
Monitoring Liver Tests can be initiated, and the injectable agent discontinued. If the original
Regular monitoring of liver tests is not required for those with no pattern of liver dysfunction was cholestatic, with the bilirubin elevated
evidence of pre-existing liver disease, normal liver enzymes pre- out of proportion to transaminases, it is best to avoid reintroduction
treatment, who do not consume alcohol, take other hepatotoxic medi- of rifampin. Such patients will sometimes tolerate rifabutin 300 mg/
cations, do not have HIV disease, are not pregnant or are less than 3 daily. The patient’s clinical condition should be monitored daily,
months postpartum, have no language barriers that preclude accurate together with liver tests at least weekly, until they have stabilized for at
clinical monitoring, and do not have a history of prior TB-drug intol- least 2 weeks, at which time monitoring can occur monthly.
erance. Some experts recommend regular monitoring of liver tests in For patients with asymptomatic increases in transaminases to
patients over 35 years of age. Patients and their providers should always greater than three times normal on standard RIPE therapy (rifampin,
be informed of possible side effects and the indications for stopping isoniazid, pyrazinamide, ethambutol), if the patient is significantly ill
medication and seeking medical advice, preferably in writing in their from tuberculosis or is infectious, pyrazinamide can be discontinued,
native language. Liver tests need to be repeated (and treatment stopped) and the patient monitored clinically daily and with liver tests weekly.
if fever, nausea, vomiting, jaundice, abdominal discomfort or malaise Alternatively, isoniazid can be discontinued, and rifampin, pyrazin-
occur. If the transaminases are elevated in such circumstances, viro- amide and ethambutol continued. If the patient is not particularly ill
logic tests to exclude coexistent viral hepatitis (A, B, C or E) should be and is noninfectious, all TB medications can be discontinued until AST
considered. and ALT are at pre-treatment level, and then TB medications reintro-
duced sequentially, initially with rifampin and ethambutol for a week,
Management of Elevated Tests of followed by the addition of a fluoroquinolone, or isoniazid.
Liver Function Management of Further Reactions
Modest elevations of hepatic transaminases (AST/ALT) are not uncom-
mon in tuberculosis patients even without known liver disease. They Following Reintroduction of Therapy
are also to be expected in patients with chronic liver disease, including If there is a further reaction during the reintroduction, the offending
alcoholism, chronic active hepatitis and cirrhosis. Monitoring of such drug should be excluded and an alternative regimen constructed. If
patients should be as in Figure PP9-1. If the pre-treatment AST/ALT pyrazinamide is the offending drug, then a regimen of rifampin and
is more than twice normal, but less than three times normal, liver isoniazid for 9 months can be used, supplemented by ethambutol until
function should be monitored weekly for 2 weeks then every 2 weeks susceptibilities are known, assuming the patient’s isolate is not drug-
until normal. If the pre-treatment AST/ALT is less than twice normal, resistant. For other drugs an alternative regimen may need to be
liver function should be repeated at 2 weeks. If the transaminase levels decided on the advice of an experienced TB physician.
have fallen further, repeat tests are only needed for symptoms. However,
if the AST or ALT rise to three or more times normal, management Further reading available online at expertconsult.com.
should be as in Figure PP9-1.
For patients initiated on standard RIPE therapy (rifampin, isonia-
zid, pyrazinamide, ethambutol), if the AST/ALT rises to three times
308
Practice Point 9 How to Manage a Patient on Anti-TB Therapy with Abnormal Liver Enzymes 309
Management of elevated liver function tests if pre-treatment tests are abnormal
Eliminate ETOH and other hepatotoxic agents
< 3x nl ≥ 3x nl > 5x nl
Begin INH, RIF, PZA, EMB Asymptomatic Symptomatic Symptomatic
Begin INH, RIF, EMB Begin RIF, EMB,

Asymptomatic
or RIF, PZA, EMB FQN consult
Liver tests increase Begin FQN, EMB,

Liver tests weekly Liver tests weekly
or symptoms develop IA consult
Hold meds until liver tests Stable or improved Liver tests increase to
return to pre-treatment x 2 weeks > 5x nl or symptoms
level or symptoms resolve develop
Liver tests monthly

Hold meds until liver
Begin RIF, EMB, tests return to
FQN consult pre-treatment level or
symptoms resolve
Liver tests increase

Liver tests weekly
to > 5x nl
INH, isoniazid; RIF, rifampin; PZA, pyrazinamide; EMB, ethambutol; FQN,
fluoroquinolone (moxifloxacin or levofloxacin); IA, injectable agent
(amikacin, streptomycin, or capreomycin; nl, normal levels)
Figure PP9-1 Management of elevated liver function tests if pre-treatment tests are abnormal. (Derived from www.heartlandntbc.org/products/management_of_the
_active_tb_patient_at_risk_of_hepatotoxicity.pdf and from Hepatotoxicity of antituberculosis therapy, Am J Respir Crit Care Med 2006; 174:935-952.)
Management of patients if tuberculosis drugs are stopped because

AST/ALT >5 times normal, or bilirubin elevated, or symptoms of toxicity
Is the patient clinically unwell or sputum microscopy positive?
Yes No
1. Consider a fluoroquinolone, Monitor liver tests

ethambutol, and an injectable weekly until they reach
agent (amikacin, streptomycin, pre-treatment level
or capreomycin)
2. Monitor liver tests weekly until
they return to pre-treatment level
then,
Figure PP9-2 Management of patients if tuberculosis drugs are stopped because 3. Discontinue injectable agent and
AST/ALT >5 times normal, or bilirubin elevated, or symptoms of toxicity. (Derived initiate rifampin (or rifabutin if the
from www.heartlandntbc.org/products/management_of_the_active_tb_patient_at_ reaction was cholestatic)
risk_of_hepatotoxicity.pdf and from Hepatotoxicity of antituberculosis therapy, Am
J Respir Crit Care Med 2006; 174:935-952.)
Practice Point 9 How to Manage a Patient on Anti-TB Therapy with Abnormal Liver Enzymes 309.e1
FURTHER READING
American Thoracic Society: Hepatotoxicity of antitubercu- Davies P.D.O., Girling D.J., Grange J.M.: Tuberculosis. In: Lal S., Singhal S.N., Burley D.M., et al.: Effect of rifampicin
losis therapy. An official ATS Statement. Am J Respir Crit Weatherall D.J., Ledingham J.G.G., Warrell D.J., eds. and isoniazid on liver function. BMJ 1972; 148-150.
Care Med 2006; 174:935-952. Oxford textbook of medicine. 3rd ed. Oxford: Oxford Ormerod L.P.: Rifampicin and isoniazid prophylactic
American Thoracic Society and Centers for Disease Control Medical Publications; 1995:638-661. therapy for tuberculosis. Arch Dis Childh 1998; 78:169-
and Prevention: Targeted tuberculin testing and treat- Horne N.W.: Modern drug treatment of tuberculosis. 7th ed. 171.
ment of latent tuberculosis infection. Am J Resp Crit Care London: Chest Heart and Stroke Association; 1990:32-35. Ormerod L.P., Horsfield N.: Frequency and type of reactions
Med 2000; 161(4 Pt 2):S221-S247. Joint Tuberculosis Committee of the British Thoracic to antituberculosis drugs. Tuberc Lung Dis 1995; 77:37-42.
British Thoracic Association: A controlled trial of six Society: Control and prevention of tuberculosis in the Ormerod L.P., Skinner C., Wales J.: Hepatotoxicity of anti-
months chemotherapy in pulmonary tuberculosis. First United Kingdom: Code of Practice 2000. Thorax 2000; tuberculosis drugs. Thorax 1996; 51:111-113.
report: results during chemotherapy. Br J Dis Chest 1981; 55:887-901.
75:141-153.
POINT
10 Use of Antibiotics for Exacerbations

of COPD
JOHANNES M.A. DANIELS | MENNO M. VAN DER EERDEN
Background Pathophysiology
Chronic obstructive pulmonary disease (COPD) is characterized by The increase of airway inflammation during exacerbations, which ulti-
chronic progressive and irreversible airflow limitation. COPD consti- mately causes increase of airflow limitation and symptoms, can be
tutes a major worldwide health burden. Airflow limitation in COPD is triggered by the following factors:
caused by an abnormal chronic inflammatory response to noxious • respiratory viruses
particles or gases and subsequent airway remodeling (Figure PP10-1). • bacteria
The primary cause of COPD is tobacco smoke, but the burning of • persistent smoking
biomass fuels is also considered to be a risk factor. A key feature of • common pollutants (nitrogen dioxide, particulates, sulfur
COPD is the occurrence of acute exacerbations (AECOPD), defined dioxide, ozone)
as a sudden worsening of symptoms beyond the usual day-to-day • allergens
variation. Exacerbations of COPD are associated with reduced quality • inadequate COPD management or non-compliance.
of life and accelerated decline in lung function and represent a sub-
stantial socioeconomic burden. Therefore, prevention and adequate VIRUSES
management of exacerbations should be an integral part of the com- AECOPDs are frequently triggered by viral upper respiratory tract
prehensive care of COPD patients. infections such as the common cold. Viruses are involved in 30–50%
of AECOPD. The etiology of respiratory viruses is supported by obser-
vational studies and in vivo experiments showing characteristic symp-
toms and lung function changes following low-dose viral infection.
The most commonly identified viruses are:
The vicious circle of inflammation, impaired mucociliary clearance • rhinovirus
and airway remodeling • respiratory syncytial virus
• coronavirus
Smoking
• influenza A and B virus
or other noxious • parainfluenza virus
gases • adenovirus.
BACTERIA
The role of bacteria as triggers for exacerbations of COPD is contro-
versial because bacteria such as nontypeable Haemophilus influenzae
Airway and Streptococcus pneumoniae often colonize the upper airways and
inflammation can contaminate sputum samples. Furthermore, in about 30% of stable
patients the lower airways are colonized with the same bacteria that
can be found during exacerbations. As a result, isolation of a potential
pathogen from sputum during an exacerbation is not necessarily proof
of bacterial infection. The following bacteria are associated with COPD
Airway remodeling Impaired
and lung function mucociliary
exacerbations:
decline clearance • Haemophilus influenzae
• Streptococcus pneumoniae
• Moraxella catarrhalis
• Staphylococcus aureus
• Pseudomonas spp.
Increased Bacterial • Enterobacteriaceae.
inflammation colonization
Differential Diagnosis
A typical AECOPD is characterized by progressive dyspnea, wheezing,
cough and increased sputum volume and/or purulence, preceded by
Triggers an upper respiratory tract infection. If the symptoms are less typical,
Exacerbations viruses, it is important to consider an alternative diagnosis:
bacteria, etc. • pneumonia
• cardiac disease (congestive heart failure, acute coronary syn-
Figure PP10-1 The vicious circle of inflammation, impaired mucociliary clear-
drome, arrhythmia)
ance and airway remodeling that underlies COPD and the possible role of airway • exacerbation of bronchiectasis
bacterial colonization and acute exacerbations in disease progression. • pulmonary embolism
310
Practice Point 10 Use of Antibiotics for Exacerbations of COPD 311
• central airway obstruction (e.g. centrally located lung cancer) especially in ICU patients. Recent studies have shown that biomarkers
• pleural effusion such as procalcitonin and C-reactive protein might play a role in the
• pneumothorax. selection of patients for antibiotic therapy. Biomarker-guided antibi-
otic therapy might yield equal results compared to selection by classic
Assessment and Diagnosis criteria, while facilitating a significant reduction in the use of antibiot-
The assessment of a patient with suspected AECOPD depends on the ics. More evidence is required, however, before biomarker selection can
severity of symptoms and whether the patient is seen in an inpatient be implemented.
or outpatient setting. Careful history taking is important to establish The choice of antibiotics can be based on previously isolated poten-
whether the symptoms are typical for AECOPD. Physical examination tial bacterial pathogens from sputum samples or, in case of empirical
should at least include vital signs, auscultation of the chest, central treatment, on local resistance patterns. The large majority of compara-
venous pressure and inspection of the extremities (pitting edema, signs tive antibiotics trials were negative, which proves that newer antibiotics
of thrombosis). If history taking and physical examination are consis- such as quinolones are not superior to older antibiotics such as
tent with AECOPD and the patient is not severely ill, one can proceed β-lactam antibiotics or tetracyclines.
with outpatient treatment. Hospital assessment is required in case of:
• severe underlying COPD Prevention of Exacerbations
• marked increase in symptoms Treatment with inhaled fluticasone and salmeterol, or inhaled tiotro-
• symptoms and signs not consistent with AECOPD pium seems to result in a reduction of exacerbations. Guidelines cur-
• signs of respiratory failure rently recommend a combination of long-acting beta-2-agonists and
• failure to respond to initial management inhalation corticosteroids in patients with an FEV1 <50% predicted
• important co-morbidities. and in the presence of two or more exacerbations in the previous year.
Hospital assessment should include history taking, physical examina- The role of maintenance macrolide antibiotics has recently been
tion, basic hematology and serum biochemistry, chest radiograph, investigated in COPD. Results show that maintenance treatment with
electrocardiogram and sputum culture. Computed tomography (CT) three times a week 500 mg of azithromycin reduces the exacerbation
pulmonary angiography should be considered, since the incidence of rate in patients with the frequent exacerbator phenotype (>2 exacerba-
pulmonary embolism in patients hospitalized with AECOPD can be as tions per year). However, the effects of long-term treatment with
high as 25%. macrolides (>1 year) on antibiotic resistance should be carefully
monitored.
Management Influenza vaccination reduces the risk for admission for pneumo-
The cornerstone in the management of AECOPD is treatment with a nia or influenza infection in the elderly and reduces mortality. There-
short course of systemic corticosteroids (e.g. prednisolone 30–60 mg). fore influenza vaccination can be recommended in patients with
Treatment with systemic corticosteroids has a beneficial effect on clin- COPD.
ical resolution and recovery of lung function. Recent evidence shows
that a short course (5 days) and a long course (14 days) of prednisolone Conclusion
are equally effective and that intravenous use is not superior to oral The role of antibiotics in the management of COPD exacerbations
administration. remains controversial and should be reserved for the severely ill, those
The role of antibiotics in the treatment of AECOPD is more con- with signs of infection or patients not responding to initial medical
troversial. Classic criteria for administration of antibiotics are increased management.
sputum purulence and other signs of infection, such as fever. Further-
more, antibiotics seem to be more effective in the more severely ill, Further reading available online at expertconsult.com.
Practice Point 10 Use of Antibiotics for Exacerbations of COPD 311.e1
FURTHER READING
Albert R.K., Connett J., Bailey W.C., et al.: COPD Clinical Koutsokera A., Stolz D., Loukides S., et al.: Systemic bio- Uzun S., Djamin R.S., Kluytmans J.A., et al.: Azithromycin
Research Network: Azithromycin for prevention of markers in exacerbations of COPD: the evolving clinical maintenance treatment in patients with frequent exacer-
exacerbations of COPD. N Engl J Med 2011; 365:689- challenge. Chest 2012; 141:396-405. bations of chronic obstructive pulmonary disease
698. Leuppi J.D., Shuetz P., Bingisser R.: Short-term vs conven- (COLUMBUS): a randomised, double-blind, placebo-
Daniels J.M., Schoorl M., Snijders D., et al.: Procalcitonin tional glucocorticoid therapy in acute exacerbations of controlled trial. Lancet Respir Med 2014; 2:361-368.
versus C-reactive protein as predictive markers of chronic obstructive pulmonary disease. JAMA 2013; Vestbo J.: Global strategy for the diagnosis, management,
response to antibiotic therapy in acute exacerbations of 309:2223-2231. and prevention of chronic obstructive pulmonary
COPD. Chest 2010; 138:1108-1115. Rizkallah J., Man S.F., Sin D.D.: Prevalence of pulmonary disease. Global Initiative for Chronic Obstructive Lung
Decramer M., Janssens W., Miravitlles M.: Chronic obstruc- embolism in acute exacerbations of COPD: a systematic Disease. Available: www.goldcopd.org/.
tive pulmonary disease. Lancet 2012; 379:1341-1351. review and metaanalysis. Chest 2009; 135:786-793.
The Gastrointestinal System
35
Orocervical Infection
ROBERT C. READ
KEY CONCEPTS secretions, with the majority being obligate anaerobes and Streptococ-
cus spp., organized into biofilms.5
• Most bacterial infections of the oropharynx and neck spaces Dental caries is idiosyncratically polymicrobial with Streptococcus
arise from dental infections. mutans being the only species consistently associated. In contrast, gin-
• Dental disease can be prevented by diet and oral hygiene and givitis has characteristic microbial specificity; the normal flora of the
is a product of the industrial age. periodontium (i.e. Streptococcus sanguis and Actinomyces spp.) is
replaced by anaerobic gram-negative rods, notably Prevotella interme-
• Neck space infections are usually polymicrobial and include dia. With chronic gingivitis there is ulceration of the mucosa, loss of
anaerobic flora.
attachment of periodontal tissue, loss of enamel and necrosis of the
• Neck space infections usually require drainage as well as anti- dental pulp, and an increase in complexity of microbial flora with a
microbial therapy. preponderance of anaerobic gram-negative rods and a number of viru-
lence factors including IgA protease.6 Host factors with associated
• Actinomycosis, nocardiosis, Lemierre’s syndrome and lung
abscesses are all examples of very difficult infections that are periodontitis include psychosocial stress, diet, smoking, alcoholism
odontogenic. and intercurrent disease.7
The usual cause of deep-seated odontogenic infection is necrosis of
• Actinomycosis and nocardiosis require prolonged antimicrobial the pulp of the tooth, followed by bacterial invasion through the pulp
therapy. chamber and into the deeper tissues.8 If a pulp abscess is allowed
• Parotitis is usually viral (mumps or enterovirus). to progress, infection will spread toward the nearest cortical plate
(Figure 35-1).
• Infections of the salivary glands are usually bacterial and associ-
ated with diabetes.
Prevention
• Infection of the esophagus is increasingly uncommon in the era Prevention of dental and periodontal infections includes interference
of highly active antiretroviral therapy (HAART).
with transmission and suppression of Strep. mutans colonization once
it has occurred. There is a strong correlation between maternal salivary
Strep. mutans infection and the presence of this organism in children.
Introduction
Infections of the oral cavity and neck include dental and periodontal
infections, deep fascial space infections of the neck, nondental oral Spread of dental infection
infections, including ulcerative and gangrenous stomatitis, and infec-
tions of the salivary glands. Infections of the esophagus mostly occur
in the context of severe underlying disease.
1 Vestibular abscess
Dental and Periodontal Infections

2 Buccal space
Epidemiology
6
Dental caries is the commonest infectious disease in humans. It starts
in infancy and is most noticeable on the chewing surfaces of the molar 3 Palatal abscess
teeth. The likelihood of dental caries is increased by high sugar intake, 2 3
poor oral hygiene and any factors that reduce salivary flow – notably
drugs (e.g. antidepressants).1 Microbiome analysis of calcified plaque 4 Sublingual space 1
samples from ancient teeth has revealed dramatic shifts since the
Buccinator
industrial revolution.2 muscle
1
Periodontal disease, including gingivitis, is related to poor oral 5 Submandibular space

4
hygiene and increasing age. Increased incidence of periodontal disease 2
is also evident in diabetics and during hormonal disturbances, includ- Platysma
ing puberty and pregnancy. Plaque contains mainly Streptococcus spp. 6 Maxillary sinus muscle
and Actinomyces spp., which probably generate an early gingivitis, 5
leading ultimately to periodontitis.3 These processes occur over many

years with incremental destruction of periodontal tissue.4 Mylohyoid muscle
Pathogenesis and Pathology Figure 35-1 Spread of dental infection. A spreading tooth abscess will encroach
upon the nearest cortical plate and its subsequent spread depends on the rela
The indigenous oral flora includes a large number of aerobic and tionship of that site to muscle attachment. (Adapted from Peterson L.J. In: Cum-
anaerobic bacteria and varies by site within the oral cavity. There are mings C.W., ed. Otolaryngology – head and neck surgery II, 2nd ed. St Louis. MO:
of the order of 1011 micro-organisms per gram wet weight of oral Mosby Yearbook; 1993:1199-1215.)
312
Chapter 35 Orocervical Infection 313
Figure 35-3 Buccal space abscess originating from right lower molar infection.
The buccal space lies between the buccinator muscle and the overlying skin and
fascia. (Courtesy of Professor I. Brook.)
Figure 35-2 Painful vestibular abscess. (Courtesy of Professor I. Brook.)
Acquisition of Strep. mutans by infants has been prevented by aggres-

sive treatment of Strep. mutans infection in mothers.9 Existing infec-
tions can be suppressed by regular cleaning with agents that include
fluoride and antimicrobial substances such as chlorhexidine. Peri-
odontal disease can be prevented by good oral hygiene and regular
rinsing with chlorhexidine. Clinical trials of vaccines to prevent peri-
odontitis have been conducted but vaccination has not yet entered Figure 35-4 Submandibular abscess originating from an infection of the 2nd
current recommended practice.10 molar tooth. (Courtesy of University of Sheffield School of Dentistry, UK.)
Clinical Features
Subgingival dental caries is asymptomatic, but destruction of enamel sufficiently pronounced to lift the tongue. This space is involved if the
results in invasion of the pulp with subsequent necrosis, eventually infected tooth apex giving rise to the disease is superior to the insertion
leading to a periapical abscess. The tooth becomes sensitive to tem- of the mylohyoid (e.g. premolars and first molars).
perature and pressure once the enamel is penetrated, and toothache The submandibular space lies between the mylohyoid muscle and
results. the skin. It becomes involved if the apex of the infected tooth is inferior
In simple gingivitis there is usually discoloration of the gum margin to the insertion of the mylohyoid muscle (e.g. third molar). Clinically,
with occasional bleeding after brushing of the teeth. There may be infection in this space causes extraoral swelling (unlike sublingual
halitosis. If gingivitis is allowed to become chronic there may be space infections) that begins at the inferior lateral border of the man-
destruction of periodontal tissue with loosening of the teeth. This may dible and extends medially to the digastric area. Occasionally the
be relatively asymptomatic or the patient may have itchy gums, tem- abscess may point spontaneously and rupture (Figure 35-4).
perature sensitivity and halitosis. Ludwig’s angina refers to a severe cellulitis of the tissue of the floor
of the mouth with involvement of the submandibular and sublingual
Complications spaces (Figure 35-5). The source of infection is almost always the
Dental pulp infections can lead to involvement of the maxillary and second and third mandibular molars. If the infection is allowed to
mandibular spaces (see Figure 35-1). Spread of infection from maxil- continue there may be local lymphadenitis, systemic sepsis and exten-
lary (upper) teeth most commonly leads to vestibular abscesses (Figure sion of the disease to involve deep cervical fascia, with a cellulitis that
35-2). Erosion of canine pulp abscesses can lead to canine space extends from the clavicle to the superficial tissues of the face. Other
abscesses if the abscess points above the insertion of the levator labii potential complications include aspiration and mediastinitis. The
superioris. This results in swelling lateral to the nose, which usually disease is almost always polymicrobial, including α-hemolytic strep-
obliterates the nasolabial fold. Buccal space abscesses can result when tococci and anaerobes such as Peptostreptococcus spp., Prevotella mela-
pulp abscesses of the molar teeth erode above or below the attachment ninogenica and Fusobacterium nucleatum.11
of the buccinator muscle; these point below the zygomatic arch and Very rarely, spread of infection from maxillary teeth may cause
above the inferior border of the mandible (Figure 35-3). orbital cellulitis or cavernous sinus thrombosis (see Chapter 21). The
When infection spreads from mandibular (lower) teeth, the com- latter is distinguished by toxemia, venous obstruction within the eye
monest result is again vestibular abscess. Deeper abscesses may point and orbital tissues (Figure 35-6), involvement of the III, IV and VI
into the sublingual and submandibular spaces. The sublingual space cranial nerves and meningismus.
lies underneath the oral mucosa and above the mylohyoid muscle (see
Figure 35-1). Posteriorly, it communicates with the submandibular Management
space. Infection within the sublingual space results in swelling of the Treatment of dentoalveolar infections includes elimination of the dis-
floor of the mouth, which may spread to involve both sides and be eased pulp and deep periodontal scaling or tooth extraction. Any
314 SECTION 2 Syndromes by Body System: The Gastrointestinal System
Deep Cervical Space Infection

Infections of the lateral pharyngeal space, the retropharyngeal space
and the prevertebral space are uncommon but life-threatening prob-
lems. The lateral pharyngeal space is funnel-shaped, with its base at
the sphenoid bone at the base of the skull and its apex at the hyoid
bone. It is bounded by the medial pterygoid muscle laterally and the
superior pharyngeal constrictor medially. Posteromedially it extends
to the prevertebral fascia and communicates with the retropharyngeal
space. The carotid sheath and cranial nerves are within the posterior
compartment of the space. The retropharyngeal space lies posterome-
a dial to the lateral pharyngeal space, between the superior constrictor
muscle and the alar portion of the prevertebral fascia. Superiorly, it
extends from the skull base of the pharyngeal tubercle down to the
level of C7 where the superior pharyngeal muscle and the prevertebral
fascia fuse.8
Unlike the lateral pharyngeal space it has few contents apart from
lymph nodes, but its importance as a site of infection relates to its
proximity to the airway and to the contents of the superior mediasti-
num. The prevertebral space extends from the skull base inferiorly to
the diaphragm. It is bounded by the two layers of prevertebral fascia:
the alar and prevertebral layers.
b
Figure 35-5 Ludwig’s angina. (a) This patient had painful cellulitis within the Epidemiology and Pathogenesis
submandibular and sublingual spaces. (b) Brawny edema was present within the Parapharyngeal infections can complicate peritonsillar abscess (see
floor of the mouth, pushing the tongue upwards. (Courtesy of University of Shef-
field School of Dentistry, UK.)
Chapter 25), but a larger proportion of infections are odontogenic or
secondary to intravenous drug abuse. Rarer sources include parotitis,
otitis and mastoiditis. The incidence of parapharyngeal infection has
declined sharply in the antibiotic era and such infections now form
less than 30% of all deep cervical infections.11,12
Infections of the retropharyngeal and prevertebral spaces most
commonly result from lymphatic spread of infection in the pharynx
or sinuses. Retropharyngeal infections are therefore commonest in
children, mainly because retropharyngeal lymph nodes are more
numerous.13 The bacteriology of deep cervical space infections reflects
the microbial flora of the originating source. Thus, infections arising
from the pharynx are often caused by Streptococcus pyogenes, whereas
odontogenic infections are polymicrobial and include Strep. mutans
and anaerobic pathogens such as F. nucleatum, P. melaninogenica,
Peptostreptococcus spp., Eikenella corrodens and Actinomyces spp.
Clinical Features
The characteristic feature of lateral pharyngeal space infection is severe
Figure 35-6 Cavernous sinus thrombosis. A patient who displays evidence of
trismus, which results from involvement of the pterygoid muscle and
severe orbital swelling caused by obstruction of orbital veins is shown. In this other muscles of mastication. There is also swelling of the lateral pha-
patient, the originating focus was infection of soft tissues of the nose. (Courtesy ryngeal wall, which pushes the tonsil toward the midline. Occasionally
of University of Sheffield School of Dentistry, UK.) there is lateral neck swelling below the angle of the mandible. The
disease can be confused with peritonsillar abscess, although the latter
should not produce trismus. The patient experiences fever, painful
dentoalveolar abscess present should be surgically drained. If drainage swallowing and pain that occasionally radiates to the ear. The infection
is not complete, antibiotic therapy is appropriate. Treatment of peri- tends to be severe and progresses rapidly. Posterior extension of the
odontal disease includes appropriate debridement and short-term process into the carotid sheath can result in suppurative jugular
antimicrobial therapy with oral metronidazole 400 mg q8h or oral thrombophlebitis, carotid artery erosion or interference with cranial
phenoxymethylpenicillin 500 mg q6h. Periodontal and vestibular nerves IX–XII. There is hyperacute sepsis, with rigors and high fever.
abscesses should be treated by drainage. There may be pain and swelling below the mandible, marked swelling
Treatment of maxillary and submandibular space infections should of the lateral pharyngeal wall, torticollis and neck rigidity. There may
always be by surgical drainage of pus. Ludwig’s angina is a life- be metastatic abscesses within the brain, lungs and bone. The major
threatening condition and the first aim of treatment is protection of organism associated with Lemierre’s syndrome (thrombophlebitis of
the airway, if necessary by emergency intubation or occasionally tra- the internal jugular vein secondary to oropharyngeal infection) is
cheostomy. Intravenous antibiotics should be administered. Benzyl- Fusobacterium necrophorum, which is usually obtained from blood
penicillin 1.2 g q4h plus metronidazole 400 mg q8h or clindamycin cultures, but may require several days of anaerobic culture to grow.
450 mg q8h are appropriate. Patients who have retropharyngeal abscess may present with fever
Management of cavernous sinus thrombosis is by surgical decom- and rigors that usually follow on from a streptococcal pharyngitis, but
pression and high-dose intravenous antibiotics, the choice of which is often there is no history of sore throat.13 A child with a retropharyngeal
influenced by whether the originating focus is dental or within soft abscess may be withdrawn and irritable. Adults may complain of
tissues. sore throat, dysphagia, neck pain and dyspnea. The neck may be
hyperextended, and there may be drooling and stridor. Examination Lateral pharyngeal and retropharyngeal abscesses can be drained
of the throat by indirect laryngoscopy may reveal bulging of the pos- fairly easily; extensive surgery should be unnecessary if infections are
terior pharyngeal wall. Potential complications include upper airway treated promptly and high-dose intravenous antibiotics are used.
obstruction as a result of anterior displacement of the posterior pha- Appropriate intravenous antibiotics include penicillin 1.2–1.8 g q3h
ryngeal wall into the oropharynx, and spontaneous rupture of the plus clindamycin 300–600 mg q8h or metronidazole 400 mg q8h, plus
abscess with aspiration pneumonia (which may complicate attempted ceftriaxone 2 g q12h. Alternatives include a carbapenem (e.g. imipe-
insertion of an endotracheal tube). Other potential complications nem or meropenem), or the combination of a penicillin (e.g. ticarcil-
include purulent pleural effusion, pericardial effusion and posterosu- lin) and a β-lactamase inhibitor (e.g. clavulanate). Antimicrobial
perior mediastinitis.14 therapy can abort abscess formation if administered at an early stage
Patients with AIDS, particularly intravenous drug users, have a of the infection.
higher incidence of deep neck infections, most commonly caused by
Staphylococcus aureus, which is often methicillin resistant. In contrast
to immunocompetent patients, there is often no leukocytosis.15 Dia- Cervical Necrotizing Fasciitis
betics are also at increased risk of deep neck infections, and in addition
to Staph. aureus, gram-negative organisms, notably Klebsiella spp., Cervical necrotizing fasciitis is a rare and extremely dangerous com-
may be isolated from these patients.12 plication of odontogenic and deep cervical space infection. The disease
is characterized by involvement of more than one neck space (usually
Diagnosis bilaterally) and contiguously spreading necrosis of connective tissue,
with cellulitis that extends below the hyoid bone to the chest wall, onto
If lateral pharyngeal space infection is suspected, the diagnosis is best the face and into the mediastinum. Most cases are odontogenic, par-
confirmed by magnetic resonance imaging (MRI) or computed ticularly after dental abscesses, but some cases follow on from tonsillar
tomography (CT) scanning. Plain radiographs are usually unhelpful. abscess or from surgical trauma to the oropharynx. Almost all cases
In contrast, a retropharyngeal space abscess can be diagnosed by a are polymicrobial, often with a single aerobic isolate (e.g. Streptococcus
lateral radiograph of the neck (Figure 35-7). The average width of the spp.) plus two or more anaerobes (mostly P. melaninogenica and F.
prevertebral soft tissue should be no more than 7 mm (average nucleatum), although any of the oral anaerobes can be involved.17
3.5 mm) at C2 and no more than 20 mm (average 14 mm) at C6.16 The typical clinical presentation is usually with dental pain and
The major clinical differential diagnosis of retropharyngeal abscess submandibular swelling over a few days, followed by rapid evolution
includes cervical osteomyelitis and meningitis. The latter can usually of fasciitis, which is extremely tender on palpation and usually associ-
be discounted when there is obvious pharyngeal swelling, but cervical ated with crepitus. Mediastinal extension can be clinically silent and
osteomyelitis may require MRI scanning of the cervical vertebral detectable only by CT of the chest, but can lead to pericarditis, pneu-
bodies for exclusion. monia or empyema. Predisposing conditions include diabetes melli-
tus, alcoholism and malignancy. Management includes surgical
Management drainage via incision along the sternocleidomastoid muscle followed
In any patient with a suspected deep neck infection, maintenance of by blunt dissection of the neck.17 Appropriate intravenous antibiotic
the airway is always the first consideration; up to one-third of patients therapy is benzylpenicillin 1.2–1.8 g q3h plus clindamycin 600 mg q8h
who have retropharyngeal abscess will require tracheostomy. If pus is in most cases, as the disease is usually odontogenic.18
shown to be present, incision and drainage of involved spaces should
be performed and intravenous antibiotic therapy should be adminis-
tered promptly in order to produce rapid and complete resolution of Actinomycosis
the infection with minimal likelihood of complications.12 Radiologic Actinomycosis is a chronic suppurative bacterial infection that princi-
evidence of gas within soft tissues increases the urgency, because pally affects the head and neck but can involve almost any system. It
expansion of lesions containing anaerobes is usually rapid. spreads directly through tissue, skin and bone, and therefore is able to
form sinuses and fistulas (see also Chapter 184).
Epidemiology and Pathogenesis

The agents that cause actinomycosis are facultative anaerobic gram-
positive commensals of the mouth. Actinomyces israelii is the most
common pathogen, but A. naeslundii, A. viscosis, A. odontolyticus and
Arachnia propionica may also cause the disease. These agents com-
monly inhabit carious teeth, dental plaque and cavities and also the
normal intestinal tract. Head and neck infection usually occurs in the
context of dental disease or dentistry, during which the normal
mucosal barriers are broken down. Thoracic involvement usually
follows aspiration of infected oropharyngeal secretions in patients who
have poor dentition. Lesions of actinomycosis consist of areas of acute
inflammation surrounded by fibrosing granulation tissue. Such mate-
rial contains ‘sulfur granules’ (colonies of organisms forming an amor-
phous center surrounded by a rosette of clubbed filaments); these
usually contain associated organisms, including Actinobacillus actino-
mycetemcomitans, Haemophilus and Fusobacterium spp., which prob-
ably contribute to the pathogenesis of the disease.
Any age group can be infected, including infants and children.
Males outnumber females by three to one.
Clinical Features
Figure 35-7 Retropharyngeal abscess. Lateral radiograph of the neck in a
patient who has a retropharyngeal abscess, showing gross expansion of pre The most common manifestation of actinomycosis is soft tissue swell-
vertebral soft tissue. (Courtesy of Mr R. Bull.) ing of the head, face or neck, usually over or underneath the mandible.
Figure 35-9 Acute necrotizing gingivitis. (Courtesy of Professor I. Brook.)
other oral structures, including the tonsils or pharynx, to cause Vin-

cent’s disease or may result in rapid necrosis and sloughing of facial
structures, producing the classic features of cancrum oris (noma).

b The disease is mostly seen in low- and middle-income countries in the
context of severe debilitation and malnutrition. In addition, poor oral
Figure 35-8 Actinomycosis. (a) This patient had chronic disease over the man hygiene, HIV infection, measles, local irritation from food impaction
dible which (b) healed with several months of antibiotics, leaving a residual chronic and smoking are associated factors.20
sinus. (Courtesy of Professor I. Brook.) Necrotizing gingivitis may begin as an aseptic necrosis secondary
to mucosal capillary stasis. In infections in which the disease spreads
superficially to involve the pharynx, it is most likely secondary to a
Occasionally the swelling is very extensive and waxes and wanes over combination of F. nucleatum and gram-negative anaerobic organisms
many months, spreading to involve other parts of the head and neck, (Bacteroides subsp. intermedius). If the disease spreads deeper into
including the scalp, palate, eyes, larynx, salivary glands, middle ear and facial tissues to cause cancrum oris, fusospirochetal organisms such as
paranasal sinuses. Sinuses and tracts develop that open into the mouth Borrelia vincenti and F. nucleatum are consistently cultured. Prevotella
and the skin (Figure 35-8). Involvement of local bone (e.g. the man- melaninogenica may also be present. Biopsies of any advancing lesion
dible) can result in periosteal reaction or frank osteomyelitis. often reveal a mat of predominantly gram-negative, thread-like bacte-
ria that cannot be positively identified.
Diagnosis
The diagnosis is usually obvious in patients who have head and neck Clinical Features
swelling, particularly in the context of poor dentition and discharging The earliest feature is a small painful red lesion that may be vesicular
sinuses yielding sulfur granules. The granules can be trapped in gauze on the attached gingiva and often in the premolar or molar region
placed over the sinus opening or by injecting and aspirating saline of the mandible, with sudden onset of painful gums (Vincent’s disease;
from the sinus; by shaking the aspirate, the granules can be seen with Figure 35-9). The disease may then progress rapidly to produce
the naked eye. Sulfur granules can also be seen in sputum on micro- halitosis and gingival bleeding. If there is involvement of the tonsils
scopic examination. Any material obtained can be cultured under and pharynx (Vincent’s angina) there is searing pain in the pharynx
anaerobic conditions. In formalin-fixed tissues, immunofluorescence with high fever, regional lymphadenopathy and anorexia. If the
can be used to identify species. There is no reliable serologic test; labo- disease spreads into deeper tissues (noma) a necrotic ulcer rapidly
ratory diagnosis depends on microscopy and culture of material from develops with painful cellulitis of the lips and cheeks, which often
the patient. sloughs, exposing underlying bone, teeth and deeper tissues
(Figure 35-10).
Management
Most patients who have actinomycosis will respond to intravenous Diagnosis
benzylpenicillin, 1.2–1.8 g q3h for 3–6 weeks, followed by oral penicil- Although the infection is usually polymicrobial, material should be
lin V, 2–4 g/day for 6–12 months. Alternative treatments include intra- obtained for Gram stain and aerobic and anaerobic culture. Debrided
venous amoxicillin or ampicillin, followed by oral amoxicillin. material is optimal for anaerobic culture. Gram stain may reveal fuso-
Chloramphenicol, erythromycin, tetracycline and clindamycin have spirochetal gram-negative organisms as well as gram-positive cocci
also been used successfully. Prolonged treatment with penicillin results and gram-negative rods.
in complete resolution of the disease, although there may be some
residual fibrosis or scarring (see Figure 35-8). While intravenous ben-
zylpenicillin has been the traditional treatment for this condition there
Management
have been reports of the use of intravenous agents that can be given In early acute necrotizing ulcerative gingivitis (Vincent’s infection),
in once-daily dosing for home therapy, including ceftriaxone, linezolid treatment with oral penicillin V 500 mg q6h and metronidazole
and imipenem.19 400 mg q8h is usually sufficient. In patients who have noma, high
doses of intravenous penicillin and metronidazole are required,
with the dose being dependent on the age and size of the patient. An
Infections of the Oral Mucosa: antibiotic to treat aerobic gram-negative rods, such as ceftriaxone,
Gangrenous Stomatitis may be necessary. Gangrenous tissues should be removed and loose
teeth extracted. The patient should be carefully rehydrated. Once
Acute necrotizing ulcerative gingivitis, or trench mouth, is an ulcer- the infection has been controlled, reconstructive surgery is often
ative necrosis of the marginal gingivae. The disease may spread to necessary.
Figure 35-11 Primary herpes simplex virus 1 stomatitis.
Figure 35-10 Noma. This is a destructive process extending from oral structures,
which is a sequela of necrotizing gingivitis and (a) is seen most commonly in
patients in low- and middle-income countries, although (b) occasionally it is seen
in elderly debilitated patients in higher-income countries. (Courtesy of Professor
I. Brook.)
Figure 35-12 Herpangina in a teenager with severe throat pain.
Infections of the Oral Mucosa:

Primary Herpetic Gingivostomatitis
Other Infections of the Oral Mucosa
Epidemiology
Herpes simplex virus (HSV)-1 and HSV-2 can cause a primary infec-
Herpangina
tion of the oral cavity, although type 1 is much more frequently Herpangina produces characteristic oropharyngeal vesicles, generally
responsible. The disease can occur in infants, although this is becom- at the junction of the hard and soft palates (Figure 35-12). It primarily
ing increasingly uncommon. Oral lesions caused by HSV-2 are seen in affects children and teenagers and generally occurs in epidemics during
sexual contacts of patients who have genital herpes and are clinically the summer. Several different coxsackieviruses, notably coxsackie A
indistinguishable from those caused by HSV-1. virus (types 1–10, 16 and 22) and less commonly coxsackie B virus
(types 1–5), have been associated with this disease. Other enterovi-
Clinical Features ruses, including echovirus, have been implicated.
Patients usually have mild disease, but they can complain of sudden
The disease may be very mild, with a few painful ulcers and no systemic fever, anorexia, neck pain, extremely sore throat and headache. The
features, or it may be more severe with fever, sore throat, malaise, lesions are often more vesicular than herpetic, and consist of multiple
headache and regional lymphadenopathy. Oral lesions tend to appear small white papules with an erythematous base that appears less
1–2 days after the onset of pain and lead to a painful, red gingiva or inflamed than that with herpetic lesions. These lesions usually spon-
palate. These symptoms generally persist for approximately 2 days. The taneously rupture within 2 or 3 days and seldom persist for more than
vesicles occur as 2–4 mm ulcers on a red background. When lesions 1 week. There may be cervical lymphadenopathy but this is unusual.
coalesce they can resemble aphthous ulcers (Figure 35-11). At this A laboratory diagnosis can be obtained by culturing swabbed material
point the disease is highly infectious. The clinical course of unmodified from the lesions. Herpes simplex virus infection can usually be distin-
primary herpetic gingivostomatitis usually lasts 2 weeks. guished on clinical grounds, but can be rapidly excluded by direct
immunofluorescence. Management consists of topical analgesia only.
Diagnosis
The clinical differential diagnosis of oral herpetic gingivostomatitis Hand, Foot and Mouth Disease
includes herpangina, varicella, herpes zoster, and hand, foot and Hand, foot and mouth disease is caused by systemic infection with
mouth disease. These diseases can usually be distinguished on the basis coxsackie group A viruses (usually serotype 16) and primarily affects
of concomitant cutaneous features. Primary herpes infection of the children, but occasionally adults. The disease consists of vesicular
mouth can occasionally be recurrent and several other recurrent dis- eruptions on the hands, wrists, feet and within the mouth. Lesions on
eases have similar oral lesions – these include minor aphthous ulcers, the hands are almost always present, but oral lesions are present in
Behçet’s syndrome, cyclical neutropenia and erythema multiforme. A 90% of patients and can occasionally be the only manifestation of the
laboratory diagnosis of herpes can be verified if necessary by poly- disease.21 The oral vesicles are often on the palate, tongue and buccal
merase chain reaction (PCR) of material obtained by swabbing the mucosa and may range from a few isolated lesions to a marked stoma-
ulcers (see also Chapter 166). titis. In addition, patients may suffer fever, malaise, conjunctival injec-
tion, headache and abdominal pain and occasionally diarrhea. If the
Management disease is confined to the oral cavity it is almost indistinguishable from
In primary herpetic gingivostomatitis oral aciclovir 200–400 mg q8h primary herpetic gingivostomatitis. Laboratory diagnosis of the disease
is appropriate therapy. can be confirmed by PCR of swab material.
Management is symptomatic. The disease is usually self-limiting a burning sensation of the tongue, which displays diffuse redness of
and rarely persists for more than 2 weeks. However, hand, foot and the entire dorsum. Most patients who have denture-related oral can-
mouth disease caused by enterovirus-71, associated with occasionally didiasis are asymptomatic. Patients who have cell-mediated defects
lethal encephalitis, has been occurring in outbreaks in South East Asia (i.e. diabetics, those on oral steroids or immunosuppressed patients)
and China over recent years.22 It may be associated with Kingella kingae mostly have the characteristic syndrome of thrush, a pseudomembra-
osteoarthritides.23 nous form of the disease in which there is a layer of white curd-like
flecks of material that can be wiped off to leave an erythematous
Aphthous Stomatitis surface, beneath which there may be bleeding points.
The cause of aphthous ulceration is unknown but a number of infec-
tious agents, including viruses, have been implicated. It usually mani- Diagnosis
fests as small ulcers of the buccal and labial mucosa, often affecting the The diagnosis is usually clinically obvious in patients who have thrush,
floor of the mouth or the inferolateral aspect of the tongue, almost but in patients who have erythematous lesions diagnosis can be made
always within the anterior part of the oral cavity; the palate and by scraping the mucosa and identifying characteristic ovoid yeasts with
pharynx are rarely involved. The ulcers are characteristically exqui- hyphal forms on microscopy. The organism can be cultured on Sab-
sitely painful, particularly during eating, and in the most severe form ouraud’s agar, but culture alone is insufficient to make the diagnosis
can lead to anorexia. The lesions are usually raised and appear grayish since the organism can be recovered from the mouth of approximately
yellow, but in severe cases they may be herpetiform with secondary 10% of completely normal individuals with no symptoms.
bacterial infection and cervical lymphadenopathy. Major aphthous
ulcers may persist for months, but minor lesions usually heal over 2 Management
weeks. They often recur, with periods of remission lasting as long as a In normal individuals the disease can usually be terminated by remov-
few years. Cultures of swabs from aphthous ulcers are negative on viral ing the cause – either inhaled steroids or broad-spectrum antibiotics
culture. – or by removing dentures at night. If necessary, patients can use 7–14
Treatment is usually symptomatic with mouth washes and anes- days of topical antifungal therapy, such as nystatin or clotrimazole,
thetic lozenges. Oral prednisolone has been used in some patients but which is usually quite sufficient to ablate the infection. Immunocom-
is generally unhelpful. Severe aphthous ulcers have been successfully promised individuals, particularly those with advanced immunosup-
treated with oral thalidomide. Ulcers are particularly severe in HIV- pression, may require systemic therapy. For additional discussion of
infected patients. candidiasis in patients who have AIDS, see Chapter 94.
Primary Syphilis
Primary chancres can occur in the mouth approximately 3 weeks after Other Oral Fungal Infections
oral sex. An ulcerating papule develops at the site of initial contact of
Treponema pallidum with the oral mucosa. The papule is painless but Histoplasma capsulatum is endemic in the midwestern USA and
is accompanied by significant regional cervical lymphadenopathy. At Central and South America. The organism is generally associated with
presentation patients are often seronegative, but darkfield microscopy lower respiratory tract infection, but oral lesions can occur, particu-
of material obtained from the ulcer may reveal spirochetes, although larly in elderly, debilitated patients who have disseminated disease. The
care should be taken to avoid contamination of the material obtained lesions tend to appear as erythematous areas that may ulcerate.27
with saliva because other Treponema species inhabit the mouth and Biopsy is usually required to establish a diagnosis. Because the infec-
may be easily mistaken for T. pallidum. Treatment is discussed in tion is usually disseminated, systemic therapy with amphotericin B is
Chapter 61. generally required (see Chapters 33 and 189).
The dimorphic fungus Paracoccidioides brasiliensis is a major cause
of systemic mycosis in Central and South America and should be
considered in patients originating from these regions. Most patients
Candida Infections of the Mouth have an oral mucosal ulcer with some surrounding edema. There may
be perioral lesions that may be ulcerated or warty. Diagnosis can be
Oral candidiasis is a common problem that usually signals local or
made by smear and culture, and treatment with oral imidazole com-
generalized disturbance of host defenses.
pounds is generally sufficient (Chapters 33 and 189).
Most patients who have oral candidiasis are at the extremes of age, but Oral Lesions in Patients Who
any individual who has recently taken oral or inhaled steroids or
broad-spectrum antibiotics is at risk. The disease is also seen in patients Have Malignancy
wearing dentures and patients who have diabetes mellitus.24 Between A common problem among cancer patients undergoing chemotherapy
1980 and 1989, rates of oropharyngeal candidiasis in hospitalized or radiotherapy is severe mucositis and stomatitis that occurs approxi-
patients increased from 0.34 to 1.6 cases per 1000, caused mainly by mately 1 week after the onset of chemotherapy.24 At this point, destruc-
the HIV epidemic.25 tion of oral epithelium is at its height with an accompanying
Yeasts are common colonizers of the oral cavity of healthy indi- disturbance of immune surveillance of oral mucosal micro-organisms.
viduals.26 Candida albicans is the most common of oral yeast isolates This leads to opportunist bacterial or fungal infection. Patients nearly
(up to 50%). The organism exists in yeast and hyphal forms. The always complain of pain and tenderness in the mouth with or without
immunopathology of mucosal candida infections is unclear, although formation of a pseudomembrane. Symptoms can persist long after
suppression of normal oral microflora by antibiotics probably permits chemotherapy has been terminated.
proliferation of yeasts. A disturbance of cell-mediated immunity is Management should include a vigorous search for a microbial eti-
partly responsible for overproliferation in patients who have HIV-1 ology; a short course of metronidazole is sometimes helpful. Some
infection and malignancy. prevention can be achieved by careful oral hygiene and effective man-
agement of xerostomia associated with chemotherapy. Once there is
Clinical Features established mucositis, topical therapy with antiseptic and anesthetic
In patients using broad-spectrum antibiotics, or who suffer from can- preparations is indicated. Aluminum hydroxide gel can be used to
didiasis as a result of denture use, lesions are often erythematous with provide symptomatic relief of painful inflammation.
Halitosis
Halitosis may affect up to 30% of the population and is the result of
the production of volatile sulfur compounds by bacteria in the process
of breaking down components of epithelial cells, salivary proteins and
food debris. The main volatile compounds include methyl mercaptan,
hydrogen sulfide and dimethyl sulfide. A wide range of oral anaerobes
are associated with this, including Porphyromonas spp., P. intermedia,
Treponema denticola, F. nucleatum, Tannerella forsythensis and Eubac-
terium spp.25,28 Clinically, halitosis is mostly associated with periodon-
titis or with abnormal tongue coating.
Management is directed at reducing the bacterial load both in
periodontitis and in tongue coating by oral hygiene measures, control
of tongue flora by brushing or scraping, and occasionally the adjunc-
tive use of antiseptic agents. a
Infections of the Salivary Glands

The most common cause of parotitis is mumps virus, but parotitis
can occasionally be caused by bacteria or other viruses, including
parainfluenza virus, coxsackievirus, echovirus, Epstein–Barr virus
and HIV.
Epidemiology
The incidence of mumps has markedly decreased in the era of child-
hood measles, mumps and rubella (MMR) vaccination, which confers
lifelong immunity. Despite this, mumps virus remains the most
common cause of parotitis. It is highly contagious by airborne droplet
transmission. Mumps infections occur in late winter and early spring;
enterovirus infections, including parotitis, are mostly seen in mid- to b
late summer. Before the introduction of the MMR vaccine in the UK
in 1988, the annual incidence of mumps was approximately 5 per Figure 35-13 Suppurative parotitis (a) in a diabetic patient who had a recent
100 000 population; however, in the postvaccine era this has declined history of dehydration secondary to diabetic ketoacidosis. (b) Pus was manually
to less than 0.5 per 100 000.29 expressed from Stensen’s duct from which Staphylococcus aureus was cultured.
(Courtesy of Dr E. Ridgway.)
Most patients who have primary bacterial parotitis are over the age
of 60 years and are frequently debilitated because of chronic illness or
have underlying diseases such as diabetes. Patients who are dehy- meningitis in children less than 15 years old in whom permanent
drated, whatever the cause, are at greatest risk. Medications that lead unilateral deafness was a recognized complication. Pancreatitis is rare.
to xerostomia include anticholinergic and occasionally diuretic agents. On examination there is smooth tender swelling that obliterates the
Poor oral hygiene increases the chances of reflux of bacteria into the angle of the jaw and may raise the pinna. Rarely, the outlet of Stensen’s
salivary gland.30 duct may be inflamed. There may be generalized symptoms, including
fever, arthralgia, malaise and headache, which generally persist for up
Pathogenesis to 1 week. Culturable virus is present in the saliva for up to 1 week
after gland enlargement. Management is essentially symptomatic.
Mumps virus is a paramyxovirus and gains entry via the respiratory Recurrent episodes of glandular swelling, particularly of the parotid
tract (see Chapter 163). The subsequent viremia allows access of the gland, can occur in children with a history of mumps. Clinical features
virus to tissues for which it has tropism, including salivary gland tissue, include recurrent parotid swelling with general malaise and pain, fre-
gastrointestinal tissue such as pancreas, testicular tissue and the central quently after a meal. Viridans streptococci are usually cultured from
nervous system. The incubation period is 18–21 days. exudate from the Stensen’s duct.
Bacterial infection of the salivary glands is normally prevented by In primary bacterial parotitis there is usually rapid onset of pain,
constant salivary flow, which removes contaminants from the ductal swelling and induration of the involved gland (Figure 35-13). Manual
systems. Dehydration, xerostomia or obstruction of the ducts can lead palpation of the gland is exquisitely painful and can result in discharge
to bacterial proliferation within the salivary glands and subsequent of pus from the duct. In addition, there are usually systemic features,
parotitis. including fever, rigors and a neutrophilia. The most frequently isolated
organisms are Staph. aureus, Strep. pyogenes, viridans streptococci and
Clinical Features Haemophilus influenzae.
The most common clinical manifestation is gradual onset of painful HIV-associated salivary gland swelling most commonly occurs as
swelling of either one or both of the parotid glands, which occurs a bilateral cystic enlargement of the parotid glands, occasionally in
14–21 days after contact with an infected individual. Pain within the association with xerostomia, dry eyes and arthralgia. Salivary gland
parotid gland can be initiated by salivation during meals, and the involvement can occur very early on in HIV infection but is most
glands are tender. Occasionally, submandibular salivary glands are commonly seen in late disease. Histologically, there are numerous
involved, but inflammation of sublingual glands is extremely rare. epithelium-lined cysts, some up to several centimeters in size, contain-
Orchitis is present in approximately 10–20% of individuals and is ing macrophages and lymphocytes. The commonest identified oppor-
bilateral in 5%, but there is no firm evidence that it causes male steril- tunistic infection of salivary glands is cytomegalovirus (CMV); about
ity. Mumps meningoencephalitis may occur in concert with parotitis, 15% of post-mortem submandibular glands of all patients who have
but patients who have mumps meningitis often do not have parotitis. AIDS have evidence of CMV inclusion bodies.31 In children, there is a
In the pre-MMR era mumps was a relatively common cause of viral strong association between HIV-parotid swelling and lymphocytic
interstitial pneumonitis. Examination usually reveals smooth bilateral biotic therapy using amoxicillin–clavulanate 1.2 g q8h or intravenous
swelling. Uneven swelling should be biopsied because 10% of salivary cefuroxime 750 mg q8h. Drainage of the duct should be assisted by
gland disease in HIV-infected patients is caused by lymphoma.32 manual massage. Occasionally steroids are necessary to suppress
inflammation and potentiate drainage. Surgical drainage of a salivary
Diagnosis gland abscess is rarely necessary.
In mumps, this can be achieved by detection of salivary IgM or by PCR
of salivary washings or of viral throat swab (see Chapter 163). A con- Parotitis Caused by
valescent rise in complement-fixing antibody occurs. In established Mycobacteria Species
viral parotitis there is elevation of serum salivary-type amylase. Rarely, Nontuberculous mycobacterial infections of the parotid gland are now
there may be biochemical evidence of pancreatitis. increasingly seen in children, in whom they present as unilateral pain-
less indurated swellings that can be mistaken for neoplasm. Diagnosis
Prevention can be made by fine-needle aspiration with cytology and culture,
The MMR vaccine consists of live attenuated measles, mumps and which may reveal organisms such as Mycobacterium scrofulaceum, M.
rubella viruses. Immunization provides protection for 90% of recipi- avium-intracellulare or M. malmoense. Management is conservative.
ents for measles and mumps and over 95% for rubella. The antibody M. tuberculosis infection of the parotid gland is rare, but is one of the
response to the mumps component is too slow for effective postexpo- differential diagnoses of parotid tumor and should be rigorously
sure prophylaxis. After the first dose of MMR, malaise, fever or rash excluded by histology of needle biopsy or fine-needle aspiration cytol-
may occur about 1 week after immunization, although this syndrome ogy before unnecessary deforming surgery is undertaken.33 The disease
usually self-terminates within 3 days. responds well to conventional antituberculous chemotherapy (see
Chapters 31 and 148).
Management
Management of viral parotitis is symptomatic. Bacterial parotitis can References available online at expertconsult.com.
usually be managed by prompt fluid replacement and parenteral anti-
KEY REFERENCES
Brook I.: Microbiology and management of peritonsillar, Pihlstrom B.L., Michalowicz B.S., Johnson N.W.: Periodon- Selwitz R.H., Ismail A.I., Pitts N.B.: Dental caries. Lancet
retropharyngeal and parapharyngeal abscesses. J Oral tal diseases. Lancet 2005; 366(9499):1809-1820. 2007; 369(9555):51-59.
Maxillofac Surg 2004; 62:1545-1550.
Maddi A., Scannapieco F.A.: Oral biofilms, oral and peri-
odontal infections and systemic disease. Am J Dent 2013;
26(5):249-254.
Chapter 35 Orocervical Infection 320.e1
REFERENCES
1. Selwitz R.H., Ismail A.I., Pitts N.B.: Dental caries. head and neck. Infect Dis Clin North Am 2007; 23. El Houmami N., Mirand A., Dubourg G., et al.: Hand,
Lancet 2007; 369(9555):51-59. 21(2):557-576, viii. Review. foot and mouth disease and Kingella kingae infections.
2. Adler C.J., Dobney K., Weyrich L.S., et al.: Sequencing 12. Brook I.: Microbiology and management of peritonsil- Pediatr Infect Dis J 2015; 34(5):547-548.
ancient calcified dental plaque shows changes in oral lar, retropharyngeal and parapharyngeal abscesses. J 24. Epstein J.B., Gangbear S.J.: Oral mucosal lesions in
microbiota with dietary shifts ofthe Neolithic and Oral Maxillofac Surg 2004; 62:1545-1550. patients undergoing treatment for leukemia. J Oral Med
Industrial revolutions. Nat Genet 2013; 45(4):450-455. 13. Thompson J.W., Cohen S.R., Reddix P.: Retropharyn- 1987; 42:132-140.
3. Pihlstrom B.L., Michalowicz B.S., Johnson N.W.: Peri- geal abscess in children: a retrospective and historical 25. Haraszthy V.I., Zambon J.J., Sreenivasan P.K., et al.:
odontal diseases. Lancet 2005; 366(9499):1809-1820. analysis. Laryngoscope 1988; 98:589-597. Identification of oral bacterial species associated with
4. Goodson J.M., Tanner A.C.R., Hassajee A.D., et al.: 14. Colmenero Ruiz C., Labajo A.D., Yanez Vilas I., et al.: halitosis. J Am Dent Assoc 2007; 138:1113-1120.
Patterns of progression and regression of advanced Thoracic complications of deeply situated serious neck 26. Manfredi M., Polonelli L., Aguirre-Urizar J.M., et al.:
destructive periodontal disease. J Clin Periodontol 1982; infections. J Craniomaxillofac Surg 1993; 21:76-81. Urban legends series: oral candidosis. Oral Dis 2013;
9:472-557. 15. Lee K.C., Tami T.A., Escavez M., et al.: Deep neck infec- 19(3):245-261.
5. Maddi A., Scannapieco F.A.: Oral biofilms, oral and tions in patients at risk for acquired immune deficiency 27. Muzyka B.C., Epifanio R.N.: Update on oral fungal
periodontal infections and systemic disease. Am J Dent syndrome. Laryngoscope 1990; 100:915-919. infections. Dent Clin North Am 2013; 57(4):561-581.
2013; 26(5):249-254. 16. Wholey M.H., Bruwer A.J., Baker H.L.: The lateral 28. Hughes F.J., McNab R.: Oral malodour – a review. Arch
6. Kilian M.: Degradation of immunoglobulins A1, A2 roentgenogram of the neck. Radiology 1958; 71:350- Oral Biol 2008; 53(Suppl.1):S1-S7.
and G by suspected principal periodontal pathogens. 356. 29. Salisbury D., Ramsay M., Noakes K.: Immunisation
Infect Immun 1982; 34:757-764. 17. Mathieu D., Neviere R., Teillon C., et al.: Cervical nec- against infectious disease: the green book. Available:
7. Clarke N.A., Hirscu R.S.: Personal risk factors for gen- rotizing fasciitis: clinical manifestations and manage- https://www.gov.uk/government/collections/immuni
eralized periodontitis. J Clin Periodontol 1995; 27:136- ment. Clin Infect Dis 1995; 21:51-56. sation-against-infectious-disease-the-green-book.
145. 18. Fihman V., Raskine L., Petitpas F., et al.: Cervical 30. Work W.P., Hecht D.W.: Inflammatory diseases of the
8. Peterson L.J.: Odontogenic infections. In: Cummings necrotising fasciitis: 8 year experience of microbiology. major salivary glands. In: Paperella M.M., Schumrick
C.W., ed. Otolaryngology – head and neck surgery II. 2nd Eur J Clin Microbiol Infect Dis 2008; 27(8):691-775. D.A., eds. Otolaryngology. Philadelphia, PA: WB Saun-
ed. St Louis: Mosby Yearbook; 1993:1199-1215. 19. Wong V.K., Turmezei T.D., Weston V.C.: Actinomyco- ders; 1980:2235-2243.
9. Kohler B., Audreen I., Jonsson B.: The effect of caries- sis. BMJ 2011; 343:d6099. 31. Wagner R.P., Tian H., McPherson M.J., et al.: AIDS-
preventive measures in mothers on dental caries in the 20. Enwonwu C.O.: Noma: a neglected scourge of children associated infections in salivary glands: autopsy survey
oral presence of the bacteria Streptococcus mutans and in sub-Saharan Africa. Bull World Health Organ 1995; of 60 cases. Clin Infect Dis 1996; 22:369-371.
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29:879-884. 21. Adler J.L., Moslow S.R., Mellin H., et al.: Epidemio- glands. In: Cummings C.W., ed. Otolaryngology – head
10. Dhingra K., Vandana K.L.: Prophylactic vaccination logical investigation of hand, foot and mouth disease. and neck surgery II. 2nd ed. St Louis, MO: Mosby Year-
against periodontal disease. Systematic review of pre- Am J Dis Child 1970; 120:309-314. book; 1993:1008-1017.
clinical studies. J Periodontol 2010; 81(11):1529-1546. 22. Abzug M.J.: The enteroviruses. Problems in need of 33. Weiner G.M., Pahor A.L.: Tuberculous parotitis: limit-
11. Reynolds S.C., Chow A.W.: Life-threatening infections treatments. J Infect 2014; 68(Suppl.1):S108-S114. ing the role of surgery. J Laryngol Otol 1996; 110:96-97.
of the peripharyngeal and deep fascial spaces of the
36
Gastritis, Peptic Ulceration and
Related Conditions
JONATHAN R. WHITE | RICHARD J.M. INGRAM | JOHN C. ATHERTON
Gastritis that spares the acid-producing corpus (antrum-predominant

KEY CONCEPTS
gastritis) is associated with increased acid secretion and duodenal
• Helicobacter pylori is a common infection worldwide, with the ulceration. Gastritis that involves the corpus (corpus-predominant or
majority of those affected remaining asymptomatic. pan-gastritis) is associated with reduced acid secretion, gastric ulcer-
• H. pylori and use of NSAIDs remain common causes of peptic ation, and risk of atrophic gastritis, metaplasia, dysplasia and gastric
ulcer disease and associated complications. adenocarcinoma.
Whilst H. pylori infection is the most common Helicobacter infec-
• Disease outcome is determined by a combination of host, tion in man, in higher-income countries other Helicobacter species
bacterial and environmental factors.
such as H. heilmannii and H. felis are present transiently in 2–6% of
• There are a number of accurate diagnostic tests to confirm H.
pylori infection but no clinically available tests to identify those
at risk of developing complications. TABLE Classification of Chronic Gastritis According
• Successful eradication treatment is effective at reducing peptic 36-1 to the Updated Sydney System
ulcer recurrence.
Type of Gastritis Etiology
• Antibiotic resistance and subsequent treatment failure pose an
important global challenge for clinicians. Nonatrophic Helicobacter pylori
Atrophic
Autoimmune Autoimmunity
Multifocal atrophic H. pylori ± dietary and other
environmental insults
Introduction Special forms
In 1983, Marshall and Warren described the bacterium now known as Chemical Aspirin/NSAIDs, bile and possibly other
Helicobacter pylori (see Chapter 182). They proposed its role in the agents
Radiation Radiation
pathophysiology of chronic active gastritis and peptic ulceration, re Lymphocytic Overt or latent celiac disease, H. pylori
cognized by the Nobel Prize for Medicine or Physiology in 2005.1 H. Noninfectious Crohn’s disease, sarcoidosis,
pylori infection is extremely common, affecting nearly half of the granulomatous vasculitides, foreign substances,
world’s population. It invariably induces a histologic chronic active idiopathic
Eosinophilic Food sensitivity, possibly other allergies
gastritis, which in itself is usually asymptomatic. However, approxi- Other infectious gastritides Bacteria other than H. pylori
mately 10–20% of infected people develop a duodenal or gastric ulcer (particularly H. heilmanni and H. felis,
in their lifetime and 1–5% develop distal gastric adenocarcinoma or mycobacteria and Treponema
primary gastric lymphoma. pallidum), viruses (particularly
cytomegalovirus), and fungi
The term ‘gastritis’ is often erroneously applied to the macroscopic (particularly Candida spp.,
appearance of ‘inflamed’ (erythematous) gastric mucosa seen at Histoplasma capsulatum and
endoscopy (Figure 36-1a). However, these appearances correlate Mucoraceae)
poorly with histologic inflammation, for which the term ‘gastritis’
Non-Helicobacter infectious gastritides are very rare, usually occur in
should be reserved. Gastritis may be subtyped from the histologic immunocompromised patients and are not discussed in this chapter.
appearance and distribution within the stomach, and these features Data from Dixon et al., American Journal of Surgical Pathology,
often indicate etiology and associated disease risk (Table 36-1). 1996;20(10):1161–1181 with permission.
a b c
Figure 36-1 Endoscopic pictures of the stomach and duodenum. (a) Erythema of the gastric antrum. This appearance correlates poorly with histologic gastritis and
may be a normal finding. (b) Duodenal ulceration. (c) Gastric ulceration. Note the clot in the base indicating recent bleeding and high risk of re-bleeding.
321
TABLE
36-2 Worldwide Causes of Duodenal and Gastric Ulceration (with Estimated Proportions)
Cause Duodenal Ulcer (% of Cases) Gastric Ulcer (% of Cases)
Infection Helicobacter pylori 75–90* 40–80*
Drugs Aspirin and NSAIDs 12–30* 30–60*
Neoplasms Zollinger–Ellison syndrome Rare Very rare

Lymphoma Very rare Rare
Gastric adenocarcinoma – 3
Other adenocarcinoma Very rare Rare
Leiomyoma – Rare
Others Crohn’s disease Rare Rare
Systemic mastocytosis Very rare Very rare
Severe systemic illness Rare Rare
*In industrialized nations NSAID-associated ulcer incidence has increased such that NSAIDs and aspirin are a more common cause of gastric ulcer than H. pylori. The
proportion of non-H. pylori non-NSAID ‘idiopathic’ ulcers is also rising.
the population. They commonly colonize domestic pets so are thought

to be zoonotically acquired.2 The resulting gastritis is usually mild, Prevalence patterns of Helicobacter pylori
though rarely and with a less well established causal link there are case
reports of associated diseases that respond to eradication.2
H. pylori 100
Peptic ulcers may be associated with some types of gastritis. A positive (%)
peptic ulcer is a macroscopic break in the gastric or duodenal mucosa
with obvious depth and definite size (usually defined as greater than 80
0.5 cm; Figure 36-1b). Erosions are smaller breaks in the mucosal
surface, which usually reflect the ulcer diathesis and should be managed 60
similarly. Although gastric and duodenal ulcers share some character-
istics, there are notable differences in their etiologies and pathogeneses 40
(Table 36-2). In industrialized populations, H. pylori is still the leading
cause of duodenal ulceration but nonsteroidal anti-inflammatory
20
drugs (NSAIDs) and aspirin use are now the leading causes of gastric
ulceration. Establishing the causative factor in ulcer pathogenesis is a
vital, as targeted treatment heals ulcers and reduces recurrence. 0
Gastric adenocarcinoma is the fifth most prevalent cancer and the 0 10 20 30 40 50 60 70
third most common cause of cancer deaths worldwide. The more Age (years)
prevalent distal form is caused by H. pylori infection, making H. pylori South Africa Algeria Saudi Côte Thailand
the leading infectious cause of human malignancy. Even the most Arabia d’Ivoire
conservative estimates place the attributable fraction of gastric adeno- Peru Brazil Chile Nepal Vietnam
carcinoma from H. pylori at 75–90%.3,4 Thus, primary prevention of
H. pylori infection could more than halve gastric adenocarcinoma
H. pylori 100
incidence. positive (%)
Epidemiology 80
PREVALENCE AND INCIDENCE 60

The epidemiology of peptic ulcer disease and gastritis reflects that of
its underlying causes – principally H. pylori infection and aspirin/
40
NSAIDs. The age prevalence of H. pylori differs markedly between
countries, but two broad patterns are found (Figure 36-2).
• In group 1 countries (predominantly low- and middle-income 20
countries [LMIC]) there is a rapid rise in prevalence before 20
b
years of age, after which point prevalence stabilizes at over 80%, 0
implying that H. pylori is acquired in childhood and persists 0 10 20 30 40 50 60 70
throughout life. Age (years)
• In group 2 countries (usually higher-income, industrialized USA (African-
Japan
USA (Caucasian-
Wales Finland
nations), the prevalence of infection increases steadily with age American) American)
at a rate of roughly 1%/year of life. Epidemiologic evidence sug-
England Wales USA France Belgium
gests that this is largely the result of a birth cohort effect.5 Thus,
about 20% of 30-year-olds have acquired the infection in child-
hood, as compared with 50–60% of 60-year-olds, because of a Figure 36-2 Prevalence patterns of Helicobacter pylori. Prevalence of H. pylori
infection in 10 low- and middle-income countries (a; group 1) and 10 higher-
changing incidence of infection in childhood over the past 60 income, industrialized countries (b; group 2). (Adapted with permission from
years. Pounder R.E., Ng D. The prevalence of Helicobacter pylori infection in different
In many countries, but in group 2 countries in particular, the overall countries. Aliment Pharmacol Ther 1995;9(Suppl 2):33–9.)
prevalence of H. pylori infection has fallen markedly over the last 30
years: in some communities in higher-income countries fewer than
10% of children and teenagers now have the infection. This is thought
Chapter 36 Gastritis, Peptic Ulceration and Related Conditions 323
in large part to be due to improvements in living conditions meaning

that children are less likely to become infected. As these childhood
cohorts age, fewer adults also are infected. However another contribu-
tor is likely to be increased antibiotic use in childhood. The incidence
of peptic ulcer disease mirrors that of H. pylori infection. As the
prevalence of H. pylori infection has fallen in progressive age cohorts
so the incidence of peptic ulcer disease has also fallen. This is a very
marked effect, such that the main cause of peptic ulceration in many
higher-income countries is now aspirin and NSAID use rather than H.
pylori infection.
a
ASSOCIATIONS
Aside from associations with age and geographic area, H. pylori is
closely associated with socioeconomic conditions, particularly in
childhood. This may explain the different prevalences of infection
found in different ethnic groups within the same geographic area.
Markers of childhood socioeconomic status that have been correlated
with prevalence of infection include general level of hygiene, water
supply and sanitation, and level of crowding in the household. These
associations further support the view that most H. pylori acquisition
is in childhood and that it persists throughout life in the absence of
effective treatment. Populations with higher prevalence of H. pylori, as
expected, have equivalently higher rates of peptic ulcer disease. b
TRANSMISSION Figure 36-3 Appearances of Helicobacter pylori and NSAID antral gastritis. (a)
H. pylori is thought to be acquired by direct human-to-human contact Antral gastritis in H. pylori infection with active (neutrophil) and chronic (lympho-
cyte) inflammation of the lamina propria and glands. The epithelial surface is typi-
in childhood. In higher-income countries it is usually acquired from cally ballooned. Helicobacter pylori organisms are not readily apparent on a
the primary caregiver but it may also be spread between children. hematoxylin and eosin stain. (b) Antral gastritis associated with NSAID use. Foveo-
Family members thus often, but not invariably, share the same strain, lar hyperplasia with a mild chronic inflammatory infiltrate and smooth muscle cells
although this may evolve in vivo to change its pathogenicity. Although are seen in the lamina propria. (Courtesy of Dr M.M. Walker.)
most infected adults acquire infection as children, there are well-
documented examples of H. pylori being acquired de novo in adult life;
several studies have suggested that overcrowding and poor sanitation Longstanding H. pylori infection leads, in some people, to atrophic
are risk factors. gastritis. This may be a precursor of gastric cancer, but also is increas-
In transfer between humans, it is unclear whether H. pylori is trans- ingly recognized as an important cause of vitamin B12 deficiency and
mitted by the fecal–oral or oral–oral route, or both. The bacterium has iron deficiency anemia. H. pylori is thought to contribute to the
been cultured with difficulty from the feces of people who have H. reduced platelet count in a proportion of people with idiopathic
pylori infection in both higher-income countries and LMIC, but it is thrombocytopenic purpura (ITP); treatment of H. pylori increases
more easily cultured from gastric reflux into the mouth and from platelet count in approximately half of these patients.7 It is now clear
vomitus. However, it appears not to persist in the mouth as, although that H. pylori infection, especially when associated with gastric atrophy,
H. pylori DNA has been found in dental plaque, H. pylori culture from offers a degree of protection against complications of gastroesophageal
dental plaque is rarely successful. In past years, transmission of H. reflux, including esophageal adenocarcinoma. Recent work also shows
pylori has been documented following insufficient sterilization of a negative association between H. pylori and autoimmune and allergic
endoscopy or gastric pH measuring equipment, although with ade- diseases, including asthma, but here causality remains unclear.8
quate sterilization this is no longer a problem. Acute H. pylori infection
by this route is thought to be the cause of the occasional outbreaks of PATHOGENESIS
epidemic acute hypochlorhydria6 observed before the discovery of H. Whether an infected person develops disease is dependent on a com-
pylori. Re-infection following successful eradication is rare in higher- bination of bacterial strain virulence, host genetic susceptibility and
income countries (1%), and is more likely to represent initial treat- environmental co-factors. Several bacterial virulence factors are found
ment failure, but re-infection rates may be higher in LMIC. more prominently in ulcer- or cancer-associated strains than in those
not associated with disease. These include:
Pathogenesis and Pathology • the presence of the cag (cytotoxin-associated gene) pathogenicity
island
PATHOLOGY AND DISEASE ASSOCIATIONS • production of an active vacuolating cytotoxin, VacA
H. pylori is a gastric infection, although it may colonize areas of gastric • certain adhesins, most notably the blood group antigen binding
metaplasia in the duodenum. In the stomach, infection causes chronic adhesin A (BabA).
active gastritis characterized by continuing neutrophil and lymphocyte The cag pathogenicity island encodes a type IV secretory apparatus,
infiltration, epithelial damage and thinning of the mucous layer through which the protein CagA, is ‘injected’ into epithelial cells. This
(Figure 36-3a). This is in contrast to gastritis caused by chemical and the apparatus itself stimulate a number of signaling pathways
agents, including NSAIDs, which is characterized by regenerative epi- resulting in cytoskeletal changes, proliferation and inflammation.9,10
thelial changes and a paucity of inflammatory cells (Figure 36-3b). About 70% of strains in the USA are cag+ and these strains colonize
Most people infected with H. pylori remain asymptomatic through- the gastric mucosa more densely, cause more inflammation and are
out their lifetime, but some will develop an associated disease. These more likely to be associated with ulcers and gastric cancer than
include: cag– strains.
• duodenal ulceration The vacuolating cytotoxin, VacA, is a pore-forming toxin. It is
• gastric ulceration particularly suited to the stomach because it is activated by acid,
• gastric adenocarcinoma arising from the distal stomach then becoming acid and pepsin resistant.11 All strains have vacA, the
• mucosa-associated lymphoid tissue (MALT) lymphoma. gene encoding the cytotoxin, but only some vacA genotypes (type s1i1)
are associated with the toxigenic phenotype12 and these are also The pathogenesis of gastric carcinoma is unclear and may differ
associated with increased prevalence of gastric cancer13 and peptic between its two main types: intestinal and diffuse. Intestinal-type
ulcer disease. Potential new virulence factors of H. pylori are still being gastric cancer is thought to occur by a step-wise process from super-
uncovered.14 ficial gastritis through atrophy to intestinal metaplasia, dysplasia and
Host genetic susceptibility to disease amongst H. pylori-infected ultimately carcinoma.20 Diffuse-type gastric cancer may occur earlier
people is well described. Polymorphisms in the interleukin-1β (IL-1β) and may arise more directly from simple H. pylori-induced gastritis
gene, which lead to more IL-1β expression in response to bacterial but the sequence is not well described.
infections, increase the risk of gastric cancer.15 Many population-
specific host genetic polymorphisms also affect disease risk. GASTRIC LYMPHOMA
Environmental co-factors are an important risk factor for disease. Primary gastric lymphomas arise in lymphoid tissue; the usual cause
Amongst H. pylori-infected people, smoking is the most important of this occurring in the stomach is H. pylori infection. Low-grade B-cell
determinant of duodenal ulceration development. Smoking and male MALT lymphomas are particularly interesting as they are driven by
sex are also important risk factors for gastric adenocarcinoma. High chronic stimulation from H. pylori antigens. A majority of these low-
salt diets predispose to gastric cancer and diets high in fresh fruits and grade lymphomas regress following H. pylori eradication, but some,
antioxidants are weakly protective. particularly those with a t(11;18) chromosomal translocation, do not.21
All patients need careful monitoring after treatment and although
DUODENAL ULCER DISEASE
these low-grade gastric lymphomas are rather indolent, most physi-
The pathogenic link between infection in the stomach and ulceration cians treat those that do not respond to H. pylori treatment with
in the duodenum is well accepted. Duodenal ulcers occur mainly in chemotherapy or low-dose radiotherapy.
patients with antrum-predominant gastritis, though the exact reasons
for the development of a particular pattern of gastritis are less clear.
The infection of the gastric antrum leads to local inflammation and a PROTECTION AGAINST
reduction in somatostatin-producing D cells, resulting in hypergas- GASTROESOPHAGEAL REFLUX
trinemia, as somatostatin inhibits gastrin production by G cells.16 Both DISEASE (GERD)
inflammation and hypergastrinemia are more marked in infection There is increasing epidemiologic evidence that people with H. pylori
with cag+ strains. High gastrin levels lead to increased basal and stimu- infection, especially those with pathogenic strains, are less likely to
lated acid output from parietal cells in the gastric corpus, which is most develop GERD and its sequelae – Barrett’s esophagus and esophageal
marked when the corpus is relatively spared of inflammation. The adenocarcinoma.22 This is of considerable interest because the inci-
resulting increased acid load entering the duodenum leads to the for- dence of these conditions has increased rapidly in higher-income
mation of adaptive gastric metaplasia (gastric mucosa in the duode- countries. Evidence suggests that reduced risk is associated with pan-
num). This can be colonized by H. pylori and local inflammation and gastritis and reduced gastric acid production, presumably as the gas-
the release of toxic bacterial products can cause ulceration. H. pylori troesophageal reflux is less damaging. In people with H. pylori infection,
also suppresses local mucosal defense mechanisms, thus increasing the its treatment may improve, worsen or not affect GERD symptoms and
tendency to ulcer development. Aspirin and NSAIDs can cause ulcers esophagitis. Thus the possibility of affecting or inducing GERD symp-
both independent of and synergistically with H. pylori infection. toms should not deter physicians from treating H. pylori, where an
indication exists.
GASTRIC ULCER DISEASE
H. pylori-associated gastric ulcers usually arise in junctional mucosa OTHER DISEASES
between antrum- and corpus-type tissues, typically on the lesser cur- H. pylori has been associated with iron deficiency anemia in the
vature. They usually occur in patients with pan-gastritis rather than absence of other causes of blood loss. This is thought usually to be due
antrum-predominant gastritis and these patients who have inflamma- to H. pylori-induced inflammation or atrophy leading to hypochlor-
tion involving the acid-producing gastric corpus usually have normal hydria, leading in turn to reduced iron absorption. In patients without
or reduced acid secretion. Although H. pylori is the most common extensive gastric atrophy H. pylori eradication may improve or nor-
cause of gastric ulceration in low- and middle-income countries, malize the blood count. Infection, gastritis and atrophy may also be
NSAIDs and aspirin use are now the leading causes in higher-income associated with B12 deficiency although this is usually mild compared
countries. They inhibit the production of local prostaglandins, princi- with autoimmune gastritis-induced pernicious anemia. Several studies
pally cyclo-oxygenase 1, that are responsible for maintaining mucosal have shown that treating H. pylori in patients with idiopathic throm-
defense leading to mucosal breakdown and ulceration. The develop- bocytopenic purpura leads to improvement in platelet counts in a
ment of ulcers in some but not all people taking these drugs is depen- proportion; this indication is now included in various guidelines
dent on multiple factors: specific drugs, dose, duration, age and other although more definitive studies would be desirable. Finally, about 1
associated co-factors. in 14 patients with functional dyspepsia sees a complete resolution of
symptoms with H. pylori treatment. Despite the poor efficacy, H.
GASTRIC ADENOCARCINOMA pylori-positive patients with functional dyspepsia usually undergo H.
The World Health Organization has classified H. pylori as a Class 1 or pylori treatment as the condition is difficult to treat using other
causal carcinogen. It is a risk factor for distal adenocarcinoma with a strategies.
relative risk of 4–9-fold and H. pylori is responsible for 75–90% of
worldwide gastric cancer.4,17,18 The relationship of H. pylori with proxi-
mal gastric adenocarcinoma is interesting. Cancers in this region Prevention
appear to have two etiologies: some are related to H. pylori infection Prevention of H. pylori infection is an attractive public health aim as
and others are related to gastroesophageal reflux.19 Thus overall in it could lead to a large reduction in the incidence of gastric adenocar-
most populations there is no association between H. pylori and gastric cinoma and peptic ulceration. It is unclear to what extent it might lead
cardia cancer. Gastric adenocarcinoma usually arises in patients with to an increase in GERD and its complications or, more controversially,
pan-gastritis or corpus-predominant gastritis. Patients with previous to other diseases of modern life such as autoimmune and allergic
duodenal ulceration (usually with antral-predominant or corpus- diseases. However, most authorities consider that the balance lies in
sparing gastritis) are relatively protected against gastric cancer. Strains favor of a benefit from H. pylori prevention. One solution would be
possessing the cag pathogenicity island and/or an active VacA cyto- immunization against H. pylori. However, although some vaccine
toxin are more likely to be associated with carcinoma than other research in animal models is encouraging, whether an effective human
strains. vaccine can be developed remains uncertain.
Clinical Features
ACUTE H. PYLORI INFECTION
H. pylori is most commonly acquired in childhood, but the clinical
features of acute infection in the community are unknown. However,
where high doses of H. pylori have been self-administered, upper
abdominal discomfort and pain occurred 3 days after dosing, followed
by vomiting and usually a resolution of symptoms by 1 or 2 weeks.23
CHRONIC H. PYLORI INFECTION

Chronic H. pylori infection is characterized by chronic active gastritis,
but this condition is usually asymptomatic. Chronic infection mani-
fests symptomatically when it causes diseases such as duodenal or
Figure 36-4 Helicobacter pylori (Gimenez stain). Other special stains that can
gastric ulceration. These may present with chronic epigastric discom- be used are the modified Giemsa stain or a silver stain such as Warthin–Starry
fort and other ‘dyspeptic’ symptoms and/or complications such as stain. (Courtesy of Dr M.M. Walker.)
hemorrhage, perforation, penetration, or gastric outflow obstruction.
In a small proportion of infected people, chronic gastritis per se
may cause symptoms although more usually such symptoms are due
to factors other than the H. pylori gastritis. Ten to fifteen infected
patients need be treated to cure one with non-ulcer dyspepsia. other tests. Biopsies should be put into a sterile solution and trans-
However, as non-ulcer dyspepsia is difficult to treat with any ferred as soon as possible to the laboratory. Methods for culture and
modality, the strategy of H. pylori treatment is recommended in many identification are discussed in Chapter 182. Cultured bacteria can be
guidelines.24 tested for antibiotic sensitivities and the main indication for culture is
previous failed treatment.
Diagnosis Histology
For all tests, other than serology, proton pump inhibitors (PPI) should Chronic active gastritis seen on standard hematoxylin and eosin
be stopped for at least 2 weeks and antibiotics for at least 4 weeks staining is strongly indicative of H. pylori infection, but unless special-
before testing, or false-negative results may occur. Diagnosis of H. ized stains are used (e.g. modified Giemsa, Gimenez (Figure 36-4),
pylori infection can be made by noninvasive tests or endoscopic Warthin–Starry, Genta or immunostaining), the bacterium may be
biopsy-based tests. Noninvasive tests include serology, the urea breath missed. Histology is expensive, but sensitive in experienced hands, and
test (UBT) and the stool antigen test. These tests are useful in primary may provide other useful information, such as the pattern of gastritis
diagnosis in young patients with dyspepsia. The urea breath test and and the presence of atrophy, metaplasia or dysplasia.
stool antigen test (but not serology) are useful in assessing the success
of H. pylori treatment. In patients undergoing endoscopy, these tests Biopsy Urease Test
are unnecessary because tests for H. pylori can be performed on gastric In this test, two gastric biopsies or one large biopsy are placed in a gel
biopsy specimens. or solution containing urea and a pH indicator. If H. pylori is present,
Following H. pylori treatment, whether and how to retest for its urease enzyme catalyzes urea hydrolysis and a color change occurs.
H. pylori depends on the treatment indication. If the treatment is These tests can be performed in the endoscopy room and are sensitive,
for uninvestigated dyspepsia, most physicians do not retest unless specific, cheap, convenient and quick. A positive result can be obtained
symptoms recur. Following gastric ulcer treatment, it is usual to in a few minutes, although for most commercial tests a 24-hour wait
repeat endoscopy to check mucosal healing as occasionally a gastric is necessary.
neoplasm can masquerade as an ulcer. In this situation, biopsy-based
tests can be repeated. In cases of duodenal ulceration, treatment NON-ENDOSCOPIC TESTS
success can be assessed noninvasively by the urea breath test or stool Urea Breath Tests
antigen test. Some physicians do not do this routinely unless symp- Several protocols exist, but in essence, the patient drinks urea solution
toms recur, but it is recommended for patients with complicated or isotopically labeled with stable 13C. If H. pylori is present, the urea is
large ulcers and our practice is to check treatment success in all patients hydrolyzed and labeled carbon dioxide can be detected in breath
with definite peptic ulceration. Serologic tests are not suitable for samples. The best UBT protocols are as specific as biopsy-based tests
checking the success of treatment as specific antibody levels fall only and are perhaps more sensitive as sampling error is avoided. The UBT
slowly. is a widely used test to check for treatment success in situations where
Many patients require endoscopy to assess indications for treat- repeat endoscopy is unnecessary, but must be performed at least 1
ment, and so tests for H. pylori can be performed at this time. The month after any antibiotic, bismuth or PPI treatment.
choice of endoscopic-based test depends upon the information
required, cost and convenience; usually only a biopsy urease test is Stool Antigen Tests
used. The simple stool antigen test is equivalent in accuracy and applicability
to UBT.25 However, the storage and handling of stool tests is crucial
ENDOSCOPIC TESTS FOR H. PYLORI and accuracy may be further reduced in the case of recent gastrointes-
Endoscopic tests are based on mucosal biopsy specimens. Infection tinal hemorrhage.
may be patchy, and so if possible two biopsies should be taken from
the usually more uniformly infected antrum to minimize sampling Serology
error. In some situations, notably after treatment, during acid- Although serology is cheap and convenient, a wide range of commer-
suppressive therapy or when intestinal metaplasia and atrophy are cial tests are available and most of these are less accurate than the stool
likely (e.g. in the elderly), the infection may be more marked in the antigen test and UBT. However, serology should still be considered in
corpus and at least two additional biopsies should be taken from there. patients where other tests may show a false-negative, such as patients
with bleeding ulcers, on PPI or with MALT lymphoma in whom other
Culture tests are negative. It may also be the best test for infection screening
Helicobacter pylori can be cultured from gastric biopsies, although in primary care, provided appropriate cut-off values are employed and
many laboratories find this difficult so sensitivity is low compared with the best locally validated test is used.
Management The management of duodenal ulcer disease diagnosed

The clearest indications for H. pylori treatment are peptic ulcer disease at upper gastrointestinal endoscopy
(whether active or previous) and low-grade MALT lymphoma.
However, H. pylori treatment is now commonly given for other indica-
tions, including iron deficiency anemia (when no other cause is found), Duodenal ulcer seen
ITP, or a family history of gastric cancer.3 Patients taking long-term at endoscopy
PPI have an increased risk of developing accelerated atrophic gastritis,
and although there is no evidence to date that this results in an Stop any NSAID or aspirin
increased risk of gastric adenocarcinoma, many physicians treat H. therapy and take biopsies for
pylori in these patients.3 Finally, in patients starting chronic or inter- Helicobacter pylori diagnosis
mittent NSAID or aspirin therapy (e.g. patients with arthritis) there is
good evidence that ulcer risk is reduced if H. pylori is first treated.
However, in high-risk patients other strategies to prevent drug-
associated ulcer are more effective, including co-prescription of PPI Helicobacter Helicobacter
and using less ulcerogenic drugs. In some communities, for example pylori positive pylori negative
Japan and north China, H. pylori is treated almost wherever it is found
because the risk of gastric cancer is high. In the USA and most of
Europe the risk–benefit is much less clear: cancer risk is lower and is Treat with first- Recent aspirin
unlikely to be much reduced by treatment in older patients. In younger line regimen or NSAID use? Yes
patients without any gastric atrophy it is likely that future cancer risk
will be reduced, however treatment may have side effects and use of UBT>4
No
combination broad-spectrum antibiotics may be detrimental to the weeks post Stop these
community through inducing resistance in H. pylori and other bacteria treatment drugs and heal
carried incidentally. ulcer with acid
Treat with Positive suppression
PEPTIC ULCER DISEASE second-line Negative
Eradication of H. pylori not only heals ulcers but also prevents their regimen or
recurrence. Therefore, once an ulcer is diagnosed at endoscopy, H. repeat Symptoms
endoscopy with Investigate for other causes
pylori infection should be sought and treated if found (Figure 36-5). persist
of covert ulcer:
This is usually done immediately, but if there is a delay in performing culture and
antibiotic No Yes • NSAID use
diagnostic tests for H. pylori, ulcer healing can begin with acid- sensitivities to • False-negative
suppressing drugs and H. pylori treatment can be started when the guide treatment Helicobacter pylori tests
infection has been confirmed. Stop • Rare causes (see Table 36.2)
• Meanwhile, heal ulcer with
UNINVESTIGATED DYSPEPSIA acid suppression
In young patients with dyspepsia, most national and other guidelines
include a ‘test and treat’ approach: noninvasive testing for H. pylori Investigate for
(thus avoiding endoscopy) and treatment if positive.3 This reduces other causes
of symptoms
the number of endoscopies performed (and therefore cost), is more
comfortable and convenient for patients, and is equivalent for success-
ful management of symptoms. The other major approach to uninves- Figure 36-5 Decision algorithm for the management of duodenal ulcer disease
tigated dyspepsia is to prescribe a fixed course of acid inhibition diagnosed at upper gastrointestinal endoscopy. UBT, urea breath test.
with a PPI and move to H. pylori test and treat if symptoms do not
settle. Which approach is better is not fully determined but economic guidelines in the future; for this reason we recommend reserving levo-
and other analyses suggest ‘test and treat’ is better if the expected floxacin to third line where possible.
H. pylori prevalence is >20%. In older patients with new dyspepsia, In areas where clarithromycin resistance is low, such as Northern
endoscopy is still performed in order to avoid delay in diagnosing Europe, clarithromycin-based triple therapy is first line (Table 36-3).
gastric cancer. Thus the age cut-off for deciding who should undergo Second-line treatment consists of bismuth quadruple therapy or
endoscopy depends on the local incidence and demographics of levofloxacin-based triple therapy. Failure of second-line therapy is an
this disease; it is usually set at between 40 and 55 years. All patients indication for endoscopy and H. pylori culturing should be carried out.
with ‘alarm’ symptoms or signs such as weight loss, dysphagia, persis- However, if this is not possible it is acceptable to prescribe a proven
tent vomiting, gastrointestinal bleeding, unexplained anemia, epigas- antibiotic regimen that has not been previously used.
tric mass, previous gastric ulcer or gastric surgery should be referred In areas where clarithromycin resistance is high or unknown, or
for upper gastrointestinal endoscopy and/or other investigations where an individual has had exposure to clarithromycin, bismuth qua-
regardless of age, both to exclude malignancy and to make a positive druple therapy is recommended as first-line empirical treatment. The
diagnosis. alternative to this regimen is sequential or concomitant therapy.
Second-line treatment is with the alternative, or with levofloxacin-
H. PYLORI TREATMENT REGIMENS based triple therapy. Antibiotic sensitivity testing should be carried out
Increasing clarithromycin resistance in many parts of the world has if these regimens fail.
changed approach to treatment. Areas are classified by prevalence of
resistance: greater or less than 15–20%. Eradication begins with the Triple Therapy
most affordable empirical treatment expected to be effective.3 Metro- This consists of a twice-daily PPI at full dose and two antibiotics
nidazole resistance is common but only partial and has only a minor (clarithromycin, and either amoxicillin or metronidazole) for 7 or 14
effect on antibiotic efficacy; thus metronidazole-containing regimens days. However, this regimen has cure rates below 80%.3 Treatment
are still used in patients with resistant strains, so the clinical utility of failures are attributed to poor compliance (though largely avoidable
testing for metronidazole resistance is limited. Levofloxacin resistance by adequate counseling about mild drug side effects), antibiotic resis-
is an increasing problem which may require further adaptions to tance, high bacterial load, PPI metabolism, smoking and strain
genotype. A 7-day regimen is commonly used but 14 days are 5–10% TABLE
more effective; cost-effectiveness of increasing dosing duration is, 36-3 Helicobacter pylori Treatment Regimens
however, unclear.
Low Clarithromycin High Clarithromycin
Bismuth Quadruple Therapy Resistance Areas Resistance Areas
This consists of a 2-week regimen with a PPI, a bismuth salt and two First-line treatment Triple therapy* Bismuth quadruple
antibiotics (metronidazole and tetracycline hydrochloride). With this Or therapy†
regimen, cure rates of around 90% have been achieved when used as Bismuth quadruple Or
therapy† Non-bismuth quadruple
first line.26 This success in part is due to the avoidance of clarithromy- therapy (sequential
cin but the main disadvantages are the daily pill burden and compli- or concomitant)§
ance, though newer combination preparations are available.
Second-line Bismuth quadruple The regimen above not
treatment therapy† used first line
Sequential and Concomitant Therapy Or Or
Sequential therapy comprises 5 days of amoxicillin with PPI, immedi- Levofloxacin-based Levofloxacin-based
ately followed by 5 days of clarithromycin, metronidazole and PPI.27 triple therapy‡ triple therapy‡
An alternative is concomitant therapy which uses the four above- Third-line treatment Based on antibiotic sensitivity testing
named agents in combination for 10–14 days, with cure rate reported
at 88%. Performance of both therapies is superior to triple therapy and Note that doses, formulations and availability of drugs vary between countries
and prescribers should check carefully with their national guidelines and
we recommend concomitant, which is becoming the more widely formularies.
used. Doses are as for triple therapy in Table 36-3 with the fourth drug *Triple therapy = PPI 12 hourly, amoxicillin 500 mg 12 hourly, clarithromycin
included.28 250–500 mg 12 hourly or metronidazole 400 mg 12 hourly for 7–14 days.
†
Bismuth quadruple therapy = PPI 12 hourly, bismuth tripotassium
Levofloxacin-Based Triple Therapy dicitratobismuthate 120 mg 6 hourly (subsalicylate or subcitrate bismuth salts
are used at different doses in other countries), tetracycline HCl 500 mg 6
This consists of this quinolone antibiotic in combination with amoxi- hourly and metronidazole 400 mg 8 hourly for 14 days.
cillin and a PPI for 10–14 days. Although it is a convenient regimen, ‡
Levofloxacin-based triple therapy = PPI 12 hourly, levofloxacin 500 mg 12
to minimize drug resistance to levofloxacin it is currently recom- hourly and amoxicillin 1 g 12 hourly for 10 days.
mended as second-line empirical therapy only, and we recommend
§
Non-bismuth quadruple therapy = see text.
Reproduced from Malfertheiner P, Megraud F, O’Morain CA, et al.:
that where possible it is reserved for third line. Management of Helicobacter pylori infection. Gut 2012;61(5):646–664.
Alternative and Adjuvant Therapies
Probiotics may improve patient tolerance of side effects of treat
ment, such as diarrhea, if given alongside eradication treatment.
Smoking cessation should be encouraged. Other potential future
experimental therapies include photodynamic therapy and therapeutic
vaccination.
KEY REFERENCES
Atherton J.C., Peek R.M. Jr, Tham K.T., et al.: Clinical and Malfertheiner P., Megraud F., O’Morain C.A., et al.: Man- Moayyedi P., Soo S., Deeks J., et al.: Eradication of Helico-
pathological importance of heterogeneity in vacA, the agement of Helicobacter pylori infection – the Maastricht bacter pylori for non-ulcer dyspepsia. Cochrane Database
vacuolating cytotoxin gene of Helicobacter pylori. Gastro- IV/Florence Consensus Report. Gut 2012; 61(5): Syst Rev 2006; (2):CD002096.
enterology 1997; 112(1):92-99. 646-664. Rhead J.L., Letley D.P., Mohammadi M., et al.: A new Heli-
Blaser M.J., Chen Y., Reibman J.: Does Helicobacter pylori Marshall B.J., Warren J.R.: Unidentified curved bacilli in the cobacter pylori vacuolating cytotoxin determinant, the
protect against asthma and allergy? Gut 2008; 57(5): stomach of patients with gastritis and peptic ulceration. intermediate region, is associated with gastric cancer.
561-567. Lancet 1984; 1(8390):1311-1315. Gastroenterology 2007; 133(3):926-936.
Correa P.: Helicobacter pylori and gastric carcinogenesis. Am McNicholl A.G., Marin A.C., Molina-Infante J., et al.: Ran- Zullo A., Hassan C., Ridola L., et al.: Standard triple and
J Surg Pathol 1995; 19(Suppl.1):S37-S43. domised clinical trial comparing sequential and con- sequential therapies for Helicobacter pylori eradication:
de Martel C., Ferlay J., Franceschi S., et al.: Global burden comitant therapies for Helicobacter pylori eradication in an update. Eur J Intern Med 2013; 24(1):16-19.
of cancers attributable to infections in 2008: a review and routine clinical practice. Gut 2014; 63(2):244-249.
synthetic analysis. Lancet Oncol 2012; 13(6):607-615.
Chapter 36 Gastritis, Peptic Ulceration and Related Conditions 327.e1
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in the stomach of patients with gastritis and peptic 1995; 270(41):23937-23940. MALT lymphomas: implications for prognosis and
ulceration. Lancet 1984; 1(8390):1311-1315. 12. Atherton J.C., Peek R.M. Jr, Tham K.T., et al.: Clinical management. Gut 2006; 55(6):886-893.
2. Fox J.G.: The non-H. pylori helicobacters: their expand- and pathological importance of heterogeneity in vacA, 22. Vakil N.B.: Review article: gastro-oesophageal reflux
ing role in gastrointestinal and systemic diseases. Gut the vacuolating cytotoxin gene of Helicobacter pylori. disease and Helicobacter pylori infection. Aliment Phar-
2002; 50(2):273-283. Gastroenterology 1997; 112(1):92-99. macol Ther 2002; 16(Suppl.1):47-51.
3. Malfertheiner P., Megraud F., O’Morain C.A., et al.: 13. Rhead J.L., Letley D.P., Mohammadi M., et al.: A new 23. Marshall B.J., Armstrong J.A., McGechie D.B., et al.:
Management of Helicobacter pylori infection – the Helicobacter pylori vacuolating cytotoxin determinant, Attempt to fulfil Koch’s postulates for pyloric Campy-
Maastricht IV/Florence Consensus Report. Gut 2012; the intermediate region, is associated with gastric lobacter. Med J Aust 1985; 142(8):436-439.
61(5):646-664. cancer. Gastroenterology 2007; 133(3):926-936. 24. Moayyedi P., Soo S., Deeks J., et al.: Eradication of Heli-
4. de Martel C., Ferlay J., Franceschi S., et al.: Global 14. Lu H., Hsu P.I., Graham D.Y., et al.: Duodenal ulcer cobacter pylori for non-ulcer dyspepsia. Cochrane Data-
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13(6):607-615. 15. El-Omar E.M., Carrington M., Chow W.H., et al.: monoclonal stool antigen test for the diagnosis of H.
5. Pounder R.E., Ng D.: The prevalence of Helicobacter Interleukin-1 polymorphisms associated with increased pylori infection: a systematic review and meta-analysis.
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col Ther 1995; 9(Suppl. 2):33-39. 16. el-Omar E.M., Penman I.D., Ardill J.E., et al.: Helico- 26. Laine L., Hunt R., El-Zimaity H., et al.: Bismuth-based
6. Harford W.V., Barnett C., Lee E., et al.: Acute gastritis bacter pylori infection and abnormalities of acid secre- quadruple therapy using a single capsule of bismuth
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10. Kwok T., Zabler D., Urman S., et al.: Helicobacter gastric cardia cancer. Gut 2008; 57(3):298-305. tion in routine clinical practice. Gut 2014; 63(2):244-
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11. de Bernard M., Papini E., de Filippis V., et al.: Low pH
activates the vacuolating toxin of Helicobacter pylori,
37
Food-Borne Diarrheal Illness
CHRISTOPHER P. CONLON
KEY CONCEPTS and leads to almost 130 000 hospitalizations and 3000 deaths.2 Figures
from the UK estimate 1.7 million cases of food-borne disease per year,
• Food-borne illness is a global problem and results in consider- with around 22 000 hospitalizations and 690 deaths.3 In both countries
able costs, morbidity and mortality. the most likely foodstuff to be associated with illness was poultry, but
• Enteric pathogens have evolved a variety of mechanisms to many foods have been implicated (Figure 37-1). Although deaths from
overcome host defences and cause disease, ranging from dif- food-borne illnesses are rare in higher-income countries, the risk is
ferent adhesion molecules to the elaboration of a variety of highest at the extremes of age, particularly the elderly, and Salmonella
toxins. infections are most commonly associated with fatal outcomes.5 In
addition to health problems, food-borne illness carries a large eco-
• The epidemiology of infections causing diarrhea varies geo-
graphically but Campylobacter and non-typhoidal salmonellae nomic burden.
remain the most common bacterial pathogens. Although most cases of food poisoning are sporadic, outbreaks are
important causes of significant illness. Between 1998 and 2008 there
• Viruses, particularly norovirus, are increasingly recognized as were 13 352 outbreaks in the USA, leading to a quarter of a million
causes of food-borne illness and diarrhea in both children and hospitalizations.6 Point source outbreaks can affect thousands of
adults.
people when the contaminated food has been distributed over a wide
• New moleclular diagnostic methods are supplanting stool geographic area. Ice cream contaminated with Salmonella affected
microscopy and culture. 224 000 people in the USA in 1994.7Although Campylobacter is the
most common bacterial cause of food-borne diarrhea, Salmonella is
• The mainstay of management of food-borne illness causing
diarrhea is adequate oral rehydration, with intravenous fluids more associated with outbreaks. This may be because Campylobacter
and antibiotics only necessary in a minority of cases. does not multiply well in food. Increasingly, outbreaks are related to
illness in food handlers and, particularly in the case of norovirus, there
• Travelers’ diarrhea is very common in short-term visitors from can be person-to-person spread from an initial food poisoning
industrialized countries to low- and middle-income countries, episode.8
and enterotoxigenic E. coli (ETEC) is a common cause
Studies in industrialized countries show that viruses are a more
worldwide.
important cause of community-acquired gastroenteritis than hitherto
recognized.9 Disease due to viruses seems more common in the winter
while that due to Salmonella or Campylobacter is more likely to occur
in the summer months.10 More recently, with the advent of molecular
testing a wider range of potential pathogens has been identified and in
Introduction up to 20% of cases more than one pathogen can be found.11 However,
Food-borne illness is defined by the World Health Organization case–control studies show that these multiple pathogens can also be
(WHO) as a disease, either infectious or toxic in nature, caused by found in asymptomatic individuals. Many bacteria identified are types
agents that enter the body through the ingestion of food; however, a of Escherichia coli that may be pathogenic in the small bowel but may
more symptom-based case definition may be more useful.1 Every be carried asymptomatically in the large bowel.12
person on the planet is at risk from food-borne illness but the risk Because there are few reporting regulations and no routine surveil-
varies geographically and also by age. Most food-borne illness results lance, data about food-borne disease in LMIC are sparse. Most deaths
in vomiting and/or diarrhea and is commonly called food poisoning. from diarrhea in the tropics are related to food and water contamina-
In practice, although most illness is related to food ingestion, some tion with estimates of up to almost two million deaths per year. Most
may be related to consuming contaminated water as well as food. In deaths occur in young children, especially those under 5 years old, with
higher-income, industrialized countries each adult consumes annually one estimate of up to a 2% case fatality rate.13
at least 500 liters of water and about 450 kg of meat and vegetables,
along with other foodstuffs and liquids. Food production and distribu- Host Susceptibility
tion have become extremely complex in industrialized countries. It is The low pH of the gastric contents provides an effective barrier to
now commonplace for food to be consumed long distances from its infection by food and water-borne pathogens. The widespread use of
source and, often, a long time after its production. There is also an H2 antagonists and proton pump inhibitors leads to achlorhydria and
increasing tendency to eat food away from the home prepared by an increased ability of bacteria to survive in the stomach.14 Mucus
others. In low- and middle-income countries (LMIC) consumption is produced in the intestine acts as a barrier to pathogen adherence to
less and food is usually produced and consumed locally. However, the the intestinal epithelium and may physically trap bacteria. Normal
lack of refrigeration and the problems of access to potable water create intestinal motility helps the mucus entrap and move potential patho-
their own risks. This chapter will consider the causes of water-borne gens through the gut.
and food-related diarrhea, its investigation and management. The normal intestinal flora, commonly termed the enteric micro-
biome, act to protect the gut from infection. These bacteria, mainly of
Epidemiology the Bacteroides and Firmicutes genera, produce short chain fatty acids
Diarrhea due to the ingestion of contaminated food and/or water is that can be toxic to some bacterial pathogens.15 In addition, the normal
common throughout the world but the incidence and causes vary flora act to occupy niches in the gut and prevent the adherence of
geographically. In the USA it is estimated that around 178 million cases pathogens, so-called colonization resistance.
of acute gastroenteritis occur each year. Infections caused by food There are undoubtedly individuals who are more susceptible to
consumed in the USA accounts for almost 50 million of these cases infectious diarrhea than others but it is unclear which genes are
328
Chapter 37 Food-Borne Diarrheal Illness 329
Distribution of different foodstuffs causing outbreaks of illness in Europe, 2010
Bovine meat and Cheese, 2.3 % Fruit, berries and juices

products thereof, 3.3% and other products N=698
thereof, 1.3 %
Pig meat and
products thereof
Eggs and egg products

4.9% 22.1 %
Other or mixed meat
and products thereof
6.0 %
Broiler meat (Gallus
gallus) and products
thereof 6.0 %
6.3 %
13.9 %
Mixed or buffet meals
Fish and fish products
7.9 %
8.9 %
8.5 %
Bakery products 8.7 %
Other foods
Crustaceans, shellfish, Vegetables and juices

molluscs and products and other products
thereof thereof
Figure 37-1 Distribution of different foodstuffs causing outbreaks of illness in Europe, 2010 (European Food Safety Authority, 20124).
involved. Some studies have identified polymorphisms in lactoferrin

genes and in those encoding CD14 that may play a role in susceptibility TABLE Doses of Infectious Agents Needed to Cause
37-1 Diarrheal Illness (ID25)
to intestinal pathogens.16 In addition, those with blood group O seem
less likely to get cholera but are more likely to get severe disease if
Enteropathogen ID25
infected.17 There is also some evidence to suggest that blood group A
secretors are more prone to norovirus infection. Shigella spp. 10–100
Giardia and Cryptosporidium parvum 30–100

Pathogenesis (see also Chapter 2)
Shiga-toxin Escherichia coli O157:H7 10–100
Bacteria, viruses, protozoa and even helminths have all been associated
with food-borne diarrhea (Table 37-1). Different pathogens have Norwalk-like virus 100
evolved a variety of methods of overcoming host resistance in order Salmonella 103–105
to cause disease. Bacteria are the most common cause of food- and
water-borne disease and are the best studied. The more pathogenic Campylobacter 103–106
organisms require a lower inoculum than others (Table 37-2). In Vibrio cholerae 106
essence, there are two ways that infection leads to diarrhea. The first
Enterotoxigenic Escherichia coli 108
is by the elaboration of toxins or some other way of damaging epithe-
lial cells that leads to net secretion of fluid into the intestinal lumen.
The second is by invasion of the gut mucosa that causes inflammation
and consequent diarrhea. The former largely involves the proximal
small bowel and the latter the distal small bowel and the colon. cholera toxin, the details of which were described some years ago.20
This toxin has five B subunits that bind to the enterocyte, allowing the
ADHERENCE active A1 subunit to enter the cell and activate adenylate cyclase
In order to cause disease, bacteria must adhere to the intestinal mucosa. (Figure 37-2). This increases intracellular cyclic AMP resulting in
They have evolved a variety of colonization factor antigens (CFA), increased secretion of chloride ions by crypt cells while also inhibiting
often on fimbriae that protrude from the bacterial cell wall. The CFA absorption of sodium and chloride ions. The net result is excessive
are usually genetically encoded on plasmids which are transferrable to secretion of fluid and electrolytes into the bowel lumen. Goblet cells
other pathogens.18 The mechanisms have been elucidated best in E. are also probably affected by the toxin causing excess mucus secretion
coli, but Salmonella (see Chapter 115) and Shigella strains use similar as well. The absorptive capacity of the large bowel is exceeded leading
mechanisms.19 to watery diarrhea. The excess mucus is responsible for the ‘rice water’
appearance of the stool.
ENTEROTOXINS Many other bacteria produce enterotoxins. Enterotoxigenic E. coli
Most cases of secretory diarrhea due to bacteria are caused by entero- (ETEC) produce a heat-labile toxin (LT) that is very similar to cholera
toxins elaborated by the pathogens. The classic example of this is toxin (see Chapter 180). Salmonella and Campylobacter also produce
TABLE
37-2 Characteristics of Selected Food-Borne Illnesses Associated with Diarrhea (Arranged by Incubation Period)
Median Incubation
Period in Hours
Organism (Range) Vomiting Diarrhea Fever Other Symptoms Common Vehicles
Histamine fish poisoning 5 min to 1 hour + +++ – Headache, flushing, urticaria Tuna, mackerel, bonito, mahi-mahi,
(scombroid) bluefish
Bacillus cereus (emetic 2 (1–6) +++ + – Fried rice

syndrome)
Ciguatera 2 (1–6) + ++ – Paresthesias, myalgias, Barracuda, snapper, grouper,

headache, arthralgia amberjack
Staphylococcus aureus 3 (1–6) +++ ++ – Ham, poultry, cream-filled pastries,

potato and egg salad
Bacillus cereus (diarrheal 9 (6–16) + +++ – Abdominal cramps Beef, pork, chicken
syndrome)
Vibrio cholerae non-O1 11 (5–96) + +++ +++ Abdominal cramps, bloody Fish, shellfish
diarrhea (25%)
Clostridium perfringens 12 (6–24) + +++ – Abdominal cramps Beef, poultry, gravy
Vibrio parahaemolyticus 15 (4–96) ++ +++ ++ Abdominal cramps, headache, Fish, shellfish

bloody diarrhea (rare)
Norovirus 24 (12–48) +++ +++ ++ Headache, myalgias Water, ice, shellfish, salads
Shigella spp. 24 (7–168) + +++ +++ Abdominal cramps, bloody Lettuce, street food
diarrhea
Enterotoxigenic 36 (16–72) + +++ + Abdominal cramps, headache, Ice, water, produce

Escherichia coli myalgias
Salmonella spp. 36 (12–72) + +++ ++ Abdominal cramps, headache, Beef, poultry, pork, eggs, dairy
myalgias products, vegetables, fruit
Vibrio cholerae O1 48 (6–120) ++ +++ + Dehydration Shellfish
Campylobacter jejuni 48 (24–168) + +++ +++ Abdominal cramps, bloody Poultry, milk
diarrhea, myalgias
Giardia lamblia 1–2 weeks + +++ – Abdominal cramps Water, raw vegetables
Watery diarrhea
Entamoeba histolytica 2–4 weeks − ++ + Bloody diarrhea Water, raw vegetables
Key: –, rare symptom (<10%); +, infrequent symptom (11–33%); ++, frequent symptom (33–66%); +++, classic symptom.
toxins but these are not usually the main pathogenetic factors for these formed in food and although the predominant symptoms are neuro-
organisms. Most of these enterotoxins act by increasing either cAMP logic, vomiting and diarrhea can be early features.
or cGMP.
PATHOGENIC MECHANISMS OF
CYTOTOXINS OTHER ORGANISMS
Unlike enterotoxins, cytotoxins cause inflammation in the intestinal Rotavirus appears to cause damage to the epithelial cells at the tips of
mucosa. They mainly affect the distal small bowel and colon producing villi in the small intestine. This appears to involve production of an
inflammatory changes that can mimic inflammatory bowel disease. enterotoxin that alters epithelial permeability. This in turn leads to loss
The classic cytotoxin is Shiga toxin elaborated by Shigella dysenteriae.21 of sugars and proteins that are osmotically active and results in a secre-
This toxin has a B subunit that adheres to the enterocyte and an A tory diarrhea.25 The mechanism of action of norovirus is uncertain but
subunit that disrupts protein synthesis in the 60S ribosome. Vascular may involve disruption of mucosal disaccharidases.
endothelium may also be a target, explaining the capillary lesions seen Some protozoa, such as Giardia lamblia, may disrupt brush border
in the mucosa. enzymes in the small bowel villi.26 This can cause moderate malabsorp-
A toxin almost identical to Shiga toxin is produced by enterohem- tion and could explain why chronic diarrhea is more a feature of these
orrhagic E. coli (EHEC), notably E. coli O157:H7. Symptoms and organisms. Cryptosporidium parvum adheres to small intestinal mucosa
pathology can be indistinguishable from dysentery.22 The O157:H7 and activates cAMP causing cholera-like diarrhea. Entamoeba histo-
strain can also cause hemolytic uremic syndrome (HUS) via effects on lytica may produce a cytopathic effect by secreting proteinases, damag-
renal vascular endothelium. It is now recognized that other non-O157 ing enterocytes and inducing inflammation.27
serotypes of EHEC can also cause HUS.23 Clostridium perfringens and
some Salmonella strains also produce similar toxins.
Clinical Features
NEUROTOXINS Diarrhea related to contaminated food and water can present in a
Some bacteria produce toxins that act primarily on the emetic center variety of ways and often the timing of onset and the accompanying
in the central nervous system and on the autonomic system causing clinical symptoms and signs can help to focus on the likely pathogens.
vomiting and diarrhea. These toxins are pre-formed in the food and Those that affect the small bowel mainly cause watery, secretory diar-
so cause symptoms within hours of ingestion. Staphylococcal food rhea and are more likely to be associated with vomiting. Pathogens
poisoning is a classic example of this.24 Botulinum toxin is also pre- that are more invasive and cause inflammatory disease predominantly
Mechanism of action of cholera toxin
Cholera bacterium Coupled

NaCl channel
Cholera toxin
(Decreased
NaCl
A1 absorption)
B units (Increased
A2 NaCl-
chloride
secretion)
Figure 37-3 Post-mortem specimen of colon showing discrete, ‘flask-like’ ulcers
GMI caused by amebic dysentery.
receptor
A2 Chloride
Cl- channel
(Chloride
Intestinal channel excess Activated enterocolitica. In such cases fever is common but vomiting only occurs
epithelial phosphorylation) protein in the minority. Occasionally, the inflammation is so severe as to
cell kinase mimic acute inflammatory bowel disease and may lead to toxic
Cell megacolon.
nucleus Protein
kinase
cAMP BLOODY DIARRHEA SEVERAL DAYS
ADP AFTER EATING
phosphorylation cAMP[] While this may classically occur with Shigella infection or amebic
dysentery (Figure 37-3), it is more common with EHEC, when symp-
(Increased cyclic AMP concentration) toms take a few days to evolve. Bloody diarrhea usually occurs in the
absence of fever. HUS may complicate diarrhea caused by E. coli
Figure 37-2 Mechanism of action of cholera toxin. A similar mechanism occurs O157:H7 and other serotypes.32 Although most cases are sporadic,
with enterotoxigenic Escherichia coli (ETEC) heat-labile (LT) toxin. large outbreaks have occurred, including one linked to ground beef
that was distributed widely in the USA.33
CHRONIC DIARRHEA
affect the large bowel. This often results in bloody diarrhea and/or
systemic symptoms including fever. The stool usually contains leuko- Diarrhea lasting more than 2 weeks is termed chronic and may occa-
cytes and red cells indicating significant inflammation. Whatever the sionally be due to infection acquired from food or water.34 The most
cause, one of the most common clinical features is dehydration, some- common is giardiasis but cryptosporidiosis and amebiasis can do this.
times severe enough to warrant hospitalization. Sometimes helminths that involve the intestines, such as schistosomia-
sis or Strongyloides stercoralis, can lead to chronic diarrhea but these
EARLY ONSET DIARRHEA WITH VOMITING are not acquired by ingestion of food.
If vomiting and diarrhea occur within a few hours of a meal the likely
cause is the ingestion of pre-formed toxins. Staphylococcus aureus and Non-infective Food Poisoning
Bacillus cereus are the most commonly involved organisms. They mul- Some foodstuffs may lead to diarrhea and/or vomiting because of
tiply and produce toxins in the food. Vomiting is usually more of a toxins in the food that are not the product of infectious agents. Most
feature than diarrhea and although severe dehydration can occur, the commonly these syndromes relate to the ingestion of mushrooms or
symptoms rarely last more than 24 hours. seafood but it should be remembered that heavy metal poisoning, such
Very similar symptoms can be produced by norovirus and other as cadmium, can cause severe gastric irritation and lead to vomiting
viruses like sapovirus and rotavirus. Again, vomiting is the more domi- and abdominal pain.
nant symptom, although the incubation period is longer. Because of
the high viral load of vomitus, person-to-person spread is common. SCOMBROID POISONING
Particular problems occur in hospitals, nursing homes and cruise The ingestion of certain oily fish, such as mackerel and tuna (Figure
ships, often with infected food-handlers the source of infection. 37-4) is associated with a syndrome of flushing, vomiting and diarrhea
within an hour of eating. The symptoms are due to excessive histamine
DIARRHEA WITHIN 24 HOURS OF EATING exposure. Poorly cleaned or stored fish contain bacteria that break
Food containing Clostridium perfringens or B. cereus will lead to diar- down fish muscle so that histamine builds up. Cooking does not
rhea after about 8–16 hours. In these cases bacteria have to multiply destroy the histamine and if enough is ingested, the symptoms follow
in the gut and generate toxins in vivo. Watery diarrhea, usually with soon afterward.
abdominal cramps, is the main feature and vomiting is unusual.
CIGUATOXIN POISONING
DIARRHEA 1–2 DAYS AFTER EATING Some tropical fish, such as barracuda, may contain a toxin, ciguatoxin,
The majority of cases of food-borne diarrhea occur 24–48 hours after that can lead to abdominal cramps and diarrhea a few hours after
eating. In sporadic cases of food poisoning, Campylobacter jejuni is the ingestion, often associated with circumoral paresthesia. The heat-
most common cause identified whereas Salmonella species, such as S. stable toxin probably derives from dinoflagellates in the food chain
enteritidis, is the most common organism associated with outbreaks.28 that are not affected by cooking the fish. The neurologic symptoms
Other less common causes include Listeria monocytogenes, Aeromonas may persist for some days afterward.
spp. and Plesiomonas shigelloides.29–31 Most cases have watery diarrhea
and many have abdominal cramps. More severe disease with clear MUSHROOM POISONING
inflammation in the colon can occur with Campylobacter and Salmo- Most of the serious complications from eating certain mushrooms are
nella and in these cases blood in the stool is not uncommon. A similar neurologic. However, nausea, abdominal pain and diarrhea can occur
syndrome can be seen with invasive E. coli infections and with Yersinia early on.35 The worst type of poisoning is that due to Amanita species
cases may be due to giardiasis but there is also a small risk (<10%) of
irritable bowel syndrome developing after travelers’ diarrhea.40
DIARRHEA IN THE IMMUNOCOMPROMISED

Before the advent of highly active antiretroviral therapy (HAART)
diarrhea was a common feature of human immunodeficiency virus
(HIV) infection, sometimes due to food-borne pathogens. Infections
with protozoa, such as Cryptosporidium parvum or Isosopora belli, were
common in the pre-HAART era. These problems are rarely seen now
in well-resourced countries where people receive HAART, but still
contribute to the burden of disease in resource-poor countries.
Patients who have received solid organ transplants or who have
hematologic malignancies or are undergoing chemotherapy are more
at risk of food-borne diarrhea because of immunosuppression. They
may be prone to some of the rarer protozoal infections but recent data
suggest that norovirus may be a significant cause of chronic diarrhea.41
Diagnosis
CLINICAL FEATURES
Figure 37-4 Mackerel and other oily fish may lead to scombroid poisoning, a
noninfective cause of food-related diarrhea. Although the symptoms of diarrheal illness are usually obvious, the
history needs to be elucidated to ensure that there is increased bowel
frequency and altered stool consistency. Diarrhea is best defined
as three or more bowel movements in 24 hours in which the stool is
loose and takes the shape of the container. Watery diarrhea is more
likely to be due to infections affecting the small bowel, such as ETEC
or viruses. Bloody diarrhea with abdominal discomfort usually reflects
large bowel involvement by organisms such as C. jejuni, S. enteritidis,
EHEC etc.
The symptoms described are typically seen in food-borne illness
causing acute diarrhea. Protozoa, like Giardia, are more likely to result
in chronic diarrhea; symptoms may persist for more than 2 weeks.
Clinical examination rarely helps in differential diagnosis but is
important to assess the hydration state and to ensure there is not a
‘surgical’ abdomen. Of note, some enteric infections, particularly
Campylobacter, are associated with extraintestinal symptoms and
signs, such as reactive arthritis and Guillain–Barré syndrome.
NONSPECIFIC LABORATORY TESTS

Blood tests might show evidence of inflammation, with a raised white
cell count or C-reactive protein. Anemia may be a feature if there is
Figure 37-5 Electron micrograph of norovirus, a common cause of diarrhea.
dysentery and biochemical tests can assess renal function.
(e.g. Amanita phalloides) when diarrhea and abdominal cramps occur RADIOLOGY
within hours followed a day or two later by hepatorenal failure which Radiographs do not help to establish an etiology of infection but
carries a substantial mortality risk. can be useful in cases of dysentery. Rarely acute infective diarrhea
can mimic inflammatory bowel disease and even lead to a toxic
Special Clinical Sydromes megacolon.
TRAVELERS’ DIARRHEA ENDOSCOPY
Travelers’ diarrhea (see also Practice Point 11) is estimated to affect Upper gastrointestinal endoscopy has no place in the investigation of
up to 50% of those traveling abroad, with as many as 11 million cases acute diarrhea but might sometimes help to diagnose giardiasis in cases
annually around the world.36 Although any of the pathogens described of chronic diarrhea. Flexible sigmoidoscopy can be helpful in those
above may be the cause, the most common one globally is ETEC.37 with dysentery and might help to distinguish the discrete ulcers (sur-
This organism produces an enterotoxin that is similar to cholera toxin, rounded by normal mucosa) seen in amebiasis from the pan-proctitis
resulting in watery diarrhea. As with any food-borne illness, Campy- in inflammatory bowel disease. Biopsies can show trophozoites ingest-
lobacter and Salmonella cause a significant proportion of travelers’ ing red cells in the tissue.
diarrhea, as does norovirus in some settings38 (Figure 37-5).
Risk factors for travelers’ diarrhea include travel from an industri- BLOOD CULTURES
alized country to an LMIC, staying in self-arranged accommodation, If the patient is febrile, it is sensible to take blood cultures but in most
eating shellfish and gastric achlorhydria.39 The highest regions for risk cases of food-borne illness causing diarrhea they will be negative.
are South Asia and South East Asia, along with Central and South However, about 1% of cases of non-typhoidal Salmonella infections
America. The poorer countries of Africa also carry a significant risk. are associated with bacteremia, particularly in the elderly or in cases
Symptoms of travelers’ diarrhea usually start within 2–3 days of occurring in the tropics.42
arrival and almost all cases occur within the first two weeks. Usually
the symptoms are short-lived but up to 40% of travelers have to alter STOOL EXAMINATION
their travel plans as a consequence and about 1% need to be hospital- Microscopy of the stool in infectious diarrhea is rarely diagnostic. The
ized. A small number of people go on to have chronic diarrhea. Some finding of white cells and/or red cells points to colonic inflammation
but their absence does not exclude colonic involvement. Some studies
have addressed the utility of testing the stool for lactoferrin, a marker TABLE Composition of Oral Rehydration Solution
37-3 Recommended by WHO
of leukocytes, as a sign of inflammation.43 However, this relatively
expensive assay is rarely used in practice. The main utility of stool
Solute g/L mmol/L
microscopy is to identify ova, cysts or parasites. Giardia trophozoites
are rarely seen but cysts may be detected. Cysts of Entamoeba, however, NaCl 2.6 Na 75; Cl 65
may be found that are from the nonpathogenic Entamoeba dispar.
Glucose 13.5 7.5
Only the finding of trophozoites allows a definite diagnosis of
amebiasis. KCl 1.5 K 20
Stool culture has been the mainstay of diagnosis in cases of infective Trisodium citrate 2.9 Citrate 10
diarrhea. Although bacteria remain the most common causes of
Total 20.5 245 osmolality
food-borne illness, stool cultures are only positive in less than 40%
of cases. Part of the reason for the low yield is that various strains of
E. coli (EIEC, ETEC, EHEC) are not routinely sought in diagnostic
laboratories and, of course, many cases are due to viruses. For the
past decade in the UK, diagnostic laboratories have been required
to screen stool specimens from cases of bloody diarrhea for E. coli
O157:H7.
ANTIGEN DETECTION AND

MOLECULAR ASSAYS
Increasingly, molecular and non-culture methods are used to diagnose
the causes of food-borne diarrhea. There are now good ELISA tests for
protozoa like Giardia, Entamoeba and Cryptosporidium.44 Real-time
polymerase chain reaction (RT-PCR) assays are now commonly used
for viruses, such as norovirus. With the availability of next-generation
sequencing, attention has turned to molecular identification of patho-
gens in stool based on 16S rRNA. However, with antigen detection or
individual PCR assays, the clinician needs to request specific tests for
suspected pathogens.45
Multiplex sequencing techniques allow for the identification of a Figure 37-6 Patients on a cholera ward in Peru receiving rehydration intrave-
nously. (Courtesy of Dr J. Sanchez.)
large number of potential pathogens direct from stool specimens.46
This has highlighted that an individual may have more than one patho-
gen identified as the potential cause of diarrhea and this is true of NUTRITION
adults and children.47 It can be difficult, however, to attribute causa- Nutrition is rarely a problem in acute diarrhea in adults but malnutri-
tion if more than one pathogen is identified but multiplex PCR assays tion is a serious problem in cases occurring in the tropics, leading to
are beginning to be used in routine labs. In many instances the ‘extra’ significant morbidity and mortality. Appropriate feeding, especially in
pathogens identified are enteropathogenic E. coli (EPEC) or enteroag- children, is important to ensure adequate protein and calorie intake.
gregative E. coli (EAEC) and the significance is unclear. Interestingly,
there is evidence that the population of bacteria in the intestines (the
ANTIDIARRHEAL AGENTS
gut microbiome) may be altered in infective diarrhea,48 particularly in There is still considerable controversy about the use of antimotility
cases of C. difficile.49 The alteration of the microbiome by cholera agents in patients with food-borne illness and diarrhea. An early study
is followed, in recovery, by repopulation of the gut bacteria suggested that loperamide might increase the severity of Shigella infec-
in adults in a manner similar to that which occurs in children as tions.54 Although this has not been confirmed by other studies, caution
they mature.50 should be exercised in using loperamide in cases with bloody diarrhea.
Loperamide is the agent of choice, however, for adults with food-borne
illnesses in order to decrease intestinal motility and secretion.55 Unlike
Management codeine, it is not absorbed. Bismuth subsalicylate has proven efficacy,
even in viral infections, and a new chloride channel blocker, crofele-
REHYDRATION mer, also shows promise.56,57
Dehydration is the most common complication of food-borne illness
so attention must focus on the hydration state of the patient in order ANTIBIOTICS
to maintain the circulation. In most cases rehydration can be safely The vast majority of food-borne infections causing diarrhea can be
and adequately achieved with oral fluids. Oral hydration has been treated symptomatically and settle spontaneously. There are some
promoted by the WHO for the primary and secondary care of diarrheal clinical scenarios, however, where antimicrobials should be used or, at
illness in the tropics. The recommended oral rehydration solution least, considered. Sometimes this is because a specific diagnosis has
(ORS) contains sodium and potassium (as chlorides) to replace losses, been made and in other situations there can be a justification for
glucose to facilitate active transport of sodium and hence water across empiric antibiotic treatment in order to reduce symptoms and
the mucosa and citrate to help correct the acidosis (Table 37-3).51 complications.
WHO also recommends zinc supplementation of ORS for children
because of large zinc losses in childhood diarrhea.52 Studies have Specific Antibiotic Therapy
shown that, for adults, rice-water-based ORS reduces diarrhea volumes Randomized controlled trials have shown that antibiotic therapy will
and, more recently, the addition of L-histidine to rice ORS has been reduce the duration of illness due to Shigella species. Quinolones
shown to be beneficial.53 remain effective in many instances but azithromycin is an alternative.58
In severe dehydration (and sometimes in hospitals in higher- Campylobacter infections, if treated within 4 days of symptoms start-
income countries) intravenous fluid replacement is used (Figure 37-6). ing, can be improved with erythromycin or azithromycin.59
The emphasis should be on volume replacement with crystalloid solu- Most non-typhoidal Salmonella infections are self-limiting.
tions that provide sufficient sodium, potassium and glucose. However, because of the risk of bacteremia in certain patient groups,
treatment can be justified. The groups at risk include children under and food samples should be collected to facilitate epidemiologic
the age of one year, adults over the age of 60 and those who are immu- investigations.
nocompromised. As with Campylobacter infections, quinolone resis-
tance is now common so azithromycin may be a better choice. Prevention
In cholera infection, fluid replacement and resuscitation are most
SANITATION
important, but tetracyclines, including doxycycline, can be given to
adults. These agents act on protein synthesis and so reduce toxin pro- The most important factor in reducing food-borne infections is the
duction in addition to their role in killing the bacteria.60 provision of safe water for drinking and washing, along with adequate
Although Shiga toxin-producing E. coli such as O157:H7 may be sanitation arrangements for the safe disposal of human waste. Modern
susceptible in vitro, the evidence suggests that antibiotic therapy water supplies and sewage systems have cut dramatically the incidence
increases the risk of HUS.61 Guidelines suggest withholding antibiotics of diarrheal diseases in higher-income countries. By contrast, the
if this infection is suspected.62 lack of such facilities explains the high burden of disease in low- and
When a protozoan cause of diarrhea is found, specific therapy is middle-income countries.
required. Giardiasis is best managed with either metronidazole or tini- FOOD HYGIENE
dazole and, particularly if the diarrhea is chronic, it is prudent to give
a cysticide (see also Chapter 114). Secondary lactose intolerance after Education and knowledge about the safe handling of food is another
giardiasis is not uncommon and a lactose-free diet might help if symp- critical factor in reducing food-borne illness. Appropriate storage,
toms persist. Infections with Isospora belli and Cyclospora cayetanensis refrigeration and cooking reduces risks. In higher-income countries,
can be treated with trimethoprim–sulfamethoxazole (co-trimoxazole). regulation plays an important role in ensuring good food hygiene in
Amebiasis can be treated with metronidazole but, as with giardiasis, it restaurants and commercial kitchens. In the UK the Food Safety Act
is sensible to give a cysticide, such as diloxanide furoate. Treatment of compels organizations to give due regard to food safety. Regulation
Cryptosporidium is difficult but some studies suggest nitazoxanide may has to be coupled with good surveillance and public health
be useful.63 involvement.
Empiric Antibiotics VACCINES

Some clinicians advocate the use of empiric antibiotics in adults with The majority of food-borne illness is not preventable by vaccination.
diarrhea and evidence of acute inflammation. A number of studies However, new recombinant cholera vaccines have been shown to be
have shown benefit but, generally, the illness is only shortened by a effective in the field and, because they target the toxin, may be effective
day or two. The potential benefits of empiric therapy must be balanced in preventing some diarrheal illness caused by bacteria producing
against the risks, which include drug side-effects, drug resistance, pro- related toxins.67 Typhoid vaccines are also moderately effective but the
longed excretion of the pathogen and infection with Clostridium dif- aim is to prevent enteric fever rather than diarrhea. The relatively new
ficile. Empiric quinolone therapy was once advocated but increasing rotavirus vaccine is also effective in preventing illness in children and
resistance along with the risk of tendon rupture and an increased it will be important to roll this out to low- and middle-income coun-
susceptibility to C. difficile infection mean these drugs can no longer tries where the need is greatest.68
be recommended for this purpose.64
ANTIBIOTICS
Travelers’ Diarrhea Although antibiotics sometimes have a role in treating food-borne
This is one condition where empiric therapy might be advised. Studies diarrhea and may sometimes be recommended for travelers, there is
have shown that a number of antibiotics given empirically can reduce really no general role for these drugs in preventing food-borne
the duration of symptoms. Bismuth subsalicylate is effective but the diarrhea.
volumes needed limit its use. Doxycycline has been shown to be effec-
tive, as has a single dose of ciprofloxacin.65 However, these studies were Conclusions
done before the more widespread resistance of enteric pathogens was Food-borne illness causing diarrhea is extremely common and very
recognized. It may be that azithromycin may be effective in some set- costly.69 Better food safety, improved sanitation and hygiene along
tings.66 Rifaximin, a non-absorbable rifamycin, might also be effective. with regulations and proper surveillance all contribute to containing
the problem. Increased public understanding of the risks associated
PUBLIC HEALTH MANAGEMENT with food-borne infections can help to reduce the incidence of disease.
All cases of food-borne diarrhea should be notified to the appropriate Continued improvement to increase access to clean water and sanita-
public health authorities. This can allow suspect food sources to be tion remains a priority in poorer countries.
investigated and might also point to the existence of outbreaks, even
when the cases are separated geographically. Ideally, stool specimens References available online at expertconsult.com.
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38
Acute Diarrhea
MICHEL DRANCOURT
KEY CONCEPTS were non-food-borne gastroenteritis (135 million cases per year) and
food-borne illness (76 million cases per year).3 A report from the US
• Diarrhea can be caused by a wide spectrum of viruses, bacteria Centers for Disease Control and Prevention (CDC) found that food-
and parasites. Multiple infections are common. borne diseases account for approximately 76 million illnesses, 325 000
• The spectrum of illness ranges from self-limited disease to a hospitalizations and 5000 deaths each year in the USA based upon
potentially deadly situation depending on the pathogen and surveillance data from multiple sources.4 In the Netherlands, the inci-
the host. dence of gastroenteritis was 45 per 100 person-years in a prospective
study.5
• In healthcare-associated diarrhea the cause is typically limited
Because some enteric pathogens such as Vibrio cholerae are not
to Clostridium difficile and norovirus.
ubiquitous, some pathogens are seasonal and some pathogens are
• Acute diarrhea can be diagnosed at the point-of-care by using responsible for epidemics, the prevalence of various pathogens respon-
rapid lateral flow and real-time polymerase chain reaction tests. sible for diarrhea is variable. The bacterial pathogens most frequently
• Recently available multiplex tests allow for a rapid syndromic found are enteropathogenic clones of E. coli, Shigella spp., Salmonella
diagnosis. enterica subsp., Campylobacter spp. and Aeromonas spp. The most
frequently identified causative viruses (outside local epidemics)
• Appropriate water networking, environmental surface cleans- include rotavirus, caliciviruses (norovirus and sapovirus), astrovirus
ing and hand hygiene are key to preventing outbreaks. and enteric adenovirus. Less prevalent viruses include paramyxovirus,
morbillivirus, rubivirus and reovirus. The prevalence of norovirus has
been recently estimated to be 12% in children under 5 years of age
Introduction hospitalized for severe diarrhea and 12% of mild and moderate diar-
rhea cases among patients of all ages.12 These authors estimated that
There is an increasingly recognized array of bacterial, parasitic and noroviruses were responsible for up to 200 000 deaths of children <5
viral organisms associated with infection of the intestinal tract which years of age in LMIC.12
can profoundly disrupt intestinal function with or without causing
acute diarrhea. Acute diarrhea is a syndrome that is frequently not SURVEILLANCE
differentiated clinically by a specific etiologic agent. The wide spectrum Not all enteric pathogens are notifiable, depending on the country.
of evolution varies from self-limited disease to death. Death is mainly Moreover, a recent study in six US states indicated that multiple steps
due to dehydration and acute diarrhea takes the highest toll among between onset of food-borne illness and its investigation by a public
children in low- and middle-income countries (LMIC). This chapter health agency could take up to 3 weeks.6
examines the viral and bacterial causes of acute diarrhea, clinically
defined by three or more loose or watery stools per day or a definite SOURCES OF PATHOGENS
decrease in consistency and increase in frequency based upon an indi- Infected persons, animals and the inanimate environment are sources
vidual baseline lasting for less than 2 weeks. Parasitic infections of the of pathogens. Indeed, diarrhea is a contagious situation where infected
gastrointestinal tract will be presented in Section 6 and diarrhea associ- persons are the main source of contamination, implying the isolation
ated with food poisoning is discussed in Chapter 37. Diarrhea associ- of the infected person as recalled by the recent outbreak of cholera in
ated with Clostridium difficile infection is covered in Chapter 40. When Haiti.7 However, some enteric pathogens are zoonotic and contami-
diarrhea lasts for 14 days it can be considered persistent; the term nated poorly cooked food is the source of infection, as in the case of
chronic generally refers to diarrhea that lasts for at least one month enteroinvasive Escherichia coli strains and Campylobacter8 and Listeria
(see Chapter 39). monocytogenes.9 Contaminated water is less likely to be a source of
infection except in circumstances where there is a leak between potable
Epidemiology and unpotable water networks. Water-borne outbreaks associated with
PREVALENCE recreational water (e.g., swimming or wading pools) are another
Acute diarrheal diseases ranked seventh in the causes of mortality in source of acute diarrhea. These are associated most frequently with
LMIC in the global disease burden series, 2013, with an estimated 1.3 Cryptosporidium (50%) in treated water sources and with toxigenic E.
million deaths (2.4 %).1 Most of these deaths occur in children under coli (25%) and norovirus (25%) in freshwater sources. When there is
the age of 5 years in LMIC and diarrhea remains among the top five a direct transmission of water-borne and food-borne pathogens, hands
causes of all deaths among children younger than age 5 years, as tabu- are increasingly recognized as vectors of enteric pathogens.10
lated in 2013.1 The incidence of acute diarrhea in the general popula- Travel is increasingly reported as a circumstance for acute diarrhea,
tion could be estimated by prospective studies such as those organized including enterotoxigenic Escherichia coli (ETEC) infection. Aeromo-
in the Food-borne Disease Active Surveillance Network (FoodNet) in nas infections have been traced to aquarium water.11
the USA. The network observed that 6% of interviewed people reported
an acute diarrheal illness during the 4 weeks preceding the interview, Pathogenesis and Pathology
that is an annualized rate of 0.72 episodes per person-year. Rates of Diarrhea reflects an increased water content of the stool, whether due
illness were highest among children younger than 5 years (1.1 episodes to impaired water absorption or active water secretion by the bowel.
per person-year) and were lowest in persons aged ≥65 years (0.32 In severe infectious diarrhea, the daily volume of stool may exceed 2
episodes per person-year).2 A study in 2000 that estimated the eco- liters. Dehydration and loss of potassium (hypokalemia) are two life-
nomic burden of both infectious and noninfectious gastrointestinal threatening consequences of severe diarrhea. Water is mainly absorbed
and liver disease in the USA found that the most prevalent diseases in the small bowel (about 8 liters a day in an adult) and further in the
335
colon. By the time the initial 8 liters of fluid reaches the ileocecal valve, blood cells. Although generally self-limiting, relapse with chronic diar-
only about 600 mL remain, representing an efficiency of water absorp- rhea is possible as well as extraintestinal infection including bacter
tion of 93%. By the time the remaining 600 mL of fluid reaches the emia. C. jejuni infection is the most often recognized infection
anus, only about 100 mL of fluid remains, generally as formed feces. preceding the development of Guillain–Barré syndrome.15 The mecha-
In the small intestine, water is absorbed by three basic mechanisms: nisms rely on the cross-reactivity between ganglioside-like motifs
‘neutral’ sodium chloride (NaCl) absorption mediated by two coupled present in C. jejuni lipopolysaccharide and those of peripheral nerves.
systems – one of which exchanges Na/H (cation exchanger), and the Also, this species has been associated with immunoproliferative small
other exchanges Cl/HCO3 (anion exchanger); ‘electrogenic’ sodium intestinal disease.16 Species other than C. jejuni and C. coli are increas-
absorption where sodium enters the cell via an electrochemical gradi- ingly isolated from the stools of patients with diarrhea, including C.
ent – this electrogenic sodium absorption mechanism is commonly fetus, mainly isolated from extraintestinal sites, and C. upsaliensis. Both
damaged during acute enteric infection; and sodium co-transport species being susceptible to cephalothin, an antibiotic usually incor-
whereby sodium absorption is coupled to the absorption of organic porated in C. jejuni-selective media, their prevalence in stools and
solutes such as glucose, many amino acids and peptides. This diarrhea may be underestimated by culture methods.
co-transport mechanism remains intact during most acute diarrheal Clostridium difficile infection is discussed in detail in Chapter 40.
disorders. It is for this reason that oral rehydration is effective during
acute diarrheal illness. Escherichia coli Infection
Osmotic diarrhea occurs when an absorbable solute, such as lactose, E. coli organisms are common inhabitants of the intestinal tract of
is not absorbed properly and retains water in the gut lumen. Infections healthy people, yet a limited number of clones are responsible for acute
that damage the intestinal epithelial cells either directly (rotavirus) or diarrhea and extraintestinal infections. E. fergusonii is frequently iso-
by a toxin (Shigella spp.) cause malabsorption and osmotic diarrhea. lated from stools yet its pathogenic role is non proven, and E. albertii
Secretory diarrhea results from an active, toxin-mediated secretion of is a possible agent of acute diarrhea.17 There are five groups of E. coli
water into the gut lumen. This is observed during cholera, and infec- organisms associated with acute diarrhea: Shiga toxin-producing Esch-
tion by Shiga-toxin producing Escherichia coli and Shigella species. erichia coli (STEC), also named enterohemorrhagic Escherichia coli
Rotavirus also produces a viral enterotoxin, the nonstructural glyco- (EHEC); enterotoxigenic Escherichia coli (ETEC); enteropathogenic
protein (NSP4). Lastly, diarrhea can result from infection-mediated Escherichia coli (EPEC); enteroaggregative Escherichia coli (EAEC); and
intestinal inflammation. After ingestion, an enteric organism colonizes enteroinvasive Escherichia coli (EIEC). STEC produce one or several
the intestinal epithelium by adhering to enterocytes. One of two path- Shiga toxins also known as verocytotoxins and are the E. coli organisms
ways are generally followed depending upon the offending organism, most frequently associated with acute diarrhea in industrialized coun-
either mucosal invasion or production of an enterotoxin. tries. These organisms, including various E. coli O157 serotypes, are
responsible for mild non-bloody and bloody acute diarrhea.18 Non-
Clinical Features O157:H7 STEC are associated with illnesses that differ from those
caused by E. coli O157:H7. Most notably, they are found later and have
BACTERIAL ENTERITIS a lower proportion of bloody diarrhea than in patients infected with
Aeromonas Infection E. coli O157:H7.19 STEC are also responsible for an estimated 80% of
Aeromonas species are inhabitants of aquatic environments worldwide, HUS cases in about 4% of patients with enteric infection. Ground beef
including rivers and lakes as well as drinking water plants and distribu- has been the major vehicle of transmission of O157 STEC, although
tion systems. Also, most pathogenic Aeromonas species can be found other vehicles contaminated by bovine manure have been reported,
in meat and dairy products. Some Aeromonas isolates encode entero- including raw milk, sausage, apple cider, and raw vegetables and non-
toxins, including an alt gene-encoded heat-labile and an ast gene- chlorinated water supply. Also, person-to-person transmission is
encoded heat-stable enterotoxin. Aeromonas enteric infection may responsible for outbreaks in communities.
range from, most commonly, an acute watery diarrhea to dysenteric ETEC produce heat-labile (LT) and heat-stable (ST) enterotoxins
illness. Symptoms may include abdominal cramps (70%), nausea and are a frequent cause of acute diarrhea in LMIC, thus being a fre-
(40%), vomiting (40%) and fever (40%). Infection is usually self- quent cause of travelers’ diarrhea. ETEC infection manifests as rela-
limiting although children may rarely be hospitalized because of dehy- tively mild watery diarrhea and abdominal cramps, but without
dration. Aeromonas caviae is the most prevalent species. Aeromonas vomiting or fever. EPEC comprise organisms characterized by an
veronii can be associated with rare cholera-like illness and dysenteric adherence factor plasmid and the chromosomal locus of enterocyte
diarrhea resembling shigellosis with bloody and purulent stools. One- effacement. These organisms are responsible for severe infantile diar-
tenth of patients are coinfected with a second enteric pathogen. Inter- rhea in LMIC, associated with fever, vomiting and prolonged evolu-
mittent and persistent diarrhea may occur for years after initial tion. Chronic diarrhea may follow EPEC infection and be responsible
infection. Aeromonas enteritis can be complicated by the hemolytic for malabsorption, weight loss and growth retardation. EIEC are
uremic syndrome (HUS) and kidney disease.13 responsible for an infection mimicking shigellosis.
EAEC are responsible, worldwide, for mild enteric infections with
Campylobacter Infection non-bloody diarrhea, abdominal pain and mild fever.
Campylobacter species are motile, gram-negative, S-shaped, micro-
aerophilic organisms responsible for zoonoses. Not only food animals Salmonella Infection
such as poultry, cattle, sheep and pigs, but also domestic pets are res- The genus Salmonella comprises motile enteric bacteria of problematic
ervoirs for worldwide human infection. Although the incidence is nomenclature. Salmonella comprises two species and the species Sal-
decreasing in the USA, Campylobacter species are still responsible for monella enterica comprises five subspecies. The vast majority of human
sporadic infections following improper handling of poorly cooked infections are due to strains of Salmonella enterica subspecies I, also
meat. Poultry is a major source of infection.14 Unpasteurized dairy isolated from warm-blooded animals, while the other Salmonella
products and water have been found to be sources for limited out- organisms are isolated from the environment and cold-blooded
breaks. The incidence of infection with Campylobacter spp. is higher animals. These organisms are further serotyped and serotype generally
in LMIC than in industrialized nations and travelers to LMIC are at correlates with the food source of infection. Notably, Salmonella
risk of Campylobacter infection. The pathogenesis of Campylobacter enterica serotype Typhi is the agent of typhoid fever. Salmonella
infections is poorly understood. C. jejuni and C. coli are the most enterica serotypes Enteritidis and Typhimurium are the most com-
frequently encountered species responsible for diarrhea. Signs and monly isolated in LMIC.
symptoms may vary from asymptomatic infections to include fever, Non-typhoidal S. enterica organisms are responsible for acute diar-
abdominal cramps and diarrhea with or without blood and fecal white rhea with fever and abdominal cramps lasting for an average of one
Chapter 38 Acute Diarrhea 337
week. Rarely, these organisms are responsible for bacteremia and on the basis of simple laboratory tests including the hemolysis of sheep
extraintestinal infections in immunocompromised patients. Contacts erythrocytes, the Voges–Proskauer test and resistance to polymyxin,
with animals and animal foods are the sources of infection with the which are all positive in the El Tor biotype. The first six historical
Enteritidis serotype, being associated with chicken and egg products. pandemics are thought to be due to the Classical biotype whereas the
Serotype Cholerasuis is adapted to cattle and serotype Dublin is on-going seventh pandemic since 1961 is due to the El Tor biotype.
adapted to pigs. The latter serotype harbors virulence traits in common V. cholerae O1 is the organism responsible for historical pandemics
with serotype Typhi, the typhoid fever agent. Typhoid fever is a life- of cholera since 1816, including the current pandemics. Most patients
threatening sepsis rarely observed in industrialized countries but still contaminated with V. cholerae O1 have an asymptomatic or self-
of public health concern in LMIC (see Chapter 115). Humans are the limited diarrhea (>75%), but massive contamination results in severe
only known reservoir for serotype Typhi, which is therefore transmit- diarrhea and large volumes of ‘rice water stools’ and dehydration.
ted by direct person-to-person contact and through contaminated Clinical manifestations include loss of skin elasticity, watery eyes,
water and food. A syndrome similar to typhoid fever is due to sero- painful muscle cramps and anuria. Dehydration leads to hypovolemic
types Paratyphi A, Paratyphi B and Paratyphi C. shock and death. Exceptional extraintestinal V. cholerae O1 bacteremia
infections have been reported.
Shigella Infection In 1992, cholera cases due to a new serogroup, V. cholerae O139
Shigella dysenteriae, Shigella flexneri, Shigella boydii and Shigella son- (Bengal), were reported in India and Bangladesh and spread rapidly
nei20are responsible for acute diarrhea. Man is the only known reser- throughout Asia. The new serogroup probably resulted from the lateral
voir for Shigella spp. and transmission is by direct contact from gene transfer of novel capsule and somatic antigen genes to the El Tor
person-to-person and by contaminated water and food. Sexual trans- strains. It causes a disease similar to that caused by V. cholerae O1
mission has been observed in homosexual males. Most cases in indus- except that adults are more frequently infected.
trialized countries are imported from LMIC. Shigella spp. are Some V. cholerae isolates do not agglutinate with anti-O1 and anti-
responsible for bacillary dysentery characterized by acute, bloody diar- O139 antisera and are therefore referred as V. cholerae non-O1 isolates.
rhea accompanied by fever and abdominal cramps. Classic dysentery V. cholerae non-O1 isolates do not produce the cholera enterotoxin
is characterized by scant stools containing mucus, pus and blood. and are responsible for mild watery diarrhea. Unlike V. cholerae O1
Shigellosis is responsible for rectal and colonic ulcerations that do not isolates, V. cholerae non-O1 isolates are responsible for extraintestinal
develop beyond the lamina propria. Rare cases of sepsis have been infection such as life-threatening sepsis, especially in patients with
observed but Shigella spp. are responsible for HUS. previous liver disease or hematologic malignancies. V. cholerae non-O1
isolates have also been recovered from other anatomical sites.
Tropheryma whipplei Infection Other Vibrio species are responsible for diarrhea. They include V.
Tropheryma whipplei is an Actinobacterium and the etiologic agent of mimicus, a species phenotypically related to V. cholerae, which is
Whipple disease.21 Besides frequent fecal carriage in children,22,23 T. responsible for diarrhea after the consumption of raw seafoods; some
whipplei has been more recently recognized as an etiologic agent of strains harboring the cholera toxin can produce cholera-like symp-
mild gastroenteritis and diarrhea in children.24 Indeed, it was not toms. In Asia, V. parahaemolyticus is the leading cause of food-borne
detected in asymptomatic children but its DNA was detected with high intestinal infections after the consumption of raw fish or shellfish. The
bacterial loads in the stools of symptomatic children, followed by species is responsible for watery diarrhea, rarely bloody diarrhea and
disappearance in children recovering from diarrhea, associated with exceptionally is responsible for severe dehydration and death. A first
seropositivity.24 Adults also may present with T. whipplei diarrhea and pandemic clone of V. parahaemolyticus serotype O3:K6 emerged in
T. whipplei must be added to the list of agents responsible for travelers’ 1996 in Taiwan and then spread throughout Asia to America, Africa
diarrhea.25 In adults, however, there is asymptomatic fecal carriage of and Russia. New serotypes emerged for a few years. V. vulnificus is
the micro-organism26 and although the ultimate sources and precise primarily responsible for life-threatening sepsis and secondary skin
routes of infection are not elucidated, colonized persons are likely infection with necrosis; however, it has an intestinal route of entry and
sources of infection by the oro-oral and oro-fecal routes of transmis- is responsible for vomiting, diarrhea and abdominal cramps after the
sion. Diagnosis relies on home-made real-time polymerase chain reac- consumption of raw oysters. Three biogroups have been defined in V.
tion (PCR) assays tested on two different specific sequences.27,28 This vulnificus, the vast majority of infections being due to biogroup 1. V.
approach increases the sensitivity of diagnosis over 16S rRNA gene fluvialis, V. furnisii and Grimontia (Vibrio) hollisae cause sporadic cases
detection.29 There is no specific treatment for T. whipplei diarrhea. of diarrhea worldwide.32 V. alginolyticus is occasionally isolated from
stools but there is little evidence for V. alginolyticus being actually
Vibrio Infection responsible for intestinal infection and diarrhea.
Vibrio species are found ubiquitously in aquatic environments and
more than 70 Vibrio spp. are classified as responsible for trauma- Yersinia Infection
related, extraintestinal infections and intestinal infections with diar- Among the numerous members of the Yersinia genus, only Y. entero-
rhea.30 Vibrio cholerae is the etiologic agent of cholera. This is a motile, colitica and Y. pseudotuberculosis have been associated with digestive
gram-negative, facultative anaerobe bacterium which requires a small tract infection. Y. enterocolitica, further divided into two subspecies
concentration of sodium for growth. V. cholerae is primarily an aquatic enterocolitica and paleartica on the basis of 16S rDNA sequencing,33
inhabitant found in freshwater rivers and lakes as well as in estuarine comprises more than 70 serotypes, five of them being associated with
and maritime environments. In these environments, V. cholerae is human infection. These strains encode for an enterotoxin and some
isolated from both the inanimate environment and from plankton and strains harbor a chromosome-borne pathogenicity island which con-
various bivalves, crabs, shrimp and prawns. A viable-but-not-cultivable tains the yersiniabactin gene, providing the organisms with iron. Y.
state has been described in which regulation may be phage-dependent.31 enterocolitica is primarily an environmental organism isolated from the
V. cholerae comprises three major subgroups, V. cholerae O1, V. chol- gastrointestinal tract of numerous animals, most commonly swine,
erae O139 and V. cholerae non-O1, widely distributed in tropical and dogs and rodents. Its distribution is mostly in Northern Europe and
sub-tropical areas, including the Gulf of Mexico for V. cholerae O1. the northern USA, reflecting its increased growth at cold temperatures.
V. cholerae O1 chromosomes contain virulence cassette and pathoge- This species is responsible for gastroenteritis associated with the con-
nicity islands, encoding virulence factors such as the pilus responsible sumption of contaminated water and food, mainly poorly cooked
for the attachment of V. cholerae O1 organisms to the intestinal epi- swine meat. The disease spectrum comprises self-limited, acute diar-
thelium, and the cholera enterotoxin responsible for the substantial rhea to terminal ileitis and mesenteric lymphadenitis mimicking
excretion of electrolytes and water in the intestinal lumen. Two bio- appendicitis. Prolonged shedding has been observed. Sepsis is an
types, designated Classical and El Tor biotypes, can be differentiated uncommon complication observed in patients with an increased iron
pool, such as thalassemic patients in Western countries,34 liver disease, which resist in the inanimate environment comprising contaminated
cancer and receiving steroid therapy. Y. enterocolitica is a prominent surfaces, water and food. Outbreaks of norovirus infection are observed
cause of bacterial sepsis associated with blood transfusion. Reactive in daycare centers where child vomiting can readily contaminate floor
arthritis is an uncommon sequela observed in HLA-B27-positive and fomites.50 Accordingly, direct evidence for animals as reservoirs
patients and immunocompromised patients; it is characterized by an for human infection is still lacking. Noroviruses are the most prevalent
asymmetrical involvement of multiple joints, including the sacroiliac cause of nonbacterial acute enteritis worldwide.51 These viruses cause
joints and the spine. large outbreaks and provoke incapacitation for a few days; they have
Y. pseudotuberculosis is rarely isolated as a cause of a self-limited therefore been included in the list B of potential bioterrorism agents
acute diarrhea; it has been associated with outbreaks of gastroenteritis by the NIAID. Outbreaks mainly occur in institutions including
after consumption of contaminated fresh fruit and vegetables.35,36 healthcare centers. Cruise ships appear to be an emerging setting for
Y. pseudotuberculosis is also responsible for pseudoappendicitis, norovirus infection. Also, air flight has been shown to be a circum-
and reactive arthritis may develop after infection with Y. pseudotuber- stance for norovirus diarrhea, for both cabin crew and passengers.52
culosis O3.37 The inanimate environment in healthcare centers is also a source for
norovirus infection, and the viruses are resistant to routine cleansing
Miscellaneous Bacteria and routine alcohol hand hygiene.53
Arcobacter are Campylobacter-like organisms occasionally isolated The diagnosis can be made within 10 minutes at point-of-care
from the stools of patients with diarrhea, including Arcobacter but- thanks to commercially available immunochromatographic tests.
zleri38 and Arcobacter cryaerophilus DNA group 1B.39 Particular culture
conditions are required for proper isolation of these fastidious organ- Astrovirus Infections
isms, therefore limiting their detection to a few studies. Listeria mono- These RNA viruses, which average 30 nm diameter, are mainly respon-
cytogenes has only recently been recognized as an agent of acute sible for acute diarrhea in children, although outbreaks in military
enteritis, but it has now been associated with several outbreaks.40 troops and hospitals have also been reported. These worldwide viruses
Enteritis typically occurs after ingestion of a large inoculum and is are responsible for 2–10% of pediatric cases of acute diarrhea. Clinical
self-limiting after a few days.41 Klebsiella oxytoca is found in the envi- signs and symptoms are nonspecific.54
ronment but its principal reservoir is the human gastrointestinal tract.
K. oxytoca has been associated with C. difficile-negative antibiotic- Enteric Adenovirus Infections
associated colitis.42 K. oxytoca organisms cause experimental colitis and Adenoviruses look like non-enveloped, 100 nm round particles con-
exhibit cytotoxicity against HEp-2 cultured cells.42 Its culture is not taining DNA and are responsible for human infections. They belong
routinely performed and requires a specific isolation agar medium. to 51 different serotypes and six subgroups, but only two serotypes
Laribacter hongkongensis is a facultative anaerobic gram-negative bacil- Ad40 and Ad41 (subgroup F) have been clearly demonstrated to be
lus that was initially reported as being responsible for acute diarrhea agents of acute diarrhea. Clinical characteristics include a higher prev-
in Asian patients.43 Case–control study indicated that eating fish and alence in children <4 years of age and a mean duration of disease of
travel were associated with L. hongkongensis acute diarrhea.44 Dys- 5–10 days, that is longer than that caused by other viruses. Prolonged
gonomonas capnocytophagoides (formerly CDC group DF-3)45 are diarrhea has been observed in immunocompromised patients.55
Captocytophaga-like organisms isolated from the stools of immuno-
Miscellaneous Viruses
compromised patients.46–48
A few other viruses have been associated with acute diarrhea, yet their
VIRAL ENTERITIS role remains to be firmly established. These include coronavirus, a
definite agent of diarrhea in animals and seldom visualized by electron
Rotavirus Infections microscopy and isolated in culture from the stools of patients with
Rotaviruses are RNA viruses appearing as 70 nm particles with a diarrhea. Likewise, torovirus is responsible for acute human gastroen-
wheel-like appearance. Based on group-specific antigens of the major teritis and is responsible for nosocomial cases. Aichi virus, a picorna-
viral structural protein VP6, rotaviruses can be classified in six groups virus, has been characterized by reverse transcription-PCR during an
A to G. Groups A to C infect humans, the other groups are found in outbreak of enteritis following the consumption of oysters in Japan.56
animals. Human rotaviruses are responsible for severe acute diarrhea Picobirnaviruses have been detected in stools of animals and humans;
with dehydration associated with childhood death in low- and middle- their significance remains to be established. Recently, cardiovirus,
income countries. In Europe, children with rotavirus-positive acute closely related to Theiler’s murine encephalomyelitis virus, has been
gastroenteritis were more likely to have lethargy, fever, vomiting and detected in the stools in 1.2% patients with acute enteritis.57
dehydration, and, therefore, more severe disease than were children
with rotavirus-negative acute gastroenteritis. Dehydration was up to
5.5 times more likely in children with rotavirus-positive acute gastro-
Prevention
enteritis than in those with rotavirus-negative acute gastroenteritis.49 The global mortality from diarrhea declined from approximately 4.6
Acquisition of rotaviruses is likely from subclinical infection in parents million annual deaths during the mid-1980s, to 2.4 million deaths in
or siblings but rotavirus infection can be a zoonosis. Rotaviruses are 1990 and to the current estimate of 1.6–2.1 million.1 The decline is
resistant in the inanimate environment which may participate as a generally attributed to global improvements in sanitation and the use
source of infection, including nosocomial outbreaks. Rotavirus infec- of glucose-electrolyte oral rehydration therapy (ORT) which has dra-
tion is seasonal, with a peak of incidence in winter/spring in temperate matically reduced acute mortality from dehydration caused by diar-
countries. Clinical symptoms include acute diarrhea for 2–3 days, rhea. In contrast to the fortunate decrease of mortality, morbidity
fever, vomiting and anorexia. Rapid diagnosis at the point-of-care can remains as high as during the previous century. However, simple,
be achieved within 15 minutes by using a commercially available cheap measures could be undertaken to make the incidence fall.
lateral-flow assay with parallel detection of adenovirus. A prospective study in India demonstrated that the promotion of hand
washing with plain soap reduced by 53% the incidence of acute diar-
Calicivirus and Norovirus Infections rhea (and of pneumonia and impetigo).58 In industrialized countries,
The family Caliciviridae includes the genera Norovirus and Sapovirus, prevention relies on increased sanitary measures in sources of enteric
both responsible for enteritis. These RNA viruses appear as <40 nm pathogens such as recreational lakes for fishing and swimming, and
nonenveloped particles. Noroviruses comprise five genotypes, the swimming pools, as well as better control over fresh foods. A lifelong
genotypes I, II and IV are responsible for human infections, the two oral vaccine against rotavirus has been recently licensed after a few
other genogroups being animal-associated. Likewise, sapoviruses com- previous attempts and its safety and preventive effects have been care-
prise five genogroups, the genotypes I, II, IV and V are responsible for fully evaluated.59 Cost-effectiveness of a vaccine against rotavirus has
human infections. These human viruses are highly contagious viruses been evaluated favorably in the Netherlands.60
Chapter 38 Acute Diarrhea 339
As for travelers, pre-travel prophylaxis relies on vaccines. There is Paratyphi C serotypes. O serotype determination is done by agglutina-
currently only one vaccine available that provides protection against tion using pooled antisera while further H serotype determination is
diarrhea caused by Vibrio cholerae and ETEC. This vaccine is licensed done by tube agglutination tests using broth culture and testing the
in only a few Western countries. Protective efficacy against cholera is two phases of the flagellar antigens. Campylobacter spp. are recovered
85%, while protection against the heat-labile toxin of ETEC reaches by using the filtration method in parallel to selective, blood-containing
67%. Current studies show a protective effect of up to 43%. Vaccina- or non-blood containing media and a micro-aerophilic atmosphere.
tion against cholera and ETEC should be recommended for at-risk Some Campylobacter spp. require 6% hydrogen in atmosphere. A 42 °C
travelers, in particular those with high exposure at their travel destina- incubation temperature allows the growth of C. jejuni and C. coli but
tion or high personal risks through fluid loss.61 Typhim Vi is a conju- not all Campylobacter and Aeromonas spp. are recovered using blood
gate vaccine aimed at prevention against typhoid fever; its safety and agar incorporating 20 µg/mL ampicillin and produce β-hemolytic
effectiveness have been favorably evaluated.62,63 During travel, system- colonies. Further identification should be done for oxidase-positive
atic administration of antibiotics including fluoroquinolones, cyclines and indole-positive colonies. Modified cefsulodin-irgasan-novobiocin
and trimethoprim–sulfamethoxazole (co-trimoxazole) is controver- agar is also suitable for the isolation of Aeromonas species. The inter-
sial. Prophylaxis may rely on the basic rules of boiling fresh water or pretation of recovery of Aeromonas in stools must be cautious since
drinking bottled water, and cooking foods. there is no strong evidence that all Aeromonas isolates from stools are
responsible for diarrheal infection.72
Blood cultures are mandatory for the diagnosis of typhoid fever as
Diagnosis well as bacteremia due to non-Typhi serotypes of Salmonella.
There is no recommended serologic test for the microbiologic diagno- The systematic search for other enteritis pathogens may depend on
sis of enteric pathogens, and the laboratory diagnosis of diarrhea relies local epidemiology, including Y. enterocolitica, Vibrio spp., K. oxytoca,
solely on direct diagnosis. Serologic testing is useful for epidemiologic L. monocytogenes and Plesiomonas shigelloides. Growth of Y. enteroco-
investigation of Campylobacter species infections.64 litica from stools is enhanced by incubation of selective media at 35 °C.
Fresh stools should be collected in a clean container with a tight A pectin agar should be used for the isolation of Y. enterocolitica from
lid. Alternatively, a transport medium incorporating buffered glycerol stools. V. cholerae will be visible as very motile, gram-negative slightly
in saline can be used. Rectal swab is an alternative specimen in selected curved bacilli cultivated using a TCBS agar after enrichment. Yellow
situations. It is well established that hospitalized patients who did not colonies of oxidase-negative bacilli can be confirmed, by 16S rDNA
enter the hospital with diarrhea are unlikely to develop diarrhea caused sequencing. In parallel to the search for pathogenic bacteria, the search
by other bacterial agents than C. difficile; therefore, stool culture for viruses should be done using electron microscope observation after
should not be performed in patients hospitalized for more than 72 negative staining as well as detection of rotavirus. Identification of
hours (the three-day rule) and a rapid detection of C. difficile toxins bacterial colonies is now routinely done by using matrix-assisted laser
should be performed.65 For routine purposes, testing a single stool desorption ionization time-of-flight mass spectrometry.73
specimen has acceptable sensitivity but testing a second specimen is
mandatory when the first one had a more than 2-hour delay in
transport.66 Management
Several techniques have been developed for the point-of-care diag- Management of acute diarrhea should include the clinical evaluation
nosis of diarrhea including the rapid (<30 minutes) agglutination- of the patient, including risk factors for specific etiology and dehydra-
based detection of rotavirus and adenovirus as well as the detection of tion; rapid diagnosis of viral diarrhea; and treatment, including rehy-
C. difficile toxins. The rapid detection of C. difficile toxins A and B dration, antibiotic treatment and symptomatic treatment. Rehydration
should be routinely performed for both out-clinic patients and hospi- is a major therapeutic measure. Oral rehydration has a higher risk of
talized patients. Point-of-care detection of Shiga toxin-producing paralytic ileus, but intravenous rehydration exposes patients to risks
Escherichia coli in children using EIA has not been evaluated favor- of intravenous therapy. For every 25 children treated with oral rehy-
ably.67 A commercially available Campylobacter antigen detection kit dration one will fail and require intravenous rehydration.74 Rapid diag-
has been favorably evaluated.68 A dipstick test for the rapid detection nosis of viral diarrhea is important in order to avoid unnecessary
of Shigella is under evaluation.69 antibiotic treatment. Because of the absence of any antiviral drug effec-
Multiplex real-time PCR assays are now commercially available for tive against the viruses responsible for acute diarrhea, the management
a 1–3-hour diagnosis of bacteria virus and parasites.70 of viral diarrhea comprises the relief of symptoms and rehydration.
Further detection of the causative organism relies on stool exami- Most acute diarrhea episodes are self-limiting and do not require anti-
nation in the clinical microbiology laboratory. Direct microscopic biotic treatment. Meta-analysis has confirmed that antibiotic treat-
examination may yield motile bacteria such as Vibrio and Salmonella ment is useful to shorten the duration of signs and symptoms in
species and parasites. Although Gram-staining analysis of stool speci- travelers’ acute diarrhea.75 When antibiotics should be prescribed,
mens may not be routinely done, it has demonstrated 66–94% sensitiv- fluoroquinolones are the drugs of first choice, and one-day treatment
ity and >95% specificity for the rapid detection of Campylobacter is advocated except for Campylobacter and Shigella infections, which
species.71 may be treated for three days.76 In the case of patients returned from
Culture of stools will focus on frequent pathogens and the system- countries where fluoroquinolone resistance is prevalent, such as Cam-
atic query of less frequent bacterial pathogens will be guided by the pylobacter spp. in Thailand, azithromycin (500 mg ×1/d) could be used
local epidemiologic situation. Pathogens routinely detected by culture for three days (see also Chapter 37 and Practice Point 11).77 Antimi-
of diarrheal stools include O157 E. coli, Shigella spp., S. enterica sero- crobial therapy for O157 E. coli enteritis remains a controversial issue
types, C. jejuni and C. coli and Aeromonas spp. Enrichment of stools because some studies reported a deleterious effect on the evolution of
in O157, O111 and O26 serotypes of E. coli can be done by using hemolytic uremic syndrome. The increasing resistance of S. enterica
specific, commercially available magnetic beads. Sorbitol MacConkey Typhi to antibiotics, notably to ciprofloxacin, makes the choice of
agar should be used for the isolation of O157 STEC as these organisms first-line antibiotic treatment of typhoid fever more problematic (see
do not ferment D-sorbitol, contrary to the vast majority of other E. Chapter 115). The majority of Y. enterocolitis gastroenteritis does not
coli strains. S. enterica serotypes are better isolated by using an enrich- require antibiotic treatment, contrary to systemic infection which
ment broth before plating onto selective media. Biochemical identifi- could be treated using trimethoprim–sulfamethoxazole (no resistant
cation of Salmonella spp. and O (somatic), H (flagellar) and Vi strain reported) or fluoroquinolones, despite the fact that a few resis-
(capsular) antigen serotyping should be performed in order to identify tant strains have been reported.78
Salmonella enteritis Typhi (the typhoid fever agent, being capsular
antigen Vi positive) and the most prevalent non-Typhi serotypes. The References available online at expertconsult.com.
Vi capsular antigen is occasionally detected in non-Typhi, Dublin and
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18. Rangel J.M., Sparling P.H., Crowe C., et al.: Epidemiol- 43. Ni X.P., Ren S.H., Sun J.R., et al.: Laribacter hongkon- 258.
ogy of Escherichia coli O157:H7 outbreaks, United gensis isolated from a patient with community-acquired 65. Thomson R.B. Jr: Specimen collection, transport, and
States, 1982–2002. Emerg Infect Dis 2005; 11:603-609. gastroenteritis in Hangzhou City. J Clin Microbiol 2007; processing: bacteriology. In: Murray P.R., Baron E.J.,
19. Klein E.J., Stapp J.R., Clausen C.R., et al.: Shiga toxin- 45:255-256. Jorgensen J.H., et al., eds. Manual of clinical microbiol-
producing Escherichia coli in children with diarrhea: a 44. Woo P.C., Lau S.K., Teng J.L., et al.: Association of ogy. 9th ed. Wasington DC: American Society for
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141:172-177. troenteritis with travel and eating fish: a multicentre 66. Valenstein P., Pfaller M., Yungbluth M.: The use and
20. Lan R., Alles M.C., Donohoe K., et al.: Molecular evo- case–control study. Lancet 2004; 363:1941-1947. abuse of routine stool microbiology: a College of Amer-
lutionary relationships of enteroinvasive Escherichia coli 45. Hofstad T., Olsen I., Eribe E.R., et al.: Dysgonomonas ican Pathologists Q-probes study of 601 institutions.
and Shigella spp. Infect Immun 2004; 72:5080-5088. gen. nov. to accommodate Dysgonomonas gadei sp. Arch Pathol Lab Med 1996; 120:206-211.
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and Whipple’s disease. J Infect 2014; 69:103-112. and Dysgonomonas capnocytophagoides (formerly CDC producing Escherichia coli in children with diarrhea: a
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a review. Infection 2007; 35:59-64. 2000; (3):CD002242.
39
Chronic Diarrhea
FLORENCE FENOLLAR
KEY CONCEPTS should be based on the analysis of feces, which is sufficient to make
the diagnosis of most infectious etiologies. Specific stepwise approaches
• Most acute diarrheas are generally due to infectious for chronic diarrhea in travelers7 (Figure 39-2), HIV-infected patients5
etiologies. (Figure 39-3) and patients suspected of Whipple’s disease (Figure
• Diarrheas persisting for longer than 4 weeks suggest a 39-4) are also proposed.8
noninfectious etiology.
• The main circumstances in which chronic infectious diarrhea is
Bacterial Causes
observed are in travelers, mainly in low- and middle-income Usual bacterial pathogens (Salmonella spp., Yersinia enterocolitica,
and tropical countries, or people living in such areas, and in Campylobacter spp., Plesiomonas shigelloides and Vibrio parahaemolyti-
immunocompromised hosts. cus), which cause acute diarrhea in the immunocompetent population,
produce more severe or prolonged infections in immunocompromised
• Clostridium difficile is mainly observed in hospitalized patients.
people.9–11 Gastrointestinal tuberculosis remains a problem in impov-
• Patients with classic Whipple’s disease are mainly Caucasian erished areas, immigrants from LMIC and HIV-infected patients.12
males with a previous history of arthralgias. Mycobacterium avium-intracellulare is also involved in chronic
• The analysis of feces is sufficient to make the diagnosis of most
infectious etiologies.
• The most essential component of any therapeutic strategy for BOX 39-1 MAIN CAUSES OF CHRONIC DIARRHEA*
immunocompromised patients is restoration of the underlying
immunologic defect. COLONIC
• Colon cancer, lymphoma
• Ulcerative colitis, Crohn’s disease
• Microscopic colitis
• Ischemic colitis
• Radiation colitis
Introduction • Gastrointestinal protozoans and helminths
Chronic diarrhea is a common symptom that reflects many • Clostridium difficile
• Ulcerating viral infections: cytomegalovirus and herpes simplex virus
conditions.1–3 Its prevalence is estimated to be 3–5%.1–3 The current
definition of chronic diarrhea is the abnormal passage of three or more SMALL BOWEL
loose or liquid stools per day for more than 4 weeks and/or a daily • Celiac disease
stool weight greater than 200 g per day.3 A clinical definition of chronic • Crohn’s disease
• Whipple’s disease
diarrhea based on symptom reporting alone will lead to an overlap • Other small bowel enteropathies (tropical sprue, amyloid, intestinal
with functional bowel disorders such as irritable bowel syndrome, in lymphangiectasia)
which stool weight does not usually increase, and ‘true’ diarrhea. As • Bile acid malabsorption
irritable bowel syndrome affects 9–12% of the population, there is • Disaccharidase deficiency
• Mesenteric ischemia
clearly the potential for inappropriate investigation of patients report- • Radiation enteritis
ing diarrheal symptoms.3 Conversely, new onset of diarrhea may • Lymphoma
reflect serious organic disease such as colonic neoplasia. Chronic diar- • Gastrointestinal protozoans and helminths
rhea continues to be a diagnostic challenge, largely because of the vast • Small intestinal bacterial overgrowth
number of conditions included in its differential diagnosis, as demon- PANCREATIC
strated in Box 39-1. • Chronic pancreatitis
Most acute diarrheas are generally due to infectious etiologies, • Pancreatic carcinoma
whereas symptoms persisting for longer than 4 weeks suggest a non- • Cystic fibrosis
infectious etiology.3 The main circumstances in which chronic infec- ENDOCRINE
tious diarrhea is observed are in travelers, mainly in low- or • Hyperthyroidism
middle-income countries (LMIC) and tropical regions, or people • Diabetes
living in such areas, in immunocompromised hosts, in hospitalized • Hypoparathyroidism
• Addison’s disease
patients with Clostridium difficile, and in patients with classic Whip- • Hormone-secreting tumors (gastrinoma, VIPoma, somatostatinoma,
ple’s disease.4 In patients infected with human immunodeficiency mastocytosis, carcinoid syndrome, medullary carcinoma of thyroid)
virus (HIV), chronic diarrhea is more common in those with a low
OTHERS
CD4 lymphocyte count.5,6 The most essential component of any thera-
• Factitious diarrhea
peutic strategy for an immunocompromised patient is restoration of • Surgical causes (postresection diarrhea, internal fistula, postvagotomy
the underlying immunologic defect such as highly active antiretroviral diarrhea, postsympathectomy diarrhea)
therapy for HIV-infected patients.5 • Drugs
In this chapter, infectious causes of chronic diarrhea are reviewed • Alcohol
• Autonomic neuropathy
and a general stepped strategy to explore chronic diarrhea (Figure
39-1) is proposed. Obtaining a detailed medical history and stools *The place of infectious etiologies (in bold) are shown among a broad spectrum
characteristics should be the first step in defining a potential etiology of noninfectious etiologies.
and guiding appropriate choice of investigations. The second step
341
Approach to the first evaluation and management of chronic infectious diarrhea
Perform initial assessment

Confirmation of chronic diarrhea (duration > 1 mo, ≥ 3 stools or 200 gram stools per day)
Inflammation (indicated by fever, presence of blood in stools)
Provide classic symptomatic treatment (Rehydration)
Remember: chronic diarrhea = more commonly noninfectious
Stratify subsequent management according to clinical and epidemiologic features
Family history: Neoplasia, inflammatory bowel, or coeliac disease
Personal history: Previous surgery in gastrointestinal tract, previous pancreatic disease, other diseases
(hyperthyroidism, diabetes, collagen-vascular disease, tumor syndromes, immunocompromised patients),
laxatives, radiotherapy, recent antibiotic therapy, alcohol
Epidemiologic clues: Travelers mainly in LMIC and tropical countries or people living in such areas,
food and water consumption?
Clinical clues: Stools characteristics (bloody, watery or fatty), abdominal pain (suggesting inflammatory bowel
disease, irritable bowel syndrome, ischemia), weight loss (suggesting neoplasm, malabsorption), dysentery,
extraintestinal manifestation such as arthralgias
Potential infectious origin of chronic diarrhea
Persistent diarrhea Immunocompromised Persistent diarrhea Nosocomial diarrhea

patients
Traveler and/or hiker (Especially HIV +) + arthralgia Onset > 3 days

after hospitalization
Consider protozoa Consider opportunistic agents Consider Consider

Giardia duodenalis Microsporidia Tropheryma whipplei Clostridium difficile
Cryptosporidium parvum Mycobacterium avium
Entaemoeba histolytica Cytomegalovirus
Cyclospora cayetanensis
Isospora belli
Obtain stool specimen for specific analyses
Positive Negative
Consider antimicrobial therapy for specific pathogens Referral to gastroenterologist for endoscopy and complete
evaluation of infectious or noninfectious causes
Specific management
Figure 39-1 Approach to the first evaluation and management of chronic infectious diarrhea.
Chapter 39 Chronic Diarrhea 343
Management of chronic diarrhea in patients

Management of chronic diarrhea in travelers
with human immunodeficiency virus infection
Prevention = Temporal association between the onset of the diarrhea

Do not drink tap water or use it to brush your teeth and the institution of protease inhibitor therapy
Do not drink unpasteurized milk or dairy products
Do not use ice made from tap water
Avoid all raw fruits and vegetables, unless they
can be peeled and you peel them yourself
Do not eat raw or rare meat and fish or meat Yes No
or shellfish that is not hot when served
Do not eat food from street vendors
Practice hand-washing (before handling food) Association with Examination of stools to
significant diarrhea look for micro-organisms
in many patients
If failed CD4 lymphocyte count < 200/µL =
think of opportunistic micro-organisms
Acute diarrhea
Positive Negative
Most patients with travelers’ diarrhea can be efficiently
treated with available pharmacological agents
Specific treatment Colonoscopy (flexible sigmoidoscopy

alone has been noted to miss up to
Chronic diarrhea =
39% of cases of cytomegalovirus colitis)
Approximately 3% of travelers who have acute diarrhea
Inclusion of ileoscopy and biopsy of
the terminal ileum = significant yield
Initial evaluation = for microsporidiosis which may obviate
3 stool specimens for examination for parasitic micro-organisms the need for upper endoscopy
Identification of No identification or no Positive Negative

a micro-organism response to specific therapy
Specific treatment Upper endoscopy

Specific treatment Empirical treatment with an
antimicrobial drug directed
toward common bacterial Figure 39-3 Management of chronic diarrhea in patients with HIV infection.
enteropathogens (if such Knowledge of CD4 lymphocyte count and type of antiretroviral therapy is useful
treatment has not already in management of patients.
been administered)
For those patients whose

conditions do not respond
CLOSTRIDIUM DIFFICILE INFECTION
Clostridium difficile is an important nosocomial pathogen (see Chapter
Empirical antiprotozoal therapy
40).16 Any patient who develops diarrhea during a hospital stay should
be routinely tested for C. difficile.16 Antibiotic therapy is the most
significant risk factor for acquiring C. difficile infection.16 The epide-
If diarrhea continues =
miology of C. difficile infection is constantly changing, influenced by
Referral to gastroenterologist for endoscopy
and complete evaluation of infectious or antibiotic usage patterns, healthcare patient environment and emer-
non-infectious causes and specific management gence of new strains.17 C. difficile infection has a wide clinical range,
from asymptomatic carriage to more severe pseudo-membranous
colitis.18 Many different tests are now available for the detection of C.
Figure 39-2 Management of chronic diarrhea in travelers. difficile including commercial enzyme immunoassay for C. difficile
toxin A, B or both16 as well as molecular diagnosis based on polymerase
chain reaction (PCR) assays, such as the Xpert C. difficile PCR assay
diarrhea in HIV-infected patients, mainly those with CD4 lymphocyte (Cepheid, Sunnyvale, California).16,17,19
counts <50/µL.13 Clinical presentation, diagnosis and treatment for One of the most important therapeutic steps is to immediately
mycobacteria is summarized in Table 39-1. discontinue the agent responsible for provoking the disease.16 In severe
Other bacteria that are responsible for chronic diarrhea are: Clos- cases, or when the infection persists, metronidazole and vancomycin
tridium difficile and Tropheryma whipplei. Finally, small intestinal bac- are the antibiotics of choice.16,20 When standard antibiotic treatment
terial overgrowth is a condition that has been described for a long time has failed, alternative treatment such as fecal microbiota transplanta-
but which is still not clearly understood.14,15 tion, may be considered (see Chapter 40).20–23
Diagnostic strategy of classic Whipple's disease depending on quantitative real-time PCR results on saliva and stool specimens
Unexplained arthralgia/arthritis, unexplained fever, weight

loss, mediastinal or mesenteric lymphadenopathy
Chronic diarrhea or
1. Saliva and stools screening qPCR
abdominal pain
Positive / Positive Positive / Negative Negative / Positive Negative / Negative
Potential contamination Western blot serology

High suspicion Excluded classic WD
Presence of inhibitors
Perform another DNA extraction

Test diluted DNA of feces
Patient’s Asymptomatic
profile carrier’s profile
2. Duodenal biopsy (PAS staining / qPCR)
Positive / Positive Positive / Negative Negative / Positive Negative / Negative
Patient treated with antibiotics 1. False-positive PCR Excluded classic WD

Or a. Perform another DNA extraction Or
Definite classic WD False-positive PAS: b. Perform IHC Potential infection without
- Perform IHC 2. True-positive PCR intestinal involvement
Figure 39-4 Diagnostic strategy of classic Whipple’s disease depending on quantitative real-time PCR results on saliva and stool specimens. IHC = immunohistochem-
istry. (Adapted from Fenollar F, Lagier JC, Raoult D. Tropheryma whipplei and Whipple’s disease. J Infect 2014;69:103-112.)
WHIPPLE’S DISEASE in the gastrointestinal tract in association with systemic involvement,

Epidemiology diverse clinical manifestations, and typical histologic lesions on PAS-
stains of small bowel biopsies. However, localized infections due to T.
Whipple’s disease (WD) is caused by the bacterium Tropheryma whip-
whipplei without gastrointestinal involvement (such as blood-culture
plei.8 The disease is considered as rare but there is no valid estimate of
negative endocarditis, neurologic infection, uveitis), acute infections
its prevalence. The typical patient is a middle-aged Caucasian man.8
(acute diarrhea, pneumonia and bacteremia), and asymptomatic car-
Humans are the only source and reservoir clearly identified for T.
riage have been described.8,24 The main clinical manifestations of
whipplei.24 The main hypothesis is that T. whipplei is acquired via oro-
classic WD are summarized in Box 39-2.
oral or fecal-oral transmission, depending on hygiene conditions.8,24
Asymptomatic carriage of T. whipplei is mainly observed in feces,
One hypothesis concerning pathogenesis of WD is that many
and less frequently in saliva and duodenal biopsies.8 In stools, a preva-
persons in any given population are exposed to T. whipplei; only some
lence from 1 to 11% is reported in the European general population.
of those with predisposing immune factors, as yet undelineated, sub-
In Europe, this rate is higher in sewer workers (from 12 to 26%), in
sequently develop the disease.8
homeless people (13%), and in relatives of patients or carriers of T.
Clinical Features whipplei (38%).24 In rural Senegal (Africa), the carriage is about 31.2%
WD is characterized by a prodromal stage with mainly arthralgia/ in the general population.24
arthritis and a much later steady-state stage typified by weight loss and/
or chronic diarrhea, and occasionally other manifestations. The time Diagnosis
between the prodromal and the steady-state stages averages 6 years but The usual tool for diagnosing classic WD is the light microscopic
in case of immunosuppressive therapy, a more rapid clinical progres- finding of magenta-stained inclusions within macrophages of the
sion may occur.8 lamina propria on periodic acid–Schiff (PAS) stain of small bowel
The spectrum of infections caused by T. whipplei is more complex biopsies (Figure 39-5a). Depending on clinical manifestations, other
than previously suspected. Classic WD is marked by histologic lesions tissues might be sampled and stained with PAS stain.8 However, it is
TABLE Bacterial, Viral and Fungal Opportunistic Pathogens Associated with Chronic Diarrhea: Presentation,
39-1 Diagnosis and Treatment
Micro-organisms Clinical Presentation Diagnosis Treatment
BACTERIAL CAUSES
Mycobacterium Chronic diarrhea, abdominal pain, weight loss, Blood: Clarithromycin 1 g, ethambutol 15 mg/kg and rifabutin
avium- night sweats, fever – specific culture 300 mg, all po q24h for 3–6 months
intracellulare Stools and colonic biopsies: Secondary prophylaxis: rifabutin 300 mg po q24h
– acid-fast stain
– culture
– PCR
Mycobacterium Chronic diarrhea, abdominal pain, weight loss, Stools and colonic biopsies: Rifampin 10 mg/kg and isoniazid 5 mg/kg, both po q24h
tuberculosis fever, night sweats – acid-fast stain for 9 months, plus
Only 15–20% of patients have concomitant – culture Pyrazinamide 20 mg/kg and ethambutol 15 mg/kg, both
active pulmonary infection – PCR po q24h for 2 months
VIRAL CAUSES
Cytomegalovirus Chronic diarrhea, cramps, tenesmus, fever, Blood: Ganciclovir 5 mg/kg and foscarnet 90 mg/kg, both iv
abdominal pain, weight loss – antigenemia q12h for 2–3 weeks
– viremia Secondary prophylaxis: valganciclovir 900 mg po q24h
Stools: PCR and foscarnet 120 mg/kg iv q24h
Colonic biopsies:
– H&E
– PCR
– viral culture
– electron microscopy
Herpes simplex Chronic diarrhea, proctitis, distal colitis, Colonic biopsies: Aciclovir 10 mg/kg po q8h for 2–3 weeks and valaciclovir
virus tenesmus, rectal pain – H&E 1 g po q12h for 2–3 weeks
– PCR Secondary prophylaxis: valaciclovir 1 g po q24h
– viral culture
– electron microscopy
FUNGAL CAUSE
Histoplasmosis Diarrhea, hematochezia, weight loss, fever, Stools: NA Severe cases: amphotericin B 0.7 mg/kg iv for 2–3 weeks
abdominal pain Colonic biopsies: Mild or moderate cases: itraconazole 200 mg po q8h for
– H&E 2–3 weeks
– PAS stain Secondary prophylaxis: itraconazole 200 mg po q24h
– silver stain
– fungal culture
H&E, hematoxylin and eosin; iv, intravenous; PCR, polymerase chain reaction; po, per os (oral).
important to note that PAS stain is not pathognomonic of WD.8 For Treatment
example, PAS-positive cells are also seen in patients with mycobacte- For a long time, the treatment of WD was empirical and trimethoprim–
rial infections.8 The presence of non-caseous granulomas composed of sulfamethoxazole was considered as mainstay treatment of WD.8 With
epithelioid cells, PAS-negative in 40% of cases, may be observed the recent culture of T. whipplei, susceptibility tests and full genome
mainly in the gastrointestinal tract and the lymphatic tissues.8 sequencing have been achieved. Genomic analysis has shown that
Immunohistochemistry (IHC) using antibodies directed against T. T. whipplei lacks the coding sequence for dihydrofolate reductase,
whipplei allows the detection of the micro-organism in various fixed which is the target for trimethoprim and in vitro tests have confirmed
tissue fragments, and in bodily fluids, providing direct visualization of that trimethoprim is not active against T. whipplei.8 Twenty-five
the bacilli (Figure 39-5b).8 This technique, which offers increased sen- percent of T. whipplei strains are in vitro resistant to sulphadiazine, a
sitivity and specificity as compared to PAS staining, is not yet widely sulphonamide compound.25 Several cases of acquired resistance and
available. relapses have also been reported with trimethoprim–sulfamethoxazole
PCR assays can detect T. whipplei in samples from a variety of tissue (TMP–SMX).8 Thus, TMP–SMX can no longer be considered as the
types and bodily fluids, including gastric and small bowel biopsies and best treatment for classic WD and should be abandoned.8
stools.8 Quantitative real-time PCR (qPCR) assay targeting repeated The only successful bactericidal regimen against T. whipplei in
sequences of T. whipplei using fluorescent labeled oligonucleotide vitro is based on the association of doxycyline and hydroxychloro-
hybridization probes for specific identification is the best tool to quine. Currently, a combined oral regimen of doxycyline (200 mg
perform the diagnosis of WD.8 A diagnostic strategy of classic WD daily) and hydroxychloroquine (200 mg thrice daily), is proposed
using this tool and depending on results on saliva and stool specimens for patients with WD.8 The duration should be at least 12 months.8
is proposed (see Figure 39-4).8 Cultivation of T. whipplei, using mam- After a course of doxycycline and hydroxychloroquine, long-term
malian cell cultures and axenic medium supplemented in amino acids (possibly lifelong) doxycycline treatment should be strongly consid-
from various specimens, including small bowel biopsies and stools, has ered, as potentially fatal neurologic or cardiac relapses have been
been achieved.24 However, this technique is not generally available. described.8 At the start of antibiotic therapy, immune reconstitution
Paradoxical western blot serology has been developed. This serol- inflammatory syndrome has been also reported and may be fatal.8
ogy may be helpful for the differentiation among PCR-positive asymp- Usually, this syndrome responds well to steroids, however the use of
tomatic carriers, who most often exhibit a strong immune response, thalidomide is sometimes required.8 Overall, only a long-term
and patients with classic WD, who usually lack or have a low immune follow-up of patients, will allow a determination of the best manage-
response. However, this technique is not generally available.8 ment of WD.
BOX 39-2 MAIN CLINICAL MANIFESTATIONS OF

PATIENTS WITH CLASSIC WHIPPLE’S
DISEASE
*
Frequent Manifestations (>50%)
• Chronic diarrhea
• Arthralgia
• Weight loss
Less Frequent Manifestations (<50%)

• Adenopathy (mainly mediastinal and mesenteric)
• Melanoderma
• Fever
Neurologic Manifestations
• Cognitive change
• Supranuclear ophthalmoplegia
• Hypothalamic manifestations
• Myoclonus
• Oculomasticatory or oculo-facial-skeletal myorhythmia
a
Cardiovascular Involvement
• Endocarditis
• Pericarditis
• Myocarditis
Pulmonary Involvement
• Pleural effusion
• Pulmonary infiltration
Ocular Involvement
• Uveitis
Other
• Noncaseating epithelioid and giant cell granulomas, most often lymph
node granulomas
SMALL INTESTINAL BACTERIAL OVERGROWTH

Small intestinal bacterial overgrowth (SIBO) is a condition caused by
an abnormal number of bacteria in the small intestine.26–28 The real
prevalence of SIBO is unknown.28 Patients with SIBO may be clinically b
asymptomatic or they may have symptoms, such as malabsorption and
diarrhea.14,26,27 This entity was first described in patients in a context Figure 39-5 Duodenal biopsies from a patient with classic Whipple’s disease.
of abnormal or postsurgical anatomy.14,28 However, predisposing con- (a) Duodenal biopsy specimen with reduced villous architecture and PAS-positive
(asterisk) macrophages in the lamina propria. Periodic acid–Schiff stain. (b) Dem-
ditions associated with SIBO have increased, including nonspecific onstration of T. whipplei by immunohistochemistry (arrows) in duodenal biopsy.
dysmotility, chronic pancreatitis, celiac disease, Crohn’s disease or Polyclonal rabbit anti-T. whipplei antibody used at a dilution of 1 : 2000 with
hypothyroidism.14,28 hemalun counterstain. (Courtesy of Hubert Lepidi.)
A fundamental problem with SIBO is the lack of a universally
accepted and applied gold standard for the diagnosis.15,26 Though not
widely accepted, the diagnosis may be suggested on small bowel culture DNA extraction and detection. Obviously, PCR will not be appropriate
with a colony count greater than 105/mL or on hydrogen breath test.26 as a routine diagnostic tool in clinical settings in endemic areas where
However, a better method and novel diagnostic options for identifying resources of the laboratories are often limited. Serologic tests for the
SIBO accurately are needed.14,15 intestinal protozoans and helminths are not really useful. If stools
The treatment of SIBO should address removal of the predisposing analysis does not reveal the cause of the diarrhea, additional tests may
condition, nutritional support and suppression of the contaminating include endoscopy. Main parasitic causes of chronic diarrhea with
bacterial flora but until now there has been no conclusive information their more relevant epidemiologic, clinical, diagnostic and therapeutic
on the most effective therapeutic approach. Many different antibiotic characteristics are summarized in Table 39-2.
regimens, such as ciprofloxacin, metronidazole and doxycycline, have
been advocated for use in SIBO but there is no consensus on the most PROTOZOAN PARASITES
efficacious dose or duration of treatment.14 Probiotics have been sug- Giardiasis
gested as a potential treatment for SIBO but there are only pilot studies Giardiasis is caused by the protozoan Giardia duodenalis (former G.
addressing their use.14 lamblia or G. intestinalis). G. duodenalis is one of the major causes of
parasitic diarrhea worldwide. In LMIC, giardiasis is pandemic, with
Parasitic Causes peak prevalence rates of up to 20% in childen <10 years of age.33 It is
The most frequent parasitic causes of chronic diarrhea are: Giardia, an important cause of chronic diarrhea in travelers returning from
Cryptosporidium and Entamoeba histolytica.4 To detect parasites, three LMIC, with an infection rate of 1–3% in short-term visitors to endemic
or more stool samples should be examined. Currently, several molecu- areas.33 Major routes of transmission are consumption of contami-
lar tools, including real-time PCR assays targeting various protozoa or nated water and food or by direct fecal-oral contact. Chronic infection
helminth DNA sequences, have become available.29–32 Stool samples has been associated with hypogammaglobulinemia, protein-calorie
mixed with ethanol allow the samples to be stored and transported at malnutrition, previous gastrectomy and use of immunosuppressive
room temperature to laboratories with the appropriate facilities for medication.33
TABLE Main Parasitic Causes of Chronic Diarrhea with their More Relevant Epidemiologic, Clinical, Diagnostic and
39-2 Therapeutic Characteristics
Modes of Transmission and
Micro- Common Epidemiologic
organisms Settings Clinical Features Diagnosis Treatment
PROTOZOANS
Giardia Fecal–oral route, IgA Most infections are asymptomatic Stools; if negative, Treatment recommended in
duodenalis deficiency Watery diarrhea/malabsorption small-bowel aspiration or symptomatic and asymptomatic
Abdominal pain biopsies: disease to reduce transmission:
– ME metronidazole 250–750 mg po
– immunofluorescence, q8h for 7 days
ELISA methods
– PCR
Cryptosporidium Fecal–oral route, Watery diarrhea/malabsorption Stools; if negative, small Generally not necessary in
parvum immunocompromised host Immunocompetent host: usually bowel aspiration or immunocompetent individuals
asymptomatic or mild self- biopsies: Severe disease/
limiting gastroenteritis, – ME with modified acid-fast immunocompromised host:
occasionally lasting more than 1 stain supportive therapy, no single
month – immunofluorescence, effective therapy; nitazoxanide
Immunocompromised host: ELISA methods may be considered
chronic, more often severe – PCR In patients with AIDS, HAART
diarrhea, dehydration, weight sufficient to achieve immunologic
loss reconstitution is most effective
Cyclospora Fecal–oral route, travel Watery diarrhea/malabsorption Stools; if negative, small TMP–SMX (co-trimoxazole)
cayetanensis bowel aspiration or 160–800 mg po q8h for 10 days
biopsies: ME with
modified acid-fast stain
Entamoeba Fecal–oral route Asymptomatic colonization: ~90% Stools; if negative, colonic Generally recommended for
histolytica Travel to tropical regions, Bloody diarrhea/dysentery biopsies: symptomatic and asymptomatic
recent emigration from – ME individuals to prevent
such region – immunofluorescence, transmission: metronidazole
ELISA methods 750 mg po q8h for 5–10 days
– PCR plus treatment for 7 days with
paromomycin 500 mg po q8h
Isospora belli Fecal–oral route, Watery diarrhea/malabsorption Stools; if negative, small TMP–SMX (co-trimoxazole)
immunocompromised host Immunocompetent host: acute- bowel aspiration or 160–800 mg po q12h for 7–10
self-limiting biopsies: days
Immunocompromised host: – ME with modified acid-fast
chronic, occasionally severe stain
diarrhea, dehydration, weight – PCR
loss
Microsporidia Fecal–oral route, Watery diarrhea/malabsorption Stools; if negative, small May be indicated in
immunocompromised host Immunocompetent host: rare cause bowel aspiration or immunocompromised patients:
of acute self-limited diarrhea colonic biopsies: albendazole 400 mg po q12h for
Immunocompromised host: chronic – ME with special stain 3 weeks
diarrhea, dehydration, anorexia, – PCR In HIV-infected patients, HAART
weight loss sufficient to achieve immunologic
reconstitution is most effective
Balantidium coli Fecal–oral route Bloody diarrhea/dysentery Stools: ME Tetracyclines po for 10 days
HELMINTHS
Strongyloides LMIC, immunocompromised Watery diarrhea/malabsorption Stools; if negative, small Ivermectin 200 µg/kg po q24h for
stercoralis host Immunocompromised host bowel aspiration or 2 days
(HTLV-1): chronic diarrhea biopsies: ME
Trichuris Fecal–oral route Bloody diarrhea/dysentery Stools; if negative, rectal Mebendazole 100 mg po q12h for
trichiura biopsies: ME 3 days
Albendazole 400–600 mg po,
single dose
ELISA, enzyme-linked immunosorbent assay; HAART, highly active antiretroviral therapy; LMIC, low- and middle-income countries; ME, microscopic examination; PCR,
polymerase chain reaction; po, per os (oral); TMP–SMX, trimethoprim–sulfamethoxazole.
The clinical spectrum of giardiasis ranges from asymptomatic car- The drug of choice for treatment is metronidazole.33 The adult
riage, through acute diarrhea to severe chronic diarrhea. Patients who dosage is 250 mg and for children 5 mg/kg three times daily for 7 days.
develop recurrent diarrhea after treatment for giardiasis may have Pregnant women may be treated with paramomycin.33
associated lactose intolerance rather than relapse of their infection.33
The most common method for diagnosis is microscopic examina- Cryptosporidiosis (see also Chapter 114)
tion of the stools for trophozoites using either wet mount or trichome Cryptosporidiosis in humans is most commonly due to Cryptospo-
stain. Immunofluorescent- and ELISA-based methods have been ridium parvum, a coccidian parasite. Cryptosporidiosis is described
developed.34 Real-time PCR procedures are also available for the detec- worldwide in both immunocompetent and immunocompromised
tion of G. duodenalis.29,32 In patients with negative stools, small bowel hosts. When clinical stool specimens are examined for Cryptosporid-
aspiration or biopsies may be considered. ium oocysts, approximately 1–3% are positive in North America and
Europe and 5–10% in LMIC. Risk factors for the acquisition of cryp- Identification of E. histolytica cysts and trophozoites requires
tosporidiosis include transmission via the fecal–oral route, contact examination of a fresh stool sample and a trichrome stain.34 New fecal
with animals, drinking contaminated water and eating contaminated antigen detection methods (monoclonal antibodies, ELISA) may also
food.34 prove useful.34 Real-time PCR procedures are available for the detec-
The clinical manifestations depend on the host reponse. In immu- tion of E. histolytica.29,32 In the presence of negative stool microscopy,
nocompetent hosts, prolonged diarrhea is uncommon.35 In immuno- colonic biopsies may sometimes be useful.
compromised hosts, such as HIV-infected patients, disease onset is Invasive disease, such as severe colitis, should be treated with met-
usually insidious.6 Diarrhea may gradually increase over weeks to ronidazole (750 mg po thrice daily) for 10 days, followed by a luminal
months. Symptoms typically persist unless there is improvement in the agent, such as diloxanide (500 mg po three times daily) or paromo-
immunologic status. mycin (500 mg po three times daily), to prevent future invasion with
Infection can be diagnosed by identification of oocysts on stools any remaining cysts.33
using modified Ziehl–Neelsen stain, immunofluorescence with mono-
clonal antibodies and commercially available ELISA.34,36 Real-time Isosporiasis
PCR procedures are also available for the detection of Cryptosporidium Isosporiasis is caused by the coccidian parasite Isospora belli. Infections
spp.29,30,32,37 In patients with negative stools, small bowel aspiration or have been described worldwide but with an increased prevalence in
biopsies may be considered. tropical and subtropical climates and in areas with poor sanitation.34
Treatment of the immunocompetent host is supportive because Transmission is associated with contaminated water, although that
cryptosporidiosis is self-limiting.34 Few options exist for HIV-infected route has not been proven.34 Little is known about the prevalence of
patients in whom highly active antiretroviral therapy fails.34 Mono- human infection. In a limited number of studies employing adequate
therapy with spiramycin, paromycin or nitazoxanide has been reported techniques, 0.1–1.8% of stools were positive.33 Isosporiasis is observed
to be active but the efficacy has not been confirmed and a majority of in patients with HIV infection, with an incidence ranging from
patients relapse.33,34 approximately 0.2 to 20% in tropical areas. I. belli has been described
also in transplant patients (liver, renal) as well as in patients with
Cyclosporiasis hematologic malignancies.
Cyclosporiasis is caused by a coccidian parasite, Cyclospora cayetanen- The predominant symptom is diarrhea. Stools are watery and
sis.38 Cyclosporiasis is described worldwide but more frequently foamy, suggesting malabsorption. While symptoms are usually self-
in tropical countries.38 Transmission occurs via the oral route, and limiting in immunocompetent hosts, patients are often ill for 6 weeks
local outbreaks have been traced to contaminated water or food to 6 months. In HIV-infected patients, isosporiasis presents with an
supply.38 insidious onset of diarrhea, weight loss and abdominal pain.33
C. cayetanensis is the cause of persistent diarrhea in immunocom- Stool specimens frequently contain Charcot–Leyden crystals and
petent and immunocompromised patients. Other common symptoms fat. Eosinophilia is frequent.34 Infection can be diagnosed by identi-
are abdominal pain and vomiting. In HIV-infected patients, C. cayeta- fication of oocysts in stools using acid-fast stains, such as the modi-
nensis results in chronic diarrhea.34 fied Ziehl–Neelsen method.34 Real-time PCR has been also developed.31
C. cayetanensis can be detected on microscopic examination on the Stool examinations may remain negative, even in cases of severe
basis of morphologic characteristics, staining properties and auto- diarrhea; therefore small bowel aspiration or biopsies may be
fluorescence under ultraviolet light.38 In contrast to Cryptosporidium, necessary.
staining is variable with the modified Ziehl–Neelsen stain. Measure- Isosporiasis responds promptly to TMP–SMX (160–800 mg, four
ment of oocysts is recommended to distinguish C. cayetanensis times daily) for 10 days in immunocompetent patients.33 For HIV-
(8–10 µm) from C. parvum (3–5 µm).34 C. cayetanensis can be also infected patients, secondary prophylaxis with TMP–SMX (160–
detected using molecular assays.38,39 In patients with negative stools, 800 mg) thrice weekly may be needed if antiretroviral therapy is
small bowel aspiration or biopsies may be considered. ineffective (see Chapter 94).33
TMP–SMX (160–800 mg, twice daily) for 10 days is the treatment
of choice.34,38 Microsporidiosis
Microsporidiosis is caused by microsporidia, intracellular protozoan
Amebiasis (see also Chapter 116) parasites.33 Two species are associated with enteric infection, Enterocy-
Amebiasis caused by Entamoeba histolytica and Entamoeba dispar is tozoon bieneusi and Encephalitozoon intestinalis. The former is more
especially prevalent in Mexico, India, Africa, and Central and South common. Little is known about the epidemiology of microsporidiosis.
America. These species are morphologically indistinguishable but can Serologic surveys suggest that infection with these organisms is
be differentiated by monoclonal antibodies and DNA probes.34 widespread.33 Spread of the organisms through environmental, person-
Infections with E. dispar are characteristically asymptomatic, do not to-person (fecal–oral, aerosolized respiratory secretions), and animal-
elicit a serologic response and are responsible for the majority of infec- to-person transmission have been postulated.33 The prevalence of
tions with Entamoeba species. In contrast, infections with E. histolytica infection in selected groups of HIV-infected patients in different coun-
result in symptomatic illness or invasive disease (2–20%) and the pro- tries has a range of 1.7–30%.34
duction of serum antibodies. In indigenous populations, asymptom- Microsporidia cause acute self-limiting diarrhea in immunocom-
atic carriage of E. histolytica is common. Major routes of transmission petent persons and in patients who have immunodeficiency other
are consumption of contaminated water and food or by direct fecal– than HIV infection.40 In immunocompromised HIV-infected patients,
oral contact.33 Individuals at highest risk for infection include persons E. bieneusi is responsible for chronic diarrhea.33 E. intestinalis is a less
who travel to low- and middle-income countries, immigrants or commonly recognized cause of chronic diarrhea.33
migrant workers from areas of high endemicity, immunocompro- Spores of microsporidia can be detected in stools and in small
mised persons, and persons housed in mental institutions.33 bowel and colonic biopsy specimens using Giemsa, Weber’s trichrome,
Patients may be asymptomatic or present with colicky abdominal or fluorochrome stains, but identification of the specific species
pain.33 Amebic dysentery is characterized by bloodstained stools with requires electron microscopy or PCR.34,41 Molecular methods have
mucus.33 The duration of the dysentery can be very variable and may become a valuable tool for the detection and identification of
last for only a few days or for several months.33 Chronic amebic colitis microsporidia.42
is clinically indistinguishable from idiopathic inflammatory bowel Albendazole can be used in the treatment of infections with
disease.34 Because corticosteroid therapy may result in perforation, E. intestinalis but not for E. bieneusi.33,42 Thus, no real therapeutic
stool examination for trophozoites should be performed prior to options exist for HIV-infected patients in whom antiretroviral therapy
making a diagnosis of inflammatory bowel disease.34 fails.34
Balantidiasis appears to act on adult as well as larval stages of the parasite, thus
Balantidiasis is caused by Balantidium coli, the only ciliate associated reducing relapse.44
with human infection.33,43 It has a widespread distribution, but is only Schistosomiasis (see Chapter 118)
rarely found in human stools (≤1% in all surveys).33,43 Many cases are
asymptomatic but chronic diarrhea can be observed.33,43 Diagnosis Colorectal schistosomiasis (usually Schistosoma mansoni infection) can
is based on demonstration of the trophozoites in stools.33,43 The present with chronic diarrhea due to the resulting inflammation of
treatment is typically 10 days for tetracycline and 5 days for the colon seen during the chronic phase in patients with heavy
metronidazole.33,43 infections.46
HELMINTHS AND CHRONIC DIARRHEA FUNGAL INFECTIONS

Strongyloidiasis (see Chapter 114) Histoplasmosis is caused by Histoplasma capsulatum, a fungus endemic
Strongyloidiasis is caused by Strongyloides stercoralis, a worldwide hel- in America and Africa13 (see Chapters 33 and 189). Severely immuno-
minth parasite.44,45 Humans are usually infected from moist soil by compromised patients are at risk of disseminated histoplasmosis,
transcutaneous penetration. S. stercoralis can be associated with per- which may involve the digestive tract and cause diarrhea.13 Histologic
sistent diarrhea, abdominal pain and weight loss with evidence of examination of PAS stain or silver-stained gastrointestinal biopsies
malabsorption, particularly when there is hyperinfection or dissemi- allow the detection of the fungus. Treatment is based on amphotericin
nated strongyloidiasis.44 This massive invasion can be observed in or itraconazole. Clinical presentation, diagnosis and treatment for his-
people debilitated by concurrent disease or malnutrition, patients toplasmosis are summarized in Table 39-2.
treated with immunosuppressive drugs harboring S. stercoralis, patients
infected with human T-cell leukemia virus 1 but not in HIV-infected Viral Causes
patients. The usual viral micro-organisms (rotavirus, astrovirus, adenovirus,
Eosinophilia is a prominent feature of this infection.45 Diagnosis norovirus) responsible for acute diarrhea are not involved in chronic
depends on demonstration of S. stercoralis larvae in stools, or in small diarrhea except maybe in specific immunocompromised hosts. Indeed,
bowel aspiration or biopsies. A single oral dose of ivermectin (200 µg/ rotavirus and astrovirus diarrhea may continue for months in children
kg/day) is the treatment of choice.45 As an autoinfection cycle takes who have defects in T cell function (e.g. DiGeorge syndrome, cartilage-
3–4 weeks to complete and the activity of ivermectin on the extraint- hair hypoplasia syndrome).47 Adenovirus is also a cause of chronic
estinal stages of the parasite remains uncertain, it has been suggested diarrhea in patients with immunodeficiency, mainly HIV-infected
to give two doses 2 weeks apart.45 patients.13 Finally, norovirus and adenovirus have also been detected
Trichuriasis as responsible for chronic diarrhea in a child after solid organ
transplantation.48
Trichuriasis caused by the whip worm Trichuris trichiura is prevalent
Cytomegalovirus and herpes simplex virus are both specifically
worldwide.44 When few worms are present there is little damage, but
responsible for chronic diarrhea due to ulcerating chronic infection in
heavy infections (more than 200 adult worms have been recovered
immunocompromised patients, including HIV-infected patients and
after anti-helminthic expulsion) can cause chronic dysentery, predis-
transplant recipients (see Chapters 80 and 94). Diagnosis and treat-
position to rectal prolapse and anemia.
ment are summarized in Table 39-2.
Most symptomatic cases can be readily diagnosed by routine
microscopic stool examinations.44 The diagnosis is made when numer-
ous worms are seen in the rectal mucosa. Treatment with mebendazole Chronic (Possibly Infectious) Diarrhea
(100 mg twice daily) for 3 days is highly effective as well as albendazole TROPICAL SPRUE
in a single dose of 400–600 mg.44
Tropical sprue is the association of chronic diarrhea, malabsorption
Trichinosis and nutritional deficiency in patients who live in or have visited tropi-
Trichinosis caused by Trichinella spiralis is widely distributed, except cal areas.49 Pathogenesis is still unknown but an infectious cause is
in Australia and parts of the South Pacific.44 The occurrence of diar- suspected.11,49,50
rhea of short duration following the ingestion of infected meat has Tropical sprue starts with an acute intestinal infection that can
been well described.44 Intestinal symptoms typically resolve spontane- affect predominantly the small or the large intestine.49,50 Macrocytic
ously. There is no reliable therapy. anemia and hypoalbuminemia are present, together with progressive
A new clinical syndrome had been reported in the Inuit population villus atrophy of the small intestine. Treatment with tetracycline, folic
in northern Canada.44 These patients presented with chronic diarrhea, acid and nutritional support is generally effective but relapses after
lasting up to 14 weeks. They also had myalgias. The manifestations treatment are common.49
differ considerably from those of classic trichinosis, suggesting that this
may be due to a distinct strain of parasite. BRAINERD DIARRHEA
A form of chronic diarrhea manifesting as outbreaks is Brainerd diar-
Capillariasis rhea, named after the city of Brainerd, Minnesota.51 The source is
Capillariasis is caused by a small nematode, Capillaria philippinensis, characteristically unpasteurized milk or untreated water. Despite
initially described in the Philippines.44 Since, Thailand has been found intensive laboratory examinations, the cause of Brainerd diarrhea
to be endemic for the disease, and few cases have been identified in remains unknown. Extensive laboratory and environmental testing did
Japan, Taiwan, Iran, Egypt and India.44 Human infection results from not identify an etiologic agent.
consumption of raw fish. C. philippinensis can cause chronic diarrhea Treatment with a wide variety of antimicrobial agents gives no
and malabsorption. significant clinical response. Most of the individuals have resolution
The detection of C. philippinensis is based on the recovery of eggs, of diarrhea within 3 years.11
larvae and/or adult worms in the feces. However, small bowel aspira-
tion or biopsies may be necessary to confirm capillariasis. Albendazole References available online at expertconsult.com.
(400 mg per day for 10 days) is currently the drug of choice since it
KEY REFERENCES
Elliott B., Chang B.J., Golledge C.L., et al.: Clostridium tures, current and developing diagnostic tests, and treat- Moore T., Rodriguez A., Bakken J.S.: Fecal microbiota
difficile-associated diarrhoea. Intern Med J 2007; ment. Aliment Pharmacol Ther 2013; 38:674-688. transplantation: a practical update for the infectious
37:561-568. Hashmey R., Genta R.M., White A.C. Jr: Parasites and diar- disease specialist. Clin Infect Dis 2014; 58:541-545.
Feasey N.A., Healey P., Gordon M.A.: Review article: the rhea. I: Protozoans and diarrhea. J Travel Med 1997; Okhuysen P.C.: Traveler’s diarrhea due to intestinal proto-
aetiology, investigation and management of diarrhoea in 4:17-31. zoa. Clin Infect Dis 2001; 33:110-114.
the HIV-positive patient. Aliment Pharmacol Ther 2011; Hashmey R., Genta R.M., White A.C. Jr: Parasites and diar- Wright S.G.: Protozoan infections of the gastrointestinal
34:587-603. rhea. II: Helminths and diarrhea. J Travel Med 1997; tract. Infect Dis Clin North Am 2012; 26:323-339.
Fenollar F., Lagier J.C., Raoult D.: Tropheryma whipplei and 4:72-75.
Whipple’s disease. J Infect 2014; 69:103-112. Kaiser L., Surawicz C.M.: Infectious causes of chronic
Grace E., Shaw C., Whelan K., et al.: Review article: small diarrhoea. Best Pract Res Clin Gastroenterol 2012;
intestinal bacterial overgrowth – prevalence, clinical fea- 26:563-571.
Chapter 39 Chronic Diarrhea 350.e1
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2011; 34:587-603. transplantation: a practical update for the infectious Microbiol Rev 2010; 23:218-234.
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and Whipple’s disease. J Infect 2014; 69:103-112. Microbiol 2013; 21:443-445. immunodeficient and immunocompetent patients.
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40
Clostridium difficile Infections in
Hospitals and Community
MARTIJN P. BAUER | ED J. KUIJPER
KEY CONCEPTS polymerase chain reaction (PCR) ribotypes. PCR ribotyping is the
most frequently used molecular typing method in Europe. This PCR
• Clostridium difficile is ubiquitous and can colonize healthy indi- band-size-based typing method exploits the variability of the inter-
viduals and animals without causing disease. genic spacer region between 16S and 23S ribosomal DNA, as well as
• All disease-causing C. difficile strains produce toxin B and toxin rDNA copy numbers.3 In comparison to other DNA-based typing
A. The role of a third toxin, binary toxin, is unclear. assays, PCR ribotyping is superior in discriminatory power, (inter-
laboratory) reproducibility and its low hands-on time. PCR ribotyping
• Antibiotic use increases the risk for C. difficile infection (CDI) is not able to differentiate between strains in an outbreak situation.
during therapy and in the period of 3 months after cessation
Recently, major advances have been made with whole genome sequenc-
of antibiotic therapy.
ing (WGS)-based typing of C. difficile strains. WGS can distinguish
• Since 2003 the epidemiology and clinical presentation of CDI strains at a single nucleotide level.4 Whole genome single-nucleotide
has changed, with the appearance of a new hypervirulent polymorphism (SNP) analysis has been developed to study the evolu-
strain, C. difficile BI/NAP1/PCR-ribotype 027. tionary relatedness of C. difficile strains and to support epidemiological
• The US Centers for Disease Control and Prevention has catego- studies of CDI transmission.5,6
rized CDI in the highest priority category of antimicrobial resis-
tance threats, based on data reported in 2015 estimating the Pathogenesis
annual burden as 453 000 cases, resulting in 29 000 deaths.
The first step in the pathogenesis of C. difficile infection is the ingestion
• In Europe, an expert group estimated 124 000 occurrences of of spores. These spores, which are highly resistant to physical and
CDI annually with at least 6000 attributable deaths. chemical attacks and may survive for years, can pass through the
stomach undamaged. After reaching the bowel, they germinate under
• Approximately 25% of community-acquired CDI occurs in indi-
viduals without previous antibiotic use or hospitalization. the influence of primary bile acids. The vegetative stages must then
colonize the mucosa, which is greatly facilitated by prior disruption of
• C. difficile has replaced methicillin-resistant Staphylococcus the resident flora, usually as a result of antibiotics. The microbiome of
aureus (MRSA) as the most common cause of healthcare- CDI patients has less diversity than that of individuals without CDI.
associated infections. The proportion of lactate-producing bacteria is increased and that of
• Recurrences of CDI still do occur and remain the biggest chal- butyrate-producing bacteria is decreased with great proportional
lenge in treating CDI. Transplantation of feces from healthy losses of firmicutes and bacteriodetes.7 A healthy microbiome may
donors is currently the only therapy for recurrent CDI infections protect against colonization by C. difficile by metabolizing primary bile
supported by a randomized trial. acids, competing for nutrients and mucosal surface, producing bacte-
riocins and influencing host defense. After successful colonization, C.
difficile may cause disease, which is mainly if not exclusively mediated
by the production of exotoxins. The large clostridial toxins TcdA and
TcdB act on epithelial cells, and after disruption of the mucosal barrier,
Microbiology on underlying stromal cells. The toxins have a similar mechanism of
The genus Clostridium belongs to the class of Clostridiaceae, which action. After binding to receptors that are as yet unknown, they are
consists of approximately 100 species. Clostridium spp. are found ubi taken up by the cell through endocytosis. The toxin inserts itself in the
quitously in the environment, soil, water and in the human and mam- endosomal membrane and cleaves itself, releasing its N-terminal
malian gastrointestinal tract as part of the commensal microbial flora. domain into the cytoplasm.8 There, it glycosylates Rho and Ras family
All diseases caused by Clostridium spp. are mediated by the secretion GTPases,9,10 influencing various cell processes. Glycosylation of RhoA,
and action of the secreted toxins, including Clostridium difficile. The Rac1 and Cdc42 leads to loss of organization of the cytoskeleton, which
symptoms of C. difficile infection (CDI) are caused by the two main can be seen as rounding of the intoxicated cells in vitro. Gap junctions
virulence factors, toxin A (TcdA) and toxin B (TcdB). All disease- are damaged, which can also be assessed in vitro by measuring the
causing C. difficile strains produce toxin B, and nearly all of the strains electric resistance over an epithelial cell layer. The vast majority of
also produce toxin A. Besides both toxin genes, the pathogenicity locus toxigenic strains produce both toxins. In spite of 48% homology, the
(PaLoc) also contains the gene encoding the proposed negative regula- toxins probably have different functions. TcdA probably plays a more
tor (tcdC) of toxin gene transcription. So-called ‘hypervirulent C. dif- important role in loss of epithelial cell polarity and epithelial integrity11
ficile strains’ contain point-mutations in tcdC, which has been proposed and TcdB is more potent. TcdB-induced activation of Rac1 leads to
as a possible explanation for their increased virulence, but the findings assembly of the NADPH oxidase complex on endosomes, resulting in
of Bakker and Cartman contradict previous reports that demonstrate the formation of reactive oxygen species and eventually cell necrosis.12
that TcdC is a major repressor of toxin production.1,2 Both toxins appear to be capable of causing disease on their own. The
Some strains that are associated with an increased mortality and resulting pathologic effect is cell necrosis, fluid secretion and a massive
morbidity also produce a third toxin, called the binary toxin since it influx of neutrophils, forming cryptabscesses, which may coalesce into
consists of two polypeptides, encoded by the cdtA and cdtB genes. The macroscopically visible pseudomembranes, plaques of pus on the
binary toxin genes are located on a 6.2 kb region called the Cdt locus, intestinal mucosa. Pathologic changes occur mainly in the colon,
or CdtLoc. C. difficile can be divided in more than 400 different although ileitis has also been described, especially after colectomy. In
351
the blood, leukocytosis is usually seen, which may rise to leukemoid and signs gradually disappear in the course of days to weeks. It may
proportions. take weeks for stools to return to completely normal. Unfortunately,
Besides the toxins TcdA and TcdB, some strains produce the binary diarrhea may recur. Depending on the number of previous CDI epi-
toxin, CDT. This ADP-ribosyltransferase causes depolymerization of sodes,15–17 age, co-morbidity, the need to continue antimicrobials for
actin, leading to protrusions on the cell surface, which may serve to other infections than CDI, humoral immune response, virulence of
increase the cell surface available for attachment of C. difficile.13 the C. difficile strain, treatment for CDI and – perhaps not causally
Although CDT is produced by the epidemic strain PCR ribotype 027 related – the use of proton pump inhibitors, recurrences develop in
and by Type 078, its contribution to virulence is unclear. Certainly, C. around 20% of cases after a first episode of CDI. Some patients suffer
difficile strains can cause severe disease without it. several recurrences, leading to debility, dehydration, malnutrition and
Studies into host factors other than the microbiome that might play protein-losing enteropathy. The majority of these recurrences are
a role in CDI pathogenesis have mainly focused on antibody responses. relapses, although some are reinfections. Without typing methods,
Although not all studies were consistent, most studies found that low which are not part of routine practice in most laboratories, this distinc-
serum or fecal levels of antibodies directed against TcdA and TcdB are tion is obviously difficult to make. An additional problem with this
associated with acquisition of CDI, more severe course of CDI, or a distinction is the fact that in some patients, more than one strain may
higher risk of recurrence. This is plausible, since CDI pathogenesis is be found at the same time. It seems most plausible that one of these
thought to be mediated primarily by toxin production in the intestinal strains represents the causative agent of the disease, whereas the others
lumen, and antibodies have been found to neutralize these toxins in represent colonization.
vitro and in vivo.
Diagnosis
Clinical Syndromes The diagnosis of CDI is primarily based on clinical symptoms in
After the gut has been successfully colonized by C. difficile, asymptom- combination with laboratory assays. Culturing C. difficile and the
atic carriage may develop, but in an estimated 15–30% of cases, symp- detection of free toxin(s) in feces samples with a cytotoxicity assay is
toms may arise. These symptoms range from mild, self-limiting regarded as the gold standard for diagnosis of CDI. However, in many
diarrhea to fulminant colitis with a systemic inflammatory response. diagnostic laboratories, culturing and cell cytotoxicity assays are not
Although the colon may be severely inflamed, fever and bloody diar- performed routinely, as they are labor-intensive and costly. Most diag-
rhea are uncommon. Complications of severe colitis are ileus, toxic nostic laboratories depend on rapid and easy-to-perform enzyme
megacolon, septic shock and colonic perforation. Physical examination immunoassays (EIAs) that are generally designed to detect C. difficile
may reveal signs of peritonitis or paralytic ileus. Blood samples may toxins A and/or B. Unfortunately, EIAs have limited specificity and/or
show a leukemoid reaction, neutrophil left shift, acute renal failure, sensitivity in an endemic situation.18 The limitations of the EIAs have
lactic acidosis and hypoalbuminemia, as a result of systemic inflam- tempted clinicians into testing multiple samples per patient and to
mation or enteric fluid and protein loss. In imaging studies, colonic develop two-step algorithms for CDI diagnosis. Due to their high
wall thickening with or without low mural attenuation, thumbprint- negative predictive values, molecular tests, such as PCRs, are valuable
ing, colonic distension, free abdominal fluid and pericolonic fat as a first screening method in a two-step testing algorithm for diagno-
stranding may be seen.14 Colonoscopy may reveal swollen, red or sis of CDI.18
friable mucosa, ulceration or characteristic pseudomembranous
colitis, i.e. plaques of pus covering the colonic mucosa (Figure 40-1). Hospital-Acquired CDI
Although the finding of pseudomembranous colitis is not entirely
specific for CDI, the association is so strong that it is often regarded as CDI is one of the most common hospital-acquired infections and is a
pathognomonic. frequent cause of morbidity and mortality among elderly hospitalized
For practical purposes, CDI has been considered severe when one patients. However, the site where the symptoms begin might not be the
or more unfavorable prognostic biomarkers are present: marked leu- same as where the infection was acquired, because patients move
kocytosis (leukocyte count >15 x109/L), decreased blood albumin between the hospital and community and there is a delay between
(<30 g/L) and rise in serum creatinine level (≥133 µmol/L or ≥1.5 C. difficile colonization and symptomatic infection. C. difficile has
times the premorbid level).14 replaced methicillin-resistant Staphylococcus aureus (MRSA) as the
Although severe colitis may be refractory to antibiotic therapy, most common cause of healthcare-associated infections. The US
necessitating colectomy, CDI usually responds. In this case, symptoms Centers for Disease Control (CDC) has categorized CDI in the highest
priority category of antimicrobial resistance threats, based on an esti-
mated annual burden of 453 000 cases with 29 000 resultant deaths.19
In Europe, an expert group estimated that CDI conferred a total cost
to the EU of approximately €3 billion/year with at least 6000 deaths
annually.20 It is difficult to estimate how common CDI is across
Europe because of a lack of standardized national surveillance schemes.
CDI was estimated to occur in 1 in 435 hospital admissions per
hospital.21
The most important risk factor for CDI is prior antibiotic use.
Antibiotic use increases the risk for CDI during therapy and in the
period of 3 months after cessation of antibiotic therapy.22 The highest
risk for CDI was found during and in the first month after antibiotic
use. All antibiotic classes, except first-generation cephalosporins, are
associated with CDI. Second- and third-generation cephalosporins,
carbapenems and fluoroquinolones are among the strongest risk
factors for CDI. The number of administered antibiotics, their dosage
and the duration of therapy are also important risk factors. Other risk
factors for CDI are: increasing age, severe underlying disease, pro-
longed duration of hospitalization, CDI pressure (defined as the sum
of a patient’s daily exposure to patients with CDI who share the same
Figure 40-1 Typical pseudomembranous colitis seen on colonoscopy. (Courtesy unit or ward divided by the length of stay of the patient at risk), gas-
of Prof. J. Bartelsman, Department of Gastroenterology, AMC, Amsterdam.) trointestinal surgery and enteral tube feeding.
Chapter 40 Clostridium difficile Infections in Hospitals and Community 353
Since 2003 the epidemiology and clinical presentation of CDI has glycopeptides are generally considered slightly more effective than
changed with the appearance of a new so called hypervirulent strain: metronidazole on the basis of clinical studies and pharmacokinetics.
C. difficile BI/NAP1/PCR-ribotype 027. Large outbreaks of severe CDI These antibiotics have the disadvantage that they cause collateral
in hospitals in Canada, the USA and Europe were reported, presenting damage by harming the intestinal microbiome, thus predisposing to
with pseudomembranous colitis and fulminant colitis, and with a recurrences of CDI. Fidaxomicin, an antibiotic that came to the market
higher mortality (30%) and recurrence rate (up to 40%) within 1–3 in 2011 for the treatment of CDI, has a narrower spectrum, and
months after treatment is completed.23 The underlying reasons for its appears associated with fewer recurrences.32,33 Nevertheless, recur-
rapid emergence and the subsequent patterns of global spread remain rences still do occur and remain the biggest challenge in treating CDI.
unknown. It was shown that two distinct epidemic lineages emerged Therefore, new antibiotics and other treatment modalities are still
in North America within a relatively short period after acquiring an being searched for. Antimicrobials that are already available for treat-
identical fluoroquinolone resistance – conferring mutation and a ment of other infections have been studied for the treatment of CDI.
highly related conjugative transposon.24 The two epidemic lineages These include fusidic acid, nitazoxanide, rifaximin and tigecyclin.
showed distinct patterns of global spread, leading to healthcare- Several new compounds have been investigated for the treatment of
associated outbreaks in the UK, continental Europe and Australia. The CDI, of which the non-absorbable oxazolidinone cadazolid, the lipo-
data suggested that the acquisition of resistance to commonly used peptide antibiotic surotomycin, and macrocyclic thiopeptide LFF571
antibiotics is a major feature of the continued evolution and persis- have been studied in published phase I clinical trials. Other treatment
tence of C. difficile 027/BI/NAP1 in healthcare settings. Certain other modalities may be divided in immunotherapy and microbial therapy.
‘ribotypes’ found in Europe are also associated with a complicated Immunotherapy concerns the administration of nonspecific intra-
course, such as Type 078.25 Despite this possible association between venous immunoglobulins or oral or intravenous polyclonal or mono-
some C. difficile types with more severe disease and outbreaks, it is clonal antibodies directed against C. difficile and the large clostridial
important not to focus on types, but on CDI in general. toxins, in order to supply additional antibodies when the patient fails
to mount a sufficient humoral immune response. The intravenous
Community-Acquired CDI administration of two monoclonal antibodies after antibiotic treat-
ment for CDI resulted in a lower percentage of recurrences as com-
Although ubiquitous, C. difficile has been regarded as a mainly noso-
pared to placebo.34 However, selection bias may have been accountable
comial pathogen since its discovery. Outbreaks have not been described
for this result, because during the study, its endpoint was changed from
outside of healthcare facilities. The concept has been that, in healthcare
reduction of symptoms in patients with diarrhea to reduction of recur-
facilities, the most susceptible population of elderly patients with
rences in only those patients who became diarrhea-free. In 2015, two
chronic co-morbidity and exposure to antibiotics is concentrated. C.
phase 3 studies have been completed to prevent recurrent CDI as
difficile may replicate in these patients and transmission may occur via
adjunctive to standard treatment.
the hands of hospital personnel, fomites and perhaps even the air,
Microbial therapy concerns the administration of probiotics, donor
which may contain spores around diarrheic patients. However, there
feces or non-toxigenic C. difficile strains, in order to restore the micro-
have always been cases that could not be linked directly to healthcare
biome and thus the colonization barrier against C. difficile. Of these,
facilities. Some of these patients had no known risk factors. Even the
‘transplantation’ of feces from healthy donors is currently the only
use of antibiotics, considered by some a necessary condition for CDI
therapy supported by a randomized trial.35 Alternative treatments
to develop, was sometimes absent. Cases of community-acquired CDI
using ‘fresh’ feces transplants such as frozen stored inoculum and cap-
incited by antibiotics have been shown to be self-limiting after stop-
sulized transplants have also been studied.36,37
ping the antibiotic. If CDI in otherwise healthy subjects runs such a
There is no high-grade evidence on how to treat CDI when oral
mild course, community-acquired CDI is probably underreported.
therapy is not possible, for example because of ileus. In severe cases of
Four European studies have found around 2% of feces submitted by
CDI with (imminent) toxic megacolon, surgery is the only remaining
general practitioners for any kind of microbiological diagnostic test to
effective treatment. This consists of subtotal colectomy with end-
be positive for C. difficile toxin.26–29 Since GPs followed their normal
ileostomy or, more recently, of the creation of a diverting loop ileos-
routine and did not order fecal testing for every patient with diarrhea,
tomy, followed by colonic lavage and flushing with vancomycin.
this patient population is probably highly selected. Typing studies of
isolates from community-acquired CDI cases have not shown clear
links to nosocomial CDI outbreaks. Interestingly, in a typing study in Infection Prevention
an endemic nosocomial setting, most CDI cases cannot be linked to
Adherence to recommended measures for the control and prevention
other cases in the same hospital.30 This suggests that many different C.
of CDI38 is vital to reduce the burden of infection. These include early
difficile strains circulate in the community and cause disease under the
diagnosis of CDI, surveillance of CDI cases, education of staff, appro-
right circumstances, i.e. when the intestinal microbiome has been
priate use of isolation precautions, hand hygiene, protective clothing,
damaged or humoral immunity fails. An unanswered question is what
environmental cleaning and cleaning of medical equipment, good
is the role of asymptomatic carriers in the circulation of C. difficile in
antibiotic stewardship, and specific measures during outbreaks. Most
the community, but also in healthcare facilities. Furthermore, it is
of these measures are common to other healthcare-associated infec-
unclear what is the most important reservoir of C. difficile in the com-
tions, but some are CDI-specific, such as careful hand washing using
munity and from what source new strains are introduced.31 Farm
soap and water (rather than alcohol hand rubs), sporicidal decontami-
animals have been suggested and typing studies have shown a lack of
nation and particular aspects of isolation and antibiotic stewardship.
species barrier between humans and certain farm animals, such as
Antimicrobial stewardship programs that reduce the use of high-risk
pigs.25 Therefore, pork and other kinds of meat may serve as a source
antibiotics may contribute to a reduction in the rate of CDI cases,
of C. difficile spores. Indeed, spores have been demonstrated in meat.
reduce inappropriate prescription of empirical CDI therapy and
On the other hand, the fact that no outbreak of CDI has ever been
improve the timeliness of treatment. Similar to other healthcare-
traced to a food source argues against this hypothesis.
associated infections, a ‘care bundle’ can be developed and imple-
mented. An example of a ‘care bundle for CDI’ could have four pillars:
Treatment of CDI isolate all patients with diarrhea, administer treatment the same day
Mild CDI that develops during the use of antibiotics may be cured by that the diagnosis is made, treat CDI according to current guidelines
stopping the antibiotic without directed treatment, but more severe and give adequate information about CDI to patients and healthcare
cases must be treated. As mentioned above, CDI usually responds to workers.
antibacterial therapy.14 Antibiotics that have traditionally been used are
oral metronidazole and oral vancomycin (or related teicoplanin). The References available online at expertconsult.com.
KEY REFERENCES
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Clostridium difficile infection in Europe: a hospital-based Diarrhea in general practice: when should a Clostridium Surveill 2013; 18(4):20381.
survey. Lancet 2011; 377(9759):63-73. difficile infection be considered? Clin Microbiol Infect van Nood E., Vrieze A., Nieuwdorp M., et al.: Duodenal
Debast S.B., Bauer M.P., Kuijper E.J., et al.: Update of 2014; 20(12):O1067-O1074. infusion of donor feces for recurrent Clostridium difficile.
the treatment guidance document for Clostridium Hensgens M.P., Goorhuis A., Dekkers O.M., et al.: Time N Engl J Med 2013; 368(5):407-415.
difficile infection (CDI). Clin Microbiol Infect 2014; interval of increased risk for Clostridium difficile infection Vonberg R.P., Kuijper E.J., Wilcox M.H., et al.: Infection
20(Suppl. 2):1-26. after exposure to antibiotics. J Antimicrob Chemother control measures to limit the spread of Clostridium dif-
Goorhuis A., Bakker D., Corver J., et al.: Emergence of Clos- 2012; 67(3):742-748. ficile. Clin Microbiol Infect 2008; 14(Suppl. 5):2-20.
tridium difficile infection due to a new hypervirulent Knetsch C.W., Lawley T.D., Hensgens M.P., et al.: Current
strain, polymerase chain reaction ribotype 078. Clin application and future perspectives of molecular typing
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the treatment guidance document for Clostridium
41
Intra-abdominal Sepsis, Peritonitis,
Pancreatitis, Hepatobiliary and Focal
Splenic Infection
P. RONAN O’CONNELL | GERARD SHEEHAN
KEY CONCEPTS cascade, can mimic peritonitis and, although initially sterile, may
progress to fulminant, life-threatening sepsis. Management of intra-
• The main pathogens in intra-abdominal sepsis are Escherichia abdominal sepsis remains one of the most challenging activities of
coli and the Bacteroides fragilis group; the former dominates modern critical care. Treatment requires surgery or percutaneous
in acute peritonitis and the latter in abscess formation. Entero- drainage, antimicrobial therapy and resuscitation. Each pillar comple-
cocci, although commonly isolated, are usually not significant.
ments the other and failure to meet an adequate standard in one, may
• Antimicrobial resistance in aerobic gram-negative bacilli has undo the others. The increase in antimicrobial resistance in gram-
increased greatly, so that previously standard regimens are no negative bacilli worldwide and the lack of new antimicrobial agents in
longer reliable in many countries. This has driven increased development raises the prospect of increased mortality in the future.1
carbapenem use and the localized emergence of carbapenem
resistance, with a reliance on less effective and more toxic
reserve options.
Microbiology
The human gastrointestinal microbiota is a complex ecosystem
• The main diagnostic modality is computed tomography (CT); with 1013–1014 microbes and >1000 species-level phylotypes. Even with
ultrasound is better in biliary tract and pelvic disease. Laparos-
demanding anaerobic techniques in reference laboratories, only a
copy has a role in appendicitis, pelvic inflammatory disease,
diverticulitis and tuberculous peritonitis. minority of these species can be cultured and a very small number are
pathogens in intra-abdominal sepsis. In health, the low pH of the
• A carbapenem or extended-spectrum penicillin/β-lactamase stomach maintains the number of organisms at <103/µL, usually viri-
inhibitor is recommended for severe intra-abdominal sepsis dans streptococci, lactobacilli or Candida species, all of low pathogenic
and for those at risk of resistant organisms, with additional potential. Proton pump inhibitors or other causes of achlorhydria may
agents as required. An echinocandin is recommended for intra-
allow the microflora of the stomach to approximate that of the small
abdominal candidiasis; fluconazole will suffice for C. albicans in
a stable patient. bowel, with increased numbers of strict anaerobes and aerobic gram-
negative bacilli, such as Escherichia coli. Many intubated patients in
• Second-look laparotomy for severe peritonitis does not improve intensive care have increased microbial density in stomach fluid, with
mortality and has been superseded by sequential CT and per- a shift towards aerobic gram-negative bacilli, including Pseudomonas
cutaneous drainage of localized collections. aeruginosa and Candida spp. Gastric feeding tubes, malignancy and
• Peritonitis from anastomotic leak post-surgery often mimics a bariatric surgery may cause similar alterations. The density of the
respiratory problem and can be difficult to diagnose on CT. A microflora progressively increases from stomach to colon. In the proxi-
low threshold for relaparotomy is appropriate. mal small bowel there are ~104–5 bacteria/µL, the terminal ileum has
107–109 organisms/µL, and the colon has >1011 bacteria/gram of feces
• Percutaneous drainage under CT guidance is the treatment of
choice for most intra-abdominal abscesses, provided the col- with >100 species that can be cultured.
lection has liquefied. Strict anaerobes outnumber aerobes in the colon by a ratio of
1000 : 1 and include various species, including Bifidobacterium,
• Spontaneous bacterial peritonitis is a life-threatening complica- Propionibacterium, Fusobacterium, Lactobacillus, Veillonella, Eubacte-
tion of cirrhosis. A low threshold for paracentesis and empiric rium and Clostridium. However, with the exception of the Bacteroides
antibiotics is appropriate.
fragilis group, Fusobacterium species and Bilophila wadsworthia, they
• Tuberculosis (TB) peritonitis is rare in the West but common generally contribute little to clinical intra-abdominal infection. The B.
worldwide. Diagnosis often requires laparoscopy, as initial tests fragilis group has greater than 20 species and the most common patho-
of peritoneal exudate are often negative. gen is the B. fragilis species itself, which although a small fraction
• Severe pancreatitis often leads to necrosis and sepsis by the (1–10%) of the group within the microflora, is the most frequent
fourth week. Prophylactic antimicrobial therapy is discouraged anaerobic pathogen (31%) and the most virulent. Other species of the
but a high index of suspicion should prompt early antimicrobial B. fragilis group often isolated in intra-abdominal sepsis are B. thetaio-
therapy, usually a carbapenem with an echinocandin. Once the taomicron (15.4%), B. ovatus (10.9%), B. vulgatus (9.4%), B. uniformis
necrotic tissue has ‘walled off’, drainage by catheter can occur (4.9%) and Parabacteroides distasonis (10%).2
followed by serial endoscopic necrosectomy. Almost all intestinal aerobic gram-negative bacilli are Enterobacte-
riaceae, which are also facultative anaerobes; E. coli is by far the com-
monest, at 109/g of feces. Less common Enterobacteriaceae typically
occur at densities of <104/g and include Klebsiella, Enterobacter, Serratia,
Proteus, Providentia, Morganella, Citrobacter and Hafnia. Other gram-
Introduction negative but strictly aerobic bacilli such as P. aeruginosa and Acineto-
Intra-abdominal infection is a common clinical problem that contrib- bacter species are usually transient and are uncommon pathogens in
utes greatly to surgical, intensive care and laboratory workloads, community-acquired intra-abdominal sepsis, but their frequency
varying from mild appendicitis to feculent peritonitis with multi- increases after hospitalization and exposure to antimicrobial agents.
organ failure (MOF). Pancreatitis, by initiating an inflammatory Enterococcus faecalis is the dominant aerobic gram-positive coccus
355
occurring in quantities as high as 1010/g in feces, with other enterococcal Clinical Presentation
species, micro-aerophilic and anaerobic streptococci at lower densities.
Animal models and clinical studies of intra-abdominal infection The history and physical examination define the urgency of interven-
have shown that the initial complex inoculum from the intestine is tion and guide decisions regarding investigations. The duration, loca-
simplified to a limited set of pathogens with E. coli, other Enterobac- tion and character of pain, and the presence of anorexia, vomiting or
teriaceae and the B. fragilis group predominating and enterococci cul- obstipation, fever or chills should be determined. Other history should
tured in a minority. The balance of evidence suggests that enterococci include recent hospitalizations and antibiotics, prior operations, travel
are unimportant in community-acquired infection but sometimes history, chronic diseases and hearing impairment.
important in hospital-acquired infection. In animal models, antimi-
crobial agents directed against aerobic gram-negative bacilli prevent Investigations
mortality, those active against anaerobes reduce abscess formation, but An erect chest (Figure 41-1) or lateral decubitus abdominal radiograph
failure to cover enterococci has no effect. Randomized clinical trials of may show free intra-abdominal air, indicating perforation. Ultrasound
antimicrobial regimens in which one arm was active against entero- of the biliary tree and pelvis, and computed tomography (CT) have
cocci and the other not, have consistently shown a lack of benefit from superseded other imaging methods (Figures 41-2 and 41-3), with CT
anti-enterococcal therapy. However, isolation of enterococci from the single best modality. Increasingly, magnetic resonance imaging
initial drainage has been associated with a higher treatment failure rate (MRI) is of use, particularly in hemodynamically stable patients in
(28% vs 14%).3 whom radiation exposure is a concern. In suspected biliary sepsis,
ultrasound rapidly confirms gallstone disease and biliary obstruction.
Laparoscopy is a valuable diagnostic and therapeutic tool for localized
Pathophysiology
In the first few minutes of peritoneal contamination, organisms are
absorbed by lymphatics and quickly removed via the thoracic duct to
the bloodstream, but at a cost of bacteremia and systemic sepsis. Mean-
while Toll-like receptors (TLRs), widely present on mesothelial cells,
initiate the innate immune response causing influx of polymorpho-
nuclear leukocytes (PMNs) and the production of pro-inflammatory
cytokines. Lipopolysaccharide (LPS) from aerobic gram-negative
bacilli, the major bacterial mediator, is recognized by the LPS receptor
complex of CD14/TLR4/myeloid differentiation protein 2 (MD-2) on
cells4 but diffusion of LPS is very slow due to its amphiphile structure
and tendency to form aggregates. Systemic and local levels of the acute
phase reactant LPS-binding protein (LBP) are greatly increased in the
first few days, enhancing the transfer of LPS to the CD-14/TLR4/
MD-2 complex and augmenting the response to LPS up to a 1000-fold.
Injury to the peritoneum exposes the underlying extracellular matrix
and also causes an innate inflammatory reaction by release of matrix-
bound pro-inflammatory cytokines (TGF-β, TNF-α and IL-1), chemo-
attractants (IL-8 and MCP-1), and growth factors (TGF-β, IGF-1,
PDGF). Expression of tissue factor, the major initiator of the extrinsic
pathway of coagulation, is upregulated by macrophages and mesothe-
lial cells which leads to a fibrinous exudate, formation of fibrin bands
and ultimately adhesions. The process resolves with in-growth of Figure 41-1 Erect chest radiograph showing free intraperitoneal air.
mesothelium to cover the injured surface and fibrinolysis driven by the
enzyme plasmin, derived from its precursor plasminogen. This is regu-
lated by tissue plasminogen activator (tPA), which increases in the
peritoneal fluid as high as 65-fold.4
Activation of the adaptive immune system takes longer. Cytokines,
released with the innate immune response, activate dendritic cells,
which function as antigen-presenting cells (APCs) to lymphocytes.
Encapsulated strains of B. fragilis are necessary for abscess formation,
and T lymphocytes are required for, and large numbers of CD4+ T cells
are present in, an abscess wall. The proliferative response of T cells
depends on amino acid (positively charged) and carboxyl or phosphate
groups (negatively charged) on each repeating unit of the B. fragilis
polysaccharide. These zwitterionic polysaccharides are processed to
low molecular weight carbohydrates by a nitric oxide-dependent
mechanism in endosomes of APCs.5
The local inflammatory response, fibrin deposition and secondary
intestinal ileus act to limit the area of inflammation. The great
omentum frequently becomes adherent, facilitated by local ileus. Thus
a visceral perforation may ‘seal’, contamination be confined and an
abscess develop. In the absence of ongoing contamination, the host
response may be sufficient to resolve the process; more often, surgical
or radiologic drainage is needed. Biologic response modifiers such as
anti-TNF therapy greatly impair these innate and adaptive immune
responses and can alter the usual clinical features leading to misdiag-
nosis, and greater likelihood of secondary liver and splenic abscesses, Figure 41-2 CT of the abdomen showing large intraloop abscess secondary to
septic shock or MOF. perforation from Crohn’s disease.
Chapter 41 Intra-abdominal Sepsis, Peritonitis, Pancreatitis, Hepatobiliary and Focal Splenic Infection 357
selected empirically, based on multicenter surveys of in vitro resistance,

the largest of which reported more than 7000 B. fragilis group blood
culture isolates from 8 to 13 centers in the USA between 2002 and 2009.
Resistance to metronidazole was found in only three isolates (<0.05%)
and smaller European and Canadian studies have confirmed its current
rarity at <1%. However, rates of resistance to both carbapenems and
piperacillin/tazobactam have risen from <1% to about 2.5% in the
USA, and to 5–10% in many European and Asian countries. Ampicillin/
sulbactam (4%) and tigecycline (4.8%) have acceptable resistance rates
but cefoxitin and cefotetan (7–21%), clindamycin (32%) and moxi-
floxacin (36%) are no longer effective.6
CHOICE OF ANTIMICROBIAL REGIMEN

Bowel injuries repaired within 12 hours, due to penetrating, blunt, or
iatrogenic trauma with intraoperative contamination, should be
treated with antimicrobial agents for 24 hours. Proximal acute perfora-
tions (stomach to proximal jejunum) and uncomplicated acute
appendicitis (without gangrene, abscess, perforation or peritonitis)
each require only 24 hours of a regimen primarily active against E. coli.
Ampicillin–sulbactam or amoxicillin–clavulanic acid is an appropriate
Figure 41-3 CT of the abdomen showing thickened gallbladder with intramural choice provided that local rates for ESBL and CRE (carbapenem-
air and pericholecystic fluid in a patient with biliary sepsis.
resistant Enterobacteriaceae) are low. An aminoglycoside (gentamicin,
tobramycin, netilmicin, amikacin) represents the narrowest spectrum
tailored to aerobic gram-negative bacilli and will also cover many
peritonitis, especially suspected appendicitis, pelvic inflammatory ESBL-producing organisms and some CRE. For most patients the risk
disease, diverticulitis and TB peritonitis. of toxicity is low for courses of short duration. Cephalosporins and
Blood cultures are recommended for all hospital-acquired intra- fluoroquinolones cover community E. coli well in countries with low
abdominal sepsis, and when the patient from the community is immu- ESBL rates, but their extensive use has been associated with C. difficile
nosuppressed or in shock, or is otherwise at risk of bacteremia. With infection, and E. coli fluoroquinolone resistance rates in many com-
the exception of appendicitis, intraoperative cultures are recom- munities now exceed 20%. Metronidazole should be added to all of
mended to detect resistant organisms, as failure rates are higher if these choices when there is a risk of B. fragilis involvement, such as
therapy is not active against all cultured pathogens, other than entero- distal small bowel and colon perforations.
cocci. A sample >0.5 mL of aspirated fluid or tissue is preferred to a Travel to and immigration from countries of high ESBL and CRE
swab. prevalence, prior hospitalization, previous antimicrobial therapy
and postoperative peritonitis are associated with more resistant patho-
Antimicrobial Therapy gens. In this context and in patients with severe sepsis, MOF or
APACHE score >15, antimicrobial regimens should be both broad
GENERAL CONSIDERATIONS spectrum and informed by local susceptibility patterns. An extended-
In choosing the optimal antimicrobial regimen the need to cover all spectrum penicillin/β-lactam inhibitor combinationa or a carbapen-
possible pathogens must be balanced against the potential adverse emb should be chosen and carbapenems are favored when ESBL is a
effects of excessively broad-spectrum regimens, namely toxicity, C. significant risk. A third-generation cephalosporin, monobactam, or
difficile superinfection and selection of resistant pathogens. The imper- fluoroquinolone are no longer reliable as initial therapy in many coun-
ative of wise antimicrobial stewardship applies, tempered by the fact tries for sicker patients. Both fourth-generation cephalosporinsc and
that failure to cover all pathogens increases mortality. This dilemma extended-spectrum penicillin/β-lactam combinations are active
has now greatly increased due to the emergence of extended spectrum against most ESBL-producing organisms but carbapenems are more
β-lactamases (ESBL) in aerobic gram-negative bacilli in most countries reliable. Addition of metronidazole is warranted in view of the small
and carbapenem resistance in some geographic locations (see rates of resistance to these agents in the B. fragilis group. For healthcare-
Chapter 180).1 associated intra-abdominal sepsis, additional coverage against
Antimicrobial therapy should be initiated without delay, as deterio- methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-
ration to severe generalized peritonitis, septic shock and MOF can resistant enterococci (VRE) or a second agent for resistant gram-
occur over a few hours. It should be continued until resolution of negative bacilli such as an aminoglycoside, tigecycline or colistin may
clinical signs of sepsis and return of gastrointestinal function. When be warranted, but stopped when culture results are negative. Because
features of infection persist or recur 5–7 days after definitive surgery, of aminogylcoside nephrotoxicity and irresversible ototoxicity, caution
a thorough diagnostic effort should be undertaken directed at abdomi- is warranted in elderly patients, in those with hearing impairment, and
nal and extra-abdominal sources. Investigations should include a CT with chronic renal or liver disease. Decompensated cirrhosis is a con-
of the abdomen and antimicrobial therapy should continue. If a traindication to aminoglycosides due to a very high incidence of neph-
patient has persistent symptoms and signs, but no evidence of a new rotoxicity and its impact on transplantation.
or persistent infection emerges, termination of antimicrobial therapy Tigecycline has a long half-life (requiring a loading dose), a large
is warranted. volume of distribution, penetrates abscesses well and covers ESBL,
CRE and VRE. However, analysis of 13 trials of infection at different
ANTIMICROBIAL RESISTANCE IN THE sites revealed a higher death rate in those receiving tigecycline mono-
B. FRAGILIS GROUP therapy compared to controls (3.9% vs 2.9%). Whether this relates to
Most clinical laboratories do not fully speciate organisms within the low serum levels and marginal activity against bacteremia or some
B. fragilis group nor determine antimicrobial susceptibilities, as results
are typically only available after infection has resolved. Susceptibility
testing of anaerobes is recommended when there is persistent isolation a
Piperacillin–tazobactam, or ticarcillin–clavulanic acid.
of the organism, when bacteremia is present, and when prolonged b
Imipenem–cilastatin, meropenem, doripenem or ertapenem.
therapy is needed. Antimicrobial therapy for anaerobic infection is c
Cefpirome, cefepime.
other reason is not clear. Despite the demonstration of efficacy as hemorrhage and preventing further contamination. Devitalized tissues
monotherapy in clinical trials of intra-abdominal sepsis, tigecycline and perforated bowel are either removed or exteriorized. No attempt
should not generally be relied upon alone. It may, however, have a role is made to perform anastomosis and the abdominal wound is left open,
as an additional agent in specific cases with ESBL, CRE or VRE. pending more definitive exploration 24–48 hours later. It is essential
Enterococci should always be covered in patients with septic shock, to avoid blood loss and hypothermia, both of which can lead to irre-
immunosuppression, prosthetic heart valves and postoperative perito- trievable coagulopathy. Handling of inflamed viscera is minimized to
nitis and a penicillin or vancomycin, is sufficient, unless VRE is of reduce the release of inflammatory mediators into the systemic
concern. Low-dose aminoglycoside is required to render the regimen circulation.
bactericidal only for enterococcal bacteremia, when endocarditis is
possible or when prosthetic cardiac valves are present. In many coun- RELAPAROTOMY
tries VRE is a common nosocomial problem. These are invariably E. Scheduled or ‘second-look’ relaparotomy became popular in the 1980s
faecium and are also usually resistant to penicillins and to high-level for diffuse peritonitis to allow abdominal irrigation and prevent recur-
aminoglycosides. If cultured from peritoneal exudate or abdominal rent abscess formation. However, experience showed that mortality
abscess pus, VRE will generally be susceptible to linezolid, daptomycin, was not decreased and there was a high incidence of intestinal fistula.
chloramphenicol or tigecycline. For patients with positive cultures for Second-look laparotomy has been superseded by CT scanning and
CRE in blood, peritonitis exudate or abscess pus, double or triple percutaneous drainage of collections and is now rarely used except for
combinations should be considered, guided by susceptibility data. In patients with mesenteric ischemia in whom doubt remains about the
the first instance a combination of tigecycline and colistin should be viability of portions of the small intestine.
chosen. There may be a role for extended-infusion of carbapenems,
aminoglycosides, rifampin or intravenous fosfomycin. WOUND CLOSURE
Wound closure is particularly problematic in the presence of peritoni-
INTRA-ABDOMINAL CANDIDIASIS tis. By definition the wound is ‘dirty’ with wound infection occurring
Candida is isolated from peritoneal samples in up to 20% of patients in 30% and dehiscence in 5–10%. The risk is increased in the elderly
presenting in the community with acute perforation but very rarely and in malnourished, obese, or diabetic patients and with sepsis syn-
progresses to invasive candidiasis. However, intra-abdominal candidia- drome. Surgical options are to close the fascial layer while leaving the
sis is a significant complication of necrotizing pancreatitis and of post- skin and subcutaneous tissue as an open wound to be closed 5–7 days
operative peritonitis, especially in those with recurrent perforation or later (delayed primary closure) or leave it to close by secondary inten-
anastomotic leak. It carries a high mortality and manifests as periton tion. In the latter situation, closure may be accelerated by use of a
itis or abscess, with or without candidemia. It is difficult to confirm a vacuum-type dressing as long as the fascial closure remains intact.
diagnosis early, yet timely antifungal therapy is required, as delay is Occasionally, intestinal distension and edema, particularly of the small
associated with increased mortality. bowel, preclude safe closure. In such circumstances, fascial closure is
Fluconazole (800 mg load, 400 mg per day) is generally effective unwise and may lead to abdominal compartment syndrome with
against C. albicans, with resistance rates of 2% or less. It is nontoxic, intra-abdominal pressures >25 mmHg. A number of surgical tech-
inexpensive and effective by intravenous and oral routes. However, niques are available to ‘silo’ abdominal contents until it is safe to close
non-albicans species now account for up to 50% of invasive isolates in the peritoneal cavity. Postoperatively, abdominal distension and falling
some centers and resistant species such as C. kruzei (100% fluconazole urinary output should raise suspicion of abdominal compartment syn-
resistant) and C. glabrata (12–30% fluconazole resistant) have become drome, which can be confirmed by measuring intravesical pressure. A
increasingly prevalent. Fluconazole is the empiric agent of choice for number of devices can facilitate temporary abdominal wall closure,
patients with mild to moderate disease, no previous azole exposure providing a degree of protection for the underlying viscera, particu-
and not in a high-risk group for C. glabrata (elderly, diabetes, cancer). larly the small bowel, from dehydration and further bacterial contami-
In contrast to azoles, which are fungistatic, the echinocandins (caspo- nation. The recently developed ABThera™ open abdomen negative
fungin, anidulafungin, micafungin) are fungicidal, generally active pressure therapy system is designed to minimize contraction of the
against all Candida spp. and are preferred for patients with moderate fascial wound edges and adherence of bowel loops to the parietal
to severe disease. Although not yet widespread, one center has reported peritoneum.8 Major complications associated with leaving the abdom-
12% of C. glabrata resistant to echinocandins. A stable patient improv- inal wound open are enteric fistula formation, retraction of the wound
ing on an echinocandin can be switched to oral fluconazole, when the edges preventing secondary closure and infection. On occasion it is
isolate is identified as C. albicans, C. paropsilosis or C. tropicalis. necessary to allow the wound to granulate and later skin graft with a
Therapy should be continued for 14 days after resolution of clinical view to eventual repair of the inevitable ventral hernia.
findings, drainage of abscess and correction of leaks. An echinocandin
can be considered empirically for critically ill patients with pancreatitis POSTOPERATIVE PERITONITIS
or intra-abdominal sepsis and no correctable cause of fever. Peritonitis following recent abdominal surgery poses a particular diag-
nostic and therapeutic challenge. It is usually from a leaking anasto-
Surgical Management motic suture line and is typically discovered between the fifth and
seventh postoperative days. The symptoms are often insidious and may
GENERAL CONSIDERATIONS mimic a cardiorespiratory complication, most commonly pulmonary
The principles of surgical management of peritonitis are closure or embolism. A high index of suspicion must exist after intestinal anas-
removal of the perforated viscus and peritoneal decontamination, fol- tomosis, especially after anterior resection or resection for Crohn’s
lowing appropriate preoperative resuscitation including antimicrobial disease. An elevated C-reactive protein on the third postoperative day
therapy. In septic patients, resuscitation takes precedence over immedi- is highly sensitive but poorly specific as an indicator of anastomotic
ate laparotomy. The decision whether to re-anastomose following leakage. Free intraperitoneal air is sometimes wrongly attributed
intestinal resection requires experienced assessment of risk factors. In to recent laparotomy and CT may not be diagnostic. There should
general, anastomosis should not be undertaken in the presence of fecal be a low threshold to decide on laparotomy, even without definitive
peritonitis, hemodynamic instability or immunosuppression. Within radiologic evidence of anastomotic leakage. When leakage is confirmed,
these guidelines, primary anastomosis can be safely undertaken in conventional wisdom dictates takedown of the anastomosis with
patients with perforated diverticular disease, avoiding the substantial proximal stoma and closure of the distal stoma. Occasionally an expe-
postoperative morbidity of a Hartmann’s procedure and the likelihood rienced surgeon may choose to repair the defect and defunction
of a permanent colostomy.7 In extreme circumstances a damage the bowel proximally, but only in a stable patient with minimal
control laparotomy may be performed with the object of arresting contamination.
PERCUTANEOUS DRAINAGE PROCEDURES clavulanic acid, are all acceptable choices for 7 days. Where ESBL rates
Percutaneous drainage and operative intervention are complementary are significant, a carbapenem is an appropriate initial choice, adjusted
rather than competitive techniques and decisions regarding which to to a narrower spectrum agent based on culture and sensitivities. Repeat
employ are largely based on CT findings. Inflammation may manifest paracentesis at 48 hours showing failure of PMNs to drop below
as a phlegmon (viable inflamed tissue), a liquefied abscess, infected 250/µL suggests a resistant bacterium or secondary peritonitis. Treat-
necrotic tissue, or a combination. Liquefied abscesses are drainable, ment failure results in mortality of 50–80% and is due to delay in
whereas phlegmonous and necrotic tissues are not. Indications for antibiotic initiation or to resistance. Albumin infusions (1.5g/kg day
percutaneous drainage include multiple and/or multi-loculated 1, 1g/kg, day 3) reduce mortality and are recommended for all patients
abscesses, abscesses with enteric communication and infected hema- with SBP.9 Long-term secondary prophylaxis with a fluoroquinolone
tomas. To avoid contamination the drainage route should not cross a is recommended after a first episode of SBP. Short-term primary pro-
sterile fluid collection or pleural space. Drainage is usually performed phylaxis is also recommended for up to 7 days in patients with variceal
following fine needle aspiration (FNA); the aspirate is used to gauge hemorrhage. The role of long-term primary prophylaxis is more con-
viscosity and document infection by Gram’s stain and culture. For troversial, but can be justified in those with poor hepatic function,
most collections, a drain should be placed to ensure complete evacu- especially while awaiting transplantation.
ation and minimize recurrence. The aspiration needle is used to insert
a guide wire or as a guide for tandem insertion of the drain. Antimi- Chronic Ambulatory Peritoneal
crobial therapy should be continued to prevent bacteremia and mini- Dialysis (CAPD) Peritonitis
mize infection of sterile tissue. Catheter size is determined by fluid
CAPD peritonitis has 1–6% mortality per episode, with an incidence
viscosity; in the majority of cases, a 8–12 F drain is sufficient. Larger
of 0.2–1.3 per patient per year. Repeated episodes may result in scleros-
drains may be needed for collections containing debris or viscous fluid
ing peritonitis, with resultant failure of dialysis and intestinal obstruc-
and can be exchanged over a guide wire. While most abscesses can be
tion. Organisms usually gain entry by touch contamination, but
drained with a single catheter, there should be no hesitation in placing
preceding exit-site infection is the cause in a minority. The etiologies
as many drains as are needed to evacuate all collections. The cavity
are coagulase-negative staphylococci (22%), Staph. aureus (15%),
should be drained as completely as possible and irrigated with saline
gram-negative bacilli (28%), fungi (2.5%) and anaerobes (2.5%), with
until the fluid is clear. Immediate imaging determines the need for
up to 20% culture-negative. Improved exit-site care and newer tech-
repositioning of the catheter or for additional drains. For cavities that
niques have caused a decline in the proportion due to staphylococci.
are completely evacuated initially and for which there are no abnormal
Diagnosis is suggested by cloudy peritoneal effluent, abdominal pain
communications to viscera, gravity drainage is sufficient. For larger or
and fever, and is confirmed by a WBC count >0.1 ×109/L, with >50%
more viscous collections and those with ongoing output due to fistu-
PMNs. Initial empiric therapy should cover both gram-positive and
lous connections, suction drainage with sump catheters is more effec-
gram-negative organisms. Cefazolin and gentamicin for 2–3 weeks is
tive. Pre-sacral collections may be drained transrectally.
the standard empiric regimen, but vancomycin and gentamicin is pre-
ferred in centers with significant rates of MRSA and a carbapenem
Primary (Spontaneous) Peritonitis should be considered in countries with high rates of ESBL. Intraperi-
Primary peritonitis is defined as infection of peritoneal fluid in the toneal administration is preferred and achieves blood levels equivalent
absence of disruption of the gastrointestinal tract. Almost all cases have to the intravenous route. Eradication of infection and continuation of
cirrhosis and are then termed spontaneous bacterial peritonitis (SBP), CAPD is usual in 80–85% of episodes but 10–15% require catheter
but other underlying causes include nephrotic syndrome and congestive removal and transfer to hemodialysis. Early removal of the catheter
cardiac failure. More advanced liver failure, gastrointestinal hemor- should occur for episodes due to CRE, P. aeruginosa, fungi, mycobac-
rhage, previous SBP, ascitic protein concentration <10 g/L and proton teria and vancomycin-resistant enterococci and should also occur if
pump inhibitors are all associated with greater risk of SBP in patients there is no response to therapy within 4 days and in those with
with chronic ascites.9 Almost all are mono-microbial and the most recurrence.
common causes are E. coli and K. pneumoniae, which translocate from
the bowel to the mesenteric lymph nodes and then to ascitic fluid via Tuberculous Peritonitis
the blood. An increasing proportion is now due to viridans streptococci, Peritonitis due to tuberculosis (TB) is rare in North America and
coagulase-negative staphylococci, Staph. aureus (including MRSA) and Western Europe but is a common cause of exudative ascites elsewhere.
fluoroquinolone-resistant and ESBL producing gram-negative bacilli. Despite anti-TB therapy, mortality varies from 15% to 52%, depending
Aeromonas hydrophila has emerged as a cause of SBP in East Asia, and on underlying conditions and early versus late diagnosis. It presents
Listeria monocytogenes and Salmonella spp. have also been described. with nonspecific symptoms, sometimes progressing to a surgical emer-
Streptococcus pneumoniae peritonitis can arise as a bacteremic compli- gency. Other conditions, especially ovarian malignancy, closely resem-
cation of pneumonia in patients with ascites or rarely via the Fallopian ble TB peritonitis and CA-125 levels can be markedly elevated, leading
tubes in healthy women and pre-menarchial girls. to a false impression of ovarian carcinoma. Definitive diagnosis is often
New onset abdominal pain and distension with evidence of sys- delayed due to the duration of TB culture. The triad of abdominal
temic sepsis in a patient with chronic ascites suggests SBP. More often swelling, pain and fever is present in only 60% of cases and doughy,
there are nonspecific symptoms, unexplained encephalopathy, worsen- tender, abdominal masses occur in only a small minority. Weight loss
ing liver or renal function, or gastrointestinal bleeding. A low threshold is often obscured by weight gain from ascites. Peritoneal fluid usually
for paracentesis is thus appropriate in patients with chronic ascites who has a lymphocytic exudate, but atypical laboratory features occur com-
have deteriorated. Ascitic fluid yielding >250 PMNs/µL defines SBP monly with cirrhosis or CAPD, including protein levels <25 g/dL and
and culture-negative ascites with >250 PMNs/µL also responds to anti- >250 PMN/dL.
microbial therapy. A patient with positive ascites culture, but with Both tuberculin skin tests and interferon-gamma release assays
<250 PMNs/µL, should be treated if symptomatic, as some progress to (IGRA) are sometimes negative but when positive should heighten
SBP. Localized abdominal signs, high ascitic PMN or protein concen- suspicion of TB. Abdominal CT often shows thickened omentum or
tration, inadequate response to treatment and polymicrobial infection peritoneal nodules suggestive of carcinoma. In selected cases a specific
all point to secondary peritonitis and the need for CT scanning and diagnosis can be made by percutaneous or endoscopic guided fine
surgical evaluation. needle aspiration (EUS FNA). Because TB peritonitis is paucibacillary,
Early diagnosis and treatment of SBP significantly improves microscopy of ascitic fluid using Ziehl–Neelsen (ZN) staining is almost
prognosis. In patients at low risk of ESBL, cefotaxime, ciprofloxa- always negative. The highly specific Xpert MTB/RIF PCR assay is useful
cin, piperacillin–tazobactam, ampicillin–sulbactam or amoxicillin– but lacks sensitivity in ascitic fluid and a negative test should not be
used to exclude TB. Sensitivity is higher in tissue samples, but likely

no higher than 80%. A positive Xpert MTB/RIF assay in ascitic fluid
in a compatible clinical setting should be taken to indicate TB perito-
nitis and will also detect multidrug-resistant TB (MDRTB). Ascitic
fluid adenosine deaminase is both highly sensitive and specific and a
normal level excludes TB. In patients with ascites of unknown cause,
laparoscopy is usually diagnostic by detection of tubercles macroscopi-
cally and granulomata microscopically. The appearance of uniform
nodules <0.5 cm with adhesions is virtually diagnostic, while hemor-
rhagic inflammation with either adhesions or nodules is highly sug-
gestive. Empiric treatment should be started while awaiting definitive
diagnosis with rifampin, isoniazid, pyrazinamide and ethambutol. In
patients at risk of MDRTB, and in patients with a PCR assay indicating
rifampin resistance, moxifloxacin and amikacin should be added.
Delay in treatment is associated with greater mortality. A minority will
experience recurrent intestinal obstruction from multiple adhesions,
which may be prevented by prednisolone 1 mg/kg for 2 months with
a slow wean over the following 2 months.
Biliary Sepsis
Biliary sepsis is usually associated with gallstone disease, pancreatic or
bile duct malignancy or previous surgery that has resulted in bile duct
obstruction. The usual pathogens are aerobic gram-negative bacilli,
enterococci are uncommon and anaerobes are rare. Acute cholecystitis Figure 41-4 CT of the abdomen showing extensive pancreatic necrosis.
is often an inflammatory but noninfective condition. If infection is
suspected because of clinical and radiologic findings, antimicrobial
therapy should be directed at aerobic gram-negative bacilli, enterococ-
cal coverage is not required and anaerobic coverage is necessary only
in patients with bile duct to bowel anastomoses and in patients with
previous biliary tract surgery. Ascending cholangitis typically presents
with rigors, right upper quadrant abdominal pain and jaundice (Char-
cot’s triad). Ultrasound is the best modality to confirm dilation of bile
ducts and the level of obstruction, usually at the lower end of the
common bile duct or intrahepatic ducts. Magnetic resonance cholan-
giogram (MRC) is particularly useful for delineation of biliary anatomy.
Treatment involves antimicrobial therapy and urgent decompression;
the technique used depends on the site of obstruction. Endoscopic
retrograde cholangiopancreatography (ERCP) with stent insertion is
used for common bile duct lesions, whereas percutaneous transhepatic
cholangiography (PTC) with stenting, with or without external drain-
age, is used for intrahepatic or hilar lesions. Occasionally, both tech-
niques are used in a so-called ‘rendezvous procedure’.
Pancreatitis
Severe disease occurs in about 25% of patients with acute pancreatitis,
determining the development of systemic inflammatory response syn-
drome (SIRS), MOF and necrotizing pancreatitis. The mortality of
severe disease is bimodal with a peak in the first week due to MOF,
with a second peak at 3–4 weeks due to pancreatic necrosis and retro- Figure 41-5 CT showing drainage of pancreatic necrosis in Figure 41-4.
peritoneal sepsis. Early multiorgan dysfunction and pancreatic necro-
sis are highly predictive of subsequent pancreatic sepsis. Early surgical
pancreatic surgery was proposed to reduce late MOF, sepsis and death, with high morbidity and mortality and has been superseded by initial
but debridement of necrotic pancreatic tissue is technically difficult, catheter drainage (Figure 41-5) followed by endoscopic retroperitoneal
with high complication rates. More than one exploration is often necrosectomy. The latter may require serial procedures until the pan-
required, leading to considerable difficulties in wound management creatic bed is cleared, which requires an experienced surgical team in
and risks enteric and/or pancreatic fistula development. Aggressive collaboration with interventional radiology. When this approach does
early surgery has been replaced by a more conservative approach not adequately evacuate the necrotic tissue, then open or laparoscopic
guided by the clinical course and sequential CT (Figure 41-4).10 debridement may be necessary in the face of ongoing multiorgan
Early prophylactic antimicrobial therapy has been proposed to dysfunction.12
diminish later pancreatic and retroperitoneal sepsis but a meta-analysis
of 14 trials,11 a Cochrane review and recent guidelines do not support
it. Routine FNA of pancreatic tissue is also not recommended. A high
Hepatic Infection
clinical index of suspicion coupled with features on CT supportive of AMEBIC LIVER ABSCESS
infected necrosis should prompt initiation of antimicrobial therapy, Focal infection of the liver progressing to abscess arises from either
typically a carbapenem and echinocandin, followed by interventional Entamoeba histolytica or bacteria and is termed amebic or pyogenic
techniques. These should be delayed where possible to allow the liver abscess (PLA) respectively; they are indistinguishable clinically
necrotic tissue to ‘wall off ’. Open pancreatic necrosectomy is associated and radiologically. Amebic liver abscess (see also Chapter 116) is
generally solitary, usually in the right lobe and 10 times more common granulomatous disease is liver abscess, usually due to Staph. aureus but
in males. Pathogenesis involves hepatocyte apoptosis causing pus with sometimes Aspergillus. It is often recurrent or persistent despite
a distinct anchovy paste like appearance. The major complications are antimicrobial therapy and drainage. There is typically a ≥1 cm sur-
pleural, pericardial or peritoneal spread, with greater mortality. Amebic rounding fibrous cuff and a thick, purulent center, which often
liver abscess is usually cured without drainage by metronidazole or requires surgical resection and prolonged corticosteroids.
tinidazole. Aspiration is recommended in severely ill patients, for A significant proportion of PLAs are associated with malignancy.
abscess cavities ≥10 cm, and in those with imminent rupture. Although Most commonly these are due to obstructing tumor of the bile ducts
aspiration is relatively contraindicated due to the risk of peritonitis, it with proximal suppuration but either primary or secondary parenchy-
may also be required to distinguish amebic abscess from PLA by Gram mal tumors with necrosis and secondary infection also occur. Non-
stain and culture for bacteria and by microscopy, antigen assay, culture metastatic colonic carcinoma may also be the origin in otherwise
or PCR, for E. histolytica. Serology is useful as all cases of invasive cryptogenic PLA, so that a thorough investigation for underlying
amebiasis are seropositive, allowing a trial of metronidazole with con- cancer is appropriate in all cases.
fidence. Amebic liver abscess is the second or third commonest para- Therapy of PLA requires prolonged antimicrobial therapy com-
sitic cause of mortality in Latin America, India and Africa. It is rare in bined with drainage by simple aspiration or more usually placement
the industrialized world, mainly occurring in immigrants but also of drainage catheter(s) under CT or ultrasound guidance. Surgical
returned short-term travelers, with only 90 cases identified in the incision and drainage or partial hepatectomy is rarely required.
greater Paris area between 2002 and 2006.13
OTHER HEPATIC INFECTIONS
PYOGENIC LIVER ABSCESS Acute jaundice, gastrointestinal symptoms with fever, and elevated
The incidence of PLA is low, varying from 1.0/100 000 in Denmark, to transaminases are the hallmarks of acute viral hepatitis A, B, C, D and
3.6/100 000 per year in the USA. However, PLA is commoner through- E. Acute hepatitis can sometimes be the dominant process in infection
out East Asia, with 17.6/100 000 per year in Taiwan, about 70% due to due to Coxiella burnetii (40%), cytomegalovirus, Epstein–Barr virus,
K. pneumoniae. Mortality in those without malignancy varies from 5 leptospirosis and toxoplasmosis. Granulomatous hepatitis, manifested
to 10%. In the West the commonest organism cultured is E. coli, with as intrahepatic cholestasis and hepatomegaly, may occur with Q fever,
anaerobes and enterococci additionally identified in those with under- secondary syphilis, disseminated TB, or Mycobacterium avium complex
lying malignancy or biliary tract obstruction. Streptococcus anginosus (MAC) and with some disseminated fungal infections. In general the
group (sometimes associated with anaerobes) rank first or second parenchyma of the liver resists bacterial infection very effectively.
worldwide in many series; other streptococci and S. aureus are rare. However patients overwhelmed by generalized sepsis and septic shock
Pseudomonas aeruginosa is cultured in about 2%, often in hospitalized often have significant liver dysfunction biochemically and substantial
patients with biliary disease. Studies using 16s ribosomal RNA pyro- diffuse parenchymal infection at autopsy.
sequencing suggest that the polymicrobial nature of PLA is underesti- Massive hepatomegaly occurs in visceral leishmaniasis, patients
mated by routine culture. These small studies identified organisms in with severe malaria often have mild hepatomegaly, and biochemical
90–100% versus 45% by culture. liver dysfunction and schistosomiasis causes chronic pipe-stem fibro-
In East Asia hypermucoviscous K. pneumoniae is the commonest sis. Toxocariasis and fascioliasis both cause eosinophilic granulomata,
cause of PLA, usually without underlying cause other than diabetes; sometimes with abscess and accompanied by significant eosinophilia.
some patients have alcoholism or chronic renal disease. A minority Both are relatively benign conditions, which are usually diagnosed
(20–30%) also have metastatic abscess of the lung, prostate, kidney, serologically and respond to albendazole. Rarely eosinophilic granulo-
spleen, psoas muscle, pleural empyema, septic thrombophlebitis, nec- matous liver abscess is due to basidiobolomycosis due to Basidiobolus
rotizing fasciitis, spinal epidural abscess or osteomyelitis. About 2% ranarum, a fungal cause of pseudotumor of the gastrointestinal tract
have brain abscess, meningitis or endophthalmitis, resulting in severe (80%) and liver (30%) that occurs in desert countries. Hydatid cyst
disability in survivors. Rare cases have emerged in the West, usually in involving the liver is commonly asymptomatic without features of
Asian immigrants. These virulent strains have capsular types K1 (60– sepsis and has distinct radiologic features.
80%) or K2, with virulence genes rmpA/A2 and magA. These PLAs
usually involve one lobe, are often solid initially, then multilocular,
and are more difficult to drain. As they mature they develop a thin Splenic Infection
wall with necrotic internal debris and gas. Despite the spread of Diffuse splenomegaly often occurs with a large variety of infections
ESBL, they have remained largely susceptible to cephalosporins and but focal infection is uncommon and manifests as splenic abscess, focal
fluoroquinolones. solid lesions (usually granulomatous), or peliosis (blood-filled cysts).
No underlying cause is defined in 20–40% of PLAs (cryptogenic). Splenic abscess usually arises due to bacteremia with coincidental
Others are due to (1) biliary obstruction from tumor, gallstone, stric- splenic infarction or hematoma, most often in patients with endocar-
ture or, rarely, clonorchiasis or ascariasis; (2) portal pyelophlebitis ditis. Other underlying causes include blunt trauma, contiguous
from appendicitis, diverticulitis, pancreatitis, inflammatory bowel spread from nearby infection, neoplasia, hematologic disorders, zoo-
disease or omphalitis; (3) contiguous extension from cholecystitis, nosis or immunodeficiency. A few specific organisms can cause an
dropped gallstone from laparoscopic cholecystectomy, perinephric abscess in an otherwise healthy spleen. Historically, splenic abscess was
abscess, subhepatic or subphrenic abscess; (4) trauma, including difficult to diagnose, presented late with high mortality and emergency
ingested migrated foreign body, which is sometimes the explanation splenectomy was required. Nowadays diagnosis occurs earlier by ultra-
for treatment failure and these are initially classified as cryptogenic for sound or CT. Percutaneous drainage combined with antimicrobial
a prolonged period. Findings suggestive of foreign body migration are therapy will cure the majority. However, covert splenic abscess can
symptoms of gastrointestinal perforation, single left lobe abscess, a result in severe sepsis and MOF. Splenic abscess may rupture resulting
thickened gastrointestinal wall in continuity with the PLA on CT, and in peritonitis or hemorrhagic shock and prompt splenectomy should
adhesions at surgery.14 be considered if this seems imminent.
Surprisingly, impaired host defense is rarely a cause of PLA, Typical presenting features include fever, left upper quadrant
except for the strong association of diabetes with hypermucoviscous abdominal pain, left shoulder pain, tender palpable spleen or an
K. pneumoniae. Other exceptions are multiple hepatosplenic Candida abdominal mass. Bacteremic splenic abscess is usually mono-microbial
abscesses (chronic disseminated candidiasis) in recovery from pro- and often with preceding splenic embolism as a complication of acute
found neutropenia, and invasive aspergillosis and mucormycosis as endocarditis. The usual pathogen is Staph. aureus, including MRSA,
part of overwhelming disseminated infection, or a complication of with a minority due to E. coli or streptococci. Hypermucoviscous K.
liver transplantation. The major complication of X-linked chronic pneumoniae is the commonest cause of splenic abscess in some Asian
countries, usually with liver abscess. Melioidosis primarily presents as In patients with advanced HIV, fever and splenic lesions are usually
lung abscess, due to soil exposure to Burkholderia pseudomallei in due to disseminated MAC or TB and less often due to lymphoma,
northeast Thailand, but also elsewhere in South East Asia, Northern Kaposi’s sarcoma (KS), Pneumocystis jirovecii or bartonellosis. Barton-
Australia and India. Splenic abscesses, usually multiple, arise in ella causes necrotizing granulomatous lymphadenitis (cat-scratch
25–33%. Ceftazidime or a carbapenem intravenously for 2 weeks fol- disease) in immunocompetent hosts and sometimes liver and splenic
lowed by doxycycline and/or trimethoprim–sulfamethoxazole for 12 lesions. In immunocompromised patients, bacillary angiomatosis in
weeks cures most cases. Yersinia enterocolitica sepsis due to chronic iron the skin mimics KS and focal splenic or hepatic lesions may develop
overload is a rare cause of multiple hepatosplenic abscesses. Splenic into blood-filled cysts (peliosis). Diagnosis is by blood culture, serol-
abscess can complicate sickle cell disease, usually as either Salmonella ogy, blood PCR or biopsy of involved lymph nodes or skin. Cure in
enteritis or Staph. aureus. In Latin America, Asia and Africa, Salmonella an immunocompromised host requires a macrolide or doxycycline for
spp., including S. typhi, cause splenic abscess, often with underlying up to 4 months. Sterile splenic abscesses responsive to corticosteroids
human immunodeficiency virus (HIV). are rarely associated with Crohn’s disease or neutrophilic
Most patients with splenic trauma are nowadays managed without dermatosis.
splenectomy but the hematoma is vulnerable to suppuration in the For a patient presenting with splenic abscess or focal splenic lesions
event of contamination, especially if splenic artery embolization is with fever, relevant history includes travel and immigration history,
used.15 The usual pathogens are Staph. aureus including MRSA and animal contact, occupation, HIV status and history of endocarditis,
aerobic gram-negative bacilli. Anaerobes such as B. fragilis, along with abdominal trauma, immunosuppressive therapy or hematologic
E. coli, are the usual pathogens when splenic abscess arises contiguously disease. Investigations should include blood cultures, serologic tests
from a left subphrenic, lesser sac or pancreatic abscess or from appen- for HIV, Bartonella and brucellosis, along with a tuberculin skin test
dicitis. Contiguous spread can also occur from perinephric abscess or and/or IGRA. Ultrasound will demonstrate most lesions but CT with
from xanthogranulomatous pyelonephritis, usually due to aerobic intravenous contrast is more sensitive. Although contraindicated in
gram-negative bacilli. Splenic abscess can complicate splenic lym- the past, image-guided splenic biopsy is increasingly performed for
phoma, leukemia or metastatic carcinoma in the spleen, usually colonic both infectious and neoplastic splenic lesions, with a higher yield from
or pancreatic. core biopsy and a lower complication rate with FNA. Contraindica-
Brucellosis remains endemic in Central and South America, Turkey, tions include coagulopathy and peliosis. Definitive cure of splenic
the Middle East, North Africa, China, India and Spain and a patient abscess will require a combination of aspiration, catheter drainage or,
may present many years after transmission with fever, abdominal pain rarely, splenectomy combined with parental antimicrobial therapy,
and a splenic abscess, typically with focal calcification. Prolonged guided by cultures of blood and splenic aspirate. However, some spe-
antimicrobial therapy is often insufficient and splenectomy may be cific microbiologic causes (melioidosis, bartonellosis and tuberculosis)
required. are typically cured by antimicrobial therapy alone.
Chronic disseminated candidiasis, invasive aspergillosis and
mucormycosis can involve the spleen along with multiple other sites. References available online at expertconsult.com.
KEY REFERENCES
Avci F.Y., Li X., Tsuji M., et al.: Carbohydrates and T cells: Leggieri N., Marques-Vidal P., Cerwenka H., et al.: Migrated related species with special attention to carbapenems
a sweet twosome. Semin Immunol 2013; 25(2):146- foreign body liver abscess: illustrative case report, system- 2006–2009. Anaerobe 2011; 17(4):147-151.
151. atic review, and proposed diagnostic algorithm. Medicine Van’t Veer C., van den Pangaart P.S., Kruijswijk D., et al.:
Burnett R.J., Haverstock D.C., Dellinger E.P., et al.: Defini- (Baltimore) 2010; 89(2):85-95. Delineation of the role of Toll-like receptor signaling
tion of the role of enterococcus in intraabdominal infec- Livermore D.: Current epidemiology and growing resistance during peritonitis by a gradually growing pathogenic
tion: analysis of a prospective randomized trial. Surgery of gram-negative pathogens. Korean J Intern Med 2012; Escherichia coli. J Biol Chem 2011; 286(42):36603-36618.
1995; 118(4):721-723. 27(2):128-142. Wexler H.M.: Bacteroides: the good, the bad, and the nitty-
da Costa D.W., Boerma D., van Santvoort H.C., et al.: McDermott F.D., Collins D., Heeney A., et al.: Minimally gritty. Clin Microbiol Rev 2007; 20(4):593-621.
Staged multidisciplinary step-up management for necro- invasive and surgical management strategies tailored to Wittau M., Mayer B., Scheele J., et al.: Systematic review
tizing pancreatitis. Br J Surg 2014; 101:e65-e79. the severity of acute diverticulitis. Br J Surg 2014; and meta-analysis of antibiotic prophylaxis in severe
Ekeh A.P., Khalaf S., Ilyas S., et al.: Complications arising 101(1):e90-e99. acute pancreatitis. Scand J Gastroenterol 2011; 46(3):
from splenic artery embolization: a review of an 11-year Roberts D.J., Zygun D., Grendar J., et al.: Negative-pressure 261-270.
experience. Am J Surg 2013; 205(3):250-254. wound therapy for critically ill adults with open abdomi- Working Group Acute Pancreatitis Guidelines: IAP/APA
Ginès P., Angeli P., Lenz K., et al.: EASL clinical practice nal wounds: a systematic review. J Trauma Acute Care evidence-based guidelines for the management of acute
guidelines on the management of ascites, spontaneous Surg 2012; 73:629-639. pancreatitis. Pancreatology 2013; e1-e15.
bacterial peritonitis, and hepatorenal syndrome in cir- Snydman D.R., Jacobus N.V., McDermott L.A., et al.:
rhosis. J Hepatol 2010; 53:397-417. Update on resistance of Bacteroides fragilis group and
Chapter 41 Intra-abdominal Sepsis, Peritonitis, Pancreatitis, Hepatobiliary and Focal Splenic Infection 362.e1
REFERENCES
1. Livermore D.: Current epidemiology and growing resis- group and related species with special attention to 11. Wittau M., Mayer B., Scheele J., et al.: Systematic
tance of gram-negative pathogens. Korean J Intern Med carbapenems 2006–2009. Anaerobe 2011; 17(4):147- review and meta-analysis of antibiotic prophylaxis in
2012; 27(2):128-142. 151. severe acute pancreatitis. Scand J Gastroenterol 2011;
2. Wexler H.M.: Bacteroides: the good, the bad, and the 7. McDermott F.D., Collins D., Heeney A., et al.: Mini- 46(3):261-270.
nitty-gritty. Clin Microbiol Rev 2007; 20(4):593-621. mally invasive and surgical management strategies tai- 12. Working Group Acute Pancreatitis Guidelines: IAP/
3. Burnett R.J., Haverstock D.C., Dellinger E.P., et al.: lored to the severity of acute diverticulitis. Br J Surg APA evidence-based guidelines for the management of
Definition of the role of enterococcus in intraabdomi- 2014; 101(1):e90-e99. acute pancreatitis. Pancreatology 2013; e1-e15.
nal infection: analysis of a prospective randomized trial. 8. Roberts D.J., Zygun D., Grendar J., et al.: Negative- 13. Cordel H., Prendki V., Madec Y., et al.: Imported
Surgery 1995; 118(4):721-723. pressure wound therapy for critically ill adults with Amoebic Liver Abscess in France. PLoS Negl Trop Dis
4. Van’t Veer C., van den Pangaart P.S., Kruijswijk D., et al.: open abdominal wounds: a systematic review. J Trauma 2013; 7(8):e2333.
Delineation of the role of Toll-like receptor signaling Acute Care Surg 2012; 73:629-639. 14. Leggieri N., Marques-Vidal P., Cerwenka H., et al.:
during peritonitis by a gradually growing pathogenic 9. Ginès P., Angeli P., Lenz K., et al.: EASL clinical practice Migrated foreign body liver abscess: illustrative case
Escherichia coli. J Biol Chem 2011; 286(42):36603- guidelines on the management of ascites, spontaneous report, systematic review, and proposed diagnostic
36618. bacterial peritonitis, and hepatorenal syndrome in cir- algorithm. Medicine (Baltimore) 2010; 89(2):85-95.
5. Avci F.Y., Li X., Tsuji M., et al.: Carbohydrates and T rhosis. J Hepatol 2010; 53:397-417. 15. Ekeh A.P., Khalaf S., Ilyas S., et al.: Complications
cells: a sweet twosome. Semin Immunol 2013; 25(2):146- 10. da Costa D.W., Boerma D., van Santvoort H.C., et al.: arising from splenic artery embolization: a review of an
151. Staged multidisciplinary step-up management for nec- 11-year experience. Am J Surg 2013; 205(3):250-254.
6. Snydman D.R., Jacobus N.V., McDermott L.A., rotizing pancreatitis. Br J Surg 2014; 101:e65-e79.
et al.: Update on resistance of Bacteroides fragilis
42
Clinical Manifestations of Acute and
Chronic Hepatitis
DAVID WYLES | JENNIFER LIN
KEY CONCEPTS phase include malaise, joint pain, myalgia, fatigue, anorexia, nausea
and vomiting, and abdominal discomfort. Malaise is the most common
• Acute hepatitis can occur with all hepatitides but is most symptom in 95% of patients. Anorexia is common but resolves early
common with hepatitis A and E, whereas chronic infection is in the course of disease. Often patients report a change in smell or
more common with hepatitis B and C. Hepatitis D only occurs taste, or a dislike for alcohol or coffee. Abdominal discomfort occurs
in association with hepatitis B.
in 60%. Coryza, photophobia and headache may also occur. These
• Symptoms of acute hepatitis are nonspecific but include symptoms may persist for days to several weeks. A serum sickness-like
malaise, fatigue, nausea/vomiting and abdominal pain. Chronic illness can occur with symptoms that include fever, urticarial skin rash
hepatitis is often asymptomatic until cirrhosis develops. and arthritis (usually affecting the wrist, knees, elbows and ankles).
• Hepatitis A usually is contracted by the fecal–oral route and is These symptoms are thought to be due to circulating immune com-
most commonly seen associated with international travel, plexes and are most common with hepatitis B (HBV) but can occur
daycare outbreaks and food-borne illnesses. with other viral hepatitides.1 The symptoms are usually self-limiting.
During the icteric phase, jaundice occurs and lasts for a few days
• Hepatitis B is most widespread in Asia, and most cases are due to several weeks and is usually preceded by dark urine and pale
to vertical transmission, where, in 90% of cases, chronic infec-
(acholic) stools. Mild pruritus occurs in 40% of patients but is usually
tion ensues. Rates of hepatitis B have drastically decreased with
widespread vaccination campaigns. transient. Anorexia and malaise typically persist throughout this phase.
Fulminant hepatic failure is defined as severe liver failure within 8
• There are seven major hepatitis C genotypes, and epidemiol- weeks of onset of symptoms. It is characterized by sudden liver dys-
ogy of hepatitis C differs greatly geographically. function resulting in coagulopathy and hepatic encephalopathy. It is a
• Hepatitis C is predominantly spread by blood exposure, with rare but serious manifestation of acute viral hepatitis. The rate is only
most cases resulting from blood transfusion or infusion of 0.015–0.5% of patients with hepatitis A, and 1–4% in patients with
blood-derived products, mass treatment of schistosomiasis, acute HBV.2–4 The risk for fulminant hepatitis increases dramatically
sharing of needles or other instruments during injection drug in patients with HBV with hepatitis D (HDV) coinfection/
use, and occupational needlestick injuries. Sexual transmission superinfection. Fulminant hepatitis from HCV is uncommon, but
is also possible, but less common than via blood exposure. patients with chronic HCV who are superinfected with HAV are at
• New direct-acting antiviral agents for hepatitis C have relatively increased risk of fulminant hepatitis, leading to the recommendation
few side-effects compared to interferon-based treatment, and that all patients with chronic HCV be vaccinated against HAV and
have changed the treatment paradigm for hepatitis C. Main HBV.5 Acute liver failure due to HEV varies from 0.6–2.8% in men to
barriers to treatment now include access to medications and 20% in pregnant women. HEV is the most common cause of fulminant
economic constraints. hepatic failure in India, while HBV is responsible for most cases in
• Hepatitis D is a defective virus dependent on hepatitis B France and Japan. Acetaminophen toxicity is the leading cause in the
surface antigen for viral replication. It can only exist as coinfec- UK and the USA.3 GB-C virus infects human beings but does not
tion or superinfection with hepatitis B. appear to cause disease. Other causes of fever and raised liver enzymes
are discussed in Practice Point 12.
• Hepatitis E mainly causes acute hepatitis and is transmitted via The physical exam is typically normal during mild acute viral hepa-
water-borne routes and as a zoonotic agent. It can cause ful-
titis. Low-grade fever may be present, and bradycardia can occur if the
minant hepatitis in pregnant women. It can be acquired by
eating uncooked pork liver sausage and animal contact. patient is significantly icteric due to effects of bile salts on the sinoatrial
node. Jaundice is more common in adults than children. Lymphade-
• Development of a vaccine for hepatitis E and improved water nopathy and splenomegaly are infrequent, while hepatomegaly is
sanitation methods have greatly reduced the incidence of common.
hepatitis E.
Overview of Chronic Hepatitis

Chronic hepatitis refers to hepatocellular inflammation and necrosis
that lasts longer than 6 months and is caused by HBV (with or without
Overview of Acute Hepatitis HDV), HCV and rarely HEV. While HAV never causes chronic infec-
Acute symptomatic viral hepatitis can occur with any of the hepatitis tion, a slowly resolving and relapsing course lasting up to 6 months
viruses, and there are no clinical features to differentiate the etiologic can be seen in 10–15% of patients.6,7 Chronic viral hepatitis can be
agent other than epidemiologic patterns that may suggest a particular differentiated from other nonviral causes of chronic hepatitis by a
virus. Despite this, symptomatic acute disease is typically associated combination of serologic and/or nucleic acid testing. Chronic viral
with hepatitis A (HAV) or E (HEV) virus infection, to a lesser extent hepatitis is the fifth most common cause of death worldwide due to
hepatitis B, and rarely encountered with hepatitis C (HCV) infection. cirrhosis and portal hypertension.8
Acute infection can be divided into four phases – incubation, pre-
icteric phase, icteric phase and convalescent phase. Incubation phase Hepatitis A
occurs from infection to onset of first symptoms and ranges from a Hepatitis A was first discovered in fecal samples of infected volunteers.9
few weeks to 6 months. Earliest symptoms that occur in the pre-icteric Hepatitis A causes outbreaks worldwide and is usually transmitted by
363
The epidemiologic risk groups for acute hepatitis A virus infection Hepatitis B
obtained from reported cases in the USA in 2007 EPIDEMIOLOGY
Approximately 5% of the world’s population (350–400 million people)
Sexual or household contact (7.8%) is infected with HBV; 75% of those infected are Asian.21 The prevalence
in Western countries is much lower at 0.3–1.5% (Figure 42-2a).22
International travel (17.5%) HBV is responsible for 50% of hepatocellular carcinoma (HCC) cases
and virtually all cases of childhood HCC.21 HBV causes roughly
Unknown
MSM (5.9%) 450 000–650 000 deaths per year from liver cirrhosis or hepatocellular
(67.7%) IVDA (1.2%) carcinoma.8 Chronic HBV infection increases the risk of HCC by 5- to
Child/employee daycare center (3.8%) 100-fold.21
Suspected food- or water-borne outbreak In many high-risk areas, including Asia, transmission of HBV
(6.5%) occurs vertically from mother to newborn,23 with about 90% of these
Contact of daycare child/employee (4.6%)
cases resulting in chronic infection.21 In areas of low prevalence, HBV
Other contact with an HAV patient (9.0%) is usually acquired in adulthood through sexual and parenteral routes,
with 90% of acute HBV cases resolving spontaneously.21 Mode of
Figure 42-1 The epidemiologic risk groups for acute hepatitis A virus infection
obtained from reported cases in the USA in 2007. Percentage of cases for which
transmission – specifically age at transmission – impacts the clinical
a specific risk factor was reported was calculated on the basis of the total number presentation; vertical transmission of HBV usually results in asymp-
of cases for which any information for that exposure was reported. Percentages tomatic disease whereas adults infected with HBV are much more
do not total 100% because multiple risk factors have been reported for a single likely to have symptomatic disease.
case. MSM, men who have sex with men; IVDA, intravenous drug abuse. (From
Zakim and Boyer’s Hepatology: A textbook of liver disease. Saunders/Elsevier;
Throughout history, several epidemics can be traced to hepatitis B,
2012: 531–9, Figure 29.2. Adapted from Daniels D, Grytdal S, Wasley A. Surveil- including an ‘icterus epidemic’ in 1885 after a smallpox vaccination
lance for acute viral hepatitis – United States, 2007. MMWR Surveill Summ 2009; campaign and several outbreaks in 1942 among US army personnel
58:1–27.) after yellow fever vaccination. It was the discovery of the Australia
antigen by Baruch Blumberg in 1963 (later renamed hepatitis B surface
antigen) that identified the viral etiology. With this discovery, blood
banks could screen donors for HBV though the assay was not very
specific. In 1973, William S. Robinson discovered hepatitis B viral
a direct fecal–oral route or through contaminated water. Risk factors DNA. In 1978, three separate scientists – Pierre Tiollais, William
for acute HAV infection in the US include international travel (45.8%), Rutter and Kenneth Murray – cloned and sequenced HBV DNA.24
household contact with person with hepatitis A (14.8%), outbreak at In the Western world, high-risk populations for HBV include intra-
daycare center (7.6%), food- or water-borne outbreaks (7.2%), men venous drug users, hemodialysis patients, homosexual men and insti-
who have sex with men (MSM) (3.9%) and injection drug use (IDU) tutionalized persons.25
(4.3%) (Figure 42-1).10 Contamination of shellfish by sewage pollution
is a continued problem since molluscs retain and concentrate viruses GENOTYPES
from water, with 359 outbreaks reported between 1980 and 2012.11 In 1998, Hiroaki Okamoto classified hepatitis B into four genotypes,
Hepatitis A results only in acute infection without a chronic carrier A–D.26 In 2004, this was expanded to genotypes A–F by Helene Norder
state. Acute viral hepatitis A may be asymptomatic, marked only by a and Lars Magnius. Genotype D is found worldwide. Genotypes B and
rise in liver function tests and detection of serologic markers of infec- C are found in Asia, A and E in Africa, and F and H in the Americas
tion. At the time of clinical presentation and transaminase elevations, (Figure 42-2b). Genotypes C, D and F are thought to be more patho-
anti-HAV IgM is detectable and is the diagnostic test of choice for genic and cause more severe liver disease, and genotypes A and B
acute HAV. Following resolution of infection or vaccination anti-HAV respond better to interferon therapy;21,24 however, a study from Taiwan
IgG is detectable. Acute HAV infection is generally a minor illness in showed that genotype B was more likely to cause HCC in young car-
children, with more than 80% of cases being asymptomatic. Adults are riers without cirrhosis.27
more likely to be symptomatic, with the case-fatality rate rising pro-
portionally to age of the infected individual.12 Clinically significant SEROLOGIC TESTING
extrahepatic manifestations of HAV infection are infrequent and After infection, there is a period of several weeks in which no markers
include minor skin rash and arthralgias.7 Pure red cell aplasia rarely can be detected in blood. HBV DNA and hepatitis B surface antigen
occurs with acute viral hepatitis and has most frequently been reported (HBsAg) then begin to rise, with HBV DNA usually detectable first.
with hepatitis A infection.13,14 Both HBV DNA and HBsAg peak before the onset of symptoms. After
Improvements in public health sanitation in combination with the onset of symptoms, HBV DNA decreases faster due to a shorter serum
development of an effective vaccine have resulted in a drastic reduction half-life but it may remain detectable in trace amount. With onset of
in the incidence of hepatitis A. Despite the existence of three HAV symptoms, hepatitis B core antibody (anti-HBc) appears. Hepatitis B
genotypes there is only a single serotype and an effective formalin surface antibody (anti-HBs) appears several weeks or months after
inactivated viral vaccine has been available since 1994.15 Since the disappearance of HBsAg. Disappearance of HBsAg marks resolution
recommendation for vaccination for all individuals at increased risk of disease though the virus may still be present latently in the liver in
in 1996 and all US-born infants in 2006, the incidence of acute hepa- the form of covalently closed circular DNA (cccDNA).24
titis A has declined 92% from 12 cases per 100 000 population in 1995 Detectable HBsAg indicates presence of active infection. Anti-HBs
to 1 case per 100 0000 population in 2007.16–18 Routine immunization indicates the development of immunity against HBV, due either to
has resulted in similar declines in Israel, Italy, Spain and Australia.16,19 prior exposure or to vaccination.
In higher-income countries, the highest risk for hepatitis A is now in Whereas anti-HBs does not differentiate between prior infection
travelers to high-risk areas.10 Passive immunization with immuno- or immunity through vaccination, anti-HBc is only present with
globulin preparations is available, however its use has fallen out of current or past infection. Anti-HBc indicates exposure to HBV but
favor with the widespread availability of vaccination and evidence that does not differentiate between current active infection versus past
vaccination is as efficacious as IVIG for prophylaxis if given less than infection or the chronicity of the infection. Anti-HBc IgM is very sensi-
14 days after exposure.20 Exceptions to this approach include immu- tive and can remain positive even in chronic HBV infections.24 Prior
nosuppressed persons and those <12 months or older than 40 years to the advent of widely available HBV DNA testing, lone detection of
of age. anti-HBc IgM was possible in the so-called ‘window period’ before
Chapter 42 Clinical Manifestations of Acute and Chronic Hepatitis 365
HBV epidemiology
High
Intermediate
a Low
B1, C, F A2 D1
A2 D1 C2
A2 D
D D3 C1
D C/D C1 B1
D1 D2? B2 B2 C2
G D D A1
F1 E A4 C1
A5 E D5
B5, C5
H F2 A3 E C5 B3
F1 F2 A1
C3
C4, D4
F3 A1
F4
Figure 42-2 HBV epidemiology. (a) Estimated global prevalence of hepatitis B virus by region. (b) Global hepatitis B virus genotype distribution. (Reprinted from Gerlich
WH. Virol J 2013; 10:239.)
levels of anti-HBs rose to detectable levels in resolving HBV infection secretion triggered by a pre-core signal. HBeAg is an immune modula-
(Figure 42-3). tor and prohibits the immune system from detecting HBcAg. As a
Another marker, hepatitis B ‘e’ antigen (HBeAg), was discovered result, HBV can proliferate and high levels of HBsAg are usually
in 1972 by Swedish virologist Lars Magnius, and along with the level detected. HBeAg is not essential for viral replication. Pre-core mutants,
of viremia it indicates level of infectivity. HBeAg is a secreted form of which do not produce eAg, can still replicate and even cause fulminant
HBcAg that has a separate signaling pathway from HBcAg, with hepatitis.24 Chronic eAg-negative HBV is associated with a longer
The course of acute HBV infections with resolution Cumulative incidence of cirrhosis (N = 3582)
Hepatitis Cumulative .4 Baseline HBV DNA Level

HBV incidence of ≥1.0×106
Log titer liver cirrhosis
DNA 1.0–9.9×105
PCR .3
Anti-HBc 1.0–9.9×104
300–9.9×103
<300
.2
HBsAg Anti-HBs
.1
Occult HBV infection
0
0 3 6 9 12 0 1 2 3 4 5 6 7 8 9 10 11 12 13
Months Year of follow-up
Figure 42-3 The course of acute HBV infections with resolution. After the infect- Figure 42-4 Impact of viral replication and the levels of hepatitis B virus (HBV)
ing event (time 0) follows a lag phase of several weeks without detectable markers. DNA in serum on the later development of cirrhosis and its complications.
Thereafter HBV DNA (within the virus) and HBsAg increase exponentially in the (Reprinted from Iloeje UH, et al. Gastroenterology 2006;130(3):678-686.)
serum. HBV DNA is detected earlier because its assay is much more sensitive. The
peak of HBV DNA and HBsAg is reached before outbreak of the acute disease
and both decrease after the onset of clinical symptoms. Initially, the HBV DNA
decreases faster because it has a shorter half-life time in serum than HBsAg.
HBsAg finally disappears whereas HBV DNA may remain detectable in traces. DEVELOPMENT OF HCC
Antibodies against the HBV core antigen (anti-HBc) appear with the onset of In the 1970s, Blumberg as well as Szmuness of the New York Blood
symptoms, the protective antibody against HBsAg (anti-HBs) appears very late, Center, noted an increased incidence of HCC in patients with chronic
usually several weeks or months after disappearance of HBsAg. Disappearance of
HBsAg is considered to be a sign of resolution but the virus often remains in occult HBV.25 Continuous HBV replication is the main driving force for HCC
form in the liver. (Reprinted from Gerlich WH. Virol J 2013; 10:239.) in HBV patients.35 High HBV DNA levels are associated with more
rapid fibrosis progression and an increased risk of HCC (Figure
42-4).36 In a study of 11 893 Taiwanese men followed for a mean of 8.5
years, the incidence of HCC was 1169 per 100 000 person-years in men
who were both HBsAg-positive and HBe-Ag positive, 324 per 100 000
duration of infection, particularly in men, and carries a poor prognosis person-years for those who were only HBsAg-positive and only 39 per
with higher rates of cirrhosis and HCC development as well as a poor 100 000 person-years for those who were HBsAg-negative.21 HBV can
response to interferon (IFN)-based therapy.28 cause HCC in the absence of cirrhosis though most cases (70–90%)
In patients with chronic HBV, an inactive carrier state may arise occur in patients with cirrhosis.21 Factors associated with HCC include
where the immune system reaches an equilibrium with the virus such male sex, older age, Asian or African ancestry, family history of HCC,
that HBsAg levels are lower and HBV DNA low or undetectable. These high HBV viral load, HBV genotype, longer duration of infection,
inactive carriers do not have HBeAg but have formed anti-HBe and by coinfection with HCV or HIV or HDV, and environmental exposures
definition have normal transaminases. Inactive carriers may transition (aflatoxin, alcohol, tobacco).21 Decreased levels of viral replication
to active disease, most often by developing chronic HBeAg-negative during antiviral treatment of HBV reduces but does not completely
HBV, as described above.28 eliminate the risk for HCC.37
The exact mechanism of HCC is unknown, though some studies
PASSIVE IMMUNITY AND VACCINATION have shown that HCC tissue is clonal expansion of truncated or re
Passive immunization through human immunoglobulin containing arranged HBV DNA. It is also thought that the insertion of HBV
high levels of anti-HBs (HBIG) was first studied by Beasley in Taiwan promoters before oncogenic genes may cause oncogenic proliferation.
in the early 1980s, showing that HBIG given immediately after birth
could prevent vertical transmission in 71% of cases.29 OVERVIEW OF CHRONIC
Active immunization through vaccination was first reported HEPATITIS B TREATMENT
when diluted Australia antigen was injected into institutionalized chil- Treatment of HBV is indicated for most patients with chronic active
dren with a significant though incomplete protection against serum infection, particularly those with an ALT above the upper limit of
with infectious HBV.30 Vaccine experiments were then conducted in normal (ULN), serum HBV DNA levels ≥2000 IU/mL, or evidence
chimpanzees,31 followed by the creation of the first human vaccine in of liver fibrosis.38–40 Nucleos(t)ide-based therapies are the mainstay of
1976 which was tested in staff and patients in hemodialysis wards.32 HBV therapy due to their high rate of antiviral efficacy (achievement
In 1980, Szmuness conducted the first placebo-controlled study with of undetectable HBV serum DNA levels) and excellent long-term
1083 homosexual males in New York and found a protection rate safety and tolerability. Among nucleos(t)ide therapies, entecavir and
of 92%.33 tenofovir have emerged as the treatments of choice due to their high
Second generation recombinant yeast-derived HBsAg vaccine was rates of viral suppression, excellent tolerability and low rates of viral
developed in the early 1980s. Three or four injections are given within resistance emergence.41,42 Lamivudine is no longer considered first-line
6–12 months to achieve long-term immunity. In 1982, the WHO therapy due to decreased antiviral potency compared to other options
recommended universal childhood vaccination. Taiwan was the first and high rates of antiviral resistance emergence.40,43 Interferon-alpha
country to begin universal childhood vaccination and administration is less frequently used given its poor tolerability and inferior antiviral
of HB immunoglobulin to infants of high risk HBsAg-positive and efficacy; however it does offer increased rates of immunologic response
HBeAg-positive mothers in 1984, with a decrease in HBsAg carrier rate and a finite duration of therapy with reasonable efficacy in select
from 10% nationwide to 1.2%.21,34 HCC in children was reduced by patients such as those with low baseline HBV RNA, ALT >2× ULN and
65–75%.21 HBV genotypes A or B.44–46
Goals of HBV therapy include achieving undetectable serum HBV of the various genotypes remains largely speculative but likely occurred
DNA levels, induction of e antibody seroconversion, loss of surface more than 500 years ago – with some genotypes (e.g. genotype 6)
antigen and ultimately appearance of surface antibody. Monitoring on emerging thousands of years ago.57 Strong evidence exists for the pres-
therapy primarily consists of serum HBV DNA levels with periodic ence of endemic circulation of HCV genotypes in various parts of the
re-assessment of HBe antigen/antibody status in patients initially posi- globe for prolonged periods of time (e.g. genotype 1 in Central Africa)
tive for e antigen. Quantitative serum surface antigen also appears useful with only relatively recent worldwide dissemination.58 Currently there
for monitoring during therapy but is currently not available in the USA. are seven recognized major HCV genotypes (numbered 1 through 7)
Duration of therapy with nucleos(t)ides is indefinite unless surface with multiple subtypes.59 Interestingly, the recent spread of many HCV
antigen loss occurs, in which case treatment is typically continued for genotypes can be traced to the arrival of various medical procedures
6–12 months and then stopped. Discontinuation of nucleos(t)ide-based (blood transfusion or the administration of injectable medications) or
therapy after e antigen seroconversion is controversial,40 with recent the more recent expansion of recreational injection drug use. In
data indicating low rates of durable response.47 Patients with advanced general, genotypes 1a and 3 predominate in the more recently infected
fibrosis or cirrhosis are generally treated for life. Unfortunately, patients with primarily IDU as a risk factor. In contrast, genotypes 1b
treatment-induced functional cure of HBV infection (loss of HBsAg and 2a or b are most commonly found in older patients infected years
and appearance of anti-HBsAb) is rare, though it may occur more ago – often as the result of exposure through contaminated blood
frequently following interferon-based therapies or prolonged suppres- products or other medical interventions (Figure 42-5).58,60
sion with nucleos(t)ides. Effective treatment of chronic HBV infection
with suppression of HBV viremia is associated with numerous benefits, Detailed HCV Epidemiology in Select
including dramatic reductions in liver disease progression, HCC and Countries/Regions
liver-related death. Reversal of cirrhosis and manifestation of end-stage Japan. The HCV epidemic in Japan is prototypical for the scenario
liver disease (ESLD) can also be seen with durable HBV DNA suppres- of a ‘mature’ cohort where the bulk of HCV transmissions occurred
sion.48,49 Research on new treatments for HBV, including immunologic from 1920 to the 1940s.61 HCV seroprevalence increases dramatically
and new antiviral targets, is ramping up with the goal of increasing the with age in Japan and is also subject to significant geographic variation
rate of functional cure following HBV therapy. within the country.62,63 Overall, the HCV prevalence in Japan (esti-
[See Chapter 155 for a detailed discussion of HBV antiviral agents mated at 0.95% in 2000) is decreasing due to population turnover with
and treatment approaches.] a contribution of excess liver-related mortality/HCC in the older
HCV-infected population.63 Geographic variation in HCV prevalence
Hepatitis C in Japan demonstrates a much higher seroprevalence rate in the South
INTRODUCTION and West regions due to unsafe medication administration practices
In a clinical molecular virology first, the discovery of the hepatitis C and spread of HCV genotype 1b, starting with treatment and eradica-
virus (HCV) as an etiologic agent of chronic hepatitis resulted from tion efforts targeted at Schistosoma japonicum in the1920s followed by
the direct cloning of the viral nucleic acid prior to identification or more widespread transmission through other medical procedures
development of a serologic test.50 This remarkable feat was followed (transfusion etc.) and injection drug use surrounding the Second
by the development of a screening antibody test and confirmation of World War.64,65 Genotype 1b remains predominant in Japan though
HCV as the etiologic agent in the vast majority of transfusion associ- the prevalence of genotype 2b, in particular, appears to be increasing
ated non-A, non-B hepatitis cases and a common cause of viral hepa- as IDU is now the major mode of transmission.66
titis worldwide.51,52 Since this seminal discovery in 1989, our Europe. Significant regional variations exist in HCV prevalence as
understanding of HCV epidemiology, natural history, clinical mani- well as the timing and composition of the populations affected. As
festations and therapeutic approaches has progressed significantly, discussed, the HCV prevalence in Northern European countries is
culminating in the arrival of remarkably well-tolerated and effective among the lowest in the world (<0.5%). A higher HCV prevalence is
oral therapy (see Chapter 155). However, despite early speculation, seen in Southern (2–3%; Spain, Italy, Portugal) and Eastern (2 to >5%;
and much like HIV-1, an effective protective vaccine remains elusive. primarily the former Soviet Union) Europe, though the timing and
risk factors associated with the epidemics are different.67 The origins
HCV EPIDEMIOLOGY and perpetuation of the HCV epidemic in Southern Europe is felt to
Global Epidemiology and Disease Burden be twofold with an initial introduction and spread through blood
The global burden of HCV infection is estimated at 185 million transfusion and other medical procedures followed by a rapid expan-
infected persons (170–200 million; 2–3% prevalence) with significant sion in IDU. Notably, studies from Spain and Italy also suggest a sig-
regional variations in HCV prevalence, genotype distribution and nificant component of nosocomial transmission.68,69 Expansion of
infected population demographics.53,54 Some generalizations include a injection drug use has facilitated a shift in genotypes to 1a, 3 and more
low HCV seroprevalence in Northern European countries (<0.5%; e.g. recently 4, with a younger population (<50 years old).67 HCV epide-
Denmark, Sweden and Finland), moderate prevalence rates in much miology is less well studied in Eastern Europe; however, the recent
of the rest of the industrialized world (0.5–2.5%; e.g. Australia, USA, expansion of HCV in this region is due to a rapid expansion of IDU
England, Italy, Spain and Japan), and a high prevalence in much of in the younger population.67
Asia (>3.0%; e.g. China and Pakistan) and Northern Africa, with the United States. The bulk of HCV transmission events occurred from
highest prevalence in Egypt (8–12%).54,55 Recent data estimate that roughly 1960 to the early 1990s, with a peak estimated incidence of
500 000 deaths annually are a result of HCV infection with the vast nearly 380 000 persons infected in 1989 (www.cdc.gov/hepatitis/
majority due to long-term sequelae of infection such as end-stage liver Statistics/IncidenceArchive.htm). Injection drug use remains the
disease and hepatocellular carcinoma.8 A recent study suggests that leading risk factor for HCV acquisition, though prior to 1992 blood
HCV-related mortality may be grossly under-recognized, at least in the transfusion was a significant means of transmission. The National
USA, with mortality related to HCV being up to five times more Health and Nutrition Examination Survey (NHANES) has character-
common than when assessed from death certificates alone. In the USA ized the HCV epidemic in the USA over several time periods with some
this translated to an increase from 16 000 HCV-related deaths in 2010 notable trends appearing in the most recent iteration. The prevalence
to almost 80 000.56 Based on these findings it seems likely that deaths of chronic HCV infection in the USA from 2003 to 2010 was estimated
related to HCV are more prevalent worldwide. to be 1.0% (2.7 million persons); this represented a drop in disease
An important facet of HCV epidemiology is the localization and prevalence from prior NHANES surveys (1.3%).70 Groups at increased
spread of particular viral genotypes across the globe. The timing for risk for HCV infection included: age >40 years old (highest in those
introduction of HCV into humans and the subsequent diversification >50), those living in poverty (defined as <2× the federal poverty level),
The estimated prevalence of HCV infection and the distribution of HCV genotypes across the world
Russia
Canada Sweden
Norway
Finland
Belgium Republic
of Korea
Turkey
Poland
UK
Syria
Germany
USA Japan
France
China
Portugal Greece
Mexico Spain
Egypt Pakistan
Colombia Italy Vietnam
Genotypes
Venezuela
G1
G1a Brazil
G1b Prevalence of
Saudi Arabia Thailand
G2 Chile HCV infection
G3 Argentina South Africa India Australia <1.0%
G4 1.0–1.9%
G5 2.0–2.9%
G6 >2.9%
Mixed or other Not studied
Figure 42-5 The estimated prevalence of HCV infection and the distribution of HCV genotypes across the world. (Reproduced with permission from John Wiley &
Sons © Negro F, Alberti A. Liver Transpl 31(2):1–3 (2011), and Center for Disease Analysis, http://c4da.com/HepC/HepMap.html.)
having less than a high school education, and non-Hispanic blacks.70 and is characterized by a high prevalence of 14.7% (9.8% HCV RNA
Estimates of HCV prevalence from NHANES should be viewed as a positive) with increasing prevalence in older age groups largely related
lower bound for HCV infection in the USA as this survey does not to iatrogenic transmission during parenteral anti-schistosomiasis
include populations at high risk for HCV infection such as homeless therapy from the 1920s until 1980s.78 While rates of HCV RNA positiv-
or incarcerated persons; including these population yields an HCV ity are approximately double in those who received parenteral anti-
prevalence estimate around 2% (>5 million persons).71 schistosomiasis therapy, they remain significantly elevated in those
without exposure to parenteral therapy.79 The highest HCV RNA-
Asia. Due to the large population, this region accounts for the major- positive rate was seen in men aged 50–54 years old (33% detectable
ity of HCV-infected persons worldwide, with more than 100 million RNA) in a 2008 survey.79 Consistent with epidemic spread in the
infected persons.54 The HCV seroprevalence in China was estimated country a single genotype, genotype 4, makes up a staggering 93% of
to be between 2.4 and 3.1% in a cross-sectional study,72 though there HCV infections in Egypt.73
has been considerable variation in other estimates based on the popu-
Australia. In 2012 the HCV seroprevalence was estimated at 1.2%
lations and locations studied.73,74 Genotype 1b predominates in
with IDU being the most common risk factor.55 Similar to the USA
China, with the major route of transmission being percutaneous/
and areas in Europe, this represents a gradual decrease in overall preva-
intravenous exposure through medical, dental or cosmetic procedures.
lence compared to prior surveys (2.3% from 1996 to 1998), perhaps
However, a recent report highlights a possible increase in IDU-related
indicating a true decrease in prevalence a decade after sustained
infections in younger persons infected with HCV genotypes 3 and 6.75
decreases in incidence were noted.73,80 The seroprevalence of HCV
Healthcare-related transmission of HCV predominates in Pakistan
shows a bimodal distribution, with a peak in those aged 20–24 years
and India. The HCV seroprevalence in Pakistan is estimated at 3.0%.76
old (2.5% in 2005) and a second peak in those aged 55–64 (4.8% in
Country-wide cross-sectional data on HCV epidemiology in India are
2005).54 Collectively genotype 1 is the most common in Australia, with
lacking. The available data suggest an HCV seroprevalence from 1–2%
genotype 1b prevalent in older persons with transfusion-associated
though some more recent data suggest it may be less than 1%.73,77
HCV.73,81 An increase in genotype 3 has been seen with IDU in young
Genotype 3 represents the most common genotype in both Pakistan
persons.81
and India.73
Africa. Outside of Egypt relatively few data on HCV epidemiology Modes of Transmission
are available, particularly in sub-Saharan Africa. Estimates of HCV HCV is most efficiently transmitted via percutaneous exposure to
prevalence range from about 2–3% across Africa with the highest blood containing HCV RNA. The means of exposure vary, with the
prevalence in the North dominated by the epidemic in Egypt. The most prevalent modes of transmission including blood transfusion or
epidemiology of HCV infection in Egypt has been extensively studied infusion of blood-derived products (prior to implementation of HCV
screening), sharing of needles or other injection implements during The appearance of HCV RNA, anti-HCV and elevated
injection drug use, improper re-use or sterilization of medications ALT in acute hepatitis C virus infection
and/or medical equipment, and occupational needlestick exposures.
Effective screening of the blood supply has been in place in the indus- Titer
trialized world since the early 1990s; currently this is carried out by 1200 Clinical symptoms
HCV RNA (IU/mL, log10)

nucleic acid testing with an extremely low risk of HCV transmission
via transfusion (≪1 in a million).82 In low- and middle-income coun- 1000
tries (LMIC) the methods of screening (nucleic acid vs. antibody) and
800
ALT (U/L)
rigor with which they are implemented vary substantially, and as such,
so does the risk of HCV acquisition from transfusion. 600 108
Globally, 35–70% of injection drug users are seropositive for HCV
400 107
though significant geographic variation exists (seroprevalence range
10–98%).83,84 HCV can survive in syringes or dried blood for a week 106
at room temperature and has been found in implements used in IDU, 200
such as cotton swabs.85–87 IDU is the most common risk factor for HCV 105
0
acquisition in the industrialized world and is the key driving force in 0 2 4 6 8 10 12–18
perpetuating the HCV epidemic in these locales. As examples, in the Time (weeks)
USA is it estimated that >60% of incident HCV infections are now due
to IDU;88 in Australia this number is over 80%.89 The contribution of HCV RNA ALT Anti-HCV
IDU to HCV transmission in LMIC is more variable.
Historically, healthcare-associated HCV transmission has been a Figure 42-6 The appearance of hepatitis C virus (HCV) RNA, anti-HCV and
major mode of HCV acquisition globally and, unfortunately, remains elevated alanine transaminase (ALT) in acute HCV infection. Measurements in
a major source of HCV transmission in many LMIC.82 Iatrogenic HCV arbitrary units.
transmission is also responsible for periodic disease outbreaks in
LMIC. Most documented outbreaks associated with medical proce-
dures in the industrialized world center on the improper re-use of Breast-feeding has not been shown to be a risk factor for HCV
multi-dose vial medications and lack of adherence to strict aseptic transmission.
technique.82,90 Patients on hemodialysis have also been shown to have
significantly higher rates of HCV seropositivity, ranging from 3 to
CLINICAL MANIFESTATIONS AND
20%.91–93 Importantly, it has been shown that strict adherence to uni- DIAGNOSTIC TESTING
versal precautions and enhanced measures to prevent exposure to Acute Infection
body fluids can eliminate the risk of HCV transmission associated with The incubation period is approximately 4–8 weeks though HCV RNA
hemodialysis.94 The risk of HCV transmission after a needlestick expo- is detectable within weeks of infection. Similarly, the time to serocon-
sure ranges from 1 to 3%.95 An increased risk of transmission is seen version is 2–3 months in most cases, though delayed appearance of
with hollow needles and deep penetrating injuries at the time of the HCV antibodies may be seen and has been documented to occur over
needlestick exposure.96 1 year after infection, particularly in those with immunosuppressive
Other less common forms of percutaneous blood exposure such as conditions such as HIV.108,109 Nearly all patients with acute HCV infec-
tattoos or scarification procedures are not felt to be major modes of tion will have some elevation in hepatic transaminase levels with values
HCV transmission; however, they may be of importance in specific typically in range of 200–1000 IU/L.68,110,111 Notably, depending on the
settings. Tattooing performed in commercial tattoo parlors adhering point in time in the course of acute HCV infection, transaminases may
to established infection control procedures should present almost no be minimally elevated above a patient’s baseline while still being within
risk for HCV transmission. Despite this, several epidemiologic studies the laboratory established ‘normal’ range (Figure 42-6).110
have identified tattoos as an independent predictor of HCV seroposi- Acute viral hepatitis due to HCV cannot be distinguished from
tivity (odds ratios from 3 to 6) even when controlling for other known other viral or nonviral causes based on the clinical presentation
HCV acquisition risk factors.97–99 In contrast, tattooing performed in alone; acute HCV infection symptoms tend to be less severe, with the
unregulated (non-commercial) settings, such as prisons, is common majority of patients being asymptomatic or having only mild, nonspe-
and likely represents a significant means of HCV transmission though cific symptoms.110,112 When present, symptoms of acute HCV infection
it is not extensively studied.100,101 include fatigue, malaise and abdominal discomfort. Symptoms indica-
While other bodily fluids (e.g. semen) can harbor virus, the role of tive of acute hepatitis such as jaundice, acholic stools and dark urine
virions from other body fluids in HCV transmission remains unclear. are uncommon (<20% of cases) and thus most cases of acute HCV
To this point, sexual transmission of HCV, with some notable excep- infection escape clinical attention unless there is a high index of
tions such as HIV+ MSM (see Practice Point 32), appears to be very suspicion.113 In a prospective study of high-risk individuals with
rare. Prospective and cross-sectional studies of long-term heterosexual IDU no cases of significant hyperbilirubinemia (>2mg/dL) or presen-
couples demonstrate exceedingly low rates of transmission, with some tations with classic acute hepatitis symptoms were recognized in 20
studies finding no evidence of transmission.102,103 In aggregate, the consecutive acute HCV infections.110 However, when present, more
evidence suggests that specifically for long-term, monogamous hetero- severe symptoms such as jaundice or flu-like symptoms may indicate
sexual couples, the risk of HCV sexual transmission is extremely low. patients who are more likely to spontaneously clear acute HCV
In line with these data are the recommendations for no change in infection.68,111,114
sexual practices for such couples with regard to HCV transmission risk Chronic HCV infection develops in roughly 75% of persons
reduction. infected, though this number is highly variable depending on the
Vertical transmission of HCV does occur, though it appears to be population being considered. Factors associated with an increased like-
less common than with HIV-1. The rate is estimated to be between 3 lihood for clearance include female sex, younger age, IL28B CC geno-
and 10% and only occurs in mothers with detectable HCV RNA.104,105 type (rs12979860) and certain HLA class II alleles (e.g. DRB1). 113–117
HIV coinfection increases the risk of vertical transmission with rates In a study of 1008 patients, persons displaying the IL28B CC genotype
of 15–20%.106,107 Unlike HIV, no specific measures are recommended were three times more likely to have cleared HCV (OR for clearance
to prevent transmission save avoiding the use of scalp monitoring. 0.33 [0.25–0.45] for persons with a T-allele) and had an overall spon-
Cesarean section has not been definitively shown to reduce the risk of taneous resolution rate of 53%.116 The impact of age and sex are high-
HCV vertical transmission and is generally not recommended.105 lighted by two well-characterized cohorts of young women infected
with HCV through a common source where spontaneous clearance membranoproliferative glomerulonephritis with immune complex
rates ranged from 42 to 44%.114,115 deposition. Renal disease presentations vary from microscopic hema-
Immunologically, clearance of infection has been associated with turia to nephrotic syndrome to acute glomerulonephritis with renal
broad and persistent CD4 and CD8 T-cell responses to HCV.118–121 failure.141 HCV seropositivity is also associated with an increased likeli-
Despite this association, it remains unclear to what degree the adaptive hood for the development of type II DM in those over 40 years of age
immune response is causative in clearance of HCV or a marker for (OR 3.77; 95% CI: 1.80–7.87).142 Further, treatment of HCV infection
other events (e.g. innate immune responses) leading to clearance and has been shown to reduce the development of DM and restore insulin
the prevention of the typical development of immune exhaustion asso- sensitivity as well as prevent medical complications in those with estab-
ciated with chronic HCV infection and expression of ligands such as lished type II DM.143,144 Evidence of HCV infection has been found in
PD-1.122,123 Evidence also points to a role for the innate immune system up to 50% of patients with PCT; though convincing evidence for HCV
in the control and, possibly, clearance of HCV infection. Natural killer treatment-induced resolution of PCT is lacking.145
(NK) cell receptor polymorphisms (KIR2DL3) have been associated
with the outcome of acute HCV infection.124 Early appearance of DISEASE PROGRESSION
broadly neutralizing antibodies has also been correlated with clearance Chronic HCV infection results in hepatic inflammation that can lead
in a well-defined single-source outbreak.125 However, clearance of to the development of progressive hepatic fibrosis, which over the
HCV in patients with agammaglobulinemia suggests that an effective course of years (usually decades) can result in the histologic endpoint
humoral response is not required for spontaneous HCV clearance.126 of cirrhosis and clinical sequelae such as portal hypertension, end-
Regardless of the mechanisms underlying HCV control and eradica- stage liver disease (encephalopathy, variceal hemorrhage, ascites) and
tion, it is clear they act early in infection. An eloquent sequencing study hepatocellular carcinoma (HCC). Early studies on the natural history
of patients with acute HCV infection documented early restriction of of chronic HCV infection demonstrated that roughly 20% of patients
HCV viral sequence diversification in persons who went on to eradi- had cirrhosis after 20 years of infection and 45% had cirrhosis by an
cate infection; while rapid and broad HCV sequence diversification estimated 30 years after infection,146–148 highlighting the major impact
was seen in those who developed chronic infection.127 duration of infection has on disease progression and suggesting a non-
linear progression as has been found in other studies.149 These esti-
Chronic Infection mates should be taken as a base case scenario from which liver disease
Chronic HCV infection is arbitrarily defined as persistent HCV RNA progression can either be accelerated or slowed based on patient/
replication and detection in serum 6 months beyond the time of infec- environmental and, possibly, viral factors. Host factors with well-
tion. Indeed in studies of acute HCV infection most patients who clear established correlations to disease progression rate include: sex – with
spontaneously do so within 12-18 weeks of identification; though females having a slower rate of progression than males; age at infection
clearance has been documented to occur up to a year or more after – younger age at infection portends a slower progression; immune
infection.111,117 During chronic infection HCV RNA is detectable in status – immunosuppression or immune dysregulation, as in the case
plasma, with viral loads in the 105–106 IU/mL range and is frequently of organ transplantation or HIV-1 coinfection, can significantly
accompanied by modest elevations in hepatic transaminases (ALT, increase liver disease progression rates (see Practice Point 32 for a
AST). Hepatic transaminases fluctuate and may be repeatedly within detailed discussion).148,150 The presence of coexistent liver disease (e.g.
the laboratory-derived normal levels (typically <40 IU/mL) in up to chronic HBV or steatohepatitis) also likely accelerates liver disease
20–30% of patients with chronic HCV infection;128–130 despite normal progression though it has not been extensively studied.
transaminases, a significant proportion will have fibrosis on biopsy.128,130 The major environmental factor impacting liver disease progres-
However, if followed longitudinally, nearly all have consistent eleva- sion in those with HCV is alcohol.147,151 While no safe level of alcohol
tions above their own baseline as judged by a decrease in transaminase consumption is recognized in those with HCV, daily intake above 50 g
levels upon successful HCV clearance (treatment or spontaneous).110 has been linked to accelerated disease progression in those with
Clinical symptoms during chronic infection are generally mild with HCV.147,152 A clear association between viral factors and disease pro-
most patients being considered asymptomatic. Nonspecific symptoms gression has remained more elusive. Genetic diversity, viral load and
such as fatigue are common but it is difficult both to quantify them genotype have all been evaluated and proposed as possible contribu-
and to establish a causal relationship with chronic HCV infection. tors to disease progression. Though the impact appears relatively
However, early studies of IFN-free HCV therapies suggest improve- modest, several studies have found an association with higher HCV
ment in fatigue-related symptoms may be frequent following success- viral loads and accelerated disease progression.153–155 A recent cross-
ful therapy.131–133 sectional study found a significant association between HCV genotype
A myriad of extrahepatic manifestations have been associated with 3 infection and the development of cirrhosis (HR 1.31) and HCC (HR
HCV infection to varying degrees, including: cryoglobulinemia (type 1.80) (Figure 42-7).156
2 and 3), glomerulonephritis, insulin resistance and type II diabetes
mellitus (DM), lymphoproliferative disorders, porphyria cutanea
tarda (PCT) and lichen planus (reviewed in reference 134). Hepatitis
Factors influencing the progression
C infection is associated with essential mixed cryoglobulinemia (type of hepatitis C virus (HCV) infection
II) and mixed cryoglobulinemia (type III); both are characterized by
polyclonal immunoglobulin production with type II also having
monoclonal immunoglobulins and rheumatoid factor.135 While pro- No fibrosis Cirrhosis
duction of cryoglobulins is quite common in chronic HCV infection 30 years
(20–50%; conversely 80–90% of patients with mixed cryoglobulinemia
have evidence of HCV infection),134–136 clinical disease manifestations • Age <40 • Age >40
and cryoglobulinemic vasculitis are less common.137 Symptoms may • Female • Male
include arthritis or athralgias, palpable purpura, skin ulcerations, renal • No alcohol • Alcohol >50g
disease and weakness or peripheral neuropathy.134 Epidemiologic • Low HCV VL • HCV GT3
• High HCV VL
studies have found an increased HCV seroprevalence (5–20%) in
42 years
patients with B-cell lymphoproliferative disorders, particularly B- 13 years
cell non-Hodgkin’s lymphoma.138 Interestingly, case reports and
reviews suggest a high rate of response or complete remission of
lymphoproliferative disorders associated with interferon-based HCV Figure 42-7 Factors influencing the progression of HCV infection. (Redrawn
treatment.139,140 Renal disease associated with HCV is typically a from Poynard T, et al. Lancet 1997; 349:825–832.)
Following the development of cirrhosis patients may remain treatment approaches vary based on the presence of cirrhosis and these
asymptomatic without clinical signs of decompensated liver disease patients also require continued medical management of their liver
for years. The estimated rate of clinical decompensation once cirrhosis disease and screening for HCC. Multiple studies have demonstrated
is present is from 5 to 10% per year with a mortality rate of the dramatic benefits that curing HCV has in reducing liver-related
approximately 5% per year.157,158 Once signs of hepatic decompensa- and all-cause mortality, with the potential for histologic regression of
tion develop the mortality rate increases dramatically, with less than fibrosis/cirrhosis.178–183
50% survival at 5 years.159 The risk of HCC is also appreciable once Outside of these groups, HCV eradication offers benefits on
cirrhosis is present in HCV infection and is estimated at 1–4% per both individual and societal levels. Fatigue, though difficult to quan-
year.157,158 Current guidelines recommend screening for HCC by tify, is commonly associated with chronic HCV infection and may
imaging on a semi-annual basis.160 be debilitating for patients.184 Multiple studies demonstrate an
Given the large number of HCV infections that occurred from the improvement in fatigue following successful therapy with an increased
1960s to the 1980s the expected future burden of HCV infection both sense of well-being and improved work productivity following
medically and economically is expected to be significant, particularly HCV eradication.133,185–187 The advent of efficacious well-tolerated
over the next decade.161,162 End-stage liver disease due to HCV has been curative therapy for HCV also suggests utility as a powerful tool to
the leading indication for liver transplantation in the USA and Western prevent onward transmission in high-risk populations such as active
Europe for a number of years and the incidence of HCC, largely due injection drug users. This concept is supported by modeling studies
to HCV, is increasing dramatically in the USA.163,164 Groundbreaking but remains to be implemented on a wide-scale basis in patients.188,189
advancements in HCV treatment have already been realized and are From an economic standpoint, HCV therapy with new DAA-based
expected to continue to evolve. Despite these achievements the effec- regimens appears cost-effective considering traditionally accepted
tive delivery of curative HCV therapy to the large number of HCV thresholds.190
infected persons, many of whom remain undiagnosed, represents a
significant logistical and economic challenge.
Hepatitis D
OVERVIEW OF HEPATITIS C TREATMENT HDV was first thought to be a marker of HBV infection,191 but experi-
The arrival of direct-acting antivirals (DAAs) for HCV has revolution- ments in chimpanzees determined that it is a defective virus that
ized therapy of this chronic viral infection, with the vast majority of requires HBsAg to complete its viral life cycle.192 Roughly 15–20
patients having interferon-alpha-free options that offer cure rates in million individuals are infected with HDV.193 Modes of HDV trans-
excess of 90% with 12–24 weeks of therapy.165–170 Interferon-alpha- mission parallel those for HBV and include percutaneous/parenteral
based therapy, which had been the standard of care for over two exposure to HDV-infected blood or body fluids and close personal/
decades, is no longer a recommended therapy for chronic HCV infec- sexual contact,194 with intravenous drug use the most common risk
tion with the exception of a small, and likely temporary, niche in the factor in the Western world. Between 17 and 90% of HBsAg-positive
treatment of patients with cirrhosis and genotype 3 HCV infec- injection drug users also test positive for HDV.195
tion.171,172 Despite the excellent efficacy and tolerability of current DAA HDV can occur as either a coinfection or a superinfection. In
regimens, treatment approaches still need to be tailored based on coinfection, simultaneous infection leads to acute hepatitis B and D,
specific virus and patient characteristics; in particular the HCV geno- and rate of progression to chronic infection is the same as in HBV
type, stage of liver disease (cirrhosis vs noncirrhotic), and prior treat- monoinfection (<5%).195 Symptoms usually parallel those of acute
ment history are key factors in determining the optimal regimen, HBV, though disease is more severe, with a mortality rate of 2–20%.196
duration and whether the inclusion of ribavirin may be necessary to Superinfection occurs when a patient with chronic HBV is infected
optimize treatment responses.171 Current treatment regimens for with HDV, resulting in severe acute hepatitis. This can be mistaken for
genotype 1 HCV most often combine a potent, pangenotypic NS5B acute HBV infection in persons with unknown HBV status or exacer-
RNA polymerase nucleotide inhibitor (e.g. sofosbuvir) with either an bation of chronic HBV infection if HDV is not suspected and tested
NS3 protease inhibitor (e.g. simeprevir) or an NS5A inhibitor (e.g. for. Up to 80% of patients with superinfection progress to chronic
ledipasvir or daclatasvir).165–167,173 An alternative treatment regimen disease, and there is increased risk of fulminant liver failure or progres-
based on a combination of an NS3 protease inhibitor boosted with sion to cirrhosis.196
ritonavir (paritaprevir/ritonavir) plus an NS5A inhibitor (ombitasvir) The hepatitis D virion is made up of the HD-antigen and nucleic
with a NS5B non-nucleoside inhibitor (dasabuvir) is also highly effica- acid (RNA) enclosed within an HBsAg coat. It has a small genome that
cious and well tolerated.168,170,174 Therapies for genotype 1 are also codes only for the HD-Ag.197 HDV makes use of cellular RNA poly-
generally active against genotypes 4 and 6. The current cornerstone of merases and host cellular machinery for transcription, replication and
therapy for genotypes 2 and 3 is an NS5B nucleotide inhibitor (sofos- translation. HBsAg is necessary for translocation of HDAg. Without
buvir) given in combination with other agents such as ribavirin or a it, HDAg localizes to the nucleus.198 HDV replicates only in the hepa-
pangenotypic NS5A inhibitor (e.g. daclatasvir).169,173,175 Given the rapid tocytes and thus cellular damage only involves the liver.199
pace of drug development and the anticipated approvals of multiple Patients with fulminant hepatitis D infection classically have ele-
additional HCV treatment regimens over the coming years, consulta- vated ALT, a liver biopsy with aggressive hepatitis, positive anti-HDV
tion on treatment guidelines updated in near-real time is recom- IgM and HBsAg with low level or undetectable levels of HBV DNA.200
mended (www.hcvguidelines.org). HDV RNA is positive in nearly all cases, however this test is not rou-
[See Chapter 155 for a detailed discussion of currently available tinely available in the USA.200 However, surveys in the 1980s showed
HCV antivirals.] that HDV may cause no or insignificant disease, indicating a wide
All patients with chronic HCV infection should be considered for spectrum of disease.197 There are eight major genotypes of hepatitis D.
therapy and are likely to benefit from viral eradication. However, Genotype 1 is most common worldwide. Genotype 2 is most common
certain populations who will experience large benefits from HCV in Japan, Taiwan and Russia. Genotype 3 is prevalent in the Amazonia
treatment and/or are very likely to experience virus-related morbidity region. Genotype 4 occurs in Japan and Taiwan, and genotypes 5–8 in
or mortality in a short timeframe should be offered therapy as soon as Africa. While HDV genotype seems to dictate clinical presentation,
possible. These groups include patients with significant liver fibrosis HBV genotype does not seem to have a profound effect.197 Genotype
(e.g. F2-F4 on a METAVIR scale), mixed cryoglobulinemia with end 3 in South America causes severe hepatitis with high risk of fulminant
organ damage, and HIV-positive patients who are at risk for acceler- disease.196
ated liver disease progression and complications.158,159,171,176,177 Liver It is estimated that 5% (15 million) of HBV carriers worldwide are
disease staging remains critical, not only to identify patients that infected with HDV.201 Hepatitis D is present worldwide but rates are
should be offered therapy in a timely fashion, but due to the fact that not uniform.202 Rates of HDV have been on the decline in Italy, Spain,
Taiwan and Turkey,198 likely due to control of HBV in these areas via in prevalence is unclear; although a cohort effect with a true decrease
HBV vaccination campaigns and systematic blood screening. However, in prevalence has been postulated.228,229 In the most recent NHANES
HDV rates are still significant in Pakistan, India, Mongolia, Iran, survey, the only factor associated with HEV seropositivity in a multi-
Vietnam and other areas where HBV remains unchecked.197 The rate variate analysis was age, with an increasing prevalence with age.227 A
of HDV in Europe has remained in equilibrium, likely due to an influx similar HEV seroprevalence of 6.8% was found in a large study of
of immigrants from areas where HDV remains endemic, such as German blood donors;230 though other data from France and Germany
Eastern Europe, Africa, the Middle East, Turkey and the former Soviet have found seroprevalence rates in the range of 20–30% or higher,
Union.197 particularly in those with animal contact.225,231
Transmission mainly occurs parenterally by intravenous drug use Several cases of HEV infection transmitted via transfusion have
or exposure to blood or blood products. Sexual or vertical transmis- been reported in Japan, Germany and France.232–234 A large study of
sion is rare.196 blood donors in the USA noted seroprevalence rates of 18–20% for
HDV usually causes a severe form of hepatitis but asymptomatic anti-HEV IgG but found no samples positive for HEV RNA.235 A
cases occur as well. The incubation period is from 3 to 7 weeks. Initial second study looking at over 160 000 plasma samples found HEV RNA
symptoms include fatigue, lethargy, anorexia, nausea and elevated liver in 16 samples; all 16 positive samples were from Europe (~0.01%
enzymes. Fulminant hepatitis D results in hepatocyte necrosis and positivity rate) while none of 50 000 samples from the USA were posi-
death in 80% of patients unless liver transplantation is performed. tive.236 When pooled plasma samples have been assessed HEV RNA
Cirrhosis develops in 15% within 1–2 years and in 70–80% within positivity rates of 10% were found.237 Though not routine at this time,
5 years.196 some experts have called for HEV RNA screening of the blood supply
HDV treatment remains limited to interferon therapy since HDV in locations with known high rates of endemic HEV infection.234
has no enzymatic proteins to be targeted by antivirals. Antivirals such
as lamivudine and adefovir have been ineffective in controlling HDV CLINICAL MANIFESTATIONS
since in most HDV patients HBV is repressed.193,203 HDV depends on The vast majority of cases are self-limited and similar in character to
HBsAg and not on HBV replication and thus does not depend on HBV acute hepatitis A. In epidemic settings the highest rate of acute viral
DNA. Lamivudine can indirectly help control HDV infection since hepatitis symptoms occurs in teenagers and young adults with a male
lamivudine-induced mutations result in mutations that may inhibit preponderance. In contrast to hepatitis A, the intrafamilial transmis-
the secretion of HDV particles.197 Intriguing data with long-term teno- sion rate of HEV appears to be low.216,238 The overall case fatality rate
fovir treatment in HIV and HDV coinfected subjects suggest a poten- in symptomatic patients is low, from 0.5–2.0%, with the notable
tial therapeutic role; however additional data are needed.204 exception of pregnant women. The demographics of infection are
somewhat different in higher-income countries where autochthonous
cases occur related to zoonotic transmissions. In this setting HEV
Hepatitis E Virus infection is more frequently seen in middle-aged and elderly males and
INTRODUCTION is associated with a higher case fatality rate of around 5%; likely in
Our understanding of hepatitis E virus (HEV) epidemiology and large part due to pre-existing liver disease with superimposed acute
disease manifestations has evolved dramatically over the last decade. HEV infection.224,239,240
Initially discovered in 1983, HEV is now recognized as a leading cause The HEV incubation is from 2 to 6 weeks, with a high rate of
of water-borne acute viral hepatitis as well as being responsible for asymptomatic infection. Hepatitis E RNA is present in blood and shed
sporadic outbreaks associated with zoonotic transmission.205,206 While in high titers in stool prior to the onset of symptoms. The period of
indistinguishable from other causes of acute hepatitis on clinical viral shedding and detectability is short, on the order of 3 weeks, and
grounds alone, HEV is well known for causing severe disease and patients may have undetectable levels of virus on clinical presenta-
mortality in pregnant women.207–209 Chronic infection is seen rarely tion.206 Moderate elevations in hepatic transaminases are common and
and almost exclusively in those with immunosuppressive condi- generally coincide with the appearance of anti-HEV IgM antibodies
tions.210,211 The recent approval of an effective HEV vaccine in China, and clinical symptoms, if present (Figure 42-9). As would be expected,
along with improvement in water safety and sanitation, suggest that HEV RNA detection appears to be more sensitive than antigen or IgM
widespread control of HEV infection may be attainable in the not too detection for the diagnosis of acute HEV infection.241 A major limita-
distant future.212 tion in the diagnosis of acute HEV infection, particularly in the USA,
is a lack of standardized assays for HEV antibodies and detection of
HEV EPIDEMIOLOGY HEV RNA. In addition concerns exist regarding variability in com-
Hepatitis E, a member of the genus Hepevirus, is a non-enveloped mercial assays, particularly anti-HEV IgG.242 There are no FDA-
positive-strand RNA virus which is primarily transmitted via a fecal– approved HEV diagnostic tests; testing is available from the CDC
oral route. Worldwide, HEV is estimated to be the leading cause of Division of Viral Hepatitis (EPN6@CDC.gov or 404-639-0722).
acute viral hepatitis, with over 3 million clinical cases, resulting from Extraheptic manifestations of HEV infection include neurologic
more than 20 million infections, and 56 000 deaths.213 Across the globe, findings/syndromes such as encephalitis, polyradiculopathy, trans-
HEV is endemic in Asia (genotype 1), Africa (genotypes 1 and 2) and verse myelitis and Guillain–Barré syndrome as well as myositis and
Mexico (genotype 2).206,214 The majority of infections in these areas are glomerulonephritis.243–247 HEV RNA has been detected in the central
associated with epidemic outbreaks transmitted via contaminated nervous system in chronically infected patients with encephalitis.243 A
water.215–217 At one time, HEV genotype 1 was also considered endemic possible association with cryoglobulinemia and rheumatologic symp-
in China,218 however this no longer appears to be the case as most toms has been suggested as well.248
infections now are zoonotic in nature and associated with genotype Several groups are at risk for severe or unusual manifestations of
4.219,220 Sporadic human cases of genotype 3 (Europe, North America) HEV infection, including pregnant women and immunosuppressed
or genotype 4 (Japan, China) infection related to transmission patients. Early studies indicated a very high rate of fulminant hepatic
from animals (particularly pigs, boar and deer), via close contact failure (FHF) and mortality, 20–30% or higher, in pregnant women
or consumption of undercooked meat, are seen in the rest of the infected with HEV.207–209,249 In a cohort study, HEV-infected pregnant
world,206,221–225 and in people eating sausages made of pork liver, that women had a three times greater risk for FHF and a six times greater
being the first source of infection in France (Figure 42-8). risk for death than non-HEV-infected pregnant women.208 The risk
In the USA the HEV seroprevalence appears to be decreasing based appears highest in the second and third trimesters and is also associ-
on data from the National Health and Nutrition Evaluation Survey ated with higher rates of preterm delivery and fetal loss.207,208 To date
(NHANES) going from 21% in NHANES III (1988–94) to 6% in the increased mortality in pregnant women has been recognized only
NHANES 2009–2010.226–228 The exact reason for the observed decrease with genotype 1 HEV infection.249
Worldwide distribution of clinical cases of HEV infection
Genotype 1 and 2 Genotype 3 Genotype 3 Genotype 4

• Endemic • Sporadic • Hyperendemic • Sporadic
• Water-borne • Zoonotic area • Zoonotic
Figure 42-8 Worldwide distribution of clinical cases of HEV infection. Note that in several countries, including in South America, there have been occasional reports
of HEV3 infection. Countries left blank are those with insufficient data. (Reprinted from Kamar N, et al. Lancet 2012; 379(9835):2477–2488.)
Chronic HEV infection is almost exclusively described in an immu-

HEV infection, virus detection at nosuppressed population; such as those with HIV/AIDS, solid organ
different sites and serologic response transplantation, or undergoing chemotherapy for hematologic malig-
nancies.210,250,251 In transplant patients the rate of development of
HEV RNA in blood chronic HEV infection appears to be around 60% based on persistent
Serum transaminase detection of HEV RNA in blood.210,211,252 While an exact time point to
HEV RNA in feces HEV IgG
HEV IgM determine chronic HEV infection has not been established, detection
Jaundice of HEV RNA for more than 3 months identifies most patients with
chronic infection.253 Symptoms of acute viral hepatitis are generally
absent, with most patients having mild nonspecific symptoms or being
asymptomatic. In many cases the only clue to the diagnosis is persis-
tent elevations in hepatic transaminases. Risk factors for the develop-
ment of chronic HEV infection include the use of tacrolimus and a
CD4 count <200 in those with HIV.211,251,252,254 Thus far all cases of
chronic infection described have been associated with genotype 3
HEV. Hepatic fibrosis with rapid progression to cirrhosis has been
noted in cases of chronic HEV.211,252,254 Treatment relies on reducing,
particularly, tacrolimus, or reversing immunosuppression (e.g. anti-
retroviral therapy) and may result in clearance in up to 30% of
patients.252 For those who do not clear with these interventions, a
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 3-month course of ribavirin appears to be the preferred therapy,
Number of weeks post infection
though optimal dose and duration have not been definitively
determined.253,254
Figure 42-9 HEV infection, virus detection at different sites and serologic
response. (Reprinted from Dalton HR, et al. Lancet 2008; 8(11):698–709.) HEV PREVENTION
Improved sanitation and water treatment are paramount for decreas-
ing HEV transmission in endemic areas where disease epidemics are
primarily associated with water-borne transmission. The other major
approach to prevention of HEV disease is the development of
an effective vaccine. Importantly, despite the existence of four HEV all HEV genotypes infecting humans, though this has not been specifi-
genotypes that cause human infection, there is only one serotype offer- cally studied as the areas where the vaccines have been studied gener-
ing promise for a single effective vaccine. Two candidate vaccines based ally experience infections only with genotypes 1 and 4. The HEV 239
on the ORF2 protein have been evaluated in human trials and appear vaccine was approved in China in 2012.
to be both well tolerated and highly efficacious, with protection rates
from 95 to 100%.255,256 Both vaccines should offer protection against References available online at expertconsult.com.
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PRACTICE The Gastrointestinal System
POINT
11 Travelers’ Diarrhea

PHILIPPE GAUTRET | PHILIPPE PAROLA
Introduction for chronic enteric infection and underlying organic gastrointestinal

disease unmasked by an episode of TD is negative. IBS should be a
Travelers’ diarrhea (TD) is the principal cause of morbidity in travelers diagnosis of exclusion in a returning traveler since it is based on clinical
returning from low- and middle-income countries, affecting 20–60% criteria without the support of any specific laboratory or imaging tests.
of travelers to higher-risk areas. TD is acquired through the consump-
tion of contaminated food or water. Poor hygiene practice in local
restaurants is likely the largest contributor to the development of TD.
Epidemiology and Risk Factors
Episodes of TD are mostly benign. Nevertheless, symptoms can be Destination is the single most important risk factor for developing
severe enough to cause substantial disruption to travel itineraries travelers’ diarrhea. A recent GeoSentinel survey indicates that high-risk
(40%) or confinement to bed (20%). Food and beverage selection,
which has long been thought to prevent TD, have actually a low impact
on the occurrence of the disease. TABLE Common Pathogens Isolated in Travelers’
PP11-1 Diarrhea by Conventional Methods
Clinical Presentation, Etiology
TD is usually defined as the passage of at least three unformed stools Pathogen % Isolation
within a 24 hour period, in association with at least one symptom of BACTERIA
gastrointestinal disease including abdominal pain (80%), nausea and
Enterotoxigenic Escherichia coli 20–50
vomiting (20%), fever (10–25%), or cramps, tenesmus, fecal urgency,
or bloody or mucoid stools (5–10%). It typically occurs in the first Enteroaggregative E. coli ?
week of arrival; the incubation time depends on the pathogens involved Enteroinvasive E. coli 5–15
and ranges from 6 to 48 hours when caused by bacteria or viruses to
1–2 weeks when caused by parasites. The episode is often self-limiting, Campylobacter jejuni 5–30
lasting 3–4 days. Severe diarrhea with dehydration can occur, although Salmonella spp. 5–25
rarely.
Shigella spp. 5–15
The etiology of TD is wide-ranging (Table PP11-1). Bacteria,
viruses and parasites may be involved. Bacteria account for 50–80% of Vibrio spp. Rare
pathogens isolated by conventional microbiological methods in
Aeromonas spp. Rare
patients suffering TD, with enterotoxigenic Escherichia coli (ETEC)
being the more frequent, followed by Campylobacter jejuni, Salmonella Plesiomonas shigelloides Rare
spp. and Shigella spp. Other bacteria are reported in Table PP11-1. Yersinia enterocolitica Rare
Viruses (essentially norovirus and rotavirus) are less commonly iso-
lated (5–25%). Parasites (essentially protozoa) are rarely implicated in Bacteroides fragilis Rare
TD (<10%). In 10–50% of the cases no pathogen is isolated by con- VIRUSES
ventional methods, suggesting that new potential agents remain to be
Norovirus 0–10
identified. However, recently available multiplex polymerase chain
reaction (PCR) tools for the detection of pathogens potentially respon- Rotavirus 0–10
sible for TD show that multiple infections are common and that some
PROTOZOA
of these pathogens are also isolated from asymptomatic travelers.
Giardia lamblia 0–10
Chronic Complications Entamoeba histolytica 0–10
Patients with TD may continue to complain of an array of persistent Cryptosporidium parvum Rare
or intermittent gastrointestinal symptoms, including diarrhea, consti-
pation, abdominal pain or discomfort, or bloating. It may be the result Cyclospora cayetanensis Rare
of a persistent infection by protozoan parasites, notably Giardia which Microsporidia spp. Rare
is by far the most common pathogen encountered in this context. The
Cystoisospora belli Rare
diagnosis can be made by stool microscopy, although even repeated
stool samples may remain negative. Empiric therapy is a reasonable
option. Other parasites (Table PP11-1) may also cause persistent diar-
rhea. Clostridium difficile should be searched for in the returned trav-
eler with persistent diarrhea, notably following use of antibiotics for BOX PP11-1 ROME III CRITERIA FOR
travelers’ diarrhea or malaria chemoprophylaxis. Campylobacter, Sal- POSTINFECTIOUS IRRITABLE BOWEL
monella and Shigella can cause symptoms and continuing pathology SYNDROME
for weeks and months until they are treated with an appropriate anti- At least 3 months of recurrent abdominal pain or discomfort, with onset at
biotic. Stool cultures are indicated for the microbiological diagnosis of least 6 months previously, associated with two or more of the following
bacterial infections in this context. features:
• Improvement with defecation
Between 5% and 10% of travelers with TD will later fulfill the Rome • Onset associated with a change in frequency of stool
II criteria for irritable bowel syndrome (IBS) that are indicated in Box • Onset associated with a change in form (appearance) of stool
PP11-1. The diagnosis of postinfectious IBS supposes that the workup
375
regions are North Africa, followed by South Central Asia and the prevalence of fluoroquinolone-resistant bacterial strains in this area,
Middle East. Small children and young adults <30 years are at higher notably Campylobacter, Shigella and Salmonella.
risk for TD compared to older travelers. Consumption of raw seafood Dietary restrictions afford no clinical benefit compared with an
in many regions, particularly in South East Asia, is associated with risk unrestricted diet. Maintaining fluid intake during episodes of diarrhea
of enteric infection by bacteria. The risk posed by raw meat has been is recommended, notably in children.
poorly studied, but it is likely to be unsafe for travelers to consume.
Moist foods as well as cold and raw items, remaining for periods of Prevention
time at room temperature before consumption, are most likely to be The majority of recent retrospective and uncontrolled studies failed to
unsafe. Tap water should be considered risky for drinking even in show that caution in food and beverage selection would translate into
hotels claiming adequate filtration and chlorination. Individuals with reduced rates of TD. Travel medicine experts feel that there is no clear
achlorhydria and those on proton pump inhibitors or H2 blockers have information to indicate whether being careful about what is consumed
been shown to be at increased risk of TD. will or will not influence rates of diarrheal illness in travelers. Further-
more, travelers may not always be able to adhere to the advice and
Management many of the factors that ensure food safety, such as restaurant hygiene,
Given the short incubation time and short duration of symptoms of are out of the traveler’s control.
TD, most travelers will be symptomatic during travel, which implies Although it has proven effective, the widespread use of antibiopro-
that self-treatment should be prescribed to travelers before their depar- phylaxis (fluoroquinolone) against TD is not recommended because
ture and transported with them. Travel medicine experts in the USA of potential drug adverse events, concern that widespread use might
and many in Europe feel that an antimicrobial agent that cures while facilitate development of resistance among extraintestinal bacterial
shortening the duration of illness represents the mainstay of therapy. pathogens and inability to define the groups for which chemoprophy-
Drugs used for symptomatic relief, including bismuth subsalicylate laxis should be recommended. The recent availability of poorly
(BSS) and loperamide, decrease the number of unformed stools passed absorbed rifaximin has renewed interest in chemoprophylaxis.
during a bout of TD but may not speed up illness recovery. Racecado- Although promising, the drug is not licensed and available in many
tril has not been evaluated in TD, although routinely used by European countries. BSS is considered safe by many experts, but is not available
travelers. Three antibiotics can be used, including fluoroquinolones, or used in Europe, Australia, or New Zealand because of concern about
rifaximin, or azithromycin. These antibiotics have been administered bismuth absorption which can cause rare but serious toxic adverse
for 3 days or for a single dose with no apparent clinically significant events including encephalopathy. Prophylactic antibiotics may be con-
difference in efficacy between the two regimens in shortening the dura- sidered for short-term travelers who are high-risk hosts (such as those
tion of TD. Usual regimens are: (1) azithromycin in a single 1000 mg who are immunosuppressed) or who are taking critical trips during
dose; (2) fluoroquinolone (ciprofloxacin 750 mg, levofloxacin 500 mg, which even a short bout of diarrhea could affect the purpose of travel.
or norfloxacin 400 mg) given once; with an incomplete response to Today, the single available immunoprophylactic vaccine is the oral
single dose, the same drug and same dosage can be repeated the next cholera vaccine, Dukoral. It has been demonstrated to provide short-
two mornings (3 days therapy); or (3) rifaximin 200 mg three times a term partial protection against ETEC diarrhea and 85% protection
day. Azithromycin is preferred for treatment when diarrhea is compli- against cholera. Research to evaluate the efficacy of immunoprophy-
cated by dysentery (passage of grossly bloody stools) or by high fever laxis is required before any recommendation can be made.
and for use in children with TD (5 mg/kg/d for 3 days) and, in the view
of some authors, when traveling to South East Asia because of the Further reading available online at expertconsult.com.
Practice Point 11 Travelers’ Diarrhea 376.e1
FURTHER READING
Connor B.A.: Chronic diarrhea in travelers. Curr Infect Dis DuPont H.L., Ericsson C.D., Farthing M.J., et al.: Expert Mues K.E., Esposito D.H., Han P.V., et al.: Analyzing
Rep 2013; 15(3):203-210. review of the evidence base for self-therapy of travelers’ GeoSentinel surveillance data: a comparison of methods
Connor B.A., Riddle M.S.: Post-infectious sequelae of trav- diarrhea. J Travel Med 2009; 16(3):161-171. to explore acute gastrointestinal illness among interna-
elers’ diarrhea. J Travel Med 2013; 20(5):303-312. Freedman D.O., Weld L.H., Kozarsky P.E., et al.: GeoSen- tional travelers. Clin Infect Dis 2014; 58(4):546-554.
Diemert D.J.: Prevention and self-treatment of traveler’s tinel Surveillance Network. Spectrum of disease and rela-
diarrhea. Clin Microbiol Rev 2006; 19(3):583-594. tion to place of exposure among ill returned travelers. N
DuPont H.L., Ericsson C.D., Farthing M.J., et al.: Expert Engl J Med 2006; 354(2):119-130.
review of the evidence base for prevention of travelers’
diarrhea. J Travel Med 2009; 16(3):149-160.
POINT
12 Febrile Transaminitis of Viral Etiology

STEVEN J. LAWRENCE
Introduction are less common with CMV. The presence of heterophile antibodies
suggests EBV infection, while a maculopapular rash should raise sus-
Fever associated with elevations in the transaminases (aspartate ami- picion for acute HIV. Because of the implications of delayed diagnosis
notransferase and alanine aminotransferase) is a common presenta- for the patient and public health, it is advisable to test for HIV in
tion of many viral infections, ranging in severity from mild and patients presenting with a mononucleosis syndrome unless EBV or
self-limited to fulminant and life-threatening (Table PP12-1). While CMV has been specifically identified.
the majority fall into the first category, it is important to identify those While EBV-specific serologic testing can confirm the diagnosis of
patients who may need further evaluation or urgent empiric therapy. EBV mononucleosis, the presence of pharyngitis, lymphadenopathy,
The patient’s immune status and geographic exposures help to narrow splenomegaly and atypical lymphocytosis is often enough to make a
the differential diagnosis (Figure PP12-1). The diagnostic approach for presumptive diagnosis. In the absence of immune compromise, or
patients presenting with a fever and elevated transaminases should severe liver disease, it is rarely necessary to confirm if a specific patho-
generally begin by exclusion of the primary hepatitis viruses. The scope gen (other than HIV) is responsible as management would not gener-
of this chapter is to describe an approach to patients with febrile ally be altered. In cases of severe disease, liver biopsy may be useful to
transaminitis caused by viral infections other than the primary viral ascertain a specific diagnosis. Management of EBV mononucleosis is
hepatitides, which are covered elsewhere (see Chapter 42). Non-viral supportive, including avoidance of abdominal trauma that could lead
infections are occasional causes of acute (e.g. rickettsial infections, to splenic rupture when splenomegaly is prominent. Ampicillin and
leptospirosis, syphilis, toxoplasmosis) or chronic (e.g. brucellosis, dis- amoxicillin should be avoided in patients with mononucleosis and
seminated mycobacterial or fungal infections) fever with elevated transaminitis until EBV infection testing is negative. CMV mononu-
transaminases, but are not considered here. cleosis in immunocompetent patients is also self-limited and rarely
requires specific antiviral therapy.
Infectious Mononucleosis Syndrome
– a Common but Usually Mild Viral Febrile Transaminitis in
Febrile Transaminitis Immunocompromised Patients
Most viral infections associated with fever and elevated transaminases While many of the same acute viral illnesses causing fever and trans
occur in immunocompetent individuals who have acute to subacute aminitis in immunocompetent patients can also affect immunocom-
infectious mononucleosis, with Epstein–Barr virus (EBV) being the promised patients, reactivation of latent CMV is common in the latter.
most common etiology. In acute EBV infection, transaminases are only In solid organ and hematopoietic stem cell transplant recipients, CMV
mildly elevated (typically 2–3 times the upper limit of normal), and infection may initially manifest as fever and elevated transaminases,
there are few if any signs or symptoms of hepatic dysfunction. Jaundice with a subsequent risk of developing end-organ disease if unrecog-
is uncommon. Abdominal tenderness, usually mild-to-moderate in nized and left untreated. Significant liver disease with CMV is rare.
severity, may be present if there is concomitant hepatosplenomegaly. Conversely, severe liver disease can be seen in primary (in children) or
Less common causes of mononucleosis include primary cytomegalo- reactivation (in adults) adenovirus infection in highly immunocom-
virus (CMV) and human herpesvirus 6 (HHV-6) infection in immu- promised patients, usually in the setting of dissemination and signifi-
nocompetent patients and primary human immunodeficiency virus cant multiorgan failure.
(HIV) type 1 infection. All may present with typical mononucleosis- Herpes simplex virus (HSV) merits special attention as a rare but
like features of fever, fatigue, pharyngitis and lymphadenopathy with serious cause of hepatic necrosis and fulminant liver failure marked
elevated transaminases, although pharyngitis and lymphadenopathy by strikingly high transaminase levels, initially without cholestatic
TABLE
PP12-1 Presentations Associated with Selected Viral Infections* Causing Fever and Transaminitis
Transaminase Elevation Mononucleosis Fulminant Hepatic Immunocompromised
Virus (Fold Above ULN) Icteric Disease Syndrome Failure Patients
EBV <3 Uncommon +++ − No
CMV (acute) <5 − ++ − No
CMV (reactivation) <5 − − − Yes
HIV (acute) <5 − + − No
HSV (acute or reactivation) >20+ Late − ++ Yes (including pregnancy)
Adenovirus (reactivation) >10 Late − + Yes
YFV >10–20 +++ − + No

VHFs >5–20 Uncommon − − No
*Excluding primary hepatitis viruses.

CMV, cytomegalovirus; EBV, Epstein–Barr virus; HIV, human immunodeficiency virus 1; HSV, herpes simplex virus 1 or 2; ULN, upper limits of normal; VHF, viral
hemorrhagic fever; YFV, yellow fever virus.
377
Approach to the patient with fever, elevated transaminases, and negative testing for primary viral hepatitis
Severe illness ?
Yes No
Residence/travel in
Immunocompromised ?
VHF endemic areas ?*
Yes No Yes No
Consider VHFs Immunocompromised ? Consider CMV, adenovirus Mononucleosis, consider

Infection control precautions HIV testing
CMV = Cytomegalovirus
HSV = Herpes simplex virus 1 or 2
HIV = Human immunodeficiency virus 1
Yes No VHF = Viral hemorrhagic fever
*Endemic areas Yellow fever = Equatorial Africa and Central/South America
Ebola/Marburg = Central and West Africa
Lassa fever = West Africa
Consider HSV, adenovirus Empiric treatment for HSV
New World arenaviruses = South America
Empiric treatment for HSV Consider liver biopsy Rift Valley fever = Sub-Saharan Africa, Arabian Peninsula
Crimean-Congo hemorrhagic fever = Africa, East Europe,
Middle East, West Asia
Figure PP12-1 Approach to the patient with fever, elevated transaminases and negative testing for primary viral hepatitis.
changes. Most patients with disseminated disease involving the liver

are immunocompromised or in late stages of pregnancy, have primary TABLE Features Differentiating Viral Etiologies of
PP12-2 Febrile Transaminitis
infection and often do not manifest with discernible skin lesions.
Because the diagnosis may be difficult to make without liver biopsy
Characteristic Epidemiologic, Clinical and
and may not be readily obvious, and because of a very high associated Virus Laboratory Features
mortality, a low index of suspicion is necessary to make a presumptive
diagnosis and to promptly start empiric anti-HSV therapy. EBV Pharyngitis, cervical lymphadenopathy,
splenomegaly, atypical lymphocytosis, heterophile
antibodies
Viral Hemorrhagic Fevers – Severe
CMV (acute) Pharyngitis, atypical lymphocytosis, lack of
Infections Usually with heterophile antibodies
Hepatic Involvement CMV (reactivation) (In immunocompromised patients) colitis, retinitis,
Nearly any severe infection causing hypoxemia or hypotension may be pneumonitis
associated with an ischemic transaminitis as a manifestation of multi- HIV (acute) Generalized lymphadenopathy, maculopapular rash,
organ failure. However, there are other serious viral infections where pharyngitis
hepatitis plays a prominent role in pathogenesis, including yellow fever HSV (acute or Herpetiform skin, oral, or genital lesions (not always
(YF) and many of the viral hemorrhagic fevers (VHF). Most of these reactivation) present), pregnancy, immunocompromised
diseases, with the exception of YF and Lassa fever, are rare, and all have
Adenovirus (In immunocompromised adults) pneumonia, colitis
a relatively restricted geographic range of endemicity that allows for (reactivation)
exclusion of infection for those who do not live in, or have not traveled
to, the respective regions (Table PP12-2) (see also Chapter 132). All YFV Jaundice, hemorrhagic diathesis, residing in or
visiting an endemic area
can cause severe illness that may include hemorrhagic sequelae. Liver
involvement is common though severity can be variable. Jaundice is VHFs Hemorrhagic diathesis, residing in or visiting an
usually only present in YF and Rift Valley fever. Because some of the endemic area
VHFs are transmissible from person-to-person, patients presenting CMV, cytomegalovirus; EBV, Epstein–Barr virus; HIV, human immunodeficiency
with a severe febrile illness with hepatic involvement in whom a VHF virus 1; HSV, herpes simplex virus 1 or 2; VHF, viral hemorrhagic fever; YFV,
cannot be geographically excluded should be promptly isolated until yellow fever virus.
Practice Point 12 Febrile Transaminitis of Viral Etiology 379
a diagnosis is confirmed. Treatment is primarily supportive for all often caused by EBV. HSV and VHFs should be considered for patients
VHFs, though ribavirin is beneficial in Crimean-Congo hemorrhagic presenting with severe illness, depending on their immune status and
fever and has been attempted for isolated cases of several others. geographic exposures.
Summary Further reading available online at expertconsult.com.

Fever with elevated transaminases is a presentation of many viral ill-
nesses. Mononucleosis is common, generally self-limited and most
Practice Point 12 Febrile Transaminitis of Viral Etiology 379.e1
FURTHER READING
Borio L., Inglesby T., Peters C.J., et al.: Hemorrhagic fever diagnosis with a poor prognosis. Liver Transpl 2005; Kaufman B., Gandhi S.A., Louie E., et al.: HSV hepatitis:
viruses as biological weapons: medical and public health 11(12):1550-1555. case report and review. Clin Infect Dis 1997; 24:334-338.
management. JAMA 2002; 287(18):2391-2405. Kahn J.O., Walker B.D.: Acute human immunodeficiency Ronan B.A., Agrwal N., Carey E.J., et al.: Fulminant
Ichai P., Roque Afonso A.M., Sebagh M., et al.: Herpes virus type 1 infection. N Engl J Med 1998; 339: hepatitis due to human adenovirus. Infection 2014;
simplex virus-associated acute liver failure: a difficult 33-39. 42(1):105-111.
POINT
13 Management of CAPD Peritonitis

CARLOS A.Q. SANTOS
Introduction Subsequent Management

Continuous ambulatory peritoneal dialysis (CAPD) is a form of renal Within 48 hours of initiating antibiotic therapy, most patients will have
replacement therapy that can be self-administered at home. It involves shown considerable clinical improvement. Once the causative micro-
multiple exchanges during the day followed by an overnight dwell. organism is identified and antibiotic susceptibilities are known, treat-
Peritonitis is an important complication of CAPD and can result in ment should be changed to narrow-spectrum agents as appropriate.
peritoneal membrane failure and switch to hemodialysis. Moreover, Refractory peritonitis, defined as failure for the effluent to clear despite
severe peritonitis can directly contribute to death. Timely recognition, 5 days of effective antibiotic therapy, warrants peritoneal dialysis cath-
diagnosis and management of CAPD peritonitis are important, with eter removal. Other indications for catheter removal include relapsing
the goal of rapid resolution of inflammation and preservation of peri- peritonitis, defined as an episode that occurs within 4 weeks of comple-
toneal membrane function. tion of therapy of a prior episode with the same organism, refractory
exit-site and tunnel infection and fungal peritonitis. At least 2 weeks
Clinical Manifestations and Diagnosis of effective antibiotic therapy must be administered before catheter
Patients with peritonitis generally present with abdominal pain and replacement is done, which necessitates the provision of interim
cloudy effluent. However, peritonitis must be presumed in any patient hemodialysis.
presenting with cloudy effluent, and peritonitis should be considered STAPHYLOCOCCUS
in any patient presenting with abdominal pain. Abdominal pain is
typically generalized and associated with rebound tenderness. The Staphylococcus aureus causes severe peritonitis and is often due to
CAPD catheter exit site and tunnel must be inspected for redness and catheter infection. Staph. aureus peritonitis with concurrent exit-site
exudate. Differential diagnoses include pancreatitis, cholecystitis, or tunnel infection is unlikely to respond to antibiotic therapy alone
enteritis, peptic ulcer disease and acute intestinal perforation. and generally warrants catheter removal. Effective antibiotic therapy
The effluent should be sent for cell count with differential, Gram
stain and culture. An effluent white blood cell (WBC) count >0.1 x109/L
(after a dwell time of ≥2 hours), with ≥50% neutrophils indicates
inflammation. Shorter dwell times can result in effluent WBC counts TABLE Intraperitoneal Antibiotics for
PP13-1 CAPD Peritonitis
≤0.1 x109/L; if ≥50% of WBCs are neutrophils, inflammation is likely
present. Two blood culture bottles should be inoculated with 5–10 mL
Continuous
of effluent at the bedside. To improve microbiologic yield, sediment (mg/L; all exchanges)
from 50 mL of effluent after centrifugation can be inoculated onto Intermittent
both solid culture and standard blood culture media. Blood cultures (per exchange, Loading Maintenance
Antibiotic once daily) Dose Dose
from two sites should be taken if sepsis is evident. Identifying the
causative micro-organism/s and antibiotic susceptibility will guide Aminoglycosides
definitive antibiotic therapy, and can indicate the source of the
Amikacin 2 mg/kg 25 12
infection.
Gentamicin or 0.6 mg/kg 8 4
Empiric Antibiotic Selection tobramycin
Empiric antibiotics should cover both gram-positive and gram- Cephalosporins

negative bacteria and must be administered urgently. Intraperitoneal Cefazolin 15 mg/kg 500 125
administration of antibiotics (allowed to dwell for at least 6 hours) is
Cefepime 1000 mg 500 125
superior to intravenous or oral routes when treating peritonitis, given
that markedly higher antibiotic concentrations can be achieved and Ceftazidime 1000–1500 mg 500 125
venipuncture will be avoided (Table PP13-1). Center- and patient-
Penicillins
specific patterns of antibiotic susceptibility should be used to guide the
choice of empiric antibiotics. Amoxicillin No data 250–500 50
For gram-positive coverage, either a first-generation cephalo Ampicillin No data None 125
sporin or vancomycin can be used. Vancomycin should be considered
for patients with a history of methicillin-resistant Staphylococcus Oxacillin or nafcillin No data None 125
colonization/infection, sepsis, or severe allergic reaction to β-lactam Penicillin G No data 50 000 units 25 000 units
antibiotics. Vancomycin should also be considered in centers with a
Quinolones
high prevalence of methicillin-resistant Staphylococcus aureus. For
gram-negative coverage, either a third- or fourth-generation cephalo- Ciprofloxacin No data 50 25
sporin, aztreonam or an aminoglycoside can be used. Notably, amino-
Others
glycosides and penicillins are incompatible when administered in the
same exchange, and vancomycin and ceftazidime should be mixed in Aztreonam No data 1000 250
>1 L of dialysis solution, and not in the same syringe or an empty Daptomycin No data 100 20
dialysis solution bag. Vancomycin and aminoglycosides can be
Vancomycin 15–30 mg/kg 1000 25
absorbed systemically and serum drug levels should be checked to every 5–7 days
decrease the risk of toxicity.
380
Practice Point 13 Management of CAPD Peritonitis 381
should be administered for at least 3 weeks. Coagulase-negative or colitis. Antibiotics must be adjusted to the sensitivity pattern, and
Staphylococcal peritonitis is typically mild and responds readily to anti- a 2–3 week duration of therapy should be prescribed.
biotic therapy. However, biofilm formation can lead to relapsing peri-
tonitis thereby necessitating catheter removal. Two weeks of antibiotic POLYMICROBIAL PERITONITIS WITH
therapy is generally sufficient. ENTERIC BACTERIA
Polymicrobial peritonitis with multiple enteric organisms signifies the
STREPTOCOCCUS AND ENTEROCOCCUS presence of intra-abdominal pathology such as diverticulitis, cholecys-
Streptococcal peritonitis is often mild whereas enterococcal peritonitis titis, ischemic colitis or appendicitis, among others. Evaluation for
can be more severe. Enterococcal peritonitis is best treated with ampi- acute abdomen must be done, and computed tomography (CT)
cillin if the organism is susceptible. Vancomycin can be used in imaging of the abdomen should be performed. Early surgical interven-
instances of ampicillin resistance. Vancomycin-resistant Enterococcus tion can be life-saving. Treatment must be tailored to the causative
(VRE) is an important emerging pathogen. Ampicillin is the antibiotic organisms and any identified intra-abdominal pathology.
of choice if the VRE is susceptible; otherwise, daptomycin can be used.
Two weeks of antibiotic therapy is sufficient for streptococcal perito- CULTURE-NEGATIVE PERITONITIS
nitis, whereas 3 weeks of antibiotic therapy is recommended for Cultures may be negative in up to 20% of cases, and can be due to
enterococcal peritonitis. recent or concurrent antibiotic use or technical reasons. If there is no
growth by 3 days, then repeat cell count with differential should be
PSEUDOMONAS AERUGINOSA obtained. If the patient is clinically improved and the repeat cell count
Pseudomonas aeruginosa peritonitis is often severe and typically due to indicates that the infection is resolving, then initial empiric treatment
catheter infection, which necessitates catheter removal. Two antibiotics should be continued for 14 days. If the repeat cell count indicates that
should be used to treat P. aeruginosa peritonitis. Intraperitoneal the infection is not resolving, then special cultures for mycobacteria
cefepime, ceftazidime, piperacillin or aminoglycosides can be given and fungi should be done. While awaiting these results, empiric anti-
along with oral ciprofloxacin (if the micro-organism is susceptible). biotics should be continued for 2 weeks if the patient is clinically
At least 3 weeks of treatment is needed. improved. If the patient is not clinically improved after 5 days of treat-
ment, then the catheter should be removed and empiric antibiotics
GRAM-NEGATIVE ENTERIC BACTERIA should be continued for another 2 weeks. Special culture results must
Gram-negative enteric bacteria, such as Escherichia coli, Proteus and be monitored.
Klebsiella can cause monomicrobial peritonitis and can be due to touch
contamination, exit-site infection, transmural migration, diverticulitis Further reading available online at expertconsult.com.
Practice Point 13 Management of CAPD Peritonitis 381.e1
FURTHER READING
Chow K.M., Szeto C.C., Cheung K.K., et al.: Predictive value Govindarajulu S., Hawley C.M., McDonald S.P., et al.: Li P.K., Szeto C.C., Piraino B., et al.: Peritoneal dialysis-
of dialysate cell counts in peritonitis complicating peri- Staphylococcus aureus peritonitis in Australian peritoneal related infections recommendations: 2010 update. Perit
toneal dialysis. Clin J Am Soc Nephrol 2006; 1(4):768-773. dialysis patients: predictors, treatment, and outcomes in Dial Int 2010; 30(4):393-423.
Edey M., Hawley C.M., McDonald S.P., et al.: Enterococcal 503 cases. Perit Dial Int 2010; 30(3):311-319. Siva B., Hawley C.M., McDonald S.P., et al.: Pseudomonas
peritonitis in Australian peritoneal dialysis patients: pre- Johnson D.W., Dent H., Hawley C.M., et al.: Associations of peritonitis in Australia: predictors, treatment, and out-
dictors, treatment and outcomes in 116 cases. Nephrol dialysis modality and infectious mortality in incident comes in 191 cases. Clin J Am Soc Nephrol 2009; 4(5):957-
Dial Transplant 2010; 25(4):1272-1278. dialysis patients in Australia and New Zealand. Am J 964.
Fahim M., Hawley C.M., McDonald S.P., et al.: Culture- Kidney Dis 2009; 53(2):290-297. Szeto C.C., Chow V.C., Chow K.M., et al.: Enterobacteria-
negative peritonitis in peritoneal dialysis patients in Aus- Kern E.O., Newman L.N., Cacho C.P., et al.: Abdominal ceae peritonitis complicating peritoneal dialysis: a review
tralia: predictors, treatment, and outcomes in 435 cases. catastrophe revisited: the risk and outcome of enteric of 210 consecutive cases. Kidney Int 2006; 69(7):1245-
Am J Kidney Dis 2010; 55(4):690-697. peritoneal contamination. Perit Dial Int 2002; 22(3): 1252.
Gould I.M., Casewell M.W.: The laboratory diagnosis of 323-334.
peritonitis during continuous ambulatory peritoneal
dialysis. J Hosp Infect 1986; 7(2):155-160.
SECTION 2 Syndromes by Body System: Bone and Joints
43
Infective and Reactive Arthritis
ARJUN GUPTA | ELIE F. BERBARI | JAMES M. STECKELBERG |
DOUGLAS R. OSMON
KEY CONCEPTS incidence rate of 2.8 per 100 000 person years, although incidence has
decreased in recent decades.5
• The incidence of infective arthritis, especially iatrogenic cases
is increasing. Risk Factors
• Underlying joint disease is the most important risk factor. Rheumatoid arthritis, diabetes mellitus, malignancy, old age, use of
• Staphylococcus aureus is the most common identified organ- systemic steroids, HIV infection, hemodialysis and prior joint surgery
ism in infective arthritis. are risk factors for bacterial arthritis.6,7 Abnormal joint architecture is
the most important risk. Biological agents that target tumor necrosis
• Synovial fluid analysis for cell count and cultures establish the factor for the treatment of rheumatoid arthritis are associated with
diagnosis of infective arthritis. a doubling of the risk of septic arthritis over traditional disease-
• The presence of crystals in the synovial fluid does not exclude modifying antirheumatic drugs (DMARDs) and can also cause severe
concomitant bacterial arthritis, as crystal arthropathy and infec- polyarticular infections.8 Behaviors that increase the risk of bactere-
tion may co-occur in the same joint. mia, such as injection drug use, also predispose the joint to infection.
Iatrogenic infection is an increasing problem1 with a recent report of
• Patients with culture-negative infective arthritis for whom there
exists a high degree of suspicion for bacterial arthritis should a multistate outbreak of fungal arthritis caused by intra-articular injec-
be treated for bacterial arthritis. tions of contaminated methylprednisolone9 and several cases of infec-
tive arthritis due to Clostridium spp. arthritis reported after tissue
• 16S rRNA gene polymerase chain reaction (PCR) has emerged allograft reconstruction surgery due to aseptic processing of donor
as a useful tool for identification of bacterial pathogens in tissue.10
culture-negative arthritis, particularly in patients pretreated
Disseminated gonococcal infection is more common among sexu-
with antibiotics.
ally active, menstruating women.5 The male : female ratio is approxi-
• Management consists of prompt drainage of the joint and mately 1 : 4. Often the microbiologic etiology of infective arthritis can
prolonged antimicrobial therapy. be predicted based on the specific risk factor predisposing to infection
(Table 43-1).11
Pathogenesis
Nongonococcal bacterial arthritis most often results from hematoge-
Introduction nous seeding of the joint space. Synovial tissue has a rich vascular
Infective arthritis is an inflammation of the joint space caused by supply but no basement membrane – factors that favor ingress of
microbial invasion. Hematogenous seeding of the joint is the most blood-borne organisms.12 The bacteremia can be primary, or second-
common mechanism of infection in native joints. The incidence of ary to an infectious focus elsewhere in the body (e.g. pneumonia,
infective arthritis in adults caused by bacteria other than Neisseria cellulitis). A focus of infection is identified in approximately 50%
gonorrhoeae is relatively low, but these infections can cause major of cases.
morbidity as a result of pain, immobility and loss of joint function. Direct inoculation of micro-organisms into the joint space due to
Successful treatment requires prompt drainage of the joint and pro- trauma, arthrotomy, arthroscopy or diagnostic and therapeutic arthro-
longed antimicrobial therapy. This chapter discusses infective arthritis centesis is another mechanism of infection. The risk of septic arthritis
in adults, with the major emphasis on bacterial infective arthritis. Viral after arthrocentesis has been reported to be 0.002–0.007%; after
and reactive arthritis are discussed briefly. Infective arthritis caused by arthroscopy it is reported to be 0.04–0.4%.13 Infection of the joint
Borrelia burgdorferi is discussed in Chapter 46, and mycobacterial space as a result of contiguous soft tissue infection or periarticular
arthritis in Chapters 31 and 32. osteomyelitis is much less common.
Bacterial adhesins play a crucial role in the establishment of infec-
tion, and differential expression of adhesins correlates with septic
Bacterial Arthritis arthritis rates in murine models.14 Once bacteria enter the joint space,
macrophage activation occurs in response to the release of bacterial
Epidemiology products.14 Release of enzymes (e.g. gelatinases) results in hydrolysis
The incidence of bacterial arthritis is rising due in part to an aging, of proteoglycans and collagen.15 Pressure necrosis of the cartilage can
immunocompromised population and an increased use of invasive occur from joint effusion. If left untreated, destruction of the articular
procedures.1 In 2005, according to the Centers for Disease Control and cartilage eventually occurs, leading to irreversible joint damage.
Prevention (CDC), there were an estimated 24 000 cases of pyogenic Staphylococcus aureus is the most common etiologic agent of infec-
arthritis that required hospitalization in the USA, of which 33% were tive arthritis in adults (Table 43-2).12,16 Methicillin-resistant Staph.
65 years of age or older.2 The CDC estimates that the incidence of aureus (MRSA) has been identified as an increasing cause of septic
septic arthritis is 6 per 100 000 individuals per year.1 These data are in arthritis in some communities.17 In young sexually active persons, N.
agreement with other published incidence rates of bacterial arthritis in gonorrhoeae is the predominant pathogen. Common skin organisms,
the general population.3,4 Disseminated gonococcal infection with such as coagulase-negative staphylococci, may cause infection follow-
associated gonococcal infective arthritis is the leading cause of hospital ing arthroscopy and intra-articular injections. Infective arthritis due
admission due to infective arthritis in the USA, with an estimated to gram-negative bacilli is more common in the elderly patients with
382
Chapter 43 Infective and Reactive Arthritis 383
TABLE
43-1 Epidemiologic and Clinical Features Associated With Specific Etiologic Agents of Infective Arthritis
Likely Etiologic Agent Clinical or Epidemiologic Setting
BACTERIA
Staphylococcus aureus Rheumatoid arthritis, injection drug use, arthroscopy, arthrotomy, polyarticular arthritis
Coagulase-negative staphylococci Arthroscopy, arthrotomy, foreign material
Neisseria gonorrhoeae Young, sexually active, history of sexually transmitted disease or unprotected sex,
menstruation, pregnancy, multiple skin lesions
Pseudomonas aeruginosa and other aerobic gram-negative bacteria Injection drug use, elderly
Anaerobes Human and animal bites, orthopedic allograft infection with allograft without sporicidal
sterilization, anaerobic infection elsewhere in body
Usual oral flora Human and animal bites
Eikenella corrodens Human bite
Pasteurella multocida Cat or dog bite
Streptobacillus moniliformis Rat bite
Neisseria meningitidis Multiple purpuric lesions
OTHER
Mycoplasma spp. Common variable hypogammaglobulinemia, urogenital procedures
Borrelia burgdorferi Resident in endemic area, known or suspected tick exposure, history of erythema
chronicum migrans
Tropheryma whipplei Other manifestations of Whipple’s disease
MYCOBACTERIA
Mycobacterium tuberculosis Positive tuberculin skin test, resident in country where disease is endemic, known
exposure history
Mycobacterium marinum Exposure to aquatic environment
Mycobacterium avium intracellulare HIV, T-cell suppression
Mycobacterium leprae Resident in country where disease is endemic
FUNGI
Sporothrix schenckii History of trauma with exposure to colonized soil (e.g. sphagnum moss)
Candida Prior known or suspected candidemia or culture-negative central infection, neutropenia
Aspergillus Prior known or suspected invasive Aspergillus infection, prolonged neutropenia
Blastomyces dermatitidis Resident in area where disease is endemic, exposure to beaver dams
Coccidioides immitis Resident in area where disease is endemic
11
Data from Smith & Piercy.
co-morbid illnesses.18 Alcoholism may predispose to pneumococcal

TABLE Etiologic Agents of Nongonococcal Bacterial septic arthritis.19
43-2 Arthritis in Adults
Micro-organisms Cases (%)
Prevention
Examples of efforts to decrease the incidence of infective arthritis
Staphylococcus aureus 68
include public health measures to prevent the acquisition of N. gonor-
Streptococci (including β-hemolytic streptococci, viridans 20 rhoeae, prophylactic foot care in patients with diabetes mellitus and
group streptococci and Streptococcus pneumoniae) eradication of injection drug use. Vaccination campaigns against Hae-
Haemophilus influenzae 1 mophilus influenzae and Streptococcus pneumoniae have resulted in a
decline in invasive infections caused by these pathogens.20 Eradication
Aerobic gram-negative bacilli 10 of the Staph. aureus carrier state with the use of topical mupirocin and
Polymicrobial and miscellaneous 1 chlorhexidine body washes might play a role in reducing the risk of
Unknown <1
infection prior to joint surgery.21 Rapid screening for Staph. aureus,
and decolonization with mupirocin has been shown to be a cost effec-
Data from Roberts & Mock.17 tive and effective method to prevent Staph. aureus nosocomial infec-
tions after surgery, as long as the prevalence of mupirocin resistance
is low.
384 SECTION 2 Syndromes by Body System: Bone and Joints
Clinical Features Fever and rigors in the setting of an inflammatory arthritis have
a low PPV for bacterial arthritis and have also been reported in crystal-
NONGONOCOCCAL INFECTIVE ARTHRITIS induced arthropathy. The erythrocyte sedimentation rate (ESR),
Nongonococcal infective arthritis is typically monoarticular and has C-reactive protein and leukocyte counts are elevated in the majority
an acute presentation with symptoms usually present for less than 2 of cases, although again the PPV of these tests in the setting of a
weeks. Patients complain of pain and limitation of motion in over 90% monoarticular inflammatory arthritis is low. A rise in the ESR may
of cases.11 Fever is an inconsistent finding.7 Physical examination help in the differential diagnosis of new joint pain and effusion in
usually reveals a large effusion and a marked decrease in active and those patients who have rheumatoid arthritis.11 The role of serum and
passive range of motion of the joint. These findings may be minimal synovial procalcitonin levels in the diagnosis of bacterial arthritis
or absent in those patients with rheumatoid arthritis, and they may be remains undefined.28 Blood cultures are positive in up to 70% of
difficult to discern in hip or shoulder infections. all patients, and more often in patients who have polyarticular
The knee is the most commonly involved native joint in adults. involvement.22
Axial joint infection is more common among injection drug users. In DGI the majority of patients have an elevated ESR, and only 50%
Polyarticular infection occurs in approximately 15% of patients, and will have an abnormal leukocyte count.25 Neisseria gonorrhoeae can be
is often due to Staph. aureus.22 It is more common among patients with detected in samples from the cervix, urethra, rectum, pharynx or urine
rheumatoid arthritis and sepsis. in 80% of patients with DGI using culture or nucleic acid amplification
The case fatality rate for patients with nongonococcal bacterial tests (NAATs).29 The sensitivity of NAATs for the detection of N.
arthritis is estimated to be between 10% and 15%, and up to half of gonorrhoeae in genital and nongenital anatomic sites is superior to
patients will have some degree of permanent loss of joint function.16,23 culture.30
Morbidity and mortality are dependent on a number of factors, includ- The diagnostic procedure of choice for bacterial arthritis is an
ing age, rheumatoid arthritis, hip or shoulder infection, delay in arthrocentesis. This should be done immediately once the diagnosis of
therapy, polyarticular infection, persistently positive joint fluid cul- joint infection is suspected so as not to delay therapy. If synovial fluid
tures, bacteremia and the virulence of the infecting organism.3,24 cannot be obtained by blind needle aspiration, then aspiration should
be done with the help of a radiologist. If necessary, an open arthrotomy
GONOCOCCAL ARTHRITIS should be performed.
Initial gonococcal infection is often asymptomatic.25 Patients with dis- Synovial fluid is often cloudy or purulent in appearance. The syno-
seminated gonococcal infection (DGI) commonly present early after vial fluid should be routinely examined for uric acid and calcium
dissemination with bacteremia, fever, polyarthralgia, tenosynovitis pyrophosphate crystals, and a leukocyte count and differential should
(typically of the hands and fingers) and multiple painless maculopapu- be obtained. The leukocyte count is usually greater than 50×109/L and
lar, pustular, vesicular or necrotic skin lesions. Asymmetric joint often greater than 100×109/L, with more than 75% polymorphonuclear
involvement is common. The knee, elbow, wrist, metacarpophalangeal leukocytes. However, these findings can also be seen in patients who
and ankle joints are the most commonly involved. This presentation have inflammatory arthritis and crystal deposition arthritis. With
has been described as the dermatitis–arthritis syndrome. If left increasing synovial fluid leukocyte count from >25–50–100×109/L, the
untreated, the patient will present later with monoarticular arthritis, likelihood ratio (LR) for bacterial arthritis increased from 2.9 to 7.7 to
usually without tenosynovitis or skin lesions. The outcome of DGI is 28.7 Synovial fluid glucose and protein levels are less informative. The
almost always satisfactory if adequate antimicrobial management is synovial fluid lactic acid and lactate dehydrogenase levels are often
provided.25 elevated, but this can be seen in other inflammatory joint disorders
In adults, the differential diagnosis of gonococcal arthritis includes as well.
gout, pseudogout, rheumatic fever, reactive arthritis and rheumatic The Gram stain is an important test, as it can provide an early guide
illnesses such as rheumatoid arthritis. Gout and pseudogout are the to therapy. It is positive in 50–75% patients with nongonococcal bacte-
most common noninfectious inflammatory arthritides that need to be rial arthritis.31
differentiated.12 They should be suspected when there is a history of Synovial fluid should be cultured for both aerobes and anaerobes
previous episodes, tophi and chondrocalcinosis on plain film. Synovial and other organisms, depending on the clinical circumstances. A study
fluid analysis using polarized light microscopy is the most useful diag- performed at the Mayo Clinic showed superior performance of the
nostic test. Bacterial arthritis may coexist with crystal associated arthri- BACTEC Peds Plus/F bottle over the conventional agar plate method
tis, and the presence of crystals does not rule out bacterial arthritis.26 for the detection of clinically significant micro-organisms from syno-
The articular manifestations of rheumatic fever last for several weeks vial fluid specimens.32 The synovial fluid culture will be positive in
but do not cause permanent joint damage. Typically there is develop- 90% of cases of nongonococcal arthritis, assuming antibiotic therapy
ment of a migratory polyarthritis involving the knees, elbows, ankles has not been started before sample collection.24 In patients with DGI,
and wrists that occurs within 1–5 weeks of the antecedent streptococcal the synovial fluid cultures are positive in 25–30% of all patients and
pharyngitis. The diagnosis of rheumatic fever is dependent on satisfy- 50% of patients who present with monoarticular arthritis. If sufficient
ing the updated Jones criteria.27 synovial fluid is obtained, an aliquot can be processed in an aerobic
Fungal and mycobacterial infection is usually monoarticular, but blood culture bottle similarly to routine blood cultures.33 This does
the presentation is usually over weeks to months. Diseases that must not obviate Gram stain and solid agar culture of synovial fluid
be distinguished from DGI include viral and reactive arthritis, rheu- specimens.
matic fever and secondary syphilis. The role of nucleic acid amplification assays, including PCR, in
detecting bacterial pathogens in patients who have infective arthritis is
not yet well defined, although the technique seems to be a promising
Diagnosis tool for the detection of infectious arthritis due to N. gonorrhoeae,
Although the history and physical examination can lead to a high index Borrelia burgdorferi and Tropheryma whipplei. A recent study demon-
of suspicion for infection, a synovial fluid culture that yields a causative strated rapid and accurate perioperative detection of Staphylococcus
micro-organism is the only definitive method for diagnosing bacterial spp. in osteoarticular infections using real time PCR.34 No additional
arthritis, although 16S rRNA gene PCR has emerged as a useful tool benefit of using PCR over culture in the diagnosis of joint infections
for identification of bacterial pathogens in culture-negative arthritis, has been established. The role of PCR in the diagnosis of bacterial
particularly in patients pretreated with antibiotics. Molecular methods arthritis is currently limited to identification of fastidious and slow
have been shown to have 100% specificity and positive predictive value growing organisms. Synovial tissue cultures are indicated only for
(PPV) in diagnosing culture-negative bacterial infections. chronic infective arthritis when mycobacterial or fungal arthritis is
Figure 43-1 MRI scan of right knee of a patient who has Staphylococcus aureus
septic arthritis. Note the soft tissue inflammation and a joint effusion.
Figure 43-2 Intraoperative photograph of right knee of a patient who has Staph-
ylococcus aureus septic arthritis. Note the damaged joint and dark brown, boggy
suspected or when synovial fluid cultures cannot be obtained by less and hyperemic synovium.
invasive techniques.
Radiology inability to adequately drain the infected joint by aspiration or arthros-

copy, either because of location or loculations of pus (Figure 43-2).11,38
Plain radiographs are not usually helpful in making an initial diagnosis
but are useful to identify concurrent osteomyelitis. Periarticular soft ANTIMICROBIAL THERAPY
tissue swelling is the most common abnormality seen on plain radio
Antimicrobial therapy should be administered as soon as the diagnosis
graphy. Notably, the radiologic appearance of periarticular erosions
is suspected and synovial fluid cultures obtained. Any delay in the
and joint space narrowing typically takes weeks. It is often difficult to
administration of antimicrobial therapy may result in significant car-
distinguish infection from inflammatory arthritis using radiographic
tilage loss. To date there are no randomized studies to help guide the
methods in the setting of rheumatoid arthritis, but the development
clinician in the antimicrobial therapy of septic arthritis. Initial antimi-
of a rapid destructive arthritis in one or two joints suggests infection.
crobial therapy should be based on the results of the Gram stain and
CT scans and MRI are more useful than plain radiographs for identify-
the specific clinical and epidemiologic setting. If no micro-organisms
ing concomitant periarticular osteomyelitis, soft tissue abscesses and
are seen on the Gram stain, empiric therapy for Staph. aureus (includ-
joint effusions, but they are expensive and most often are not necessary
ing MRSA), streptococci and gonococci (in young sexually active
(Figure 43-1).35
adults) should be given. Vancomycin should be administered if the
initial Gram stain shows gram-positive cocci or empirically if no
Management organisms are seen on the Gram stain, in patients at high risk for
The keys to the management of infective arthritis are: MRSA infection and when methicillin resistance rates are high in the
community. Most experts administer 2–4 weeks of intravenous anti-
• drainage of the purulent synovial fluid; microbial therapy for the treatment of nongonococcal septic arthritis.39
• debridement of any concomitant periarticular osteomyelitis; and In most cases this can be administered on an outpatient basis after an
• administration of appropriate parenteral antimicrobial therapy. initial period of hospitalization. Suggested antimicrobials for specific
Patients with suspected bacterial arthritis in whom culture remains
negative should be treated similarly to patients with bacterial arthritis. pathogens causing infective arthritis are shown in Table 43-3. Oral
In one study, no significant difference in laboratory markers or clinical antimicrobial therapy with an effective agent with excellent bioavail-
outcome was found between culture positive and culture-negative ability, such as ciprofloxacin or linezolid, is also acceptable, particu-
arthritis.36 Experimental models of septic arthritis suggest that early larly if compliance with oral therapy can be assured and risk of
drainage and antimicrobial therapy prevent cartilage destruction. fluoroquinolone resistance in suspected pathogens, particularly N.
Local antimicrobial therapy may cause a chemical synovitis and is not gonorrhoeae, is considered low.
advised.12 Joint immobilization and elevation is useful for symptom- The initial drug of choice for gonococcal septic arthritis is paren-
atic relief, but early active range of motion exercises are beneficial for teral ceftriaxone (see Table 43-3).40,41
ultimate functional outcome.
SYNOVIAL FLUID DRAINAGE Viral Arthritis

The optimal method of drainage of an infected joint remains contro-
versial, in part because no well-controlled randomized trials exist to Arthritis is a common complication of infections with hepatitis B
guide therapy.37 Therapy of each patient should be individualized. virus, erythrovirus B19 (formerly paravovirus B19), rubella and alpha-
Many adults with septic arthritis have been managed with repeated viruses, and is relatively rare with mumps virus, enteroviruses, adeno-
joint aspirations instead of surgical debridement.24 Patients with DGI viruses and herpesviruses.42 The mechanisms by which viruses cause
rarely require repeat joint aspirations, arthroscopy or arthrotomy.25 arthritis include joint invasion during viremia, immune complex
The use of arthroscopy has expanded in recent years because of the deposition, insertion of the viral genome into the host DNA promoting
improved ability to adequately visualize and drain purulent material. autoimmunity through an ‘altered self ’, and immune dysregulation.43-45
Typically, viral arthritis occurs during the prodromal stage of
DEBRIDEMENT viral infection and is associated with a rash. Symmetric polyarticular
Recommended indications for surgical debridement have included involvement, including the small joints of the hands, is typical. No
effusions that fail to resolve with 7 days of conservative therapy and specific pattern of joint involvement is unique to a specific viral
TABLE
43-3 Antibiotic Therapy of Infective Arthritis in Adults for Selected Bacterial Micro-organisms
Micro-organisms Antibiotic Therapy Alternative Therapy
Staphylococcus Methicillin-sensitive Nafcillin or oxacillin 1.5–2.0 g iv q4h Vancomycin 15 mg/kg iv q12h

aureus strains or
Cefazolin (or other first-generation cephalosporins in
equivalent dosages) 1–2 g iv q8h
Methicillin-resistant Vancomycin 15 mg/kg iv q12h Consult a specialist in infectious diseases
strains Linezolid 600 mg iv/po q12h
Penicillin-sensitive streptococci or Aqueous crystalline penicillin G 20 × 106 U iv q24h either Vancomycin 15 mg/kg iv q12h, not to exceed 2 g
pneumococci continuously or in six equally divided doses in 24h unless serum levels are monitored
or
Ceftriaxone 2 g iv or im q24h
or
Cefazolin 1 g iv q8h
Enterococci or streptococci with an MIC Aqueous crystalline penicillin G 20 × 106 U iv q24h either Vancomycin 15 mg/kg iv q12h, not to exceed 2 g
≥0.5 µg/mL or nutritionally variant continuously or in six equally divided doses, plus in 24h unless serum levels are monitored
streptococci (all enterococci causing gentamicin sulfate 1 mg/kg iv or im q8h
infection must be tested for or
antimicrobial susceptibility in order to Ampicillin sodium 12 g iv q24h either continuously or in
select optimal therapy) six equally divided doses
Neisseria gonorrhoeae Ceftriaxone 1 g im or iv q24h for 24–48 h after clinical Ciprofloxacin 400 mg iv q12h for 24–48 h after
improvement followed by clinical improvement
Cefixime 400 mg po q12h for 1 week or
or Ofloxacin 400 mg iv q12h for 24–48h after clinical
Ciprofloxacin 500 mg po q12h for 1 week improvement
or or
Ofloxacin 400 mg po q12h for 1 week Spectinomycin 2 g im q12h for 24–48 h after
clinical improvement followed by
Ciprofloxacin 500 mg po q12h for 1 week
or
Ofloxacin 400 mg po q12h for 1 week
Enterobacteriaceae Ceftriaxone 2 g iv q24h Levofloxacin 500 mg po q24h

or
Pseudomonas aeruginosa, Cefepime 2 g iv q12 h or other β-lactam (based on
Enterobacter spp. in vitro susceptibility)
Recommendations are for patients with normal renal function, who are not allergic to the medication and are modified based on results of in vitro sensitivities.
etiology. Diagnosis is based on historic and clinical clues (Table 43-4)

and diagnostic testing is specific for each individual virus, the details BOX 43-1 MICRO-ORGANISMS ASSOCIATED WITH
of which are discussed in the relevant chapters. There has been a REACTIVE ARTHRITIS
re-emergence of arthritogenic arboviruses (Chikungunya virus, Ross Definite association
River virus) in different parts of the world.46 Viral arthritis is usually • Chlamydia trachomatis
self-limiting but may progress to a chronic arthropathy especially in • Shigella flexneri
Chikungunya where less than 40% of patients had full recovery of • Salmonella enteritidis
• Salmonella typhimurium
symptoms after 1 year follow-up.47 • Yersinia enterocolitica
Treatment is directed at symptom relief with analgesics and is dis- • Yersinia pseudotuberculosis
cussed in the chapters devoted to specific viruses. Prevention of viral • Campylobacter jejuni.
arthritis is dependent on vaccination against the specific pathogen.
Data from Hughes & Keat.48
Reactive Arthritis (Reiter’s

Syndrome)
Typically, reactive arthritis begins several weeks after an antecedent
Reactive arthritis describes the acute onset of an inflammatory arthritis infection. The initial clinical presentation is usually asymmetric oligo-
soon after an infection elsewhere in the body in which micro-organisms articular arthritis without prominent constitutional symptoms. The
cannot be cultured from the synovial fluid. In some instances, organ- syndrome also occurs without any identifiable symptoms of infection,
isms in an aberrant persistent state (for example, Chlamydia tracho- particularly in cases that follow sexually acquired acquisition of typical
matis) and enteric bacterial genetic material have been detected in the pathogens.
affected joints. Patients with reactive arthritis can develop extra- Laboratory abnormalities are nonspecific and include mild eleva-
articular manifestations such as the classic triad of arthritis, urethritis tions in the leukocyte count, ESR and C-reactive protein. Stool tests,
and conjunctivitis. Many affected persons are HLA-B27-positive. urogenital swabs and serology can sometimes identify a preceding or
Micro-organisms associated with reactive arthritis are detailed in concomitant infection with one of the pathogens that classically induce
Box 43-1.48 A study evaluating the risk of reactive arthritis following a reactive arthritis. Arthrocentesis should be performed for diagnostic
large outbreak of E. coli O157:H7 and Campylobacter species found an purposes to rule out bacterial arthritis.
incidence of arthritis of 17.6% and 21.7%, respectively, in patients who Reactive arthritis is normally a self-limited disease, but chronic
developed moderate or severe gastroenteritis symptoms.49 arthritis and sacroiliitis can occur in up to 15–30% of patients.
TABLE
43-4 Clinical or Epidemiologic Features of Infective Arthritis Caused by Selected Viruses
Viral Agent Epidemiologic Features Clinical Characteristics Outcome
Rubella (including No prior vaccination; 51–61% of Symmetric arthritis of the metacarpal and proximal Spontaneous resolution in days to
rubella vaccine) rubella cases; 0–14% of patients phalangeal joints, wrist, elbow, ankle, knee; weeks but may be chronic or recur
receiving vaccination. Less common onset variable in relationship to rash. May mimic
with new vaccine. Ratio of rheumatoid arthritis. Post vaccination disease
women : men – 9 : 1 less symptomatic
Erythrovirus B19 60% of adult cases, females > males. Sudden severe polyarticular arthritis in small joints. Spontaneous resolution most common.
Childcare providers or school May mimic rheumatoid arthritis Chronic arthritis can occur
teachers; unusual in children
Hepatitis A 10–14% of cases of hepatitis A; typical Often associated with rash Resolves spontaneously
risk factors for acquisition of
hepatitis A
Hepatitis B 10–25% of cases of hepatitis B; typical Severe arthritis of sudden onset, symmetric, May last 1–3 weeks. Typically resolves
risk factors for acquisition of polyarthritis involving hand and knee; morning during the preicteric phase. Chronic
hepatitis B stiffness is considerable; skin rash may be arthritis may occur with chronic
present including urticaria hepatitis B infection
Hepatitis C Typical risk factors for acquisition of Can occur with acute or chronic infection. Sudden May resolve spontaneously. Has been
hepatitis C onset; joint pain in hands, wrists and shoulders reported to persist for months and
often greater than physical findings. May mimic recur
rheumatoid arthritis. Distinct from
cryoglobulinemia with hepatitis C
HIV Typical HIV-associated risk factors. Most cases are monoarticular but monoarticular Usually resolves in several weeks. May
Approximately 8% of HIV infected and polyarticular presentations occur. Distinct persist for months
patients affected from Reiter’s syndrome or psoriatic arthritis
which also occur in HIV-infected individuals.
Occurs in multiple stages of HIV infection
Arthropod-borne May occur in epidemics. May be associated with Spontaneous resolution is typical.
Chikungunya East Africa, India, South East Asia, rash. Constitutional symptoms may be present Chronic arthritis is unusual except
Philippines with Chikungunya and Sindbis virus
O’nyong-nyong East Africa
Sindbis virus Sweden, Finland, Russia
Ross River agent Australia, New Zealand, New Guinea
Barmah Forest Australia
virus
Data from Smith & Piercy,11 Siegel & Gall42 and Naides.43
Treatment is with anti-inflammatory agents. The role of antibacterial fared much better than those given placebo.50 Prevention of infection
therapy is controversial. Randomized trials evaluating the efficacy of is reliant on effective prevention and treatment of precipitating ante-
antimicrobials in patients with reactive arthritis have been limited by cedent infections.
small numbers of patients. Recently a double blind placebo controlled
trial showed that Chlamydia spp. (C. trachomatis and C. pneumoniae) References available online at expertconsult.com.
PCR-positive patients given combination antibiotics for 6 months
KEY REFERENCES
Baron E.J., Miller J.M., Weinstein M.P., et al.: A guide to Coakley G., Mathews C., Field M., et al.: BSR & BHPR, Phillips P.E.: Viral arthritis. Curr Opin Rheumatol 1997;
utilization of the microbiology laboratory for diagnosis BOA, RCGP and BSAC guidelines for management of the 9(4):337-344.
of infectious diseases: 2013 recommendations by the hot swollen joint in adults. Rheumatology (Oxford) 2006; Smith J.W., Piercy E.A.: Infectious arthritis. Clin Infect Dis
Infectious Diseases Society of America (IDSA) and the 45(8):1039-1041. 1995; 20(2):225-230, quiz 31.
American Society for Microbiology (ASM) (a). Clin Infect Dubouix-Bourandy A., de Ladoucette A., Pietri V., et al.: Smith R.M., Schaefer M.K., Kainer M.A., et al.: Fungal
Dis 2013; 57(4):485-488. Direct detection of Staphylococcus osteoarticular infec- infections associated with contaminated methylprednis-
Carter J.D., Espinoza L.R., Inman R.D., et al.: Combination tions by use of Xpert MRSA/SA SSTI real-time PCR. J olone injections. N Engl J Med 2013; 369(17):1598-
antibiotics as a treatment for chronic Chlamydia-induced Clin Microbiol 2011; 49(12):4225-4230. 1609.
reactive arthritis: a double-blind, placebo-controlled, Frazee B.W., Fee C., Lambert L.: How common is MRSA in Shmerling R.H., Delbanco T.L., Tosteson A.N., et al.: Syno-
prospective trial. Arthritis Rheum 2010; 62(5):1298- adult septic arthritis? Ann Emerg Med 2009; 54(5): vial fluid tests. What should be ordered? JAMA 1990;
1307. 695-700. 264(8):1009-1014.
Centers for Disease Control and Prevention: CDC Grand Geirsson A.J., Statkevicius S., Vikingsson A.: Septic arthritis Uckay I., Tovmirzaeva L., Garbino J., et al.: Short parenteral
Rounds: the growing threat of multidrug-resistant in Iceland 1990-2002: increasing incidence due to iatro- antibiotic treatment for adult septic arthritis after suc-
gonorrhea. MMWR Morb Mortal Wkly Rep 2013; 62(6): genic infections. Ann Rheum Dis 2008; 67(5):638-643. cessful drainage. Int J Infect Dis 2013; 17(3):e199-e205.
103-106. Gupta M.N., Sturrock R.D., Field M.: A prospective 2-year
Centers for Disease Control and Prevention: Recommenda- study of 75 patients with adult-onset septic arthritis.
tions for the laboratory-based detection of Chlamydia Rheumatology (Oxford) 2001; 40(1):24-30.
trachomatis and Neisseria gonorrhoeae – 2014. Recom- Margaretten M.E., Kohlwes J., Moore D., et al.: Does this
mendations and reports. MMWR Morb Mortal Wkly Rep adult patient have septic arthritis? JAMA 2007; 297(13):
2014; 63(RR-02):1-19. 1478-1488.
Chapter 43 Infective and Reactive Arthritis 387.e1
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arthritis in Iceland 1990-2002: increasing incidence due elderly. J Am Geriatr Soc 1985; 33(3):170-174. et al.: Direct detection of Staphylococcus osteoarticular
to iatrogenic infections. Ann Rheum Dis 2008; 20. Ross J.J., Saltzman C.L., Carling P., et al.: Pneumococcal infections by use of Xpert MRSA/SA SSTI real-time
67(5):638-643. septic arthritis: review of 190 cases. Clin Infect Dis 2003; PCR. J Clin Microbiol 2011; 49(12):4225-4230.
2. DeFrances C.J., Cullen K.A., Kozak L.J.: National Hos- 36(3):319-327. 36. Coakley G., Mathews C., Field M., et al.: BSR & BHPR,
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3. Cooper C., Cawley M.I.: Bacterial arthritis in an English ment. J Bone Joint Surg Br 1998; 80(3):471-473. 37. Gupta M.N., Sturrock R.D., Field M.: Prospective com-
health district: a 10 year review. Ann Rheum Dis 1986; 22. Larkin S.A., Murphy B.S.: Preoperative decolonization parative study of patients with culture proven and high
45(6):458-463. of methicillin-resistant Staphylococcus aureus. Orthope- suspicion of adult onset septic arthritis. Ann Rheum Dis
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Incidence and sources of native and prosthetic joint 23. Dubost J.J., Fis I., Denis P., et al.: Polyarticular 38. Mathews C.J., Kingsley G., Field M., et al.: Management
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seminated gonococcal infection in women. Obstet 2-year study of 75 patients with adult-onset septic management of native shoulder septic arthritis. J Shoul-
Gynecol 2012; 119(3):597-602. arthritis. Rheumatology (Oxford) 2001; 40(1):24-30. der Elbow Surg 2013; 22(3):418-421.
6. Kaandorp C.J., Van Schaardenburg D., Krijnen P., et al.: 25. Goldenberg D.L., Reed J.I.: Bacterial arthritis. N Engl J 40. Uckay I., Tovmirzaeva L., Garbino J., et al.: Short par-
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and the effect of anti-TNF therapy: results from the Committee on Rheumatic Fever, Endocarditis, and tis. Am Fam Physician 1996; 54(6):2009-2015.
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nisolone injections. N Engl J Med 2013; 369(17):1598- citonin in the diagnosis of bone and joint infection: a 45. Schnitzer T.J., Penmetcha M.: Viral arthritis. Curr Opin
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10. From the Centers for Disease Control and Prevention: Infect Dis 2013; 32(6):807-814. 46. Suhrbier A., Jaffar-Bandjee M.C., Gasque P.: Arthrito-
Update: allograft-associated bacterial infections–United 30. O’Brien J.P., Goldenberg D.L., Rice P.A.: Disseminated genic alphaviruses – an overview. Nat Rev Rheumatol
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11. Smith J.W., Piercy E.A.: Infectious arthritis. Clin Infect patients and a review of pathophysiology and immune 47. Couturier E., Guillemin F., Mura M., et al.: Impaired
Dis 1995; 20(2):225-230, quiz 31. mechanisms. Medicine (Baltimore) 1983; 62(6):395- quality of life after chikungunya virus infection: a
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of risk factors. Arthroscopy 1992; 8(2):213-223. Recommendations and reports. MMWR Morb Mortal 24(3):190-210.
14. Shirtliff M.E., Mader J.T.: Acute septic arthritis. Clin Wkly Rep 2014; 63(RR-02):1-19. 49. Garg A.X., Pope J.E., Thiessen-Philbrook H., et al.:
Microbiol Rev 2002; 15(4):527-544. 32. Shmerling R.H., Delbanco T.L., Tosteson A.N., et al.: Arthritis risk after acute bacterial gastroenteritis. Rheu-
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knees. Clin Orthop Relat Res 2004; 427:179-183. 33. Hughes J.G., Vetter E.A., Patel R., et al.: Culture with Combination antibiotics as a treatment for chronic
16. Morgan D.S., Fisher D., Merianos A., et al.: An 18 year BACTEC Peds Plus/F bottle compared with conven- Chlamydia-induced reactive arthritis: a double-blind,
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17. Roberts N.J., Mock D.J.: Joint Infections. In: Reese R.E. 34. Baron E.J., Miller J.M., Weinstein M.P., et al.: A guide to
BRF, ed. Joint infections: a practical approach to infec- utilization of the microbiology laboratory for diagnosis
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54(5):695-700. Infect Dis 2013; 57(4):485-488.
44
Acute and Chronic Osteomyelitis
SHIREESHA DHANIREDDY | SANTIAGO NEME
KEY CONCEPTS immunization. A second peak in incidence occurs in older adults9

and includes vertebral osteomyelitis, with an incidence of approxi-
• Osteomyelitis is one of the oldest diseases ever described. mately 2 per 100 000 in both France and Sweden.10,11 Recent studies
• Bone is normally resistant to infection but large inocula of have stressed a growing role for community-acquired strains of
bacteria, trauma or the presence of foreign bodies may over- methicillin-resistant Staphylococcus aureus (CA-MRSA) in acute hema-
whelm host defenses and lead to infection. togenous osteomyelitis.8,12,13
The epidemiology of chronic osteomyelitis is less well documented.
• Optimization of co-morbidities (e.g. diabetes mellitus, obesity, Cases are more frequently due to prior trauma or instrumentation
tobacco dependence, intravenous drug use) is key to
than to prior hematogenous infection. The enormous burden of war
prevention.
and civil unrest, expansion and aging of human populations, and rapid
• Several infection prevention strategies (e.g. perioperative anti- increases in automobile transport (and associated trauma) are all likely
microbial prophylaxis, chlorhexidine use for incisional site to have increased the prevalence of chronic osteomyelitis. A single
preparation) have been associated with decreased surgical site example is the pandemic of type 2 diabetes. It is estimated that up to
infection rates. 25% of persons with diabetes will have a foot ulcer at some time during
• Technology advances (e.g. magnetic resonance imaging, per- their life14 and approximately 20% of patients attending foot ulcer
cutaneous tissue sampling, molecular testing) have increased clinics have osteomyelitis complicating the ulceration.15
our ability to diagnose osteomyelitis.
• Definitive treatment often requires a combination of antimicro- Pathogenesis, Pathology
bial therapy and surgical debridement. and Classification
• A multidisciplinary care team model has been associated with MICROBIAL FACTORS
improved outcomes. The pathogenesis of osteomyelitis begins with access and attachment16
of organisms to bone either via hematogenous spread or from a con-
tiguous focus of infection. Hematogenous spread may be from an
obvious or an inapparent focus of infection or bacteremia. The con-
Introduction and Epidemiology tiguous focus may be infected soft tissue, a joint, orthopedic instru-
The osteomyelitic left fibula of the largest articulated fossil specimen mentation or an area of chronic ulceration overlying bone.17
of Tyrannosaurus rex, ‘Sue’, on display in the Field Museum of Natural Staphylococci are the most common agents of bone infection.
History in Chicago,1 vividly illustrates the ancient relationship between Staph. aureus possesses numerous cell wall-associated adhesins medi-
vertebrate bones and microbial pathogens, and the highly conserved ating specific attachment to a wide variety of extracellular matrix pro-
biologic responses that have evolved to protect the host from this teins found in bone18 (Figures 44-2 and 44-3). These include fibronectin,
interaction. These responses, at their most successful, will prevent sep-
ticemic death and contain infection within a small part of the bone,
either arresting and eradicating the infection, or creating a situation in
which the infected portion of bone can be expelled from the body. It Acute hematogenous osteomyelitis in preschool children
is common, however, for the eradicative responses to be incomplete,
leading to chronic suppurative infection associated with pain, poor
function and ill health, and sometimes with progressive disability. This Hospital 160
morbidity is as debilitating for the survivor of modern trauma, mili- incidence
per 140
tary conflict or sepsis developing osteomyelitis today as it will have
100000
been for ‘Sue’ over 65 million years ago. at risk 120
Despite this, modern experiences from well-organized and skilled Boys
per year
multidisciplinary teams suggest that high rates of arrested infection Girls
100
and restored function can be achieved.2,3 Difficulties in delivering
success for all patients are partly due to variations in the interplay of
80
microbial virulence and host biology, the extent of pre-treatment
damage to bone and soft tissues, and the clinical team’s judgment and
60
technical skill.
The epidemiology of acute osteomyelitis has been studied in the 40
northern and southern hemispheres4–6 (Figure 44-1). In all locations
hematogenous osteomyelitis is a disease of children and adolescents 20
and is much less common in adulthood. Incidence is greater in the
southern hemisphere. High rates are seen in Polynesians and in New 0
Zealand, in Maori children compared to Caucasians,4,5 but the relative Scotland England N.Z. W.Aust N.Z. W.Aust
importance of microbial, genetic, socioeconomic and cultural factors & Wales (European) (European) (Maori) (Aboriginal)
is unknown. In the northern hemisphere, rates of acute and subacute
hematogenous osteomyelitis in children have declined,6 facilitated Figure 44-1 Acute hematogenous osteomyelitis in preschool children. (Data
by elimination of Haemophilus influenzae osteomyelitis7,8 through from Gillespie W. J.: Int J Epidemiol 1985; 14(4):600-606.)
388
Chapter 44 Acute and Chronic Osteomyelitis 389
virulence regulators.20 Adherent bacterial growth leads to the forma-

tion of a biofilm, an adherent consortium of micro-organisms
enmeshed in an exocellular polysaccharide. Organisms within a biofilm
often manifest different phenotypes from planktonic ones, being much
less susceptible to antimicrobial agents and to host defenses, and hence
capable of prolonged survival.21
Small colony variants are another potential mechanism for persis-
tence.22 Altered gene expression affects metabolic pathways, growth
rates, expression of virulence factors and antibiotic susceptibility. Small
colony variants have been shown capable of persisting intracellularly
in endothelial cells, fibroblasts and osteoblasts, and have been recov-
ered from clinical cases of chronic osteomyelitis.23
HOST FACTORS
In hematogenous infection the pathogen most commonly localizes to
the metaphysis of a large long bone just beneath the growth plate. The
most common sites are therefore femur, tibia, humerus, radius and
ulna, but any bone can be involved and periosteal or epiphyseal seeding
can occur. Extension across the growth plate is impeded in children;
following epiphyseal fusion this route becomes possible and the joint
can be involved. This is also the case in neonates since the joint capsule
extends past the growth plate and encompasses some of the metaphysis
as well as the epiphysis.
Figure 44-2 Endosteum of bone showing staphylococci near the endosteal
Haversian canal. In vitro incubation of bone chips with Staphylococcus aureus Infection triggers an acute inflammatory response, which in the
interrupted at 48 hours (scanning electromicrograph). (From Norden C.W., Gil- rigid mechanical microenvironment of bone causes raised intraosse-
lespie W.J., Nade S.: Infections in bones and joints. Boston: Blackwell Scientific ous pressures that contribute to vascular thrombosis. Infection may be
Publications; 1994, with permission.) contained, in the resulting region of bone death, by the surrounding
inflammation.
If infection is arrested at an early stage the effects on bone may be
minimal. If infection progresses, pus may track to other areas of the
bone along the medullary canal or through the Haversian systems in
cortical bone from the medulla to the outer surface of the cortex. Here
it may strip the periosteum (especially in the young where it is less
adherent) and form a subperiosteal abscess. This may contribute to a
bacteremia and major septicemic illness, or it may track out into the
soft tissues and eventually form abscesses or a draining sinus.
ESTABLISHMENT OF CHRONICITY
Dead bone acts as an inert surface for biofilm formation and is sur-
rounded by acute inflammation and suppuration. Both the inflamma-
tory cytokines and mediators released during infection, and in some
cases bacterial products themselves, can trigger bone resorption either
by osteoclast activation or by stimulating phagocytic cells to take on a
bone-resorbing phenotype.24,25 Hence bone is lost from around the
dead area, potentially ultimately separating it from the surrounding
living bone to form the sequestrum. At the same time, where periosteal
stripping has occurred, the resulting periosteal reaction produces a
shell of new bone, the involucrum, around the dead bone. This will
not be seen where the periosteal tissues themselves have been destroyed
by infection or by pre-existing ulceration. Pus drains via one or more
Figure 44-3 Staphylococci enmeshed in glycocalyx near the Haversian ostium. cloacae in the involucrum or from cortical breaches. This situation is
In vitro incubation of bone chips with Staphylococcus aureus interrupted at 48 compatible with life and function since the draining infection assumes
hours (scanning electromicrograph). (From Norden C.W., Gillespie W.J., Nade S.: a less aggressive nature and the mechanics of the bone can be preserved
Infections in bones and joints. Boston: Blackwell Scientific Publications; 1994, with by a well-developed involucrum. The patient does, however, suffer
permission.)
ongoing bone pain, drainage, and debility. Flares in infection can also
affect the soft tissues, bone or a neighboring joint, or lead to abscess
laminin, osteopontin, bone matrix sialoprotein and collagen. Other formation or bacteremia.
adhesins mediate attachment to components of thrombus such as
fibrinogen and thrombospondin. Patients with hematogenous osteo- MICROBIOLOGY
myelitis commonly report some form of antecedent blunt injury to the The earliest descriptions established the primacy of Staph. aureus as a
affected part. This may have exposed bone matrix proteins (by micro- cause of osteomyelitis26 and this remains the case today, accounting for
fracture of their mineral covering) and produced local thrombus to over 50% of cases in pure or mixed growth.27,28 In recent years the
which staphylococci can attach. Where bone is directly exposed, necro- prevalence of MRSA has increased,12 with community-acquired strains
sis of the outer surface provides an ideal substrate for bacterial attach- (CA-MRSA) of increasing importance worldwide. Where environmen-
ment and subsequent invasion. tal contamination has been prominent, as in open fractures or blast
Post-attachment events include the elaboration of toxins that injuries, or where infection arises from chronic wounds with their
directly contribute to necrosis of tissues. In Staph. aureus the synthesis attendant complex polymicrobial flora, a wider variety of pathogens is
of these is controlled by quorum sensing mechanisms19 and global seen, including Enterobacteriaceae and Pseudomonas aeruginosa.29,30
The latter is also associated with specific situations and risk factors,
often involving initial interaction with a cartilaginous area adjoining Anatomic classification of osteomyelitis in adult long bones
bone, such as:
• puncture injuries to the foot through the soles of sneakers (train-
ing shoes) causing osteochondritis of the metatarsophalangeal Stage 1 (medullary osteomyelitis)
joint;31
Necrosis limited to medullary contents and
• malignant otitis externa involving the junction of the external
endosteal surfaces
auditory meatus and the skull base;32 Etiology: hematogenous
• hematogenous seeding to vertebral end-plates in intravenous Treatment: early: antibiotics, host alteration
drug users and renal dialysis patients; and late: unroofing; intramedullary reaming
• chronic long bone osteomyelitis after open fracture and multiple
procedures.
Anaerobes can play primary or synergistic roles in osteomyelitis,
and their prevalence likely increases with targeted efforts to isolate Stage 2 (superficial osteomyelitis)
them.33 Low-virulence organisms, such as coagulase-negative staphy-
Necrosis limited to exposed surfaces
lococci or enterococci, are common in mixed infections, especially in Etiology: contiguous soft tissue infection
diabetic foot osteomyelitis34 or where infection arose in association Treatment: early: antibiotics, host alteration
with orthopedic instrumentation (even if hardware has subsequently late: superficial debridement, coverage;
been removed). Propionibacterium acnes has also been associated with possible ablation
prosthetic joint infections, particularly shoulders.35
Worldwide, infection with Mycobacterium tuberculosis remains
important.36,37 In appropriate geographic areas, Brucella spp. are
important causes of spondylodiscitis.38 Salmonella typhi and non Stage 3 (localized osteomyelitis)
typhoidal Salmonella spp. cause osteomyelitis in Africa, both in and Well marginated and stable before and after
out of the context of sickle cell anemia or coincident HIV infection. debridement
Also of geographic importance are endemic fungal diseases including Etiology: trauma; evolving stages 1 and 2; iatrogenic
coccidioidomycosis, histoplasmosis and blastomycosis, all of which Treatment: antibiotics, host alteration, debridement,
can produce bone lesions, as can late stage mycetomas. Kingella kingae dead space management; temporary
stabilization, bone graft optional
may cause childhood infections in Israel and France; for unclear
reasons, this is not the case worldwide.28 Many pathogens, including
atypical mycobacteria, Nocardia, melioidosis, yeasts, actinomycetes
and even Treponema pallidum, are unusual but well-documented eti- Stage 4 (diffuse osteomyelitis)
ologies. Where chronic bone infection has been associated with exten-
sive antibiotic exposure, multidrug-resistant organisms (MDROs) are Circumferential and/or permeative; unstable before
common. and/or after debridement
Etiology: trauma; evolving stages 1 and 2 and 3;
iatrogenic
PATHOLOGY Treatment: antibiotics, host alteration, stabilization
The histologic appearances of osteomyelitis mirror the physiologic (open reduction and internal fixation),
processes. The inflammatory response to infection raises intraosseous external fixation (Ilizarov); debridement,
pressure leading to impaired blood flow and ischemic necrosis. Thus, dead space management; possible ablation
in acute osteomyelitis the histology reveals bacteria, pus and throm-
bosed blood vessels, while necrotic bone sequestra are characteristic of
chronic osteomyelitis. The hallmarks are acute inflammatory cells
within bone, and bone death, which may be associated with acute Figure 44-4 Anatomic classification of osteomyelitis in adult long bones.
inflammation in the adjoining soft tissues, ulceration or purulence. (Adapted with permission from Mader J.T., Calhoun J. Osteomyelitis. In: Mandel
G, Bennet J, Dolin R, eds. Infectious diseases. New York: Churchill Livingstone;
Bacteria or fungi may rarely be demonstrable on special staining. As 1995:1039–52.)
chronic infection develops, chronic inflammatory cells are admixed to
the acute picture, and enhanced osteoclastic activity can be seen along-
side new bone formation. In some infections, including tuberculosis,
granuloma formation occurs. affect prognosis. The staging system also suggests different surgical
strategies to precede antibiotic therapy and in some cases predicts the
CLASSIFICATION reconstructive approach likely to be required.
Osteomyelitis can be classified in several ways. Temporal classifications,
namely acute, subacute and chronic, help to articulate the urgency and Prevention
nature of treatment and prospect of cure. Pathogenetic classifications, Since bone infection is relatively uncommon, an extensive literature
namely hematogenous and contiguous foci, can direct attention to the on its prevention is lacking. Appropriate treatment of open fractures
likely spectrum of causative pathogens. This scheme also indicates with debridement, antibiotics, stabilization and where needed, plastic
whether the disease is ‘inside-to-out’ (hematogenous) and effectively surgery for soft tissue cover has a demonstrated role in reducing infec-
chronic in the bone by the time infection drains to the soft tissues, or tion and subsequent risk of chronic osteomyelitis.40 Surgical site infec-
‘outside-to-in’ (contiguous focus), where there is often a substantial tion prevention ‘bundles’ (for example, pre-surgical shower with
soft tissue problem to manage at the earliest point that bone is involved. antiseptic, perioperative antimicrobial prophylaxis, chlorhexidine use
Anatomic schemes can helpfully draw attention to specific challenges for incisional site preparation, Staph. aureus testing and decontamina-
linked to regional anatomy; for example, the epidemiology and treat- tion) may help reduce surgical site infections potentially leading to
ment of skull base, long bone, diabetic foot and spinal osteomyelitis osteomyelitis.41–43 Careful attention to pressure offloading can facilitate
differ. primary healing and the secondary prevention of ulceration in the
Most helpful is the eponymous anatomic-physiologic staging system diabetic foot and other pressure situations.44 Similarly, pressure sore
developed by Cierny and Mader39 (Figure 44-4). This details both the risk assessment and care is essential in the prevention of decubitus
extent of bony involvement and key local and systemic factors that may ulcers and the osteomyelitis that sometimes complicates them.
Figure 44-6 Chronic active osteomyelitis in the femur. This case of osteomyelitis
was secondary to a fracture and open reduction and internal fixation 30 years
before. This axial, contrast-enhanced, fat-suppressed T1-weighted MRI scan
shows cortical thickening and a focal intraosseous fluid collection with an enhanc-
ing rim, communicating via a sinus tract to the surface of the thigh (arrow).
new routes. Where soft tissue loss preceded bone infection, continuous
drainage or exposure of bone leads to persistent wounds. The abnor-
Figure 44-5 Chronic osteomyelitis. The patient is a 30-year-old man who was mal soft tissue envelope is often confounded by scars from previous
born in Pakistan and who, as a child, had chronic osteomyelitis caused by Staphy- surgery, which can form preferential routes for sinus formation.
lococcus aureus. He is asymptomatic now except for occasional pain in the hip Progressive bony changes can include the expulsion of fragments
and a limp. The radiograph shows destruction of the femoral head and acetabu- or the whole of a sequestrum leading to self-arrest of infection. Relapse
lum, chronic changes in the femoral shaft and fusion of the right hip joint. (Cour-
tesy of Dr Joseph Mammone.) can occur decades after initial injury and infection. Pathologic fracture
of the osteomyelitic bone may occur, especially if a mechanically sound
involucrum has failed to form. Rarely, after decades of continuous
Clinical Features drainage, chronic osteomyelitis can be complicated by the develop-
ment of squamous cell carcinoma or sarcoma in the soft tissue or bone.
ACUTE OSTEOMYELITIS This may be presaged by increased pain, swelling, drainage or changes
Classically, acute osteomyelitis presents as an acute septic illness with in the character of the ulcer tissue.
agonizing pain localized to a bone.45 Small children unable to localize
or verbalize their pain may instead refuse to move a whole limb. There OSTEOMYELITIS IN SPECIFIC
is high fever, prostration and systemic upset. Bacteremia complicates ANATOMIC SITUATIONS
up to 50% of cases. The accounts above relate particularly to long bone osteomyelitis but
As the infection progresses, worsening sepsis is accompanied by other important manifestations exist that are worthy of comment.
increasing pain and bony tenderness together with soft tissue edema.
Intra- or extraosseous abscesses may form. Without treatment, the Vertebral Osteomyelitis
outcome is either septicemic death or a prolonged febrile illness that The entity of infective discitis is recognized in childhood but is of
resolves when pus drains spontaneously via a sinus. particular significance in adults, especially the elderly.49 Disc space and
spinal infections may be postsurgical, in which case there is a greater
SUBACUTE OSTEOMYELITIS likelihood of coagulase-negative staphylococci or other low-virulence
The decline in acute hematogenous osteomyelitis of childhood has organisms being responsible; the majority of infections are, however,
been accompanied by a greater proportion of cases with longer and of hematogenous origin and due to Staph. aureus or the Enterobacte-
more insidious histories, and with less systemic or local signs.46 Often, riaceae. It is suggested that the latter find a route, via the venous system,
the first finding is early radiologic change visible at presentation, unlike from sites of infection in bowel or urinary tract via retrograde flow
the case for classic acute osteomyelitis (see below). These bone lesions into Batson’s venous plexus which envelops the vertebrae. Osteomyeli-
are usually painful and may mimic tumors47 and hence are usually tis from hematogenous seeding in adults often involves the vertebral
managed with biopsy or complete excision, often before they are re bodies due to their rich, sluggish blood supply. Seeding just beneath
cognized as being infective. An unfortunate consequence of this is that the vertebral end-plate is rapidly followed by involvement of the disc
microbiologic workup is sometimes not ordered at the time of the and the other adjoining vertebrae, setting up a pattern of a disc-space-
initial evaluation. Prognosis is, however, usually good.48 centered infection. This process may occur at multiple separate or
contiguous levels, as the extensive collateral vasculature facilitates
CHRONIC OSTEOMYELITIS spread of infection, and is often accompanied by paraspinal or psoas
In chronic osteomyelitis, there is rarely a fever unless an acute flare is abscess formation. Infection may track to form anterior or posterior
occurring. A degree of malaise is common, and often noticed by the epidural abscesses. These represent retropulsion of disc space contents
patient only after successful treatment. The most consistent features or mechanical instability of the spine from bone destruction, and can
are bone pain, continuous or intermittent wound drainage, and cause cord compression or cord infarction, with paraplegia that may
impaired function; this may be profound (Figures 44-5 and 44-6). be irreversible (Figures 44-7 to 44-9). Nerve root irritation or com-
Draining sinuses may change location and number over time through pression at the lateral foraminae can lead to radicular symptoms and
spontaneous remissions and relapses, healing and reopening via old or hence presentations with chest or abdominal pain rather than back
Figure 44-7 Vertebral osteomyelitis. A sagittal, contrast-enhanced conventional

spin echo MRI scan (T1-weighted) demonstrates a posteriorly located epidural
abscess at the L4–L5 vertebral level with an enhancing rim and displacement of Figure 44-9 Vertebral osteomyelitis. A myelogram showing posterior compres-
the nerve roots anteriorly. (Courtesy of Dr Joseph Mammone.) sion of the spinal cord by an inflammatory mass. Note the involvement of adjacent
vertebral end-plates and the intervertebral disc. (Courtesy of Dr Joseph
Mammone.)
equinus deformity. This leads to sites of excessive pressure, notably

under the metatarsal heads, the heel, on the dorsal aspects of the inter-
phalangeal joints and on the ends of the toes. In the context of loss of
protective sensation and reduced skin compliance due to disordered
sweating and lubrication, together with changes in collagen cross
linking from excessive nonenyzmatic glycosylation, the result is ulcer-
ation. Alternatively, in dense neuropathy, sensation may be so impaired
that foreign objects can accidentally fall inside footwear and be unno-
ticed, or be trodden on barefoot, and cause injury.
Ulceration may involve the periosteum or a joint capsule and
hence allow infection to gain access to bone directly or via a chronic
septic arthritis. Diabetic foot osteomyelitis therefore most commonly
involves a metatarsal head (extending variably into the shaft and meta-
tarsophalangeal joint), the phalanges at the interphalangeal joints or
the terminal tuft, or the calcaneum. Infections of the bones of the
midfoot may arise from soft tissue spread or because Charcot neuro-
osteoarthropathy has led to collapse of the plantar arch and a ‘rocker
bottom’ foot with plantar ulceration. Subsequent progression of i
nfection is as for other sites, with the frequent development of spread-
ing cellulitis, abscesses (that may be in the deep compartments of the
foot) and necrosis. Fever is by no means universal, even with signifi-
cant deep infection, and when present indicates severe disease with
possible accompanying bacteremia or necrotizing fasciitis. Pain is sub-
Figure 44-8 Vertebral osteomyelitis. A sagittal, turbo spin echo MRI scan stantially less than would normally be expected because of neuropathy;
(T2-weighted) from the same patient as the scan in Figure 44-7. (Courtesy of Dr
Joseph Mammone.) as a result presentation is delayed, especially in patients with inade-
quate access to good foot healthcare (Figure 44-10).
pain. Tuberculosis of the spine manifests in similar ways. Back pain is Osteomyelitis Complicating Decubitus Ulcers
an almost universal feature and, with or without fever, should always Decubitus ulcers occur where prolonged loading due to immobility
raise the possibility of spinal infection. interacts with poor quality soft tissue due to debility, especially if also
complicated by neuropathy or cognitive impairment. Bone pain is a
Diabetic Foot Osteomyelitis variable complaint; bone is often visible or palpable in large pressure
The peripheral neuropathy of diabetes has sensory, autonomic and ulcers, and fragments may regularly be exfoliated into the drainage or
motor components. Motor neuropathy causes differential loss of func- dressings. The sites most commonly involved are areas of maximal
tion of the distally innervated intrinsic foot musculature, resulting in pressure ulceration. Lesions may be bilateral. The soft tissue compo-
changes to the biomechanics of the foot with clawing of toes and an nent is a dominant feature of the clinical problem; where the patient
involvement of the sacrum, pelvis, spinal column and clavicle than is

common in pyogenic hematogenous osteomyelitis. Pain is the domi-
nant symptom, of insidious onset and therefore chronic at the time of
presentation; wound drainage is not a feature. Some patients have
other clinical manifestations making up the SAPHO syndrome (syno-
vitis, acne, palmoplantar pustulosis, hyperostosis, osteitis);53 others
have some but not all of these features, or other conditions such as
sacroiliitis or inflammatory bowel disease; and yet other patients have
nondestructive, culture-negative chronic osteomyelitis of similar
appearances in single bones. Many accounts have emphasized a resolu-
tion of symptoms as the patient reaches adulthood, but a proportion
of patients definitely have persistent pain and evidence of ongoing
inflammation.54
The particular importance of this condition lies in its combination
of diffuse bone involvement (offering no defined target for curative
surgery) with unpredictable responses to medical therapies. These
have included anti-inflammatory antibiotics such as tetracyclines and
macrolides, nonsteroidal anti-inflammatories and bisphosphonates.
Because there is no surgical solution for most cases and no clear
medical therapy to offer, the prognosis can sometimes be worse than
that predicted for a pyogenic chronic osteomyelitis.
Diagnosis
CLINICAL FEATURES
Osteomyelitis should be suspected whenever a patient presents with
bone or limb pain and fever. Differentials include soft tissue abscess
Figure 44-10 Osteomyelitis in a diabetic patient. Diabetic patient with osteo- (which does not rule out osteomyelitis), necrotizing fasciitis, pyomyo-
myelitis and destruction of proximal second phalanx and metatarsal as well as sitis and, occasionally, tumor. Pointers to chronic osteomyelitis include
second metatarsal-phalangeal joint. (Courtesy of Dr Joseph Mammone.)
draining sinuses or chronic wounds that will not heal despite appropri-
ate wound care, especially if in the context of risk factors for pressure
becomes systemically unwell this often reflects the development of ulceration. Visible or palpable bone is virtually pathognomonic of
abscesses, spreading soft tissue infection and/or bacteremia, rather bone involvement, as is the expulsion of bony sequestra; a sterile metal
than being directly due to the osteomyelitis. However, extensive probe has been shown to be useful for palpating bone in the diabetic
involvement of bone is possible, particularly in the pelvis, and possible foot, with a high specificity for underlying osteomyelitis.55–57
involvement of the hip joint should be considered in patients with very Blood Tests
advanced ulceration involving the structures around the hip.
Elevations of inflammatory markers such as C-reactive protein (CRP)
Skull Base Osteomyelitis and erythrocyte sedimentation rate (ESR) are common, and in the
This condition is most common in elderly diabetic males and com- absence of other causes have good specificity;58,59 however, in a propor-
mences as a malignant otitis externa that then involves the petrous tion of cases, levels will be falsely normal.60
temporal bone.50 It is also recognized in some postneurosurgical situ- Radiology
ations when midline involvement of the skull base is possible. Caus- Plain Radiographs. Plain radiologic appearances are normal in
ative agents include P. aeruginosa, staphylococci or Enterobacteriaceae, early acute osteomyelitis,61 becoming abnormal after 10–14 days when
though it may be hard to persuade surgeons to take biopsies for culture sufficient bone resorption has taken place to be visible on radiographs,
because of the complex anatomic relationships of the bones of the skull and when periosteal reaction has laid down enough new mineral to be
base to major neurovascular structures. Severe headache with referred opacified.62 Subcortical lucency is often seen when chronic septic
ear and facial pain can occur, as can cranial nerve palsies. Overall,
arthritis leads to osteomyelitis of the subarticular bone. Areas of bone
significant morbidity and mortality still results and prolonged treat-
death are visible as denser parts of bone once the osteopenia of disuse
ment is required.51
and inflammation has reduced the mineral density of the surrounding
Mandibular Osteomyelitis viable bone. Over time, sclerotic areas and mature involucrum develop
Infections of mandibular reconstructions manifest as swelling and through the laying down of new bone. Fragmentation of sequestrum
drainage from surgical wounds that resolve only with surgical debride- or of the infected segment of bone, including cortical breaches and
ment and targeted antibiotics. Infection of the native mandible is pathologic fracture, occurs later in the disease.
uncommon and is largely dealt with in dental practice. Localized As a diagnostic tool, plain radiology is limited by the time required
infections associated with carious teeth manifest as pain, loosening of for typical changes to appear. Although the combination of destructive
the tooth, and possibly a dental sinus draining beneath or lateral to and reparative responses with evidence of bone death is relatively
the jaw. pathognomonic, particularly when serial films allow assessment over
time (infection leads to rapid change compared to tumor), in some
Chronic Relapsing Multifocal locations plain films are relatively unhelpful due to poor anatomic
Osteomyelitis (CRMO) definition (e.g. in the spine) or because neuro-osteoarthropathy leads
Another uncommon but important condition, CRMO denotes a to abnormal appearances that can be confused with infection (as in
culture-negative form of chronic bone inflammation (as seen histo- the diabetic foot).63
logically on bone biopsy) that does not produce the bone destruction Ultrasound. Ultrasound can be useful for the detection of soft tissue
typical of pyogenic osteomyelitis, and that arises apparently hemato collections and also for examining the periosteum. It can show peri-
genously.52 Classically lesions are self-limiting, with different sites osteal edema and elevation with subperiosteal pus, which can be aspi-
being involved at different times; there is a greater tendency for rated under image guidance,64 and can demonstrate sinus tracts and
Figure 44-11 24-hour bone scintigram of the hands. The patient is a 50-year-old Figure 44-12 Leukocyte scintigram of the hands. This scan is from the same
diabetic with a draining ulcer at the top of the right thumb (arrow). A biopsy grew patient as the scan in Figure 44-11. Again there is intense uptake in the distal first
Staphylococcus aureus. There is intense uptake in distal first phalanx and in mul- phalanx, but there is no accumulation of leukocytes in the multiple neuropathic
tiple neuropathic joints. (With permission from Jacobson A.F., Harley J., Kipsky joints. (With permission from Jacobson A.F., Harley J., Kipsky B., Pecoraro R.
B., Pecoraro R. Diagnosis of osteomyelitis in the presence of soft tissue infection Diagnosis of osteomyelitis in the presence of soft tissue infection and radiologic
and radiologic evidence of osseous abnormalities. AJR Am J Roentgenol 1991; evidence of osseous abnormalities. AJR Am J Roentgenol 1991; 157:807–12.)
157:807–12.)
TABLE well suited for identifying sequestra and soft tissue abscesses. It is easily
44-1 Tests for Osteomyelitis affected by the presence of metalware, involves a significant radiation
dose, and does not provide physiologic information about the intraos-
Positive Negative
Sensitivity Specificity Predictive Predictive
seous environment though it will identify cavities within bone. Other
Test (%) (%) Value (%) Value (%) than for assessment of union and when MRI is contraindicated or
unavailable, MRI scanning is preferred to CT.67
Three-phase 95 33 53 90
bone scan Magnetic Resonance Imaging. MRI provides information on
soft tissues including sinus tracts, bone anatomy, and intraosseous
Gallium scan 81 69 71 80
edema and abscess formation. It is the most valuable of the imaging
Indium-labeled 88 85 86 87 modalities in osteomyelitis,67 including in diabetic foot osteomyelitis
white blood where this is required,68–71 with high sensitivity and if reported by an
cell scan
expert, specificity (Figure 44-13). It is prone to postsurgical and pos-
MRI 95 88 93 92 tinstrumentation artifacts, with signal voids being created by metal-
ware and by microscopic metallosis persisting even after metalware
Adapted from White L.M., Schweitzer M.E., Deely D.M., et al. Study of
osteomyelitis: utility of combined histologic and microbiologic evaluation of removal. Slow resolution of changes makes MRI of uncertain value in
percutaneous biopsy samples. Radiology 1995; 197:840-892. monitoring response to treatment, but it has proved very valuable in
primary diagnosis and in surgical planning.
Bone Biopsy
cortical breaches. In all of these respects it is limited by the specifica-
tion of the machine, the build of the patient and the skill of the The criterion standard for diagnosing osteomyelitis is the culture of
operator. microbes from reliably obtained samples of bone, accompanied by
inflammation in histologic samples. Bone biopsy may be performed
Isotope Scanning. Isotope scanning consists of several different safely either surgically or as a percutaneous procedure72–74 under CT
modalities of different value. Triple phase bone scans are sensitive or fluoroscopic guidance. This is particularly useful in situations where
but nonspecific and while a negative scan largely rules out infection, there is a desire to avoid surgery, or when surgery is not always required
the need to use other tests as well limits cost-effectiveness (Table for success (e.g. in the spine75and diabetic foot73). Bone samples or
44-1, Figures 44-11 and 44-12). White cell scans, despite being much those of adjoining soft tissue are recommended in preference to super-
more complex to perform, have a greater specificity and so can be ficial swabs or biopsies of sinus tracts, which have a greater range
useful. Fluorodeoxyglucose-positron emission tomography (FDG- of organisms present that usually do not reliably represent the
PET) appears to be promising in studies to date.65,66 deep flora.73,76 Obtaining multiple deep samples, and using separate
Computed Tomography. CT has a place in surgical planning for instruments to avoid cross-contamination, increases sensitivity and
the assessment of non-unions and complex bony architecture, and is specificity of culture in revision arthroplasty77 and by extrapolation, in
chronic osteomyelitis too. A range of conditions including use of broth Management

enrichment culture is advised to maximize the chance of isolating the
causative pathogens; despite which some 15–20% of chronic cases are ACUTE OSTEOMYELITIS
culture-negative. Molecular diagnostic methods are still not in routine Initial Actions
use as a solution to this problem.78–80 The priority is to start antibiotics promptly in order to reduce
further complications of bacteremia and progressive bone death and
destruction. Acute osteomyelitis should therefore be diagnosed clini-
cally, prompting blood cultures and any other rapid cultures (e.g.
aspiration of a collection) and initiation of empiric treatment without
undue delay.
A thorough clinical and laboratory assessment should be per-
formed. Hematologic and biochemical testing provide a broader
picture of the degree of systemic upset, plain radiology helps to rule
out fracture and define pre-existing disease and a definitive confirma-
tory test such as MRI or white cell scanning can be organized.
Antibiotic Therapy
Intravenous antibiotics should be initiated empirically and must
include an agent active against Staph. aureus; the need to include activ-
ity against MRSA should be considered carefully based on risk factors
and local prevalence. Once microbiologic data are available, antimicro-
bial therapy should be de-escalated to target culture results (Table
44-2). In children, initial parenteral antibiotic therapy for 48–72 hours
followed by transition to oral therapy, provided the clinical response
has been prompt, the organism is susceptible to highly bioavailable oral
therapy and adherence to the agreed regimen can be assured, has been
shown to be an effective strategy.81–84 In acute osteomyelitis without
complications, 3–4 weeks of therapy is generally adequate; this may
need to be extended for longer periods if bony sequestrum is present
and operative debridement has not been performed. Data are lacking
in neonates to recommend shorter course parenteral therapy, there-
fore, 4 weeks of parenteral therapy is advised in this population.81
The Role of Surgery
Figure 44-13 T1-weighted image of the foot. The scan reveals forefoot amputa-
tion and a normal signal in distal tibia, talus and posterior calcaneus. The interior
Surgery is not necessary in every case but orthopedic review is essential
portion of the calcaneus has edema. The remainder of the tarsal bones have been if available. Most surgeons no longer favor routine initial surgical
destroyed and replaced by a low signal inflammatory mass. management.85 Surgery should be reserved for clinical or radiographic
TABLE
44-2 Antimicrobial Therapy for Infections of Bone
ANTIMICROBIAL AGENT OF CHOICE
Organism Agent Alternative Agents
Staphylococcus aureus (methicillin-sensitive) Nafcillin or oxacillin 2 g q6h iv Cefazolin, vancomycin, clindamycin
Staph. aureus (methicillin-resistant) Vancomycin 1 g q12h iv Trimethoprim–sulfamethoxazole plus rifampin
Streptococcus pneumoniae Penicillin G 5 × 106 U q6h iv* Cefazolin, vancomycin, clindamycin
Group A β-hemolytic streptococci Penicillin G 5 × 10  U q8h iv

6
Cefazolin, vancomycin, clindamycin
Enterococci Ampicillin 2 g q4h iv† Vancomycin
Haemophilus influenzae (β-lactamase-negative) Ampicillin 2 g q4h iv Trimethoprim–sulfamethoxazole, ceftriaxone
Haemophilus influenzae (β-lactamase-positive) Ceftriaxone 1 g q12h iv Trimethoprim-sulfamethoxazole
Klebsiella pneumoniae Ceftriaxone 1 g q12h iv Ciprofloxacin, piperacillin, imipenem
Escherichia coli Cefazolin 1 g q8h iv Ciprofloxacin, ceftriaxone, imipenem
Pseudomonas aeruginosa Ciprofloxacin 400 mg q12h iv or ceftazidime 1 g q8h iv Piperacillin plus aminoglycoside, aztreonam
Serratia marcescens Ceftriaxone 1 g q12h iv Imipenem, trimethoprim-sulfamethoxazole,

ciprofloxacin
Salmonella spp. Depends on sensitivity test; choose between ampicillin,

ceftriaxone, imipenem, ciprofloxacin
Bacteroides spp. Clindamycin 600 mg q8h iv Imipenem, metronidazole
*If susceptible or intermediate resistance. If high level resistance, use ceftriaxone 1 g q24h or vancomycin 1 g q12h.
†
If susceptible. If ampicillin resistant but vancomycin susceptible, use vancomycin. If resistant to both, check susceptibility to tetracyclines, chloramphenicol or
experimental agents.
evidence of abscess formation, necrosis, or failure of response to anti-

microbial therapy. For vertebral osteomyelitis from hematogenous Diabetic foot infections
seeding, surgery is reserved for patients who require spine stabilization
or drainage of paraspinal or epidural abscesses.
Initial evaluation
Prognosis
Acute osteomyelitis, diagnosed and treated promptly with appropriate Laboratory
antibiotics, carries a good prognosis with several studies showing cure • Culture (curette/aspirate)
rates of over 90% without major sequelae.84 However, when diagnosis • Radiographs
or treatment is delayed, and in a minority of cases despite appropriate
therapy, serious sequelae can occur. Secondary septic arthritis can have Clinical
a serious impact on longer term function in neonates or adults, and • Severe or deep infection?
growth plate disturbance adjacent to a metaphyseal focus can lead to No • Systemic toxicity? Yes
limb length discrepancy or angular deformity.86 Chronic infection is to all • Metabolic instability? to any
highly likely if significant bone necrosis occurs. • Poor compliance or poor
home support?
CHRONIC OSTEOMYELITIS Treatment and further evaluation

Initial Actions
Consider • Initial empiric antibiotic
Whereas time is of the essence in acute osteomyelitis, this is not gener- therapy based on clinical Hospitalize
outpatient
ally the case in chronic infection. Here, a process of patient-centered management presentation and Gram-
goal setting is required to ensure that realistic treatment aims are stained smear
defined. As long as the patient remains medically stable, imaging • Consider surgical
consultation
and other diagnostics should usually be undertaken before antibiotics • Bedrest, leg elevation,
are commenced, planning for the surgery that will be necessary in edema control
most situations. While most spinal infection can be treated with pro- • Wound care
longed antibiotics without surgery, achieving reliable arrest of infec- • Frequent re-evaluation
tion in the pelvis or long bones generally requires an operation (Figures
44-14 and 44-15).
Bone lesion
The Role of Surgery on radiograph
There is a range of surgical debridement methods and reconstructive
techniques, all geared towards control of infection, removal of the
sequestra, dead space obliteration (for example, antibiotic beads fol-
No Yes
lowed by bone grafts), skeletal stabilization and healing, and restora-
tion of healthy soft tissue cover. Procedures include intramedullary
reaming, limited cortical debridement, cortical windowing to access Clinical concern re: MRI scan (preferred)
large and complex sequestra and endomedullary cavities, and segmen- early osteomyelitis or leukocyte scan
tal resection for extensive disease.87 In some cases conservative and
reconstructive techniques are inappropriate and amputation provides
the quickest and most acceptable route back to health. Plastic surgical
techniques have proved exceedingly important in permitting postop- Negative Positive
erative soft tissue closure without excessive tension, largely through
free muscle flaps with microvascular anastomosis. Advanced orthope- Treat for soft tissue infection
• Antibiotics for ~2 weeks
dic methods, such as the Ilizarov technique,88 allow the management • Follow-up imaging
of segmental defects and their reconstruction, using distraction osteo- Consider bone
genesis to regenerate bone, or stabilizing the defect to accept a vascu- biopsy and culture
larized bone transfer such as a free fibula graft.89 This technique
involves complete resection of diseased bone leaving a large gap and a Treat for osteomyelitis
cut far up-stream of the necrotic bone which creates an intermediate • Antibiotics for ≥6 weeks Positive
• Follow-up imaging
fragment which is slowly translocated (by means of guidewires attached
to an elaborate external fixation device) leading to the growth of new
bone along the axis thus filling the gap. These technologies allow the Figure 44-14 Diabetic foot infections. Algorithmic approach to diagnosis and
surgeon to be much more radical in removing dead and infected tissue, management. (Adapted with permission from Lipsky B.A., Pecoraro R.E., Wheat
thereby reducing the likelihood of recurrence. L.J. The diabetic foot. Soft tissue and bone infection. Infect Dis Clin North Am
For diabetic foot infections, surgical debridement and resection of 1990; 4:409–32.)
involved bone, revascularization if needed, and antimicrobial therapy
is the most aggressive approach. However, several retrospective studies
suggest that antibiotic alone or in conjunction with minimal debride-
ment can arrest the infection in the majority of cases.90,91,92 Antibiotic Therapy
While the role of surgery has been stressed here, some patients have Given the wide range of potential pathogens and the increasing preva-
no surgical options that offer a better quality of life than the disease lence of multidrug-resistant organisms (MDROs), empiric therapy
itself imposes. Finally, some conditions respond well enough to pro- should, whenever possible, be avoided until reliable deep samples have
longed culture-directed antibiotic therapy and conservative wound been obtained for culture. It is safe in the vast majority of patients to
care, with optimization of co-morbidities, that surgery can be deferred stop antibiotics at least 2 weeks before planned surgery or biopsy,
until the results of this strategy are clear. Many infections of spine, skull provided the patient’s prior history of infection and antibiotic response
base and the diabetic foot fall into this category, and a patient-centered is considered carefully and mechanisms for urgent review are put in
approach is always important. place. Patients must understand the rationale for the antibiotic-free
Investigation and management of chronic osteomyelitis
Pain, drainage, fever
Sedimentation rate,
imaging
No lesion or
nondiagnositc
Needle biopsy MRI scan
Lesion identified Negative
Organism identified No organism identified Repeat X-ray

in 2 weeks
Definitive antibiotic Preceding infection No preceding

therapy based Negative
in wound infection
on culture
Empiric antibiotic Consider other

Repeat biopsy
therapy diagnoses
Resolution Disease Organism No organism

progression identified identified
Open biopsy Definitive antibiotic Open biopsy

therapy based
on culture
Consider other Definitive antibiotic Consider other Definitive antibiotic

diagnoses therapy based diagnoses therapy based
if negative on culture if negative on culture
Figure 44-15 Investigation and management of chronic osteomyelitis.
period and know what to do if infection is flaring in advance of even calcium sulfate (plaster of Paris),97,98 and in some situations (espe-
planned definitive diagnosis or treatment. cially when surgical treatment is not undertaken) in using entirely oral
Once samples are obtained, empiric therapy can begin. As for acute regimens. A systematic review of available literature found no evidence
osteomyelitis the choice of regimen must include activity against of superior outcomes with any particular antibiotic choice or route of
staphylococci, but given the higher prevalence of methicillin-resistant administration in all types of bone and joint infection;99 a systematic
Staph. aureus and coagulase-negative staphylococci, and the increased review specifically of diabetic foot osteomyelitis reached similar
likelihood of isolating gram-negative pathogens, initial cover is fre- conclusions.90 However, adequately powered, randomized studies to
quently broader in spectrum. Regimens will need to balance the ben- answer these important questions directly are still lacking.
efits of early appropriate therapy for all likely pathogens (favoring a Duration of antibiotic therapy in chronic osteomyelitis varies sub-
broader spectrum) against risks of Clostridium difficile diarrhea and stantially between and within centers. Where it is possible to have
selection of MDROs in the patient flora and hospital environment confidence in the judgment of the surgeon regarding the completeness
(favoring a narrower spectrum). of resection of dead bone, a logical scheme is to give 4–6 weeks of
Definitive antimicrobial regimens should, when possible, be based therapy following complete resection (and potentially less for more
on culture and sensitivity results. There is experience in using pro- localized disease), and much more prolonged therapy when dead bone
longed intravenous therapy for up to 6 weeks including via outpatient is known to persist.15 The precise duration of this can be tailored to
parenteral antibiotic therapy (OPAT) programs,93 in using switch regi- the specific circumstances of the patient, recognizing that relapse is
mens to move much earlier to oral therapy,94 in relying largely on much more likely in this situation. The goal therefore becomes to
locally delivered treatment using antibiotic-loaded bone cement95,96 or deliver a disease-free period while on therapy, during which important
biologic events may occur (expulsion of a sequestrum, consolidation ulcers, not with osteomyelitis specifically.100,101 The topic remains a
of an involucrum, healing of a fracture or non-union) or even key controversial one with advocates on both sides.102,103 Granulocyte-
milestones important to quality of life. If amputation has been neces- colony stimulating factor has also been evaluated as adjunctive therapy
sary, then the duration of postoperative antibiotic treatment can be for diabetic foot infection; although it has not been shown to improve
based on the degree of infection in the remaining soft tissue and bone. likelihood of healing and resolution, it has been shown to decrease
need for amputation.104
Soft Tissue Management
The soft tissues are critical as barriers to re-infection and as a delivery Conclusions
vehicle for host defenses and antibiotics. Their importance is often
underestimated. Effort must be made to ensure the removal of chroni- Osteomyelitis remains a fascinating and challenging condition
cally scarred and indurated soft tissues, surgical wound closure without requiring more basic and translational research. The development of
dead spaces or excessive tension, coverage of debrided bone with consensus definitions and the widespread adoption of standardized
healthy tissue, and for chronic wounds not appropriate for surgery, an classification and staging systems is an essential step in enabling multi
optimized wound-healing environment. This includes fastidious pres- center studies to develop the most cost-effective diagnostic and thera-
sure offloading in decubiti and diabetic foot ulcers,44 assessment and peutic protocols. These will need to be developed and implemented by
optimization of local vascularity (arterial and venous) and of systemic multidisciplinary teams that together can provide the surgical, medical
factors (hematocrit, oxygenation, nutrition and the minimizing of and psychological expertise that patients with osteomyelitis so fre-
drugs that affect healing). quently need if they are to achieve the best possible outcomes. Devel-
opment of competencies in these teams is perhaps the greatest priority
Adjunctive Factors of all so that more patients can experience, now, the best of what
Careful attention to co-morbidities as listed above is important for current treatments can offer.
bone as well as for soft tissue healing. Of other specific adjunctive
ACKNOWLEDGMENT
therapies used, virtually none has an established evidence base. A sys-
tematic review of diabetic foot osteomyelitis found no evidence to The authors would like to acknowledge Anthony R. Berendt for his
support any specific adjunctive therapies in diabetic foot osteomyeli- previous material.
tis.90 In particular, the use of hyperbaric oxygen has been associated
with more complete healing and lower amputation rates in both ran- References available online at expertconsult.com.
domized and non-randomized studies in patients with diabetic foot
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76. Zuluaga A.F., Galvis W., Saldarriaga J.G., et al.: Etio- 120. 97. Bouillet R., Bouillet B., Kadima N., et al.: Treatment of
logic diagnosis of chronic osteomyelitis: a prospective 86. Tudisco C., Farsetti P., Gatti S., et al.: Influence of chronic osteomyelitis in Africa with plaster implants
study. Arch Intern Med 2006; 166(1):95-100. chronic osteomyelitis on skeletal growth: analysis at impregnated with antibiotics. Acta Orthop Belg 1989;
77. Atkins B.L., Athanasou N., Deeks J.J., et al.: Prospec- maturity of 26 cases affected during childhood. J 55(1):1-11.
tive evaluation of criteria for microbiological diagno- Pediatr Orthop 1991; 11(3):358-363. 98. Chang W., Colangeli M., Colangeli S., et al.: Adult
sis of prosthetic-joint infection at revision arthroplasty. 87. Parsons B., Strauss E.: Surgical management of chronic osteomyelitis: debridement versus debridement plus
The OSIRIS Collaborative Study Group. J Clin Micro- osteomyelitis. Am J Surg 2004; 188(1A Suppl.):57-66. Osteoset T pellets. Acta Orthop Belg 2007; 73(2):238-
biol 1998; 36(10):2932-2939. 88. Green S.A.: Osteomyelitis. The Ilizarov perspective. 243.
78. Jambhekar N.A., Kulkarni S.P., Madur B.P., et al.: Orthop Clin North Am 1991; 22(3):515-521. 99. Stengel D., Bauwens K., Sehouli J., et al.: Systematic
Application of the polymerase chain reaction on 89. Tu Y.K., Yen C.Y.: Role of vascularized bone grafts in review and meta-analysis of antibiotic therapy for
formalin-fixed, paraffin-embedded tissue in the recog- lower extremity osteomyelitis. Orthop Clin North Am bone and joint infections. Lancet Infect Dis 2001;
nition of tuberculous osteomyelitis. J Bone Joint Surg 2007; 38(1):37-49, vi. 1(3):175-188.
Br 2006; 88(8):1097-11101. 90. Berendt A.R., Peters E.J., Bakker K., et al.: Diabetic foot 100. Chen C.E., Ko J.Y., Fong C.Y., et al.: Treatment of dia-
79. Kobayashi N., Bauer T.W., Sakai H., et al.: The use of osteomyelitis: a progress report on diagnosis and a betic foot infection with hyperbaric oxygen therapy.
newly developed real-time PCR for the rapid identifi- systematic review of treatment. Diabetes Metab Res Foot Ankle Surg 2010; 16(2):91-95.
cation of bacteria in culture-negative osteomyelitis. Rev 2008; 24(Suppl.1):S145-S161. 101. Oliveira N., Rosa P., Borges L., et al.: Treatment of
Joint Bone Spine 2006; 73(6):745-747. 91. Game F.L., Jeffcoate W.J.: Primarily non-surgical man- diabetic foot complications with hyperbaric oxygen
80. Rak M., Barlic-Maganja D., Kavcic M., et al.: Com- agement of osteomyelitis of the foot in diabetes. Dia- therapy: a retrospective experience. Foot Ankle Surg
parison of molecular and culture method in diagnosis betologia 2008; 51(6):962-967. 2014; 20(20):140-143.
of prosthetic joint infection. FEMS Microbiol Lett 92. Jeffcoate W.J., Lipsky B.A.: Controversies in diagnos- 102. Berendt A.R.: Counterpoint: hyperbaric oxygen for
2013; 343(1):42-48. ing and managing osteomyelitis of the foot in diabetes. diabetic foot wounds is not effective. Clin Infect Dis
81. Howard-Jones A.R., Isaacs D.: Systematic review of Clin Infect Dis 2004; 39(Suppl. 2):S115-S122. 2006; 43(2):193-228.
duration and choice of systemic antibiotic therapy for 93. Tice A.D., Hoaglund P.A., Shoultz D.A.: Outcomes of 103. Barnes R.C.: Point: hyperbaric oxygen is beneficial for
acute haematogenous bacterial osteomyelitis in chil- osteomyelitis among patients treated with outpatient diabetic foot wounds. Clin Infect Dis 2006; 43(2):188-
dren. J Paediatr Child Health 2013; 49(9):760-768. parenteral antimicrobial therapy. Am J Med 2003; 192.
82. Nelson J.D.: Acute osteomyelitis in children. Infect Dis 114(9):723-728. 104. Cruciani M., Lipsky B.A., Mengoli C., et al.:
Clin North Am 1990; 4(3):513-522. 94. Daver N.G., Shelburne S.A., Atmar R.L., et al.: Oral Granulocyte-colony stimulating factors as adjunctive
83. Bachur R., Pagon Z.: Success of short-course paren- step-down therapy is comparable to intravenous therapy for diabetic foot infections. Cochrane Database
teral antibiotic therapy for acute osteomyelitis of therapy for Staphylococcus aureus osteomyelitis. J Syst Rev 2013; (8):CD006810.
childhood. Clin Pediatr (Phila) 2007; 46(1):30-35. Infect 2007; 54(6):539-544.
45
Infections of Prosthetic Joints and
Related Problems
SHADI PARSAEI | JAMES KEENEY | JONAS MARSCHALL
KEY CONCEPTS prosthetic material ages, from 0.5% after 1 year of implant surgery to
1.4% after 10 years.4 Compared with hip and knee joint arthroplasty,
• Prosthetic joint infections (PJI), most commonly seen after knee shoulder and other joint replacement surgeries are less frequently per-
and hip arthroplasty, continue to increase as the volume of joint formed; the respective infection risk is not well-characterized but
replacement surgery rises. appears to be between 0.7 and 2% within 5 years.5,6 The risk of infec-
• Few risk factors, such as cigarette smoking, are modifiable. tion increases significantly after repeat arthroplasty and may range
from 5% to 10%.
• Present day evidence-based preventive measures have signifi- A number of predisposing risk factors for PJI have been identified.
cantly lowered the risk of PJI.
Diabetes,7 obesity,8,9 immunosuppression and rheumatoid arthritis10
• Management of PJI requires a multidisciplinary effort by the are comorbidities predictive for PJI in analyses of large populations.
orthopedic surgeon, infectious disease physician, clinical micro- Cigarette smoking is among the few modifiable risk factors and should
biologist and physical therapist. be discontinued prior to surgery. History of a previous PJI of the same
• Few comparative effectiveness studies exist to optimally guide joint11 increases infection risk secondary to increasingly damaged
the management team. tissues and impaired circulation. Intraoperatively, procedure duration
is a major determinant of subsequent infection risk.12 In the postopera-
• Best outcomes are achieved with a two-stage approach: tive period, problems with wound healing, such as hematoma forma-
removal of the infected joint, targeted antibiotic treatment, tion and superficial wound infection, increases the risk of PJI, as does
followed by prosthetic joint implantation after a certain time
concurrent infection at another body site.
interval.
In attempts to identify patients at high risk for the development of
PJI and to further quantify this, Berbari and colleagues at the Mayo
Clinic developed a risk prediction model based on factors such as body
Introduction mass index, immunosuppression, previous surgery in the respective
As unprecedented numbers of the world’s population enter an age joint, ASA score, and duration of surgery. This score has not been vali-
where osteoarthritis may affect joint health, joint replacement surgery dated but may provide stratification for reporting purposes and when
(i.e. arthroplasty) has become quite commonplace. Arthroplasties are measuring the impact of interventions.13 Currently, the National Noso-
performed for a variety of reasons but have a common goal: to improve comial Infections Surveillance (NNIS) score is widely used in the sur-
patient quality of life by alleviating pain, restoring joint function and veillance of all types of postoperative infections to account for
preserving mobility. Unfortunately, a small percentage of patients may differences in the case mix and is based on 1) ASA score, 2) degree of
experience complications, among the most serious of which is the contamination, and 3) procedure time.
development of prosthetic joint infection (PJI). While preventive prac-
tices have attenuated the individual risk and the incidence rate of PJI, Pathogenesis and Pathology
the witnessed increase in global prevalence corresponds to the sheer The pathogenesis of PJI is a complex and dynamic process of events.
increase in volume of arthroplasties performed.1 Infection of an implanted joint occurs via three main routes: 1) inocu-
Management of foreign body-related infections is challenging as lation at time of implantation; 2) per continuitatem (e.g. the develop-
they require considerable logistic effort between the patient and the ment of a superficial wound infection that subsequently tracks down
multidisciplinary medical team. Patients often need diagnostic testing, to the implant); and 3) hematogenous seeding.
surgery, hospitalization and extended antibiotic therapy with decreased In joint surgery that does not involve replacing the joint surface,
quality of life until joint function is restored. The economic impact of the inherent risk of infection is considerably lower; therefore, increased
PJI is not solely limited to direct hospital and medication costs, but susceptibility to infection is due to presence of foreign material as it
also derives from patient work days lost. The economic and societal provides a surface to support bacterial adhesion. Infection at time of
burden of PJI should not be underestimated as it is expected to increase prosthesis insertion is closely related to the biofilm-forming capacity
significantly given the number of projected arthroplasties.2 of micro-organisms that contaminate the surgical site.14 ‘Biofilm’ refers
In the following text, we will discuss the epidemiology, risk factors, to a complex bacterial community within an extracellular matrix.
clinical features, diagnostic workup, medical and surgical management Anchored on the surface of foreign material, micro-organisms behave
and, lastly, preventive measures for PJI. It is important to highlight that differently than in their free-floating planktonic state. By lying dormant
the management approach can differ depending on the geographic or fostering antibiotic-resistant phenotypes, this community acts as a
area, reflective of the scarcity of high-level evidence. shield to avoid the immune system’s local inflammatory response at
the host-prosthesis interface. Abscess and sinus tract formation may
Epidemiology ensue as means of tissue decompression. With sustained inflammation,
Forty years ago, 1 out of 10 patients who underwent total joint arthro- osteoclast activation with eventual bone loss and implant loosening
plasty developed an infection.3 In the age of widely implemented sur- can occur.
veillance systems for postoperative infections and evidence-based best Hematogenous seeding requires bacteremia, which may or may not
practices for infection prevention, rates of PJI are lower than reported have a recognized source. Although an infrequent event,15 seeding of
in early registries: 0.5–1% in total hip arthroplasty (THA) and 1–2% the prosthetic joint is a real concern during Staphylococcus aureus
in total knee arthroplasty (TKA). The risk of infection increases as the bacteremia,16 as this pathogen can cause metastatic infection.
399
Microbiology suffice for the purpose of decision-making. Other classification systems

include one proposed by McPherson et al.24 Important determinants
The microbiology of PJI is mostly defined by skin organisms. for classifying PJI include implant stability and the integrity of the
Coagulase-negative staphylococci (CNS) and Staphylococcus aureus periprosthetic tissue envelope. Both aspects are relevant for surgical
constitute half of all PJI. Staph. aureus is an organism often encoun- management and outcome.
tered at any time following joint implantation. While it has a predilec-
tion for causing acute PJI, it can exhibit a different phenotype, termed
‘small-colony variants’– notable for slower growth and intracellular Diagnosis
sequestration. In contrast, CNS are notable for their biofilm-forming The diagnosis of PJI is challenging as it requires synthesis of different
capacity and may present with low-grade to acute severity and in both modalities. A thorough history, including time of implant surgery, time
early and late infections. Streptococci (any group) and enterococci are from surgery to symptom onset and history of previous surgeries in
responsible for approximately 10% of PJI. Propionibacterium acnes, an that joint are of great importance. History of implant material intoler-
anaerobic gram-positive organism of low virulence, can be associated ance or antibiotic allergies are also relevant. In addition to the physical
with shoulder PJI. A skin commensal, it may be difficult to ascertain exam, establishing a diagnosis of PJI requires information from radio-
whether it is a true pathogen. graphic studies and laboratory tests (e.g. peripheral blood white cell
Gram-negative PJI comprise 15% of all infections.17 When encoun- count, inflammatory markers, joint fluid analysis and microbiology).
tered, they are more frequently seen in older patients compared with However, some clues, such as the operative site appearance, intraopera-
PJI due to other pathogens. Nearly one-fifth of PJI are polymicrobial. tive cultures and histopathologic specimens, can only be obtained with
Growth of multiple organisms suggests a shorter time frame since the surgery. The clinician should consider the pretest probability of a
original surgery.18 Clinically, soft tissue defects and wound drainage are patient having a PJI when synthesizing the available information and
seen. Fungi constitute 1% of all infections, largely consisting of Candida be aware that there are no robust clinical predictors of PJI. Until
species. Immunosuppression is a predisposing factor. recently, one additional complicating feature was that the criteria to
Another category of periprosthetic infections are the so-called define PJI were not uniform. To address this, Parvizi and colleagues
‘culture-negative PJI’,19 encountered in at least 7% of all PJI.19 It is proposed a revised approach to PJI diagnosis in 2011.25 However, in
unclear how often these culture-negative PJI are true PJI, and, if indeed 2012, an expert panel consisting of North American and European
infections, what might be the causative pathogen(s). It is fair to assume professionals issued a consensus statement to serve as guidelines for
that sampling bias (number and location of sampling) can lead to both diagnostic criteria and management of PJI.26 Per this statement,
under-recognition of the most common pathogens. Previous antibi- the following findings are considered definitive evidence of PJI: 1) a
otic exposure suppressing bacterial growth at time of culture, fastidi- sinus tract that communicates with the prosthesis, 2) purulence around
ous micro-organisms not detected by conventional culturing, and the joint without alternative explanation, and 3) at least two intraop-
noninfectious inflammatory entities are some proposed explanations. erative cultures with the same pathogen. There are many clinical con-
PCR methodology has been used to identify possible organisms,20–22 stellations that are less predictive of PJI.
however, results have been mixed. Recently, a study suggested that the
role of PCR may be limited to patients with antibiotic exposure before LABORATORY (INCLUDING MICROBIOLOGY LAB)
diagnostic workup.21 Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
along with the peripheral white blood cell count (WBC) are often
Clinical Features obtained as part of the routine workup in patients with suspected PJI.
The spectrum of possible clinical features is broad and, in part, These tests are readily available in clinical laboratories but are nonspe-
explained by the degree of virulence of the causative organism, func- cific markers of inflammation that can be elevated in many different
tionality of the host’s immune defense, degree of tissue compromise clinical scenarios. As supported by a meta-analysis of laboratory
and route of infection. Pain is universally present in PJI, typically studies, no single laboratory value can be used to make the diagnosis
continuous in nature, independent of whether the infection occurred of PJI.27 Elevated CRP has a pooled sensitivity of 88% and specificity
days or years after implantation. Local erythema, warmth, swelling, of 74%, ESR a sensitivity of 75% and a specificity of 70%, respectively.
joint effusion, purulent discharge and sinus tract formation are all The Infectious Diseases Society of America (IDSA) guidelines recom-
possible signs and symptoms; however, their absence does not rule out mend obtaining one of the two tests while acknowledging that a com-
PJI. Differentiating these features from other inflammatory processes bination yields better diagnostic performance.26 Normal inflammatory
can be challenging. For example, aseptic loosening can present with markers may suggest an alternative diagnosis to PJI.28 The use of syno-
intermittent, subacute to chronic pain and loss of functionality. Cel- vial fluid biomarkers such as interleukin-6 and procalcitonin29 have
lulitis in the tissues overlying the prosthesis can present with redness been examined in few studies, but are not yet widely available.
and tenderness to palpation but does not necessarily imply deeper If the diagnosis remains unclear, arthrocentesis may provide
infection. Other potential clinical scenarios include progressive infec- additional information. After excluding patients with inflammatory
tion with osteomyelitis of the long bones and secondary bloodstream conditions and those who presented early after TKA, Trampuz and
infections. colleagues identified a synovial fluid leukocyte count above 1700/µL
to have 94% sensitivity and 88% specificity for PJI; a differential count
CLINICAL CLASSIFICATION of >65% neutrophil percentage was associated with 94% sensitivity
Many experts in the field have classified PJI by ‘route of infection’. and 98% specificity.30 In a larger study examining patients after TKA,
Infection at the time of surgery and contiguous spread may be subsumed a cut-off of 1100 cells/µL yielded 91% sensitivity and 88% specificity,
as locally induced infections, whereas hematogenous seeding originates respectively, and neutrophil >64% had 95% sensitivity and specificity
from a distant focus and may occur at any stage of the implant life and for PJI.31 When patients with inflammatory arthritis were included
is thought to be the principal mode of infections that occur years after and a higher threshold of nucleated cells was chosen, similar test
prosthetic joint placement. ‘Time to presentation’ is the basis of an characteristics could be elicited.32 These thresholds are closer to those
older classification system where PJI is defined by the time period used in native joint arthritis. A recent meta-analysis confirmed the
between implantation and symptom onset. An infection within 3 value of leukocyte count and neutrophil percentage as means for iden-
months is considered ‘early’, between three and 24 months as ‘delayed’, tification of PJI, with better performance in the TKA setting.33 Unless
and after 24 months, ‘late’.23 While primarily designed for optimal antibiotics have been started prior to arthrocentesis, synovial fluid
surgical management, it may provide clues about the etiology of infec- cultures are essential in identifying the causative pathogen. The pooled
tion (Figure 45-1). The clinical utility of this classification has been sensitivity was 72% and 95% specificity in a meta-analysis of preopera-
questioned and differentiating acute from chronic infection may tive cultures.34 Given low sensitivity, it has been suggested that synovial
Chapter 45 Infections of Prosthetic Joints and Related Problems 401
PJI classification
Time to presentation scheme
Principal mode Clinical presentation Common pathogens Clinical associations

of infection
0
Contiguous Constant joint pain Staph. aureus RA
EARLY
Effusion GNB Older patients

Overlying erythema Polymicrobial Surgical site infection
Sinus tract Sinus tracts
3
Contiguous ± features from above (< virulent org) Shoulder arthroplasty
(tends to more subtle) Coag-neg staph
Time to presentation
Persistent joint pain P. acnes

(in months)
DELAYED
24
Hematogenous ± features from above Staph. aureus
seeding ± systemic symptoms
LATE
Figure 45-1 PJI classification.
fluid be inoculated into blood culture bottles to improve microbial If there is no pathogen detected with conventional aerobic and
recovery.35 anaerobic cultures, 16S rRNA PCR may be a useful tool.41 This molecu-
Intraoperative aerobic and anaerobic cultures are the gold standard lar method relies on the detection of conserved genetic information in
for detecting an infection. In select patients, mycobacterial and fungal bacteria and is fast and sensitive. In general, it does not allow for
cultures may be added. Atkins and colleagues showed that with three determining antibiotic resistance; however, new kits (i.e. Xpert®
samples growing the same bacteria, the likelihood of PJI, compared to MRSA/SA and GenoType® BC kit) can detect the presence of the mecA
histopathology as the gold standard, was 94%.36 The consensus is to resistance gene.42
obtain at least three samples of periprosthetic tissue, but ideally, five Sonication, an optional adjunct to conventional cultures, consists
or more. A single sample with Staph. epidermidis may be discarded as of ultrasound waves in a fluid bath that removes biofilm layers and
potential contaminant but the same does not apply to a single culture planktonizes embedded bacteria from the surface of the prosthesis. The
of Staph. aureus. Gram stain is not required given its low sensitivity.37,38 rationale is that prosthetic material biofilm needs to be removed for
We do not recommend incubating cultures for longer than 7 days as higher culture yield.43,44 In combination with 16SrRNA PCR, sonica-
even fastidious anaerobic organisms such as P. acnes usually grow tion has good discriminatory power between PJI and aseptic loosen-
within this time frame. We advise using tissue specimens instead of ing.45 It is somewhat better than vortexing, which can be used in labs
swabs, even in the setting of sinus tract formation,39 as they are more where sonication is not available.46 Both techniques appear helpful
reliable. If the patient is febrile, blood cultures should be added to the when the patient had antibiotic exposure prior to explant. Addition-
diagnostic workup. ally, other novel, non-culture-based technologies are on the horizon
Histopathology has been the gold standard in demonstrating neu- (e.g. Matrix-Assisted Laser Desorption/Ionization-Time of Flight
trophilic inflammation in the periprosthetic tissues and may be uti- (MALDI-TOF)).
lized when the diagnosis of PJI has not been established preoperatively.
However, this feature is not specific to infection,40 is subject to sam- RADIOLOGY
pling bias, and depends on the pathologist’s skills; in addition, histo- Imaging alone cannot distinguish PJI from noninfectious problems,
pathology does not yield the causative pathogen. Although mentioned but may provide insight regarding the presence of infection. Therefore,
in the IDSA practice guidelines, it is not thought to provide the best current guidelines recommend obtaining a plain radiograph. Bone
evidence for PJI. lucency at the bone-cement interface, osteolysis, and subperiosteal
bone growth are findings potentially suggestive of an underlying infec- DAIR (debridement, antibiotics and implant retention) may be
tious process. Radiographic changes can be detected in about 50% of chosen if an infection manifests early after arthroplasty and if the tissue
septic joints, depending on the duration of untreated infection. Use of envelope is largely intact. In these cases, it is felt that the implant can
both CT and MRI are limited due to artifacts from the prosthetic be ‘saved’ and does not necessitate removal. Indeed, this approach can
material and are therefore not commonly obtained. Bone scans are be successful if the pathogen is known and targeted antibiotic treat-
nonspecific for detection of infection but a related modality, radiola- ment is possible.55 Recent data from a large prospective multicenter
beled leukocyte scintigraphy, represents the imaging gold standard, cohort suggested that close to 60% treated with DAIR demonstrate
despite the same problem with frequent false-positive tests.47 FDG-PET/ successful outcomes; 30% eventually required implant removal given
CT is a novel method combining nuclear imaging with CT methodol- failure, and 10% were placed on long-term suppressive antibiotics as
ogy. Still relatively expensive, its role remains to be determined.48 ongoing infection was suspected. Certain pathogens respond well to
this approach (e.g. ciprofloxacin-susceptible gram-negative bacteria).56
DIFFERENTIAL DIAGNOSIS DAIR is less likely to result in a successful outcome if Staph. aureus is
In a clinical scenario concerning for PJI, a few diagnoses deserve con- involved. Staphylococcal PJI managed with DAIR exhibited better out-
sideration. Aseptic loosening, the most commonly encountered, refers comes when treated with a biofilm-active regimen.57
to a mechanical loosening of the prosthetic material and typically is Joint excision (i.e. resection arthroplasty) is one of the approaches
accompanied by joint pain and a sensation of instability with move- of last resort, leaving the patient without a functional joint. It may be
ment. Radiographically indistinguishable from PJI, it demonstrates suitable for non-ambulating patients, those with limited bone stock,
periprosthetic lucency or hardware dislocation but, as its name sug- and if no options for medical treatment remain. A variation of this
gests, has negative cultures. In contrast, the term ‘mechanical failure’ approach is arthrodesis, which irreversibly removes joint function;
is reserved for material problems such as prosthesis component frac- this is a potential option for salvaging knee or ankle joints. Amputa-
ture – a relatively rare occurrence. Metallosis is a local and chronic tion of the infected limb is rarely necessary nowadays.
inflammatory reaction caused by the release of metal debris from the Lastly, long-term antibiotic suppression is an option for poor
aging pseudocapsule.49 Gout can affect prosthetic joints and is identi- surgical candidates, if contraindication to surgery exists, or in select
fied by crystals in microscopy.50 patients who do not wish to undergo further procedures. It consists of
long-term administration of oral antibiotics directed against the
known pathogen without attempting to cure the infection. How much
Management this approach can reduce the implant failure rate in the long term is
Once the diagnosis of PJI has been established, it is essential for ortho- uncertain.58
pedic and infectious diseases services to partner in management. Man- In summary, the success of the surgical management depends
agement success depends on thorough debridement of infected tissue, largely on the strategy chosen and the thoroughness of the operating
removal of the prosthetic joint (if indicated) and targeted antimicro- surgeon when debriding infected tissue. The details of the surgical
bial treatment. Often, the medical management will follow the surgical approach, however, are not easy to standardize and to compare across
management as favored by the orthopedic surgeon. The modalities are: centers; therefore, considerable variation exists. Additionally, the
1) two-stage exchange; 2) one-stage exchange; 3) debridement, antibi- value of antibiotic-impregnated spacers has never been reliably
otics and implant retention (‘DAIR’); 4) definitive resection with or determined.59
without arthrodesis; and 5) amputation. It is imperative that com-
munication between orthopedics and infectious diseases continue for MEDICAL MANAGEMENT
the entire treatment duration and other team members, such as nurses, Much information on medical treatment has been inferred from the
physical therapists and primary care providers are included in the osteomyelitis and septic arthritis literature, but whether these findings
treatment plan. The IDSA and other entities have published manage- can be generalized to PJI, is unclear. Studies suggest that the success
ment guidelines.26,51 Observing evidence-based guidelines for PJI has rates of intravenous and oral treatment are similar but state that the
been documented to improve patient outcomes.52 amount of scientific evidence is limited.60,61
Different management cultures prevail in different geographic
SURGICAL MANAGEMENT areas. In North America, typical empiric treatment consists of gram-
In two-stage exchange, the infected joint is explanted, periprosthetic positive ± gram-negative coverage (e.g. vancomycin ± a β-lactam anti-
tissue is debrided and an antibiotic-impregnated articulating spacer biotic). This is a reflection of high MRSA prevalence and the fact that
(such as vancomycin, aminoglycosides or clindamycin) is placed for CNS are often methicillin-resistant, in which case vancomycin is the
tissue expansion and low level functionality between stages. Antibiotic standard treatment. In areas of low MRSA prevalence, a first genera-
treatment is delivered, then followed by an antibiotic-free period. This tion cephalosporin alone may be sufficient. Definitive treatment targets
allows for monitoring of antibiotics to evaluate for infection recur- the detected pathogen and its resistance pattern. Please consult the
rence prior to joint reimplantation. Some experts recommend com- following paragraphs for more information regarding recommended
pleting joint fluid analyses during this window. This interval often antibiotics for individual pathogens. Very limited data are available
varies (usually 2–8 weeks) based on the surgeon’s preference. While from comparative effectiveness studies and randomized controlled
this two-staged approach requires two hospital admissions, multiple trials; most evidence is based on uncontrolled observational studies.
procedures, time without a functional joint and considerable logistic Methicillin-susceptible staphylococcal species, more commonly
effort, it is characterized by higher success rates compared to one-stage implicated in PJI, can be treated with anti-staphylococcal penicillins,
exchange.51 However, there are no randomized control trials to guide such as oxacillin, or a cephalosporin such as cefazolin. An alternative
optimal management.53 In one review of 30 studies, with >1000 of particular value for Outpatient Parenteral Antimicrobial Therapy
patients, the overall success rate of two-stage exchange was 87%.54 It (OPAT) is ceftriaxone, a once-daily administered cephalosporin.62 The
is the preferred approach in the USA and for virulent pathogens such standard treatment for both MRSA and CNS is vancomycin. The deci-
as Staph. aureus. sion whether to treat CNS has to be weighed carefully as they may be
One-stage exchange is a straightforward replacement of the contaminants, particularly if there is only a single positive specimen.
infected prosthesis with new hardware accompanied by thorough Daptomycin is a newer antibiotic that has assumed a significant role
debridement of infected tissue. Its success may be hampered by for PJI treatment as a second-line option to vancomycin and may
residual infection that can be transferred to the new implant. Reinfec- specifically be of value for treating MRSA PJI.63,64 The study by Byren
tion may occur in 3–26% of cases. Success is most likely with less viru- et al.63 (daptomycin compared against standard treatment) is one of
lent organisms. It is usually not selected in cases with a sinus tract the few randomized trials published to date. Daptomycin is also active
present. against other staphylococci, streptococci, and, although less studied in
Chapter 45 Infections of Prosthetic Joints and Related Problems 403
osteoarticular infections, enterococci.65 Enterococci, while mostly of as endorsed by the Centers for Disease Control and Prevention (CDC),
low virulence, can be challenging to treat; if susceptible, ampicillin is IDSA, and other organizations.73 Applied to joint replacement surgery,
the antibiotic of choice. these preventive measures cover the following areas: 1) patient selec-
For gram-negative PJI, β-lactams are preferred (i.e., penicillins/β- tion for arthroplasty; 2) skin preparation; 3) perioperative antibiotic
lactamase-inhibitor combinations, cephalosporins and carbapenems). prophylaxis; 4) postsurgical management; and 5) surveillance for post-
Oral ciprofloxacin is an alternative for susceptible organisms. operative infection as recommended by both the US CDC and their
Gram-positive anaerobes (e.g. P. acnes), present in up to 10% of European counterpart, the ECDC (www.ecdc.europa.eu). PJI is con-
samples, are covered by common empiric treatment options, such as sidered a surgical site infection if it occurs within 1 year of the index
the combination of vancomycin with a third-generation cephalospo- surgery (pointing to the important role of post-discharge surveillance
rin. The drug of choice for P. acnes is penicillin. Cephalosporins are an for obtaining accurate rates). These data is invaluable when measuring
alternative, but vancomycin is also active. For gram-negative anaer- the impact of infection prevention interventions.
obes, metronidazole should be added. Preoperatively, modifiable risk factors (smoking, hyperglycemia)
For culture-negative PJI, it is more difficult to determine the best should be addressed. Immunosuppression is not a contraindication to
medical treatment. Treatment must be selected based on assumptions arthroplasty. In HIV-infected patients, the CD4 cell count should
about the likely organisms and usually includes vancomycin and a approach normal levels. For those receiving immunosuppressive
β-lactam for gram-negative coverage. There is wide variation of pre- therapy, it is advised that the responsible medication be temporarily
ferred regimens.66 withheld. Screening for staphylococci and corresponding decoloniza-
tion has been shown to reduce SSI rates in a landmark study by Bode
Duration of Treatment et al.74 This requires considerable logistic effort, may generate mupi-
The optimal duration of treatment for PJI has never been well- rocin resistance and does not protect against recolonization. A meta-
established and follows the surgical approach taken. Moreover, the analysis including orthopedic surgeries found that infection rates
selected mode of delivery varies among different geographic areas. could be reduced by decolonizing all patients or only those with
Early studies of osteomyelitis suggested that the likelihood of infection confirmed Staph. aureus carriage.75 Despite these data, screening and
recurrence is higher if treatment is shorter than 4 weeks. In the USA, decolonization is not a recommended measure. Antibiotics typically
treatment duration is usually 6–8 weeks via a peripherally-inserted administered for perioperative prophylaxis include first and second
central catheter (PICC). This intravenous course is rarely followed by generation cephalosporins (e.g. cefazolin or cefuroxime). Exceeding 24
oral antibiotics. Comparisons of shorter versus longer durations have hours of prophylaxis has not been shown to reduce infections. Whether
never been done for PJI (e.g. comparing 4 versus 6 weeks). A recent vancomycin should be part of the perioperative prophylaxis in areas
nonrandomized study was able to document similar outcomes with 6 of high MRSA prevalence has been debated;76,77 no threshold of MRSA
weeks versus 12 weeks of antibiotics.67 In Europe, common strategies prevalence has been determined that would make the addition of van-
include an initial intravenous course of 2 weeks, followed by up to 10 comycin useful.78 We recommend vancomycin for known MRSA car-
weeks of oral treatment. The IDSA guidelines suggest that a step-down riers and those with β-lactam allergies.
approach from intravenous to oral medication is in order as long as State-of-the-art instrument sterilization is key in prevention. Addi-
an antibiotic with high bioavailability is selected (e.g. ciprofloxacin or tionally, the surgical site should be prepared with hair clippers rather
trimethoprim/sulfamethoxazole). The scientific evidence behind this than razors. Intraoperatively, a checklist is recommended to fulfill all
strategy is weak. preventive measures (including skin antisepsis with an alcoholic
chlorhexidine preparation or equivalent, surgical hand disinfection,
The Role of Rifampin
maximum barrier precautions, limited number of personnel in the
Rifampin is a bactericidal drug often used in combination with other operating room (OR), and others). OR traffic should be restricted to
agents for treatment of staphylococcal infections. Rifampin may affect the minimum. Room air particles and airborne bacteria should be
bacteria within biofilm given its effect on stationary-phase bacteria. As reduced as much as possible. Laminar air flow is no longer thought to
biofilm formation on retained prosthetic material is associated with be a required element of OR ventilation.79 Keeping the operating time
recurrence of infection, rifampin is considered an important adjunc- as short as possible is associated with lower infection rates; however,
tive treatment. Zimmerli and colleagues documented the added benefit this depends on the complexity of the surgery, among other factors.
of treating retained infected prostheses with rifampin along with cip- Postoperatively, the risk of late PJI is harder to influence. Dental
rofloxacin for methicillin-susceptible staphylococci.68 Additional data procedures were thought to represent a clear risk for hematogenous
support these findings while suggesting that thorough debridement is infection. Updated recommendations by the American Dental Associa-
essential for success of combination therapy.69,70 Drawbacks with tion and the Academy of Orthopaedic Surgeons state that evidence for
rifampin are frequent occurrences of side effects such as hepatotoxicity PJI during dental work is low and routine antibiotic prophylaxis is not
and the potential for drug–drug interactions. Whereas ciprofloxacin is advised.80 Likewise, asymptomatic bacteriuria does not require antibi-
not recommended for many infections (due to adverse events and otic treatment as it has not significantly increased the risk of PJI.81
increasing gram-negative resistance), when combined with rifampin, Some data, however, challenge this recommendation.82
it is frequently utilized as an oral regimen for treatment of staphylococ-
cal PJI in Europe. Combination therapy with intravenous medications
such as vancomycin or cephalosporins has not been extensively tested. Conclusion
Monitoring the Treatment Response We will continue to see an increase in PJI as the number of implanted
Unlike other infections, no test of cure exists for PJI. Clinical response, artificial joints continues to rise. While a number of preventive mea-
functional status and laboratory parameters (CRP, ESR) can be used sures, diagnostic tools and therapeutic aspects have been elucidated,
to determine whether treatment can be stopped. Serial CRPs have been much remains to be learned as our current management strategies are
studied as a means to determine when antibiotic treatment can be built on a handful of comparative studies. In a survey of research needs
safely discontinued but their value remains uncertain.71 How to best identified by infectious disease practitioners, the highest rank was
monitor treatment response remains an understudied area. assigned to randomized controlled trials on PJI.83 With further study,
we may better understand the role of additional prevention measures
(coated prosthetic implants, Staph. aureus vaccines), diagnostics (soni-
Prevention cation coupled with molecular techniques) and treatment (antimicro-
Best practices for prevention of surgical site infections was first laid bial combinations).
out in detail by Mangram et al. in 1999.72 Since then, information has
been accumulated and parlayed into more recent recommendations, References available online at expertconsult.com.
KEY REFERENCES
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Infect Dis 1998; 27(5):1247-1254. series and review of the literature. Infect Dis Clin Pract Watters W. 3rd, Rethman M.P., Hanson N.B., et al.: Preven-
Berbari E.F., Marculescu C., Sia I., et al.: Culture-negative 2008; 16:224-229. tion of orthopaedic implant infection in patients under-
prosthetic joint infection. Clin Infect Dis 2007; Kurtz S.M., Lau E., Watson H., et al.: Economic burden of going dental procedures. J Am Acad Orthop Surg 2013;
45(9):1113-1119. periprosthetic joint infection in the United States. J 21(3):180-189.
Beswick A.D., Elvers K.T., Smith A.J., et al.: What is the Arthroplasty 2012; 27(8 Suppl.):61-65 e1. Wieland B.W., Marcantoni J.R., Bommarito K.M., et al.: A
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prostheses? Systematic review of longitudinal studies in on controversial issues in the diagnosis and treatment of for osteoarticular infections due to methicillin-
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Velez D., et al.: Are antibiotics necessary in hip arthro- Mangram A.J., Horan T.C., Pearson M.L., et al.: Guideline Zimmerli W., Widmer A.F., Blatter M., et al.: Role of
plasty with asymptomatic bacteriuria? Seeding risk with/ for prevention of surgical site infection, 1999. Hospital rifampin for treatment of orthopedic implant-related
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471(12):3822-3829. Control Hosp Epidemiol 1999; 20(4):250-278, quiz 79-80. Foreign-Body Infection (FBI) Study Group. JAMA 1998;
Esteban J., Sorli L., Alentorn-Geli E., et al.: Conventional Marculescu C.E., Berbari E.F., Hanssen A.D., et al.: Outcome 279(19):1537-1541.
and molecular diagnostic strategies for prosthetic joint of prosthetic joint infections treated with debridement
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Chapter 45 Infections of Prosthetic Joints and Related Problems 404.e1
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46
Lyme Disease
JOHN N. AUCOTT | BENJAMIN J. LUFT
KEY CONCEPTS Burgdorfer and colleagues isolated and cultivated the causative agent
B. burgdorferi from the midgut of Ixodes ticks, and others soon detected
• Lyme disease is an increasingly common tick-borne infection the organism in clinical specimens.5
that has strong geographic and seasonal epidemiology.
• Borrelia burgdorferi, the agent of Lyme disease, is a spirochetal Epidemiology
bacterium that has evolved unique mechanisms to persist in its Lyme borreliosis occurs widely throughout North America, Europe
host reservoir and in man. and Asia.6 In the USA Lyme disease is the most common vector-borne
• The human host immune response to B. burgdorferi is often disease, and the seventh most commonly reported of all notifiable
inadequate to eradicate untreated infection. infectious diseases.7 A national surveillance case definition was adopted
in the USA in 1990 to establish uniform and specific diagnostic criteria
• Lyme disease is a multisystem infection with early and late
for surveillance and was revised most recently in 2011.8,9 Most cases in
manifestations that may occur over weeks to years.
the USA have been reported in the northeast, upper Midwest and
• Erythema migrans, the hallmark skin lesion of initial infection, Pacific coastal regions. Even within these regions, local distribution is
has a variety of appearances including the classic ring within a highly variable with focal epidemics of disease.10 Since surveillance was
ring target lesion, as well as non-classic presentations that may begun by the Centers for Disease Control and Prevention (CDC) in
not be easily recognized by patients and inexperienced 1982, the number of cases has continued to expand dramatically with
practitioners.
approximately 30 000 cases reported annually. Analysis of laboratory
• Neurologic Lyme disease may present in the early dissemi testing results from large commercial labs in the USA suggests that the
nated phase of infection with any combination of aseptic men- number of cases of Lyme disease may be 10-fold higher than reported
ingitis, cranial nerve palsy (especially seventh nerve) and to the CDC, with an estimated true number between 240 000 and
radiculopathy. 444 000 infected patients in 2008.11 The yearly incidence in high risk
• The most common late manifestation of Lyme disease in North populations such as participants in Lyme disease vaccine trials may be
America is oligoarthritis, typically presenting as knee synovitis above 1 in a 100, with seroprevalence as high as 5%.12
with swelling. The upsurge in cases in the USA is a result of reforestation of land
used for farming a generation ago, creating environments suitable for
• The diagnosis of Lyme disease depends on the stage of infec-
the deer population expansion and the outward migration of people
tion. The presence of typical manifestations of disease with
serologic confirmation is most useful for later stages of disease. from cities to suburban areas.13 In the last decade, the geographic range
of Lyme disease has continued to expand with cases now being reported
• Treatment of Lyme disease is primarily with oral antibiotics such with increasing frequency in northern New England, Wisconsin, Vir-
as doxycycline and amoxicillin. Intravenous antibiotics are ginia and Pennsylvania.14 Areas of emerging risk have been predicted
reserved for neurologic disease and difficult to treat cases of based on sampling of infected Ixodes nymphs in eastern Maine, the
late Lyme arthritis.
Illinois/Indiana border, the New York/Vermont border and south-
• Post-treatment Lyme disease syndrome may occur after the western Michigan.15
treatment of any stage of Lyme disease and may present with
chronic symptoms that overlap with fibromyalgia and chronic Enzootic Cycles of
fatigue syndrome.
B. burgdorferi Infection
The infecting organism, B. burgdorferi, is maintained in and transmit-
ted by ticks of the Ixodes ricinus complex, including Ixodes scapularis
in the northeast and central USA, Ixodes pacificus on the west coast of
History the USA, Ixodes ricinus in Europe and Ixodes persulcatus in Asia (see
Lyme borreliosis is caused by the tick-borne spirochetes of the Borrelia Chapter 12).
burgdorferi sensu lato complex. The first documented case of Lyme The life cycle and feeding habits of I. scapularis are well understood
disease was found by polymerase chain reaction (PCR) of DNA from (Figure 46-1). This tick has a three-stage life cycle (larva, nymph and
a 5300-year-old deceased human recovered from a frozen glacier in adult) that spans 2 years. Larvae hatch from fertilized eggs in late
the Italian Alps.1 The cutaneous manifestation, acrodermatitis chron- spring and feed once for 2 or more days in midsummer. Preferred
ica atrophicans (ACA), was first described in Germany by Alfred hosts are rodents and other small mammals.16 The following spring
Buchwald in 1883. Arvid Afzelius subsequently described erythema they molt into nymphs and feed again for 3 or 4 days, with the same
chronicum migrans (ECM) in Sweden, and speculated that the rash host range. Humans, who are not the preferred host, usually acquire
was associated with tick bites.2 French physicians Garin and Bujadoux Lyme disease from infected nymphs. After this second blood meal, the
reported the first case of a neurologic manifestation, meningoradicu- nymphs molt into adults. Adult I. scapularis has a narrower host range,
loneuritis, and Bannwarth described lymphocytic meningitis. In 1975, with a preference for deer. Mating occurs on deer when the female
Steere and colleagues delineated the disease in the USA while investi- deposits her eggs and the cycle begins anew.
gating a cluster of cases thought to be juvenile rheumatoid arthritis in In endemic areas, 30% or more of nymphs may be infected with
Lyme, Connecticut.3 The acute skin lesion erythema migrans (EM) was B. burgdorferi; the rate of infection in adult ticks may be even higher,
soon linked to the development of arthritis, and seroepidemiologic but infection rates in unfed larvae are less than 1%. This pattern sug-
studies implicated Ixodes ticks as the vectors responsible for EM.4 Willy gests that ticks acquire B. burgdorferi from reservoir hosts rather than
405
Life cycle of Ixodes scapularis
ter Spr
win i ng
nd
ll a
Fa
Eggs laid
Adults
mate
Larva develops
Fem in 1 month
ale
Nymph Male
Ye Larva feeds
molts to a
r1
adult tick
Summer
Summer
ar
Ye
2
Nymph feeds
Nymph
Larva
dormant
er
Sp i nt
rin
g an dw
Fall
Figure 46-1 Life cycle of Ixodes scapularis (also known as Ixodes dammini). The life cycle spans 2 years. Eggs hatch in the spring; six-legged larvae develop and feed
once in the summer, acquiring Borrelia burgdorferi from their preferred host, the white-footed mouse. Next spring, the larvae molt into eight-legged nymphs, which
feed once; mice are the preferred host, humans not being necessary for the ticks’ life cycle. The nymphs molt into adult male and female ticks; mating often occurs
while the female feeds on a deer, and the male may remain on the deer, the female falling off and then laying eggs. (Adapted, with permission, from an illustration by
Nancy Lou Makris in Rahn D.W, Malawista S.E. Ann Intern Med 1991; 114: 472–81.)
transovarian transmission. The white-footed mouse, Peromyscus leu-

copus, is the primary reservoir host for I. scapularis. As long as the Biology of B. burgdorferi
organism, ticks, small rodents, especially mice and deer are all present Borrelia burgdorferi sensu lato complex encompasses several species of
in the environment, the enzootic cycle will continue. Borrelia that cause human infection. Borrelia burgdorferi sensu stricto
Variation in vector–host prevalence and relationships provide the (hereafter referred to as B. burgdorferi) is the etiologic agent of Lyme
primary explanation for regional variation and lower incidence of disease in North America, while B. burgdorferi, B. garinii and B. afzelii
Lyme disease in California 17 and southeast USA.18 A primary determi- are all important in Eurasian disease. Clinical isolates differ in their
nant of transmission risk after a known tick bite is the duration of tick outer surface protein expression22 and genetic composition.23 Although
attachment before removal.19 A tick attached for greater than 36 hours there is overlap in the clinical manifestation of infection between the
has the greatest likelihood of transmitting B. burgdorferi. Congenital different species of Borrelia, certain species have been associated with
transmission has been reported20 but the evidence regarding the clini- a greater propensity toward particular disease manifestations. For
cal significance and frequency of infection resulting from transplacen- instance, B. burgdorferi is more commonly associated with late Lyme
tal transfer is inconclusive. Sexual transmission of Lyme disease has arthritis, B. garinii with neurologic disease, and B. afzelii with a chronic
been hypothesized, but is unproven. skin infection called ECM.6 Several other species belonging to the Bor-
Lyme disease is a highly seasonal illness, with individuals exposed relia burgdorferi sensu lato complex are occasionally isolated in symp-
to natural outdoor habitats in the spring and early summer months at tomatic patients including B. spielmanii, B. bisettii, B. americana, B.
greatest risk; this is when Ixodes nymphs are most active.14,21 A second andersonii and B. kurtenbachii. Borrelia miyamotoi, which is phyloge-
smaller peak of illness occurs in the fall months when adult ticks are netically close to relapsing fever Borrelia, is now a recognized pathogen
feeding. that causes a Lyme-like disease in the northern hemisphere.24
Chapter 46 Lyme Disease 407
B. burgdorferi strains may differ in their host specificity and the Histologic studies of affected tissues have provided evidence for
degree of human pathogenicity. These strains have been categorized immune-mediated inflammation in response to B. burgdorferi infec-
according to two different typing methods. The first is based on the tion. EM lesions display a perivascular and interstitial lymphohistio-
outer-surface protein C (OspC) type and the second on polymor- cytic infiltrate with plasma cells in the dermis.43 Endomyocardial
phisms of the 6S-23S rRNA intergenic spacer region (RST). RST1 (Osp biopsies have revealed similar changes in the heart, with a focal peri-
C type A) is associated with hematogenous dissemination and greater vascular infiltrate of mononuclear cells and fibrin deposition in both
inflammatory responses in patients with early stage Lyme disease and the endocardium and myocardium.44 Biopsies of affected nerves show
with higher likelihood of chronic symptoms after completion of anti- inflammatory infiltrates around endoneurial and perineurial vessels
biotic therapy for late Lyme arthritis.25,26 without vessel necrosis.45 Synovial biopsies from involved joints have
The complete DNA sequence of 22 strains of Borrelia is known.27 revealed synovial lining cell hyperplasia and hypertrophy, vascular
The genetic makeup of B. burgdorferi is unusual with one large linear proliferation and lymphocytic infiltration of the subsynovial areas.
chromosome and several smaller linear and circular plasmids. The Aggregates of T and B cells, often with lymphoid follicle formation,
genome of B. burgdorferi is notably lacking genes encoding for enzymes are common and may be concentrated in perivascular areas with oblit-
for the de novo synthesis of metabolites and as such is highly dependent eration of vessels but without vessel necrosis.3 Spirochetes have been
on the host environment.28 Also, no genes for known bacterial toxins visualized in skin lesions,46 heart tissue44 and synovium,47 but not in
have been identified. Surprisingly, Borrelia burgdorferi does not use peripheral nerves.
iron, but manganese instead.29 Two major glycolipids, BbGL-I and II,
which account for 36% of the total lipid mass of Bb, likely function as Clinical Features
the main components of the cell membrane, and are unique among The most recognizable feature of Lyme disease is the rash of EM that
bacteria to B. burgdorferi.30 Unlike Treponema pallidum, B. burgdorferi occurs at the bite site of an infected tick. When untreated, Lyme disease
can be grown in culture although a specialized medium is required and is often a multisystem systemic infection that has both early and late
cultures are not available for routine clinical use. B. burgdorferi can manifestations of infection. Like syphilis, Lyme borreliosis has been
penetrate endothelial monolayers and survive intracellularly in cul- called a ‘great imitator’; its symptoms range from cutaneous to mus-
tured fibroblasts, although the organism is thought to establish extra- culoskeletal, cardiac to neurologic.48 The presentation of Lyme disease
cellular infection in vivo.31 can be confounded by coinfection with other tick-borne illnesses (i.e.
Evasion of the host immune system is a hallmark of B. burgdorferi anaplasmosis, flaviviruses and babesiosis) that may occur in similar
infection. The organism may hide its surface lipoproteins and other geographical areas.49
antigenic components by coating them with host plasmin and other Lyme disease, human granulocytic anaplasmosis and babesiosis not
proteins.32 Antigenic variation of Vmp-like sequence protein (VlsE), a only share a common tick vector (I. scapularis), but also exhibit over-
35-kDa lipoprotein protein, may allow for immune evasion in a lapping clinical features of acute infection such as fever, malaise and
manner similar to that seen in relapsing fever.33 Outer-surface proteins fatigue.50 Despite these similarities, recognition of coinfection may be
such as OspE and related protein families (Erps) can act as comple- crucial to guide choice of antibiotic therapy especially for babesiosis,
ment regulatory-acquiring surface proteins (CRASPs) binding the which is not treated with doxycycline.51
complement inhibitory factor H and causing resistance to complement-
mediated killing.34 EARLY LYME DISEASE
An important question is how B. burgdorferi avoids destruction in Lyme disease most often begins with EM at the site of a tick bite
the presence of the vigorous specific T- and B-cell responses that are (Figures 46-2 to 46-4). In an unclear number of patients, estimated at
usually apparent within a few weeks of onset of disease. One hypothesis 18% in one study,52 this skin lesion is missed or absent and the initial
is that low levels of infection may be perpetuated through mechanisms manifestation of Lyme disease is one of a viral-like illness or no acute
such as survival in sequestered, immunologically protected sites.35 symptoms. Approximately 10% of individuals who become infected
Borrelia burgdorferi disseminates preferentially to certain target may not be acutely symptomatic.53 The interval between tick bite and
organs such as the musculoskeletal and nervous system. Tissue local- appearance of EM varies from a few days to a month (median 7 days).
ization to areas rich in collagen may be mediated by the decorin The lesion begins as an erythematous papule and expands over several
binding proteins Dbp A/B.36 Animal models of neurologic Lyme days to achieve a median diameter of 15 cm. The CDC cites 5 cm (in
disease using the rhesus macaque monkey model show localization to largest diameter) as the minimum diagnostic criterion for EM in
the dorsal root ganglia.37 order to increase the specificity of the diagnosis and to distinguish this
HOST IMMUNE RESPONSE AND
GENETIC FACTORS
Lyme disease is an inflammatory infection where the lipoproteins of
Borrelia burgdorferi are capable of stimulating pro-inflammatory cyto-
kines and chemokines through activation of the innate and adaptive
immune system.38 Binding of toll-like receptor 2 (TLR2) on macro-
phages results in activation of the innate immune response by a signal-
ing cascade leading to activation of NF-κB resulting in production of
pro-inflammatory cytokines.39 In addition, B. burgdorferi RNA induces
Type I and III interferons via toll-like receptor 7 contributing to pro-
duction of cytokines.40
The early cytokine/chemokine response is characterized by
interferon-gamma-dependent Th1 responses with elevated levels of
the CD4 and CD8 T-cell chemokines CXCL9 and CXCL10.28,41 The
polymorphonuclear neutrophil (PMN) chemokine CCL8 (IL-8) is not
elaborated consistent with the paucity of polymorphonuclear infil-
trates in the skin lesions of EM.41 The earliest evidence of humoral
immunity occurs several weeks after an infecting tick bite, and approx-
imately 1 week after the identification of EM, with increasing levels of Figure 46-2 Erythema migrans. A typical annular, flat, erythematous lesion with
IgG antibodies produced in the months succeeding untreated a sharply demarcated border and partial central healing. (Courtesy of Dr Steven
infection.42 Luger, Old Lyme, Connecticut, USA.)
lesion from other diagnoses.8 Although lesion size >5 cm is a useful

diagnostic criterion, it should not be used to exclude EM when clinical
and epidemiologic characteristics are suggestive of Lyme disease. Tran-
sient and localized inflammatory reaction at the bite site after tick
attachment is common; these reactive lesions are typically much
smaller and decrease in size when re-examined in several days and are
not indicative of infection. EM lesions tend to occur at sites not com-
monly seen in community-acquired cellulitis such as the axilla, popli-
teal fossa, back and abdomen. Cellulitis lesions are typically irregular
in shape and tender to palpation; EM lesions can be remarkably
asymptomatic, despite their often striking appearance.
The lesions of EM are generally annular with a sharply demarcated
round or oval outer border and an erythematous or bluish hue. Lesions
may sometimes show partial central clearing, but classic ring within a
ring target lesions are less common in North America than uniformly
colored lesions.54,55 EM can be indurated, have central vesiculation or
Figure 46-3 Erythema migrans. A lesion with a dusky center, a common variant. even become necrotic. EM lesions are often mistaken for spider bites,
(Courtesy of Dr Steven Luger, Old Lyme, Connecticut, USA.) which can lead to misdiagnosis.56,57
A lesion that may be mistaken for Lyme disease occurs with south-
ern tick-associated rash illness (STARI), which results from a bite of
the Amblyomma americanum tick, not known to transmit B. burgdor-
feri.58 The infectious agent of STARI is currently unknown, but it is
assumed to be infectious and typically responds to doxycycline therapy.
STARI can occur concomitantly with human monocytic ehrlichiosis
(HME), which is also transmitted by the same tick vector.
EARLY DISSEMINATED DISEASE

In prospective studies, 45–60% of patients with EM lesions had a posi-
tive PCR on blood.59,60 This has been interpreted as demonstrating that
bloodstream invasion may be relatively common early in the course of
infection and related to the genotype of the infecting organism.61
Patients may experience systemic symptoms before or after the EM
lesion is recognized. Malaise, fatigue, lethargy, headache, fever and
chills, arthralgia and myalgia are particularly common, each occurring
in one-half or more of patients. Symptoms may fluctuate rapidly and
can be intermittent or constant.
Secondary skin lesions of disseminated disease may occur anywhere
on the body and resemble primary lesions but are usually smaller,
show less expansion with time, are more irregular in shape and lack
indurated centers. These manifestations of early disseminated infec-
tion appear to be more common in the USA than in Europe and may
reflect biologic differences in infecting organisms. EM, secondary skin
lesions and associated symptoms resolve, even without antibiotic
therapy, a median of 28 days after onset. In untreated patients, recur-
rent crops of evanescent lesions may occur, and fatigue, intermittent
a musculoskeletal pain and headaches may persist for months.62
Carditis
Patients with untreated early disseminated Lyme disease occasionally
develop carditis, generally a few weeks to a few months after EM. The
primary clinical manifestation of Lyme carditis is heart block, which
may fluctuate from first-degree to complete heart block over minutes
to hours and generally resolves spontaneously within a few weeks, even
in untreated patients. Palpitations from an arrhythmia or unexplained
syncope from high-degree atrioventricular block may be the present-
ing manifestation of Lyme disease.63 Rare cases of myocarditis with
sudden cardiac death have been reported.63
Early Neurologic Manifestations
Early neurologic disease occurs in 15% of North American patients.
Studies of cerebrospinal fluid (CSF) in early disseminated disease have
shown that some patients may have PCR evidence of early B. burgdor-
b feri central nervous system (CNS) infection without objective evidence
of neurologic disease.64 In one study of European EM, symptoms such
Figure 46-4 Multiple erythema migrans lesions. Lateral (a) and posterior (b) as headache, neck pain, difficulty concentrating and parasthesias were
views of the same patient with multiple erythematous macules of EM. Secondary
lesions result from hematogenous spread. They may occur anywhere in the body.
not significantly different among those with or without CSF pleocyto-
Secondary lesions are usually of uniform color and lack induration. (Courtesy of sis. Those with pleocytosis were more likely to have radicular pain,
Dr Steven Luger, Old Lyme, Connecticut, USA.) facial nerve palsy or meningeal signs.65
The classic manifestations of early neurologic Lyme disease Late Neurologic Syndromes
typically include a combination of lymphocytic meningitis, cranial The early North American literature documented a mild, predomi-
neuritis and radiculoneuritis collectively known as Garin–Bujadoux– nantly sensory, peripheral neuropathy and subtle encephalopathy that
Bannwarth (MPN–GBB) or Bannwarth’s syndrome. Neurologic may occur months to years after the onset of untreated Lyme
symptoms generally begin a few weeks after EM (median 4 weeks), disease.70,77,78 The diagnosis of Lyme encephalopathy hinges on the
although patients can initially present with neurologic manifestations presence of cognitive deficits involving primarily short-term memory
alone, especially with B. garinii in European Lyme disease. and concentration which can be quantified by neuropsychologic
Papilledema with raised intracranial pressure is a complication that testing and serologic or microbiologic evidence of antecedent infection
has been reported exclusively in children. with B. burgdorferi. Chronic fatigue, headaches and sleep disturbance
Cranial neuritis and radiculitis may occur with or without associ- frequently accompany these abnormalities and can be very problem-
ated meningitis. Cranial neuropathy, particularly CN VII palsy, is atic. The symptoms of Lyme encephalopathy have a large degree of
common; other involved nerves can include CN V involvement with overlap with the cognitive symptoms of post-treatment Lyme disease
pain, and CN VIII/IX involvement with hearing or vestibular dysfunc- syndrome (PTLDS). While the pathogenesis of late Lyme encepha-
tion. The most common neurologic complication of Lyme disease in lopathy is most likely due to persistent untreated CNS infection, the
the USA is seventh nerve palsy; bilateral involvement may occur. pathophysiology of PTLDS is unknown and has spawned controversy.
Occurrence of VII nerve palsy in the summer months in Lyme- It has been hypothesized that PTLDS is due to a toxic metabolic syn-
endemic areas has a 25% chance of being due to Lyme disease.66 Rare drome whose origin is outside the CNS and not due to ongoing infec-
cases of oculomotor, neuro-ophthalmologic and Horner’s syndrome tion of the CNS.79
have been reported.67,68 Chronic sensory polyneuropathy due to axonal damage from a
Radiculoneuropathy with dermatomal pain may be difficult to mononeuropathy multiplex process has been described. The most
diagnose as it is largely indistinguishable from mechanical radiculopa- common manifestations include peripheral neuropathy with sensory
thy due to spinal disc disease or early shingles before the onset of rash. deficits in a patchy distribution.77
Radiculopathy may involve more than one dermatome. Peripheral
nerve abnormalities usually involve sensory nerves manifesting as Chronic Skin Involvement
intermittent parasthesias, but may include motor nerves and, rarely, Chronic skin involvement (acrodermatitis chronicum atrophicans) as
the brachial plexus.69 a late manifestation of Lyme disease occurs primarily in Europe.2 It
Parenchymal disease of the brain is rare in North America with usually occurs in an acral distribution and is characterized by viola-
occasional reports of seizure and more commonly spasticity, ataxia ceous discoloration and swelling at a site where EM occurred years
and other white matter tract signs.70 Lyme disease presenting as psy- earlier. The lesion eventually becomes atrophic. Acrodermatitis chron-
chiatric disorders has been reported.71 In Europe CNS disease due to icum atrophicans is thought to result from local persistence of B.
B. garinii is more common. Rarely, cases of demyelinating encepha- afzelii, which has been isolated from a lesion 10 years after onset.80
lopathy mimicking multiple sclerosis have been reported.72 Lichen sclerosus et atrophicus or morphea-like lesions have also been
described.81
PERSISTENT OR LATE LYME DISEASE
If left untreated the signs and symptoms of early disease will either Diagnostic Investigations
resolve or disseminate as described above. However, in as many as GENERAL PRINCIPLES OF DIAGNOSIS
50% of untreated patients who resolve their initial symptoms, the Lyme disease can be a diagnostic challenge for the clinician and the
infection will recrudesce later in life and develop long-term manifesta- laboratory alike. The diagnosis of Lyme disease depends upon the
tion of Lyme disease.62,73 Predominant complications are involvement clinical manifestations and the stage of presentation. The gold stan-
of the joints and, less commonly, the nervous system, but case reports dard for infection remains laboratory culture of the causative organism
have described involvement of multiple organs, including the from clinically involved tissue.61 However, this technique is not rou-
liver, subcutaneous tissue, muscle and eye structures, leading to tinely available. Confirmation is also possible with identification of
blindness.73 Borrelia-specific DNA utilizing PCR on joint fluid,82 and occasionally
in blood or CSF.83
Late Lyme Arthritis In practice, the diagnosis of Lyme disease starts with establishing a
Individuals who have untreated Lyme disease are at high risk of devel- pre-test probability of disease based on the characteristic clinical fea-
oping arthritis with evidence of joint swelling and synovitis. Brief, tures in combination with individual risk factors. Risk for infection is
intermittent attacks of migratory musculoskeletal pain commonly significantly impacted by exposure time in an endemic region and by
begin early in Lyme disease and may persist for months. Rarely, these presentation during the peak months of early summer when nymph
early manifestations may progress to frank arthritis. More commonly, stage ticks are feeding.14
Lyme arthritis occurs in 60% of untreated EM patients at a median of Laboratory confirmation of a clinical diagnosis is recommended by
6 months after the initial infection, as a result of recrudescence of a the Infectious Diseases Society of America (IDSA) 2006 guidelines in
latent infection. It usually presents as an inflammatory mono- or oli- all cases of Lyme disease, with the exception of typical cases of EM in
goarticular arthritis involving the large weight bearing joints, particu- an endemic region (The 2006 guidelines are currently being updated
larly the knee. As with other symptoms of early or late disseminated and publication is expected in late 2016).51 A two-tiered approach was
disease, patients often have no recollection of an EM rash and arthritis recommended by participants in a national conference on serologic
may be the presenting manifestation of Lyme disease. Effusions may diagnosis of Lyme disease held in 1994 under the sponsorship of the
be very large (100 mL or more) and cause popliteal cysts; these cysts CDC.84 Specificity is increased by the two-tier approach in which all
may then rupture and result in a pseudothrombophlebitis syndrome. positive or equivocal enzyme-linked immunosorbent assay (ELISA)
Attacks last a few days to a few weeks and over time (months to years) results are confirmed by western immunoblotting (Box 46-1). The
decrease in severity, frequency and duration. Only a minority of currently recommended criteria for a positive western blot and the
patients develop radiographic evidence of erosions of cartilage or timing of when to use IgM versus IgG results are given in Box 46-1.
bone.74 Arthritis has been reported to be milder in children than in The CDC two-tier system using an ELISA and confirmatory western
adults.75 Differentiation from rheumatoid arthritis is rarely a problem. blot is widely used as a substitute for bacteriologic isolation. Unfortu-
Although occasional cases of small joint involvement have been nately the sensitivity of the two-tier testing strategy is poor in very early
reported, Lyme arthritis is clinically and immunogenetically different disease, especially in cases with single EM lesions.85 An acute phase
from rheumatoid arthritis.76 serology in patients with EM will be positive in approximately 40%
BOX 46-1 RECOMMENDATIONS OF THE SECOND The usual serologic response in Lyme disease
NATIONAL CONFERENCE ON
SEROLOGIC DIAGNOSIS OF
LYME DISEASE IgM IgG
Sponsored by the Centers for Disease Control and Antibody

titer
Prevention, the Association of State and Territorial
Public Health Laboratory Directors and the Michigan
Department of Health
The two-tier testing protocol requires that all samples be tested Normal range
first by enzyme immunoassay (EIA) or immunofluorescence assay
(IFA). If the EIA or IFA test is positive or equivocal a western blot
analysis is obtained. 0 8 16 24 32 1 2 3
If the patient has had symptoms for less than or equal to 30 Weeks Years
days, an IgM and IgG western blot is used for interpretation. When Time after onset of symptoms
the patient has had symptoms for more than 30 days, the IgG
western blot is used for interpretation and the results of the IgM
western blot are not used to confirm the diagnosis. Figure 46-5 The usual serologic response in Lyme disease. Specific IgM
The IgM should not be used if the patient has been ill for more becomes detectable 1–2 weeks after symptom onset and the appearance of
erythema migrans. The later appearance of IgG is frequently concurrent with
than 30 days. Convalescent testing using the two-tiered testing
systemic manifestations. IgG is nearly always elevated with late disease. Typically,
system is not sensitive in individuals who have been promptly IgM falls over 4–6 months; although some patients remain IgM positive for pro-
treated for early Lyme disease.88 longed periods after treatment.
• An IgM blot is considered positive if two of the following
three bands are present: 24 kDa (OspC), 39 kDa (BmpA) and
41 kDa (Fla)
using the standard 2-tier testing.86 Seroreactivity may be related to the
• An IgG blot is considered positive if five of the following 10 genotype of the infecting organism.87 In addition, prompt antibiotic
bands are present: 18, 21 (OspC), 28, 30, 39 (BmpA), 41 (Fla), treatment may prevent seroconversion, especially in the IgG response,
45, 58, 66 and 93 kDa. with only 64% of patients seropositive on convalescent serology done
at the end of treatment, rendering convalescent post-treatment serol-
ogy insensitive in confirming infection.42,88 Serology becomes much
Two-tiered testing for Lyme disease more sensitive in untreated disseminated infection associated with
neurologic, cardiac and rheumatic manifestations occurring after the
first month of infection.
Enzyme
Immunoassay The serologic response to B. burgdorferi has been well characterized
(EIA) (Figure 46-5).42 Specific IgM antibody, directed initially primarily
First test or against the flagella of the organism, is detectable a few weeks after
Immunofluorescence disease onset. The response broadens to include additional antigens
Assay over time, and peaks by 3–6 weeks. Generally, IgM antibody falls to
(IFA) within the normal range by 6 months, but occasionally it may remain
elevated for longer, confusing the distinction between a persistently
positive convalescent serology and a new acute exposure. Specific IgG
antibody is detectable a few weeks after IgM and is directed against the
Positive
same antigen. However, IgG antibodies may not peak until many
Negative months after disease onset. In untreated infection, the two-tier testing
or
result strategy becomes more sensitive as IgM antibodies are formed during
equivocal result
weeks 3 and 4 of infection.89
The C6 IgG ELISA test which measures antibodies against a con-
served sequence of the variable major protein-like sequence-expressed
(vlsE) locus of B. burgdorferi and has similar sensitivity and specificity
Signs or symptoms Signs or symptoms
> 30 days
to the standard two-tiered testing using IgM/IgG ELISA and western
< 30 days
blot.90 C6 antibody testing is more sensitive for the B. burgdorferi
species present in Europe which are often poorly detected by either
ELISA or western blot tests in use in the USA. The C6 test may be more
lgM and lgG IgG western blot sensitive in detecting an early IgG response than the current cut-off
Second test
western blot only used for IgG western blots (5 bands). Future serologic tests may focus
on measuring an expanded number of antibody responses against an
Consider alternative diagnosis expanded number of Borrelia antigens.91
or Laboratory testing should be used mainly for confirmation of clini-
If patient with signs/symptoms consistent cally suspected active infections. Due to the persistence of antibodies
with Lyme disease for < 30 days, over long periods of time, and the high rates of remote exposure in
consider obtaining a convalescent serum
some populations, the use of serology for screening asymptomatic
patients is problematic. All of these limitations raise the need for reli-
Osp, outer-surface protein; Fla, flagella. able direct tests for detecting B. burgdorferi using molecular techniques
Adapted from CDC: http://www.cdc.gov/lyme/healthcare/clinician such as PCR or antigen detection.
_twotier.html
DIAGNOSIS OF EARLY LYME DISEASE
The diagnosis of early Lyme disease with EM is based on an accurate
and complete physical exam of the patient. EM is the classic skin lesion
of Lyme disease and can be confused with little else in its typical ‘ring
within a ring’, bull’s eye appearance. However, atypical presentations logic disease will not have high enough antibody levels to be positive
may lead to misidentification.92 The appearance of EM can be mim- on two-tier serologic testing.103 Radiculoneuropathy is diagnosed by
icked by other conditions and caution must be exercised when making the clinical examination. Diagnosis is confirmed by excluding mechan-
this diagnosis in non-endemic areas 54 ical causes, other infections like syphilis, and confirming exposure with
Diagnosis of viral-like presentations without rash requires the dem- positive serum IgG serology.
onstration of IgM antibodies for acute illnesses of short, weeks-long The peripheral neuropathy associated with late neurologic mani-
durations and IgG antibodies in illness durations of greater than 1 festations of Lyme disease mimics other sensory neuropathies such as
month. Commonly-associated laboratory findings of acute Lyme diabetes; however, a history of previous non-neurologic Lyme disease
disease include mildly elevated liver transaminase levels and low- may be present. Peripheral neuropathy and radiculoneuropathy cause
normal white blood cell counts with occasional lymphopenia.93,94 a mononeuritis multiplex pattern with evidence of axonal damage and
Atypical lymphocytosis or prominent neutrophilia should prompt without demyelination abnormalities on electromyography and
examination for an alternative diagnosis. Thrombocytopenia or severe peripheral nerve conduction studies.78 Although peripheral nervous
leukopenia should raise the suspicion of human granulocytic anaplas- system test findings are not specific for Lyme disease, abnormal find-
mosis.95 Prominent rhinitis, cough and signs of respiratory infection ings indicate a definite disorder of the nervous system and confirma-
are unusual in Lyme disease and should suggest an alternate tion of the clinical diagnosis by serology is considered diagnostic.
diagnosis. Sensory symptoms in the absence of an abnormal nerve conduction
study (NCS) may be due to small fiber neuropathy which can be con-
DIAGNOSIS OF EARLY DISSEMINATED firmed by skin biopsy with quantitative small fiber assessment.104
INFECTION While late Lyme encephalopathy is felt to be due to persistent
The diagnosis of early disseminated disease can be suspected when untreated CNS infection, the etiology of cognitive symptoms in Lyme
multiple cutaneous lesions result from early hematogenous dissemina- disease is poorly studied and a source of controversy. Most likely the
tion. The rate of seropositivity in patients with disseminated skin clinical manifestations of persistent symptoms are multifactorial espe-
lesions is much higher than in those with single EM lesions.85 Seeding cially when symptoms persist in the post-treatment setting.79 Serum
of the CNS may occur during the early disseminated phase and can be IgG western blot analysis should be positive in patients with Lyme
detected by lumbar puncture in those with clinically suspected encephalopathy. CSF pleocytosis is not an absolute feature, and when
meningitis. present is at a much lower level than with acute meningitis. Case series
have shown that most patients will have either a CSF pleocytosis or
Neurologic Lyme Disease (Lyme Neuroborreliosis) evidence of an elevated CSF protein level.78 A specific antibody response
Lyme meningitis is characterized by lymphocytic pleocytosis (<300 in CSF is not always detectable with CSF Lyme disease, but is helpful
WBC) with a B-cell predominance, elevated protein and usually when positive.
normal CSF glucose. In one study of children, Lyme meningitis was
unlikely when the CSF neutrophils exceeded 10% of the cells.96 The Diagnosis of Late Lyme Arthritis
presence of coexisting cranial neuritis or prior skin lesion consistent The typical patient with late Lyme arthritis who has monoarticular
with EM or the presence of papilledema were present in 88% of chil- inflammatory arthritis can be confused with reactive arthritis, crystal-
dren with Lyme meningitis.96 Algorithms have been proposed to help induced arthritis or septic arthritis. At initial presentation, bacterial
distinguish Lyme meningitis from summer viral causes of meningitis infection must always be excluded. The pattern of brief, recurrent
such as enteroviruses.97 attacks is more frequent in Lyme disease than other common forms
Use of CSF diagnostics is highly variable in clinical practice and of acute arthritis. Furthermore, patients who have Lyme arthritis are
fraught with difficulty. Borrelia PCR in CSF is available, but highly virtually always highly IgG western blot seropositive. Attacks of arthri-
insensitive, presumably because of the low numbers of organisms tis are accompanied by an inflammatory joint fluid containing a few
present in CSF.83 The B-cell chemokine CCL 13 has also been reported hundred to 50 000 white blood cells, mostly polymorphonuclear, ele-
to be elevated in CSF and is likely responsible for the predominance vations in protein and normal glucose.105 PCR of synovial fluid has
of B-cells in the CSF and localized antibody production.98 The index been shown to successfully detect B. burgdorferi DNA with an esti-
of specific intrathecal antibody production comparing CSF to serum mated sensitivity of approximately 70–80%.82
levels of specific anti-Borrelia antibodies is the gold standard for CNS Radiographs of affected joints most often show only soft tissue
infection, and is highly specific but insensitive in the first several weeks swelling, but when joint inflammation has persisted for many months,
of CNS infection.99 In late neuroborreliosis the sensitivity of the CSF there may be pannus formation and erosions of underlying cartilage
to serum index is not well defined, varying between 50% and 90% in and bone.76 Some patients develop enthesopathy with calcifications of
different groups of patients.100,70 Many CSF samples are sent without tendon and ligament attachment sites.
a simultaneous serum sample, rendering the calculation of the
CSF : serum ratio impossible. In protracted cases of neuroborreliosis
the IgG : albumin ratio can be found with oligoclonal banding of CSF Management
proteins. The rare patients who have demyelinating encephalopathy The primary goals of therapy for Lyme disease are the more rapid reso-
must be distinguished from patients who have multiple sclerosis; posi- lution of the presenting signs and symptoms of infection and the
tive peripheral serology or CSF PCR, combined with an exposure prevention of later stages of disease through the eradication of the
history, is very helpful in this circumstance.72 In cases of neurobor- infection. Most authorities agree that Lyme disease is most responsive
reliosis with a multiple sclerosis-like illness with increased IgG anti- to antibiotic therapy early in the course of the disease with a lower risk
body synthesis and oligoclonal bands, the CSF to serum index should of post-treatment Lyme symptoms. Late neurologic and arthritic
be a positive.101 involvement, however, are less predictably responsive. In all stages of
Neuroimaging of neuroborreliosis can show inflammation of the Lyme disease the clinical response to therapy may be delayed beyond
CNS or spinal cord with increased T2 signal on MRI with contrast the treatment duration. If objective signs of relapse or failure to
enhancement.70 As the spirochete appears to have an affinity for oli- respond to therapy occur, patients may need a second course of treat-
godendroglia, the abnormalities are more common in white matter ment; however, many repeat courses of therapy or excessively pro-
than gray. Active lesions appear hypermetabolic on PET imaging.102 longed treatment are not recommended.106
Seventh nerve palsy caused by Lyme disease is indistinguishable In vitro antibiotic sensitivity testing does not reliably predict clinical
from idiopathic Bell’s palsy clinically, but Lyme disease is one of very response and is not available in clinical practice. There is little informa-
few causes of bilateral seventh nerve palsy and, by this stage of disease, tion available regarding the emergence of antibiotic resistance either
patients are typically seropositive. Rarely, patients with early neuroin the zoonotic hosts or in man. Current treatment recommendations
TABLE
46-1 Suggested Antibiotic Regimens for Lyme Disease
Early disease Doxycycline, 100 mg po, q12h for 10–21 days, or
• Amoxicillin 500 mg, q8h for 14–21 days, or
• Cefuroxime axetil, 500 mg po, q12h for 14–21 days
Erythromycin and azithromycin less effective than other choices but can be used with caution in patients allergic to
preferred antibiotics
• Erythromycin, 250–500 mg po, q6h for 21 days, or azithromycin 500 mg daily for 7 days
Lyme arthritis Initial treatment:

• Doxycycline, 100 mg po, q12h for 28 days, or
• Amoxicillin 500 mg each po, q8h for 28 days
If initial treatment fails consider retreatment with second course of oral antibiotics or
Ceftriaxone sodium, 2 g iv, daily for 14–28 days
Neurologic manifestations For facial nerve paralysis without meningitis:

• Doxycycline, 100 mg po, q12h for 14–21 days, or
• Amoxicillin, 500 mg po, q8h for 14–21 days
Additional signs (e.g. Lyme meningitis, Ceftriaxone, 2 g iv, daily for 14-28 days, or possible alternatives:
radiculopathy, encephalitis) • Cefotaxime sodium, 2 g iv, q8h for 28 days, or
• Doxycycline, 100 mg po, q12h for 14–28 days
Lyme carditis Mild disease with PR interval >300 milliseconds

• Doxycycline, 100 mg po, q12h for 14–21 days, or
• Amoxicillin, 500 mg po, q8h for 14–21 days
Severe disease with PR interval > 300 milliseconds, second or third-degree heart block:
• Ceftriaxone, 2 g iv, daily for 14–21 days
During pregnancy Localized, early disease:
• Amoxicillin, 500 mg po, q8h for 21 days
Other manifestations:
• Ceftriaxone, 2 g, daily for 14–28 days
(Table 46-1) represent a distillation of available evidence and will no oral doxycycline or amoxicillin. Those with PR intervals >300 millli-
doubt be refined in time.51,106 seconds or with second or third-degree block should receive intrave-
nous ceftriaxone or cefotaxime.106 Heart block caused by carditis may
EARLY LOCALIZED AND EARLY progress suddenly, necessitating a temporary pacemaker in approxi-
DISSEMINATED DISEASE mately one-third of patients, but permanent pacing is rarely neces-
If antibiotic therapy is initiated early in the course of Lyme disease, sary.112 Hospitalization with cardiac monitoring is prudent in patients
EM typically resolves promptly and later stage disease is prevented. Of who have cardiac symptoms of syncope, dyspnea or chest pain and in
antibiotics studied to date, amoxicillin (500 mg q8h for 14–21 days), those with a PR interval >300 milliseconds while antibiotic therapy is
doxycycline (100 mg q12h for 10–21 days) and cefuroxime axetil instituted.51 Patients may be switched from intravenous to oral therapy
(500 mg q12h for 14–21 days) have been the most effective.51 Doxycy- after resolution of the heart block if otherwise stable.
cline therapy has the advantage of being effective against Anaplasma
phagocytophilum, which may occur as a coinfection from the same tick NEUROLOGIC MANIFESTATIONS
species. Patients without EM and with viral-like symptoms of tick- Data on the treatment of neurologic manifestations are derived pri-
borne infection may be treated empirically depending on the severity marily from clinical experience. The tendency for spontaneous resolu-
of illness while awaiting results of testing. Alternatively patients may tion of Bell’s palsy, the fluctuating course of meningitis, the clinical
be followed closely with acute and convalescent serology in cases of variation of neurologic syndromes and the delayed emergence of the
mild severity. subtle deficits associated with late neurologic Lyme disease must all be
The pediatric dose range of amoxicillin is 50 mg/kg per day divided considered in evaluating the clinical response to antibiotic therapy.
three times a day. If possible, doxycycline should be avoided in chil- Intravenous antibiotics are recommended for the treatment of
dren under the age of 8 years and during pregnancy because of the documented neurologic disease with the exception of isolated facial
possibility of staining of the teeth; however, doxycycline is recom- palsy without meningitis. Most experts prefer a 10–28-day course of
mended for use regardless of age when infection with Rocky Mountain treatment with ceftriaxone, 2 g q 24 hours. In patients at risk of cho-
spotted fever or anaplasmosis is suspected of being a coinfection or lecystitis, a known complication of ceftriaxone, cefotaxime, 2 g q 8
is in the differential diagnosis.107 Tetracyclines may predispose the hours, is an acceptable alternative. It may not necessary to document
patient to sun-sensitive rashes or severe sunburn and patients should clearing of all CSF abnormalities before discontinuation of therapy
be counseled on how to protect themselves using sunscreens and pro- because clearing of inflammation may lag behind bacteriologic
tective clothing. Penicillin-allergic young children can be treated with cure.51,113 Oral doxycycline has been studied as an alternative to ceftri-
cefuroxime or erythromycin, but results with macrolide antibiotics axone in European neuroborreliosis, but experience with this approach
have been less satisfactory than those with penicillin, amoxicillin in the USA is limited.114,115
or tetracyclines.51 Azithromycin has been studied systematically and Patients who have facial palsy should undergo a careful neurologic
found to be less effective than amoxicillin.108 First generation cephalo- evaluation and if there is suspicion of coexisting meningitis a CSF
sporins such as cephalexin and quinolone antibiotics are not effective examination may be performed. CSF invasion has been demonstrated
therapy for Lyme disease.109,110 Herxheimer-like reactions, with inten- by PCR in patients who have minimal CNS complaints and facial palsy,
sification of fever and arthralgias, may occur shortly after initiation of most of whom have clinically silent CSF pleocytosis.116 If facial palsy
therapy in some patients.111 is the only clinical abnormality and CSF is normal, current practice is
to administer oral antibiotics for 14-21 days, a practice that has resulted
CARDITIS in favorable outcomes. Long-term follow-up of this group is important
Patients with cardiac Lyme disease and first-degree atrioventricular and, if CSF examination is not possible and there is a clinical suspicion
block with PR interval of <300 milliseconds can usually be treated with of meningitis, the option to administer intravenous antibiotics should
be considered. Some evidence has emerged that oral doxycycline may The prognosis after treatment of neurologic Lyme disease is mixed.
be sufficient even in patients with CSF involvement thereby arguing Facial palsy itself resolves completely or almost completely in nearly
against the need for lumbar puncture in patients without clinical all patients (121 of 122 patients in one series).122 However, patients
meningitis.115 presenting for treatment with late neurologic disease may have slow
and incomplete resolution of the symptoms and occasionally also the
Arthritis signs of neurologic involvement.123 Resolution of neuropathy may be
Patients with late Lyme arthritis are typically treated initially with 28 very gradual (taking place over months) and, with chronic involve-
days of oral antibiotic therapy. Patients who have concurrent neuro- ment, this response may be incomplete. In one report, only one-half
logic involvement or who develop neurologic disease after initial oral of patients who had late neurologic symptoms showed either resolu-
therapy should receive intravenous treatment in which case ceftriax- tion or sustained improvement after 6 months of follow-up after a
one or cefotaxime for 2–4 weeks are the agents of choice.117 2-week course of ceftriaxone.78 Those who did not respond, however,
Patients with persistent or recurrent synovitis after initial therapy did not show progressive worsening.
should receive a second course of oral therapy or intravenous therapy. The treatment of early or late stages of Lyme disease may be
If PCR results remain positive after 60 days of treatment some authori- complicated by a constellation of persistent symptoms of fatigue,
ties recommend one final 30-day course of oral antibiotics. Anti- musculoskeletal and cognitive symptoms without physical or labora-
inflammatory therapy is used for treatment of patients after three tory findings of arthritis or neurologic disease, termed PTLDS.
courses of antibiotics or in those with a negative synovial fluid PCR. Early investigators observed that patients with early Lyme disease
Initial treatment with nonsteroidal anti-inflammatory agents and may have lingering symptoms after completion of antibiotic therapy
hydroxychloroquine are recommended.118 that can be similar in appearance to fibromyalgia or chronic
Use of methotrexate in consultation with a rheumatologist may be fatigue.124,125 The likelihood of delayed resolution of symptoms is
considered in patients with recurrent synovitis after adequate antibi- greatest in patients who have prominent systemic symptoms or facial
otic therapy, with arthroscopic synovectomy being reserved for those palsy at initial presentation.126,127 The most severe end of the illness
failing to respond to medical management.82,118,119 spectrum of PTLDS has been described in population-based studies
Some investigators believe that administration of intra-articular where patients often had delayed treatment, initial misdiagnosis or
corticosteroids given before antibiotic therapy increases the risk of non-ideal initial therapy.127-129 Patients treated for neurologic Lyme
persistent arthritis117 but the use of articular injection after completion disease in Europe have reported rates of PTLDS ranging from
of antibiotic therapy continues. Adjunctive treatment measures should 25–50%.123,130
include evacuation of large effusions and limitation of weight bearing A proposed case definition of PTLDS has been suggested by the
during acute attacks. IDSA in their 2006 guidelines.51 The central feature of PTLDS is the
presence of symptoms that persist or recur in the 6 months after
PREGNANCY completion of recommended antibiotic therapy of a physician docu-
Case reports have provided convincing evidence that B. burgdorferi can mented case. When these symptoms persist for more than 6 months,
cross the placenta.20 Stillbirth and neonatal death have been attributed they are termed PTLDS. The most commonly reported symptoms are
to B. burgdorferi transmitted from mother to fetus in utero, but the fatigue, musculoskeletal pain and cognitive complaints. A range of
evidence to support this conclusion is still incomplete.120 The vast other symptoms have also been reported such as sleep disruption and
majority of pregnancies complicated by maternal Lyme disease have sensory symptoms.128 Serology using the two-tier testing is not a reli-
normal outcomes. B. burgdorferi has not been linked statistically to able method to confirm prior Lyme disease in patients being evaluated
congenital anomalies and no increased risk of an adverse outcome of for PTLDS. Due to prior treatment more than half of patients with
pregnancy has been associated with asymptomatic seropositivity or PTLDS are seronegative or may have only residual IgM antibodies on
history of previous Lyme disease.121 It is appropriate to maintain a western blot testing despite the remote clinical documentation of a
lower threshold for institution of aggressive antibiotic therapy for definite case of Lyme disease.129,131
suspected Lyme disease during pregnancy, but women should be reas- Objective findings have been difficult to document in PLTDS.
sured that no cases of fetal Lyme disease have occurred with currently Unlike patients with persistent arthritis after treatment of late Lyme
recommended antibiotic regimens. Doxycycline and other tetracy- arthritis, patients with PTLDS have arthralgias and musculoskeletal
clines should be avoided during pregnancy. pain, but rare evidence of joint synovitis.132 Neurologic symptoms have
also been difficult to document objectively.132 Case reports of PTLDS
have suggested that small fiber sensory neuropathy and autonomic
Prognosis neuropathy may play a role in these neurologic symptoms, and as a
The prognosis after treatment of Lyme disease is generally favorable. result they are difficult to document.104 There is some evidence that
In all stages of Lyme disease the clinical response to therapy may be postural orthostatic tachycardia syndrome (POTS) is one possible
delayed beyond the treatment duration with continued improvement mechanism for the symptoms of fatigue.133
over a period of weeks to months. Minor lingering symptoms usually The severity of illness in PTLDS has a large spectrum from ‘annoy-
resolve spontaneously and do not necessarily indicate continued infec- ing symptoms’ to an illness with deficits on cognitive testing and
tion requiring further antibiotic therapy. Repeat serologic testing is not declines in health-related quality of life.134,135 There is loss of health-
useful in evaluating the response to therapy as the seroevolution after related quality of life in approximately 10% of those studied,136,123
treatment is not predictive of response to therapy in any given patient. which may be related to fatigue and development of depressive
Persistence of symptoms after treatment of early Lyme disease may be symptoms.135,137
associated with lack of seroconversion.108 Symptoms of PTLDS overlap with those of other symptom-based
Persistent illness may occur after the recommended antibiotic syndromes such as idiopathic fibromyalgia and chronic fatigue syn-
treatment of any stage of Lyme disease. The best understood post- drome.138,139 The lack of specific biomarkers to establish the etiology
treatment illness occurs after antibiotic treatment of late Lyme arthritis of symptoms in these overlapping groups has led to the appearance of
and is termed antibiotic-refractory late Lyme arthritis. This condition the term ‘Chronic Lyme disease’ to describe this diverse group of
occurs in approximately 10% of patients after completion of antibiotic patients. Many patients who seek evaluation for Chronic Lyme disease
therapy and is characterized by persistent signs of joint synovitis.117 will not meet the case definition of PTLDS and may be found to have
The joint effusions are usually PCR-negative for B. burgdorferi and may another specific non-Lyme related diagnosis.138,140 Because of the non-
respond to treatment with agents such as Plaquenil or methotrexate, specificity of these symptoms and lack of biomarkers for PTLDS many
suggesting that the pathogenesis may involve inflammatory mecha- patients seeking evaluation for Chronic Lyme disease will not be able
nisms that may not be dependent on persistent infection.118 to be assigned a specific diagnosis, but may meet the criteria for
fibromyalgia or CFS.140,141 It is unknown what percentage of these PTLDS, new antibiotic regimens will need to be developed that are
patients may have the sequelae of a remote unrecognized tick-borne directed toward the latent and persisting stage of the organism.157
disease.141 Further research, to elucidate the mechanisms underlying persistent
symptoms after Lyme disease, and controlled trials of new approaches
Underlying Mechanisms of PTLDS to the treatment and management of these patients are needed.158
Despite extensive study, PTLDS remains an enigmatic condition. The
underlying pathogenesis is not understood and even its clinical validity Prevention
as the sequelae of an infectious disease remains controversial. Con- Community-based prevention of Lyme disease can include interven-
trolled clinical trials provide evidence that symptoms are more tions to decrease the vector and pathogen abundance in human envi-
common and severe after treatment of Lyme disease than in the general ronments as well as efforts to increase personal protection behaviors.159
population and are not primarily due to pre-existing depression.136,142 If possible, it is preferable to prevent Lyme disease by avoiding high-
In addition, evidence is emerging regarding the possible immune risk environments, personal protection techniques and avoidance of
pathophysiology of post-Lyme disease syndrome. Borrelia lipoprotein prolonged tick attachment if a tick bite occurs. Personal protection
antigens are highly inflammatory and retained antigens after killing of including protective clothing measures such as wearing light-colored
Borrelia has been shown in the mouse model and hypothesized in clothing to provide a background that contrasts with the ticks is often
human illness.143,144 Evidence for specific immune response patterns recommended.51 Permethrin treatment of clothing is a highly effective
and autoimmunity are also emerging as a potential mechanism for means of decreasing tick attachment and is widely used by the mili-
PTLDS.145 In one study of European patients treated for EM, patients tary.160 The use of insect repellent containing N,N-diethyl-M-toluamide
with elevated IL-23 levels during acute disease were associated with the (DEET) and the prompt removal of ticks reduce the risk of Lyme
subsequent development of PTLDS.146 Anti-neural antibodies have disease.161 Tick removal is best accomplished quickly and directly with
been reported in PTLDS147 and antibodies to endothelial cell growth the use of tweezers or special tools for tick removal.
factor (ECGF) have been described in both early and late Lyme Antibiotic prophylaxis after tick removal is often confused by
disease.148 patients and practitioners with treatment of established Lyme disease.
Genetic predisposition to autoimmunity in Lyme disease is best The efficacy of antibiotic prophylaxis for the prevention of Lyme
described in late Lyme arthritis where HLA-DR4 predisposes to the disease was examined in a meta-analysis of four placebo-controlled
development of persistent Lyme arthritis that does not respond to trials using single dose doxycycline or a 10-day course of either penicil-
antibiotic treatment.149 Patients who are HLA-DR4 positive and who lin, amoxicillin or tetracycline. In these studies the rate of Lyme disease
have treatment-resistant Lyme arthritis have also been shown to have was reduced from 2.2% in the controls to 0.2% in those treated. The
a strong immune response to an epitope on OspA that cross-reacts authors concluded that the evidence supported the use of antibiotic
with human lymphocyte function antigen 1 (LFA-1), which may serve prophylaxis when administered within 72 hours of an engorged Ixodes
as an autoantigen.150 In addition, the TLRI polymorphism (1805GG), tick bite in an endemic region for Lyme disease.162 It is estimated that
which is present in 50% of Caucasians, has been implicated in persis- one case of Lyme disease would be prevented for every 50 patients
tent autoimmune arthritis after antibiotic treatment.151 treated with prophylactic antibiotics. Prophylactic antibiotics may be
To complicate our understanding of post-antibiotic Lyme disease, cost-effective in endemic regions if the risk of transmission following
recent animal studies have demonstrated residual organisms and pos- tick bites is greater than 0.01.163
sibility of persistence of B. burgdorferi in mice and primates previously There is currently no Lyme disease vaccine available for human use.
treated with antibiotics.152–154 Whether antibiotic-tolerant ‘persister’ A recombinant vaccine based on OspA, LYMErix™, was approved for
organisms play a role in human PTLDS remains unknown, although use in the past but was subsequently withdrawn from the market due
results from a small xenodiagnoses study report the identification of to poor sales.164 Efficacy was reported to be 79% after three doses, but
B. burgdorferi by PCR in a patient with PTLDS.155 would have required booster shots to maintain effective immunity.12
Individuals who received the vaccine are not reliably protected now.
TREATMENT OF PTLDS New recombinant-based vaccines currently under development are
Previous controlled clinical trials with intravenous antibiotics have expected to have a broad range of specificity against the variants of B.
failed to provide convincing evidence that antibiotics provide sus- burgdorferi distributed throughout the world.
tained improvement in fatigue or other symptoms, although the inter-
pretation of the study results has been controversial.134,135,139,156 If References available online at expertconsult.com.
persistent infection is found to contribute to the pathogenesis of
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Bloodstream, Heart and Vessels
47
Sepsis
TOM VAN DER POLL | WILLEM JOOST WIERSINGA
KEY CONCEPTS remain an important clinical problem in the future, caused by a com-
bination of factors, including the aging population, aggressive thera-
• Sepsis is a life-threatening condition that arises when the pies for chronic diseases (in particular malignancies) and emerging
body’s response to an infection injures its own tissues and antibiotic resistance.
organs.
• Sepsis case fatality rates have declined, however its incidence Definition
is increasing at least in part due to an aging population and In clinical practice, sepsis is a vague diagnostic term used to describe
aggressive therapies for chronic diseases.
patients with one or more abnormalities in organ function in the
• Pneumonia, peritonitis, urinary tract infections and soft tissue context of a suspected infection. In an attempt to be more precise, a
infections are – in descending order – the most important Consensus Conference held in 1991 defined sepsis as a systemic
sources of sepsis. inflammatory response syndrome (SIRS) in the presence of a sus-
• Pattern-recognition receptors are the central components of pected or proven infection.1 This definition introduced four so-called
the innate immune system that spot invading bacteria and initi- SIRS criteria, based on temperature (>38 °C or <36 °C), heart rate
ate the immune response. These receptors recognize and are (>90/minute), respiratory rate (>20/minute or arterial CO2 <32 mmHg)
activated by conserved motifs expressed by pathogens named and white blood cell count (>12 ×109 cells/L or <4 ×109 cells/L).1 In
pathogen-associated molecular patterns, but can also be stim- order to define SIRS, at least two of these four criteria had to be met.
ulated by danger-associated molecular patterns or alarmins It was recognized that SIRS is not specific for sepsis: noninfectious
released during inflammatory stress. diseases, such as trauma, pancreatitis and burns, can also be associated
• The host response to sepsis is characterized by both pro- and with SIRS. Severe sepsis was defined as sepsis accompanied by acute
anti-inflammatory reactions and depends on the causative organ dysfunction, septic shock as sepsis together with refractory
pathogen and the premorbid condition of the host. Pro- hypotension.1 These definitions were modified during a second con-
inflammatory responses include cytokine release, and activa- sensus conference in 2001. Specifically, the sepsis definition was revised
tion of the complement system, the coagulation system and to include infection plus the presence of at least any one of a set of
the vascular endothelium; anti-inflammatory responses can criteria including clinical, hemodynamic, laboratory and organ dys-
result in immune suppression, at least in part due to apoptotic function parameters (Box 47-1).2 While the criteria for severe sepsis
loss of lymphoid cells.
remained similar, septic shock was defined more explicitly as refrac-
• The host response to infection and noninfectious injury is not tory hypotension (systolic blood pressure <90 mmHg or mean arterial
fundamentally different. blood pressure <70 mmHg) despite adequate fluid resuscitation.
Sepsis should be distinguished from bacteremia, which is defined as
• Implementation of the Surviving Sepsis Campaign guidelines
for the management of sepsis is associated with improved the presence of viable bacteria in the blood. Only one-third of patients
outcome. The most important components of the guidelines with severe sepsis have a positive blood culture.3
are structured in two ‘bundles’ of care: an initial management Notably, the current sepsis definition is a matter of debate. Most
bundle to be accomplished within 3–6 hours of presentation clinicians use the term sepsis to indicate a severely ill patient with
and a management bundle to be accomplished within 24 hours. suspected infection in need for hospitalization and acute treatment,
while the current definition also captures patients with mild disease.
• Future human sepsis studies should consider the substantial
heterogeneity of patients and type of infections as well as the Therefore, it has recently been proposed to include evidence of organ
predominant phenotype of the immune response, pro- or anti- dysfunction in the criteria for sepsis, or to use only the term severe
inflammatory/immune suppressive, at time of inclusion. sepsis.4 In addition, it should be realized that the clinical and labora-
tory manifestations of sepsis are not unique to patients with docu-
mented infection. Indeed, patients with noninfectious critical illness
often are indistinguishable from patients with severe infection. Criti-
Introduction cally ill patients, either with or without infection, can develop ‘multiple
Sepsis is a clinical syndrome caused by a deregulated host response to organ dysfunction syndrome’, which can already be present upon ICU
an infection. Any infection can result in sepsis, and multiple organ- admission. Many patients progress to develop a subacute condition
isms, bacterial, fungal and viral, can initiate a septic response. Sepsis referred to as ‘persistent critical illness’, characterized by organ dys-
is considered the final common pathway by which the vast majority function that lasts for weeks or even months.5 In any case, sepsis is a
of patients with severe infection die. It is the most frequent cause of life-threatening condition that arises when the body’s response to an
death in hospitalized patients, predominantly affecting patients with infection injures its own tissues and organs.
underlying disabilities or co-morbidities. Knowledge of pathogenetic
mechanisms that contribute to organ failure in sepsis has increased Clinical Signs and Symptoms
tremendously during the last decades. Unfortunately, this has not The clinical signs and symptoms of sepsis are variable, depending on
resulted in specific therapies targeting components of the derailed host the initial source of infection, the causative pathogen, the type and
response, in spite of a large series of clinical trials evaluating such extent of organ dysfunction, the premorbid condition of the patient
interventions. Nonetheless, the outcome of sepsis has improved in and the delay before consulting a physician and/or start of treatment.
recent years, at least in countries with modern Intensive Care Unit Box 47-1 (‘general variables’) provides a list of possible signs and
(ICU) facilities, most likely due to improved general clinical practices symptoms of sepsis.2 The most common sources of sepsis are, in
and use of sepsis treatment guidelines. It is expected that sepsis will descending order, pneumonia, intra-abdominal, urinary tract and soft
415
416 SECTION 2 Syndromes by Body System: Bloodstream, Heart and Vessels
BOX 47-1 DIAGNOSTIC CRITERIA FOR SEPSIS BOX 47-2 RISK FACTORS FOR SEPSIS
Sepsis = infection (documented or suspected) + some of the following Host Factors
General Variables Higher age (>65 years of age)
Fever (core temperature >38.3 °C/101 °F) Male gender
Hypothermia (core temperature <36 °C/96.8 °F) Black race
Heart rate >90/min or >2 SD above the normal value for age Nutrition
Tachypnea Vaccination status
Altered mental status Genetic polymorphisms
Significant edema or positive fluid balance (>20 mL/kg over 24 hours) Co-morbidities
Hyperglycemia (plasma glucose >120 mg/dL or 7.7 mmol/L) in the Diabetes
absence of diabetes Chronic obstructive pulmonary disease
Inflammatory Variables Cancer
Leukocytosis (WBC count >12 ×109/L) Chronic renal disease
Leukopenia (WBC count <4 ×109/L) Chronic liver disease
Normal WBC count with >10% immature forms Cancer
Plasma C-reactive protein >2 SD above the normal value Human immunodeficiency virus infection
Plasma procalcitonin >2 SD above the normal value Use of immunosuppressive agents
Hemodynamic Variables Environmental Factors
Arterial hypotension (SBP <90 mmHg, MAP <70, or an SBP decrease Poor socioeconomic status
>40 mmHg in adults or <2 SD below normal for age) Seasonal variation and contacts
SvO2 >70% Disease outbreaks
Cardiac index >3.5 L/min/m2 Travel
Organ Dysfunction Variables Hospital Factors
Arterial hypoxemia (PaO2/FI O2 <300) Duration of hospitalization
Acute oliguria (urine output <0.5 mL/kg/h or 45 mmol/L for at least Antibiotic resistance
2 hours) Catheters (urine catheters, intravenous lines etc.)
Creatinine increase >0.5 mg/dL Complications of surgery (wound infection, emergency vs elective
Coagulation abnormalities (INR >1.5 or aPTT >60 s) surgery)
Ileus (absent bowel sounds)
Thrombocytopenia (platelet count <100 ×109/L)
Hyperbilirubinemia (plasma total bilirubin >4 mg/dL or 70 mmol/L)
Tissue Perfusion Variables
Hyperlactatemia (>1 mmol/L) all ICU admissions.9 The incidence of severe sepsis was recently
Decreased capillary refill or mottling
reported to increase,10 although at present it is not clear whether this
Severe sepsis = sepsis + organ dysfunction represents a true increase or a change in coding and registration prac-
Septic shock = sepsis + hypotension (refractory to intravenous fluids) or tices.3,8 Nonetheless, sepsis can be expected to occur more frequently
hyperlactemia* due to aging of the population and increased use of aggressive thera-
pies for a variety of diseases including cancer. Even more uncertainty
*Hyperlactemia in typically ≥4 mmol/L.
aPTT, activated partial thromboplastin time; INR, international normalized
exists about the incidence of severe sepsis in lower income settings.
ratio; MAP, mean arterial blood pressure; SBP, systolic blood pressure; Extrapolation of incidence rates in the USA results in an estimated
SvO2, mixed venous oxygen saturation; WBC, white blood cell. global incidence of 15–19 million cases per year,11 although the true
Data from Levy MM, et al. Crit Care Med 2003;31(4):1250–1256. incidence likely is much higher.
Large surveys have indicated that the mortality of severe sepsis and
septic shock is between 25% and 50%, with the extent and number of
organ failures as the strongest denominators of an adverse outcome.8
tissue infections, each resulting in specific symptoms (Figure 47-1). A recent study conducted in Australia and New Zealand using an ICU
Organ failures most frequently occur in the respiratory and cardiovas- registry of more than one million patients admitted from 2000 to 2012
cular systems3 (Figure 47-2). Respiratory failure commonly manifests provided compelling evidence for gradually declining case fatality rates
as the acute respiratory distress syndrome, defined as hypoxemia for severe sepsis from 35% in 2000 to 18.4% in 2012.12 Each year
and bilateral infiltrates of non-cardiac origin.6 Cardiovascular com- absolute mortality decreased 1.3% and after adjusted analysis mortal-
promise consists primarily of hypotension persisting after adequate ity decreased throughout the study period with an odds ratio of 0.49
volume expansion, while cardiac dysfunction can also occur.3 Brain in 2012 using the year 2000 as reference. Remarkably, in the absence
dysfunction may present as coma or delirium, whereas critical illness of co-morbidities and older age, the case fatality rate of severe sepsis
polyneuropathy and myopathy are common complications in patients or septic shock was below 5% in 2012. The annual reduction in mortal-
with prolonged ICU stay. Acute kidney injury is characterized by a ity did not differ between patients with severe sepsis and other diag-
decreased urinary output with rising serum creatinine levels; many noses, suggesting that overall improvement in ICU practice rather than
sepsis patients require renal replacement therapy. Other common in the management of sepsis patients is responsible.12 This important
manifestations of sepsis include ileus, elevated transaminases, altered investigation, which used the same diagnostic criteria during the entire
glycemic control, thrombocytopenia and disseminated intravascular observation period, confirmed declining mortality rates derived from
coagulation, adrenal dysfunction and sick euthyroid syndrome.3 large retrospective analyses, which could have been caused by varia-
tions in the definition of sepsis.8 Importantly, since the incidence of
Incidence and Mortality sepsis increases while its short-term case fatality rate decreases, the
Information about the incidence of sepsis is mostly based on admin- number of sepsis survivors has grown. Many of these patients live with
istrative databases generated for another purpose, especially reim- post-sepsis sequelae, including worsening of chronic co-morbidities,
bursement. As a consequence, the reported incidence of severe sepsis and cognitive and physical impairments.13 Of note, sepsis survivors are
varies depending on the case definition and diagnosis codes to identify at risk for early death, with 5-year mortality rates as high as 75%.14
patients.7,8 Nonetheless, it is generally accepted that sepsis and severe
sepsis are leading causes of death, and the most frequent cause of death Risk Factors
in non-coronary ICUs in high-income countries.8 In the USA the Risk factors for the development of severe sepsis relate to the
annual incidence of severe sepsis is estimated at approximately 300 susceptibility to acquire an infection and/or the probability of devel
cases per 100 000 person-years population, representing about 10% of oping acute organ dysfunction once infected (Box 47-2). Chronic
Chapter 47 Sepsis 417
The many faces of sepsis: the most common sources and symptoms of sepsis
Altered mental
status
Tachypnea
Tachycardia
CNS
d
Pneumonia
a
Fever or
hypothermia
Bloodstream
e infections
Peritonitis
b
Skin/soft
c Urinary tract Edema tissue
f
Figure 47-1 The many faces of sepsis: the most common sources of sepsis (in descending order) are pneumonia, peritonitis (e.g., caused by a perforation of the
intestines or cholangitis), urinary tract infection, skin/soft tissue infection and central nervous system (CNS) infection. Bloodstream infections include endocarditis and
catheter-associated infections. The clinical signs and symptoms of sepsis are variable and depend on the initial source of infection, the causative pathogen, the type
and extent of organ dysfunction, the premorbid condition of the patient, and the delay before consulting a physician and/or start of treatment. (Reprinted from: (a)
Kumar & Clark’s Medical management and therapeutics, Saunders. © 2011: pp. 473–531. (b) Chen C-K, Su Y-J, Lai Y-C et al. Am J Emerg Med 2008; 26(7):838.e3–838.
e5. © 2008. (c) Campbell-Walsh Urology, 9th ed. Figure 84-8, Saunders Elsevier. © 2007. (d) Autopsy pathology: a manual and atlas. Elsevier; 2009: 167–276. © 2009.
(e) Moreillon, P. Endocarditis and endarteritis, in Cohen J, et al. ed. Infectious diseases, 3rd ed., Figure 47-6. Elsevier. © 2010. (f) Ta-Lun Kao, Man-Ling Kao, Am J Emerg
Med 2012; 30(1):258.e3-258.e5. © 2012.)
co-morbidities are present in 54–65% of sepsis patients.15 Certain dis- with a reduced risk for developing acute lung injury and an increased
eases increase the risk for sepsis, including chronic obstructive pulmo- risk for acute kidney injury in sepsis patients.15
nary disease, chronic renal or liver disease, diabetes, cancer and human Established risk factors for severe sepsis include age, male gender
immunodeficiency virus infection. Similarly, the use of immunosup- and black race. The incidence of severe sepsis strongly rises in older
pressive agents increases the likelihood of infection and thereby sepsis. adults and more than 50% of cases occur in individuals above the age
Less is known about risk factors for development of organ dysfunction of 65 years.16 Whereas the majority of investigations report a higher
secondary to infection, but these presumably include underlying risk for men to develop sepsis, the extent of gender-dependent differ-
health status, pre-existing organ function and delay of therapeutic ences in risk and outcome of sepsis differs between reports, most likely
intervention.16 Even so, there is evidence that chronic co-morbidities caused by differences in the duration between time of infection and
impact on both infection risk and sepsis outcome. For example, dia- study enrolment. It is uncertain whether the increased sepsis risk in
betes patients are at higher risk for infection. Diabetic sepsis patients males is caused by an enhanced risk of acquiring infection or develop-
present less often with respiratory tract infections and more often with ing organ failure. Gender dissimilarities in behavior, social factors,
urinary tract and skin/soft tissue infections when compared with chronic co-morbidities and biology may all contribute to the higher
patients without diabetes.15 On the other hand, diabetes is associated incidence of sepsis in males. Black race is associated with a higher
Common complications of sepsis
Brain dysfunction:
coma/delirium
Acute lung injury
Cardiovascular dysfunction
(including shock)
Complications
of sepsis Liver injury
(hyperbilirubinemia)
b
Acute kidney injury
Ileus
DIC (with thrombocytopenia)
Figure 47-2 Common complications of sepsis. The most common include brain dysfunction, acute lung injury, acute kidney injury, ileus, cardiovascular dysfunction
(including shock), disseminated intravascular coagulation (DIC) (with thrombocytopenia) and liver injury. Insets show (a,b) a chest radiograph and CT-scan of acute
respiratory distress syndrome, (c) an abdominal radiograph showing dilated loops of small bowel and multiple air/fluid levels consistent with an ileus and (d) a child with
purpura fulminans as a manifestation of severe DIC. (Reprinted from: (a,b) Grainger RG, et al. ed. Grainger & Allison’s Diagnostic radiology, 4th ed. London, Harcourt;
2001. (c) Donahue TR, Hiatt JR, Sepsis, in Vincent JL, et al. ed. Textbook of critical care, 6th ed., Figure 24-2. Elsevier. © 2011. (d) Thompson ED, Herzing KD, Fever and
rash, in Zaoutis LB, Chiang VW ed. Comprehensive pediatric hospital medicine, Figure 62-7. Mosby. © 2007.)
incidence of severe sepsis, almost double that of whites, caused by both whites to die from severe sepsis.17 The fact that racial differences are
a higher infection rate and an increased risk of developing acute organ not entirely explained by differences in socioeconomic factors or access
failure.17 In a large population-based study conducted in the USA the to care suggest that genetic variation plays a role.
difference in sepsis incidence between blacks and whites was evident Several environmental factors influence the risk for sepsis. For
by age 20 and persisted thereafter. After adjusting for poverty levels example, a poor socioeconomic status enhances the risk for blood-
and hospital effect, black race remained independently associated with stream infection.18 In addition, infections causing sepsis show seasonal
higher severe sepsis incidence. Moreover, blacks are more likely than variation, with respiratory tract infections occurring more frequently
in colder periods of the year and genitourinary tract infections more

often in summer.8 The outcome of sepsis also shows seasonal differ- TABLE Bacterial Exotoxins Implicated in Sepsis
47-1 Pathogenesis
ences, with higher case fatality rates in winter despite comparable
disease severity.
Toxin Micro-organism Examples
Causative Agents and Pore-forming

toxins
Staph. aureus A-hemolysin
Panton–Valentine leukocidin (PVL)
Virulence Factors Strep. pyogenes Streptolysin-O
Historically, gram-negative bacteria are the predominant organisms
that cause sepsis. However, the incidence of gram-positive sepsis has Strep. pneumoniae Pneumolysin
steadily increased. A recent large clinical trial on the effectiveness of E. coli Hemolysin
anti-TLR4 (Toll-like receptor 4) therapy that included 1961 patients
Superantigens Staph. aureus Toxic shock syndrome toxin-1
with severe sepsis found gram-negative infections in 35% of patients, (TSST-1)
gram-positive infections in 27% and mixed gram-negative/gram- Staphylococcal enterotoxins (SE)
positive infections in 11% of patients.19 In a large survey done in 2007 A–F
that aimed to investigate the patterns of infection in ICUs and included Strep. pyogenes Streptococcal pyrogenic toxin A
more than 14 000 patients from 75 countries, gram-negative bacteria (SPEA)
accounted for 62% of positive isolates on the ICU, gram-positive bac- Streptococcal pyrogenic toxin C
teria for 47% and fungi for 19%.20 The rise in the incidence of fungal (SPEC)
Streptococcal mitogenic toxin Z
infections is worrisome since it is associated with a high mortality. (SMEZ)
Important risk factors for candidemia include immunosuppressed or
neutropenic state, prior intense antibiotic therapy and colonization Enzymes Staph. aureus Coagulase
DNAse
in multiple sites. Overall, the most commonly isolated gram-positive Proteases
bacterial pathogens are Staphylococcus aureus and Streptococcus pneu-
moniae, and the most common gram-negative pathogens are Esche- Strep. pyogenes IL-1β convertase
Proteases
richia coli, Klebsiella spp. and Pseudomonas aeruginosa.21 In patients
with more co-morbidities and a protracted stay on the ICU more Strep. pneumoniae Proteases
infections due to resistant staphylococci, Acinetobacter, Pseudomonas
spp. and Candida spp. are seen.20
In order to be successful, pathogens need to adhere, pass the
mucosal barrier and multiply while circumventing host defense Structure of lipopolysaccharide
systems.21,22 Pathogens causing sepsis harbor an impressive arsenal of
virulence factors, known as the ‘virulome’, which can work together
in a regulated manner to assault the host.21 Genes encoding virulence O-specific polysaccharide chain Core glycolipid
factors are frequently clustered in so-called pathogenicity islands
within or outside chromosomes; these pathogenicity islands are usually
absent in non-virulent species of the same strain. Different virulence
factors are expressed by a single pathogen dependent on the stage of Lipid A
infection. An important part of tissue damage due to sepsis pathogens n
O-specific (outer) (inner)
is caused by microbial toxins.21,23 Bacterial toxins can be divided into oligosaccharide core oligosaccharide
three classes. Type I toxins disrupt host cells without the need to enter subunit
the cells. These include superantigens produced by Staph. aureus and
Streptococcus pyogenes. Superantigens can cause polyclonal activation Figure 47-3 Structure of lipopolysaccharide (LPS). LPS is composed of a lipid
of CD4+ T cells, which is considered to play a prominent role in the moiety, designated lipid A (the biologically active part of LPS), and a hydrophilic
pathogenesis of toxic shock syndromes. Type II toxins are toxic for polysaccharide chain, consisting of the O-chain and a core part.
eukaryotic membranes and destroy cell membrane integrity. Eminent
examples include hemolysins and phospholipases. Type III toxins, also
known as A/B toxins, have a binary structure with a specific binding TLR4 (see further). By itself, LPS has no intrinsic, toxic properties.
moiety (the B component) and an active enzymatic component (the Other examples of key bacterial PAMPs are peptidoglycan, lipopep-
A moiety). Whereas cholera toxin, anthrax lethal toxin and Shiga-like tides (constituents of many pathogens), lipoteichoic acid (a cell wall
toxin are widely studied examples of type III toxins, many more component of gram-positive bacteria), flagellin (factor in the mobility
common sepsis pathogens, such as Staph. aureus, Strep. pneumoniae, of bacteria) and bacterial DNA.
Strep. pyogenes, E. coli and P. aeruginosa, secrete type III toxins during Quorum sensing, defined as the ability of bacteria to assess their
invasive infection. These toxins work in concert to disrupt host defense population density, is used by bacteria to influence the behavior of
mechanisms and barriers to invasion, thereby facilitating invasion and surrounding bacteria (Figure 47-4). The quorum sensing apparatus
dissemination of pathogens. Some bacterial toxins can be injected into also plays a key role in biofilm formation, which is slimy layers of
host cells by syringes called type III secretion systems. Table 47-1 lists bacteria in which micro-organisms can protect themselves against the
examples of bacterial exotoxins implicated in sepsis. host defense mechanisms and antibiotics. Quorum sensing has an
Molecular components of invading pathogens that contribute to important role in regulating tissue invasion by bacterial pathogens,
virulence and that are recognized by host defense receptors are called and inhibitors of quorum sensing may provide new opportunities for
pathogen-associated molecular patterns or PAMPs. A prominent prevention of invasive infection.
example of a PAMP implicated in sepsis pathogenesis is lipopolysac-
charide (LPS), often referred to as endotoxin24 (Figure 47-3). LPS is a Laboratory-Based Diagnostics
part of the outer membrane of gram-negative bacteria, accounting for The following laboratory-based diagnostic tests can be regarded as a
approximately 70% of the outer leaflet. LPS is essential for viability for first set of parameters to help establish the diagnosis, detect any level
all pathogenic gram-negative bacteria and one of the most potent proof organ failure and identify the causative agent. Biomarkers are devel-
inflammatory molecules known in biology. Small amounts can cause oped to monitor the immune response, titrate therapy and as prog-
severe toxicity in animals and humans by activation of a host receptor, nostic markers.
tance.27,28 Lastly, the surviving sepsis guidelines (discussed in more

The central role of quorum sensing in microbial pathogenesis
and virulence detail below) recommend the use of the 1,3 beta-D-glucan assay,
mannan and anti-mannan antibody assays, if available and if invasive
candidiasis is in the differential diagnosis.28
Low population density Quorum sensing High densities;
threshold population full virulence BIOMARKERS
level or host stress gene expression
Biomarkers for sepsis that help early diagnosis or predict outcome are
increasingly showing promise for clinical application.29 In theory, bio-
markers could assist in rapid diagnosis of infection and/or in identifi-
cation of patients with a high likelihood of complications and death.
To be suited for point-of-care testing, their measurement must be
simple, rapid, cost-effective and positively affect patient outcome.
C-reactive protein (CRP), procalcitonin and soluble triggering recep-
tor expressed on myeloid cells (TREM)-1 are elevated in patients with
sepsis and have been suggested as potential biomarkers for diagnosis
of infection in patients presenting with severe sepsis. The use of mul-
Virulome turned off: Virulome turned on: Virulome turned on: timarker panels that pool biomarkers might increase their usability.
Quiescent, avoid Replication and early Late vir genes
Combining procalcitonin, soluble TREM-1 and the neutrophil CD64
host detection vir genes activated activated
index demonstrated a high performance in diagnosing sepsis in
two independent cohorts of critically ill patients.30 At present, much
Figure 47-4 The central role of quorum sensing in microbial pathogenesis and
virulence. Regulation of the bacterial virulome by quorum sensing: early virulence
research is devoted to the potential value of molecular biomarkers in
(vir) genes include adhesins, invasion genes and expression of anticomplement sepsis, being either blood leukocyte messenger or non-coding RNAs.29
and antiphagocytic measures; late vir genes include exotoxins, superantigens, Circulating microRNAs represent another emerging class of potential
cytotoxins, replication activation, genetic exchange and antibiotic resistance biomarker for sepsis.31 In addition, it is anticipated that the inclusion
expression. (Reproduced from van der Poll T, Opal SM. Lancet Infect Dis
2008;8(1):32–43.)
of relatively common human polymorphisms that influence the sus-
ceptibility and outcome from sepsis may be included in future multi-
panel biomarker platforms.32 At present, however, none of the currently
tested markers has sufficient specificity or sensitivity for diagnosis, risk
HEMATOLOGIC EVALUATION stratification or to monitor response to therapy to be routinely
Sepsis can be accompanied with both a neutrophilic leukocytosis or employed in clinical practice.28,33
leukopenia, the latter of which is a poor prognostic sign. Toxic granu-
lation of neutrophils (increased band forms) might suggest bacterial
infection. Low platelet counts can suggests diffuse intravascular coagu-
Pathophysiology and Host Response
lation (DIC), which is also characterized by prolonged prothrombin HISTORICAL PERSPECTIVE
or activated partial thromboplastin time, low fibrinogen levels and For many years sepsis was considered to be the consequence of an
elevated markers of fibrinolysis (fibrin degradation products or overwhelming inflammatory reaction of the patient to invading micro-
D-dimer levels).25 Coagulation disorders in sepsis are discussed in organisms. This paradigm was based on animal experiments con-
more detail below. ducted in the 1980s and 1990s, wherein high doses of bacteria or
bacterial products (in particular LPS) were infused.21 These early sepsis
BIOCHEMICAL EVALUATION models failed to capture the complex pathophysiology of the syn-
Renal and liver tests will give an idea of the extent of potential organ drome. Indeed, intravenous administration of bacteria or bacterial
damage and should be monitored during the course of sepsis. A components causes a strong activation of different pro-inflammatory
creatinine increase >0.5 mg/dL or 44.2 µmol/L, or marked hyperbili- protein cascades, including cytokines, which led to the term ‘cytokine
rubinemia (plasma total bilirubin >4 mg/dL or 70 µmol/L) are indica- storm’. In these systemic challenge models elimination or inhibition
tions of organ dysfunction. Both hyperglycemia and hypoglycemia of a number of pro-inflammatory cytokines, most notably tumor
are seen in the event of severe sepsis. Albumin, which is the main necrosis factor (TNF)-α and interleukin (IL)-1, confers a profound
protein responsible for plasma colloid osmotic pressure and acts as a protective effect against lethality. Additional studies showed that
carrier for several endogenous and exogenous compounds, is often TNF-α and IL-1β were also sufficient to induce shock, i.e., administra-
decreased in patients with sepsis due to capillary leakage, an altered tion of recombinant forms of these cytokines reproduced many of the
hepatic metabolism and poor nutrition. An elevated plasma lactate clinical features of severe sepsis. These findings were the basis for
(>1 mmol/L) level is an indicator of poor tissue perfusion. Arterial multiple clinical trials in patients with sepsis seeking to inhibit TNF-α,
blood gas analysis often shows a metabolic acidosis with compensatory IL-1 or other pro-inflammatory mediators. Now, many years later, it
respiratory alkalosis; acidosis and hypoxia are markers of severe is clear that the assumption that excessive inflammation is the basis
disease. for an adverse outcome of a septic patient requires reconsideration.
Infection elicits a much more multifaceted, variable and extended host
IDENTIFICATION OF PATHOGENS AND response, which varies depending on the causative pathogen (load and
SOURCE OF INFECTION virulence) and the host (genetic composition and co-morbidity), with
At least two sets of blood cultures (both aerobic and anaerobic bottles) distinctive reactions at local, regional and systemic levels (Figure 47-5).
should be taken before the administration of antibiotic therapy. Urine The configuration and progression of the host response likely alter
and sputum cultures should be sampled in addition to wound, cere- over time in parallel with the clinical course. In general, pro-
brospinal fluid, joint or any body fluid as indicated. If an exotoxin is inflammatory reactions (initiated by the innate immune system to
suspected in septic shock appropriate isolates should be collected for facilitate clearance of invading pathogens) are held responsible for
determination of toxin production. Unfortunately a causative agent ‘collateral’ tissue damage in severe sepsis, whereas anti-inflammatory
can be identified in around only 60% of septic patients.3,26 Rapid, responses (meant to limit excessive activity of inflammation) may
non-culture-based diagnostic methods (polymerase chain reaction, promote the development of secondary infections. However, a clear
MALDI-TOF mass spectrometry, microarrays) are becoming increas- separation between SIRS and the ‘compensatory anti-inflammatory
ingly available and can be become helpful for the quick identification response syndrome’ (CARS), a concept for a two-staged host response
of pathogens and determination of potential antimicrobial resis- to sepsis introduced in the late 1990s,34 does not seem to exist.
The host respose to sepsis
Excessive inflammation causing collateral damage (tissue injury)

Perpetuation of inflammation Damage-associated
Pro-inflammatory
molecular patterns
Load virulence Cytokines Complement Coagulation
response
Proteases products proteases

Reactive oxygen
Pathogen-associated species
molecular patterns
CLRs
Host-pathogen
Leukocyte Complement Coagulation Necrotic

interaction
TLRs activation activation activation cell death

NLRs
Neuroendocrine regulation Impaired function of Inhibition of pro-
RLRs immune cells inflammatory gene
transcription
Vagus
nerve Apoptosis
Environment of T, B and
Immune suppression
Celiac Brain dendritic cells

Genetics Norepinephrine
Age ganglion
Co-morbidity Anti-inflammatory
Acetylcholine HPA Expansion of cytokines
Medication
axis regulatory T
Soluble cytokine
Spleen and myeloid
Inhibition of pro- receptors
suppressor cells
inflammatory Negative regulators
cytokine production of TLR signaling
Impaired Epigenetic regulation
Catecholamines phagocytosis
cortisol
Adrenals
Immune suppression with enhanced susceptibility for secondary infections
Figure 47-5 The host response to sepsis is characterized by both pro-inflammatory responses (top panel) and anti-inflammatory immune suppressive responses (bottom
panel), resulting from an interaction between host factors (e.g., genetic composition, age, co-morbidity and medication), and pathogen factors (e.g., microbial load and
virulence). Inflammatory responses are initiated by interaction between pathogen-associated molecular patterns expressed by pathogens and pattern recognition recep-
tors expressed by host cells either at the cell surface (Toll-like receptors – TLRs – and C-type lectin receptors – CLRs), in the endosome (TLRs) or in the cytoplasm (Nod-
like receptors – NLRs – and RIG-I-like receptors – RLRs). The consequence of exaggerated inflammation is collateral tissue damage and necrotic cell death, which results
in the release of damage-associated molecular patterns, ‘danger molecules’ that perpetuate inflammation at least in part by acting on the same pattern recognition
receptors triggered by pathogens.
PATHOGEN RECOGNITION SYSTEMS inflammation can be perpetuated by stimulation of PRRs by so-called

The innate immune system can sense pathogens via a limited number danger-associated molecular patterns (DAMPs or alarmins). Alarmins
of pattern-recognition receptors (PRRs). PRRs recognize the con- are endogenous molecules released by cells injured directly by bacteria
served motifs expressed by micro-organisms called PAMPs.21,35 Four or indirectly as a consequence of, for example, ischemia or necrosis
classes of PRRs have been identified: Toll-like receptors (TLRs), C-type (Table 47-3).36 PRRs implicated in the recognition of alarmins include
lectin receptors (CLRs), RIG-I-like receptors (RLRs) and NOD-like TLRs (most notably TLR4), NLRs and the receptor for advanced glyca-
receptors (NLRs) (Table 47-2).35 NLRs are further subcategorized tion end-products (RAGE). Although low concentrations of alarmins
based on differences in the N-terminal domains: NODs are NLRs that may assist the host in eradicating pathogens, sustained and/or strong
recognize common fragments of bacterial peptidoglycan, while the release of alarmins undoubtedly is harmful. Alarmins are also released
largest NLR group, comprising 14 members, has an N-terminal pyrin during sterile injury such as after trauma or severe pancreatitis, giving
domain (PYD) and is therefore called NLRP. Several members of the further support to the concept that the pathogenesis of multiple organ
NLR-family, including NLRP1, NLRP3 and NLRC4 can assemble mul- failure in sepsis and noninfectious critical illness is not fundamentally
timolecular complexes termed inflammasomes in response to various different.3,5
activators. Figure 47-6 provides a simplified presentation of interac-
tions between TLRs and the three major classes of sepsis pathogens. POTENTIAL TYPES OF DEREGULATED
PRRs recognize different components of pathogens, and their acti- HOST RESPONSES
vation results in upregulation of inflammatory gene transcription and The host response to sepsis is influenced by many factors, including
initiation of innate immunity. During an adequate innate immune burden and virulence of the pathogen, and age, co-morbidities and
response the interaction between PAMPs and PRRs results in a bal- genetic composition of the patient. Sepsis likely results from a dis-
anced reaction that eliminates the infection. As a consequence, mice turbed homeostasis wherein the body is no longer capable of respond-
deficient for one or more of these PRRs commonly are more suscep- ing to infection in a balanced manner. The abrupt hyperinflammatory
tible for experimentally induced infection. However, when bacteria reaction induced by intravenous administration of high-dose bacteria
overwhelm the capacity of the innate immune system to clear the in animals, producing the ‘cytokine storm’ described above is a very
infection, resulting in progression to sepsis, the interactions between rare phenomenon in clinical practice, possibly only seen to some
pathogens and PRRs evolve into a deregulated response that no longer extent in patients with meningococcal meningitis or post-splenectomy
benefits the host. One aspect that contributes herein is the fact that pneumococcal sepsis. Most instances of sepsis develop from an
infection that more gradually progresses, which especially in elderly

TABLE Pattern Recognition Receptors and patients is associated with a more blunted inflammatory response.37 In
47-2 Their Ligands fact, the vast majority of sepsis patients already show signs of a sup-
pressed immune response on admission to the hospital, as reflected by
Pattern
Recognition
a reduced capacity of blood leukocytes to respond to bacterial antigens.
Receptor Ligand Origin of Ligand Nonetheless, early deaths in sepsis, generally due to cardiovascular
collapse and multiple organ dysfunction, likely are predominantly
TOLL-LIKE RECEPTORS (TLRs)
driven by excessive inflammatory reactions. Clearly, much still has to
TLR1 Triacyl lipoprotein Bacteria be learned about the pathophysiology of sepsis. Figure 47-5 shows a
TLR2 Lipoprotein Bacteria, viruses, self simplified representation of the host response to sepsis, divided in
pro-inflammatory and immune suppressive reactions. Key aspects of
TLR3 Double-stranded RNA Viruses the various types of host reactions are described in more detail below.
TLR4 Lipopolysaccharide Bacteria, viruses, self
Pro-inflammatory Mediators and Responses
TLR5 Flagellin Bacteria Cytokines. Experimental sepsis is associated with enhanced release
TLR6 Diacyl lipoprotein Bacteria, viruses of multiple cytokines. Elimination or inhibition of multiple pro-
inflammatory cytokines (including TNF-α, IL-1β, IL-12, IL-17, IL-18,
TLR7 Single-stranded RNA Bacteria, viruses, self
interferon-γ and macrophage migration inhibitory factor) improves
TLR8 Single-stranded RNA Bacteria, viruses, self survival in fulminant sepsis models.38 As discussed above, the models
TLR9 CpG-DNA Bacteria, viruses, self
used to study the role of these cytokines in severe sepsis do not ade-
quately mimic the clinical syndrome. Many trials have been conducted
NOD-LIKE RECEPTORS (NLRs) in patients with severe sepsis evaluating the efficacy of pro-inflammatory
NOD1 Peptidoglycan (iE-DAP) Bacteria cytokine inhibition, especially targeting TNF-α and IL-1.39 Moreover,
NOD2 Peptidoglycan (MDP) Bacteria
C-TYPE LECTINS (CLRs) TABLE Alarmins (and Their Receptors) Implicated in

Dectin-1 β-Glucan Fungi 47-3 the Pathophysiology of Sepsis
Dectin-2 β-Glucan Fungi
Group Alarmin Receptors
MINCLE SAP130 Fungi, self
Extracellular matrix Fibronectin TLR4
RETINOIC-ACID-INDUCIBLE GENE (RIG)-I-LIKE RECEPTORS (RLRs) components Hyaluronan TLR4, NLRP3
Heparan sulfate TLR4
RIG-I Short double-stranded RNA Viruses Biglycan TLR4
MDA5 Long double-stranded RNA Viruses Stress-response Heat shock proteins TLR2, TLR4
molecules High mobility group box-1 TLR4
LGP2 Unknown Viruses
Histones TLR2, TLR4
The innate immune system recognizes pathogens by four main classes of Nucleic acids (RNA, DNA) TLR3, TLR7, TLR9
pattern recognition receptors. The table shows the main receptors, their main Immunomodulatory Calprotectin TLR4
ligands and the origin of these ligands. Note that some receptors also proteins β-defensins TLR1/TLR2, TLR4
recognize ‘self’ antigens, primarily in the context of injury, wherein self Surfactant protein A TLR4
antigens function as alarmins to the host. Surfactant protein D TLR2, TLR4
iE-DAP, g-D-glutamyl-meso-diaminopimelic acid; MDP, muramyl dipeptide;
MINCLE, macrophage-inducible C-type lectin; SAP130, Sin3A-associated Others Fibrinogen TLR4
protein of 130kDa; MDA5, melanoma differentiation-associated gene 5; Tenascin-C TLR4
LGP2, Laboratory of genetics and physiology-2. Uric acid NLRP3
Adapted from Takeuchi O, Akira S. Cell 2010;140(6):805–820.
Figure 47-6 Innate recognition of sepsis pathogens

by Toll-like receptors (TLR). (a) The complexity of the Innate recognition of sepsis pathogens by Toll-like receptors
interaction between innate immune receptors and
fungi: three distinct components of the cell wall of
Candida albicans are recognized by four different Lipoproteins
host receptors: N-linked mannosyl residues are detected Budding (TLR2)
by the mannose receptor, O-linked mannosyl residues yeast Beta-glucans Bacterial DNA
are sensed by TLR4 and β-glucans are recognized (dectin 1/TLR2)
by the dectin/TLR2 complex. (b) Gram-positive and
(TLR9)
gram-negative bacteria are recognized by partially over- O-linked Lipoteichoic acid
lapping and partially distinct repertoires of TLRs. Gram- mannosides (TLR2)
positive pathogens exclusively express lipoteichoic acid, (TLR4)
gram-negative pathogens exclusively express lipopoly- Lipopolysaccharide
saccharide; common PAMPs include peptidoglycan, (TLR4)
lipoproteins, flagellin and bacterial DNA. (Reproduced N-linked Peptidoglycan
from van der Poll T, Opal SM. Lancet Infect Dis 2008;
mannosides (TLR2)
8(1):32–43.)
(mannose
receptor) Flagellin
(TLR5)
a Candida spp. b Gram-negative bacteria c Gram-positive bacteria

TABLE Clinical Sepsis Trials that Have Tested Pathogenesis of disseminated intravascular coagulation
47-4 Biologic Response Modifiers
Target Strategy
LPS/bacterial products/cytokines
Endotoxin (lipopolysaccharide, Anti-LPS antibodies (HA-1A, E5)
LPS) and LPS signaling LPS inhibiting strategies (bactericidal
permeability increasing protein (BPI),
taurolidine, polymyxin B, alkaline
phosphatase, lipid emulsion)
Toll-like receptor 4 antagonists (Eritoran,
TAK-242) Tissue factor- Dysfunctional Impaired
Anti-CD14 antibody mediated thrombin anticoagulant fibrinolysis due
generation mechanisms to PAI-1
Tumor necrosis factor (TNF) Antibodies (monoclonal and polyclonal)
Soluble receptor constructs
Interleukin-1 (IL-1) Interleukin-1 receptor antagonist

(IL-1RA)
Inadequate
Platelet activating factor (PAF) Small molecule inhibitors
Fibrin formation
fibrin removal
PAF acetylhydrolase
Eicosanoids Ibuprofen
Soluble phospholipase A2 inhibitor
Nitric oxide L-NMMA

Methylene blue Fibrin deposition
Enhanced coagulation Antithrombin

Tissue factor pathway inhibitor (TFPI)
Recombinant human activated protein C Figure 47-7 Pathogenesis of disseminated intravascular coagulation (DIC). DIC
Protein C concentrate is caused by a combination of enhanced activation of the coagulation system
Soluble thrombomodulin (mediated by tissue factor) and impaired anticoagulant and fibrinolytic mecha-
Heparin nisms. PAI-1, plasminogen activator inhibitor type 1.
Immune suppression Immunoglobulins

Interferon-gamma Complement System. Activation of the complement system forms
Granulocyte colony stimulating factor an integral part of the innate immune response to infection.41 Sepsis
(G-CSF) is associated with elevated plasma levels of the anaphylatoxins C3a and
Granulocyte-macrophage colony C5a, reflecting systemic activation of the complement system. Activa-
stimulating factor (GM-CSF)
tion of the C5a receptor triggers a cascade of pro-inflammatory signal-
Endocrinopathy Corticosteroids ing events. Although intended to boost protective immunity, excessive
Vasopressin C5a activity can be harmful in the setting of fulminant sepsis. Indeed,
Others Selenium neutralization or genetic absence of C5a and its receptors (C5a recep-
Lactoferrin tor and C5L2) improves survival during abdominal sepsis or endotox-
Bradykinin antagonists emia in mice. Inhibition of C5a activity is currently considered an
Statins
Extracorporal hemoperfusion attractive therapeutic option in sepsis.41
Adapted from Marshall JC. Trends Mol Med 2014;20(4):195–203. Activation of Coagulation and Malfunction of
the Vascular Endothelium
Sepsis is associated with a net procoagulant state due to activation of
other therapeutic strategies seeking to inhibit pro-inflammatory medi- coagulation concurrent with impaired function of anticoagulant and
ators, including platelet-activating factor (PAF), prostaglandin antago- fibrinolytic mechanisms (Figure 47-7).42 The most severe manifesta-
nists, bradykinin antagonists and high-dose corticosteroids, failed to tion of a disturbed hemostatic balance in sepsis is the syndrome of
demonstrate benefit in treated patients (Table 47-4).39 disseminated intravascular coagulation (DIC), with an estimated inci-
dence between 30% and 50% in severe sepsis. Tissue factor is the main
HMGB1. HMGB1 is a highly conserved non-histone nuclear protein driver of coagulation activation in sepsis. In normal homeostasis,
that is either released passively during cell injury or secreted actively tissue factor is not exposed to circulating blood cells; upon exposure
upon inflammatory stimuli.40 Depending on specific post-translational to pathogens or pro-inflammatory cytokines tissue factor becomes
redox modifications HMGB1 can act as a cytokine via receptors such exposed on the surface of mononuclear cells and endothelial cells and/
as RAGE and TLR4 or as a chemotactic factor. HMGB1 levels are or in microparticles shed from a variety of cell types. Tissue factor
elevated during sepsis, and postponed treatment (24 hours after the together with Factor VIIa activates Factor X, subsequently leading to
challenge) of mice with antibodies to HMGB1 diminished lethality of thrombin and fibrin generation. Procoagulant events are controlled
experimental abdominal sepsis.40 There is no clinical development by three major anticoagulant proteins: antithrombin, tissue factor
program for anti-HMGB1 treatment of sepsis. pathway inhibitor (TFPI) and activated protein C (APC). Besides func-
S100A8/9. S100A8/9 is a heterodimeric protein also known as cal- tioning as an anticoagulant, APC has clear anti-inflammatory and
protectin, which is an abundant cytoplasmic protein in neutrophils.38 barrier protective effects. Several clinical trials in sepsis patients have
S100A8/9 functions as an alarmin that can promote systemic inflam- been performed focusing on the restoration of (supra) physiologic
mation through activation of TLR4. Patients with sepsis display ele- levels of these natural anticoagulant proteins. Antithrombin and
vated circulating levels of S100A8/9 and mice deficient for this protein TFPI failed to reduce mortality in randomized clinical trials in sepsis
are protected from endotoxin shock and E. coli-induced abdominal patients;43 although recombinant human APC reduced 28-day mortal-
sepsis. On the other hand, S100A8/9-deficient mice display enhanced ity in a first pivotal phase III trial,44 resulting in the approval for thera-
bacterial dissemination and a reduced survival during gram-negative peutic use in patients with severe sepsis, a subsequent study in septic
pneumonia, illustrating the double-edged sword character of innate shock patients did not confirm this protective effect,45 causing the
immunity.38 retraction of recombinant human APC from the market.
Microvascular leak is an important feature of severe sepsis.46 Under Apoptosis of immune cells has been implicated in immune dys-
physiologic conditions vascular barrier function is maintained by function and mortality in sepsis. Most cells that undergo enhanced
endothelial cells and associated cell–cell junctions and extracellular apoptosis in sepsis are of lymphoid origin. Post-mortem studies done
components such as the glycocalyx. In severe sepsis endothelial perme- shortly after death due to sepsis demonstrated a marked apoptosis-
ability increases, resulting in tissue edema. The pathophysiologic induced loss of B cells, CD4 T cells and follicular dendritic cells.
mechanisms that contribute to vascular leak have been studied in great Besides the spleen, lungs also showed proof for immune suppression;
detail, both in preclinical models and in observational studies in both organs displayed increased expression of ligands for T-cell inhibi-
patients. Sphingosine-1-phosphate (S1P) is one of the most studied tory receptors on parenchymal cells.50 Animal studies have suggested
mediators in this context. Plasma S1P can activate its receptor S1P1 on that enhanced apoptosis of lymphocytes contributes to sepsis lethal-
endothelial cells, thereby maintaining vascular integrity. Alterations in ity.37 Of note, patients who remain on the ICU for prolonged periods
the hemostatic balance can influence vascular barrier function via of time after sepsis admission frequently have ongoing infectious foci
activation of protease activated receptor (PAR)1, wherein thrombin despite antimicrobial therapy or reactivation of latent viruses.37 It has
can enhance permeability while APC exerts barrier protective effects. been suggested that the immune suppression that accompanies severe
Another player in maintenance of vascular integrity is angiopoietin-1 sepsis can be a target for therapeutic intervention, for example by
via activation of the Tie2 receptor. Angiopoietin-2 is a functional immune stimulation therapy such as provided by interferon-γ, IL-7
antagonist of angiopoietin-1 that can disrupt endothelial barrier func- and granulocyte-macrophage colony stimulating factor or by co-
tion. Microvascular barrier increasing agents are considered promising inhibitory molecule blockade, such as anti-programmed cell death
options for sepsis treatment. These include S1P agonists, angiopoietin-1/ receptor-1 antibodies,37 although this option is not endorsed by others.
Tie-2 agonists and angiopoietin-2 antagonists.46 Clearly, much research is needed to establish the causal contribution
of immune suppression to adverse sepsis outcome.
Organ Dysfunction GENE POLYMORPHISMS IN SEPSIS
Tissue hypoperfusion, caused by hypotension, reduced red cell deform-
A classic study has shown that people who are placed with adoptive
ability, microvascular thrombosis and/or dysfunction of the vascular
parents unrelated to them early in life have an almost sixfold increased
endothelium with loss of barrier integrity, plays a major role in the
risk of death from infections if one of their biologic parents dies of an
development of organ dysfunction.3 Nonetheless, impaired organ
infection before the age of 50, thereby establishing the fact that human
function can occur in the absence of gross macrovascular anomalies.
host genetics are a key determinant for the risk to acquire an infec-
Postmortem studies of patients who died of sepsis indicate that sepsis
tion.51 Variation in host genetics not only influence the risk of acquir-
does not produce significant cell death. Indeed, cell death is predomi-
ing sepsis, but can also affect the severity of the inflammatory response
nantly limited to lymphocyte compartments in sepsis patients, whereas
and degree of organ failure.32 For example, IL-6 gene polymorphisms
viability of other cell types is largely intact, and the extent of cell death
increase the risk of organ failure and death in patients with sepsis,
is disproportionately minor relative to the severe manifestations of
while gene polymorphisms in IL-8 and protein C are associated with
organ dysfunction.47 Mitochondrial dysfunction and altered cellular
more severe organ failure and the development of septic shock.32,52
bioenergetics have been implicated in sepsis-induced organ dysfunc-
Variations that affect gene expression through epigenetic modifica-
tion, although further research is warranted to establish a causal
tions, such as DNA methylation, histone modifications and expression
relationship.47
of microRNAs, may also impact sepsis outcome.53 Although these
recent developments have increased our insights into the pathogenesis
Anti-inflammatory Mechanisms and of sepsis, the incorporation of these genetic markers into triaging or
Immune Suppression treatment protocols awaits further clinical testing of their value in
Abundant pro-inflammatory reactions generated in response to an everyday clinical practice.
overwhelming bacterial multiplication can be inhibited via humoral,
cellular and neural mechanisms. The so-called neuro-inflammatory Prevention
reflex can inhibit inflammation upon sensory input transmitted
Preventive measurements that aim to reduce the incidence of sepsis
through the afferent vagus nerve to the brainstem, by stimulation of
include selective vaccination for people at risk, diligent infection
the efferent vagus nerve and subsequent activation of the splenic nerve
control for high-risk patients, use of prophylactic antibiotic therapies
in the celiac plexus, norepinephrine release in the spleen and acetyl-
and early recognition and treatment of infection. The introduction of
choline secretion by a subset of CD4+ T cells.48 The neurotransmitter
the 7-valent pneumococcal conjugate vaccine (PCV7) into the United
acetylcholine suppresses pro-inflammatory cytokine release by macro-
States childhood immunization program has substantially reduced the
phages. The in vivo relevance of the neuro-inflammatory reflex is illus-
incidence of vaccine-serotype invasive pneumococcal sepsis, which has
trated by animal studies showing that vagotomy renders animals more
been sustained a decade after its introduction.54 In the hospital, careful
vulnerable to endotoxin shock, while stimulation of the efferent vagus
infection control practices should be implemented during the care of
nerve reduces systemic inflammation in experimental sepsis.
sepsis patients: hand washing, expert nursing care, catheter care,
The majority of sepsis patients show evidence for immune suppres-
barrier precautions, airway management, elevation of the head of the
sion, which is in part reflected by the consistent finding that blood
bed and subglottic suctioning are all part of the surviving sepsis guide-
leukocytes from these patients are less capable of releasing pro-
lines described in more detail below.28
inflammatory cytokines upon stimulation with bacteria or bacterial
products.21,37 The extent of immunosuppression is associated with
mortality in patients with sepsis.49 Autopsy studies have revealed Therapy
strong functional impairments of splenocytes harvested from patients The Surviving Sepsis Campaign was created in 2002 and covers severe
who had died of sepsis.50 The mechanisms that underlie this phenom- sepsis management guidelines and a sepsis performance improvement
enon have not been fully elucidated; likely anti-inflammatory cyto- program, composed by an international consortium of critical care,
kines, particularly IL-10 and transforming growth factor (TGF)-β infectious disease and emergency medicine professional societies. The
are involved, as well as inhibition of signaling by PRRs, partially due second revision of the guidelines was published in 2013.28 Box 47-3
to epigenetic modifications of essential promoter regions, play a summarizes the current recommendations for sepsis treatment,
role. In addition, lipid mediators (prostaglandin E2) and hormones arranged according to element of care and grade of evidence. Table
(epinephrine, glucocorticoids, vasoactive intestinal peptide, α- 47-5 summarizes recommendations on antimicrobial therapy in sepsi
melanocyte stimulating hormone) may contribute to inhibition of (Table 47-5). The most important components of the guidelines are
inflammation during sepsis. structured in two ‘bundles’ of care: an initial management bundle to
TABLE
47-5 Recommendations on Antimicrobial Therapy in Sepsis
RECOMMENDATION
1 Administration of effective intravenous antimicrobials within the first hour of recognition of severe sepsis or septic shock as the goal of therapy.
2a Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or viral) and that penetrate
in adequate concentrations into tissues presumed to be the source of sepsis.
2b Antimicrobial regimen should be reassessed daily for potential de-escalation.
3 Consider the use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially
appeared septic, but have no subsequent evidence of infection.
4a Combination empirical therapy for neutropenic patients with severe sepsis and for patients with difficult-to-treat, multidrugresistant bacterial pathogens
such as Acinetobacter and Pseudomonas spp. For patients with severe infections associated with respiratory failure and septic shock, combination
therapy with an extended spectrum beta-lactam and either an aminoglycoside or a fluoroquinolone is for P. aeruginosa bacteremia. A combination of
beta-lactam and macrolide for patients with septic shock from bacteremic Streptococcus pneumoniae infections.
4b Empiric combination therapy should not be administered for more than 3–5 days. De-escalation to the most appropriate single therapy should be
performed as soon as the susceptibility profile is known.
5 Duration of therapy typically 7–10 days; longer courses may be appropriate in patients who have a slow clinical response, undrainable foci of infection,
bacteremia with S. aureus; some fungal and viral infections or immunologic deficiencies, including neutropenia.
6 Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin.
7 Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause.
Recommendations according to the Surviving Sepsis Campaign international guidelines for the management of severe sepsis and septic shock. Quality of
evidence varies between ungraded to level 1C according to Grading of Recommendations Assessment, Development and Evaluation (GRADE) system (also
refer to BOX 47-3). Choice of the specific antibiotic therapy is quite variable depending on suspected source and geography. Please refer to local guidelines.
Adapted from Dellinger RP, et al. Crit Care Med. 2013 Feb;41(2):580–637.
BOX 47-3 SURVIVING SEPSIS GUIDELINES FOR SEVERE SEPSIS AND SEPTIC SHOCK
GRADE ELEMENT OF CARE
Resuscitation
1C Early goal-directed resuscitation during first 6 hours after recognition
2B Initial fluid resuscitation with crystalloid with consideration of the addition of albumin
1C Initial fluid challenge in patients with tissue hypoperfusion with suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids
1C Fluid challenge technique continued as long as there is hemodynamic improvement
1B Norepinephrine as the first choice vasopressor to maintain MAP ≥65 mmHg
1B Epinephrine when an additional agent is needed to maintain adequate blood pressure
Vasopressin 0.03 units/minute can be added with weaning of norepinephrine if tolerated
2C Dopamine as an alternative vasopressor to norepinephrine in highly selected patients (e.g., patients with low risk or arrhythmias and either known
marked LV systolic dysfunction or low heart rate)
1C Dobutamine infusion administered or added to vasopressor (if in use) in the presence of (a) myocardial dysfunction as suggested by elevated
cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion, despite achieving adequate intravascular volume and MAP
2C Not using intravenous hydrocortisone if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability and, if used,
dosed at 200 mg per day
1B In the absence of tissue hypoperfusion, critical coronary artery disease/myocardial ischemia, or acute hemorrhage, target a hemoglobin of 7–9 g/dL
Infection Control
1C Blood cultures before antibiotic therapy
1C Imaging studies performed promptly to confirm potential source of infection
1B/1C Administration of broad-spectrum antibiotic therapy within 1 hour of diagnosis of septic shock and severe sepsis without septic shock
1C Reassess antibiotic therapy with microbiology and clinical data to narrow coverage as appropriate
1D 7–10 days of antibiotic therapy guided by clinical response
1C Source control with attention to risks and benefits of the chosen method within 12 hours of diagnosis
Respiratory Support
1A/1B Use a low tidal volume and limitation of inspiratory plateau pressure strategy for ALI/ARDS
1B Apply a minimal amount of PEEP in ALI
2C Higher rather than lower PEEP for patients with sepsis-induced ARDS
2C Recruitment maneuvers in sepsis patients with severe refractory hypoxemia
2C Prone positioning in sepsis-induced ARDS with PaO2/FiO2 ratio <100 in facilities that have experience with such practice
1B Head of bed elevation in mechanically ventilated patients unless contraindicated
1C Use a conservative fluid strategy for established ALI/ARDS with no evidence of tissue hypoperfusion
1B Use weaning protocols
Central Nervous System Support
1B Use sedation protocols, targeting specific titration endpoints
1C Avoid neuromuscular blockers if possible in the septic patient without ALI/ARDS
2C Use a short course of neuromuscular blocker not >48 hours for patients with early, severe ARDS
General Supportive Care
1A A protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are >180 mg/dL,
targeting an upper blood glucose <180 mg/dL
2B Equivalency of continuous veno-veno hemofiltration or intermittent hemodialysis
1A Prophylaxis for deep vein thrombosis
1A Use stress ulcer prophylaxis to prevent upper gastrointestinal bleeding
2C Administer oral or enteral feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48
hours after a diagnosis of severe sepsis/septic shock
2C Address goals of care, including treatment plans and end-of-life planning (as appropriate) within 72 hours of ICU admission
GRADE: Numeral represents strength of recommendation (1 = recommended; 2 = suggested); letter represents level of evidence, from high (A) to low (D).
MAP, mean arterial pressure; LV, left ventricular; PEEP, positive end-expiratory pressure; ALI, acute lung injury; ARDS, acute respiratory distress syndrome.
Adapted from Dellinger RP, et al. Crit Care Med 2013;41(2):580–637 and Angus DC, van der Poll T. N Engl J Med 2013;369(9):840–851.
postponed antibiotic therapy in patients with severe sepsis is associated

BOX 47-4 SURVIVING SEPSIS CAMPAIGN with increased mortality,56 indicating that antibiotics covering all
BUNDLES probable pathogens should be given as early as possible. Empirical
Bundles (care elements) to be completed within 3 hours of the time of antifungal therapy should be limited to patients at high risk for inva-
presentation to the emergency department, or within 3 hours of (poten- sive candidiasis. Once culture results become available, de-escalation
tial) diagnosis on hospital wards or in the intensive care unit. of initial broad spectrum antibiotic therapy is safe and may reduce
1. Measure lactate level. the appearance of resistant micro-organisms, as well as possible drug
2. Obtain blood cultures prior to the administration of antibiotics.
3. Administer broad-spectrum antibiotics. toxicity and costs. The additional value of combination antimicrobial
4. Administer 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L therapy to appropriate single-agent therapy in severe sepsis is not
(36 mg/dL). established. Current guidelines endorse combination antimicrobial
Bundles (care elements) to be completed within 6 hours of the time of therapy only for sepsis in neutropenic patients or sepsis caused by
presentation to the emergency department, or within 6 hours of (poten-
tial) diagnosis on hospital wards or in the intensive care unit. Pseudomonas.28
1. Apply vasopressors (for hypotension that does not respond to initial
fluid resuscitation) to maintain a mean arterial pressure ≥65 mmHg.
2. In the event of persistent arterial hypotension despite volume resus-
Future Perspectives and Conclusion
citation (septic shock) or initial lactate ≥4 mmol/L (36 mg/dL): Severe sepsis is one of medicine’s oldest problems. Although case fatal-
a) Measure central venous pressure ity rates of sepsis have declined in recent years, sepsis remains a major
b) Measure central venous oxygen saturation health burden worldwide due to its increasing incidence and emerging
3. Remeasure lactate if initially elevated.
antibiotic resistance. While knowledge of the pathophysiology of sepsis
From Dellinger RP, et al. Crit Care Med 2013;41(2):580–637. has increased tremendously, specific therapies are still lacking. Clinical
trials seeking to modify the host response to the benefit of the patient
have failed, which at least in part is caused by an inability to select
patients with a high likelihood of treatment success. Indeed, thus far
sepsis trials have used broad entry criteria, based on clinical presenta-
be accomplished within 3–6 hours of presentation and a management tion, giving little respect to the fact that these criteria are applicable to
bundle to be accomplished within 24 hours (Box 47-4). Implementa- a variety of disease manifestations. Sepsis is an extremely heteroge-
tion of the bundles is associated with improved outcome.55 neous syndrome and it is highly unlikely that current trial entry criteria
The principles of the initial management bundle are to provide capture a population that can benefit from different potential inter-
cardiorespiratory resuscitation and diminish the immediate danger of ventions varying from anti-inflammatory and/or anticoagulant to
the underlying infection. Resuscitation involves intravenous fluids, immune stimulatory. The future of sepsis treatment likely lies in the
vasopressors and mechanical ventilation where needed. The initial development of diagnostic strategies that identify subgroups of patients
management of infection entails identifying the most likely source of that might benefit from targeted therapies and that can monitor treat-
infection, obtaining cultures, instigating empiric antimicrobial therapy ment responses. In addition, as sepsis mortality declines, more atten-
and pus drainage where appropriate. The choice of empirical antibiotic tion should be given to non-mortal outcomes, with focus on long-term
treatment depends on the site of infection, the location the infection sequelae and quality of life.
was acquired (i.e., community, nursing home or hospital), medical
history, and local microbial susceptibility patterns. Inadequate or References available online at expertconsult.com.
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Chapter 47 Sepsis 426.e1
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48
Infections Associated with
Intravascular Lines and Grafts
WINFRIED V. KERN
KEY CONCEPTS including Candida and other fungi as well as enteric gram-negative
bacilli and Pseudomonas aeruginosa have been implicated.
• Intravascular catheter-related infections (CRI) are a leading
cause of healthcare-associated infections. The implementation
of bundles for prevention can reduce 60–75% of these infec-
Pathogenesis
tions; prevention strategies need to focus on extraluminal and Colonization of intravascular devices may occur by either of two main
endoluminal colonization by pathogens. routes.8 Extraluminal colonization, originating from the skin insertion
site and migrating along the extraluminal surface, is the predominant
• Antimicrobial-coated catheters are an additional option for
mechanism in short-term catheters such as the non-tunneled central
infection prevention if the rate of CRI in a given healthcare
institution remains high; antibiotic lock solutions are an addi- venous catheters used most frequently in intensive care units. Intralu-
tional option in individuals in whom other attempts for infection minal colonization, originating from colonization of the catheter hub,
prevention have failed. or less commonly from contaminated infusate, is the predominant
mechanism in longer-term lines including tunneled CVCs used for
• For the diagnosis of CRI, the semiquantitative culture (roll cancer chemotherapy or parenteral nutrition. Less commonly, devices
plate) of the catheter tip and paired blood cultures with assess-
become colonized hematogenously, from a distant site of infection
ment of the differential time to positivity are the methods of
choice. (Figure 48-1). The relative likelihood of each of the two main routes
is important for preventive measures and diagnosis of catheter-related
• Line removal in addition to antimicrobial therapy remains a infection in a particular clinical setting.1,2
most important therapy component in patients with septic The ability of micro-organisms to form a biofilm on the surface of
shock and the line as the likely source, in patients with deep an intravascular catheter is important to explain the development and
localized infection, such as tunnel infection, frank cellulitis,
persistence of CRI.9–13 Bacterial cell surface proteins interact with host
pocket infection or port abscess, and in patients with CRI due
to Staphylococcus aureus or Candida spp. extracellular matrix components, and later produce polysaccharides
that serve as intercellular adhesins. The resulting biofilm comprises
• The management of arterial graft infection is interdisciplinary host proteins, microcolonies of the infecting organisms and the extra-
and includes primarily surgical revision with graft removal in cellular polysaccharide matrix (slime) they produce, extracellular
most cases and targeted antimicrobial therapy. DNA, and often accessory microbial matrix components, allowing not
only persistence of organisms in a relatively protected environment,
but also some dispersal of organisms into the environment (and
bloodstream). Antibiotics at doses much higher than those needed to
Introduction kill organisms in planktonic state may still be insufficient to kill sessile
Intravascular lines and devices are used increasingly for the adminis- bacteria within a biofilm.14 This explains why systemic antibiotics
tration of fluids, medication, blood products and nutrition, for hemo- alone often do not eliminate infection until the line is removed.
dynamic monitoring and for hemodialysis. All kinds of intravascular Biofilm-forming capacity is a characteristic of many micro-
catheters and devices carry a risk of infection, and catheter-related organisms and is not restricted to staphylococci, which are the domi-
bloodstream infection (CRBSI) has become a leading cause of bacte- nant species of CRBSI. Different properties apart from production of
remia and fungemia. The associated morbidity, mortality and increased cell surface-attached extracellular polysaccharides facilitate biofilm
length of hospital stay are substantial.1–4 Approximately 3 in every 1000 formation, depending on surface properties, attachment capacity,
patients admitted to acute care hospitals will acquire bacteremia, and available nutrients and interaction with host or environmental
almost one-third of these are CRBSIs. molecules.10–13
Epidemiology Clinical Features

The risk of infection associated with intravascular devices varies with CRI may be local or systemic or both.
the device used. Peripheral cannulae, usually only in place for up to
72 hours, bear a low risk of bloodstream infection, although the fre- LOCAL INFECTION
quency of their use still implies significant morbidity. The majority of Localized catheter infections include exit site infection, tunnel infec-
serious catheter-related infections (CRI) are associated with central tion and pocket infection (Figure 48-2). They may present with signs
venous catheters (CVCs).5 Tunneled and cuffed or surgically implanted of inflammation, purulence or frank cellulitis. Local infection may
catheters carry lower rates of infection than standard non-tunneled coexist with systemic infection (frank purulence may be predictive of
CVCs, with totally implantable ports having the lowest rates (Table CRBSI), but may also exist independently.15,16 The vast majority of
48-1). However, the cumulative incidence of CRBSI in patients with CRBSIs occur without local signs9 and the absence of such signs is no
tunneled hemodialysis catheters may be as high as 40–50% after 6 reassurance against a diagnosis of CRBSI in a febrile patient.
months.6
In addition to the type of catheter used, factors during insertion, SYSTEMIC INFECTION
as well as patient factors, predispose to catheter-related infection CRBSI may present with fever and chills, with or without severe sepsis
(Table 48-2).7 Typical micro-organisms causing CRBSI are coagulase- or septic shock, and should be considered in a patient without an
negative staphylococci and Staphylococcus aureus, but many others obvious alternative source of infection. Blood cultures growing Staph.
427
TABLE
48-1 Rates of Bloodstream Infection (BSI) Caused by the Various Types of Devices Used for Vascular Access
Rates of Device-Related BSIs per Rates of Device-Related BSIs per
100 Catheters 1000 Catheter Days
Catheter Type Pooled Mean 95% CI Pooled Mean 95% CI
Peripheral venous cannulas
Plastic catheters 0.2 0.1–0.3 0.6 0.3–1.2
Steel needles 0.4 0.0–2.3 1.6 0.0–9.1
Cutdowns 3.7 0.1–20.6 8.8 0.2–49.3
Arterial catheters used for hemodynamic monitoring 1.5 0.9–2.4 2.9 1.8–4.5
Central venous catheters
Standard noncuffed, nonmedicated 3.3 3.3–4.0 2.3 2.0–2.4
Antibiotic-coated 0.2 0.0–1.0 0.2 0.1–1.4
Control nonmedicated 4.4 3.5–5.5 — —
Antiseptic-impregnated 3.1 2.4–3.9 2.9 2.3–3.7
Control nonmedicated 3.8 1.5–7.8 — —
Peripherally inserted central catheters (PICCs) 1.2 0.5–2.2 0.4 0.2–0.7
Silver-impregnated cuffs 3.3 1.9–5.4 3.2 1.9–5.3
Tunneled but noncuffed 12.4 10.7–16.6 1.8 1.4–2.0
Pulmonary artery catheters 1.9 1.1–2.5 5.5 3.2–12.4
Heparin-bonded 0.4 0.2–0.9 2.6 1.1–5.2
Hemodialysis catheters
Noncuffed 16.2 13.5–18.3 2.8 2.3–3.1
Cuffed 6.3 4.2–9.2 1.1 0.7–1.6
Tunneled and cuffed central venous catheters 20.9 18.2–21.9 1.2 1.0–1.3
Subcutaneous central venous ports 5.1 4.0–6.3 0.2 0.1–0.2
Peripherally inserted central ports 0.0 0.0–2.8 0.0 0.0–0.1
Intra-aortic balloon counter-pulsation devices 1.9 0.9–3.6 5.5 2.5–10.5
Left ventricular assist devices 22.5 17.5–28.5 4.5 3.6–5.7
Based on 206 published prospective studies in which every device was evaluated for infection.
From Kluger and Maki, Infect Control Hosp Epidemiol 2000; 21:95-96.5 Copyright University of Chicago Press.
aureus, coagulase-negative staphylococci or Candida species suggest is to reduce the populations of skin micro-organisms at the time of
the diagnosis. For definitions of catheter colonization, local infection insertion and during subsequent manipulations, dressings and care.
and CRBSI see Table 48-3.
Maximum Sterile Barrier Precautions
Prevention The use of maximum sterile precautions, similar to those used in the
operating theater (including sterile gown, gloves and cap, and a large
Catheter-related infections are preventable. Prevention strategies are sterile drape) significantly reduces infection when compared with stan-
multifaceted (Table 48-4) and address both extraluminal and endolu- dard precautions (sterile gloves, small sterile drape).2,3,24,25 This
minal colonization. They may include the use of tunneled or totally approach has also been found to reduce CRI associated with pulmo-
implanted catheters, antimicrobial lock solutions, and antimicrobial- nary artery catheters.26
coated catheters.17 Proper institution of catheter-care bundles can
reduce 60–75% of CRBSIs;18–23 a number of recent comprehensive Choice of Cutaneous Antiseptic
practice guidelines are available, e.g., the US Centers for Disease There has been controversy about the most effective cutaneous anti-
Control and Prevention Healthcare Infection Control Practices Advi- septic. Chlorhexidine was associated with greater efficacy than
sory Committee (HICPAC) guidelines, and others.2,3,24 Local guideline povidone-iodine in earlier trials, but an essential element in most
implementation with education of staff about key measures, training iodine-containing as well as chlorhexidine-containing products has
and audit/feedback is effective. been alcohol. In addition, the chlorhexidine concentration appears to
As CRI follows either extraluminal or endoluminal colonization, be critical (0.5% or 2%). Currently, the recommendation is to use 2%
prevention strategies should focus on these two potential routes. chlorhexidine preparation with alcohol before catheter insertion and
during dressing changes, with 70% alcohol, tincture of iodine, or an
PREVENTION OF COLONIZATION OF iodophor as an alternative.2,3,24,27,28
THE EXTERNAL SURFACE OF THE LINE
Measures to prevent extraluminal colonization are of primary impor- Site of Catheter
tance with short-term lines, where the role of microbial colonization The femoral vein should be avoided for central venous access in adults.
of the insertion site is crucial in the pathogenesis of infection. The aim The subclavian site is associated with a smaller risk of infection than
Chapter 48 Infections Associated with Intravascular Lines and Grafts 429
TABLE
48-2 Risk Factors for Intravascular Device-Related Bloodstream Infection
Risk Factors (Number of Studies) Relative Risk or Odds Ratio
Patient characteristics Underlying disease:
Acquired immune deficiency syndrome (2) 4.8
Neutropenia (2) 1.0–15.1
Gastrointestinal disease (1) 2.4
Surgical service (1) 4.4
Placement in intensive care unit or coronary care unit (3) 0.4–6.7
Extended hospitalization (3) 1.0–6.7
Other intravascular devices (2) 1.0–3.8
Systemic antibiotics (3) 0.1–0.5
Active infection at another site (2) 8.7–9.2
High APACHE III score (1) 4.2
Mechanical ventilation (1) 2.0–2.5
Transplant patient (1) 2.6
Features of insertion Difficult insertion (1) 5.4

Maximal sterile barriers (1) 0.2
Tunneling (2) 0.3–1.0
Insertion over a guidewire (8) 1.0–3.3
Insertion site:
Internal jugular vein (6) 1.0–3.3
Subclavian vein (5) 0.4–1.0
Femoral vein (2) 3.3–4.8
Defatting insertion site (1) 1.0
Use of multilumen catheter (8) 6.5
Catheter management Routine change of iv set (2) 1.0

Nurse: patient ratio
1 : 2.0 61.5
1 : 1.5 15.6
1 : 1.2 4.0
1 : 1 1.0
Inappropriate catheter usage (1) 5.3
Duration of catheterization >7 days (5) 1.0–8.7
Colonization of catheter hub (3) 17.9–44.1
Parenteral nutrition (2) 4.8
Adapted from Safdar et al., Medicine (Baltimore) 2002; 81(6):466-479.
Potential sources of infection of a percutaneous intravascular device (IVD)
Contaminated
catheter hub
Endogenous Contaminated
• Skin flora infusate
Skin organisms Extrinsic Extrinsic
Endogenous • HCW hands • Fluid
• Skin flora • Medication
Extrinsic Intrinsic
• HCW hands • Manufacturer
• Contaminated
disinfectant
Fibrin sheath Skin

thrombus
Vein
Hematogenous spread
from distant infection
Figure 48-1 Potential sources of infection of a percutaneous intravascular device (IVD). These include contiguous skin flora, contamination of the catheter hub and
lumen, contamination of infusate and hematogenous colonization of the IVD from distant, unrelated sites of infection. HCW, healthcare worker. (From Crnich and Maki,
Clin Infect Dis 2002; 34(9):1232–1242.8 Copyright The University of Chicago Press.)
a b
Figure 48-2 Subacute port pocket infection with purulent secretion (a), and (b) drained infusion port pocket abscess with evidence of intravascular device-related
inflammation. ((b) from Raad et al., Lancet Infect Dis 2007; 7(10):645–657.16 Copyright Elsevier 2007.)
TABLE Proposed Definitions for Intravascular Device (IVD)-Related Colonization, Local Infection and Bloodstream
48-3 Infection, Based on Microbiologic Confirmation of the IVD as the Source
IVD colonization • Positive semiquantitative* (or quantitative†) culture of the implanted portion or portions of the IVD
• Absence of signs of local or systemic infection
Local IVD infection • Positive semiquantitative* (or quantitative†) culture of the removed IVD or a positive microscopic examination
or culture of pus or thrombus from the cannulated vessel
• Clinical evidence of infection of the insertion site (i.e. erythema, induration or purulence), but
• Absence of systemic signs of infection and negative blood cultures, if done
IVD-related bloodstream infection (BSI) If the IVD is removed:

• Positive semiquantitative* (or quantitative†) culture of the IVD or a positive culture of the catheter hub or
infusate (or positive microscopic examination or culture of pus or thrombus from the cannulated vessel) and
one or more positive blood cultures, ideally percutaneously drawn, concordant for the same species, ideally
by molecular subtyping methods
• Clinical and microbiologic data disclose no other clear-cut source for the BSI
If the IVD is retained:
• If quantitative blood cultures are available, cultures drawn both from the IVD and a peripheral vein (or
another IVD) are both positive and show a marked step-up in quantitative positivity (fivefold or greater) in
the IVD-drawn culture
or
• If automated monitoring of incubating blood cultures is available, blood cultures drawn concomitantly from
the IVD and a peripheral vein (or another IVD) show both are positive, but the IVD-drawn blood culture turns
positive more than 2 hours before the peripherally drawn culture
*Roll plate of cannula segment(s) >15 cfu

†
Sonication culture of cannula segment(s) ≥103 cfu.
Adapted from Crnich and Maki, Clin Infect Dis 2002; 34(9):1232-1242.8
the femoral or internal jugular site, and is preferred,1,3,24 although in and fixed with a transparent dressing, have been the subject of a meta-
recent analyses the differences have been smaller than previously.29 The analysis of eight randomized controlled trials.31 Although their use was
internal jugular site is at risk of infection because of its proximity to associated with a trend towards reduction of vascular catheter infec-
oropharyngeal secretions, the difficulty of applying an occlusive dress- tion, the number of sponges needed to prevent one infection was high
ing and the presence of hair. Peripherally inserted central catheters and their use has been uncommon. A subsequent trial confirmed the
(PICC lines) are inserted in the superior vena cava via the veins of the preventive efficacy of sponges, showing a 70% decreased rate of
upper arm. No recommendation is available for a preferred site of CRBSI.32
insertion to minimize infection risk for a tunneled CVC.
Dressings PREVENTION OF ENDOLUMINAL

Adhesive dressings are recommended for the prevention of extralumi- CONTAMINATION
nal colonization. The advantages of sterile, transparent, semiperme- Number of Lumens
able polyurethane dressings are that they allow regular observation of Randomized controlled trials and meta-analyses (two meta-analyses
the line site, permit showering and require less frequent replacement. reaching differing conclusions)33,34 have not conclusively shown that
Changes should be done every 7 days, or sooner, if they are no longer more lumens bears a higher risk for CAI. However, the English guide-
intact or if moisture collects under the dressing. Early reports described lines suggest using the minimum number of ports or lumens in
a high rate of colonization of the exit site with these dressings. A meta- practice.3
analysis comparing transparent with gauze dressings, however, found An additional recommendation is the use of a dedicated single-
no significant difference in rates of CRBSI.30 Gauze dressings are con- lumen catheter to administer lipid-containing solutions, but the evi-
sidered a valuable alternative to adhesive dressings. Chlorhexidine- dence for this recommendation is poor, and HICPAC considered this
impregnated sponges, which can be placed over the line insertion site unresolved.2
TABLE Guideline for the Prevention of Intravascular Device-Related Bloodstream Infection: Selected
48-4 Recommendations
Recommendation Level of Evidence
General measures Educate all healthcare personnel, periodically assess knowledge and designate only trained personnel IA
and –
Ensure adequate nursing staffing levels in intensive care units IB
Use hospital-specific or collaborative-based performance improvement initiatives in which multifaceted IB
strategies are ‘bundled’ together to improve compliance with evidence-based recommended practices
Hand hygiene and Perform hand hygiene procedures, either by washing hands with conventional soap and water or with IB
aseptic techniques alcohol-based hand rubs. Maintain aseptic technique for the care of intravascular catheters
CVC site Avoid using the femoral vein for central venous access in adult patients IA
Use a subclavian site, rather than a jugular or a femoral site, in adult patients to minimize infection risk IB
for nontunneled CVC placement
Maximal sterile barrier Use cap, mask, sterile gown, sterile gloves and a sterile full body drape, for the insertion of CVCs, PICCs, IB
precautions or guidewire exchange
Use a sterile sleeve to protect pulmonary artery catheters during insertion IB
Skin preparation Prepare clean skin with a 0.5% chlorhexidine preparation with alcohol before central venous catheter and IA
peripheral arterial catheter insertion and during dressing changes. If there is a contraindication to
chlorhexidine, tincture of iodine, an iodophor, or 70% alcohol can be used as alternatives
Catheter site dressing Use either sterile gauze or sterile, transparent, semipermeable dressing to cover the catheter site IA
regimens
Replace dressings used on short-term CVC sites at least every 7 days for transparent dressings, except in IB
those pediatric patients in which the risk for dislodging the catheter may outweigh the benefit of
changing the dressing
Monitor the catheter sites visually when changing the dressing or by palpation through an intact dressing IB
on a regular basis, depending on the clinical situation of the individual patient. If patients have
tenderness at the insertion site, fever without obvious source, or other manifestations suggesting local
or bloodstream infection, the dressing should be removed to allow thorough examination of the site
Replace catheter site dressing if the dressing becomes damp, loosened, or visibly soiled IB
Maintenance Remove IVD as soon as no longer required IA
There is no need to replace peripheral catheters more frequently than every 72–96 hours to reduce risk IB
of infection and phlebitis in adults
Do not routinely replace CVCs, PICCs, hemodialysis catheters, or pulmonary artery catheters to prevent IB
catheter-related infections
Use povidone-iodine antiseptic ointment or bacitracin/gramicidin/polymyxin B ointment at the IB

hemodialysis catheter exit site after catheter insertion and at the end of each dialysis session only if
this ointment does not interact with the material of the hemodialysis catheter per manufacturer’s
recommendation
Do not use guidewire exchanges routinely for nontunneled catheters to prevent infection IB
Do not use guidewire exchanges to replace a nontunneled catheter suspected of infection IB
Use a guidewire exchange to replace a malfunctioning nontunneled catheter if no evidence of infection is IB

present
Replace peripheral catheters in children only when clinically indicated IB
Do not routinely replace CVCs or PICCs solely for prevention of infection IB
Do not remove CVCs or PICCs solely because of fever unless IVD infection is suspected but replace II
catheter if there is purulence at the exit site, especially if the patient is hemodynamically unstable and
IVD-related BSI is suspected
Technology Use antimicrobial-coated or antiseptic-impregnated CVC in adult patients if institutional rate of BSI is IB
high despite consistent application of preventive measures and catheter likely to remain in place >5
days (no data or recommendations for pediatric patients)
Use a chlorhexidine-impregnated sponge dressing for temporary short-term catheters in patients older IB
than 2 months of age if the CLABSI rate is not decreasing despite adherence to basic prevention
measures, including education and training, appropriate use of chlorhexidine for skin antisepsis, and
maximal sterile barrier precautions
Use prophylactic antimicrobial lock solution in patients with long-term catheters who have a history of II
multiple CRBSI despite optimal maximal adherence to aseptic technique
BSI, bloodstream infection; CVC, central venous catheter; IVD, intravascular device; PICC, peripherally inserted central catheter.
Evidence levels: IA, strongly recommended for implementation and supported by well-designed experimental, clinical or epidemiologic studies; IB, strongly
recommended for implementation and supported by some experimental, clinical or epidemiologic studies and a strong theoretical rationale; II, suggested for
implementation and supported by suggestive clinical or epidemiologic trials or a theoretical rationale.
Adapted from O’Grady et al., Clin Infect Dis 2011; 52(9):e162-193.2
Heparin use may be appropriate in a few selected cases, for example for the
Catheter-related thrombosis is frequent and may be complicated by prevention of recurrent infection in patients with long-term tunneled
CRI. A meta-analysis of 14 trials indicates that the risk of catheter- or implanted lines who experience multiple episodes of confirmed
related thrombosis is significantly reduced by prophylactic-dose infection despite optimum antiseptic practice.2,3
heparin.35 The risk of microbial colonization of the CVC was also Taurolidine is a new addition for ALT.43,44 In a meta-analysis of
significantly reduced, but not that of CRBSI. The recent HICPAC and six randomized controlled trials conducted from 2004 through 2013
epic guidelines while evaluating more recent studies and systematic involving 431 patients and 86 078 catheter-days, taurolidine lock
reviews of the topic36 conclude that the evidence to recommend the solution (containing in addition heparin or citrate/heparin) was asso-
routine use of heparin to reduce CRBSI remains insufficient. Citrate ciated with a significantly lower incidence of CRBSI when compared
locks, in particular with antibiotics, appear to be more effective.37 Of to heparin lock solutions (risk ratio 0.34).45 The effect was better
note, many patients receive heparin for deep vein thrombosis prophy- for gram-negative than for gram-positive bacteria. Although tauro-
laxis, and some catheter manufacturers recommend heparin flushes to lidine locks are used with increasing frequency, more studies are
maintain patency in infrequently accessed and hemodialysis lines or warranted.
implanted ports. Ethanol locks have been studied, in particular in pediatric
patients.36,37,46–48 A protective effect on CRBSI has not been proven, and
there are safety concerns including increased risks of catheter occlu-
Antimicrobial Locks in Prevention sion.48,49 Minocycline/EDTA lock solutions have been studied with
Antimicrobial lock treatment (ALT) means instillation of concentrated some success in hemodialysis patients. Other new lock solutions (e.g.,
(‘supratherapeutic’) solutions of antibiotics or other antimicrobially gentamicin/EDTA, gentamicin/L-arginine, or 7% citrate/0.05% meth-
active substances into the catheter to dwell for a period of time – ylene blue/0.165% parabens) await evaluation.50–55
several hours or more until the catheter hub is reaccessed. The idea is
enhanced activity in biofilms sufficient for prevention of microbial Replacement of Administration Sets
growth and sterilization.38-40 Stability of concentrated solutions is an Replacement of intravenous administration sets no more frequently
important issue.41,42 than every 96 hours is proven as safe and cost-effective. Administration
As a prophylactic measure, ALT was primarily studied in hemodi- sets for parenteral nutrition should be changed every 24 hours, and for
alysis patients (Figure 48-3). As a routine, ALT cannot be recom- blood products should be disposed of after the infusion or after 12
mended for prevention of CRBSI outside the hemodialysis setting. Its hours, whichever is sooner.2,3
Forest plot of studies of antimicrobial lock solutions for prevention of central line-associated bloodstream infection
Events/ Events/ %
Author Population RR (95% CI) Treatment Control Weight
Handrup Pediatric hematology 0.29 (.12, .66) 7/17500 26/18571 7.46

Broom HD patients 0.17 (.02, 1.63) 1/3614 3/1834 1.21
Dumichen Pediatric hematology 0.24 (.05, 1.13) 2/6576 9/7233 2.55
Moran HD patients 0.30 (.15, .60) 11/39827 30/32933 10.02
Sofroniadou HD patients 0.11 (.01, .87) 1/1652 9/1641 1.45
Oguzhan HD patients 1.84 (.34, 10.04) 4/3368 2/3099 2.11
Maki HD patients 0.29 (.12, .72) 6/25274 20/24395 6.44
Hemmelgam HD patients 0.29 (.11, .80) 5/12500 15/10949 5.40
Bisseling TPN patients 0.09 (.01, .72) 1/5370 10/4939 1.46
Zhang HD patients 0.08 (.01, .65) 1/17781 11/16299 1.47
Seliem Critically ill neonates 0.23 (.08, .63) 5/1111 13/652 5.27
MacRae HD patients 0.67 (.20, 2.18) 5/2273 6/1818 4.09
Sanders Hematology 0.19 (.05, .68) 3/501 11/353 3.61
Filippi Critically ill neonates 0.10 (.01, .80) 1/455 11/522 1.48
Kim HD patients 0.14 (.02, 1.15) 1/2273 7/2244 1.41
Saxena HD patients 0.53 (.38, .73) 96/58035 56/17885 23.65
Weijmer HD patients 0.27 (.13, .56) 9/8181 33/8048 9.09
Garland Critically ill neonates 0.33 (.14, .78) 7/854 18/723 7.00
Bleyer HD patients 0.30 (.01, 7.42) 0/2336 1/2118 0.62
Mclntyre HD patients 0.08 (.01, .59) 1/3252 10/2470 1.46
Betjes HD patients 0.14 (.01, 2.56) 0/1519 4/1885 0.74
Dogra HD patients 0.12 (.01, 2.23) 0/3280 3/2643 0.72
Pervez HD patients 0.20 (.02, 1.82) 1/1613 4/1311 1.29
Overall (I-squared = 12.3%, P = .293) 0.31 (.24, .40) 168/219145 312/164565 100.00
Note: Weights are from random-effects analysis
–1 1 10
Figure 48-3 Forest plot of studies of antimicrobial lock solutions for prevention of central line-associated bloodstream infection. Individual and combined estimates
of relative infection risk. CI, confidence interval; HD, hemodialysis; RR, relative risk; TPN, total parenteral nutrition. (From Zacharioudakis et al., Clin Infect Dis 2014;
59(12):1741–1749.38 Copyright Oxford University Press 2014.)
OTHER STRATEGIES FOR PREVENTION MULTIFACETED APPROACH, SYSTEM SUPPORT

Tunneled or Totally Implanted Devices AND QUALITY INDICATORS
Long-term tunneled or totally implanted venous access devices are To implement the prevention measures outlined above a multifaceted
associated with lower rates of infection than non-tunneled long-term approach is needed. The combination of several simple measures (the
lines, with totally implanted systems having the lowest rates. For ‘prevention bundle’ approach)24 may substantially reduce the inci-
patients requiring long-term intermittent access, totally implanted dence of CRBSI. Most prominent was the ‘Pronovost’ study of 108
devices are preferred. For situations where frequent or regular access hospitals in Michigan, which evaluated five prevention measures
is needed, a tunneled line is preferable.2,3 (hand hygiene, maximum sterile barrier precautions, chlorhexidine
Tunneling of short-term internal jugular or femoral lines reduces skin antisepsis, avoidance of the femoral site where possible and
infection rates. However, the apparent risk reduction associated with prompt removal of unnecessary lines) with system and organizational
the tunneling of nutrition catheters, for example, disappeared com- support. This resulted in a 66% decrease in CRBSI 18 months after the
pletely with the introduction of a specialist nutrition nurse in one initiation of the program and sustained reductions thereafter.18
study,56,57 suggesting that rigorous aseptic nursing care is more Surveillance and feedback of infection rates can reduce the inci-
significant. dence of CRBSI without any additional intervention.19 Rates of infec-
tion rise when inexperienced staff are responsible for line care, and
Vascular Access in Hemodialysis specialist ‘IV teams’ reduce CRBSI rates.
A well-functioning vascular access is critical for an efficient hemodi- Performance measures and quality indicators for internal use and
alysis (HD). Native arteriovenous fistulas (AVF), described by Brescia for external reporting and quality assurance have been recommended
and Cimino, have commonly been used, and have been considered and are a requirement in national or regional hospital systems. Evalu-
optimal in terms of longevity and complication rate.58 Alternatives are ation should involve both process and outcome measures that need to
prosthetic arteriovenous fistula and CVC. In a recent meta-analysis of be linked with infrastructure (multidisciplinary teams, involvement of
62 studies, CVC was associated with a much higher risk of death, infec- and support by the senior management, leadership, accountability)
tion, cardiovascular events and hospitalization than AVF or a graft as and competency assessments.2,3,69–71
hemodialysis access.59 Graft use was also associated with increased risk
of death, infection and hospitalization. Avoiding CVC whenever fea- Diagnosis
sible and early conversion to a permanent access such as AVF or graft
CLINICAL DIAGNOSIS
reduces deaths and CRBSI-related mortality.60
Clinical features are unreliable for the diagnosis of catheter-related
Antimicrobial Catheters and Cuffs infection. Fever and chills have poor specificity, whereas classic local
inflammation signs at the line site are specific but have poor sensitiv-
There have been major attempts to coat or impregnate catheters or ity.15 Removal of a catheter in response to clinical suspicion alone in a
cuffs with antimicrobial or antiseptic agents such as chlorhexidine/ febrile patient results in unnecessary removal in 70–80% of cases.26 It
silver sulfadiazine, minocycline/rifampin, platinum/silver and ionic is therefore preferable to make a diagnosis of catheter-related infection
silver.61–65 A systematic review concluded that rates of CRBSI were microbiologically, ideally while the catheter remains in place.
reduced when antimicrobial CVCs were used. The best effects were
obtained with minocycline/rifampin-impregnated catheters, catheters DIAGNOSTIC METHODS WITH THE CATHETER
treated internally and externally with silver or chlorhexidine/silver IN SITU
sulfadiazine.61,62
In the absence of septic shock, a ‘watchful waiting’ approach has been
According to a Cochrane review, catheter impregnation made no
shown in a randomized trial to be a safe alternative to immediate CVC
significant difference to the rates of clinically diagnosed sepsis and
removal in patients in intensive care.72 Its safety was confirmed in a
all-cause mortality, although differences were observed in the rate of
multicenter, observational study in 18 Spanish ICUs.73 An exception
CVC colonization depending on the patient population and the cath-
to this approach are those patients where the consequences of missing
eter in situ retention time.66 A systematic review of 48 trials investigat-
a catheter-related infection are potentially more serious, such as in the
ing 10 intervention catheters indicated that rifampin-based impregnated
presence of an intravascular foreign body.
CVC was the only type of impregnated/coated CVC that reduced cath-
To rule out the catheter as a source of unexplained fever, diagnostic
eter colonization and CRBSI.63
techniques with a high negative predictive value are required.
The different substances used for coating may differ in their efficacy
to prevent colonization of specific types of organism.64,65 CVC coating Culture of the Insertion Site or Hub
with the combination of chlorhexidine/minocycline/rifampin may Routine surveillance cultures of the skin around the catheter insertion
solve this problem.67,68 Taken together, the evidence is that antimicro- site, and swabs of the catheter hub have failed to predict line sepsis and
bial CVCs should not routinely be used. They may be used and become therefore, in the absence of clinical suspicion, these methods are
cost-effective in selected high-risk patients if CRBSI rates remain above unhelpful.74–77 Several investigators have noted that catheter-related
the locally agreed benchmark, despite the implementation of a com- bacteremia is uncommon when these cultures are negative (negative
prehensive prevention strategy. predictive value >90%).74,75,77 However, a firm prediction rule prospec-
tively validated and assessed against alternative procedures is not
Catheter Replacement available.
Routine replacement of peripheral vascular devices after 72–96
hours has not been shown to reduce the infection risk. The catheter Acridine Orange Leukocyte Cytospin,
should be removed when complications occur or when it is no longer Endoluminal Brush
required. Aspiration of a 50–100 µL sample of blood from the catheter and direct
There is no evidence that routine replacement of CVCs at sched- examination using acridine orange leukocyte cytospin (AOLC) is a
uled time intervals (day 3 or 7) versus changing catheters when clini- rapid diagnostic method, giving a result in 30–60 minutes. The sample
cally indicated will reduce CRBSI rates. is spun, stained with acridine orange and examined for the presence
Guidewire exchange should not be used in confirmed catheter- of bacteria using ultraviolet microscopy. First evaluated favorably in
related infection. It may be used in cases of suspected line infection neonates, the sensitivity in adults has been very variable.78 Endolumi-
without evidence of local infection of the line site. The tip should be nal brushing of the catheter before sampling has been proposed to
sent for culture and if infection is confirmed, the new catheter should increase sensitivity.79 However, risks of embolization or induced bac-
be removed and access established at an alternative site.2,3 teremia cannot be excluded. AOLC followed by Gram staining yielded
96% sensitivity and 92% specificity.80 AOLC has not been widely incubated for 24–48 hours; the presence of >15 cfu correlated with
adopted, and a recommendation regarding its use is not possible. local signs of inflammation in the patients studied, most of whom had
short-term peripheral catheters rather than CVCs. A meta-analysis of
Paired Quantitative Blood Cultures and 14 trials of this method in short-term CVCs found sensitivities and
Differential Time to Positivity specificities of 84% and 85%, respectively.82 A significant limitation of
Paired quantitative blood cultures involves taking blood cultures this method is that it analyses only the extraluminal portion of the
simultaneously from the line and peripherally, and culturing with a catheter. The accuracy of this technique in diagnosing CRBSI in long-
quantitative technique. A positive blood culture from the line with term CVCs, for which the intraluminal colonization is more impor-
colony counts several times higher than the peripheral culture is pre- tant, has a reported sensitivity of only 45%.91
dictive of CRBSI.1,81 Different cut-off points of between four- to tenfold
are used for prediction of CRBSI; often a 5 : 1 ratio is proposed for a Quantitative Culture of Catheter Tip
positive diagnosis.1 A meta-analysis found this to be a rather accurate Several quantitative methods have been described. Flushing of the
test for diagnosis of CRBSI, with 75% sensitivity and 97% specificity catheter tip with broth examines only the internal surface. Vortexing
for short-term lines and 93% and 100%, respectively, for long-term the tip in 1 mL sterile water allows the release of organisms from both
lines.82 The technique is labor-intensive and expensive; hence it is not the internal and external surfaces of the catheter.92 A threshold of
widely used. 103 cfu/mL correlates with systemic signs of infection, with or without
The differential time to positivity (DTP) technique uses a similar catheter-associated bacteremia, and exhibits 88% specificity and 97%
concept, but takes advantage of automatic blood culture machines that sensitivity in critically ill patients. This is a technique that is still used
continuously detect ‘time to positivity’. The ‘time to positivity’ is with success.
inversely proportional to the inoculum.83 Therefore it is a less labor- The alternative using sonication of the catheter tip in broth gave
intensive method of estimating differences in bacterial load between inferior to similar results.93,94 Quantitative culture of catheter segments
the two samples. When a blood culture taken from the CVC becomes was more accurate than roll plate and qualitative methods.95 A meta-
positive at least 2 hours earlier than that taken peripherally at the analysis showed pooled sensitivity and specificity of quantitative
same time, it is highly predictive of CRBSI. An example is shown in segment culture for short-term catheters of 82% and 89%, respec-
Figure 48-4.84 tively, and 83% and 97%, respectively, for long-term catheters.82
DTP has been validated in oncology, hematology and pediatrics.83–88
A meta-analysis demonstrates a 89% sensitivity and 87% specificity for Direct Examination of Catheter Tip
short-term catheters and 90% and 72%, respectively, for long-term Gram staining or acridine orange staining of the catheter tip appears
catheters.88 In daily practice, sensitivity and specificity tend to be lower, to offer good sensitivity and specificity but is labor-intensive and has
but DTP remains an easy technique with minimal added costs. not been widely adopted.93,96
However, in about a quarter of cases, insufficient blood for culture can
be aspirated via the line.89 Management
LINE REMOVAL
DIAGNOSTIC METHODS REQUIRING In the presence of septic shock with the line as the likely source, the
LINE REMOVAL line should be removed and antibiotics commenced.1–3 Other indica-
Semiquantitative Culture of Catheter Tip tions for early line removal include deep localized infection such as
Semiquantitative culture (roll plate) of the catheter tip, described by tunnel infection, frank cellulitis, pocket infection or port abscess. CRIs
Maki et al.,90 is the most widely used method of catheter culture. The caused by Staph. aureus or Candida spp. meet with high failure rates
distal catheter segment is rolled across the surface of an agar plate and with the line left in place, and therefore line removal is recommended
Distribution of differential time to positivity (DTP) values for the 30 episodes of primary bacteremia in
adult hematology patients with febrile neutropenia
Number of episodes 30
25
20
15
10
0
–10 –9 –8 –7 –6 –5 –4 –3 –2 –1 1 2 3 4 5 6 7 8 9 >10
DTP range (hours)
Figure 48-4 Distribution of differential time to positivity (DTP) values for the 30 episodes of primary bacteremia in adult hematology patients with febrile neutropenia.
Red bars represent episodes classified as central line-associated bloodstream infection. (From Freeman et al., Infect Control Hosp Epidemiol 2013; 34(1):89–92.84 Copy-
right University of Chicago Press 2012.)
with these organisms. The same is probably true of Pseudomonas and The increase may be partly related to increasing numbers of immuno-
possibly other aerobic gram-negatives. Catheter infections compli- compromised patients with long-term tunneled catheters and of infec-
cated by septic thrombosis, endocarditis or osteomyelitis also require tions due to contaminated infusate.1 Retrospective studies have shown
line removal. With tunneled or surgically implanted lines, every high relapse rates if the catheter is not removed;102 anecdotal success
attempt should be made to confirm the diagnosis of CRI in order to has been reported with systemic antibiotics plus antibiotic lock therapy
avoid unnecessary line removal. With coagulase-negative staphylo- for salvage of tunneled catheters.103
cocci, treatment with prolonged antibiotics plus lock therapy may be
successful without line removal. Success of this approach has been Candida Species (see Chapter 49)
claimed with other organisms, provided no complications are present, All cases of catheter-related candidemia should be treated with sys-
in cases where line salvage is required.1–3 temic antifungals to avoid sight-threatening candidal endophthalmitis
or other metastatic infection.1 Prospective studies have identified cath-
EMPIRIC ANTIBIOTIC CHOICE eter retention as a risk for persistent candidemia or increased mortal-
Antibiotics for suspected CRI are often started empirically. The choice ity.91,104 Failure to remove the catheter was associated with poorer
will depend on clinical severity and risk factors of the patient. Direct response to antifungals in a large retrospective study of patients with
staining of a catheter insertion site swab, or of the catheter itself, may cancer, provided the candidemia was catheter-related.105 Clinical char-
help guide therapy.96 Although evidence is lacking to support a par- acteristics that suggest a non-catheter source for the candidemia
ticular choice of antibiotic combination for empiric treatment, usually included disseminated infection at diagnosis, recent chemotherapy
a glycopeptide is chosen, because of the high prevalence of MRSA and and neutropenia; characteristics that implicated the catheter included
other gram-positives. The addition of broad-spectrum gram-negative isolation of C. parapsilosis, paired blood culture techniques supportive
(including pseudomonal) cover is appropriate in cases of severe sepsis of a catheter source of candidemia, and parenteral nutrition.
or immunocompromise.1 Antibiotics can be streamlined when cul- Fluconazole 400 mg/day after an initial loading dose has been
tures become positive. shown to be as effective as amphotericin in non-neutropenic patients
with candidemia, with less associated toxicity.106 Echinocandins have
ANTIBIOTIC CHOICE FOR TARGETED THERAPY been shown in more recent studies to be non-inferior to fluconazole,
AND DURATION and in one study the drug (anidulafungin) was, in fact, superior, and
Coagulase-Negative Staphylococci (CNS) this improved response over fluconazole included patients with C.
albicans and the subgroup of ICU patients. Therefore, for empiric
CNS are the commonest cause of CRI but also the commonest con- treatment before speciation and sensitivity results are available, an
taminants. To confirm the diagnosis of coagulase-negative staphylo- echinocandin is now recommended.104 For targeted treatment, the
coccal CRBSI, at least two positive blood cultures, of which one should ESCMID guideline also recommends an echinocandin. Fluconazole is
be from a peripheral sample, are needed.91 If the line has been removed, recommended with marginal strength only, except for C. parapsilosis
the patient responds clinically well and lacks risk factors for compli- (which is often less susceptible to echinocandins). In the rare cases in
cated disease (such as a prosthetic graft), a 5–7-day course of antibiotic which the catheter cannot be removed early, an echinocandin or lipo-
is likely to be sufficient.1 somal amphotericin B is likely to be superior to any of the azole drugs,
If it is preferable that the line be retained, and the patient lacks risk which appear to poorly penetrate into biofilms.
factors for complicated disease, it is reasonable and acceptable to try Non-tunneled CVCs should be removed; in the case of a tunneled
treatment with the line in situ. Eighty percent of CRBSI caused by CNS line it is important to determine if the candidemia is catheter-related
may be successfully treated without catheter removal, with a 20% or secondary to another source such as the gastrointestinal tract. If the
chance of recurrent bacteremia. The IDSA guidelines recommend a catheter is the source, it should be removed. Duration of treatment
10–14-day course of systemic antibiotic and antibiotic lock therapy for should be 14 days after the last positive blood culture and when signs
non-tunneled lines or 7 days of systemic antibiotic followed by 14 days of infection have resolved.1,104
of lock therapy for tunneled lines.1
Staphylococcus aureus COMPLICATIONS
Staphylococcus aureus is associated with more complicated or meta- Persistence of fever and/or bacteremia 72 hours after catheter removal
static infections, such as septic thrombosis or endocarditis.97 Duration and initiation of appropriate antibiotics should prompt a search for
of treatment will depend on the likelihood of such complications. complicated or secondary infection including septic thrombosis, endo-
Persistence of fever and/or bacteremia 72 hours after catheter removal carditis and osteomyelitis. This is particularly important in the case of
and adequate antibiotic treatment predicts complicated disease.91 Staph. aureus and Candida infection. If a secondary infection is found,
Transesophageal echocardiography (TEE) in patients with Staph. antibiotic treatment needs to be prolonged to a minimum of 4–6
aureus bacteremia establishes a diagnosis of endocarditis by Duke Cri- weeks. Superficial septic thrombosis may necessitate excision of the
teria in 23% of patients.98 Transthoracic echocardiography was associ- vein; septic thrombosis of the great central veins and arteries requires
ated with a sensitivity of just 32%. The IDSA guidelines recommend anticoagulation in addition to antibiotic treatment.1
TEE in all patients with Staph. aureus bacteremia to rule out endocar-
ditis, which would necessitate an extension of treatment to 4–6 weeks.1
However, the likelihood of endocarditis is very low in patients with ANTIBIOTIC LINE LOCK TREATMENT (ALT)
nosocomial Staph. aureus bacteremia without the following: spinal ALT involves instilling antibiotics at high concentration (>100 times
infection, nonvertebral osteomyelitis, hemodialysis, >4 days’ bactere- the minimum inhibitory concentration [MIC] of the organism) at
mia, presence of a permanent intracardiac device.99 sufficient volume to fill the lumen of the catheter, and leaving them in
For treatment of uncomplicated Staph. aureus bacteremia, not less place for a period of several hours or even days while the catheter is
than 14 days of treatment following catheter removal is recom- not in use (such as overnight).39 In in vitro studies these higher con-
mended.100 In selected cases where salvage of a tunneled line is required, centrations of antibiotics were needed to kill sessile bacteria in a
in the absence of complications and with a negative TEE, the IDSA biofilm, and most in vivo studies have shown higher rates of successful
guidelines suggest 14 days of systemic antibiotics plus lock therapy. It catheter salvage using antibiotic locks in addition to systemic
is not clear whether daptomycin is superior to vancomycin in MRSA treatment.39,107–109
infection. Many antibiotics can be used in this way. Stability and compatibil-
ity with heparin or citrate, effective dwell times, diffusion out of the
Gram-Negative Bacilli catheter lumen as well as absorption to the catheter internal surface
The incidence of gram-negative CRI is increasing.101,102 Pseudomonas need to be considered. Vancomycin, cefazolin and aminoglycosides
aeruginosa, Klebsiella spp. and Enterobacter spp. are most common. are stable for >7 days at high concentrations (1–5 mg/mL). Other
TABLE
48-5 Antibiotic Lock Solutions Commonly Used and Tested for Stability at Dwell Times of at Least 24 h
Anticoagulants
Antibiotic/Antiseptic Concentration/Dosage (mg/mL) Heparin (IU/mL)* Citrate (mg/mL) EDTA (mg/mL)
Vancomycin 2–5 0–5000† 40 –
‡
Daptomycin 1–5 0–5000 – –
Gentamicin 1–2.5 – 40 –
Gentamicin 1–5 0–5000 – 30
Amikacin 1–40 0–5000 – –
Cefazolin 1–5 0–5000 – –
Ceftazidime 1–5 0–5000 – –

†
Ciprofloxacin 0.1–1 0–2500 – –
Minocycline 1–3 – – 30
Linezolid 1–2 0–2000 – –
Caspofungin 2–10 – – –
AmB 1–2.5 0–5000 – 30
L-AmB 2–10 – – –
AmB, amphotericin B; L-AmB, liposomal AmB.

Note: physicochemical and biologic stability at room temperature or at 4 °C is usually much longer.
*Usual dose of heparin in non-hemodialysis patients is 100 IU/mL.
†
Check for precipitates in the presence of heparin.
‡
Reconstituted in lactated Ringer’s solution (with 45–50 mg Ca per L).
Adapted from Zacharioudakis et al.,38 Justo and Bookstaver,39 Droste et al.,41 Bookstaver et al.,42 Joshi and Hart,108 Del Pozo et al.,111 Walraven and Lee.112
well-studied and commonly used solutions for ALT with and without spread from a distant site (such as an infected intravascular catheter)
anticoagulants are shown in Table 48-5.38–42,51,108,110,111 may also occur. Once present, micro-organisms can adhere to the graft
Ethanol 70% is incompatible with polyurethane catheters and with and form biofilms similar to those seen in CRI. In this way they can
heparin and has been associated with some increased risk of throm- evade host defense and antibiotic activity, making treatment without
bosis. There is no firm evidence that ethanol for ALT is equally effec- graft removal extremely difficult.
tive and as safe as the classic ALT solutions.
Antifungal lock therapy has also been studied.39,112 On the basis of CAUSATIVE ORGANISMS
the available in vitro and in vivo data, echinocandins and amphotericin Staphylococci are the most commonly implicated pathogens, with
B appear to be the most promising strategies here. Ethanol is also Staph. aureus being responsible for 40–50% or more of all deep wound
effective in vitro. and graft infections.113–115,119 Gram-negative bacteria account for up to
one-third of such infections and anaerobes may be implicated in
patients with ischemic tissue. Early infection is more likely to be caused
Arterial Graft Infections by Staph. aureus or gram-negative organisms, with less virulent organ-
isms such as CNS, enterococci and streptococci being implicated late.
Introduction Rare organisms include Streptococcus anginosus and related strep-
tococci,120 mycobacteria,121–123 fungi124 and Coxiella burnetii (the agent
Reconstructive surgery of occluded or aneurysmal arteries may involve of Q fever).125–129 There have been several cases of Mycobacterium bovis
the implantation of either an autologous vein graft, a prosthetic graft graft infection subsequent to intravesical BCG instillation for bladder
or an endograft. Cryopreserved allografts are also used. Arterial graft cancer.122,123
infection (AGI), more common with prosthetic grafts, is a feared com-
plication, which may lead to limb loss or death.
Prevention
Epidemiology Prior to elective vascular surgery, attempts should be made to reduce
a patient’s individual risk factors for infection. Diabetic control and
The risk of AGI varies with the site of the graft, with higher rates nutritional state should be optimized, and local or distant sites of
associated with lower limb revascularization and lower rates in aortic infection eradicated or minimized.
graft replacement. Many patient or operative factors may influence the Despite being classified as clean procedures, the risk of implanta-
risk of infection, including diabetes, prolonged operating time, mal- tion of prosthetic material justifies the use of prophylactic antibiotics
nutrition and lower limb infection at the time of surgery.113–117 in vascular surgery. A meta-analysis has examined 34 RCTs of preven-
tive measures in arterial surgery.130 Prophylactic systemic antibiotics
Pathogenesis reduced the risk of wound infection and early graft infection by
Early AGI (<30 days) is relatively uncommon and usually secondary between three-quarters and two-thirds (RR 0.25 and 0.31, respec-
to early groin or lower limb wound infection. Lower limb AGI more tively). Prophylaxis continued >24 hours was not beneficial. Other
commonly presents beyond 4 months, and aortic graft infection may interventions including preoperative bathing or showering with
present years later.113 Intraoperative contamination of the graft with antiseptic agents or suction groin-wound drainage lack evidence
skin flora may occur in as many as 56% of arterial grafts,118 implying of effectiveness. No benefit was demonstrated in this analysis from
this as the likely route of acquisition for the majority of graft infections. rifampin-impregnated grafts in preventing either early or late
Contiguous spread from local wound infection or hematogenous infection.
First- or second-generation cephalosporins are commonly used for

prophylaxis in vascular surgery. Glycopeptides should be given only to
patients with current or previous MRSA colonization or infection, or
in settings with a high prevalence of MRSA.131 There is no firm recom-
mendation to screen for Staph. aureus nasal carriage and implement
targeted decolonization treatment before vascular surgery.132
Clinical Features
Early infection will often present with local signs of cellulitis, purulent
drainage or wound dehiscence in combination with systemic signs of
sepsis. Early infection with virulent organisms may quickly progress to
pseudoaneurysm formation and hemorrhage, whereas more indolent
infection may present with cutaneous sinus tracts or graft thrombosis.
Thoracic aortic graft or endograft infection following endovascular
repair procedures is often complicated by fistula with the esophagus a
or the bronchial tree. This represents a dramatic event requiring emer-
gency multidisciplinary management.133,134
Late AGI will more typically present with unexplained, often
relapsing fever, fatigue, secondary adjacent (e.g., vertebral osteomyeli-
tis or psoas abscess) or distant foci. Acute complications such as cata-
strophic gastrointestinal hemorrhage from aortoenteric fistula, aortic
rupture, graft migration, acute ischemia and septic shock also occur.
Diagnosis
Before empiric antibiotics are started, >2 blood cultures need to be
taken. Imaging studies are critical. Fluid collections around the graft
are highly suggestive of AGI, although it may be a normal finding in
the early postoperative period. Deep fluid collections should be aspi-
rated for culture, preferably prior to antibiotic treatment in a hemo-
dynamically stable patient. Fluid cultures may, however, be negative
in infections caused by less virulent organisms such as CNS. Eubacte-
b
rial PCR should be performed with culture-negative aspirates.
Contrast CT imaging may show failure of the graft to become
Figure 48-5 Contrast CT scans showing extensive perigraft inflammation and
incorporated into adjacent tissues, perigraft fluid or gas (Figure fluid with psoas abscess and contiguous vertebral osteomyelitis (arrow) in a patient
48-5), pseudoaneurysm formation, focal bowel wall thickening or with an infected aortic endograft due to chronic Q fever (a) and extensive perigraft
intragraft thrombus (Figure 48-6). Sinography, in which contrast is fluid in a patient with an infected left-sided aortoiliac graft (b).
injected into a cutaneous sinus, may show tracking of dye along a
non-incorporated infected graft. Ultrasound may be used to identify HA
infrainguinal pseudoaneurysm formation or graft thrombus. Nuclear
medicine scans are unhelpful in the early postoperative period
when they are likely to be falsely positive, but may be useful in difficult
late cases. A major advance has been positron emission tomography
(PET) integrated with computed tomography (PET/CT) with 18F- CHA
fluorodeoxyglucose (Figure 48-7). Several studies have shown this
technique to have greater sensitivity and specificity for diagnosing graft
infection than other imaging modalities.136–138
Management VP
The management of arterial graft infection is interdisciplinary and
AO
includes primarily surgical revision and targeted antimicrobial
therapy.114,115,139,140 Antimicrobial therapy needs to be instituted early
and is usually continued for at least 4 weeks postoperatively, depend-
ing on the surgical revision and repair.
In patients with severe sepsis/septic shock, empiric antibiotics cov-
ering a range of nosocomial pathogens including Staph. aureus are FP
initiated, e.g., combining a glycopeptide with an antipseudomonal
Figure 48-6 Contrast CT scan, in the oblique position, showing a filling defect
penicillin, to be rationalized in the light of positive culture results. in the common hepatic artery at the distal end of the vascular prosthesis (arrow).
AO, abdominal aorta; CHA, common hepatic artery; VP, vascular prosthesis.
OPTIONS FOR SURGICAL INTERVENTION (Reprinted from Nagai et al., Circ Cardiovasc Imaging 2014; 7:206-208.135 Copy-
The choice of the surgical intervention must consider the location of right American Heart Association 2014.)
the graft, extent of infection, virulence of the organism, options for
preserving distal perfusion and a patient’s condition. and graft re-infection.139 Attempts at revascularization including
For infrarenal aortic grafts, the gold-standard approach is total replacement with fresh or cryopreserved allograft, however, appear
excision of the graft with bypass through a noninfected (extra- encouraging in more recent reports.140–144 For infrainguinal graft infec-
anatomic) site, most often axillobifemoral, to restore distal perfusion. tion, complete excision is usually required, with either in situ grafting
Risks of this approach include stump blowout, bypass thrombosis with autogenous vein or extra-anatomic prosthesis. Graft excision and
a b
Figure 48-7 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) (a) and combined PET/computed tomography views (b) illustrating the 18F-FDG
uptake at the abdominal aorta and proximal iliac arteries (arrows) in a patient with immunosuppression and Staphylococcus aureus bacteremia.
in situ replacement with a prosthetic graft has greater patency but is been described in selected patients, using surgical debridement of the
expected to be associated with higher rates of re-infection, and has graft bed, followed by the placement of a muscle flap. In recent obser-
generally been recommended only as a holding procedure in low- vational studies of reconstructive surgery, the use of rifampin bonding
virulence infections. or soaking, silver impregnation, use of antibiotic-based polymethyl-
A meta-analysis of surgical options for low-virulence infections of methylacrylate beads and systemic therapy that includes rifampin has
aortic grafts145 questioned whether extra-anatomic bypass should been associated with improved results.115,116,141,143,144,146–149
remain the gold standard, as in situ replacements were associated with
fewer adverse events. Successful management without graft removal has References available online at expertconsult.com.
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a multicentre review. Interact Cardiovasc Thorac Surg 46(1):148-155. grafts for abdominal aortic infections with intraopera-
2015; 20(6):701-706. 131. Enzler M.J., Berbari E., Osmon D.R.: Antimicrobial tive evidence of microorganisms. J Vasc Surg 2011;
120. Bonnet E.P., Arista S., Archambaud M., et al.: Strepto- prophylaxis in adults. Mayo Clin Proc 2011; 86(7):686- 53(5):1274-1281.
coccus milleri group infection associated with digestive 701. 142. Charlton-Ouw K.M., Sandhu H.K., Huang G., et al.:
fistula in patients with vascular graft: report of seven 132. Verhoeven P.O., Gagnaire J., Botelho-Nevers E., et al.: Reinfection after resection and revascularization of
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121. Umer I., Mocherla S., Horvath J., et al.: Mycobacte- aureus nasal carriage: an update. Expert Rev Anti Infect 2014; 59(3):684-692.
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Scand J Infect Dis 2014; 46(11):813-816. 133. Capoccia L., Mestres G., Riambau V.: Current tech- cularisation for femoropopliteal graft infection: ten
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69(2):154-160.
49
Systemic Candidiasis
BENOIT PILMIS | ZHI-TAO YANG | FANNY LANTERNIER |
OLIVIER LORTHOLARY
KEY CONCEPTS Distribution of Candida Species

Although the isolation frequencies may vary, in 95% of Candida-
• Risk factors associated with invasive candidiasis are mainly iat- related infections the pathogens involved are C. albicans, C. glabrata,
rogenic, associated with mechanical mucocutaneous barrier
C. parapsilosis, C. tropicalis and C. krusei.7,8
damage, Candida overgrowth due to broad-spectrum antibi-
otic use and general immune suppression. C. albicans remains the predominant species causing invasive can-
didiasis, representing 57.4% of candidiasis in intensive care units in
• Overall incidence of Candida bloodstream infection (BSI) has one country-wide study.9 In humans, it generally colonizes regions
increased worldwide, while the distribution of Candida species such as the oropharynx, lower respiratory, gastrointestinal and genito-
varies according to geography. urinary tract.8–10 The frequency of isolation of species other than C.
• Candida albicans remains the most common species isolated albicans varies according to the characteristics of the patient popula-
during Candida BSI, while a shift towards non-albicans species tion. C. glabrata is the second most common yeast isolated as part of
is observed especially in intensive care units and hematology normal flora and has emerged as an important opportunistic fungal
patients. pathogen all around the world,10 especially among the elderly, those
• Appropriate empiric treatment is associated with higher sur- with neoplasia and patients previously exposed to azoles and/or echi-
vival rates in patients with Candida BSI, while poor survival rate nocandins.11 C. parapsilosis is found commonly on the skin surface and
is associated with advanced age, increased APACHE II score has a better adherence to materials like acrylic in glucose-containing
and neutropenia. solutions and total parenteral nutrition solutions because of biofilm
production. It causes 30% of the candidemia cases among newborns
• The frequency of Candida endophthalmitis and Candida cho-
whereas the rate is 10–15% among adults and even higher in Southern
rioretinitis is not negligble. All patients with Candida BSI
should undergo a dilated ophthalmologic evaluation to exclude Europe and South America. The frequency of C. parapsilosis isolation
Candida chorioretinitis/endophthalmitis. is associated with echinocandin prescriptions.12 C. tropicalis is more
commonly seen among immunocompromised patients (hematologic
malignancies). C. krusei accounts for about 2–4% of all bloodstream
infections caused by Candida species and is especially important in
patients with hematologic malignancies and bone marrow transplants.
One of the major reasons for the emergence of this yeast is the increas-
ing use of fluconazole worldwide. C. guilliermondii is a relatively rare
species which is being isolated with increasing frequency from blood
Introduction and has been found to be isolated more frequently in patients with
Candida species are the most common cause of fungal infections in prior cardiovascular or gastrointestinal surgery. Overall, the increased
humans. Candidemia is the fourth most common cause of nosocomial proportion of non-albicans species is due in part to greater use of
bloodstream infections in the USA and in Europe1–5 and has a signifi- antifungals such as fluconazole and echinocandins.13,14
cant impact on patient outcome and on hospitalization cost. Candidia-
sis epidemiology is changing. Over the past two decades, species other Transition From Colonization to Infection
than C. albicans (primarily C. glabrata, C. krusei, C. tropicalis and C. C. albicans is a common member of the human microbiota. Candida
parapsilosis) have emerged. These non-albicans species are now respon- colonization among hospitalized patients may be crucial for the suc-
sible for up to 50% of all cases in some centers and are associated with cessful establishment of Candida-related infections. A study showed
intrinsic resistance (C. krusei) or reduced susceptibilities to azoles (C. that 64% of ICU patients were colonized with Candida species and all
glabrata) or to echinocandins (C. parapsilosis) in intensive care unit those with invasive infection had evidence of prior colonization.
(ICU) hospitalized patients. Changes in fungal epidemiology is a Molecular typing of Candida strains from patients with symptomatic
complex issue, with growing evidence supporting the idea that the or asymptomatic candiduria demonstrates that patients with recurrent
global shift in the epidemiology of candidemia and invasive candidiasis candiduria relapse due to the same isolate.15
is most likely driven first and foremost by a widespread use of antifun-
gal agents, especially azoles and echinocandins.6 This emerging issue
RISK FACTORS FOR CANDIDIASIS
justifies antifungal stewardship in high-risk centers. Candida is a commensal organism; to become a pathogen, normal
defense mechanism impairment is necessary. C. albicans infections are
Pathogenesis Epidemiology often endogenous, occurring after an ecologic shift, disruption of
natural barriers or immune system impairment. Invasive candidiasis is
EPIDEMIOLOGY most often healthcare-related. However, the rate of community-
Yeasts that belong to the genus Candida are widely spread in the envi- acquired infection is not to be underestimated; it has been found to be
ronment. The group is highly heterogeneous and contains close to 200 as high 36.5% among 1354 episodes of bloodstream infection, and has
species. An increasing incidence of fungal infections with Candida spp. been found to be significantly higher in North America (63.5%) than
has been noted in immunocompromised patients such as those staying in Europe (22.4%), according to the SENTRY Antimicrobial Surveil-
in ICUs, postsurgical and neutropenic patients. Colonization rates lance Program 2008–2009.16 Introduction of newer therapeutic modal-
increase with severity of illness, duration of hospitalization and broad- ities for advanced life support has changed dramatically the incidence
spectrum antibiotic exposure. of candidiasis since the last decade. Factors associated with higher risk
439
BOX 49-1 RISK FACTORS FOR INVASIVE Pathogenesis

CANDIDIASIS IN ADULTS AND INTERACTION OF CANDIDA SPECIES WITH
CHILDREN HOST EPITHELIAL SURFACES AND
Hematologic or solid malignancies
BIOFILM GENERATION
Renal failure Candida’s capacity for mucosal adherence, biofilm formation and pro-
Neutropenia duction of tissue-damaging hydrolytic enzymes are important viru-
Severe acute pancreatitis lence factors. To successfully persist within the host environment,
Organ transplantation
Prolonged stay in the intensive care unit either as a commensal or as a pathogen, Candida first has to adhere to
High APACHE II score and then colonize host surfaces, such as biomaterial of medical devices
Hemodialysis or the host’s mucosal surfaces. The process of initial adherence of
Usage of broad-spectrum antibiotics Candida to human epithelial surfaces is complex and multifactorial.
Usage of antifungal agents
Presence of central venous catheters After overcoming total free energy of cell surface interaction between
Mechanical ventilation Candida and epithelial cells, adherence of Candida is then mediated by
Total parenteral nutrition specific molecules, referred to as Candida adhesins, with correspond-
Use of immunosuppressive agents ing ligands on the host cells. Once adherence to mucosal surfaces has
Prior colonization due to Candida spp.
Surgical procedures been established, colonization and growth of Candida is required to
maintain the presence of the organism. The capacity to generate a
For Neonates and Children, in Addition to Above Cited Factors biofilm on host surfaces is attributed to the persistence of Candida.
Prematurity Once the biofilm has formed, the EPS encasing the cells may con-
Low birth-weight
Low APGAR score tribute to persistence of the organism by direct (sequestration of anti-
Congenital malformations accompanied by primary immune deficiencies microbial substance, limiting diffusion or alteration of cell genotypes)
(e.g. DiGeorge syndrome) or indirect ways (e.g. positive regulation of several candidal adhesion
genes by transcription factor Bcr1).23 Dispersion of yeast cells from the
Based on Yapar N. Epidemiology and risk factors for invasive candidiasis. mature biofilm has been shown to directly contribute to virulence.
Ther Clin Risk Manag 2014;10:95–105.
Following adhesion to host cell surfaces and hyphal growth, C. albicans
hyphae can secrete hydrolytic enzymes that have been proposed to
facilitate active penetration into these cells. However, the production
of candidiasis are mainly associated with mechanical barrier damage of these enzymes is highly strain-dependent. Candida hyphae can
caused by the use of intravenous catheters, mucosal ulceration intro- invade epithelial cells and lead to superficial mucocutaneous infec-
duced by cytotoxic chemotherapy or radiotherapy, digestive surgery tions, which occasionally can become chronic (chronic mucocutane-
and Candida overgrowth due to broad-spectrum antibiotic use.17 ous candidiasis). Adhesins such as agglutinin-like sequence 3 (ALS3)
Other risk factors of invasive candidiasis associated with general are hyphae-associated proteins important for adhesion. Cell invasion
immune suppression are neutropenia, long-term use of steroids, age is possible by endocytosis or active penetration. In brief, the pathogen
(the newborn or the aged), parenteral nutrition, neoplastic disease, icity of Candida is mediated by a number of virulence factors that
solid organ or bone marrow transplantation and less frequently those facilitate adherence to mucosa, the ability to evade host defenses, and
infected by the human immunodeficiency viruses (HIV). Primary production of tissue-damaging hydrolytic enzymes.
immunodeficiencies such as congenital neutropenia, chronic granulo-
matous disease and CARD9 deficiencies also predispose to invasive LOCAL AND SYSTEMIC ANTI-CANDIDA IMMUNITY
candidiasis. Risk factors are listed in Box 49-1.18 The first anti-Candida defense is skin and digestive tract mucosa. Epi-
thelial cells of host mucosal surfaces represent the first line of defense
Susceptibility of Candida Species against Candida infection. Receptors (such as Toll-like receptors
[TLRs] and C-type lectin receptor [CLRs], mannan receptor) on cell
to Antifungals surfaces recognize conserved patterns of Candida. Dectin-1 belongs to
Resistance mechanisms have been described in Candida spp. Several the CLRs family, and recognizes the yeast form of Candida spp. Dectin
mechanisms are combined to result in development of clinically rele- 2 recognizes the hyphal form of Candida spp. Cell surface recognition
vant resistance. Fluconazole resistance can be caused by alterations in of Candida is responsible for intracellular signaling pathway and cyto-
sterol biosynthesis, mutations in the drug target (the enzyme sterol kine production. The ability of Candida to switch between yeast and
14α demethylase, which lowers its affinity for fluconazole) or its over hyphal growth forms is related to virulence. The recognition of C.
expression with overexpression of ERG11 encoding for this enzyme, albicans hyphae, rather than yeast form, induces mitogen-activated
or of genes coding for membrane transport proteins of the ABC trans- protein kinase (MAPK) phosphorylation, which combined with
porter (CDR1/CDR2) or the major facilitator (MDR1) superfamilies. nuclear factor kappa B (NF-κB) activation results in production of
Similarly, Candida isolates that were found with reduced susceptibility interleukin (IL)-6 and granulocyte macrophage colony-stimulating
to echinocandins had mutations in selected regions (hot spots) of fks1 factor (GM-CSF).24 This pathway is probably important for discrimi-
or fks2 encoding the echinocandin target enzyme (1,3)-β-D glucane nating between colonizing yeast and invasive hyphal form. Dendritic
synthase. At least 18 distinct mutations in fks1 of C. albicans or related cells play a pivotal role in linking innate and acquired immunity, which
species (C. tropicalis and C. krusei) have been reported19 while in C. promote the differentiation of T-helper (Th) cells into Th1, Th2, Th17
glabrata isolates, in contrast to other Candida species, these mutations and Treg cells. Cytokine production after Candida activation drives
involve both fks1 and fks2. Fluconazole resistance has to be expected, the differentiation of naïve CD4 T cells to IL-17-producing T cells that
especially in C. glabrata, C. inconspicua, C. rugosa, C. norvegensis and have a key role in mucosal immunity. Neutrophils and macrophages
some other rare species. There is most often cross-resistance between play a major role in Candida killing.
fluconazole and voriconazole and posaconazole.20 Moreover there is a
comparable susceptibility spectrum of the three echinocandins (mica- Clinical Manifestations
fungin, caspofungin anidulafungin) among Candida spp. It appears
that some species, such as C. parapsilosis and C. guillermondii, exhibit CANDIDA BLOODSTREAM INFECTION (BSI)
decreased susceptibilities to all echinocandins. There are two reference Epidemiology and Risk Factors
methods for the evaluation of in vitro susceptibility to antifungals: Candida spp. are currently the fourth most common nosocomial
CLSI and EUCAST21,22 (Table 49-1). bloodstream isolates in American and European studies.5 However,
Chapter 49 Systemic Candidiasis 441
TABLE
49-1 EUCAST and CLSI Antifungal Clinical Breakpoints, 201421,22
MIC BREAKPOINT (MG/L)
Antifungal C.
Agent C. albicans C. glabrata C. krusei C. parapsilosis C. tropicalis guilliermondii
S≤ R> S≤ R> S≤ R> S≤ R> S≤ R> S≤ R>
Amphotericin 1 1 1 1 1 1 1 1 1 1 – –
B (EUCAST)
Amphotericin ≤2 >2 ≤2 >2 ≤2 >2 ≤2 >2 ≤2 >2 ≤2 >2

B (CLSI)
Anidulafungin 0.03 0.03 0.06 0.06 0.06 0.06 0.002 4 0.06 0.06 – –
(EUCAST)
Anidulafungin ≤0.25 ≥1 ≤0.12 ≥0.5 ≤0.25 ≥1 ≤2 ≥8 ≤0.25 ≥1 ≤2 ≥8

(CLSI)
Caspofungin – – – – – – – – – – – –
(EUCAST)
Caspofungin ≤0.25 ≥1 ≤0.12 ≥0.5 ≤0.25 ≥1 ≤2 ≥8 ≤0.25 ≥1 ≤2 ≥8

(CLSI)
Micafungin 0.016 0.016 0.03 0.03 – – 0.002 2 – – – –

(EUCAST)
Micafungin ≤0.25 ≥1 ≤0.06 ≥0.25 ≤0.25 ≥1 ≤2 ≥8 ≤0.25 ≥1 ≤2 ≥8

(CLSI)
Fluconazole 2 4 0.002 32 – – 2 4 2 4 – –
(EUCAST)
Fluconazole ≤2 ≥8 ≤32 ≥64 – – ≤2 ≥8 ≤2 ≥8 – –

(CLSI)
Itraconazole – – – – – – – – – – – –
(EUCAST)
Itraconazole ≤0.12 ≥1 – – – – – – – – – –
(CLSI)
Voriconazole 0.12 0.12 – – – – 0.12 0.12 0.12 0.12 – –

(EUCAST)
Voriconazole ≤0.12 ≥1 – – ≤0.5 ≥2 ≤0.12 ≥1 ≤0.12 ≥1 – –

(CLSI)
Posaconazole 0.06 0.06 – – – – 0.06 0.06 0.06 0.06 – –

(EUCAST)
Posaconazole – – – – – – – – – – – –
(CLSI)
EUCAST, European Committee on Antibiotic Susceptibility Testing; CLSI, Clinical and Laboratory Standards Institute. S, susceptible; R, resistant.
their incidence varies according to geographic area, but overall inci- The diagnosis of candidiasis is still a major challenge, especially in
dence of Candida bloodstream infection, also called candidemia, has the ICU, and it is often made late in the course of the infection. This
increased worldwide, reaching up to 7% increase annually in France,25 can be explained by several factors: clinical manifestations are nonspe-
while the distribution of Candida spp. varies according to geography. cific, blood cultures may be positive with delay in the course of infec-
The mortality rate remains high despite the advent of new antifungal tion, or patients in ICU may receive antifungals as prophylaxis or as
agents, and has been associated with severity of clinical features and pre-emptive therapy, which may render samples negative at the time
inappropriate management. The gastrointestinal tract and skin are the of testing.28 Classically, an episode of candidemia is defined as the
two most important portals of entry. Although C. albicans has long isolation of Candida spp. from one or more blood cultures in a patient
been the most common species isolated during candidemia, a shift with temporally related clinical signs and symptoms. Furthermore, the
towards non-albicans species is observed, as noted previously.9,11,25,26 In turnaround time (TAT) of final report or the time to positivity (TTP)
one recent prospective active surveillance study of 2507 episodes of of blood culture varies from different Candida species.29 Usage of
candidemia in the Paris area, the increasing incidence of candidemia parenteral nutrition was associated with shorter TTP, while previous
observed over time was ascribed to C. albicans and C. glabrata but not exposure to antifungal agents was associated with longer TTP. Alterna-
to increasing incidence of other species.27 tive procedures based on the detection and quantification of fungal
biomarkers and metabolites (mannan and anti-mannan antibodies,
Clinical Presentation and Diagnosis glucans) have been developed to improve and anticipate the detection
Clinical presentation of Candida BSI is not specific compared to that of candidemia.30 Although supported by the recent ESCMID Guide-
of bacteremia. It generally presents as fever and worsening of clinical lines, their pragmatic clinical usefulness remains a matter of debate.30
status, in a patient with risk factors who is not responding to antibacte-
rial therapy. When Candida disseminates, multiple organs are usually Management and Prognosis
involved, with the liver, spleen, kidney, myocardium and eye the most Treatment of candidemia has changed significantly in recent years due
common, and less frequently the brain. to a growing number of newly available agents, the compliance to 2009
IDSA and 2012 ESCMID guidelines by physicians, and the progress of the general increase of Candida infection and the growing number of
antifungal susceptibility testing of Candida spp. (clinical breakpoints, at-risk patients. In general, prognosis is poor with one-year mortality
CBPs)6,31,32 (Table 49-2). Most Candida spp. are usually susceptible to risk up to 50% and substantial relapse rates.40
amphotericin B and echinocandins, but resistance or dose-dependent
susceptibility has been described either naturally (C. glabrata and C. Risk Factors and Epidemiology
krusei for fluconazole; C. parapsilosis for echinocandins) or after previ- Candida endocarditis may be associated with several host predisposing
ous exposure to the drugs (e.g. C. glabrata for echinocandins; C. lusita- conditions: intravenous drug use, indwelling foreign bodies (catheters,
niae for amphotericin B). prosthetic heart valves, pacemakers), immunosuppression, prolonged
The time of treatment initiation is a key factor for the favorable use of broad-spectrum antibiotic therapy, malnutrition and diabetes
outcome of invasive candidiasis. Therefore, if candidemia is suspected, mellitus.40,41 Half of Candida endocarditis cases occurred in patients
blood cultures should be taken even in the absence of fever. In the with prosthetic heart valves, compared with only 20% of cases of
critically ill unstable patient, delays in antifungal administration nonfungal endocarditis. C. albicans was responsible for 40% of Candida
predict death.33 Consequently, empiric treatment has to be started endocarditis, followed by C. parapsilosis, especially in intravenous drug
immediately after blood cultures grow yeasts (without waiting for the users, C. tropicalis, C. guilliermondii and C. glabrata.
results of identification of Candida spp. and susceptibility tests).
Important considerations in empirical antifungal choice include the Clinical Presentation and Diagnosis
following: knowledge of local resistance patterns; presence of risk The physical findings and usual symptoms of Candida endocarditis are
factors; pharmacodynamics/pharmacokinetics of the antifungal agent. not significantly different from those of bacterial endocarditis with the
The most important factor in initial therapy is the presence of hemo- exception of the occurrence of large emboli to major vessels. In addi-
dynamic instability. The value of empirical antifungal therapy has been tion, endophthalmitis may also complicate Candida endocarditis.
addressed in several retrospective studies,34 which showed appropriate Complications are similar to those of bacterial endocarditis, including
empiric treatment was associated with higher survival rates. Flucon- valve perforation, mycotic aneurysms, but with a higher frequency of
azole has been shown inferior, compared to anidulafungin, in the large emboli responsible for the severity of the disease. Diagnostic
subgroup of patients with high APACHE scores and those with infec- criteria are similar to those for bacterial endocarditis. Blood cultures
tion with C. krusei and C. glabrata.35 All three available echinocandins usually show persistent candidemia, and echocardiography frequently
had similar efficacy but were less toxic in immunocompetent and reveals valvular vegetations that are often large. Although transthoracic
immunocompromised adults with invasive candidiasis, compared to echocardiography can show vegetations, transesophageal echocardiog-
amphotericin B and its liposomal formulation.36 Another advantage of raphy is more sensitive and especially useful in patients with prosthetic
using an echinocandin is the low potential for drug–drug interactions. valve Candida endocarditis. Examination of vegetations or emboli
According to the North American and European guidelines,6,31 echi- by histopathology shows yeast forms and by culture yields Candida
nocandins are recommended for first-line treatment of candidemia in species. The diagnostic contribution of serum biomarkers has been
non-neutropenic patients, while echinocandin or lipid formulation of evidenced recently in the MYCENDO study, the sensitivity of
amphotericin B is recommended in neutropenic patients. For patients 1,3-β-glucan and mannan/anti-mannan antibody detection in serum
with hemodynamic instability or with recent azole exposure, echino- were 100% and 83%, respectively.41 A recent study from Iran evaluated
candin is strongly recommended. Liposomal amphotericin B or vori- polymerase chain reaction (PCR) on tissue and blood for the diagnosis
conazole can be used as an alternative.6,31 Treatment duration depends of fungal endocarditis (Candida and Aspergillus) and showed the sen-
on the extent of organ involvement. For candidemia without meta- sitivity, specificity, positive and negative predictive values for the PCR
static complications, treatment length is 2 weeks after documented test were 87.5%, 94.4%, 87.5% and 94.4%, respectively.42 However,
clearance of Candida from the bloodstream, resolution of symptoms blood culture remains the criterion for the diagnosis of infective endo-
and resolution of neutropenia. Intravenous catheter removal is strongly carditis. The rate of blood culture-negative endocarditis has decreased
recommended for non-neutropenic patients with candidemia. In with the use of innovative noninvasive methods. This ‘blood culture-
addition, all patients with candidemia should undergo a dilated negative’ endocarditis was mainly caused by previous antibacterial
ophthalmologic evaluation at least once and a transesophageal echo- treatment, related to fastidious micro-organisms (e.g. HACEK bacte-
cardiography to exclude Candida endophthalmitis or Candida endo- ria, Candida spp., etc.), while ‘true’-negative endocarditis was due to
carditis, because of a significant rate (16% of patients with candidemia) intracellular bacteria that cannot be routinely cultured with currently
of ocular involvement and poor prognosis of endocarditis. available techniques, and should be diagnosed by PCR on excised
In spite of the advances achieved in the diagnosis and treatment of cardiac valve tissue43 (see also Chapter 51).
candidiasis since the last decade, candidemia still causes a high and
even increasing mortality rate (up to 50%), especially in immunocom- Treatment
promised patients and in ICUs.37 Several studies showed that 4-week The recommended treatment of Candida endocarditis is summarized
mortality rates and costs of care increased significantly when empirical in American (2009) and European (2012) guidelines6,31,32 (Table 49-2).
therapy was delayed or inadequate or according to Candida species (i.e. In native valve or prosthetic valve Candida endocarditis, a combined
C. krusei vs other species). Poor survival rate was associated with approach using both surgery and antifungal therapy is strongly re
advanced age, increased APACHE II score, neutropenia and inappro- commended. The antifungal regimen of choice is liposomal ampho-
priate empiric antifungal therapy. However, the results of other studies tericin B, or an echinocandin with or without flucytosine. Treatment
on the topic of timing of administration have yielded conflicting should be continued for at least 6 weeks following surgery. In patients
results. with pacemakers, implantable defibrillators or assist devices, removal
of the device appears mandatory. All patients who cannot undergo
CANDIDA ENDOCARDITIS surgical resection of the affected valve should receive chronic suppres-
Incidence sive therapy with fluconazole (voriconazole in patients with suscepti-
Candida endocarditis is one of the most serious manifestations of ble Candida glabrata endocarditis). Surgery should be performed
candidiasis and is the most common cause of fungal endocarditis, early, whenever possible, particularly in patients with prosthetic
causing over half of all the cases. Candida endocarditis accounts for valves.
only 2% of all cases of endocarditis38 and complicates candidemia in
up to 15% of patients. It comprises three different clinical entities: HEPATOSPLENIC CANDIDIASIS
native valve endocarditis, prosthetic valve endocarditis and cardiac Chronic disseminated candidiasis is also known as hepatosplenic
device-related infective endocarditis.39 During the past decade, the candidiasis. The disease most often involves the liver and spleen;
incidence of Candida endocarditis has increased simultaneously with involvement of lungs, kidneys and other organs have also occasionally
TABLE
49-2 IDSA and ESCMID Guidelines for the First-Line Treatment of Candidiasis6,31,32
2009 IDSA Guidelines 2012 ESCMID Guidelines
CANDIDEMIA (BSI)
Non-neutropenic adults Fluconazole 800 mg (12 mg/kg) loading dose, then Echinocandin for 14 days after the end of candidemia
400 mg (6 mg/kg) daily or an echinocandin for 2
weeks after documented clearance of Candida from
the bloodstream and resolution of symptoms
attributable to candidemia
Neutropenic adults Echinocandin or LFAmB 3–5 mg/kg daily or 2 weeks Echinocandin or LFAmB 3–5 mg/kg daily for 14 days after the last
after documented clearance of Candida from the positive blood culture.
bloodstream, resolution of symptoms attributable to Individuals who have negative blood cultures for more than 14 days but
candidemia, and resolution of neutropenia remain neutropenic at approximately day 28 should be evaluated for
the resolution of clinical signs and symptoms including exclusion of
endocarditis and endophthalmitis by appropriate examination. But
defining an exact and appropriate duration of therapy is still an issue
of debate.
Chronic Disseminated Fluconazole 400 mg (6 mg/kg) daily for stable patients LFAmB followed by prolonged treatment of fluconazole. The duration of
Candidiasis LFAmB 3–5 mg/kg/d or AmB-d 0.5–0.7 mg/kg/d for antifungal treatment appears to be at least 8 weeks
severely ill patients; after patient is stable, change to
fluconazole
Therapy should be continued for weeks to months, until
calcification occurs or lesions resolve
CANDIDA URINARY TRACT INFECTION
Symptomatic cystitis Fluconazole 200 mg/d (3 mg/kg) for 2 weeks Fluconazole; amphotericin B deoxycholate ± flucytosine
No recommended duration of treatment
Pyelonephritis Fluconazole 200–400 mg/d (3–6 mg/kg) for 2 weeks Caspofungin 70/50 mg for 9–28 days; fluconazole ± flucytosine;
lipid-based amphotericin B ± flucytosine
No recommended duration of treatment
OSTEOARTICULAR INFECTION
Osteomyelitis Fluconazole 400 mg (6 mg/kg) daily for 6–12 months or Surgical debridement; fluconazole 400 mg for 6–12 months; liposomal
LFAmB 3–5 mg/kg daily for several weeks, then amphotericin B 3 mg/kg or amphotericin B lipid complex 5 mg/kg for
fluconazole for 6–12 months 2–6 weeks followed by fluconazole 400 mg for 5–11 months
Septic arthritis Fluconazole 400 mg (6 mg/kg) daily for at least 6 weeks Liposomal amphotericin B 3 mg/kg/ABLC 5 mg/kg 2 weeks, followed by
or LFAmB 3–5 mg/kg daily for several weeks, then fluconazole 400 mg for 4 weeks; fluconazole 400 mg for ‡6 weeks
fluconazole to completion
CNS CANDIDIASIS LFAmB 3–5 mg/kg with or without 5-FC 25 mg/kg qd Liposomal amphotericin B 3 mg/kg for 10 weeks + flucytosine 150 mg/
for several weeks, followed by fluconazole kg for 10 weeks, followed by fluconazole 3 mg/kg for 5 weeks
400–800 mg (6–12 mg/kg) daily Liposomal amphotericin B 3 mg/kg for 4 weeks + fluconazole 6 mg/kg
Treat until all signs and symptoms, CSF abnormalities, for 4 weeks
and radiologic abnormalities have resolved. Removal
of intraventricular devices is recommended
CANDIDA AmB-d 0.7–1 mg/kg with 5-FC 25 mg/kg qd; or Liposomal amphotericin B 5 mg/kg alone or combined with flucytosine
ENDOPHTHALMITIS fluconazole 6–12 mg/kg daily; surgical intervention for 25mg/kg qd is recommended when the susceptibility of the isolate is
patients with severe endophthalmitis or vitreitis unknown. In susceptible isolates fluconazole or voriconazole are the
Duration of therapy is at least 4–6 weeks as determined drugs of choice. In the case of vitreal involvement, vitrectomy and
by repeated examinations to verify resolution intravitreal injection of amphotericin B are recommended in addition
to systemic therapy
Antifungal treatment duration varied between 2 and 12 weeks
CANDIDA INFECTION OF THE CARDIOVASCULAR SYSTEM ENDOCARDITIS
Pericarditis or LFAmB 3–5 mg/kg with or without 5-FC 25 mg/kg qd; Surgery within 1 week; liposomal amphotericin B ± flucytosine for 6–8
myocarditis or AmB-d 0.6–1 mg/kg daily with or without 5-FC weeks, followed by fluconazole; caspofungin ± flucytosine
25 mg/kg qd; or an echinocandin
Surgery is recommended and treatment should continue
for at least 6 weeks after valve replacement and
should continue for a longer duration in patients with
perivalvular abscesses and other complications
LFAmB 3–5 mg/kg daily; or fluconazole 400–800 mg
(6–12 mg/kg) daily; or an echinocandin
Infected pacemaker, LFAmB 3–5 mg/kg with or without 5-FC 25 mg/kg qd; Removal
ICD or VAD or AmB-d 0.6–1 mg/kg daily with or without 5-FC
25 mg/kg qd; or an echinocandin
NEONATAL AmB-d 1 mg/kg daily or fluconazole 12 mg/kg daily for Liposomal amphotericin B 3 mg/kg/day
CANDIDIASIS 3 weeks Micafungin <40 kg 2–4 mg/kg
Caspofungin loading dose 70 mg/m2/day, followed by 50 mg/m2/day
The optimal duration of therapy is 14 days after blood cultures are
sterile
been described. Hepatosplenic candidiasis occurs in immunosup- CENTRAL NERVOUS SYSTEM (CNS)
pressed patients, particularly those with prolonged and profound neu- CANDIDA INFECTION
tropenia, such as those intensively treated for an acute myeloblastic Candida infects both parenchymal brain tissue and the meninges,
leukemia. usually as a complication of hematogenous disseminated candidiasis.
Approximately 50% of patients with Candida meningitis have Candida
Incidence and Risk Factors infections in other organs.47
In the absence of antifungal prophylaxis, the incidence of hepato-
splenic candidiasis ranges from 3% to 29% in patients suffering from Etiology
acute leukemia. Common risk factors for developing candidiasis C. albicans is the most frequent species responsible for neurocandidia-
are acute leukemia, disruption of cutaneous or mucosal barriers, sis but the latter can occur with other species, such as C. parapsilosis
intravascular catheter, prolonged neutropenia, administration of or C. tropicalis. When systemic candidiasis is prolonged, it can affect
broad-spectrum antibiotics, total parenteral nutrition and Candida the CNS and induce diffuse encephalopathy with diminished con-
colonization at multiple sites.44 sciousness in which the predominant lesions are microabscesses. The
severity of the illness and its temporal profile (acute or chronic) may
Clinical Diagnosis be conditioned by the size of the inoculum.
The most common clinical feature of hepatosplenic candidiasis is
isolated fever that fails to respond to broad-spectrum antimicrobial Risk Factors
therapy. Hepatomegaly or splenomegaly, abdominal pain and right All the features predisposing to the appearance of systemic candidiasis
upper quadrant tenderness are also reported. Liver function tests are also favor the development of CNS candidiasis. Some hereditary or
generally abnormal with increased serum alkaline phosphatase and less acquired alterations of the immune system can also condition the
commonly elevated transaminases. Inflammatory markers are gener- appearance of CNS candidiasis (premature neonates, chronic granu-
ally elevated. It is noteworthy that the diagnosis of hepatosplenic lomatous disease, myeloperoxidase deficiency, chronic mucocutaneous
candidiasis is generally made after neutrophil recovery. Clinical signs candidiasis, severe combined immunodeficiency, specific IgA defi-
generally improve 2–8 weeks after starting antifungal therapy. ciency, AIDS, CARD9 mutations). Candida species can be introduced
iatrogenically into the CNS and induce meningitis after a lumbar
Radiologic Investigations puncture or neurosurgical procedures. Other populations at risk for
Imaging is useful for diagnosis and monitoring of patients with hepa- Candida-related meningitis are extremely low birth-weight neonates
tosplenic candidiasis. Computed tomography (CT) demonstrated low and intravenous drug users.
sensitivity and was conclusive in only 20% of patients with hepato-
splenic candidiasis. Magnetic resonance imaging is more accurate and Clinical Diagnosis of Candida CNS Infection
sensitive than computed tomography or ultrasonography for diagnosis Meningitis. Typically, the onset of meningitis is subacute, usually
and follow-up of hepatosplenic candidiasis.45 The positron emission with fever, headache and diminished consciousness. Meningeal signs
tomography (PET) scan appears more sensitive than CT to detect are frequently found during examination. Focal clinical presentation,
hepatosplenic lesions. Furthermore, 18FDG uptake evaluates lesion cranial nerve involvement, papilledema or seizures are infrequent. In
activity and may disappear earlier in patients with hepatosplenic can- 25% of patients there is evidence of candidemia. Postneurosurgical
didiasis than CT lesions and might be helpful for hepatosplenic can- Candida meningitis usually appears in patients who have undergone
didiasis monitoring. craniotomy and in those in whom a cerebrospinal fluid (CSF) drain
has been inserted.
Microbiologic and Histopathologic Examinations Cerebral Microabscesses. The infection may take the form of dis-
Almost 20% of patients with hepatosplenic candidiasis have positive seminated microabscesses (<3 mm). Focal clinical signs (hemiparesis,
blood cultures. Tissue cultures are positive in only 20% of cases of aphasia) are infrequent. Cerebral CT and lumbar puncture do not
hepatosplenic candidiasis. The majority of cases are due to C. albicans usually contribute to diagnosis. Patients with microabscesses are gen-
but other species have occasionally been reported. Usually the diagno- erally diagnosed with systemic candidiasis.
sis of hepatosplenic candidiasis requires liver biopsy for histopatho-
logic and/or microbiologic confirmation. The disease is associated Diagnostic Investigations
with granulomas, necrosis with minimal inflammatory reaction and Lumbar puncture to obtain cerebrospinal fluid (CSF) for culture and
microabscesses with severe inflammatory reaction. Ultrasonography analysis is essential for establishing the diagnosis. CNS Candida infec-
guided percutaneous biopsy is now the established method for diag- tion should be suspected in patients with neurologic symptoms with
nosis. To visualize yeasts and pseudo-hyphae in liver, it is important isolation of Candida from the CSF or isolation of Candida from
to use Gomori–Grocott staining. Biomarkers may allow earlier detec- another normally sterile site in patients who have pleocytosis on CSF
tion of hepatosplenic candidiasis. There are limited data on the use of analysis.
(1,3)-β-D-glucans in serum for hepatosplenic candidiasis diagnosis.
Mannan/anti-mannan detection appears useful for and remained posi- Treatment of Candida Meningitis
tive until day 130 after the initiation of antifungal treatment, although The standard induction therapy for Candida meningitis is liposomal
it has not been validated in large studies. amphotericin B combined with flucytosine. Flucytosine is added
because of its excellent penetration into CSF and brain tissue.48 In
Treatment patients infected with fluconazole-susceptible Candida spp., oral high-
Treatment of underlying malignancy is crucial when hepatosplenic dose fluconazole may be used as step-down after an initial several-week
candidiasis is diagnosed. The IDSA recommends treating hepato- course of amphotericin B (Table 49-2).
splenic candidiasis for 3–6 months31 (Table 49-2). Fluconazole is re
commended as first-line therapy at a dosage of 6 mg/kg/day for CANDIDA ARTHRITIS AND OSTEOMYELITIS
clinically stable patients, whereas liposomal amphotericin B (3–5 mg/ Candida arthritis and osteomyelitis are rare; however, the frequency
kg/day) is preferred in critically ill patients. Another approach is an has increased steadily in parallel with reported cases of candidemia.
initial intensive phase with amphotericin B for 2 weeks followed by The majority of the patients with Candida arthritis and osteomyelitis
fluconazole treatment. Stopping treatment before 6 months may be present with local pain confirmatory tenderness, erythema and edema,
possible once radiologic lesions and clinical and biologic signs have whereas systemic inflammatory response is usually absent. Only one-
disappeared. Adjuvant corticosteroid therapy could benefit patients third of patients have fever and have limitation of function and
with hepatosplenic candidiasis but this requires further study.46 movement.49
Consistent with a predominantly hematogenous process, many inoculation has occurred early during candidemia, and that the ocular
patients have two or more sites of infection. Candida osteomyelitis can lesions require some time to evolve and become visible. Of all the
involve the spine (vertebrae and intervertebral discs), femora, ribs, Candida species, C. albicans was observed to have the greatest propen-
sternum, humeri and synovial joints. The most common distribution sity to cause ocular candidiasis. In contrast, C. parapsilosis was associ-
of infected sites for adults was vertebrae (7 times more common than ated with ocular manifestations significantly less frequently. A recent
in children), ribs and sternum. For pediatric patients, the classic study showed that C. albicans candidemia and higher β-D-glucan
pattern consists in the involvement of long bones of the lower extrem- values were two risk factors of ocular candidiasis, as determined by
ity (femur >14 times more common than in adults), humerus and multivariate regression analysis.50
vertebra/ribs. Candida arthritis starts as a suppurative synovitis, and a The treatment of Candida endophthalmitis necessitates the use of
high percentage of cases extend to osteomyelitis. The risk factors for parenteral antifungal agents, especially amphotericin B combined with
Candida osteomyelitis are the same as for candidemia. 5-FC, or fluconazole51 (Table 49-2). Duration of therapy is at least 4–6
Diagnosis requires microscopic examination and culture (percuta- weeks as determined by repeated examinations to verify resolution.
neous needle aspiration), radiographic examination and histopathol- Patients with severe endophthalmitis or vitritis usually undergo surgi-
ogy. The most common radiologic abnormalities are bone destruction, cal intervention by vitrectomy, whereas patients with chorioretinitis
extension to soft tissues, increase of radionuclide scan uptake, decrease usually do not require surgical interventions. Although antifungal
of intervertebral space, and epidural abscess, which is nonspecific and treatment leads to confirmed resolution or stabilization of ocular
can be observed in bacterial infection. abnormalities and favorable outcome for Candida chorioretinitis,
According to the IDSA practice guidelines and review of the litera- 14-week mortality in patients with endophthalmitis remains as high
ture, the management of Candida osteomyelitis requires prolonged as 50%. In addition, follow-up fundoscopic examination should also
antifungal therapy and surgical debridement31 (Table 49-2). Flucon- be considered in severely immunosuppressed patients, even if the
azole and lipid formulation of amphotericin B showed high concentra- first fundoscopic examination yielded negative results, especially in
tion in bone marrow and are recommended intravenously initially patients with C. albicans bloodstream infection and a high level of
followed by oral fluconazole for 6–12 months, for achieving complete β-D-glucan.32
response. Echinocandins may offer a therapeutic option in treatment
of Candida osteomyelitis. In osteomyelitis and septic arthritis, surgical
debridement is strongly recommended. For infected prosthetic joints, Conclusion
removal is recommended for most cases. The number of immunosuppressed patients has increased significantly
in recent years. These patients are at risk for opportunistic infections,
OCULAR CANDIDIASIS especially fungal infections. Candida spp. are the most common cause
Candidemia is known to lead to hematogenous dissemination and of fungal infections, leading to a range of life-threatening invasive
metastatic ocular infection, of which two distinct abnormalities have diseases. Although C. albicans remains the main responsible species,
been described: Candida endophthalmitis with vitritis and Candida non-albicans species are emerging because of new therapy strategies
chorioretinitis. The frequency was 1–1.6% and 2–9%, respectively, but such as antifungal prophylaxis, secondary prophylaxis and pre-emptive
a recent study50 has shown a higher frequency, with eye involvement therapy for immunosuppressed patients. The pathogenesis and prog-
in 16% of cases of candidemia, mostly presenting as chorioretinitis. As nosis of invasive candidiasis are affected by the host immune status.
mentioned above under management of Candida BSI, all patients with Choice of antifungal treatment should depend on infection location
candidemia should undergo a dilated ophthalmologic evaluation to and severity, local epidemiology and pre-exposure to antifungal agents,
exclude Candida endophthalmitis. not only including triazoles, but also echinocandins.
Most patients with ocular lesions found at fundoscopy do not
exhibit symptoms of ocular involvement. Ocular lesions can be found References available online at expertconsult.com.
before or after antifungal therapy, which suggests hematogenous
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10. Pfaller M.A., Diekema D.J.: Epidemiology of invasive miology of invasive fungal infections in the intensive 43. Tattevin P., Watt G., Revest M., et al.: Update on blood
mycoses in North America. Crit Rev Microbiol 2010; care unit: results of a multicenter Italian survey culture-negative endocarditis. Médecine Mal Infect
36(1):1-53. (AURORA Project). Infection 2013; 41(3):645-653. 2015; 45(1–2):1-8.
11. Lortholary O., Desnos-Ollivier M., Sitbon K., et al.: 27. Lortholary O., Renaudat C., Sitbon K., et al.: Worri- 44. Kontoyiannis D.P., Luna M.A., Samuels B.I., et al.:
Recent exposure to caspofungin or fluconazole influ- some trends in incidence and mortality of candidemia Hepatosplenic candidiasis: a manifestation of chronic
ences the epidemiology of candidemia: a prospective in intensive care units (Paris area, 2002–2010). Intensive disseminated candidiasis. Infect Dis Clin North Am
multicenter study involving 2,441 patients. Antimicrob Care Med 2014; 40(9):1303-1312. 2000; 14(3):721-739.
Agents Chemother 2011; 55(2):532-538. 28. Zirkel J., Klinker H., Kuhn A., et al.: Epidemiology 45. Semelka R.C., Shoenut J.P., Greenberg H.M., et al.:
12. Blanchard E., Lortholary O., Boukris-Sitbon K., et al.: of Candida blood stream infections in patients with Detection of acute and treated lesions of hepatosplenic
Prior caspofungin exposure in patients with hemato- hematological malignancies or solid tumors. Med Mycol candidiasis: comparison of dynamic contrast-enhanced
logical malignancies is a risk factor for subsequent 2012; 50(1):50-55. CT and MR imaging. J Magn Reson Imaging 1992;
fungemia due to decreased susceptibility in Candida 29. Huang L., Zhang Y.Y., Sun L.Y.: Time to positivity of 2(3):341-345.
spp.: a case–control study in Paris, France. Antimicrob blood culture can predict different Candida species 46. Legrand F., Lecuit M., Dupont B., et al.: Adjuvant cor-
Agents Chemother 2011; 55(11):5358-5361. instead of pathogen concentration in candidemia. Eur ticosteroid therapy for chronic disseminated candidia-
13. Chow J.K., Golan Y., Ruthazer R., et al.: Factors associ- J Clin Microbiol Infect Dis 2013; 32(7):917-922. sis. Clin Infect Dis 2008; 46(5):696-702.
ated with candidemia caused by non-albicans Candida 30. Cuenca-Estrella M., Verweij P.E., Arendrup M.C., et al.: 47. Voice R.A., Bradley S.F., Sangeorzan J.A., et al.: Chronic
species versus Candida albicans in the intensive care ESCMID* guideline for the diagnosis and management candidal meningitis: an uncommon manifestation of
unit. Clin Infect Dis 2008; 46(8):1206-1213. of Candida diseases 2012: diagnostic procedures. Clin candidiasis. Clin Infect Dis 1994; 19(1):60-66.
14. Playford E.G., Marriott D., Nguyen Q., et al.: Candi- Microbiol Infect 2012; 18(Suppl. 7):9-18. 48. Slavoski L.A., Tunkel A.R.: Therapy of fungal meningi-
demia in nonneutropenic critically ill patients: risk 31. Pappas P.G., Kauffman C.A., Andes D., et al.: Clinical tis. Clin Neuropharmacol 1995; 18(2):95-112.
factors for non-albicans Candida spp. Crit Care Med practice guidelines for the management of candidiasis: 49. Gamaletsou M.N., Kontoyiannis D.P., Sipsas N.V., et al.:
2008; 36(7):2034-2039. 2009 update by the Infectious Diseases Society of Candida osteomyelitis: analysis of 207 pediatric and
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1703. guideline for the diagnosis and management of Candida and risk factors of ocular candidiasis. Diagn Microbiol
16. Pfaller M.A., Moet G.J., Messer S.A., et al.: Candida diseases 2012: patients with HIV infection or AIDS. Clin Infect Dis 2012; 73(2):149-152.
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tions and antifungal resistance patterns in community- 33. Taur Y., Cohen N., Dubnow S., et al.: Effect of antifun- ocular candidiasis in patients with candidemia: clinical
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microb Agents Chemother 2011; 55(2):561-566. 54(1):184-190.
50
Myocarditis and Pericarditis
ADAM Z. BANKS | G. RALPH COREY
KEY CONCEPTS arrhythmias occur in the setting of a systemic febrile illness or after an
upper respiratory tract infection.
Myocarditis The incidence of infectious myocarditis in the general population
• Chronic myocarditis can cause subacute deterioration of
is unknown. In a prospective study of Finnish military recruits con-
cardiac function predating development of idiopathic dilated ducted over several years, a mean annual incidence of 0.02% was
cardiomyopathy. found.2 The prevalence of clinically significant myocarditis is higher in
children and young adults, and is thought to be a major cause of
• Parvovirus B19 and HHV-6 are the most frequently isolated sudden cardiac death in adults under the age of 40 years.3–5 Within
viruses in patients with viral myocarditis; enteroviruses are immunosuppressed patients, myocarditis is more prevalent, affecting
found less commonly than previously expected.
approximately 50% of acquired immunodeficiency syndrome (AIDS)
• Immunocompromised patients are at higher risk for clinically patients at autopsy.6
significant myocarditis and are uniquely at risk for opportunistic
pathogens. Pathogenesis and Pathology
• Diagnosis is now made with a multidisciplinary approach incor- In myocarditis, damage to cardiac myocytes appears to involve four
porating cardiac magnetic resonance imaging and endomyo- possible mechanisms:
cardial biopsy. • direct cytopathic effects of an infectious agent
• Treatment is currently focused on supportive care and heart • cellular injury secondary to circulating exogenous or bacterial
failure management; ongoing trials are examining immunosup- toxins
pressive regimens. • cell-mediated or humoral immunologic response to the inciting
agent or induced neoantigens
Pericarditis
• cellular injury caused by generalized inflammation.
• The most prevalent noninfectious causes of pericardial disease Histologically, both myocyte necrosis and infiltration by inflammatory
are malignancies, uremia and connective tissue disorders (SLE, cells (including neutrophils, lymphocytes, macrophages, plasma cells,
rheumatoid arthritis). eosinophils and/or giant cells) in the absence of ischemia are patho
• Pain is usually retrosternal with radiation to the trapezius ridge;
gnomonic of the disease (Figure 50-1).The pathologic abnormalities
it is exacerbated by lying supine and relieved by leaning associated with myocarditis vary depending on the etiologic agent and
forward. host response. Coxsackievirus, for example, appears to infect myocytes
directly while infection with parvovirus B19 involves the vascular
• A pericardial friction rub is the pathognomonic physical exam endothelium. The time after infection influences the histologic appear-
finding, characterized by a scratchy or grating sound best ance. In addition, analysis of endomyocardial biopsy (EMB) specimens
appreciated along the left sternal border with respirations sus-
pended and the patient leaning forward.
obtained during infection with different agents shows considerable
overlap. Thus, a histologic diagnosis of myocarditis usually does not
• Echocardiography is the first-line imaging modality; computed indicate the agent responsible.
tomography and cardiac magnetic resonance imaging can be
considered for evaluation of complex disease, extracardiac BACTERIA
disease and when echocardiography is limited by body habitus. Bacteria may cause myocarditis by several mechanisms. Bacteremia
• Myopericarditis may be present if there is evidence of cardiac caused by a variety of species may result in metastatic foci within the
dysfunction or elevation of cardiac biomarkers.
Myocarditis
Epidemiology
The term myocarditis applies to a variety of disease states that produce
inflammation of the myocardium. Acutely, myocarditis ranges from
an asymptomatic illness with reversible changes to fulminant myocar-
dial necrosis and death. In chronic myocarditis, lymphocytic infiltra-
tion of the myocardium, may cause subacute deterioration of cardiac
function; indeed, chronic myocarditis may predate the development
of ‘idiopathic’ dilated cardiomyopathy. Approximately 10% of new
onset unexplained cardiomyopathy is attributable to myocarditis.1
Although frequently ascribed to inflammation caused by infection,
myocarditis may be seen in allergic reactions, drug reactions and in
association with systemic inflammatory disease. Acute infectious myo- Figure 50-1 Acute viral myocarditis, with a characteristic mononuclear
carditis is suggested when unexplained heart failure or malignant infiltrate.
446
Chapter 50 Myocarditis and Pericarditis 447
myocardium. These include streptococcal and staphylococcal bactere- the myocardium. Rocky Mountain spotted fever (caused by Rickettsia
mia, meningococcemia, brucellosis, salmonellosis, listeriosis, Whip- rickettsii) and scrub typhus (caused by R. tsutsugamushi ) infections
ple’s disease, etc. However, the resulting myocardial dysfunction is may cause transient cardiac dysfunction in severe illness, which clears
only clinically significant in a subset of patients with overwhelming with disease resolution. Coxiella burnetii (the agent of Q fever), an
infections. In contrast, myocardial involvement in bacterial endocar- important cause of endocarditis in selected locations (e.g. France), is
ditis is more common and is often clinically significant. Bacteria (espe- a rare cause of myocarditis, but may progress to congestive heart
cially Staphylococcus aureus) may directly invade the myocardium failure (CHF) and death.12
from infected valves to cause abscesses, valvular failure and conduction
abnormalities, or may embolize throughout the myocardium to cause PARASITES
global ventricular dysfunction. Cardiac infections caused by salmonel- Several parasites are known to cause chronic myocarditis and myocar-
lae are particularly serious; mural involvement responds poorly to dial dysfunction, primarily in the developing world. Chagas disease
antibiotics and, without surgical therapy, mortality nears 100%.7 (American trypanosomiasis), distributed in Central and South
Bacterial toxin production can also be clinically significant. Subtle America, is caused by the protozoan Trypanosoma cruzi. The organism
evidence of toxin-mediated myocarditis can be detected in as many as enters the human host via the bite of the reduviid bug. Rarely, patients
two-thirds of patients who have diphtheria, occurring 1–2 weeks after develop myocarditis during acute infection, when myocardial parasites
the onset of illness, often when the oropharyngeal manifestations are are abundant. More common is biventricular failure from chronic
improving.8 Patients who have electrocardiographic (ECG) changes myocarditis, which occurs in 30% of infected individuals.
consistent with myocarditis have a mortality rate three to four times Trichinella spiralis is another parasite with worldwide distribution
that of patients who have normal tracings, with atrioventricular nodal that has been linked to fatal myocarditis. Myocarditis generally devel-
and left bundle branch block carrying mortality rates of 60–90%.9 ops in severe infections, in which the cardinal features of periorbital
Finally, cardiac involvement (including myocarditis) occurs in up edema, myositis, fever and eosinophilia are present. Recent consump-
to 50% of cases of acute rheumatic fever. ‘Molecular mimicry’ (e.g. tion of poorly cooked pork enhances the likelihood of this diagnosis.
immunologic cross-reactivity to cardiac antigens elicited by strepto- Other parasites and/or their ova, including Ascaris, Schistosoma and
coccal products) underlies the postulated pathogenesis of this disease, Taenia solium, may lodge in the myocardium during their systemic
as group A streptococci have not been identified in myocytes. phase. Eosinophilia in acute CHF should prompt a search for their
presence.
SPIROCHETES
Spirochetes, such as Borrelia burgdorferi, the etiologic agent of Lyme VIRUSES
disease, are an important cause of myocarditis with cardiac manifesta- Viral infections are the most common cause of myocarditis in the
tions occurring in approximately 8% of patients.10 The cardiac mani- Western world (Table 50-1). Molecular techniques have shown entero-
festations of Lyme disease may occur in an isolated manner, or viruses to be less common than expected. Parvovirus B19 and human
coincident with other features such as erythema chronicum migrans herpesvirus 6 (HHV-6) were the most frequently isolated viruses in
or neurologic abnormalities. The most prevalent abnormality is atrio- patients with viral myocarditis in 2005, accounting for 56% and 18%
ventricular block, but some patients have evidence of diffuse myoperi- of infections, respectively.13 The following viruses were also identified:
cardial involvement. Myocardial involvement is also common in cases enterovirus (9.4%), adenovirus (1.6%), Epstein–Barr virus (2%), and
of fatal leptospirosis (Weil’s disease), where arrhythmias or cardio- cytomegalovirus (CMV) (0.8%). Cases of myocarditis from influenza
genic shock may occur in conjunction with hepatorenal or central A, particularly H1N1, and influenza B have recently been identified
nervous system syndromes. At autopsy, myocardial inflammation, after the 2009 H1N1 epidemic.14
coronary arteritis and aortitis are common. Until recently, evidence of a causal link between enterovirus infec-
During late syphilis, gummatous involvement of the myocardium tion and myocarditis was primarily circumstantial, since many patients
is a rare cause of myocarditis. Cardiac manifestations include conduc- report an antecedent viral syndrome.15 Increased enteroviral antibody
tion abnormalities and myocardial infarction usually involving the left titers or a fall in convalescent titers have been offered as evidence that
ventricle at the base of the interventricular septum.11 Rickettsiae enteroviruses are the causative agents, but these infections are common
produce systemic vasculitis by endothelial invasion, which can involve in the general population and positive serologies are nonspecific.
TABLE
50-1 Infectious Causes of Myocarditis
Occurrence/Importance Normal Host Immunocomprised Host
INDUSTRIALIZED COUNTRIES
Common and/or important Viruses: Parvovirus B19, human herpesvirus 6, Viruses: HIV, CMV, EBV, varicella-zoster virus
coxsackieviruses (A and B), influenza echovirus, (VZV), adenovirus, parvovirus
cytomegalovirus (CMV), Epstein–Barr virus (EBV), Fungi: Candida, Aspergillus, Cryptococcus
influenza viruses (A and B), adenovirus, hepatitis B Parasites: Toxoplasma gondii, Trypanosoma cruzi
virus, hepatitis C virus
Bacteria: Corynebacterium diphtheriae, Borrelia spp.,
any organism associated with infective endocarditis
Parasites: Trichinella spiralis, Trypanosoma cruzi
Uncommon Viruses: adenovirus, respiratory syncytial virus, Fungi: Histoplasma, Blastomyces, Coccidioides
hepatitis B virus, ?hepatitis C virus imitis, zygomyces
Bacteria: staphylococci, streptococci, meningococci,
Salmonella, Listeria, Clostridium, Rickettsia,
Bartonella, Ehrlichia, Campylobacter jejunii
LOW- AND MIDDLE-INCOME COUNTRIES Viruses: poliovirus, mumps virus, rubella virus, arenaviruses, dengue virus, rabies virus, chikungunya virus,
Ebola virus, yellow fever virus
Bacteria: Leptospira spp.
Parasites: Trypanosoma cruzi, Trypanosoma gambiense
IMMUNOCOMPROMISED PATIENTS Physical examination may reveal tachycardia out of proportion to

Immunocompromised patients are subject to the same infections as the height of fever or degree of heart failure. Cardiac auscultation may
the immunocompetent; however, their risk for clinically significant demonstrate muffled heart sounds, transient murmurs or ventricular
myocarditis is high and they are uniquely at risk for opportunistic gallops; friction rubs are uncommon and indicate pericardial involve-
pathogens. Prior to highly active antiretroviral therapy (HAART) ment. In severe cases, signs of CHF are present.
cardiac disease in the human immunodeficiency virus (HIV) popula- The electrocardiographic manifestations of myocarditis are usually
tion was primarily related to myocardial and pericardial disease with transient and occur more frequently than clinical myocarditis. ST
up to 40% demonstrating cardiac abnormalities. The increasing use of elevations and T wave inversions may be seen acutely, and reflect the
HAART therapy, however, has led to a significant decrease in the focal nature of the myocardial inflammation. These changes usually
incidence of myocarditis or pericarditis. Coronary artery disease has return to normal within 2 months. Atrial and ventricular arrhythmias
become the leading cause of heart disease in the HIV population in are common in severe cases. Atrioventricular nodal or intraventricular
higher-income countries related to lipodystrophy and the metabolic conduction defects denote involvement of the conduction system
syndrome caused by HAART.16 and suggest more widespread disease or specific etiologies (e.g. Lyme
Although HIV itself has been cultured from heart tissue17 and carditis).
shown to be present by in situ hybridization,18 it is only rarely present
in myocytes. Thus, whether the virus causes heart failure, sets the stage
for other cardiotropic pathogens (e.g. CMV), or is a correlate for the
Diagnosis
causative nutritional wasting present in late-stage AIDS is unknown. The diagnosis of myocarditis is often difficult and requires a high index
While uncommon in the United States, in sub-Saharan Africa oppor- of suspicion. When unexplained CHF or malignant arrhythmias occur
tunistic pathogens are still a common cause of myocardial disease. In in the setting of an acute febrile illness, the clinical diagnosis of infec-
an autopsy study of 16 patients with cardiomyopathy, myocytes were tious myocarditis is suggested. CHF of recent onset mandates that the
infected with Toxoplasma gondii in 19%, Mycobacterium avium– physician first consider ischemic, valvular, or congenital disease in the
intracellulare in 13% and Cryptococcus neoformans in 19%.19 differential diagnosis. Other causes of acute myocardial dysfunction,
Other disseminated fungal infections (such as disseminated candi- such as rheumatologic disease, endocrinopathies, electrolyte distur-
diasis, aspergillosis and histoplasmosis) or viral infections such as bances and toxin exposure (e.g. ethanol, cocaine and heavy metals),
herpes simplex virus or varicella-zoster virus may also present with must also be ruled out.
myocarditis in the immunocompromised patient, but can usually be Viral serologies or polymerase chain reaction (PCR) are not indi-
identified by associated findings. CMV is an important pathogen in cated for routine management as they have a high prevalence in the
organ and hematopoietic stem cell transplant recipients. In heart population with a low specificity for myocarditis. In a study of 124
transplant recipients, CMV infection is a risk factor for a form of patients with clinically suspected myocarditis the serum serology was
immune-mediated cardiac rejection that presents as accelerated coro- only concordant with the nested PCR from the endomyocardial biopsy
nary atherosclerosis; importantly, prophylactic ganciclovir signifi- (EMB) in 5 of 124 cases.22
cantly reduces the incidence of this complication.20–21 ECG changes are important, but given the high incidence of non-
Important noninfectious causes of myocarditis are listed in Table specific ST segment and T wave changes seen in acute viral syndromes,
50-2. Considering these noninfectious sources is a key step in the they alone are nondiagnostic. Similarly, laboratory abnormalities such
diagnosis of myocarditis, as the treatment and prognosis will differ. as leukocytosis and an elevated erythrocyte sedimentation rate are also
nonspecific. Serum creatinine phosphokinase (CPK), CPK-MB and
Clinical Features troponin T (a cardiac contractile protein) do signify myocardial injury
and are important, but do not differentiate the cause of that injury.
Acute myocarditis ranges from an asymptomatic state to rapidly pro- However, in contrast to ischemic necrosis, in which CPK levels return
gressive myocardial dysfunction and death. Complaints on presenta- to normal within 72 hours, elevated CPK levels may persist for 6 days
tion may include fever, fatigue, malaise, chest pain, dyspnea and in myocarditis.23
palpitations. Chest pain may be vague, pleuritic (suggesting pericardial Echocardiograms in myocarditis commonly show variable degrees
involvement) or angina-like. The majority of patients have no precor- of cardiac dysfunction, often with striking focal wall motion abnor-
dial discomfort. malities. Dyskinesia or akinesia is most often biventricular. Echocar-
diographic changes generally resolve within a few days in parallel with
the clinical course; if progressive ventricular dysfunction is demon-
TABLE strated, chronic myocarditis may be suggested.
50-2 Noninfectious Causes of Myocarditis Many other imaging modalities for diagnosing acute myocarditis
have been studied. However, validation of these diagnostic tools has
Connective tissue disorders Systemic lupus erythematosus,
rheumatoid arthritis, systemic
been challenging in the absence of a reliable gold standard. Cardiac
sclerosis, dermatomyositis, magnetic resonance imaging (CMR) is able to distinguish between the
polymyositis different etiologies of myocardial damage, including myocarditis, isch-
Idiopathic inflammatory/infiltrative Kawasaki disease, sarcoidosis, giant
emia and other cardiomyopathies.24 The high spatial resolution and
disorders cell myocarditis contrast used in CMR allows for small areas of injury to be identified,
which is useful for diagnosis of myocarditis since it often presents as
Insect and arachnid stings Wasp, scorpion, spider stings
focal or patchy inflammation of the ventricles.
Medications Cocaine, ethanol, arsenic, Despite advances in imaging techniques, EMB is still considered
cyclophosphamide, daunorubicin, the reference technique for diagnosis of myocarditis. Rarely, a biopsy
adriamycin, sulfonamides, will identify specific disease processes (i.e. toxoplasmosis, CMV, giant
tetracycline, methyldopa
cell myocarditis, trichinosis, sarcoidosis, amyloidosis) for which
Post-irradiation myocarditis therapy is available or for which a prognosis can be given. However,
Peripartum myocarditis it remains limited by the lack of sensitivity and specificity along with
its invasive nature. A working standard, termed the Dallas criteria, has
Pheochromocytoma been used since 1986 to define the histologic findings consistent with
Thrombotic thrombocytopenic purpura myocarditis. Even in post-mortem specimens with proven myocardi-
Thyrotoxicosis
tis, the probability of diagnosing myocarditis based on the Dallas
criteria with one biopsy was only 17–28%, which increased to
approximately 67% with more than five biopsies.25–28 Recently efforts infection is identified antimicrobial therapy should be directed at the
have focused on improving the yield of EMB with the use of immu- causative pathogen. As noted above, viruses are the most likely cause
nohistochemical staining and nested PCR for viral genomes. In expe- of myocarditis, but patients with viral myocarditis most commonly
rienced hands the procedure is relatively safe, although deaths have present after viral replication has ceased.
occurred. Biopsy studies have generally been carried out in cases of Most studies of immunosuppressive therapy have not influenced
fulminant myocarditis. Late biopsy is unhelpful as histologic evidence outcome. Randomized controlled trials of both immunosuppressive
of myocarditis resolves in 3–4 weeks. therapy (prednisone + cyclosporine or azathioprine) and intravenous
In recent years the use of the Dallas criteria as the sole diagnostic immunoglobulin failed to show any benefit.38–39 In contrast, the BICC
modality for myocarditis has fallen out of favor. Currently a multidis- trial in 2008 randomized viral myocarditis patients to interferon-
ciplinary approach is advocated which includes histologic appearance, beta-1b (Betaferon) versus placebo. At 6 months patients treated with
immunohistochemical staining, nested PCR for viral genomes, as well Betaferon had improved NYHA functional status and 100% of the
as CMR imaging.29 The use of molecular techniques (nested PCR) in patients receiving Betaferon had no evidence of virus within the myo-
conjunction with EMB has increased the ability to detect viral cardium. This was documented by EMB at eight sites evaluated by both
genomes.30–32 However, due to the uncertainty regarding the number the Dallas Criteria and PCR. At 10-year follow up patients who had
of biopsy specimens required to attain high clinical sensitivity, a posi- demonstrated viral clearance by EMB at 6 months, either spontane-
tive PCR result is diagnostic while a negative PCR does not exclude ously or with Betaferon, had a statistically lower rate of mortality.40-42
viral disease.33 In 2009, guidelines on CMR for myocarditis were pub-
lished. CMR was recommended for a subset of patients with new-onset
CHF where viral myocarditis was a likely etiology and standardized Pericarditis
diagnostic criteria based on CMR were proposed.34–35
Fortunately, most cases of myocarditis are mild and resolve spon-
taneously. With this said, EMB should be performed only when results
Epidemiology
will potentially change management. Current guidelines published in Interest in the pericardium dates to antiquity. Homer and Maximus
2007 recommend against routine EMB in new onset-CHF, but do relate the history of the ‘hairy hearts of heroes’ such as Aristomenes,
recommend its use in 14 distinct scenarios where EMB would alter the legendary Messinian warrior; his heart was cut out in battle and
management.33 Transplant recipients and immunosuppressed patients found to be ‘stuffed with hair’, probably the first recorded case of
represent exceptions where routine biopsy may be warranted. A thor- fibrinous pericarditis. Medical advances in antibiotics, surgery, anti-
ough history (with attention to epidemiologic detail) and physical neoplastic therapy and hemodialysis have altered the spectrum and
examination will diagnose most nonviral etiologies, in which signs and prognosis of pericardial disease. Imaging has also made an impact;
symptoms other than CHF frequently dominate the presentation. A since the advent of echocardiography pericardial effusions are now
complete blood count with differential should be performed to rule readily diagnosed.
out eosinophilia (which may suggest parasitic infection or hypersen- The incidence of pericardial inflammation detected in several
sitivity myocarditis). In the febrile patient, blood cultures should be autopsy series ranges from 2% to 6%, whereas clinically apparent
obtained. Testing for HIV should always be performed given the high pericarditis is diagnosed in only about 1 out of 1000 hospital admis-
prevalence of myocarditis in patients with AIDS; testing for Lyme sions. The frequency of each etiologic process depends upon the clini-
disease, Chagas disease and autoimmune diseases should be performed cal setting.
in the appropriate clinical context. Testing for CMV in blood is
unlikely to be helpful because CMV reactivation in the presence of Pathogenesis and Pathology
unrelated acute febrile illnesses is common. EMB should also be con- The pericardium forms a strong, flask-shaped sac that encloses the
sidered in the setting of progressive clinical deterioration. Unfortu- heart and the origins of the great vessels. It is composed of a fibrous
nately the historical, physical examination, laboratory and imaging outer layer and an inner serous membrane formed by a single layer of
findings remain largely nonspecific in myocarditis with overlap of mesothelial cells. This membrane is attached to the epicardium to form
other CHF syndromes. The diagnosis requires a high degree of suspi- the visceral pericardium; it reflects upon itself, lining the inside of the
cion as well as exclusion of common etiologies of CHF. collagen-based fibrous layer to form the parietal pericardium. The
visceral pericardium continuously produces a clear pericardial fluid,
which serves as a lubricant; it is also the source of excess fluid in disease
Management states. The human pericardium normally contains up to 50 mL of this
The natural history of acute infectious myocarditis is variable, although fluid, which drains via the thoracic and right lymphatic ducts into the
the majority of cases run a benign course. Acute cardiac dysfunction circulation. Pericardial effusions develop in response to pericardial
does not predict chronic impairment, as most of these individuals injury or secondary to other processes that alter the secretion and
demonstrate normalization of cardiac function within 1 month. drainage of pericardial fluid. The pathologic changes seen in acute
General measures target cardiac dysfunction and arrhythmias asso- pericarditis are those of nonspecific inflammation with cellular infil-
ciated with myocarditis. Animal models have demonstrated that exer- tration, fibrin deposition and the outpouring of pericardial fluid.
cise during viral myocarditis is associated with more extensive These changes may resolve spontaneously, or may organize with
histologic damage; thus, bed rest may be important. Conventional fibrous adhesions between the epicardium and visceral pericardium,
therapy has included diuretics, angiotensin-converting enzyme (ACE) the visceral and parietal pericardium, or the pericardium and adjacent
inhibitors and beta-blockade, as for any CHF patient. Rarely, fulmi- sternum and pleura (Figure 50-2). Thus, inflammation, fluid exuda-
nant myocarditis requires the use of inotropic support, intra-aortic tion and fibrin organization account for the cardinal manifestations of
balloon pumps or ventricular assist devices as a bridge to the resump- pericarditis: chest pain, pericardial effusion and constriction.
tion of cardiac function.36 Unfortunately, there are no clinical or labo- The causes of this pericardial inflammation are numerous, includ-
ratory indicators to identify those patients who will recover; indeed, ing both noninfectious (Box 50-1) and infectious (Table 50-3)
patients who have fulminant myocarditis may have a better prognosis etiologies.
than those with nonfulminant myocarditis.37
As arrhythmias are probably associated with the majority of deaths NONINFECTIOUS AGENTS
in acute myocarditis, all hospitalized patients should be monitored on The three most prevalent noninfectious causes of pericardial disease
telemetry. Care should be exercised with any antiarrhythmic agent but are malignancies, uremia and connective tissue disorders. It is impera-
sustained arrhythmias should be treated aggressively. Complete heart tive to rule out these diagnoses before presuming a diagnosis of acute
block can occur and serial ECGs should be followed. If a specific infectious pericarditis.
VIRUSES
The most common etiologies of viral pericarditis have been thought
to include coxsackie A and B, echovirus type 8, adenovirus and HIV
(see Table 50-3). These viruses have only rarely been isolated from
pericardial fluid or tissue; as such, evidence for viral causation of
pericardial inflammation is based upon isolation of virus from other
sites, such as stool, and by demonstration of a fourfold rise in serum
antibody titers. Most recently, PCR testing has found evidence of
adenovirus, enterovirus, HHV-6 and CMV in pericardial fluid and
tissue from patients with acute pericarditis.43
BACTERIA AND OTHER INFECTIOUS AGENTS

Bacteria cause pericarditis by a number of different mechanisms.
Hematogenous seeding of the pericardium may occur during the
course of bacteremia caused by a variety of organisms. In the pre-
antibiotic era, most cases of purulent pericarditis were seen as compli-
cations of bacteremia or pneumonia. Today, extension of infection
from a contiguous focus within the chest is seen as a postoperative
or post-traumatic complication. Highly invasive bacterial infections
within the heart, such as staphylococcal endocarditis, may erode
into the pericardium from a perivalvular abscess to cause purulent
pericarditis. The microbiology of bacterial pericarditis continues to
evolve (see Table 50-3). Before antibiotics, uncontrolled pneumococ-
cal, streptococcal or staphylococcal pulmonary infections were most
Figure 50-2 Heart at autopsy of a patient who had acute suppurative pericardi- frequently implicated. Streptococci and staphylococci remain impor-
tis. The parietal pericardium has been stripped from the specimen, revealing a tant pathogens today (particularly in traumatic and post-thoracotomy
‘bread and butter’ appearance. pericarditis), with gram-negative bacilli, atypical bacteria and Candida
also assuming important roles. Pericardial involvement has also been
documented in the course of such illnesses as tularemia, brucellosis,
BOX 50-1 NONINFECTIOUS CAUSES OF salmonellosis, legionellosis, meningococcal disease and Q fever.44
PERICARDITIS Pericarditis caused by Mycoplasma deserves mention, but has
Idiopathic proved difficult to identify in pericardial fluid. Therefore, autoimmune
Connective tissue disorders phenomena have been invoked to explain the association. In one
Acute rheumatic fever, systemic lupus erythematosus, rheumatoid report, Mycoplasma pneumoniae, M. hominis and Ureaplasma urealyti-
arthritis, scleroderma, mixed connective tissue disease, Wegener’s cum were isolated from pericardial fluid and/or tissue cultures in five
granulomatosis, polyarteritis nodosa, temporal arteritis
Metabolic patients with large pericardial effusions.45 Treatment with doxycycline
Uremia, hypothyroidism after drainage of the effusions resulted in resolution in all cases. Peri-
Malignancies carditis caused by Mycoplasma spp. is thus more common than previ-
Lung cancer, breast cancer, leukemia, lymphoma, melanoma, others ously recognized, and fluid obtained for culture should be analyzed for
Acute myocardial infarction
Post-myocardial infarction syndrome (Dressler syndrome) these organisms.
Dissecting aortic aneurysm Mycobacteria continue to be important causes of acute pericarditis,
Traumatic pericardial effusion and constrictive pericarditis, particularly in low-
Chest trauma, postsurgical hemopericardium, pacemaker insertion, and middle-income countries. The incidence of tuberculous pericar-
cardiac catheterization, esophageal rupture, pancreatic–pericardial
fistula ditis among patients who have pulmonary tuberculosis ranges from
Post-irradiation 1% to 8%.46 While the overall incidence of tuberculous pericarditis has
Sarcoidosis, amyloidosis, inflammatory bowel disease, Behçet’s disease, significantly declined in the USA, countries with a high prevalence of
familial Mediterranean fever, tumor necrosis factor-associated periodic tuberculosis and HIV such as South Africa continue to have a higher
syndrome (TRAPS), cryopryin-associated periodic syndrome (CAPS)
Medications burden of disease. In a study from the Western Cape province of
Procainamide, hydralazine, isoniazid, phenylbutazone, dantrolene, South Africa, tuberculous pericarditis was the most common cause of
doxorubicin, dilantin, methysergide, minoxidil pericardial effusions and accounted for 69.5% of the 233 cases of
pericardial effusion. Of note, 50% of patients were HIV-positive.47
Despite the advent of HAART, extrapulmonary tuberculosis does
• Neoplasms may cause pericarditis or effusions by direct involve- still have to be considered in the USA in at-risk patients. Data from
ment of the pericardium or by obstruction of the pericardial the North Carolina Division of public health from 1993 to 2006
lymphatic drainage. identified over 6000 cases of tuberculosis, with extrapulmonary
• Uremic pericarditis is characterized by the appearance of a involvement in 1299.48 However, a minority of these cases had peri-
shaggy, fibrinous exudate without cellular infiltration. cardial involvement.
• Collagen vascular diseases (most commonly systemic lupus ery- Histoplasma capsulatum is the most common cause of fungal peri-
thematosus and rheumatoid arthritis) have a propensity to carditis; in large outbreaks, pericarditis was noted in 6% of patients
involve the pericardium; immune complex deposition is thought who had symptomatic histoplasmosis. It most commonly develops as
to be primary in the pathogenesis of autoimmune pericardial a noninfectious inflammatory response that resolves without therapy.
disease. Occasionally, seeding of the pericardium occurs in the course of dis-
seminated infection. In contrast, pericarditis has only rarely been
INFECTIOUS AGENTS reported in cases of severe coccidioidomycosis. In the immunosup-
A variety of microbes have been reported to cause pericarditis. Chief pressed or post-thoracotomy patient, infection caused by Candida
among these are viruses, which can produce a clinical syndrome of spp., Aspergillus fumigatus or Cryptococcus has occasionally resulted
myopericarditis, but other infectious agents are also implicated. from fungemia or direct inoculation.
TABLE
50-3 Infectious Causes of Pericarditis
Cause of Acute Pericarditis Incidence (%) in Western Countries Predisposition Diagnostic Approaches
IDIOPATHIC Frequent 50–70% Unknown
INFECTIOUS
Viruses
Enterovirus, echovirus Common 30% PCR
Cytomegalovirus, influenzavirus Frequent 1-10% Serology, PCR
Human immunodeficiency virus Rare Serology
Miscellaneous (adenovirus, parvovirus B19, varicella-zoster Rare <1% Serology, PCR

virus, Ebstein–Barr virus, mumps, hepatitis A, B, C)
Bacteria
Coxiella burnetii 7% Serology
Tuberculosis 4% (7% of tamponade) Chronic alcohol use, HIV Culture, PCR
Gram-negative rods, staphylococci, Streptococcus Rare <1% Chronic alcohol use, Culture, PCR
pneumoniae immunosuppression
Miscellaneous (e.g. Chlamydia, Mycoplasma, Legionella, Rare <1% Serology

Leptospira , Borrelia bugdorferi, Listeria)
Fungal
Candida species, histoplasmosis, coccidioidomycosis, Rare <1% Immunosuppression Culture, PCR

blastomycosis, aspergillosis
Parasitic
Toxoplasma gondii Rare <1% Serology, PCR
Entamoeba histolytica Rare <1% Serology
Echinococcus granulosus Rare <1% Serology
Schistosoma spp. Rare <1% Serology, histology
NONINFECTIOUS
Metabolic Disorders
Uremic, dialysis-related Frequent Creatinine, urea
Hypothyroidism TSH
Vasculitis and connective tissue disease Estimated from specific population:
Rheumatoid arthritis Frequent 20–30% rheumatoid

factor
Systemic lupus erythematosus, scleroderma Frequent 20% Specific antibodies
Rheumatic fever 20–50% Children
Miscellaneous: Sjögren’s syndrome, Reiter syndrome, Rare <1% Specific antibodies

ankylosing spondylitis, Wegener’s granulomatosis,
giant-cell arteritis, polymyositis, Behçet’s syndrome,
familial Mediterranean fever, other autoinflammatory
syndromes, dermatomyositis, polyarteritis, Churg–Strauss
syndrome, thrombotic thrombocytopenic purpura
Neoplastic Disorders Estimated from specific population:
Primary: mesothelioma, sarcoma, fibroma, lipoma, Rare <1% Pericardiocentesis

carcinoma, lymphoma, carcinoid
Secondary (metastatic or direct spread) Frequent Pericardiocentesis
Radiation Rare <1%
Post-injury Syndrome
Myocardial infarction, and postmyocardial syndrome 5–10% cases
Pericardial perforation (cardiac, surgery, percutaneous 1–3%

procedures)
Esophageal perforation, aortic dissection, pneumonia, Rare <1% CT scan

pulmonary embolism, empyema

TABLE
50-3 Infectious Causes of Pericarditis (Continued)
Cause of Acute Pericarditis Incidence (%) in Western Countries Predisposition Diagnostic Approaches
Association with Other Syndromes
Inflammatory bowel disease, Loffler syndrome, Stevens– Rare <1%

Johnson syndrome, giant-cell aortitis, hypereosinophilic
syndromes, acute pancreatitis
Drugs
Procainamide, hydralazine, methyldopa, reserpine, minoxidil, Rare <1%

phenylbutazone, bromocriptine, amiodarone etc.
Post-irradiation Rare <1%
PERICARDITIS IN AIDS
In contrast to other immunocompromised states, pericardial disease
in patients who have AIDS is quite common. Effusions are frequently
noted in end-stage AIDS (occurring in 16–40% of patients) and are
associated with a poor prognosis. Etiologies include a variety of patho-
gens (including viruses, bacteria, fungi and mycobacteria), although
in the majority of cases no causative agent can be defined. Malignant
effusions secondary to lymphomatous involvement of the pericardium
have also been noted. Although extrapericardial disease suggested spe-
cific infectious or malignant etiologies in 55% of patients who had
pericardial effusions in one trial, these assumptions proved incorrect
for all those in whom pericardiocentesis was performed.49 As a result,
in HIV pericardiocentesis is often necessary for accurate diagnosis.
Clinical Features
Acute pericarditis is most often recognized by presentation with chest
pain. The pain is usually precordial or retrosternal, often with radia-
tion to the trapezius ridge or neck; it is exacerbated by lying supine,
coughing or by deep inspiration, with relief upon sitting upright or
forward. The discomfort may be caused by inflammation of the adja-
cent pleura, accounting for the pleuritic component of the pain. This Figure 50-3 Cardiomegaly in a patient who has pericarditis. The presence of a
‘water-bottle’ heart on this plain film suggests a large pericardial effusion.
pain is distinguished from the pain of ischemia by its quality, its dura-
tion (may last for days without therapy) and the absence of associated
factors.
A pericardial friction rub is the pathognomonic physical finding of ECG changes in acute pericarditis imply inflammation of the peri-
pericarditis. Characterized as scratchy or grating, it is best appreciated cardium. Thus, in uremic or neoplastic pericardial effusions, charac-
along the left sternal border with respirations suspended and the teristic ECG changes are often absent. Cardiac arrhythmias are
patient leaning forward. The classic friction rub has three components, uncommon in isolated pericardial disease; their presence implies myo-
corresponding to atrial systole, ventricular systole and the rapid ven- cardial involvement. The ECG typically evolves through four stages
tricular filling phase of early diastole, although one or more of these during acute pericarditis.
phases are usually absent. Of note, the friction rub frequently waxes • Diffuse ST-segment elevation (usually concave up) with recipro-
and wanes in intensity and may disappear altogether with the accumu- cal ST depression in aVR and V1 accompanies the onset of chest
lation of fluid. The pericardial rub may again become prominent in pain and is virtually diagnostic of pericarditis; these findings are
tamponade, in which the pericardium rubs against the adjacent pleura. present in 50% of patients who have acute pericarditis.50 PR
Pericardial effusions range from the asymptomatic to those causing depression in the inferolateral leads is frequently seen in this
cardiac tamponade. The rate of fluid accumulation is a major deter- stage (Figure 50-4).
minant in physiologic manifestations. When the effusion develops • ST and PR segments normalize, typically several days later.
slowly, the pericardium may stretch to accumulate as much as 2 liters • Diffuse T wave inversions develop, generally after ST segments
of fluid. The normal pericardium, however, can accommodate the become isoelectric.
rapid accumulation of only 100–200 mL of fluid before signs and • ECG changes normalize; long-term inversion of T waves suggests
symptoms of tamponade develop. Examination will reveal jugular ‘chronic’ pericarditis.
venous distension, the most common physical finding in tamponade.
A fall of 10 mmHg or more in systolic blood pressure during inspira- Diagnosis
tion (pulsus paradoxus) is recognized as a hallmark of tamponade, Several studies have established the utility of using a stepped approach.51
although it may be absent if hypotension is already present. One study prospectively evaluated 231 consecutive patients who had
Enlargement of the cardiac silhouette on routine radiography does acute pericardial disease of unknown cause.52 Pericardiocentesis was
not usually occur until at least 250 mL of fluid has accumulated in the performed in patients who had tamponade, suspicion of purulent
pericardium. Other findings on chest radiogram, such as a ‘water pericarditis or symptoms and/or effusion persisting for more than 1
bottle’ heart (Figure 50-3) or a prominent fat stripe sign, are found week after initiation of nonsteroidal anti-inflammatory drug (NSAID)
only in large pericardial effusions. therapy. Pericardial biopsy was undertaken if clinical activity persisted
Figure 50-4 Electrocardiogram of a patient who has early acute pericarditis. Note the presence of diffuse ST segment elevation and PR depression in the inferolateral
leads (arrows). 25 mm/s; 10.0 mm/mV; F–W 0.05–100.
at 3 weeks and the etiology was unknown. Despite this extensive evalu- TABLE
ation, a diagnosis was confirmed in only 32 patients: neoplasia in 13, 50-4 Etiology of Large Pericardial Effusions
tuberculosis in 9, rheumatic disease in 4, purulent pericarditis in 2,
Etiology % of 75 Diagnoses
toxoplasmosis in 2 and viral pericarditis in 2. Diagnostic yield was
substantial when pericardiocentesis or biopsy was performed to relieve Malignancy 27
tamponade, but poor when used solely for diagnostic purposes. We
Viral 16
undertook a prospective nonrandomized trial of all patients who had
large pericardial effusions hospitalized at our institution in the early Collagen vascular disease 14
1990s. These patients underwent a similar stepped approach, with Radiation 11
subsequent subxiphoid pericardial biopsy and drainage of their effu-
sions.53 Microbiologic analysis of pericardial fluid and tissue allowed Uremia 11
diagnoses to be established in 53 out of 57 patients, confirming prior Mycobacterial 5
reports of high diagnostic yield when stepped algorithms are used
Mycoplasma 3
for large effusions. More than one-third of the patients had malig-
nancy or a history of irradiation to the thorax for malignancy. Infec- Bacterial 1
tions (mostly viral), noninfectious inflammatory disease and uremia Idiopathic 5
were also frequently implicated (Table 50-4). Unexpected pathogens
included CMV in three patients, herpes simplex virus 1 in one, M. Other 8
pneumonia in two, Mycobacterium avium complex in one and Myco- From Corey G.R., et al., Am J Med 1993; 95:209-213.
bacterium chelonei (see Table 50-3 ) in one patient. No patients showed
evidence of coxsackievirus A or B infection. A comparison of diagnos-
tic yield between pericardial fluid and biopsy demonstrated that fluid
analysis was far more sensitive for malignancy; tissue provided addi- physical examination, ECG and chest radiograph (to rule out intratho-
tional information only in infected patients in whom fluid was not racic malignancy, tuberculosis or a widened mediastinum suggestive
available for analysis. of aortic dissection), an echocardiogram, and routine laboratory
In summary, acute pericarditis is most often viral or idiopathic in studies including complete blood counts, serum chemistries, serial
etiology; as such, invasive workups are usually unnecessary. Early cardiac enzymes, thyroid function tests; blood cultures should be
intervention will often yield diagnosis and therapeutic benefits in large obtained for the febrile patient. If the suspicion for pericarditis is high
effusions, tamponade, or presentation concerning for purulent an anti-nuclear antibody should be sent to risk-stratify for autoim-
pericarditis. mune pericarditis. The diagnosis of tuberculous pericarditis should
A wide variety of infectious and noninfectious agents can cause always be considered and if there is any suspicion a tuberculin skin test
acute pericarditis and/or pericardial effusions (Tables 50-1 and 50-2). should be placed. A specific etiology will not be apparent in most
For acute chest pain, initial evaluation should focus on conditions that patients, and a diagnosis of viral or idiopathic pericarditis will be made.
may be rapidly fatal. Thus, myocardial infarction, aortic dissection, Because either entity typically follows a brief and benign course, a
purulent pericarditis and cardiac tamponade should be systematically full diagnostic evaluation is not appropriate. The confirmation of a
ruled out. An appropriate workup includes a thorough history and specific virus is unnecessary, as serologic titers are quite nonspecific.
hospitalization.56 Prednisone, however, is the drug of choice in peri-

carditis associated with connective tissue disease.
Idiopathic or viral pericarditis generally follows a benign, self-
limited course but the occasional patient will present with recurrent
pericarditis. Colchicine has shown promise in reducing recurrences in
several recent randomized controlled trials. The COPE and CORE trial
demonstrated that colchicine, in addition to aspirin or NSAIDs,
reduced disease recurrence and symptom duration in both primary
and recurrent pericarditis, respectively. A multicenter randomized
controlled trial, ICAP, confirmed these results.57 Based on these trials
colchicine should be used as first-line therapy for disease recurrence,
rather than corticosteroids.58–59 Anakinra, a recombinant human
interleukin-1β receptor antagonist, has recently been shown to have a
potential benefit for both adult and juvenile patients with treatment-
refractory idiopathic pericarditis.60 Pericardiectomy is reserved for
those with constrictive pericarditis or failure of intensive medical
therapy.61
Intravenous antibiotics and surgical drainage of the pericardium
remain the mainstays of therapy for purulent pericarditis. Pericardio-
centesis urgently performed for the critically ill patient does not
Figure 50-5 Chest CT scan of a patient who has a large crescent-shaped peri-
obviate the need for complete drainage and irrigation; fluid may reac-
cardial effusion. cumulate rapidly and sequelae such as constriction may develop in
hours. There is no rationale for intrapericardial antibiotic administra-
tion, as pericardial penetration of antibiotics is excellent.
Tuberculous pericarditis remains a diagnostic and therapeutic
challenge. Clinical features are nonspecific, the disease course is con-
However, since significant pericardial effusion may accumulate even fusing and laboratory evaluation is often nondiagnostic, particularly
in idiopathic disease, all patients should be carefully evaluated and in low prevalence settings and in patients who have localized disease.
monitored for evidence of hemodynamic compromise on physical Although large effusions are more likely to be tuberculous, up to 50%
examination. If found, it can be confirmed by echocardiogram and of tuberculous effusions resolve spontaneously despite ongoing tissue
treated with fluid aspiration or surgery. infection. The tuberculin skin test may be negative in up to 30% of
Echocardiography has replaced other methods for the detection of patients as a result of cutaneous anergy yet may be positive in the
pericardial fluid and evaluation for tamponade. With experience, patient who has acute idiopathic pericarditis. Suggestive findings
operators can detect as little as 20 mL of excess fluid posterior to the include a recent history of pulmonary tuberculosis, a positive sputum
left ventricle. Echocardiography can also provide ancillary data in smear or culture or a high pericardial fluid adenosine deaminase
assessing the patient who has an effusion. Increased respiratory flow level.62 Even granulomatous inflammation of the pericardium is not
variation across the mitral valve with Doppler echocardiography is diagnostic, as this may be demonstrated in pericardial disease from
characteristic of tamponade. In addition, other etiologies of myocar- other causes, such as histoplasmosis, sarcoidosis and rheumatoid
dial dysfunction can be ruled out. Finally, the echocardiogram can arthritis. Additionally, a negative biopsy of the pericardium does not
direct attempts at pericardiocentesis by identifying the location of rule out tuberculous pericarditis, as removal of the entire pericardium
pericardial fluid. may be necessary to demonstrate clear-cut evidence of tuberculosis.63
Computed tomography (CT) scans of the chest are primarily Definitive diagnosis rests upon the demonstration of the tubercle
helpful in the diagnosis of pericardial thickening though significant bacillus in pericardial fluid and/or tissue. However, the need for early
effusions are also readily demonstrated (Figure 50-5). In addition, CT therapy demands that treatment often be undertaken based upon a
scans are more sensitive for the demonstration of small parenchymal presumptive diagnosis. Initial treatment should consist of four drugs
nodules and mediastinal lymphadenopathy than is conventional including isoniazid and rifampin until sensitivities are known. The use
radiography, and thus have clinical utility in the diagnosis of malignant of concomitant prednisone to reduce pericardial inflammation has
or tuberculous pericarditis. been shown to lower mortality, reduce symptom duration and need
Recently published guidelines for the use of CT and CMR in peri- for pericardiectomy,64 however a recent large randomized trial sug-
cardial disease state that echocardiography is still the first-line imaging gested that adjunctive steroids do not reduce the risk of tamponade or
modality for pericardial disease, but CT/CMR should be considered in death.65 Complete pericardiectomy is advocated for those who have
the setting of complex disease, extracardiac disease, operative planning recurrent effusions or cardiac compression with constrictive physiol-
and when echocardiography is limited by body habitus.54 ogy after 4–6 weeks of therapy as early pericardiectomy is associated
with reduced morbidity and mortality.66,67
Management Myopericarditis also deserves special mention since the diagnosis
Randomized controlled trials in the treatment of pericarditis are changes management. Myopericarditis occurs when the primary
limited, and management at this point is driven by expert opinion. In process is pericarditis. Elevation of cardiac biomarkers, ECG changes
2004 the European Society of Cardiology published the first set of and wall motion abnormalities by echocardiogram are evidence of
guidelines for management of pericardial disease. Medical therapy is some degree of myocardial injury. If there is a suspicion of myoperi-
tailored to the cause of pericarditis and the co-morbidities of the carditis, CMR should be performed as myocardial involvement
patient. Aspirin or NSAIDs are effective in reducing symptoms of changes pharmacologic management, follow-up and advice on physi-
pericarditis and are the agents of choice for idiopathic or viral pericar- cal activity. Myopericarditis mandates serial echocardiograms to
ditis.55 The most frequent cause of recurrence or disease persistence is ensure the return of cardiac function, avoidance of physical activity,
inadequate dosages or duration of anti-inflammatory agents. While and dose-reduction of NSAIDS.68–70
corticosteroids relieve symptoms, they have been demonstrated to
increase the risk of side effects, recurrences and duration of References available online at expertconsult.com.
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carditis and myositis: case presentation and review of JACC White Paper. J Am Coll Cardiol 2009; 53(17):1475. first choice therapy for recurrent pericarditis. Arch
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15. Muir P., Nicholson F., Tilzey A.J., et al.: Chronic relaps- percutaneous left ventricular assist device as a bridge to 59. Imazio M., Brucato A., Cemin R., et al.: A randomized
ing pericarditis and dilated cardiomyopathy: serological recovery from myocarditis. Am J Cardiol 2007; 99:1755- trial of colchicine for acute pericarditis. N Engl J Med
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16. Nitsekhe M., Mayosi B.M.: Cardiac manifestations of Long term outcome of fulminant myocarditis as com- for the management of resistant idiopathic recurrent
HIV infection: an African perspective. Nat Clin Pract pared with acute (nonfulminant) myocarditis. N Engl J pericarditis: initial experience in 10 adult cases. Ann
Cardiovasc Med 2009; 6:120-127. Med 2000; 342:690-695. Rheum Dis 2014; 73(12):2215-2217.
17. Calabrese L.H., Proffitt M.R., Yen-Lieberman B., et al.: 38. Mason J., O’Connell J., Herskowicz A., et al.: A clinical 61. Fowler N.O.: Pericardial disease. Heart Dis Stroke 1992;
Congestive cardiomyopathy and illness related to the trial of immunosuppressive therapy for myocarditis. 2:85-94.
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ated with isolation of retrovirus from myocardium. 39. McNamara D.M., Holubkov R., Starling R.C., et al.: nosine deaminase activity in tuberculous pericarditis.
Ann Intern Med 1987; 107:691-692. Controlled trial of intravenous immune globulin in Thorax 1986; 41:888-889.
18. Currie P.F., Jacob A.J., Foreman A.R., et al.: Heart recent-onset dilated cardiomyopathy. Circulation 2001; 63. Cheitlin M.D., Serfos L.J., Sbar S.S., et al.: Tuberculous
muscle disease related to HIV infection: prognostic 103:2254-2259. pericarditis: is limited pericardial biopsy sufficient for
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19. Shaboodien G., Maske C., Wainwright H., et al.: Preva- in enterovirus-associated cardiomyopathy. J Am Coll 64. Strang J.I., Gibson D.G., Mitchinson D.A., et al.: Con-
lence of myocarditis and cardiotropic virus infection in Cardiol 2012; 1295-1296. trolled clinical trial of complete open surgical drainage
Africans with HIV-associated cardiomyopathy, idio- 41. Kuhl U., Pauschinger M., Schwimmbeck P.L., et al.: and of prednisone in treatment of tuberculous pericar-
pathic dilated cardiomyopathy and heart transplant Interferon-beta treatment eliminates cardiotropic dial effusion in Transkei. Lancet 1988; 2:759-763.
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24:218-223. patients with myocardial persistence of viral genomes and Mycobacterium indicus pranii in tuberculous peri-
20. Valantine H.A., Gao S.Z., Menon S.G., et al.: Impact of and left ventricular dysfunction. Circulation 2003; carditis. N Engl J Med 2014; 371:1121-1130.
prophylactic immediate posttransplant ganciclovir on 107:2793-2798. 66. Fennell W.M.P.: Surgical treatment of constrictive
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1999; 100:61-66. sistence in the myocardium is associated with progres- 67. Trautner B.W., Darouiche R.O.: Tuberculous pericar-
21. Maisch B., Schonian U., Crombach M., et al.: CMV- sive cardiac dysfunction. Circulation 2005; ditis: optimal diagnosis and management. Clin Infect
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22. Mahfoud F., Gartner B., Kindermann M., et al.: Virus access using the PerDUCER and flexible percutaneous ditis. Expert Rev Cardiovasc Ther 2013; 11(2):193-201.
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dilated cardiomyopathy. Scand J Infect Dis Suppl 1993; 1,383 infections. Medicine 2000; 79:109-123. 70. Friedrich M.G., Sechtem U., Schulz-Menger J., et al.:
88:33-43. 45. Kenney R.T., Li J.S., Clyde W.A., et al.: Mycoplasmal International Consensus Group on Cardiovascular
24. Assomull R.G., Lyne J.C., Keenan N., et al.: The role of pericarditis: evidence of invasive disease. Clin Infect Dis Magnetic Resonance in Myocarditis. J Am Coll Cardiol
cardiovascular magnetic resonance in patients 1993; 58-62. 2009; 53(17):1475.
51
Endocarditis
FRANCK THUNY | GILBERT HABIB | DIDIER RAOULT |
PIERRE-EDOUARD FOURNIER
KEY CONCEPTS rheumatic heart disease is highly prevalent, this trend is less evident
and streptococcal IE still predominates.10 Currently, healthcare-
• Infective endocarditis (IE) is a severe disease for which inci- associated IE accounts for 25% of cases,11 and IE involving prosthetic
dence and mortality rate remain elevated. valves and CIED represents 20% and 10% of cases, respectively.7,12
• The epidemiology of IE has changed over the past decades, About 5% of prosthetic valves become infected. Mechanical valves are
with the emergence of healthcare-associated infections. more likely to be infected within the first 3 months of implantation,
whereas in bioprosthetic valves this tends to occur after 1 year. Early
• The diagnosis of IE remains a challenge, although systematic prosthetic valve IE occurs within 60 days of valve implantation, the
microbiologic testing and the adoption of new imaging tech-
common infecting organisms being Staphylococcus aureus, coagulase-
niques have contributed to improving the diagnostic rate.
negative staphylococci (CoNS), gram-negative bacilli and Candida
• Blood cultures remain the cornerstone for the diagnosis of IE. species. Late prosthetic valve IE occurs 60 days or more after valve
implantation. Staphylococci, oral streptococci and enterococci are the
• Standardized and efficient therapeutic protocols are available
for the most common clinical situations and causative agents. common causative organisms. Infections of CIEDs occur within a few
months of implantation and most commonly present as generator
pocket infections. These are caused by staphylococci in 75% of cases.
Infective endocarditis may be split into blood culture-positive or
Introduction and Definitions culture-negative. Blood culture-positive endocarditis represents
Endocarditis is defined as an inflammation of the endocardial surface
of the heart. This may include heart valves, mural endocardium or the BOX 51-1 CLASSIFICATION AND DEFINITIONS OF
endocardium that covers prosthetic valves, pacemaker/defibrillator INFECTIVE ENDOCARDITIS
leads and catheters. Infective and non-infective-related causes of endo-
carditis must be distinguished. In most cases the inflammation is IE According to Location of Infection and Presence or Absence of
Intracardiac Material
related to a bacterial or fungal infection. Infective endocarditis (IE) is
• Left-sided native valve IE
a serious disease the incidence of which has not decreased despite • Left-sided prosthetic valve IE (PVE)
prevention strategies. The mortality rate is high, with more than one- • Early PVE (<1 year)
third dying within a year of diagnosis.1,2 IE must be classified according • Late PVE (>1 year)
to the location of infection, the mode of acquisition, the degree of • Right-sided IE
• Device-related IE (permanent pacemaker or cardioverter-defibrillator)
infection and the presence of recurrence (Box 51-1).3
The management (prevention, diagnosis, treatment and follow-up) IE According to the Mode of Acquisition
of patients with endocarditis should be based on a team approach • Healthcare-associated IE
involving specialists in cardiology, infectious diseases, cardiothoracic • Nosocomial: IE developing in a patient hospitalized >48 h prior to
the onset of signs/symptoms of IE
surgery and other appropriate specialists as needed. This multidisci- • Non-nosocomial: Signs and/or symptoms of IE starting <48 h after
plinary approach is crucial for a better prognosis and should be initi- admission in a patient with healthcare contact defined as:
ated as soon as the diagnosis is suspected.4–6 Patients with severe IE 1. Home-based nursing or intravenous therapy, hemodialysis, or
should be rapidly referred to referral centres. intravenous chemotherapy <30 days before the onset of IE; or
2. Hospitalized in an acute care facility <90 days before the onset
of IE; or
Epidemiology 3. Resident in a nursing home or long-term care facility
• Community-acquired IE
Although the incidence of IE has remained stable in Europe and the • Signs and/or symptoms of IE starting <48 h after admission in a
USA over the last 30 years (20–100 episodes per million person-years), patient not fulfilling the criteria for healthcare-associated infection
as well as its mortality (10–26% in-hospital mortality),1 its epidemiol- • Intravenous drug abuse-associated IE
ogy has changed.7 Previously, IE was mostly a community-acquired • IE in an active injection drug user without alternative source of
infection
disease affecting young patients with rheumatic heart disease. Cur-
rently, it involves older male patients with no known valve disease, Active IE
suffering from co-morbidities, or with a prosthetic valve or cardiovas- • IE with persistent fever and positive blood cultures; or
cular implantable devices (CIED); it often results from healthcare- • Active inflammatory morphology found at surgery; or
• Patient still under antibiotic therapy; or
associated procedures (intravascular catheters, surgical wounds, • Histopathologic evidence of active IE
indwelling prosthetic devices).8 The peak incidence is 145 episodes/
million person-years between 70 and 80 years old.7,9 Recurrence
In industrialized countries, although geographical variations are • Relapse
• Repeat episodes of IE caused by the same micro-organism <6
observed, rheumatic heart disease currently accounts for <20% of IE months after the initial episode
cases. Congenital heart diseases represent 15% of cases, with bicuspid • Re-infection
aortic valve and mitral valve prolapse being most frequent. New pre- • Infection with a different micro-organism; or
disposing factors have emerged, all of which are associated with • Repeat episode of IE caused by the same micro-organism >6
months after the initial episode
increased risk of bacteremia, including valve prostheses, valve sclerosis,
CIED and intravenous drug abuse. Such a change has been paralleled Adapted from Habib G, Eur Heart J 2009; 30(19):2369–2413 with
by a reduction in the incidence of streptococcal IE and an increase in permission.
staphylococcal IE.1 In low- and middle-income countries, where
456
Chapter 51 Endocarditis 457
80–90% of cases. Although virtually any bacterium or fungus can cause morbillorum, Strep. anginosus, Strep. intermedius and Strep. constella-
IE, gram-positive bacteria including streptococci, staphylococci and tus; the latter three species have a special ability to form abscesses and
enterococci are by far the most common.13 In 10–20%, blood cultures cause disseminated infection. Digestive streptococci, also referred to
remain negative. In most of these cases, negativity of blood cultures is as group D streptococci, form the ‘Strep. gallolyticus’ group. Strep. gal-
explained by the antibiotic treatment started prior to blood cultures. lolyticus and enterococci are increasingly prevalent in elderly patients
Fastidious micro-organisms, especially strictly or facultative intracel- and may be associated with colon tumors. Both oral and digestive
lular bacteria, are the second commonest cause of culture-negative IE streptococci are usually susceptible to penicillin G, although penicillin
and account for ~5% of all IE. resistance is increasingly reported. Species within the Abiotrophia and
Granulicatella, also found in the human digestive tract, are nutrition-
Etiologies ally variant or ‘defective’ streptococci, often exhibiting a reduced peni-
Infectious and noninfectious causes of endocarditis should be distin- cillin susceptibility. Among Enterococcus species, E. faecalis and E.
guished (Box 51-2). Oral (formerly viridans) streptococci, group D faecium are the main species causing IE. These species often exhibit a
streptococci (e.g. Streptococcus gallolyticus), staphylococci and entero- reduced antibiotic susceptibility and should be tested for susceptibility
cocci are the most frequent causative pathogens, involved in almost to penicillins, aminoglycosides and glycopeptides.
85% of IE cases.11 Among gram-negative bacterial agents of IE, HACEK group
Staphylococci have emerged as one of the most frequent causes of bacteria (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella,
IE, and represent 30% of all episodes.2,11,14,15 Staphylococcus aureus and Kingella) are responsible for 5–10% of native valve community-
coagulase-negative staphylococci are more often found in intravenous acquired IE. These bacteria are members of the oral flora, require
drug users, in patients with prosthetic valve endocarditis, and in those prolonged blood culture and increasingly produce β-lactamases. Fungi
with healthcare-related IE.15,16 A substantial increase in the rate of account for ~2% of IE cases, mostly nosocomial. They often cause
staphylococcal IE has been reported, especially in the USA, where severe IE.
chronic hemodialysis, diabetes and intravascular devices are the three In ~15% of cases the etiology cannot be found by blood cultures.18
main factors associated with IE due to Staph. aureus.15,17 Coagulase- Although cases of blood culture-negative endocarditis are often related
negative staphylococci (CoNS) are the main cause of prosthetic valve to previous antibiotic therapy (commonly in streptococcal IE), a sub-
endocarditis, although cases of native valve community-acquired IE stantial number result from intracellular bacteria: Coxiella burnetii
caused by CoNS can occur. Due to their high level of antibiotic resis- (the cause of Q fever), Bartonella spp., Brucella spp., Legionella spp.,
tance, staphylococcal isolates causing IE should be tested for oxacillin Mycoplasma spp., Tropheryma whipplei (the cause of Whipple’s
and glycopeptide susceptibility. disease); fungi: Candida spp., Aspergillus spp.; or other fastidious
Streptococci causing IE mostly belong to the oral and gut flora. organisms: Abiotrophia spp., Propionibacterium acnes.19 Tables 51-1
Oral streptococci, comprise several species of the oral microbiota such and 51-2 summarize the distribution of the microbial etiologies
as Strep. sanguinis, Strep. mitis, Strep. salivarius, Strep. mutans, Gemella according to the different regions and the site of infection.
It should be noted that endocarditis can also occur as a complica-
tion of other pathologic conditions such as autoimmune diseases and
neoplasia (marantic endocarditis).19,20 Libman-Sacks endocarditis rep-
BOX 51-2 CAUSES OF ENDOCARDITIS resents the majority of noninfective endocarditis cases. This form is
INFECTIONS the commonest cardiac manifestation of systemic lupus erythematosus
‘Standard’ Bacteria and is associated with primary or secondary antiphospholipid syn-
Oral (viridans) streptococci drome.21 Endocarditis has been described in other autoimmune condi-
Streptococcus gallolyticus (and other group D streptococci) tions such as rheumatoid arthritis. Immunologic inflammation can
Streptococcus pneumoniae be observed during rheumatic fever (see Chapter 52). Thrombotic
Streptococcus pyogenes sterile vegetations can be observed in the context of neoplasia (espe-
Enterococci
Staphylococcus aureus cially lung and pancreas) due to hypercoagulable states and, some-
Coagulase-negative staphylococci times, with antiphospholipid antibodies. Loeffler’s endocarditis is a
Enterobacteriaceae form of restrictive cardiomyopathy with eosinophilic proliferation in
Fastidious Bacteria endocardial and myocardial tissue. Finally, foreign material rejection
HACEK group or allergic phenomena may be a cause of non-infective porcine bio-
Coxiella burnetii prosthetic valve endocarditis.20
Bartonella spp.
Propionibacterium acnes
Tropheryma whipplei Pathogenesis
Abiotrophia ssp.
Mycoplasma spp. PREDISPOSING HOST FACTORS
Legionella spp. IE develops most commonly on the mitral valve, closely followed
Corynebacterium diphtheriae in descending order of frequency by the aortic valve, the combined
Finegoldia magna mitral and aortic valve, the tricuspid valve and, rarely, the pulmonary
valve. The normal valve endothelium is very resistant to colonization
Fungi and infection by circulating bacteria. However, any mechanical lesion
Candida spp. of this endothelium will result in exposure of the underlying extracel-
Aspergillus spp.
lular matrix proteins, the production of tissue factor and the deposi-
Virus (Controversial) tion of fibrin and platelets as a normal healing process. The Venturi
Enterovirus effect also contributes to the development and location of this non-
NONINFECTIVE CAUSES bacterial thrombotic endocarditis. This effect explains why bacteria
Acute rheumatic fever and the fibrin-platelet thrombus are deposited on the sides of the
Libman-Sacks endocarditis (antiphospholipid syndrome) low-pressure sink that lies just beyond a narrowing or stenosis.
with systemic lupus These lesions constitute an ideal nidus for bacterial adherence and
without systemic lupus infection.22,23
Rheumatoid arthritis
Marantic endocarditis (neoplasia) Endothelial damage may result from mechanical damage due
Loeffler’s endocarditis to turbulent blood flow in cases of congenital cardiac abnormalities
or prosthetic valves, or lesions made by electrodes or catheters.
TABLE
51-1 Causative IE Agents by IE Type by Region in 2781 Patients with Definite Endocarditis
REGION
Total Cohort North America South America Europe Other P value for the
n = 2781 n = 597 n = 254 n = 1213 n = 717 Difference
(%) n (%) n (%) n (%) n (%) Between Regions
Staph. aureus 869 (31) 256 (43) 43 (17) 339 (28) 231 (32) <0.001
Coagulase-negative staphylococci 304 (11) 69 (12) 18 (7) 156 (13) 61 (9) 0.005
Viridans group streptococci 483 (17) 54 (9) 66 (26) 198 (16) 165 (23) <0.001
Strep. bovis 165 (6) 9 (2) 17 (7) 116 (10) 23 (3) <0.001
Other streptococci 162 (6) 38 (6) 16 (6) 66 (5) 42 (6) 0.86
Enterococci 283 (10) 78 (13) 21 (8) 111 (9) 73 (10) 0.05
HACEK 44 (2) 2 (0.3) 6 (2) 19 (2) 17 (2) 0.02
Fungi/yeast 45 (2) 20 (3) 3 (1) 13 (1) 9 (1) 0.002
Polymicrobial 28 (1) 8 (1) 1 (0.4) 13 (1) 6 (1) 0.60
Culture-negative 277 (10) 41 (7) 51 (20) 123 (10) 62 (9) <0.001
Other 121 (4) 22 (4) 12 (5) 59 (5) 28 (4) 0.61
HACEK, Haemophilus spp., Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens and Kingella kingae; PVE, prosthetic valve
infective endocarditis.
From Murdoch DR, et al. Arch Intern Med 2009; 169(5):463–473.
TABLE
51-2 Causative IE Agents by IE Type in 2781 Patients with Definite Endocarditis
NATIVE VALVE IE INTRACARDIAC-MATERIAL IE
Drug Abusers Non-Drug Abusers PVE Other Devices
n = 237 n = 1644 n = 563 n = 172
n (%) n (%) n (%) n (%)
Staph. aureus 160 (68) 457 (28) 129 (23) 60 (35)
Coagulase-negative staphylococci 7 (3) 148 (9) 95 (17) 45 (26)
Viridans group streptococci 24 (10) 345 (21) 70 (12) 14 (8)
Strep. bovis 3 (1) 119 (7) 29 (5) 5 (3)
Other streptococci 5 (2) 118 (7) 26 (5) 7 (4)
Enterococci 11 (5) 179 (11) 70 (12) 10 (6)
HACEK 0 (0) 30 (2) 13 (2) 1 (1)
Fungi/yeast 3 (1) 16 (1) 23 (4) 2 (1)
Polymicrobial 6 (3) 16 (1) 5 (1) 0 (0)
Culture-negative 12 (5) 154 (9) 65 (12) 18 (11)
Other 6 (3) 62 (4) 38 (7) 10 (6)
HACEK, Haemophilus spp., Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens and Kingella kingae; PVE, prosthetic valve
infective endocarditis.
From Murdoch DR, et al. Arch Intern Med 2009;169(5):463–473.
Alternatively, endothelial damage can result from inflammation, as in 51-2). IE pathogens possess several surface adhesins that mediate
rheumatic carditis, or from degenerative valve lesions, as in elderly attachment to extracellular matrix proteins of the host. These adhesins
individuals.24,25 are collectively referred to as MSCRAMMs, for microbial surface com-
The pathogenesis of pacemaker IE is similar. Shortly after implan- ponent reacting with adhesive matrix molecules. They include both
tation, the development of a fibrin-platelet thrombus (similar to the proteins and polysaccharides.
nonbacterial thrombotic endocarditis described above) involves the In Staphyloccus aureus, fibrinogen-binding protein A (also called
generator box and conducting leads. After 1 week, the connective clumping factor A or ClfA) and fibronectin-binding protein A (FnBPA)
tissue proliferates, partially embedding the leads in the wall of the vein are involved in valve colonization and invasion, whereas other
and endocardium. This layer may offer partial protection against infec- MSCRAMMs seem less implicated.26 In streptococci, several surface
tion during a bacteremia. proteins as well as platelet-activating factors and exopolysaccharides
are involved in bacterial adherence to damaged valves.
CHARACTERISTICS OF THE MICRO-ORGANISMS Direct invasion of endothelial cells may also occur in certain cir-
The organisms most frequently responsible for IE are also those with cumstances, as was demonstrated in experimental endocarditis with
the greatest ability to adhere to and colonize damaged valves22 (Table Staph. aureus.26 During inflammation, endothelial cells express a
variety of molecules, including integrins of the β1 family (very late Health and Care Excellence, in the UK, does not recommend any
antigen, VLA), which bind fibronectin. Fibronectin bound to endo- prophylaxis for any patient and before any procedure, whether dental
thelia is a ligand for pathogens expressing fibronectin-binding pro- or not (www.nice.org.uk/CG064). However, neither strategy has been
teins, including Staph. aureus. This interaction triggers internalization associated with an increase in oral bacteria-associated IE, supporting
of the attached microbes by the host cell. Thus, local inflammation due the concept of reducing the indications of antibiotic prophylaxis for
to degenerative lesions, e.g., arteriosclerosis, or undetermined condi- dental procedures.43,44
tions, may promote direct endothelial infection. These events may also Currently, four groups of patients still require IE prophylaxis: (1)
be important in the pathogenesis of IE due to intracellular pathogens patients with prosthetic valves or prosthetic material used for cardiac
such as C. burnetii, Legionella spp. and Bartonella spp.27 valve repair; (2) patients with history of a previous IE; (3) cardiac
transplant patients with a valvular defect; and (4) patients with a
THE ROLE OF TRANSIENT BACTEREMIA limited number of congenital heart diseases (cyanotic congenital heart
disease without surgical repair or with complete surgical repair <6
The role of transient bacteremia was demonstrated in animals with
months or with residual defect).35 Patients with mitral valve prolapse
catheter-induced aortic valve vegetations and dental manipulation.28
or with bicuspid aortic valve do not require prophylaxis. Similarly, the
Both the magnitude of bacteremia during dental procedures (duration
number of dental procedures requiring prophylaxis has been reduced
and bacterial load) and the ability of the pathogen to attach to damaged
to those involving manipulation of the oral mucosa, with the exception
valves were important. The most common bacteremias are spontane-
of routine anesthetic injections. Likewise, only respiratory procedures
ous consequences of daily routine procedures such as chewing or tooth
involving incision of the respiratory mucosa, not bronchoscopy,
brushing. Such bacteremias last less than 10 minutes and contain
require prophylaxis.3,35
<100 cfus/mL of blood.29 Healthcare-associated bacteremias, such
No prophylaxis is recommended in patients with CIED undergoing
as in chronic hemodialysis patients, form a new risk for IE.17,30 dental, gastrointestinal or urogenital procedures. However, because of
the high incidence of pacemaker-associated IE, antistaphylococcal
THE ROLE OF HOST DEFENSES prophylaxis is recommended for pacemaker implantation.35
IE is most often due to gram-positive organisms, and rarely to gram- The choice of antibiotics for prophylaxis is detailed in Table 51-3.
negative bacteria (Table 51-2). The reason is probably multifactorial. For dental procedures, amoxicillin or ampicillin, 2 g orally one hour
Differences in bacterial adherence to damaged valves may be one before the procedure (50 mg/kg in children), is the first choice. For
explanation. However, differences in the susceptibility of gram-positive CIED implantation, intravenous cefazolin (2 g) or vancomycin (2 g)
and gram-negative bacteria to serum-induced killing may also contrib- may be used.
ute. The C5b–C9 membrane-attack complex of complement kills Fenollar et al. have demonstrated that endocarditis develops in up
gram-negative bacteria by perforating their outer membrane. In con- to 40% of patients with acute Q fever and a pre-existing valvular
trast, complement does not kill gram-positive bacteria because they defect.45 This mostly occurs in patients >40 years and may be prevented
lack an outer membrane, and their plasma membrane is protected by a one-year treatment of doxycycline (200 mg/d) plus hydroxychlo-
from the membrane-attack complex by the thick surrounding pepti- roquine (200–600 mg/d) orally for 1 year.46
doglycan. Yet, some gram-negative bacteria may carry thick capsules
or other modifications of their surface that help them resist
complement-induced killing.
Diagnosis
Although gram-positive bacteria are resistant to complement, they DIAGNOSTIC STRATEGY
may be the targets of other nonspecific immune factors such as platelet In cases with a high suspicion of IE, appropriate antibiotics must be
microbicidal proteins (PMPs). Platelets, which are a major component started early (once blood cultures have been obtained) as delay may
of the vegetations, are key players in the nonspecific defense against IE have negative effects on clinical outcomes. Diagnosis of IE usually
as they produce PMPs that kill bacteria by damaging their plasma relies on the association of an infectious syndrome and evidence of
membrane. In patients with IE, causative micro-organisms are consis- recent endocardial involvement. This is the cornerstone of the various
tently resistant to PMP-induced killing, whereas in other types of classifications and scores proposed to facilitate the difficult diagnosis
infection they are susceptible to PMPs.31 of this disease. The criteria by Von Reyn and colleagues use only results
Humoral and cellular immunity seem to play only a limited role in from blood cultures and the presence of a new regurgitant murmur or
defense against IE, and immunization studies in experimental endo- a predisposing heart disease to define endocarditis.47 The subsequent
carditis gave contradictory results.32 IE is not more frequent in immu- Duke criteria include echocardiographic detection of the typical lesions
nocompromised patients than in immunocompetent people.33 (vegetations, abscess, new prosthetic dehiscence) as a major diagnostic
criterion.48 In 2002 C. burnetii serology as a new major criterion was
added (Box 51-3).49 The sensitivity of these modified criteria is limited,
Prevention however, especially in the early stage of IE, in cases of negative blood
For decades, antibiotic prophylaxis has been prescribed prior to inva- cultures and in the presence of prosthetic valve or pacemaker/
sive (notably dental) procedures, because of a supposed risk of IE.34 defibrillator leads. Other scoring systems using a combination of non-
However, several international guidelines published since 20027,35–38 specific clinical signs and biologic results have been proposed to
converged towards a drastic reduction in antibiotic indications in improve the early diagnosis of IE.50 Polymerase chain reaction (PCR)
patients with at-risk cardiac conditions. These changes were motivated techniques, immunohistochemistry, MRI and molecular imaging
by the discrepant results from studies on the role of dental procedures might be integrated into future diagnostic classifications.
in the genesis of IE,39–41 as compared to the frequency of transient,
short duration bacteremias resulting from daily activities (chewing, CLINICAL PRESENTATION
tooth brushing, flossing).42 Prophylaxis is not recommended in gastro- Although fever in a patient with a cardiac predisposition (heart valve
intestinal and urogenital procedures, but any gastrointestinal or disease, intracardiac materials, congenital heart disease) is the most
urogenital infection should be treated prior to the procedure. Regard- frequent feature leading to diagnosis (almost 50% of cases),14 clinical
ing IE from dental origin, good oral hygiene is probably the most histories are highly variable (Box 51-4). The classical cutaneous mani-
effective preventive method. However, disagreements exist regarding festations of endocarditis: Janeway lesions and Osler’s nodes in the
prophylaxis for dental procedures. The American Heart Association skin, and retinal Roth spots (see figures in Chapter 13) do not occur
and European Society of Cardiology propose antibiotic prophylaxis in reliably and/or are inapparent. Therefore, a high index of suspicion
patients at highest risk of IE (prosthetic valves, congenital heart disease and low threshold for investigation are essential. Blood cultures and
and previous history of IE),3,35 whereas the National Institute for echocardiography still remain the cornerstone for diagnosis.
TABLE
51-3 Recommended Antibiotic Prophylaxis for At-Risk Procedures
Single Dose 30–60 min Before Procedure
Adults Children
Dental Procedures
Oral route Amoxicillin or 2 g 50 mg/kg

Ampicillin 2 g 50 mg/kg
Unable to take oral antibiotics Ampicillin or 2 g iv or im 50 mg/kg iv or im

Ceftriaxone 2 g iv or im 50 mg/kg iv or im
Allergy to penicillin – oral route Cephalexin or 2 g 50 mg/kg

Clindamycin or 600 mg 20 mg/kg
Clarithromycin 500 mg 15 mg/kg
Allergy to penicillin – unable to take oral antibiotics Cefazolin or 2 g iv or im 50 mg/kg iv or im

Ceftriaxone or 2 g iv or im 50 mg/kg iv or im
Clindamycin 600 mg iv or im 20 mg/kg iv or im
CIED Implantation Cefazolin or 2 g iv or im

Vancomycin 2 g iv
iv, intravenous; im, intramuscular.

Adapted from Habib et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the Task Force on the Prevention,
Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by the European Society of Clinical Microbiology and
Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC) for Infection and Cancer. Eur Heart J 2009;30(19):2369-2413.
BOX 51-3 DEFINITION OF INFECTIVE ENDOCARDITIS ACCORDING TO THE PROPOSED MODIFIED

DUKE CRITERIA
DEFINITE IE MAJOR CRITERIA
Pathologic Criteria 1. Blood culture positive for IE:
1. Micro-organisms demonstrated by culture or histologic exami- Typical micro-organisms consistent with IE from two separate blood
nation of a vegetation, a vegetation that has embolized, or an cultures: viridans streptococci, Streptococcus bovis, HACEK group,
Staphylococcus aureus; or community-acquired enterococci, in the
intracardiac abscess specimen; or
absence of a primary focus; or micro-organisms consistent with IE
2. Pathologic lesions; vegetation or intracardiac abscess con- from persistently positive blood cultures, defined as follows: at least
firmed by histologic examination showing active endocarditis. two positive cultures of blood samples drawn >12 h apart; or all of 3
or a majority of ≥4 separate cultures of blood (with first and last
Clinical Criteria
sample drawn at least 1 h apart); or
1. Two major criteria; or Single positive blood culture for Coxiella burnetii or antiphase I IgG
2. One major criterion and three minor criteria; or antibody titer >1 : 800.
3. Five minor criteria. 2. Evidence of endocardial involvement:
Echocardiogram positive for IE defined as follows –
Possible IE Oscillating intracardiac mass on valve or supporting structures, in the
1. One major criterion and one minor criterion; or path of regurgitant jets, or on implanted material in the absence of
2. Three minor criteria. an alternative anatomic explanation; or
Abscess; or
Rejected IE New partial dehiscence of prosthetic valve or new valvular regurgitation
1. Firm alternate diagnosis explaining evidence of infective endo- (worsening or changing of pre-existing murmur not sufficient).
carditis; or MINOR CRITERIA
2. Resolution of infective endocarditis syndrome with antibiotic 1. Predisposition, predisposing heart condition or injection drug
therapy for 4 days; or use.
3. No pathologic evidence of infective endocarditis at surgery or 2. Fever, temperature >38 °C.
autopsy, with antibiotic therapy for ≤4 days; or 3. Vascular phenomena, major arterial emboli, septic pulmonary
4. Does not meet criteria for possible infective endocarditis, as infarcts, mycotic aneurysm, intracranial hemorrhage, conjunc-
above. tival hemorrhages and Janeway lesions.
4. Immunologic phenomena: glomerulonephritis, Osler’s nodes,
Roth’s spots and rheumatoid factor.
5. Microbiologic evidence: positive blood culture but does not
meet a major criterion as noted above or serologic evidence
of active infection with organism consistent with IE.
MICROBIOLOGIC DIAGNOSIS Blood Cultures

Precise clinical and microbiologic diagnosis is mandatory to guide Blood cultures remain the cornerstone of IE diagnosis. The volume of
therapy. To reduce the rate of IE without diagnosis and improve blood cultured is critical because bacteremia is often of low grade.
patient management, the timing and type of tests may be standardized Three sets (containing one aerobic and one anaerobic bottle) of blood
in a diagnostic kit with all vials and tubes required for blood culture, cultures consisting of ≥10 mL of blood should be taken before antibi-
serology of the most common agents of blood culture-negative endo- otic administration.27 The use of >3 blood culture sets may not improve
carditis (BCNE) and polymerase chain reaction (PCR) from blood.18 the diagnostic yield. Blood culture bottles that contain resins may limit
the inhibitory effect of antibiotics. Antibiotic susceptibility testing of Table 51-4 lists the principal organisms of this group, and diagnostic
cultured isolates is mandatory. assays.27 Thuny et al. have developed an algorithm for the workup of
BCNE (Figure 51-1).52
Serologic Testing
In cases of BCNE caused by fastidious organisms, the diagnosis may Valve Culture
be obtained by serology for C. burnetii, Bartonella spp., Brucella meli- If the patient undergoes surgery, it is of the utmost importance to
tensis, Legionella pneumophila, Mycoplasma pneumoniae and Aspergil- obtain valve samples for cultures and other microbiologic tests. The
lus spp.51 These agents require specific treatments and follow-ups. importance of cultures cannot be emphasized enough.
Polymerase Chain Reaction
BOX 51-4 SIGNS, SYMPTOMS AND SITUATIONS Polymerase chain reaction (PCR) has a role in the identification of
WHEN IE SHOULD BE SUSPECTED pathogens in BCNE, especially when performed on excised valves.
Amplification of the 16S ribosomal RNA is the most useful as it
1. New regurgitant heart murmur. enables, when combined with sequencing, to detect and identify any
2. Embolic events of unknown origin. bacterium.53 However, in a few cases of Enterococcus IE, bacterial DNA
3. Sepsis of unknown origin (especially if associated with IE
is able to persist in cardiac valves for months to years after completion
causative organism).
4. Fever: the most frequent sign of IE. IE should be suspected of a well-conducted treatment for IE.54
if fever is associated with: PCR performed on EDTA blood, has lower sensitivity than on valve
(a) Intracardiac prosthetic material (e.g. prosthetic valve, biopsies.19,55
pacemaker, implantable defibrillator, surgical baffle/
conduit Histopathology
(b) Previous history of IE Because histology can confirm the diagnosis by revealing valvular
(c) Previous valvular or congenital heart disease inflammation, vegetation, organisms or other changes consistent with
(d) Other predisposition for IE (e.g. IVDA) endocarditis, histology of the resected valve remains the gold standard
(e) Predisposition and recent intervention with associated for the diagnosis of IE.56 Special stains may help guide the etiologic
bacteremia diagnosis: Gram stain, periodic acid–Schiff (PAS) stain for Whipple’s
(f) Evidence of congestive heart failure
disease, Giemsa and Warthin–Starry stains for numerous bacteria
(g) New conduction disturbance
(h) Positive blood cultures with typical IE causative organism including Bartonella spp., Ziehl–Neelsen stain for Mycobacteria spp.
or positive serology for chronic Q fever and Gimenez stain for C. burnetii and Legionella spp. When histologic
(i) Vascular or immunologic phenomena: embolic event, lesions are consistent with IE but culture and PCR are negative, auto-
Roth spots, splinter hemorrhages, Janeway lesions, immunohistochemistry using the patient’s serum may be used.57
Osler’s nodes*
(j) Focal or nonspecific neurologic symptoms and signs Other Assays
(k) Evidence of pulmonary embolism/infiltration (right-sided In patients with porcine valvular bioprostheses who develop relapsing
IE) IE without any identified causative micro-organism, the presence of
(l) Peripheral abscesses (renal, splenic, cerebral vertebral) of anti-pork antibodies should be investigated.20
unknown cause
IMAGING DIAGNOSIS
*See Chapter 13.
Adapted from Habib G, Eur Heart J 2009; 30(19):2369-2413 with The role of imaging is to detect the endocardial lesions and the extra-
permission. cardiac complications of IE.58 Sometimes the portal of entry can
be diagnosed. At the level of the endocardium, the lesions include
TABLE
51-4 Intracellular Bacteria Causing Blood Culture-Negative Endocarditis
Pathogen Diagnostic Procedure Proposed Therapy
Brucella spp. Blood cultures Doxycycline (200 mg/d) + TMP–SMX (960 mg x 2/d) +

Serology rifampin (300–600 mg/d) po for ≥3 months
Culture, immunohistology and PCR from valvular biopsies
Coxiella burnetii (agent of Q Serology: IgG phase I >1 : 800 Doxycycline (200 mg/d, to be adapted to serum level) +
fever) Tissue culture, immunohistology and PCR from valvular hydroxychloroquine (200–600 mg/d, to be adapted to
biopsies or blood serum level) po
Or doxycycline (200 mg/d, to be adapted to serum level) +
ofloxacin (400 mg/d) po for ≥18 months88
Bartonella spp. Blood cultures Ceftriaxone (2 g/d) or ampicillin (or amoxicillin, 12 g/d) iv or
Serology: IgG ≥1 : 800 doxycycline (200 mg/d) po for 6 weeks + gentamicin
Culture, immunohistology and PCR from valvular biopsies (3 mg/kg/d) iv for 3 weeks89
Mycoplasma spp.* Serology Newer fluoroquinolones for >6 months

Culture, immunohistology and PCR from valvular biopsies
Legionella spp.* Blood cultures Erythromycin (3 g/d) iv for 2 weeks, then po for 4 weeks +
Serology rifampin (300–1200 mg/d) or ciprofloxacin (1.5 g/d) po for
Culture, immunohistology and PCR from valvular biopsies 6 weeks
Tropheryma whipplei† (agent Histology and PCR from valvular biopsies Doxycycline (200 mg/d, to be adapted to serum level) +
of Whipple’s disease) hydroxychloroquine (200–600 mg/d, to be adapted to
serum level) po for ≥18 months90
po, per os; iv, intravenous; TMP–SMX, trimethoprim–sulfamethoxazole.

*Newer fluoroquinolones are more potent than ciprofloxacin against intracellular pathogens such as Mycoplasma spp., Legionella spp. and Chlamydia spp.
†
Treatment of Whipple IE remains highly empirical. Successes were reported with long-term (>1 year) TMP–SMX therapy.
Adapted from Brouqui and Raoult, Clin Microbiol Rev 2001; 14(1):177–207 and J Exp Med 2005; 201(10):1627–1635.
Diagnostic strategy for the identification of the causative agents of blood culture-negative endocarditis
If valvular biopsies
Blood cultures are available
If negative
If negative
16S rRNA PCR for
Rheumatoid factor bacteria, 18S rRNA PCR
Q fever and for fungi
Bartonella serologies
Antinuclear antibodies
Histologic examination
If negative Other serologies
Dedicated PCR for (Brucella melitensis, If negative
Bartonella spp. and Legionella pneumoniae,
Tropheryma whipplei Mycoplasma Dedicated PCR for Streptococcus
from EDTA blood pneumoniae, western blot spp., Enterococcus spp.,
for Bartonellla spp.) Staphylococcus aureus, Bartonella
spp., Tropheryma whipplei
If negative
If negative
Septifast PCR
specifically targeting Anti-pork antibodies in
various micro-organisms patients with porcine
including streptococci bioprosthesis Auto-
and staphylococci immunohistochemistry
Figure 51-1 Diagnostic strategy for the identification of the causative agents of blood culture-negative endocarditis.
vegetations, periannular abscesses, pseudoaneurysms, fistula, perfora- American guidelines, repeat TTE ±TEE should be considered during
tions, chordae rupture, valvular aneurysms, or prosthetic dehiscence. follow-up of uncomplicated IE to detect new silent complications and
The extracardiac complications that can be evaluated by imaging monitor vegetation size. However, the timing and mode (TTE or TEE)
include ischemic cerebral events resulting from vegetation emboli, of repeat examination depend on the initial findings, type of micro-
other embolic events (spleen, kidneys, coronary arteries, mesenteric organism, and initial response to therapy.3,4 The systematic use of TEE
arteries, liver, etc.), metastatic infections (spondylodiscitis, peripheral in this monitoring is reasonable in the first two weeks of treatment
arthritis) and hemorrhagic events. because the majority of complications occur during this period
although it is not based on strong evidence.
Echocardiography The identification of vegetations, abscess, pseudoaneurysms,
This remains an accurate method to detect endocardial involvement fistula, valvular perforation, or new prosthetic valve dehiscence will
in IE and must be done rapidly and repeated weekly as soon as IE is confirm the diagnosis in most, though not all, cases.
suspected.59,60 Transthoracic echocardiography (TTE) should be used The sensitivity of TTE for the diagnosis of vegetations is about 75%,
initially since a normal scan in low-risk patients provides a rapid, non- but it may be reduced in case of low echogenicity, very small vegeta-
invasive confirmation that the diagnosis is unlikely. TTE is superior to tions and in IE affecting intracardiac devices or prostheses. TEE
transesophageal echocardiography (TEE) for hemodynamic assess- enhances the sensitivity to ~85–90% for the diagnosis of vegetations,
ment of valvular dysfunction and probably for detecting anterior while >90% specificity has been reported for both TTE and TEE. The
cardiac abscesses. Because of its global higher sensitivity and specific- sensitivity of TTE for the diagnosis of abscesses is ~50%, compared
ity, TEE is recommended in all cases of (1) a negative TTE associated with 70–90% for TEE. Specificity >90% has been reported, for both
with high clinical suspicion, (2) poor TTE quality, (3) prosthetic valves TTE and for TEE4,59 (Figure 51-2).
or intracardiac device and (4) a positive TTE.59 AHA/ACC 2014 guide- An erroneous diagnosis of IE may occur in several situations,
lines recommend performing TEE to diagnose possible IE in patients including differentiating between vegetations and thrombi, prolapsed
with Staph. aureus bacteremia without a known source.4 However, the cusp, cardiac tumors (myxoma or fibroelastoma), myxomatous
cost-effectiveness of TTE prior to TEE among these patients remains changes, Lambl’s excrescences or strands. Innovative techniques
unknown.61,62 may resolve these issues, e.g. multislice computed tomography (CT),
Although some guidelines state that TEE is not mandatory in iso- molecular imaging and magnetic resonance imaging (MRI). All these
lated right-sided native valve IE with good quality TTE examination techniques are complementary to echocardiography but do not
and unequivocal echocardiographic findings, performing TEE is rea- replace it.58
sonable, at least once, to rule out an association with a complicated
left-sided IE. Multi-Slice Computed Tomography
Follow-up echocardiography to monitor complications and Recent advances in the temporal and spatial resolution of multislice
response to treatment is mandatory. According to the European and CT scanners allow high-resolution cardiac imaging. Currently, the
a b
Figure 51-2 Patient with a destructive aortic infective endocarditis. Trans-esophageal echocardiography (a) and surgical view (b) showing a large pseudo-aneurysm
(black arrow) and aortic vegetations (white arrow).
Figure 51-3 Cardiac computed tomography scan of patient with an infective endocarditis on an aortic bioprosthetic valve. The imaging shows a pseudoaneurysm with
a prosthetic dehiscence (arrow) at the level of the anterior part of the annulus.
major application of multislice CT is in the evaluation of coronary patients with a definite or possible diagnosis to detect neurologic com-
artery disease but it has been used also for heart valve disease, such as plications, which are important for the final diagnosis and the risk
aortic stenosis and, more recently, in IE. stratification.
ECG-gated cardiac CT scan can identify valvular and perivalvular
damage of IE. The diagnostic performance of CT for the detection of Molecular Imaging
evident abnormalities for IE compared with TEE is good with a sensi- 18F-fluorodeoxyglucose (FDG)-PET/CT scans (performed under low
tivity of 97% and a specificity of 88%. Although small vegetations and carbohydrate regimens) are promising in the setting of prosthetic valve
leaflet perforations could be missed, CT provides more accurate ana- IE and pacemaker/CIED infection.70–74 For the diagnosis of prosthetic
tomical information regarding the perivalvular extent of abscesses/ valve IE, the sensitivity and a specificity of PET/CT are respectively
pseudoaneurysms than TEE, especially in prosthetic valve IE (Figure 73% and 80%. Interestingly, adding abnormal FDG uptake around the
51-3). Thus echocardiography and CT scan are complementary.63-65 prosthetic valve as a new major criterion significantly increases the
sensitivity of the modified Duke criteria at admission from 70% to
Magnetic Resonance Imaging 97%. This result is due to a significant reduction in the number of
The main utility of MRI is the identification of silent cerebral compli- possible diagnoses (Figure 51-4). This supports the use of PET/CT in
cations of IE. Systematic MRI detected subclinical cerebrovascular the difficult diagnostic situations of prosthetic valve endocarditis and
complications in ~50% of patients, and this may modify disease thus the addition of an abnormal FDG uptake as a novel major crite-
management.66–68 In a single-centre study, MRI identified cerebral rion in the modified Duke classification.71 However, several limitations
lesions in 82% of 130 patients with suspected or definite IE. Solely of PET/CT remain, especially false-positive results when this technique
on the basis of these MRI results, and excluding microhemorrhages, is performed too early after the implantation of the prosthetic valve.
the diagnostic classification of 32% of the cases of non-definite These may be related to the early postoperative inflammation around
endocarditis was upgraded to either definite or possible.66 The same the sewing ring.
investigators demonstrated that both cerebral and abdominal MRI PET/CT has also been investigated in the diagnosis of CIED
findings affected diagnosis, but only cerebral MRI affected clinical infections. Here the sensitivity ranges from 80% to 89% and its
management plans.69 Therefore, cerebral MRI is reasonable in stable specificity from 86% to 100%.73–75 Finally, PET/CT may reveal the
Day 0 Day 9
a C
HPL H H
Day 2
PRF RP AR
Figure 51-4 Results of trans-esophageal echocardiography (TEE) studies and 18F-FDG PET/CT in a case of suspected aortic bioprosthetic valve infective endocarditis
(IE). The first TEE (a) showed a minimal thickening of the aortic root wall in a patient with fever and positive blood cultures for Pseudomonas aeruginosa. The 18F-FDG
PET-CT performed 2 days after the first TEE showed an early hyperfixation around the aortic prosthesis (b, arrows). The second TEE (c), performed nine days after,
showed the development of a periprosthetic abscess (arrow).
source of infection, e.g., a bowel cancer. Gallium-67, indium-111 or aneurysms.79 The intracranial arteries are the predilection site espe-
99mtechnetium-HMPAO-labeled-leukocyte scintigraphy is another cially at the distal branching points of the middle cerebral artery. Their
option for imaging infection, both with or without incorporation with reported frequency of 2–4% is probably an underestimate since some
CT images. Unlike PET/CT this method is more specific for infection, of them are clinically silent.80 As the clinical presentation is highly
but is more time-consuming.76 A study showed that the sensitivity and variable (focal neurologic deficit, headache, confusion, seizures) and
the specificity of 99mtechnetium-radiolabeled leukocyte scintigraphy in the prognosis is poor, imaging should be performed to detect them in
patients with suspected prosthetic valve IE and an inconclusive echo any case of IE with neurologic symptoms.3 CT or magnetic resonance
were 57% and 78%, respectively. This modality might be better than (MR) angiography may be used to detect infectious aneurysms.81 Con-
PET/CT in the context of an early prosthetic valve IE suspicion.77 ventional angiography remains the gold standard and should be per-
Employing other labeled mediators involved in host–pathogen formed when non-invasive techniques are indeterminate with a
interaction, some investigators developed novel imaging methods in remaining suspicion.
animal models.78 Figure 51-5 proposes an algorithm for using imaging
modalities in IE.
Management
The Imaging of Infectious Aneurysms GENERAL PRINCIPLES
Infectious (mycotic) aneurysms result from septic arterial embolism Management by a multi-disciplinary team is strongly recommended
to the intraluminal space or vasa vasorum, or from subsequent spread by the international guidelines.3-5,53,82,83 One of the challenges is to
of infection through the intimal vessels. Because of the involvement rapidly introduce antibiotics and, at the same time, use strategies iden-
of the muscular layer, infectious aneurysms are actually pseudo- tifying patients who require close monitoring and urgent surgery.
Proposed algorithm of management of infective endocarditis including the recent imaging modalities
IE suspicion
TTE/TEE Modified Duke criteria
Possible IE or
Definite IE
rejected IE with high suspicion
Antibiotics Antibiotics
Hemodynamic Patient
Prosthetic valve Native valve
impairment stable
Prognostic Cerebral MRI

assessment PET/CT 2013
Whole body CT
Modified Duke
Cardiac CT
criteria*
Repeat echo
Surgery Cerebral MRI Definite IE

Whole body CT
Cardiac CT
Repeat echo Possible IE Possible IE
Cerebral MRI
Whole body CT
Low risk or CI Cardiac CT
High risk Repeat echo
for surgery
Follow-up Follow-up
99m
Figure 51-5 Proposed algorithm of management of infective endocarditis including the recent imaging modalities. * Use technetium-radiolabeled leukocyte scin-
tigraphy in patients with suspected early prosthetic valve infective endocarditis rather than 18F-FDG-PET/CT.
ANTIBIOTIC THERAPY
• Empirical antibiotic therapy is chosen based on the most likely
Basic Rules infecting organisms. Native valve endocarditis (NVE) may be
• Prompt treatment is needed as delayed and/or inappropriate treated with ampicillin–sulbactam or amoxicillin–clavulanate,
antibiotic therapy is complicated by sepsis, multiple organ dys- and gentamicin for synergistic coverage of streptococci. Patients
function syndrome, worsening of valvular damage and sudden with a history of intravenous drug use should be treated
death. with oxacillin or (flu)cloxacillin, and gentamicin, to cover for
• Antibiotics should not be administered to febrile patients with methicillin-sensitive staphylococci. Penicillin-allergic patients
heart murmurs without first obtaining blood cultures. should be empirically treated with vancomycin, and gentamicin.
• Antibiotic therapy should use intravenous bactericidal drugs. • For prosthetic valve endocarditis (PVE) possibly being caused by
• The initial antibiotic choice is empirical, determined by clinical MRSA or CoNS, empirical therapy should combine vancomycin
history and physical examination findings, and later adapted to and gentamicin, plus rifampin, as it can penetrate the biofilm of
microbiologic findings. most of the pathogens.
• High concentrations of antibiotics in the serum are desirable to resistant and vancomycin-resistant staphylococci and multidrug-
ensure penetration into vegetations. Doses should be adjusted resistant enterococci.
for renal function, and therapeutic drug monitoring used where • Culture-negative IE due to fastidious intracellular pathogens
appropriate. requires specific antibiotic regimens (Table 51-4).
• Drug treatment of PVE is longer (at least 6 weeks) than that of • Therapeutic schemes recommended for the most common
NVE (2–6 weeks), but qualitatively similar, except for staphylo- pathogens are presented in Tables 51-5 to 51-7.
coccal PVE that should include rifampin (rifampicin) whenever
the strain is susceptible to this agent. Penicillin-Susceptible Streptococci
• Synergistic drug combinations are important against enterococ- Adult NVE caused by penicillin-susceptible viridans streptococci, Strep.
cal IE, where combining β-lactams with aminoglycosides is man- bovis and other streptococci (minimum inhibitory concentration
datory to ensure treatment success. [MIC] of penicillin of ≤0.1 µg/mL) should be treated with one of the
• The three most problematic microbes with respect to antibiotic regimens detailed in Table 51-5. Most cases should be treated with
resistance are penicillin-resistant streptococci, methicillin- antibiotics for 4 weeks, except patients with uncomplicated NVE
TABLE
51-5 Suggested Treatment for Native Valve Endocarditis Due to Streptococci
Antibiotic Dosage and Route Duration (Weeks) Level of Evidence
Penicillin-Susceptible Viridans Streptococci and S. gallolyticus*
Standard Treatment
Penicillin G 12–18 million U/d iv in 6 doses 4 IB

Or amoxicillin (or ampicillin) 100–200 mg/kg/d iv in 4–6 doses 4 IB
Or ceftriaxone† 2 g/d iv or im in 1 dose 4 IB

Pediatric doses:‡
Penicillin G 200 000 U/kg iv in 4–6 doses
Amoxicillin 300 mg/kg iv in 4–6 doses
Ceftriaxone 100 mg/kg/d iv or im in 1 dose
Two-Week Treatment
Penicillin G 12–18 million U/d iv in 6 doses 2 IB
Or Amoxicillin (or ampicillin) 100–200 mg/kg/d iv in 4–6 doses 2 IB
Or Ceftriaxone† 2 g/d iv or im in 1 dose 2 IB
With:
Gentamicin§ 3 mg/kg/d iv or im in 1 dose 2 IB
or netilmicin 4–5 mg/kg/d iv or im in 1 dose
Pediatric doses:‡ 2 IB
Penicillin, amoxicillin (or ampicillin) and ceftriaxone as above.
Gentamicin 3 mg/kg/d iv or im in 1 or 3 doses
β-lactam allergic patients
Vancomycin¶ 30 mg/kg/d iv in 2 doses 4 IC

Pediatric doses:‡
40 mg/kg/d iv in 2–3 doses
Penicillin-Resistant (MIC 0.125–2 mg/L) Strains
Standard Treatment
Penicillin G 24 million U/d iv in 6 doses 4 IB
Or amoxicillin (or ampicillin) 100–200 mg/kg/d iv in 4–6 doses 4 IB
With:
β-lactam allergic patients
Vancomycin¶ 30 mg/kg/d iv in 2 doses 4 IC

Pediatric doses:‡
40 mg/kg/d iv in 2–3 doses
With:
Gentamicin§ 3 mg/kg/d iv or im in 1 dose 2
iv, intravenous; im, intramuscular. See Table 51-8 footnotes for evidence level and class information.
*Notes for other streptococcal species: (i) short-term 2 weeks’ therapy should not be used due to the lack of experience; IE due to nutritionally variant streptococci
(e.g. Abiotrophia) should include aminoglycosides for at least 4 weeks.
†
Preferred for outpatient therapy.
‡
Pediatric doses should not exceed adult doses.
§
Renal function and gentamicin concentrations in the serum should be monitored once a week. When given in a single daily dose, pre-dose (trough) concentrations
should be <1 mg/L and post-dose (peak; 1 hour after injection) concentrations should be c. 10–12 mg/L.
¶
Vancomycin concentrations in the serum should achieve 10–15 mg/L at pre-dose (trough) level and 30–45 mg/L at post-dose level (peak; 1 hour after infusion is
completed).
Adapted with modifications from European Society of Cardiology Eur Heart J 2009; 30(19):2369–2413 and American Heart Association 2005; 111(23):e394-e434
guidelines.
TABLE
51-6 Antibiotic Treatment of Endocarditis Due to Enterococcus Spp.
β-Lactam and Gentamicin-Susceptible Strains (for Resistant Isolates, See Footnotes)
Amoxicillin 200 mg/kg/d iv in 4–6 doses 4–6§ IB

Or ampicillin 200 mg/kg/d iv in 4–6 doses 4–6§ IB
With: 3 mg/kg/d iv or im in 2–3 doses 4–6
Gentamicin* Pediatric doses:‡
Amoxicillin (or ampicillin) 300 mg/kg/d iv in 4–6 doses
Gentamicin 3 mg/kg/d iv or im in 3 doses
Or
Vancomycin† 30 mg/kg/d iv in 2 doses 6 IC
With:
Gentamicin* 3 mg/kg/d iv or im in 2–3 doses 6
Pediatric doses:‡
Vancomycin 40 mg/kg/d iv in 2–3 doses.
Gentamicin as above
iv, intravenous; im, intramuscular; po, per os. See Table 51-8 footnotes for evidence level and class information.
In cases of high-level resistance to gentamicin (MIC >500 mg/L): if susceptible to streptomycin, replace gentamicin with streptomycin, 15 mg/kg/d iv in 2 doses (IB);
otherwise, use a more prolonged course of β-lactam therapy. The combination of ampicillin with ceftriaxone was suggested against gentamicin-resistant E.
faecalis86 (IIA, IIB).
In cases of β-lactam resistance: (i) if due to β-lactamase production, replace ampicillin with ampicillin–sulbactam or amoxicillin with amoxicillin–clavulanate (IC); (ii) if
due to PBP5 alteration, use vancomycin-based regimens.
In cases of multidrug resistance to aminoglycosides, β-lactams and vancomycin: some suggested alternatives are: (i) linezolid 1200 mg/d iv or po in 2 doses for ≥8
weeks (IIA, IIC) (control hematologic toxicity); (ii) quinupristin–dalfopristin 22.5 mg/kg/d in 3 doses ≥8 weeks (IIA, IIC); (iii) β-lactam combinations including imipenem
plus ampicillin or ceftriaxone plus ampicillin for ≥8 weeks (IIB, IIC).
*Monitor renal function and gentamicin concentrations in the serum.
†
Monitor vancomycin concentrations in the serum.
‡
§
6 weeks of therapy recommended for patients with symptoms of >3 months’ duration and in PVE.
Adapted with modifications from European Society of Cardiology Eur Heart J 2009; 30(19):2369–2413 and American Heart Association 2005; 111(23):e394-e434
guidelines.
caused by sensitive viridans streptococci and of less than 3 months’ β-lactam resistance and vancomycin resistance are mainly observed
duration for whom a short-course therapy with ceftriaxone and gen- in E. faecium. However, dual resistance is rare and β-lactams might be
tamicin for 2 weeks is recommended. used against vancomycin-resistant strains and vice versa. Varying
IE caused by nonresistant enterococci, resistant viridans streptococci results were reported with quinupristin–dalfopristin, linezolid, dapto-
(MICs of penicillin G of >0.5 µg/mL), or nutritionally variant viridans mycin and tigecycline. Such situations require the expertise of an infec-
streptococci and PVE caused by penicillin-G-susceptible viridans strep- tious disease specialist.
tococci or Strep. bovis should be treated as detailed in Tables 51-5
and 51-6. Methicillin- and Vancomycin-Susceptible
Enterococcal PVE generally responds as well as disease involving Staphylococci
native valves. Six weeks of treatment is recommended for patients with NVE caused by methicillin-susceptible Staph. aureus (MSSA) may be
symptoms of enterococcal IE of more than 3 months’ duration, with treated using one of the schemes detailed in Table 51-7:
relapsed infection, or with PVE.
• Daptomycin, 6 mg/kg/d, has been approved for the treatment of
Staph. aureus right-sided IE.
Penicillin-Resistant Streptococci
Except for Strep. gallolyticus and group A streptococci, which are still Methicillin-Resistant and Vancomycin-Resistant
susceptible to penicillin, all streptococci may demonstrate intermedi- Staphylococci
ate penicillin resistance (MIC of 0.1–1 mg/L) or full penicillin resis- Methicillin-resistant Staph. aureus (MRSA) produces low-affinity
tance (MIC >1 mg/L). Treatment of IE due to penicillin-susceptible penicillin-binding protein 2A (PBP2A), which confers cross-resistance
and penicillin-resistant streptococci is qualitatively similar, except that to most β-lactams. They are usually resistant to multiple antibiotics,
short-course (2 weeks) therapy should not be used in case of resistance, leaving only vancomycin to treat severe infections (Table 51-7). Treat-
and combinations of β-lactams with aminoglycosides are preferred in ment for healthcare-associated MRSA (HC-MRSA) and community-
these cases (Table 51-5).84 Vancomycin should be used in patients acquired MRSA (CA-MRSA) is similar.
allergic to penicillin. NVE caused by MRSA should be treated using one of the schemes
presented in Table 51-7:
Multidrug-Resistant Enterococci • Treatment with linezolid may be used as an alternative to van-
Most (>80%) enterococcal IE cases are due to E. faecalis, followed by comycin in infections caused by MRSA. However, white blood
E. faecium and rarely other enterococci. E. faecalis and E. faecium cell counts, red blood cell counts and platelet counts need to be
are frequently resistant to gentamicin.85 An aminoglycoside MIC monitored frequently while the patient is on linezolid. After the
>500 mg/L is synonymous with loss of bactericidal synergism with cell fourth week of therapy, the risk of hematologic and neuropathic
wall inhibitors. Streptomycin may remain active in such cases, and complications rapidly increases.
thus be used instead. An alternative against gentamicin-resistant E. • Daptomycin, 6 mg/kg/d, has been approved for the treatment of
faecalis combines ampicillin with ceftriaxone,86 which synergize by Staph. aureus right-sided IE. Observational studies have also
inhibiting complementary PBPs. Otherwise, more prolonged courses shown that daptomycin is efficient to treat left-sided IE and IE
of β-lactams or vancomycin must be envisioned (Table 51-6). involving a CIED.
TABLE Suggested Treatment for Native Valve and Prosthetic Valve Endocarditis Due to Staphylococci (See
51-7 Suggestions for Right-Sided IE in Footnotes)
NATIVE VALVES
Methicillin-Susceptible Staphylococci
Oxacillin 12 g/d iv in 4–6 doses 4–6 IB

Or (flu)cloxacillin 12 g/d iv in 4–6 doses
With: 3 mg/kg/d iv or im in 2–3 doses 3–5 days
Gentamicin* Pediatric doses:§
Oxacillin or (flu)cloxacillin 200 mg/kg/d iv in 4–6 doses
Penicillin-Allergic Patients or Methicillin-Resistant Staphylococci
Vancomycin† 30 mg/kg/d iv in 2 doses 4–6 IB

With: 3 mg/kg/d iv or im in 2–3 doses 3–5 days
Vancomycin 40 mg/kg/d iv in 2–3 doses 200 mg/kg/d iv in
4–6 doses
PROSTHETIC VALVES
Methicillin-Susceptible Staphylococci
Oxacillin 12 g/d iv in 4–6 doses ≥6 IB

Or (flu)cloxacillin With: 12 g/d iv in 4–6 doses ≥6 IB
Rifampin‡ 1200 mg/d po in 2 doses ≥6
and 3 mg/kg/d iv or im in 2–3 doses 2
Oxacillin and (flu)cloxacillin as above. Rifampin 20 mg/kg/d
iv or po in 3 doses
Penicillin-Allergic Patients or Methicillin-Resistant Staphylococci
Vancomycin† 30 mg/kg/d iv in 2 doses ≥6 IB

With: 1200 mg/d po in 2 doses ≥6
Rifampin‡ 3 mg/kg/d iv or im in 2–3 doses 2
and Pediatric doses:§
Gentamicin* As above
iv, intravenous; im, intramuscular; po, per os. See Table 51-8 footnotes for evidence level and class information.
*The clinical benefit of gentamicin addition has not been formally demonstrated. Its use is optional. Renal function and gentamicin concentrations in the serum
should be monitored once a week (twice in case of renal failure). When given in three divided doses, pre-dose (trough) concentrations should be <1 mg/L and
post-dose (peak; 1 hour after injection) concentrations should be between 3 and 4 mg/L.
†
Monitor vancomycin concentrations in the serum as indicated in Table 51-8.
‡
Rifampin (rifampicin) is believed to play a special role in prosthetic device infective endocarditis (PVE), because it helps eradicate bacteria attached to foreign
material. Rifampin should never be used alone, because it selects for resistance at a high frequency (c. 10−6).
§
Adapted with modifications from European Society of Cardiology Eur Heart J 2009; 30(19):2369-413 and American Heart Association 2005;111(23):e394-e434
guidelines.
PVE caused by MRSA should be treated using a combination of van- HACEK micro-organisms may be treated using one of the follow-
comycin, rifampin and gentamicin (Table 51-7). ing schemes:
Vancomycin-intermediate Staph. aureus (VISA) (MIC 4–16 mg/L) • Ceftriaxone, 2 g/d iv or im for 4 weeks.
and hetero-VISA (MIC <2 mg/L, but with subpopulations growing at • Ampicillin, 12 g/d by continuous pump or in six equally divided
higher concentrations) have emerged worldwide, and were associated doses daily, combined with gentamicin, 3 mg/kg/d iv or im in
with IE treatment failures.87 Moreover, few highly vancomycin- two to three doses for 4 weeks.
resistant Staph. aureus (MIC >32 mg/L) carrying a vancomycin-
resistance cassette acquired from enterococci were isolated from Non-HACEK Species
infected patients. IE caused by vancomycin-resistant Staph. aureus Most non-HACEK gram-negative bacteria involved in IE occur in
should be treated by an infectious disease specialist. patients with PVEs, and less frequently in intravenous drug users.
Escherichia coli and Pseudomonas aeruginosa are the most frequently
reported, followed by other Enterobacteriaceae.
HACEK-Related Species The treatment of IE caused by non-HACEK gram-negative bacteria
Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella and Kingella may be performed using the following schemes:
species are fastidious organisms that represent less than 5% of all • For P. aeruginosa, ceftazidime, cefepime or imipenem, combined
IE cases. Because they grow slowly, MIC tests may be difficult to inter- with high-dose aminoglycoside for 6 weeks.
pret. Some HACEK bacilli now produce β-lactamases, thus ampicillin • For enterobacteriaceae (e.g., E. coli, Proteus mirabilis), antibiotic
is no longer the first-line option. Conversely, they are susceptible to regimen should systematically be adapted to the antibiogram
ceftriaxone, other third- and fourth-generation cephalosporins, and results, due to the increasing incidence of multidrug-resistant
quinolones. Enterobacteriaceae wordwide.
TABLE
51-8 Indications and Timing of Surgery in Native (NVE) and Prosthetic Valve (PVE) Infective Endocarditis
Indications Timing* Class Level of Evidence
HEART FAILURE
Aortic or mitral IE or PVE with severe acute regurgitation or valve obstruction or fistula causing Emergency I B
refractory pulmonary edema or cardiogenic shock
Aortic or mitral IE with severe acute regurgitation or valve obstruction and persisting heart Urgent I B
failure or echocardiographic signs of poor hemodynamic tolerance (early mitral closure or
pulmonary hypertension)
Aortic or mitral IE or severe prosthetic dehiscence with severe regurgitation and no heart failure Elective IIa B
Right heart failure secondary to severe tricuspid regurgitation with poor response to diuretic Urgent/elective IIa C
therapy
UNCONTROLLED INFECTION
Locally uncontrolled infection (abscess, false aneurysm, fistula, enlarging vegetation) Urgent I B
Persisting fever and positive blood cultures >7–10 days not related to an extracardiac cause Urgent I B
Infection caused by fungi or multiresistant organisms Urgent/elective I B
PVE caused by staphylococci or gram-negative bacteria (most cases of early PVE) Urgent/elective IIa C
PREVENTION OF EMBOLISM
Aortic or mitral IE or PVE with large vegetations (>10 mm) following one or more embolic Urgent I B
episodes despite appropriate antibiotic therapy
Aortic or mitral IE or PVE with large vegetations (>10 mm) and other predictors of complicated Urgent I C
course (heart failure, persistent infection, abscess)
Aortic or mitral or PVE with isolated very large vegetations (>15 mm)† Urgent IIb C
Persistent tricuspid valve vegetations >20 mm after recurrent pulmonary emboli Urgent/elective IIa C
Class I: evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective. Class II: conflicting evidence and/or divergence of
opinion about the usefulness/efficacy of the given treatment or procedure. Class IIa: weight of evidence/opinion is in favor of usefulness/efficacy. Class IIb:
usefulness/efficacy is less well established by evidence/opinion. Class III: evidence of general agreement that the given treatment or procedure is not useful/
effective, and in some cases may be harmful.
Level of evidence A: data derived from multiple randomized clinical trials or meta-analyses. Level of evidence B: data derived from a single randomized clinical trial or
large non-randomized studies. Level of evidence C: consensus of opinion of the experts or small studies, retrospective studies, registries.
*Emergency surgery: surgery performed within 24 h; urgent surgery: within a few days; elective surgery: after at least 1 or 2 weeks of antibiotic treatment.
†
Surgery may be preferred if procedure preserving the native valve is feasible.
Adapted from Thuny F., et al. Lancet 2012;379(9819):965–975 with permission.
BCNE graphic observation before an elective surgical procedure is per-

The empirical treatment of BCNE is the same as that of culture- formed.3 Even though the majority of these recommendations are not
positive IE. Treatments of IE due to rare pathogens and outcome supported by strong evidence, a recent randomized trial demonstrated
criteria are summarized in Table 51-4. Treatment durations in the that surgery performed within 48 hours after diagnosis significantly
table are indicative, and based on selected case reports. reduced the risk of systemic embolism in patients with >10 mm veg-
etation associated with severe valvular dysfunction.99
PROGNOSTIC ASSESSMENT AND INDICATIONS However, the patients with IE usually have co-morbidities that
OF CARDIAC SURGERY increase the operative risk. Thus, optimal management must take into
At admission, immediate assessment of prognosis should be done to account the benefit/risk ratio of early valve surgery in each patient. The
identify high-risk patients who need closer monitoring and more operative mortality in active IE is 6–25%. Preoperative shock, HF,
aggressive treatment such as early surgery.12,53,91 Many predictors of renal insufficiency, impaired left ventricular function, prosthetic valve
death have been identified, including clinical, biologic and echocar- IE, perivalvular abscess, and high logistic Euroscore have been identi-
diographic variables.14,92–94 During the past decade, surgical indications fied as the strongest predictors of operative mortality.91,100 One
have greatly increased, and we have entered into the era of early approach is to classify the prognostic severity and the operative mor-
surgery. Currently, valvular surgery is performed during the active tality on the basis of risk scores, which will make management deci-
phase of the disease in around 40–60% of patients.95–98 International sions more standardised and easier. Recent studies have validated such
guidelines provide clear recommendations on the surgical indications risk models that incorporate clinical variables available at the
during the active phase of the disease (Table 51-8).3,4 Heart failure bedside.93,101 A calculator of the embolic risk has been recently devel-
(HF) or high risk of HF, uncontrolled infection and high embolic risk oped and validated.102
are the three main situations in which cardiac surgery is required. In intravenous drug users, indications for surgery and the periop-
European guidelines have also established an optimal timing for each erative approach are the same as for non-addicts but should be more
indication: emergency surgery (within 24 hours) or urgent surgery conservative overall since these patients have a much higher incidence
(within a few days) basis, irrespective of the duration of antibiotic of recurrent IE, usually due to continued drug abuse.
treatment. In other cases, surgery can be postponed to allow 1 or 2
weeks of antibiotic treatment under careful clinical and echocardio- References available online at expertconsult.com.
KEY REFERENCES
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62. Palraj B.R., Sohail M.R.: Appropriate use of echocar- nostic yield of FDG positron-emission tomography/ Arch Intern Med 2003; 163:226-230.
diography in managing Staphylococcus aureus bactere- computed tomography in patients with CEID infec- 90. Fenollar F., Celard M., Lagier J.C., et al.: Tropheryma
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63. Fagman E., Perrotta S., Bech-Hanssen O., et al.: ECG- 76. Erba P.A., Conti U., Lazzeri E., et al.: Added value of 1721-1730.
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Eur Radiol 2012; 22(11):2407-2414. infectious endocarditis. J Nucl Med 2012; 53(8):1235- 96(11):892-897.
64. Feuchtner G.M., Stolzmann P., Dichtl W., et al.: Mul- 1243. 92. San Roman J.A., Lopez J., Vilacosta I., et al.: Prognos-
tislice computed tomography in infective endocardi- 77. Hyafil F., Rouzet F., Lepage L., et al.: Role of radiola- tic stratification of patients with left-sided endocardi-
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53(5):436-444. echocardiography. Eur Heart J Cardiovasc Imaging 93. Hasbun R., Vikram H.R., Barakat L.A., et al.: Compli-
65. Gahide G., Bommart S., Demaria R., et al.: Preopera- 2013; 14(6):586-594. cated left-sided native valve endocarditis in adults: risk
tive evaluation in aortic endocarditis: findings on 78. Panizzi P., Nahrendorf M., Figueiredo J.L., et al.: In classification for mortality. JAMA 2003; 289(15):1933-
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578. by targeting pathogen-specific prothrombin activa- 94. Chu V.H., Cabell C.H., Benjamin D.K. Jr, et al.: Early
66. Duval X., Iung B., Klein I., et al.: Effect of early cere- tion. Nat Med 2011; 17(9):1142-1146. predictors of in-hospital death in infective endocardi-
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in infective endocarditis: a prospective study. Ann dilemma: management of infectious intracranial 95. Sohail M.R., Martin K.R., Wilson W.R., et al.:
Intern Med 2010; 152(8):497-504, W175. aneurysms complicating endocarditis. Lancet Infect Medical versus surgical management of Staphylococcus
67. Cooper H.A., Thompson E.C., Laureno R., et al.: Sub- Dis 2006; 6(11):742-748. aureus prosthetic valve endocarditis. Am J Med 2006;
clinical brain embolization in left-sided infective 80. Corr P., Wright M., Handler L.C.: Endocarditis- 119(2):147-154.
endocarditis: results from the evaluation by MRI of related cerebral aneurysms: radiologic changes with 96. Lalani T., Cabell C.H., Benjamin D.K., et al.: Analysis
the brains of patients with left-sided intracardiac solid treatment. AJNR Am J Neuroradiol 1995; 16(4):745- of the impact of early surgery on in-hospital mortality
masses (EMBOLISM) pilot study. Circulation 2009; 748. of native valve endocarditis: use of propensity score
120(7):585-591. 81. White P.M., Teasdale E.M., Wardlaw J.M., et al.: and instrumental variable methods to adjust for
68. Snygg-Martin U., Gustafsson L., Rosengren L., et al.: Intracranial aneurysms: CT angiography and MR treatment-selection bias. Circulation 2010; 121(8):
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2008; 47(1):23-30. we really achieve a 1-year mortality rate lower than included propensity score analysis. Am Heart J 2008;
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effects of early cerebral and abdominal magnetic reso- Intern Med 2010; 170:211-212. 98. Tleyjeh I.M., Ghomrawi H.M., Steckelberg J.M., et al.:
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fluorodeoxyglucose positron emission tomography- tive endocarditis due to penicillin-resistant viridans ditis. N Engl J Med 2012; 366(26):2466-2473.
computed tomography. Circulation 2012; 126(14): group streptococci. Clin Infect Dis 2007; 44(12):1585- 100. Alexiou C., Langley S.M., Stafford H., et al.: Surgery
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prosthetic valve endocarditis: increased valvular UK and Ireland 2001–2002: the BSAC Bacteraemia 101. Sy R.W., Chawantanpipat C., Richmond D.R., et al.:
18F-fluorodeoxyglucose uptake as a novel major cri- Resistance Surveillance Programme. J Antimicrob Che- Development and validation of a time-dependent risk
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sion tomography in patients with suspected pacing tion: treatment of Enterococcus faecalis endocarditis 102. Hubert S., Thuny F., Resseguier N., et al.: Prediction
system infections may play a critical role in difficult with ampicillin plus ceftriaxone. Ann Intern Med 2007; of symptomatic embolism in infective endocarditis:
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computed tomography for identification of cardiovas- persistent methicillin-resistant Staphylococcus aureus
52
Rheumatic Fever
ABBY DOUGLAS | KUMAR VISVANATHAN
Establishing reliable estimates of ARF incidence is difficult, particularly

KEY CONCEPTS in low- and middle-income countries (LMIC); estimates of the indus-
• Acute rheumatic fever (ARF) is a result of a nonsuppurative trialized world suggest an annual incidence of 1 per 100 000; with some
inflammatory response to recent pharyngeal infection with countries such as Greece as low as 0.1 per 100 000. At the other end of
group A streptococcus (GAS). the spectrum, Sudan has an estimated 826 incident cases per 100 000,
• ARF is largely a disease of low- and middle-income countries, with many other LMIC suffering from very high rates as well.1 Aborigi-
with issues such as overcrowding, poor sanitation and lack of nal Australians in northern Australia have one of the highest inci-
access to timely medical care key risk factors. dences in the world (508 per 100 000) despite being part of an
industrialized nation. Recent estimates put the global burden at a
• Its cardinal manifestations are carditis, inflammatory arthritis,
minimum of 18.1 million people affected, with clear regional differ-
Sydenham’s chorea, erythema marginatum and subcutaneous
nodules. ences, as seen in Figure 52-1. The incidence of ARF has fallen in most
areas of the world, however the Americas have shown a slight increase
• Diagnosis relies on clinical criteria and the demonstration of and the Western Pacific region has had a steady increase2 over recent
recent GAS infection (via throat culture, serology or rapid years. To what degree this may be due to increased rate of diagnosis is
antigen test). unclear. In industrialized nations, there can be sporadic outbreaks,
• Treatment of ARF is largely supportive. such as that which occurred in Salt Lake City in the USA in 1985. It
would seem that more virulent group A streptococci are to blame for
• ARF can result in permanent damage to heart valves, known these instances.3
as rheumatic heart disease (RHD), and the more episodes of
It is estimated that RHD kills between 233 000 and 468 000 people
streptococcal infection-induced ARF in a single individual, the
more likely there will be RHD. per year globally, and there are an estimated 282 000 new cases diag-
nosed annually,4 with 95% of these people living in LMIC.5 Encourag-
• Clearance of GAS colonization should be performed with a ingly, worldwide, overall mortality rates are falling (0.96/100 000 in
single injection of benzathine penicillin G (BPG). 1995–9 to 0.65/100 000 in 2005–7).1 The Indigenous Australian group
• Primary prophylaxis (treatment of acute GAS pharyngitis) is also have the highest mortality rate, at 23.8 per 100 000.
crucial to prevent ARF in endemic populations. First episodes of ARF occur most commonly in children between
the ages of 5 and 15 years. It is uncommon to present in the first 2
• Secondary prophylaxis (prevention of recurrent ARF episodes) years of life. (Whether this is because of a need for multiple ‘primary’
is achieved by 3-4 weekly benzathine penicillin G injections.
infections or simply reflective of a more immature immune response
• Vaccine research and development is ongoing. is not known.) Conversely, initial episodes become rare beyond the
age of 35. Incidence is equal in both males and females, although
females appear more likely to suffer Sydenham’s chorea and mitral
stenosis. The attack rate of ARF after untreated streptococcal exudative
Acute rheumatic fever (ARF) is an autoimmune condition arising tonsillitis in military recruitment camps has been carefully studied; it
from group A streptococcus infection, characterized by nonsuppura- is consistently around 3%.
tive, inflammatory lesions of heart valves, brain, joints and skin. Less
commonly, cardiac muscle, pericardium or lungs are involved. In its Pathogenesis
classically described form, ARF presents as a febrile and essentially ARF results from an abnormally vigorous and tissue-specific immu-
self-limited illness. However, inflammation of the heart valves has the nologic response in a susceptible host to an infection with GAS. Previ-
potential for chronic progressive damage, known as rheumatic heart ously this was thought to be caused only by certain ‘rheumatogenic’
disease (RHD). Globally RHD remains the most common cause of strains of GAS, however data show that a wide variety of serotypes have
acquired heart disease and cardiac morbidity in childhood. been identified in communities with high burdens of ARF and RHD.6–8
The pathologic hallmark of ARF is the Aschoff body, which consists
Epidemiology and History of a granulomatous nodule usually located in the connective tissue
Original descriptions of the disease date to Thomas Sydenham (1624– around small vessels.
89), but it was not until 1812 that William Charles Wells made the Whilst not proven beyond doubt, molecular mimicry appears to be
association of rheumatism and carditis. Associations with sore throat the likely underlying pathogenic mechanism given the presence of
became evident in the 1880s and by the turn of the 19th century his- epitopes in human tissue that are immunologically similar to GAS
topathologic descriptions were available through the work of Ludwig antigens. This was one of the first examples of this mechanism
Aschoff. described in clinical disease.9 Cross-reacting antibodies bind epitopes
Rheumatic fever is a disease of poverty and social injustice. It is in human myosin, laminin and vimentin in valvular connective tissue
indicative of community disadvantage. During the 1900s it became leading to pericarditis and valvulitis.10 Antibodies also cross-react with
progressively uncommon in industrialized countries. Conversely, it proteins in the synovium and articular cartilage causing arthritis. In
became increasingly recognized in resource-poor countries. Sydenham’s chorea, there are antibodies that cross-react with neurons
In the West, the incidence of ARF and RHD began to decline before of the caudate and subthalamic nuclei, in particular, targeting the
the availability of antibiotics, and dropped dramatically through the neuronal cell antigen called lysoganglioside GM1.11
early 1960s and 1970s. Improvements in living, sanitation and medical Cell-mediated immune responses are also elevated early in ARF,
care, as well as reduction in household crowding, are proposed to have suggesting early T-cell activation may be critical in pathogenesis. The
made the greatest impact in reducing the incidence of GAS infections. M protein of GAS contains both T- and B-cell epitopes. The M protein
471
Prevalence of rheumatic heart disease in children aged 5–14 years
Prevalence of rheumatic
heart disease (cases per 1000)
0.3
0.8
1.0
1.8
1.3
2.2
3.5
5.7
Figure 52-1 Prevalence of rheumatic heart disease in children aged 5–14 years. The circles within Australia and New Zealand represent indigenous populations.
(Courtesy of JR Carapetis.)
(as well as streptococcal pyogenic exotoxins) can also act as a superan-

tigen to further augment the immune response. Recent research sug- TABLE Guidelines for the Diagnosis of Initial Attack
52-1 of Rheumatic Fever*
gests a ‘two hit approach’ where initially antibodies bind to surface
antigens on the endothelium of heart valves with subsequent extrava-
Supporting Evidence
sation of T cells through the activated endothelium.12 Increased Minor of GAS Throat
numbers of CD4 and CD8 lymphocytes are found in blood and heart Major Manifestations Manifestations Infection
valve tissue in those with ARF. VCAM and ICAM are chemotactic
Carditis Clinical findings: Positive throat culture
receptors that are expressed on the endothelial cell surface during the Polyarthritis Arthralgia, fever Rapid streptococcal
inflammatory response13–15 and certain chemokines have been identi- Chorea Laboratory findings: Ag test
fied that are involved specifically in the ARF inflammatory milieu.16 Erythema marginatum Elevated acute Elevated or rising Ab
Certain polymorphisms of genes encoding chemotaxins have been Subcutaneous nodules phase reactants titer:
(CRP, ESR) Antistreptolysin,
found to predispose patients to ARF.17 Prolonged PR anti-DNaseB,
Recent interest has been focused on the innate immune system. interval antihyaluronidase
Toll-like receptors (TLRs) form an essential component of microbial
recognition and subsequent innate immune response. Polymorphisms *Jones criteria, updated 1992.23
GAS, group A streptococcus; CRP, C-reactive protein; ESR, erythrocyte
in TLR-2 have been shown to have a strong association with risk of sedimentation rate.
ARF.18 Polymorphisms of the soluble pathogen recognition receptor
mannose binding lectin have also been associated with ARF suscepti-
bility.19 There has been much interest in detecting an HLA association in latency between first and recurrent episodes. Acute illness may
with ARF, however studies have given conflicting results.20 present with a variety of signs and symptoms. The most important of
Previously it was assumed that pharyngeal infection with GAS was these are described as ‘major manifestations’ in the modified Jones
required in order to precipitate ARF. This was challenged by an Aus- criteria currently used for diagnosis (Table 52-1). They include cardi-
tralian group who found that ARF commonly occurred in the absence tis, polyarthritis, chorea, subcutaneous nodules and erythema margin-
of GAS, and was encountered in those with pyoderma caused by atum. Other additional features have been associated with ARF but are
groups C and G streptococci.21 Indeed, responsible groups C and G less specific, and are hence termed ‘minor manifestations’. These
streptococci have been shown to exchange key virulence determinants include fever, prolonged PR interval, raised white cell count, CRP and
with GAS and this may explain the link with ARF.22 ESR. Most manifestations of ARF are accompanied by fever (chorea
Patients who have suffered an initial attack of ARF continue to have may occur in isolation). Temperatures rarely exceed 39 °C (102.2 °F)
a significant predilection for recurrence following subsequent GAS and are very responsive to salicylate therapy.
infections. This risk appears greatest in the first 2 years after primary Arthritis is the most common major manifestation, occurring in
presentation and wanes considerably after 5 years. 75% of first attacks, and is usually one of the first symptoms. Carditis
occurs in just under half of all cases, whereas chorea (15%), subcutane-
Clinical Features ous nodules and erythema marginatum (10% each) are less common
The onset of ARF always follows a latent period after a streptococcal and often difficult to diagnose. The most common presentation is
sore throat or possibly skin infection. The average latent period is 19 fever and polyarthritis, with or without the murmur of mitral
days, although it can range from 1 to 5 weeks. There is no difference regurgitation.
Chapter 52 Rheumatic Fever 473
The arthritis seen in ARF tends to be migratory, asymmetric,

polyarticular and predominantly affects the large joints. Each joint
is severely affected for a few days to a week, and returns to normal
within 2–3 days. Examination may reveal erythematous, painful,
swollen joints, which may contain sterile purulent effusion. There
are atypical cases of only monoarticular involvement, or persistent
and additive disease24 and a subgroup may have polyarthralgia only
without evidence of arthritis. The hallmark of rheumatic fever arthro
pathy is its exquisite response to nonsteroidal anti-inflammatory
medication.
Carditis is more common in younger patients. ARF can affect the
pericardium (usually asymptomatic, present only with a subtle peri-
cardial rub or effusion), the myocardium (hard to detect without the
assistance of echocardiography performed by highly experienced oper-
ators, and rarely a cause of cardiac failure) or the endocardium (the
most common and important). Initially valves become inflamed,
friable and often regurgitant. With time, and especially with repeated
infections, the valves stiffen, become thickened and shortened, and
eventually stenotic. Occasionally the valvular chordae can also shorten.
The mitral valve is by far the most commonly affected. The aortic valve
is also commonly affected, whereas disease of the pulmonary or tri-
cuspid valve is rare (Figure 52-2).
Clinically, a pansystolic murmur consistent with mitral regurgita-
tion is the most common sign, sometimes associated with the low-
pitched mid-diastolic (Carey Coombs) murmur. This is heard over the
left ventricular impulse and is associated with acute valvulitis. Sinus a
tachycardia is a common feature and first-degree or greater degrees of
heart block are also possible (Figure 52-3).
Cardiac failure is possible in the acute phase of rheumatic fever.
Rarely, it can even be life-threatening. Using echocardiography it is
evident that the congestive heart failure is due to acute valvular dys-
function, rather than myocarditis. Accordingly, troponin levels are
usually not elevated.
Perhaps the most intriguing manifestation of ARF was named by
the English physician Thomas Sydenham. He described Sydenham’s
chorea in 1686, also known as St Vitus’ dance. It occurs in between
1% and 30% of cases of rheumatic fever, and may follow a latent
period of up to 6 months after the primary infection. It commonly
occurs in isolation from other symptoms, and is far more common in
females and those under the age of 20.25 Choreiform movements most
frequently involve the face, arms and hands. It is generalized in almost
80% of patients and is unilateral in the remainder. The patient’s
tongue may dart erratically when protruded. Classic patterns of the b
chorea also include the ‘milk-maid’s grip’ (the rhythmic squeezing
Figure 52-2 (a) Chest radiograph of a 15-year-old boy who had multiple recur-
when grasping the examiner’s fingers), the ‘spooning’ position (a rences of acute rheumatic fever, showing gross cardiac enlargement and failure.
flexion of the wrists and extension of the fingers when the hands are He had mitral regurgitation and stenosis, and aortic regurgitation and stenosis.
extended) and the ‘pronator sign’ (when the arms and palms are out- He died 2 days after this radiograph was taken, of intractable cardiac failure. (b)
turned when held above the head). All movements worsen upon pur- Post-mortem cardiac examination of the same boy, showing thickened, shortened
mitral valve cusps with calcific vegetation and thickened chordae tendinae. (Pho-
poseful action or with anxiety and disappear during sleep. The chorea tographs kindly provided by Professor Bart Currie, Darwin, NT, Australia.)
typically lasts for 1–2 months, and is almost always gone within 6.
Studies looking at the EEG patterns of patients with Sydenham’s
chorea show a parieto-occipital localization in almost 90% with later- Less common clinical symptoms seen in ARF include ‘rheumatic
alization in a little over 50%. Almost a third had abnormalities seen pneumonia’, referring to pulmonary infiltrates seen in some patients
even after clinical symptoms had resolved. Magnetic resonance (MR) with acute carditis. Mild elevations in liver transaminases, microscopic
scanning rarely if ever reveals pathology; positron emission tomogra- hematuria, pyuria and proteinuria are occasionally found. Blood
phy (PET) imaging can reveal abnormalities, especially in the basal C-reactive protein (CRP) and erythrocyte sedimentation rate are
ganglia, but is rarely used in clinical settings.26,27 usually impressively elevated in the acute phase of disease.
Erythema marginatum and subcutaneous nodules are both rare There is a separate clinical entity known as post-streptococcal reac-
manifestations of ARF. The rash is pink and serpiginous, beginning as tive arthritis. It has a shorter incubation period after bacterial infec-
a macule which then clears centrally (Figure 52-4). Multiple lesions tion, can follow non-group A streptococci and does not have the same
affect the trunk and limbs, but rarely the face, and can move in front dramatic responsiveness to salicylates. It carries no long-term risk of
of the examiner, appearing more vasomotor than truly cutaneous. carditis, and therefore does not need any long-term secondary prophy-
Although they can be present for weeks to months, this does not cor- laxis. That said, this is a difficult diagnosis to make in an area with
relate with ongoing rheumatic inflammation. Nodules in ARF usually highly endemic rheumatic fever. Hence some authorities recommend
appear some weeks after the onset of fever and arthralgia. They are treating this for a year, and discontinuing if no evidence of carditis is
most common over bony surfaces and tendons, for example at the found.
elbows, knees or Achilles tendon, even the spinous processes. Typically A group of disorders known as pediatric autoimmune neuropsy-
they are painless and often strongly associated with severe carditis. chiatric disorders associated with streptococci (PANDAS) warrant
attention; they include some of the tic disorders, some patients with
Tourette’s syndrome and obsessive–compulsive symptoms. They all
have a temporal association with GAS infection. Some studies have
associated antineuronal antibodies with the development of these con-
ditions, but this remains inconclusive. The majority seem to have
concurrent cardiac complaints. Currently there are insufficient data to
support universal secondary prophylaxis in this group of patients.28 In
populations where ARF remains highly prevalent, it may be very dif-
ficult to differentiate PANDAS from unrelated neurologic disorders.
Diagnosis
There remains no definitive diagnostic test for ARF. In 1944, Jones
developed the first set of diagnostic criteria, which were later revised
in 1992. The updated Jones criteria (Table 52-1) apply to the initial
diagnosis of ARF. Their careful application is critical to arrive at the
correct diagnosis, given the ongoing implications for secondary pro-
phylaxis and cardiac follow-up. At least two major manifestations, or
one major and two minor manifestations are required, in addition to
evidence of recent streptococcal infection. Exceptions to the criteria
exist, allowing a ‘presumptive diagnosis’: rheumatic chorea may be
diagnosed in the absence of other manifestations or preceding strep-
tococcal infection. Low-grade carditis may also occur as a delayed
presentation, after streptococcal titers have fallen.
The modified Jones criteria are not beyond reproach. When one
considers that merely fever and arthralgia, along with an elevated CRP
would be diagnostic, the necessity to include recent streptococcal
disease becomes evident. Because the presentation can vary between
individuals, careful exclusion of differential diagnoses is important
(see Table 52-2).
Evidence of recent GAS infection may be demonstrated by a posi-
tive throat swab and culture, rapid antigen test or positive antistrep-
tococcal serology. Within 2 months of onset, approximately 80% of
patients with ARF will have an antistreptolysin antibody titer greater
than 200 Todd units/mL. If one of the other serologic tests (anti-
DNase B, antihyaluronidase) is also performed, the sensitivity exceeds
90%. The utility of serology, in the absence of culture, is clearly limited
in areas with high prevalence of streptococcal impetigo, as children
will have continually positive results.
In some populations, such as Aboriginal Australians,29 Mexicans
and Turks,30 the B cell antigen D8/17 first developed by Zabriskie
Figure 52-3 Electrocardiographic changes in a young adult with acute rheu- et al.31 is expressed in a high percentage of those affected by ARF, a
matic fever, showing evolution over 18 days from complete heart block to second- moderate amount in close family members, and yet sparsely in the
degree (Wenckebach) block to first-degree block and then to normal sinus rhythm. general community. It appears to be inherited in a non-HLA-associ-
(Reproduced with permission from Bishop W, Currie B, Carapetis J, Kilburn C. A
subtle presentation of acute rheumatic fever in remote northern Australia. Aust N
ated and autosomally recessive manner.32,33 However, this association
Z J Med 1996;26:241–2.)
TABLE Differential Diagnoses of the Three Most

52-2 Common Major Manifestations of Acute
Rheumatic Fever
Polyarthritis Carditis Chorea
Connective tissue Innocent murmur Systemic lupus

disease erythematosus
Immune complex Mitral valve prolapse Drug reaction

disease
Septic arthritis Congenital heart Wilson’s disease

(including disease
gonococcal)
Viral arthropathy Infective endocarditis Tic disorder
Henoch–Schönlein Hypertrophic Choreoathetoid

purpura cardiomyopathy cerebral palsy
Reactive arthropathy Myocarditis (viral or Encephalitis

idiopathic)
Figure 52-4 Erythema marginatum on the trunk of an 8-year-old Caucasian boy. Sickle cell anemia Pericarditis (viral or Huntington’s chorea
The pen mark shows the location of the rash approximately 60 minutes previously. Infective endocarditis idiopathic) Intracranial malignancy
(Photograph kindly provided by Professor Mike South, Royal Children’s Hospital, Leukemia or lymphoma Chorea gravidarum
Adelaide, Australia.)
has not been replicated in other populations34,35 and cannot currently benefits of antibiotics in the treatment of GAS pharyngitis (prevention
be recommended as a marker of susceptibility to ARF. of ARF, suppurative sequelae and attenuating symptoms) do not out-
The increasing specificity of the Jones criteria is appropriate for weigh cost, adverse drug reactions and potential for induction of resis-
Western communities where the incidence is low and overdiagnosing tance in other organisms.45
ARF leads to unnecessary prescribing of long-term antibiotics. There are few data showing conclusive reduction in the incidence
However, in LMIC and other populations where the incidence remains of ARF in LMIC as a result of primary prophylaxis. A systematic review
high, a greater sensitivity is desirable, given the profound morbidity found that one case of ARF was prevented for every 53 sore throats
of undertreated cardiac disease. Indeed, in northern Australia, the treated;46 however, a large randomized controlled trial in New Zealand
diagnostic criteria for ARF have been expanded to include aseptic did not show any reduction in ARF.47 Additionally, not all cases of
monoarthritis, polyarthralgia and subclinical endocarditis as major ARF are preceded by an obvious sore throat, making prevention dif-
manifestations in high risk patients.36 ficult. Importantly, LMIC also require aggressive measures to improve
Echocardiographic recognition of clinically silent carditis is not housing, control skin disease, advance education of health staff
included in the modified Jones criteria. However, it is increasingly and the wider community and attempt to close social and health
recognized that these lesions may progress and warrant attention. disparities.48,49
Recent studies in LMIC on screening schoolchildren with echocar-
diography detected 2.2–3% prevalence of RHD. Only 2.2 per 1000 USE OF VACCINES IN PRIMARY PREVENTION
cases were detected in corresponding groups based on clinical Several vaccine candidates against GAS infection are in various stages
grounds.37 Many other groups have also performed echocardiographic of preclinical and clinical development, including M-protein-based
screening and confirm the large burden of subclinical disease.38,39 The non-M-protein vaccine candidates. The M protein contains both a
World Health Organization (WHO) therefore incorporated echocar- hypervariable N region and a conserved C terminal region. The hyper-
diographically diagnosed, clinically silent, rheumatic valve involve- variable N region has been shown to be highly immunogenic and can
ment into recent guidelines, stating they should be treated as RHD induce strain-specific immunity. The C terminal region is an attractive
until proven otherwise. The natural history of subclinical carditis in candidate as it is highly conserved among GAS serotypes allowing
patients with ARF is variable however. A systematic review of studies more global immunity.15 Some of the obstacles of GAS vaccine devel-
of subclinical endocarditis revealed that only half of patients diagnosed opment are related to the complexity of the global epidemiology
had persistence or deterioration of their valve disease in the following of GAS infection, the limited number of geographically specific anti-
2 years.40 In light of this, the WHO recently developed stricter guide- gens able to be incorporated into one vaccine and issues around induc-
lines for the echocardiographic diagnosis of subclinical carditis with tion of autoimmunity and vaccine safety.50 Unfortunately, widespread
the aim to identify those more likely to have significant irreversible rollout of a tested, cost-effective and efficacious human vaccine
valve damage.41 Furthermore, it is not known whether use of antibiotic remains some years away.
prophylaxis in asymptomatic subclinical carditis improves the prog-
nosis of the disease42 and more research is needed before any recom- SECONDARY PROPHYLAXIS
mendation can be made. In addition, the financial costs in providing After an initial attack of ARF, patients are at higher risk of recurrence
accurate echocardiography in LMIC remains a sizable stumbling after subsequent streptococcal upper respiratory infections. This risk
block. is highest in the first few years after the initial attack and fades there-
after. With each relapse, the likelihood of more significant RHD
Prevention increases. Secondary prophylaxis (see Table 52-4), which refers to
Primary prophylaxis (antibiotic therapy of GAS upper respiratory tract ongoing antibiotic prescription after an episode of ARF, reduces the
infection) has been the cornerstone of primary prevention since the rate of ARF recurrence,51 the severity of RHD,5 mortality52 and is asso-
widespread availability of antibiotics. As treatment initiated within 8 ciated with regression of RHD.53–55 Optimum preventive responses
days of the onset of symptoms, oral or intramuscular penicillin is have been achieved with 3-weekly benzathine penicillin G injections,
effective at preventing subsequent development of rheumatic fever (for although 4-weekly injections are often given to improve compliance
suggested dosing of antibiotics, see Table 52-3). Recent data from New and decrease cost.51,56 Daily oral penicillin is a somewhat less effective
Zealand suggest daily amoxicillin is noninferior to twice-daily penicil- alternative and compliance can be problematic.51 Penicillin-allergic
lin V for the treatment and eradication of streptococci.44 patients should be offered erythromycin. It is recommended, however,
In regions where ARF remains prevalent, primary prophylaxis is that true penicillin allergy is confirmed (preferably by an allergist) as
important. In settings where the disease is now rare, however, the penicillin is the optimum treatment.
TABLE
52-3 Recommended Doses of Antibiotics for Primary Prophylaxis of Rheumatic Fever*
Antibiotic Route In Children (<27 kg) In Those ≥27 kg Frequency Duration
PENICILLINS
Penicillin V (phenoxymethylpenicillin) po 250 mg 500 mg 2–3 times daily 10 days
Benzathine penicillin G im 450 mg (600 000 U) 900 mg (1.2 million U) – Single dose
Amoxycillin po 1 g 1 g Daily 10 days
FOR INDIVIDUALS ALLERGIC TO PENICILLIN
Narrow-spectrum cephalosporin (cephalexin)† po Variable 10 days
Clindamycin po 20 mg/kg per day in 3 divided doses 10 days
Azithromycin po 12 mg/kg once daily 5 days

Clarithromycin po 15 mg/kg per day in 2 divided doses 10 days
*Doses as recommended by the American Heart Association.43

†
To be avoided in those with immediate (type 1) hypersensitivity to a penicillin.
po, per os; im, intramuscular.
TABLE
52-4 International Recommendations for Secondary Prophylaxis of Acute Rheumatic Fever*
Intramuscular Benzathine Interval of Benzathine
Benzylpenicillin (Dose by Weight) Benzylpenicillin Injections Oral Alternative Treatments (Dose) Duration
<27 kg: 600 000 IU 28 days; 21 days if having Phenoxymethylpenicillin (250 mg twice a No carditis: for 5 years or until 21 years
≥27 kg: 1 200 000 IU recurrent attacks day); sulphonamide (<27 kg: 500 mg of age†
daily; ≥27 kg 1000 mg daily); Resolved carditis: for 10 years or until
macrolide (dose variable) 21 years of age†
RHD: for 10 years or until 40 years of
age†; consider lifelong if high risk
*Doses as recommended by the American Heart Association.43

†
Whichever is longer.
The duration of secondary prophylaxis is determined by risk of controlled by paracetamol or codeine until the diagnosis is made.
recurrent disease. Certainly the data supporting the first 5 years is Meta-analysis has shown no long-term benefits in those using anti-
strong. It is also judged on the degree of pre-existing heart disease, the inflammatory agents (steroidal or nonsteroidal) and hence this enables
patient’s age and the time since the last ARF episode. Recommenda- clinicians to choose to withhold them for diagnostic purposes with
tions vary between expert groups (see Table 52-4). Data from the 1990s reassurance.
suggest antibiotic cessation may be considered at 21 years of age, or at The more potent anti-inflammatory action of corticosteroids is
least 10 years after the last attack, if there is no evidence of residual often employed when salicylates fail or when there is severe carditis.36
carditis.57 For those with moderate carditis (based on at least moderate For example, 40–60 mg/day of oral prednisolone or even intravenous
clinical or echocardiographic valvular dysfunction) some groups methylprednisolone in fulminant cases can be considered. As men-
would consider cessation of prophylaxis only after age 35 years and tioned above, there is no concrete evidence that this improves long-
more than 10 years after the last clinical relapse. In those with severe term outcome or carditis severity.58 All anti-inflammatory agents
carditis or post-surgical intervention, prophylaxis is recommended at should be tapered as there is a risk of rebound if stopped abruptly.
least until 40 years of age, if not lifelong. The management of cardiac failure includes use of diuretics,
On a regional and national level, the establishment of formal angiotensin-converting enzyme inhibitors, fluid restriction and man-
control programs is highly desirable.48 Such a program requires agement of atrial fibrillation. It is now a rare situation to require valve
national commitment (including budgetary), a centralized registry of surgery for life-threatening cardiac failure in the acute setting. Valve
patients and ideally a multidisciplinary steering committee for appro- surgery is more often required for chronic disease. In recent years there
priate oversight. Priorities include education and advocacy, case has also been a trend to offer valve repair or valvuloplasty rather than
finding through surveillance, coordinating secondary prophylaxis and replacement, or to use homograft or xenograft valves rather than
follow-up. mechanical prostheses (to avoid the need for anticoagulation). This
trend further highlights the need for regular monitoring of chronic
Management valvular disease, as late surgical repair is technically difficult with an
The main initial aims of management in ARF are to confirm the diag- extensively damaged valve.
nosis, treat any cardiac failure and decrease inflammation. Ensuring Mild cases of chorea do not usually require treatment. If chorea
ongoing secondary prophylaxis and clinical follow-up are important. impairs normal daily activities, or causes significant distress, pharma-
While there is no evidence that acute treatment reduces the likelihood cologic intervention is reasonable. Carbamazepine and sodium valpro-
or severity of long-term valvular damage,58,59 there is considerable ate are the first-line agents recommended, however response may not
potential symptomatic benefit for the patient. Hospital admission is be seen for 1–2 weeks.62,63 Associated anxiety can respond to behav-
recommended to ensure relevant investigations are performed in a ioural therapy. Plasmapharesis and intravenous immunoglobulin have
timely manner, medical treatment is conducted, and education for been shown to have benefit in a small trial, but cannot yet be recom-
patient and family takes place. mended as mainstream treatment.64 Salicylates and steroids have no
Initial investigations should include attempts at proving recent role in chorea therapy.
streptococcal infection through throat cultures and at least two of the In established rheumatic heart disease, there is no specific treat-
serologic tests. Additionally, an ESR, CRP, white blood count, chest ment other than for the complications of this disease such as heart
radiograph and, if possible, an echocardiogram, should be ordered in failure, atrial fibrillation, infective endocarditis and stroke. In Chapter
every patient. Other investigations may be required to exclude alter- 51, guidelines for the use of antibiotic prophylaxis to prevent infective
nate diagnoses, including blood cultures for infective endocarditis, endocarditis are discussed in detail.
viral serology and autoimmune markers.
Previously bed rest was recommended. This is no longer the case, Prognosis and Follow-Up
provided heart failure is adequately controlled. Ongoing active strep- ARF resolves spontaneously, usually within 12 weeks, even if left
tococcal infection warrants treatment with antibiotics. Oral penicillin untreated. With treatment, most patients will be able to leave hospital
V or amoxicillin is reasonable, or erythromycin if allergic. Intravenous in less than 2 weeks. The likelihood of developing RHD relates to the
administration is not required unless the patient is unable to take oral severity of the acute carditis and the number of episodes of subsequent
medication. recurrent ARF. Some 30–50% of all people with ARF will eventually
Anti-inflammatory medications are used as they result in rapid develop RHD, increasing to 70% in patients with severe carditis on
symptomatic improvement for patients, with fevers and arthralgias initial presentation. Where available, all patients should be added to a
resolving generally within 1–3 days. Aspirin has been the traditional local registry to facilitate appropriate follow-up, which should include
drug of choice, however there is emerging evidence for naproxen regular medical and dental reviews and regular echocardiograms.
(10–20 mg/kg/day in two divided doses) as a safer alternative.60,61
Occasionally anti-inflammatories are withheld to allow characteristic References available online at expertconsult.com.
clinical features (e.g. migratory polyarthritis) to appear. Pain can be
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Dale J.B., Fischetti V.A., Carapetic J.R., et al.: Group A immune process and anti-S. pyogenes vaccine. Frontiers Tubridy-Clark M., Carapetis J.R.: Subclinical carditis in
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PRACTICE Bloodstream, Heart and Vessels
POINT
14 Management of Pericardial Effusion

FREDERIQUE GOURIET | PIERRE-YVES LEVY
Introduction diography is essential in situations of emergency life support. The

size of the effusion can be quantified, and hemodynamic consequences
Effusive pericarditis regardless of etiology can occur as a clinically can often be detected. Small effusions accumulating behind the left
isolated syndrome or as a result of a systemic disease. Possible com- ventricle can be visualised well by echography. Echocardiography is
plications of pericarditis include: cardiac tamponade, which is an also useful for the detection of clinically silent pericardial effusions
accumulation of fluid that can cause severe compression; recurrent which are revealed during the investigation of another disease. CT or
pericarditis occurring after an interval free of symptoms; and finally, magnetic resonance imaging is especially sensitive for the search for
constrictive pericarditis which prevents the diastolic filling of the mediastinal or lung parenchymal associated pathologies, allowing
heart. Chronic forms with a 3-month evolution may also take all these the diagnosis of pericarditis (Figure PP14-2) or origin of the underly-
forms. Recurrent pericarditis is probably the most common complica- ing tumor. Doppler imaging is useful to define diastolic function
tion of pericarditis, affecting approximately 20–30% of patients after and distinguish between a constrictive pericarditis and restrictive
a first episode of acute pericarditis. In higher-income countries an cardiomyopathy.
etiologic diagnosis of pericardial effusion is generally not made and
50–85% of effusions remain unexplained, classified as idiopathic
pericarditis. Etiology
The causes of pericarditis are numerous and can be divided into infec-
Clinical Features tious and noninfectious (see Chapter 50; Table 50-3). In most cases
Pericardial effusion may be asymptomatic or may cause cardiac tam- of pericarditis the cause cannot be determined, and they are classified
ponade. Clinical examination in this context will show distended as idiopathic.
jugular veins and a paradoxical drop in systolic blood pressure during
inspiration. Enlargement of the cardiac silhouette is visible on a stan- DIAGNOSIS OF PERICARDIAL EFFUSION
dard chest radiograph, if at least 250 mL of liquid has accumulated. In (Figure PP14-3)
large effusions, a water bottle appearance is classic (Figure PP14-1). Traditionally, non-invasive serological tests have yielded few diagno-
The electrocardiogram is abnormal in 90% of patients with acute ses, perhaps explaining the reluctance of some physicians to order
pericarditis and characteristic signs occur in approximately 50% of these tests and hence the large proportion of cases labelled as idio-
patients. In early stages, ST segment elevation without morphologic pathic. Systematic serological testing (Figure PP14-3) has reduced to
change in QRS occurs in all leads. A few days later the ST segment some extent the number of these undiagnosed cases.
returns to its baseline and a modification of the T wave appears. This
inversion of the T wave usually occurs after the return to normal Pericardiocentesis
appearances of the ST segment, which differentiates the pattern from Apart from cases with tamponade, which requires urgent pericardial
that of a myocardial infarction. In large pericardial effusions, reduced drainage, pericardial fluid analysis should be considered when a diag-
QRS voltage can occur. nosis of malignancy, tuberculosis or bacterial infection is suspected,
Cardiovascular imaging is a useful aid in the diagnosis of pericar- and can also be considered when anti-inflammatory treatment is
ditis and in the search for the cause of pericardial effusion. Echocar- poorly tolerated or unsuccessful. When the pathologic examination is
Figure PP14-2 Thoracic computed tomography scan: constrictive pericarditis

Figure PP14-1 Chest radiograph. Classic water bottle aspect in pericarditis. with pericardial thickness in a patient with tuberculous pericarditis.
478
Practice Point 14 Management of Pericardial Effusion 479
Suggested approach to investigate the etiologic diagnosis of pericardial effusion
Diagnosis of pericarditis on basic investigation:

Clinical symptoms, ECG, chest radiography
Echocardiography
Acute pericarditis Chronic pericarditis Tamponade
Noninvasive testing *
Pericardial effusion
>20 mm, chronic,
tamponade, bacterial
or neoplasia suspicion
No diagnosis and/or No diagnosis and/ Pericardiocentesis:

good response with or inefficacy of general chemistry
empirical treatment empiric treatment and/ (protein fluid, glucose,
or complications blood cell count, LDH)
CT scan looking for

Stop Positive cytology Negative cytology
cancer
Tumor markers - Standard culture

carcinoembryonic - Molecular biology:
antigen (CEA), PCR for specific agent:
alfafeto protein, viral, mycobacteria
carbohydrate antigens - Mycobacteria culture
CA 125, CA 72-4, - Molecular biology
CA 15-3, CA19-9 (16SRNA, 18SRNA)
*Proposed serologic and other noninvasive test for etiologic diagnosis of pericarditis
Serologic test PCR on nasal swab Noninfectious tests Cultures
Toxoplasma gondii Enterovirus Thyroid-stimulating hormone Blood culture
Human immunodeficiency virus Adenovirus Antinuclear antibodies
Cytomegalovirus Influenza virus
Parvovirus B19 Metapneumovirus
Epstein–Barr virus Rhinovirus
Hepatitis B, C virus Parainfluenza virus
Borrelia burgdorferi
Chlamydia spp.
Brucella melitensis
Legionella pneumophila
Coxiella burnetii
Bartonella quintana - B. henselae
Rickettsia conorii - R. typhi
Figure PP14-3 Suggested approach to investigate the etiologic diagnosis of pericardial effusion.
not conclusive, a systematic evaluation of the pericardial fluid, using steroidal anti-inflammatory drugs are often effective in eliminating
molecular biology techniques, may lead to the identification of a spe- symptoms. Aspirin in a dose of 2–3 g per day and nonsteroidal anti-
cific etiologic diagnosis. The use of these molecular tests is particularly inflammatory drugs are preferred treatments. Colchicine showed
useful when patients received antibiotic treatment in advance or when equivalent efficacy in numerous studies when added to a conventional
there is a suspicion of tuberculosis. anti-inflammatory therapy, and it has been shown to reduce signifi-
cantly the rate of recurrent pericarditis. The use of corticosteroids
Management should be reserved for patients who do not respond to symptomatic
Pericardial puncture and drainage (pericardiocentesis) is a life-saving treatments or when pericarditis is associated with autoimmune or
procedure in cardiac tamponade and decompensation. The percutane- autoinflammatory disease. Intravenous antibiotics and surgical drain-
ous puncture may be guided by fluoroscopy or by echocardiography. age remain indispensable as treatment for purulent pericarditis. Peri-
Sometimes a surgical procedure is needed. In most cases puncture can cardiectomy is reserved for recurrent pericarditis, for which medical
be rapidly and securely performed. treatment has failed. Only a third of patients respond to the treatment
The therapy of pericardial effusion should ideally target the etiol- with drainage. The role of corticosteroids in tuberculous pericarditis
ogy. In 40–50% of cases pericardial effusion is associated with a known has been controversial (see Practice Point 8) but a recent large random-
underlying disease; in such cases, treatment should be directed towards ized trial suggested that adjunctive steroids do not reduce the risk of
the underlying disease. Symptomatic treatment of pain and monitor- tamponade or death (see Further reading).
ing for the development of hemodynamic complications are the keys
to the treatment of idiopathic or presumed viral pericarditis. Non Further reading available online at expertconsult.com.
Practice Point 14 Management of Pericardial Effusion 480.e1
FURTHER READING
Imazio M., Adler Y.: Management of pericardial effusion. Mayosi B.M., Ntsekhe M., Bosch J., et al.: Prednisolone and disorders. Part 2: emerging applications. Tex Heart Inst J
Eur Heart J 2013; 34(16):1186-1197. Mycobacterium indicus pranii in tuberculous pericarditis. 2014; 41(2):135-143.
Levy P.Y., Corey R., Berger P., et al.: Etiologic diagnosis N Engl J Med 2014; 371(12):1121-1130.
of 204 pericardial effusions. Medicine (Baltimore) 2003; Etiologic Diagnosis
82(6):385-391. Tools for Diagnosis and Evaluation Imazio M., Hoit B.D.: Post-cardiac injury syndromes: an
Levy P.Y., Fournier P.E., Charrel R., et al.: Molecular analy- of Pericarditis emerging cause of pericardial diseases. Int J Cardiol 2013;
sis of pericardial fluid: a 7-year experience. Eur Heart J Cheitlin M.D., Armstrong W.F., Aurigemma G.P., et al.: 168(2):648-652.
2006; 27(16):1942-1946. ACC/AHA/ASE 2003 guideline update for the clinical Levy P.Y., Moatti J.P., Gauduchon V., et al.: Comparison of
Lorbar M., Spodick D.H.: ‘Idiopathic’ pericarditis – the cli- application of echocardiography: summary article: a intuitive versus systematic strategies for aetiological diag-
nician’s challenge [nothing is idiopathic]. Int J Clin Pract report of the American College of Cardiology/American nosis of pericardial effusion. Scand J Infect Dis 2005;
2007; 61(1):138-142. Heart Association Task Force on Practice Guidelines 37(3):216-220.
Maisch B., Seferovic P.M., Ristic A.D., et al.: Guidelines on (ACC/AHA/ASE Committee to Update the 1997 Guide- Lestuzzi C.: Neoplastic pericardial disease: old and current
the diagnosis and management of pericardial diseases lines for the Clinical Application of Echocardiography). strategies for diagnosis and management. World J Cardiol
executive summary; The Task Force on the diagnosis and Circulation 2003; 108(9):1146-1162. 2010; 2(9):270-279.
management of pericardial diseases of the European Goenka A.H., Wang H., Flamm S.D.: Cardiac magnetic Syed F.F., Mayosi B.M.: A modern approach to tuberculous
society of cardiology. Eur Heart J 2004; 25(7):587-610. resonance imaging for the investigation of cardiovascular pericarditis. Prog Cardiovasc Dis 2007; 50(3):218-236.
PRACTICE Bloodstream, Heart and Vessels
POINT
15 Mediastinitis and Sternal

Osteomyelitis
CHRISTOPH SCHIMMER | RAINER G. LEYH
Introduction wound infection. The majority of patients show wound secretion,

leukocytosis, elevated C-reactive protein (CRP) and/or procalcitonin
Median sternotomy is the method of choice in cardiac surgical inter- (PCT) and elevated temperature. The diagnosis of mediastinitis
ventions. The reported incidence of postoperative sternal wound infec- or sternal osteomyelitis is proven if pathogens are cultured from a
tions ranges between 0.5% and 8%. However, when there is mediastinitis sample taken under sterile conditions from the organ or body cavity
and sternal osteomyelitis, mortality is high (14–47%). The US Centers (Figure PP15-1).
for Disease Control and Prevention in 1996 defined mediastinitis as: The microbiology of mediastinitis reflects the likely origin of the
(1) bacteria can be isolated from cultures of mediastinal tissue or fluid; infection, either arising as an extension from orocervical pathology
(2) evidence of mediastinitis is seen during surgery; or (3) one of the (see Chapter 35) or as a complication of cardiothoracic surgery. In
following conditions – chest pain, sternal instability, or fever (>38 °C; both cases though, infections are predominantly polymicrobial.
100.4° F) are present and there is either purulent discharge from the Aerobic organisms include pharyngeal flora, staphylococci and entero-
mediastinum or bacteria can be isolated from a blood culture of drain- bacteriaceae, usually mixed with anaerobic streptococci and Bacteroi-
age originating from the mediastinal area. Internationally, the classifi- des spp. Much less commonly infections (especially those involving
cation of El Oakley and Wright for mediastinitis is mostly used. This bone) are caused by Mycobacteria or fungi, particularly Candida spp.
classification is based on the onset of the mediastinitis as well as the and occasionally Aspergillus.
existence of risk factors (Table PP15-1). Simple surface wound swabs are unlikely to be informative and a
Risk factors include endogenous, patient-related factors (age, deep tissue biopsy is required. Antimicrobial therapy should then be
obesity, diabetes mellitus, chronic pulmonary disease, thoracic wall directed towards the causative organisms. A broad spectrum antibiotic
irradiation, sternal osteoporosis, renal failure) and exogenous factors such as piperacillin-tazobactam is a reasonable first choice.
related to the surgical intervention and hospital stay, use of bilateral The surgical management of postoperative mediastinitis has
internal thoracic arteries, inadequate surgical techniques and immu- changed several times over recent years and has not been standardized
nosuppression. Prospective and retrospective studies have underscored yet. The current concept is purely based on retrospective studies. Pro-
the significance of risk factors, as they are targets for preventive mea- spective randomized controlled clinical trials have not yet been per-
sures (see Further reading). formed, and are urgently needed. In the early days of heart surgery,
Reducing sternal wound infections lowers mortality and morbidity. mediastinitis was mostly treated by surgical revisions, including
It also cuts costs by avoiding further surgical and pharmacological
therapies and shortens hospital stay. Economic aspects of mediastinitis
and sternal osteomyelitis were calculated in a matched case–control
study. In Germany in the years 2006–2008, the median costs of a CABG
case were reported to be EUR 36 261 per infected patient, and EUR
13 356 per patient without infection (p < 0.0001).
Diagnosis and Treatment

The diagnosis of postoperative mediastinitis or sternal osteomyelitis
is usually made clinically based on the typical signs of a local
TABLE Classification of Mediastinitis According to El

PP15-1 Oakley and Wright
Type Description
I Mediastinitis presenting within 2 weeks after operation in the

absence of risk factors
II Mediastinitis presenting at 2–6 weeks after operation in the

absence of risk factors
IIIA Mediastinitis type I in the presence of one or more risk factors
IIIB Mediastinitis type II in the presence of one or more risk factors
IVA Mediastinitis type I, II, or III after one failed therapeutic trial
IVB Mediastinitis type I, II, or III after more than one failed
therapeutic trial
V Mediastinitis presenting for the first time more than 6 weeks
after operation
Adapted from El Oakley RM, Wright JE. Postoperative mediastinitis:

classification and management. Ann Thorac Surg 1996;61:1030-6. Figure PP15-1 Mediastinitis and sternal osteomyelitis.
481
multiple open dressing changes and followed by sternal rewiring or PRIMARY OR DELAYED FLAP CLOSURE
secondary healing. This approach had a mortality rate of up to 45%. Multiple surgical techniques have been developed for the final closure
Thoracic instability and subsequent mechanical ventilation are disad- of the thorax. A common element of all surgical interventions is the
vantages of secondary healing. Prolonged immobilization predisposes treatment of any possible infection. Nevertheless, the optimal timing
to complications such as pneumonia, thrombosis and muscle weak- for reclosure remains difficult to predict. In the past, reclosure by
ness. A devastating complication resulting from an open sternum is means of secondary healing was the preferred treatment. Currently,
right ventricular laceration, which is associated with high mortality. closure by osteosynthetic material or plastic reconstruction procedures
These miserable outcomes prompted the development of further treat- is preferred. The advantages of rewiring are its practicality and the
ment procedures. The aim of treatment is to bring the infection under minimally invasive approach required to achieve restabilization of the
control; this requires radical surgical removal of infected and necrotic thorax. The major disadvantage of this method is the requirement of
tissue, including infected or necrotic bone, and of all foreign material sternal integrity before operation. This condition is not always met
(including wires and osteosynthesis material). This is followed by after prolonged periods of treatment. Plastic reconstruction often is
ample debridement of the wound and surrounding soft tissue and by the only means to reclose the thorax in a stable fashion. Mostly the
antiseptic irrigation. Currently, the further treatment strategies for pectoralis major muscle is used unilaterally or bilaterally with or
mediastinitis or sternal osteomyelitis differ mainly in two options: (1) without disinsertion of the tendon. Other options are flaps of omentum,
primary sternal reclosure, and closed mediastinal catheter suction/ the latissimus dorsi or rectus abdominis muscles. Due to the presence
irrigation; or (2) the use of negative-pressure wound therapy (NPWT). of immunological cells, omentum provides potent host defense against
In addition, there are various other modalities of managing postopera- the infection. In addition, the strong blood supply of the omentum
tive mediastinitis or sternal osteomyelitis, such as primary or delayed (gastroepiploic artery) delivers antibiotics and blood cells, and hence
flap closure. contributes to combat the infection. Moreover, the omentum absorbs
wound secretions and fits flexibly into the mediastinum. Based on
PRIMARY RECLOSURE WITH SUCTION/ these properties the omentum is called ‘the policeman of the abdomen’.
IRRIGATION SYSTEM However, additional soft tissue trauma, as well as further possible
The primary reclosure procedure with continuous antibiotic irrigation complications (hernias, necrosis, etc.) are disadvantages of this recon-
was developed by Shumaker and Mandelbaum in 1963. The advantages structive approach. Surgical revision after plastic reclosure is difficult
are the immediate stabilization of the thorax and the mechanical if not impossible to achieve, especially in emergency situations.
cleansing of the infected site by irrigation. Plastic reconstructions that
may complicate future surgery (especially in emergency situations) are Conclusion
not necessary. A major disadvantage, however, is that drainage cannot
be performed for an extended period of time due to the formation of The basic requirements for uncomplicated wound healing are aseptic
drainage gullies. Furthermore, the drainage system limits the patient’s surgery, perfect osteosynthesis and optimal antimicrobial prophylaxis.
mobility. The risk of re-infection is also increased by the introduction The causes of postoperative mediastinitis or sternal osteomyelitis are
of osteosynthetic material to the wound site. multifactorial. Therefore, a substantial risk reduction can never be
achieved by a single measure. Only with multiple individual measures
NEGATIVE-PRESSURE WOUND can a marked risk reduction be attained. At first, all treatment strate-
THERAPY (NPWT) gies follow the principles of septic surgery, i.e., opening the infected
wound and subsequent removal of all foreign material used for sternal
Negative-pressure wound therapy (NPWT) represents the newest
closure, including necrotic tissue and pus. This is followed by ample
treatment option for postoperative mediastinitis or sternal osteomy-
debridement of the wound and surrounding soft tissue, antiseptic
elitis. The advantage of negative-pressure wound therapy is that even
irrigation and thereafter negative-pressure wound therapy. Even
without primary closure, stabilization of the thorax can be achieved
without evidence from RCTs, this approach has proved to be safe and
by application of a vacuum. This results in the removal of infectious
successful for the management of postoperative mediastinitis or sternal
secretions, reduction of edema, and stimulation of circulation as well
osteomyelitis.
as granulation of the surrounding soft tissue. This allows the adapta-
tion of the edges of the wound, immediate postoperative extubation Further reading available online at expertconsult.com.
and mobilization of the patient.
Practice Point 15 Mediastinitis and Sternal Osteomyelitis 482.e1
FURTHER READING
El Oakley R.M., Wright J.E.: Postoperative mediastinitis: mortality, excess length of hospitalization, and extra Eingriffen. Z Herz- Thorax- Gefäßchir 2002; 16:163-
classification and management. Ann Thorac Surg 1996; costs. Infect Control Hosp Epidemiol 1999; 20:725-730. 175.
61:1030-1036. Losanoff J.E., Richman B.W., Jones J.W.: Disruption and Robicsek F., Fokin A., Cook J., et al.: Sternal instability after
Ennker I.C., Ennker J.C.: Management of sterno- infection of median sternotomy: a comprehensive review. midline sternotomy. J Thorac Cardiov Surg 2000; 48:
mediastinitis. HSR Proc Intensive Care Cardiovasc Anesth Eur J Cardiothorac Surg 2002; 21:831-839. 1-8.
2012; 4:233-241. Lu J.C., Grayson A.D., Jha P., et al.: Risk factors for sternal Schroeyers P., Wellens F., Degrieck I., et al.: Aggressive
Fowler V.G., O’Brien S.M., Muhlbaier L.H., et al.: Clinical wound infection and mid-term survival following coro- primary treatment for poststernotomy acute mediastini-
predictors of major infections after cardiac surgery. Cir- nary artery bypass surgery. Eur J Cardiothorac Surg 2003; tis: our experience with omental- and muscle flaps
culation 2005; 12:358-365. 23:943-949. surgery. Eur J Cardiothorac Surg 2001; 20:743-746.
Franco S., Herra A.M., Atehortua M., et al.: Use of steel Luckraz H., Murphy F., Bryant S., et al.: Vacuum- Sjögren J., Malmsjö M., Gustafsson R., et al.: Poststernot-
bands in sternotomy closure: implications in high-risk assisted closure as a treatment modality for infections omy mediastinitis: a review of conventional surgical
cardiac surgical population. Interact Cardiovasc Thorac after cardiac surgery. J Thorac Cardiovasc Surg 2003; treatments, vacuum-assisted closure therapy and presen-
Surg 2009; 8:200-2005. 125:301-305. tation of the Lund University Hospital mediastinitis algo-
Graf K., Ott E., Vonberg R.P., et al.: Economic aspects of Mangram A.J., Horan T.C., Pearson M.L., et al.: Guidelines rithm. Eur J Cardiothorac Surg 2006; 30:898-905.
deep sternal wound infections. Eur J Cardiothorac Surg for prevention of surgical site infection (CDC). Infect
2010; 37:893-896. Control Hosp Epidemiol 1999; 20:247-278.
Kirklin K.B., Briggs J.P., Trivette S.L., et al.: The impact Peivandi A., Quinkenstein E., Dahm M., et al.: Schwere ster-
of surgical-site infections in the 1990s: attributable nale Wundkomplikationen nach kardiochirurgischen
Obstetric and Gynecologic Infections
53
Vaginitis, Vulvitis, Cervicitis and
Cutaneous Vulval Lesions
JACK D. SOBEL
KEY CONCEPTS Bacterial Vaginosis

• The value of long-term maintenance fluconazole regimens for
recurrent vulvovaginal candidiasis is confirmed in multiple Epidemiology
studies.
Bacterial vaginosis is the most common cause of vaginitis in women
• There are no new antifungal agents or new widely available of child-bearing age. It has been diagnosed in 17–19% of women
diagnostic tests. seeking gynecologic care in family practice or student healthcare set-
• The role of sexual transmission in bacterial vaginosis is increas-
tings.1 The worldwide prevalence ranges from 11% to 48% of women
ingly confirmed. of reproductive age, with variation according to population studied.2
The prevalence increases considerably in symptomatic women attend-
• Vaginal molecular microbiome studies provide new insights ing STD clinics, reaching 24–37%. Bacterial vaginosis has been
into the pathophysiology of bacterial resistance and facilitate observed in 16–29% of pregnant women. Gardnerella vaginalis has
diagnosis. been found in 10–31% of virgin adolescent girls, but is found signifi-
• Vaginal trichomoniasis remains prevalent worldwide and facili- cantly more frequently among sexually active women, reaching a prev-
tates HIV transmission. alence of 50–60% in some at-risk populations.
Evaluation of epidemiologic factors has revealed few clues as to the
• Desquamative inflammatory vaginitis emerges as a common
cause of purulent vaginitis in perimenopausal women.
cause of bacterial vaginosis. Use of an intrauterine device and douch-
ing was found to be more common in women with bacterial vaginosis.
• Mycoplasma genitalium is now recognized as a cause of Bacterial vaginosis is significantly more common among black and
cervicitis. sexually active women, including lesbians.

Bacterial vaginosis is not due to a single organism or species and is the
Vaginitis result of massive overgrowth of mixed complex flora or microbiota,
including Bacteroides spp., G. vaginalis, Mobiluncus spp., genital myco-
Vaginal symptoms are extremely common, and vaginal discharge is plasma and previously noncultivable anaerobes.1 There is little inflam-
among the 25 most common reasons for consulting physicians in mation, and the disorder represents a disturbance of the vaginal
private office practice in the USA. Vaginitis is found in more than one- microbial ecosystem rather than a true infection of tissues. The over-
quarter of women attending sexually transmitted disease (STD) clinics. growth of mixed flora is associated with a loss of the normal Lactobacil-
Not all women with vaginal symptoms have vaginitis; approximately lus spp.-dominated vaginal flora. Experimental studies in human
40% of women with vaginal symptoms will have some type of vaginitis volunteers and studies in animals indicate that inoculation of the
(Table 53-1). vagina with individual species of bacteria associated with bacterial
vaginosis (e.g. G. vaginalis) rarely results in bacterial vaginosis. There
is considerable support for the role of sexual transmission, including
TABLE
Causes of Vaginitis in Adult Women the higher prevalence of bacterial vaginosis among sexually active
53-1
young women than among sexually inexperienced women, and bacte-
Common Infectious Vaginitis rial vaginosis-associated micro-organisms are more frequently iso
• Bacterial vaginosis (40–50%) lated from the urethras of male partners of females with bacterial
• Vulvovaginal candidiasis (20–25%) vaginosis.1
• Trichomonal vaginitis (15–20%) The cause of the overgrowth of anaerobes, Gardnerella, Mycoplasma
Uncommon Infectious Vaginitis and Mobiluncus spp., is unknown. Theories include introduction of
new pathogens, increased pH and loss of the restraining effects of the
• Foreign body with secondary infection
• Desquamative inflammatory vaginitis (clindamycin responsive) predominant Lactobacillus spp. flora. Normal women are predomi-
• Streptococcal vaginitis (group A) nantly colonized by hydrogen peroxide-producing strains of lactoba-
• Ulcerative vaginitis associated with Staphylococcus aureus and toxic cilli, whereas women with bacterial vaginosis have reduced population
shock syndrome numbers of lactobacilli, and the species present lack the ability to
• Idiopathic vulvovaginal ulceration associated with HIV
produce hydrogen peroxide.2 Previously, the hydrogen peroxide pro-
Noninfectious Vaginitis duced by lactobacilli was thought to inhibit pathogens associated with
• Chemical/irritant bacterial vaginosis, however the protective role of hydrogen peroxide
• Allergic, hypersensitivity and contact dermatitis (lichen simplex) is now controversial.
• Traumatic
• Atrophic vaginitis
Accompanying the bacterial overgrowth in bacterial vaginosis is the
• Postpuerperal atrophic vaginitis increased production of amines by anaerobes, facilitated by microbial
• Desquamative inflammatory vaginitis (corticosteroid responsive) decarboxylases. Volatile amines in the presence of increased vaginal pH
• Erosive lichen planus produce the typical fishy odor. Trimethylamine is the dominant abnor-
• Behçet’s disease, pemphigus syndromes
• Idiopathic
mal amine in bacterial vaginosis. It is likely that bacterial polyamines
together with the organic acids found in the vagina in bacterial
483
484 SECTION 2 Syndromes by Body System: Obstetric and Gynecologic Infections
vaginosis (acetic and succinic acid) are cytotoxic, resulting in exfolia- • adherent, white, nonfloccular homogeneous discharge
tion of vaginal epithelial cells and creating the vaginal discharge. G. • positive amine test, with release of fishy odor on addition of 10%
vaginalis attaches avidly to exfoliated epithelial cells, especially at the potassium hydroxide to vaginal secretions
alkaline pH found in bacterial vaginosis. The adherence of Gardnerella • vaginal pH >4.5
organisms results in the formation of the pathognomonic clue cells. • presence of clue cells on light microscopy.
Using broad-range DNA probes, new molecular methods have identi- The presence of clue cells is the single most reliable predictor of
fied at least 35 new bacterial phylotypes (species) previously nonculti- bacterial vaginosis. Clue cells are exfoliated vaginal squamous epithe-
vable in women with bacterial vaginosis, including Atopobium vaginae, lial cells covered with G. vaginalis, giving the cells a granular or stippled
Megasphaera spp. and Clostridial spp. BVAB I, II and III, offering new appearance with characteristic loss of clear cell borders. Occasionally,
insights into pathogenesis.3,4 clue cells covered exclusively by curved gram-negative rods belonging
to Mobiluncus spp. can be demonstrated. Gram strain of vaginal secre-
Prevention tions is extremely valuable in diagnosis, with a sensitivity of 93% and
Since the pathogenesis of bacterial vaginosis is obscure, preventive specificity of 70%, but uncommonly used except in the research
measures have not been forthcoming. Because of the suspected role of setting.
sexual transmission, barrier contraception may reduce occurrence, and Although cultures for G. vaginalis are positive in almost all cases
avoiding douching is recommended. of bacterial vaginosis, G. vaginalis may be detected in 50–60% of
women who do not meet the diagnostic criteria for bacterial vaginosis.
Clinical Features Accordingly, vaginal culture has no part in the diagnosis of bacterial
vaginosis. DNA probes for G. vaginalis are both sensitive (95%) and
As many as 50% of women with bacterial vaginosis may be asymptom- moderately specific (95–99%), but are not widely used because of
atic. An abnormal malodorous vaginal discharge, often described as costs and lack of insurance reimbursement. Point-of-care diagnostic
fishy, that is infrequently profuse and often appears after unprotected cards are available for rapid diagnosis, measuring pH, amines or
coitus and following menses, is usually described. Pruritus, dysuria and sialidase; in addition, commercial tests using polymerase chain reac-
dyspareunia are rare. Examination reveals a nonviscous, grayish-white, tion (PCR) molecular technology are now widely available but are
adherent discharge. expensive.
Bacterial vaginosis has been incorrectly considered to be largely of
nuisance value only. There is now considerable evidence of serious
obstetric and gynecologic complications of bacterial vaginosis, Management
including asymptomatic bacterial vaginosis diagnosed by Gram stain. The most widely used therapy remains oral metronidazole or tinida-
Obstetric complications include chorioamnionitis, pre-term labor, zole. Most studies using multiple divided dose metronidazole regimens
prematurity and postpartum fever.5 Gynecologic sequelae are post of 800–1200 mg/day for 1 week achieved clinical cure rates in excess
abortion fever, posthysterectomy fever, cuff infection and chronic of 90% immediately, and of approximately 80% at 4 weeks. Although
mast cell endometritis. An association is reported between untreated single-dose therapy with 2 g metronidazole achieves comparable
bacterial vaginosis and cervical inflammation and low-grade dyspla- immediate clinical response rates, higher recurrence rates have been
sia.6 Bacterial vaginosis is a risk factor for human immunodeficiency reported. The CDC-recommended regimen is metronidazole 500 mg
virus (HIV) acquisition and transmission.7 Bacterial vaginosis is also a twice-daily for 7 days.9 The beneficial effect of metronidazole results
risk factor for acquisition of herpes simplex virus 2, gonorrhea and predominantly from its anti-anaerobic activity and because G. vagina-
chlamydial infection.8 lis is susceptible to the hydroxymetabolites of metronidazole. Although
Mycoplasma hominis and Mobiluncus curtisii are resistant to metroni-
Diagnosis dazole, the organisms are usually not detected at follow-up visits of
Signs and symptoms are unreliable in the diagnosis of bacterial vagi- successfully treated patients. Metronidazole and tinidazole are consid-
nosis (Table 53-2). The clinical diagnosis can reliably be made in the ered therapeutic equivalents although tinidazole has fewer of the com-
presence of at least three of the following Amsel objective criteria: monly experienced side effects.
TABLE
53-2 Diagnostic Features of Infectious Vaginitis
Normal Candida Vaginitis Bacterial Vaginosis Trichomonas Vaginitis
Symptoms None or physiologic Vulvar pruritus, soreness, Malodorous moderate Profuse purulent discharge,
leukorrhea increased discharge, discharge offensive odor, pruritus, and
dysuria, dyspareunia dyspareunia
Discharge
Amount Variable, scant to moderate Scant to moderate Moderate Profuse
Color Clear or white White White/gray Yellow
Consistency Floccular nonhomogeneous Clumped but variable Homogeneous, uniformly Homogeneous
coating walls
‘Bubbles’ Absent Absent Present Present
Appearance of vulva Normal Introital and vulvar erythema, No inflammation Erythema and swelling of vulvar
and vagina edema and occasional and vaginal epithelium
pustules, vaginal erythema (strawberry cervix)
pH of vaginal fluid <4.5 <4.5 >4.7 5.0–6.0
Amine test (10% Negative Negative Positive Occasionally present
potassium hydroxide)
Saline microscopy Normal epithelial cell, Normal flora, blastospores Clue cells, coccobacillary PMNS +++, motile trichomonads
lactobacilli predominate (yeast) 40–50% flora predominate, (80–90%), no clue cells,
pseudohyphae absence of leukocytes, abnormal flora
motile curved rods
10% Potassium Negative Positive (60–90%) Negative (except in Negative
Hydroxide Microscopy mixed infections)
Chapter 53 Vaginitis, Vulvitis, Cervicitis and Cutaneous Vulval Lesions 485
Topical therapy with 2% clindamycin cream once daily for 7 days, Delayed hypersensitivity in natural infection can also be demon-
clindamycin ovules for 3 days or metronidazole gel 0.75% adminis- strated. The predominant host defense response is provided by the
tered daily for 5 days have been shown to be as effective as oral met- numerous polymorphonuclear leukocytes (PMNs), which respond
ronidazole, without any of the side effects of the latter.9 Recently, to chemotactic substances released by trichomonads and are capable
metronidazole gel at higher concentration of 1.5% has become avail- of killing T. vaginalis without ingesting trichomonads. T. vaginalis
able but is of questionable advantage. destroys epithelial cells by direct cell contact and cytotoxicity. The
In the past, asymptomatic bacterial vaginosis was not treated, espe- urethra, paraurethral, Bartholin’s and Skene’s glands are infected
cially because some patients improve spontaneously over several in the majority of patients, and organisms are occasionally isolated
months. However, the growing evidence linking asymptomatic bacte- from urine.
rial vaginosis with numerous obstetric and gynecologic upper tract
complications has caused reassessment of this policy, especially with Prevention
additional convenient topical therapies.5,10 Asymptomatic bacterial Sexual transmission of trichomonads is efficiently prevented by use of
vaginosis should be treated before pregnancy, in women with cervical barrier contraception. Spermicidal agents such as nonoxynol-9 also
abnormalities and before elective gynecologic surgery. Routine screen- reduce transmission. Re-infection of women is common, hence the
ing for and treatment of asymptomatic bacterial vaginosis in preg- mandatory requirement of treatment, preferably simultaneously, of all
nancy remains controversial, pending the outcome of studies proving sexual partners with metronidazole. Women can acquire the disease
that therapy of bacterial vaginosis reduces pre-term delivery and from other women, but men do not usually transmit infection to
prematurity.11 other men.
Despite indirect evidence of sexual transmission, no study has
documented reduced recurrence rates of bacterial vaginosis in women
whose partners have been treated with a variety of regimens, including
Clinical Features
metronidazole. Accordingly, most clinicians do not routinely treat Infection with Trichomonas spp. in women ranges from an asymptom-
male partners. atic carrier state to severe acute inflammatory disease.14 Vaginal dis-
After therapy with oral metronidazole, approximately 30% of charge is reported by 50–75% of women diagnosed with trichomoniasis;
patients initially responding experience recurrence of symptoms however, the discharge is not always described as malodorous. Pruritus
within 3 months.1 Reasons for recurrence are unclear, including the occurs in 25–50% of patients and is often severe. Other symptoms
possibility of re-infection, but recurrence more likely reflects vaginal include dyspareunia, dysuria and, rarely, frequency of micturition.
relapse, with failure to eradicate the offending organisms and Lower abdominal pain occurs in fewer than 10% of patients and
re-establish the normal protective Lactobacillus spp. dominant vaginal should alert the physician to the possibility of concomitant salpingitis
flora. Management of bacterial vaginosis relapse includes oral or caused by other organisms. Symptoms of acute trichomoniasis often
vaginal metronidazole, or topical clindamycin, usually prescribed for appear during or immediately after menstruation. Although contro-
14 days. Approaches including exogenous Lactobacillus spp. recoloni- versial, the incubation period has been estimated to range from 3 to
zation using selected bacteria-containing suppositories have been 28 days.
encouraging. Maintenance antimicrobial agents administered per Physical findings represent a spectrum depending on the severity
vagina twice weekly for 4–6 months have been reasonably effective in of disease. Vulvar findings may be absent, but are typically character-
controlling symptoms but cure is elusive.12 ized in severe cases by diffuse vulvar erythema (10–33%), edema and
a copious, profuse and malodorous vaginal discharge,14 which is often
described as being yellow–green and frothy, but is frequently grayish-
Trichomoniasis white.14 Frothiness is seen in a minority of patients and is more com-
monly seen in bacterial vaginosis.
The vaginal walls are erythematous and in severe cases may be
Epidemiology granular in appearance. Punctate hemorrhages (colpitis macularis) of
Studies estimate that 3–5 million American women contract tricho- the cervix may result in a strawberry-like appearance that, although
moniasis annually, with a worldwide distribution of approximately 180 apparent to the naked eye in only 1–2% of patients, is present in 45%
million annual cases.1,13 The prevalence of trichomoniasis correlates of cases on colposcopy.14
with the overall level of sexual activity of the specific group of women The clinical course of trichomoniasis in pregnancy is identical to
under study, being diagnosed in about 5% of women in family plan- that seen in the nonpregnant state, and when untreated it is associated
ning clinics, in 13–25% of women attending gynecology clinics, in with premature rupture of membranes and prematurity. Trichomonia-
50–75% of prostitutes and in 7–35% of women in STD clinics. In many sis is reported to facilitate HIV transmission. Trichomoniasis is a risk
higher-income countries recent surveys indicate a decline in the inci- factor for development of posthysterectomy cellulitis, tubal infertility,
dence of trichomoniasis, although increasing in women aged >40 years. cervical neoplasia and pelvic inflammatory disease.15
Prevalence of infection is significantly higher in African-American
women.13 Diagnosis
None of the clinical features of vaginitis caused by Trichomonas spp.
Pathogenesis and Pathology are sufficiently specific to allow a diagnosis of trichomonal infection
Sexual transmission is the dominant method of introduction of based on signs and symptoms alone (see Table 53-2). Definitive diag-
Trichomonas vaginalis into the vagina.1 T. vaginalis was identified in nosis requires the demonstration of the organism. Vaginal pH is mark-
the urethra of 70% of men who had had sexual contact with infected edly elevated, almost always above 5.0, and not infrequently 6.0. On
women within the previous 48 hours. There is also a high prevalence saline microscopy, an increase in the number of PMNs is almost invari-
of gonorrhea and bacterial vaginosis in women with trichomoniasis, ably present. The ovoid parasites are slightly larger than PMNs and are
and all are significantly associated with use of nonbarrier methods of best recognized by their motility. The wet mount is positive in only
contraception. 40–80% of cases (low sensitivity). Gram stain is of little value because
Recurrent trichomoniasis is common and is indicative of a lack of of its inability to differentiate PMNs from nonmotile trichomonads,
significant protective immunity. Nevertheless, an immune response to and use of Giemsa, acridine orange and other stains has no advantage
Trichomonas spp. does develop, as indicated by low titers of serum over saline preparations. Although trichomonads are often seen on
antibody, but this is insufficient for diagnostic serology. Antitrichomo- Papanicolaou (Pap) smears, this method has a sensitivity of only
nal IgA has been detected in vaginal secretions, but a protective role is 60–70% when compared with saline preparation microscopy, and
not defined. false-positive results are not infrequently reported.
Culture including ‘In-Pouch’, although recognized as more sensitive found a higher rate of pre-term birth (RR 1.8) compared to control
than microscopy for detecting the presence of trichomonads (95% women.18
sensitivity), is now being replaced by non-culture molecular methods
including antigen detection, DNA probes and most efficiently by
nucleic acid amplification testing.16 Vulvovaginal Candidiasis
Management Epidemiology
Vulvovaginal candidiasis (VVC) accounts for approximately one-third
Therapy is indicated in all nonpregnant women diagnosed with Tricho- of vaginitis cases. In the USA, Candida spp. are now the second com-
monas vaginitis, even if asymptomatic, and consists of administering monest cause of vaginal infections.19
the 5-nitroimidazole group of drugs – metronidazole, tinidazole and It is estimated that 75% of women experience at least one episode
ornidazole – which are all of similar efficacy.9 Oral therapy as opposed of VVC during their child-bearing years, and approximately 40–50%
to topical vaginal therapy is preferred because of infection of the experience a second attack. A small subpopulation of women of unde-
urethra and periurethral glands, which provide sources for endoge- termined magnitude, probably 5–8% of adult females, suffers from
nous recurrence. Treatment of all sexual partners is mandatory. repeated, recurrent, often intractable episodes of Candida vaginitis.19
Treatment consists of oral metronidazole, 500 mg every 12 hours Point-prevalence studies indicate that Candida spp. may be isolated
for 7 days, which has a cure rate of 95%. Comparable results have been from the genital tract of approximately 20% of asymptomatic, healthy
obtained with a single oral dose of 2 g metronidazole, achieving cure women of child-bearing age. The natural history of asymptomatic
rates of 82–88%. The latter cure rate increases to greater than 90% colonization is unknown, although animal and human studies suggest
when sexual partners are treated simultaneously. The advantages of that vaginal carriage continues for several months and perhaps years.
single-dose therapy include better patient compliance, lower total dose, Several factors are associated with increased rates of asymptomatic
shorter period of alcohol avoidance and possibly decreased incidence vaginal colonization with Candida spp., including pregnancy (30–
of subsequent vaginitis caused by Candida spp. A disadvantage of 40%), use of oral contraceptives, uncontrolled diabetes mellitus and
single-dose therapy is the need to insist on simultaneous treatment of frequency of visits to STD clinics. The rarity of isolation of Candida
sexual partners. spp. in premenarchal girls, the lower prevalence of Candida vaginitis
The 5-nitroimidazoles are not in themselves trichomonacidal, but after menopause and association with hormone replacement therapy
low-redox proteins reduce the nitro group, resulting in the formation emphasize the hormonal dependence of VVC.
of highly cytotoxic products within the organisms. Aerobic conditions
interfere with this reduction process and decrease the antianaerobic
activity of the 5-nitroimidazoles. Most strains of T. vaginalis are highly
susceptible to metronidazole, with minimum inhibitory concentra- THE ORGANISM
tions (MICs) of 1 mg/L. Similar efficacy results are reported with tini- Between 85% and 90% of yeasts isolated from the vagina are Candida
dazole but the latter has a superior tolerance profile. albicans strains. The remainder are other species, the commonest of
Patients not responding to an initial course often respond to an which are C. glabrata and C. tropicalis. Non-albicans Candida spp.,
additional standard course of 7-day therapy. Some patients are refrac- although less virulent, are capable of inducing vaginitis and are often
tory to repeated courses of therapy, even when compliance is assured more resistant to conventional therapy. Some, but not all, recent
and all sexual partners are known to have been treated. If re-infection surveys indicate an increase in VVC caused by non-albicans Candida
is excluded, these rare patients may have strains of T. vaginalis that are spp., particularly C. glabrata.20
resistant to metronidazole, which can be confirmed in vitro. Increased Candida organisms gain access to the vaginal lumen and secretions
doses of metronidazole and longer duration of therapy are necessary predominantly from the adjacent perianal area. This finding is borne
to cure these refractory patients. The patients should be given maximal out by epidemiologic typing studies. Candida vaginitis is seen pre-
tolerated dosages of oral metronidazole of 2–4 g/day for 10–14 days. dominantly in women of child-bearing age, and only in the minority
Rarely, intravenous metronidazole, in dosages as high as 2–4 g/day, of cases can a precipitating factor be identified to explain the transfor-
may be necessary, with careful monitoring for drug toxicity. Consider- mation from asymptomatic carriage to symptomatic vaginitis in indi-
able success has been observed in treating resistant infections with oral vidual patients.
tinidazole; although the optimal dose to be used is unknown.17 Most
investigators use high-dose tinidazole 1–4 g/day for 14 days.17 Rare HOST FACTORS
patients not responding to nitroimidazoles can be treated with topical A number of host factors are associated with increased asymptomatic
paramomycin. vaginal colonization by Candida spp. and with Candida vaginitis.
Side effects of metronidazole include an unpleasant or metallic During pregnancy, the vagina is more susceptible to vaginal infection,
taste. Other common side effects include nausea (10%), transient neu- resulting in higher incidences of vaginal colonization, vaginitis and
tropenia (7.5%) and a disulfiram-like effect when alcohol is ingested. lower cure rates. The high levels of reproductive hormones result in a
Caution should be exercised when 5-nitroimidazoles are used in higher glycogen content in the vaginal environment, which provides
patients taking warfarin. Long-term and high-dose therapy increase an excellent carbon source for growth and germination of Candida
the risk of neutropenia and peripheral neuropathy. In experimental spp. Furthermore, estrogens enhance vaginal epithelial cell avidity for
studies, metronidazole has been shown to be mutagenic for certain Candida spp. adherence, and a yeast cytosol receptor or binding system
bacteria, indicating a carcinogenic potential, although cohort studies for estrogen has been documented. These hormones also enhance yeast
have not established an increase in cancer morbidity. Thus, the risk mycelial formation. Several studies have shown increased VVC associ-
to humans of short-term low-dose metronidazole treatment is ated with oral contraceptive use21 and uncontrolled diabetes mellitus.
extremely small. Superinfection with Candida spp. is by no means Testing for diabetes has been recommended for women with recurrent
uncommon. VVC; however, the yield is low, and not justified in otherwise healthy
Treatment of symptomatic trichomoniasis in pregnancy is identi- pre-menopausal women.
cal.9 Metronidazole readily crosses the placenta and, because of concern Symptomatic VVC is frequently observed during or after courses
for teratogenicity, previously some considered it prudent to avoid its of systemic antibiotics. Although no antimicrobial agent is free of
use in the first trimester of pregnancy, however use of metronidazole this complication, broad-spectrum antibiotics, such as tetracycline,
throughout pregnancy is now accepted. Topical clotrimazole and and β-lactams are mainly responsible, and are thought to act by elimi-
povidone-iodine jelly offer minimal benefit. Some concern exists about nating the normal protective vaginal bacterial flora. The natural micro-
treating asymptomatic trichomoniasis in pregnancy because one trial biome provides a colonization resistance mechanism and prevents
germination of Candida spp. The provider of this protective function introduction of yeast as a cause for recurrent VVC is doubtful. Recur-
is suspected to be Lactobacillus spp.22 Lactobacillus–Candida interac- rent VVC frequently occurs in celibate women and only a minority of
tion includes competition for nutrients, steric interference with adher- male partners of women who have recurrent VVC are colonized with
ence of Candida spp. and elaboration of bacteriocins that inhibit yeast Candida spp. Most studies aimed at treating male partners have not
proliferation and germination. reduced the frequency of recurrent episodes of vaginitis.24
Candida spp. may cause cell damage and resulting inflammation by Vaginal relapse implies that incomplete eradication or clearance of
superficial hyphal invasion of epithelial tissue. Yeast proteases and Candida spp. from the vagina occurs after antimycotic therapy. Organ-
other hydrolytic enzymes facilitate cell penetration with resultant isms persist in small numbers in the vagina and result in continued
inflammation, mucosal swelling, erythema and exfoliation of vaginal carriage of the organisms, and when host environmental conditions
epithelial cells. The characteristic nonhomogeneous vaginal discharge permit, the colonizing organisms increase in number and undergo
consists of a conglomerate of hyphal elements and exfoliated nonviable mycelial transformation, resulting in a new clinical episode.
epithelial cells with few PMNs. Candida spp. may also induce symp- Whether recurrence is caused by vaginal re-infection or relapse,
toms including hypersensitivity immune-based reactions, particularly women with recurrent VVC differ from those with infrequent episodes
in women with idiopathic recurrent VVC (see Noninfectious vaginitis in their inability to tolerate small numbers of Candida organisms
and vulvitis, below).23 re-introduced or persisting in the vagina. Recurrent VVC is rarely
Oral and vaginal candidiasis correlate well with depressed cell- caused by drug resistance.19
mediated immunity in debilitated or immunosuppressed patients.23 Women who are HIV-infected have higher vaginal colonization
This is particularly evident in patients who have chronic mucocutane- rates than seronegative women, but the attack rate of symptomatic
ous candidiasis and acquired immunodeficiency syndrome (AIDS). VVC appears similar. Reports of chronic, severe recurrent VVC are
largely unsubstantiated. Recurrent VVC in the absence of other risk
PATHOGENESIS OF RECURRENT AND CHRONIC factors for HIV is not an indication for HIV testing.19
CANDIDA VAGINITIS Recent reports indicate an important role for host genetic factors
Evaluation (Figure 53-1) of women with recurrent vaginitis usually that explain racial blood group and family predilections to VVC.
fails to reveal any precipitating or causal mechanism.19 In the past, Genetic factors include quantity of vaginal mannose-binding lectin
investigators attributed frequent episodes to repeated fungal re- (MBL) which is reduced in vaginal secretions of women with recurrent
inoculation of the vagina from a persistent intestinal source or to VVC. Other genetic factors influence host immune reactivity in
sexual transmission.19 response to Candida antigen.25,26
The intestinal theory is based on recovery of Candida spp. on rectal
culture in almost 100% of women with VVC. Typing of simultaneously Prevention
obtained vaginal and rectal isolates almost invariably reveals identical In women with recurrent VVC linked to systemic antibiotics, prophy-
strains. This theory has been criticized because of lower concordance lactic antimycotics are justified. A useful regimen is fluconazole 150 mg
between rectal and vaginal cultures in patients with recurrent VVC. once weekly for the duration of antibiotic therapy. No other dietary or
Moreover, long-term therapy with oral nonabsorbable nystatin is not alternative method, such as the use of probiotic preparations of lacto-
effective in preventing recurrences. It is likely that frequent relapses of bacilli, has stood the test of time in preventing VVC.27 In women prone
VVC originate from a vaginal and not an intestinal reservoir. Vaginal to VVC, avoiding the use of oral contraceptives, intrauterine devices
persistence of Candida spp. is possibly a consequence of use of fungi- and the contraceptive sponge is prudent.
static and not fungicidal drug therapy.
Although sexual transmission of Candida organisms occurs via
vaginal intercourse and orogenital contact, the role of sexual re-
Clinical Features
The most frequent symptom of VVC is vulvar pruritus because vaginal
discharge is not invariably present and is frequently minimal.19
Risk factors for recurrent vulvovaginal candidosis
Although described as typically cottage cheese-like in character, the
discharge may vary from watery to homogeneously thick. Vaginal sore-
ness, irritation, vulvar burning, dyspareunia and external dysuria are
commonly present. Odor, if present, is minimal and nonoffensive.
Host factors Genetic factors
Non-secretor
Examination frequently reveals erythema and swelling of the labia and
HIV Behavioral factors
Black vulva (Figure 53-2), often with discrete pustulopapular peripheral
Uncontrolled Oral contraceptives
diabetes Familial Sponge/IUD
Corticosteroids Polymorphism Intercourse
Antibiotics (frequency)
HRT Orogenital sex
Vulvar
Microbial (NAC)
dermatosis
↑ Vaginal
Host factors colonization
Antibiotics
Uncontrolled
Behavioral factors
diabetes
Idio- Intercourse
HIV
pathic Orogenital sex
Dietary (?)
Atopy
Recurrent Candida vaginitis
Figure 53-1 Risk factors for recurrent vulvovaginal candidosis. HRT, hormone Figure 53-2 Typical Candida vulvovaginitis with bilateral symmetric erythema
replacement therapy; NAC, non-albicans Candida spp.; IUD, intrauterine device. and edema of vestibule and labia.
TABLE Therapy for Vaginal Candidiasis –

53-3 Topical Agents
Drug Formulation Dosage Regimen
*Butoconazole 2% cream 5 g q24h for 3 days
*Clotrimazole 1% cream 5 g q24h for 7–14 days

100 mg vaginal tablets 1 tablet q24h for 7 days
100 mg vaginal tablets 2 tablets q24h for 3 days
500 mg vaginal tablets 1 tablet, single dose
*Miconazole 2% cream 5 g q24h for 7 days

100 mg vaginal 1 suppository q24h for
suppository 7 days
200 mg vaginal 1 suppository q24h for
suppository 3 days
1200 mg vaginal 1 suppository, single
suppository dose
Econazole 150 mg vaginal tablet 1 tablet q24h for 3 days

Figure 53-3 Severe Candida vulvovaginitis with bilateral painful fissure forma-
tion in the vulva. Fenticonazole 2% cream 5 g q24h for 7 days
*Tioconazole 2% cream 5 g q24h for 3 days

6.5% cream 5 g, single dose
lesions and linear fissures (Figure 53-3). The cervix is normal and
vaginal mucosal erythema with adherent whitish discharge is present. Terconazole 0.4% cream 5 g q24h for 7 days
Characteristically, symptoms are exacerbated in the week before the 0.8% cream 5 g q24h for 3 days
80 mg vaginal suppository 80 mg q24h for 3 days
onset of menses, with some relief with the onset of menstrual flow.
Nystatin 100 000 U vaginal tablets 1 tablet q24h for 14 days
Diagnosis *Drugs available over the counter, without prescription.
The relative lack of specificity of symptoms and signs precludes a
diagnosis that is based only on history and physical examination. Most
patients with symptomatic VVC may be readily diagnosed on the TABLE
basis of simple microscopic examination of vaginal secretions and 53-4 Classification of Vulvovaginal Candidiasis
finding of a normal pH. A wet mount or saline preparation has a
sensitivity of 40–60%. The 10% potassium hydroxide preparation is
more sensitive in diagnosing the presence of germinated yeast. A Candida albicans Non-albicans Candida spp.
normal vaginal pH (4.0–4.5) is found in Candida vaginitis, and the + Resistant Candida albicans (rare)
Infrequent episodes or
finding of a pH in excess of 4.5 should suggest the possibility of bacte- + History of recurrent vulvovaginal candidiasis
rial vaginosis, trichomoniasis or a mixed infection.19 Mild-to-moderate vaginitis or
Although routine fungal cultures are unnecessary, vaginal culture + Severe vulvovaginal candidiasis
should be performed in the presence of negative microscopy in a Normal host or
Abnormal host, for example, uncontrolled
symptomatic patient. The Pap smear is unreliable, being insensitive diabetes, pregnancy, immunocompromised
and positive in only about 25% of cases. There is no reliable serologic
technique for the diagnosis of Candida vaginitis. Unfortunately, no
reliable laboratory test based upon rapid antigen detection is available
commercially. DNA probes and PCR studies are reliable and now single-dose topical regimens. Although short-course regimens are
widely available. effective for mild and moderate vaginitis, cure rates for severe and
complicated vaginitis are lower.
Management Oral systemic azoles available for the treatment of VVC include
ketoconazole 400 mg BD for 5 days, itraconazole 200 mg/day for 3 days
TOPICAL AGENTS FOR ACUTE CANDIDA (or every 12 hours single-day regimen) and, fluconazole 150 mg single
VAGINITIS dose.29 All the oral regimens achieve cure rates in excess of 80%. Oral
Antimycotics are available for local use as creams, vaginal tablets and regimens are preferred by women because of convenience and lack of
suppositories (Table 53-3). There is little to suggest that the formula- local side effects. None of the systemic regimens is approved for use
tion of the topical antimycotic influences clinical efficacy.28 Extensive during pregnancy. Hepatotoxicity with ketoconazole precludes its
vulvar inflammation dictates local vulvar application of antimycotic widespread use in VVC.
cream and, if severe, in combination with a topical steroid. VVC is classified as uncomplicated or complicated on the basis of
The average mycologic cure rate of 7- and 14-day courses of nystatin the likelihood of achieving clinical and mycologic cure with short-
is 75–80%. Azoles appear to achieve slightly higher clinical mycologic course therapy (Table 53-4). Uncomplicated VVC is far the more
cure rates than the polyenes (nystatin): 85–90%. Although many common, is caused by highly sensitive C. albicans and, provided that
studies have compared the clinical efficacies of the various azoles, there the severity is mild to moderate, patients respond well to all topical or
is little evidence that any one azole agent is superior to others. Topical oral antimycotics, including single-dose therapy. In contrast, patients
azoles are remarkably free of local and systemic side effects; neverthe- who have complicated VVC have a relatively resistant organism, a host
less, the initial application of topical agents is not infrequently accom- factor or a severity of infection that dictates more intensive and pro-
panied by local burning and discomfort. longed therapy lasting 7–14 days. Most non-albicans Candida infec-
tions respond to conventional topical or oral antifungals provided they
SYSTEMIC AGENTS FOR ACUTE are administered for sufficient duration. However, vaginitis caused by
CANDIDA VAGINITIS C. glabrata often fails to respond to azoles and may require treatment
There has been a major trend toward shorter treatment courses with with vaginal capsules of boric acid 600 mg/day for 14 days.30 Patients
progressively higher antifungal doses, culminating in highly effective with severe vulvovaginitis require more prolonged systemic or topical
therapy. The former can be provided by two additional doses of fluco-

nazole 150 mg every 72 hours after the first dose.31
TREATMENT OF RECURRENT VULVOVAGINAL

CANDIDIASIS
The management of women who have recurrent VVC aims at control
rather than cure. The clinician should first confirm the diagnosis of
recurrent VVC. Uncontrolled diabetes mellitus must be controlled and
use of corticosteroids or other immunosuppressive agents should be
discontinued where possible. Unfortunately, in the majority of women
with recurrent VVC, no underlying or predisposing factor can be iden-
tified. Recurrent VVC requires long-term maintenance with a suppres-
sive prophylactic regimen. Because of the chronicity of therapy, the
convenience of oral treatment is apparent, and the best suppressive
prophylaxis has been achieved with weekly oral fluconazole at a dosage
of 150 mg.32 An effective topical prophylactic regimen consists of
weekly vaginal suppositories of clotrimazole 500 mg.
Figure 53-4 Vulvar psoriasis resulting in pruritus vulva and misdiagnosed as
Candida vulvovaginitis.
Atrophic Vaginitis
Although the majority of women with mild-to-moderate atrophy are
asymptomatic, clinically significant atrophic vaginitis is not rare. of a normal vaginal pH, normal saline and potassium hydroxide
Because of reduced endogenous estrogen, the epithelium becomes thin microscopy, and, ultimately, a negative yeast culture. Unfortunately,
and lacking in glycogen, which contributes to a reduction in lactic acid given the anticipated 20% colonization rates in normal asymptomatic
production and an increase in vaginal pH. This change in the environ- women, occasionally a positive yeast culture in a symptomatic patient
ment encourages the overgrowth of nonacidophilic coliform organ- reflects the presence of an innocent bystander and not the cause of the
isms and the disappearance of Lactobacillus spp., in itself of no clinical vulvovaginal symptoms. The only logical way of establishing the role
significance. of Candida spp. in this context is to treat with an oral antifungal agent
With advanced atrophy, symptoms include vaginal dryness and and assess the clinical response.
soreness, dyspareunia and occasional spotting or discharge. Burning is Once a local chemical irritant or allergic reaction is suspected, a
a frequent complaint and is often precipitated by intercourse. The detailed inquiry into possible causal factors is essential. Offending
vaginal mucosa is thin, with diffuse redness, occasional petechiae or agents or behaviors should be eliminated wherever possible, including
ecchymoses with few or no vaginal folds. Vestibular atrophy may also avoiding chemical irritants and allergens (e.g. soaps, detergents). The
be apparent and discharge may be serosanguinous, thick or watery, immediate management of severe vulvovaginal symptoms of nonin-
and the pH of the vaginal secretions ranges from 5.5 to 7.0. The wet fectious etiology should not rely on topical corticosteroids, which are
smear frequently shows small, round epithelial or parabasal cells which rarely the solution and high-potency corticosteroid creams frequently
represent immature squamous cells that have not been exposed to cause intense burning. Local relief measures include sodium bicarbon-
sufficient estrogen. The Lactobacillus spp.-dominated flora is replaced ate sitz baths, emollients and oral antihistamines.
by mixed flora of gram-negative rods. Bacteriologic cultures in these A syndrome of hyperacidity of the vagina causing overgrowth of
patients are unnecessary, and can be misleading. lactobacilli has been suggested but not confirmed. The proposed syn-
The treatment of atrophic vaginitis consists of topical vaginal or drome of cytolytic vaginosis is characterized by vulvovaginal burning,
less favorably systemic estrogen. Nightly use of half or all the contents irritation, soreness and dyspareunia, and is usually incorrectly diag-
of an applicator of estradiol for 1–2 weeks is usually sufficient to allevi- nosed as VVC. The finding of large numbers of lactobacilli on wet
ate the atrophic vaginitis, and is then followed by maintenance long- mount and a low pH, together with extensive squamous epithelial cell
term estradiol therapy. cytolysis is said to confirm the diagnosis. Recommended therapy for
cytolytic vaginosis is douching using sodium bicarbonate to elevate the
Noninfectious Vaginitis and Vulvitis low vaginal pH and suppress growth of lactobacilli but requires nega-
tive vaginal yeast cultures.
Women frequently present with acute or chronic vulvovaginal symp- Desquamative inflammatory vaginitis (DIV) is a recently recog-
toms caused by noninfectious etiologies. Symptoms are indistinguish- nized not uncommon cause of vulvovaginal burning, and purulent
able from those of infectious syndromes, but are most commonly non-malodorous vaginal discharge accompanied by dyspareunia.33
confused with those of acute Candida vaginitis, including pruritus, DIV occurs predominantly in perimenopausal Caucasian women with
irritation, burning, soreness and variable discharge. symptoms unresponsive to HRT. Examination reveals a purulent dis-
Noninfectious causes include irritants (physical [e.g. minipads] or charge and variable vaginal rash associated with squamous cell desqua-
chemical [e.g. spermicides, povidone-iodine, topical antimycotics, mation. Vaginal pH is elevated and microscopy reveals a marked
soaps and perfumes, topical 5-fluorouracil]) and allergens, which are increase in inflammatory and parabasal cells. A prompt response to
responsible for immunologic acute and chronic hypersensitivity reac- intravaginal 2% clindamycin or 10% hydrocortisone cream occurs but
tions, including contact dermatitis (e.g. latex condoms, antimycotic prolonged therapy may be necessary.
creams). An enormous list of topical factors responsible for local
inflammatory reactions and symptoms exists and many more have yet Vulvitis
to be defined. Depending on the site of contact, symptoms may be
vaginal or vulvar. Included in this category are systemic dermatoses Most of the important infectious and noninfectious causes of vulvitis
that may present in the vulva (e.g. psoriasis, Figure 53-4) or vulva- have been described in the section on vaginitis. Human papillomavirus
specific dermatosis (e.g. lichen sclerosus). and genital herpes are described in Chapter 63 and Chapter 62, respec-
A noninfectious mechanism may coexist with or follow an infec- tively. Bacterial vulvitis or cellulitis due to streptococci, anaerobes and
tious process, and should be considered when the three common infec- gram-negative rods occurs rarely and should be diagnosed by clinical
tious causes and hormone deficiency are excluded and in the presence features and bacterial culture. Specific antimicrobial treatment is
indicated. Occasionally a Bartholin’s abscess creates a painful swelling endocervical swab specimen and observing the latter against a white
in the vulva. This can be due to Neisseria gonorrhoeae or to a variety background.
of pathogens, particularly gram-positive organisms. A Bartholin’s cyst Trichomoniasis is associated with ectocervical squamous epithelial
infection should be treated with appropriate antibiotics and occasion- mucosal inflammation, giving the cervix a ‘strawberry’ appearance due
ally may require drainage. Other causes of vestibulitis or vulvitis to microscopic focal patchy petechiae (colpitis macularis) in 5–20% of
include lichen sclerosus, erosive lichen planus and theoretically any patients.14 Primary herpes cervicitis may be associated with severe
cause of dermatosis or dermatitis such as psoriasis (see Figure 53-4), necrosis that is reminiscent of cervical cancer. Most commonly,
eczema, pemphigus and hidroadenitis suppurativa. primary herpetic cervicitis is characterized by increased surface vascu-
larity, and micro- and macro-ulcerations with and without necrotic
areas. Asymptomatic shedding of herpesvirus occurs in the absence of
Cervicitis cervical lesions.
Epidemiology Diagnosis
The presence of a purulent exudate in the cervical os has been highly Mucopurulent cervicitis is confirmed when a Gram-stained specimen
associated with cervical infection with Chlamydia trachomatis, N. gon- of green or yellow endocervical exudate reveals more than 30 PMNs
orrhoeae, herpes simplex virus and cytomegalovirus. Infection with T. per high-power field.1 Microscopic examination of cervical mucus
vaginalis correlates with colpitis macularis and inflammatory changes from a patient with mucopurulent endocervicitis reveals an overabun-
of the ectocervix.34,35 Not infrequently, mucopurulent endocervicitis or dance of inflammatory cells, obliterating the background ferning
ectocervicitis is seen in the absence of these pathogens, indicating that pattern. A similar excess of inflammatory cells can be found in a Pap
additional, as yet unrecognized causes exist. Mycoplasma genitalis has smear. These two microscopic studies are not reliable in identifying
been identified as a cause of mucopurulent cervicitis.36,37 A role for the underlying cause of mucopurulent cervicitis. For a diagnosis of C.
disruption of vaginal flora, specifically overgrowth of anaerobes as trachomatis cervicitis, culture techniques to identify the obligate intra-
typified in bacterial vaginosis in causing cervical inflammation has parasites served as the gold standard in the past. Now the development
been proposed. Rare causes of cervicitis include Mycobacterium tuber- of the more widely available enzyme-linked immunosorbent assay
culosis and Actinomyces israelii, the latter almost invariably in the pres- antigen detection tests has been replaced by highly sensitive DNA
ence of intrauterine devices. Although the most important and amplification techniques, allowing diagnosis not only from cervical
prevalent infection of the cervix is undoubtedly human papillomavi- and vaginal specimens, but also by screening urine specimens. Gram
rus, this virus does not cause cervicitis and is discussed in Chapter 167. stain of cervical mucus may reveal intracellular gram-negative diplo-
The prevalence of genital chlamydial infection ranges from 8 to cocci, but has low sensitivity and specificity in the diagnosis of gono-
40%.38 Risk factors include young age, unmarried status, lower socio- coccal cervicitis. PCR diagnosis of M. genitalium is required but is not
economic conditions, number and recent change of sexual partner, widely available.37 Although Pap smears in herpetic cervicitis are useful
ectopy, oral contraceptive use and concurrent gonococcal infection; the in revealing multinucleated giant cells, viral culture and fluorescein-
last may reactivate latent chlamydial infection and increases shedding conjugated monoclonal antibodies have now been replaced by PCR.
of chlamydia from the endocervix.39 Risk factors for gonococcal muco- The clinical differentiation of the various causes of cervicitis is not
purulent cervicitis are identical to those of Chlamydia spp. but also possible, but requires the aforementioned diagnostic tests, recognizing
include urban dwelling, prostitution, illicit drug use and minority that frequently more than one etiologic agent may be present simulta-
racial status. Up to 60% of women with N. gonorrhoeae have coinfec- neously because many of the pathogens share risk factors and behavior.
tion with chlamydia.38 Herpetic cervicitis is rare in the absence of Overdiagnosis of cervicitis is common. All too frequently physiologic
genital lesions and is most commonly associated with first episode, changes in the appearance of the cervix, in spite of the use of colpos-
primary disease with an 80% viral isolation rate.35 Cytomegalovirus is copy, are interpreted as reflecting pathologic cervicitis. Regrettably,
thought to be responsible for approximately 5% of cases of cervicitis after failed attempts to identify pathogenic micro-organisms, patients
and is usually asymptomatic. When it is isolated from cervical secre- are needlessly treated with cervical ablative techniques. Cervical ectopy
tions, the detection may not imply a causal relationship. is often mistaken for cervicitis with eversion of endocervical columnar
cells, and is commonly seen in women on oral contraceptives.39 Other
Clinical Features physiologic changes related to childbirth and dilatation of the cervical
Cervicitis is frequently asymptomatic and is detected on routine pelvic canal are mistakenly diagnosed as cervicitis. Equally important is the
examination. Alternatively, cervical inflammation is recognized failure to recognize that a friable, abnormal cervix may reflect dysplasia
because of signs and symptoms of concomitant infection (e.g. vaginal and neoplasia, emphasizing need for colposcopy and biopsy.
trichomoniasis, genital herpes or salpingitis). Mucopurulent cervicitis
may result in a purulent vaginal discharge. Accordingly, cervical specu- Management
lum evaluation should be an essential part of vaginal examination in Antimicrobial regimens for infectious cervicitis are provided in the
women with an abnormal discharge. Mucopurulent endocervicitis chapters on pelvic inflammatory disease, gonorrhea and chlamydial
results in swelling and erythema of the zone of ectopy, associated with infections40 (see Chapter 54, Chapter 65 and Chapter 188).
friability, contact bleeding, spotting and a yellow or green endocervical
exudate. The purulent discharge is best appreciated by obtaining an References available online at expertconsult.com.
KEY REFERENCES
Babula O., Lazdane G., Kroica J., et al.: Frequency of of Maternal–Fetal Medicine Units: Failure of metronida- Manhart L.E., Gillespie C.W., Lowens M.S., et al.: Standard
interleukin-4 (IL-4) -589 gene polymorphism and zole to prevent preterm delivery among pregnant women treatment regimens for nongonococcal urethritis have
vaginal concentrations of IL-4, nitric oxide, and with asymptomatic Trichomonas vaginalis infection. N similar but declining cure rates: a randomized controlled
mannose-binding lectin in women with recurrent vulvo- Engl J Med 2001; 345(7):487-493. trial. Clin Infect Dis 2013; 56:934-942.
vaginal candidiasis. Clin Infect Dis 2005; 40:1258-1262. Ling Z., Kong J., Liu F., et al.: Molecular analysis of the Pirotta M., Gunn J., Chondros P., et al.: Effect of Lactobacil-
Fredricks D.N., Fiedler T.L., Marrazzo J.M.: Molecular iden- diversity of vaginal microbiota associated with bacterial lus in preventing post-antibiotic vulvovaginal candidia-
tification of bacteria associated with bacterial vaginosis. vaginosis. BMC Genomics 2010; 7(11):488. sis: a randomised controlled trial. BMJ 2004; 329:548.
N Engl J Med 2005; 353:1899-1911. Manhart L.E., Critchlow C.W., Holmes K.K., et al.: Muco- Smeekens S.P., van de Veerdonk F.L., Kullberg B.J., et al.:
Klebanoff M.A., Carey J.C., Hauth J.C., et al., National Insti- purulent cervicitis and Mycoplasma genitalium. J Infect Genetic susceptibility to Candida infections. EMBO Mol
tute of Child Health and Human Development Network Dis 2003; 187:650-657. Med 2013; 5:805-813.
Sobel J.D., Brooker D., Stein G.E., et al.: Single oral dose Sobel J.D., Kapernick P.S., Zervos M., et al.: Treatment of Sobel J.D., Reichman O., Misra D., et al.: Prognosis and
fluconazole compared with clotrimazole topical therapy complicated Candida vaginitis: comparison of single and treatment of desquamative inflammatory vaginitis.
of Candida vaginitis. Fluconazole Vaginitis Study Group. sequential doses of fluconazole. Am J Obstet Gynecol Obstet Gynecol 2011; 117:850-855.
Am J Obstet Gynecol 1995; 172:1263-1268. 2001; 185:363-369. Sobel J.D., Wiesenfeld H.C., Martens M., et al.: Maintenance
Sobel J.D., Chaim W.: Treatment of Candida glabrata vagi- Sobel J.D., Nyirjesy P., Brown W.: Metronidazole-resistant fluconazole therapy for recurrent vulvovaginal candidia-
nitis: a retrospective review of boric acid therapy. Am J trichomoniasis. Treatment with tinidazole. Clin Infect Dis sis. N Engl J Med 2004; 351:876-883.
Obstet Gynecol 2003; 189:1297-1300. 2001; 33:1341-1346.
Chapter 53 Vaginitis, Vulvitis, Cervicitis and Cutaneous Vulval Lesions 491.e1
REFERENCES
1. Holmes K.K., Stamm W.E., Sobel J.D.: Lower genital 14. Wolner-Hanssen P., Krieger J.N., Stevens C.E., et al.: 28. Nurbhai M., Grimshaw J., Watson M., et al.: Oral versus
tract infections in women: cystitis, urethritis, vulvo- Clinical manifestations of vaginal trichomoniasis. intra-vaginal imidazole and triazole anti-fungal treat-
vaginitis, and cervicitis. In: Holmes K.K., Mardh P.-A., JAMA 1989; 261:571-576. ment of uncomplicated vulvovaginal candidiasis
Sparling P.F., et al., eds. Sexually transmitted diseases, 15. Moodley P., Wilkinson D., Connolly C., et al.: Tricho- (thrush). Cochrane Database Syst Rev 2007; (4):
4th ed. New York: McGraw Hill; 2008:629-640. monas vaginalis is associated with pelvic inflammatory CD002845.
2. Eschenbach D.A., Davick P.R., Williams B.L., et al.: disease in women infected with human immunodefi- 29. Sobel J.D., Brooker D., Stein G.E., et al.: Single oral dose
Prevalence of hydrogen peroxide producing Lactobacil- ciency virus. Clin Infect Dis 2002; 34:519-522. fluconazole compared with clotrimazole topical therapy
lus species in normal women and women with bacterial 16. Schwebke J.R., Hobbs M.M., Taylor S.N., et al.: Molecu- of Candida vaginitis. Fluconazole Vaginitis Study
vaginosis. J Clin Microbiol 1989; 27:251-256. lar testing for Trichomonas vaginalis in women: results Group. Am J Obstet Gynecol 1995; 172:1263-1268.
3. Fredricks D.N., Fiedler T.L., Marrazzo J.M.: Molecular from a prospective U.S. clinical trial. J Clin Microbiol 30. Sobel J.D., Chaim W.: Treatment of Candida glabrata
identification of bacteria associated with bacterial vagi- 2011; 49:4106-4111. vaginitis: a retrospective review of boric acid therapy.
nosis. N Engl J Med 2005; 353:1899-1911. 17. Sobel J.D., Nyirjesy P., Brown W.: Metronidazole- Am J Obstet Gynecol 2003; 189:1297-1300.
4. Ling Z., Kong J., Liu F., et al.: Molecular analysis of the resistant trichomoniasis. Treatment with tinidazole. 31. Sobel J.D., Kapernick P.S., Zervos M., et al.: Treatment
diversity of vaginal microbiota associated with bacterial Clin Infect Dis 2001; 33:1341-1346. of complicated Candida vaginitis: comparison of single
vaginosis. BMC Genomics 2010; 7(11):488. 18. Klebanoff M.A., Carey J.C., Hauth J.C., et al., National and sequential doses of fluconazole. Am J Obstet
5. Hillier S.L., Krohn M.A., Cassen E., et al.: The role of Institute of Child Health and Human Development Gynecol 2001; 185:363-369.
bacterial vaginosis and vaginal bacteria in amniotic Network of Maternal–Fetal Medicine Units: Failure of 32. Sobel J.D., Wiesenfeld H.C., Martens M., et al.: Mainte-
fluid infection in women in preterm labor with intact metronidazole to prevent preterm delivery among preg- nance fluconazole therapy for recurrent vulvovaginal
fetal membranes. Clin Infect Dis 1995; 20(Suppl. 2):276- nant women with asymptomatic Trichomonas vaginalis candidiasis. N Engl J Med 2004; 351:876-883.
278. infection. N Engl J Med 2001; 345(7):487-493. 33. Sobel J.D., Reichman O., Misra D., et al.: Prognosis and
6. Platz-Christensen J.J., Sundstrom F., Larsson P.G.: Bac- 19. Sobel J.D.: Vulvovaginal candidosis. Lancet 2007; treatment of desquamative inflammatory vaginitis.
terial vaginosis and cervical intraepithelial neoplasia. 369:1961-1971. Obstet Gynecol 2011; 117:850-855.
Acta Obstet Gynecol Scand 1994; 73:586-668. 20. Spinillo A., Capuzzo E., Egbe T.O., et al.: Torulopsis 34. Kiviat N.B., Paavonon J.A., Wolner–Hanssen P., et al.:
7. Martin H.L., Richardson B.A., Nyange P.M., et al.: glabrata vaginitis. Obstet Gynecol 1995; 85:993-998. Histopathology of endocervical infection caused by
Vaginal lactobacilli, microbial flora and risk of human 21. Foxman B.: Epidemiology of vulvovaginal candidiasis: Chlamydia trachomatis, herpes simplex virus, Tricho-
immunodeficiency virus type 1 and sexually transmit- risk factors. Am J Public Health 1996; 80:329-331. monas vaginalis and Neisseria gonorrhoeae. Hum Pathol
ted disease acquisition. J Infect Dis 1999; 180:1863-1869. 22. Hooton T.M., Roberts P.L., Stamm W.F.: Effects of 1990; 21:831-837.
8. Cherpes T.L., Meyn L.A., Krohn M.A., et al.: Associa- recent sexual activity and use of a diaphragm on the 35. Wald A., Zeh J., Selke S., et al.: Virologic characteristics
tion between acquisition of herpes simplex virus type 2 vaginal microflora. Clin Infect Dis 1994; 19:274-278. of subclinical and symptomatic genital herpes infec-
in women and bacterial vaginosis. Clin Infect Dis 2003; 23. Fidel P.L. Jr, Sobel J.D.: Immunopathogenesis of recur- tions. N Engl J Med 1995; 333:770-785.
37:319-325. rent vulvovaginal candidiasis. Rev Clin Microbiol 1996; 36. Lusk M.J., Konecny P.: Cervicitis: a review. Curr Opin
9. Workowski K.A., Berman S., Centers for Disease 9:335-348. Infect Dis 2008; 21(1):49-55.
Control and Prevention: Sexually transmitted diseases 24. Spinillo A., Carrato L., Pizzoli G.: Recurrent vulvovagi- 37. Manhart L.E., Critchlow C.W., Holmes K.K., et al.:
treatment guidelines. MMWR Morb Mortal Wkly Rep nal candidiasis: results of a cohort study of sexual trans- Mucopurulent cervicitis and Mycoplasma genitalium.
2006; 55:1-98. mission and intestinal reservoir. J Reprod Med 1992; J Infect Dis 2003; 187:650-657.
10. Hillier S.L., Nugent R.P., Eschenbach D.A., et al.: Asso- 37:353-447. 38. Cates W., Wasserheit J.N.: Genital chlamydial infec-
ciation between bacterial vaginosis and preterm deliv- 25. Babula O., Lazdane G., Kroica J., et al.: Frequency of tions: epidemiology and reproductive sequelae. Am J
ery of a low birth-weight infant. N Engl J Med 1995; interleukin-4 (IL-4) -589 gene polymorphism and Obstet Gynecol 1991; 164:1771-1778.
333:1737-1742. vaginal concentrations of IL-4, nitric oxide, and 39. Critchlow C.W., Wolner-Hanssen P., Eschenbach D.A.,
11. Hauth J.C., Goldenberg R.L., Andrews W.W., et al.: mannose-binding lectin in women with recurrent vul- et al.: Determinants of cervical ectopia and of cervicitis:
Reduced incidence of preterm delivery with metronida- vovaginal candidiasis. Clin Infect Dis 2005; 40:1258- age, oral contraceptives, specific cervical infection,
zole and erythromycin in women with bacterial vagino- 1262. smoking, and douching. Am J Obstet Gynecol 1995;
sis. N Engl J Med 1995; 333:1732-1736. 26. Smeekens S.P., van de Veerdonk F.L., Kullberg B.J., et al.: 173:534-543.
12. Reichman O., Akins R., Sobel J.D.: Boric acid addition Genetic susceptibility to Candida infections. EMBO 40. Manhart L.E., Gillespie C.W., Lowens M.S., et al.: Stan-
to suppressive antimicrobial therapy for recurrent bac- Mol Med 2013; 5:805-813. dard treatment regimens for nongonococcal urethritis
terial vaginosis. Sex Transm Dis 2009; 36:732-734. 27. Pirotta M., Gunn J., Chondros P., et al.: Effect of Lacto- have similar but declining cure rates: a randomized
13. Sutton M., Sternberg M., Koumans E.H., et al.: The bacillus in preventing post-antibiotic vulvovaginal can- controlled trial. Clin Infect Dis 2013; 56:934-942.
prevalence of Trichomonas vaginalis infection among didiasis: a randomised controlled trial. BMJ 2004;
reproductive-age women in the United States, 2001– 329:548.
2004. Clin Infect Dis 2007; 45:1319-1326.
54
Infections of the Female Pelvis,
Including Septic Abortion
PAUL NYIRJESY | K. ASHLEY BRANDT
mechanisms are poorly understood. Postinfectious scarring (e.g. intra-

KEY CONCEPTS
tubal adhesions, tubal occlusion, peritubal scarring and damaged fim-
• Pelvic inflammatory disease (PID) is usually an ascending infec- brial ostia) results in the long-term sequelae of PID.
tion, caused by organisms found in the cervix or vagina. As noted earlier, PID occurs mainly among sexually active women.
• Although gonococcal and chlamydial infection causes about Multiple organisms have been implicated as etiologic agents of PID
50% of PID cases, newly recognized pathogens such as Myco- (Table 54-1). The rates of isolation of these organisms vary with geo-
plasma genitalium and abnormal flora also found in women graphic region, duration of infection and the site of sampling (i.e.
with bacterial vaginosis also play a role in PID. cervix, fallopian tubes or endometrium). The most commonly recov-
ered organisms are Neisseria gonorrhoeae and Chlamydia trachomatis,
• Clinical diagnosis of PID can lead to under- and over-diagnosis.
Imaging studies, such as pelvic ultrasound, endometrial biopsy followed by organisms associated with BV (e.g. Gardnerella vaginalis,
and laparoscopy, can all play a role in complicated cases. Mycoplasma hominis, Prevotella bivia and Porphyromonas, Prevotella
and Peptostreptococcus spp.) and Mycoplasma genitalium. Rates of iso-
• Quinolone-resistant Neisseria gonorrhoeae has led to changes lation of 10–20% in the upper genital tract, and as high as 85% (5–27%
in treatment recommendations for PID. in studies from Europe vs 44–70% in those from North America) in
• Postpartum endometritis is a polymicrobial infection, usually the lower genital tract, have been reported for N. gonorrhoeae. For C.
caused by normal or abnormal vaginal flora, which should be trachomatis, rates of 1.2–31% in the upper and 31% in the lower genital
treated with broad-spectrum antibiotics. tract have been reported.1,2,5 Approximately 10–40% of women who
have untreated gonococcal or chlamydial cervical infection will develop
• Necrotizing fasciitis is a rare but potentially life-threatening
form of episiotomy infection. upper tract infection. Recently, M. genitalium has emerged as a recog-
nized etiologic pathogen, with a prevalence as high as 15% in women
• Infection remains a major cause of death following abortion. with PID.6 However, even in the setting of gonococcal or chlamydial
cervicitis, PID is a polymicrobial infection. STD organisms may initiate
inflammation of the tubal mucosa which in turn facilitates the invasion
of the mucosa by organisms endogenous to the lower genital tract.1
Infections of the female pelvis constitute a diverse group. This chapter Finally, in rare situations sometimes associated with intrauterine
considers three groups of infections: pelvic inflammatory disease devices, pelvic actinomycosis can cause an indolent form of PID with
(PID), postpartum and postabortal infections, and postsurgical gyne- tubo-ovarian abscesses (see also Chapter 184).
cologic infections.
Prevention
Prevention is directed at reducing the risk of acquiring an STD and at
Pelvic Inflammatory Disease early detection and treatment of lower tract infections. Women
screened and treated for asymptomatic chlamydial infection are nearly
Epidemiology 60% less likely than unscreened women to develop PID.7 Prompt and
Pelvic inflammatory disease (PID) is an acute clinical syndrome that correct treatment of upper tract infections will ameliorate some of the
occurs when vaginal or cervical organisms ascend into the upper long-term sequelae.
female reproductive tract.1 Depending on which areas are infected, PID
manifests itself as endometritis, parametritis, salpingitis, oophoritis,
pelvic peritonitis, tubo-ovarian abscess, periappendicitis, perihepatitis
(Fitz–Hugh–Curtis syndrome) and perisplenitis. TABLE Common Etiologic Agents of Pelvic
54-1 Inflammatory Disease
PID and sexually transmitted diseases (STD) share many risk
factors; in the USA, 40–80% of PID is attributed to STD. Bacterial
Aerobic bacteria Neisseria gonorrhoeae
vaginosis (BV) is commonly found in women with PID.2 Risk factors Chlamydia trachomatis
include younger age, unmarried status, lower socioeconomic status, Gardnerella vaginalis
sexual behavior (number of sexual partners, coitarche, acquiring new Escherichia coli
partners), substance abuse, poor healthcare behavior (e.g. non- Streptococcus spp.
compliance with treatment instructions), douching and intrauterine
device insertion.1,3 In studies from the USA and Europe, about three- Anaerobic bacteria Bacteroides spp.
quarters of women who had PID were under 25 years of age, and about Peptostreptococcus spp.
Peptococcus spp.
one-half had never been pregnant.1 Oral contraceptive users tend to Prevotella spp.
have clinically and laparoscopically milder infection than non-users Porphyromonas spp.
and may have a lower risk of chlamydial PID.4 Mycoplasmas Mycoplasma hominis
Mycoplasma genitalium
Data from Weström L., Eschenbach D.: Pelvic inflammatory disease. In: Holmes
Most cases result when organisms ascend from the endocervix to the K.K., Sparling P.F., Märdh P.-A., et al., ed., Sexually transmitted diseases. New
mucosa of the endometrium and fallopian tubes, although the precise York: McGraw–Hill; 1999:783–8091
492
Chapter 54 Infections of the Female Pelvis, Including Septic Abortion 493
Clinical Features clear leukocytes per high power field, or a positive test (culture or
polymerase chain reaction) for either N. gonorrhoeae or C. trachoma-
The most common clinical complaint with PID is bilateral lower tis are also useful in establishing the diagnosis. Erythrocyte sedimen-
abdominal or pelvic pain. Other complaints include an abnormal tation rate, C-reactive protein and complete white blood cell count
vaginal discharge, dyspareunia, dysmenorrhea, abnormal uterine may be helpful. Pelvic and endovaginal ultrasound can detect find-
bleeding and, in more severe cases, nausea, vomiting, fever and diffuse ings consistent with severe PID, including tubo-ovarian abscesses,
abdominal pain. The hallmark findings of PID are cervical motion dilated fallopian tubes and cul-de-sac fluid. Ultrasound is less useful
tenderness and uterine or adnexal tenderness in the absence of other in mild or atypical clinical presentations. Computed tomography
potential causes of the illness. Whereas gonococcal PID tends to have (CT) scanning has the same limitations as ultrasound. In severe
an abrupt, fulminant presentation within 1 week of the onset of cases of PID with atypical ultrasound findings, CT can be useful.13
menses, chlamydial PID is characterized by milder symptoms, often For example, spiral CT scanning optimizes identification of small air
described as just a dull pain, and findings. A woman who has chla- bubbles that are specific for abscess.14
mydial PID may be unaware of the infection and may present as a More invasive tests may also be considered in a woman where PID
relatively asymptomatic contact of a male with urethritis. The clinician is suspected. Endometrial biopsy documenting endometrial neutro-
should be alert to adnexal masses or fullness as the signs of chlamydial phils or plasma cells confirms the diagnosis but requires at least 24
infection. Women who have human immunodeficiency virus (HIV) hours for processing. Purulent material from the peritoneal cavity
infection and PID may present with more clinically severe disease.8 obtained by culdocentesis may support the diagnosis of PID but can
The common complications and sequelae of PID include ectopic also occur with other intra-abdominal infections such as appendicitis.
pregnancy, tubal infertility, recurrent PID, chronic abdominal pain, Laparoscopy is the gold standard for the diagnosis and staging of acute
tubo-ovarian abscesses, pelvic adhesions and chronic pelvic pain. A PID. The minimum criteria for visual confirmation of PID include
woman’s risk of ectopic pregnancy increases 7- to 10-fold after an hyperemia of the tubal surface, edema of the tubal wall and a sticky
episode of PID. The number of episodes of PID, patient age and the exudate on the tubal surface and from the fimbriated end when
severity of tubal inflammation determined at laparoscopy influence patent.15
the fertility prognosis of PID.1 PID caused by chlamydial infection may
result in more infertility than PID caused by gonococci. Recurrent
pelvic infections will develop in up to one-third of affected women. Management
Chronic abdominal pain lasting more than 6 months occurs in 15–18% Management of a patient who has PID includes therapy, education,
of women after PID. Pyosalpinx, tubo-ovarian abscesses and pelvic careful follow-up and partner management. The goal is to cure the
adhesions occur in 15–20% of women who have had PID and often patient, prevent recurrences and, ultimately, to preserve fertility.
require surgical intervention. Mortality from acute PID, although rare, Empiric treatment should be instituted as soon as the diagnosis is
can occur with a ruptured tubo-ovarian abscess and subsequent peri- suspected. Because PID is typically polymicrobial, therapy must be
tonitis. The mortality rate from this complication of PID is 6–8%. broad-spectrum. Several antimicrobial regimens have been highly
effective in achieving clinical cure of PID.11 Studies from the pre-
Diagnosis antibiotic era documented infertility rates after PID of 60–70%, indi-
Even for experienced clinicians, the diagnosis of PID is often challeng- cating that institution of antimicrobial therapy influences fertility
ing. The traditional clinical signs and symptoms of PID are neither outcome.1
sensitive nor specific. Based on clinical findings alone, there is an PID should always be treated with a minimum of two antibiotics
estimated 65–90% positive predictive value for detecting PID.9 Lapa- for at least 10–14 days (Table 54-2). The combination regimen of an
roscopy confirms salpingitis in 45–89% of women who have clinically extended-spectrum parenteral cephalosporin plus doxycycline pro-
diagnosed PID. Of women who have clinically diagnosed PID, 6–45% vides good coverage for most potential pathogens, including
have normal fallopian tubes and 5–33% have other conditions, includ- β-lactamase-producing strains. However, the recommended outpa-
ing ectopic pregnancy, appendicitis, hemorrhagic ovarian cysts, endo- tient regimen for PID in the UK includes a triple antibiotic regimen
metritis, pelvic adhesions and torsion of an adnexal structure.5,10 consisting of a single dose of intramuscular ceftriaxone 500 mg fol-
Conversely, false-negative clinical diagnoses for PID range from 16% lowed by doxycycline 100 mg twice daily plus metronidazole 400 mg
to 47%.10 The diagnoses prior to laparoscopy in women who have twice daily for 14 days.16 An alternative parenteral inpatient regimen
laparoscopically confirmed PID include ectopic pregnancy, ovarian is clindamycin plus an aminoglycoside. Oral regimens listed in Table
cysts or tumors, endometriosis, fibroids, appendicitis, pyelonephritis 54-2 also provide excellent coverage. However, with recent data sug-
and uncertain diagnosis. Although laparoscopy can be used to obtain gesting that quinolone-resistant N. gonorrhoeae (QRNG) is becoming
a more accurate diagnosis, it is neither readily available in most cases more common, quinolones are no longer recommended for first-line
nor justifiable in clinically mild disease. therapy unless QRNG is not suspected, based on either negative testing
Women who have lower abdominal tenderness, adnexal tenderness or low local prevalence of this organism.17 In addition to emerging
or cervical motion tenderness – the Centers for Disease Control and QRNG, data from the CDC’s Gonococcal Isolate Surveillance Project
Prevention (CDC) minimum criteria – should be treated for PID if (GISP) describes declining susceptibility of cefixime among urethral
there is no other diagnosis that is considered.11 One analysis on a large N. gonorrhoeae isolates.18 As a result, cefixime is no longer recom-
number of women enrolled in a clinical trial showed that lower mended as a first-line treatment for gonococcal infection at any dose.
abdominal tenderness alone was the most sensitive of the physical Additionally, emerging studies consistently demonstrate suboptimal
findings.12 However, many clinicians are uncomfortable treating for eradication rates of M. genitalium with the current regimens recom-
PID based on history and physical examination alone. mended to treat NGU. The PID Evaluation and Clinical Health
Tests to document an inflammatory and infectious process in (PEACH) study revealed that 41% of M. genitalium-positive women
the lower genital tract can be used to increase the sensitivity of the experienced microbiologic failure, and 44% experienced clinical
clinical signs. A pregnancy test should be done to make sure that the failure.6 Given the absence of specific commercial diagnostic testing of
pain is not caused by an ectopic pregnancy. In a patient with lower M. genitalium and increasing macrolide resistance, azithromycin is no
abdominal or pelvic tenderness, the presence of an increased number longer recommended to treat patients with PID potentially caused by
of leukocytes (a ratio of more than 1 : 1 white blood cells to vaginal M. genitalium. A 14-day course of moxifloxacin 400 mg is probably
epithelial cells) or findings consistent with BV on a wet mount are acceptable, and this extended course should effectively treat cases of
considered supportive of a diagnosis of PID. Similarly, an endocervi- macrolide-resistant PID caused by M. genitalium.19
cal Gram stain, obtained after cleaning the ectocervix, showing Data from a large randomized clinical trial comparing inpatient
gram-negative intracellular diplococci, 30 or more polymorphonu- and outpatient therapy indicate that outpatient therapy is associated
TABLE
54-2 Recommended Treatment of Pelvic Inflammatory Disease
ORAL TREATMENT
Regimen A Either Ceftriaxone 250 mg im, or

Cefoxitin 2 g im plus probenecid 1 g po in a single dose concurrently, or
Other parenteral third-generation cephalosporin (e.g. ceftizoxime or cefotaxime)
Plus Doxycycline 100 mg po q12h for 14 days
With or without Metronidazole 500 mg po q12h for 14 days
Regimen B* Either Ofloxacin 400 mg po q24h for 14 days, or

Levofloxacin 500 mg po q24h for 14 days
With or without Metronidazole 500 mg po q12h for 7 days
PARENTERAL TREATMENT
Regimen A Either Cefotetan 2 g iv q12h, or

Cefoxitin 2 g iv q6h
Plus Doxycycline 100 mg iv or po q12h
Regimen B Plus Clindamycin 900 mg iv q8h
Gentamicin loading dose iv or im (2 mg/kg body weight) followed by a maintenance dose of 1.5 mg/kg;
single daily dosing may be substituted
Parenteral regimens should be continued for 48 hours after substantial clinical improvement. Doxycycline 100 mg po q12h or clindamycin 450 mg po q6h should then
be administered for a total of 14 days.
*This regimen should not be used if quinolone-resistant N. gonorrheae is suspected.
Data from Centers for Disease Control and Prevention: Sexually transmitted diseases treatment guidelines 2010. MMWR Morb Mortal Wkly Rep 2010; 59:1–1109.
hours after administration of antibiotics suggests medical failure and

TABLE Recommendations for Hospitalizing Patients requires drainage (e.g. percutaneous or transvaginal under sono-
54-3 who have Pelvic Inflammatory Disease graphic guidance, or via laparoscopy or laparotomy). Leaking or rup-
tured abscesses require immediate laparotomy after stabilization of the
Uncertain tolerance or Substance abusers
compliance with Nausea and vomiting
patient. Extensive surgery such as complete hysterectomy is rarely indi-
outpatient regimen Follow-up at 72 hours after starting antibiotic cated except in life-threatening complications such as extensive
treatment is problematic necrotic myometrium.
Complicating factors Pregnancy
Suspected pelvic or tubo-ovarian abscess Postpartum Endometritis and
Severe illness Temperature over 38.3 °C (101 °F)
White blood cell count >15 x109/L
Cesarean Section
Peritoneal signs
Septic Epidemiology
Uncertain diagnosis Failure to respond clinically to outpatient Postpartum endometritis, an infection of the uterus, is the most
treatment common cause of maternal postpartum fever and includes the inflam-
Inability to exclude surgical emergencies
(ectopic pregnancy, appendicitis)
matory conditions of endometritis, endomyometritis and endopara-
metritis. It can be categorized into early infection (i.e. onset within 48
hours of delivery) and late infection (i.e. onset 2 days to 2 weeks after
delivery). The most significant risk factor for postpartum endometritis
with similar short- and long-term treatment outcomes in women with is Cesarean section; the incidence of postpartum endometritis after
mild to moderate PID.6 Hospitalization is recommended for women vaginal delivery is 2–5% whereas the rate after Cesarean section ranges
whose tolerance or compliance with outpatient regimens is uncertain, from 20% to 55%.22 Postpartum upper tract infections following
or who have factors that complicate treatment, severe illness or an vaginal delivery are about 10 times more common in low- and middle-
uncertain diagnosis (Table 54-3). income countries than in higher-income countries as a result of
Supportive therapy includes hydration, bed rest in the semi-Fowler unclean delivery practices, traditional birth practices and the high
position to localize the infection to the pelvis, pelvic rest and pain prevalence of STDs in some populations.23
relief. The patient should abstain from sexual intercourse until test-of-
cure studies and resolution of signs and symptoms. All sexual partners Pathogenesis and Pathology
in the previous 30 days should be evaluated and presumptively treated Early postpartum endometritis usually is associated with non-elective
for gonococcal and chlamydial infection. Explicit and clear patient Cesarean section and is probably the result of direct uterine contami-
education cannot be overemphasized in the treatment of PID, espe- nation by organisms in the amniotic cavity. This is in contrast to
cially in the context of outpatient management. women with late postpartum endometritis, which usually develops
The incidence of ascending infection among pregnant women who after vaginal delivery. The timing of late infections suggests an ascend-
have intact membranes is unknown but is believed to be rare.20 ing infection similar to the mechanisms for PID. Wound infections
However, given the high risk of miscarriage and preterm delivery after Cesarean section may be the result of a direct contamination of
associated with PID, pregnant women who have PID must be hospital- the wound by organisms in the endometrium at the time of surgery.
ized and given parenteral antibiotic therapy.11 Postpartum endometritis is a mixed aerobic–anaerobic infection
Women who have tubo-ovarian abscesses should be hospitalized (Table 54-4). Ureaplasma urealyticum and M. hominis have also been
and begun on broad-spectrum antibiotics (aminoglycoside plus isolated from the endometrium and blood of infected women, but
clindamycin or metronidazole). Most abscesses with a diameter of their significance is not clear.24C. trachomatis is associated with the late
4–6 cm, but only 40% of those that are 10 cm or larger, respond to form of postpartum endometritis.25 Group A β-hemolytic streptococ-
antibiotics alone.21 Increasing abscess size or failure to defervesce 72 cal endometritis is rare; clustered cases are probably related to a
second-generation cephalosporins (cefoxitin or cefotetan) or the

TABLE Common Endogenous Micro-organisms extended-spectrum penicillins (ticarcillin–clavulanate or sulbactam–
54-4 Identified as Potential Etiologic Agents in ampicillin).30 The combination of aminoglycoside plus clindamycin
Postoperative Pelvic Infections remains appropriate.32 Once-daily administration of aminoglycosides
appears to be effective and safe.32 Women should continue to receive
Aerobic bacteria Streptococcus spp.
Enterococcus spp.
parenteral therapy until fever has resolved, uterine tenderness and
Staphylococcus aureus abdominal pain are gone, and white blood cell count has normalized.
Staphylococcus epidermidis Subsequent oral antibiotic therapy with erythromycin or doxycycline
Escherichia coli is indicated only in women who require it for a documented chla-
Klebsiella pneumoniae
Gardnerella vaginalis
mydial infection for a total of 10–14 days.
Reasons for failure to respond to antimicrobial therapy include
Anaerobic bacteria Bacteroides spp. inappropriate antibiotics (enterococcal infection or resistant anaerobic
Peptostreptococcus spp.
Prevotella bivia
infection), pelvic or wound abscess, or ovarian vein thrombophlebitis.
Prevotella disiens When postpartum septic pelvic thrombophlebitis is suspected, heparin
Fusobacterium spp. should be given.31 Late postpartum endometritis can be managed in
Mycoplasmas Mycoplasma hominis the same way as PID (see Table 54-2).
Ureaplasma urealyticum
Episiotomy Infections
common source, often a caregiver. Herpes simplex endometritis has Epidemiology
also been reported.26 Bacteremia occurs in 10–20% of patients and Episiotomy infections are rare. The rate of infection of episiotomies is
most common blood isolates are group B streptococci, Gardnerella 0.1% overall but increases to 1–2% of episiotomies with third- or
vaginalis and Peptostreptococcus spp. fourth-degree extensions. Rarely, they can have severe and even fatal
consequences.
Prevention
The only intervention that clearly reduces the risk of endometritis is Pathogenesis and Pathology
the use of prophylactic antibiotics for patients requiring a non-elective Episiotomy infections have been classified into four categories based
Cesarean section after labor or rupture of membranes, with a two- on the depth of infection in the soft tissue: simple infection, superficial
thirds to three-quarters reduction in infection.22,27,28 fascial infection, superficial fascial necrosis and myonecrosis.33 Bacteria
implicated in episiotomy infections include skin pathogens, strepto-
Clinical Features cocci and staphylococci, and bacteria associated with vaginal flora.
Risk factors for postpartum endometritis include duration of labor, Clostridium perfringens and C. sordellii are likely if myonecrosis is
length of time membranes remain ruptured, presence of STDs or of present. Methicillin-resistant Staphylococcus aureus has also been
BV, number of vaginal examinations, use of internal fetal monitoring reported as a cause of episiotomy infection.34
and socioeconomic status.24,29,30
Postpartum endometritis should be suspected in any woman who Prevention
develops significant fever (oral temperature 38.5 °C [101.3 °F] or Treatment standards reducing the liberal or routine use of episioto-
higher in the first 24 hours after delivery or 38 °C [100.4 °F] or higher mies, which increase the risk of third- and fourth-degree tears, may in
for at least 4 consecutive hours, 24 hours or more after delivery). The turn prevent infections. In the USA between 1980 and 2005 there was
diagnosis of postpartum endometritis can be made on the basis of an overall decline in the use of episiotomy from 64% to 19%.35
clinical features of fever and when signs such as abdominal pain,
uterine tenderness, foul lochia, increased uterine bleeding and uterine Clinical Features
subinvolution, are present. Late-onset endometritis tends to have a The simple wound infection is a local infection of the incision site in
mild, subacute clinical presentation. the skin and the superficial fascia. Clinically there is edema and ery-
Acute complications of postpartum endometritis include pelvic thema only along the incision. A superficial fascial infection resembles
abscess and puerperal ovarian vein thrombophlebitis. Puerperal a cellulitis with erythema, edema and pain. Often, infection of the
ovarian vein thrombophlebitis, an acute thrombosis of one or both episiotomy site may be associated with dehiscence. A superficial infec-
ovarian veins, is usually associated with postpartum endometritis, with tion may be indistinguishable from an early superficial fascial infection
an onset of 2–4 days after delivery, and can cause septic pulmonary with necrosis (necrotizing fasciitis). Necrotizing fasciitis involves all
emboli. The reported incidence is 1 in 2000 deliveries.31 Chronic com- layers of the superficial fascia (and may involve the deep fascia). Skin
plications and sequelae result from postinfectious scarring. anesthesia may precede the skin breakdown because of nerve involve-
ment. As nutrient vessels are occluded, the skin may turn dusky and
Diagnosis develop bullae and then frank necrosis. Subcutaneous gas may be
A complete blood cell count and blood cultures should be obtained present with the mixed infection. These patients often have evidence
from all patients before starting therapy. Tests for the detection of of marked toxicity out of proportion to the clinical findings. In myo-
cervical infection with N. gonorrhoeae and C. trachomatis should be necrosis, pain is often the dominant feature. Patients are extremely
obtained from all women at risk of STDs. Endometrial cultures are toxic, restless and confused or disoriented.
rarely used in clinical practice. If an adnexal mass is felt on examina-
tion, ultrasound or CT can be used to confirm the diagnosis. Diagnosis
Prompt diagnosis is of paramount importance because necrotizing
Management fasciitis and myonecrosis are rapidly progressive. Frozen-section
Postpartum endometritis is commonly treated parenterally with a examination of full-depth biopsy specimens has been helpful in the
broad-spectrum antibiotic regimen with activity against Bacteroides diagnosis of necrotizing fasciitis.36 Emergent surgical exploration is
fragilis and other penicillin-resistant anaerobic bacteria, such as warranted if necrotizing fasciitis or myonecrosis is suspected.
Management tive age who presents with fever, abdominal pain and bleeding. Details
of the procedure, especially microbiologic studies and pathology of the
Management of a simple episiotomy wound infection includes opening aborted tissues, may be helpful. Physical examination findings include
of the incision and exploration to ensure that there is no accumulated uterine tenderness, foul or purulent cervical discharge and products of
blood or a rectovaginal opening. Any superficial fascial infection conception at the cervical os. In more severe infections the patient may
should be managed with broad-spectrum antibiotic coverage (e.g. be hypotensive or in shock. The presence of cervical or vaginal lacera-
ampicillin–gentamicin with metronidazole or clindamycin) and tions should be determined. Women who have clostridial infection
observed closely. After initial management and control of the infection, may have severe disseminated intravascular hemolysis.
early repair in the immediate postpartum period can be considered in While fatal infections involving C. sordellii occur in 0.58 per 100 000
a patient with dehiscence secondary to infection.37 medical abortions, infection with this pathogen may have atypical
More extensive surgical exploration should be undertaken if ery- features.39 Classic features of infection, such as fever, purulent dis-
thema and edema extend beyond the incision site, if there is no charge, uterine tenderness and elevated white blood cell count, are
improvement in 24–48 hours after starting antibiotics, if the patient notably absent until the patient is in shock; the only early warning may
deteriorates, or if the patient has severe systemic manifestations. In the be excessive uterine bleeding.40
case of necrotizing fasciitis, the superficial fascia will separate easily Complications of septic abortion seen in severe stages include
from the deep fascia with a probe or finger (this does not occur in respiratory distress syndrome, septic shock, renal failure, abscess for-
healthy tissue), the incisions will be bloodless and the exudate will be mation, septic pelvic vein thrombophlebitis and septic emboli, and
serosanguinous rather than purulent. Surgical debridement of all disseminated intravascular coagulopathy; death may occur. Chronic
necrotic and pale tissue should be performed promptly and broad- complications are similar to those of PID.
spectrum antibiotic therapy should be instituted. The wound should
be left open after debridement with further surgery dependent on the
patient’s progress.
Diagnosis
Myonecrosis is a rare event that is usually caused by C. perfringens Except for women who have mild, early, uncomplicated postabortion
or C. sordellii but may result from an extension of necrotizing fasciitis endometritis, all women should have blood and cervical cultures as
through the deep fascia to the muscle. Therapy includes high-dose well as a complete blood cell count and urinalysis. Upright and flat
penicillin and urgent surgical debridement. Hyperbaric oxygen therapy abdominal and pelvic radiographs should be done to look for air in
remains controversial and should be considered adjunctive therapy. the abdominal cavity, dilated bowel and gas in the uterus. Pelvic ultra-
sound can detect retained tissue and other fluid collections and the
disruption of the myometrium by fluid or gas. CT is useful in assessing
Postabortion Sepsis the entire abdomen. Laparoscopy can be used to examine the uterus
for perforation but is suboptimal for a detailed examination of the
Epidemiology bowel.38
Postabortion sepsis is an ascending infection of the female pelvis after
spontaneous or induced abortion. Inflammatory conditions associated Management
with infectious complications of abortion are similar to those for PID Any woman who has an incomplete or failed abortion or retained
but can be complicated by retained, poorly perfused tissue or uterine clotted or liquid blood (hematometra) should undergo immediate
or bowel trauma. The mortality from abortion in higher-income coun- re-evacuation,41 as retained tissue serves as a nidus for infection. The
tries is low and abortion accounts for about 5% of all maternal mortal- recommended treatment of PID (see Table 54-2) is appropriate for a
ity in the USA. Infection is the major cause when mortality does result woman with early, uncomplicated postabortion infection. The patient
from abortion complications (up to 33% in the USA).38 In low- and should be evaluated 48 hours after institution of therapy. If fever or
middle-income countries (LMIC) the World Health Organization esti- pain persists, then the patient should be hospitalized and evaluated as
mates that illegal abortion accounts for 25–50% of the 500 000 mater- above.
nal deaths that occur each year. Women who have more severe illness should be hospitalized and
begun on broad-spectrum antibiotics such as ampicillin, gentamicin
Pathogenesis and Pathology and clindamycin. If clostridial infection is suspected, high-dose peni-
The bacteria associated with postabortion sepsis are similar to those cillin therapy should be used in place of ampicillin. These patients
in PID. However, the potential of direct uterine or bowel injury and should be monitored closely and aggressively evaluated for uterine
retention of the products of conception after an abortion enlarges perforation and bowel injury. In the case of suspected C. sordellii infec-
the spectrum to enteric organisms, including C. perfringens. In LMIC, tion, some experts recommend the combination of clindamycin and
tetanus is a cause of mortality after abortion. More recently, C. sordellii imipenem–cilastatin.42 Laparotomy with possible hysterectomy should
has been associated with fulminant infections, secondary to lethal toxic be performed if there is failure to respond to uterine evacuation and
shock-like syndrome, in women undergoing medical abortion with medical therapy, uterine perforation with necrotic myometrium or
mifepristone.39 suspected bowel injury, pelvic and adnexal abscesses, or clostridial
myometritis. Indications for a total hysterectomy with removal of
adnexa include a discolored, woody appearance of the uterus and
Prevention adnexa, clostridial sepsis, pelvic tissue crepitation and gas in the uterine
Prevention measures include providing effective and acceptable con- wall on radiographs.
traception and appropriate medical management of abortion. Prophy-
laxis for cervical and vaginal infections, particularly for BV, before
voluntary termination of pregnancy decreases the risk of postabortal
infection.11 Prompt diagnosis and effective treatment of endometritis
Postoperative Gynecologic
after the procedure is extremely important as delayed treatment is a Infections
common feature in cases of death from septic abortion.
Epidemiology
Clinical Features Hysterectomy is the most frequently performed elective surgical pro-
The diagnosis of septic abortion should be considered in any woman cedure among women of reproductive age in the USA.35 The spectrum
who has a temperature of 38 °C (100.4 °F) or higher on two occasions of postoperative infections after hysterectomy includes vaginal cuff
more than 24 hours after an abortion and in any woman of reproduc- cellulitis, pelvic cellulitis, vaginal cuff abscess, pelvic abscess and
wound infections.27 Rates of infection after abdominal hysterectomy In a vaginal cuff abscess patients typically have fever 2–3 days post-
range from 11% to 38% without, and from 4% to 8% with, antibiotic operatively and report vaginal fullness. On examination, a tender pal-
prophylaxis. For vaginal hysterectomies, infection rates vary between pable collection will be found above the vaginal surgical margin. A
12% and 64% without, and between 0% and 10% with, antibiotic phlegmon would be diagnosed if a tender mass is felt in one or both
prophylaxis.43 Risk factors for postoperative infection include duration parametrial areas and if no abscess is identified on radiographic
of surgery, younger age, lower socioeconomic status and the presence studies. Pelvic abscesses may sometimes present many weeks after
of BV. surgery. Wound infections are characterized by pain, marginal cellulitis
and purulent exudate. Septic pelvic vein thrombophlebitis and osteo-
Pathogenesis and Pathology myelitis pubis are rare complications of gynecologic surgery.
Bacterial contamination of the operative site with flora of the lower
reproductive tract occurs primarily at the vaginal incision. Hospitaliza- Diagnosis
tion itself, regardless of whether antimicrobial prophylaxis is given, Microbiologic cultures obtained from drained abscesses are useful in
changes the vaginal flora, resulting in an increase in colony counts guiding therapy. Cultures of the vaginal cuff are likely to be contami-
of Escherichia coli, Enterococcus faecalis and Bacteroides spp. and a nated with vaginal flora. Abdominal and pelvic ultrasound and CT
decline in Staphylococcus epidermidis and Streptococcus and Peptostrep- scans are useful to confirm the presence of a fluid collection when
tococcus spp. pelvic abscesses are suspected.
Postoperative infections involve a mix of aerobic and anaerobic
bacteria from the lower reproductive tract (see Table 54-4). Bacteroides Management
fragilis and Fusobacterium spp. are more common in infections than Patients who have pelvic cellulitis should be treated with a broad-
when they are found in normal vaginal flora. spectrum parenteral antibiotic regimen, such as a second-generation
cephalosporin (cefoxitin or cefotetan), extended-spectrum penicillin
Prevention (ticarcillin–clavulanate or sulbactam–ampicillin), or an aminoglyco-
Patients undergoing elective hysterectomy should be screened and, if side plus clindamycin, for 24–36 hours after the patient becomes afe-
necessary, treated for BV several weeks before surgery. Preoperative brile. Cuff abscesses should be managed similarly, and the abscess
single-dose antibiotic prophylaxis substantially reduces the rate of should be drained. Vaginal cuff cellulitis can be managed on an out-
postoperative febrile morbidity in these procedures.27,43 patient basis with oral antibiotics such as amoxicillin–clavulanic acid,
but patients should have a follow-up evaluation 72 hours after starting
therapy.
Clinical Features Medical therapy that covers gram-negative aerobes and anaerobes
Postoperative fever itself does not indicate infection but should prompt (aminoglycoside–clindamycin or aminoglycoside–metronidazole) is
the clinician to evaluate the patient for one. In pelvic cellulitis, symp- often successful in treating smaller postoperative pelvic abscesses that
toms usually occur 2–3 days after surgery and include fever (tempera- are inaccessible to drainage. Patients who fail to respond to medical
ture over 38 °C [100.4 °F]) and increasing abdominal and pelvic pain therapy alone (no defervescence in 72 hours or enlarging abscess)
that may not be symmetric.44 Pelvic tenderness without palpable mass require laparotomy and drainage or excision. Abscesses accessible from
is found on bimanual examination. a cutaneous surface should be drained. Patients should be treated with
Histologic vaginal cuff cellulitis will develop in all women postop- parenteral antibiotics until all signs and symptoms have resolved.
eratively as part of the normal healing process; most cases resolve Some clinicians give post-discharge outpatient treatment with met-
without antibiotic therapy. Women who have more severe cellulitis will ronidazole and amoxicillin for 1 week after discharge in those patients
complain of increasing central or lower abdominal pain, vaginal dis- who responded to medical management. All patients who have pelvic
charge and low-grade fever, usually within the first 2 weeks postopera- abscesses should be re-evaluated 2 weeks after discharge to ensure no
tively. Bimanual pelvic examination may show only mild pelvic recurrence of the abscess has occurred.
tenderness to deep palpation. Speculum examination will show a
tender, indurated, hyperemic vaginal surgical margin. References available online at expertconsult.com.
KEY REFERENCES
Beal M.W.: Update on medication abortion. J Midwifery Hemsell D.L., Nobles B., Heard M.C.: Recognition and Peipert J.F., Ness R.B., Blume J., et al.: Clinical predictors of
Womens Health 2007; 52:23-30. treatment of post-hysterectomy pelvic infections. Infect endometritis in women with symptoms and signs of
Beigi R.H., Weisenfeld H.: Pelvic inflammatory disease: new Surg 1988; 7:47-68. pelvic inflammatory disease. Am J Obstet Gynecol 2001;
diagnostic criteria and treatment. Obstet Gynecol Clin Hemsell D.L.: Prophylactic antibiotics in gynecologic and 184:856-864.
North Am 2003; 30:777-793. obstetric surgery. Rev Infect Dis 1991; 13(Suppl. Soper D.E.: Diagnosis and laparoscopic grading of acute
Cates W., Rolfs R.T., Aral S.O.: Sexually transmitted diseases, 10):821-841. salpingitis. Am J Obstet Gynecol 1991; 164:1370-1376.
pelvic inflammatory disease and infertility: an epidemio- Horner P., Blee K., Adams E.: Time to manage Mycoplasma Watts D.H., Eschenbach D.A., Kenny G.E.: Early postpartum
logic update. Epidemiol Rev 1990; 12:199-220. genitalium as an STI: but not with azithromycin 1 gram. endometritis: the role of bacteria, genital mycoplasmas,
Centers for Disease Control and Prevention: Sexually trans- Curr Opin Infect Dis 2014; 27(1):68-74. and Chlamydia trachomatis. Obstet Gynecol 1989;
mitted diseases treatment guidelines, 2010. MMWR Morb Maharaj D.: Puerperal pyrexia: a review. Part I. Obstet 73:52-60.
Mortal Wkly Rep 2010; 59:1-110. Gynecol Surv 2007; 62:393-399. Weström L., Eschenbach D.: Pelvic inflammatory disease.
French L.M., Smaill F.M.: Antibiotic regimens for endome- Ness R.B., Soper D.E., Holley R.L., et al.: Effectiveness of In: Holmes K.K., Sparling P.F., Märdh P.-A., et al., eds.
tritis after delivery (Cochrane Review). Cochrane Data- inpatient and outpatient treatment strategies for women Sexually transmitted diseases. New York: McGraw–Hill;
base Syst Rev 2004; (4):CD001067. with pelvic inflammatory disease: results from the Pelvic 1999:783-809.
Grimes D.A., Cates W. Jr, Selik R.M.: Fatal septic abortion Inflammatory Disease Evaluation and Clinical Health
in the United States, 1975–1977. Obstet Gynecol 1981; (PEACH) Randomized Trial. Am J Obstet Gynecol 2002;
57:739-744. 186:929-937.
Chapter 54 Infections of the Female Pelvis, Including Septic Abortion 497.e1
REFERENCES
1. Weström L., Eschenbach D.: Pelvic inflammatory 16. Clinical Effectiveness Group: UK national guideline for 30. Watts D.H., Krohn M.A., Hillier S.L., et al.: Bacterial
disease. In: Holmes K.K., Sparling P.F., Märdh P.-A., the management of pelvic inflammatory disease 2011. vaginosis as a risk factor for post-cesarean endometritis.
et al., eds. Sexually transmitted diseases. New York: London (UK: British Association for Sexual Health and Obstet Gynecol 1990; 75:52-58.
McGraw–Hill; 1999:783-809. HIV; 2011:18. 31. Duff P., Gibbs R.S.: Pelvic vein thrombophlebitis: diag-
2. Sweet R.L.: Role of bacterial vaginosis in pelvic inflam- 17. Centers for Disease Control and Prevention: Update to nostic dilemma and therapeutic challenge. Obstet
matory disease. Clin Infect Dis 1995; 20(Suppl. 2):271- CDC’s sexually transmitted diseases treatment guide- Gynecol Surv 1983; 38:365-373.
275. lines, 2006: fluoroquinolones no longer recommended 32. French L.M., Smaill F.M.: Antibiotic regimens for
3. Farley T.M.M., Rosenberg M.J., Rowe P.J., et al.: Intra- for treatment of gonococcal infections. MMWR Morbid endometritis after delivery (Cochrane Review).
uterine devices and pelvic inflammatory disease: an Mortal Wkly Rep 2007; 56:332-336. Cochrane Database Syst Rev 2004; (4):CD001067.
international perspective. Lancet 1992; 339:785-788. 18. Centers for Disease Control and Prevention: Oral ceph- 33. Shy K.K., Eschenbach D.A.: Fatal perineal cellulitis
4. Wolner-Hanssen P., Eschenbach D.A., Paavonen J., alosporins no longer a recommended treatment for from an episiotomy site. Obstet Gynecol 1979; 54:292-
et al.: Decreased risk of chlamydial pelvic inflammatory gonococcal infections. MMWR Morbid Mortal Wkly 298.
disease associated with oral contraceptive use. JAMA Rep 2012; 61(31):590-594. 34. Rotas M., McCalla S., Liu C., et al.: Methicillin-resistant
1990; 263:54-59. 19. Horner P., Blee K., Adams E.: Time to manage Myco- Staphylococcus aureus necrotizing pneumonia arising
5. Cates W., Rolfs R.T., Aral S.O.: Sexually transmitted plasma genitalium as an STI: but not with azithromycin from an infected episiotomy site. Obstet Gynecol 2007;
diseases, pelvic inflammatory disease and infertility: an 1 gram. Curr Opin Infect Dis 2014; 27(1):68-74. 109:533-536.
epidemiologic update. Epidemiol Rev 1990; 12:199-220. 20. Watts H.D., Brunham R.C.: Sexually transmitted dis- 35. DeFrances C.J., Cullen K.A., Kozak L.J.: National Hos-
6. Ness R.B., Soper D.E., Holley R.L., et al.: Effectiveness eases, including HIV infection in pregnancy. In: pital Discharge Survey: 2005 annual summary with
of inpatient and outpatient treatment strategies for Holmes K.K., Sparling P.F., Märdh P.-A., et al., eds. detailed diagnosis and procedure data. Vital Health Stat
women with pelvic inflammatory disease: results from Sexually transmitted diseases. New York: McGraw–Hill; 2007; 13(165):1-209.
the Pelvic Inflammatory Disease Evaluation and Clini- 1999:1089-1132. 36. Stamenkovic I., Lew P.D.: Early recognition of poten-
cal Health (PEACH) Randomized Trial. Am J Obstet 21. Amstey M.S., Sweet R.: Definition of pelvic abscess. Am tially fatal necrotizing fasciitis: use of frozen-section
Gynecol 2002; 186:929-937. J Obstet Gynecol 1993; 168:740-741. biopsy. N Engl J Med 1984; 310:1689-1693.
7. Scholes D., Stergachis A., Heidrich F.E., et al.: Preven- 22. Faro S., Martens M.G., Mannill H.A., et al.: Antibiotic 37. Ramin S.M., Ramus R.M., Little B.B., et al.: Early repair
tion of pelvic inflammatory disease by screening for prophylaxis: is there a difference? Am J Obstet Gynecol of episiotomy dehiscence associated with infection. Am
cervical chlamydial infection. N Engl J Med 1996; 1990; 162:900-909. J Obstet Gynecol 1992; 167(4 Pt 1):1104-1107.
334:1362-1366. 23. Meheus A.: Women’s health: importance of reproduc- 38. Grimes D.A., Cates W. Jr, Selik R.M.: Fatal septic abor-
8. Sweet R.L., Landers D.V.: Pelvic inflammatory disease tive tract infections, pelvic inflammatory disease and tion in the United States, 1975–1977. Obstet Gynecol
in HIV-positive women. Lancet 1997; 349:1265-1266. cervical cancer. In: Germain A., Holmes K.K., Piot P., 1981; 57:739-744.
9. Centers for Disease Control and Prevention: Sexually et al., eds. Reproductive tract infections: global impact 39. Meites E., Zane S., Gould C.: Fatal Clostridium sordellii
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10. Sellors J., Mahony J., Goldsmith C., et al.: The accuracy 24. Watts D.H., Eschenbach D.A., Kenny G.E.: Early post- 40. Miech R.P.: Pathophysiology of mifepristone-induced
of clinical findings and laparoscopy in pelvic inflamma- partum endometritis: the role of bacteria, genital myco- septic shock due to Clostridium sordellii. Ann Pharma-
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12. Peipert J.F., Ness R.B., Blume J., et al.: Clinical predic- 26. Hixson M.J., Collins J.H.: Postpartum herpes simplex 42. Beal M.W.: Update on medication abortion. J Mid-
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13. Taourel P., Pradel J., Fabre J.M., et al.: Role of CT in and obstetric surgery. Rev Infect Dis 1991; 13(Suppl. 8(Suppl. D):115-129.
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CT MRI 1995; 16:151-164. 28. Maharaj D.: Puerperal pyrexia: a review. Part I. Obstet treatment of post-hysterectomy pelvic infections. Infect
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1376.
55
Complications of Pregnancy:
Maternal Perspectives
GUILLAUME DURAND | FLORENCE BRETELLE | FLORENCE FENOLLAR
KEY POINTS Epidemiology

• Poverty is the most important risk factor for maternal infections INCIDENCE AND PREVALENCE
during pregnancy. In the general population, the attributable risk of infection causing
• During pregnancy:
adverse pregnancy outcomes depends on the prevalence of infections
• Avoid raw or undercooked fresh meat and refrigerated in the population as well as on the socioeconomic and cultural factors
ready-to-eat food not freshly prepared that influence health, health behavior and healthcare-seeking behavior.
• Peel or wash raw fruit and vegetables to remove contaminat- All infections that manifest with fever increase the risk of pre-term
ing soil birth due to the release of pyrogens that increase myometrial activity.
• Wash hands after disposing of cat litter or gardening. Between 2000 and 2010 nearly 4.9 million children <5 years of age
• Fever is a frequent reason for consulting a physician during
worldwide died of infectious diseases. About 7.6 million of those
pregnancy. deaths (around 40%) occurred in neonates.1 The average annual rate
of reduction of the neonatal mortality globally accelerated between
• Irrespective of the etiology, fever may have serious conse- 2000 and 2010 (2.1% per year), but was slower than the reduction in
quences due to poor embryonal and fetal tolerance of hyper- mortality of children aged >1 month old (2.9% per year) and maternal
pyrexia, and fever increases the risk of premature delivery. mortality (4.2% per year).4 However, the neonatal mortality rate varies
• Urinary tract infections are the most common infections during by geographic area (from 3% per year for low- and middle-income
pregnancy. countries to 1.5% per year for other counties4), as do stillbirths (occurs
in 7 per 1000 births in the USA, in comparison to 90 per 1000 births
• Infections in pregnancy can be asymptomatic but usually
manifest with symptoms similar to those in nonpregnant
in low- and middle-income countries5). Tuberculosis (TB) is also a
individuals. major public health concern: 4.4 million women were infected in 2010
worldwide,6 and human immunodeficiency virus (HIV) infection is an
• In the event of premature rupture of membranes, fever sug- important trigger of TB during pregnancy with an 10-fold increased
gests chorioamnionitis. risk.7,8 Maternal mortality caused by TB is around 6–10% in low HIV
• In the event of fever during pregnancy, bacteriologic examina- prevalence areas and increases to 15% in regions of high HIV preva-
tion of the urine must be conducted together with viral serol- lence9,10 (see Chapters 96, 99 and 101).
ogy as well as serology for Coxiella burnetii. Sexually transmitted infections, including trichomoniasis, gonor-
rhea, Chlamydia infection and syphilis, have also been associated with
• In the event of cervicovaginal symptoms or suspected chorio-
amniotis, vaginal specimens are required.
adverse pregnancy outcomes, including pre-term birth, pre-term pre-
mature rupture of membranes (pPROM), low birth-weight and post-
partum infection.11,12
In Africa, infection is the leading cause of child mortality. Many
deaths are associated with malaria, which remains a problem in
endemic regions because Plasmodium falciparum infections during
pregnancy, notably placental parasitism, is rarely associated with fever,
Introduction and therefore remain undetected, and so untreated.13 Incidence of
Infections occur frequently during pregnancy and represent an impor- malaria in Africa has decreased, with a peak at 0.7 million in 2004,1
tant cause of morbidity and mortality among mothers, fetuses and and the prevalence in Africa between 1990 and 2011 was 38.2%
neonates. Infection in the mother can have nonspecific fetal or obstet- (peripheral parasitemia) and 39.9% (placental parasitemia). In the
ric effects. It can lead to miscarriage, preterm birth or fetal death but same period and geographical area, the prevalence of syphilis, Neisseria
it can also lead to fetal malformations and growth restriction. Indeed, gonorrhoeae, Chlamydia trachomatis and Trichomonas vaginalis was
64% of worldwide deaths in children aged less than 5 years are related respectively 3.5%, 2.7%, 6.1% and 17.8%, according to Chico et al.14
to infectious diseases, with 40% affecting neonates.1 The proportion The stillbirth rate was 800 000 per year in Africa between 1990 and
of neonatal mortality caused by infections is estimated at 50%,2 and 2011.14 Of note, the cases of measles decreased from 0.477 million in
around 9–15% of stillbirths are linked to infection.3 Medical progress, 2000 to 0.114 in 2010,1 despite a recurrence in Europe since 2009. In
such as effective antibiotics and vaccines, in combination with South East Asia, Al-Taiar et al. found the incidence of early onset sepsis
improved living conditions have modified the sequelae of infections, (EOS) three days before birth at 0.62 per 1000 live births.2 Group B
yet infectious morbidity in pregnancy remains a serious problem. streptococci (GBS) remains the most common single pathogen of EOS,
From the infectious standpoint, there are two periods of risk for and Klebsiella spp. were the most common gram-negative bacteria
the fetus. The first is during pregnancy: maternal infection, symptom- causing death.2 Indeed, Klebsiella spp., Staphylococcus aureus and Esch-
atic or not, can infect the fetus directly if the micro-organism has erichia coli were responsible for 55% of neonatal sepsis.15
tropism for the fetus or placenta, causing embryopathy, stillbirth, or In higher-income countries, Onderdonk et al. demonstrate that
prematurity; or indirectly in case of serious maternal illness with a risk pre-term delivery was the leading cause of mortality in the USA.16 GBS
of preterm labor. The second period of risk is linked to the possible continues to be a leading cause of perinatal infections,17 particularly
contamination of the neonate during delivery, resulting in sepsis or serotype III.18 Furthermore, a French study found GBS and E. coli, in
initiation of a chronic infection (Figure 55-1). respectively 58.5% and 22% of neonatal sepsis.19 The reported rates of
498
Chapter 55 Complications of Pregnancy: Maternal Perspectives 499
Potential sites of bacterial infection within the uterus
Amniotic fluid
Uterus
Placenta
Amnion Fetus
Chorioamnionitis
Funisitis
Chorion
Fetal infection
Choriodecidual
infection
Amniotic fluid
Decidua infection
Choriodecidual
infection
Myometrium Cervix
Vagina
Figure 55-1 Potential sites of bacterial infection within the uterus. (Reproduced from Goldenberg RL, et al. N Engl J Med 2000;18;342(20):1500–7.)
TABLE
55-1 Implications of Specific Infections on Pregnancy
Impact on Mother and Child Prevention Management
Listeriosis Mild maternal infection Early diagnosis in any febrile illness in Ampicillin 2 g iv q6h plus gentamicin
Serious impact on the fetus: amnionitis, pre-term pregnancy, cervical and blood cultures 2 mg/kg q8h for 1 week
birth, septic abortion, stillbirth, fatality rate for Listeria monocytogenes
3–50% Avoid implicated foods (e.g.
unpasteurized cheese)
Lyme disease Erythema migrans in the mother, risk of Protective clothes in tick-infected areas Early treatment with amoxicillin 500 mg
transmission unknown, probably low (rural forest); remove ticks po q6h for 10–30 days or ceftriaxone
Pre-term birth, stillbirth, syndactyly, cortical 2 g iv for 14 days
blindness, rash
Varicella-zoster Rare in adults, fever, malaise followed by rash, IgG testing if exposed In cases of pneumonia: hospital
20% risk of varicella pneumonia If no IgG: varicella-zoster immunoglobulin admission, respiratory support,
Risk of abortion, stillbirth 125 units/10 kg, max 625 units im, aciclovir 10–15 mg/kg for 7 days
Congenital varicella (limb hypoplasia, cortical <96h after exposure Ultrasound assessment of the fetus
atrophy, retardation, IUGR, cutaneous scars,
microphthalmia)
Measles Increased maternal mortality secondary to Passive immunization in susceptible Depending on symptoms
pneumonia exposed women with pooled
Risk of prematurity immunoglobulins 0.25 mL/kg within 6
Developmental abnormalities (e.g. congenital days of exposure
heart disease, cleft lip, cerebral leukodystrophy Avoid measles vaccine in pregnancy
and cyclopia have been reported)
LBW, low birth-weight; IUGR, intrauterine growth retardation.
GBS colonization in the genital tract range from 5% to 40%, with an neonates born from infected pregnant women are asymptomatic at
average transmission rate to the neonate of 60%. The rates of early- birth. Fourteen percent of cases of listeriosis in the USA occur during
onset GBS infection in the neonate, especially in pre-term and low- pregnancy, with an ethnic disparity: 43% concern Hispanic women.
birth-weight babies, can be as high as 3 per 1000 births; however, the Pre-term labor is reported in 64% of cases of infections with listeriosis
role of GBS in the occurrence of pre-term birth remains unclear. during pregnancy.24 However, there has been a decrease in cases of
Studies in the USA attributed an infectious disease to the causality listeriosis during pregnancy since 199925 (Tables 55-1 and 55-2).
of 12.9% of stillbirths (of which 41.9% were under 24 weeks’ gesta-
tion), with an unexplained racial disparity: non-Hispanic black women CLINICAL SYNDROMES
had a stillbirth risk 2.3-fold higher than non-Hispanic white women, Prevalence rates of HIV in pregnant women are increasing all over the
with a fourfold higher risk for Hispanic women.20,21 In the same study, world but have reached endemic proportions in low- and middle-
Parvovirus was found in 2% of cases. Of course, these rates are estima- income countries. The impact of maternal HIV infection shows an
tions, especially due to the difficulty of identifying some microbes, like increased risk of adverse obstetric outcomes, including abortion,
Parvovirus and Ureaplasma urealyticum.22 The seroprevalence of cyto- prematurity, low birth-weight and stillbirth, but only if the disease
megalovirus (CMV) is around 50% in the United Kingdom, as opposed is active.12,26 However, the main risk remains mother-to-child trans-
to 98% for South Asian women born in South Asia,23 and 90% of mission, with perinatal HIV transmission rates reported to occur with
TABLE
55-2 Implications of Some Sexually Transmitted Diseases on Pregnancy
Impact on Mother and Child Prevention Management
Neisseria gonorrhoeae Ophthalmia neonatorum, pre-term Silver nitrate 1% or tetracycline eye Spectinomycin 2 g im, ceftriaxone 250 mg
delivery, puerperal infections ointment im, or standard antimicrobial treatment
Chlamydia trachomatis Ophthalmia neonatorum, puerperal Tetracycline eye ointment Erythromycin 500 mg for 4–7 days
infections, pre-term delivery
Bacterial vaginosis Risk of pre-term birth Case detection and treatment is still Metronidazole 250 mg q8h for 3–7 days or
under study Erythromycin base 333 mg q8h for 3–14 days
Trichomonas vaginalis Risk of pre-term birth Case detection and treatment no Metronidazole 2 g single dose
proven effect
Condylomata Risk of respiratory papillomatoses Case detection and treatment Topical trichloroacetic acid (85%)/surgery
acuminatum 1/80–1/1500
Herpex simplex Neonatal herpes (50% in mother History from pregnant woman, In case of active lesions, Cesarean section or
with primary herpes at delivery) careful inspection of the genital vaginal delivery under aciclovir
tract on the day of delivery 200–400 mg q8h (under study)
HIV Transmission: 25–45% Antiretroviral therapy according to Avoid long labor, rupture of membranes <4h
Risk of abortion, pre-term delivery, the most recent guidelines Treat with antiretroviral therapy, according to
puerperal infections Elective Cesarean section the most recent guidelines
No breast-feeding
15–40% of births among HIV-infected women, and around 1–2% with and postpartum endometritis. Postpartum infections consist of genital
highly active antiretroviral therapy during pregnancy (see Chapter tract infections, puerperal mastitis, pelvic thrombophlebitis, UTIs,
101).27 Pregnancy can mask the clinical manifestations of TB8 and wound infections, complications of anesthesia, and other infectious
classic clinical symptoms, such as cough, sputum and hemoptysis, are complications. Postpartum endometritis seems to be a mixed infection
less common.28 Normal chest radiography is found in 14% in HIV- with aerobic and anaerobic bacteria from the genital tract. Genital tract
associated cases, which compromises its validity and effectiveness.29 infections of the uterus are the most common cause of puerperal infec-
Pulmonary TB is associated with a twofold increased risk of pre-term tion and are categorized as endometritis, endomyometritis or endo-
birth, low birth-weight, and sixfold increased risk of perinatal death.30 parametritis, depending on the extent of the infection. Wound and
Urinary tract infections (UTIs) are the most common infections in episiotomy infections occur frequently. After Cesarean section, wound
pregnancy, with or without clinical signs or symptoms, and are caused infection, defined as erythema, positive discharge, and/or positive
by micro-organisms that are part of the normal fecal flora, with E. coli wound cultures, varies between 5% and 10%, with emergency cases at
(80–90% of infections), facultative gram-negative bacteria, including higher risk of infection. Septic thrombophlebitis is a rare complication
Klebsiella, Proteus, Enterobacter and Pseudomonas spp., and gram- of pregnancy, with reported incidence rates of 1 per 2000 deliveries.
positive bacteria such as staphylococci and GBS. Asymptomatic bac- The incidence of puerperal mastitis is estimated at around 1% in lac-
teriuria is found in 4–7% of pregnant women, of whom 25–30% will tating women.
develop pyelonephritis later in pregnancy. UTIs are a leading cause of
pre-term birth.31 E. coli multidrug resistance, including extended spec- BURDEN OF DISEASE, MORBIDITY
trum β-lactamases (ESBL), is increasing globally, but with lower resis- AND MORTALITY
tance rates observed from urine isolates than from those of bacteremia.32 Intra-amniotic infection diagnosed on clinical criteria occurs in 1–5%
This important therapeutic problem should be quickly addressed of pregnancies, with or without ruptured membranes. Consequences
during pregnancy because of limited choice of drugs.33 However, of are preterm birth, pPROM and postpartum and neonatal infections.
note, McGready et al. found low antibiotic resistance levels of E. coli The mother and the fetus are put at risk with pPROM as it is associated
in pregnant women with pyelonephritis in Thailand.34 with preterm birth and frequent infectious morbidity. Ascending
Upper respiratory tract infections are common but of limited con- infections, either the cause or the result of pPROM, may lead to intra-
sequence for mother and child. In contrast, pneumonia is a serious amniotic infection, chorioamnionitis, placentitis and fetal infections,
illness for a pregnant woman, and is especially linked to Streptococcus including pneumonia and bacteremia. In contrast, ascending UTIs
pneumoniae, Haemophilus influenzae, group A β-hemolytic strepto- clearly play a role in the etiology of pre-term delivery and neonatal
cocci and coagulase-positive staphylococci. Chickenpox virus can death.
cause serious neonatal varicella if infection occurs between 5 days prior
and 2 days after the birth. Before 20 weeks’ gestation, the virus can RISK FACTORS
cause fetal chickenpox. Seroprevalence in the United Kingdom is esti- The primary infectious risk factor for poor pregnancy outcome,
mated at about 95%.23 Chickenpox can cause severe maternal pneu- including preterm birth, pPROM, spontaneous abortion, perinatal
monia during pregnancy that justifies antiviral treatment. morbidity and mortality, and maternal infections, does not relate to a
Gastrointestinal infections caused by viruses are usually mild with specific micro-organism, but rather to a perturbation of the vaginal
no harm to the pregnancy and no need for specific medication. The ecosystem and to bacterial vaginosis in particular.36–41 Preterm birth
burden of hepatitis E virus is unknown, but fulminant hepatitis E continues to increase despite available tocolytic treatments.42 Infection
occurs more frequently during pregnancy, and has been associated is one target in the effort to stem this rise.43 Among infections, bacterial
with a mortality rate of 20% among women in the third trimester (see vaginosis (BV) is a cause of late miscarriage and pre-term birth. Its
Chapter 42).35 Meningitis is rare except for areas in which HIV and prevalence varies highly according to risk factors and countries44 and
cryptococcal meningitis are endemic. Bacterial endocarditis is also its diagnosis also presents problems.45 BV is suspected in cases of mal-
uncommon and incidence rates vary from 1 per 4000 to 1 per 16 000 odorous discharge or abnormal leukorrhoea adherent to the vaginal
deliveries. walls and clinical manifestations are used as the diagnostic criteria.
The overall incidence of postpartum infections varies between 1% However, BV is asymptomatic in approximately 50% of cases. The
and 10%, depending on the definitions used, particularly for mastitis Nugent score on Gram smears is a diagnostic test that defines normal
vaginal flora, BV, or intermediate abnormal flora.46 The complexity of may also gain access to the amniotic cavity through intact membranes
this score limits its adoption, and its subjectivity requires that it be or after invasive procedures such as amniocentesis, chorionic villous
performed by experienced microbiologists to ensure consistency.45,47 sampling, umbilical blood sampling and cervical cerclage.
Moreover, it does not identify several bacterial morphotypes associ- Micro-organisms of interest during pregnancy are summarized in
ated with BV, in particular, Atopobium vaginae, and it underestimates Table 55-3. Symptomatic UTIs are more frequent in pregnancy for
BV recurrence.45,47,48 several reasons, including decreased ureteric muscle tone and activity,
The consequences of poverty are the most important risk factors dilation of the ureter and renal pelvis because of the progesterone
for maternal infections during pregnancy. Poor women are more sus- effect, and mechanical obstruction caused by an enlarging uterus,
ceptible to malnutrition, at increased risk of sexually transmitted dis- changes of the bladder and alterations in the properties of urine during
eases (STDs), with less adequate sanitary conditions and reduced pregnancy. Wound infections, often caused by group A or group B
access to preventive and curative healthcare than those who are finan- streptococci, or Clostridium perfringens, are determined by the surgical
cially better off. techniques used. In most cases of mastitis, Staph. aureus is the respon-
Factors known to increase the risk for wound infections are age, sible micro-organism, although Staphylococcus epidermidis and viri-
obesity, bacterial contamination, operating time and duration of pre- dans streptococci may also be isolated and are of questionable
operative hospitalization, emergency procedures, number of vaginal significance.
examinations, duration of internal fetal monitoring, length of labor Q fever is a widespread zoonosis caused by Coxiella burnetii,
and underlying maternal disease. an intracellular gram-negative bacterium recognized as a potential
category-B bioweapon. Human primary infection is asymptomatic or
presents as isolated fever, hepatitis, or pneumonia. It spontaneously
Pathogenesis and Pathology resolves but may become a chronic endocarditis in patients with val-
IMMUNITY vular lesions, arterial aneurysm, or prosthesis or in those who are
Current data from the literature indicate that pregnancy is a specific immunocompromised.57 During pregnancy, Q fever may result in
and unique immune condition, with differential responses depending obstetric complications including spontaneous abortion, intrauterine
on the micro-organisms and stage of pregnancy. The decidua contains growth retardation or fetal death, and premature delivery. In addition,
a high number of immune cells, such as macrophages, natural killer pregnant women exhibit an increased risk of Q fever endocarditis even
cells and regulatory T cells, which seem to be indispensable for decid- in the absence of underlying valvular lesions.58 This phenomenon has
ual formation.49,50 Therefore the trophoblast is an active immunologic been reproduced in C57BL/6 mice, where infection followed by
organ. The fetus also plays an active role; the immunologic response repeated pregnancies was shown to result in spontaneous abortion,
during pregnancy is a complex interaction of maternal, placental and perinatal death and endocarditis in some animals.59
fetal responses. Fetal damage can occur without passage through the
placenta, especially if infection leads to release of pro-inflammatory
cytokines (such as tumor necrosis factor (TNF-) alpha and gamma, Prevention
IL-12, IL-6) and alteration of the cytokine balance, which then induces Elimination of poverty and improvement of antenatal and obstetric
an inflammatory response in the fetus.51 care in deprived groups of society are primary strategies to prevent
The normal course of pregnancy is associated with a variety of adverse pregnancy outcomes. The challenge of identifying women at
changes in humoral and cellular immunity, such as a loss in CD4+ cells risk of adverse obstetric outcomes is still a subject of intensive research.
and other alterations in T-cell subsets,52–56 and is a succession of three Early markers of infection-related pre-term birth are needed to iden-
states. The first, from the beginning of pregnancy to the start of the tify a subset of women at risk for pre-term delivery who could benefit
second trimester, and the third, before birth, are pro-inflammatory from antimicrobial therapy. A vaginal pH ≥5.0 and the presence of
states. The second, in contrast, is an anti-inflammatory state. Reports vaginal neutrophils at a rate of more than five per oil-field on Gram
on T-cell subsets during pregnancy have been conflicting. Some studies stain were found to be strongly associated with early pre-term birth.60
have found a progressive fall in the CD4+ count throughout pregnancy, Overall, at present the most potent factors found to be associated with
from a mean of 950 cells/mL before 18 weeks to 720 cells/mL at term. early spontaneous pre-term birth are a positive cervical–vaginal fetal
Others have either reported a U-shaped CD4+ cell count profile during fibronectin test and elevated alpha-fetoprotein, alkaline phosphatase
pregnancy, with a minimum at approximately 32 weeks of gestation and granulocyte colony-stimulating factor serum levels, along with a
(CD4 of 30% and a CD4+ count of 876 cells/mL), or have found stable shortened cervical length.61,62
CD4 levels and CD4:CD8 ratios during pregnancy with a rise (rebound) In order to reduce the risk of listeriosis and toxoplasmosis, it is
afterwards. Despite conflicting laboratory data, most studies agree important to avoid raw or undercooked fresh meat and refrigerated
that the humoral immune response in pregnancy is similar to that ready-to-eat food that is not freshly prepared (e.g. cold meats, salads,
in nonpregnant women but that the cellular immune response is soft cheese and pâté), peel or wash raw fruit and vegetables to remove
diminished. contaminating soil, and wash hands after disposing of cat litter or
gardening (to remove soil). Prevention of TB is based on isoniazid
PATHOGENESIS therapy. In case of HIV infection and possible TB, isoniazid therapy
The pathogenesis of most infections is similar in pregnant and non- should be taken for 6 months, in addition to the antiretroviral
pregnant women except for possible alterations in the immune system therapy.63
as noted above. Of specific interest is the role of infectious agents in Prevention of malaria is based on chemoprophylaxis and antivecto-
the onset of labor or, more importantly, of pre-term labor. Although rial measures. Prophylaxis depends on the level of resistance of chlo-
the exact mechanism of the onset of labor is still part of the human roquine among the geographical area. In high resistance areas, the
parturition puzzle, there is convincing evidence for the role of prosta- association of atovaquone–proguanil and malarone are usable, whereas
glandins in the initiation of parturition. Phospholipase A2, produced chloroquine should be used in low resistance regions. Travel to regions
by many micro-organisms but especially by anaerobes, might be one of high chloroquine resistance during pregnancy should be strongly
of the mechanisms of pre-term initiation of labor. Micro-organisms discouraged. Doxycycline is contraindicated in second and third tri-
can stimulate the release of cytokines, such as interleukins and TNF mesters of gestation. Protection against mosquitoes is based on nets
that stimulate prostaglandin precursors, thus leading to uterine and mosquito repellent. Diethyltoluamide (DEET) is contraindicated
contractions. during pregnancy. An antimalaria intermittent preventive therapy
In theory, the amniotic cavity is sterile, protected by the placental associated with the use of insecticide-treated mosquito nets signifi-
membranes. With the onset of labor and the rupture of membranes, cantly reduced low birth-weight and neonatal mortality, highlighting
bacteria may ascend and result in an amniotic infection. Pathogens its importance to reducing mortality in endemic countries.64
TABLE
55-3 Summary of Micro-organisms of Interest During Pregnancy
Increased Susceptibility to
Micro-organisms Infection in Pregnant Women Embryopathy Neonatal Infection
BACTERIA
Group B streptococcus No No Yes
Escherichia coli No No Yes
Listeria monocytogenes Yes No Yes
Mycobacterium tuberculosis Yes No Yes
Haemophilus influenzae No No Yes
Mycoplasma hominis No No Yes
Ureaplasma urealyticum No No Yes
Chlamydia spp. No No Yes
Neisseria gonorrhoeae No No Yes
Treponema pallidum No No Yes
Coxiella burnetii Increased risk of chronic Q fever Yes Yes
VIRUSES
Parvovirus B19 No No Yes
Cytomegalovirus No Yes Yes
Varicella-zoster No Controversial Yes
Rubella No Yes Yes
Measles No No Yes
HIV No Controversial Yes
Herpes simplex No Yes Yes
Hepatitis B No No Yes
Hepatitis C No No Yes
Hepatitis E No Unknown Unknown
Enterovirus No No Yes
PARASITES
Plasmodium spp. No No Yes
Toxoplasma gondii No Yes Yes
FUNGI
Candida albicans Yes No Yes
Case detection and treatment of genitourinary infections is recom- standards during delivery decrease the risk for puerperal infection. The
mended in pregnant women who note an abnormal discharge. Screen- indications for cervical cerclage have to be carefully weighed against
ing for GBS in pregnant women is still a subject of debate. Between the risks and only performed in case of previous late abortion or early
5% and 40% of pregnant women are colonized with GBS, an impor- pre-term delivery. Antibiotic prophylaxis in cases of long, complicated
tant source of perinatal morbidity and mortality. A strategy based on or operative deliveries is effective, although antibiotic resistance is a
late prenatal cultures, followed by intrapartum treatment with penicil- limiting factor. Mastitis can be prevented through good nursing tech-
lin or other broad-spectrum antibiotics is recommended. Others argue niques, including strict hygiene measures. Administration of hyperim-
that routine antimicrobial treatment with a broad-spectrum antibiotic munoglobulins to prevent congenital cytomegalovirus in cases of
is optimal for pregnant women at high risk of adverse pregnancy out- primary CMV infection does not significantly modify the course of
comes in order to reduce the incidence of infectious complications CMV infection during pregnancy.68
such as pre-term birth, neonatal infections and maternal infectious Another part of infection prevention during pregnancy is vaccina-
morbidity.65 The calculation of risk may be based solely on laboratory tion. Indeed, in addition to maternal protection, the transplacental
findings or on clinical and obstetric factors. passage of maternal immunoglobulin G during the last trimester of
Intercourse during pregnancy is not a risk factor for pre-term gestation, and immunoglobulin A secretion into milk after birth,
birth.66,67 After correcting for STDs, there is little evidence of a causal provides protection to the fetus and neonate during the first few
relation between sexual intercourse and pre-term birth. Detection and months, a period of immune system immaturity.69 The American
treatment of maternal bacteriuria in early pregnancy could reduce the College of Obstetricians and Gynecologists, and the Advisory Com-
risk of pyelonephritis, pre-term delivery and neonatal mortality. mittee on Immunization Practice recommend vaccination with inac-
Prevention of puerperal infections is a major concern in obstetrics. tivated influenza vaccine, tetanus toxoid, reduced diphtheria toxoid
Antenatal detection and treatment of STDs as well as high hygienic and acellular pertussis (after 20 weeks of gestation, regardless of
previous vaccinations).70,71 Evidently, there are many different policies the same way as for nonpregnant women (acid-fast bacilli microscopy,
among countries. For example, pertussis vaccination is recommended culture growth, DNA detection).
in the UK from 28 to 32 weeks of pregnancy,72,73 but only the seasonal For women with a short cervix, measured by ultrasound or with
influenza vaccination is recommended in France.74 Globally, all cervical dilation in mid-pregnancy, a strong clinical and microbiologic
bacterial or viral inactivated vaccines or toxoids are theoretically evaluation should be proposed with C-reactive protein and vaginal
usable. However, live vaccines (tuberculosis, measles, mumps, rubella, samples. Amniocentesis is generally not performed because of the risk
chickenpox and human papillomavirus) are contraindicated because of pPROM.
of theoretical risks of transmission. Vaccination against flu during Postpartum endometritis is a clinical diagnosis supplemented by a
pregnancy remains important because of an increased morbidity cervical swab for culture to identify pathogens that may require addi-
and mortality, with many adverse outcomes such as pre-term birth tional measures besides antibacterial therapy. Isolation of group A
and low birth-weight, in addition to the risk of complicated flu for the streptococci should lead to isolation of the patient whereas that of GBS
mother (acute respiratory distress syndrome). Moreover, there is a should prompt further action in relation to the neonate. GBS diagnosis
higher rate of hospitalizations and deaths among infants <6 months.75 is available by real-time quantitative polymerase chain reaction (PCR)
from a vaginal swab.
Clinical Features
Infections in pregnancy can be asymptomatic but usually manifest Management
with symptoms similar to those in nonpregnant individuals.76–79 The
A number of interventions with proven value in the management of
course of the infection may be worse because of different immune
morbidity related to infection during pregnancy are discussed. The
responses and because of the potential hazards for the outcome of
serologic screening and subsequent management of viral infections,
pregnancy and the well-being of the fetus. Overall, fever is a frequent
including rubella, toxoplasmosis, CMV, HIV and others, is discussed
reason for consulting a physician during pregnancy.
in Chapter 56 and Practice Points 16 and 17.
Urinary tract infections can be asymptomatic or manifest with
Although the initiating mechanism of pre-term labor is unknown,
signs of cystitis such as burning urination and dysuria. Fever and flank
the potential role of ascending infection and intrauterine inflamma-
pain occur with ascending UTIs. The clinical diagnosis of intra-
tion is clear. Consequently, attempts to prolong gestation and improve
amniotic infection is based upon fever, uterine tenderness, fetal tachy-
pregnancy outcome using antimicrobials (using antibiotics such as
cardia, leukocytosis and elevated C-reactive protein, with or without
erythromycin, while amoxicillin–clavulanic acid should be avoided
ruptured membranes. In the event of premature rupture of the mem-
due to increasing enterocolitis necrosis)80 is recommended among
branes, fever suggests chorioamnionitis.
women with pre-term rupture of membranes, or with previous pre-
Gastrointestinal infections appear as diarrhea and are usually self-
term birth (prophylaxis during second and third trimesters). Overall,
limiting and without complications. Acute appendicitis can be a diag-
for bacterial infections, after empirical treatment antibiotic therapies
nostic dilemma as the clinical presentations differ from those seen in
should be adapted to antibiograms if bacteria have been isolated from
nonpregnant women, and may manifest as upper right quadrant pain
samples.
with nausea and vomiting, without leukocytosis or fever. Placental
As bacteriuria in pregnancy, if untreated, may lead to pyelonephri-
parasitism of P. falciparum (one-quarter of pregnant women in
tis in up to a third of women, with potential hazards for mother and
endemic regions of Africa) rarely presents with fever.13
fetus, screening and management in pregnancy is justified. Antibiotic
Diagnostic criteria for postpartum endometritis include fever,
treatment is effective in clearing asymptomatic bacteriuria and in
uterine and/or adnexal tenderness, purulent or foul lochia and leuko-
reducing the risk of pyelonephritis in pregnancy.81
cytosis in the absence of other signs of infection within the first five
Antibiotic treatment has been shown to be highly effective for
days after delivery. Late postpartum endometritis may occur weeks
the cure of symptomatic cystourethritis; however, there are insufficient
after delivery. Retention of placental products has to be excluded.
data to recommend any specific treatment regimen for symptomatic
Puerperal mastitis occurs with breast engorgement and milk stasis,
urinary tract infections during pregnancy. Accordingly, susceptibility
often in the second or third week after delivery. The onset of sporadic
tests should be obtained. Most antibiotics studied were shown to
mastitis is rather sudden, with breast tenderness, chills, fever, malaise
be very effective, while complications are rare.82 Common antimicro-
and headache mimicking a flu-like syndrome. The breast may show
bial treatment options include a 3-day course of trimethoprim–
foci of local infection characterized by erythema, tenderness and
sulfamethoxazole (only during the second or third trimesters) or a
warmth. The development of a breast abscess is rare in lactating
7-day course of nitrofurantoin or cephalexin. In view of the high rate
women.
of recurrence of bacteriuria in pregnancy, suppressive therapy is re
commended up until 2 weeks postpartum in women with recurrent
Diagnosis bacteriuria. Pyelonephritis requires admission for parenteral adminis-
Most infections that manifest with clinical signs and symptoms do not tration of antibiotics and careful monitoring.
give rise to diagnostic difficulties, as they are related to specific infec- Penicillin is the drug of choice in women with lower respiratory
tions of the urinary or reproductive tract, or to common infections in tract infections caused by pneumococci. Because of possible cardio-
the community. In the event of fever during pregnancy, bacteriologic pulmonary complications, β-mimetic tocolytic drugs should be
examination of the urine must be conducted together with viral serol- avoided or, if necessary, administered with caution. Isoniazid is not
ogy as well as serology for Coxiella burnetii. teratogenic and is usable at any stage of pregnancy. Treatment of
Microbiologic diagnosis rests mainly on the culture of the sample TB remains the same as for nonpregnant women: 2 months of
based on clinical manifestations and identification of isolated colonies rifampin, isoniazid, pyrazinamide and ethambutol, followed by
using mass spectrometry or phenotypic technique. The diagnosis of 4 months of isoniazid plus rifampin.83 Supplementation of pyridoxine
UTI is based on quantitative cultures with more than 100 000 cfu/mL is recommended if isoniazid is taken. It is also recommended to
clear-voided urine (midstream) in asymptomatic patients, or more supplement the infant at birth with vitamin K if the mother takes
than 100 cfu/mL in symptomatic patients. The key to the care of lower rifampin.
respiratory tract infections is an early diagnosis, with careful clinical Malaria treatment depends on the gravity and the parasite species
evaluation and examination, if possible, of a sputum sample and a (see Practice Point 38 for a detailed discussion). Serious bouts of P.
blood culture. In the event of cervicovaginal symptoms or suspected falciparum should be treated by intravenous artesunate, in association
chorioamnionitis, vaginal specimens are required. In patients with with quinine if in a multiresistant area (South Asia). The association
meningitis, a spinal tap with Gram stain, culture and chemical analysis of atovaquone–proguanil is usable in non-serious malaria. Studies on
of the cerebrospinal fluid is indicated. A TB diagnosis is explored in artesunate in pregnancy did not show any risk for the fetus, but its
toxicity in animal models has led to a careful use, according to the • Category B: Either animal reproduction studies have failed to
benefit/risk balance.84–86 demonstrate a risk to the fetus and there are no adequate and
Treatment of gastrointestinal infections is usually not necessary well-controlled studies in pregnant women, or animal reproduc-
during pregnancy except when the problems persist and interfere with tion studies have shown an adverse effect, but adequate and
the mother’s health. Treatment of postpartum genital infection well-controlled studies in pregnant women have failed to dem-
includes appropriate antibiotics with good anaerobic coverage. After onstrate a risk to the fetus in any trimester. Examples: penicillin,
Cesarean section the desired results have been obtained with a combi- cephalosporin, monobactam, aminoglycoside (group 2), eryth-
nation of clindamycin and gentamicin.87 The reduction of endometri- romycin, clindamycin, sulfonamides.
tis by some two-thirds and the decrease in wound infections justifies • Category C: Animal reproduction studies have shown an adverse
a policy of routine prophylactic antibiotics to women undergoing elec- effect on the fetus and there are no adequate and well-controlled
tive or non-elective Cesarean section.88 studies in humans. However, potential benefits may warrant use
The treatment of early wound infections may require excision of of the drug in pregnant women despite potential risks. Examples:
the necrotic tissue and antibiotic treatment with a cephalosporin or aminoglycoside (group 1), chloramphenicol, macrolides, fluoro-
clindamycin. Surgical closure of Cesarean section has been shown to quinolones, trimethoprim-sulfamethoxazole.
be successful and requires less healing time. The procedure may be • Category D: There is positive evidence of human fetal risk based
carried out under general or local anesthesia, and antibiotic prophy- on adverse reaction data from investigational or marketing expe-
laxis is generally used. Episiotomy incisions should not be re-sutured rience or studies in humans, but potential benefits may warrant
but given time to heal by granulation, unless the sphincter muscle or use of the drug in pregnant women despite potential risks.
the rectal mucosa is involved. Example: doxycycline.
Therapy of mastitis includes continuation of lactation and treat- • Category X: Studies in animals or humans have demonstrated
ment with a penicillinase-resistant penicillin or a cephalosporin, given fetal abnormalities or there is evidence of fetal risk based on
orally except in severe cases. Ice packs, breast support, analgesia and human experience or both, and the risk of the use of the drug in
regular emptying of the infected breast may help to prevent abscesses pregnant women clearly outweighs any possible benefit. The
(treated by surgical incision and drainage). drug is contraindicated in women who are or may become
pregnant.
ANTIBIOTICS IN PREGNANCY
Antibiotics are frequently used during pregnancy. Several studies have
shown that 25–40% of pregnant women take antibiotics, mainly in the Conclusions
second trimester, while the incidence of antibiotic intake is around 5% Infectious diseases are important risk factors for maternal and neona-
in the first trimester. Administration of a drug to a pregnant woman tal morbidity and mortality and can be detected early with improved
presents a unique problem. Most drugs or chemical substances taken outcomes or prevented entirely. Maternal mortality due to infection is
during pregnancy can cross the placenta to some extent throughout an unbearable tragedy and must be addressed by improved access to
pregnancy, but the fetus is at highest risk during the first 3 months of modern obstetric care for all pregnant women. This care must be
gestation. affordable, even in resource-limited countries, and should be a priority
Risk factors have been assigned to all levels of risk that a drug poses for governments and international agencies. A substantial portion of
to the fetus (A, B, C, D, and X). The definitions used for the risk pre-term births can be prevented with improvements in the detection
factors, described by Briggs et al.,89 are summarized below. and management of infections during pregnancy. Further research is
• Category A: Controlled studies in women fail to demonstrate a required to identify women and babies at risk, and to develop preven-
risk to the fetus in the first trimester (and there is no evidence tive, diagnostic and management strategies to enhance care.
of a risk in later trimesters), and the possibility of fetal harm
appears remote. References available online at expertconsult.com.
KEY REFERENCES
Al-Taiar A., Hammoud M.S., Cuiqing L., et al.: Neonatal Goldenberg R.L., Thompson C.: The infectious origins of providing immunological protection to the newborn: a
infections in China, Malaysia, Hong Kong and Thailand. stillbirth. Am J Obstet Gynecol 2003; 189(3):861-873. review. Vaccine 2014; 32(16):1786-1792.
Arch Dis Child Fetal Neonatal 2013; 98(3):F249-F255. Kuhn P., Dheu C., Bolender C., et al.: Incidence and distri- Mor G., Cardenas I.: The immune system in pregnancy: a
Chico R.M., Mayaud P., Ariti C., et al.: Prevalence of bution of pathogens in early-onset neonatal sepsis in the unique complexity. Am J Reprod Immunol 2010;
malaria and sexually transmitted and reproductive tract era of antenatal antibiotics. Paediatr Perinat Epidemiol 63(6):425-433.
infections in pregnancy in sub-Saharan Africa: a system- 2010; 24(5):479-487. Onderdonk A.B., Lee M.L., Lieberman E., et al.: Quantita-
atic review. JAMA 2012; 307(19):2079-2086. Lawn J.E., Kinney M.V., Black R.E., et al.: Newborn survival: tive microbiologic models for preterm delivery. J Clin
Desai M., ter Kuile F.O., Nosten F., et al.: Epidemiology and a multi-country analysis of a decade of change. Health Microbiol 2003; 41(3):1073-1079.
burden of malaria in pregnancy. Lancet Infect Dis 2007; Policy Plan 2012; 27(Suppl. 3):iii6-iii28. Pillay T., Khan M., Moodley J., et al.: Perinatal tuberculosis
7:93-104. Liu L., Johnson H.L., Cousens S., et al.: Global, regional, and HIV-1: considerations for resource-limited settings.
Edmond K.M., Kortsalioudaki C., Scott S., et al.: Group B and national causes of child mortality: an updated sys- Lancet Infect Dis 2004; 4(3):155-165.
streptococcal disease in infants aged younger than 3 tematic analysis for 2010 with time trends since 2000. Stillbirth Collaborative Research Network Writing Group:
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Gibbs R.S.: The origins of stillbirths: infectious diseases. feeding after maternal immunisation during pregnancy:
Semin Perinatol 2002; 26(1):75-78.
Chapter 55 Complications of Pregnancy: Maternal Perspectives 504.e1
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56
Fetal Implications of Maternal
Infections in Pregnancy
ARI BITNUN | HYTHEM AL-SUM | GREG RYAN
KEY CONCEPTS discussed. A brief summary of infections transmitted primarily at the

time of delivery is given at the end of the chapter.
• All women who are planning pregnancy should be educated
about the risks of infections in pregnancy and taught strategies GEOGRAPHY
to mitigate these risks. There is considerable geographic variation in the risk of exposure to
• Serologic testing for HIV, hepatitis B, rubella and syphilis is pathogens associated with congenital and perinatal infections. This
recommended for all pregnant women. variation may be related to: the biology of the pathogen, such as when
the pathogen is transmitted by an arthropod vector; culinary practices
• Routine antenatal serologic testing for cytomegalovirus and (including handling and ingestion of raw meat as in the case of toxo-
Toxoplasma gondii is not warranted.
plasmosis); regional variation in breast-feeding practices; immuniza-
• With timely diagnosis and implementation of appropriate inter- tion uptake rates for rubella and other vaccine-preventable diseases.
ventions, perinatal transmission of HIV, hepatitis B, syphilis and
herpes simplex virus, and possibly toxoplasmosis and CMV, can
be prevented.
• No newborn infant should be discharged without clarifying
BOX 56-1 INFECTIOUS AGENTS KNOWN TO
maternal HIV, hepatitis B and syphilis infection status. CAUSE CLINICALLY SIGNIFICANT
CONGENITAL INFECTION
• The majority of infants with congenital CMV, varicella, parvovi-
rus B19, syphilis and toxoplasmosis are asymptomatic at birth. VIRUSES
Herpesviruses
• Treatment of congenital syphilis and toxoplasmosis and symp- Cytomegalovirus
tomatic congenital CMV improves long-term pediatric outcome. Herpes simplex virus
Varicella-zoster virus
• Women presenting in labor with limited or no antenatal care Parvovirus B19
require a careful genital examination, diagnostic testing for Rubella virus
Chlamydia trachomatis and Neisseria gonorrhoeae and certain Measles virus
other pathogens, and serologic testing for rubella, HIV, hepa- Enteroviruses
titis C, hepatitis B and syphilis. Coxsackie B
Echoviruses
Polioviruses
Parechoviruses
Human immunodeficiency viruses
The number of pathogens capable of infecting the fetus, and the spec- HIV-1
trum of fetal and neonatal disease caused by various infectious agents, HIV-2
Lymphocytic choriomeningitis virus
has expanded substantially. Advances in molecular technology (e.g. Hepatitis B virus
polymerase chain reaction [PCR]) and wider availability of intrauter- Vaccinia
ine diagnostic testing (e.g. maternal serum screening, ultrasound, Smallpox
amniocentesis, fetal blood sampling) have provided new opportunities Adenovirus
Western equine encephalitis virus
to link pathogens with clinical sequelae. Congenital infection in preg- Venezuelan encephalitis virus
nancy may come to clinical attention through: West Nile virus
• a history of maternal risk factors BACTERIA
• known maternal exposure
• documented acute maternal infection Treponema pallidum
Mycobacterium tuberculosis
• laboratory screening during pregnancy Listeria monocytogenes
• detection of fetal abnormalities on ultrasound or serum Brucella spp.
screening Campylobacter fetus
• suggestive clinical findings in the neonate, infant or child. Salmonella typhi
Borrelia burgdorferi
Depending on the scenario, a range of infections should be considered Coxiella burnetti
in the differential diagnosis.
Fortunately, the vast majority of maternal infections have no delete- PROTOZOA
rious effects on the fetus, either because there is no transplacental Toxoplasma gondii
Plasmodium spp.
transmission or because fetal infection is asymptomatic. Fear and poor Trypanosoma cruzi
understanding of risk on the part of the parents or physicians can lead
to unnecessary interventions in pregnancy. FUNGI
Epidemiology Adapted with permission from Guerina N.G.: Semin Perinatol 1994;
Although many micro-organisms can potentially cause congenital 18(4):305–320
(intrauterine) infection (Box 56-1),1 only more common agents are
505
TABLE
56-1 Factors Associated with Maternal–Fetal Infection
Association Pathogen
Seasonality (in North America) Parvovirus B19 (winter, spring)

Rubella (winter, spring)
Enterovirus (summer, autumn)
West Nile virus (summer, autumn)*
Handling/ingestion of uncooked, previously unfrozen meat Toxoplasma gondii
Exposure to children:
Daycare CMV, parvovirus B19
School Parvovirus B19
Household CMV, parvovirus B19
Travel to certain geographic regions Toxoplasma gondii, Mycobacterium tuberculosis, Plasmodium spp.,
Trypanosoma cruzi, Borrelia burgdorferi, Brucella spp., hepatitis B
virus, arboviruses, rubella
Kitten/cat feces within 21 days of primary infection (handling animals, kitty litter, Toxoplasma gondii
gardening)
Number of sexual partners, sex industry worker/partner, illicit drug use HSV, hepatitis B virus, hepatitis C virus, HIV, Treponema pallidum
Sexually active adolescents CMV, HSV, hepatitis B virus, hepatitis C virus, HIV, Treponema pallidum
Unimmunized (e.g. immigrants from lower- and middle-income countries) Rubella

Incomplete immunization Measles, mumps, tetanus, diphtheria, poliomyelitis, hepatitis B, VZV
*Most arbovirus infections occur in the summer and autumn when the vector is active; an important exception to this is Japanese encephalitis virus that can circulate
year round in certain tropical and subtropical regions of South East Asia.
For abbreviations, see text.
The geographic distribution of certain pathogens may change over status, placental function and the timing of infection relative to fetal
time, particularly arthropod-borne or zoonotic infections. An example development.
of this is the recent introduction of West Nile virus to North America.
Pathogen
OTHER FACTORS ASSOCIATED Why certain pathogens have a propensity for causing congenital infec-
WITH INFECTION tions is incompletely understood. It may reflect the tendency of certain
Epidemiologic factors associated with maternal–fetal infection are organisms to invade the mother’s bloodstream, thereby coming in
summarized in Table 56-1. The risk of congenital infection often contact with the placenta and fetus. Inoculum size, as measured by
reflects maternal immunity rates as well as the risk of exposure to the quantity of pathogen in the blood, can be an important factor for some
pathogen. For example, annual seroconversion rates to cytomegalovi- pathogens. This is the case for human immunodeficiency virus (HIV),
rus (CMV) for healthcare workers, usually in the range of 2–4%, are where viral load is the key driver of transmission risk.
significantly lower than those in daycare workers or susceptible parents The specific manifestations of different pathogens reflect the timing
of children in daycare (12–45%).2 of infection at vulnerable stages of organogenesis, as well as the pro-
pensity to affect specific organs and tissues. Rubella and varicella-
zoster viruses (VZV) cause developmental anomalies through cell
Pathogenesis and Pathology death, inhibition of cell growth or chromosomal damage. Inflamma-
Neonatal infections may be acquired in the following ways: tion, and resulting tissue destruction, is thought to be responsible for
• transplacentally (congenital) by direct transmission to the amni- the structural abnormalities characteristic of HSV, congenital syphilis
otic fluid or from the genital tract via the cervical canal, during and congenital toxoplasmosis. Parvovirus B19 (B19V) can cause fetal
pregnancy or just before delivery. The placenta can be infected anemia leading to hydrops by binding to the P antigen on erythrocyte
and even act as a repository for pathogen growth; precursors and thereby inhibiting the normal erythropoiesis in the
• at the time of birth (perinatal) through vaginal secretions and second trimester.
blood; Postnatal persistence of CMV, HSV, Toxoplasma gondii and rubella
• during the neonatal period, from the mother, her breast milk or can result in progressive tissue damage and the onset or worsening of
other sources. clinical disease later in life. Thus, hearing loss associated with congeni-
Intrauterine infection may result in spontaneous abortion, stillbirth, tal CMV can manifest itself after 2 years of age, and the chorioretinitis
preterm delivery, physical anomalies, intrauterine growth restriction of congenital toxoplasmosis can recur in later years, despite prior
(IUGR) (rubella, enterovirus, herpes simplex virus [HSV]) and post- therapy.3,4 A progressive panencephalitis may occur with congenital
natal persistence of infection (rubella, CMV, HSV, toxoplasmosis). rubella, with onset typically in the teenage years.5
Certain outcomes are determined by the timing and site of
infection: Maternal Immunity
• embryonic: structural malformations, spontaneous abortion Before Conception. Preconception immunity in the immunocom-
• fetal: stillbirth, neurologic sequelae petent mother is usually protective to the fetus. Exceptions include
• placental: preterm birth, stillbirth and neonatal death. viruses with known latency, such as CMV and occasionally HSV,
rubella (when maternal immunity has waned), untreated Treponema
FACTORS AFFECTING FETAL DISEASE pallidum and HIV. Maternal immunosuppression, whether primary or
The risk of transplacental transmission and disease manifestations are secondary, can increase the risk of fetal disease. Thus, congenital toxo-
influenced by a multitude of factors, including the pathogen’s propen- plasmosis can follow reactivation of latent T. gondii infection during
sity for causing fetal infection, the pregnant woman’s immunologic pregnancy in HIV-infected women.
Chapter 56 Fetal Implications of Maternal Infections in Pregnancy 507
The time period before conception during which infection may • Avoid eating unpasteurized milk or cheese and undercooked
occur without causing fetal damage is unknown. In the immunocom- meat (Listeria spp., Brucella spp., T. gondii).
petent mother, it is advisable to have an interval of 7–9 months between • For those with high-risk behaviors, such as intravenous drug use
T. gondii infection and conception. Over 50% of infants born to or multiple sexual partners, provide information on the risks
mothers with primary or secondary syphilis will have congenital infec- posed by HIV, hepatitis B, hepatitis C, syphilis and other sexually
tion, decreasing to 40% with early latent syphilis and to ≤10% with transmitted infections.
late latent infection.6 • Inform their physician following exposure to individuals with
During Pregnancy and Before Delivery. The risk of transpla- suspected or confirmed infections with parvovirus B19 (ery-
cental transmission and severity of disease are increased with primary thema infectiosum, ‘fifth’ disease, ‘slapped cheek’ syndrome),
maternal infection during pregnancy. Thus, the rate of intrauterine chickenpox/shingles or pertussis (whooping cough).
CMV transmission is about 50% with primary maternal infection, but • Women with recurrent genital herpes should inform their physi-
only 1% among previously seropositive mothers. cian if they are experiencing clinically evident recurrences, and
For certain infections acquired late in gestation, the fetus is at high whether they are on suppressive antiviral therapy for this
risk of severe disease when delivered before transplacental transfer of condition.
specific antibody has taken place. For example, the mortality from VZV • Immunity to rubella, hepatitis B virus, HIV and syphilis should
infection acquired transplacentally from a mother who develops skin be routinely assessed during pregnancy.
lesions from 5 days prior to delivery to 2 days after delivery is 18% in
the absence of treatment.7 Severe enterovirus disease in the neonate is
ACTIVE AND PASSIVE IMMUNIZATION
typically seen following maternal infection during the last two weeks Ideally, all pregnant women should be immune to measles, mumps,
of pregnancy.8 rubella, tetanus, diphtheria, poliomyelitis, hepatitis B and VZV, either
by natural infection or by vaccination. Influenza vaccine is recom-
Placenta mended for all pregnant women. Pneumococcal vaccine is recom-
In early pregnancy, the developing placenta effectively excludes most mended for women at high risk of pneumococcal disease.
pathogens. As the placenta matures this barrier becomes more perme- Inactivated vaccines are generally considered safe, although some
able, making transplacental transmission more possible. For a variety physicians wait until after the first trimester to administer them. Live
of pathogens, including CMV, rubella, T. pallidum, Plasmodium spp. viral or bacterial vaccines should be avoided during pregnancy.
and Mycobacterium tuberculosis, placental infection may occur without However, if live vaccine is inadvertently administered, women can
fetal infection. Thus, the placenta can prevent infections from reaching generally be reassured that adverse outcome is exceedingly rare. In an
the fetus, in part by serving as a physical barrier to the pathogen. In evaluation of 680 infants born to mothers who received rubella vaccine
addition, placental macrophages and local production of antibodies within 3 months before or during pregnancy from the USA, UK,
and cytokines may be important. Germany and Sweden, no cases of congenital rubella syndrome
occurred.11 In a 10-year Varivax Pregnancy Registry review, no cases
Fetus of congenital varicella syndrome were observed among 629 mother–
Fetal disease may result from many pathogens at any time during infant pairs following inadvertent vaccination during pregnancy.12
pregnancy. In general, transplacental transmission is less likely early in Immune globulin products may be indicated following exposure to
gestation, but the results of such infection are more likely to be severe. measles, hepatitis A or B virus, tetanus, varicella or rabies and, in the
Thus, the proportion of fetuses that are congenitally infected with T. case of certain travel, to poliomyelitis, yellow fever, typhoid and hepa-
gondii rises from 15% following first trimester maternal infection to titis B virus. There are limited observational data in support of the use
60% following third trimester maternal infection. However, severe of CMV hyperimmune globulin in preventing transmission of CMV
congenital disease is seen at birth in 40% of children infected during to the fetus in primary CMV infection during pregnancy.13–15
the first trimester, but only rarely in those infected during the third
trimester.9 Deficiencies in both humoral and cellular immune function SCREENING FOR INFECTION
of the fetus contribute to the increased risk of severe disease through DURING PREGNANCY
unchecked tissue damage, organ dysfunction and teratogenicity. Routine antenatal screening for syphilis, hepatitis B and HIV infection
Certain pathogens are associated with particular effects at certain and rubella immunity is warranted for all women. Rubella screening
stages of cell development. Maternal rubella infection in pregnancy alerts the physician to which mothers require postpartum immuniza-
prior to 16 weeks, but not thereafter, is associated with the develop- tion. Also, if susceptible women have known exposure or disease, the
ment of congenital defects.10 Congenital varicella syndrome occurs physician can confirm acute infection through study of a second ‘con-
almost exclusively before 20 weeks’ gestation; the highest risk of about valescent’ serum sample 10–21 days later. Antenatal screening for
2% occurs if the mother had VZV infection between 13–20 weeks’ syphilis and HIV allows for treatment of the mother as well as preven-
gestation.7 tion of infection in the infant. Hepatitis B virus screening allows for
preventive management of the infant of the hepatitis B surface antigen
(HBsAg)-positive mother.
Prevention The general value of routine antenatal screening for CMV, as prac-
Prevention of maternal infection in pregnancy should include educa- ticed in some countries, is debatable, because of the difficulty in inter-
tion, immunization, laboratory screening, monitoring for evidence of preting serology results and the lack of an effective vaccine or clear
infection and, where appropriate, intervention. evidence for interventions to prevent or ameliorate the sequelae of fetal
infection. However, establishing immune status prior to pregnancy
EDUCATION AND EXPOSURE AVOIDANCE may be of benefit to certain women at high risk, such as daycare
While exposure to potential pathogens during pregnancy cannot be workers, in order to allow more proactive preventive measures. If there
completely eliminated, relatively simple interventions can offer signifi- are specific ultrasound findings suggestive of CMV infection, then
cant protection. All women who are planning pregnancy should be amniotic fluid culture or PCR is considered the gold standard for
given advice pertinent to infection prevention: prenatal diagnosis of fetal CMV.
• Wash hands thoroughly before eating and before and after food Screening for toxoplasmosis is not universally recommended, but
preparation (enteric pathogens, Listeria spp., T. gondii). some have argued for its implementation.16 Toxoplasma gondii-specific
• Wash hands after coming in contact with saliva, stool, urine or IgM antibody can persist for more than a year in about one-third of
other body secretions (enteric pathogens, Listeria spp., CMV, infections, making it difficult to establish the timing of maternal infec-
rubella). tion. If T. gondii-specific IgM is detected during pregnancy, additional
TABLE
56-2 Microbiologic Testing for Maternal Infections During Pregnancy
Pathogen Direct Detection Serology Additional Considerations
Cytomegalovirus • Rarely helpful unless immune • Seroconversion confirms acute • False-positive IgM very common
compromised host infection • IgG avidity recommended to aid in timing maternal
• IgM in acute sera infection if screening IgM is reactive
Hepatitis B • HBV DNA in blood (should • HBsAg • Chronic carriers typically display reactive HBsAg,
be done if HBsAg positive) • For HBsAg-positive persons do reactive HBcAb and nonreactive HBsAb
HBsAb, HBcAb, HBeAg and • Presence of HBeAg indicates higher infectiousness
HBeAb • Risk of transmission increases with higher DNA load
(>6 log10 copies/mL [>200 000 IU/mL])
Hepatitis C • Hepatitis C RNA in blood • Reactive serology • Risk of transmission increases with higher RNA load
• Risk of transmission increased threefold in context
of poorly controlled HIV infection
Herpes simplex virus • PCR of lesion scraping • Seroconversion confirms acute • Prenatal serology not universally recommended;
infection (rarely helpful) negative serology usually excludes infection
• Type specific maternal serology may be of benefit
in management of newborns of women with first
episode genital herpes at or near delivery
B19V • PCR on fetal blood, ascites or • Seroconversion confirms acute • If initial serology negative after exposure, the
amniotic fluid infection serology should be repeated in 4–6 weeks to
• IgM in acute sera assess for seroconversion
Rubella • PCR on nasopharyngeal or • Seroconversion • Women found to be seronegative should be

urine samples • IgM in acute sera vaccinated after delivery
Treponema pallidum • Dark-field microscopy of • Serologic panel* (treponemal plus • Consultation with an expert in the field is
cutaneous lesion samples non-treponemal tests; also see recommended to aid with interpretation of reactive
Table 56-9) serology results
• Non-treponemal titer of 1 : 1 – 1 : 4 most consistent
with latent syphilis or treated syphilis with serofast
state
• Non-treponemal titers ≥1 : 16 most consistent with
primary or secondary syphilis
Toxoplasma gondii • Rarely helpful unless immune • Seroconversion • Confirmatory testing in reference laboratory is
compromised host • T. gondii IgM and IgG (screen) recommended for suspected recent infection†
• T. gondii IgM can remain positive for a year or
more after infection
• Low avidity IgG suggestive of infection acquired in
preceding 3–6 months
Varicella-zoster virus • PCR of lesion sample • Seroconversion • In immunocompetent women who have no history
of varicella and are found to be seronegative,
vaccination should be considered after delivery
*In some jurisdictions a treponemal test is used as the initial screen, in others a non-treponemal test is used; treponemal tests include the Chemiluminescent
Immunoassay (CLIA), Chemiluminescent Microparticle Agglutination (CMIA), Treponemal pallidum Particle Agglutination (TPPA), Fluorescent Treponemal
Antibody-ABSorbed (FTA-ABS), Treponemal pallidum enzyme immunoassay (TP-EIA) and Microhemagglutination test for antibodies to Treponema pallidum
(MHA-TP) tests; non-treponemal tests include the Rapid Plasma Reagin (RPR) and Venereal Disease Research Laboratory (VDRL) tests.
†
The standard maternal serologic panel performed at the Palo Alto Toxoplasma Serology Laboratory (www.pamf.org/serology/) includes IgG (Sabin Feldman dye test),
IgM ELISA, AC/AH and IgG avidity testing.
serologic testing through a reference laboratory (see Table 56-2) Screening for Congenital Infections in Newborns
should be undertaken.17 If serology results are suggestive of recent The cost-effectiveness of screening neonates for congenital infections
infection, amniotic fluid testing by PCR can be used to confirm fetal has not been established.16 Nevertheless, routine neonatal screening for
infection.17 Practitioner-based testing for acute toxoplasmosis in the congenital toxoplasmosis is practiced in several countries.18,19 Detec-
absence of a community-based program should be discouraged in tion of T. gondii-specific IgM in newborn dried blood spots has been
countries where screening and treatment are not routine. used for this purpose. Some have also advocated routine neonatal
CMV screening.20 Testing of urine or saliva by PCR (or culture) is most
MONITORING FOR EVIDENCE OF INFECTION commonly used. The value of routine testing of the birth dried blood
(CLINICAL MANIFESTATIONS AND spot for CMV is uncertain because of limited sensitivity.21
ULTRASOUND FINDINGS)
INTERVENTION
Maternal Illness A variety of interventions are available to prevent congenital infections.
Rash in pregnancy requires exclusion of syphilis, rubella, B19V and These are detailed in the management section below.
enterovirus infection. Arthritis occurs with B19V infection as well as
with rubella. In the presence of acute mononucleosis-like symptoms,
Epstein–Barr virus, CMV, T. gondii and HIV infection must be Clinical Features
considered. FETAL ABNORMALITIES
The features of in utero infections are summarized in Table 56-3. Most
Fetal Ultrasound affected fetuses appear normal on ultrasound and, in those with
Ultrasound findings of in utero infection are provided in the clinical detectable abnormalities, findings pathognomonic for a particular
features section below and in Table 56-3. pathogen are relatively rare.22,23
SPONTANEOUS ABORTION AND STILLBIRTH

TABLE Sonographically Detectable Features of Pregnancy loss has been associated with infection with CMV, entero-
56-3 In Utero Infection virus, HSV, HIV, B19V, rubella, T. pallidum and T. gondii. Fetal loss
General IUGR: all etiologies
occurring with any maternal viral infection requires comprehensive
Hydrops fetalis: parvovirus B19, CMV, syphilis, pathologic and microbiologic evaluation to determine the pathogenic
toxoplasmosis, HSV, coxsackie B3 role of the infection.
Placentamegaly: CMV, syphilis
Anemia*: parvovirus B19, CMV SYNDROMES OF CONGENITAL INFECTION
Head and Hydrocephalus: toxoplasmosis, CMV, enterovirus General
neck Microcephaly: CMV, rubella, HSV, varicella, toxoplasmosis
Intracranial calcification: CMV, toxoplasmosis, HSV, rubella,
Most newborn infants with congenital CMV, B19V, syphilis or toxo-
HIV, West Nile virus, lymphocytic choriomeningitis virus plasmosis are asymptomatic at birth. Prematurity is typical of congeni-
tal syphilis and common in perinatal HSV infection. IUGR can occur
Heart Congestive heart failure: parvovirus B19, syphilis, CMV,
toxoplasmosis
with rubella, CMV, toxoplasmosis and, occasionally, enteroviruses.
Pericardial effusion: parvovirus B19, syphilis, CMV, Routine investigation of premature or growth-restricted infants for
toxoplasmosis possible congenital infection rarely yields positive results. The clinical
Cardiac defects: rubella, mumps (not proven) findings in congenital infections are summarized in Table 56-4.
Myocarditis: enterovirus, parvovirus B19
Abdomen Hepatosplenomegaly: CMV, rubella, toxoplasmosis, HSV,

Sepsis-Like Illness
syphilis, enterovirus, parvovirus B19 HSV acquired just before delivery or intrapartum may present as a
Echogenic bowel: CMV, toxoplasmosis perinatal syndrome, often without skin lesions, and resemble neonatal
Hepatic calcifications: CMV, toxoplasmosis
Meconium peritonitis: CMV, toxoplasmosis
sepsis or pneumonitis. An early laboratory clue is abnormal liver
Ascites: parvovirus B19, CMV, toxoplasmosis, syphilis enzymes. Shock, coagulopathy, fulminant hepatitis and, often, skin
lesions follow. Congenital tuberculosis and enteroviral infections can
Extremities Limb reduction, limb restriction: varicella
also present in this way.
*Detectable by assessing middle cerebral artery peak systolic velocity.
For abbreviations, see text. Hepatitis
Enteroviruses, HSV and T. gondii can cause overwhelming acute neo-
natal liver failure in the first week of life. Other infections, including
CMV and B19V, can also present with hepatic features.
TABLE
56-4 Selected Clinical Findings in Congenital Infections
System Clinical Feature Pathogens
GENERAL Prematurity Syphilis, HSV

IUGR All etiologies, including tuberculosis
DERMATOLOGIC Purpura (usually appearing on the first CMV, toxoplasmosis, syphilis, rubella, HSV, enterovirus, parvovirus B19
day of life)
Vesicles HSV, syphilis, varicella, CMV, parvovirus B19, enterovirus
Maculopapular exanthem Syphilis, measles, rubella, enterovirus
Cutaneous scars Varicella, HSV
MUSCULOSKELETAL Pseudoparalysis Syphilis

Bone lesions Syphilis, rubella
Limb paralysis with atrophy and cicatrices Varicella
CENTRAL NERVOUS SYSTEM Microcephaly CMV, toxoplasmosis, rubella, varicella, HSV

Cerebral calcifications CMV and HSV (usually periventricular); toxoplasmosis (widely
distributed); HIV (basal ganglia)†
Hydrocephalus Toxoplasmosis, CMV, syphilis
Sensorineural hearing loss CMV, rubella, syphilis, toxoplasmosis
OCULAR* Chorioretinitis HSV, VZV, rubella, CMV, toxoplasmosis, West Nile virus
Cataract Rubella, HSV, VZV, toxoplasmosis, syphilis
Optic atrophy HSV, VZV, rubella, CMV, toxoplasmosis, syphilis
Microphthalmia Rubella, HSV, toxoplasmosis, CMV, varicella
Keratoconjunctivitis HSV
Pigment retinopathy Rubella
Glaucoma Rubella, toxoplasmosis, syphilis
Iritis HSV, rubella, syphilis
Horner syndrome VZV
CARDIOPULMONARY Congenital heart disease Rubella, mumps (not proved)

Hydrops, ascites, pleural effusions Parvovirus B19, CMV, toxoplasmosis, syphilis
HEPATOSPLENIC Hepatosplenomegaly CMV, rubella, toxoplasmosis, HSV, syphilis, enterovirus, parvovirus B19
Progressive hepatic failure and clotting Echovirus, coxsackie B virus, enterovirus, HSV, toxoplasmosis
abnormalities
Jaundice CMV, toxoplasmosis, rubella, HSV, syphilis, enterovirus
HEMATOLOGIC Anemia with hydrops Parvovirus B19, syphilis, CMV, toxoplasmosis
*Congenital CMV has also been associated with anophthalmia, Peter’s anomaly and coloboma; eye findings associated with congenital infections reviewed in
reference 25.
†
Cerebral calcifications can rarely be seen with congenital rubella, West Nile virus and lymphocytic choriomeningitis virus.
Central Nervous System majority of such infections, both symptomatic and asymptomatic, are
Central nervous system (CNS) involvement may occur with all of the followed by delivery of a healthy term infant. A recent study has sug-
congenital infections (as well as with perinatally acquired HSV and gested that 11% of children who were transfused in utero for B19V-
enteroviral infections), although initial findings may be very subtle. associated anemia may have neurologic sequelae.29
Clinical symptoms and signs may be preceded by ophthalmologic and The most common clinical manifestations of congenital infection
neuroimaging findings. CNS calcifications are seen in congenital CMV, with parvovirus B19 are pregnancy loss and fetal anemia leading to
toxoplasmosis, HSV, HIV, rubella and lymphocytic choriomeningitis nonimmune hydrops. The rate of fetal loss has been estimated at
virus (LCM). 5–9%, although it remains unclear what proportion of these losses are
specifically due to B19V infection.28 Nonimmune hydrops is uncom-
Cardiac mon, occurring in 0–1.6% of B19V infections.
Rubella infection causes structural defects including patent ductus
arteriosus and pulmonary valve stenosis. B19V may cause high-output Rubella
fetal congestive heart failure with resulting prenatal closure of the The clinical features of congenital rubella syndrome (CRS) can be
foramen ovale and Epstein’s anomaly, and occasionally acute and divided into transient abnormalities in newborns and infants, perma-
chronic lymphocytic myocarditis.24 Viral myocarditis is characteristi- nent structural defects and late onset abnormalities.30 Common tran-
cally caused by coxsackie B virus or other enteroviruses. sient manifestations include low birth-weight, hepatosplenomegaly,
bony lucencies and thrombocytopenia with or without purpura. Struc-
Ophthalmologic tural defects include congenital heart disease (patent ductus arteriosus,
Ophthalmologic abnormalities are seen in a variety of congenital pulmonary stenosis), eye abnormalities (cataract, microphthalmia,
infections.25 retinopathy), CNS defects (developmental delay, microcephaly) and
sensorineural or central deafness. Late onset manifestations, occurring
Deafness in 10–20% of individuals, include diabetes mellitus and other endo-
Sensorineural deafness is a common sequela of congenital CMV and crinopathies, vascular defects such as hypertension due to renal disease,
rubella, as well as of untreated T. gondii and T. pallidum infections. deafness, glaucoma and other eye abnormalities, and progressive
One-third of sensorineural hearing loss in childhood is caused by rubella panencephalitis.31
congenital CMV infection. Of rubella-infected infants, 80% or more
are deaf, often as the only significant sequela. Given the progressive Treponema pallidum
nature of impairment, serial hearing evaluations to age 6–9 years are Most commonly, physicians are required to investigate the asymptom-
recommended for CMV-infected infants. atic infant whose mother had positive serologic results for syphilis.
Among such infants, occult findings may include chorioretinitis,
SPECIFIC INFECTIONS radiographic evidence of bone disease and hematologic or cerebrospi-
Cytomegalovirus nal fluid (CSF) abnormalities.
Between 85 and 90% of children with congenital CMV infection are Common clinical manifestations in symptomatic infants include
asymptomatic at birth.26 Common clinical manifestations in symp- hepatosplenomegaly, rash (maculopapular or desquamating), general-
tomatic newborns include IUGR, petechiae, thrombocytopenia, jaun- ized lymphadenopathy, skeletal abnormalities (pseudoparalysis, radio-
dice and hepatosplenomegaly. More severely affected infants may also graphic changes), or persistent nasal discharge (snuffles). At this stage,
have microcephaly, CNS calcifications, chorioretinitis or sensorineural neurosyphilis is often asymptomatic and diagnosed solely on the basis
hearing loss. of CSF abnormalities. Late onset sequelae observed in children (or
Long-term neurocognitive sequelae develop in 40–60% of infants adults) beyond 2 years of age include malformations of bone (frontal
who are symptomatic at birth compared to 10–15% who are asymp- bossing, high arched palate, saber shins, saddle nose), teeth (Hutchin-
tomatic.26 Microcephaly, multiple periventricular or intraparenchymal son teeth, mulberry molars) and skin (rhagades), interstitial keratitis,
calcifications, and to a lesser extent chorioretinitis, are predictive of sensorineural deafness, Clutton’s joints (symmetric joint swelling) and
poor cognitive outcome and motor disability. Among asymptomatic neurocognitive decline (neurosyphilis).32
infants at birth, isolated sensorineural hearing loss is the most common
Toxoplasma gondii
adverse sequela. Hearing loss may be late in onset, fluctuating
and progressive, necessitating long-term follow-up (see Deafness The diversity of findings may be classified according to timing of
above). symptomatology as: symptomatic neonatal disease; disease in the first
months of life, usually with neurologic and ophthalmologic findings;
Herpes Simplex Virus sequelae of previously undiagnosed infection (i.e. chorioretinitis later
Intrauterine HSV infection is rare, accounting for about 5% of HSV in childhood) and subclinical disease. Severely affected children may
infections of the newborn.27 The classic triad of skin vesicles or scar- present with the classic triad of hydrocephalus, intracranial calcifica-
ring, eye lesions and microcephaly or atrophic brain changes resulting tions and chorioretinitis. Of asymptomatic infected infants, half will
in porencephaly, encephalomalacia and ventriculomegaly occurs in have abnormalities on cranial imaging or on careful ophthalmologic
one-third of cases. It may follow primary or recurrent, symptomatic examination. In the absence of treatment, the majority of children who
or asymptomatic HSV-1 or HSV-2 maternal infection at any stage of were asymptomatic at birth go on to develop chorioretinitis, often
gestation. many years later.33
Acquisition just before delivery can lead to disease identical to that
acquired at delivery, except that it occurs within the first 48 hours of Varicella-Zoster Virus
life. The presence of even a single vesicle should prompt ophthalmo- Congenital varicella syndrome (or fetal varicella-zoster syndrome,
logic examination, lumbar puncture with CSF analysis and cranial better reflecting the pathogenesis), includes cicatricial skin scars, eye
imaging. abnormalities including microphthalmia, hypoplastic limbs and auto-
nomic nervous system damage causing gastroesophageal reflux with
Parvovirus B19 (B19V) or without CNS abnormalities. This occurs almost exclusively with
Seroprevalence studies indicate that approximately half the women of maternal varicella infection acquired before 20 weeks’ gestation.7,34
childbearing age are susceptible to B19V and that the annual serocon- Generally, after 20 weeks, manifestations include skin scars, as with
version rate among such women is about 1.5%. The risk of transpla- postnatal VZV infection, and childhood shingles. Only rarely has this
cental transmission of infection is approximately 30%.28 The vast syndrome been reported after gestational zoster.7
BOX 56-2 MATERNAL HISTORY RELEVANT TO CONGENITAL INFECTIONS

MATERNAL HISTORY • had mononucleosis-like syndrome? (CMV, toxoplasmosis, HIV)
Underlying illness and medications • had swollen glands? (CMV, toxoplasmosis, HIV)
Previous history of sexually transmitted disease (HSV, syphilis, chlamydia, • had arthritis? (rubella, parvovirus B19)
gonorrhea, HIV) • had a rash? (rubella, parvovirus B19, syphilis, enterovirus)
Drug or alcohol use, current and previous Has her husband/partner had any particular illness?
Travel during pregnancy (consider culinary practices and other factors in • Skin sores anywhere? (HSV, syphilis, HIV)
region traveled) SEROLOGIC TESTING*
Occupation:
• Working with children wearing diapers or who have disabilities (CMV) Hepatitis B surface antigen and serology for HIV, rubella and T. pallidum
• Working with elementary school children (parvovirus, rubella) • What was timing of testing?
• Working with animals or raw meat products (toxoplasmosis) • If high risk, was testing repeated during the third trimester or at deliv-
• Sex trade workers (HIV, syphilis, tuberculosis, hepatitis B virus, hepa- ery (HIV, T. pallidum)?
titis C virus) • If high risk of blood-borne infections, was hepatitis C testing also
Household exposure to young children (CMV) performed?
During pregnancy: Has the patient … CMV testing†
• eaten raw meat or tasted it while cooking? (toxoplasmosis) • What was timing of testing and why was testing performed (maternal
• consumed unwashed vegetables? (food-borne pathogens, symptoms, routine)?
toxoplasmosis) • If testing was done, clarify IgG, IgM and IgG avidity results.
• changed kitty litter without wearing gloves? (toxoplasmosis) Toxoplasma gondii testing†
• worked in soil/garden without wearing gloves? (toxoplasmosis) • What was timing of testing and why was testing performed (maternal
• had any illness she might not have mentioned until now? symptoms, routine)?
• had cold sores? (HSV) • Clarify serologic tests done and whether this included reference labo-
• had dysuria, burning, itching? (HSV) ratory testing (see Table 56-2)
*Should clarify all serology testing done and why.

†
Testing for these pathogens is not routinely recommended in most jurisdictions.
Diagnosis TABLE Evaluation of Neonate with Suspected

Antenatal diagnosis of fetal infection requires a multidisciplinary 56-5 Congenital Infection
approach to exclude noninfectious causes and to obtain maternal and
fetal studies. In the absence of fetal disease, invasive prenatal testing is CLINICAL Physical examination (age, height, weight, head
usually not warranted because the predictive value of positive and circumference) to identify prematurity, IUGR,
microcephaly
negative results cannot be used as a basis for management decisions. Liver/spleen size
For example, most infants with congenital CMV infection are asymp- Ophthalmologic examination (by pediatric expert)
tomatic and do not suffer sequelae.
LABORATORY Complete blood count and smear
Liver transaminase levels
MATERNAL SYMPTOMS AND Bilirubin level, direct and indirect
SEROLOGIC TESTING CSF examination (cells, protein, with pertinent
The possibility of fetal infection may be raised because of a history of antibody detection; see Table 56-6)
Laboratory testing (detection of agent, maternal and
maternal screening serologic results or fetal ultrasound findings. infant (not cord) serology)
Maternal history relevant to congenital infections is summarized in Serology for suspected pathogens
Box 56-2. Hold pre-transfusion blood for possible additional
Demonstration of pathogen-specific IgG seroconversion during tests
pregnancy provides robust evidence of recent maternal infection. A OTHER Cranial CT scan with enhancement
single positive IgG does not distinguish recent from remote infection. Long-bone radiographs (if syphilis or rubella likely)
The specificity of most IgM assays is poor and therefore a positive Placental pathology
Audiology assessment
result should be not used in isolation to establish a diagnosis. In the Multidisciplinary follow-up
case of reactive IgM to CMV and toxoplasmosis, IgG avidity testing
can be helpful in determining the acuity of infection; low avidity IgG For abbreviations, see text.
typically indicating infection acquired within the past 3–6 months.
Interpretation of syphilis serology requires experience and careful con- absence of sonographic abnormalities, the utility of amniotic fluid
sideration of the clinical context. This is increasingly true given the testing for CMV is questionable since most infections remain
recent shift in some jurisdictions from use of non-treponemal tests asymptomatic.
(RPR [Rapid Plasma Reagin], VDRL [Venereal Disease Research Labo-
ratory]) to treponemal enzyme and chemiluminescence immunoas- NEONATAL TESTING
says for screening.35,36 In evaluating the neonate with suspected congenital infection, it is
necessary to review the maternal history, including serologic screening
FETAL TESTING (see Box 56-2), antenatal ultrasound examinations (see Table 56-3),
Testing for the presence of suspected pathogens in amniotic fluid or evaluate the infant clinically (Tables 56-4 and 56-5), attempt detection
fetal blood can be helpful diagnostically, but should only be under- of the pathogen in the neonate (Table 56-6) and undertake judicious
taken if these results will affect management. In the vast majority of maternal and infant serologic testing pertinent to the most likely diag-
fetuses with congenital toxoplasmosis, the organism can be detected in noses (see Table 56-6).
amniotic fluid by PCR after 18 weeks’ gestation, assuming maternal The best evidence for infection with CMV, enterovirus, HSV,
infection occurred at least 4 weeks prior.37 Fetuses infected with CMV B19V, rubella and T. gondii comes from detection of the agent in
are likely to have detectable virus (by PCR or culture) after 20–22 culture or by molecular techniques in the neonate. Although uncom-
weeks’ gestation as fetal kidney infection is common. However, in the mon, detection of spirochetes in clinical samples (such as nasal
TABLE
56-6 Microbiologic Investigation of the Infant with Suspected Congenital Infection
Follow-up Testing of Infant and Selective
Infection Maternal Testing at Birth Neonate (Not Cord Blood) Comments
CMV • Serology to establish maternal • Virus detection in urine or saliva within 2–3 • Passive maternal antibody disappears at 4–9
sero-status weeks of birth to confirm congenital months
infection • Negative infant and maternal antibody rules out
• Virus detection in blood and CSF may be congenital CMV
of value in assessing for extent of disease • Intrapartum transmission and postpartum breast
• Serology (IgG, IgM) milk transmission is common (these infections
can be significant in extremely premature
neonates)
Enterovirus • Virus detection in stool, • Virus detection in stool, oropharynx, blood, • Detection of the organism in the neonate
oropharynx, blood CSF confirms infection
• Serology • Serology • Serology not readily available in many
jurisdictions
• Selective testing of paired infant and maternal
sera appropriate to infant, maternal or
community isolates
HSV • Serology to establish maternal • Virus detection in skin vesicles, oropharynx, • In neonatal disease, diagnosis primarily by direct
sero-status conjunctiva, stool, blood, CSF detection of the organism
• Serology (IgG, IgM) • Negative infant and maternal antibody rules out
congenital infection (type-specific serology
preferred if available)
Parvovirus B19 • Serology (IgM, IgG) • Virus detection by PCR in blood, bone • Infected infants and their mothers may lack IgM
• Virus detection by PCR in marrow antibody
blood • Serology (IgM and IgG)
Rubella • Serology (IgG, IgM) • Virus detection in urine, nasopharynx, CSF, • Infected infants may shed virus for a year or
blood more
• Serology (IgG, IgM) on serum and • Negative infant serology at 6–12 months usually
selectively CSF (IgM) rules out infection
Toxoplasma • Serology • Direct detection by PCR in CSF, blood, • To determine the acuity of maternal infection,
gondii • If screening serology reactive urine and other samples reference laboratory testing and interpretation is
– reference laboratory testing* • Reference laboratory testing* recommended*
• Histopathology, culture, PCR of placenta • Repeated serology testing of infant to 6–12
months; negative infant serology at 6–12
months usually rules out congenital infection
• IgM and IgA negative in 25% of congenitally
infected neonates
T. pallidum • Serology (screening tests vary • Detection of spirochetes in nasal • Consultation with an expert in the field is
by jurisdiction)† secretions, skin lesions, etc. by darkfield recommended to aid with interpretation of
microscopy reactive serology results
• Serology (treponemal and non-treponemal • No test at birth can differentiate between the
tests)† asymptomatic infected and uninfected neonate
• In uninfected infants, passively transferred
antibody usually clears by 6 months (VDRL, RPR)
and 12–15 months (treponemal tests)
VZV • Serology to establish maternal • Virus detection in skin lesions and, where • Intrauterine infections commonly manifest only
sero-status appropriate, blood and CSF as persistent antibody and childhood zoster
• Serology (IgG and IgM) • Negative infant serology at 6–12 months rules
out congenital infection
*The standard maternal serologic panel performed at the Palo Alto Toxoplasma Serology Laboratory (www.pamf.org/serology/) includes IgG (Sabin Feldman dye
test), IgM ELISA, AC/AH and IgG avidity testing; the standard neonatal panel includes IgG (Sabin Feldman dye test), IgM ISAGA and IgA ELISA.
†
In some jurisdictions a treponemal test is used as the initial screen, in others a non-treponemal test is used; treponemal tests include the Chemiluminescent
Immunoassay (CLIA), Chemiluminescent Microparticle Agglutination (CMIA), Treponemal pallidum Particle Agglutination (TPPA), Fluorescent Treponemal
Antibody-ABSorbed (FTA-ABS), Treponemal pallidum enzyme immunoassay (TP-EIA) and Microhemagglutination test for antibodies to Treponema pallidum
(MHA-TP) tests; non-treponemal tests include the Rapid Plasma Reagin (RPR) and Venereal Disease Research Laboratory (VDRL) tests.
discharge in a neonate with snuffles) provides definitive proof of con- • Newborn infants of seropositive mothers will have reactive IgG
genital syphilis. due to transplacental transfer of maternal antibody.
Serologic testing of the neonate can be helpful, with several impor- • False-negative IgM tests are common in congenital infections
tant caveats: due to CMV, VZV, B19V and toxoplasmosis. The rubella-specific
• A single blanket serologic screen (syphilis, toxoplasmosis, IgM test, by contrast, is highly sensitive and specific.
rubella, CMV, herpesvirus [STORCH]) is of little utility; a more Serologic documentation of maternal infection and acute and
directed approach based on the clinical presentation is required. follow-up serology in the infant over the first months or year of life
• Cord blood is not acceptable for specific antibody testing for can be diagnostic, albeit not sufficiently quickly to facilitate therapeutic
CMV, T. pallidum or T. gondii because of false-positive and false- decisions. Passively transferred antibody will disappear during the first
negative results. Total cord IgM levels may be falsely elevated 6–18 months of life, whereas antibody persists or rises in the infected
through contamination by maternal blood. infant. In the case of possible congenital CMV, interpretation of
follow-up serology is more complicated, as infection may also be Long-term follow-up will identify progressive hearing loss and visual
acquired at birth or postnatally, through breast milk or other contact. deterioration, endocrinopathies and subacute panencephalitis.
Management Treponema pallidum

All infected women should receive penicillin therapy appropriate to
GENERAL their stage of disease. If serology has been positive for <1 year (early
A thorough understanding of the consequences of infection in preg- latent syphilis), a single dose of intramuscular benzathine penicillin G
nancy is required to counsel parents regarding fetal risks and possible 2.4 million units is recommended.44 If the patient has been seropositive
courses of action. Selected maternal infections should prompt a metic- for ≥1 year (late latent syphilis), benzathine penicillin G 2.4 million
ulous antenatal ultrasound. Invasive testing may be indicated if fetal units in a single weekly intramuscular dose for three successive weeks
abnormalities are detected on ultrasound. After delivery, additional is required. Maternal CSF examination (protein, cell count, non-
information about contagiousness, breast-feeding and risk of trans- treponemal and selectively treponemal antibody tests) is required only
mission in subsequent pregnancies should be conveyed. Comprehen- if neurosyphilis is suspected; it is not routinely required in patients
sive long-term pediatric follow-up is required to identify and manage with infectious syphilis if the neurologic examination is negative.
the spectrum of cognitive, motor, visual, hearing and other impair- Retreatment during pregnancy is unnecessary if titers followed
ments that may follow some of these infections. monthly continue to fall.44 In the presence of penicillin allergy, desen-
sitization is the preferred management; any other therapy will neces-
SPECIFIC INFECTIONS sitate treatment of the infant after birth. All women with positive
Cytomegalovirus syphilis serology require testing for other sexually transmitted infec-
The management of a pregnant woman with serologic evidence of tions, including HIV and repeat syphilis testing in the third trimester
acute CMV infection is difficult, in part because it is not possible to to establish if a fourfold drop in non-treponemal titer has occurred.
predict the outcome and most infants born to such women are normal. All recent sexual contacts should also be tested and treated for syphilis
Termination of pregnancy is an option when significant abnormalities and screened for other sexually transmitted infections.
are detected on fetal ultrasound. The potential role of antenatal treat- All infants born to seropositive mothers should be evaluated for
ment of the mother with CMV-immune globulin13–15 or valganciclo- possible congenital syphilis. Quantitative non-treponemal serology
vir38 in preventing congenital CMV infection or disease is intriguing, (RPR/VDRL) should be done in all cases. Cord blood should not be
but requires further study.39 used as it may be falsely negative or positive. The extent of investigation
Neurologic outcome cannot be reliably predicted until the infant is of the infant will depend on the timing and adequacy of maternal
2 or 3 years of age, during which time head growth and achievement therapy, placental pathology and initial evaluation of the infant.45 A
of developmental milestones should be closely monitored. Infants with full evaluation, including complete blood count (CBC), treponemal
abnormal cranial imaging are more likely to have cognitive and other and non-treponemal serology, long bone radiographs and CSF analysis
deficits on follow-up.40 Progression of existing retinal lesions or (including non-treponemal CSF titers) is indicated for those deemed
delayed development of chorioretinitis during childhood has been to be at risk.
reported in about 20% of children, whereas hearing loss will develop The decision to treat an infant for possible congenital syphilis
in about 30% of children, as late as school age. Children with asymp- should follow a thorough evaluation of the maternal history, as well as
tomatic congenital CMV infection show no differences in IQ or other the infant’s clinical manifestations, laboratory results and radiographic
neuropsychologic testing compared with uninfected children. findings.45 Aqueous crystalline penicillin G 50 000 U/kg administered
Most authorities now recommend a 6-month course of oral val- intravenously every 8–12 hours (depending on age) for 10 days is the
ganciclovir treatment for infants with moderate or severe symptomatic recommended regimen for infants less than one month of age
congenial CMV. In a recently completed phase III trial, language and (100 000–150 000 U/day).45 For older children the same dose should be
receptive communication scores were significantly better in those who administered every 4–6 hours (200 000–300 000 U/day). Follow-up of
received 6 months compared to 6 weeks of therapy.41 Intravenous all infants is required to ensure that the appropriate fall in titers occurs
ganciclovir remains an option for children who are unable to tolerate and that treatment or retreatment is not required.
oral medication or in whom medication absorption is a concern.
However, the IV formulation is less well tolerated, with two-thirds Toxoplasma gondii
developing neutropenia and half requiring dose reduction.42 Treatment of toxoplasmosis with spiramycin prior to 18 weeks’ gesta-
tion is recommended by some experts as it may reduce the rate of
Herpes Simplex Virus transmission to the fetus.17 Once congenital infection is established,
As intrauterine infection is rare, infected women should be assured the combination of pyrimethamine and sulfadiazine is administered
that maternal infection is common but that fetal infection is unusual. with the goal of improving fetal outcome.17 The regimen currently
recommended for treatment in North America is given in Table 56-7
B19V
(see also Practice Point 16).
After documented maternal infection, serial ultrasounds should be The outcome of congenitally infected infants whose treatment
performed for approximately 10–12 weeks to identify the anemic (or was started at birth has been shown to be substantially better than
hydropic) fetus. Excellent results have followed intrauterine transfu- that of historic controls either untreated or treated for one month
sion for anemic fetuses, until the transient marrow aplasia resolves.43 only.46 Normal cognitive, neurologic and auditory outcome was
Hydropic fetuses with an intermediate hemoglobin and high reticulo- observed in all children who did not have neurologic disease at birth.
cyte count, in whom the process is resolving spontaneously, need not Furthermore, more than 70% of those with moderate or severe neu-
be transfused. There are no data at present to recommend fetal intra- rologic disease at birth had a normal cognitive and/or neurologic
venous immune globulin (IVIG) therapy. outcome and none had sensorineural hearing loss. In contrast, when
Rubella infants were untreated, late sequelae after subclinical disease included
Rubella is generally a benign illness in adults, but has potentially dev- active chorioretinitis in 85%, including some cases of blindness or
astating consequences in the fetus. Maternal infection during the first impaired vision, developmental delay in 20–75% and moderate hearing
trimester results in fetal infection in approximately 80% of cases, the loss in 10–30%.
vast majority of which will have serious congenital defects and the
option of pregnancy termination should be discussed. PERINATAL INFECTIONS
Infected infants should be considered infectious for the first year These occur as a result of ascending infection and preterm premature
of life unless repeated nasopharyngeal and urine cultures are negative. rupture of the membranes (PPROM) or through intrapartum
TABLE
56-7 Treatment of Toxoplasmosis in the Fetus and Infant
Manifestation of Disease Medication Dosage (PO) Duration of therapy
In pregnant women with acute Spiramycin 1 g q8h without food Until fetal infection documented or
toxoplasmosis (first 21 weeks excluded at 21 weeks; if
of pregnancy or until term if documented, in alternate months
fetus not infected) with pyrimethamine, leukovorin,
and sulfadiazine until term (France)
If fetal infection confirmed after Pyrimethamine and Loading dose: 100 mg/day in two divided Until term (leukovorin is continued 1
week 17 of gestation or if doses for 2 days then 50 mg/day week after pyrimethamine is
maternal infection acquired Sulfadiazine and Loading dose: 75 mg/kg per day in two discontinued)
in last few weeks of gestation divided doses (maximum 4 g/day) for 2
days then 100 mg/kg per day in two
divided doses (maximum 4 g/day)
Leukovorin (folinic acid) 10–20 mg/day
Congenital Toxoplasma gondii Pyrimethamine and Loading dose: 2 mg/kg per day for 2 1 year
infection in the infant days, then 1 mg/kg per day for 2–6
months, then this dose every Monday,
Wednesday and Friday
Sulfadiazine and 100 mg/kg per day in two divided doses 1 year
Leukovorin 10 mg 3 times a week 1 year
Corticosteroids (prednisolone) have 1 mg/kg per day in two divided doses Until resolution of elevated (≥1 g/dL)
been used when CSF protein is CSF protein level or active
≥1 g/dL and when active chorioretinitis that threatens vision
chorioretinitis threatens vision
Adapted with permission from Hohlfeld P., Daffos F., Thulliez P., et al.: Journal of Pediatrics 1989; 115(5 Pt 1):765–769; and Remington J., Klein J.O., Wilson C.B.,
et al., ed.: Infectious diseases of the fetus and newborn infant, 7th ed. Philadelphia, PA: Elsevier; 2011: 918–1041
TABLE
56-8 Preventive Strategies and Intrapartum Management for Selected Perinatally Acquired Infections
Micro-organism Clinical Situation Preventive Management and Comments
Enterovirus Active maternal enteroviral infection (i.e. • Attempt to defer delivery in order to allow maternal antibody to develop and cross placenta
fever, abdominal pain) at delivery
HBV* Mother HBsAg-positive or status • Neonatal passive plus active immunization†

unknown • Universal neonatal immunization recommended in most jurisdictions
• Follow-up testing of infants to determine infection and immunity status
• Breast-feeding is not contraindicated
HCV Maternal serology positive • Follow-up testing of infant to determine infection status
• Breast feeding is not contraindicated
HSV Maternal lesions at delivery • Cesarean section for active lesions or primary infection in (late) pregnancy
• Swab skin, oropharynx, eyes, rectum for HSV PCR/culture‡
• Active observation of neonate for signs of infection
• IV aciclovir for infected neonates
HIV-1* HIV-positive mother • Maternal antenatal combination antiretroviral therapy

• Intrapartum intravenous zidovudine§
• Elective Cesarean section if maternal viral load >1000 copies/mL
• Single or combination antiviral therapy of infant¶
• Breast feeding contraindicated in most jurisdictions
• Follow-up testing of infant to determine infection status
VZV Maternal lesions within 5 days before to • Varicella-zoster immune globulin as soon as possible after birth
2 days after delivery • Aciclovir therapy of neonate if develops disease
• Postpartum immunization of immunocompetent women who have no history of varicella and
are seronegative
*For women with unknown status at delivery (e.g. no antenatal care) – serology testing for HBsAg, HIV, syphilis and possibly hepatitis C should be performed; HIV
serology, HBsAg and syphilis should be done stat.
†
Both vaccine and HBIG indicated for infants of HBsAg-positive mothers; for infants of unknown-status mothers the need for HBIG depends on infant’s gestational
age and availability of maternal HBsAg test results.
‡
Infants with symptoms or signs of clinical disease and those whose initial swabs are positive for HSV should undergo lumbar puncture and be treated with IV
aciclovir.
§
In some jurisdictions intrapartum IV zidovudine is recommended for all HIV-positive women, in others only if maternal viral load >400 copies/mL
¶
Combination antiretroviral therapy to the infant should be considered in situations where maternal viral load is elevated at delivery.
transmission. Their management and prevention are summarized in newborn in the first months of life. The most common symptoms are
Table 56-8. undifferentiated fever and aseptic meningitis. A sepsis-like syndrome
with or without myocarditis and hepatitis is occasionally seen; this is
Specific Infections commonly associated with a nonspecific febrile illness in the mother
Enterovirus and Parechovirus. Enteroviruses and parechovi- in late pregnancy.8 Pleconaril is a potential therapeutic agent47 but is
ruses are among the commonest pathogens encountered by the not currently available outside of a research setting. Given the
likelihood that an infected infant has received no passive maternal failure or prematurity. Isolation of the exposed hospitalized infant is
antibody, high-dose IVIG may be used in the acutely ill infant, although required.
its efficacy has not been demonstrated. Human Immunodeficiency Virus (HIV). In the absence of
intervention, the risk of vertical HIV transmission is approximately
Herpes Simplex Virus (HSV). The risk of neonatal HSV infection 25–40%. With appropriate interventions, transmission can be reduced
is approximately 60% following a first episode primary maternal infec- to less than 2%.
tion (mother has no serum antibodies to HSV-1 and -2 at onset of a Prevention of vertical HIV transmission is achievable through anti-
new infection) and 25% following first-episode non-primary maternal retroviral therapy of the mother and infant and, where appropriate,
infection (mother has a new infection with one type and serum anti- elective Cesarean section (viral load >1000 copies/mL). Optimal pre-
bodies to the other type).48,49 In contrast, fewer than 2% of neonates ventive therapy consists of combination antiretroviral therapy to the
born to mothers with recurrent genital HSV infection will become mother throughout pregnancy or beginning in the second trimester,
infected. However, because most adult infections are asymptomatic, intrapartum IV zidovudine and 6 weeks of oral zidovudine for the
60–80% of neonatal HSV infections are acquired from mothers with infant (see Chapter 100). In resource-poor settings, other antiretrovi-
no history of genital lesions. Obtaining third trimester genital samples ral regimens may be employed. Elective Cesarean section can reduce
for HSV culture or PCR from asymptomatic women is not recom- the risk of transmission by half among women who received no anti-
mended as results are not predictive of intra-partum viral shedding. retroviral therapy.
Type-specific (HSV-1, HSV-2) maternal serology has been recom-
mended for asymptomatic women whose partners have a history of Hepatitis B Virus (HBV). Perinatal HBV transmission occurs
genital HSV.50 Type-specific serology can also be used to distinguish most often during labor and delivery. Overall, fewer than 5% of
between first-episode primary, first-episode non-primary and recur- cases are due to in utero transmission. The risk of perinatal transmis-
rent HSV infection in women with a first clinical episode of genital sion is 70–90% if the mother is HBsAg-positive and HBeAg-positive
HSV in pregnancy.49 This strategy has been recommended by the compared to 5–20% if the mother is HBsAg-positive but HBeAg-
American Academy of Pediatrics to guide management of the exposed negative. Hepatitis B DNA load is an independent predictor of peri-
infant.49 natal transmission and of immunoprophylaxis failure. Antiviral
For women with a first-episode genital herpes during pregnancy prophylaxis with lamivudine, telbivudine or tenofovir during the third
or those with multiple recurrences, oral aciclovir or valaciclovir trimester may reduce immunoprophylaxis failure and has been recom-
from 36 weeks until delivery has been used to reduce the risk of mended for women whose HBV DNA load is >6 log10 copies/mL
active lesions at delivery and thus the need for Cesarean section.51–53 (>200 000 IU/mL).60,61
Both animal and human data suggest that maternal treatment with Hepatitis B vaccination initiated at birth with or without hepatitis
aciclovir is safe throughout pregnancy.54 Cesarean section is generally B immune globulin is highly effective in preventing perinatal infection.
recommended for women with active genital lesions at birth or a Infants of carrier mothers should receive 0.5 mL hepatitis B immune
primary clinical infection, particularly in the last part of pregnancy, globulin (HBIG) within 12 hours of birth and hepatitis B vaccine at
although this may not prevent neonatal infection.48 Fetal scalp elec- birth, 1–2 months and 6 months of age. Infants born to mothers of
trodes should be avoided. Viral cultures should be obtained from the unknown status should receive the first dose of hepatitis B vaccine
maternal cervix at birth. Infant samples (i.e. urine, mouth, nasophar- within 12 hours of birth and complete the vaccination course as indi-
ynx, conjunctiva, stool/rectum) should be obtained at 12–24 hours and cated above. The need for and timing of HBIG depends on avail
the child carefully observed for symptoms of neonatal HSV requiring ability of maternal HBsAg results and the gestational age at
therapy.49,55 Initial evaluation of all infants with suspected or con- delivery.62
firmed HSV infection must include CSF PCR to detect subclinical Hepatitis C Virus (HCV). The vertical transmission rate of HCV
CNS disease. is approximately 5%. The risk of transmission is almost three times
Neonatal HSV infection may manifest as disseminated disease, higher from women who are co-infected with HIV. Transmission from
involving multiple organs, most notably the lungs and liver, localized mothers who are HCV RNA-negative is uncommon. Confirmation of
CNS disease or as isolated skin/mucosal lesions. Skin lesions may be HCV infection in infancy requires the detection of HCV RNA after 1
absent in disseminated and CNS disease. Aciclovir therapy for pre- month of age or the presence of HCV antibodies after 18 months of
sumed or confirmed HSV infection should be prescribed at a dose of age. Among vertically infected infants followed for 10–15 years, 20%
60 mg/kg per day intravenously every 8 hours for 14–21 days.55 For clear the infection, 50% have chronic asymptomatic infection and 30%
isolated skin and mucosal surface involvement, 14 days is sufficient, have chronic active infection.63
whereas 21 days of therapy is required with disseminated disease,
encephalitis, or in the presence of an abnormal CSF profile. While Group B Streptococcus (GBS). Of the 10–35% of women asymp-
mortality is reduced with therapy, morbidity remains significant.56 tomatically carrying GBS, 50% of infants will be colonized on skin and
Contact isolation of an infant with lesions is required. mucous membranes. Of those colonized, 1–2% will develop early-
Suppressive oral aciclovir through 6 months of life (300 mg/m2 onset GBS disease. Two alternative approaches (screening, risk factor
TID) following treatment for neonatal HSV disease has been shown to identification) to the prevention of GBS disease have been developed,
improve neurocognitive outcome at 12 months of age in those with with a 70% reduction in the incidence of early-onset disease.64 Accord-
evidence of CNS involvement.57 In neonates with disease confined to ing to the more effective screening approach, all pregnant women
the skin and mucosal surfaces, suppressive aciclovir reduces the rate of should be screened at 35–37 weeks’ gestation for anogenital GBS colo-
cutaneous recurrences. Recurrent HSV encephalitis with aciclovir- nization. Intrapartum antibiotics should be offered to all culture-
resistant virus, while on suppressive aciclovir therapy, has recently positive women, regardless of risk factors. If the results of cultures are
been reported.58 unknown at the time of labor, intrapartum antibiotics are used in the
presence of prematurity (<37 weeks’ gestation), prolonged rupture of
Varicella-Zoster Virus (VZV). Neonates whose mothers develop membranes (≥18 hours) or intrapartum fever (≥100.4 °F/38 °C). Also,
peripartum chickenpox from 5 days before to 48 hours after delivery women with a previously infected infant, GBS bacteriuria during the
are at high risk of severe disease, due to the lack of protective passive current pregnancy or a history of postpartum GBS sepsis are treated
maternal antibody. Their risk of severe disease is between 20 and 50% with intrapartum antibiotics (see Practice Point 17). In geographic
and their risk of death is approximately 20% in the absence of inter- regions with differing epidemiologic data, this approach may not be
vention.7 All such infants should receive a dose of 125 U (1.25 mL or appropriate.
1 vial) of zoster immune globulin intramuscularly as soon as possible Absence of Antenatal Care. For women with inadequate antena-
after birth.59 Aciclovir at a dose of 1500 mg/m2 per day should be given tal care, detection of infection is required at delivery, as summarized
to symptomatic neonates, with dose adjustments for liver and renal in Table 56-9.
Viral contamination of milk with rubella, HSV and CMV has

TABLE Evaluation of Women Presenting in Labor also been reported, but serious sequelae have not generally occurred.
56-9 with Minimal/No Antenatal Care* CMV acquired through breast milk can pose a risk to extremely pre-
mature infants. In this setting, the potential benefits and risk of
Mother Genital examination for findings suggestive of sexually
transmitted disease
breast-feeding need to be considered. Mothers with herpetic lesions
• Cultures for Chlamydia trachomatis, Neisseria on their breasts should refrain from breast-feeding from the affected
gonorrhoeae side(s). They should cover active lesions and wash their hands before
Serologic testing for HIV†*‡, HBsAg*, HCV, syphilis breast-feeding.
(treponemal and non-treponemal testing)
Ensure follow-up care
Contaminated milk has been implicated in neonatal infection with
Staphylococcus aureus, GBS, Mycobacterium spp. and possibly Klebsiella
Infant Prophylactic eye care pneumoniae and Salmonella spp. In mothers who have active pulmo-
Serologic testing for HIV*‡, HBsAg†, HCV, syphilis
(treponemal and non-treponemal testing) nary tuberculosis, contact with the infant must be avoided until the
First dose of hepatitis B vaccine and HBIG if the results mother has received adequate antituberculous therapy and is no longer
of HBsAg cannot be obtained soon enough considered to be infectious. In the setting of mastitis, breast feeding
Ensure follow-up care can usually be continued; in the presence of a breast abscess or frank
*If the mother is not available for testing, serologic testing of the infant can be pus, temporary discontinuation of breast-feeding on the affected side
done (HIV, HBV, HCV and syphilis). is warranted.65
†
HBsAg, HIV testing and syphilis should be done stat in order to allow for
‡
prompt initiation of preventive interventions if the mother tests positive. Breast-Feeding and Drug Therapy
HIV viral load testing may be considered in situations where late pregnancy
acquisition is suspected (the interval between infection and seroconversion
The American Academy of Pediatrics recommends that breast-
can be up to 3 months). feeding be discontinued while a nursing mother is being treated with
For abbreviations, see text. metronidazole, and warns about the use of nitrofurantoin and sulfa
drugs, which can cause hemolysis in glucose-6-phosphatase-deficient
infants.66 Although it would be unusual for an effective maternal medi-
BREAST-FEEDING cation to be contraindicated because of risks to the infant through
Contraindications and Precautions with breast milk, physicians should be aware of information specific to
Breast-Feeding agents being used. Frequent feeding exposes the infant to more drug
In higher-income countries, breast-feeding is contraindicated if the than feeding at 4-hourly intervals. Mothers can be encouraged to avoid
mother is infected with HIV, human T-cell lymphotrophic virus 1 frequent feedings to reduce drug exposure and the consequent changes
(HTLV-1) or HTLV-2.65 In resource-poor settings, the potential benin the infant’s gastrointestinal flora and risk of oropharyngeal
efits and harms associated with breast versus formula feeding need to candidiasis.
be carefully weighed. Breast-feeding is not contraindicated with hepa-
titis B or C infection. References available online at expertconsult.com.
KEY REFERENCES
Anonymous: Syphilis. In: Kimberlin D.W., Brady Dollard S.C., Grosse S.D., Ross D.S.: New estimates of the McLeod R., Boyer K., Karrison T., et al.: Outcome of
M.T., Jackson M.A., et al., eds. Red Book. Elk Grove prevalence of neurological and sensory sequelae and treatment for congenital toxoplasmosis, 1981–2004:
Village, IL: American Academy of Pediatrics; 2015:755- mortality associated with congenital cytomegalovirus the National Collaborative Chicago-Based, Congenital
768. infection. Rev Med Virol 2007; 17(5):355-363. Toxoplasmosis Study. Clin Infect Dis 2006; 42(10):
Best J.M.: Rubella. Semin Fetal Neonatal Med 2007; Enders G., Miller E., Cradock-Watson J., et al.: Conse- 1383-1394.
12(3):182-192. quences of varicella and herpes zoster in pregnancy: pro- Montoya J.G., Remington J.S.: Management of Toxoplasma
Brown Z.A., Wald A., Morrow R.A., et al.: Effect of sero- spective study of 1739 cases. Lancet 1994; 343(8912): gondii infection during pregnancy. Clin Infect Dis 2008;
logic status and Cesarean delivery on transmission rates 1548-1551. 47(4):554-566.
of herpes simplex virus from mother to infant. JAMA Fiumara N.J., Lessell S.: Manifestations of late congenital Pan C.Q., Lee H.M.: Antiviral therapy for chronic hepatitis
2003; 289(2):203-209. syphilis: an analysis of 271 patients. Arch Dermatol 1970; B in pregnancy. Semin Liver Dis 2013; 33(2):138-146.
De Jong E.P., Lindenburg I.T., van Klink J.M., et al.: Intra- 102(1):78-83. Revello M.G., Lazzarotto T., Guerra B., et al.: A randomized
uterine transfusion for parvovirus B19 infection: long- Kimberlin D.W., Jester P.M., Sanchez P.J., et al.: Valganci- trial of hyperimmune globulin to prevent congenital
term neurodevelopmental outcome. Am J Obstet Gynecol clovir for symptomatic congenital cytomegalovirus cytomegalovirus. N Engl J Med 2014; 370(14):1316-
2012; 206(3):204 e1-204 e5. disease. N Engl J Med 2015; 372(10):933-943. 1326.
Degani S.: Sonographic findings in fetal viral infections: a Kimberlin D.W., Whitley R.J., Wan W., et al.: Oral acyclo-
systematic review. Obstet Gynecol Surv 2006; 61(5): vir suppression and neurodevelopment after neonatal
329-336. herpes. N Engl J Med 2011; 365(14):1284-1292, 61.
Chapter 56 Fetal Implications of Maternal Infections in Pregnancy 516.e1
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and chronic lymphocytic myocarditis and high
PRACTICE Obstetric and Gynecologic Infections
POINT
16 Treatment of a Positive Toxoplasma

Titer in Pregnancy
RONALD A. NICHOLS | THEODORE B. JONES
Introduction have been considered. In the USA, routine screening for toxoplasmosis
in pregnancy is rarely recommended, but in some other countries
Toxoplasmosis is a leading cause of infection-related food-borne death screening is repeated serially in pregnancy, particularly in France.
worldwide. While serologic evidence of toxoplasmosis is common,
clinically recognized disease is infrequent in immunologically compe-
tent people. This does not hold true for the situation in pregnancy, Investigation
however. When symptomatic or asymptomatic infection is acquired The focus of this Practice Point is on immunocompetent pregnant
during pregnancy, Toxoplasma gondii readily crosses the placenta to women who have had a ‘positive’ test for antibody to T. gondii. The
infect the fetus, often with significant adverse implications. It is esti- impetus for the screening test may have resulted from a recent mater-
mated that 15% of childbearing women (15–44 years old) are infected nal exposure or an abnormal finding on a targeted prenatal ultrasound.
with Toxoplasma gondii. This leads to an incidence of congenital toxo- Depending on the laboratory, this will be either a positive IgG titer, or
plasmosis of 400 to 4000 cases per year. In North America, approxi- possibly a positive titer for both IgG and IgM. Evaluation for falling or
mately one pregnancy in 1000 is affected, with higher rates reported rising titers is standard, but unless timing is fortuitous, titers are
in Europe. Because early treatment of the mother may decrease the risk usually stable.
of infection of the fetus and diminish sequelae, appropriate manage-
ment of the mother is essential. DIFFICULTIES IN INTERPRETATION OF
Since the majority of infected women are either asymptomatic or SEROLOGIC RESULTS
have nonspecific and transient symptoms, the diagnosis is rarely made There are several substantial problems in the interpretation of results:
clinically. Rather, the healthcare provider and the woman are typically
faced with a positive serologic test without clear information on when
• Poor sensitivity and specificity of many of the commercially
available tests. Confirmation of a serological diagnosis of acute
the infection was acquired. An inappropriate interpretation may result maternal infection in the USA is recommended by a reference
in unwarranted psychologic distress, unnecessary evaluations and laboratory with extensive experience in the area.
treatments, and occasionally, an unnecessary termination of preg-
nancy. In the USA, a recent study of obstetricians and gynecologists
• Potential markers for acute infection, such as IgM and IgA, may
persist long after the risk of transmission to the fetus ends. This
revealed that few were aware that ‘positive’ IgM antibody did not neces- may diminish the ability of positive IgM and IgA results that may
sarily indicate acute infection, or that the US Food and Drug Admin- be true positives to establish acuteness of infection. For this
istration had sent out an advisory about problems with serologic tests reason, when the IgM is reported as being ‘positive’, the possi-
for toxoplasmosis. bilities are that it can be a false-positive (with the rate of false-
positives dependent on the test and the laboratory), a true-positive
Pathogenesis indicative of recent infection, or a true positive but simply
The definitive hosts of T. gondii are felines, and people are infected by reflecting persistence of IgM antibody.
direct or indirect contact with oocysts excreted by cats. The oocysts • Third, the history and physical examination rarely adds to the
that are spread in cat litter or soil or sand contaminated by cat feces clinician’s ability to determine the acuteness of infection.
are highly infective. When ingested by animals or humans they result A summary of testing results and interpretation is presented in Table
in cysts in host tissues (predominately skeletal muscle, brain, myocar- PP16-1, and is further explored below.
dium and eyes). In addition, humans can be infected when uncooked
or inadequately cooked meat containing viable cysts is ingested. Rarely, NEGATIVE ANTI-TOXOPLASMA GONDII IgG
humans can also be infected by blood transfusions (see Chapters 56 AND IgM
and 194). An initial maternal serologic screening test that yields negative IgG and
During acute infection, toxoplasmosis is disseminated widely. IgM antibodies should be interpreted as absence of toxoplasmosis
Though the risk of transmission in the first trimester (10–15%) is the infection. Women with such results are at risk of acquiring acute infec-
lowest, its impact on the fetus is greatest, resulting in severe sequelae tion during pregnancy, possibly resulting in congenital toxoplasmosis.
or death. Infection in the second trimester has been associated with a Primary prevention messages should be strongly recommended,
25–40% transmission and has been found to have nonfatal effects in including good hand hygiene, and it may be prudent to use gloves and/
most circumstances. The highest proportion of fetuses infected occurs or mask when handling cat feces and gardening. Subsequent repeat
in the third trimester (>60% transmission). However, nearly all affected testing is required if one wishes to exclude infection later on in the
fetuses have mild or asymptomatic manifestations. pregnancy.
The classic triad of clinical features in severely infected infants who
survive includes hydrocephalus, intracranial calcifications and chorio- ONLY IgG TITER AVAILABLE, AND IS POSITIVE
retinitis. Asymptomatically infected infants are typically not recog- Ideally, paired sera (IgG and IgM) or IgM on a new serum specimen
nized at birth, but many, if not most, are thought to be at risk of should be ordered because a single positive IgG titer provides no infor-
subsequently developing chorioretinitis, hearing loss or subtle neuro- mation about the timing of infection. While the presence of IgG anti-
logic manifestations. body with a negative IgM antibody excludes recent infection, it may
The economic impact of congenital toxoplasmosis is substantial, indicate exposure or infection with toxoplasmosis for more than one
and screening programs to detect infection in pregnancy or at birth year. If performed early in pregnancy, no further investigation is
517
TABLE
PP16-1 Toxoplasmosis Maternal Serum Results
IgG Equivocal IgG Positive IgG Negative
IgM Equivocal Indeterminate result, order Probable past infection with T. gondii, repeat IgM Probably not infected or false-positive IgM. If
repeat paired sera determination exposure expected, get second sample
IgM Positive Possible early acute infection, Acute infection, check for rising titers, consider Possible acute infection, recheck IgG incubation
repeat testing in 3 weeks amniocentesis for PCR of AF toxoplasmosis DNA period or early infection
IgM Negative Retest for IgG antibodies Infected with T. gondii, usually over 1 year No evidence of infection, patient at risk,
emphasize primary prevention
AF, amniotic fluid; PCR, polymerase chain reaction.
required for toxoplasmosis. If performed late in pregnancy, there is an assess acuteness of infection. Results should be interpreted in consulta-
outside possibility that acute infection may have arisen earlier in preg- tion with the reference laboratory. The two tests most often employed
nancy, with subsequent disappearance of IgM. Any clinical suspicion to assess acuteness of infection are IgG avidity and differential agglu-
of toxoplasmosis should prompt screening at birth. tination testing, but numerous other tests may be used by reference
laboratories. If these additional results are consistent with acute infec-
INITIAL NEGATIVE IgG TITER WITH POSITIVE tion or if they do not exclude acute infection, the woman should be
OR EQUIVOCAL IgM TITER managed as below.
IgG antibodies appear within 2 weeks of infection with toxoplasmosis
and persist indefinitely. When the IgG is negative, it is highly likely that Management
the IgM is falsely positive. These initial test results would not eliminate
the possibility that the woman could be in the process of seroconver- STUDIES DIAGNOSTIC OF OR CONSISTENT
sion. Therefore, repeat testing with paired sera (IgG and IgM) should WITH ACUTE INFECTION IN PREGNANCY OR
be collected approximately 3 weeks after the initial collection. If the IMMEDIATELY BEFORE CONCEPTION
IgG titer remains negative, then the IgM result is probably falsely posi- The medical management is directed by the suspected timing of mater-
tive. Unless there are other features suggesting active infection, no nal infection. If results are consistent with infection immediately
further investigation is needed. Recent acquisition of infection is before or just after conception, the risk of delivering an infected baby
strongly suggested if the IgG titer converts to positive or there is a is low. Either the fetus is not infected or if the fetus is infected it is
significant increase in the IgM titer. likely to abort. However, the fetus that does survive becoming infected
early in pregnancy has a much greater chance of manifesting severe
INITIAL OR SUBSEQUENT POSITIVE IgG TITER, manifestations of an in utero infection. The possibility of congenital
AND IgM TITER IS POSITIVE toxoplasmosis or vertical transmission from a maternal reinfection is
In the absence of seroconversion or a three- to fourfold titer increase, considered rare and unusual. When infection occurs later, the risk of
interpretation at this stage is challenging because this information by having a viable but affected infant is much greater. The risk of vertical
itself does not establish timing of infection. Though IgM antibody transmission of infection when the mother seroconverts during preg-
levels rise within days of the infection and remain present – in general, nancy increases dramatically as the pregnancy advances.
for 2–3 weeks – they have been reported to persist as long as 2–3 years In all cases of suspected or confirmed infection during pregnancy,
in as many as 27% of women when immunosorbent agglutination the mother should immediately be started on treatment (see below)
assays are used. Thus, this may confound additional efforts at clinical for the duration of pregnancy and the fetus should be assessed by
assessment with serology and other studies in the mother and poten- ultrasound. Amniocentesis for polymerase chain reaction (PCR) for
tially in the fetus. Toxoplasmosis gondii DNA in amniotic fluid should be strongly con-
sidered as it is considered one of the best methods for diagnosing fetal
HISTORY AND EXAMINATION OF THE MOTHER infection antenatally. Prenatal diagnosis may provide assistance to
Although symptoms are usually absent or nonspecific in over 90% those patients contemplating whether to continue their pregnancy. In
of women with primary toxoplasmosis infection in pregnancy, a addition, the results may influence the need for postnatal therapy and
careful history and examination might detect symptoms that provide treatment in neonates. Fetal ultrasound may show features consistent
a clue to the onset of the disease. The development of lymphadenopa- with infection, especially increased size of the ventricles and intracra-
thy, typically involving one node or several nodes, is often a useful nial calcifications. Negative studies do not exclude fetal involvement
clinical marker. Pregnant women who have recently experienced and studies may need to be performed serially. With or without fetal
mononucleosis-like symptoms with a negative work-up should raise abnormalities, amniocentesis should be considered at 18 weeks or later.
suspicion for toxoplasmosis exposure and be evaluated. The physical If performed, the amniotic fluid should be tested by PCR. Reference
examination should look for abnormal lymphadenopathy and ocular laboratories may do additional testing on amniotic fluid, such as
disease. mouse or cell culture inoculation. Although PCR can be falsely positive
or falsely negative, if it is positive, treatment of the mother should be
SEROLOGIC STUDIES IN THE MOTHER switched to pyrimethamine and sulfadiazine (discussed below). While
Pregnant women are often screened for a variety of processes (e.g. some experts suggest the use of fetal blood sampling or cordocentesis
rubella, HIV), and this serum might have been stored. If available, to detect the parasite or a fetal immunologic response, antigen testing
prior stored serum should be tested for antibody to T. gondii. The utilizing PCR on amniotic fluid is probably safer.
results may be very helpful in determining the chronicity of infection.
Additional testing is required on available or newly acquired serum. If TREATMENT OF THE MOTHER
repeat testing on specimens run in parallel (i.e. testing is performed If maternal infection is present, the patient should be started on
on all specimens at the same time) shows or has shown seroconversion oral spiramycin 3 g daily in divided doses on an empty stomach. Spi-
or a fourfold or greater rise in titer, then infection is most likely acute. ramycin is a macrolide antimicrobial agent with similarities to eryth-
Usually titers are stable, and further testing is required in specialized romycin. It crosses the placenta and reaches concentrations in the
or reference laboratories. A battery of tests is usually performed to placenta up to five times higher than that in the serum. It is also
Practice Point 16 Treatment of a Positive Toxoplasma Titer in Pregnancy 519
distributed in breast milk. While spiramycin reduces the transmission adverse reactions associated with sulfonamides, including concerns of
of toxoplasmosis from the pregnant mother to the fetus, it will not alter kernicterus. The major adverse reaction to pyrimethamine is dose-
the severity of disease in an already infected fetus. When the fetus is related bone marrow suppression. To assess hematologic abnormali-
known to be infected, pyrimethamine and sulfonamides are more ties, testing is recommended at least once weekly to detect anemia,
active than spiramycin. Hence, ultrasound or amniotic fluid findings leukopenia and thrombocytopenia.
suggestive of fetal involvement should prompt a change of treatment Although other drugs have been used to treat toxoplasmosis, there
to pyrimethamine and a sulfonamide. A variety of dosage regimens is minimal experience with them in the context of pregnancy and fetal
have been used, but currently suggested is pyrimethamine 25 mg/day infection.
and sulfadiazine 2 g orally every 12 hours, with supplemental folinic
acid (leucovorin) 10–20 mg/day. When treatment of the mother is TERMINATION OF PREGNANCY
initiated, it should be continued for the duration of the pregnancy. Many women with ‘positive’ serology for toxoplasmosis have had
Pyrimethamine use should be avoided in the first trimester due to unnecessary termination of pregnancy. Positive IgG and IgM serology
reports of possible teratogenic effects. Both pyrimethamine and sulfa- alone is not an indication for termination. Most of these women will
diazine are folate antagonists and may suppress maternal and fetal not have infected fetuses. However, should an infection be diagnosed,
bone marrow production. Hence, leucovorin 10–20 mg by mouth appropriate long-term treatment of the infant often leads to a healthy
daily and periodic monitoring of complete blood counts are outcome. Termination should only be considered when there is docu-
recommended. mented evidence of fetal involvement, especially if infection was
It is important to emphasize that while treatment of the woman acquired early in the first trimester. However, affected fetuses have had
with primary toxoplasmosis is suggested by most experts, the effective- promising outcomes with treatment of the mother followed by treat-
ness of prenatal treatment is not clear. Conflicting results have been ment of the infant.
noted in controlled and uncontrolled cohort studies: controlled studies
failed to demonstrate benefit in treated women compared to untreated OTHER CONSIDERATIONS
women, while several uncontrolled studies found a higher risk for Several studies have suggested that women with T. gondii antibodies
congenital toxoplasmosis in untreated neonates. A recent systematic appear to be at greater risk for prenatal depression and anxiety. This
review further demonstrated the problem, with five studies demon- may increase the risk of poorer pregnancy and fetal outcomes as well
strating benefit while four failed in this regard. as a greater risk for postpartum depression.
Spiramycin is a macrolide with possible adverse reactions including
nausea, vomiting, anorexia and diarrhea. Sulfadiazine has typical Further reading available online at expertconsult.com.
Practice Point 16 Treatment of a Positive Toxoplasma Titer in Pregnancy 519.e1
FURTHER READING
Hotop A., Hlobil H., Gross U.: Efficacy of rapid treatment sis based on avidity of IgG. J Infect Dis 1993; 167:691- Rabilloud M., Wallon M., Peyron F.: In utero and at birth
initiation following primary Toxoplasma gondii infection 777. diagnosis of congential toxoplasmosis. Pediatr Infect Dis
during pregnancy. Clin Infect Dis 2012; 54(11): Montoya J.G., Remington J.S.: Management of Toxoplasma J 2010; 29:421-425.
1545-1552. gondii infection during pregnancy. Clin Infect Dis 2008; Sensini A.: Toxoplasma gondii infection in pregnancy:
Jones J.L., Dietz V.J., Power M., et al.: Survey of obstetricians– 47:554-565. opportunities and pitfalls of serological diagnosis. Clin
gynecologists in the United States about toxoplasmosis. Peterson E.: Toxoplasmosis. Semin Fetal Neonatal Med 2007; Microbiol Infect 2006; 12:504-512.
Infect Dis Obstet Gynecol 2001; 9:23-31. 12:214-223. The SYROCOT (Systematic Review on Congenital Toxo-
Kravetz J.D., Ferderman D.G.: Toxoplasmosis in pregnancy. Peyron F., Wallon M., Liou C., et al.: Treatments for toxoplasmosis) Study Group: Effectiveness of prenatal treat-
Am J Med 2005; 118:212-216. plasmosis in pregnancy. Cochrane Database Syst Rev 2000; ment for congenital toxoplasmosis: a meta-analysis of
Lappalainen M., Kosela P., Koskiniemi M., et al.: Toxoplas- (2):CD001684. individual patients’ data. Lancet 2007; 369:115-122.
mosis acquired during pregnancy: improved serodiagno-
PRACTICE Obstetric and Gynecologic Infections
POINT
17 A Pregnant Patient with a Previous

Pregnancy Complicated by Group B
Streptococcal Disease in the Infant
UPTON D. ALLEN
Introduction solid blood agar. Slide agglutination tests or other tests used to detect
GBS antigen may be used to enable specific identification of GBS.
The group B streptococcus (GBS, Streptococcus agalactiae) remains an While nucleic acid amplification tests (NAAT) and other rapid GBS
important cause of invasive disease in neonates and pregnant women. assays are available, their utility in the intrapartum setting remains
The disease presents as an early-onset form (<7 days after birth), a limited.
late-onset form (7 days to 3 months after birth) and a very late form
(>3 months after birth). Disease among infants usually presents as
bacteremia, pneumonia and meningitis. However, they may experience Prevention
other syndromes, including soft tissue and bone infection. Current Vaccination against GBS is currently the subject of research. Chemo-
case-fatality rates are less than 5% for term infants, but they are higher prophylaxis has become established as a preventive strategy. Intrapar-
in premature neonates (early-onset disease, 20% and 5% for late-onset tum chemoprophylaxis has the potential of preventing neonatal as well
disease). as maternal GBS disease.
Internationally, there is no consensus on whether a risk-factor
based or a screening approach should be used to identify pregnant
Epidemiology women for IAP. Some countries do not have specific recommendations
The organism colonizes the gastrointestinal tract of humans, with the for routine antenatal screening based on the perceived risks versus
genitourinary tract being the most common site for secondary spread. benefits in their regions. The most widely accepted recommendations
Colonization rates among pregnant women range from 15 to 35%. are those proposed by the US Centers for Disease Control and Preven-
Data from the USA have suggested that prior to the implementation tion (Figure PP17-1). While screening is a major component of these
of recommendations to prevent early-onset GBS using maternal intra- recommendations, the guidelines do provide indications for IAP in
partum antimicrobial prophylaxis (IAP), the incidence of GBS neona- situations where the GBS status is unknown. Based on the above re
tal disease was 1–4 cases per 1000 live births. Among these cases, commendations, the following apply.
early-onset disease occurred in approximately 1–2 infants per 100
colonized women and was responsible for 75% of cases among infants. SCREENING
Since the widespread use of IAP, the incidence of early-onset GBS All pregnant women (exceptions noted) should be screened at 35–37
disease has decreased significantly (by approximately 80%), resulting weeks’ gestation for vaginorectal colonization. The exceptions are
in an incidence of less than 1 case per 1000 live births. women who had previous infants with invasive GBS disease and
The incidence of early-onset disease is higher in infants born to women with GBS bacteriuria during the current pregnancy, as these
women less than 20 years of age and to African-American women in women should be managed presumptively by receiving IAP without
the USA. Intrapartum risk factors include premature onset of labor the need for further screening.
(<37 weeks’ gestation), prolonged rupture of membranes (≥18 hours) Because lower vaginal and rectal cultures are recommended, cul-
and intrapartum fever (≥100.4 °F/≥38 °C and chorioamnionitis). Addi- tures should not be collected by speculum examination. Laboratories
tional risk factors include heavy GBS vaginal colonization, previous should report results to both the anticipated site of delivery and the
delivery of an infant with GBS disease and low maternal levels of anti- healthcare provider who ordered the test.
GBS capsular antibody. Women who have GBS bacteriuria are also at
an increased risk of delivering an infected infant with early-onset IAP INDICATED
disease. This is related in part to the fact that women who have GBS • Women identified as GBS carriers during the current pregnancy. At
bacteriuria are usually heavily colonized vaginally with GBS. Bacteri- the time of labor or rupture of membranes, IAP should be
uria caused by GBS is associated with an increased risk of pre-term offered.
labor. • Women who have previously given birth to an infant who had GBS
disease. Prenatal screening is not necessary.
Microbiology • Women with GBS bacteriuria. These women are usually heavily
colonized with GBS. Women who have symptomatic or asymp-
Group B streptococci are represented by several serotypes, including tomatic GBS urinary tract infections in pregnancy should be
Ia, Ib and II–IX. While all serotypes may cause disease in humans, managed according to current standards of care for urinary tract
serotype III is the main cause of early-onset meningitis as well as late- infections in pregnancy.
onset GBS disease among neonates. • A risk factor-based approach is employed if the colonization status
The optimal method for GBS screening involves collection of a is not known at the time of labor or rupture of membranes and any
single vaginal–anorectal swab or two separate swabs from the vagina of the following risk factors is present. Gestation less than 37 weeks,
and rectum. Swabs should be placed in a transport medium if the duration of membrane rupture of 18 hours or longer, or intra-
bacteriology laboratory is off-site and subcultured onto selective broth partum temperature ≥100.4 °F (≥38 °C). If these women are
medium. After overnight incubation, the specimen is subcultured onto febrile due to chorioamnionitis, appropriate broad-spectrum
520
Practice Point 17 A Pregnant Patient with a Previous Pregnancy Complicated by Group B Streptococcal Disease in the Infant 521
Indications for intrapartum antibiotic prophylaxis
Vaginal and rectal GBS screening cultures at 35–37 weeks' gestation

for ALL pregnant women unless patient had GBS bacteriuria during
the current pregnancy or a previous infant with invasive GBS
Intrapartum prophylaxis indicated Intrapartum prophylaxis not indicated
• Previous infant with invasive GBS disease • Previous pregnancy with a positive GBS screening culture (unless a culture
• GBS bacteriuria during current pregnancy was also positive during the current pregnancy)
• Positive GBS screening culture during current • Bacteriuria in previous pregnancy (unless an indication for GBS prophylaxis
pregnancy (unless a planned Cesarean delivery, in the is present in the current pregnancy)
absence of labor or amniotic membrane rupture, is • Planned Cesarean delivery performed in the absence of labor or
performed) membrane rupture (regardless of maternal GBS culture status)
• Unknown GBS status (culture not done, incomplete or • Negative vaginal and rectal GBS screening culture in late gestation,
results unknown) and any of the following: regardless of intrapartum risk factors
• Delivery at <37 weeks' gestation * If amnionitis is suspected, broad-spectrum antibiotic therapy that includes
• Amniotic membrane rupture ≥18 hours an agent known to be active against GBS should replace GBS prophylaxis.
• Intrapartum temperature ≥100.4°F (≥38°C)*
• Intrapartum NAAT (if available) positive for GBS
Figure PP17-1 Indications for intrapartum antibiotic prophylaxis to prevent perinatal group B streptococcus disease under a universal prenatal screening strategy
based on combined vaginal and rectal cultures collected at 35–37 weeks’ gestation from all pregnant women.
TABLE
PP17-1 Alternative Antibiotic Regimens for Intrapartum Antimicrobial Prophylaxis
Drugs Doses Comments
Penicillin 5 million units iv load, then 2.5 million units iv q4h Preferred agent
Ampicillin 2 g iv load, then 1 g iv q4h Alternative agent
Cefazolin 2 g iv load, then 1 g iv q8h Use if risk of anaphylaxis is low in penicillin-allergic patient
Clindamycin 900 mg iv q8h Use if risk of anaphylaxis is high in penicillin-allergic patient and the GBS isolate is
known to be susceptible to clindamycin and erythromycin
Vancomycin 2 g iv load, then 1 g iv q12h Use if risk of anaphylaxis is high in penicillin-allergic patient and the susceptibility of
the GBS isolate is unknown or the isolate is known to be resistant to clindamycin
antimicrobial therapy that includes an agent that is active against NEWBORN MANAGEMENT FOLLOWING IAP
GBS should replace intrapartum chemoprophylaxis. The use of IAP influences the management of neonates born to
mothers who have received IAP. The suggested approach to manage-
IAP NOT INDICATED ment of such neonates is shown in Figure PP17-2.
• Women who are colonized and have a planned Cesarean section Management of a Pregnant Woman
prior to rupture of membranes. These women are at an extremely
low risk of delivering an infant with early-onset GBS. Who Previously Gave Birth to a GBS-
• Women with positive GBS screening cultures in a previous preg- Affected Newborn
nancy (unless a culture is also positive in the current pregnancy
or GBS bacteriuria is present). Intrapartum prophylaxis is recommended in the setting of the previ-
• Women with negative vaginal and rectal GBS screening cultures ous delivery of a baby who had GBS disease. Routine vaginal–rectal
in late gestation (regardless of risk factors). screening for GBS is not necessary in this setting. However, it would
be appropriate to obtain urine cultures at antenatal visits to determine
whether GBS bacteriuria is present, given that these women are at an
Infection Control in the Neonatal increased risk of having pre-term labor. If GBS bacteriuria is present,
appropriate antibiotic treatment is recommended.
Nursery Penicillin G (5 million units intravenously initially followed by
Adequate hand hygiene is regarded as the most effective way to prevent 2.5 million units intravenously q4h) should be given intrapartum
the spread of GBS within a nursery. The routine culturing of babies to until delivery (Table PP17-1). Ampicillin (2 g intravenously initially
determine colonization status and the treatment of asymptomatic car- and then 1 g intravenously q4h until delivery) is an acceptable
riers are not recommended. In the event of an outbreak, cohorting of alternative.
ill and colonized infants and the use of contact precautions should Women who are allergic to penicillin but who are at low risk of
occur. anaphylaxis may receive cefazolin 2 g initially, then 1 g q8h. If the
isolate has been shown to be susceptible to clindamycin and erythro-

Management of neonates whose mothers received intrapartum
antimicrobial prophylaxis (IAP)
mycin, clindamycin may be used. Vancomycin should be reserved for
women who are at high risk of anaphylaxis in the setting where sus-
ceptibility testing of the GBS isolate has not been performed.
Mother received IAP Group B streptococci are associated with septic abortion, urinary
Maternal antibiotics
for suspected
tract infections, chorioamnionitis, wound infection and endometritis.
chorioamnionitis Although IAP may have a beneficial effect on endometritis, an assess-
Symptoms/signs of sepsis in neonate ment is necessary in the immediate postpartum period in order to
guide further antibiotic therapy directed at the mother.
The newborn infant of a mother who has received intrapartum
prophylaxis requires a special management approach, as outlined in
Figure PP17-2. However, if the infant is believed to have invasive GBS
Yes Yes No
disease, the following apply:
• Ampicillin plus an aminoglycoside is the initial treatment of
presumed GBS disease.
• Limited diagnostic • Penicillin G may be given alone when group B streptococcus is
evaluation
proved to be the etiologic agent and clinical and microbiologic
IAP given ≥ 4 hours before delivery responses have been documented.
• Empiric therapy
• In cases of meningitis, a second lumbar puncture at 24–48 hours
after the start of treatment is recommended by some experts; this
may have prognostic significance.
≥ 37 weeks’ gestation and
duration of membrane No Yes
• Bacteremia without a focus should be treated for a minimum of
10 days. Uncomplicated meningitis should be treated for 14–21
rupture < 18 hours days (longer periods of treatment are needed in infants who have
complicated courses and ventriculitis).
• No evaluation
• Osteomyelitis should be treated for a minimum of 4 weeks.
• Since there is a high incidence of co-infection among multiple
No Yes
• No therapy birth siblings of an index case with GBS disease, they should be
• Observe for at least 48 observed or evaluated for sepsis as clinically indicated.
hours in hospital
• Limited evaluation*
• Observe for at least 48
< 37 weeks’ gestation or
hours in hospital
duration of membrane
rupture ≥ 18 hours • If sepsis suspected, full
evaluation** and
empiric therapy
* A limited evaluation includes: blood culture (at birth) and

complete blood count (CBC) with differential and platelet count
(at birth and/or at 6–12 hours of life).
** A full diagnostic evaluation includes: blood culture, complete blood
count, white blood cell differential and platelet counts, chest
radiograph (if respiratory abnormalities are present), and lumbar
puncture (if patient is stable enough to tolerate the procedure and
sepsis is suspected).
Figure PP17-2 Management of neonates whose mothers received intrapartum

antimicrobial prophylaxis (IAP).
Practice Point 17 A Pregnant Patient with a Previous Pregnancy Complicated by Group B Streptococcal Disease in the Infant 522.e1
FURTHER READING
Allen U.D., Navas L., King S.M.: Effectiveness of intrapar- streptococcal disease in a university hospital. Clin Micro- streptococcal disease in neonates. N Engl J Med 2002;
tum penicillin prophylaxis in preventing early-onset biol Infect 2007; 13:322-324. 347:233-239.
group B streptococcal infection: results of a meta- Money D., Allen V.M.: The prevention of early-onset neo- Trijbels-Smeulders M., de Jonge G.A., Pasker-de Jong
analysis. Can Med Assoc J 1993; 149:1659-1665. natal group B streptococcal disease. J Obstet Gynaecol Can P.C.M., et al.: Epidemiology of neonatal group B strepto-
American Academy of Pediatrics. Group B streptococcal 2013; 35(10):e1-e10. coccal disease in the Netherlands before and after the
infections. In: Kimberlin D.W., Brady M.T., Jackson Queensland Maternity and Neonatal Clinical Guidelines introduction of guidelines for prevention. Arch Dis Child
M.A., et al., eds. Red book 2015. Report of the Committee Program: Early onset Group B streptococcal disease. Fetal Neonatal Ed 2007; 92:F271-F276.
on Infectious Diseases, 26th ed. Elk Grove Village, IL: Document number: MN10.20-V2-R15: November Zangwill K.M., Schuchat A., Wenger J.D.: Group B strepto-
American Academy of Pediatrics; 2015:745-750. 2010. Available: https://www.health.qld.gov.au/qcg/ coccal disease in the United States, 1990: report from a
Angstetra D., Ferguson J., Giles W.B.: Institution of univer- documents/g_gbs5-0.pdf. multistate surveillance system. MMWR Morb Mortal
sal screening for group B streptococcus (GBS) from a risk Royal College of Obstetricians and Gynaecologists: Green- Wkly Rep 1992; 41:25-32.
management protocol results in reduction of early-onset top Guideline No. 36 2nd ed. July 2012. Available:
GBS disease in a tertiary obstetric unit. Aust N Z J Obstet www.rcog.org.uk/en/guidelines-research-services/
Gynecol 2007; 47:378-382. guidelines/gtg36/.
Mereghetti L., Lanotte P., Rochoux A., et al.: Application of Schrag S.J., Zell E.R., Lynfield R., et al.: A population based
the French guidelines for preventing neonatal group B comparison of strategies to prevent early-onset group B
SECTION 2 Syndromes by Body System: Urinary Tract
57
Cystitis and Urethral Syndromes
STEPHEN T. CHAMBERS | SARAH C. METCALF
KEY CONCEPTS Asymptomatic bacteriuria is common, does not need treatment

and in most circumstances can be regarded as stable colonization
• Cystitis is common and most uncomplicated cases respond similar to commensalism at other mucosal sites (Table 57-2). It poses
readily to antimicrobial therapy. a risk only during pregnancy, instrumentation and urological surgery.
• Complicated cases are associated with anatomic or functional
abnormalities, have an increased risk of therapeutic failure and Pathogenesis
require further investigation.
INFECTING ORGANISMS
• In women, short-course therapy of 5 days is recommended with In uncomplicated cystitis, more than 95% of infections are caused by
nitrofurantoin or co-trimoxazole for 3 days. Fosfomycin (single a single organism, most commonly Escherichia coli (80–90% of cases).
dose) is active in extended-spectrum beta-lactamase (ESBL) Staphylococcus saprophyticus accounts for 10–20% of cases in young
infections. In men, 7 days is recommended. women, especially during late summer and autumn (Table 57-3).5 A
• Asymptomatic bacteriuria should not be treated except in small number of types of uropathogenic E. coli (UPEC) account for
pregnancy or where there is a risk of complications from most UTIs and fluoroquinolone and trimethoprim–sulfamethoxazole-
instrumentation. resistant clones have become widespread. UPEC sequence type 131 has
• Avoid treating coincidental asymptomatic bacteriuria in
also acquired ESBL multiresistance genes (mostly CTX-M-type),6 and
patients with nonspecific symptoms. Harm is more likely to community-associated infections with this organism are now a major
result than benefit. clinical problem in the USA, Europe, India and elsewhere.7,8 In many
cases there are no discernible risk factors but others are healthcare-
• Antimicrobial stewardship programs have an important role in associated. Many infected patients carry a high load of these organisms
promoting appropriate treatment and minimizing the spread in the feces.9 Carbapenem-resistant Klebsiella pneumoniae bacteriuria
of resistant organisms.
is a much less common etiology, but is associated with multiple
co-morbidities and healthcare exposure.10
Complicated infections and infections among the institutionalized
Urinary tract infections (UTIs) are the second most common infec- elderly may be polymicrobial (30% of cases), particularly when stones
tious cause for consultation and prescription of antibiotics among are present. There is an increased incidence of resistant gram-negative,
primary care physicians, and are a common cause of morbidity in Pseudomonas aeruginosa and yeast infections in this group. Urease-
institutional care settings. Most infections are limited to the lower producing organisms (Proteus, Providencia and Morganella spp.) are
urinary tract causing cystitis, but may cause pyelonephritis and of concern because urease leads to the precipitation of struvite
bacteremia. (MgNH4PO4.6H2O), and stone formation. Organisms such as Group
B streptococci and enterococci are rare causes of UTI, although mid-
stream urine cultures overestimate their frequency.11
Acute Cystitis
MECHANISMS
Epidemiology Cystitis is almost always caused by ascending infection. The increased
susceptibility of women to UTI is probably related to the shorter
The global incidence of UTIs is estimated to be 2–3%, or at least 150 distance between the anus and urethral orifice, shorter length of
million cases per annum, of which most are cystitis.1 In the first 3 urethra and absence of the antibacterial barrier provided by prostatic
months of life UTIs are about three times more common in males than fluid. In other respects the pathogenesis is similar in men and women
females.2 Thereafter infections occur more frequently in females.3 The (Figure 57-1).
incidence of UTIs among young women increases sharply with onset
of sexual intercourse with rates of 0.5–0.7 UTIs per person year. Rates Colonization
subsequently fall during the thirties and then rise at about 1% per The region between the anus and urethra is normally colonized by
decade. About 50% of adult women report at least one UTI during specialized flora, including lactobacilli that inhibit colonization with
their life. Among college women more than two-thirds of acute enteric organisms. Spermicides (nonoxynol-9), diaphragms, estrogen
episodes may be attributable to sexual intercourse. At least 20% of deficiency and antibiotics (particularly β-lactams) inhibit these organ-
women suffer a second infection within 6 months of the first. Risk isms and increase colonization by uropathogens.
factors for symptomatic UTI include asymptomatic bacteriuria during Some women with recurrent UTIs have persistent UPEC coloniza-
childhood, previous UTI, and use of a diaphragm and spermicide tion of the periurethral area, where they adhere strongly to vaginal
(Table 57-1). epithelial cells. Non-secretors of histo-blood group antigens (Lewis
Men have low rates of UTI until advanced age when they rise dra- blood group [Le(a+b−)] and recessive [Le(a−b−)] phenotypes) are at
matically. This is associated with abnormalities of the urinary tract and greater risk of recurrent UTI.12 Likewise, bowel carriage of E. coli pos-
lack of circumcision. A lowered CD4 count is a risk factor in HIV- sessing DNA sequences for P fimbriae is more common among patients
infected men.4 with the P blood group.13
In the elderly, both concurrent disease of the urinary tract and
other medical conditions contribute to the high prevalence of UTI Ascent
(Table 57-2). Instrumentation is associated with an increased risk of Bacteria normally enter the bladder by ascending along the mucosal
infection of 1% in ambulatory patients and 5–10% in hospitalized sheath. This may result from mechanical instrumentation, sexual activ-
patients. ity and motility of the organisms.
523
524 SECTION 2 Syndromes by Body System: Urinary Tract
TABLE
57-1 Risk Factors for Lower Urinary Tract Infection
Young adults Women Past history of UTI Parity
Sexual intercourse Diabetes
Diaphragm use Primary biliary cirrhosis
Spermicide Sickle cell anemia
Pregnancy Instrumentation
Men Lack of circumcision Insertive anal intercourse
Low CD4 count
Elderly people Women Loss of estrogen effect Abnormalities of urinary tract
Incomplete emptying of bladder Rectoceles
Bladder diverticula Urethroceles
Men Strictures Prostatic disease (e.g. benign enlargement, loss of
bactericidal secretions)
Condom catheter drainage
Both genders Neurologic disease Cerebrovascular disease
E.g. Alzheimer’s disease and Parkinson’s disease
Neurogenic bladder Calculi
Instrumentation Urethral catheterization
TABLE Prevalence of Bacteriuria in Different Age Pathogenesis of cystitis

57-2 Groups
Group Prevalence (%) Urine flow
Females Schoolgirls 1.2

Sexually active young women 2–4
Women High osmolarity
>60 years 6–8 Glycine betaine Urea
70 years 5–10 pH
80 years 20 Tamm–Horsfall
Institutionalized elderly 30–50 protein
Males Childhood to middle age <1 Fimbrial
Men
IgA binding
60–65 1–3
>80 years >10
Institutionalized elderly 20–30
Bladder
wall
TABLE TNF and IL-2, 6, 8
57-3 Organisms Associated with UTIs
inflammatory
Peri-urethral response
Common Escherichia coli
organisms Staphylococcus
colonization
Ascending route
saprophyticus
of infection
Less common Klebsiella spp. Pseudomonas Urethra
organisms Enterobacter spp. aeruginosa
Proteus spp. Acinetobacter spp.
Morganella spp. Serratia spp.
Figure 57-1 Pathogenesis of cystitis. Factors favoring bacterial persistence and
Citrobacter spp. Yeasts
infection include bacterial binding to bladder mucosa (fimbriae), and high bacte-
Group B streptococcus Corynebacterium
rial growth rates despite high osmolarity and urea concentrations and low pH.
Enterococci urealyticum
Factors favoring bacterial elimination include high urine flow rate, high voiding
Rare organisms Haemophilus influenzae Salmonella spp. frequency, bactericidal effects of bladder mucosa, secreted proteins that bind to
Mycobacterium tuberculosis Shigella spp. fimbrial adhesins and the inflammatory response. IL, interleukin; TNF, tumor
Anaerobes Adenovirus (type 11) necrosis factor.
Unproven causes Gardnerella vaginalis

Ureaplasma urealyticum globose series of glycolipids.15 Attachment of bacteria to the mucosa
Mycoplasma hominis
activates an inflammatory response, including production of tumor
necrosis factor (TNF) and interleukin (IL)-2, IL-6 and IL-8, and attrac-
tion of inflammatory cells.16 In contrast, most organisms causing
Fimbriae: Role in Mucosal Adherence asymptomatic bacteriuria possess neither fimbriae nor incite an
and Inflammation inflammatory response.
Symptomatic bacteriuria is associated with bacteria possessing type I
(mannose-sensitive) fimbriae that initiate colonization of the bladder Biofilms and Intracellular Bacterial Communities
and attach to uroepithelial cells. These fimbriae are not expressed Uropathogenic E. coli readily form sessile communities or biofilms on
thereafter, preventing binding to Tamm–Horsfall protein and immu- the mucosal surfaces, and can invade both mature epithelial cells and
noglobulin A (IgA), and decreasing recognition by phagocytic cells, immature basal cells.17 Intracellular organisms can multiply, shuttle
which also possess type I receptors.14 Type II fimbrial attachment back to the lumen, or enter the cytosol forming intracellular communi-
(mannose-resistant) is mediated by P fimbriae (Gal-Gal), which are ties.18 A subset may also establish dormant intracellular reservoirs with
associated with pyelonephritis, and attach receptors possessing the the potential to re-emerge.19
Chapter 57 Cystitis and Urethral Syndromes 525
a b c
Intensity
60000
40000
d
20000
0
5 10 15 20 25 30
e f g µm
Figure 57-2 Electron microscopy findings in urine from women with cystitis. TEM analysis of human cystitis urine specimens (a) revealed large collections of bacteria
associated with nuclei and other cellular debris. These collections of bacteria from human urines (b) have similar morphology and organization as those recovered from
intact murine intracellular bacterial communities (c). Bacteria and filaments were also observed intracellularly within exfoliated epithelial cells in a urine sample quickly
fixed and analyzed from an E. coli cystitis patient (d). SEM analysis of cystitis urines deemed positive for intracellular bacterial communities and filaments captured large
bacterial biofilm-like collections (e and f) composed of bacteria with a smaller, more coccoid morphology than typical E. coli. Long filaments were also captured by SEM
(g). Scale bars: 2 µm (a and d); 1 µm (b and c); 5 µm (e and f). (Courtesy of Rosen D., Hooton T., Stamm W. et al.: Detection of intracellular bacterial communities in
human urinary tract infection. PLoS Med 2007: (4)e329.)
During this process UPEC may acquire long filamentous mor- by interference with adhesion receptors and agglutination of
phologies that resist phagocytosis and their presence in urine is the bacteria.22
hallmark of recent residence of sessile colonies (Figure 57-2). Infection
may trigger the shedding of epithelial cells facilitating excretion of
infecting organisms. Prevention
Urodynamics NORMAL URINARY TRACT
Voiding promotes elimination of free bacteria from the urinary Behavioral Changes
tract which is potentially compromised by low urine flow rate, infre- Recurrent or closely spaced symptomatic UTIs cause considerable
quent voiding, incomplete bladder emptying and reflux of urine.20 morbidity and anxiety. Patients are often told to empty their bladder
Neurologic disease, diabetes, debility and anatomic changes impair completely, maintain a high fluid intake and to void after intercourse.
bacterial clearance by these mechanisms, particularly in the elderly. In These measures are unlikely to be harmful, but there is little evidence
postmenopausal women, urinary incontinence, cystocele and post- of efficacy. Women who use a diaphragm and spermicide should con-
voiding residual urine are the most common risk factors for UTI21 sider alternative methods of contraception. Postmenopausal women
(Table 57-2). with recurrent UTI have been shown to benefit from the application
of estriol vaginal cream (0.5 mg/day for 2 weeks then twice weekly)23
Growth in Bladder Urine but this is less effective than nitrofurantoin.
Uropathogens grow well in urine whereas gonococci and anaerobes
are inhibited. Uropathogens effectively access a broad range of metab- Chemoprophylaxis
olites, scavenge iron and compensate for the inhibitory effects of If the measures above fail, chemoprophylaxis should be considered
urine (high osmolarity, high/low pH and high urea concentrations) by following two or more symptomatic UTIs within 6 months, or three
the intracellular accumulation of osmolytes from urine (e.g. glycine or more over 12 months (Table 57-4). Consider a 6-month trial but if
betaine). the previous pattern recurs, prophylaxis for 2 years may be appropriate.
Postcoital prophylaxis has excellent efficacy and less exposure to anti-
Immune Response microbials.24 Vaginal and oral candidiasis and gastrointestinal symp-
Locally produced urinary antibodies produced in response to febrile toms can be troublesome with continuous prophylaxis. Nitrofurantoin
UTI (monomeric and dimeric IgA and IgG) decrease adherence is an excellent agent because it has minimal effects on the fecal flora,
Postmenopausal and Elderly Women

TABLE Drug Regimens for Prophylactic Therapy Clinical suspicion of UTI should be aroused by new onset, or worsen-
57-4 Administered as a Single Dose at Night ing dysuria, urgency, suprapubic pain or fevers.32 Asymptomatic bac-
Drug Dose
teriuria is very common in elderly patients, not associated with an
increased morbidity or mortality and can readily co-exist with other
Nitrofurantoin 50 mg symptoms. Similarly, symptoms such as chronic frequency, chronic
Trimethoprim 100 mg dysuria and hesitancy are common and nonspecific and often fail to
respond to treatment of coexisting bacteriuria.33 Anorexia, fatigue, diz-
Trimethoprim–sulfamethoxazole (co-trimoxazole) 480 mg
ziness, confusion, poor appetite, chronic nocturia and urinary incon-
Cephalexin 125 mg tinence suggest a cause other than UTI.
Hexamine hippurate 1.0 g
Diagnosis
The diagnosis of UTI can be proven by culture of an adequately col-
lected urine sample, and is especially essential in males and children.
A presumptive diagnosis can be made in sexually active women when
and resistance during treatment is rare. Use of trimethoprim– typical clinical features and pyuria occur and sexually transmitted
sulfamethoxazole (TMP–SMX) for as long as 5 years is effective and infections are unlikely.34 A culture should be performed if a compli-
well tolerated. Methenamine salts, which are converted to formalde- cated infection is suspected or symptoms have relapsed within a month
hyde in urine, have been used, but clinical trial data are lacking. of treatment. In the elderly where the diagnosis is unclear, manage-
ment of symptoms, re-hydration and observation is reasonable. About
ABNORMAL URINARY TRACT half of suspected UTIs in women recover within a week without
Any lesions in the urinary tract should be corrected if possible. Uro- treatment.
logic referral is essential when abnormalities are found. Large residual
volumes and high pressure may require intermittent self-catheterization. PYURIA
Low-dose chemoprophylaxis is often effective. The preferred method for assessment of pyuria is microscopic exami-
nation of uncentrifuged fresh urine using a hemocytometer, although
Other Nonpharmacological Approaches counts per microscopic field are adequate. Urine from adult patients
Meta-analysis of trials of cranberry juice have failed to show a consis- with symptomatic UTI almost always (>96%) contain more than 10
tent reduction in symptomatic UTIs, although this approach is safe leukocytes/mL. Pyuria occurs less frequently in asymptomatic bacteri-
with few adverse effects. The optimum dosage and method of admin- uria of pregnancy (50% positive) and the elderly (90% positive).
istration has not been determined.25 Pyuria alone is not a reliable predictor of infection, as white cells
may originate from vaginitis and other causes of inflammation within
Other Prevention Strategies
the urinary tract (Table 57-5). The absence of pyuria essentially
Competitive exclusion of uropathogens using currently available oral excludes cystitis if the pre-test probability is low.
probiotics (i.e. lactobacilli) are ineffective but vaginal application holds Urine dipsticks using esterase detect a minimum of eight white
some promise.26,27 There is some evidence that the oral immunostimu- blood cells per high power field and have a sensitivity of 88–95% and
lant agent OM-89 available in Europe may be of benefit.28 Intravesical specificity of 94–98% compared with the counting chamber method.
instillation of avirulent bacteria, inhibition of pilus biogenesis, and The presence of blood, rifampin (rifampicin), nitrofurantoin, biliru-
soluble receptor analogs (mannosides) that act as antiadhesives are bin and ascorbic acid may result in a false-negative test, whereas
under investigation.29 trichomonads, imipenem and amoxicillin-clavulanate may give a
VACCINE false-positive test.35
There is no vaccine currently available. Any benefit from vaccines of
type I and type II pili and heat-killed UPEC wanes over several weeks.
Vaccines from iron receptors and fimbrial adhesins (FimH) are under
investigation. Anatomic and functional abnormalities may limit
vaccine applicability.30,31 TABLE Conditions Associated With Pyuria but
57-5 Without Culturable Bacteria Using Standard
Clinical Features Bacterial Isolation Techniques
SYMPTOMATIC INFECTION Recent Treatment of UTI
Pre-menopausal Women and Men Organism not culturable on usual Adenovirus
The dominant complaint in cystitis is usually painful micturition bacterial media Anaerobes
(dysuria), which may be associated with frequency, urgency, strangury, Chlamydia trachomatis
initial and terminal hematuria, suprapubic discomfort and voiding Fungal infections
Herpes simplex
small amounts of turbid urine. Low-grade fever may occur, but is Leptospirosis
usually absent. Mycobacterium tuberculosis
Dysuria caused by bacterial cystitis should be distinguished from Neisseria gonorrhoeae
that caused by vaginitis, vulvitis and urethritis (see Chapter 53). Noninfectious causes Cyclophosphamide therapy
Vaginal discharge, pruritus or dyspareunia point to vaginitis. Labial Foreign bodies
discomfort on micturition suggests vulvitis, often caused by genital Glomerulonephritis
Interstitial cystitis
herpes or candidiasis. In urethritis, report of a new sex partner, ure- Neoplasms
thral discharge, mucopurulent cervicitis or bartholinitis may be Stones
present. Chlamydia trachomatis and Neisseria gonorrhoeae are common Transplant rejection
causes. Men may present with epididymo-orchitis. Dysuria from inter- Trauma
Tubulointerstitial disease
stitial cystitis and Mycobacterium tuberculosis infection may cause con- Vaginal contamination
fusion, but usually persists despite initial treatment.
TABLE Value of Quantitative Urine Culture in Diagnosis of Urinary Tract Infection with Gram-negative Bacilli
57-6 in Women
Number of Specimens Organisms/mL of Urine Sensitivity (%) Specificity (%)
Asymptomatic women Two >105 >95 >80

Symptomatic women with pyuria One >10 5
51 99
One >103 80 90
One >102 95 85
DETECTION OF BACTERIA Vigorous antimicrobial stewardship efforts are needed as inappro-

Experienced laboratories can reliably detect 108 organisms per liter in priate prescribing of antimicrobial agents is common in UTI.37 Guide-
unstained specimens on microscopy. The nitrite test is reliable for lines may produce improvement when coupled with clinician
gram-negative bacilli infection in first morning specimens but not education, audit and feedback. Multi-faceted educational interventions
other samples. can be useful if they involve the patient, medical and allied health
communities and local barriers to change are addressed.38 Patient-
Midstream Urine Specimens based interventions and physician reminders also show promise.39
A clean midstream specimen is suitable for analysis as this minimizes Follow-up visits at 7–14 days after completion of therapy provide
the confounding effects of contamination from the first few milliliters the opportunity to obtain urine cultures if symptoms persist, and to
of urine. The sensitivity and specificity of quantitative culture for discuss the importance of the diagnosis. It is essential to relieve anxiety
diagnosis of UTI is dependent on the presence of symptoms and pyuria about sexual activity and perceived long-term consequences.
(Table 57-6). In symptomatic women with pyuria (>10 white blood
cells/mL) a single count of more than 105/mL has a very high specificity ACUTE BACTERIAL CYSTITIS
(>99%) but a low sensitivity (51%) for UTI.36 For this reason a bacte- In women short-course therapy (3–7 days) has become the standard
rial count greater than 103/mL is often used for identifying significant of care because this improves compliance, lowers cost, has fewer side
bacteriuria in routine laboratories, representing 10 organisms on a effects and decreases the likelihood of the emergence of resistant
plate if a 0.01 mL loop is used. Specimens from males are less likely to strains without loss of efficacy.40 Treatment algorithms are given in
be contaminated and lower counts (>103cfu/mL) are highly predictive Figures 57-3 and 57-4. Short-course therapy is contraindicated in com-
of infection. Gram-positive bacteria and yeasts in urine tend to be plicated infections, discussed below.
associated with lower counts than gram-negative bacilli.
In practice, poor collection of specimens and delays in processing Choice of Initial Therapeutic Agent
without refrigeration permit bacterial multiplication, and may provide The spread of resistant organisms has prompted review of recommen-
confusing results. Obstruction, antimicrobial agents and diuresis can dations for empiric therapy. Nitrofurantoin is the preferred agent for
cause false-negative results. acute cystitis as resistance is low, it produces minimal damage to the
bowel flora and has efficacy equivalent to TMP–SMX.41,42 TMP–SMX
Suprapubic Aspiration is appropriate unless resistance rates of E. coli and other gram-negative
Any bacterial count from urine from a suprapubic aspiration is signifi- organisms exceed 20%. The expected clinical and bacterial success
cant because the technique avoids contamination. Provided the patient rates for a 10% resistance rate in gram-negative infections will be 92%
has a full bladder, this procedure is safe and generally acceptable. and 89%, and for a 20% resistance rate 88% and 84%, respectively.43
Improved response rates can be expected in those who have not had
Catheter Specimens previous infection with TMP–SMX-resistant organisms, recent use of
Catheterization specifically for a urine culture may be justifiable if the TMP–SMX or another antimicrobial agent, recent hospitalization or
patient is unable to cooperate with other methods of obtaining urine recurrent UTI in the past year. Fosfomycin trometamol is effective as
samples. Catheterization rarely leads to false-positive results, but may single-dose therapy for uncomplicated cystitis and given as three doses
introduce bacteria into the bladder. Straight plastic catheter or bag 3 days apart in complicated lower UTIs.44,45 Beta-lactam agents have
techniques are satisfactory. lower efficacy rates to other agents and use requires careful follow-up.
Ertapenem is an alternative parenteral agent for complicated infec-
IMAGING OF THE URINARY TRACT tions.46 Quinolones should be reserved for patients with upper tract
Investigations of the urinary tract should be considered in all men who involvement unless other agents cannot be used.
have a UTI although this may not be necessary in young healthy men The decision to change antimicrobial policy is made more difficult
with a single episode that responds promptly to treatment. In contrast, if reliable estimates of resistance rates in the local setting are lacking.
imaging is not cost-effective in women unless there is evidence of an Resistance rates reported by clinical laboratories may overestimate
unusual clinical pattern, such as urinary infection in childhood, treat- community resistance rates as samples from patients who have failed
ment failure, persistent microscopic hematuria or pyuria at follow-up therapy or are at a high risk of resistance are over-represented.
after treatment. The identification of Proteus spp. in urine may indicate Some antibiotics, such as penicillins, may interfere with the effec-
the presence of calculi. An ultrasound examination of the renal tract, tiveness of oral contraceptives by altering the enterohepatic recycling
including post-micturition bladder volumes, are adequate in most of estrogen and reducing the contraceptive effect. Women who use oral
instances. Cystoscopy rarely yields useful information in women with contraceptives may need to use barrier methods of contraception while
acute cystitis. on treatment.
Management RECURRENT INFECTIONS

The cornerstone of management is effective antimicrobial therapy that About one-half of adult women will have another infection within 1
should be individualized according to patient tolerability and local year, many within 3 months and recurrences may occur in clusters.
epidemiology (Table 57-7). Drinking large amounts of fluids and alka- Most recurrences are likely to be re-infection from a persistent reser-
linizing agents may decrease urine bacterial counts and improve symp- voir in the fecal flora, but it is hard to exclude recrudescence from an
toms, but adds little to effective antimicrobial therapy. intracellular source within bladder epithelial cells. With treatment of
TABLE
57-7 Drug Treatment Regimens for Therapy for Bacterial Cystitis
Estimated
Estimated Microbiological
Drug Dose Clinical Efficacy Efficacy Comments Adverse Effects
FIRST LINE AGENTS
Nitrofurantoin 100 mg BD 5 days with 84–95% 86–92% Minimal potential to cause Common: nausea, headache.
(macrocrystalline) meals resistance, avoid if Uncommon: hypersensitivity
pyelonephritis suspected reactions, lupus-like syndrome,
hemolytic anemia, peripheral
neuropathy, interstitial
pneumonitis, pulmonary
fibrosis
Trimethoprim– 160 mg/800 mg q12h 90–100% 90–100% Resistance widespread in Common: nausea, vomiting,
sulfamethoxazole for 3 days some areas anorexia.
(co-trimoxazole) Uncommon: hypersensitivity
reactions, hemolysis in G6PD
deficiency, hyperkalemia
Trimethoprim 300 mg q24h for 3 days Useful if adverse effects from

sulfonamides
Fosfomycin trometamol 3 g sachet single dose Approx. 91% 78–83% First choice for ESBL’s Common: diarrhea, nausea,
headache.
Uncommon: vaginitis, rash
Pivmecillinam 400 mg BD 3–7 days 55–82% 74–84% Not widely available. Use if Common: nausea, vomiting,
multiresistant infection diarrhea
suspected including ESBL
SECOND LINE AGENTS
Amoxicillin-clavulanate 500/125 mg q12h Approx. 75% Approx. 75% Avoid in penicillin allergy Common: loose motions,
3 days nausea, vomiting.
Uncommon: hypersensitivity
reactions, abnormal liver
function tests
Cephalexin 250 mg q8h Not well studied
Cefpodoxime proxetil 100 mg q12h Approx. 84% Approx. 80%

3 days
Quinolones e.g. 250 mg BD 85–98% 81–98% Progressive resistance. Avoid Common: nausea, vomiting, rash
ciprofloxacin 3 days where possible
each episode, 20–30% will cease having recurrences. If episodes are

closely spaced, self-administered therapy, preferably after obtaining a TABLE Possible Toxicities of Antimicrobial Agents
57-8 in Pregnancy
urine specimen, postcoital therapy or prophylaxis can be considered.
Self-initiated therapy should be reserved for those who are not at risk
Agent Toxicity
of sexually transmitted infections or pregnancy, and who do not have
significant co-morbid conditions. Treatment of asymptomatic bacte- Trimethoprim sulfonamides Antifolate activity and megaloblastic
riuria in this group is associated with an increase in symptomatic anemia
UTI.47 A treatment algorithm is given in Figure 57-5. Sulfonamides (protein bound) Kernicterus of newborn
COMPLICATED INFECTIONS Sulfonamides/nitrofurantoin Hemolytic anemia in glucose-6-

phosphate dehydrogenase
Complicated infections are more likely to be caused by unusual organ- deficiency
isms and should be treated for 7–14 days. Patients who fail short-
course treatment often have abnormalities of the urinary tract (e.g. Tetracycline Fatty liver/hepatic necrosis in
mother, stained teeth in baby
stones, diverticula, strictures, chronic bacterial prostatitis). These
should be corrected where possible. Fluoroquinolones Not approved
Amoxicillin Safe unless hypersensitivity

UTIs IN PREGNANCY
In pregnancy asymptomatic bacteriuria (4–7% of women) poses a risk Cephalexin Safe unless hypersensitivity
for acute pyelonephritis (15–40% of cases) during the third trimester
and the puerperium. It has been associated with abnormalities of the
urinary tract, increased risk of pre-eclampsia, lowered fetal birth prompt treatment of each episode. All such patients need investiga-
weight, prematurity and increased perinatal mortality rates. tions of the urinary tract after delivery.
The risks can be prevented by early detection and eradication of There is probably no absolute contraindication to any antimicro-
asymptomatic bacteriuria. In the first instance a 3-day course of bial agent during pregnancy, but caution is urged with some agents.
therapy is appropriate (Figure 57-6). If relapse or re-infection occurs, The β-lactams (e.g. amoxicillin, amoxicillin-clavulanate, cephalexin)
then the patients should be re-treated. At that stage the simplest strat- are considered safe and the antifolate activity of trimethoprim and
egy is to institute prophylaxis (e.g. nitrofurantoin 50 mg at night), TMP–SMX is minimal in short courses and probably safe between 16
although some prefer close surveillance with repeated cultures and and 30 weeks of gestation (Table 57-8).
MALES
Treatment of uncomplicated bacterial
cystitis in a nonpregnant woman
Lower tract UTI in males may be complicated by infection of prostatic
fluid, even if there is no clinical prostatitis. For this reason there is
reluctance to treat men with short regimens. A 7-day regimen rather
Bacterial cystitis in than longer treatment is effective and does not lead to undue recur-
nonpregnant women rence provided prostatitis has been excluded.48 Long-term suppressive
therapy may be helpful for frequent recurrences.
Treat with a 3-day course

ASYMPTOMATIC BACTERIURIA
Asymptomatic bacteriuria is best left untreated except in pregnancy.
Re-treat In elderly patients it is extremely common, and the organisms often
lack virulence factors. Treatment may cause an increase in symptom-
Follow-up after 7–14 days
atic UTIs including in those with renal transplants.49 Antimicrobial
Symptoms persist or recur
therapy is associated with adverse effects, the potential for develop-
Culture urine ment of resistant strains and financial cost.47,50
INVASIVE PROCEDURES
Asymptomatic bacteriuria should be treated if a patient is to undergo
Sterile: Significant an invasive procedure of the genitourinary tract. Mucosal trauma may
cure growth cause postprocedural bacteremia, and occasionally septic shock and
death. The antimicrobial agent should be selected on the basis of the
sensitivity of the infecting organism. Likewise, it is prudent to treat any
urinary infections before the insertion of permanent indwelling
Identical pathogen: Resistant to devices, particularly prosthetic joints.
relapse or failure initial therapy
New pathogen TREATMENT IN THE PRESENCE
(re-infection) OF RENAL FAILURE
No investigation If treatment is truly indicated, drugs that achieve adequate urine con-
Ultrasound of urinary centrations in the presence of renal failure should be used. The best
tract levels may be achieved with penicillins and cephalosporins. Trime-
Ultrasound or CT No investigation thoprim and fluoroquinolones will probably achieve adequate concen-
trations, whereas nitrofurantoin, sulfamethoxazole and doxycycline
are present in very low concentrations when creatinine clearance falls
Figure 57-3 Treatment of uncomplicated bacterial cystitis in nonpregnant below about 0.16 mL/s.
women.
Approach to management of older women with suspected urinary tract infection
Women >65 years

suspicion of UTI
Alert and mobile Frail elderly UTI-specific signs/symptoms

Nonspecific symptoms/signs of UTI Nonspecific signs/symptoms of UTI Dysuria
Rehydrate Muddled thought processes New/worsening
Review medicine e.g. diuretics, Altered character of urine urgency/frequency
psychotropics Review medications New/worsening incontinence
Observe 5–7 days Hydrate Gross hematuria
Observe 48 hours Suprapubic/costovertebral pain
Symptoms resolve – no action Send urine sample to laboratory

Symptoms persist dipstick negative - stop Consider empiric antimicrobial
Symptoms persist therapy
Dipstick positive – send specimen to laboratory Stop if culture negative
Symptoms resolve – do not treat regardless of laboratory result
Symptoms persist – consider short course of treatment
Figure 57-4 Approach to management of older women with suspected urinary tract infection.
Treatment of recurrent bacterial Treatment of asymptomatic bacteriuria in pregnancy

cystitis in a nonpregnant woman
Recurrent bacterial cystitis Asymptomatic bacteriuria

in a nonpregnant woman with in a pregnant woman
normal urinary tract
Treat with 3-day course
Proven UTI
Follow-up 7–14 days

Culture urine
Treat with 3-day course
Sterile: Significant
cure growth
Diaphragm/spermicide Further antibiotic Postmenopausal

Change contraceptive therapy Estriol cream Identical pathogen: New pathogen
relapse or failure (re-infection)
Culture urine Treat with

at each visit 3-day course
Postcoital or long- Self-medication: Physician control:
term low dose 3-day course 3-day course
prophylaxis Prophylaxis until
4–6 weeks
postpartum
Urine culture
if symptoms
persist No investigation Ultrasound of
postpartum urinary tract
Ultrasound or CT
Figure 57-5 Treatment of recurrent bacterial cystitis in a nonpregnant woman.
Figure 57-6 Treatment of asymptomatic bacteriuria in pregnancy.

INFECTIONS WITH CANDIDA SPP.
Infections with Candida spp. may occur either from hematogenous
spread or via the ascending route. There is an increased risk in those the urine. Furthermore, many patients responded to antibiotic therapy,
with diabetes, prolonged antimicrobial therapy and instrumentation suggesting that this was essentially a bacterial urethritis with little
of the urinary tract. The natural history has not been well defined, but infection of the bladder. A randomized controlled trial found that
most infections are asymptomatic, limited to the lower urinary tract trimethoprim (300 mg daily) was superior to placebo in women with
and may resolve in otherwise normal patients. Asymptomatic candi- dipstick-negative acute dysuria, suggesting that infection is one cause
duria does not require treatment unless urinary manipulation is of this syndrome.53
needed.51 Multiple other causes have been suggested, including chemicals
Symptomatic candiduria should always be treated. Oral fluconazole (e.g. bubble baths and deodorants), trauma, atrophic vaginitis in post-
(200 mg/day, 14 days) is the treatment of choice, although some menopausal women and psychologic factors, but are mostly unproven.
species such as Candida krusei may be resistant.52 Intravenous ampho- A gradual onset of dysuria with bladder symptoms, particularly on
tericin B (0.3–0.7 mg/kg/day, 7–14 days) has prolonged renal excretion filling, suggests interstitial cystitis/bladder pain syndrome and often
and is usually effective. Oral flucytosine often fails with development co-exists with fibromyalgia and irritable bowel syndrome.54
of resistance. Bladder washouts clear funguria but the effect is tran-
sient. Echinocandins may be effective despite minimal urinary Management
excretion. All sexually active women with the acute dysuria syndrome should be
evaluated for C. trachomatis with a nucleic acid amplification test
performed on first-catch urine. A pelvic examination should be carried
Urethral Syndromes out to exclude genital herpes, and other causes of vulvovaginitis. Acute
symptoms often resolve within a few days but antimicrobial therapy
Pathogenesis and Clinical Features used for treating UTI may be helpful, particularly if pyuria is present.
Following the introduction of quantitative bacterial counts, about half With chronic dysuria, other pelvic, bladder and urethral pathology
of women with acute symptoms of cystitis did not have significant should be excluded with imaging and, possibly, cystoscopy, particu-
bacteriuria and were said to have acute urethral syndrome or dysuria- larly if pyuria or hematuria is present. Antidepressants are often pre-
pyuria syndrome. When it is not caused by C. trachomatis, the acute scribed but the benefit is unproven.
urethral syndrome was associated with periurethral colonization with
uropathogenic organisms and very low numbers of these organisms in References available online at expertconsult.com.
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urinary tract infections in women. N Engl J Med 1989; 33. Mody L., Juthani-Mehta M.: Urinary tract infections in 50. Wagenlehner F., Naber K.: Editorial commentary:
320:773-787. older women: a clinical review. JAMA 2014; 311(8):844- asymptomatic bacteriuria–shift of paradigm. Clin Infect
13. Johnson J.: Virulence factors in Escherichia coli urinary 854. Dis 2012; 55(6):778-780.
tract infections. Clin Microbiol Rev 1991; 4:80-128. 34. Bent S., Nallamothu B., Simel D., et al.: Does this 51. Sobel J., Kauffman C., McKinsey D., et al.: Candiduria:
14. Orskov I., Ferenc A., Orskov F.: Tamm-Horsfall protein woman have an acute uncomplicated urinary tract a randomized, double-blind study of treatment with
orosomucoid is the normal urinary slime that traps type infection? JAMA 2002; 287:2701-2710. fluconazole and placebo. The National Institute of
I fimbriated Escherichia coli. Lancet 1980; 1:887. 35. Beer J., Vogt A., Neftel K., et al.: False positive results for Allergy and Infectious Diseases (NIAID) Mycoses Study
15. Lindstedt R., Baker N., Falk P., et al.: Binding specifici- leukocytes in urine dip stick test with common antibi- Group. Clin Infect Dis 2000; 30(1):19.
ties of wild-type and cloned Escherichia coli strains otics. BMJ 1996; 313:25. 52. Fisher J., Sobel J., Kauffman C., et al.: Candida urinary
recognising globo-A. Infect Immun 1989; 57:3389-3394. 36. Stamm W., Counts G., Running K., et al.: Diagnosis of tract infections – treatment. Clin Infect Dis 2011;
16. Hedges S., Svanborg A.: The mucosal cytokine response coliform infection in acutely dysuric women. N Engl J 52(Suppl. 6):S457.
to urinary tract infections. Int J Antimicrob Agents 1994; Med 1982; 307(8):463-468. 53. Richards D., Toop L., Chambers S., et al.: Response to
4:89-93. 37. Denes E., Prouzergue J., Ducroix-Roubertou S., et al.: antibiotics of women with symptoms of urinary tract
17. Opal S.: Communal living by bacteria and the patho- Antibiotic prescription by general practitioners for infection but negative dipstick urine test results: double
genesis of urinary tract infections. PLoS Med 2007; urinary tract infections in outpatients. Eur J Clin Micro- blind randomised controlled trial. BMJ 2005; 331:143-
4(12):e349. biol Infect Dis 2012; 31(11):3079-3083. 146.
18. Rosen D., Hooton T., Stamm W., et al.: Detection of 38. Gerber J., Prasad P., Fiks A., et al.: Effect of an 54. Teichman J., Parsons C.: Contemporary presenttion of
intracellular bacterial communities in human urinary outpatient antimicrobial stewardship intervention on interstitial cystitis. Urology 2007; 69:41.
tract infection. PLoS Med 2007; 4:e329. broad-spectrum antibiotic prescribing by primary care
19. Barber A.E., Norton J.P., Spivak A.M., et al.: Urinary pediatricians: a randomized trial. JAMA 2013; 309(22):
tract infections: current and emerging management 2345-2352.
strategies. Clin Infect Dis 2013; 57(5):719-724.
58
Prostatitis, Epididymitis and Orchitis
FLORIAN M.E. WAGENLEHNER | ADRIAN PILATZ |
WOLFGANG WEIDNER | KURT G. NABER
KEY CONCEPTS at the National Institutes of Health (NIH)2,3. The term chronic pelvic
pain syndrome (CPPS) was chosen, because it has not been scientifi-
• Symptomatic prostatitis exists in acute and chronic forms. cally demonstrated either that CPPS is primarily a disease of the pros-
• Enterobacteriaceae are the most frequent causes of bacterial tate or that it is an inflammatory process.2,3
prostatitis.
Epidemiology
• The majority of symptomatic chronic prostatitis cases are non-
bacterial at the time of diagnosis. DEFINITION AND NOMENCLATURE
Acute bacterial prostatitis (ABP; NIH I) is an acute febrile illness that
• Empiric antimicrobial therapy should be initiated in acute bac-
terial prostatitis according to local susceptibility rates.
may be characterized by intense pain in the perineum and rectum,
fever, voiding difficulties, systemic symptoms of sepsis and a tender,
• Fluoroquinolones are recommended as first choice in chronic swollen prostate on rectal examination. The chronic prostatitis syn-
bacterial prostatitis, if pathogens are tested susceptible. dromes – chronic bacterial prostatitis (CBP) or chronic prostatitis/
• Bacterial ascension is the most common cause for acute chronic pelvic pain syndrome (CP/CPPS) – cause symptoms that in
epididymitis. the majority of cases cannot be differentiated from each other (Table
58-2). Patients with CBP (NIH II), however, often present with recur-
• Sexually transmitted diseases (STDs) and common uropatho- rent urinary tract infections (UTI). Pathogens must be present in
gens have to be considered. expressed prostatic secretion (EPS) or VB3 for a conclusive diagnosis
• The clinical spectrum ranges from mild epididymal tenderness of CBP.4 In patients who have signs of inflammation (CP/CPPS; NIH
to a severe systemic illness. IIIA), leukocytes (neutrophils, macrophages) are present in EPS or VB3
or in ejaculate. In noninflammatory CP/CPPS (NIH IIIB) no signs of
• Microbiologic evaluation should include urine culture and
testing for appropriate sexually transmitted infections (STDs) in
inflammation are detectable. In asymptomatic inflammatory prostati-
sexually active patients. tis (NIH IV), detected either by prostatic histology or by the presence
of leukocytes in seminal fluid or in prostate secretion during evalua-
• Empiric antimicrobial therapy should be chosen according to tion for other disorders, patients have no subjective symptoms (see
the most probable pathogens. Table 58-1).
• Fluoroquinolones with activity against Chlamydia trachomatis
are first choice for all patients with epididymitis except for INCIDENCE AND PREVALENCE
those with gonorrhea. Acute prostatitis is nowadays more frequently seen after urological
interventions, such as prostatic biopsy for diagnosis of prostate cancer.
Surveillance studies uniformly report prostatitis/febrile infection in
approximately 3–4% after prostate biopsy.5 In five studies surveying
Prostatitis 10 617 men, 873 participants met various criteria for prostatitis, rep-
resenting an overall rate of 8.2%, with prevalence ranging from 2.2%
The diagnosis of prostatitis syndrome refers to a variety of inflamma- to 9.7%. In the USA in almost 2 million visits annually, prostatitis was
tory and noninflammatory conditions that may not always affect the listed as a diagnosis. Prostatitis was more commonly diagnosed in men
prostate gland itself. In 1978 a classification system1 was developed to aged 36–65 than in men 18–35 years old.6–9 A diagnosis of chronic
differentiate inflammatory from noninflammatory prostatitis, that was prostatitis can have a quality of life impact similar to a diagnosis of
followed by a consensus conference classification in 1999 (Table 58-1) angina or Crohn’s disease.10 Thus, prostatitis is a major healthcare
TABLE
58-1 Classification of Prostatitis Syndromes3
Category Characteristic Clinical Features Bacteriuria* Inflammation†
I. Acute bacterial Acute urinary tract infection (UTI) + +
II. Chronic bacterial Recurrent UTI caused by the same organism + +
III. Chronic prostatitis/chronic pelvic Primarily pain complaints, but also voiding complaints and
pain syndrome (CP/CPPS) sexual dysfunction
A. Inflammatory subtype‡ − +
B. Noninflammatory subtype§ − −
IV. Asymptomatic Diagnosed during evaluation of other genitourinary diseases − +
*In chronic bacterial prostatitis VB2 can be sterile and bacteriuria can only be detected in expressed prostatic secretion (EPS) or VB3.
†
Objective evidence of an inflammatory response in EPS, post-prostate massage urine or semen or by histology.
‡
Formerly termed ‘nonbacterial prostatitis’.
§
Formerly termed ‘prostatodynia’.
(Reprinted from Schaeffer A.J. Int J Antimicrob Agents 1999; 11(3–4):205-211.)
532
Chapter 58 Prostatitis, Epididymitis and Orchitis 533
issue, perhaps as important as the other two major prostatic diseases, Clinical Features and Diagnosis
benign hyperplasia and carcinoma.11
CBP is documented in 5–10% of patients who have chronic symp- ABP is diagnosed by its clinical presentation.7,17,25 It presents as an acute
toms.6,12 About half of these men have inflammatory CP/CPPS (NIH febrile illness with irritative and obstructive voiding symptoms. Pros-
IIIA) with an elevated leukocyte count in prostatic fluid;4, 6,12–17 the tatic massage is contraindicated and the diagnosis depends upon:
remainder are categorized as having noninflammatory CP/CPPS (NIH • urine and blood cultures;
IIIB). This is a diagnosis of exclusion and, in most cases, it cannot be • a gentle examination of the prostate that demonstrates acute
proven that the symptoms arise from the prostate itself. Approximately inflammation; and
10% of men suffering an episode of ABP continue to suffer CBP and • urinalysis, which usually demonstrates pyuria.
a further 10% progress to chronic prostatitis/CPPS.18 Depending on the patient’s history, two different types of ABP –
The most frequent form of prostatitis is asymptomatic inflamma- spontaneous and manipulated – have been described.26
tory prostatitis (NIH IV). Significant scientific interest in this entity Prostatic abscesses may occur in patients who have acute prostatitis.
has evolved because of probable involvement in the initiation of pros- This diagnosis is made by clinical examination and transrectal
tate cancer and its correlation to male infertility.19–21 ultrasonography.
Patients presenting with chronic prostatic complaints should have
RISK FACTORS a prostatic massage to localize the infection. The method of choice is
UTIs are the major underlying determinant of both ABP and CBP. the Meares and Stamey localization technique (Figure 58-1).27 Although
Strains of Escherichia coli responsible for both ABP and CBP appear to increased numbers of leukocytes may be found in the EPS, it is gener-
have at least similar or even more urovirulence determinants to the E. ally accepted that over 10 neutrophils per high-power field indicates
coli strains that cause pyelonephritis.22,23 Prostatic calculi can account prostatitis.16,20 In patients for whom an EPS cannot be obtained,
for recurrences of CBP.4 Bacterial microcolonies enclosed within bio- increased numbers of neutrophils in the urine after prostatic massage
films inside prostatic acini and ducts can be a focus for bacterial per- (VB3) is an indication of prostatitis if first voided urine (VB1) and
sistence.16 Inflammatory CP/CPPS may be due to intraprostatic reflux midstream urine (VB2) do not contain these cells. In patients who have
of urine causing inflammation.24 CBP, bacterial pathogens will be present in the EPS or VB3 in larger
numbers, usually a 10-fold higher concentration than in the VB1 and
VB2.17,23 A simpler screening test to assess inflammation/infection is the
two-glass pre- and post-massage test (PPMT). Compared with the
four-glass test, the PPMT has a rather good concordance with the four-
TABLE Symptoms in Patients with the Chronic glass test for the initial evaluation.28 The PPMT is therefore a reason-
58-2 Prostatitis Syndromes able alternative when EPS cannot be obtained or when microbiologic
assistance is not available (EPS, due to its usually small volume, has to
Urethral symptoms Burning in the urethra during voiding be processed and plated immediately).
Discharge The role of Chlamydia trachomatis and Ureaplasma urealyticum in
Difficult urination bacterial prostatitis is uncertain and there are no widely accepted cri-
Stranguria
Frequency teria for defining prostatitis due to these or other atypical pathogens
Nocturia (Table 58-3).29–31
A proportion of men who have CBP have bacteriospermia (>103 cfu/
Prostatic symptoms Pressure behind pubic bone
Perineal pressure tension in testes and epididymis mL) and the organisms present are usually identical to those in the
Inguinal pain EPS.32 As semen cultures identify significant bacteriospermia in only
Anorectal dysesthesia about 50% of semen specimens from men with CBP,33 culture of the
Diffuse anogenital syndromes ejaculate alone is not sufficient to diagnose CBP.25,33
Lower abdominal discomfort
Biochemical analysis of EPS has been used as an additional diag-
Sexual dysfunction Loss of libido nostic criterion for CBP but these observations have not been shown
Erectile dysfunction to be sufficiently sensitive or specific to add to the diagnosis (Figure
Ejaculatory dysfunction
Pain during or after orgasm 58-2).17,23 The pH is usually increased (>7.8) in the EPS from patients
who have CBP.
Other symptoms Myalgia
Headache
Prostate biopsy under ultrasonographic guidance is mainly used for
histology.4,13,34 Inflammatory findings in the prostate are usually
TABLE
58-3 Prostatitis Infections by Unconventional Fastidious Pathogens
Species Clinical Features Comment
Haemophilus influenzae Single case reports
Neisseria gonorrhoeae Associated with history of gonococcal urethritis Decreasing due to effective antibiotic treatment
Mycobacterium tuberculosis Urogenital manifestation Associated with HIV infection
Anaerobes Prostatic abscesses
Brucella spp. Disseminated disease Consumption of unpasteurized dairy products

and occupational contact
Candida spp. In immunocompromised patients with indwelling

urinary catheters
Coccidioides immitis, Blastomyces dermatitidis, Disseminated disease Associated with HIV infection
Histoplasma capsulatum
Trichomonas vaginalis Chronic inflammation May be associated with urethritis
Meares and Stamey localization technique
1. Approximately 30 minutes before taking the specimen, the patient should drink 400 mL of liquid (two glasses). The test starts when the patient wants
to void
2. The lids of four sterile specimen containers, which are marked VB1, VB2, EPS and VB3, should be removed. Place the uncovered specimen containers on
a flat surface and maintain sterility
3. Hands are washed
4. Expose the penis and retract the foreskin so that the glans is exposed. The foreskin should be retracted throughout
5. Cleanse the glans with a soap solution, remove the soap with sterile gauze or cotton and dry the glans
6. Urinate 10–15 mL into the first container marked VB1
7. Urinate 100–200 mL into the toilet bowl or vessel and without interrupting the urine stream, urinate 10–15 mL into the second container marked VB2
8. The patient bends forward and holds the sterile specimen container (EPS) to catch the prostate secretion
9. The physician massages the prostate until several drops of prostate secretion (EPS) are obtained
10. If no EPS can be collected during massage, a drop may be present at the orifice of the urethra and this drop should be taken with a 10 mL calibrated
loop and cultured
11. Immediately after prostatic massage, the patient urinates 10–15 mL of urine into the container marked VB3.
First voided urine (VB1) Midstream urine (VB2) Expressed prostate secretion (EPS) Urine after prostate massage (VB3)
Figure 58-1 Meares and Stamey27 localization technique to diagnose chronic bacterial prostatitis. Prostate secretion can be more readily obtained if the patient has
not ejaculated for approximately 3–5 days before the examination.
nonspecific and the primary indication for biopsy is to exclude pros-

Diagnostic criteria of chronic bacterial tatic cancer.
prostatitis by EPS analysis Evaluation of bladder emptying by flow rate measurements and
ultrasonography is useful in patients who have voiding disturbances.34
In the presence of abnormal flow rate measurements, further studies,
Decrease
such as cystourethrogram, urethrocystoscopy and urodynamics should
Enzymes (acid phosphatase, be performed to differentiate between functional and anatomic
lysozyme) changes.
Cations (zinc,magnesium, Prostatic sonography may demonstrate prostatic calculi (Figure
pH value calcium) 58-3). Prostatic calculi may serve as nidi for pathogens and may lead
LDH5/LDH1 Specific gravity to CBP; however, as they are common and increase with age, their role
IgA, IgG, IgM Cholesterol remains controversial. Figure 58-4 outlines the diagnostic investigation
Citric acid of patients who present with possible CBP.25
PAF
Chronic prostatitis/chronic pelvic pain syndrome is a less specific
diagnosis. In CP/CPPS (NIH IIIA) inflammatory cells in the EPS with
Increase negative cultures from both the EPS and VB3 are found. Although
numerous investigators have attempted to demonstrate that CP/CPPS
(NIH IIIA) is due to difficult-to-culture pathogens such as C. tracho-
Figure 58-2 Diagnostic criteria of chronic bacterial prostatitis by expressed matis or genital mycoplasmas, there is no consensus that these organ-
prostatic secretion analysis. LDH, lactate dehydrogenase; PAF, prostatic antibac- isms cause CP/CPPS (NIH IIIA).29,35,36 As a result, this diagnosis is
terial factor.
currently poorly defined and is presumed to be caused by largely
unknown etiologic and pathogenetic processes.
In CP/CPPS (NIH IIIB) neither inflammatory cells nor positive
cultures are found in EPS and VB3. For a better discrimination of NIH
TABLE
58-4 Dissociation Constants of Fluoroquinolones
Quinolone PKa1 PKa2
Ciprofloxacin 6.1 8.7
Enoxacin 6.3 8.7
Fleroxacin 5.5 8.1
Gatifloxacin 6.0 9.2
Levofloxacin 6.1 8.2
Lomefloxacin 5.8 9.3
Moxifloxacin 6.4 9.5

Figure 58-3 Transrectal ultrasonography of the prostate with diffuse calcifica-
tions (prostatitis calcarea). Norfloxacin 6.3 8.4
Ofloxacin 6.0 8.2
Pefloxacin 6.3 7.6

Sparfloxacin 6.3 8.8
Diagnostic management in patients with

suspected chronic bacterial prostatitis
IIIA from NIH IIIB, novel parameters, such as interleukin-8, have been
Recurrent UTI, or symptoms of pelvic pain/cystitis investigated.37,38
Localization studies
Management
ACUTE BACTERIAL PROSTATITIS
Antimicrobial treatment should be initiated immediately in patients
Positive for Urine culture (VB2) who have ABP after blood and urine cultures have been obtained.
prostatic infection positive? Prostatic massage is contraindicated. Parenteral treatment with a fluo-
roquinolone or a β-lactam with an aminoglycoside are appropriate
initial regimens, depending on antibiotic pretreatment and regional
Negative for 1. Acute UTI treated susceptibility rates. After initial improvement, a switch to an oral
prostatic infection 2. Nonprostate penetrating regimen according to susceptibility testing is appropriate and should
antimicrobials be prescribed for about 2–4 weeks. Optimal antibiotics would be fluo-
roquinolones, if tested susceptible.
Treatment – appropriate
Diagnosis chronic PROSTATIC ABSCESS
antimicrobials for
bacterial prostatitis
adequate time A prostatic abscess may require drainage in addition to antimicrobial
treatment. Occasionally, anaerobes or mixed infections may be respon-
Workup for recurrent
sible for the abscess. Cultures should always be obtained and, if fungal
urinary tract infection infection is suspected, the laboratory should be informed. Most treat-
ment regimens should include an agent effective against anaerobes.
Prostatic abscesses can be drained through the urethra, the perineum
Infection or the rectum.
Yes No
resolved?
CHRONIC BACTERIAL PROSTATITIS
Symptoms Further In patients who have possible CBP an appropriate antimicrobial agent
resolved? treatment that has optimal pharmacokinetics for prostatic secretion and tissue is
important.39 Antibacterial diffusion into prostate secretion depends
upon the lipid solubility, molecular size and pKa of the agent.36 For
Satisfactory example, trimethoprim, a weak base with a pKa of 7.4, penetrates well
No
response? into the acid prostatic secretion. However, because the pH of prostatic
No Yes fluid in patients who have CBP is often alkaline, concentrations in
prostatic secretion may be inadequate.40,41 In contrast, the fluoroqui-
Removal of infective tissue
by TURP or open surgery if nolones exist as zwitterions with a pKa in acid and alkaline milieus42
CPPS (III) Cured all other options fail (Table 58-4). Due to the relatively large differences in pKa values of the
different fluoroquinolones (Table 58-4), the prostatic fluid:plasma
concentration ratios range from 0.10 to 1.57 (Table 58-5).43–49 The
Figure 58-4 Diagnostic management in patients with suspected chronic bacte- concentration of some fluoroquinolones in the alkaline seminal fluid
rial prostatitis. TURP, transurethral resection of prostate; UTI, urinary tract infec- may even exceed that in plasma (Table 58-5).45,47 There exists a positive
tion. (Modified from Schaeffer et al. Consensus statement on prostatitis. The
assessment and management of male pelvic pain syndrome, including prostatitis,
correlation of the isoelectric points of the fluoroquinolones and the
Paris: Health Publications; 2006:343-375.) prostatic secretion to plasma concentration ratios, investigated in vol-
unteers (Figure 58-5).
Other studies have examined fluoroquinolone concentrations in
prostatic tissue obtained at transurethral resection and they appear to
be consistently at or above corresponding plasma concentrations.50
TABLE Median Concentrations of Fluoroquinolones in Prostatic and Seminal Fluid and Fluid to Plasma
58-5 Concentration Ratios (Normalized to a Dose of 400 Mg)
Prostatic Ratio of Seminal Ratio of
Dose Subjects Fluid Prostatic : Plasma Fluid Seminal : Plasma
Quinolone (400 Mg) Time (H) (N) (Mg/L) Concentration* (Mg/L) Concentration Reference
Norfloxacin po 1–4 7 0.08 0.10 n.d. – Naber & Sorgel44
Ciprofloxacin iv 4 8 0.18 0.20 5.06 7.1 Naber et al.48
Fleroxacin po 2–4 8 1.00 0.28 5.80 1.7 Naber & Sorgel44
Levofloxacin po 3 8 1.42 0.29 5.14 1.0 Bulitta et al.43
Ofloxacin iv 4 5 0.66 0.33 2.05 4.0 Naber et al.49
Enoxacin po 2–4 10 0.29 0.39 2.19 2.2 Naber & Sorgel44
Lomefloxacin po 4 7 1.38 0.48 2.03 1.2 Naber & Sorgel44
Gatifloxacin po 4 7 1.03 1.29 1.75 1.0 Farker et al.,46 Naber et al.47

Moxifloxacin po 3–4 8 3.99 1.57 2.43 1.0 Wagenlehner et al.45
n.d., no data.
*Ordered according to prostatic fluid to plasma ratios.
The microbiological and clinical efficacy, as well as the adverse

Positive correlation of isoelectric points and
prostatic secretion to plasma concentration ratios effect profile, of different oral fluoroquinolones are comparable.60 The
optimal treatment duration of fluoroquinolones in the treatment of
CBP is still not clear; however, it ranges between at least 2 and 4 weeks.
Ratio 1,6
PS PL
In fluoroquinolone-resistant cases, alternative antimicrobial agents
tested for the treatment of CBP are co-trimoxazole, β-lactams and
1,4
tetracyclines, but no conclusive evidence can be drawn regarding the
role of nonfluoroquinolone antibiotics in the treatment of CBP. In the
1,2
case of CBP due to fluoroquinolone-resistant strains, prolonged treat-
ment with co-trimoxazole for 2–3 months is recommended. In patients
1,0 with CBP caused by obligate intracellular pathogens, macrolides
showed higher microbiological and clinical cure rates compared to
0,8 fluoroquinolones.60
CBP can be a relapsing illness and recurrent episodes are best
0,6 managed by continuous low-dose suppressive therapy with an effective
regimen such as a fluoroquinolone, intermittent treatment whenever
0,4 symptoms recur, or efforts to resect infected prostatic tissue, particu-
larly prostatic calculi, in order to effect a surgical cure.6 The last is
0,2 rarely successful and should only be carried out with very specific
indications.
0,0
6,6 6,8 7,0 7,2 7,4 7,6 7,8 8,0 8,2 CHRONIC PROSTATITIS/CHRONIC PELVIC
Isoelectric point PAIN SYNDROME
Inflammatory CP/CPPS (NIH IIIA) is managed with α-blockers for
Figure 58-5 Positive correlation of the isoelectric points and the prostatic secre- 3–6 months, although a recent study has not shown any improved
tion to plasma concentration ratios (PS/PL) of nine quinolones (see Table 58-5) effect compared to placebo.61 A pollen extract (cernilton) has been
(Pearson correlation, P = 0.013). (Modified from Wagenlehner et al. Int J Antimi- shown to significantly improve pain and total symptoms, specifically
crob Agents 2008; 31(1):21-26.)
in patients with CP/CPPS (NIH IIIA).62
Therapy of CP/CPPS is currently performed according to a pheno-
typic approach algorithm, called UPOINTS.63,64 This phenotype system
These investigations, however, resemble a mixture of different phar- includes the urinary symptoms, psychosocial dysfunction, organ-
macokinetic compartments (e.g. intracellular, extracellular, interstitial specific finding, infection, neurological/systemic symptoms, tender-
compartment). Therefore assessment of concentrations in the pros- ness of muscles and sexual dysfunction, producing the acronym
tatic fluid is the more precise method. Macrolides also penetrate into UPOINTS. Each domain is diagnosed clinically, linked to specific
prostatic and seminal fluids very well; however, due to their restricted mechanisms of symptom productions or progression, and associated
gram-positive activity, they play only a limited role in the monotherapy with specific therapies. Therapy is recommended in a multimodal way,
treatment of CBP.39,51 individualized to the patient’s phenotype. Urinary symptoms are
Most studies in patients who have CBP have not been well con- treated by alpha-blockers and/or antimuscarinic agents, psychosocial
trolled and have been variably designed.50,51 As a result, comparison is dysfunction by psychological/psychosomatic techniques and in addi-
difficult. Duration of therapy has ranged from 14 to 150 days and tion, if needed by antidepression medication, organ-specific (prostate)
follow-up investigation has not been standardized. An EPS should be inflammation by quercetin, cernilton and/or anti-inflammatories,
obtained from all patients at 4–8 weeks and at 6 months after treatment infection signatures other than CBP by antibiotics, neurologic/systemic
to ensure that the pathogens have been eradicated.52 pain by amitriptyline, gabapentin, neuromodulation and/or acupunc-
Overall, it appears that 60–80% of patients who have Escherichia ture, muscle tenderness by physical therapy and sexual dysfunction by
coli and other Enterobacteriaceae can be cured with a 4- to 6-week phosphodiesterase 5 inhibitors, and testosterone supplementation,
course of therapy (Table 58-6).53–59 amongst others.
TABLE Eradication of Pathogens (Bacteriologic Cure) in Patients with Chronic Bacterial Prostatitis Treated with
58-6 Fluoroquinolones
Number of Duration of
Daily Dosage Duration of Evaluable Bacteriologic Follow-Up
Quinolone (Mg) Therapy (Days) Patients Cure (%) (Months) Year Of Study References
Norfloxacin 800 28 14 64 6 1990 Schaeffer & Darras53
Ofloxacin 400 14 21 67 12 1989 Pust et al.54
Ciprofloxacin 1000 14 15 60 12 1987 Weidner et al.55
Ciprofloxacin 1000 28 16 63 21–36 1991 Weidner et al.56
Ciprofloxacin 1000 60–150 7 86 12 1991 Pfau57
Ciprofloxacin 1000 28 34 76 6 2000 Naber et al.58
Ciprofloxacin 1000 28 78 72 6 2001 Naber59

Lomefloxacin 400 28 75 63 6 2001 Naber59
Only studies are listed in which the diagnosis was derived from application of the Meares and Stamey technique and a follow-up of at least 6 months was available.
TABLE
Classification of Epididymitis and Orchitis
Prevention
58-7
While cases with STDs could be reduced by adequate sexual education,
Granulomatous prevention of bacterial ascension through the vas deferens by vasec-
Acute Epididymitis or Epididymitis or tomy is highly effective. Although cases with acute epididymitis after
Epididymo-orchitis Orchitis Viral Orchitis
vasectomy are reported, the etiology is supposed to be of nonbacterial
Neisseria gonorrhoeae Mycobacterium Mumps (e.g. immunologic) origin. In addition, surgical therapy might be
tuberculosis beneficial in those patients with subvesical obstruction to prevent
Chlamydia trachomatis Treponema pallidum Enteroviruses future UTIs.68
Although vaccination decreased the prevalence of mumps orchitis,
Escherichia coli Brucella spp. recent data report that mumps orchitis is possible despite previous
Streptococcus pneumoniae Sarcoid vaccination.67
Klebsiella spp. Fungal
Clinical Features
Salmonella spp. Parasitic
The leading symptoms are typically unilateral scrotal pain and epididy-
Other urinary tract pathogens Idiopathic mal swelling. About 30% of patients notice concomitant dysuria,69
Idiopathic while the presence of typical urethritis symptoms largely depends on
the patient group with prevalence rates from 0% to 73%.69,70 The clini-
cal spectrum ranges from mild epididymal tenderness to a severe sys-
temic illness. Fever >37.5°C has been reported in up to 75% of patients
with 20% shivering.69 Frequently the tail of the epididymis is involved
first. However, spread to the whole epididymis and further, the testis,
is seen in up to 90% of patients.69,71 This is the reason why many studies
Epididymitis and Orchitis use the term ‘epididymo-orchitis’. Severe cases include those with
scrotal wall induration, epididymal abscess formation and secondary
Epidemiology testicular infarction.71
Acute epididymitis is a common condition with recent epidemiological Although receiving adequate antimicrobial therapy, about 20% of
data from the UK reporting incidence rates of about 25/10 000 person- patients still show a pathologic epididymal enlargement 3 months after
years.65 However, studies on the prevalence of epididymitis are scarce therapy.71 More important than the possible development of chronic
and subjected to specific cohorts. In this context, epididymitis seems epididymitis is the risk for recurrences in up to 10% of patients.70,71 In
to be more common among military personnel and individuals who young patients impairment of semen quality is of major relevance with
have high-risk sexual behaviors.66 persistent oligozoospermia and azoospermia in about 40% of patients
In contrast to epididymitis, isolated orchitis is a rare condition since after initial recovery.21
the broad introduction of mumps vaccination.67 In patients with mumps, testicular involvement regularly appears
in about 40% of patients 5–10 days after initial parotitis and patients
Pathogenesis and Pathology typically suffer a unilateral painful and enlarged testis.67 While post-
As early as 1927 Campbell concluded that epididymitis is a result of inflammatory azoospermia has been reported in 15% of patients with
pathogen ascension through the urogenital tract. This hypothesis was unilateral involvement, bilateral orchitis is associated with up to 60%
confirmed by studies investigating simultaneously pathogens isolated of azoospermia.72
from the urine/urethra and epididymis.66 Ascension is possible by both
STDs (e.g. Chlamydia trachomatis, Neisseria gonorrhoeae) and common Diagnosis
enteric pathogens (e.g. E. coli, Pseudomonas spp.). In addition, a sys- Acute epididymitis is a clinical diagnosis with patients typically com-
temic spread of viral pathogens might be plausible. However, the role plaining of an enlarged and painful epididymis.69–71 In young patients
of viruses is largely unknown. it is essential to rule out testicular torsion. Scrotal ultrasound is benefi-
Table 58-7 shows the pathogens causing the different types of epi- cial for the assessment of severe cases including epididymal abscess
didymitis/orchitis. In terms of acute orchitis, etiologic data are limited formation, and secondary testicular infarctions as well as those
to mumps virus. cases with large reactive hydroceles hindering adequate palpation.
Laboratory investigations including white blood cell count and enteric organisms are presumed, levofloxacin or ofloxacin for 10 days
C-reactive protein are useful for confirmation and monitoring. Uri- should be the first choice. Patients are nowadays usually treated on an
nalysis can be helpful as relevant leukocyte counts can be found in outpatient basis. Hospitalization will be limited to cases with severe
about 80% of patients.69,71 Standard urine cultures will usually reveal pain, high fever, or when patients are noncompliant. Re-evaluation is
an enteric pathogen in older patients. However, it is essential to screen suggested if symptoms do not subside within 3 days. In patients with
sexually active patients for STDs.73 In a prospective setting, a causative confirmed STDs, the therapy of sex partners is mandatory to prevent
bacterial pathogen can be identified in about 70% of cases.70 Unfortu- re-infection and spread of STDs.
nately, it has been reported that up to 50% of patients receive an As an adjunct to therapy, bed rest, scrotal elevation, and analgesics
inadequate diagnostic workup.73 are historically recommended. However, randomized studies are not
In patients with suspicion of mumps orchitis, C-reactive protein available on this aspect.
and α-amylase can be useful as laboratory parameters in blood.67 Since Surgical therapy is only rarely necessary and should be limited to
serology has a low sensitivity and specificity, PCR analysis should be patients with refractory epididymitis and those with secondary testicu-
performed. lar infarctions.69 Of note, epididymal abscess formation – a classic
indication for surgery – has been shown to completely resolve under
Management conservative therapy in a recent large case series.72
Empiric antimicrobial therapy is of utmost importance and has to No specific antiviral treatment is recommended for mumps
consider the most probable pathogens. According to current Centers orchitis.
for Disease Control and Prevention (CDC) guidelines in patients with
suspicion of STDs, 250 mg ceftriaxone intramuscularly in a single dose References available online at expertconsult.com.
plus doxycycline 100 mg orally BID for 10 days are recommended. If
KEY REFERENCES
Berger R.E., Alexander E.R., Harnisch J.P., et al.: Etiology, and seminal fluid and in prostatic tissue. Andrologia 2003; Wagenlehner F.M., Pilatz A., Waliszewski P., et al.: Reducing
manifestations and therapy of acute epididymitis: pro- 35(5):331-335. infection rates after prostate biopsy. Nat Rev Urol 2014;
spective study of 50 cases. J Urol 1979; 121(6):750-754. Nelson W.G., De Marzo A.M., Isaacs W.B.: Prostate cancer. 11(2):80-86.
Eickhoff J.H., Frimodt-Moller N., Walter S., et al.: A N Engl J Med 2003; 349(4):366-381. Wagenlehner F.M., Schneider H., Ludwig M., et al.: A
double-blind, randomized, controlled multicentre study Pilatz A., Wagenlehner F., Bschleipfer T., et al.: Acute epi- pollen extract (Cernilton) in patients with inflammatory
to compare the efficacy of ciprofloxacin with pivampicil- didymitis in ultrasound: results of a prospective study chronic prostatitis–chronic pelvic pain syndrome: a mul-
lin as oral therapy for epididymitis in men over 40 years with baseline and follow-up investigations in 134 ticentre, randomised, prospective, double-blind,
of age. BJU Int 1999; 84(7):827-834. patients. Eur J Radiol 2013; 82(12):e762-e768. placebo-controlled, phase 3 study. Eur Urol 2009; 56(3):544-
Krieger J.N., Nyberg L. Jr, Nickel J.C.: NIH consensus defi- Rusz A., Pilatz A., Wagenlehner F., et al.: Influence of uro- 551.
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Naber K.G., Sorgel F.: Antibiotic therapy – rationale and Urology 2009; 73:538-542.
evidence for optimal drug concentrations in prostatic
Chapter 58 Prostatitis, Epididymitis and Orchitis 538.e1
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538.e2 SECTION 2 Syndromes by Body System: Urinary Tract
70. Eickhoff J.H., Frimodt-Moller N., Walter S., et al.: A study with baseline and follow-up investigations in 134 73. Garthwaite M.A., Johnson G., Lloyd S., et al.: The
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epididymitis in ultrasound: results of a prospective
59
Complicated Urinary Infection,
Including Postsurgical and
Catheter-Related Infections
LINDSAY E. NICOLLE
KEY CONCEPTS bacteremia, sepsis syndrome and death may occur. Rates of symptom-
atic catheter-acquired UTI in patients with short-term catheters range
• Complicated urinary tract infection (UTI) occurs in individuals from 0.2–4.81/1000 catheter days.9 Bacteremia complicates less than
with underlying functional or structural abnormalities of the 1% of patients with catheter-acquired UTI,6 but the catheterized
genitourinary tract. urinary tract is the source for 21% of episodes of healthcare-acquired
• Genitourinary abnormalities promote infection through bacteremia.10
obstruction of urine flow and persistence of organisms in pro- Between 5% and 10% of individuals resident in long-term care
tected environments within the genitourinary tract. facilities have a chronic indwelling catheter.11 The prevalence of bacte-
riuria in these subjects is 100%. The urinary tract of residents with
• A wide spectrum of micro-organisms are isolated which are
often relatively resistant to antimicrobials. chronic indwelling catheters is the source of over half of all bacteremic
episodes identified in these facilities.11
• Prevention of complicated UTI requires correction of predis-
posing genitourinary abnormalities, wherever possible. Pathogenesis
• Pre-intervention antimicrobial prophylaxis is recommended for The major factor contributing to the initiation and persistence of
selected urological procedures to prevent postprocedure bacteriuria in complicated UTI is an impaired ability to clear organ-
symptomatic infection. isms from the urinary tract. This may be attributable to:
• A urine specimen for culture should always be obtained prior • obstruction of urine flow and incomplete emptying with voiding;
to antimicrobial treatment. • organisms surviving in protected environments, such as an
infected stone or bacterial biofilm on a catheter; or
• Antimicrobial selection is based on clinical presentation, anti-
microbial susceptibility and patient tolerance. • increased introduction of organisms into the bladder through
interventions such as intermittent catheterization.
• Asymptomatic bacteriuria should only be treated in pregnant A wide variety of genitourinary abnormalities are associated with
women or prior to an invasive urological procedure. complicated UTI (Table 59-2). The abnormality may be transient – for
instance, the presence of a noninfected stone, a cystoscopy procedure
or short-term catheterization. In this situation, once the abnormality
is corrected there is no longer an increased risk of UTI. If the abnor-
mality cannot be corrected, as in a patient who has an ileal conduit or
Introduction
This chapter discusses urinary tract infections (UTIs) occurring in
individuals with abnormalities of the genitourinary tract, designated
‘complicated UTI’. This includes UTIs following urologic surgery and Infection Rates After Genitourinary Surgery,
infections associated with indwelling urologic devices including TABLE Extracorporeal Shock Wave Lithotripsy or
59-1 Catheterization in the Absence of
urinary catheters, i.e. intermittent catheterization and both short-term
(<30 days) and long-term (>30 days) indwelling catheters. Urinary Antimicrobial Prophylaxis
infection in pregnant women is not addressed (see Chapter 57).
Proportion Infected
Procedure Postprocedure
Epidemiology
Transurethral prostatectomy1 6–64%
The incidence of complicated urinary infection on a population basis
has not been reported. In the setting of structural or functional abnor- Transurethral procedure with 26% (sepsis 4.4%)
instrumentation for stone extraction2
malities of the genitourinary tract or after urologic interventions, the
frequency of UTI may be exceptionally high (Table 59-1). The yearly Ureteroscopy2 35% (4–25% febrile)
prevalence of urinary infection for males over age 70 is 5%, and virtu- Extracorporeal shock wave lithotripsy
ally all of this is complicated infection.7 The urinary tract is reported (ESWL)3
to be the source for 8–30% of patients admitted to the intensive care
Negative urine culture before ESWL 1.5%
unit with severe sepsis or septic shock; the mortality rate for these
patients is 10–20%.8 The urinary tract also accounts for one-third of Positive urine culture before ESWL 21% (sepsis 4.5%)
bacteremic episodes in elderly individuals presenting to the emergency
Catheterization
department with bacteremia, most of whom have abnormalities such
as obstruction or indwelling catheters.9 Urodynamic studies4 1.5–36%
Between 70% and 80% of hospital-acquired UTI is attributed to Indwelling catheter5 3–7%/day
indwelling urethral catheters. The rate of acquisition of bacteriuria is 6
Clean intermittent catheterization 2.95/100 patient days
3–5% of exposed subjects per catheter day.6 While catheter-associated (0.41/100 symptomatic)
infection is usually asymptomatic, symptomatic infection including
539
TABLE
TABLE Genitourinary Abnormalities Associated with 59-3 Bacteria Isolated in Complicated UTI
59-2 an Increased Frequency of UTI
Proportion of
Type of Lesion Examples Total Organisms
Organism Isolated* (%)
Obstructing lesion Tumor, stricture, urolithiasis, prostatic
hypertrophy, diverticulum, pelvicalyceal GRAM-NEGATIVE ORGANISMS
junction obstruction, congenital
abnormality, renal cysts Escherichia coli 21–54
Foreign body Indwelling catheter, ureteric stent, Klebsiella pneumoniae 1.9–17

nephrostomy tube Citrobacter spp. 4.7–6.1
Functional abnormality Neurogenic bladder, vesicoureteral reflux, Enterobacter spp. 1.9–10
cystocele
Proteus mirabilis 0.9–10
Metabolic illness Diabetes mellitus, medullary sponge
kidney, post renal transplantation Providencia spp. 1.9
Urinary instrumentation Prostatectomy, cystoscopy, urologic Pseudomonas aeruginosa 2.0–19
surgery
Other gram-negative organisms 6.1–23
Urinary diversion Ileal conduit, neobladder
GRAM-POSITIVE ORGANISMS
Enterococci 6.1–23
with a neurogenic bladder maintained on intermittent catheterization, Coagulase-negative staphylococci 1.3–3.7

there is a continued risk of recurrent UTI. Staphylococci aureus 0.9–2.0
Organisms gain access to the bladder in a patient with an indwelling
Group B streptococci 1.2–3.5
urethral catheter through several routes:
• introduced into the bladder from the periurethral flora at the Other gram-positive organisms 1.9
time of initial introduction of the catheter; Yeast 0–7
• ascending biofilm from organisms in the periurethral area on the *Data on frequency of isolation of different bacterial species derived from
outside of the catheter; or
references.14–17
• intraluminally by ascension up the catheter.
The intraluminal route appears to be more important in men, likely
because women have a shorter urethra, which facilitates extraluminal
ascent.
Bacterial biofilm forms along the surface of foreign bodies in the gram-negative organisms such as Pseudomonas aeruginosa and other
genitourinary tract, including ureteral stents, nephrostomy tubes or nonfermenters, and gram-positive organisms such as Enterococcus fae-
indwelling catheters.12 A biofilm is an adherent colony of micro- calis and group B streptococci. Coagulase-negative staphylococci are
organisms, encased in copious extracellular matrix. It also incorporates frequently isolated, although seldom cause symptomatic infection.
urine constituents such as calcium, magnesium and Tamm–Horsfall Candida spp. are usually isolated from individuals characterized by
protein. The biofilm provides a relatively protected environment for prolonged or repeated courses of antimicrobial drugs, diabetes and
micro-organisms by interfering with local host defenses and diffusion presence of an indwelling catheter.19 Anaerobic organisms are isolated
of antibiotics, thus contributing to persistent and relapsing infection. rarely, and then only in the setting of complex urologic abnormalities
UTI may also be acquired in urologic practice when organisms are and abscess formation in the urinary tract.
transmitted between patients on inappropriately cleaned diagnostic or The urease-producing organisms, principally Proteus mirabilis,
therapeutic equipment. Contamination is a risk when instruments are Providencia stuartii and Morganella morganii, are common pathogens
not appropriately changed or cleaned between patients or when fluid isolated from patients with indwelling devices. Rarely, more unusual
is left standing for prolonged periods at room temperature. Shared use urease-producing organisms such as Ureaplasma urealyticum or Cory-
of urinometers or urine collecting devices among patients with nebacterium urealyticum D2 are isolated. Urease production maintains
indwelling catheters has also been identified as a cause of outbreaks of an alkaline environment in the urinary tract, leading to the formation
infection in healthcare facilities. of struvite stones or catheter encrustation, and promoting persistence
of infection.
Microbiology Increased antimicrobial resistance among the infecting bacteria
isolated from complicated UTI is promoted by:
A wide variety of organisms are isolated from individuals who have
complicated UTI (Table 59-3).13–17 Escherichia coli remains the single
• repeated antimicrobial courses for recurrent UTI; and
most important infecting organism, but is isolated relatively less fre-
• the high frequency of healthcare acquisition.
Some infecting organisms, such as P. aeruginosa, are intrinsically
quently than reported for acute uncomplicated UTI. Incomplete more resistant to antimicrobials, while others such as E. coli or
voiding allows less virulent organisms to become uropathogens. E. coli K. pneumoniae have acquired genetic elements for resistance. The
strains isolated from complicated urinary infection may express fewer urinary tract is the most common site of isolation of resistant
E. coli virulence factors (see Chapter 57) compared with strains iso- gram-negative organisms of current concern, including extended-
lated from acute uncomplicated UTI.18 spectrum β-lactamase (ESBL) and carbapenemase-producing Entero-
The distribution of infecting organisms varies with factors such as: bacteriaceae.20
• whether organisms are isolated from initial or recurrent
infection;
Prevention
• whether acquisition is healthcare- or community-acquired;
• there is an indwelling urinary device; and GENERAL MEASURES
• previous antimicrobial exposure. UTI in the abnormal genitourinary tract occurs because of the pres-
Common organisms isolated include Enterobacteriaceae such as ence of an underlying abnormality or an intervention that impairs
Klebsiella, Citrobacter, Serratia, Proteus and Providencia spp., other normal defenses and allows the introduction and persistence of
Chapter 59 Complicated Urinary Infection, Including Postsurgical and Catheter-Related Infections 541
micro-organisms. Therefore, the most important interventions to Local anti-infective measures have not been effective to prevent
prevent UTI are: catheter-acquired infection.6,26 Daily perineal cleansing with either
• to identify and, wherever possible, correct underlying abnor- soap or disinfectant, addition of disinfectants such as povidone–iodine
malities; and or chlorhexidine to the drainage bag, or routine irrigation with normal
• to avoid nonessential interventional procedures. saline or antiseptics do not decrease the rate of infection. The use of
Prophylactic antimicrobial therapy does not decrease the frequency catheters impregnated with silver alloy does not decrease the frequency
of symptomatic urinary infection for most non-surgical patients with of symptomatic UTI.27 Use of nitrofurazone-coated catheters may
complicated UTI.13,21,22 Non-antimicrobial interventions, such as use slightly decrease the frequency of symptomatic UTI, but are associated
of cranberry products, are also not effective.23 The therapeutic poten- with increased adverse effects and catheter removal.27
tial of bacterial interference, which establishes asymptomatic bacteri- The use of antimicrobials for preventing infection in patients with
uria with an avirulent E. coli strain to prevent symptomatic infection spinal cord injury maintained on intermittent catheterization has been
in selected high risk patients, is currently being investigated.24 Renal controversial. Clinical trials report antimicrobial prophylaxis may
transplant patients receive 6 months’ postoperative prophylaxis with prevent infection, in the early postinjury period only, but at the cost
trimethoprim–sulfamethoxazole (TMP–SMX) to prevent pneumocys- of increased antimicrobial resistance with re-infection. Therefore, pro-
tis pneumonia and other infections, which also prevents both asymp- phylactic antimicrobials are not recommended for these patients.21 The
tomatic and symptomatic UTI.25 use of hydrophilic catheters also does not decrease the frequency of
It is important to follow appropriate aseptic technique for diagnos- symptomatic urinary infection.28
tic and surgical interventional procedures. All fluids used in urologic Individuals with chronic indwelling catheters are uniformly bacte-
procedures must be handled in a manner that ensures sterility. Equip- riuric, with two to five organism types usually isolated.11 The incidence
ment must be disassembled after a procedure and reassembled using rate of acquisition of bacteriuria with a new organism is similar to that
sterile components before the next procedure. Institutions should of short-term indwelling catheters, i.e. 3–5% per day. Recommended
establish and maintain appropriate infection surveillance programs for procedures for catheter management are similar for long-term and
healthcare-acquired UTI to monitor endemic infection rates and the short-term catheters, although there are no studies that document the
effectiveness of infection prevention programs.26 effectiveness of specific practices for decreasing the risk of infection
for long-term catheters. Systemic antimicrobial therapy given to eradi-
CATHETER-ACQUIRED INFECTION cate asymptomatic bacteriuria does not decrease the incidence of sub-
Prevention of catheter-acquired urinary infection is an important sequent symptomatic infection, while re-infection with resistant
element of healthcare infection prevention and control programs organisms occurs.25 Avoiding trauma to the catheter and early identi-
(Table 59-4). The most important practice in preventing catheter- fication and management of catheter obstruction will decrease the
acquired UTI is to use an indwelling catheter only for restricted indica- incidence of symptomatic infection for patients with long-term
tions and, if a catheter must be used, to minimize the duration of catheters.
catheterization.6,26 When a catheter is necessary, aseptic technique for
insertion and maintenance of a closed urinary drainage system are POSTOPERATIVE INFECTION
important practices. The perioperative use of antimicrobials for selected urologic proce-
Patients receiving antimicrobial therapy have a decreased incidence dures encompasses two issues:
of infection acquisition during the initial 4 days of catheterization • treatment of pre-existing bacteriuria to prevent the complica-
compared with patients who do not receive antimicrobials. After the tions of invasive infection; and
first 4 days, the infection rates are similar, but patients receiving anti- • prophylaxis to prevent postoperative infection in individuals
microbials develop infection with more resistant organisms. Therefore, without positive pre-intervention urine cultures.
antimicrobial therapy to prevent infection when an indwelling catheter Preoperative treatment of bacteriuria is indicated for selected uro-
is in situ is currently not recommended.6,26 logic procedures to prevent postoperative bacteremia and sepsis1
(Table 59-5). This practice is recommended for cystourethroscopy
with manipulation, transrectal prostate biopsy, shock wave lithotripsy,
ureteroscopy, surgery with intestinal transpositions and, for selected
patients, for removal of external urinary catheters, cystourethrostomy,
TABLE Interventions to Prevent Catheter-Acquired and urodynamic studies.1,29
59-4 Infection There is no generally accepted ‘standard’ antimicrobial regimen for
Proven effective Use catheter only for accepted indications:
prophylaxis.1,29 A fluoroquinolone, or an aminoglycoside with or
• measurement of urine output in ICU without a cephalosporin, is frequently used. Studies have also docu-
• selected surgical procedures mented the efficacy of TMP–SMX and second- and third-generation
• management of acute urinary retention or cephalosporins, including cefotaxime, ceftriaxone, cefotetan, cefoxitin
urinary obstruction
• assistance in healing pressure ulcer or skin
and ceftazidime. The regimen selected should consider both patient
grafts in selected patients with urinary tolerance and likelihood of antimicrobial resistance.
incontinence The usual prophylactic regimen is one dose 1–2 hours preopera-
• as an exception, at patient request to improve tively.1,29,30 The shortest effective duration of therapy is preferred to
comfort (e.g. end of life care)
Remove catheter promptly when no longer
limit cost, adverse effects, and the emergence of antimicrobial-resistant
indicated organisms.
Maintain closed drainage system
Antibiotics first 4 days (not recommended)
Possibly effective Aseptic insertion

Clinical Features
Antibiotics for last 48 h of catheterization The clinical presentations of complicated UTI are diverse, and vary
Antimicrobial decontamination of gut along a spectrum from asymptomatic bacteriuria without a measur-
Proven not effective Daily meatal care with soap or antiseptic able host response to septic shock and death. Infection may be localized
Disinfectant (formaldehyde, chlorhexidine, to the bladder or may involve the kidney and, in men, the prostate.
hydrogen peroxide) in drainage bag Clinical features of symptomatic infection are usually consistent with
Silver alloy-coated antimicrobial catheters
Continuous antibiotic or antiseptic irrigation
lower UTI, including frequency, suprapubic discomfort, dysuria and
urgency. With renal infection the characteristic presentation of fever
Data from Gould et al.26 and costovertebral angle tenderness may occur. Urinary obstruction or
TABLE
59-5 Prophylactic Antimicrobial Therapy in Genitourinary Surgery to Prevent Postoperative UTI
Infection Rate Without Infection Rate With
Procedure Regimen Prophylaxis (%) Prophylaxis (%)
TRANSURETHRAL INSTRUMENTATION
UTI with stone extraction Cefotaxime 1 g iv, one dose29 25 8.5
Various1 5.7% 2.1%
TRANSURETHRAL RESECTION1 PROSTATE
Bacteriuria Various 26% 9.1%
Clinical sepsis Various 4.4% 0.7%
TRANSPLANTATION
Renal transplantation Trimethoprim–sulfamethoxazole 160–800 mg 35 8

q24h for 4 months
trauma to the genitourinary mucosa predispose to bacteremia and crystals precipitated by the alkaline urine generated by the urease. If a
more severe systemic presentations of infection. persistent fungal infection is identified, there may be a fungus ball in
Presenting symptoms may not, however, be straightforward. Infec- the bladder or kidney, which may be associated with obstruction.
tion may manifest with only lower UTI irritative symptoms despite the
presence of upper tract infection. For postsurgical infections or infec- RECURRENT INFECTION AFTER
tion in the presence of an indwelling catheter, trauma to the bladder ANTIMICROBIAL THERAPY
mucosa may lead to invasive infection and fever. In males, recurrent Early recurrent infection after antimicrobial therapy is characteristic
bladder infection may be secondary to chronic bacterial prostatitis. of individuals with persistent genitourinary abnormalities. Infection
may be symptomatic or asymptomatic and may represent:
PRESENTATIONS IN UNIQUE PATIENT GROUPS • relapse with recurrence of the pre-therapy infecting organism
For patients who have a spinal cord injury with a neurogenic bladder, after therapy due to persistence in the genitourinary tract; or
the usual irritative lower tract symptoms may be absent because of • re-infection with introduction of a new organism.
altered sensation associated with the neurologic injury.21 Signs and For men, the prostate must also be considered as a potential source
symptoms suggestive of UTI in these patients, in addition to fever, for relapsing infection. Bacteriologic cure rates at 4–6 weeks (long-
kidney pain or tenderness and bladder discomfort, may include a new term follow-up) are consistently less than 50% (i.e. recurrent bacteri-
onset or increase in urinary incontinence, increased sweating, increased uria is the expected outcome) (Table 59-6). When the underlying
spasticity and a general sense of being unwell. Autonomic dysreflexia abnormality promoting infection cannot be corrected, recurrent infec-
may occur in patients with spinal cord injury at cervical or high tho- tion with organisms of increasing antimicrobial resistance is a common
racic levels. Patients with multiple sclerosis may present with increased outcome. Some patients may have frequent infections for years, with
fatigue and deterioration in neurologic function. In patients who have ultimate acquisition of highly resistant organisms.
undergone renal transplantation, localizing symptoms and signs may
be absent or minimal in the early post-transplant period, despite the
presence of bacteremia. This lack of symptoms may be due to immu- Diagnosis
nosuppressive therapy or uremia. Clinical symptoms alone are not sufficient for a diagnosis of compli-
Infection in individuals who have indwelling catheters or obstruc- cated UTI. For definitive diagnosis an appropriately collected urine
tion may present as fever without any localizing genitourinary find- specimen must be obtained for bacterial culture. The large variety of
ings. For patients without indwelling catheters, however, a diagnosis of potential infecting organisms, together with the increased likelihood
UTI in the febrile patient who has a positive urine culture and no of antimicrobial resistance, means that obtaining a pre-therapy urine
localizing findings must be critically evaluated. In populations with a culture is essential for appropriate antimicrobial management of
high prevalence of asymptomatic bacteriuria, the large majority of patients who experience complicated UTI. Blood cultures should also
such episodes are not attributable to UTI.31 be obtained from patients who have evidence of sepsis, including
Occasionally, symptoms of the underlying genitourinary abnor- symptoms such as high fever, rigors, hypothermia and acute
mality may be prominent. For instance, if a UTI occurs in the setting confusion.
of a ureteral stone, symptoms of renal colic may predominate. The
bacteriuric patient with diabetes mellitus who develops papillary URINE SPECIMEN
necrosis may also present with symptoms of renal colic. Infections with The urine specimen must be collected before initiating antimicrobial
Enterobacteriaceae (usually E. coli and K. pneumoniae) in hyperglyce- therapy, using a urine collection method that limits contamination.
mic patients with diabetes mellitus may present as emphysematous Urine specimens should be forwarded promptly to the laboratory for
cystitis or pyelonephritis. Acute bacterial prostatitis usually presents semiquantitative culture and appropriate susceptibility testing. A
with prominent symptoms of urethral obstruction, including clean-catch voided specimen or, if a voided specimen cannot be
retention. obtained, a specimen obtained through in and out catheterization, is
usually appropriate. For individuals who have indwelling catheters,
PRESENTATIONS WITH UNIQUE urine is collected by aseptic aspiration from the catheter port. Patients
INFECTING ORGANISMS with obstruction for whom a urologic procedure for decompression is
Infection by specific organisms may also produce a unique clinical undertaken may have specimens obtained by ureteric catheterization
presentation. Catheter obstruction is associated with urease-producing or percutaneous aspiration of the renal pelvis. There is no satisfactory
organisms, the most common of which is P. mirabilis. Corynebacterium way to avoid contamination when collecting specimens for culture
urealyticum infection is associated with the clinical syndrome of from patients who have an ileal conduit or surgically created neoblad-
encrusted cystitis. This is encrustation of the bladder wall by struvite der. The conduit or neobladder will always be colonized with bacteria,
TABLE
59-6 Bacteriologic Outcome After Antimicrobial Therapy of Complicated UTI
Regimen Follow-up After Therapy Cure (%) Re-infection (%)
COMPLICATED URINARY INFECTION
Lomefloxacin15 5–9 days 59 5.9

4–6 weeks 43 19
Trimethoprim–sulfamethoxazole15 5–9 days 33 1.5

4–6 weeks 28 9.2
Imipenem-cilastatin32 5–9 days 63.3 NS

4–6 weeks 46.9 NS
Ceftazidime-avibactam32 5–9 days 67.4 NS

4–6 weeks 50 NS
UTI SECONDARY TO SPINAL CORD INJURY
Norfloxacin 14 days32 5–7 days 53 14

8–12 weeks 16 NS
Various antimicrobials: 7–14 days33 1 week 47 NS
Various antimicrobials: ≥28 days 33

1 week 41 NS
CHRONIC INDWELLING CATHETER
Ciprofloxcacin/ofloxacin 14 days34 1 week 42 NS
NS, not stated.
with a quantitative count of 105 cfu/mL or more with the same

TABLE Quantitative Bacteriology in the Diagnosis of organism(s) isolated on two consecutive occasions are recommended
59-7 Complicated UTI for diagnosis.25 In practice, however, a single specimen achieving
counts of 105 cfu/mL or more is usually interpreted as bacteriuria.
Clinical Presentation Bacteriologic Count
A single infecting organism is usual, but some patients have more
Asymptomatic bacteriuria ≥105 cfu/mL in two consecutive than one species isolated. The patient who has a long-term indwelling
urine specimens catheter or other chronic device will usually have persistent polymi-
Symptomatic urinary infection ≥104 cfu/mL in one specimen; ≥105 crobial bacteriuria, and up to 25% of elderly nursing home residents
if collected by external catheter; without catheters may have more than one organism isolated.11
≥102 cfu/mL collected by in and Unusual uropathogens such as U. urealyticum or Haemophilus
out catheter influenzae will not be isolated by routine laboratory methods for urine
Percutaneous aspiration in Any quantitative count culture. If infection is localized proximal to a complete ureteric
hydronephrosis obstruction, the culture may also be negative. Of course, urine cultures
Diuresis, diuretic therapy, renal Lower quantitative counts (<105/mL) may also be negative if the patient has received effective antimicrobial
failure, selected infecting may occur in these situations therapy prior to collecting the urine specimen.
organisms (e.g. Candida
albicans) PYURIA
Pyuria is evidence for inflammation within the urinary tract, and may
and clinical judgment is necessary to interpret the relevance of the be attributed to many causes other than infection. Underlying abnor-
culture result. malities associated with complicated UTI, prostatitis, urethritis due to
Foreign devices in the urinary tract, including indwelling urethral chlamydial infection, inflammation following a surgical procedure or
catheters, ureteric stents, and nephrostomy tubes, are rapidly coated with an indwelling device may all be associated with pyuria in the
with a bacterial biofilm after insertion. Organisms isolated from urine absence of infection. As both symptomatic and asymptomatic UTI are
specimens obtained through such devices reflect the microbiology of usually accompanied by pyuria, this finding does not discriminate
the biofilm on the inner surface of the catheter as well as of bladder between symptomatic and asymptomatic infection. A dipstick test or
urine. Therefore, it is suggested that chronic indwelling catheters in urinalysis that shows evidence of pyuria is consistent with but not
situ 14 days or longer should be changed before specimen collection diagnostic of UTI. A negative test for pyuria is, however, reliable to
and prior to initiation of antimicrobial therapy.26 The urine specimen exclude a diagnosis of urinary infection.
is collected through the newly inserted catheter, which is free of biofilm
so only bladder urine is sampled, leading to a more reliable identifica- Management
tion of the infecting bacterial species. Essential elements in approaching the management of UTI in the
setting of an abnormal genitourinary tract include:
QUANTITATIVE BACTERIOLOGY • evaluation of the severity and localizing findings of the clinical
Current recommendations for interpretation of quantitative bacteriol- presentation;
ogy in the diagnosis of complicated UTI are provided in Table 59-7. • appropriate pre-therapy diagnostic specimen collection;
UTI may be diagnosed if the quantitative count of organisms in urine • selection of initial antimicrobial therapy;
culture is 104 cfu/mL or more when symptoms consistent with genito- • an assessment of the need for genitourinary investigation or
urinary infection are present, although ≥105 cfu/mL are isolated from urologic interventions to characterize or correct any abnormality
most symptomatic patients. With specimen collection by intermittent for source control and to prevent recurrence; and
or in and out catheter, 102 cfu/mL or more is sufficient to confirm • review of urine culture results, once available, to confirm the
bacteriuria. For individuals who are asymptomatic, two specimens antimicrobial regimen is optimal.
Supportive therapy should be given as appropriate depending on

the severity of the clinical presentation. Replacement of a chronic TABLE Oral Therapeutic Regimens for the Treatment
59-8 of Complicated UTI
indwelling catheter prior to initiating antimicrobial therapy is associ-
ated with more rapid defervescence and a decreased frequency of
Agent Dose
symptomatic relapse, as well as providing a more accurate urine speci-
men for culture.35 Amoxicillin 500 mg q8h
Amoxicillin–clavulanate 500 mg q8h or 875 mg bid

ASYMPTOMATIC BACTERIURIA
Asymptomatic bacteriuria should be treated only in pregnant women Cephalexin 500 mg q6h
or prior to an invasive genitourinary procedure.25 Treatment of asymp- Cefuroxime axetil 500 mg q12h
tomatic bacteriuria in the elderly, school-age girls, healthy women,
diabetic women, renal transplant patients and patients with intermit- Cefpodoxime proxetil 100 mg q12h
tent or indwelling catheters is not indicated.25 Antimicrobial therapy Ceftibuten 400 mg q24h
does not decrease morbidity of infection but is associated with a
Cefixime 400 mg q24h
greater frequency of negative outcomes, including the emergence of
resistant organisms and adverse drug effects. Screening for bacteriuria Nitrofurantoin 50–100 mg q6h
is not indicated except in populations for whom treatment of asymp- Nitrofurantoin monohydrate/ 100 mg q12h
tomatic bacteriuria is recommended. macrocrystals
ANTIMICROBIAL THERAPY Norfloxacin 400 mg q12h

Whenever possible, empiric therapy should be avoided and antimicro- Ciprofloxacin 250–500 mg q12h
bial therapy specific for the infecting organism(s) isolated in urine
Ciprofloxacin extended release 1 g q24h
culture should be prescribed. This is usually possible if the patient has
mild symptoms. When the patient’s symptoms are severe enough to Ofloxacin 400 mg q24h or 200 mg q12h
warrant immediate empiric therapy, it is essential that a urine culture Levofloxacin 200–500 mg q24h
be obtained before initiating the antimicrobial. The empiric antimi-
crobial regimen should be re-evaluated once culture results are avail- Trimethoprim 100 mg q12h
able, usually 48–72 hours after the specimen was collected. Trimethoprim–sulfamethoxazole 160 mg trimethoprim–800 mg
Initial parenteral therapy is preferred for individuals who have: sulfamethoxazole q12h
• hemodynamic instability;
• nausea and vomiting, or for whom oral intake is not possible;
• questionable absorption of oral antimicrobials; or infection. It is effective for most strains of vancomycin-resistant
• infection with known or suspected resistant organisms for which Enterococcus. Many resistant strains, including ESBL-producing and
oral therapy is not available.
The majority of patients can be managed without hospitalization or carbapenemase-producing Enterobacteriaceae, remain susceptible to
with a limited (24–72 hours) admission to a short-stay unit for initial fosfomycin or pivmecillinam as well as nitrofurantoin but the clinical
parenteral therapy. Parenteral therapy is switched to oral therapy once efficacy of these agents for complicated UTI is not established.20
the patient is stable and pre-therapy urine culture results are available For gram-positive organisms, such as group B streptococci and
to assist in selecting the appropriate medication. susceptible Enterococcus spp., amoxicillin is the treatment of choice.
The antimicrobial agents appropriate for therapy are similar to
Parenteral Therapy
those recommended in the treatment of acute uncomplicated UTI or
acute nonobstructive pyelonephritis (Tables 59-8 and 59-9). The selec- For parenteral therapy, an aminoglycoside antimicrobial remains a
tion of a specific antimicrobial agent is based upon clinical presenta- treatment of choice because of the documented efficacy of this group
tion, the known or suspected infecting organism and its susceptibilities, of drugs over many years of use, and the continued susceptibility of
patient tolerance, documented efficacy and, in some cases, cost. most uropathogens. The nephrotoxicity and ototoxicity of aminogly-
There are many clinical trials addressing the treatment of compli- cosides are seldom a problem if the duration of therapy is limited, with
cated UTI, but these do not identify a single preferred regimen in a an early switch to oral therapy following initial clinical improvement
specific clinical situation.13 Thus, there is no ‘standard’ regimen with and review of the urine culture.
respect to agent, dose or duration. Studies have generally enrolled Many other parenteral antimicrobial agents are effective, including
diverse patient populations for whom different outcomes with therapy penicillins (piperacillin and piperacillin–tazobactam), cephalosporins
would be anticipated on the basis of underlying abnormalities. The (cefazolin, cefuroxime, cefotaxime, ceftriaxone, ceftazidime, ceftaro-
severity of illness also varies, with patient clinical presentations ranging line), carbapenems (doripenem, imipenem, ertapenem, meropenem)
from an increase in incontinence or bladder spasms to a life-threatening and fluoroquinolones (levofloxacin, ciprofloxacin) (Table 59-9). If
illness with bacteremia. Enterococcus spp. might be present, ampicillin should be added. The
increasing prevalence of ampicillin resistance in E. faecium and E.
Oral Therapy faecalis in many institutions means that vancomycin may be necessary
Many agents are effective for oral therapy (Table 59-8). The fluoroqui- to treat healthcare-acquired enterococcal infection. Carbapenems are
nolone antimicrobials as a class have been most widely studied and considered first line parenteral therapy for infections with ESBL-
recommended.15,32,35 Benefits of fluoroquinolones include a wide anti- producing Enterobacteriaceae.20 Clinical trials of doripenem35 and
microbial spectrum and good patient tolerance. The main concern is ertapenem36 report outcomes equivalent to fluoroquinolones or ceftri-
increasing antimicrobial resistance of uropathogens with the wide- axone, but there is limited reported experience to date for infections
spread use of this class of antimicrobials. The isolation of a with ESBL-producing organisms. Optimal parenteral therapy for
fluoroquinolone-resistant ESBL-producing E. coli or K. pneumoniae is aminoglycoside-resistant carbapenemase-producing Enterobacteria-
an increasing problem and may be a therapeutic challenge. Amoxicillin– ceae is not yet established.
clavulanic acid is effective for the treatment of some of these strains
Duration of Therapy
and nitrofurantoin may be effective for E. coli bladder infections.
Nitrofurantoin should be avoided in subjects with pyelonephritis or Few reported studies have directly addressed the question of the appro-
renal impairment, and is not effective for P. mirabilis or P. aeruginosa priate duration of therapy. The usual recommended duration is 7–14
TABLE
TABLE Parenteral Regimens for the Treatment of 59-10 Treatment Regimens for Fungal UTI
59-9 Complicated UTI in Patients with Normal
Renal Function Agent Dose Cure Rate (%)
Amphotericin B: 0.3–1 mg/kg single dose 75

Agent Dose parenteral or 6 mg/kg total dose
Ampicillin 1 g q6h Amphotericin B: Continuous, 50 mg/L for 72–88
Piperacillin 3 g q6h bladder irrigation 5 days
Ticarcillin–clavulanate 3.1 g q6h Fluconazole 50–400 mg q24h for 7 days 70–80

5-Flucytosine 50–150 mg/kg q6h 70
Piperacillin–tazobactam 4 g piperacillin–500 mg
tazobactam q8h Data from Pappas et al.40
Cefazolin 1–2 g q8h
Cefotaxime 1 g q8h
Ceftriaxone 1 g q24h In patients with renal failure, renal perfusion is decreased and
antimicrobials may not reach infected renal tissue or achieve high
Ceftazidime 1 g q8–12h
urine levels. The aminoglycosides, in particular, may be less effective.10
Cefepime 1–2 g q12h The fluoroquinolone antimicrobials, TMP–SMX, trimethoprim and
extended-spectrum β-lactam antimicrobials appear to be effective in
Ceftaroline 600 mg q12h
the treatment of UTI in the presence of significant renal failure. A more
Ceftazidime-avibactim 500 mg/125mg q8h prolonged duration of antimicrobial therapy may be necessary to cure
Imipenem 500 mg q6h UTI in these patients.
An additional potential therapeutic problem is the patient who has
Meropenem 500 mg q6h or q8h normal measured renal function and satisfactory urinary antimicro-
Ertapenem 1 g q24h bial levels but disparate kidney function. If the function of one kidney
is severely impaired relative to the other, blood flow is preferentially
Doripenem 500 mg q8h
increased in the functioning kidney and, despite adequate bladder
Gentamicin 5 mg/kg q12h or q24h urine antibiotic levels, little antibiotic will be filtered by the poorly
Tobramycin 5 mg/kg q12h or q24h
functioning kidney. Antimicrobial treatment may then not eradicate
infection localized to the poorly functioning kidney. This is an expla-
Amikacin 15 mg/kg q12h or q24h nation for relapsing infection in some patients.
Trimethoprim–sulfamethoxazole 160 mg trimethoprim–800 mg
sulfamethoxazole q12h TREATMENT OF FUNGAL INFECTION
Treatment of asymptomatic funguria is not beneficial and is not
Ciprofloxacin 400 mg q12h
recommended.40
Levofloxacin 500 mg q24h The treatment of choice for symptomatic fungal infection is fluco-
Ofloxacin 400 mg q12h nazole, which is the only azole antifungal excreted in the urine (Table
59-10). The usual dose is 200 mg/day for 7–14 days.40 Some non-
albicans Candida spp., particularly C. krusei and C. glabrata, have
decreased susceptibility or are resistant to fluconazole. Flucytosine is
days.13,21 In a prospective randomized trial, 2 weeks of ciprofloxacin effective for some resistant strains, but flucytosine resistance may
therapy was as effective as 4 weeks for men presenting with febrile emerge rapidly when this agent is used alone. For selected patients with
urinary infection.37 A prospective randomized clinical trial of spinal Candida cystitis, a single dose of amphotericin B deoxycholate may be
cord injured patients showed that 14 days of ciprofloxacin therapy effective, given its prolonged excretion. Previously, bladder irrigation
resulted in fewer symptomatic relapses post-therapy than a 3-day with amphotericin B was a recommended therapy. This approach,
course.38 Whether an alternate treatment duration of between 3 and however, is uncomfortable and time-consuming, and is no longer con-
14 days would be as effective is not known. sidered first line therapy.
• For selected clinical situations alternative durations of therapy Voriconazole and posaconazole, as well as the echinocandin anti-
are appropriate: if symptomatic infection is associated with an fungals caspofungin, anidulafungin and micafungin, and amphoteri-
indwelling catheter which must remain in situ, it is recom- cin B lipid formulations, are not excreted into the urinary tract and
mended that the duration of therapy be as short as possible, are not recommended.
usually 5–7 days, to limit the emergence of resistant organisms;
• where relapsing infection is from a prostate source, 6 or 12 weeks SUPPRESSIVE THERAPY
of antimicrobial therapy is recommended; Suppressive therapy is long-term antimicrobial therapy given to
• after successful extracorporeal shock wave lithotripsy for an prevent morbidity from recurrent symptomatic urinary infection for
infected struvite stone, continuation of antimicrobial therapy is individuals with underlying abnormalities that cannot be definitively
recommended for at least 4 weeks to prevent relapse and sterilize cured (Figure 59-1). For these patients, suppressive therapy may
residual stone fragments.39 prevent symptomatic episodes or progression to renal failure.41
A renal transplant patient with symptomatic recurrences attributed
TREATMENT OF PATIENTS WITH to persistent infection of a native kidney is one example where this
RENAL FAILURE approach might be considered. Suppressive therapy may also be con-
Patients who have abnormalities of the genitourinary tract are more sidered for men who have frequent recurrent episodes of symptomatic
likely to have impaired renal function. Renal function should be evalu- urinary infection from a prostate source and in whom prolonged anti-
ated, if not already known, for patients who present with complicated microbial therapy has failed to cure the prostate infection. Continuous
UTI. If there is renal impairment appropriate modifications in anti- suppressive therapy is also recommended to prevent further stone
microbial dose are necessary. Nitrofurantoin and tetracyclines other enlargement and preserve renal function for the few individuals with
than doxycycline should be avoided. a struvite (infection) stone that cannot be completely removed.
Long-term suppressive therapy is, however, infrequently indicated

and should be used selectively because of the potential for adverse
effects including development of infection with resistant organisms.
Indications for Investigation

An important aspect of the management of UTIs is determining when
to undertake urologic or imaging investigations to characterize abnor-
malities in the genitourinary tract (see also Chapter 60). The underly-
ing abnormality may already be known, such as the presence of an
indwelling catheter. In selected other patients, genitourinary investiga-
tions should be considered. These clinical scenarios include:
• patients presenting with sepsis and hemodynamic instability
may require urgent evaluation to identify an abscess or obstruc-
tion requiring immediate source control;
• delayed or incomplete clinical response to appropriate antimi-
crobial therapy;
Figure 59-1 Nephrocalcinosis complicated by relapsing Pseudomonas aerugi- • early recurrence of symptomatic infection after therapy;
nosa infection. Plain film of the abdomen showing multiple bilateral renal stones. • patients with well-characterized abnormalities but increased fre-
This woman has had recurrent stone formation since the age of 18 despite dietary quency or severity of infection; and
manipulation and repeated lithotripsy. Urinary infection with P. aeruginosa was
identified at 24 years of age with subsequent recurrent episodes of symptomatic
• symptomatic fungal infection, where a fungus ball in the bladder
upper tract infection. She has been maintained on suppressive ciprofloxacin or kidneys should be excluded.
therapy for over 15 years with control of symptomatic infection.
KEY REFERENCES
Darouiche R.D., Hull R.A.: Bacterial interference for pre- Practice Guidelines from the Infectious Diseases Society Nicolle L.E., Bradley S., Colgan R., et al.: IDSA guideline for
vention of urinary tract infection. Clin Infect Dis 2012; of America. Clin Infect Dis 2010; 50:625-663. the diagnosis and treatment of asymptomatic bacteriuria
55:1400-1407. Lo E., Nicolle L., Coffin S.E., et al.: Strategies to prevent in adults. Clin Infect Dis 2005; 40:643-654.
D’Hondt F., Everaert K.: Urinary tract infection in patients catheter-associated urinary tract infection in acute care Pappas P.G., Kauffman C.A., Andes D., et al.: Clinical prac-
with spinal cord injuries. Curr Infect Dis Rep 2011; hospitals. Infect Control Hosp Epidemiol 2014; 35(5):464- tice guidelines for the management of candidiasis: 2009
13:544-551. 479. update by the Infectious Diseases Society of America.
Gettman M.T., Segura J.W.: Struvite stones: diagnosis and Naber K.G., Bishop M.C., Bjerklund-Johansen T.E., et al.: Clin Infect Dis 2009; 48:503-535.
current treatment concepts. J Endourol 1999; 13:653-658. Guidelines on the management of urinary and male genital Stickler D.J.: Bacterial biofilms in patients with indwelling
Gould C.V., Umscheid C.A., Agarwal R.K., et al.: HICPAC tract infections. Arnhem: European Association of catheters. Nat Clin Pract Urol 2008; 5:598-608.
Guideline for prevention of catheter-associated urinary Urology; 2006:1-126. Wolf J.S., Jr, Bennett C.J., Omochowski R.R., et al.: Best
tract infections 2009. Infect Control Hosp Epidemiol 2010; Nicolle L.E.: Urinary tract infections in the elderly. Clin practice policy statement on urologic surgery antimicro-
31:319-326. Geriatr Med 2009; 25:423-436. bial prophylaxis. J Urol 2008; 179:1379-1390.
Hooton T.M., Bradley S.F., Cardenas D.D., et al.: Diagnosis, Nicolle L.E.: Urinary tract infections: Life-threatening infec-
prevention and treatment of catheter-associated urinary tions. Crit Care Clin 2013; 29:699-715.
tract infection in adults. 2009 International Clinical
Chapter 59 Complicated Urinary Infection, Including Postsurgical and Catheter-Related Infections 546.e1
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1. Wolf J.S., Jr, Bennett C.J., Omochowski R.R., et al.: Best study in patients with spinal cord lesion. J Urol 1994; 30. Orr P., Nicolle L.E., Duckworth H., et al.: Febrile
practice policy statement on urologic surgery antimi- 151:105-108. urinary infection in the institutionalized elderly. Am J
crobial prophylaxis. J Urol 2008; 179:1379-1390. 17. Bjerklunk Johansen T., Cek M., Naber K.G., et al.: Hos- Med 1996; 100:71-77.
2. Das Gupta R., Grabe M.: Preoperative antibiotics before pital acquired urinary tract infections in urology 31. Vasquez J.A., Patzan L.D.G., Stricklin D., et al.: Efficacy
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Endourol 2009; 23:1567-1569. antibiotics. Data from the PEP and PEAP studies. Int J cilastatin in the treatment of complicated urinary tract
3. Fourcade R.O., the Cefotaxime Cooperative Group: Antimicrob Ag 2006; 28(Suppl. 1):S90-S100. infections including acute pyelonephritis, in hospital-
Antibiotic prophylaxis with cefotaxime in endoscopic 18. Takahashi A., Kanamaru S., Kurazono H., et al.: Esche- ized adults: results of a prospective, investigator blinded,
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83. possess similar phylogenics, virulence genes, and 32. Waites K.B., Canupp K.C., DeVivo M.J.: Efficacy and
4. Charton M., Vallencien G., Veillon B., et al.: Use of anti- O-serogroup profiles. J Clin Microbiol 2006; 44:4589-

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Infectious Diseases

Jonathan Cohen, William G. Powderly, Steven M. Opal, MD

Associate Editors (Educational Content)

Courtney D. Chrisler, MD Bethany Davies, MRCP,

Content Strategist: Belinda Kuhn

Last digit is the print number: 9 8 7 6 5 4 3 2 1

Preface to the Fourth Edition xiv 11 Necrotizing Fasciitis, Gas Gangrene,

VOLUME 1 12 Arthropod Vectors of Medical

The Eye 150

SECTION IJ Syndromes by 17 Endophthalmitis 158

Skin and Soft Tissue 75 18 Infectious Retinitis and Uveitis 165

10 Cellulitis, Pyoderma, Abscesses, and Other

20 Encephalitis and Myelitis 189 34 Management of the Infected Cystic

21 Brain Abscess and Other Focal Pyogenic

22 Tetanus and Botulism 208 PP8 When to Use Corticosteroids in Noncentral

23 Transmissible Spongiform Encephalopathies

ROGER BAYSTON I IVAN PELEGRIN

PPIO Use of Antibiotics for Exacerbations of

The Gastrointestinal System 312

The Respiratory System 229 36 Gastritis, Peptic Ulceration and Related

37 Food-Borne Diarrheal Illness 328

31 Tuberculosis 271 42 Clinical Manifestations of Acute and Chronic

33 Fungal Pneumonias 292 PP12 Febrile Transaminitis of Viral Etiology 377

PPB Management of CAPD Peritonitis 380 55 Complications of Pregnancy: Maternal

43 Infective and Reactive Arthritis 382 56 Feta! Implications of Maternal Infections in

45 Infections of Prosthetic Joints and Related

Urinary Tract 523

57 Cystitis and Urethral Syndromes 523

58 Prostatitis, Epididymitis and Orchitis 532

59 Complicated Urinary Infection, Including

50 Myocarditis and Pericarditis 446

PP15 Mediastinitis and Sternal Sexually Transmitted Diseases 559

Obstetric and Gynecologic

53 Vaginitis, Vulvitis, Cervicitis and Cutaneous

54 Infections of the Female Pelvis, Including 64 Lymphogranuloma Venereum, Chancroid

65 Management of Gonorrhea 592 75 Bioterrorism and Biodefense 670

REBECCA A. LILLIS I DAVID H. MARTIN

Nosocomial Issues 684

76 Infectious Complications Following Surgery

67 Pathogenesis of Fever 605

68 Fever of Unknown Origin (FUO) 611

69 The Potential Role of Infectious

PP22 Infection-Related Hemophagocytic 79 Infections in the Cancer Patient 723

80 Infections in Hematopoietic Stem Cell

Environmental and Occupational 81 Heart, Lung and Heart-Lung

84 Kidney and Pancreas Transplant

85 Vasculitis and Other Immunologically 94 Opportunistic Infections: Management and

86 Splenectomy and Splenic Dysfunction 775 95 Immune Reconstitution Disorders in Patients

87 Vaccination of the lmmunocompromised

97 Neoplastic Disease 874

89 Epidemiology of HIV Infection 812

Prevention 824 100 HIV Infection in Children 900

90 Bio-behavioral Interventions to Prevent HIV

91 HIV Vaccines: Past Failures and Future

102 Principles of Management of HIV in the

PP33 Antiretroviral Management in Major Tropical Syndromes: Systemic

ll8 Schistosomiasis 1026

Principles of International ll9 Cestode and Trematode

106 Geography of Infectious Diseases 938

107 Travel Medicine 948

Major Tropical Syndromes: Skin and

109 Endemic Treponematoses 961 123 Leishmaniasis 1059

124 Chagas Disease (American

llO Human African Trypanosomiasis 966