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Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Readers are
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Library of Congress Cataloging-in-Publication Data

Pulmonary manifestations of pediatric diseases / [edited by] Nelson L.
Turcios, Robert J. Fink.--1st ed.
p. ; cm.
Includes bibliographical references.
ISBN 978-1-4160-3031-7
1. Pulmonary manifestations of general diseases. 2. Pediatric respiratory diseases. I. Turcios, Nelson L.
II. Fink, Robert J., 1948-
[DNLM: 1. Lung Diseases--etiology. 2. Adolescent. 3. Child. 4. Infant. 5. Lung Diseases--diagnosis.
6. Signs and Symptoms, Respiratory. WS 280 P9825 2009]
RJ431.P85 2009
618.920 2–dc22

Acquisitions Editor: Dolores Meloni

Developmental Editor: Elena Pushaw
Project Manager: Jagannathan Varadarajan
Design Direction: Steven Stave
Publishing Services Manager: Hemamalini Rajendrababu
Marketing Manager: Courtney Ingram

Printed in the United States of America

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


To my loving wife, Minnie, and to our children, Nelson, Jr., and Melissa, for
their love, patience, and encouragement during the preparation of “the book.”
To my parents, Aurora Trinidad and José Mártir, even when you are not here,
I know you are always with me. I miss you. To my sisters, Olga Nelly and
Lillian Marina, for their support. I also recognize that my participation in
editing this book was made possible only because of the lessons learned from
so many wonderful patients, families, and colleagues.

Nelson L. Turcios, M.D.

To my wife, Lois, who has always been at my side to support and encourage me
throughout my career. To my mother, Mary P. Fink, who instilled in me the love
of reading and academics. To my father, Dr. L. Jerome Fink, who introduced me
to the joys and rewards of a career in medicine. To all the parents who have
entrusted me with the care of their most precious children. And to my dream
for a cure for cystic fibrosis and for a world free of lung disease and pollution,
in which all children are born free, to live and breathe free.

Robert J. Fink, M.D.


Pediatric pulmonology can trace its roots to under discussion by the American Board of
the 1940s and 1950s when early pioneers in Pediatrics as to whether it should be recog-
the field recognized pediatric lung disorders nized as its own, distinct subspecialty. How-
as being significantly different from their ever, pediatric pulmonology, still in its
adult pulmonary counterparts. In 1938, nascent stages, was seen as lacking the
Dr. Dorothy Andersen published an autopsy knowledge base to distinguish it as a unique
series; it was the first to describe the combina- subspecialty. With this primary criticism,
tion of diarrhea, pancreatic abnormalities, and the application was denied.
pneumonia seen in young infants. She coined By the 1980s, the field had developed to
the name, “cystic fibrosis of the pancreas.” such an extent that its appeal to be recognized
Scarcely more than a decade later, in New as a boarded subspecialty was met with well-
York City, Dr. Paul A. di Sant’Agnese discov- deserved success. In 1985, pediatric pulmo-
ered the sweat defect of patients with cystic nology became an established subspecialty
fibrosis. This landmark finding would lead of the American Board of Pediatrics. The
to the development of the sweat test for first board examination was given on July 1,
the diagnosis of cystic fibrosis, a test which 1986, and 158 candidates were certified. Over
is still widely used today. the next 22 years, more than 500 pediatri-
In 1967, Dr. Edwin L. Kendig published cians have become board-certified pediatric
the first pediatric pulmonology textbook, pulmonologists.
Disorders of the Respiratory Tract in Children. Pediatric pulmonology now has a consid-
This decade was marked by the development erable presence at all major children’s hospi-
of the first comprehensive treatment pro- tals, not only in the United States, but
gram for cystic fibrosis in Cleveland, Ohio. worldwide. Diseases addressed by pediatric
The National Cystic Fibrosis (CF) Foundation pulmonologists include cystic fibrosis,
was formed and CF Centers began to develop asthma, chronic lung disease of prematurity,
at most children’s hospitals. The “CF Club” ventilator dependency, sleep disorders, pri-
began to hold annual conferences in conjunc- mary ciliary dyskinesias, recurrent pneumo-
tion with the SPR-APS (now Pediatric nia, interstitial lung disease, airway and
Academic Societies (PAS)). The CF Club (now pulmonary anomalies, lung transplantation,
the North American CF Conference) and and many other, less common conditions.
the American Thoracic Society conferences Pulmonary function testing, fiberoptic lar-
brought together physicians and researchers yngoscopy and bronchoscopy, genetic test-
who shared a common interest in CF, asthma, ing and counseling, and polysomnography
and pediatric lung disease. Many pediatric are some of the tools commonly used for
pulmonologists today still benefit from the the diagnosis and monitoring of pediatric
fellowship, intellectual stimulation, and sci- pulmonary disorders.
entific presentations at these conferences. The knowledge base of pediatric pulmo-
The 1970s saw the advent of more forma- nology has grown dramatically since the
lized fellowship programs in cystic fibrosis 1970s. Annually, hundreds of clinical and
and pediatric lung disease. Major advances research articles are published in peer-
were made in the diagnosis and treatment reviewed journals on various respiratory dis-
of pediatric asthma during this decade. For orders that affect the entire pediatric age
the first time, pediatric pulmonary physiol- group. Numerous textbooks are devoted
ogy was described, and pediatric pulmonary exclusively to cystic fibrosis, pediatric
function testing was developed and used asthma, pediatric interstitial lung disease,
to assess the clinical course of lung disorders sudden infant death syndrome, chronic
in children. Because of the tremendous lung disease of prematurity, sleep disorders,
advances in medical knowledge in the pediatric pulmonary function testing, and
1970s, pediatric pulmonology rapidly pediatric lung imaging. The “Bible” for
matured as a subspecialty. By the end of the every pediatric pulmonologist, Disorders of
decade, pediatric pulmonology was already the Respiratory Tract in Children, is now in

viii Preface

its 7th edition. Once criticized as an under- their field of expertise offer the reader the
developed field with an insufficient knowl- benefit of their accumulated insight and expe-
edge base, after a mere 30 years it has rience. The pulmonary manifestations of
become impossible for the modern pediatric pediatric extrapulmonary diseases are com-
pulmonologist to read all of the pertinent mon and often misdiagnosed. The authors of
literature in the subspecialty. the chapters in this book hope that their
As the body of medical information efforts lead to early recognition and prompt
grows and the field of pediatric pulmonol- treatment of this very variable, but important,
ogy matures, it has become increasingly evi- group of respiratory manifestations.
dent that even disorders and conditions not We also hope that this textbook will
primarily associated with the lung often become an invaluable reference for pediatric
have significant ramifications on lung func- pulmonologists, pediatricians, and other
tion and health. It is on these effects and health professionals not only to educate,
interactions that this textbook is focused. but also to improve patient care, for this
The first of its kind, Pulmonary Manifesta- has always been our most important
tions of Pediatric Diseases presents a fresh endeavor.
outlook on how the clinician can think
about diseases addressed in this textbook. Nelson L. Turcios, MD
Chapters contributed by some of the most Robert J. Fink, MD
distinguished and recognizable physicians in

I am pleased to take this opportunity to Senior Editor, for her extraordinary efforts
acknowledge my daughter Melissa, for her towards making this project possible, and
invaluable contributions. She spent more to Jagannathan Varadarajan, our Project
hours logged onto the computer and on the Manager, for his diligence and attention to
telephone during the editing and proofread- detail. Lastly, and most importantly, we must
ing of this book that I can’t thank her enough. also thank Ginny Doyle, Health Sciences
I am also grateful to Elizabeth Herron and Professional Representative, for her encour-
Linda Scott for their invaluable help in agement to pursue this enterprise.
finding pertinent literature. We also acknowledge the outstanding
We are particularly indebted to our many group of reviewers for their thoughtful
renowned and dedicated authors whose comments: Drs. Balu Athreya, Victor
scholarly and practical contributions repre- Chernick, Bernard Cohen, Marc Eberhardt,
sent the essence of this endeavor. Addition- Hugh E. Evans, Santiago Martinez, Seza
ally, the highly professional and devoted Ozen, Arnold C. G. Platzker, Jean-Paul
staff at Saunders/Elsevier merits our grati- Praud, José Salcedo, Girish Sharma, and
tude, in particular Elena Pushaw, our Edito- William W. Waring.
rial Assistant for her kind guidance,
technical knowledge, and unrelenting sup-
port. Our thanks also go to Dolores Meloni, Nelson L. Turcios, MD



Professor of Pediatrics – Neonatology, Baylor Assistant Professor of Pediatrics, University of
College of Medicine, Attending Neonatolo- Massachusetts Memorial Medical Center,
gist Director, Chronic Pulmonary Care Team, Worcester, Massachusetts
Texas Children’s Hospital, Houston, Texas Pulmonary Manifestations of Systemic Vasculitis
Chronic Lung Disease of Infancy


SHERMAN J. ALTER, M.D. Professor of Pediatrics, New York University
Associate Professor of Pediatrics, Boonshoft
School of Medicine, Director, Pediatric Gas-
School of Medicine Wright State University,
troenterology and Nutrition, Children’s
Director, Division of Pediatric Infectious Dis-
Medical Center, New York University, New
eases, Children’s Medical Center, Dayton, Ohio
York, New York
Pulmonary Manifestations of Parasitic Diseases
Pulmonary Manifestations of Gastrointestinal
Professor of Medicine and Pediatrics, UMDNJ-
New Jersey Medical School, Vice-Chairman, J. MARC MAJURE, M.D.
Department of Physical Medicine and Reha- Associate Clinical Professor of Pediatrics, Duke
bilitation, New Jersey Medical School-Univer- University, Attending Physician, Division of
sity Hospital, Newark, New Jersey Pediatric Pulmonary and Sleep Medicine,
Pulmonary Manifestations of Neuromuscular Duke University Medical Center, Durham,
Diseases North Carolina
Pulmonary Manifestations of Rheumatoid
Assistant Professor of Pediatrics – Section of
Neonatal – Perinatal Medicine, Baylor Col- CARLOS MILLA, M.D., M.P.H
lege of Medicine, Attending Neonatologist, Associate Professor of Pediatrics, Stanford Uni-
Texas Children’s Hospital, Houston, Texas versity, Attending Physician, Division of
Chronic Lung Disease of Infancy Pediatric Pulmonology, Children’s Hospital
Medical Center, Palo Alto, California
MICHAEL R. BYE, M.D. Pulmonary Manifestations of Endocrine and
Professor of Clinical Pediatrics, Columbia Uni- Metabolic Diseases
versity, Attending, Pediatric Pulmonary
Medicine, Morgan Stanley Children’s Hospi-
tal, New York- Presbyterian Hospital, New
Professor of Pediatrics, Duke University, Direc-
York, New York
Pulmonary Manifestations of Human Immunode- tor Pediatric Pulmonary and Sleep Medicine,
ficiency Virus (HIV) Infection Duke University Medical Center, Durham,
North Carolina
Pulmonary Manifestations of Rheumatoid
Attending Physician, Division Pediatric Hema-
tology and Oncology, Hospital J P Garrahan,
Buenos Aires, Argentina BRIAN P. O’SULLIVAN, M.D.
Pulmonary Manifestations of Hematologic and Professor of Pediatrics, University of
Oncologic Diseases Massachusetts, Director Cystic Fibrosis Cen-
ter, Associate Director Pediatric Pulmonology,
EDWARD FELS, M.D. University of Massachusetts Memorial Chil-
Fellow in Adult and Pediatric Rheumatology, dren’s Medical Center, Worcester,
Duke University Medical Center, Durham, Massachusetts
North Carolina Pulmonary Manifestations of Systemic
Pulmonary Manifestations of Rheumatoid Diseases Vasculitis

xii Contributors


Associate Professor of Pediatrics, UMDNJ-New Professor of Pediatrics – Neonatology, Baylor
Jersey Medical School, Attending Physician, College of Medicine, Chief, Neonatology
Center for Human Genetics & Molecular Service, Texas Children’s Hospital, Houston,
Biology, New Jersey Medical School – Uni- Texas
versity Hospital, Newark, New Jersey Chronic Lung Disease of Infancy
Pulmonary Manifestations of Genetic Diseases


Associate Professor of Pediatrics, Wright State
C.D. EGLA RABINOVICH, M.D., M.P.H University, Attending Pulmonologist, Divi-
Assistant Professor of Pediatrics, Duke Univer-
sion of Pediatric Pulmonology, The Chil-
sity, Attending Physician, Division of Pediat-
dren’s Medical Center, Dayton, Ohio
ric Rheumatology, Duke University Medical Pulmonary Manifestations of Immunosuppressive
Center, Durham, North Carolina Diseases other than Human
Pulmonary Manifestations of Rheumatoid Immunodeficiency Virus (HIV) Infection


RAUL C. RIBEIRO, M.D. Assistant Professor of Pediatrics, Keck School of
Director, Leukemia / Lymphoma Division, Medicine, University of Southern California
Director, International Outreach Program, at Los Angeles, Pediatric Cardiologist, Divi-
St Jude’s Children’s Research Hospital, Pro- sion of Pediatric Cardiology, Childrens Hos-
fessor, Pediatrics, College of Medicine, Uni- pital Los Angeles, Los Angeles, California
versity of Tennessee Health Science Center, Pulmonary Manifestations of Cardiac Diseases
Memphis, Tennessee
Pulmonary Manifestations of Hematologic and
Oncologic Diseases NELSON L. TURCIOS, M.D.
Director, Pediatric Pulmonology & Asthma Insti-
tute, Somerville, New Jersey, Attending Physi-
CARLOS RODRÍGUEZ-GALINDO, M.D. cian, Division of Pediatric Pulmonology/
Attending Physician, Division of Pediatric Cystic Fibrosis, UMDNJ- Robert Wood John-
Hematology and Oncology, St Jude’s son University Hospital, New Brunswick,
Children’s Research Hospital, Memphis, New Jersey
Tennessee Pulmonary Manifestations of Dermatologic
Pulmonary Manifestations of Hematologic and Diseases
Oncologic Diseases Pulmonary Manifestations of Parasitic Diseases
Pulmonary Manifestations of Renal Diseases


Assistant Consulting Professor of Medicine,
Assistant Professor of Pediatrics, Keck School
Division of Rheumatology and Immunology,
of Medicine, University of Southern
Duke University Medical Center, Durham,
California at Los Angeles, Attending Pulmo-
North Carolina;
nologist, Division of Pediatric Pulmonology,
Associate, Carolina Arthritis, Wilmington,
Childrens Hospital Los Angeles, Los Angeles,
North Carolina
Pulmonary Manifestations of Rheumatoid
Pulmonary Manifestations of Cardiac Diseases


ROBERT SIDBURY, M.D., M.P.H. Chair of Paediatrics and Child Health, Head of
Assistant Professor of Pediatrics, Harvard Med- Paediatric Pulmonology, School of Child
ical School, Attending Physician, Division of and Adolescent Health, University of Cape
Pediatric Dermatology, Children’s Hospital Town, Red Cross Childrens Hospital, Cape
of Boston, Boston, Massachusetts Town, South Africa
Pulmonary Manifestations of Dermatologic Pulmonary Manifestations of Human Immunode-
Diseases ficiency Virus (HIV) Infection

Chronic Lung Disease of Infancy


Historical Overview 1 Minimal Ventilation 14

Definitions of Bronchopulmonary High-Frequency Oscillatory Ventilation 14
Dysplasia 2 Vitamin A 15
Epidemiology 4 Systemic Corticosteroids 15
Pathogenesis 4 Inhaled Corticosteroids 16
Prenatal Events 5 Inhaled Nitric Oxide 16
Hyperoxia and Oxidant Stress 5 Caffeine 17
Mechanical Ventilation and Volutrauma 6 Superoxide Dismutase 17
Infection 6 Summary 17
Inflammation 7 Outcome 17
Bombesin-like Peptides 7 Mortality 17
Nutrition 7 Respiratory Infections 18
Genetic Factors 7 Pulmonary Function 18
Pathology 8 Neurodevelopment 18
Clinical Features 9 Growth 19
Physical Examination 9 Tracheobronchomalacia 19
Chest Radiograph 9 Glottic and Subglottic Damage 20
Clinical Course 9 Tracheal Stenosis, Bronchial Stenosis, or
Cardiopulmonary Function 10 Granuloma Formation 20
Management 11 Monitoring 21
Respiratory Care 11 Cardiovascular Monitoring and
Nutrition and Fluid Management 12 Oxygenation 21
Diuretics 12 Growth 21
Bronchodilator Therapy 13 Development, Vision, and Hearing 21
Corticosteroids 13 Coordination of Care and Discharge
Prevention 13 Planning 21
Antenatal Corticosteroids 13 References 22
Fluid Restriction 14

Historical Overview RDS and required prolonged mechanical ven-

tilation with high inflation pressures and
Bronchopulmonary dysplasia (BPD) or inspired oxygen concentrations. The pathol-
chronic lung disease of the premature com- ogy was characterized by abnormalities of
prises a heterogeneous group of respiratory the terminal airways, the hallmark of which
diseases of infancy that usually evolve from was an intense interstitial fibrosis and hy-
an acute respiratory disorder experienced by perplasia of the smooth muscle (Fig. 1-1).
a newborn. Chronic lung disease of the pre- Affected infants experienced chronic respira-
mature most commonly occurs in infants tory failure, with hypoxemia and hyper-
with birth weights less than 1500 g, and capnia, and many developed cor pulmonale.
especially in infants with birth weights less More recently, as the use of antenatal ster-
than 1000 g and who are treated for respira- oids and surfactant replacement therapy has
tory distress syndrome (RDS). This entity was resulted in increased survival of smaller pre-
first described by Northway and colleagues1,2 term infants, the features of the so-called
in 1967 in premature infants who had severe new BPD differ from the older descriptions

2 Pulmonary Manifestations of Pediatric Diseases

Figure 1-1. A, Classic bron-

chopulmonary dysplasia in a
9-month-old, former premature
(25 weeks gestation) infant. Micro-
scopically, there is marked hyper-
expansion of airspaces
compressing adjacent paren-
chyma. Focal interstitial fibrosis
also is noted. (Hematoxylin and
eosin, 20.) B, Secondary pulmo-
nary hypertension in the same
patient is reflected microscopically
by marked muscularization of the
normally thin-walled intralobular
arterioles. (Hematoxylin and eosin,
100.) C, Classic bronchopulmon-
ary dysplasia in a 2-year-old, former
premature (26 weeks gestation)
infant. The lungs grossly show
hyperinflated pale areas alternating
with areas of collapse and pleural
retraction, producing pseudofis-
sures. (Courtesy of Megan K. Dishop,
MD, Department of Pathology, Texas
Children’s Hospital and Baylor Col-
lege of Medicine, Houston, TX.)

and include milder respiratory distress that dysplasia” (BPD) and “chronic lung disease of
often requires minimal ventilatory support infancy” (CLDI) are sometimes used inter-
with low fractions of inspired oxygen changeably to describe chronic respiratory
(FiO2) preceding the chronic condition.3-6 disease after treatment for RDS in preterm
Pathologic examination typically shows an infants. A working definition of BPD is neces-
arrest in pulmonary development and sary because it is from BPD that most cases of
alveolarization, with simplification of the CLDI arise. Three clinical definitions have been
terminal airways (Fig. 1-2). used to define BPD in neonates, as follows:
• Oxygen requirement at 28 days postnatal
Definitions of • Oxygen requirement at 36 weeks post-
Bronchopulmonary Dysplasia menstrual age (PMA)9,10
• Diagnostic criteria proposed by a National
The terminology used to describe chronic Institute of Child Health and Human
lung disease arising from neonatal insults is Development (NICHD) workshop based
confusing. The terms “bronchopulmonary on gestational age and disease severity11,12

Figure 1-2. A, Normal lung in a 2-year-old, former term (38 weeks gestation) infant. (Hematoxylin and eosin, 20.)
B, Chronic neonatal lung disease with “new” bronchopulmonary dysplasia pattern in an 8-month-old, former premature
(29 weeks gestation) infant. The lung architecture is altered with diffuse mild enlargement of airspaces with simplification
and deficient septation. (Hematoxylin and eosin, 20.) (Courtesy of Megan K. Dishop, MD, Department of Pathology, Texas
Children’s Hospital and Baylor College of Medicine, Houston, TX.)
Chapter 1 — Chronic Lung Disease of Infancy 3

In the 1990s, several studies showed that • Patients who are less than 32 weeks gesta-
administration of supplemental oxygen at tion are assessed at 36 weeks PMA or
36 weeks PMA rather than 28 days postnatal when discharged home, whichever comes
age more accurately predicted abnormal first.
pulmonary outcome at 2 years of age.9,10 In • Patients who are equal to or greater than
one study, the positive predictive value for 32 weeks gestation are assessed at 29 to
abnormal outcome in very-low-birth-weight 55 days of life or when discharged home,
(VLBW) infants (birth weight <1,500 g) whichever comes first.
(63% versus 38%) was better for supplemen- At the time of assessment, patients are
tal oxygen administration at 36 weeks PMA evaluated for the severity of their disease.
than at 28 postnatal days.10 Outcome was Infants who received treatment with sup-
normal in 90% of infants who did not receive plemental oxygen for at least 28 postnatal
oxygen at 36 weeks PMA. As a result, the def- days are classified as having mild, moderate,
inition of BPD as requiring administration or severe BPD, depending on the extent of
of supplemental oxygen at 36 weeks PMA oxygen supplementation and other respira-
became widely used. tory support.11
A precise definition of BPD is especially In a study from the NICHD Neonatal
important when outcomes are compared Research Network of infants with BPD who
among different centers or when new thera- were born at less than 32 weeks gestational
peutic interventions are tested. The increased age and with birth weight less than 1000 g,
survival of extremely-low-birth-weight (ELBW) these criteria predicted pulmonary and neuro-
infants (birth weight <1,000 g or gestational developmental outcomes at 18 to 22 months
age <30 weeks) suggested that the definition corrected age.11 The severity of BPD (mild,
of BPD could be refined to include infants moderate, severe) was associated with use of
with milder disease and account for develop- pulmonary medications (30%, 41%, 47%)
mental changes that occur with increasing and rehospitalization for pulmonary disease
gestational age. In 2001, the NICHD work- (27%, 34%, 40%). The incidence of any
shop proposed diagnostic criteria for BPD that neurodevelopmental impairment, including
included gestational age and disease severity cerebral palsy, blindness, hearing deficit re-
(Table 1-1).12 This scheme divides patients quiring amplification, and lower mental and
into the following two groups based on gesta- psychomotor development index scores,
tional age, which determines the timing of also increased with the severity of BPD.
clinical assessment for BPD: The patients who had severe BPD often

Diagnostic Criteria for Bronchopulmonary Dysplasia Proposed by National Institute of

Table 1-1 Child Health and Human Development Workshop

Time of 36 wk PMA or discharge to home* >28 days but <56 days postnatal age or
assessment discharge to home*
Mild CLD Treatment with oxygen >21% for at least Breathing room air by 56 days postnatal age or
28 days plus discharge*
Breathing room air at 36 wk PMA or
Moderate CLD Need{ for FiO2 <30% at 36 wk PMA or Need{ for FiO2 <30% at 56 days postnatal age or
discharge* discharge*
Severe CLD Need{ for FiO2 30% and/or positive Need{ for FiO2 30% and/or positive pressure
pressure (IPPV or NCPAP) at 36 wk PMA or (IPPV or NCPAP) at 56 days postnatal age or
discharge* discharge*

*Whichever comes first.

At the time of the workshop, a physiologic test to confirm oxygen requirement had yet to be defined.
CLD, chronic lung disease of the premature; IPPV, intermittent positive-pressure ventilation; NCPAP, nasal continuous positive
airway pressure; PMA, postmenstrual age.
From Jobe AH, Bancalari E: Bronchopulmonary dysplasia. Am J Respir Crit Care Med 163:1723-1729, 2001.
4 Pulmonary Manifestations of Pediatric Diseases

had substantial associated morbidity during levels for acceptable oxygen saturation.16
their hospitalization at birth, such as severe The overall incidence of BPD was 23% of
intraventricular hemorrhage (25%), peri- the VLBW infants, and increased with
ventricular leukomalacia (10%), necrotizing decreasing birth weight. Compared with
enterocolitis (14%), late-onset infection the entire cohort, there were increased pro-
(54%), and postdischarge deaths (5%), and portions of males with BPD and severe BPD
were often treated with postnatal corticos- (54% for entire cohort, 60% for males with
teroids (78%). In this cohort, many infants BPD, and 67% for males with severe BPD).
who needed oxygen during the first 28 days In an 8-year (1994 to 2002) retrospective
of life no longer required oxygen at 36 weeks cohort study of six NICUs, the overall inci-
PMA and might not have been classified dence of BPD remained constant at 12%
as having BPD. This study did not include for preterm infants born before 33 weeks
an objective physiologic measure of oxygen gestation.17 Although there has been no
requirement, however. These criteria, espe- change in the overall incidence of BPD,
cially with the addition of a physiologic test, there has been a significant decline in the
may improve the ability to compare thera- incidence of severe BPD, from 10% in 1994
peutic interventions in clinical trials and to 4% in 2002, with severe BPD defined as
evaluate long-term outcomes. requiring positive-pressure respiratory sup-
In most neonatal intensive care units port (i.e., mechanical ventilation or contin-
(NICUs), supplemental oxygen is adjusted uous positive airway pressure [CPAP]) at 36
to maintain the infant’s oxygen saturation weeks PMA. The risk for any degree BPD
within a target range. As a result, the use of increases with mechanical ventilation, as
supplemental oxygen depends partly on described in a case-cohort study conducted
the NICU policy for the target range, which at two centers (two Boston hospitals and
varies among centers. To standardize the use Babies’ and Children’s Hospital in New
of supplemental oxygen, the NICHD work- York), in which the higher rate of BPD in
shop also proposed that the need for oxygen Boston (22% versus 4%) reflected the higher
less than or greater than 30% be confirmed rate of mechanical ventilation (75% versus
by a physiologic test. Such a test was devel- 29%) and surfactant administration (45%
oped, based on oxygen administration and versus 10%) as part of the initial respiratory
oxygen saturation, including a timed room management of VLBW infants.16 The risk of
air challenge in selected patients. It was BPD increases with decreasing birth weight.
found to be safe, feasible, and reliable.13 In BPD is rare in infants older than 32 weeks
a prospective multicenter study of VLBW gestation.
infants who remained hospitalized at 36
weeks PMA,14 fewer infants had BPD when
the physiologic definition was used (25% Pathogenesis
versus 35%) compared with the clinical
definition (oxygen supplementation at 36 The etiology of BPD is multifactorial.
weeks PMA), and there was less variation Inflammation caused by mechanical venti-
among centers. lation, oxygen toxicity, or infection plays
an important role. The lung seems to be
most vulnerable before the saccular stage
Epidemiology of development, which occurs at approxi-
mately 31 to 34 weeks gestation, and during
The rate of BPD varies among institutions. which alveolar formation is initiated.18,19
In a report from the NICHD Neonatal The preterm lung is especially at risk of
Research Network (1995 to 1996), the rate injury because of its structural and func-
of BPD ranged from 3% to 43% in the 14 tional immaturity. Lungs in preterm infants
participating centers.15 Variability in inci- have poorly developed airway supporting
dence among centers may reflect neonatal structures, surfactant deficiency, decreased
risk factors or care practices, such as target compliance, underdeveloped antioxidant
Chapter 1 — Chronic Lung Disease of Infancy 5

mechanisms, and inadequate fluid clearance airway remodeling, hyperreactivity, and

compared with term infants.20 inflammatory alterations similar to that
seen in BPD.28 Higher degrees of hyperoxia
(FiO2 0.95) for shorter durations (72
Prenatal Events hours) result in inhibition of distal airway
branching with simplification of architec-
Many events that occur before birth affect
ture in fetal mouse lung explants.29
the development of the lung. In infants less
The imbalance between pro-oxidant and
than 27 weeks gestation—the period of high-
antioxidant systems in a preterm neonate in
est risk for development of BPD—the human
favor of pro-oxidant processes also may
lung is in the saccular stage of development;
contribute to the development of BPD.30-32
alveolarization begins at approximately 32
Preterm infants have few antioxidant
weeks and proceeds through 40 weeks
defenses and are often exposed to supple-
PMA.21 Any factor that has an adverse effect
mental oxygen to treat pulmonary insuffi-
on this process leads to disruption of lung
ciency. They also are prone to infection, and
architecture and alveolar simplification, a
many of the proinflammatory cytokines
hallmark of the “new BPD.”22
activate the production of reactive oxygen
Inflammation, as discussed later, is consid-
species (ROS), such as superoxide free radi-
ered one of the central aspects in the patho-
cal, hydrogen peroxide, hydroxyl free radical,
genesis of BPD. Several studies suggest that
and singlet oxygen, which are produced
the timing, the type, and the intensity of the
as the result of oxidative stress. In addition,
inflammatory response that determine the
preterm infants have higher plasma and
subsequent effects on the developing preterm
tissue-free iron concentrations compared
lung.23 A series of studies in fetal rabbits and
with term infants, which can promote the
fetal sheep showed that intra-amniotic expo-
propagation of ROS.
sure to interleukin (IL)-1 or endotoxin accel-
The toxicity of these ROS, particularly
erated lung maturation and the synthesis
in response to exposure to hyperoxia, has been
of surfactant proteins.24 In these studies,
shown in experimental animals; when
repeated exposure to proinflammatory agents
exposed to equal to or greater than 0.50 FiO2,
did not cause progressive inflammation, but
they exhibited irreversible changes in lung
rather induced tolerance and suppression of
growth and DNA synthesis.32 At the cellular
fetal monocyte function.25 If IL-1 or endo-
level, ROS cause the uncoupling of respira-
toxin treatment was done with two doses,
tion from adenosine triphosphate (ATP) syn-
given 7 days apart, the fetal monocytes
thesis and disruption of the outer mito-
reacted in a manner similar to that seen in
chondrial membrane. Subsequently, this
adult sheep.25 Concomitant treatment with
disruption allows release of pro-apoptotic fac-
corticosteroids and IL-1 or endotoxin initially
tors, such as cytochrome-c, apoptosis-inducing
suppressed the inflammatory response, but
factor, and pro-caspases, from the mitochon-
caused an exaggerated inflammatory response
dria into the cytosol, leading to cell death.31
at 5 to 15 days post-treatment.26,27 Antenatal
Various antioxidant defenses are available
exposure to endotoxin and corticosteroids
in mature human organisms to combat this
modulates lung injury and maturation in a
oxidative stress. They include superoxide
time-dependent manner.
dismutase, catalase, glutathione-S-transfer-
ase (GST), and glutathione peroxidase, and
Hyperoxia and Oxidant Stress nutrients such as vitamins A and E, iron,
copper, zinc, and selenium, which help pre-
High concentrations of inspired oxygen can vent oxygen toxicity. Preterm infants have
damage the lungs, although the exact level inadequate antioxidant defenses and are at
or duration of exposure that is unsafe is risk of oxygen free radical damage. In some
unknown. In a study conducted in neonatal species, antioxidant enzyme concentrations
rats, exposing neonatal rat pups to moder- are lower in preterm than term animals,33
ate hyperoxia (FiO2 0.50) for 15 days caused and are poorly induced in response to
6 Pulmonary Manifestations of Pediatric Diseases

oxidative stress.34 Similarly, activities of with lower tidal volumes (5 mL/kg and
catalase, glutathione peroxidase, and copper/ 10 mL/kg).44
zinc superoxide dismutase in human cord In two retrospective cohort studies (n ¼ 235
blood are lower in preterm than in term and n ¼ 188), the authors found that increased
newborns.35 In a small study of preterm ventilation resulting from large tidal volumes
infants (gestational age 25 to 30 weeks), cop- resulted in hypocarbia, a risk factor for
per/zinc superoxide dismutase levels were subsequently developing BPD.7,45 In vitro
greater in infants who subsequently devel- cyclic cell stretch has been shown to upregu-
oped BPD; these infants also had a higher late the expression of proinflammatory cyto-
cumulative oxygen exposure.36 These results kines by human alveolar epithelial cells
suggest that in preterm infants with BPD, without any structural cell damage.46,47 Tidal
superoxide dismutase activity is upregulated volumes large enough to cause similar cell
and may be a marker for increased oxygen stretch in vivo, without causing structural
exposure and potentially increased reactive damage, may similarly initiate the cascade
oxygen metabolites. of proinflammatory cytokines, recruiting
inflammatory cells and causing tissue dam-
age. All of the above-described pulmonary
Mechanical Ventilation and insults occur at a time when most preterm
Volutrauma infants have a relative adrenocortical insuffi-
ciency, which may potentiate the inflamma-
Lung injury associated with mechanical ven- tory effects.
tilation contributes to the development of
BPD, and it is known that positive-pressure
ventilation typically induces bronchiolar Infection
lesions.37 Pulmonary interstitial emphysema
is a result of barotrauma and is associated Although the role of infection is incompletely
with a high incidence of CLDI. understood, infants exposed to antenatal and
Disruption of airways may occur early in postnatal infection seem to be at higher risk
the course of treatment and may be mani- for developing BPD.46 Antenatal chorioam-
fested by increased pulmonary resistance.38 nionitis may play a key role in the production
In one study of ventilated preterm infants of a fetal pulmonary inflammatory response
in the first 5 days after birth, mean pulmo- to the release of proinflammatory cyto-
nary resistance was significantly greater in kines.48,49 This response can lead to aberrant
infants who subsequently developed BPD wound healing and fibrosis, causing inhibi-
compared with infants who did not.39 tion of alveolarization and vascular develop-
Animal studies suggest that volutrauma is ment, hallmarks of the new BPD. Similarly,
more important than barotrauma in causing infants who developed late-onset sepsis (>3
airway injury.16,18,40 Distention of the air- days of age) were more likely to need long-
ways to near-maximum lung volume causes term mechanical ventilation, and were more
shear injury, capillary leak, and pulmonary likely to develop BPD.50 In a retrospective
edema.41,42 In studies in preterm lambs and study, early tracheal colonization also pre-
rabbits and in adult rats, animals given large disposed to the subsequent development
tidal volume breaths had significantly worse of BPD.51
pulmonary mechanics and showed histologic Nosocomial infection plays a role in some
evidence of widespread lung injury.37,43,44 In cases of CLDI, especially in association with
newborn lambs, large tidal volumes seem to a symptomatic patent ductus arteriosus PDA,
impair the response to subsequent surfactant particularly in ELBW infants. In a series
administration.44 In one study, preterm of 119 ELBW infants who had mild or no
lambs ventilated with large tidal volumes initial RDS, BPD was significantly more
(20 mL/kg) showed lower compliance, lower likely to occur with patent ductus arteriosus
ventilatory efficiency, higher recovery of (odds ratio [OR] 6.2) and sepsis (OR 4.4).52
protein, and lower recovery of surfactant The risk of BPD increased substantially in
by 6 hours compared with animals ventilated infants with both conditions (OR 48.3).
Chapter 1 — Chronic Lung Disease of Infancy 7

Neither ductal ligation nor prophylactic use disorder.59,60 In infants 28 weeks gesta-
of low-dose indomethacin initiated in the tional age, elevated urine BLP levels in the
first 24 hours has been shown to reduce sig- first 4 days after birth were associated with
nificantly the incidence of CLDI, however. an increased risk of BPD.61
Specific organisms also may play a role. In
one report, development of BPD was asso-
ciated with isolation of Ureaplasma urealyti- Nutrition
cum in tracheal aspirates performed on the
Premature infants have very poor nutritional
first (before surfactant administration) and
reserves and are at high risk for being mal-
fourth days of mechanical ventilation in
nourished and entering a catabolic state if
infants less than 28 weeks gestational age.53
not provided with adequate nutrition. The
goal of postnatal nutrition is to provide ade-
Inflammation quate substrate to approximate the intrauter-
ine rate of growth. In VLBW infants, this
Macrophages, lymphocytes, and platelets in goal can be extremely difficult to achieve for
the lung release multiple inflammatory me- the following reasons62:
diators, including cytokines, lipid mediators, • Fluid restriction to prevent pulmonary
and platelet factors, which interact with endo- edema
thelial and epithelial cells.54 The airspaces of • Heart failure secondary to a patent ductus
ventilated preterm infants contain many arteriosus
proinflammatory and chemotactic factors that • Use of postnatal corticosteroids
are present in greater concentration in infants • Decreased gastrointestinal absorption sec-
who subsequently develop BPD.12,54-57 The ondary to suspected or proven necrotizing
presence of these mediators is associated with enterocolitis
complement activation, increased vascular • Hypoxia and chronic respiratory acidosis
permeability, protein leakage, and mobiliza- • Anemia of prematurity
tion of neutrophils into the interstitial and • Medications that increase metabolic
alveolar compartments. Release of ROS, rate, such as methylxanthines and b-
elastase, and collagenase by activated neutro- sympathomimetics
phils can damage lung structures. Interaction Malnutrition or undernutrition renders an
between macrophages and other cell types infant more susceptible to injury resulting
may perpetuate the production of proinflam- from hyperoxia, volutrauma/barotrauma,
matory mediators and sustain the cycle of and infections, and impairs the infant’s abil-
lung injury. Persistence of factors such as mac- ity to recover from this injury.63 In addition,
rophage inflammatory protein-1 and IL-8 and infants with BPD are significantly more
decreases of counter-regulatory cytokines likely to have lower early protein and total
such as IL-10 may lead to unregulated and energy intake.64
persistent inflammation.12
Genetic Factors
Bombesin-like Peptides
The pathogenesis of BPD is complex, with an
Injury may be mediated partly by bombe- intricate interaction of preterm birth, the in
sin-like peptides (BLP), which are derived utero environment, inflammation/infection,
from pulmonary neuroendocrine cells and fluid management, vascular maldevelop-
play an important role in normal lung ment, surfactant deficiency, mechanical ven-
growth and maturation. In one study, the tilation, the balance of oxidative stress and
number of BLP-positive cells was greater in antioxidant systems, and nutrition. Not all
infants who died with BPD than in con- factors are required to develop BPD, and
trols.58 In a baboon model, urine BLP levels severe BPD may develop in infants who have
were increased soon after birth in animals a benign perinatal course. It had been postu-
who developed BPD, and administration lated that there might be a genetic predis-
of anti-BLP antibody attenuated the position to develop BPD. Several studies
8 Pulmonary Manifestations of Pediatric Diseases

have looked at the development of BPD in Finally, the role of allelic variants of vari-
singleton and multiple gestation VLBW ous surfactant proteins in the development
infants.65-69 In the earliest study comparing of RDS and BPD has been explored. Specifi-
the rate of BPD among 108 VLBW twins, it cally, the surfactant protein A (SP-A) allele
was reported that BPD in one twin signifi- 6A-6 is more common in infants with
cantly predicted BPD in the other twin BPD.78 Many loss-of-function mutations of
(adjusted OR 12.3, P <.001), even after adjust- the surfactant protein B (SP-B) gene have
ing for birth weight, gestational age, gender, been reported. The clinical phenotype can
RDS, pneumothorax, and patent ductus vary, ranging from chronic respiratory fail-
arteriosus.67 More recently, in a multicenter ure to refractory hypoxic respiratory failure
retrospective study of 450 twin pairs born at in the neonatal period.79-81 One group
32 weeks, the concordance of BPD was higher looked at polymorphisms in intron 4 of
in monozygotic twins than predicted, after the SP-B gene. They found that BPD was
controlling for all covariates. more common in infants who had the poly-
In addition to twin studies, many other morphisms in intron 4.82 The definition of
investigators have attempted to look for can- BPD that they used was that of oxygen
didate genes that may predispose to develop- requirement at 28 postnatal days, however;
ing BPD. Genes involved in the differential if the definition of oxygen requirement at
regulation of lung development and the 36 weeks PMA was used, there were no dif-
response to lung injury have been probed to ferences in the wild-type versus the intron
determine whether they participate in the 4 variants.
pathogenesis of BPD. Two separate studies
looking at polymorphisms of angiotensin-
converting enzyme (ACE) hypothesized that Pathology
increased ACE activity, leading to increased
aldosterone production and increased water In surfactant-treated ELBW infants, the char-
retention, would increase the incidence of acteristic pathologic finding of BPD is disrup-
BPD. Kazzi and Quasney70 found that the tion of lung development.12 Decreased
polymorphism that conferred increased ACE septation and alveolar hypoplasia lead to
activity showed increased incidence of BPD, fewer and larger alveoli. Reduced microvas-
whereas Yanamandra and colleagues71 did cular development also may occur. These
not find an association between ACE activity changes have been observed in infants who
and incidence of BPD. died of BPD,83 biopsy specimens from severely
Other groups have examined the role of affected infants, and a baboon model of the
polymorphisms in the gene encoding for disorder.18 These findings are in contrast to
GST. GST is an innate defense mechanism BPD seen in infants before the availability of
against ROS and is found in various human surfactant replacement therapy. The promi-
tissues. A polymorphism of the GST-P1 gene nent pathologic findings in those cases were
produces two isoforms, one of which is airway injury, inflammation, and parenchy-
significantly more efficient in eliminating mal fibrosis.12,83 Similar changes may be seen
oxidative toxins.72,73 In a small pilot study in surfactant-treated infants who develop
of 35 infants with BPD, it was shown that severe BPD. In severely affected infants, fibro-
infants who developed BPD were more likely sis, bronchial smooth muscle hypertrophy,
to have the less efficient form of the and interstitial edema may be superimposed
enzyme.74 Groups that have attempted to on the characteristic reduced numbers of
determine the role of various polymorphisms alveoli and capillaries. Pulmonary vascular
of the anti-inflammatory cytokines IL-4 changes, such as abnormal arterial musculari-
and IL-10, the anti-inflammatory transform- zation and obliteration of vessels, may occur.
ing growth factor-b (TGF-b), and the Lung injury also is associated with in-
proinflammatory chemokine monocyte che- creased elastic tissue formation and thick-
moattractant protein-1 have found no asso- ening of the interstitium. These tissue
ciation between allelic variants and the deformations may compromise septation
development of BPD.75-77 and capillary development. Disturbed
Chapter 1 — Chronic Lung Disease of Infancy 9

elastic tissue maturation was shown in a Physical Examination

study of 44 infants, 23 to 30 weeks gesta-
tional age, who died at 5 to 59 days of The physical examination is variable. Infants
age.84 In infants with high respiratory scores usually are tachypneic, and depending on
computed from supplemental oxygen con- the extent of pulmonary edema or atelectasis
centration and mean airway pressure, the or both, they may have mild to severe retrac-
volume, density, and absolute quantity of tions, and crackles may be audible. Intermit-
elastic tissue were significantly greater than tent expiratory wheezing may be present in
those of infants with low scores or control infants with increased airway reactivity.
infants. Alveolar and duct diameters and
septal thickness also were greater. With
increased elastic tissue content and thick-
Chest Radiograph
ened interstitium, the lungs tend to collapse As BPD evolves, the chest radiograph becomes
at end expiration and have a low functional diffusely hazy, reflecting inflammation or pul-
residual capacity (FRC). monary edema or both (Fig. 1-3A), with low
to normal lung volumes. There may be areas
of atelectasis that alternate with areas of gas
Clinical Features trapping, related to airway obstruction from
secretions or other debris. The chest radio-
BPD predominantly affects ELBW infants, graph in infants who develop severe BPD
and most affected infants are ventilator- shows hyperinflation (Fig. 1-3B). Streaky den-
dependent from birth with severe RDS sities or cystic areas may be prominent,
requiring surfactant therapy. The evolution corresponding to fibrotic changes. During
to BPD typically is recognized at approxi- acute exacerbations, pulmonary edema may
mately 2 weeks of age as pulmonary func- be apparent (Fig. 1-3C).
tion deteriorates rather than improves. The
infant remains ventilator-dependent, and
the concentration of supplemental oxygen Clinical Course
must be increased to maintain adequate
oxygen saturation. Wide swings in oxygena- Most infants improve gradually during the
tion may occur, likely caused by intermit- next 3 to 4 months. As pulmonary function
tent atelectasis. improves, infants can be weaned to CPAP,

Figure 1-3. A, Chest radiograph

of a former preterm (25 weeks ges-
tation) infant on day of life (DOL)
10, with evolving lung disease.
The diffuse haziness indicates pul-
monary edema or inflammation or
both. B, Chest radiograph of the
same infant, now on DOL 285,
A B with a tracheostomy tube in place.
Note the extreme degree of hyper-
inflation and air trapping. Also
evident are diffuse interstitial mark-
ings representing areas of fibrosis.
C, Chest radiograph of the same
infant, now on DOL 317. Cystic
areas can be seen with hyperinfla-
tion, prominent lung markings,
and areas of opacification, nearly
obliterating bilateral heart borders.
Significant pulmonary edema also
C is present, as seen by the marked
diffuse bilateral haziness.
10 Pulmonary Manifestations of Pediatric Diseases

then supplemental oxygen alone, until they Cardiopulmonary Function

can maintain adequate oxygenation breath-
ing room air. Some infants develop severe Abnormalities of pulmonary function in
BPD that leads to prolonged ventilator severe BPD include decreased tidal volume,
dependence. The clinical course during the increased airway resistance, and low dynamic
first few weeks after birth includes marked lung compliance, which become frequency
instability with frequent changes in oxyge- dependent. Uneven airway obstruction leads
nation and intermittent episodes of acute to air trapping and hyperinflation with
deterioration requiring increased ventilator abnormal distribution of ventilation.86
support. The marked instability typically Bronchomalacia can result in airway collapse
improves after 4 to 6 weeks. during expiration, and severely affected in-
Severely affected infants may develop pul- fants can have hypoxemia and hypercapnia.
monary hypertension and cor pulmonale.85 Pulmonary vascular resistance is increased
Elevated pulmonary vascular resistance may because of reduced cross-sectional area of
impair pulmonary lymphatic drainage and pulmonary vessels (Fig. 1-4). In addition,
exacerbate interstitial edema. In some cases, alveolar hypoxia in underventilated areas
anastomoses develop between pulmonary of the lung induces local vasoconstriction.
and systemic vessels that may worsen the Intact vessels in well-ventilated areas of the
pulmonary hypertension.85 lung accept a disproportionate amount of

Q = 0.33 V = 0.33

Q = 0.33 H 2O
Right Left
V = 0.33 heart
Q = 0.33 H2O

Lymphatics V = 0.33
Figure 1-4. A, Schematic H2O H 2O
representation of the inter- H2O
action of the heart and lungs
in a normal infant. The pul- A
monary vascular resistance
is low, and matching of ven-
tilation (V) and perfusion Q=0 V=0
(Q) is uniform. Interstitial Obliterated
fluid is cleared effectively
by pulmonary lymphatics.
B, Derangements of the
heart-lung interaction in
bronchopulmonary dyspla-
sia. There is mismatching of Q = 0.7
ventilation (V) and perfusion Right Left
heart V = 0.9 heart
(Q) with gas trapping. Pul-
monary vascular resistance Q = 0.3 H2O H2O
is elevated because of vascu-
lar obliteration and regional
hypoxic vasoconstriction.
Increased capillary filtration V = 0.1
produces interstitial edema, H2O H2O H2O H2O H2O H2O H2O H2O
and lymphatic drainage of
the lung is impaired by ele-
vated right heart pressures. B
Chapter 1 — Chronic Lung Disease of Infancy 11

pulmonary blood flow. Because these vessels strategy did not change the relative risk of
are already fully recruited and dilated, the death or BPD at 36 weeks PMA, the primary
additional flow results in elevated pressure outcome.90 Although the very low tidal
and increased right ventricular afterload. The volumes associated with high-frequency oscil-
high microvascular pressure promotes latory ventilation (HFOV) might be expected
increased fluid filtration into the perivascular to reduce the rate of BPD, only one of two
interstitium. Elevated right atrial pressure large trials comparing HFOV and conven-
inhibits pulmonary lymphatic drainage, tional ventilation in patients at the highest
further promoting pulmonary edema. risk showed an effect.91,92 This finding sug-
gests that routine initial use of HFOV gener-
ally is not warranted.
Management The most appropriate range of arterial oxy-
genation in preterm infants with acute or
The management of infants with BPD chronic respiratory failure is unknown. High
begins with prevention, attempting to avoid levels of oxygen saturation seem to offer no
or minimize contributory factors. advantages, however, and pulmonary injury
may result from the increased concentration
of supplemental oxygen required to maintain
Respiratory Care higher saturations, as shown by two studies.
In the STOP-ROP trial, providing supplemen-
Respiratory care of an infant with developing tal oxygen to maintain higher compared with
or established BPD is supportive and should routine oxygen saturation (96% to 99% versus
aim to minimize additional lung injury by 89% to 94%) in infants with prethreshold
judicious use of mechanical ventilation and retinopathy of prematurity did not reduce
supplemental oxygen. Early use of continu- progression to threshold retinopathy of pre-
ous distending pressure in at-risk infants maturity or the need for peripheral retinal
reduces the need for subsequent positive- ablation.93 The incidence of pulmonary
pressure ventilation.87 The COIN trial com- events, including pneumonia/exacerbation
pared CPAP with mechanical ventilation in of BPD, and the need for oxygen, diuretics,
infants born at 25 to 28 weeks gestation. In and hospitalization at 3 months corrected
a preliminary report, the authors found that age was higher, however, in the higher satura-
there were no significant differences in the tion group. Similarly, in the BOOST trial, in
incidence of BPD (oxygen treatment at 36 infants less than 30 weeks gestation who were
weeks PMA), days of respiratory support, oxy- oxygen dependent at 32 weeks PMA, no
gen treatment, hospital stay, incidence of differences were detected in growth and
grade III or IV intraventricular hemorrhage, neurodevelopment at 12 months corrected
cystic periventricular leukomalacia, or home age—the primary outcomes—between the
oxygen use.88 There was an increased rate of groups maintained at high (95% to 98%) or
pneumothorax in the CPAP group. standard (91% to 94%) oxygen saturation
If mechanical ventilation is needed, the ranges.94 Infants in the high saturation group
lowest peak airway pressure necessary to ven- received oxygen for a longer time, however,
tilate adequately should be used, and large and had higher rates of oxygen dependence
tidal volumes should be avoided. Although at 36 weeks PMA and home oxygen therapy.
this strategy is supported by few data in Respiratory management in infants with
human neonates, the use of lower than rou- developing or established BPD should ensure
tine tidal volumes decreased mortality and adequate tissue oxygenation to promote
increased the number of ventilator-free days growth and prevent pulmonary arterial hyper-
in adults with acute respiratory distress syn- tension that can result from chronic hypox-
drome.89 In addition, in a multicenter trial emia, and should minimize lung injury from
conducted by the NICHD Neonatal Research excessive oxygen levels or mechanical ventila-
Network, the need for ventilator support at tion. Although the safest levels are unknown,
36 weeks PMA was significantly lower in the oxygen saturation is generally maintained in
minimal ventilation group, although this the 85% to 95% range, with PaO2 greater than
12 Pulmonary Manifestations of Pediatric Diseases

50 mm Hg, and PaCO2 should be allowed to strong correlation between low vitamin E
increase to 50 to 60 mm Hg or possibly even levels in the cord blood and on the third
higher in infants with the most severe disease day of life and the subsequent development
as long as the pH is normal. When the infant of BPD,102 but further studies are needed
is able to maintain adequate PaCO2 and PaO2 before the routine use of vitamin E supple-
on the lowest ventilator settings, weaning mentation can be recommended. Another
from assisted ventilation should be attempted. key antioxidant that is deficient in preterm
Episodes of hypoxemia should be avoided infants is vitamin C. In a pilot study with pre-
because these are associated with increased mature baboons, high-dose vitamin C treat-
airway resistance.95,96 Supplemental oxygen ment did not prevent pulmonary oxygen
may be needed for several months or longer toxicity.103 Of concern is that vitamin C in
in the most severe cases. high doses can induce oxidative stress and
have adverse effects on the developing
lung.31 At this time, it is recommended that
Nutrition and Fluid Management specific vitamin deficiencies should be
avoided in infants with BPD by providing
Nutrition is a key component of the man- adequate supplementation.
agement of infants with BPD. Nutrition, Inflammatory changes in the lungs of
supplied enterally or parenterally or both, infants with BPD promote water retention.
must be sufficient to promote somatic As a result, these infants tolerate excess fluid
growth and the development of new alveoli; administration poorly,97,104 and fluids should
this should facilitate weaning from mechan- be modestly restricted (140 to 150 mL/kg/day)
ical ventilation and decrease vulnerability to to avoid pulmonary edema. Further restric-
infection that is associated with malnutri- tion may be needed in severely affected
tion.97,98 Energy also must be sufficient to infants. Additional supplementation of hu-
meet the demands of increased work of man milk or formula with calories or protein
breathing. Plans for dietary support of or both may be required to ensure adequate
infants with BPD who fail to thrive should nutrition in these infants.
consider that an excessive intake of carbo-
hydrate might be associated with increased
CO2 production and impair respiratory Diuretics
function further. Insufficient caloric intake
may potentiate oxygen toxicity and impair Administration of the loop diuretic furose-
cell multiplication and lung growth. Defi- mide, hydrochlorothiazide, or spironolac-
ciencies in sulfur-containing amino acids tone, which acts on the distal tubule, results
may reduce lung glutathione, an important in acute, nonsustained improvements in
antioxidant.30 The adequacy of nutrition pulmonary mechanics.105-107 The improve-
should be monitored closely, and growth ment in pulmonary mechanics seen with
charts for weight, head circumference, and furosemide administration may be indepen-
length should be maintained.97,98 dent of its diuretic effect, as venous capaci-
Vitamin deficiency may occur and inter- tance increases, and pulmonary blood flow
fere with lung healing. Vitamin A is an essen- decreases in response to furosemide adminis-
tial micronutrient for the normal growth and tration.108 In a Cochrane systematic review
differentiation of epithelial cells. Vitamin A and meta-analysis, however, diuretic admin-
levels are lower in infants with severe BPD istration did not reduce the need for ventila-
than in infants without BPD.99,100 In animal tor support, reduce the duration of hospital
models, low vitamin A levels contribute to stay, or improve long-term outcomes.
airway abnormalities, such as loss of ciliated Long-term administration of a diuretic is
epithelium or squamous metaplasia, similar often complicated by metabolic abnormal-
to histologic changes seen in BPD, and these ities, such as a hypokalemic, hypochloremic
changes are reversed by normalization of metabolic alkalosis, hypercalciuria leading
vitamin A levels.101 Vitamin E is another to nephrocalcinosis, osteopenia, impaired
important micronutrient and is a ubiquitous growth, and hearing loss (with furosemide
antioxidant. A small study has shown a administration).
Chapter 1 — Chronic Lung Disease of Infancy 13

Although no evidence exists for long-term reduces inflammation and improves lung
benefit, diuretics frequently are used in the mechanics, facilitating extubation.112,113 Sys-
management of infants with BPD to improve temic corticosteroid use is associated with
pulmonary function acutely. This use of di- short-term adverse effects, however, such as
uretics may be beneficial in infants with a pul- hyperglycemia, glucosuria, and hypertension,
monary exacerbation thought to be caused by and mortality is not reduced. In addition, out-
pulmonary edema or to reduce the effects of come studies have suggested that cortico-
circulatory overload after a packed red blood steroid treatment, especially dexamethasone,
cell transfusion. Whether diuretic therapy may contribute to poor neurodevelopmental
facilitates optimal nutrition by reducing the outcome and cerebral palsy.114 These con-
need for fluid restriction requires further cerns led the American Academy of Pediatrics
study. If diuretics are used, close monitoring Committee on Fetus and Newborn to recom-
of serum electrolytes is needed, and supple- mend that the routine use of dexamethasone
mentation may be required to compensate should be avoided and its use limited to
for urinary losses. extreme circumstances.115 That the likelihood
of dexamethasone treatment leading to
adverse outcomes is influenced by the base-
Bronchodilator Therapy line risk of developing BPD was suggested
by a meta-regression analysis.116 Whether
Infants with severe BPD have increased base-
infants at extremely high baseline risk for
line airway resistance that increases further
developing BPD would benefit from dexa-
with periods of hypoxemia, leading to respira-
methasone remains to be established in
tory decompensation owing to bronchocon-
clinical trials.
striction. This condition is sometimes treated
Data on the use of inhaled steroids are insuf-
with inhaled bronchodilators, a practice that
ficient to recommend their routine use.117
has been extrapolated from the treatment
Corticosteroids given via a metered dose
of asthma. Infants with BPD treated with
inhaler and holding chamber or nebulized
b-agonists respond with a short-term increase
budesonide have been used successfully, how-
in compliance and tidal volume and decrease
ever, even in patients younger than 1 year.118
in airway resistance.109,110 This treatment
The inhaled route is the preferred route for
has not been shown to affect long-term out-
preventing side effects of systemic cortico-
come, however. In one trial in which 173 ven-
steroids. Infants with CLDI treated with
tilator-dependent infants less than 31 weeks
inhaled corticosteroids should be monitored
gestation were randomly assigned to inhaled
for potential side effects, including delayed
salbutamol (albuterol), beclomethasone,
growth, increased blood pressure, osteoporo-
combination salbutamol and beclometha-
sis, adrenal suppression, and cataracts.
sone, or placebo, treatment resulted in no
difference in duration of mechanical ventila-
tion or oxygen supplementation, diagnosis
or severity of BPD at 28 days, or survival.111 Prevention
The efficacy of anticholinergic agents in
the treatment of BPD has not been studied Antenatal Corticosteroids
in randomized trials. Individual infants can
Antenatal corticosteroids given to women at
be treated with bronchodilators to achieve
risk for preterm delivery decreases the risk of
short-term improvement in pulmonary
RDS, intraventricular hemorrhage, and mor-
mechanics. Continued use should depend
tality. They should be given to any pregnant
on clinical response assessed by improvement
woman 24 to 34 weeks gestation with intact
in gas exchange and respiratory effort.
membranes at high risk for preterm delivery
within 7 days of administration. Treatment
Corticosteroids does not decrease the incidence of BPD,
however, partly because increased survival
Administration of systemic corticosteroids has resulted in more infants at risk for the
to infants with evolving or established BPD condition.
14 Pulmonary Manifestations of Pediatric Diseases

Fluid Restriction because of excess adverse events in infants

treated with dexamethasone. There was no
Higher fluid intake associated with a lack difference between ventilator groups in the
of postnatal weight loss during the immedi- combined primary outcome of death or
ate postnatal period has been proposed as BPD. At 36 weeks PMA, the proportion of
a predisposing risk factor for BPD. This infants requiring mechanical ventilation
hypothesis is supported by a retrospective was significantly less in the minimal group
report of premature infants (birth weight (16% versus 1%).
401 to 1,000 g) from the Neonatal Research The lack of difference in lung injury
Center study that found infants who either between the minimal and routine ventilation
died or developed BPD had a higher fluid groups may be due partly to an insufficient
intake and a lower weight loss during the first sample size. Another reason may be that target
10 days of life compared with infants who levels of PCO2 rather than tidal volume distin-
survived without BPD.119 Small trials of fluid guished the groups because the former usually
restriction have not shown a consistent is not measured continuously, and the
effect on the development of BPD, although difference in PCO2 between groups was small.
this strategy may minimize pulmonary Because ventilated infants continued to
edema.120,121 In one study, 168 ventilated breathe spontaneously, the measured PCO2
infants, gestational age 23 to 33 weeks, were reflected the selected airway pressure (which
randomly assigned to receive routine fluid determines the tidal volume) and rate and
volumes (60 mL/kg on the first day, progress- the infant’s own ventilation. Spontaneous
ing to 150 mL/kg on the seventh day) or 80% breathing may have resulted in the modest
of routine volume.120 Similar proportions in increase in PCO2 in the minimal ventilation
each group had BPD (26% versus 25%) and group and minimized the difference between
survived without oxygen dependency at 36 groups.
weeks PMA (58% versus 52%). Significantly
fewer restricted infants received postnatal
corticosteroid treatment (19% versus 43%), High-Frequency Oscillatory
however, suggesting that their clinicians Ventilation
may have considered them less ill than were
controls. In addition, the duration of oxygen HFOV, a technique of rapid ventilation with
requirement was significantly associated very small tidal volumes, reduces lung
with colloid infusion. injury in animal models compared with
conventional ventilation. Nearly all trials
Minimal Ventilation comparing HFOV with conventional venti-
lation performed in preterm infants at risk
Ventilation with high tidal volumes results in for the disorder since surfactant replace-
mechanical injury to the lung. Mechanical ment therapy has been available show no
ventilation with small tidal volumes and effect on the rate of BPD.92,123-126
target goals of modest permissive hypercap- In one trial in 500 preterm infants, 601
nia (PCO2 50 to 55 mm Hg) may protect the to 1,200 g birth weight, the proportion of
lung from mechanical injury. The benefit infants who survived without BPD was
of permissive hypercapnia has not been slightly greater with HFOV (56% versus
shown definitively in newborns at high risk 47%).91 This study was performed in centers
for BPD, although additional studies are experienced in the use of HFOV and fol-
needed.90,122,123 In one trial, infants with lowed strict protocols for management. Sim-
birth weight 501 to 1,000 g requiring ilar results may not be achieved at centers
mechanical ventilation before 12 hours of with less experience or without strict proto-
age were randomly assigned to minimal ven- cols.92,127 It is recommended that conven-
tilation (target PCO2 >52 mm Hg) or routine tional ventilation with low tidal volumes
ventilation (PCO2 <48 mm Hg) and a course and modest hypercapnia, rather than HFOV,
of dexamethasone or placebo.90 The trial was be employed as the initial mode of mechan-
stopped after enrollment of 220 infants ical ventilation for most preterm infants.127
Chapter 1 — Chronic Lung Disease of Infancy 15

Vitamin A development of BPD at 36 weeks PMA and

the need for oxygen supplementation at 28
Extremely preterm infants may have vita- postnatal days, and promoted earlier extuba-
min A deficiency, which may promote the tion, compared with control.113,131 Survival
development of BPD. Possible mechanisms did not improve with treatment, however.
include impaired lung healing, increased In addition, systemic corticosteroid use was
squamous cell metaplasia, reduced alveolar associated with short-term adverse effects,
number, increased susceptibility to infec- including hypertension, hyperglycemia, poor
tion, and increased loss of cilia.128 Supple- growth, and gastrointestinal bleeding and
mentation with vitamin A reduces the risk perforation.113,131
of BPD in susceptible infants. Systematic reviews of long-term outcome
In the largest trial, 807 infants with birth (4 years of age) suggest that postnatal dexa-
weight 401 to 1,000 g who received mechan- methasone use increases neurodevelop-
ical ventilation or supplemental oxygen at mental delay and cerebral palsy.115,116,132,133
24 hours of age were randomly assigned to A review that included nine randomized con-
receive 5000 IU vitamin A intramuscularly trolled trials of postnatal corticosteroids ad-
three times per week for 4 weeks or a ministered within the first week of life found
sham injection.128 The combined outcome that the risk of cerebral palsy was greater
of death or BPD (oxygen requirement at 36 among surviving infants who were treated
weeks PMA) occurred significantly less often compared with controls (24% versus 14%, rel-
in the vitamin A group compared with con- ative risk 1.75, 95% confidence interval 1.25
trol group (55% versus 62%). No clinical or to 2.44).116 A potential problem in the inter-
biochemical evidence of vitamin A toxicity pretation of these results is that many infants
was detected. In a subsequent study of the enrolled in trials of corticosteroids were trea-
original cohort, vitamin A supplementation ted with dexamethasone by their clinicians
did not differ from placebo in reduc- in addition to the study drug (open-label treat-
ing hospitalizations or pulmonary prob- ment).132 Children who participated in one of
lems after discharge from the nursery.129 In the trials134 included in the above-mentioned
addition, at a corrected age of 18 to 22 systematic reviews115,116,132,133 were evalu-
months, there were no differences in mor- ated at school age.135 Among the original
tality or neurodevelopmental impairment cohort of 262 infants, 159 survived to school
between the treated and nontreated infants. age, and 146 were included in follow-up
Some clinicians provide supplemental vita- (evenly distributed between treatment and
min A (5000 IU intramuscularly three times control groups). Clinically significant dis-
per week for 4 weeks) to infants 1,000 g abilities (motor skills, coordination, visual
birth weight who require ventilatory support motor integration, and IQ) were more com-
within 24 hours after birth. The decision to mon among children from the treatment
treat may depend on a balance of factors, group (39% versus 16%). Differing rates of dis-
such as the local incidence, the value of a ability persisted when the children who
modest decrease in BPD, and the need for received open-label dexamethasone treat-
repeated intramuscular injections.130 ment were excluded from the analysis (41%
versus 21%).
Systemic Corticosteroids Even when administered in low doses or
when other agents aside from dexametha-
Administration of systemic corticosteroids sone are used, systemic corticosteroids are
reduces the risk of BPD. Routine use of cortico- associated with serious adverse effects. In a
steroid therapy is not recommended, how- multicenter trial, mechanically ventilated
ever, because there are concerns about ELBW infants were randomly assigned to
significant short-term and long-term adverse hydrocortisone therapy or placebo to deter-
effects. In systematic reviews by the Cochrane mine whether prophylaxis of early adrenal
database, treatment with corticosteroids insufficiency affected clinical stability and
(usually dexamethasone) before 96 hours of incidence of BPD.136 Infants receiving hy-
age or at 7 to 14 days of age reduced the drocortisone were treated with 1 mg/kg/day
16 Pulmonary Manifestations of Pediatric Diseases

for 12 days and then 0.5 mg/kg/day for birth weight 1,250 g who were mechani-
3 days. Enrollment was discontinued early cally ventilated at 3 to 14 days of age were
because of an increase of spontaneous gas- randomly assigned to a 4-week course of
trointestinal perforation in the hydrocor- beclomethasone (tapering dose of 40 mg/kg/
tisone group (9% versus 2%). Overall day to 5 mg/kg/day) or placebo.137 The need
survival without BPD did not differ between for supplemental oxygen at 28 days (43% ver-
groups. sus 45%) and 36 weeks PMA (18% versus 20%)
Although most of the data show the neg- was similar in the beclomethasone and pla-
ative impact of corticosteroids, with risk of cebo groups. Beclomethasone significantly
short-term and long-term adverse effects reduced the rate of systemic corticosteroid
including impaired neurodevelopmental use (relative risk 0.8) and mechanical ventila-
outcomes, it remains unclear whether there tion (relative risk 0.8) at 28 days of age. No
is a potential role for corticosteroids in adverse effects were observed. In a separate
selected populations. In the meta-analysis report from the same trial, beclomethasone
described earlier,116 there was a significant therapy was associated with slightly lower
negative correlation between the corticoster- median basal cortisol levels (5 mg/dL versus
oid effect on combined outcome of death 6 mg/dL) compared with placebo, but similar
and cerebral palsy and the rate for BPD in response to cosyntropin stimulation.138
the control groups. The rate of BPD was
used as a marker for the risk for BPD and
was not a variable available at trial entry. Inhaled Nitric Oxide
This relationship suggests that in a popula-
tion of preterm infants at high risk for Inhaled nitric oxide (iNO) is used in the
BPD, corticosteroid therapy may decrease management of term neonates with hy-
the risk of death or cerebral palsy. At pres- poxic respiratory failure, but little is known
ent, the American Academy of Pediatrics about the effects of iNO in the preterm pop-
and the Canadian Pediatric Society recom- ulation. Multiple physiologic effects of
mend that dexamethasone should not be nitric oxide are known. Exposure to chronic
used routinely in VLBW infants to treat or hypoxemia leads to remodeling that
prevent chronic lung disease because of its includes increased proliferation of pulmo-
limited short-term benefits, no apparent nary vascular smooth muscle, leading to
long-term benefits, and substantial risk of increased pulmonary vascular pressures,
short-term and long-term complications.115 and eventual right ventricular hypertrophy
They further recommend that dexametha- and cor pulmonale. Several animal studies
sone use should be limited to controlled have shown that iNO prevents or amelio-
trials. Outside of a trial, corticosteroids rates this remodeling of the pulmonary vas-
should be used only in exceptional clinical cular bed.139-142 Of particular concern is the
circumstances, such as an infant who effect of iNO on coagulation; iNO is known
requires maximal ventilatory and oxygen to increase bleeding time in adult patients,
support. In this case, the parents should be presumably via a cyclic guanosine mono-
made aware of potential risks and agree to phosphate–dependent mechanism causing
treatment. platelet dysfunction.143,144 In a preterm
infant already at risk for intraventricular
hemorrhage, this complication would add
Inhaled Corticosteroids significant long-term morbidity.
Several studies of the use of iNO in pre-
In a systematic review and meta-analysis by term neonates have been conducted, and
the Cochrane database, early postnatal several included BPD as an outcome.145-149
administration of inhaled corticosteroids A Cochrane systematic review and meta-
did not prevent BPD, but was associated analysis has shown that the use of iNO in
with lower rates of systemic corticosteroid infants less than 35 weeks of age does not
treatment.117 In the largest trial, 253 infants show any benefit in terms of survival with-
with gestational age less than 33 weeks and out BPD; there also is a trend toward an
Chapter 1 — Chronic Lung Disease of Infancy 17

increase in the combined outcome of severe found in the rate of oxygen dependence at
intraventricular hemorrhage or periventri- 28 postnatal days or 36 weeks PMA.154 At 1
cular leukomalacia.150 year of age, infants who received rhSOD had
less respiratory illness, however. Growth
and neurodevelopmental status were similar.

Caffeine has been shown to reduce the fre- Summary

quency of apnea of prematurity and the need
for mechanical ventilation.151 A study of Multiple strategies are needed to prevent
1917 infants with birth weight 500 to 1,250 g BPD in high-risk patients.
showed that the rate of BPD (a secondary out- • Although antenatal corticosteroids do not
come) in infants treated with caffeine was sig- affect the incidence of BPD, they reduce
nificantly lower than in the placebo group the risk of RDS and intraventricular hem-
(36% versus 47%).151 The rates of adverse orrhage, and improve survival in preterm
outcomes—specifically death, brain abnor- infants. Antenatal corticosteroids should
malities by head ultrasonography, and necro- be given to pregnant women at high risk
tizing enterocolitis—were not different for preterm delivery.
between the two groups. This cohort has been • Excessive fluid administration should be
followed to assess the primary outcome mea- avoided in ELBW infants, and fluids
sure, which is the combined rate of mortality should be restricted to minimize the
and neurodevelopmental disability in survi- development of pulmonary edema. Use
vors at a corrected age of 18 to 21 months, of colloid infusions should be avoided.
and the authors more recently reported • Conventional ventilation with low tidal
improved survival without neurodevelopmen- volumes and reasonable ventilation goals
tal disability in the caffeine-treated group.152 (initially, PaCO2 50 to 55 mm Hg) should
Neurodevelopmental outcomes in this cohort be used in preterm infants with respira-
also will be followed up at 5 years of age. tory failure in most cases. In centers expe-
rienced with the technique, HFOV may be
an appropriate alternative.
Superoxide Dismutase • Optimal nutrition should be provided to
Preterm infants may have inadequate anti- promote somatic and lung growth.
oxidant defense because of nutrient defi- Administration of supplemental vitamin
ciencies or immature enzyme development. A (5000 IU intramuscularly three times
Postnatal administration of antioxidants per week for 4 weeks) to ELBW infants
such as superoxide dismutase may protect who require early respiratory support
against oxidant injury, although additional should be considered.
evidence is needed. In one study performed • Routine use of postnatal dexamethasone
after replacement surfactant became avail- should be avoided.
able, 33 infants with birth weight 700 to • Use of iNO to prevent BPD should await
1,300 g who were mechanically ventilated publication of follow-up studies.
for RDS were randomly assigned to intra- • Caffeine decreases the rate of BPD in infants
tracheal administration of recombinant 500 to 1,250 g, without neurodevelopmen-
human copper/zinc superoxide dismutase tal sequelae at 18 to 21 months of age.
(rhSOD) (2.5 mg/kg or 5 mg/kg) or saline
every 48 hours while they remained intu-
bated, for up to seven doses.153 Clinical Outcome
outcomes did not differ between groups.
Tracheal aspirate inflammatory markers Mortality
(neutrophil chemotactic activity, albumin
concentration) were lower, however, in the Infants with severe BPD have a higher risk
rhSOD groups than in the control group. In of mortality than unaffected infants or
a larger multicenter trial, no difference was infants with mild disease. Death usually is
18 Pulmonary Manifestations of Pediatric Diseases

caused by respiratory failure, unremitting history of BPD had findings consistent with
pulmonary hypertension with cor pulmo- airflow obstruction and air trapping. In
nale, or sepsis. The risk of mortality another study, 39 preterm infants (mean
increases with the duration of mechanical gestational age 29.8 weeks) with BPD had
ventilation. In one report, among 47 infants serial measurements of pulmonary function
mechanically ventilated for more than 27 from 1 to 36 months of age.163 Compared
days, 20 died.155 In another study of 144 with normal controls, infants with BPD
newborns who required prolonged mechan- had evidence of decreased pulmonary func-
ical ventilation after birth, death occurred in tion that remained fairly constant up to 6
35% and 90% of infants ventilated for months of age, and steadily improved by
2 months and more than 4 months.156 At the 36-month follow-up. All of these infants
30 days of age, the mean airway pressure still had mildly reduced pulmonary func-
and a diagnosis of bacterial sepsis during tion parameters (approximately 85% of nor-
the previous month were significant predic- mal) at the 36-month follow-up. These
tors of mortality. In patients who still findings are consistent with formation of
required ventilation at 60 days of age, mean new alveoli in early infancy, leading to
airway pressure and oxygen concentration improved compliance. Airway growth is
were the best predictors. slow during the first 6 months after birth,
but subsequent faster growth results in
improved conductance.
Respiratory Infections
Late Childhood
Infants with BPD are at increased risk In some patients, abnormal pulmonary func-
for respiratory infections, including respira- tion persists through later childhood. In one
tory syncytial virus (RSV), which may be study, children 11 years old who had BPD
life-threatening.157 Episodes of wheezing had diminished airflow and higher residual
that suggest bronchiolitis or asthma also volume compared with controls, but few
are common before 2 years of age.158 Respi- had abnormalities that were clinically signif-
ratory illnesses contribute to high rates of icant.164 Similar findings were noted in a
rehospitalization, especially in the first year small but more contemporary series of
of life.159-161 In one report, infants with patients with moderate to severe BPD, of
BPD were rehospitalized more often during whom most had pulmonary function testing
the first year (58% versus 35%) and more at 24 months of age and at a mean of 8.8
likely to be readmitted for respiratory illness years.165,166 Among 18 children, 15 had mild
(39% versus 20%) than controls.159 to severe airflow limitation, with mean
forced expiratory volume in 1 second
Pulmonary Function (FEV1) and forced mid-expiratory flow (FEF
25%-75%) less than 60% of predicted in 4
Early Childhood and 9 children. Abnormalities in childhood
Infants with severe BPD may have abnormal correlated with reduced maximal airflow
pulmonary function tests for many years, values at functional residual capacity (FRC)
even though some are asymptomatic.158 measured in infancy. Most children had no
Pulmonary function normalizes in early signs of airway obstruction, although three
childhood in most cases, however, espe- had reduced exercise tolerance, and one used
cially in infants with milder disease. In one medication for asthma-like symptoms.
study, 28 children (<3 years old) with a his-
tory of prematurity (mean gestational age Neurodevelopment
26.4 weeks, mean birth weight 898 g) and
BPD underwent routinely scheduled infant Infants with severe BPD are at increased risk
lung testing at a mean age of 68 weeks.162 for neurodevelopmental sequelae. In a large
Compared with a previously studied group cohort of ELBW infants cared for in the
of healthy term infants, infants with a centers of the NICHD Neonatal Research
Chapter 1 — Chronic Lung Disease of Infancy 19

Network and evaluated at 18 to 22 months Growth

corrected age, BPD was a significant risk fac-
tor for abnormal neurologic examination and The effect of BPD on long-term growth is
scores less than 70 (>2 standard deviations uncertain. Poor growth of infants with BPD
below the mean) on the mental development was seen in some follow-up studies, although
index and psychomotor development index others have shown no difference from unaf-
scales of the Bayley Scales of Infant Develop- fected infants. One study followed 20 pre-
ment.167 In a separate study, follow-up at 3 term infants with BPD for 2 years after term
years of age showed that significantly more PMA.173 The infants were severely growth
VLBW infants with BPD had scores less than restricted at term, with the average weight
70 for the mental development index (21% and height less than or equal to the 3rd per-
versus 11% and 4%) and psychomotor devel- centile. Growth accelerated as respiratory
opment index (20% versus 9% and 1%) com- symptoms improved. At 2 years, weight for
pared with control groups of unaffected boys and girls was 3rd to 10th percentile,
VLBW infants and term infants.168 In another and height was 10th to 25th percentiles for
report from the same center, children with boys and girls respectively. In another series
BPD had poorer receptive and expressive lan- of 16 affected children evaluated at 2 years,
guage skills at 3 years old compared with height and weight were less than 10th per-
controls.169 centile in 37% and 25%, respectively.174
The effect of BPD on outcome persists In other reports, BPD does not seem to
through school age. In one study, VLBW affect growth at 8 to 10 years of age, which
infants with BPD tested at 8 to 10 years old might be influenced more by factors other
scored poorest on all eight measures of cog- than respiratory disease, such as low birth
nitive performance compared with control weight.172,175 In one report, infants with
groups of term and unaffected VLBW in- BPD were significantly smaller than unaf-
fants.170 In another report, neuromotor out- fected infants.175 After adjustment for con-
come was evaluated at approximately 10 founding variables, however, no significant
years of age in children who had severe BPD differences were detected.
and required home oxygen therapy and was
compared with neuromotor outcome of un-
affected preterm controls.171 Neurologic Tracheobronchomalacia
abnormalities, including subtle neurologic
signs, cerebral palsy, microcephaly, and behav- Abnormalities of the trachea and bronchi
ioral problems, were significantly more preva- always must be considered in infants with
lent in the BPD group (71% versus 19%). BPD who remain persistently ventilator-
More than half of the BPD group had abnor- dependent.176 Depending on the series,
malities of gross or fine motor skills or both. 16% to 50% of infants with BPD show
When interpreting follow-up studies such evidence of tracheobronchomalacia at bron-
as the above-cited studies, many factors choscopy.177-180 Owing to acute collapse of
influence outcome, including incidence of the airways, leading to a marked increase
neurologic risk factors (e.g., cranial ultra- in total airway resistance and decreased air-
sound abnormalities), neurosensory prob- flow, infants can experience life-threatening
lems (e.g., retinopathy of prematurity, episodes that are characterized by extreme
hearing impairment), hospital course, and difficulty in ventilation.176 The use of bron-
poor social environment. In one study, chodilators generally worsens or prolongs
infants with BPD evaluated at 8 years had these episodes.
significantly poorer psychoeducational and Acquired tracheobronchomalacia is dif-
school performance test scores than con- ferentiated clinically from congenital tra-
trols.172 Most variance in academic achieve- cheobronchomalacia by a history of airway
ment was attributed to the lowest recorded intubation and mechanical ventilation. Other
pH or PaO2 and the father’s socioeconomic lesions that cause airway compression, such
status. as vascular rings, hypertensive enlarged
20 Pulmonary Manifestations of Pediatric Diseases

pulmonary arteries, and hyperinflated lobes, only inspiratory stridor. Postextubation stri-
must be ruled out. Acquired tracheobron- dor is a significant marker for the presence
chomalacia in CLDI has been attributed to of moderate to severe subglottic stenosis or
barotrauma, chronic or recurrent infection, laryngeal injury.
and local effects of artificial airways. The Risk factors for laryngeal injury include
immature trachea is a highly compliant struc- intubation for 7 days or more and three or
ture that undergoes progressive stiffening more intubations.186 These same factors also
with age.181 These changes seem to parallel are associated with acquired subglottic ste-
changes in cartilage mechanics, rather than nosis. Use of inappropriately large endotra-
passive properties of tracheal smooth muscle. cheal tubes also is an important risk factor
Infants with abnormal central airway col- for the development of subglottic stenosis.
lapse may be asymptomatic at rest or have A tube size-to-gestational age (in weeks)
wheezing, often unresponsive to broncho- ratio greater than 0.1 has been correlated
dilator therapy. Wheezing becomes promi- with acquired airway obstruction.187
nent with increased expiratory effort, and
cyanotic spells may result. Tracheal Stenosis, Bronchial
One treatment modality available after this Stenosis, or Granuloma Formation
diagnosis is made is CPAP via nasopharyn-
geal, endotracheal, or tracheostomy tube.182 Acquired tracheal and bronchial stenosis or
Zinman has shown that by providing suffi- granuloma formation has been reported in
cient CPAP to prevent collapse of the affected infants with CLDI 3 weeks to 17 months
segment, dynamic lung compliance is in- old.180 Endoscopic findings consist of airway
creased, and airway resistance is decreased.183 narrowing or obstruction by thickened respi-
ratory mucosa or circumferential nodular or
Glottic and Subglottic Damage polypoid granulations in the distal trachea,
often extending into main bronchi.188
Endotracheal intubation has been associated Stenosis and granulation formation may
with injury to supraglottic, glottic, subglottic, not be complications of CLDI per se, but
and tracheal tissues in newborns.184-185 Some instead may be the result of extended endo-
degree of epithelial damage after endotracheal tracheal intubation and vigorous suctioning
intubation is common, ranging from focal techniques. Because these lesions tend to
epithelial necrosis over the arytenoid or cri- occur in the distal trachea and right-sided
coid cartilages or vocal cords to extensive bronchi, repeated mucosal injury from suc-
mucosal necrosis of the trachea. Because tion catheters has been implicated as the
superficial lesions seen at the time of extuba- likely mechanism.
tion often resolve without sequelae, early Acute mucosal injury to the carina and
endoscopy after tracheal extubation overesti- main bronchi occurs from unrestricted or
mates the possibility of long-term damage. “deep” suctioning.189 The size of the catheter
The relationship between acute laryngeal or should be small enough (usually 5F to 6F in
subglottic damage and development of newborns) so as not to occlude the artificial
acquired subglottic stenosis is unclear. airway completely, avoiding excessive nega-
Acquired subglottic stenosis has been tive pressure.190 Catheters with multiple side
reported to occur in about 10% of previ- holes on several planes are less likely to cause
ously intubated neonates. Clinical manifes- invagination of airway mucosa into the cath-
tations include postextubation stridor, eter than catheters with single side or end
hoarseness, apnea, and bradycardia; failure holes. Use of negative pressures greater than
to tolerate extubation; and cyanosis or pal- 50 to 80 cm H2O increases the likelihood of
lor. Similar manifestations can result from mucosal damage and does not increase the
vocal cord injuries, glottic or subglottic cysts efficiency of secretions removal.191 The most
or webs, laryngomalacia, or extrathoracic important preventive measure is to limit pas-
tracheomalacia. Fixed lesions of the glottis sage of the suction catheter to the distal tip
and subglottis often produce biphasic stri- of the artificial airway, so that the airway
dor, whereas variable lesions usually cause mucosa is protected from injury.192
Chapter 1 — Chronic Lung Disease of Infancy 21

Monitoring occlusion, to assess the severity of pulmo-

nary hypertension, to test the reactivity to
Infants with BPD need close monitoring to oxygen or vasodilators, and to assess for
minimize further lung injury, reduce the development of large systemic-pulmonary
risks of pulmonary and systemic hyperten- collaterals.196 Systemic blood pressure
sion, and promote adequate growth and should be monitored routinely because of
development. This monitoring should begin the risk of systemic hypertension.191,192
during hospitalization and continue after Systemic hypertension should be treated if
discharge. it is detected.

Cardiovascular Monitoring Growth

and Oxygenation
As previously noted, nutrition is an impor-
The pulmonary circulation in infants with tant component of the care of infants with
BPD has structural, functional, and anatomic CLD. Hospitalized infants should be
abnormalities.189,190 Structural alterations weighed two to three times per week, and
include smooth muscle hyperplasia, increased length and head circumference should be
fibroblast incorporation, and adventitial measured weekly. Biochemical monitoring,
thickening. Functional abnormalities include including measurement of blood urea nitro-
impaired vasodilation and increased hypoxic gen, albumin, calcium, phosphorus, and
vasoconstriction. Anatomic changes include alkaline phosphatase, may assist with nutri-
decreased total blood vessel mass and de- tional assessment. Serum electrolytes should
creased total surface area. These changes be followed in infants on diuretic therapy,
can result in pulmonary arterial and systemic and supplements should be provided as
arterial hypertension, eventually leading to needed. Infants who exhibit oromotor dys-
right and left ventricular hypertrophy.193 function or other feeding disorders inhibit-
The major approach to avoid or treat pulmo- ing growth should be evaluated and receive
nary hypertension is maintaining adequate specific intervention.
oxygenation, although pharmacologic treat-
ment may be required in severe cases.189,190
Generally, in infants with severe BPD who do Development, Vision, and Hearing
not have pulmonary hypertension, oxygen
saturations are maintained greater than 92%; As discussed previously, infants with BPD
in infants with pulmonary hypertension, generally have poorer neurodevelopmental
saturations are maintained higher (94% to outcomes than unaffected infants.168 Devel-
96%).194 opmental assessment should begin while
Serial echocardiographic screening for pul- the infant is still hospitalized and continue
monary arterial hypertension is recom- on a regular basis after discharge. Infants
mended in premature infants with BPD who should have serial eye examinations to
have gestational age at birth of less than or detect retinopathy of prematurity or other
equal to 25 weeks or birth weight less than eye disorders, and receive appropriate inter-
or equal to 600 g, small for gestational age, vention. Routine hearing screening should
requirement for prolonged mechanical be done to detect impairment, with early
ventilation, oxygen requirement out of pro- intervention by an audiologist if needed.
portion to the severity of lung disease, or
persistent poor growth despite adequate
caloric intake.195 A pediatric cardiologist Coordination of Care and
should follow patients with pulmonary Discharge Planning
arterial hypertension. Cardiac catheteriza-
tion may be recommended for patients Infants with severe BPD usually have a pro-
with severe pulmonary hypertension to longed hospitalization and require substan-
rule out anatomic cardiac disease, pulmo- tial planning for discharge to home and
nary vein stenosis, or pulmonary vein postdischarge care. Discharge should be
22 Pulmonary Manifestations of Pediatric Diseases

planned by a multidisciplinary care team 11. Ehrenkranz RA, et al: Validation of the National
Institutes of Health consensus definition of bron-
that ideally includes individuals with skills chopulmonary dysplasia. Pediatrics 116:1353-
in neonatology, pulmonology, nursing, 1360, 2005.
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sia. Am J Respir Crit Care Med 163:1723-1729,
nutrition, physical and occupational ther- 2001.
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can ease the transition from the hospital to a physiologic definition of bronchopulmonary
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176. Doull IJM, Mok Q, Tasker RC: Tracheobronchoma- 188. Grylack LJ, Anderson KD: Diagnosis and treat-
lacia in preterm infants with chronic lung disease. ment of traumatic granuloma in tracheobronchial
Arch Dis Child Fetal Neonatal Ed 76:F203-F205, tree of newborn with history of chronic intuba-
1997. tion. J Pediatr Surg 19:200-201, 1984.
177. Downing GJ, Kilbride HW: Evaluation of airway 189. Brodsky L, Reidy M, Stanievich JF: The effects of
complications in high-risk preterm infants: appli- suctioning techniques on the distal tracheal
cation of flexible fiberoptic airway endoscopy. mucosa in intubated low birth weight infants.
Pediatrics 95(4):567-572, 1995. Int Ped Otorrrhinolaryngol, 14:1-14, 1987.
178. Greenholz SK, et al: Surgical implications of 190. Hodge D: Endotracheal suctioning and the infant:
bronchopulmonary dysplasia. J Pediatr Surg a nursing care protocol to decrease complications.
22(12):1132-1136, 1987. Neonatal Netw, 77:202-207, 1991.
179. Lindahl H, et al: Bronchoscopy during the first 191. Kuzenski BM: Effect of negative pressure on tra-
month of life. J Pediatr Surg 27(5):548-550, 1992. cheobronchial trauma. Nurs Res, 27:260-263,
180. Miller RW, et al: Tracheobronchial abnormalities 1978.
in infants with bronchopulmonary dysplasia. 192. Runton N: Suctioning artificial airways in chil-
J Pediatr 111(5):779-782, 1987. dren: appropriate technique. Pediatr Nurs 18:
181. Shaffer TH, Bhutani VK, Wolfson MR, et al: In vivo 115-118, 1992.
mechanical properties of the developing airway. 193. Malnick G, et al: Normal pulmonary vascular
Pediatr Res 25:143-146, 1989. resistance and left ventricular hypertrophy in
182. Panitch HB, Allen JL, et al: Effects of CPAP on lung young infants with bronchopulmonary dysplasia:
mechanics in infants with acquired tracheo- an echocardiographic and pathologic study. Pedi-
bronchomalacia. Am J Resp Crit Care Med 150: atrics 66(4):589-596, 1980.
1341-1346, 1994. 194. Kotecha S, Allen J: Oxygen therapy for infants
183. Zinman R: Tracheal stenting improves airway with chronic lung disease. Arch Dis Child Fetal
mechanics in infants with tracheobronchomala- Neonatal Ed 87(1):F11-4, 2002.
cia. Pediatr Pulmonol 19(5):275-281, 1995. 195. Abman SH: Monitoring cardiovascular function in
184. Strong RM, Passy V: Endotracheal intubation: infants with chronic lung disease of prematurity.
complications in neonates. Arch Otolaryngol Arch Dis Child Fetal Neonatal Ed 87(1):F15-8,
103:329-335, 1977. 2002.
185. Fan LL, Flynn JW, et al: Predictive value of stridor 196. Apkon MNR, Lister G: Cardiovascular abnormal-
in detecting laryngeal injury in extubated neo- ities in BPD, in Chronic Lung Disease of Infancy.
nates. Crit Care Med 10:453-455, 1982. Bland RD, Coalson JJ, Eds. Marcel Dekker: New
186. Fan LL, Flynn JW, et al: Risk factors predicting York p. 321-356, 2000.
laryngeal injury in intubated neonates. Crit Care
Med 11:431-433, 1983.

Pulmonary Manifestations of
Human Immunodeficiency Virus
(HIV) Infection

Epidemiology 28 Chronic Pulmonary Infections 42

Pathogenesis 29 Immune Reconstitution Inflammatory
Acute Respiratory Infections 29 Syndrome 42
Bacterial Pneumonia 30 Bronchiectasis 43
Mycobacterial Infection 32 Malignancy 43
Viral Infection 35 Diagnostic Evaluation of an HIV-1-
Pneumocystis Infection 37 Infected Child with Pulmonary
Fungal Infection 40 Manifestations 43
Chronic Lung Disease 41 Summary 44
Lymphocytic Interstitial Pneumonia 41 References 44
Interstitial Pneumonitis 42

Respiratory complications in children in- pneumonia-specific mortality rates are three

fected with human immunodeficiency virus to six times higher than the rates of HIV-1-
(HIV) are common and responsible for sub- negative patients.4
stantial morbidity and mortality.1 With The burden of HIV-associated respiratory
advances in diagnostic, therapeutic, and disease in developing countries often occurs
preventive strategies for HIV, the spectrum in the context of existing high rates of
of childhood respiratory disease has childhood pneumonia, poverty, coexisting
changed. In developed countries, programs malnutrition, suboptimal immunization
to prevent perinatal HIV-1 transmission, coverage, and under-resourced or inacces-
early diagnosis of HIV-1 infection in infants, sible health care facilities. HIV-infected chil-
and use of Pneumocystis prophylaxis and dren have a higher risk of respiratory
highly active antiretroviral therapy (HAART) infections and diseases and of more severe
have led to a substantial decline in pediatric illness compared with immunocompetent
HIV incidence and associated respiratory children. Increasing evidence also suggests,
infections.2 In contrast, the major burden however, that HIV-exposed but uninfected
of pediatric HIV now exists in developing children also are at greater risk of respiratory
countries.3 In these areas, acute and chronic infections and illnesses compared with chil-
HIV-associated respiratory disease remain a dren born to uninfected mothers.
major cause of childhood morbidity and
mortality.1,4 This situation is compounded
by limited access to appropriate health care Epidemiology
and antiretroviral therapy. In the absence of
HAART, 90% of HIV-1-infected children may Globally, there are approximately 33.2 mil-
develop a severe respiratory illness sometime lion HIV-1-infected individuals, of whom 2.5
in the course of their HIV disease.1,4 Pneumo- million are children younger than 15 years
nia is the most common cause of hospita- old.3 Most of these HIV-1-infected children—
lization in African HIV-1-infected children; almost 2.2 million—reside in sub-Saharan

Chapter 2 — Human Immunodeficiency Virus (HIV) Infection 29

Africa.3 In 2006, there were an estimated The primary target cell of HIV-1 is the
420,000 new HIV-1 infections in children human CD4þ lymphocyte. The HIV-1
(370,000 in sub-Saharan Africa) and approx- gp120 envelope protein binds to the CD4þ
imately 330,000 childhood deaths from molecule on the host cell membrane with
HIV-1 (290,000 in sub-Saharan Africa).3 Con- high affinity. This binding allows the virus
versely, in the last decade in developed to enter the T cell and to integrate its genome
countries, the number of HIV-infected into the host DNA. HIV-1 also infects mono-
children has greatly declined because of a cytes and macrophages but with less marked
dramatic reduction in perinatal HIV trans- cytopathic effects. Infected monocytes serve
mission.2 New cases of HIV-1 infection in as a reservoir for HIV-1, allowing further
children in developed countries occur pre- spread of the virus throughout the body.5
dominantly in adolescents secondary to Infection with HIV-1 results in progressive
sexual transmission; most adolescents depletion of the CD4þ helper lymphocytes.
remain asymptomatic until adulthood.2 This depletion serves as a marker of the sever-
HIV-1 infection and AIDS have dispropor- ity of HIV-1 infection because the incidence
tionately affected minority populations in of opportunistic infections and other compli-
the United States. cations correlates with the number and per-
Most new HIV-1 infections in children centage of CD4þ lymphocytes, particularly
occur through perinatal transmission in utero, in children older than 1 year.6
intrapartum, or through breastfeeding. Breast- The ability to produce cytokines, such as
feeding may account for 40% of infants interleukin-2 and interferon-, is progres-
becoming infected after delivery, especially sively lost in HIV-1-infected children. Natu-
in developing countries, where mothers con- ral killer cell–mediated cytotoxicity also is
tinue to breastfeed for prolonged periods or reduced in HIV-1-infected children. In addi-
mixed feeding is introduced early. tion, B cell dysfunction with defective
The impact of HIV-1 on children is com- humoral immunity further predisposes to
pounded by maternal HIV-1 infection. Infec- severe infection.7
tion rates in African women are two to five
fold higher than in men, with women of
childbearing age most affected.3 In many Acute Respiratory Infections
countries in sub-Saharan Africa, more than
20% of pregnant women are HIV-1-infected. Respiratory infection was the most common
As a result, many HIV-1-exposed children cause of death in children younger than 6
may be cared for by ill mothers, and other years of age in a U.S. cohort of HIV-1-
caregivers, or be orphaned. Maternal illness infected children in the pre-HAART era; the
and inability to work exacerbates the cycle of frequency of pulmonary disease as a cause
poverty and child illness. Children living in of death was greatest in infants, with 56%
sub-Saharan Africa are particularly vulnerable of respiratory-related deaths occurring
to HIV-1-associated illness because access to within the first year of life.8 The rate of
antiretroviral therapy and appropriate medi- acute respiratory infections and opportunis-
cal care may be very limited or unaffordable. tic infections has decreased dramatically
with the use of HAART (Table 2-1).5-9 Before
HAART, bacterial pneumonia, Pneumocystis
pneumonia (PCP), disseminated Mycobacte-
Pathogenesis rium avium-intracellulare complex (MAC),
and tracheobronchial candidiasis were the
HIV-1 is a retrovirus, belonging to a group of most frequent respiratory infections, occur-
heterogeneous, lipid-enveloped RNA viruses. ring at an event rate of more than 1 per
Another retrovirus, HIV-2, is relatively rare 100 child-years; these all have declined
and causes a less severe AIDS-like syndrome. substantially with HAART (see Table 2-1).5,9
HIV-1 has two major viral envelope pro- Although the frequency of bacterial infec-
teins—the external glycoprotein gp120 and tions has declined substantially, pneumonia
the transmembrane glycoprotein gp41. or secondary respiratory failure remains the
30 Pulmonary Manifestations of Pediatric Diseases

Table 2-1 Impact of HAART on Opportunistic Respiratory Infections


Incidence Rate per 95% CI Incidence Rate per 95% CI
100 Child-Years 100 Child-Years
PCP 1.3 1.1-1.6 0.1 0.04-0.2
Bacterial pneumonia 11.1 10.3-12.0 2.2 1.8-2.6
Bacteremia 3.3 2.9-3.8 0.4 0.2-0.5
Disseminated MAC 1.8 1.5-2.1 0.1 0.1-0.3
Tracheobronchial or esophageal 1.2 1.0-1.5 0.1 0.03-0.2

CI, confidence interval; HAART, highly active antiretroviral therapy; MAC, Mycobacterium avium-intracellulare complex; PCP,
Pneumocystis pneumonia.

predominant cause of death in children HIV-1 infection has been associated with
receiving HAART, accounting for 27% of an increase in the antimicrobial resistance
deaths.5 In children not receiving HAART patterns of bacterial pneumonia, with impli-
or children resistant to antiretroviral ther- cations for empiric antibiotic therapy.11
apy, acute respiratory infections are com- Methicillin-resistant S. aureus (MRSA) has
mon, often severe, and the most frequent increasingly emerged as a pathogen in HIV-
cause of hospitalization or death. Bacteria, 1-infected children.16 Data on the preva-
mycobacteria, viruses, Pneumocystis, or fungi lence of penicillin-resistant pneumococcal
may cause respiratory infections; mixed infection are variable, but no clear differ-
infections also commonly occur (Table 2-2). ences in clinical outcome for susceptible
and resistant strains have been shown except
Bacterial Pneumonia for isolates with high-level resistance.21
Etiologic diagnosis of bacterial pneumonia
Before HAART, bacterial pneumonia was the is difficult because signs are nonspecific, coin-
most common serious infection in HIV-1- fection with more than one organism occurs
infected children with an event rate of 11 frequently, and culture of upper respiratory
per 100 child-years9; this rate has declined tract secretions or sputum may reflect coloni-
to 2.2 in the HAART era (see Table 2-1).5 zation rather than pathogenic organisms.
Pneumonia, particularly caused by Streptococ- Blood culture, may be useful because of
cus pneumoniae, Haemophilus influenzae type higher rates of bacteremia, occurring in ap-
b, and Staphylococcus aureus, is a major cause proximately 15% of HIV-1-infected children
of hospitalization and death in children hospitalized for pneumonia.11,16 Empiric
in developing countries.10-12 S. pneumoniae therapy for pneumonia should include
is the most important bacterial pathogen in broad-spectrum antibiotics, based on the local
HIV-1-infected and uninfected children.11-16 prevalence of antimicrobial resistance and
HIV-1-infected children also are at increased recent use of prophylactic or therapeutic
risk for recurrent infections. antibiotics (see Table 2-2).1,6 A combination
S. aureus is an increasingly important cause of a b-lactam with an aminoglycoside or a
of pneumonia in HIV-1-infected children and second-generation or third-generation cepha-
is the most common pathogen in catheter- losporin alone is appropriate empiric therapy.
associated bacteremia.16,18 Staphylococcal The choice of antimicrobial agent should be
pneumonia may be complicated by empyema, modified according to culture results and
pneumatoceles, or lung abscess (Fig. 2-1). susceptibility testing.
A wider range of bacteria, including gram neg- The outcome of HIV-1-infected children
ative pathogens such as Klebsiella pneumoniae, with bacterial pneumonia is worse than the
Pseudomonas aeruginosa, H. influenzae, non- outcome for immunocompetent children
typhoid salmonella, and Escherichia coli, cause with more severe disease and higher case-
pneumonia with or without bacteremia in fatality rates.1,4 In addition, HIV-1-exposed
HIV-1-infected children.11,12,16,19,20 but uninfected children have higher rates of
Chapter 2 — Human Immunodeficiency Virus (HIV) Infection 31

Table 2-2 Etiology and Therapy of Lower Respiratory Infections in HIV-Infected Children


Bacterial pneumonia Streptococcus pneumoniae Broad-spectrum antibiotic—b-lactam with an
aminoglycoside or a second- or third-generation
Haemophilus influenzae Add antistaphylococcal antibiotics if S. aureus
Staphylococcus aureus suspected or vancomycin if methicillin-resistant
S. aureus suspected
Nontyphoid salmonella
Klebsiella pneumoniae
Streptococcus milleri
Escherichia coli
Moraxella catarrhalis
PCP Pneumocystis jiroveci Trimethoprim-sulfamethoxazole
Corticosteroids if hypoxic
Mycobacterial Mycobacterium tuberculosis Isoniazid, rifampin, pyrazinamide as induction for
2 mo (add fourth drug if suspected drug resistance
or smear-positive pulmonary TB or smear-negative
pulmonary TB with extensive parenchymal
involvement or severe extrapulmonary TB or severe
concomitant HIV disease); then maintenance with
isoniazid, rifampin for 4-7 mo for pulmonary TB
Mycobacterium bovis Corticosteroids if endobronchial disease, pericardial
effusion, meningitis
Mycobacterium avium- Surgical excision of localized disease; 4-drug therapy
intracellulare complex for disseminated disease (isoniazid, rifampin,
ethambutol, ofloxacin or ciprofloxacin)
Clarithromycin plus ethambutol
Viral pneumonia Respiratory syncytial virus
CMV Ganciclovir for CMV
Human metapneumovirus
Parainfluenza viruses 1 and 3
Influenza viruses A and B Neuraminidase inhibitor for influenza A or B
Measles virus High-dose vitamin A for measles
HSV Acyclovir for HSV
Varicella-zoster virus Acyclovir for varicella-zoster virus
HPV types 6 and 11 Laser or surgery, topical therapy for HPV
Fungal Candida species Topical nystatin or oral itraconazole, fluconazole
Aspergillus species Amphotericin B
Histoplasma capsulatum Amphotericin B, itraconazole, fluconazole for mild
Cryptococcus neoformans Amphotericin B, itraconazole, fluconazole
Coccidioides immitis Amphotericin B, itraconazole, fluconazole for mild

CMV, cytomegalovirus; HPV, human papillomavirus; HSV, herpes simplex virus; PCP, Pneumocystis pneumonia; TB, tuberculosis.

treatment failure and mortality compared inactivated vaccines (diphtheria, pertussis,

with children born to uninfected mothers.16 tetanus toxoid; inactivated poliovirus;
Prevention of bacterial pneumonia H. influenzae type b; hepatitis B; and pneu-
through immunization is an important strat- mococcal conjugate vaccine) should be given
egy, although the efficacy may be reduced in to HIV-1-infected children at the usual
HIV-1-infected children. Immunization with recommended age.22 Use of the H. influenzae
32 Pulmonary Manifestations of Pediatric Diseases

Mycobacterial Infection

Respiratory disease also may result from infec-

tion with numerous mycobacteria. Mycobac-
terium tuberculosis is the most common cause
of respiratory infection, but localized or
disseminated disease from Mycobacterium bovis
or the nontuberculous mycobacteria (NTM),
particularly MAC may occur (see Table 2-2).
In high tuberculosis (TB) prevalence areas,
M. tuberculosis is an important cause of acute
pneumonia and of chronic respiratory infec-
tion in HIV-1-infected children. Culture-
confirmed pulmonary TB has been reported
in approximately 8% to 15% of children
hospitalized with acute pneumonia in
Figure 2-1. Chest x-ray of a young child with S. aureus
infection showing a large pneumatocele. these areas.11,12,16,29 The incidence of TB
usually primary infection, than in non-HIV
type b conjugate vaccine potentially may infected children is higher in HIV-1-infected
reduce Hib invasive disease by 46% to children.29-32 Coinfection with M. tuberculo-
93% in immunocompetent vaccine recipi- sis and HIV-1 results in more rapid dete-
ents.23,24 The efficacy of this vaccine against rioration of immune dysfunction, viral
invasive disease is reduced, however, in HIV- replication, and HIV-1 progression, and other
1-infected children not receiving antiretrovi- more frequent and severe infections.33-36
ral therapy (44% in HIV-infected compared HIV-1-infected children with TB may pre-
with 96% in uninfected children).19 The sent with nonspecific signs, such as weight
pneumococcal conjugate vaccine has lower loss, failure to thrive, or fever; with signs
efficacy in HIV-1-infected children25-27; nev- and symptoms of acute pneumonia or air-
ertheless, it reduces the incidence of invasive way obstruction (Fig. 2-2); or with chro-
disease caused by vaccine strains by 65% and nic, persistent respiratory symptoms.29,33-36
prevents 13% of radiologically confirmed Cavitary lung disease, or extrapulmonary
pneumonia in HIV-1-infected children not spread. (Fig. 2-3) occurs more commonly in
receiving HAART.25 Immunization also HIV-1-infected children. Multidrug-resistant
reduces the incidence of infection with drug- TB is increasingly prevalent in TB-endemic
resistant pneumococcal strains.25 Reimmu- areas and has a poor prognosis.37 In the
nization after 3 to 5 years is recommended. United States, multidrug-resistant TB is
Adolescents should receive the 23-valent
polysaccharide vaccine.9
Intravenous immunoglobulin (IVIG) is cur-
rently recommended in HIV-1-infected chil-
dren with hypogammaglobulinemia (IgG <4
g/L); two or more severe bacterial infections
in a 1-year period; failure to form antibodies
to common antigens; or chronic parvovirus
B19 infections.14,22,28 IVIG may not offer
additional protection, however, if children
are taking trimethoprim-sulfamethoxazole
(TMP-SMX) prophylaxis.14 Moreover there is
no evidence to suggest that IVIG therapy
offers additional protection for children
receiving HAART. Children with bron-
Figure 2-2. Chest x-ray of a child with culture-con-
chiectasis may benefit from monthly immu- firmed tuberculosis showing compression of the trachea
noglobulin infusions.22 by lymph nodes.
Chapter 2 — Human Immunodeficiency Virus (HIV) Infection 33

Figure 2-3. A, Chest x-ray of a child with miliary tuberculosis with diffuse nodules, producing a “snowstorm” appear-
ance. B, Chest CT scan of a child with miliary tuberculosis showing multiple diffuse small nodules.

uncommon, reported in 2.8% of foreign- young children.6,43 Primary and secondary

born and 1.4% of U.S.-born cases.32 prophylaxis is recommended for severely
Localized or disseminated M. bovis infec- immunosuppressed children based on CD4þ
tion, including pneumonia, has been reported counts.43,44
in HIV-1-infected children occurring weeks to Establishing the diagnosis of pulmonary
years after receiving bacille Calmette-Guérin TB is difficult in HIV-1-infected children,
(BCG) immunization.38-40 The most common for whom clinical scoring systems have not
manifestation of M. bovis disease is ulceration been developed, and in whom anergy may
at the site of vaccination or localized lymph- reduce the reliability of the tuberculin skin
adenopathy; systemic dissemination occurs test. A tuberculin skin test of 5mm or more
more rarely. The risk of disseminated BCG of induration is regarded as positive.7 Tests
disease is greatly increased in HIV-1-infected of T lymphocyte interferon-¡ production
infants.38 The clinical presentation of are promising. A study of children with sus-
disseminated M. bovis may be indistinguish- pected TB reported that the T cell–based
able from M. tuberculosis infection.40 enzyme-linked immunospot assay (ELI-
Disseminated M. bovis infection has a poor SPOT) had a higher sensitivity than the
prognosis with a case-fatality rate of approxi- tuberculin skin test. In HIV-1-infected chil-
mately 50%. dren, the ELISPOT sensitivity was 73% com-
NTM, particularly MAC, may cause pared with 36% for the skin test.45
disseminated disease, including pulmonary Definitive diagnosis and drug resistance
infection, in severely immunosuppressed testing require culture confirmation of M.
HIV-1-infected children; isolated pulmonary tuberculosis.46 Sputum induction was
disease is rare.41 The incidence of NTM dis- reported more recently to be effective and
ease has declined significantly from a rate of safe for culture confirmation in infants and
1.8 per 100 child-years before HAART to 0.1 children, with the yield from a single
after HAART (see Table 2-1).5,9 Children with induced sputum equivalent to that obtained
pulmonary disease are at high risk for dissem- from three gastric lavages.47 Induced spu-
ination; 72% may develop systemic disease tum should be the primary diagnostic
within 8 months.6 Disseminated MAC seems procedure in a child with suspected pulmo-
to be more common in children who have nary TB. In contrast, the culture yield from
transfusion-acquired HIV-1 rather than peri- a single bronchoalveolar lavage (BAL) is
natal acquisition.42 Disease occurs in adults lower than that from three properly per-
with CD4þ counts less than 50 cells/mL; how- formed consecutive gastric lavages.48 The
ever, the threshold is less well established in efficacy of polymerase chain reaction has
34 Pulmonary Manifestations of Pediatric Diseases

been disappointing, with sensitivity on gas- months even years, and a normal radiograph
tric aspirates ranging from 45% to 83% in is not a criterion for discontinuing therapy.6
HIV-1-negative children.46 For children receiving HAART, the antiret-
Definitive diagnosis of M. bovis or MAC roviral regimen should provide optimal TB
relies on isolation of the organism from the and HIV-1 therapy and minimize potential
blood or biopsy specimens.6 If lymphade- toxicity and drug interactions.35,49 Rifampin
nopathy is present, an aspirate and culture induces hepatic cytochrome P-450 enzymes
can be diagnostic. Multiple mycobacterial and may reduce levels of antiretroviral
blood cultures may be necessary to improve agents, particularly protease inhibitors (Pls)
the yield. Culture is essential to differentiate and non-nucleoside reverse transcriptase
NTM from M. tuberculosis and to determine inhibitors (NNRTIs). Rifampin should not
drug susceptibilities. be used in conjunction with single protease
The response to standard TB therapy in inhibitors except for ritonavir.6 Alternatively,
HIV-1-infected children is poorer than in rifampin may be used in conjunction with
HIV-1-negative children, with lower cure rates ritonavir-boosted saquinavir, provided that
and higher mortality.36,37 Optimal therapy high-dose ritonavir boosting (400mg) is
for HIV-1-infected children has not been used.6 Concurrent rifampin with the non-
tested in well-designed clinical studies. nucleoside reverse transcriptase inhibitor
Empiric therapy for pulmonary TB in HIV-1- delavirdine is not recommended; however,
infected children should include three drugs use with efavirenz is possible. Use with nevi-
(isoniazid, rifampin, pyrazinamide) daily for rapine is recommended only when there are
a 2-month induction period; a fourth drug no other options because of the potential
(ethambutol, ethionamide, or streptomycin) decrease in nevirapine levels. Rifabutin is a
should be added if drug resistance is suspected less potent inducer of the P-450 enzymes,
or if there is smear-positive pulmonary TB, and is a suitable alternative to rifampin, but
smear-negative pulmonary TB with extensive there is limited experience with its use in
parenchymal involvement, severe extrapul- children. Adjustments in dosage of rifabutin
monary TB, or severe concomitant HIV-1 and coadministered antiretroviral drugs
disease.6,35,37,49 may be necessary because some drugs
After the induction phase, therapy with decrease rifabutin levels, whereas others
two drugs (isoniazid, rifampin) should be increase levels. For antiretroviral-naı̈ve chil-
continued either daily or three times a dren, the timing of HAART after initiation of
week.22,49 Directly observed therapy (DOT) TB therapy depends on the clinical and
is advised to promote adherence and reduce immunologic severity of disease. In children
the rate of treatment relapse or failure. with severe clinical illness or advanced HIV-
Because high rates of treatment failure occur 1 infection, HAART should be started 2 to
in children treated for 6 months, some 8 weeks after TB therapy to minimize the risk
guidelines recommend 9 months.6,49,50 For of immune reconstitution inflammatory
extrapulmonary TB, the duration of therapy syndrome (IRIS), to optimize adherence,
may be increased to 12 months.6,49 Therapy and to differentiate potential side effects sec-
for drug-resistant TB should be individua- ondary to TB or antiretroviral drugs.49,51-54
lized, using a minimum of three drugs, at Management of BCG disease is difficult.
least two of which are bactericidal. Adjunc- The inherent resistance of M. bovis to pyrazi-
tive corticosteroids may be beneficial in namide, inherent intermediate resistance of
children with complicated TB, including some strains to isoniazid, and the emer-
pericardial disease, meningitis, or an endo- gence of resistance owing to inappropriate
bronchial lesion with airway obstruction; a therapy complicate treatment.55 Although
suggested regimen is 1 to 2mg/kg/day of localized BCG disease is usually self-limited
prednisone tapered over 6 to 8 weeks. A in immunocompetent children, in HIV-1-
chest radiograph should be obtained at infected children, treatment is warranted
baseline and repeated 2 to 3 months into because of the risk of dissemination and
therapy to evaluate response; however, the poor outcome.40 Surgical excision of loca-
chest radiograph may remain abnormal for lized lymphadenopathy is one option.
Chapter 2 — Human Immunodeficiency Virus (HIV) Infection 35

Alternatively, therapy with four drugs (isoni-

Indications for Pneumocystis
azid, rifampin, ethambutol, ofloxacin, or Table 2-3 Pneumonia Prophylaxis in HIV-
ciprofloxacin) in high doses is recom- Infected Children
mended. The optimal duration of therapy is
unknown, but at least 9 months of treatment AGE CD4þT LYMPHOCYTE COUNT*
is recommended, based on experience with 4-6 wk to 12 All patients regardless of
adults.56 mo{ CD4þcount
Treatment of MAC should consist of com- 1-5 yr <500/mm3or <15%
bination therapy with a minimum of two >5 yr <200/mm3or <15%
drugs because monotherapy with a macro- *If CD4þ counts are unavailable, prophylaxis should be given
lide leads rapidly to resistance.6 Initial {
to all symptomatic children indefinitely.100
HIV-exposed children should receive prophylaxis from
recommended therapy is clarithromycin or 4-6 weeks to 4 months; thereafter, prophylaxis may be
azithromycin with ethambutol. Rifabutin discontinued if HIV infection has been excluded, and the
mother is not breastfeeding.
may be added as a third drug in patients Data from references 22 and 100.
with severe disseminated infection; addition
to ciprofloxacin, amikacin, or streptomycin
may be considered depending on the sever- prevent recurrence. Lifelong prophylaxis
ity of illness. is indicated; the safety of discontinuing
For prevention of mycobacterial disease, secondary prophylaxis in the context of sus-
the BCG vaccine may be beneficial for HIV- tained immune restoration after HAART has
1-exposed but uninfected children in areas not been well studied in children.
of high TB prevalence. Chemoprophylaxis
with isoniazid is recommended for a child
who has been exposed to a household con- Viral Infection
tact with TB after active TB disease has been
excluded or for a child with evidence of TB Although respiratory viruses are identified
infection (tuberculin skin test >5mm indu- less frequently in HIV-1-infected children
ration but asymptomatic with a normal hospitalized for pneumonia (approximately
chest radiograph).6,22,49 A study in a high 15%) compared with HIV-1-negative chil-
TB prevalence area found that isoniazid pro- dren (45%), the absolute burden of hospital-
phylaxis given to HIV-1-infected children ization for viral-associated pneumonia is
regardless of tuberculin skin reactivity or a twofold to eightfold greater in HIV-1-
household TB contact substantially reduced infected children.58 HIV-1-infected children
TB incidence by almost 70% and mortality in whom respiratory viruses are identified
by more than 50%. The effect of isoniazid are more likely to develop pneumonia, to
occurred in all categories of clinical HIV-1 have a more prolonged hospital stay, and
illness and in children of all ages. Isoniazid to have a higher case-fatality rate than
prophylaxis should be considered for HIV- HIV-1-uninfected children. Respiratory syn-
1-infected children living in TB endemic cytial virus (RSV) is the most common cause
areas, especially children who are not taking of viral pneumonia, although human
HAART.57 metapneumovirus is emerging as an impor-
Primary prophylaxis for NTM with azithro- tant respiratory pathogen with a spectrum
mycin or clarithromycin should be con- of disease similar to RSV.59 Other respiratory
sidered for severely immunosuppressed viruses causing lower respiratory tract in-
children (Table 2-3) as follows: children young- fection include cytomegalovirus (CMV), ade-
er than 1 year, CD4þ less than 750/mL; chil- novirus, influenza, parainfluenza, and
dren 1 to 2 years old, CD4þ less than 500/mL; measles (see Table 2-2).58 Treatment may be
children 2 to 6 years old, CD4þ less than beneficial for specific viral pathogens. For
75/mL; children 6 years or older, CD4þ less influenza A or B, a neuraminidase inhibitor,
than 50/mL.22 Rifabutin may be an alternative such as oseltamivir or zanamivir, can reduce
agent in children older than 6 years. Second- the severity of illness and complications.22
ary prophylaxis should be given to children Concurrent bacterial infection has been
with a history of disseminated MAC to reported in 30% to 50% of children
36 Pulmonary Manifestations of Pediatric Diseases

hospitalized with viral pneumonia.16 Pneu- considered in children with mild immuno-
mococcal conjugate vaccine reduces the inci- suppression.22 Varicella vaccine should be
dence of hospitalization for viral-associated considered at 12 to 15 months for asymptom-
pneumonia, suggesting that more severe atic or mildly symptomatic HIV-1-infected
pneumonia requiring hospitalization may children without immunosuppression (Cen-
be the result of viral and S. pneumoniae ters for Disease Control and Prevention cate-
coinfection.60 Influenza vaccine should be gories N1 and A1); vaccine should not be
given annually to all HIV-1-infected children administered to symptomatic immunosup-
at the start of the influenza season.22 The pressed children because of the potential
efficacy of the humanized monoclonal spe- for disseminated disease. Administration of
cific antibody against RSV (palivizumab) or varicella-zoster globulin should be considered
RSV IVIG has not been well evaluated in for HIV-1-infected children exposed to vari-
HIV-1-infected children. Nevertheless, chil- cella or zoster who have no prior history of
dren at risk for severe RSV infection, such as varicella infection or immunization and who
HIV-1-infected infants born prematurely, have not received immunoglobulin within
children younger than 2 years with chronic 2 weeks of exposure.
lung disease, or severely immunosuppressed Measles may result in severe pneumonia
children, may benefit from palivizumab pro- in HIV-1-infected children; measles may
phylaxis. A dose should be given monthly for present without the typical skin rash,
the duration of the RSV season. making the diagnosis particularly difficult.66
CMV is a herpesvirus that can cause pri- Children with suspected measles should be
mary pneumonitis or severe, disseminated given a single high dose of vitamin A
disease in HIV-1-infected children.6 CMV because studies in HIV-1-negative children
infection is more likely to occur in children have shown that vitamin A reduces morbid-
with low CD4þ counts. Coinfection with ity and mortality from measles-associated
CMV and HIV-1 results in more rapid pro- pneumonia.67 Measles, mumps, rubella vac-
gression of HIV-1 disease.6,61 The incidence cine (MMR), a live attenuated vaccine,
of CMV infection has decreased with the should be given to HIV-1-infected children
use of HAART.5,9 CMV may occur in associa- at 12 months of age, unless they are severely
tion with other pathogens, especially Pneu- immunocompromised.22 HIV-1-infected chil-
mocystis.62 Treatment of CMV disease dren exposed to measles should receive a
focuses on preventing disease progression dose of intramuscular immunoglobulin
and not on cure. Ganciclovir is most widely regardless of immunization status.
used, with drug dosing separated into induc- Human papillomavirus (HPV) type 6 or
tion and maintenance dosage.6,22 Prophy- type 11 may produce lesions in the oral cav-
laxis against CMV with oral ganciclovir or ity, pharynx, and larynx and rarely in the
valganciclovir should be given to severely lower airways or lungs; the disease has a ten-
immunosuppressed children or children dency to recur.68 Clinically, the disease may
with a history of disseminated CMV disease manifest as progressive hoarseness, stridor,
to prevent recurrence.63 There are few data wheezing, and respiratory distress.69 Rarely,
on the safety of discontinuing prophylaxis lung nodules, cysts, recurrent pneumonia,
after sustained immune reconstitution on emphysema, or atelectasis occurs in immu-
HAART has occurred. nocompetent children.68,69 Little is known
Other herpesvirus infections may also about the epidemiologic risk of disease in
involve the respiratory tract in HIV-1-infected HIV-1-infected children. An increased preva-
children. Oral herpes simplex virus lesions lence of HPV in HIV-1-infected compared
may spread to involve the upper airways and with HIV-1-uninfected women has been
the larynx, resulting in croup64; disseminated reported; however, the rate of HPV transmis-
disease including pneumonia also may occur. sion to children has not been associated
Pneumonia may occur as a complication of with the HIV-1 status of the mother or
varicella-zoster virus infection.65 Intravenous child.70,71 Laryngeal HPV lesions are diffi-
acyclovir is recommended for therapy; high- cult to treat. Therapy is directed at main-
dose oral acyclovir or valacyclovir may be taining airway patency, so obstructing
Chapter 2 — Human Immunodeficiency Virus (HIV) Infection 37

papillomas should be removed. Adjuvant chest retractions.77 Infants younger than 6

therapy using intralesional cidofovir has months are especially at risk for PCP and
been reported to result in regression and have an acute, severe illness characterized
reduced need for surgery in HIV-1-uninfected by rapidly prominent and progressive hy-
children.72 poxia and increasing respiratory distress.77
In HIV-1-infected children not taking
HAART, four clinical variables have been
Pneumocystis Infection reported to be associated with PCP: age
younger than 6 months, respiratory rate
Children with HIV-1 who are not taking greater than 59 breaths/min, arterial hemo-
HAART or TMP-SMX prophylaxis are at high globin saturation less than 92%, and
risk of developing PCP. Pneumocystis jiroveci absence of a history of vomiting.78 Clinical
(formerly Pneumocystis carinii) originally was signs may be compounded by coinfection
classified as a protozoan. Studies of RNA with bacterial or viral pathogens.16,62,79
sequences show a similarity between fungi Most children have significant hypoxemia
and P. jiroveci, and the organism is now classi- with an alveolar-arterial oxygen gradient
fied as a fungus. Two morphologic forms of greater than 30mmHg.
the organism are found in infected lungs: Laboratory findings include a normal
thin-walled, single-nucleated trophozoites white blood cell count, elevated serum lac-
adherent to type I pneumocytes, and thick- tate dehydrogenase (LDH), and normal IgG
walled cysts containing four to eight single- level. LDH values greater than 1000 IU/L are
nucleated sporozoites. The organism attaches associated with PCP, but they are nonspecific
to the alveolar epithelium, resulting in des- and may reflect the extent of lung involve-
quamation of alveolar cells. As the infection ment.80,81 The chest radiograph usually
progresses, a diffuse desquamative alveolitis shows a diffuse pattern, which progresses to
ensues, and alveoli become filled with a foamy alveolar opacification (Fig. 2-4); however,
exudate consisting of alveolar macrophages hyperinflation, focal infiltrates, cavities, a
and cysts. Interstitial inflammation develops. miliary pattern, pneumothoraces, pleural
PCP was the most common opportunistic effusion, or even a normal appearance also
infection in HIV-1-infected infants before may occur.82,83 Less commonly, PCP may
widespread prenatal HIV-1 screening, TMP- manifest with a pneumothorax, cyst, pneu-
SMX prophylaxis, and HAART.9 In the United matoceles, or a bronchiolitis-like picture.83,84
States, the incidence of PCP has declined sub-
stantially from 1.3 per 100 child-years before
HAART to 0.1 after HAART.5,9 In developed
countries, PCP occurs most commonly in
infants born to women with unrecognized
HIV-1 infection.73 In developing countries,
PCP remains a frequent presentation of HIV-
1 infection in infants and a major cause of
severe pneumonia and death.10,16,74-76 The
incidence of PCP ranges from 8% to 49%
among HIV-1-infected African children hospi-
talized for pneumonia.16,74-76 Increasingly,
PCP also has been reported in older HIV-1-
infected children; 25% of cases in a Zambian
postmortem study occurred in children older
than 6 months.10 Moreover, HIV-1-exposed
but uninfected children have been described
to have a higher risk of PCP compared with
children born to HIV-1-uninfected mothers.16
Children with PCP most commonly have Figure 2-4. Chest x-ray of an infant with Pneumocystis
acute onset of cough, fever, tachypnea, and pneumonia showing diffuse interstitial infiltrates.
38 Pulmonary Manifestations of Pediatric Diseases

PCP is associated with high mortality rang- Transbronchial biopsy may be positive 10
ing from 35% to 87% with higher rates days after starting therapy; the sensitivity
in children with respiratory failure requir- of biopsy is 87% to 95%.6,8
ing mechanical ventilation.74-76,85,86 Timely Because P. jiroveci cannot be cultured,
anti-Pneumocystis therapy may improve the identification requires special stains.77 Silver
outcome, as suggested by historical compari- methenamine, toluidine blue O, and calco-
sons and adult studies in which early use of fluor white are useful for staining cyst forms,
corticosteroids has been associated with whereas Giemsa, modified Wright-Giemsa,
improved survival.87-89 Mutations in P. jiro- and modified Papanicolaou stains iden-
veci dihydropteroate synthetase genes—a tify trophozoites.77,87 Fluorescein-conjugated
key enzyme target of TMP-SMX—have been monoclonal antibodies provide greater sensi-
described in HIV-1-infected patients with tivity, detecting the cyst and trophozoite
PCP, especially with widespread use of TMP- forms.87 Polymerase chain reaction tech-
SMX prophylaxis.87 The clinical importance niques with a high sensitivity and specificity
of mutant strains is unclear, however, and and potential to improve diagnostic accuracy
the response to TMP-SMX treatment varies. are promising, but currently are used mainly
HIV-1-exposed but uninfected children as a research tool.
may also be at increased risk of PCP.16 Empiric therapy for Pneumocystis should be
Transmission of P. jiroveci from an HIV-1- given to any HIV-1-infected child with sus-
infected mother to her HIV-1-uninfected pected PCP because untreated infection is
infant has been reported in a few cases.90-92 usually fatal.77 The most effective therapy is
HIV-1-exposed children may be at risk for TMP-SMX (15 to 20mg/kg/day of TMP) intra-
PCP as a result of close and early exposure venously three to four times a day for 21
to the organism from the mother, reduced days (see Table 2-4).6,22,77,87 Oral treatment
passage of functional maternal antibody, can be used if intravenous therapy is not fea-
impaired cell-mediated immunity, or con- sible, if disease is mild, or after clinical
comitant malnutrition. improvement occurs. The response to ther-
Definitive diagnosis requires identifica- apy may be slow with clinical improvement
tion of P. jiroveci from sputum, bronchial observed by 5 to 7 days.77 Adverse reactions
washings, or lung tissue. Induced sputum to TMP-SMX occur in approximately 15%
using nebulized hypertonic saline has been of cases, but treatment should be discontin-
used to diagnose PCP in children; a positive ued only if reactions are severe, such as neu-
yield has been reported in infants 1 month tropenia or a severe skin rash.22,77,93
of age.75 In this procedure, the child inhales Intravenous pentamidine (4mg/kg/once
a mist of 3% to 5% saline generated by a jet daily) may be an alternative treatment for
nebulizer for 10 to 15 minutes. The diag- children who cannot tolerate TMP-SMX, or
nostic yield using this technique depends who have not responded after 5 to 7 days of
on collection of an adequate specimen. TMP-SMX (see Table 2-4).6,22 Pentamidine is
Nasopharyngeal aspirates have been used associated with a high incidence of adverse
to identify P. jiroveci, but the yield is lower reactions, including pancreatitis, hyperglyce-
than with induced sputum.74-76 Induced mia and hypoglycemia, renal dysfunction,
sputum combined with nasopharyngeal cardiac dysrhythmias, fever, neutropenia,
aspirates may provide a higher yield than and hypotension.94 Patients who show clini-
either technique alone; the sensitivity and cal improvement after 7 to 10 days of intrave-
specificity for induced sputum and naso- nous pentamidine may be switched to an oral
pharyngeal aspirates for diagnosis of PCP drug to complete 21 days of therapy. Other al-
compared with the yield on autopsy have ternative anti-Pneumocystis agents include
been reported to be 75% and 80%.76 BAL atovaquone, dapsone with trimethoprim,
with fiberoptic bronchoscopy is the diag- trimetrexate glucuronate with leucovorin,
nostic procedure of choice in young chil- and clindamycin with primaquine, but
dren, with reported sensitivity of 55% to there is little information on the efficacy or
97%.6 Transbronchial biopsy is not recom- tolerability of these regimens in children
mended unless BAL is nondiagnostic.6 (see Table 2-4).6,22
Chapter 2 — Human Immunodeficiency Virus (HIV) Infection 39

Table 2-4 Treatment of Pneumocystis Pneumonia in Children*


TMP-SMX 15-20mg/kg TMP/75-100mg/kg SMX Intravenous or oral First choice. Oral therapy
per day q6h only if mild disease or
after clinical
improvement occurs
Pentamidine 4 mg/kg once daily Intravenous Use in children who
cannot tolerate TMP-
SMX or when no
response after 5-7 days.
High incidence of side
effects. Should not be
administered with
didanosine owing to
risk of pancreatitis
Atovaquone 30-45 mg/kg/day Oral Limited experience
in children
Trimetrexate No studies in children of established Intravenous Limited experience
glucuronate doses. Adult dose 45mg/m2/day in children
with leucovorin trimetrexate glucuronate with
20mg/m2 leucovorin q6h
Dapsone and No studies in children of established Oral Limited experience
trimethoprim doses. Adult dose 100mg dapsone in children
daily (pediatric equivalent 2mg/kg)
and 15mg/kg trimethoprim
Primaquine and No studies in children of established Oral/intravenous Limited experience in
clindamycin doses. Primaquine adult dose 30mg children. Most effective
daily orally (pediatric equivalent alternative therapy for
0.3mg/kg daily orally). Clindamycin adults with PCP
adult dose 600mg intravenously unresponsive to
q6h for 10 days, then 300-450mg primary therapy
orally q6h for 11 days (pediatric
equivalent 10mg/kg q6h orally or

*Corticosteroids should be added for children with hypoxia.

PCP, Pneumocystis pneumonia; TMP-SMX, trimethoprim-sulfamethoxazole

Corticosteroids are recommended in hy- A few case reports have described the use of
poxemic children. Although no controlled surfactant to improve pulmonary function in
trials on the use of corticosteroids in children children with severe PCP.96,97 Children with
have been performed, corticosteroid use has PCP may be co-infected with bacterial or viral
been reported to reduce the need for mechan- pathogens16,62,79; additional antimicrobial
ical ventilation and to improve survival com- therapy for these should be used when appro-
pared with historical controls.88,89,95 Studies priate. Specifically, CMV co-infection has
of hypoxemic HIV-1-infected adults with been associated with more severe disease
PCP found that corticosteroids improve oxy- requiring mechanical ventilation and a poor
genation and reduce the incidence of respira- outcome. The effect of corticosteroid therapy
tory failure when used within 72 hours of for PCP on CMV pneumonitis is unclear.
starting anti-Pneumocystis therapy.87,89 Corti- Because of the high mortality and morbid-
costeroids are recommended for patients ity associated with PCP, prevention should be
with a PaO2 less than 70mmHg or an alveo- the primary objective. Prevention of PCP is
lar-arterial oxygen gradient greater than an important and effective intervention, if
35mmHg.6 The optimal dose and duration initiated in HIV-1-exposed infants within the
have not been determined, but a recom- first weeks of life.98 Oral TMP-SMX is the most
mended regimen is prednisone, 2mg/kg/day effective prophylactic agent.17,22 In the only
for 7 to 10 days with tapering doses over the randomized controlled study of TMP-SMX
next 10 to 14 days.88 prophylaxis in HIV-1-infected children,
40 Pulmonary Manifestations of Pediatric Diseases

mortality was reduced by 43% and morbidity, pentamidine preclude its use in younger
including hospitalization, was reduced by children.
23% in Zambia.99 The impact on mortality
occurred in children of all ages, suggesting
that prophylaxis may also provide protection Fungal Infection
against bacterial infections.99 TMP-SMX pro-
phylaxis (150mg/m2/day of TMP) may be Chronic Candida infection is common in
given three times a week (single dose on 3 con- HIV-1-infected children and may produce
secutive days, or two divided doses on consec- oropharyngeal, laryngeal, or esophageal can-
utive or alternate days). didiasis and promote the development of
Current recommendations for PCP prophy- gastroesophageal reflux disease.5,6,9,106 The
laxis include the following (see Table 2-3)22,100; incidence of tracheobronchial or esopha-
• All infants born to HIV-1-infected mothers geal candidiasis has declined substantially
from 6 weeks of age until HIV-1 infection with HAART (see Table 2-1).5,9 Infection of
has been excluded in the child and the the upper airways may result in Candida
mother is no longer breastfeeding. supraglottitis, epiglottitis, and a croup-like
• All HIV-1-infected children from 6 weeks of picture.107,108 Laryngeal candidiasis may
age until 1 year. HIV-1-infected children manifest as severe acute airway obstruc-
older than 1 year should receive prophy- tion.107 Pulmonary disease may also occur
laxis if their CD4þ counts are less than in the context of severe disseminated disease.
15% of lymphocytes or if they have symp- Uncomplicated oropharyngeal candidiasis
tomatic HIV-1 disease. A higher CD4þ can be treated with topical therapy (see
threshold for providing prophylaxis may Table 2-2).109 Oral fluconazole, itraconazole,
be applicable in developing countries, how- or ketoconazole are effective alternative
ever, as evidenced by a trial in Zambia agents.6,22,110 For esophageal disease, flucon-
where prophylaxis reduced mortality in chil- azole or itraconazole is recommended.6,22
dren, even in children with higher CD4þ Other fungal infections, including aspergil-
counts.99 Prophylaxis should be continued losis, histoplasmosis, cryptococcosis, and
indefinitely regardless of age or CD4þ counts coccidioidomycosis, may produce respira-
when HAART is unavailable.100 tory illness usually in the context of severe
• Prophylaxis should be continued in chil- immunosuppression and disseminated dis-
dren taking HAART for at least 6 months. ease (see Table 2-2). Pulmonary cryptococcosis
There is little information on the safety of without dissemination may manifest with
discontinuing prophylaxis after immune fever, intrathoracic adenopathy, and pulmo-
reconstitution has occurred. Discontinua- nary infiltrates.6 Occasionally, pulmonary
tion of prophylaxis may be considered in cryptococcosis may be asymptomatic and
children with confirmed immune restora- manifest on routine chest x-rays as pulmo-
tion for 6 months or more as indicated by nary nodules. Pulmonary coccidioidomycosis
two measurements of CD4þ greater than may produce nodules, cavities, or diffuse
25% at least 3 to 6 months apart in chil- reticulonodular infiltrates associated with
dren 2 to 6 years old.101 fungemia and systemic disease. Children
Lifelong prophylaxis should be given to all with severe pulmonary cryptococcosis should
children who have had an episode of PCP; be treated with amphotericin B; maintenance
the safety of discontinuing secondary prophy- therapy with fluconazole or itraconazole
laxis in the context of immune reconstitution can be substituted after improvement has
has not been established. If TMP-SMX is not occurred.6,8,22 Mild or moderate pulmonary
tolerated or cannot be used, alternatives cryptococcosis can be treated with oral flu-
include dapsone (2mg/kg once daily), paren- conazole or itraconazole.6,22 Lifelong suppres-
teral pentamidine (4mg/kg every 2 to 4 sive therapy with fluconazole or itraconazole
weeks), or aerosolized pentamidine (300mg is necessary to prevent relapse.6 There are
via Respigard II inhaler every 4 weeks) if the few data on treatment of pulmonary coc-
child is older than 5 years.6,22,102-105 Safety cidioidomycosis in children, and recomm-
and efficacy concerns regarding aerosolized endations are based on adult data, with
Chapter 2 — Human Immunodeficiency Virus (HIV) Infection 41

amphotericin B recommended for the acute Persistent or recurrent pneumonia is an

illness followed by long-term suppressive important cause of chronic lung disease. In
therapy with fluconazole or itraconazole.6,111 African children, TB commonly produces
Alternatively, in mild disease therapy may be chronic lung disease.30,32-35
initiated with fluconazole or itraconazole.6

Lymphocytic Interstitial Pneumonia

Chronic Lung Disease
LIP, resulting from diffuse interstitial lympho-
cytic infiltration of the lungs, is common in
Chronic lung disease was reported as com-
HIV-1-infected children. The etiology is
mon in HIV-1-infected children before
unknown, but evidence suggests that infec-
HAART.112,113 A longitudinal birth-cohort
study before widespread HAART usage tion with Epstein-Barr virus may initiate a
reported a cumulative incidence of chronic lymphoproliferative response in the presence
radiographic lung changes in HIV-1-infected of HIV-1 infection.114 Clinically, children
children of 33% by 4 years of age.112 The most develop chronic respiratory symptoms, prin-
cipally cough and mild tachypnea.115 Lym-
common chronic radiologic changes were
phoproliferation occurring in other organs
increased bronchovascular markings, reticular
may produce generalized lymphadenopathy,
densities, or bronchiectasis (Fig. 2-5).112,113
These radiographic findings were associated bilateral nontender parotid enlargement, and
with an increased frequency of tachypnea, hepatosplenomegaly.115-117 Digital clubbing
frequently occurs. Hypoxia, if present, is usu-
crackles and clubbing, and a decreased oxygen
ally mild. Children may survive for years with
saturation. Resolution of these chronic
changes was associated with reduced CD4þ a course characterized by recurrent episodes of
cell counts and higher viral loads, and thus acute lower respiratory tract infections.118 Cor
pulmonale or bronchiectasis may develop.119
may be an indication of progression of HIV-1
Children with LIP have moderately ele-
vated serum IgG and LDH levels and titers to
The spectrum of chronic lung disease in
viral capsid antigen of Epstein-Barr virus.114
HIV-1-infected children includes lympho-
Chest radiographs often show a diffuse reticu-
cytic interstitial pneumonia (LIP), interstitial
lonodular pattern, more pronounced cen-
pneumonitis, immune reconstitution inflam-
matory syndrome (IRIS), bronchiectasis, trally (Fig. 2-6A), which may be difficult to
distinguish from pulmonary or miliary TB
malignancies, and bronchiolitis obliterans.
(see Fig. 2-3A).117 Clinically, mild respiratory
illness, the presence of parotid enlargement,
and a reticulonodular pattern on chest x-
ray or computed tomography (CT) scan may
help to distinguish children with LIP from
children with miliary TB.117 Peribronchiolar
thickening alone or normal chest radiographs
also may occur.116,117 Radiographic lesions
may resolve in association with worsening
immune status.120,121 Respiratory status may
improve with the use of HAART122; among
HIV-1-infected adults with LIP, HAART has
been reported to result in resolution of radio-
graphic abnormalities.122
High-resolution CT may improve diagnos-
tic certainty; typical features include microno-
dules of 1 to 3mm in diameter, with a
perilymphatic distribution, and subpleural
Figure 2-5. Early radiologic evidence of chronic HIV-
associated lung disease showing increased broncho- nodules (see Fig. 2-6B).123 The role of nuclear
vascular markings. scanning in confirming the diagnosis has not
42 Pulmonary Manifestations of Pediatric Diseases

increases. Corticosteroids are tapered to 0.5

to 0.75mg/kg on alternate days, provided
that the arterial oxygen saturation remains
adequate.127 Further tapering may be possi-
ble as long as adequate oxygenation is
maintained. No data exist on the use of
inhaled corticosteroids.
LIP is categorized as a World Health Orga-
nization stage 3 AIDS-defining illness and is
an indication for initiating HAART in chil-
dren who are not yet receiving antiretroviral

Interstitial Pneumonitis

Non-specific interstitial pneumonitis may

occur in children with AIDS. The clinical
manifestations are cough, progressive dys-
pnea, and hypoxemia; chest radiographs
show interstitial pneumonitis. Interstitial
pneumonitis may be difficult to distinguish
from LIP or TB without open lung biopsy,117
which is required for definitive diagnosis.

Chronic Pulmonary Infections

Chronic infection, resulting from recurrent

or persistent pneumonia, may produce
chronic lung disease. Infection with
Figure 2-6. A, Chest x-ray of a child with lymphocytic M. tuberculosis is a particularly important
interstitial pneumonia showing multiple nodular densities
throughout the lung fields. B, High-resolution chest CT
and prevalent cause of chronic lung disease
scan of a child with lymphocytic interstitial pneumonia in developing countries.29,30,33-35,117 Distin-
showing a diffuse micronodular pattern. guishing pulmonary or miliary M. tuberculo-
sis from LIP may be difficult; generally,
children with LIP are older and less severely
been well studied, but diffuse pulmonary ill, enlarged parotid glands may occur, and
gallium uptake has been reported in an HIV- chest radiograph shows a reticulonodular
1-infected child with LIP.124 Definitive diagno- pattern.117 A few case reports have described
sis requires lung biopsy.116 Lung biopsies chronic P. jiroveci infection occurring in
reveal collections of lymphoid aggregates, HIV-1-infected children, usually manifest-
often with germinal centers, surrounding the ing with cystic disease or with pneumato-
airways and a significant interstitial infiltrate cele formation.84,129
composed primarily of lymphocytes.
Treatment is symptomatic, including anti-
biotics for acute infections and inhaled Immune Reconstitution
bronchodilators. Oxygen is administered Inflammatory Syndrome
for hypoxia as needed. Although there are
no trials of efficacy, case reports indicate a With increasing use of HAART, IRIS asso-
response to systemic corticosteroids.125-127 ciated with mycobacterial infection and
Oral corticosteroids are recommended for with other opportunistic infections such as
children with hypoxia.127 A suggested regi- CMV has been reported.130 IRIS may occur
men is prednisone, 2mg/kg/day for 2 to weeks to months after initiation of HAART
4 weeks, until the arterial oxygen saturation and may result either from unrecognized
Chapter 2 — Human Immunodeficiency Virus (HIV) Infection 43

mycobacterial infection or from a florid and aggressive treatment of intercurrent infec-

immune response directed against a myco- tions. Use of IVIG therapy at 600mg/kg per
bacterial antigen in patients already receiv- dose at monthly intervals may be beneficial.
ing therapy for mycobacterial infection.130
IRIS has been described with different myco-
bacterial species, including M. tuberculosis,
M. bovis, or MAC infection.51,131,132 Most
HIV-1-infected children have an increased risk
cases of IRIS have been described in HIV-1- of malignancy; malignant tumors occur in
infected adults,52,53 but IRIS is increasingly
2.5% of children with AIDS in the United
being recognized in HIV-1-infected children
States.134 Non-Hodgkin lymphoma is most
from high TB prevalence areas.51,54
common, followed by Kaposi sarcoma, leio-
Clinically, IRIS is characterized by a seem-
myosarcoma, and Hodgkin lymphoma.135,138
ingly paradoxical worsening in signs with
Infection with Epstein-Barr virus has been
increasing lymphadenopathy, new clinical
associated with the development of non-
and radiologic respiratory signs, and
Hodgkin lymphoma in HIV-1-infected
fever.51,53,54,132 The tuberculin skin test may children, including children with mild immu-
become positive, and chest radiographs may
nosuppression.135 Primary non-Hodgkin
show development of lymphadenopathy or
lymphoma may arise in a lymph node or be
new infiltrates.53,54 IRIS must be distinguished
extranodal.134,135 AIDS-related non-Hodgkin
from other infections, multidrug-resistant
lymphoma may occur in almost any
TB, or secondary to nonadherence to TB
extranodal site, including the lungs; in addi-
therapy.53 To minimize the risk of IRIS,
tion, pulmonary disease may result from
HIV-1-infected children with confirmed or
dissemination from a primary focus.
probable TB should be treated with antitu- In African HIV-1-infected children, Kaposi
berculous drugs for 2 to 8 weeks before
sarcoma is the most common AIDS-defining
starting HAART.49,53 When IRIS develops in
malignancy, probably because of the preva-
a child who was unknown to have TB,
lence of human herpes virus-8 infec-
therapy for TB should be initiated. If lymph-
tion.136-138 Human herpesvirus-8 may be
adenopathy or respiratory manifestations are
transmitted to a child from an infected
particularly severe, oral corticosteroids may
mother.138 The most common clinical presen-
be beneficial, although there are no con- tation is of violaceous plaques on the skin.139
trolled trials in children.53 Kaposi sarcoma lesions may produce upper
airway obstruction. Pulmonary dissemination
may result in persistent cough, chronic pro-
Bronchiectasis gressive dyspnea, and fever; hemoptysis may
occur with endobronchial lesions.137-139
Bronchiectasis may occur secondary to acute
Abnormalities on chest radiograph include
or chronic infection, including M. tuberculosis;
bilateral adenopathy; perihilar infiltrates;
after recurrent bacterial infections; after a
pleural effusion; or combinations of intersti-
severe viral lower respiratory tract infection; tial, alveolar, or nodular patterns. The finding
or as a consequence of LIP.119,133 Develop-
of poorly marginated discrete lesions on CT
ment of bronchiectasis may be associated
scan might be specific for Kaposi sarcoma.140
with the severity of immunosuppression; of
Definitive diagnosis is made by lung biopsy.
23 HIV-infected children (median age 7.5
years) with bronchiectasis, all had CD4þ cell
counts less than 100cells/mm3.133 Clinical
manifestations include increased sputum pro- Diagnostic Evaluation of an
duction, halitosis, abnormalities on chest aus- HIV-1-Infected Child with
cultation, and digital clubbing. Bronchiectasis Pulmonary Manifestations
should be suspected radiologically when there
are persistent infiltrates or atelectasis in the An HIV-1-infected child often presents with
same anatomic area for longer than 6 months. fever and tachypnea. The differential diagnosis
High-resolution CT is useful to confirm the is extensive, and a systematic approach based
diagnosis. Therapy includes physiotherapy on the clinical course of HIV-1 infection and
44 Pulmonary Manifestations of Pediatric Diseases

epidemiologic context is useful. Most severe for Pneumocystis. For children with milder
complications are infectious, and the likeli- illness, oral antibiotics may be indicated, or
hood increases with decreasing CD4þ cell specific treatment may be given according
counts. Many lower respiratory tract infections to the etiology (see Table 2-2).
are due to coinfections, such as bacterial-viral,
bacterial-bacterial, viral-Pneumocystis, or bac-
terial-Pneumocystis.16 Progressive ventricular Summary
dysfunction and cardiomyopathy also occur
in HIV-1-infected children, associated with Acute and chronic respiratory diseases are
immunocompromise.141,142 It is important an important cause of morbidity and mor-
to exclude cardiac involvement with conges- tality in HIV-1-infected children. The bur-
tive heart failure as a cause of respiratory den of childhood HIV and associated
manifestations. respiratory illness occurs predominantly in
If a child has acute severe respiratory developing countries. Antiretroviral therapy
symptoms, chest x-ray, oxygen saturation, has changed the spectrum of pulmonary
complete blood count, and blood cultures diseases in HIV-1-infected children, result-
should be obtained. Hypoxia with a diffuse ing in a marked reduction in opportunistic
interstitial infiltrate may suggest PCP. A dif- respiratory infections.
fuse miliary pattern may suggest TB, but this
also can be confused with LIP. For etiologic References
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Pulmonary Manifestations
of Immunosuppressive Diseases
Other than Human
Immunodeficiency Virus Infection

Primary Immunodeficiencies 50 Diagnosis and Treatment of

Deficiencies in Immunoglobulin Respiratory Abnormalities in a Child
Production 50 with Secondary Immunocompromise
Deficiencies in Cellular Immunity 53 Owing to Cancer or
Deficiencies in Phagocyte Numbers, Function, Transplantation 74
and Opsonization 59 Radiography 74
Secondary Immunodeficiencies 62 Sputum and Nasopharyngeal Washes, and
Overview 62 Other Indirect Methods for Pathogen
Factors Contributing to the Secondary Detection 74
Immunodeficient State 63 Flexible Bronchoscopy 75
Pulmonary Complications of Cancer Transthoracic Needle Aspiration Biopsy 75
Therapy 64 Open Lung Biopsy 75
Transplant-Related Pulmonary Summary 76
Complications 67 References 76

Infection in an immunocompromised child defenses for even an immunocompetent host.

presents many diagnostic challenges. In The anatomy of the lung, lung products, cell
patients with primary immunodeficiencies, receptors, and host cellular responses all con-
the clinician is often faced with the difficulty tribute to the normal lung defense and disease
of not only diagnosing the infectious agent prevention. A defect in any of these defenses
in the lung but also determining whether this can result in an increased susceptibility to
child with “too many” respiratory infections infection.
actually has an underlying immune problem This chapter first focuses on the primary
predisposing to repeat or atypical infections. immunodeficiencies and the associated cel-
Many of the basic defects in patients with lular defects that predispose to pulmonary
the primary immunodeficiencies come into infections. In this section the discussion of
play in those who are immunosuppressed by roles of specific cell types in lung defenses
cancer chemotherapy or by specific antirejec- provides background for the discussion of
tion therapies after organ transplantation: immune defects arising from cancer chemo-
decreased number or function of B lympho- therapy or use of immunosuppressive drugs
cytes, T lymphocytes, and phagocytic cells as after organ transplantation. Although this
well. The conducting airways branch 20 to portion of the chapter cannot provide an
25 times between the trachea and the alveoli. exhaustive review of all pulmonary abnorm-
The large surface area of the conducting air- alities in primary immunodeficiency states,
ways and alveolar surfaces (>70m2 in an we will also focus on the major immunode-
adult) poses a great challenge for the lung ficiencies as examples of alterations in the

50 Pulmonary Manifestations of Pediatric Diseases

cellular immune system and their pulmo- immunoglobulin and T cell defects. The
nary manifestations. Readers are referred to knowledge of the genetic defects underlying
several more recent reviews for more details these immunodeficiency states continues to
on primary immunodeficiency states.1-6 grow; there are now more than 10 known
The focus of the chapter changes to the gene alterations associated with the pheno-
general principles underlying the immune type of SCID.4 As the molecular genetics
and nonimmune pulmonary complications of these diseases becomes better understood,
of cancer chemotherapy and immunosup- the ability to treat the severe forms of pri-
pressive therapy after organ transplanta- mary immunodeficiency disease with stem
tion. Many of the cellular defects described in cell transplant (SCT) or gene therapy has
the section on primary immunodeficiencies improved in recent years.
come into play in those patients with second-
ary immunocompromise. The chapter con-
cludes with a discussion of diagnostic tools Deficiencies in Immunoglobulin
available for defining the underlying causes Production
of pulmonary abnormalities in patients with
immunodeficiency or immunosuppression. Overview
IgG and IgA are found in the epithelial
airway–lining fluid and play important roles
Primary Immunodeficiencies in lung defense against bacteria. Deficien-
cies in these antibodies occur in many
This section focuses on the pulmonary mani- primary immunodeficiencies and usually
festations of primary immunodeficiency result in chronic sinopulmonary infections.
diseases. More than 100 primary immunode- Secretory IgA is the predominant immuno-
ficiency diseases are well-characterized clini- globulin isotype present in airway secretions.2
cally or at the molecular level, or both.1,4 Secretory IgA serves several functions, includ-
Antibody deficiencies are the most common ing neutralization of viruses and exotoxin,
primary immunodeficiency diseases, account- enhancement of lactoferrin and lactoperoxi-
ing for about 70% of cases.7 Patients with dase activities, and inhibition of microbial
deficiencies in antibody production typically growth. Because dimeric IgA is able to bind
acquire infections from encapsulated (Strepto- two antigens simultaneously, it is capable of
coccus pneumoniae, Haemophilus influenzae, forming large antigen-antibody complexes.
and Staphylococcus species) and gram-negative In this manner, IgA neutralizes microbes,
(Pseudomonas species) organisms. Chronic facilitates their removal by mucociliary clear-
fungal and opportunistic infections are rare. ance, inhibits microbial binding to epithelial
Viral infections are handled normally, with cells, and inhibits uptake of potential aller-
the exception of enteroviruses, which can gens. Although concentrations of IgG in
cause persistent meningoencephalitis.3,7 the upper airway are less than the concentra-
In contrast, defects in T cell function lead tions of IgA, all IgG subclasses are detectable
to infections by viruses and opportunistic in respiratory secretions, and it is the primary
organisms. Affected infants can present antibody found in lower respiratory secre-
early in life with chronic diarrhea and failure tions. As opposed to IgA, which is actively
to thrive. Persistent infections with opportu- transported into the airway, IgG reaches
nistic organisms (Candida albicans, Pneumo- the airway largely by transudation through
cystis jiroveci [formerly P. carinii]) and viral the mucosa. IgG functions by opsonizing
infections often can be fatal.3,7 Patients with microbes for phagocytosis and killing, activat-
T cell defects cannot reject allografts, placing ing the complement cascade, and neutralizing
them at risk for fatal graft-versus-host disease many bacterial endotoxins and viruses.
(GVHD) if they receive nonirradiated blood Deficiencies in IgA and IgG result in loss of
or blood product transfusions. Infants with mucosal protection against numerous patho-
severe combined immunodeficiency (SCID) gens. Selective IgA deficiency (defined by
have absent T cell and B cell function, placing a serum IgA concentration <0.05mg/mL)
them at risk for infections manifested by may be asymptomatic; it is often detected
Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases 51

in healthy individuals during routine blood Patients with X-linked agammaglobulin-

donor screening. Symptomatic individuals emia have a block in differentiation at all
present with various manifestations, includ- stages of B cell development, whereas T cell
ing recurrent sinusitis, otitis media, pharyngi- numbers and function are preserved. Ini-
tis, bronchitis, pneumonia, chronic diarrhea, tially, infants with X-linked agammaglobu-
and autoimmune syndromes. Individuals linemia are protected by circulating
with associated IgE deficiency tend to have maternal antibodies, but later develop recur-
less serious pulmonary disease, in contrast to rent sinopulmonary infections and may
individuals with normal or high IgE, who in progress to bronchiectasis.9,11,12
addition to the aforementioned disorders Similar to X-linked agammaglobulinemia,
may have allergic respiratory problems and common variable immunodeficiency is
pulmonary hemosiderosis. IgA deficiency is characterized by impaired antibody pro-
associated with increased frequency of neo- duction of all major classes. In contrast to
plastic and autoimmune disorders.2 IgG defi- X-linked agammaglobulinemia, patients
ciency is associated with recurrent otitis with common variable immunodeficiency
media, sinusitis, bronchitis, and pneumonia. have normal numbers of circulating B cells;
In addition, recurrence of airway infections however, these B cells do not differentiate
may result in chronic airway injury with into antibody-secreting plasma cells. Com-
bronchiectasis more frequently in patients mon variable immunodeficiency affects
with IgG deficiency than in patients with males and females, and in some cases seems
isolated IgA deficiency. The combination of to be inherited in an autosomal domi-
altered opsonic activity and bronchiectasis nant pattern with incomplete penetrance.
can result in chronic colonization with Patients can present in infancy but may pre-
respiratory pathogens, such as Pseudomonas sent in late childhood to adulthood. Common
aeruginosa. variable immunodeficiency likely represents
Compared with IgG and IgA, IgM seems several different genetic disorders.13-16
to play little role in lung defense. Most Isolated IgA deficiency is the most com-
IgM remains in the vascular space owing to mon primary immunodeficiency disease,
its high molecular weight. IgM does gain with an incidence of 1 in 333 to 1 in 700 in
access to the airway, however, by exudation whites. The clinical manifestations of isolated
or by active secretion via secretory compo- IgA deficiency vary. Some affected patients
nents. IgM is capable of agglutinating bacte- are asymptomatic, whereas others can have
ria and activating the complement cascade. recurrent respiratory and gastrointestinal
IgE seems to participate in immunity to infections, allergy, and increased incidence
parasites. It binds to the parasites, and eosino- of autoimmune disease and malignancies.2,3
phils bind to the opsonized organisms via Because these patients can make IgG, how-
the IgE Fc receptors. Eosinophils are stimu- ever, bronchiectasis is uncommon compared
lated to release granular contents, resulting with X-linked agammaglobulinemia or com-
in lysis of the parasite. The major manifes- mon variable immunodeficiency.
tation of the presence of IgE in the respira- Isolated IgM deficiency is not associated
tory tract is related to its role in allergic with recurrent respiratory infections. Indi-
disease. viduals with IgM deficiency seem to have a
specific defect in B lymphocyte maturation,
Specific Diseases but the B lymphocytes are capable of secret-
Antibody production is altered in many pri- ing other antibody isotypes. The autosomal
mary immunodeficiency states (Table 3-1). recessive form of hyper-IgM syndrome
Severe recurrent infections associated with is caused by deficiency in nucleotide-
bronchiectasis occur with combined defi- modifying enzymes, UNG (uracil nucleoside
ciencies in IgA and IgG production. X-linked glycosylase) and AID (activation-induced
agammaglobulinemia, the first primary im- cytidine deaminase), expressed only in B
munodeficiency disease to be recognized, by cells that operate on sequential steps in anti-
Bruton in 1952,8 has been found to result body class switching.17 This form of hyper-
from mutations in Bruton tyrosine kinase.9,10 IgM syndrome is accompanied by decreased
Table 3-1 Primary Immunodeficiencies with Antibody Underproduction

Pulmonary Manifestations of Pediatric Diseases

X-linked agammaglobulinemia X-linked Xq21.3- Deficiency in Bruton <1% circulating B cells Recurrent sinopulmonary
(Bruton agammaglobulinemia) Xq22 tyrosine kinase infections
Block in B cell differentiation Most manifest in infancy, 20%
manifest in 3-5 yr old
Deficiency in Bronchiectasis in right middle
immunoglobulins of all lobe and bases
types and isotypes
IgA deficiency Variable (1/333- 17p11 TACI Deficient isotype switch to IgA Bacterial pneumonias, sinus
1/700 births) disease
Possibly Others Associated gastrointestinal
6p21.3 infections
Increased atopy and neoplastic
and autoimmune disorders
Common variable AD with 17p11.2 TACI Impaired production of all Onset from early childhood to
immunodeficiency (likely incomplete major antibody classes adulthood
several diseases) penetrance 2q33 ICOS Absent immunoglobulins Increased susceptibility to
recurrent sinopulmonary
16p11.2 Others Normal number of B cells Leads to bronchiectasis
22q13.1- Failure to differentiate into Associated with autoimmunity
22q12.21 antibody-secreting cells in 20%
Abnormal T cells in 60%
Autosomal recessive AR Mutations in m, a, l5, All isotypes, decreased B cells Severe bacterial infections
agammaglobulinemia BLNK, or LRRCE genes
Immunoglobulin heavy chain AR D14q32 D immunoglobulin Decreased IgG1, IgG2, IgG4, Recurrent bacterial infections
deletions heavy chains IgE, IgA1, IgA2
ICOS deficiency AR 2q33 Mutation in ICOS gene Decreased all isotypes Recurrent bacterial infections
Hyper-IgM syndrome AR 12p13 Mutation in AID and Decreased IgG and IgA Recurrent bacterial infections
12q23- Deficient B cell switching
2q24.1 Normal T cells

AD, autosomal dominant; AID, activation-induced cytidine deaminase; AR, autosomal recessive; ICOS, inducible T cell costimulator; TACI, transmembrane activator and calcium modulator
and cyclophilin ligand interactor; UNG, uracil nucleoside glycosylase.
Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases 53

levels of IgG and IgA, resulting in an defense. Bronchial-associated lymphoid tis-

increased propensity to bacterial infection sue comprises intraepithelial lymphocytes,
(see Table 3-1).17 macrophages, dendritic cells, and natural
Isolated IgE deficiency has not been killer (NK) and NK-T cells that recognize for-
reported. IgE deficiency in combination with eign substances, invading organisms or their
IgG4 deficiency has been described in a exoproducts, and products of cell injury
patient who had recurrent otitis media and using innate receptor systems. The dendritic
sinusitis. Hyper-IgE syndrome is discussed in cells or macrophages interact with them
the section focusing on phagocytic disorders. and interact with lymphocytes to create the
cellular immune responses, or to signal anti-
Diagnosis body production. These cells migrate to local
In patients with suspected immunoglobulin lymph nodes, tonsils, or adenoids; process
deficiency, quantitation of total serum IgA antigens; generate cytokines; and generate
and IgG, and IgG subclasses should be per- the adaptive immune responses. Extensive
formed along with measurement of the anti- reviews of humoral (B cell mediated) and
body response to protein (diphtheria and cellular (T cell mediated) immunity, antigen
tetanus toxoids) and polysaccharide (S. presentation, and cellular activation are well
pneumoniae, H. influenzae, Neisseria meningi- beyond the scope of this chapter; however,
tidis) vaccines. In addition, flow cytometry we briefly discuss the roles of T lympho-
to quantify B and T cell numbers and B cytes and cellular immunity with respect to
and T cell stimulation studies should be lung defense.
done if immunoglobulin levels are low. Spe- Several types of T lymphocytes contribute
cific genetic studies can be done to identify to lung immunity and tissue pathology.18-23
patients with several of the immunoglobu- Two major types of antigen receptors are
lin primary immunodeficiency diseases used by T lymphocytes—the gd T cell recep-
(see Table 3-1). tor (discussed later) and the ab receptor
(used by the CD4þ and CD8þ T cell popula-
Treatment tions). The ab T cell mounts cytolytic
IgG-deficient patients with recurrent respira-
responses to infected cells, makes cytokines,
tory tract infections often benefit from pro-
and stimulates B cell responses (see later). ab
phylactic antibiotics, intravenous gamma
T cells expressing the receptor protein, CD4,
globulin therapy, and the use of airway
are termed T helper cells. CD4þ T cells recog-
clearance techniques. Patients with selective nize antigens presented via the MHC class II
IgA deficiency are treated symptomatically antigen and provide effector function pri-
for respiratory, gastrointestinal, and aller- marily by the release of cytokines. T helper
gic problems. Because most preparations cells can be differentiated further phenotyp-
of gamma globulin contain IgA, the use of ically into Th1 and Th2 populations based
gamma globulin increases the risk of ana- on their profiles of cytokine production.
phylaxis if the recipient has anti-IgA anti- Th1 cells differentiate in the presence of
bodies. Transfusion of blood products interleukin (IL)-12 and IL-18, and produce
presents a similar problem for these indivi- interferon-g, IL-2, and tumor necrosis fac-
duals. In patients with a combined IgA and tor-a in response to antigen. These cells
IgG deficiency who need immunoglobulin have been regarded as responsible for the
therapy or the transfusion of blood pro- delayed hypersensitivity response to viral
ducts, it is crucial to ensure that the recipi- or bacterial infection, stimulating local mac-
ent does not have IgA antibodies or use a rophage activation and neutrophil recruit-
preparation that does not contain IgA. ment, and altering specific T cell responses.
Th2 cells are driven to differentiate by the
Deficiencies in Cellular Immunity presence of IL-4, and in the presence of
antigen they respond by making IL-4, IL-5,
Overview IL-10, and IL-13. These cytokines are respon-
Bronchial-associated lymphoid tissue func- sible for driving B lymphocytes to make
tions in the development of adaptive lung antibodies and lead to the recruitment and
54 Pulmonary Manifestations of Pediatric Diseases

activation of basophils and eosinophils. The births.7 Children with defects in T cell func-
Th2 phenotype has been associated with an tion can present with abnormal ability to limit
allergic/asthmatic phenotype in mouse “usual” childhood respiratory viral infections,
models and human studies.24 which can be persistent or life-threatening
ab T cells expressing CD8 are cytotoxic (e.g., respiratory syncytial virus [RSV], parain-
cells. In response to peptides presented by fluenza virus, influenza virus, and adenovi-
the MHC class I molecules, CD8þ T cells rus). Common childhood viral infections,
function in target cell toxicity. CD8þ T cell such as varicella-zoster virus and measles, can
toxicity is mediated by the release of cellular cause serious lung infections in immunode-
granules containing perforin (perturbs the ficient or immunosuppressed children. Chil-
cell membrane) and granzymes (disrupt dren with T cell immunodeficiencies are
target cells by altering intracellular targets). more susceptible to opportunistic patho-
In addition, CD8þ T cells can initiate apop- gens—agents that typically do not cause
tosis in target cells by Fas-FasL interactions. infections except in the context of immunode-
CD8þ cells reinforce viral defenses by ren- ficiency or immunosuppression, such as cyto-
dering adjacent cells resistant to infection, megalovirus (CMV) and P. jiroveci (Fig. 3-1).
presumably by release of interferons. Children with T cell deficiencies can present
Three additional subsets of T cells con- in the first months of life with diarrhea and
tribute to innate lung responses, including failure to thrive, or with persistent infections
recognition and elimination of tumor cells with Candida albicans, P. jiroveci, varicella-zos-
and certain pathogens using limited sets of ter virus, adenovirus, RSV, or CMV.7,34 Patients
conserved recognition receptors. NK cells with T cell primary immunodeficiency disease
are bone marrow–derived lymphocytes that may show abnormalities in antibody produc-
are distinct from either B or T cells. NK-T tion because B cell function in antibody pro-
cells are T cells that express the NK cell duction is T cell–dependent. T cell primary
marker, NK1, a highly restricted/limited rep- immunodeficiency disease can manifest with
ertoire of the CD3/T cell receptor complex bacterial infections as in patients with primary
with specificity for antigens presented in antibody deficiencies as described earlier.3
association with CD1. These cells most Severe combined immunodeficiency
closely resemble CD4þ T cells in terms of (SCID) is an immunodeficiency character-
cytokine production. Finally, gd T cells have ized by a severe reduction in the number
a limited diversity of T cell receptors that or function of T cells, which results in the
recognize self and bacterial/protozoan anti- absence of adaptive responses (Table 3-2).
gens. These innate lymphocytes are consid-
ered to be a first line of defense against
tumors and infection, and in modulating
inflammation in the lung.25,26
T cell responses are tightly regulated. T cell
responses are necessary to eliminate patho-
gens and for immune memory; lack of T cell
function can lead to serious life-threatening
infections.1,3,4,6,7,27 Uncontrolled responses
can cause autoimmune inflammatory dis-
eases, however.28-33 In this section, we dis-
cuss primary immunodeficiency disease
associated with T lymphocyte dysfunctions.

Specific Diseases
Mutations in the function of B cells or T cells Figure 3-1. Chest radiograph shows bilateral interstitial
result in immunodeficiencies of antibody pro- and alveolar infiltrates in a child with acute lymphocytic
duction, cellular immunity, or both. The inci- leukemia and Pneumocystis jiroveci (formerly P. carinii)
pneumonia. (From Long S, et al: Principles and Practice of
dence of these deficiencies is unknown, but Pediatric Infectious Disease, 2nd ed. Philadelphia, Churchill
has been estimated to be 1 in 10,000 live Livingstone, 2003. page 578)
Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases
Table 3-2 Primary Immunodeficiencies with T Cell Defects (Examples)

gc deficiency XL Xq13.1 Mutations in common g chain of IL-2, Markedly decreased Severe infections with opportunistic organisms
IL-4, IL-7, IL-9, IL-15, and IL-21 natural killer cells soon after neonatal period
Markedly decreased Manifest with failure to thrive, chronic diarrhea,
T cells persistent thrush, pneumonia, sepsis
Decreased serum
CD45 deficiency AR 1q31- Mutation in CD45 gene As per gc SCID As above
Jak3 deficiency AR 19p13.1 Janus kinase-3 deficiency (Jak3) As per gc SCID As above
IL7Ra deficiency AR 5p13 Mutation in IL7RA gene Marked decrease in As above
T cells
Decreased serum
CD3d deficiency AR 11q23 Mutation in CD3D gene As per IL7Ra As above
CD3e deficiency AR 11q23 Mutation in CD3E gene As per IL7Ra As above
ADA deficiency AR 20q13.11 Mutation in ADA gene As per gc SCID As above
Axial skeletal abnormalities


Pulmonary Manifestations of Pediatric Diseases
Table 3-2 Primary Immunodeficiencies with T Cell Defects (Examples)—Cont’d

RAG1/2 AR 11p13 Mutation in RAG-1 or RAG-2 Markedly decreased T As above
deficiency and B cell numbers
Decreased serum
Defective VDJ
Artemis AR 10p13 Mutation in artemis gene As above for RAG1/2 As above
Other T Cell Defects
X-linked hyper- XL Xq26- Mutations in CD40 ligand (CD154) Normal T cells Neutropenia, thrombocytopenia, opportunistic
IgM syndrome Xq27 Only IgM and IgD infections
bearing B cells
CD8 deficiency AR 2q12 Mutation in CD8A gene Absent CD8, normal As for Artemis
CD4 numbers
TAP-1 and TAP-2 AR 6p21.3 Mutation in TAP-1 or TAP-2 As for CD8 deficiency As for CD8, vasculitis occurs
DiGeorge AD 22q11.2 TBX1 Decreased or absent Cardiac and thymic defects, variable TCID
syndrome CD3þ cells

AD, autosomal dominant; AR, autosomal recessive; SCID, severe combined immunodeficiency; TCID, T cell immunodeficiency; XL, X-linked.
Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases 57

This disease phenotype is the consequence deficiency. DiGeorge syndrome is usually

of mutations in at least 10 different genes due to gene defects on chromosome 22,
located on six different chromosomes (see leading to abnormal development of the
Table 3-2).4,5 Four lymphocyte phenotypes third and fourth pharyngeal pouches dur-
have been identified associated with SCID, ing embryogenesis. This leads to aberrant
based on the effects of the mutation on development of several organs, including
T cell, B cell, and NK cell maturation the thymus, parathyroid glands, and heart.
(TBþNKþ, TBþNK, TBNKþ, TBNK) The degree of thymic hypoplasia varies,
(see Table 3-2). SCID causes severe infec- resulting in a variable severity in the T cell
tions with opportunistic infections in the deficiency.3,36 In 80% of patients, the
neonatal period. immunodeficiency is mild. Severe T cell
Because of lack of graft rejection capabil- deficiency and secondary deficient anti-
ity, these infants are at risk for GVHD if body responses can result from the thymic
transfused with nonirradiated blood prod- hypoplasia, however, leading to a severe
ucts. They are also at risk for severe systemic disease phenotype (approaching SCID in
infection when immunized with live viruses severity). It is important to evaluate the
(e.g., polio, measles, or varicella) or with presence of a thymus in patients with con-
bacille Calmette-Guérin. Diagnosis is possi- otruncal cardiac defects and hypocalcemia
ble at birth, with most affected infants hav- because the T cell deficiency in DiGeorge
ing lymphopenia (<2000 lymphocytes/mL syndrome places these patients at risk of
blood) and decreased in vitro proliferation GVHD after transfusion with nonirradiated
studies.5 Even in the absence of a normal blood products.3,36
thymus, T cell development can be Not all T cell immunodeficiencies mani-
achieved after SCT, and this is the standard fest with a severe propensity for infections.
of care for these infants. Survival is Isolated CD8þ T cell developmental and sig-
improved if SCT occurs within the first 4 naling defects can have a milder form of
weeks of life.5 The improved survival of immunodeficiency. Mutations in the CD8a
early transplants is attributed to the acqui- molecule prevent the final assembly of the
sition of opportunistic infections and their CD8þ T cell receptor signaling complex.
complications. Mutations in the MHC-1 molecule (binds
The X-linked form of hyper-IgM syndrome to the T cell receptor) caused by TAP1/TAP2
is caused by a defect in the CD40 ligand mutations or a mutation in the TAP-binding
(CD40L) expressed by activated CD4þ T cells protein prevent normal antigen presenta-
(see Table 3-2). The CD40-CD40L interaction tion to the T cell receptor. These mutations
is crucial in B cell–T cell signaling. A defect cause a deficiency in CD8þ T cell function
in this interaction results in normal to ele- but no deficiency in the CD4þ T cells,
vated IgM; reduced serum IgG, IgA, and and lead to a milder disease phenotype
IgE; and reduced memory B cells.17,35 In (see Table 3-2).1,5-7
addition to the immunoglobulin defects, The dysregulation of cellular immunity can
patients with X-linked hyper-IgM syn- lead to immunodeficiency, autoimmunity,
drome have opportunistic infections, neu- and malignancy, as described previously for
tropenia, thrombocytopenia, seronegative X-linked hyper-IgM syndrome (Table 3-3).
arthritis, inflammatory bowel disease, and Wiskott-Aldrich syndrome is an X-linked dis-
greater likelihood of malignancies. The order characterized by eczema, thrombocyto-
increased risk of opportunistic infections, penia with small defective platelets, and
autoimmune diseases, and malignancies is recurrent infections. Patients with Wiskott-
attributed to defective T cell–antigen-pre- Aldrich syndrome have impaired response to
senting cell interactions owing to the polysaccharides and protein antigens and
CD40L defect. P. jiroveci pneumonia has aberrant T cell function.37 Systemic and
been reported in 40% of patients with chronic sinopulmonary infections develop
mutations in CD40L. in the first year of life. Pulmonary infections
The cellular immunodeficiency in DiGeorge can be caused by encapsulated bacteria
syndrome results from primary T cell (S. pneumoniae), viruses (herpes simplex virus),
Pulmonary Manifestations of Pediatric Diseases
Table 3-3 Other Defined Immunodeficiency Syndromes with Autoimmunity or Malignancies

Wiskott-Aldrich XL Xp11.22-11.23 Mutation in Cytoskeletal defect Thrombocytopenia
syndrome WASP gene affecting Immunodeficiency
hematopoietic stem
cell derivatives Autoimmune disease
Progressive decrease in T cells
Ataxia-telangiectasia AR 11q22-q23 ATM Disorder of cell cycle Thymic hypoplasia
checkpoint leading to Increased a-fetoprotein
instability Telangiectasia
Sensitivity to Ionizing Radiation
Increased risk of malignancies, particularly lymphoid
X-linked XL Xq25 SH2D1A Altered adapter protein Uncontrolled T cell proliferation in Epstein-Barr virus
lymphoproliferative regulating intracellular infection, fatal mononucleosis, ineffective viral
disease signaling elimination, lymphoma, hypogammaglobulinemia
ALPS1a AR 10q24.1 CD95 Excessive CD4CD8 ab Autoimmunity
TCRþ T cells Hypergammaglobulinemia
Defective lymphocyte Lymphoproliferation
Increased risk of lymphoma
ALPS1b AR 1q23 CD95L As above As above, plus lupus syndrome
ALPS2b AR 2q33-2q34 CASP8 Defective lymphocyte Recurrent bacterial and viral infections
apoptosis and Autoimmunity, hypergammaglobulinemia,
activation lymphoproliferation

ALPS, autoimmune lymphoproliferative syndrome; AR, autosomal recessive; CASP, caspase; SH2D1A, gene encoding SAP (signaling lymphocytic activation molecule [SLAM]-associated protein);
XL, X-linked.
Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases 59

or opportunistic organisms (P. jiroveci).3,37 Treatment

Patients rarely survive beyond teenage years Treatment depends on the specific immuno-
without SCT. Death usually results from infec- deficiency. Prophylactic antibiotics, antiviral
tion, vasculitis, autoimmune cell cytopenias, agents, or intravenous immunoglobulin can
or lymphoreticular malignancy.37 be used to prevent or ameliorate serious infec-
Ataxia telangiectasia is another complex tions.40 For severe T cell deficiency, SCT early
disease resulting from a disorder of cell cycle in life can be lifesaving. Thymic transplants
regulation that leads to chromosomal have been performed to reconstitute the T cell
instability. Ataxia telangiectasia represents a defects in DiGeorge syndrome.36 Gene therapy
combined immunodeficiency associated has been investigated for specific primary
with neurologic, cutaneous, and immune immunodeficiency disease, but success has
abnormalities.7 These patients have recur- been tempered by the occurrence of leukemia
rent sinopulmonary infection. Their cells in subjects resulting from the insertion of the
have defective DNA repair and are sensitive retrovirus vectors near oncogenes.41 Newer vec-
to ionizing radiation. A concern is that tors may improve the safety of this mode of
repeated exposure to x-rays used in usual therapy.
diagnostic studies places them at risk for lym-
phoreticular cancers and adenocarcinoma.38
Several cellular defects can result in Deficiencies in Phagocyte Numbers,
unchecked cell proliferation and susceptibil- Function, and Opsonization
ity to infections and to tumors. X-linked lym-
phoproliferative disease is another example of Overview
immunodeficiency from aberrant cellular Neutrophils constitute about half the circulat-
control (see Table 3-3). In X-linked lympho- ing white blood cell population, and their pri-
proliferative disease, there is failure to control mary function is phagocytosis and killing of
proliferation of cytotoxic T cells after infection invading pathogens. For the neutrophil to
with Epstein-Barr virus (EBV).39 The most accomplish this, it must respond to signals in
common presentation is severe infectious the area of injury; adhere and transmigrate
mononucleosis, which is fatal in 80% of through the vascular endothelium; migrate to
patients. The defect is in the gene encoding the area of infection; and recognize the patho-
an adapter protein, SH2D1A, a protein that gen, phagocytose, and kill it. Interruption of
helps regulate the proliferation of T cells any of these steps would leave the host suscep-
and NK cells. Autoimmune lymphoproli- tible to infections. When the neutrophil has
ferative syndrome results from defects in migrated into the tissue, its primary purpose
cellular apoptosis (regulated cell death) is to recognize, ingest, and destroy pathogens.
mediated by CD95 (FAS). These patients have Phagocytosis comprises two steps: recognition
autoimmunity, hypergammaglobulinemia, and internalization of the foreign material into
lymphoproliferation, and excessive numbers the phagosome. Killing or neutralization
of CD3þ, CD4, and CD8 T lymphocytes involves a secretory response. Materials may
(see Table 3-3).5 bind directly to the neutrophil, resulting in
ingestion, or opsonization by serum proteins
occurs. Neutrophils exhibit specific Fc-
Diagnosis mediated binding and nonspecific binding
In an infant with possible T cell deficiency, using complement receptors CR1 and CR3.
total blood lymphocyte counts are a reason- Intracellular killing generally is associated with
able place to begin for diagnosis. Functional the initiation of the respiratory burst. The
studies (immunoglobulin responses to pro- importance of this process is shown by
tein and polysaccharide antigen immuniza- patients with chronic granulomatous disease
tions), activation studies, and B, T, and NK (discussed later), whose neutrophils cannot
cell markers can define the nature of the undergo the oxidative burst.42 Deficiencies in
deficiency further. Finally, specific genetic neutrophil numbers, ability to migrate, opso-
studies can be conducted to identify several nization, phagocytosis, or function can render
of the defined mutant genes. the host susceptible to infection (Table 3-4).
Table 3-4 Examples of Immunodeficiency Syndromes with Abnormal Neutrophils, Chemotaxis, or Opsonization

Pulmonary Manifestations of Pediatric Diseases

Neutrophil Numbers
Kostmann syndrome AD 19p13.3 or 1p22 Defects in ELA2 Mistrafficking or repression Neutropenia
or Gfi1 of neutrophil elastase Susceptibility to bacterial and
fungal infections
Congenital neutropenia AD 19p13.3 ELA2 defect As per Kostmann syndrome As above
Cyclic neutropenia AD 19p13.3 ELA2 defect As per Kostmann syndrome Susceptibility to infection at
nadir of neutrophil counts
X-linked neutropenia XL Xp11.22-11.23 WASP Defective regulator of actin Neutropenia, infections as per
cytoskeleton Kostmann syndrome
LAD1 AR 21q22.3 INTG2 (CD18) Defective neutrophil and Delayed umbilical stump
lymphocyte migration separation, recurrent gingivitis
from blood
Lack CD18 Absent tissue neutrophils, blood
Hyper-IgE syndrome ADv 4q21 Unknown Unknown High IgE and eosinophilia
Skin abscesses, pneumonia with
pneumatocele formation
CGD AD Xp23 CYBB;gp91phox Absent cytochrome b 70% Granulomatous lesions of lung,
of cases skin, lymph nodes, and liver:
XL 16q24 CYBA;p22phox Absent cytochrome b <5% Staphylococcus aureus,
of cases Burkholderia cepacia,
Serratia marcescens, Nocardia
AR 7q11.23 NCF1;p67phox Cytochrome positive and Aspergillus species
1q225 NCF2;p67phox
IFNgR1 deficiency AR, AD 6q23 IfngR1 Loss of IFN-g binding Severe infections: Salmonella,
HSV, CMV, parainfluenza, RSV,
IFNgR2 deficiency AR, AD 21q22 IfngR2 Loss of IFN-g binding As above
Complement C2 AR 6p21.3 C2 defect Absent complement activity Pyogenic infection, vasculitis,
Complement C3 AR 19p13.3-p13.2 C3 defect As above Recurrent pyogenic infections
MBL deficiency AR 10q11.2-q21 MBL2 Deficiency in MBL2 Increased pyogenic infections
and sepsis

AR, autosomal recessive; AD, autosomal dominant; ADv, autosomal dominant with variable penetrance; CGD, chronic granulomatous disease; CMV, cytomegalovirus; HSV, herpes simplex
virus; IFN-g, interferon-g; LAD, leukocyte adhesion defect; MBL, mannose binding lectin; RSV, respiratory syncytial virus; SLE, systemic lupus erythematosus; XL, X-linked.
Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases 61

Specific Diseases the reduced nicotinamide adenine dinucleo-

Defects in neutrophil numbers, such as tide phosphate (NADPH) oxidase complex
Kostmann syndrome and cyclic neutropenia, responsible for production of superoxide.3,46
can result from a deficiency in elastase 2 Onset of the disease occurs early in life, with
(see Table 3-4). In cyclic neutropenia, periph- pulmonary infection the most frequent
eral blood counts oscillate in about a 21-day presentation, with fungal organisms pre-
cycle with a nadir approaching an absolute dominating.3,46 Five organisms cause most
neutrophil count (ANC) of 0 and a peak near infections in chronic granulomatous disease:
normal. Life-threatening infections occur S. aureus, Burkholderia cepacia, Serratia marces-
during days around the nadir of neutrophil cens, Nocardia species, and Aspergillus species.
counts. In Kostmann syndrome, the neutro- Bacteremia is rare. Patients with mutations
penia is static. One variant of Kostmann syn- leading to the complete loss of the inter-
drome is caused by a deficiency in ELA2 feron-g receptors (IFNgR1 and IFNgR2) are less
(coding for neutrophil elastase 2). Mutations capable of killing mycobacteria and intracellu-
causing a deficiency of Gfi1 (a zinc finger lar organisms. These patients have been iden-
transcriptional repressor oncoprotein) result tified because of extreme susceptibility to
in ELA2 deficiency and neutropenia.43,44 nontuberculous mycobacteria.46 Viral agents,
Deficiencies in neutrophil migration from including herpes simplex virus, CMV, and
the circulation can result in recurrent infec- RSV, also present severe problems. Mortality
tions. Patients with leukocyte adhesion defi- is high because of recurrent severe infection.
ciency are unable to recruit neutrophils into Opsonization is necessary for neutrophil
sites of inflammation, and, as a result, they killing of several organisms. Serum proteins
sustain recurrent, life-threatening infec- reach the lung through transudation in
tions.45 Patients with leukocyte adhesion response to inflammation, including the
deficiency lack the normal b2 integrins to complement family and mannose-binding
allow neutrophil recruitment from the cir- lectin (MBL) (see Table 3-4). The comple-
culation. These patients have peripheral ment protein cascade is activated by three
neutrophilia, but do not form pus and have independent pathways: (1) the classic path-
difficulty localizing infections because of way, which is activated by antigen-antibody
their defect in neutrophil migration. Recur- complexes (involving IgG or IgM); (2) the
rent infections of the skin, upper and lower alternative pathway, which is activated by
airways, bowel, and perirectal area are com- foreign carbohydrates, such as bacterial
mon and are usually caused by Staphyloccocus and fungal components; and (3) the lectin
aureus or gram-negative bacilli.46 pathway (involving MBL44). The comple-
When neutrophils arrive at the site of ment system functions to coat foreign parti-
infection, defective function can limit their cles in opsonin via the alternative pathway,
ability to clear infection. Job syndrome making the particles more likely to be pha-
(hyper-IgE syndrome) is caused by an gocytosed, to activate phagocytic cells by
unclear defect in phagocyte function and is the local release of chemotactic agents such
characterized by recurrent skin and lower as C5a, and to lyse cells through the activa-
respiratory tract infections, eczema, elevated tion of the late complement components
IgE levels, and eosinophilia. Symptoms C5, C6, C7, C8, and C9 (the membrane
occur within the first month of life with attack complex). Other important aspects
severe eczema, mucocutaneous infections, of the complement pathway are the genera-
sinusitis, and lower respiratory tract infec- tion of anaphylatoxins, such as C3a and
tions with S. aureus or H. influenzae. Devel- C5a, which cause the release of vasoactive
opment of empyema, lung abscesses, and mediators from mast cells, and the genera-
persistent pneumatoceles is common. tion of C3b and C4 on the cell surface,
Chronic granulomatous disease is the most where they interact with specific receptors
common phagocyte disorder, with the on phagocytic cells.47
X-linked form accounting for two thirds of Complement deficiency is associated with
the reported cases (see Table 3-4). Chronic recurrent infections, glomerulonephritis, or
granulomatous disease is caused by defects in collagen vascular diseases such as systemic
62 Pulmonary Manifestations of Pediatric Diseases

lupus erythematosus. Early complement defi- IFNgR1, and IFNgR2) can be measured using
ciencies are associated with systemic lupus flow cytometry. Oxidative burst can be meas-
erythematosus, glomerulonephritis, or other ured using assays for superoxide production
rheumatologic diseases. Pneumonia has been or by measuring NADPH oxidoreductase func-
described in association with C1 deficiency, tion in specialized laboratories. Measuring
although bacterial meningitis is a more com- the CH50 or AH50 can perform functional
mon manifestation. Pneumonia complicated screening for complement deficiency. Specific
by empyema, pneumatoceles, and liver complement components and MBL can be
abscesses has been described as a consequence measured using immunoassays.
of C1r deficiency. Autoimmune disorders
are associated with C2 and C4 deficiency, Treatment
although bacterial infections also occur in Cyclic neutropenia and congenital neutrope-
children with C2 deficiency (the most com- nias can be treated with granulocyte colony-
mon complement deficiency). C3 deficiency stimulating factor.43 Prophylactic antibiotics
(clinically the most severe and least common and antifungal agents, and aggressive therapy
of the complement deficiencies) is associated during acute infections are keys for long-term
with autoimmune disorders and recurrent survival. Patients with chronic granuloma-
infections. C3 acts as an opsonizing agent tous disease also are treated with prophylactic
and plays roles in the classic and alternative trimethoprim-sulfamethoxazole, antifungal
pathways. C3 deficiency results in otitis therapy, and recombinant human inter-
media, pneumonia, sepsis, meningitis, and feron-g. In addition, SCT has been performed
osteomyelitis, most commonly caused by with success in patients with chronic granulo-
S. pneumoniae, N. meningitidis, Klebsiella spe- matous disease.43,46 Treatment of opsonic
cies, Escherichia coli, and Streptococcus pyogenes. defects (complement and MBL) also involves
C5 deficiency produces a complex defect prophylactic antibiotics and immunization
owing to the loss of chemotactic and anaphyla- against encapsulated organisms. Replacement
toxin activities; it leads to decreased lung therapy is usually ineffective.
clearance of S. pneumoniae, but not S. aureus,
in C5-deficient mice. The late complement
deficiencies (C5 through C9) impair serum bac- Secondary
tericidal and cytolytic activities. Susceptibility Immunodeficiencies
to systemic infection with encapsulated organ-
isms, such as N. meningitidis and S. pneumoniae, Overview
is increased; however, pulmonary infections
are uncommon. C3 deficiency manifests with Predisposition to infection occurs when there
the most severe disease phenotype.44 is an imbalance between the invading organ-
MBL also participates in opsonization ism and the host’s ability to prevent the infec-
through activation of the complement path- tion. This imbalance can occur because of the
way.44 MBL deficiency is common, occurring organism itself (portal of entry, type of organ-
in 10% of the general population.48 Although ism, antibiotic resistance, virulence factors) or
infections are uncommon in healthy individ- host factors that prevent the ability of the host
uals, MBL deficiency in patients receiving che- to prevent or limit invasion. Host defenses
motherapy or SCT or with specific leukemias consist of innate and adaptive processes.
can result in suppression of phagocytic activ- Innate immunity provides the initial defense
ity. MBL deficiency is associated with autoim- against infection, whereas adaptive immunity
mune and inflammatory diseases.48 develops slowly and provides specific defense
against specific invading organisms and mem-
Diagnosis ory to protect from reinfection.
Assessment of neutrophil deficiency begins Earlier in this chapter, we discussed pri-
with performing cell counts and assessing mary defects in the immune system and
the ANC. Specialized laboratories can perform how they predispose to infections. In this
specific measures of neutrophil chemotaxis section, the focus is on secondary immuno-
and oxidative burst. Receptor levels (CD18, deficiencies that arise after childhood
Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases 63

cancers and chemotherapy, and related to respiratory epithelium also serves functions
transplantation (heart, liver, kidney, and in the regulation of water and ion movement
lung transplantation, and SCT). Many of into the airway mucus,51 and serves as its
the concepts presented earlier apply to the own reservoir for injury repair.50
secondary immunodeficient states. Defi- The respiratory epithelium also performs
cient numbers of lymphocytes or phago- more specific interactions with the innate
cytic cells or defective functions that can and adaptive immune systems. Alveolar type
occur in the primary immunodeficiency dis- II cells manufacture surfactant proteins A and
ease also can occur secondary to the under- D (described later).52,53 The respiratory epi-
lying malignancy, chemotherapeutic agents thelium can be induced to produce numer-
used for the cancer, or immunosuppression ous bioactive cytokines,54 and express
after transplantation. The common themes numerous adhesion molecules that support
and several disease-related processes that interactions between the epithelial cell and
occur and predispose the host to lung com- inflammatory cells recruited to the lung.
plications are reviewed. We first consider The other epithelial layers throughout the
the broad issues that apply in the secondary body serve similar functions. Disruption of
immunodeficiency states in general, then the epithelial layer by injury caused by che-
focus on problems specific to cancer chemo- motherapeutic agents, irradiation, or GVHD
therapy, solid organ transplantation, SCT, can allow invasion by potentially pathogenic
and lung transplantation. organisms, such as S. aureus, gram-negative
bacilli, and Candida species, which normally
colonize the various epithelial surfaces.
Factors Contributing to the Bypassing the epithelial barrier by transcuta-
Secondary Immunodeficient State neous catheters provides potential routes of
entry for infection. Treatment with broad-
The airway epithelium is more than a pas- spectrum antibiotics reduces the normal flora
sive barrier to airway water loss or a passive at the epithelial surfaces, allowing over-
fortification against bacterial and viral infec- growth of potentially more invasive organ-
tion. Published data support the active par- isms and potentially selecting for antibiotic-
ticipation of the airway epithelium in the resistant organisms (Table 3-5).
regulation of airway smooth muscle tone, The underlying disease state or chemother-
the physical removal of inhaled substances apy (cytotoxic or immunosuppressive) can
through ciliary clearance, and secreting or alter the numbers or function of lymphocytes
transporting broad-spectrum antimicrobial and phagocytic cells, resulting in immunode-
substances. Finally, the respiratory epithelium ficient states similar to those discussed earlier
is a functional interface between the patho- in the sections on primary immunodeficiency
gen and innate or adaptive immune response. disease. Organ failure resulting from the under-
The airway epithelium is a pivotal structure lying disease state or secondary to chemother-
in respiratory physiology and pathology. apy can reduce further the host defenses to
The respiratory epithelium participates in infection (e.g., renal failure with uremia, liver
passive lung immunity in many different failure with loss of complement or MBL
ways. The epithelium presents a physical bar- production, splenectomy secondary to malig-
rier to viral and bacterial invasion, lining the nancy). Thrombocytopenia may reduce heal-
respiratory tract from the nose to the alveoli ing, extending the duration of breakdown of
with a wide range of cell phenotypes.49,50 Cil- the epithelial barriers. The underlying disease
iated epithelial cells are important in moving or its treatment can alter the nutritional state
mucus up the airway, removing particulate of the patient, further limiting healing and
material, and injury to these cells by agents epithelial barrier functions (see Table 3-5).
such as oxidants can alter ability to remove Moreover, the patient’s previous “immune
mucus from the airway. Tracheobronchial experience” can alter his or her ability to fight
glands and goblet cells are important sources infection. Preexisting antibody or immune
of airway mucus, which nonspecifically traps memory can help protect the patient when sub-
particulates and potential pathogens. The sequently exposed to the potentially infectious
64 Pulmonary Manifestations of Pediatric Diseases

Factors Predisposing to Infection and Pulmonary Complications after Cancer Therapy

Table 3-5 or Organ Transplantation
Underlying Disease
Alteration in neutrophil, lymphocyte, or platelet function secondary to underlying disease, malignancy,
or autoimmune state
Organ dysfunction secondary to underlying malignancy or autoimmune state
Change in Physical Barriers
Breakdown in physical barriers owing to mucositis, defective healing, chemotherapy, graft-versus-host disease
Changes in colonizing bacteria and fungi
New routes of entry (intravenous catheters, shunts)
Use of Broad-Spectrum Antibiotic Therapy for Acute Infections or Prophylaxis (“Rule Out” Infection)
Eliminate normal flora and allow secondary bacterial or fungal overgrowth
Select resistant organisms
Quantitative Defects in Normal Circulating Blood Cells
Qualitative Differences in Function of Lymphocytes and Phagocytic Cells
Lymphocytes: antibody production and cytotoxic cells
Neutrophil and macrophage functional defects
Defective wound healing
Organ Dysfunction
Liver, heart, or renal failure; asplenia or splenic hypofunction
Epithelial defects allowing bacterial invasion
Diabetes mellitus
Nutritional Defects
Iron deficiency
Vitamin deficiency
Catabolic state
Previous Infections
Colonization (respiratory, gut, renal system)
Previous viral infections with persistent virus (EBV, CMV, HSV, herpesvirus 6)
Preexisting immunity owing to immunization or infection
Concurrent Infection
Infections acquired from donor organs or blood products
Naturally occurring infection that causes further immunosuppression

CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus.

agent. CMV is a good example of an opportu- or as complications to the cancer therapy

nistic infection that can be ameliorated if the (Table 3-6). Superior vena cava syndrome and
patient had previous immune experience or tracheal compression can complicate the ini-
exposure. Alternatively, CMV infection can be tial presentation of tumors or tumor ther-
life-threatening in a patient on chemotherapy apy (see Chapter 7). Space-occupying tumors
or immunosuppressants after organ transplan- (non-Hodgkin lymphoma, Hodgkin disease,
tation with no previous immune experience. acute lymphoblastic leukemia, neuroblastoma,
Ewing sarcoma, thyroid tumors, thymoma,
Pulmonary Complications of Cancer rhabdomyosarcoma) can cause obstruction or
Therapy compression of the superior vena cava and tra-
chea, resulting in respiratory distress. Superior
Pulmonary complications of cancer therapy vena cava syndrome also can be a complica-
can arise from the primary malignancy, from tion of thrombosis secondary to central lines
infections resulting from immunosuppression, in cancer patients. Patients may complain of
Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases 65

Table 3-6 Pulmonary Complications of Malignancies, Transplantation, and Related Medications


Immunosuppression (related to primary Bacterial infection Alveolar hemorrhage
neoplasm or secondary to chemotherapy
or radiation therapy)
Pulmonary invasion Viruses (HSV, EBV, VZV, Superior vena cava
RSV, adenovirus) syndrome or superior
mediastinal syndrome
Airway obstruction with secondary infection Mycobacteria (M. Drug reactions
tuberculosis and atypical
Leukemia and lymphomatous involvement Fungi (Aspergillus, Secondary neoplasms
with Nocardia, Pneumocystis) Pulmonary embolism
Leukostasis Pulmonary edema
Leukemic cell lysis Airway obstruction owing
Hyperleukocytic reaction to mucositis
ARDS, acute lung injury
Interstitial pneumonitis
(drug or radiation induced)

ARDS, acute respiratory distress syndrome; EBV, Epstein-Barr virus; HSV, herpes simplex virus; RSV, respiratory syncytial virus;
VZV, varicella-zoster virus.

dyspnea, orthopnea, hoarseness, chest pain, tumors within the thoracic or abdominal cav-
cough, or syncope. On examination, patients ities can impair normal excursion of the dia-
may present with signs of superior vena cava phragm, impair normal chest wall motion,
obstruction (cyanosis, swelling of face, neck, or decrease available volume for lung expan-
or upper arms), stridor or wheezing, and signs sion. Benign tumors (ganglioneuroma, tera-
of pleural or pericardial effusions.55 In these toma) can grow slowly and allow the child
patients, presentation with signs and symp- to adapt to the pulmonary function abnor-
toms of airway obstruction can be a medical/ mality with minimal symptoms until critical
surgical emergency. Surgical airway manage- restrictive deficits are present. Likewise,
ment can be lifesaving. Occasionally, airway slow-growing tumors in the neck or mediasti-
decompression must be accomplished with num can cause upper airway or tracheal com-
radiation therapy, steroids, or other chemo- pression. Primary lung tumors are rare in
therapeutic agents.55 children56; however, secondary invasion can
The hyperleukocytosis syndrome (cells occur. Lung tumors may manifest as hemop-
>100,000/mL) can occur in 50% of children tysis or postobstructive pneumonias, and usu-
with acute lymphoblastic leukemia and acute ally manifest in an advanced state. In
myeloblastic leukemia in the chronic phase addition, extrinsic compression of an airway
(see Chapter 7). Pulmonary injury is the result can occur as a result of tumor or adenopathy,
of hyperviscosity leading to sluggish blood leading to stridor, wheezing, or postobstruc-
flow and aggregation of leukeuric cells; this tive pneumonia. Secondary invasive solid
can lead to oxygenation defects and pulmo- tumors (Ewing sarcoma, neuroblastoma) on
nary endothelial injury, leading to pulmo- either side of the diaphragm can lead to pul-
nary hemorrhage. Chest radiographs show monary impairment—intrathoracic tumors
diffuse interstitial haziness. Therapy is aimed by decreasing available space for lung expan-
at decreasing the circulating cell numbers, sion; extrathoracic tumors by impeding dia-
and includes leukapheresis and exchange phragmatic excursion—leading to restrictive
transfusion.55 lung disease. Finally, intracranial tumors can
Tumors can lead to pulmonary dysfunction lead to central apnea or central hypoventila-
by occupying space (see Chapter 7). Large tion syndromes.55
66 Pulmonary Manifestations of Pediatric Diseases

Treatment of tumors with chemothera- (see Table 3-7). Chronic side effects include
peutic agents or radiation therapy can lead diffuse alveolar damage, interstitial fibrosis,
to secondary pulmonary complications interstitial pneumonitis, and bronchiolitis
(Table 3-7). Improved cancer survival has obliterans syndrome. In addition, radiation
led to increasing awareness of short-term therapy to the lungs, mediastinal structures,
and long-term pulmonary complications of and vertebrae can cause abnormal growth
cancer therapies (chemotherapy and radia- and lead to restrictive lung disease as the child
tion therapy).55,57-60 In addition to causing continues to grow.
direct injury to the lung itself, disruption Pulmonary infections are common com-
of the epithelial barriers or host primary plications of cancer therapies.55,61 Neutro-
defenses by cancer therapy (radiation ther- penia and subsequent infection are major
apy, cancer chemotherapy, immunosuppres- dose-limiting complications of these thera-
sive agents) or secondary organ dysfunction pies. Neutropenia is defined as an ANC of
(kidney, liver, heart) can lead to pulmonary less than 1500/mL, and the risk of infection
dysfunction or pneumonia (see Tables 3-5 increases with ANC values of less than 1000/
and 3-6). mL. The magnitude and duration of the neu-
Acute and chronic side effects of chemo- tropenia determine the risk of infection by
therapy have been recognized (see Table 3-7). many agents (see Table 3-6).55,61 Chemother-
Acute side effects include hypersensiti- apy can result in altered neutrophil function,
vity reactions, bronchospasm, and urticaria breakdown of mucosal barriers, and other

Table 3-7 Complications of Chemotherapeutic Agents

Agent Complication
Carboplatin Hypersensitivity
Etoposide Hypersensitivity
Asparaginase Hypersensitivity
Vindesine Bronchospasm
Vinblastine Bronchospasm
Cyclophosphamide Urticaria, angioedema


Agent Complication
Radiation therapy Pneumonitis, fibrosis
Bleomycin Diffuse alveolar damage, interstitial fibrosis/pneumonia, bronchiolitis
obliterans syndrome
Alkylating Agents
Busulfan Diffuse alveolar damage, interstitial fibrosis
Cyclophosphamide Diffuse alveolar damage, interstitial pneumonia, interstitial fibrosis,
diffuse pulmonary hemorrhage
Melphalan Diffuse alveolar damage, interstitial fibrosis
Carmustine Diffuse alveolar damage, interstitial pneumonitis
Lomustine Diffuse alveolar damage, interstitial pneumonitis
Semustine Diffuse alveolar damage, interstitial pneumonitis
VM-26 Noncardiogenic pulmonary edema
Cyclophosphamide Noncardiogenic pulmonary edema
Cytarabine Noncardiogenic pulmonary edema, pulmonary hemorrhage
Methotrexate Noncardiogenic pulmonary edema, hypersensitivity pneumonitis
Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases 67

dysfunctions (organ dysfunction, nutrition; the surface of donor cells, or recipient anti-
summarized in Table 3-5) that allow microbial gen-presenting cell presentation of donor-
invasion, or prevent the child from fighting derived peptides for solid organ transplants
infection or healing mucosal surfaces appro- (Fig. 3-2). SCT is different because the donor
priately.55,61,62 Alkylating agents, purine ana- T cells engraft, then respond to the recipient
logues, and newer monoclonal antibody (GVHD). The ablative therapy before SCT
regimens can cause prolonged, severe, multili- removes host T cells. The immunosuppres-
neage cytopenias.62 These infections include sive agents involve many classes of drugs
common bacterial pathogens at the skin often used in combination, which differ in
(S. aureus, other staphylococci, gram-negative their specificity for cell types or subtypes,
bacilli) or mucosal surfaces (Streptococcus viri- or signaling pathway used by the effector
dans, other streptococci, Enterococcus, gram- cells (Table 3-8).63,64
negative bacilli). Opportunistic infections In addition to their immunosuppressive
can occur owing to impaired neutrophil effects, the use of these agents (see Table 3-8)
and humoral immunity (members of the can be accompanied by significant side
herpesvirus family, fungal infections includ- effects with pulmonary implications. Cyclo-
ing P. jiroveci, and Toxoplasma). In the immu- sporine and tacrolimus have significant
nocompromised state, common childhood renal side effects: nephrotoxicity occurring
infections may be life-threatening (e.g., in 5% to 50%, and blood pressure abnor-
RSV, varicella).34,55,61,62 The febrile, neutro- malities in 25% to 70% of treated patients.63
penic child is at great risk for sepsis or pneu- Mycophenolate mofetil may have fewer
monia. Diagnostic evaluation and treatment renal complications, but causes bone mar-
of this group of patients are discussed row suppression and increases rates of sepsis.
subsequently. The use of monoclonal antibodies, such as
basiliximab or daclizumab, may decrease
renal toxicity by allowing lower doses of
Transplant-Related Pulmonary cyclosporine or tacrolimus. Post-transplant
Complications lymphoproliferative disorder (PTLD) and

Transplantation has become the curative

treatment for many immunodeficiency dis-
Regulatory Apoptosis
eases and for organ failure. Solid organ
transplantation (liver, kidney, heart) is now
so successful that more than 80% of chil- Paralyzed
dren survive to become adolescents and Resting memory T (anergic)
adults,63 largely owing to improvements in
immunosuppression and antimicrobial pro-
phylaxis regimens. Immunosuppression Effector
requires a balance: On the one hand, there
is the need to prevent allograft rejection
and to preserve organ function; on the Cytotoxic Helper
other hand, this suppression leaves the host
susceptible to infections, including pulmo-
nary infection. The side effects of these Th1 Th17 Th2
agents can result in secondary organ failure
Figure 3-2. T cell responses can take many directions:
and further pulmonary complications.63,64 Following an encounter with an antigen-presenting cell,
Transplant rejection is mediated primarily naive T cells can respond in various ways, including
by T cells, although B cell–mediated anti- apoptosis (programmed cell death), the induction of
effector T cells, the induction of regulatory T cells, and a
body production plays a role in hyperacute form of immunologic paralysis known as anergy. After
rejection (caused by preformed antibody to initial T cell expansion, a few cells survive as long-lasting
donor antigens, including HLA antigens). memory cells, ready to respond rapidly in the event of
later exposure to the same antigen. (From Taussig L,
Acute and chronic cellular rejection Landau L: Pediatric Respiratory Medicine, 2nd ed. St Louis,
involves T cell recognition of antigen on Mosby, 2008, p 43.)
Table 3-8 Immunosuppressive Agents Used in Transplantation


Pulmonary Manifestations of Pediatric Diseases

Corticosteroids Potent, but least specific of immunosuppressive agents
Negative regulation effect in lymphocytes by directly inhibiting transcription factors AP-1 and NF-kB
Anti-AP-1 effect: blocks IL-2 production
Anti-NF-kB effect: prevents upregulation of IL-1, IL-2, IL-3, IL-6, IFN-g, CD40 ligand, TNF-a, GMCSF, MHC molecules
Interfere with breakdown of cytokine mRNA and interfere with tyrosine phosphorylation
Inhibit functions of many nonlymphoid cells, including APC, inhibiting MHC class II expression
Calcineurin inhibitors Inhibit T cell activation by binding to intracellular immunophyllins
Calcineurin, a calmodulin-activated serine-threonine phosphatase, dephosphorylates inactive NFAT, leading to nuclear translocation
and subsequent activation of T cells
Cyclosporine Binds to cyclophilin A, inhibiting action
Inhibits production of IL-1b, IL-2, IL-6, IL-8, IFN-g, and TNF-a
Inhibits Jun N terminal kinase and p38 pathways
Suppresses antigen presentation by APC
Tacrolimus Binds to FK-binding protein 12, inhibiting action
Activity as for cyclosporine
Preferentially inhibits Th1 cells over Th2 cells
Less anti-HLA antibody formation
Inhibits glucocorticoid-induced apoptosis of antigen-stimulated T cells
Azathioprine Antimetabolite agent: inhibits DNA and RNA production
Lymphocytes use de novo pathway for purine synthesis. Blocks de novo synthesis, preventing clonal expression of T cells and B cells
Inhibits DNA synthesis, purine metabolism, nucleotide synthesis, and CD28 costimulation pathway
Inhibits production of AMP and GMP
Results in suppression of all hematopoietic cell lines
Mycophenolate mofetil More potent and selective inhibitor of de novo purine pathway
No significant effect on hematopoietic or neutrophil populations
Inhibits proliferation of T cells and B cells, blocks antibody formation, and decreases generation of NK cells
Target of rapamycin inhibitors Bind to kinase named target of rapamycin, preventing translation of mRNA responsible for cell cycle regulation
Sirolimus (rapamycin) Inhibits FK binding proteins
Prevents T cell proliferation by blocking progress from G1 to S phase
Inhibits growth factor–driven proliferation of smooth muscle, fibroblasts, and endothelial cells—leads to high incidence of
anastomotic dehiscence when used in lung transplantation
Everolimus Same activity as sirolimus
Polyclonal antilymphocyte Polyclonal antibody made in animals specific for target cell lines (lymphocytes, thymocytes, T cell lines)
antibodies Lymphocyte depletion owing to complement-mediated opsonization or Fas-mediated apoptosis
Cause profound, long-lasting lymphopenia
Very nonspecific—contain antibodies to wide variety of lymphocytes and costimulatory molecules
Monoclonal antibodies More specific, directed against specific T cell antigens or cytokine receptors

Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases

OKT3 (Muromonab-CD3) Murine IgG2a monoclonal antibody directed against the epsilon subunit of CD3
CD3 facilitates translation expression of TcR-a and TcR-b chains on cell surface for intracellular killing—needed for CD4þ cell activation
Initially activates T cells, causing cytokine release, but within hours causes internalization of TcR-a and TcR-b chains, rendering T cell
unresponsive to antigen
Causes nonspecific T cell depletion
M-CD3 also causes T cell opsonization and removal from circulation by liver and spleen
Causes apoptosis of activated T cells and NK-T cells
Daclizumab Humanized mouse monoclonal
Basiliximab Human/mouse chimeric monoclonal antibody
Directed against a-chains of CD25 molecule (IL-2 receptor)
Inhibits IL-2 induced T cell proliferation
Eliminates activated T cells through Fas-Fas ligand interactions (apoptosis)
No depletion of other T cell populations
Efalizumab Humanized mouse IgG1 against CD11a chain
Non–lymphocyte depleting
Blocks LFA-1:ICAM-1 interactions preventing T cell adhesion, activation, and trafficking
LEA29Y Antibody against CD80 and CD86 (B7 molecules), a costimulatory signal necessary for T cell activation
Rituximab Human-mouse chimeric anti-CD20 (B cell antibody): depletes B cells, eliminating hyperacute antibody-mediated rejection in cardiac,
renal, and liver transplantation
Alemtuzumab Anti-CD52/campath-1H
Humanized IgG1 antibody: depletes T cells by complement-mediated cell lysis (T, B, NK, and dendritic cells, not hematopoietic
stem cells)
FTY720 Sphingosine-1 phosphate receptor agonist
Reduces recirculation of lymphocytes from lymph nodes back into the circulation, causes peripheral lymphopenia

AP-1, activating protein 1; NF-kB, nuclear factor kappa B; Anti-AP-1: anti-activating protein 1; IFN-g, interferon gamma; TNF-a, tumor necrosis factor alpha; GMCSF, granulocyte-macrophage-
colony stimulating factor; MHC, major histocompatibity complex; APC, adenomatous polyposiscoli; LFA-1, lymphocyte function associated antigen; ICAM-1, intercellular adhesion
molecule; NK-T, natural killer T lymphocytes.

70 Pulmonary Manifestations of Pediatric Diseases

secondary malignancies can result from long- Renal Transplantation

term immunosuppression in a small but Renal transplants were among the first suc-
significant number of patients. It is important cessful transplants done in children. With
to differentiate these noninfectious complica- current immunosuppressive protocols, the
tions from infection in this group of patients. 1-year graft survival is expected to be greater
The overall risk of infection or rejection in than 90% with an acute rejection rate of
a transplant patient results from the balance 22%.74 Ten-year graft survival approaches
of net state of immunosuppression, the type 70%. Complications of immunosuppressive
of transplant, and the degree of exposure to therapy include hypertension (70%), PTLD
the particular pathogen (see Table 3-5).63,64 (7%), malignancy (17%), and overall retrans-
Comorbid conditions (preexisting or second- plantation rates of 25% (improved with
ary to the transplantation or immunosup- newer immunosuppressive protocols). The
pressive agents) can increase susceptibility incidence of immunosuppressive nephrotox-
to infectious or noninfectious complications icity is uncertain because of difficulties in dis-
further (see Table 3-6). Infectious complica- tinguishing drug toxicity from chronic
tions of solid organ transplantation occur in rejection.63 Use of mycophenolate mofetil
a predictable pattern.65 Based on the type of or sirolimus for maintenance prevents signif-
organism and the timing of occurrence, icant renal dysfunction and can be steroid-
prophylactic regimens have developed over sparing. CMV and EBV infections are
the years to prevent these infections,63-68 common in immunosuppressed renal trans-
including the use of prophylaxis for P. jiroveci, plant patients because of the lack of effective
Candida, and CMV. Latent infections (either immunization before transplant and the
latent in the host or the donor organ) occur high incidence of infection by these viruses
early after transplantation (CMV, herpes sim- in adult donors. In one study, 12% of kidney
plex virus, EBV), as can azole-resistant fungal recipients developed CMV disease—the inci-
infections. Duncan and Wilkes64 review the dence of developing CMV disease increased
common “time lines” for appearance of vari- significantly if the donor was seropositive.75
ous infectious agents and the effects of pro-
phylaxis on the appearance of these agents. Liver Transplantation
Significant progress has been made in pediat-
Heart Transplantation ric liver transplantation, largely owing to
The 10-year survival of cardiac transplant in improvements in immunosuppressive thera-
children is 60% to 80%.63 With this good pies. The current 10-year survival rate is 80%
prognosis, prevention of acute rejection while to 85% after liver transplantation.63,64,76
minimizing the side effects of immunosup- Side effects of immunosuppression in this
pressive agents is important.63,69 Freedom group include nephrotoxicity (5%), hyper-
from acute rejection after 5 years was found tension (28%), PTLD (5% to 7%), secondary
to be 40% with cyclosporine, 56% with tacro- malignancy (12%), and organ failure requir-
limus, and 62% with mycophenolate mofetil ing retransplantation (5% to 10%). EBV and
treatment for immunosuppression.63,69 This CMV infections pose major problems in the
suppression comes with a price of nephrotox- liver transplant patient.63,76 Many protocols
icity (4%), hypertension (35%), PTLD (17%), include prophylaxis for CMV with intrave-
and secondary malignancies (1% to 4%). In nous or oral ganciclovir for 3 months post-
addition, chronic rejection can lead to organ transplantation.
failure requiring retransplantation (5%).70-72 Hepatopulmonary syndrome and porto-
Infectious and noninfectious events can pulmonary hypertension can present major
cause pulmonary complications as listed in problems in the patient before transplanta-
Table 3-6. Pneumonias in heart transplant tion.77,78 Hepatopulmonary syndrome is
patients are frequently multimicrobial in characterized by pulmonary vascular dilation
origin; CMV was the most common single and abnormal gas exchange (see Chapter 5).
pathogen and copathogen in this patient Structurally, the parenchyma of the lung is
group.70-73 Many of these infections likely normal, but there is generalized vasodilation
resulted from reactivation of latent infection. at the capillary level resulting in arteriovenous
Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases 71

communication (shunt) and severe hypox- provides a point of possible narrowing of

emia. Hepatopulmonary syndrome is recog- the airway. Infectious agents can be trans-
nized as an independent risk factor for death ferred passively from the donor to the recip-
in patients with advanced liver disease. Porto- ient during transplantation. The additional
pulmonary hypertension is a process defined complications related to lung transplanta-
by pulmonary hypertension associated with tion likely account for the lower survival
portal hypertension. Histologically, it appears statistics compared with other solid organ
identical to primary pulmonary hypertension transplants (1-year survival 77%, 3-year sur-
with smooth muscle hypertrophy, intimal vival 63%, and 5-year survival 54%).80 Graft
fibrosis, and plexiform lesions in small lung failure accounts for most deaths in the first
injury. It is initially asymptomatic, but evolves 60 days post-transplant (56%), whereas
to rapidly progressive impairment of right infection is an uncommon cause of early
heart function. The prognosis is poor, with death. Late deaths primarily result from
mean survival of 15 months after diagnosis. obliterative bronchiolitis (62%), infection
Hepatopulmonary syndrome frequently re- (22%), and malignancies (14%).80,81
verses after liver transplantation, whereas por- Immunosuppression after lung transplan-
topulmonary hypertension seems to resolve tation often consists of cyclosporine or tacro-
less frequently. Both of these entities must be limus, corticosteroids, and mycophenolate
considered in a patient with dyspnea before mofetil. The steroid dose is commonly
or just after liver transplantation.77,78 tapered 2 to 3 months post-transplant.80,81
Infection, allograft rejection, PTLD, and
Lung Transplantation obliterative bronchiolitis are major pulmo-
Lung transplantation presents a unique set of nary complications in the post-transplant
problems for the balance of immunosuppres- period. The antibiotic regimen is tailored to
sion in the transplanted organ (prevention of the most likely pathogens. In a patient with-
rejection versus risk of infection) in part out cystic fibrosis, a first-generation cephalo-
because the transplanted lung is an interface sporin is likely the first-line treatment, unless
between the outside environment and the a center has a high incidence of methicillin-
host defenses. The large epithelial surface area resistant S. aureus. In cystic fibrosis patients,
in the conducting airways and at the alveolar antibiotics are directed to the pathogens
surfaces (>70m2 in the adult) poses a great present in the most recent respiratory cul-
challenge for the lung defenses, particularly ture; antifungal agents are initiated based
in the context of immunosuppression. The on previous or current positive cultures.
anatomy of the lung, lung products, cell Viruses can pose serious problems in a post–
receptors and subsequent signaling mecha- lung transplant patient; as in other solid organ
nisms activated, and host cellular responses transplants, CMV and EBV are important
all contribute to the normal lung defense pathogens.81 Most centers use ganciclovir or
and disease prevention. A defect in any of valganciclovir as prophylaxis for the first 5 to
these defenses can result in an increased sus- 6 months post-transplant. In the context of
ceptibility to infection or increased propen- immunosuppression, however, infection by
sity to inflammation, which can lead to common respiratory viruses (particularly
rejection or development of obliterative bron- RSV, parainfluenza virus, adenovirus, or vac-
chiolitis (see later) that can be life-threatening cinia) can be life-threatening. Prophylaxis
in the lung transplant patient.76,79-81 with palivizumab (anti-RSV monoclonal anti-
Immunosuppressive agents used to pre- body) can provide passive immunity for
vent transplant rejection alter the lung young infants at risk for RSV infection. It also
defenses. Local alteration of lung defenses is advantageous to keep these children out of
contribute further to propensity to infec- the daycare setting. Aside from acute pneu-
tion: denervation of the transplanted organ monias, viral infections may be associated
results in decreased cough reflex; ischemic with early graft loss and rapid development
injury to the mucosa causes impairment in of obliterative bronchiolitis.
mucociliary clearance; the anastomosis PTLD occurs more commonly in pediatric
between host and transplanted organ lung transplant patients than in adults.
72 Pulmonary Manifestations of Pediatric Diseases

Because the first response to development of SCT recipients provides strong evidence that
PTLD is reduction in immunosuppression, immunopathologic response contributes to
survival from PTLD often is complicated by the development of obliterative bronchiolitis
episodes of rejection or obliterative bronchi- in the transplant setting. After lung trans-
olitis. Use of rituximab (anti-CD-20 anti- plantation, recurrent episodes of acute rejec-
body) has resulted in a significant reduction tion are a risk factor for developing
in morbidity and mortality from PTLD. obliterative bronchiolitis. Early and accurate
Allograft rejection is less common in chil- diagnosis of acute rejection and aggressive
dren than in adults; however, surveillance treatment are thought to be important in
and timely and accurate diagnosis of rejec- preventing the long-term development of
tion may be more important and more diffi- obliterative bronchiolitis. Because of sam-
cult in children because of the frequency of pling limitations in transbronchial biopsies
respiratory viral infections. Spirometry is and risk associated with performing the
employed after lung transplantation to biopsy itself, investigators have sought sensi-
assess allograft function, and evidence for tive and noninvasive methods to detect early
restrictive lung disease is concerning for acute rejection and obliterative bronchiolitis.
the development of acute or chronic rejec- In 1993, a consensus statement suggested
tion. Computed tomography (CT) scans using the term “bronchiolitis obliterans syn-
can be helpful in assessing for changes asso- drome,” defined by changes in pulmonary
ciated with rejection. Lung biopsy remains function as a possible surrogate marker for
the only accurate method of diagnosing obliterative bronchiolitis.82 These recommen-
acute and chronic rejection; however, the dations were later modified to use forced mid
utility of lung biopsy is limited by sampling expiratory flow in addition to changes in
error (small samples obtained with the pedi- forced expiratory volume in 1 second (focus-
atric biopsy forceps and skip areas). Rejec- ing on early changes in small airways), and
tion is diagnosed on the basis of standard to use percent predicted values in addition to
histopathologic markers, and immunosup- absolute values (to account for lung growth
pressive therapy is adjusted accordingly.80 in small children).83 Other surrogate clinical
Obliterative bronchiolitis (formerly bronchi- markers of obliterative bronchiolitis have
olitis obliterans) is rare in healthy children, but been investigated, including cytokine mea-
its incidence is markedly increased in the con- surements, measurement of cell surface recep-
text of lung transplantation or SCT. Oblitera- tors, and soluble cytokines and receptors in
tive bronchiolitis is characterized by partial or bronchoalveolar lavage (BAL).79 BAL neutro-
complete occlusion of the lumens of terminal philia in the absence of detectable infectious
and respiratory bronchioles by inflammatory agents has been shown to be a reproducible
and fibrous tissue. The initiating event in the marker of obliterative bronchiolitis in adult
chain of events that leads to obliterative bron- and pediatric transplant patients.79
chiolitis is unclear. The primary trigger is The optimal therapy for obliterative bron-
thought to relate to epithelial injury in the chiolitis in lung transplant and SCT patients
small airways leading to transient derange- is controversial. Alteration of immunosup-
ments in epithelial cell function or local necro- pressive agents (see Table 3-8), inhaled cyclo-
sis. This local necrosis leads to the generation sporine, extracorporeal phosphophoresis,
of fibrinopurulent exudates that induce and the use of macrolide antibiotics have been
ingrowth of myofibroblasts, cellular prolifera- studied in small groups of patients with vari-
tion, capillary immigration, and the develop- able results.79 Despite these therapies, it is esti-
ment of an intraluminal polyp. Ongoing mated that 35% to 60% of long-term survivors
injury to the airway epithelium perpetuates of lung transplantation develop obliterative
this process, leading to narrowing or oblitera- bronchiolitis, which is the most common
tion of the airway lumen. cause of death in this patient population.79
Although injury and infection likely play a
role in the changes that lead to obliterative Stem Cell Transplantation
bronchiolitis, the high incidence of oblitera- SCT presents an even greater challenge to
tive bronchiolitis in lung transplant and the host defenses against pneumonia and
Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases 73

lung injury because of the combined chal- embolism. Chronic obstructive pulmonary
lenges of the initial conditioning regimen disease can be detected in 20% of long-term
and the need for the recipient to develop a survivors of SCT; this is mainly associated
functional immune system from donor- with chronic GVHD, but other risk associa-
derived stem cells. Serious infection occurs tions include the preparatory regimen (total
in the first 2 years after SCT in 50% of reci- body irradiation (TBI), methotrexate) and
pients with uncomplicated transplants from infection.34,86 Mortality can be high, partic-
histocompatible sibling donors and in 80% ularly if there is an early onset and rapid
to 90% of recipients from matched unre- decline in forced expiratory volume in 1 sec-
lated donors. ond. Immunosuppressive therapies may be
The immune deficits after SCT can be beneficial, but less than 50% of patients
categorized into three phases. In the pre- receiving such therapies show improvement
engraftment phase (0 to 30 days post-trans- in lung function or symptoms. Late-onset
plant), infections arise primarily as a result pulmonary disease includes obliterative
of prolonged neutropenia and breaks in bronchiolitis, cryptogenic organizing pneu-
the mucosal barriers resulting from muco- monia (formerly bronchiolitis obliterans–
sitis from the induction regimen before organizing pneumonia87,88), diffuse alveolar
transplant. Myelosuppressive drugs can pro- damage, and interstitial pneumonia.34,86
long this period. Repopulation of the lungs PTLD is often associated with T cell dys-
by donor-derived alveolar macrophages and function in the presence of EBV. The mean
recovery of circulating neutrophil counts interval to development of PTLD was 5 to
occur during this period. Recovery of 6 months post-transplantation, with a
lymphocyte counts takes longer (the post- cumulative incidence of 1% at 10 years.
engraftment phase, 30 to 100 days post- The use of quantitative polymerase chain
transplant), and cellular immunity remains reaction for EBV DNA has improved diagno-
impaired. Response to alloantigens may sis dramatically. Using the EBV viral load,
not return for at least 6 months after SCT, patients can be identified with low tumor
and return of B cell function and humoral burden. Use of rituximab (anti-CD20 mono-
antibody production may take 1 year (late clonal antibody) has shown promise in the
phase, >100 days post-transplant).34,61,84 treatment of PTLD in SCT patients.86
The temporal sequence of the immuno- Obliterative bronchiolitis develops in
logic recovery and immunosuppressive ther- 10% of SCT recipients who develop
apy determines SCT recipients’ susceptibility GVHD.79 As with obliterative bronchiolitis
to pulmonary infection at any given time in lung transplant recipients, immunologic
point. During the pre-engraftment phase, and nonimmunologic factors are believed
patients are most susceptible to bacterial to play a role in the development of obliter-
infections and viral infections, including her- ative bronchiolitis in SCT recipients. These
pes simplex virus, CMV, and RSV. After neu- nonimmunologic factors include the pre-
trophil recovery (postengraftment phase), SCT conditioning regimen, intercurrent ill-
T cell and B cell immunity remains abnormal, ness (particularly viral pneumonitis), the
predisposing the patient to infections use of immunosuppressive medications,
with fungi, viruses, mycobacteria, and para- and the underlying disease that necessitated
sites. Patients can remain susceptible to the SCT. Viral agents, such as CMV, adenovi-
encapsulated organisms because of inability rus, influenza, parainfluenza, and RSV, have
to generate specific antibody responses. The been implicated in the development of
development of GVHD further increases sus- obliterative bronchiolitis. Several medica-
ceptibility to infection.34,61,84-86 tions have been used in SCT recipients for
Several noninfectious complications the treatment of chronic GVHD and obliter-
occur after SCT, including airway obstruc- ative bronchiolitis; however, response was
tion by mucositis, diffuse alveolar hemor- usually limited to skin, soft tissue, and oral
rhage, pulmonary edema, and pulmonary mucosa.
74 Pulmonary Manifestations of Pediatric Diseases

Diagnosis and Treatment Histoplasma) infection, and pulmonary

of Respiratory Abnormalities edema or early obliterative bronchiolitis,
in a Child with Secondary rejection, and GVHD. Consolidation can
arise from bacterial infections (S. pneumoniae,
Immunocompromise Owing to H. influenzae, S. aureus, gram-negative organ-
Cancer or Transplantation isms, M. tuberculosis, or atypical mycobac-
teria) and fungal infections (Cryptococcus,
In an immunocompromised child, aspects of Nocardia, Aspergillus, Mucor), and pulmonary
the medical history, physical examination, thromboembolic disease, pulmonary hemor-
and routine microbial surveillance (or previ- rhage, and pulmonary edema. Nodular infil-
ous antibody titers) are important first steps. trates arise from bacterial infections, fungal
Timing of the symptoms relative to drug infections, P. jiroveci pneumonia, and M.
therapies or changes in immunosuppressants tuberculosis. The early changes of obliterative
could point to the infection or noninfectious bronchiolitis manifest as hyperinflation with
complications. The presence of sinusitis, oti- clear lung fields. There is considerable over-
tis media, and rhinitis would point to respira- lap between these basic radiographic patterns
tory virus infections as an important and their causes, so more aggressive diagnos-
consideration. The presence of severe muco- tic studies are indicated to show the cause
sitis or evidence of skin GVHD could point and direct appropriate therapy.34,65
to anaerobic organisms, oral flora, or gut CT scan of the chest is particularly useful
enterics as causes for the respiratory symp- when the chest radiograph is negative, or
toms or infiltrates on chest x-ray. The history when findings on chest x-ray are nonspe-
and physical examination can only suggest cific. CT is useful in defining areas of lung
the causes of lung complications or lung involvement for more invasive studies (e.g.,
symptoms and physical findings, however. biopsy, BAL). Spiral CT and ventilation/per-
Because there is a good probability of full fusion studies can be diagnostic if pulmo-
recovery if the pathogen is uncovered, early nary thromboembolism is a consideration.
and aggressive diagnostic studies are war- A “mosaic” pattern of lung hyperinflation
ranted to direct appropriate antimicrobial or and infiltrate can suggest the development
antiviral therapy. This is particularly true in of obliterative bronchiolitis.
the context of fever in a neutropenic patient.

Sputum and Nasopharyngeal

Radiography Washes, and Other Indirect Methods
for Pathogen Detection
Pulmonary changes on chest radiographs
may be delayed or modified in an immuno- Spontaneous or induced sputum samples can
compromised patient because of the inability be studied by culture and special stains for pul-
to generate an inflammatory response. Still, monary pathogens: Gram stain, fungal stains,
the time course, evolution, and appearance acid-fast bacillus stain, and silver stains can be
of the pneumonias can provide important performed to diagnose bacterial and fungal
diagnostic clues. Radiographic changes in causes of pulmonary infiltrates. Blood cultures
an immunocompromised child can be classi- are rarely positive, but can be diagnostic for
fied according to their appearance: (1) diffuse bacterial pneumonias. In addition, nasal aspi-
alveolar or interstitial pneumonias, (2) loca- rates can be studied by immunologic methods
lized alveolar lobar or lobular consolidation, or culture to identify common viral pathogens
(3) nodular infiltrates or abscesses, or (4) (RSV, influenza, parainfluenza viruses, adeno-
hyperinflation.34,65 Interstitial/alveolar infil- virus) that can cause pulmonary infections in
trates can arise from viral (CMV, RSV, vari- immunocompromised patients. Viral cultures
cella-zoster virus, adenovirus) and fungal can be useful in detecting the common viral
(P. jiroveci pneumonia, Cryptococcus, Candida, pathogens in addition to members of the
Chapter 3—Pulmonary Manifestations of Immunosuppressive Diseases 75

herpesvirus family (CMV, herpes simplex invasive Aspergillus), in addition to helping

virus). Genetic probes are available to detect to identify acute rejection (lung transplant),
CMV and EBV in blood samples, and quantita- GVHD, and obliterative bronchiolitis (SCT
tive polymerase chain reaction can provide a and lung transplant).34,80 Most centers have
measure of viral load. Probes also are available a protocol for surveillance post-transplanta-
for detecting P. jiroveci, Legionella, Mycobacte- tion to screen for rejection. Open biopsy is
rium, and Mycoplasma. These studies also can usually needed to make the diagnosis of oblit-
be applied to samples obtained by more inva- erative bronchiolitis.
sive methods (bronchoscopy and lung biopsy) Lung lavage can be done in intubated
as described subsequently. patients by passing a catheter through an
existing endotracheal tube and performing
saline washes. This technique is “blind,”
Flexible Bronchoscopy but can provide important diagnostic mate-
rial in a critically ill child too sick to tolerate
Flexible fiberoptic bronchoscopy can provide standard BAL techniques.
BAL or bronchial lavage samples and biopsy
materials for diagnosis of pulmonary compli-
cations in immunocompromised patients.
Transthoracic Needle Aspiration
Bronchoscopy with lavage performed early in
the course of evaluation of an immunocom- Needle aspiration of the lung under CT or
promised patient can enhance the probability fluoroscopic guidance can have high yields
of identifying a pathogen in the lung. BAL in sampling peripheral lung lesions (particu-
can provide materials for culture (i.e., bacte- larly suspected fungal lesions) that cannot
rial, viral, fungal, acid-fast bacillus), cytology, be reached by standard flexible fiberoptic
and immunohistochemistry, potentially iden- bronchoscopy techniques. The major risks
tifying pathogens in the lung. In addition, of transthoracic biopsy are pneumothorax
bronchoscopy can identify endobronchial and bleeding. In addition, because of the
obstruction owing to infection or tumor. Pro- small needle size, sampling error can occur
tected brush specimens can decrease the (“missing” nearby involved areas).
potential for BAL samples to be contaminated
by upper airway flora during passage through
the nasopharynx. Although bronchoscopy Open Lung Biopsy
with BAL can provide important diagnostic
information, it has limitations. BAL cultures Open lung biopsy remains the gold stan-
in patients already on broad-spectrum anti- dard for diagnosis of pulmonary abnormal-
biotics are often negative. Pathogens present ities in an immunocompromised patient. It
in small numbers (e.g., P. jiroveci, mycobacteria) allows the surgeon to obtain adequate quanti-
may be missed on stains or cytology, although ties of lung tissue for analysis, provides the
more sensitive polymerase chain reaction tech- opportunity to sample multiple sites, and
niques may increase the yield. Invasive patho- allows the surgeon to visualize and select opti-
gens (Aspergillus) may be missed by lavage mal sites for biopsy. The use of a mini-thora-
when obvious on biopsy samples. cotomy or video-assisted thoracoscopic
Bronchoscopy also can be used to perform surgery allows for a smaller incision. Although
transbronchial lung biopsies.34,80 Transbron- open lung biopsy provides the most definitive
chial biopsy can be difficult in young children information in an immunocompromised
because the size of available bronchoscopes patient, timing of the biopsies and the poten-
and their small suction channel (1.2 mm) tial need for repeated biopsies (particularly if
require obtaining several samples for ade- rejection and obliterative bronchiolitis are
quate material for histology and culture. In considerations) limit the use of this tech-
older children, small adult bronchoscopes nique. A patient who does not respond to
can be used with standard size biopsy forceps. therapy based on other diagnostic techniques
These biopsy samples can help in identifying (including bronchoscopy and needle biopsy)
pathogens missed by standard BAL (e.g., usually would benefit from open biopsy.
76 Pulmonary Manifestations of Pediatric Diseases

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Pulmonary Manifestations
of Cardiac Diseases

Overview of the Cardiovascular Vascular Anomalies That Cause Airway

Circulation 79 Obstruction 89
Pulmonary Circulation 79 Lesions with Increased Venous Admixture 92
Bronchial Circulation 80 Idiopathic Pulmonary Arterial
Lymphatic Circulation 80 Hypertension 95
Cardiovascular Lesions That Increase Other Pulmonary Conditions Associated with
the Work of Breathing 80 Cardiac Disease or Surgery 96
Large Volume Left-to-Right Shunts 81 Summary 96
Outflow or Inflow Obstruction of the References 97
Systemic Ventricle 87

Sharing the same body cavity, the heart and Overview of the
lungs are closely interconnected by Cardiovascular Circulation
the pulmonary vasculature. An increase or
decrease in pulmonary vascular pressures The cardiopulmonary vascular system com-
leads to changes in the blood vessels, which prises two components: the pulmonary cir-
directly affect the airways, lung interstitium, culation and the bronchial circulation. The
alveoli, and pleura. Heart disease often leads bronchial circulation constitutes a very
to respiratory failure as a result of its impact small portion of the output of the left ven-
on gas exchange, water/solute exchange, tricle, and it supplies part of the tracheo-
and pulmonary mechanics. The appearance bronchial tree with systemic arterial blood.
of lung disease secondary to cardiac disease The pulmonary circulation constitutes the
depends on whether the changes in the pul- entire output of the right ventricle, and it
monary vascular pressures are acute or supplies the lung with the mixed venous
chronic. Clinical manifestations of cardiac blood draining from all the tissues of the
disease include pulmonary edema, pleural body. This blood undergoes gas exchange
effusion, hypoxemia, pulmonary hyperten- with alveolar air in the pulmonary capil-
sion, atelectasis, and plastic bronchitis. laries. Under normal circumstances, these
Noninfectious pulmonary complications, systems change with the maturational stage
such as bronchiectasis, prolonged postoper- of the individual. It is important to under-
ative mechanical ventilation, extubation stand the vascular changes that occur with
failure, airway complications (e.g., tracheo- normal growth over time. A brief review of
bronchomalacia, subglottic stenosis, bron- the cardiovascular circulation follows.
chial stenosis), and obstructive sleep apnea,
have been extensively described in pediatric
patients after cardiac surgery.1-4 Although Pulmonary Circulation
many of the physiologic mechanisms are
similar, this chapter concentrates on pediat- The normal mature pulmonary circulation
ric heart diseases and disorders that have an is a low-resistance system compared with
impact on the pulmonary system. the general systemic circulation.5 Despite

80 Pulmonary Manifestations of Pediatric Diseases

receiving about the same amount of blood do the other systemic arteries (dilation in
flow, the pulmonary arterial pressure is only response to hypoxia). Conversely, the pulmo-
about 20% of the systemic circulation pres- nary arteries constrict to hypoxia. The bron-
sure. The plasticity of the pulmonary circu- chial arteries arise from the aorta and the
lation can be attributed to two related intercostal arteries, and then divide along
factors: (1) the pulmonary vessels are thin- with the bronchial divisions. Despite the
walled and dilate with mild increases in differences between the pulmonary and bron-
pressure, and (2) this augmentation of the chial circulations, there are intricate intercon-
vessel radius passively recruits underper- nections between them. Anastomotic vessels
fused vessels, which leads to an increase in connect the bronchial arteries to the pulmo-
overall cross-sectional area. nary arterioles and to the pulmonary veins.
In contrast to the mature pulmonary circu- These anastomotic connections permit flexi-
lation, the fetal pulmonary resistance is bility of flow to and from pulmonary and
higher than the systemic resistance. The high bronchial circulations. The drainage of the
pulmonary system resistance in the fetus per- bronchial arteries to a vascular plexus permits
mits shunting of blood from the systemic great flexibility of bronchial venous drainage.
venous to the systemic arterial circulation via The bronchial venous drainage can move to
the ductus arteriosus to the aorta and through either the right or the left side of the heart.
the foramen ovale to the left atrium. The fol- Extrapulmonary bronchial vessels supplying
lowing three factors contribute to the high large airways drain to the right atrium
fetal pulmonary circulation resistance: (1) In through the azygos and hemiazygos veins.
the fetus, the pulmonary arteries are exposed The intrapulmonary vessels drain to the pul-
to the full systemic blood pressure via the duc- monary veins and to the left atrium. The
tus arteriosus, and their walls are very muscu- venous drainage permits flexibility in drain-
lar. (2) The fetal lung exists in an airless state. age route, depending on changing hemody-
(3) There is hypoxic vasoconstriction within namic pressures.
the intrauterine environment.
With the onset of air breathing and infla-
tion of the lungs, the pulmonary circulatory Lymphatic Circulation
resistance decreases with the loss of the pla-
The pulmonary lymphatic circulation lies in
cental circulation. The inflation of the lungs
the connective tissue of the lung. There is
causes expansion of the pulmonary vessels,
continuous filtration of liquid and protein
and the increase in oxygenation results in
through the lung microcirculation. Passive
vasodilation. With subsequent involution
flow of liquids proceeds along a pressure
of the arterial muscle, there is remodeling
gradient to reach the lymphatic capillaries
of the pulmonary arteries. This remodeling
and is returned via active pumping to the
involves thinning of the arterial muscular
systemic circulation. Disruption of the intra-
wall and the normal branching and growth
vascular pulmonary pressures also alters the
of the airways and alveoli. Although the pul-
lymphatic circulation.5,7
monary veins have thinner walls compared
with the arteries, veins do have a muscular
layer, which can become hypertrophied in
response to elevated pulmonary pressure.5,6 Cardiovascular Lesions That
Increase the Work of
Bronchial Circulation
Generally, three types of cardiovascular prob-
In contrast to the pulmonary circulation, the lems cause disturbances in mechanical func-
bronchial circulation is small, carrying only tion of the lungs and increase the work
1% of the cardiac output. The bronchial of breathing: (1) large volume left-to-right
arteries carry oxygenated blood to the lungs shunts, (2) outflow or inflow obstruction
as part of the general systemic circulatory sys- of the systemic ventricle, and (3) vascular
tem. Bronchial arteries respond to stimuli, as anomalies that obstruct the airways.
Chapter 4—Pulmonary Manifestations of Cardiac Diseases 81

Large Volume Left-to-Right Shunts declines postnatally, signs of pulmonary con-

gestion develop quickly.
Lesions that allow communication between Numerous factors have been identified
the systemic and pulmonary circulations and that influence the decrease in pulmonary
cause a large left-to-right shunt are the most vascular resistance associated with the tran-
frequent congenital cardiac anomalies. These sition to extrauterine life. In the immediate
include common problems such as ventricular postnatal period, the expansion of the
septal defect (VSD), atrial septal defect (ASD), alveoli, the increase in alveolar PO2, and
and patent ductus arteriosus (PDA), and the decrease in the alveolar PCO2 cause
defects with similar physiologic conse- recruitment of pulmonary capillaries and
quences, but more complex anatomy, such as dilation of pulmonary arterioles, decreasing
single ventricle, aorticopulmonary window, pulmonary vascular resistance. As the
and truncus arteriosus. These lesions are char- arterial musculature becomes thinner, and
acterized by the recirculation of oxygenated new vessels gradually grow in the lungs,
blood through the lungs and pulmonary vas- pulmonary vascular resistance decreases
cular congestion. The shunt produces exces- even further. Finally, the postnatal decline
sive pulmonary blood flow and increased in hematocrit—so-called physiologic ane-
return of pulmonary venous blood to the left mia—also contributes significantly to the
side of the heart. In addition, when the abnor- decrease in pulmonary vascular resistance
mal communication is large and occurs at the by reducing blood viscosity.
level of the ventricles or great vessels, the high Left-to-right shunts can cause increased
pressure of the left side of the heart is transmit- symptoms after the decrease in the pulmo-
ted to the pulmonary circulation, causing nary arterial pressure and pulmonary vascular
pulmonary artery hypertension. resistance that normally occurs after birth. As
The volume of blood traversing the pul- mentioned before, these shunts can be intra-
monary circulation in the presence of an cardiac (ASD, VSD, or atrioventricular septal
anomalous intracardiac communication or defect) or extracardiac (PDA or aorticopul-
between the great arteries depends on the monary window). Intracardiac shunts usually
size of the communication and the relative are associated with increased pulmonary
resistances of the pulmonary and systemic blood flow without an increase in pressure in
circulations. When the communication is the early stage of the disease. Extracardiac
small, it offers a high resistance to the passage shunts (depending on their size) may expose
of blood. As a result there is a large pressure the pulmonary vascular circulation to sys-
decrease between the high-pressure chamber temic pressures that would cause earlier devel-
and vessel (usually, the left ventricle or aorta) opment of vascular changes. Shunt lesions,
and the low-pressure chamber or vessel such as a VSD, ASD, or PDA, may not cause a
(usually, the right ventricle or pulmonary significant murmur in a neonate because of
artery), and the left-to-right shunt is limited. the normally elevated pulmonary vascular
When the communication is large, there is resistance at birth causing the shunting to be
virtually no resistance to the flow of blood low velocity. As the pulmonary vascular resis-
from the systemic to the pulmonary side of tance decreases to normal levels over the first
the circulation. Consequently, the pressures 1 to 2 months of life, the shunt becomes more
become equal in both sides, and the size of prominent. The normal systemic vascular
the shunt is no longer governed by the size resistance is about 25 Wood units/m2, and
of the communication, but rather by the normal pulmonary vascular resistance is
relative magnitudes of the systemic and pul- about 3 Wood units/m2, so blood shunts from
monary vascular resistances. Because the the left (systemic) circulation to the right (pul-
pulmonary vascular resistance of the term monary) circulation.
newborn is very high, it is not surprising that
even large communications such as those Pathophysiology of Pulmonary Edema
caused by a large VSD or PDA produce little and Pleural Effusion
left-to-right shunt for days, or even weeks, One of the main pathophysiologic effects of
after birth. As pulmonary vascular resistance the left-to-right shunt is to redistribute part
82 Pulmonary Manifestations of Pediatric Diseases

of the left ventricular output from the sys- of this fluid buildup, or edema, is the accumu-
temic to the pulmonary circulation (Fig. 4-1). lation of fluid around the bronchovascular
When this occurs, pulmonary blood flow bundles. This accrual of bronchovascular bun-
increases, increasing the right ventricular dle fluid can be seen on chest radiographs,
afterload, left ventricular preload, left atrial particularly in the fissures.
pressure, and the work performed by the heart When the pulmonary lymphatic system
muscle. In normal circumstances, the venous cannot clear the interstitial fluid, the fluid
pressure in the lung is low and varies only a lit- accumulation must leave by other means.
tle during the cardiac cycle. An increase in left One route is to form a transudate through
ventricular end-diastolic or left atrial pressure the interlobular septa and then to the pleu-
can cause increased pressure in the pulmo- ral space, which leads to pleural effusion.
nary veins, however, with subsequent pres- When in the pleural space, the liquid is
sure increases in the capillary vessels and absorbed into the parietal pleural lym-
then in the pulmonary arteries. As a result, phatic system. Transport of interstitial fluid
fluid starts to accumulate in the interstitium to the pleural space reduces the possibility
and alveoli, causing pulmonary edema. of alveolar edema, which is associated with
Edema usually forms in response to increased altered gas exchange and pulmonary
pulmonary venous pressures. As the intravas- mechanics. In contrast, pleural effusion
cular pressure increases, more extravascular alone generally is not associated with
fluid is filtered through the pulmonary inter- severe derangements in pulmonary func-
stitium to the lymphatic system. When this tion. Alterations in blood flow and in pul-
microvasculature filtration system becomes monary vascular pressures are associated
overwhelmed, there is accumulation of fluid with pathologic changes in the pulmonary
in the interstitial lung tissue.8 An early feature arteries (Table 4-1).

↑ Pulmonary blood flow and

↑ PA, PV pressure
O2 Pulmonary edema and
• Pulmonary edema
• Large airway obstruction airway obstruction
• Small airway obstruction ⋅ ⋅
• Areas of V/Q = 0
• ↓ PO2
• ±↑ PCO2

↓ Systemic flow and

↑ adrenergic tone
• Redistribution
Large L → R shunt
systemic flow
• ↑ Pulmonary blood flow • ↑ O2 extraction
• ↑ PA, PV, LA pressures • ↓ Respiratory muscle
• ↑ RV afterload, LV preload perfusion
Postnatal ↓ [Hb]
• ↓ O2 transport
• ↑ L → R shunt
Figure 4-1. Pathophysiology of a large left-to-right shunt. Proceeding in a clockwise direction, this schema shows the
factors that contribute to respiratory and circulatory compromise. With a large left-to-right (L ! R) shunt, pulmonary
blood flow and pulmonary arterial (PA), pulmonary venous (PV), and left atrial (LA) pressures increase, as does right ven-
tricular (RV) afterload and left ventricular (LV) preload. These changes promote pulmonary edema formation, and cause
large or small airway obstruction. The restrictive and obstructive lung disease creates areas of the lung with true intrapul-
monary shunt (V/ _ Q
_ ¼ 0), and can depress arterial PO2 and increase arterial PCO2. Because of the reduced systemic perfu-
sion and increased adrenergic tone, systemic blood flow is redistributed, O2 extraction increases, and respiratory muscle
perfusion is diminished. The postnatal decline in hemoglobin concentration [Hb] further aggravates the circulatory imbal-
ance by decreasing O2 transport and increasing further the left-to-right shunt. (From Lister, and G Perez Fontan JJ. Congenital
Heart Disease and Respiratory Disease in Children. Loughlin G and Eigen H. Eds. Baltimore, Williams & Wilkins, 1994, p 603.)
Chapter 4—Pulmonary Manifestations of Cardiac Diseases 83

Diagnoses Associated with

Table 4-1 Increased Pulmonary Arterial
Patent ductus arteriosus
Aorticopulmonary window
Truncus arteriosus
Postsurgical shunts
Blalock-Taussig (subclavian artery to ipsilateral
pulmonary artery)
Potts (descending aorta–left pulmonary artery)
Waterston (ascending aorta–right pulmonary
Atrium Figure 4-2. Plexiform lesion on lung biopsy specimen of
Atrial septal defect a patient with severe pulmonary arterial hypertension.
Common atrium
Total or partial anomalous pulmonary venous resistance with a right-to-left shunt is
connection defined as Eisenmenger syndrome.
Transposition of the great arteries with atrial septal
defect Clinical Findings of Acute Increased
Ventricle Pulmonary Venous Pressure
Ventricular septal defect Patients with acute pulmonary edema may
Single ventricle be asymptomatic in the early stages. On aus-
Atrioventricular canal cultation, the lung sounds can be normal, or
Associated lesions with ventricular septal defect there may be mild wheezing. As the condi-
Transposition of the great arteries tion progresses with alveolar edema, the
Double-outlet right ventricle patient may experience tachypnea and possi-
Tricuspid atresia without pulmonary stenosis ble cough productive of foamy secretions. At
Mitral atresia this stage, coarse crackles (rales) are usually
heard. Conditions associated with acute
increase of pulmonary venous pressure are
The earliest change to increased pressure
outlined in Table 4-2.
in the pulmonary arteries is medial thick-
The chest radiograph is more sensitive
ening, which is the response to increased
than the history or physical examination in
intramural vascular pressure. The medial
detecting acute elevation of pulmonary
thickening may come about from hypertro-
venous pressure (Fig. 4-3). The chest radio-
phy and hyperplasia of smooth muscle cells.
graph shows increased vascular markings
The next change is an increase in intimal
and changes in the cardiac silhouette,
thickening. Intimal thickening can be due
depending on the underlying heart disease.
to an increase in the number of cells or an
Kerley B lines are seen in the periphery of
accumulation of dense fibrous tissue. The
the lungs, indicating accumulation of fluid
development of irreversible change is her-
alded by the formation of plexiform lesions
Diagnoses Associated with Acute
(Fig. 4-2). Increase of Pulmonary Venous
Table 4-2
As the pulmonary vascular disease gradu- Pressure
ally worsens from the increased pressure,
Aortic regurgitation
the pulmonary vascular resistance also
Left atrium
increases and results in decreased pulmo-
Mitral regurgitation
nary blood flow. When the pulmonary vas-
Mitral stenosis or obstruction
cular resistance becomes higher than the
Left ventricular failure
systemic vascular resistance, the shunt flow
(initially left-to-right shunt) reverses direc-
Pericardial tamponade
tion, leading to a right-to-left shunt. At this
point, the elevated pulmonary vascular
84 Pulmonary Manifestations of Pediatric Diseases

in the interlobular septa. Alveolar edema is lobe bronchus).9 In addition, there is usually
represented radiologically as fluffy infiltrates. compression of small intraparenchymal air-
Pleural effusion may also appear, usually ways by engorged peribronchial vessels or
bilaterally beginning with blunting of the by bronchial wall or peribronchial edema.
costophrenic angles (Fig. 4-3). The term “cardiac asthma” is often applied
Even with interstitial edema and pleural to describe the wheezing caused by compres-
effusion, pulmonary function changes little sion of large and small intrathoracic airways.
in patients with acute increased pulmonary Affected infants often may have respiratory
venous pressure. Alveolar edema is associated symptoms so prominent that they over-
with significant decreases in the PaO2, how- shadow or mask the underlying cardiac dis-
ever. With increased alveolar flooding, there ease. The shunt may be recognized only
is also a decrease in lung volume and compli- when a clinician notes the coexistence of
ance. Airway resistance increases because of cardiomegaly and air trapping on a chest
the decrease in lung volume and liquid filling radiograph. Bronchial compression at these
the airway lumen. locations also can produce lobar emphysema
Pulmonary edema renders the alveoli or atelectasis. This complication is seen most
unstable, and it makes the lung stiff, frequently in 2 to 9-month-old infants. The
increasing the work that the respiratory age range predilection may be linked to the
muscle must perform to maintain adequate gradual decrease of pulmonary vascular resis-
ventilation. Pulmonary edema is not the tance over the first few months of life that
only mechanism, however, by which the results in an increase in pulmonary blood flow
work of breathing becomes greater in sub- and the small airway caliber and less cartilagi-
jects with a left-to-right shunt. These patients nous airway support in infants.6 Evaluation
can also develop extrinsic airway com- for underlying cardiac disease also should be
pression. Pulmonary “overcirculation” along part of the assessment of an infant or young
with pulmonary hypertension may cause child with atelectasis or lobar emphysema.
extrinsic compression of the main and lobar Pulmonary edema, and the mechanical
bronchi by enlarged pulmonary arteries (usu- disturbances that it produces, also impairs
ally affecting the right main stem bronchus, gas exchange within the lung. In the pres-
the lingular and left upper lobe bronchi, or ence of a left-to-right shunt, overall ventila-
the left main stem bronchus) or by distention tion to perfusion is low, and there are areas
of the left atrium (affecting the left lower that are perfused but not ventilated (true
right-to-left intrapulmonary shunt). How-
ever, the recirculation of arterial blood
through the lung and the high saturation of
pulmonary arterial blood (owing to the
left-to-right shunt) minimize the effects,
of intrapulmonary right-to-left shunting on
arterial oxygen saturation. Arterial PO2 and
PCO2 are usually near-normal, unless there
is respiratory fatigue caused by increased
respiratory rate and effort.
Patients with ASD are usually asymptom-
atic in early life, although they may have
an increased incidence of respiratory tract
infections. With the onset of pulmonary
hypertension (usually in adulthood), dys-
pnea and fatigue may occur. Patients with
left-to-right shunts at the aortic and ventric-
ular levels may develop biventricular con-
gestive heart failure in infancy. Symptoms
Figure 4-3. Pleural effusion in a child with severe con- include dyspnea, grunting, apnea, and poor
gestive heart failure. feeding. The early congestive heart failure
Chapter 4—Pulmonary Manifestations of Cardiac Diseases 85

also predisposes these infants to respiratory accumulation of pulmonary edema. In par-

infections and poor growth. When the disease ticular, the combination of diuretics and
has progressed to Eisenmenger syndrome, all inotropic drugs can decrease filling pressure
patients have cyanosis (at rest and during in the left atrium and reduce pulmonary
exercise) and dyspnea. The clubbing that is microvascular pressure, attenuating edema
apparent is due to chronic hypoxia; the formation. Depending on the specific lesion
peripheral tissue capillaries dilate to increase and the size of the patient, often interven-
the oxygen supply, causing digital swelling. tional cardiac catheterization offers an alter-
Other symptoms that occur after disease pro- native to cardiac surgery. These less invasive
gression to Eisenmenger syndrome are chest techniques are currently widely used for the
pain, syncope, and hemoptysis. The hemop- closure of secundum ASDs and PDAs.
tysis can be caused by pulmonary infarction
from low pulmonary blood flow or conges- Clinical Manifestations of Chronic
tion, polycythemia, or bronchial arterial Increased Pulmonary Venous Pressure
bleeding. Several conditions are associated with
Patients with PDA characteristically have chronic increased pulmonary venous pressure
a continuous murmur. When the disease (Table 4-3). The gradual onset of increased pul-
progresses to Eisenmenger syndrome, a monary venous pressure leads to an almost
patient with an uncorrected PDA has differ- imperceptible onset of symptoms. These early
ential cyanosis (upper body is pink and symptoms may include dyspnea, fatigue, and
lower body is blue owing to right-to-left decrease in endurance or exercise tolerance.
shunt beyond the left subclavian artery).
Isolated digital clubbing of the toes without
clubbing of the fingers may occur because of
the difference in upper versus lower body
Diagnoses Associated with
oxygenation. Chronic Increase of Pulmonary
Table 4-3
Venous Pressure
Treatment of Large Volume
Aortic Valve
Left-to-Right Shunts
Aortic regurgitation
Although corrective or palliative surgery is the
Aortic stenosis
ultimate therapy for each of the conditions
Left Atrium
described in this section, initial medical man-
Atrial myxoma
agement is essential for stabilizing an infant
Ball-valve thrombus
with critical congestive heart failure. For an
Cor triatriatum
infant with large left-to-right shunt, treatment
Left Ventricle
traditionally has focused on improving myo-
Chronic heart failure
cardial function, removing excess fluid accu-
Congenital subaortic stenosis
mulated in the lungs, and, in some patients,
Constrictive pericarditis
providing assisted respiration. These infants
Hypertrophic cardiomyopathy
have increased caloric needs, and close assess-
Restrictive cardiomyopathy
ment of growth is an essential part of their
Mitral Valve
management and part of the decision-making
Mitral regurgitation
process in determining the timing of correc-
Mitral stenosis
tive surgery. They have increased energy
Pulmonary Veins
requirements and sometimes have difficulty
Congenital pulmonary vein stenosis
feeding secondary to shortness of breath.
Mediastinal fibrosis
In an acutely decompensated infant, an
Mediastinal neoplasms
intravenous inotropic agent, such as dopa-
mine, dobutamine, or isoproterenol, is most
Veno-occlusive disease
useful. For long-term use, a medication that
Thoracic Aorta
can be given enterally, such as digoxin, is
Coarctation of aorta
more appropriate. Diuretics can improve
Supravalvular aortic stenosis
respiratory function by controlling the
86 Pulmonary Manifestations of Pediatric Diseases

When these patients are otherwise stable,

symptoms may be minimal. Acute increases
in cardiac output (e.g., fever or exercise) or
decreases in filling time (e.g., tachyarrhy-
thmias) can lead to sudden worsening of
dyspnea (Fig. 4-4). Hemoptysis is a late com-
plication and is caused by rupture of the
dilated bronchial anastomotic vessels.
Pediatric patients can have a severe, rapidly
progressive form of veno-occlusive disease.10
This form of veno-occlusive disease can be
sporadic or familial. The initial chest radio-
graph may show only cardiomegaly with
mild lung changes, or may show pulmonary
effusion or edema (Fig. 4-5). These patients
present with progressive dyspnea and then
syncope. As a postcapillary form of pulmo-
nary hypertension, patients are often mis-
Figure 4-5. Chest radiograph of a child with pulmonary
diagnosed as having arterial hypertension. veno-occlusive disease.
Although cardiac catheterization and com-
puted tomography (CT) of the chest can be
diagnostic,11 a lung biopsy may be needed vascular congestion, atelectasis, and pleural
to confirm the diagnosis. On pulmonary func- effusion.14 Vasodilators should be used spar-
tion tests, there is reduction of vital capacity, ingly and extremely cautiously in pediatric
forced expiratory volume in one second, and patients with veno-occlusive disease. Consul-
arterial oxygen saturation or diffusing capac- tation with a lung transplant team is recom-
ity for carbon monoxide.12 There is no effec- mended at the time of diagnosis.
tive medical or surgical therapy for most of As with acute increased pulmonary venous
these cases. There have been some case reports pressure, the chest radiograph may be the
that immunosuppressant therapy may ame- most sensitive noninvasive test to alert the
liorate the disease progression.13 Although clinician to the possibility of chronic venous
gentle vasodilator therapy may be effective hypertension. On the radiograph, the pul-
in some cases, use of vasodilator therapy also monary arteries become attenuated initially
can lead to (sometimes acutely) increased at the bases and then toward the apex. Kerley
B lines appear due to the presence of dilated
lymphatics and interlobular fibrosis, rather
than owing to interstitial edema, as in the
patient with acute increased pulmonary
venous pressure. Diffuse nodularity resulting
from hemosiderin-laden macrophages may
fill the lower lobe alveoli. Rarely, ossified
nodules also may be found at the lung bases
(Fig. 4-6).
The chest radiograph also is useful in deter-
mining the level of the venous obstruction.
If the level of obstruction is preventricular
(atrial myxoma or cor triatriatum), the left
ventricular silhouette may be normal,
although the left atrium may show an
enlarged shadow. If the level of obstruction
is at the ventricle due to myocardial disease
Figure 4-4. Acute decompensation of a patient with
chronic pulmonary venous hypertension after sponta- or to valvular disease, the heart is likely to
neous left pneumothorax. appear enlarged on the chest radiograph.
Chapter 4—Pulmonary Manifestations of Cardiac Diseases 87

Figure 4-6. High-resolution CT scan of the chest of a

patient with idiopathic/sporadic pulmonary veno-occlu- Figure 4-7. Photomicrograph of lung biopsy specimen
sive disease. taken from a child with pulmonary venous obstruction.
Note the thickened walls of the pulmonary vein with nar-
rowing of the lumen. Also note the dilated capillaries in
Initial changes in pulmonary function are the interstitium.
due to congestion of the lungs and interstitial
edema. Pulmonary congestion and interstitial
edema may lead to decreases in airway caliber aorta, interruption of the aortic arch, and
with a decrease in forced expiratory volume obstruction to pulmonary venous return.
in one second. With increasing years, chronic These anomalies generally are characterized
changes, including interlobular fibrosis by decreased systemic perfusion and pulmo-
develop and lead to a decrease in lung recoil nary venous congestion. Infants with
and volume. In time, the chronic hemody- obstruction of the left heart usually develop
namic and pulmonary functional limitation clinical manifestations at an earlier post-
may lead to changes in respiratory muscle natal age and have more severe respiratory
function as shown by decreases in maximal compromise because closure of the ductus
strength. arteriosus, which usually occurs within the
With the chronic interstitial edema, lym- first few days after birth, may substantially
phatic distention, and possible intermittent reduce blood flow through the aorta and
extravasation of blood into the interstitium, decrease systemic perfusion. When the pul-
interstitial fibrosis develops around septa and monary artery pressure is suprasystemic,
blood vessels. The pulmonary veins show as in total anomalous pulmonary venous
characteristic changes of medial hypertrophy. return and obstruction, ductus closure elim-
Later venous changes include intimal thick- inates a mechanism for amelioration of the
ening and fibrosis (Fig. 4-7). An external elastic pulmonary hypertension via right-to-left
membrane characteristic of arteries may shunting. The pulmonary and systemic
form—the so-called arterialization of the pul- venous congestion can occur precipitously.
monary veins. These venous changes are
pathognomonic of pulmonary venous hyper- Pathophysiology of Obstruction of the
tension but nonspecific as to the underlying Systemic Ventricle
causes. Calcium deposition and ossification The problems occurring with left heart
are the most extreme changes, however, which obstruction arise from its effects on systemic
are seen only in long-standing mitral stenosis. blood flow, ventricular loading, and pulmo-
nary function. For a better understanding of
the pathophysiology of left ventricular
Outflow or Inflow Obstruction of the obstruction, it is helpful to separate the
Systemic Ventricle lesions into outflow and inflow obstruction.
Anomalies that commonly cause left-sided Left Ventricular Outflow Obstruction.
(systemic ventricular) obstruction include These lesions cause an increased afterload of
aortic stenosis or atresia, coarctation of the the left ventricle, which is tolerated very
88 Pulmonary Manifestations of Pediatric Diseases

poorly if the obstruction is severe or if it occurs The findings on chest radiograph also vary
abruptly. The hemodynamic consequences of with the severity of the obstruction. Severe
outflow obstruction are increased ventricular obstruction may show edema on the chest
end-diastolic, left atrial, and pulmonary film, along with left ventricular enlargement.
venous and pulmonary arterial pressures, In most patients with mild or moderate aortic
which cause variable degrees of pulmonary stenosis, the heart size is normal or only
venous congestion and pulmonary edema mildly enlarged. Intervention for aortic ste-
(interstitial and alveolar) and obstruction nosis, when indicated, can be accomplished
of large and small airways, just as with the by percutaneous balloon valvuloplasty in
large left-to-right shunt. In the most severe the cardiac catheterization laboratory or by
forms of obstruction, usually found in neo- surgical valvulotomy or valve replacement.
nates, there are always signs of poor systemic
perfusion (increased capillary refill time, Coarctation of the Aorta
decreased or absent peripheral pulses, cool Coarctation of the aorta often manifests as a
extremities) accompanied by lactic acidosis. discrete stenosis in the proximal thoracic
aorta, just opposite the PDA insertion. There
Left Ventricular Inflow Obstruction. is a wide spectrum of this disease, however,
These anomalies (i.e., mitral atresia or steno- including long segment coarctation and
sis) impede left ventricular filling and increase abdominal coarctation. Associated lesions,
the afterload on the right ventricle. The pre- such as PDA, VSD, aortic stenosis, or mitral
load on the right ventricle also becomes stenosis, also affect the pathophysiology
increased by the excess blood flow entering and clinical presentation.
the right ventricle from the portion of the pul- The clinical presentation of isolated coarc-
monary venous return, which is shunted from tation of the aorta varies. Newborns with
the left to the right atrium through the fora- severe coarctation and PDA closure present
men ovale. The impairment of systemic perfu- with congestive heart failure and cardiogenic
sion depends on the amount if any, of shock or low cardiac output. If a right-to-left
anterograde (aortic) flow from the systemic ductal shunt is present, differential cyanosis
ventricle and the right-to-left shunt, through of the lower extremities is seen. On the other
the ductus arteriosus. When there is atresia end of the spectrum, coarctation can manifest
of the mitral or aortic valve, the left-to-right later in childhood when systolic hypertension
atrial shunt represents the only means for or a heart murmur is being evaluated. The sys-
blood to reach the systemic circulation (via tolic blood pressure in the upper extremity is
the right ventricle and through the ductus elevated proximal to the coarctation, and
arteriosus to the descending aorta). there is a gradient noted between the arm
and leg systolic blood pressures. The arterial
Aortic Stenosis pulse in the leg is diminished and delayed
Aortic stenosis causes a spectrum of disease when palpated at the same time as the arm
in children, based on the severity of the val- pulse. The blood pressure and pulse should
vular narrowing. The valvular pathology be evaluated in all four limbs.
involves thickening of the tissue and vary- The chest radiograph of an infant with
ing degrees of separation of the commis- severe coarctation of the aorta usually shows
sures. Clinical findings vary widely with cardiomegaly and pulmonary vascular con-
the severity of the valvular obstruction. gestion. In older children being evaluated
Most children with mild aortic stenosis have for a murmur or hypertension, the heart size
normal growth and development and come usually is not prominent, and in isolated
to a cardiologist’s attention when a heart coarctation, the pulmonary markings are
murmur is heard. On the other end of the normal. The contour of the aortic arch is
spectrum, infants with critical aortic steno- often abnormal, with an indentation seen
sis can be hemodynamically unstable and at the site of coarctation (the “3” sign). Rib
exhibit severe endocardial fibroelastosis at notching also can occur in older patients;
birth, requiring immediate relief of the this is caused by erosion of the inferior rib
obstruction through interventional cardiac by the collateral circulation or dilated inter-
catheterization or a surgical approach. costals arteries.
Chapter 4—Pulmonary Manifestations of Cardiac Diseases 89

Treatment for many children consists of An example of the latter is the pulmonary
surgical repair of the coarctation. This is usu- artery sling. The left pulmonary artery arises
ally performed via a left thoracotomy. Some- from an elongated main pulmonary artery
times, when an associated lesion also is being or distally from the right pulmonary artery.
repaired, a sternotomy is performed.15 Percu- It crosses the midline between the trachea
taneous balloon angioplasty, stent placement, and the esophagus, sometimes with a cross-
or both, for a discrete coarctation or re- over segment of the left pulmonary artery
coarctation are other treatment options.16-18 supplying the right upper lobe. This condi-
tion also is strongly associated with long
segment congenital tracheal stenosis.
Vascular Anomalies That Cause The most likely types of vascular rings
Airway Obstruction include double aortic arch and right aortic
arch with aberrant left subclavian artery,
Compression of the trachea and bronchi can
which arises from the descending aorta and
be caused by developmental abnormalities of
passes behind the esophagus. The vascular
both of the major arterial branches of the
ring is completed by the left ligamentum
aorta or the pulmonary vessels (Table 4-4). arteriosum, which courses from the origin
These lesions, which generally arise from fail-
of the left subclavian artery to the left pulmo-
ure of normal regression of one or more seg-
nary artery (Fig. 4-8). The left subclavian
ments of the early fetal paired branchial
arches, can produce substantial distortion
of the trachea and large bronchi.19 The most
common types involve either complete
encirclement of the tracheoesophageal com-
plex by vascular structures (vascular rings)
or compression of the trachea or bronchi by
vessels that follow an anomalous trajectory.

Causes of Vascular Compression A

Table 4-4 of the Airway in Children
• Anomalies of the aorta
 Double aortic arch
 Interrupted aortic arch (after surgical repair)
 Right-sided aortic arch
• With aberrant left subclavian artery
• With mirror-image branching and right
ligamentum arteriosum
 Left-sided aortic arch
• With aberrant right subclavian artery and
right ligamentum arteriosum
• Right-sided descending aorta with right
ligamentum arteriosum
 Cervical aortic arch
• Absent pulmonary valve syndrome
• Aberrant left pulmonary artery (‘pulmonary B
artery sling’)
• Acquired cardiovascular disease
Figure 4-8. A 5-year-old boy with a right-sided aortic
arch and aberrant left subclavian artery. A, Axial CT scan
 Dilated cardiomyopathy of the thorax shows compression of the trachea by the
 Aneurysm aberrant artery (arrow). B, Three-dimensional volume ren-
dered image (posterior view) shows the right-sided aortic
• Ascending aorta
arch (white arrow on right) and the aberrant left subclavian
 Ductus arteriosus artery (white arrow) arising from the descending aorta.
Adapted from McLaren CA, Elliott MJ, Roebuck DJ: Vascular (Adapted from McLaren CA, Elliott MJ, Roebuck DJ: Vascular
compression of the airway in children. Paediatr Respir Rev compression of the airway in children. Paediatr Respir Rev
9:85-94, 2008. 9:85-94, 2008.)
90 Pulmonary Manifestations of Pediatric Diseases

artery often originates from an outpouching

of the descending aorta, called Kommerell
diverticulum. Other patterns of right aortic
arch include mirror-image branching and
right ligamentum arteriosum, anomalous
innominate arising farther to the left than
usual and passing anterior to the trachea,
anomalous left carotid artery arising further
to the right than usual and passing anterior
to the trachea, and aberrant right subclavian
As a group, vascular anomalies obstruct
the intrathoracic airways exclusively. Conse-
quently, their manifestations are predomi-
nantly expiratory and include wheezing
and lung hyperinflation. When the com-
pression is severe, inspiratory stridor also is
heard indicating the relatively fixed nature Figure 4-9. Lateral projection of a barium esophago-
gram in a 3-month-old infant with a double aortic arch
of the obstruction. Infants are often brought causing posterior compression of the esophagus.
to medical attention when an intercurrent
infection causes increased respiratory dis-
tress. Some patients are labeled as having
“recurrent bronchitis” or “steroid-resistant an uncommon radiographic finding is an
asthma” before the diagnosis of a vascular anterior esophageal indentation with a pos-
ring is made. In older children, a (often terior impression on the tracheal air col-
more “loose”) vascular ring can manifest umn. This combination is seen when the
with dysphagia or choking. Other patients left pulmonary artery originates from the
remain asymptomatic and are diagnosed right pulmonary artery (pulmonary artery
incidentally. sling). The anomalous left pulmonary artery
Barium esophagogram is an important tool must find its way to the left lung anterior to
for the initial evaluation of infants and chil- the esophagus and posterior to the trachea.
dren suspected to have airway compression In the process, it passes over the right main
by an anomalous vessel. A large posterior stem bronchus, behind the trachea, and
esophageal indentation in association with down over the left main stem bronchus,
an anterior notch in the tracheal air column and may compress any of these structures,
is usually caused by complete vascular rings frequently causing air trapping or atelectasis
(double aortic arch or a right aortic arch with in either lung.
an aberrant left subclavian artery or ligamen- The diagnosis of vascular rings and slings is
tum arteriosum or both) encircling the tra- confirmed by magnetic resonance imaging
chea and esophagus (Fig. 4-9). (MRI)20 and computed tomography (CT).
A complete vascular ring can be associated These are the most useful imaging techniques
with intracardiac defects, such as VSD, because they provide information about the
which can divert attention from the extra- tracheobronchial tree, the cardiovascular
cardiac anomalies. Another radiographic structures, and their relationship to each
finding is the presence of an isolated ante- other. CT data are generally useful to diagnose
rior tracheal indentation. This pattern the type and severity of airway compression,
occurs when there is an anomalous innomi- but multiplanar reconstruction and three-
nate artery that arises too far from its nor- dimensional volume rendered images provide
mal origin and has to cross the midline in further useful information. Virtual bronchos-
front of the trachea. In contrast to the com- copy images also can be generated from CT
plete vascular rings, anterior tracheal com- data but rarely add diagnostic information
pression may be an incidental observation and cannot yet be used as a substitute for flex-
and produce few to no symptoms. Finally, ible bronchoscopy. MRI has excellent contrast
Chapter 4—Pulmonary Manifestations of Cardiac Diseases 91

resolution and multiplanar imaging capabil- stenosis, if present. Surgery does not usually
ities.20 Evaluation of cardiac anatomy and eliminate all the respiratory manifestations
physiology with MRI is usually superior to immediately, if ever, because the residual
CT. Most MRI studies for vascular compres- tracheal obstruction tends to persist for
sion are quite prolonged (>30 minutes), how- months. In some cases, it is unclear whether
ever, requiring sedation or general anesthesia the airway ever becomes normal.21
in young children. Sedation risks for children
with a compromised airway are significant. Congenital Absence of the Pulmonary
In practice, the increased speed and quality Valve
of multiplanar reconstruction provided by Congenital absence of the pulmonary valve
CT technology means that CT is used more is characterized by the presence of enlarged
often than MRI in most centers. A limitation pulmonary arteries and hypoplastic pulmo-
of MRI and CT is that obliterated vascular seg- nary valve cusps. This lesion often occurs
ments (e.g., the ligamentum arteriosum or an in association with tetralogy of Fallot, VSD,
atretic aortic arch) cannot be directly visual- and right ventricular outflow tract obstruc-
ized. Echocardiography is essential for the tion. There is also a strong association with
evaluation of associated congenital heart dis- DiGeorge syndrome.
ease and usually clearly shows abnormal vas- Regurgitation of blood through the pulmo-
cular structures. Echocardiography is useful nary outflow tract results in extremely
to the surgeon for understanding complex enlarged pulmonary arteries (Fig. 4-10). These
three-dimensional relationships. Cross-sec- arteries compress the trachea and main stem
tional imaging is probably much better than bronchi, causing lobar collapse or lobar
bronchoscopy at determining the nature of emphysema and severe respiratory distress.
the vascular compression of the airway. Yet, Airway compression can be unilateral or bilat-
current CT and MRI techniques do not eral. Respiratory difficulty occurs as the pul-
reliably distinguish, between dynamic and monary artery becomes gradually dilated
static airway narrowing. This is an important when the postnatal decrease in pulmonary
practical issue because many children with vascular resistance increases left-to-right
prolonged airway compression develop sec- shunting and pulmonary regurgitation. Surgi-
ondary malacia. Flexible bronchoscopy is cal repair of the cardiac anomaly and place-
currently the best technique for this purpose. ment of an artificial pulmonary valve are
Airway malacia should be assessed only when invariably necessary. As a result of the residual
the patient is breathing spontaneously. Diag- tracheomalacia, there is, in many patients, a
nostic catheter angiography has largely been need for mechanical ventilation for weeks or
replaced by cross-sectional imaging. months after surgical repair even if the hemo-
Surgery is advised for symptomatic dynamic function is near-normal, and there is
patients with diagnostic imaging evidence no regurgitation.
of tracheal compression. The left arch is
generally small, nondominant (hypoplas- Pathophysiology of Respiratory
tic), and often transected in patients with Manifestations
double aortic arch. Compression produced From a clinical point of view, all the cardio-
by a right aortic arch and aberrant left sub- vascular anomalies we have described until
clavian artery with a ligamentum arterio- now are characterized by the severity of
sum is relieved by transection of the latter. their respiratory manifestations. Regardless
Anomalous innominate or carotid arteries of the exact nature of the anomaly, these
cannot be divided; attaching the adventitia manifestations always include an increase
of these vessels to the sternum usually in the work that the respiratory system must
relieves the tracheal compression. An anom- perform to maintain adequate ventilation.
alous left pulmonary artery is corrected dur- The increased work takes a further toll on
ing cardiopulmonary bypass by division at the already limited energy reserves of most
its origin and reimplantation to the main patients and often leads to respiratory fail-
pulmonary artery with the simultaneous ure as the first indication of the presence
repair of a long segment congenital tracheal of the anomaly.
92 Pulmonary Manifestations of Pediatric Diseases

predominant respiratory abnormality.

Whether it is caused by direct compression
of the trachea and large bronchi by enlarged
vessels or heart chambers or by narrowing
of the small intraparenchymal airways by
edema, the obstruction is almost always
intrathoracic, and as such is exacerbated
during expiration. In these patients, respira-
tion tends to be slower and deeper, and the
physical examination reveals wheezing and
prolonged expiration. The chest x-ray shows
The increase in the work of breathing
represents a challenge for patients who are
A usually in a poor nutritional state and
whose respiratory muscles may have a
reduced ability to increase their blood flow
because of reduced systemic perfusion. In
addition, the mechanical abnormalities pro-
duced by the disease itself tend to decrease
the efficiency with which the respiratory
system uses its limited resources (Fig. 4-11).
The development of severe retractions
creates an extra burden on the diaphragm,
B which for the same amount of work per-
Figure 4-10. Tetralogy of Fallot and absent pulmonary formed by the lungs has to use more energy
valve syndrome with airway compression in a 15-month- to deform the rib cage. Likewise, flattening
old boy. A, CT volume-rendered image shows compres- of the diaphragm in the presence of airway
sion of the left main bronchus (arrow). B, Axial CT scan
of the thorax shows severe compression of the airway obstruction causes the muscle to generate
between the vertebral body and the grossly enlarged pul- less volume displacement for the same degree
monary arteries. (From McLaren CA, Elliott MJ, Roebuck DJ: of fiber shortening and diminishes its area of
Vascular compression of the airway in children. Paediatr
Respir Rev 9:85-94, 2008.) apposition to the rib cage. Under such condi-
tions, it is not unsurprising that the energy
cost of breathing becomes extraordinary.
The mechanisms responsible for the Such demands cannot always be fully met,
increase in work of breathing vary depend- particularly under stressful conditions. Respi-
ing on the mechanical alterations produced ratory failure then develops.
by each cardiovascular anomaly. Most
patients with a large left-to-right shunt or
a left ventricular obstruction develop pul- Lesions with Increased Venous
monary edema. As a result, their alveoli Admixture
become unstable and collapse, causing an
increase in the force that the respiratory Cyanotic children have defects that allow
muscles have to generate to overcome the venous blood to mix with arterial oxygenated
elastic recoil of the lungs. Under these cir- blood. Children may have an isolated right-
cumstances, intercostal and subcostal retrac- to-left shunt or obstruction to pulmonary
tions develop, and the respiratory pattern blood flow in addition to the right-to-left
becomes rapid and shallow. The patient fre- shunt. Another example of cyanotic heart dis-
quently tries to preserve lung volume by ease is when the great arteries are transposed,
closing the glottis at the end of expiration, causing the systemic venous blood to return
producing a grunt. directly to the aorta. Examples of each of these
A group of children with similar heart dis- types of cyanotic heart lesions are discussed
ease can develop airway obstruction as their subsequently.
Chapter 4—Pulmonary Manifestations of Cardiac Diseases 93

↓ Muscle
↓ Energy
↓ Nutrition

Alveolar collapse

Pulmonary edema
Energy Compensation
available Airway obstruction

Work of

Rib cage distortion

↓ Diaphragmatic length Efficiency Respiratory
Fatigue failure

Figure 4-11. Schematic representation of the balance between the energy available to the respiratory muscles and the
work that these muscles do during breathing in the presence of mechanical alteration. Whether the balance tips toward
compensation or respiratory failure depends not only on the relative magnitudes of the energy available to the muscles
and the increased workload (represented by the weights on both sides of the balance) but also on the efficiency with
which the energy is transformed into work (represented by the position of the fulcrum). The presence of heart disease,
alveolar collapse, pulmonary edema, and airway obstruction can increase the workload; poor nutrition, decreased blood
flow, and, in general, the inability of the muscle’s contractile machinery to transduce energy into work can decrease the
energy available. Under such circumstances, decreased efficiency caused by rib cage distortion (retractions), a flattened
diaphragm, or muscle fatigue can easily displace the fulcrum to the left, precipitating respiratory failure. (From Lister, G
and Perez Fontan JJ. Congenital Heart Disease and Respiratory Disease in Children. Loughlin G and Eigen H. Eds. Baltimore,
Williams & Wilkins, 1994, p 603.)

Tricuspid Atresia the main underlying physiologic issue,

Infants with tricuspid atresia do not have a whether it is the need to increase pulmonary
normal pathway for blood to flow from the blood flow, decrease pulmonary overcircula-
right atrium to the right ventricle because tion, or eliminate interatrial obstruction.
the tricuspid valve is not patent. The blood
in the right atrium instead takes a path Tetralogy of Fallot
across an ASD to mix with the oxygenated When there is an obstruction to pulmonary
blood in the left atrium. Patients with tricus- outflow and a right-to-left shunt, the pulmo-
pid atresia can have normally related great nary blood flow can decrease to less than sys-
arteries, D-transposed great arteries, or temic flow (Table 4-5). The most common
L-transposition of the great arteries. Some cardiac anomaly associated with decreased
have pulmonary stenosis or atresia, and pulmonary arterial pressure is tetralogy of
some have VSDs of varying sizes. Associated Fallot.
cardiac anomalies may produce decreased, With low pulmonary blood flow, the bron-
increased, or normal pulmonary blood flow. chial circulation may assume a more promi-
Patients with decreased pulmonary blood nent role in supplying blood to the lungs
flow appear cyanotic, while patients with
excessive pulmonary blood flow develop
congestive heart failure. Patients with tricus- Diagnoses Associated with
pid atresia who present in the first days of life Table 4-5 Decreased Pulmonary Arterial
are typically cyanotic, have a leftward supe-
rior axis and left ventricular hypertrophy Ebstein anomaly
on electrocardiogram, and have decreased Pulmonary valvular stenosis with patent foramen
pulmonary vascular markings on chest
Tetralogy of Fallot
radiograph. Surgical palliation is directed at
94 Pulmonary Manifestations of Pediatric Diseases

for gas exchange. With severe pulmonary D-Transposition of the Great Arteries
outflow obstruction, cyanosis appears early, D-transposition of the great arteries is a cya-
occurring when the patient is crying or notic heart lesion that occurs when the
straining. The mechanism is presumed to be aorta arises from the right ventricle, and
an increase in pulmonary vascular resistance the pulmonary artery arises from the left
by a Valsalva-like maneuver. The cyanosis ventricle (ventriculoarterial discordance).
becomes severe, and the children are usually A parallel circulation is set up, and a mixing
dyspneic. Their characteristic pose, squatting lesion (VSD, ASD, or PDA) is essential for
to relieve their shortness of breath, is believed survival.
to help increase systemic resistance, which Clinically, an infant who does not have
increases the pulmonary blood flow and adequate mixing appears severely cyanotic.
improves their oxygenation. On physical A hyperoxia test can be performed to distin-
examination, these children have cyanosis, guish cyanotic heart disease from severe
digital clubbing, and growth failure. Electro- pulmonary disease by placing the patient
cardiograms and echocardiograms show on 100% FiO2 for 10 minutes. If the PO2
right ventricular and atrial hypertrophy. On increases greater than 150mmHg, pulmo-
chest radiograph, there is a prominent right nary disease should be suspected. The classic
ventricle and a small pulmonary artery, chest radiograph is described as an “egg on a
which appears as the characteristic “boot- string” because the great vessels are in an
shaped” cardiac silhouette (Fig. 4-12). anteroposterior relationship (Fig. 4-13). The
Except for significant hypoxemia, there chest radiograph also can appear normal in
are minimal alterations in pulmonary func- these patients, or may exhibit increased pul-
tion. One study found reduced lung volumes monary vascular markings and enlarged car-
in young adults with congenital pulmonic diac silhouette if a large VSD is present.23 If
stenosis compared with normal controls. It mixing of the pulmonary and systemic cir-
has been proposed that low pulmonary culations is inadequate at birth, an atrial
blood pressures can cause pulmonary hypo- septostomy can be performed in the cardiac
plasia.22 Patients with tetralogy of Fallot catheterization laboratory to create an ASD.
undergo complete surgical repair; sometimes This palliative procedure is followed by the
severely ill cyanotic infants require a pallia- arterial switch surgery, with reimplantation
tive Blalock-Taussig shunt before definitive of the coronary arteries to restore normal
repair. circulatory flow.

Figure 4-12. Chest radiograph of a child with tetralogy Figure 4-13. Chest radiograph of a child with D-trans-
of Fallot. position of the great arteries.
Chapter 4—Pulmonary Manifestations of Cardiac Diseases 95

Idiopathic Pulmonary Arterial

Pulmonary Hypertension
Hypertension Table 4-6 Diagnostic Classification

Although idiopathic pulmonary arterial Pulmonary Arterial Hypertension

hypertension (IPAH) is not a primary cardiac Familial
disease, children with IPAH are usually Sporadic
referred to pediatric cardiologists for evalua- Related to:
tion of their symptoms or cardiomegaly or Connective tissue disease
both (Fig. 4-14). Children with IPAH (previ- Congenital heart disease
ously known as primary pulmonary hyper- Portal hypertension
tension) have a worse prognosis than Human immunodeficiency virus infection
adults.24 The definition of pulmonary arte- Drugs and toxins
rial hypertension is the same for children Other—type 1 glycogen storage disease, Gaucher
disease, hemoglobinopathies, myeloproliferative
and adults: mean pulmonary arterial pres- disorders, hereditary hemorrhagic telangiectasia
sure greater than 25mmHg at rest or greater (Rendu-Osler-Weber disease)
than 30mmHg during exercise, with normal Pulmonary Arterial Hypertension with
pulmonary artery wedge pressure (i.e., <15 Significant Venule or Capillary Involvement
mmHg), and an increased pulmonary vas- Pulmonary veno-occlusive disease
cular resistance index (>3 Wood units/m2). Familial
The diagnosis of IPAH is made only when all Sporadic
other causes of pulmonary hypertension have Pulmonary capillary hemangiomatosis
been ruled out (Table 4-6).24,25 A careful fam- Persistent Fetal Circulation (Persistent
Pulmonary Hypertension of the Newborn)
ily history also must be obtained to rule out
Pulmonary Venous Hypertension
familial pulmonary arterial hypertension. Pulmonary venous obstruction (discrete)
Children with IPAH often have insidious Left-sided heart disease
onset of vague symptoms, including fatigue, Pulmonary Hypertension Associated with
decreased endurance, or abdominal pain Disorders of Respiratory System or Hypoxemia
(older children and adolescents may have Hyaline membrane disease
chest pain). They also may present with recur- Bronchopulmonary dysplasia
rent exertional or nocturnal syncope. If the Congenital diaphragmatic hernia
child with IPAH fails to respond to vasodilator Pulmonary hypoplasia
therapy or is not treated in this manner, the Alveolar capillary dysplasia
prognosis is poor. The pulmonary arteries Cystic fibrosis
become greatly dilated throughout the lung Chronic obstructive pulmonary disease
parenchyma (Fig. 4-15), and patients develop Interstitial lung disease
progressive right heart failure accompanied Sleep-disordered breathing
by hemoptysis. Alveolar hypoventilation disorders
Chronic exposure to high altitude
Pulmonary Hypertension due to Chronic
Thrombotic or Embolic Disease
Thromboembolic obstruction of proximal
pulmonary arteries
Thromboembolic obstruction of distal pulmonary
Pulmonary embolism (tumor, parasites, foreign
Histiocytosis X
Fibrosing mediastinitis
Adenopathy and tumors

Figure 4-14. Chest radiograph of a child with idiopathic From Rosenzweig EB, Widlitz AC, Barst RJ: Pulmonary arterial
pulmonary arterial hypertension. hypertension in children. Pediatr Pulmonol 38:2-22, 2004.
96 Pulmonary Manifestations of Pediatric Diseases

Other Pulmonary Conditions

Associated with Cardiac Disease
or Surgery

Plastic Bronchitis
Plastic bronchitis can occur in children and
adults.26,27 The disease is characterized by
severe obstruction of the large airways by bron-
chial casts (Fig. 4-17). Affected patients are usu-
ally classified by the type of airway cast.26 Type I
or inflammatory casts have fibrin, eosinophils,
and Charcot-Leiden crystals. Type II or nonin-
Figure 4-15. Explanted lung from a young adolescent
girl with idiopathic pulmonary arterial hypertension. Note flammatory/acellular casts consist primarily of
the markedly dilated pulmonary arteries extending to the mucin with a paucity of cells. Type II casts usu-
peripheral portions of the lung. ally occur in children with cyanotic congenital
heart disease and after cardiac surgery. A new
classification scheme has been proposed that
Diagnosis generally starts with an echo- is based on the associated disease and the histol-
cardiogram with Doppler, to evaluate the ogy of the cast.27 Treatment usually consists
cardiac anatomy, and if a shunt is present, of urgent/emergency removal of the casts
to determine shunt flow direction and to from the large airways by means of flexible or
quantify the shunt velocity (Fig. 4-16). rigid bronchoscopy. Aerosolized medications
Patients proceed to cardiac catheterization (rhDNase, heparin, tissue plasminogen activa-
for measurement of pressures and evalua- tor) and other medications (corticosteroids,
tion of response to acute therapy (e.g., nitric low-dose azithromycin) also have been used
oxide, prostacyclin). If the child fails to in published case reports.28-31 Thoracic duct
respond to vasodilator therapy, the progno- ligation has been performed in two patients
sis is poor. with Fontan circuits who had recurrent epi-
Few pulmonary function changes other sodes of plastic bronchitis that failed to respond
than cyanosis occur with disease progres- adequately to medical management.32
sion. Until congestive heart failure occurs,
the lung parenchyma is relatively spared.
Increase in airway resistance with mild non- Summary
reversible airway obstruction has been
reported, in these patients, however. Because of the close proximity and in-
terconnected circulatory systems of the car-
diac and respiratory system, alteration in
cardiac function has profound effects on



Figure 4-17. Bronchial casts (“plastic bronchitis”)

Figure 4-16. Echocardiogram of a patient with severe removed by flexible fiberoptic bronchoscopy from a
pulmonary arterial hypertension. There is severe right ven- patient with congenital heart disease with acute airway
tricular and right atrial dilation. obstruction and respiratory failure.
Chapter 4—Pulmonary Manifestations of Cardiac Diseases 97

the entire respiratory system. Understanding 15. Dittrich S, et al: Comparison of sodium nitroprus-
side versus esmolol for the treatment of hyperten-
the physiologic mechanisms of this interrela- sion following repair of coarctation of the aorta.
tionship and the early signs and symptoms of Interact Cardiovasc Thorac Surg 2:111-115, 2003.
dysfunction of the cardiopulmonary circula- 16. Weber HS, Cyran SE: Endovascular stenting for
native coarctation of the aorta is an effective alter-
tory systems can aid in the early detection native to surgical intervention in older children.
and initiation of best available treatment for Congen Heart Dis 3:54-59, 2008.
children with cardiac disease. 17. Lee CL, et al: Balloon angioplasty of native coarcta-
tion and comparison of patients younger and older
than three months. Circ J 71:1781-1784, 2007.
18. Mendelsohn AM, Lloyd TR, Crowley DC, et al: Late
References follow-up of balloon angioplasty in children with a
native coarctation of the aorta. Am J Cardiol
1. Ip P, Chiu CS, Cheung YF: Risk factors prolonging 74:696-700, 1994.
ventilation in young children after cardiac surgery: 19. McLaren CA, Elliott MJ, Roebuck DJ: Vascular com-
Impact of noninfectious pulmonary complications. pression of the airway in children. Paediatr Respir
Pediatr Crit Care Med 3:269-274, 2002. Rev 9:85-94ss, 2008.
2. Thomas B, et al: Chronic respiratory complications 20. Malik TH, et al: The role of magnetic resonance
in pediatric heart transplant recipients. J Heart imaging in the assessment of suspected extrinsic
Lung Transplant 26:236-240B, 2007. tracheobronchial compression due to vascular
3. Bandla HP, et al: Pulmonary risk factors compro- anomalies. Arch Dis Child 91:52-55, 2006.
mising postoperative recovery after surgical repair 21. Murphy TM, et al: Pulmonary function sequelae in
for congenital heart disease. Chest 116:740-747, children with operated vascular rings. Chest
1999. 86(2):295, 1984.
4. Weissman C: Pulmonary complications after car- 22. De Troyer A, Yernault J-C, Englert M: Lung hypo-
diac surgery. Semin Cardiothorac Vasc Anesth plasia in congenital pulmonary valve stenosis. Cir-
8:185-211, 2004. culation 56:647-651, 1977.
5. Broaddus VC: Cardiac disease. In Murray JF, ed: Pul- 23. Levin DL, et al: D-Transposition of the great vessels
monary Complications of Systemic Disease. New in the neonate: A clinical diagnosis. Arch Intern
York, Marcel Dekker, 1992, pp 149-190. Med 137:1421-1425, 1977.
6. Lister G, Pitt BR: Cardiopulmonary interactions in 24. Rosenzweig EB, Widlitz AC, Barst RJ: Pulmonary
the infant with congenital cardiac disease. Clin arterial hypertension in children. Pediatr Pulmonol
Chest Med 4(2):219-232, 1983. 38:2-22, 2004.
7. Bates DV: Inter-relationships between cardiac and 25. Simonneau G, et al: Clinical classification of pul-
pulmonary function. In: Respiratory Function in monary hypertension. J Am Coll Cardiol 43:
Disease, 3rd ed. Philadelphia, WB Saunders, 1989, 5S-12S, 2004.
pp 250-264. 26. Brogan TV, et al: Plastic bronchitis in children:
8. Remetz MS, Cleman MW, Cabin HS: Pulmonary A case series and review of the medical literature.
and pleural complications of cardiac disease. Clin Pediatr Pulmonol 34:482-487, 2002.
Chest Med 10(4):545-592, 1989. 27. Madsen P, Shah SA, Rubin BK: Plastic bronchitis:
9. Stanger P, Lucas R, Edwards J: Anatomic factors New insights and a classification scheme. Paediatr
causing respiratory distress in acyanotic congenital Respir Rev 6:292-300, 2005.
heart disease: Special reference to bronchial 28. Wang G, et al: Effective use of corticosteroids in treat-
obstruction. Pediatrics 47:760-769, 1969. ment of plastic bronchitis with hemoptysis in Chi-
10. Wagenvoort CA, Wagenvoort TN, Takahashi T: Pul- nese adults. Acta Pharmacol Sin 27:1206-1212, 2006.
monary veno-occlusive disease: Involvement of 29. Wakeman MK, et al: Long-term treatment of plastic
pulmonary arteries and review of the literature. bronchitis with aerosolized tissue plasminogen
Hum Pathol 16:1033-1041, 1985. activator in a Fontan patient. Pediatr Crit Care
11. Resten A, et al: Pulmonary hypertension: CT of the Med 6:76-78, 2005.
chest in pulmonary venoocclusive disease. AJR Am 30. Kamin W, Klar-Hlawatsch B, Truebel H: Easy
J Roentgenol 183:65-70, 2004. removal of a large mucus plug with flexible paedia-
12. Thadani U, et al: Pulmonary veno-occlusive disease. tric bronchoscope after administration of rhDNase
QJM 44:133-159, 1975. (Pulmozyme). Klin Padiatr 218:88-91, 2006.
13. Sanderson JE, et al: A case of pulmonary veno- 31. Schultz KD, Oermann CM: Treatment of cast bron-
occlusive disease responding to treatment with chitis with low-dose oral azithromycin. Pediatr Pul-
azathioprine. Thorax 32:140-148, 1977. monol 35:139, 2003.
14. Davis LL, et al: Effect of prostacyclin on microvas- 32. Shah SS, Drinkwater DC, Christian KG: Plastic
cular pressures in a patient with pulmonary veno- bronchitis: Is thoracic duct ligation a real surgical
occlusive disease. Chest 108:1754-1756, 1995. option? Ann Thorac Surg 81:2281-2283, 2006.

Pulmonary Manifestations
of Gastrointestinal Diseases

Gastroesophageal Reflux Disease 99 Diagnostic Approach 110

Pathophysiology 99 Clinical Management 110
Developmental Aspects 100 Hepatopulmonary Syndrome 111
Congenital Anomalies 100 Clinical Manifestations 111
Diagnosis 102 Pathophysiology 111
Diagnostic Approach 103 Diagnostic Approach 112
Reflux as Etiology of Pulmonary Clinical Management 113
Pathology 104 Pancreatitis 114
Gastroesophageal Reflux Disease and Etiology 114
Asthma 105 Pulmonary Manifestations 114
Apparent Life-Threatening Events 105 Pathophysiology 115
Heiner Syndrome 106 Diagnostic Approach 116
Diagnostic Approach 107 Clinical Management 116
Inflammatory Bowel Disease 108 Acknowledgments 117
Pulmonary Manifestations 108 References 117
Clinical Manifestations 110

This chapter addresses the pulmonary in- The pulmonary involvement concurrent
volvement observed in gastrointestinal dis- with gastrointestinal diseases is often clini-
eases, particularly gastroesophageal reflux cally subtle and requires a high index of suspi-
(GER), Heiner syndrome, inflammatory bowel cion. The radiologic manifestations might lag
disease (IBD), the hepatopulmonary syn- behind the establishment of respiratory com-
drome (HPS), and pancreatitis. Although the promise, and only specialized testing such as
purported mechanisms currently invoked to high-resolution computed tomography (CT),
explain their concurrent associations vary, permeability studies with labeled proteins, or
several general modes of involvement include comprehensive pulmonary function tests
(1) the direct effect of spillage of food or gastric (PFTs) may be sensitive enough to detect the
contents into the airway, resulting in aspira- evolving pathophysiology. Increased use of
tion pneumonia; (2) a secondary, immune- these techniques, in addition to bronchoal-
mediated process, inflaming specific elements veolar lavage and validation of various bio-
of the lung; and (3) injury to the lung from markers, would allow better definition of the
medications used to treat specific gastrointes- prevalence of these disorders and their natural
tinal disorders, such as sulfa derivatives or history. As in many fields of pediatrics, the
immunosuppressive agents integral to the data on pulmonary manifestations of gastro-
management of IBD. The true etiology of the intestinal diseases are limited by sample size
observed involvement is still unclear, and and general research investment. Much of
much work is being done to unravel the the data is extrapolated from adult studies or
molecular mechanisms at play. This is a fruit- animal models.
ful field for translational research and wide For the most part, management is support-
open for the development of novel pharmaco- ive and conservative. Increasing recognition
logic agents with precise targets. of specific entities such as immune-mediated

Chapter 5—Pulmonary Manifestations of Gastrointestinal Diseases 99

alveolitis or granulomatous involvement of chronic bronchitis/bronchiolitis, chronic

the airway would result in the implementa- cough, asthma, and apparent life-threatening
tion of therapies that can be lifesaving or sig- events (ALTEs).3,4 Neonatal conditions that
nificantly improve the patient’s prognosis. are associated with a heightened risk of
GER include prematurity, postrepair eso-
phageal atresia with or without associated
tracheoesophageal fistula, congenital dia-
Gastroesophageal Reflux phragmatic hernia, and chronic lung disease
Disease of infancy.

GER, defined as the passage of gastric con-

tents into the esophagus, is a common phys- Pathophysiology
iologic event of little consequence in most
infants. It occurs throughout the day, and is It is now believed that the primary mecha-
most frequent in the immediate postprandial nism responsible for reflux in children is
period. In the first 3 months of life, more an inappropriate relaxation of the lower
than 50% of full-term infants regurgitate esophageal sphincter.5 In contrast to in
more than once a day, and 15% regurgitate adults, the resting pressure of the sphincter
more than four times a day. These numbers is rarely abnormally low in children. Other
increase from 4 to 6 months of age, when factors contributing to reflux in this patient
greater than 80% regurgitate. By the time population include reduced esophageal
the child is 18 months old, the prevalence capacitance and increased intra-abdominal
of reflux decreases to 5%.1 pressure. Important developmental factors
In contrast to GER, gastroesophageal reflux also play a role, including decreased fundic
disease (GERD) refers to the significant clinical compliance, discoordination of gastric emp-
manifestations of excessive reflux, which tying, and the shorter length of the intra-
manifest in a wide spectrum of settings, in- abdominal esophagus. Esophageal peristal-
cluding failure to thrive, irritability, feeding sis and mucosal protective factors are less
difficulties (especially feeding aversion), bleed- efficient in infants, especially when born
ing, and anemia. Extraesophageal manifes- prematurely, and this helps explain the
tations include chronic hoarseness, upper increased occurrence of pathologic reflux
airway obstruction owing to vocal cord ede- in this vulnerable population.5
ma, recurrent bronchitis or pneumonia, and Experimental work in animals and some
exacerbation of reactive airway disease.2 studies in humans suggest that pulmonary
The pulmonary manifestations of GERD involvement in the presence of acid reflux
are controversial. Pathophysiologically, it is can be the result of at least two very different,
often impossible to ascribe a causal relation- but potentially complementary or synergistic
ship to these two phenomena, presenting mechanisms. Exposure of the lower esophagus
a which-came-first conundrum: Are the pul- of kittens to hydrochloric acid has been asso-
monary complications observed in children ciated with a mild increase in measured bron-
with reflux a direct result of the exposure of chial smooth muscle tone.6-9 Similar results
the airway to acid or gastric contents, or are have not been consistently documented in
the cough, bronchospasm, and deranged dia- adults or in children, although evidence sug-
phragmatic mechanics the primary causes of gests that there is a loss of protective lower
the suspected reflux? Acid spillage into the esophageal sphincter tone in the presence of
distal esophagus may trigger increased vagal established esophagitis. A second mechanism
tone resulting in bronchospasm and worsen- considered pertinent to the pathophysiology
ing reflux as the infant mobilizes abdominal of reactive airways in the presence of reflux is
muscles to aid in exhalation against the the stimulation, through vagal mediators, of
bronchospasur constricted airways. receptors in the upper airway by microaspira-
The clinical manifestations of airway tion of acid or other irritants.10,11
disease in which reflux is suspected as an eti- Loss of the protective reflexes, which nor-
ologic factor include recurrent pneumonia, mally prevent aspiration from above, would
100 Pulmonary Manifestations of Pediatric Diseases

aggravate pulmonary manifestations in any A particularly dangerous form of aspiration

patient with concomitant risk factors. The occurs when stool softeners and laxatives
most vulnerable children presenting with containing mineral oil are administered
pulmonary signs and symptoms suggestive orally for management of chronic constipa-
of GERD are children with associated neuro- tion. Medium-chain triglycerides (MCT) oil
muscular handicaps that place them at risk used to increase the caloric density of formu-
for aspiration.12,13 las also may cause a lipoid pneumonia when
aspirated. Lipoid pneumonia can manifest
insidiously from continued microaspiration,
Developmental Aspects but also can have a sudden onset when a
large aspiration of lipid occurs. Oropharyn-
The mechanisms that coordinate breathing geal discoordination, loss of protective cough
and swallowing are not fully developed until reflexes, and airway penetration all contrib-
34 weeks gestation.14 Premature infants are ute to the development of lipoid pneumonia.
often treated for apnea suspected to be The pulmonary injury can manifest insidi-
caused by reflux; however, acidic and non- ously over months or years with tachypnea
acidic events occur frequently in this popula- and unexplained fever, but little cough or
tion, and they are not always causally related congestion.21 The findings on radiologic
to the respiratory irregularities or apnea that studies can be impressive (Fig. 5-1).
occurs regularly in this setting of central ner-
vous system immaturity.15-17 The technique
of intraluminal electrical impedance, which Congenital Anomalies
is limited to institutions with a research inter-
Infants born with congenital anomalies
est, allows identification not only of the
direction and volume of the bolus (antegrade affecting the oropharynx and other midline
structures (e.g., cleft palate, laryngotracheal
or retrograde), but also the effectiveness of
cleft) and infants with disproportionately
the esophageal clearance mechanisms.18
When paired with a pH sensor, this tech- large tongues or small mandibles (macroglos-
nique can shed light on important factors sia, as seen in various syndromes or in the
not otherwise detected with the more com- Pierre Robin sequence) are at a major disad-
monly used gold standard,—prolonged pH vantage with respect to their capacity to
intraesophageal monitoring.19 prevent aspiration from above and in the
As infants mature, the larynx descends and presence of reflux (Fig. 5-2).22,23 The presence
of abnormal communication between the
moves more effectively to provide a tight
esophagus and the airway (tracheoesophageal
seal during sucking and to close the trachea
with a well-developed epiglottis; the risk of
aspiration decreases significantly.20 For
many former premature infants, however,
the vulnerabilities can persist for years and
become a major challenge in their day-to-
day management; this is especially the case
with infants who have sustained intracranial
bleeds or injuries, infants with hydrocepha-
lus, infants with anoxic encephalopathy,
and infants who have required prolonged
respiratory support and artificial orogastric
or gavage feedings.3 In children who are fed
by gastrostomy tube, GER is common even
when studies before gastrostomy tube place-
ment are negative for GER. Figure 5-1. Aspiration of mineral oil resulted from treat-
In children with spastic cerebral palsy and ment of constipation in a 14-year-old child with profound
mental retardation and seizure disorder. Extensive, severe,
other syndromes that may include men- bilateral basilar chronic pneumonia is documented in this
tal retardation, constipation is common. chest CT scan.
Chapter 5—Pulmonary Manifestations of Gastrointestinal Diseases 101

Children with neuromuscular disorders,

including children with certain forms of
spastic cerebral palsy, spinal muscular atro-
phy, or bulbar involvement, can have recur-
rent aspiration because of their inability to
coordinate the five muscle groups that form
the intrinsic muscles of the larynx. These
groups are innervated by the trigeminal,
facial, hypoglossal, and vagus nerves, along
with the important branches, the superior
and recurrent laryngeal nerves. Sensory
abnormalities and autonomic dysfunction
(such as encountered in children with familial
and nonfamilial dysautonomic syndromes)
can result in prominent and life-threatening
lung disease (Fig. 5-3; see Fig. 5-2).25
Figure 5-2. CT scan of a patient with nemaline myopathy Another at-risk group for chronic reflux
and compromised chest motion secondary to his paralytic
thorax shows extensive basilar atelectasis and pneumonia and pulmonary disease are children with
resulting from recurrent aspiration. Bronchiectasis also is congenital diaphragmatic hernia.26,27 The
present bilaterally. presence of the herniated viscus during the
development of the lung often becomes
the most life-threatening component of
fistulas) results in spillage of saliva and the defect because it profoundly affects lung
particulate food into the airway. Even after development and results in pulmonary
repair of the fistula, most children with hypertension.28 The pulmonary compro-
these anomalies have a dysmotility of mise poses the most serious prognostic
their foregut, with more severe GER, and implications for the child. The effects on
increased likelihood of associated tracheo- esophageal motility can be serious; often
malacia or laryngomalacia.24 there is an associated delayed gastric empty-
Serious respiratory and gastrointestinal ing and severe feeding intolerance.26 Infants
complications, such as recurrent pneumo- born with congenital diaphragmatic hernia
nia, obstructive airway disease, airway
hyperreactivity, GERD, and esophageal ste-
nosis, are frequent in patients with a history
of esophageal atresia/tracheoesophageal fis-
tula, although the frequency of such events
seems to decrease significantly with age.
Because chronic aspiration can lead to recur-
rent pneumonia and impaired pulmonary
function, it is essential in patients with a his-
tory of esophageal atresia/tracheoesophageal
fistula that these recognized respiratory
complications be excluded before respiratory
symptoms are simply attributed to “asthma.”
Common etiologies of respiratory symptoms
in patients with a history of esophageal
atresia/tracheoesophageal fistula include
retained secretions owing to impaired muco-
ciliary clearance secondary to tracheomala- Figure 5-3. Chest x-ray in a patient with familial dysauto-
cia, and aspiration related to impaired nomia (Riley-Day syndrome) shows hyperinflation, extensive
esophageal peristalsis or esophageal stricture right upper lobe and parahilar areas of atelectasis, and pneu-
monia. Oropharyngeal and gastroesophageal reflux also
or both, recurrence of the tracheoesophageal were documented. The patient’s x-rays improved after a
fistula, or GERD. Nissen fundoplication was performed.
102 Pulmonary Manifestations of Pediatric Diseases

often also have various degrees of pulmo-

Differential Diagnosis of Vomiting
nary hypertension, which is usually propor- Table 5-1 in Pediatric Patients
tional to the extent of lung hypoplasia. GER
is a major problem after surgical repair of
Pyloric stenosis
the diaphragm because with the stomach
in the chest during fetal development, these
Intestinal stenosis/atresia
infants fail to develop a cardiac sphincter,
and their esophagus tends to be short and
Hirschsprung disease
intrinsically dysmotile, as is the rest of the
foregut. After surgery (even if an antireflux
procedure is performed at the initial sur-
gery), recurrence of GER is common when
Central nervous system infections
there is a paraesophageal hernia or slippage
of the antireflux wrap. This is a common
event when the diaphragm is repaired with
a Gore-Tex patch owing to stretch of the
Metabolic Disorders
patch with growth of the infant allowing
Organic acidurias
slippage of the stomach through the wrap.
There is also an increased risk of reflux in
Hereditary fructose intolerance
esophageal atresia because even after esoph-
Urea cycle defects
ageal anastomosis, these infants are at very
Fatty acid oxidation defects
high risk for esophageal stricture at the site
Central Nervous System Disorders
of the anastomosis and poor distal esopha-
geal motility. Similar to infants with con-
Ventricular or intracerebral hemorrhage
genital diaphragmatic hernia, these infants
Chronic subdural hematoma
rarely have a competent gastroesophageal
Gastrointestinal Etiologies
Penetration of gastric contents, acid, or
Acute appendicitis
nasal or oral secretions into the airway has
deleterious effects on the surface epithe-
lium, triggering the production of mucus,
Allergic enteropathies
the recruitment of inflammatory cells, and
the activation of inflammatory pathways.
Surfactant damage, alveolar obliteration,
Hepatitis (infectious, autoimmune, metabolic,
atelectasis, and progressive parenchymal drugs)
damage result. As a result, interstitial fibrosis Miscellaneous
can develop with secondary changes in the Medication side effects
pulmonary circulation.29 Lead toxicity
Dysautonomic crisis


The differential diagnosis of vomiting in vomiting is typically projectile and nonbilious.

a child is multifactorial (Table 5-1), and a The presence of bilious vomiting is always an
diagnosis of “reflux” should not be consid- emergency because it can result from malrota-
ered seriously until other important reasons tion or intussusception. Delay in diagnosis of
for vomiting are ruled out by a thorough his- volvulus can have catastrophic consequences,
tory and physical examination. When neces- with ischemic damage to the midgut. Vomit-
sary, ancillary tests help define potentially ing also is a common clinical manifestation
serious etiologies of vomiting. of an underlying infection in infants and chil-
Vomiting in an infant is often the presenting dren, including central nervous system in-
symptom for an underlying structural prob- fection, urinary tract infection, otitis media,
lem or obstruction. In pyloric stenosis, the and pneumonia. Inborn errors of metabolism
Chapter 5—Pulmonary Manifestations of Gastrointestinal Diseases 103

often manifest with vomiting and failure to to answer a specific clinical question. A
thrive. In specific disorders, intolerance to cer- guiding principle in the choice of test to
tain carbohydrates (galactose, fructose) or to identify reflux is to consider how the results
proteins (urea cycle disorders) can confuse would help guide or change management.30
the clinical picture and result in inappropriate Radiologic visualization of the esophagus
management for presumed reflux. Because the and stomach is neither particularly sensitive
child is vomiting, tests designed to identify nor specific to identify reflux, but radiogra-
reflux of gastric contents into the esophagus phy is an excellent and widely available
would invariably be positive, reinforcing the screening test for detecting anatomic de-
false assumption of reflux as the underlying fects, such as the critical conditions of
primary pathology. obstruction or malrotation.
The modified barium swallow, performed
Diagnostic Approach under videofluoroscopic control with the
guidance of a feeding or speech therapist
Given the numerous tests available to iden- who works closely with the radiologist, can
tify reflux (Table 5-2), it behooves the practi- provide extremely useful information
tioner to choose the most appropriate test regarding the mechanics of suck and

Diagnostic Tests Used in the Investigation of Gastroesophageal Reflux–Associated

Table 5-2 Pulmonary Involvement


Barium swallow/upper Commonly available; inexpensive; best suited Poor specificity; procedure performed
GI series to identify anatomic abnormalities supine; easy to elicit reflux in
frightened, crying infant
Modified barium Allows accurate definition of phases of Requires collaboration between
swallow swallow and abnormal structural positions experienced speech/feeding and
of involved structures; physiologic posture; radiology services; not widely
helps in the management of infants and available
children with dysphagia and other feeding
Prolonged pH probe Accurate capture of acid reflux events; allows Does not identify nonacidic reflux
monitoring correlation with symptoms; reflects events; difficult to perform in
esophageal acid clearance; presents children receiving nasogastric or
physiologic events over time (18-24 hr), continuous feedings; not useful in
and their timing during the day and night; the identification of GER-related
helps in titration of antacid therapy ALTEs (see text)
Milk scan Affords a more physiologic setting to Insensitive to detect aspiration,
determine gastric emptying compared with unless it occurs while isotope is still
inert barium in the stomach; requires child to be
completely immobile for >1 hr
under the gamma camera
Salivagram High concentration of isotope allows better Not commonly performed; no
demonstration of aspiration from above; standards available
helps in visualizing retropharyngeal
pooling and esophageal clearance
Intraluminal Best test available to show bidirectional fluid Available only in a very limited
impedance movement in the esophagus; acid and number of centers at present;
nonacid events can be identified analysis is time-consuming and
dependent on experience of reader
Polysomnography Provides a wealth of physiologic data Only performed in a few pediatric
reflective of most systems potentially centers in the U.S.; requires
involved in ALTE episodes—EEG, air flow, overnight hospitalization (home
end-tidal CO2, EMG, abdominal and chest monitoring sometimes available
wall motion, saturation, ECG video through commercial services)
recording, and pH probe; allows temporal
correlation between variables

ALTE, apparent life-threatening event; ECG, electrocardiogram; EEG, electroencephalogram; EMG, electromyogram; GER,
gastroesophageal reflux; GI, gastrointestinal.
104 Pulmonary Manifestations of Pediatric Diseases

swallow and the safety of oral feedings performed with slender probes that have
(Fig. 5-4).31,32 This study is performed with proximal and distal sensors; this allows
the infant in a more physiologic position determination of the level reached by the
(sitting up, as opposed to lying down, as is acid refluxate in the esophagus. It also is use-
the case for a routine upper gastrointestinal ful in determining the adequacy of acid-
series) while various textures and barium suppressive therapy, a recurrent and very
consistencies are offered via a nipple or relevant clinical issue that arises when
cup. In addition to delineating the appropri- symptoms persist despite what is believed
ateness of lip and tongue coordination, to be an appropriate dose of H2-blocker or
bolus propulsion, and traverse through the proton pump inhibitor.
retropharynx and into the upper esophagus, A gastric scintiscan using a Tc 99m–
the test allows an appreciation of the esoph- labeled meal also can be performed. This
ageal sweeping peristaltic waves and the study allows detection of reflux and quanti-
effective relaxation of the lower esophageal fies gastric emptying over 2 hours. In some
sphincter during swallows. cases, markedly delayed gastric emptying
Monitoring of the changes in acidity appears to contribute to the reflux.
occurring in the esophagus is still consid-
ered one of the most valuable diagnostic
tests to quantify acid reflux and to deter- Reflux as Etiology of Pulmonary
mine its correlation to symptoms such as Pathology
irritability, neck posturing and arching,
feeding refusal, or nocturnal cough.33 The Determining the possible contribution of
pH probe monitoring test can now be reflux to pulmonary disease remains a formi-
dable challenge. As already noted, no single
test can help make the distinction between
aspiration or reflux of food and saliva from
above, or of acid and gastric contents from
below. Correlation with respiratory events,
including apnea, bronchospasm, and cough,
requires the simultaneous recording of multi-
ple variables, usually best performed in a
sleep laboratory or similarly specialized test-
ing facility. Polysomnography allows mea-
surement of airflow and chest movements
and cardiovascular parameters and oxygen
saturation, while also capturing REM sleep
and, if indicated, swallowing movements.
Correlating events that are separated by
milliseconds and trying to determine cause-
and-effect relationships can be a daunting
task and can help explain the dearth of
“definitive” studies pertaining to this topic.
Theoretically, labeling of saliva with nuclear
isotopes should provide a sensitive way to
detect aspiration of secretions from above.34,35
The “salivagram” has never been validated as a
useful tool for this indication, however.36 It
sometimes provides information on esopha-
geal clearance and even gastric emptying,
similar to a formal gastric emptying test per-
Figure 5-4. Direct tracheal aspiration documented dur- formed with labeled formula or solids.37 Iden-
ing a modified barium swallow in a patient with bulbar
dysfunction. Retention of the contrast material at the level tifying aspiration of gastric contents during
of the vallecula also can be appreciated. a gastric emptying test depends on the
Chapter 5—Pulmonary Manifestations of Gastrointestinal Diseases 105

aspiration event occurring while there is still patients documented the presence of abnor-
sufficient isotope left in the stomach. It does mal pH monitoring studies in more than
not easily or reliably duplicate the clinical 60% of infants and children with asthma.
setting of nocturnal aspiration. Nevertheless, only half of the patients with
chronic asthma and abnormal pH studies ever
reported gastrointestinal symptoms (includ-
Gastroesophageal Reflux Disease
ing vomiting, regurgitation, and heartburn)
and Asthma
suggestive of underlying reflux disease. No
The etiologic role of GERD in some patients clinical features of asthma predicted which
with the more refractory forms of asthma has children had abnormal pH scores.
not been firmly established, although there There is no pediatric experience that helps
is evidence (albeit controversial) to suggest predict which children with asthma but with-
that aggressive management of GERD can out GER symptoms might benefit from empiric
change the natural history of unremitting antireflux therapy, or how to approach patients
steroid dependency and severe bronchial with severe asthma who have negative pro-
inflammation in some patients.38 For most longed esophageal pH probe studies. Regarding
patients with uncomplicated asthma, how- surgery, a review of six case series involving
ever, it is unclear to what degree stimulation 258 patients with steroid-dependent asthma
of esophageal vagal mediators plays a role in showed that 85% of patients who under-
triggering or aggravating bronchospasm, or went an antireflux operation (fundoplica-
even whether reflux exerts its deleterious tion) were reported to have a decrease in
effects in this population through (micro) the frequency and intensity of their asthma
aspiration and airway penetration.39 attacks and were able to reduce their bron-
chodilator and anti-inflammatory medica-
Clinical Management tion dose. The American Thoracic Society
Typical acid reflux symptoms are often and the National Institutes of Health Expert
absent in patients with asthma referred to Panel on the Diagnosis and Management
a pediatric gastroenterologist for evalua- of Asthma have issued recommendations to
tion. Severe bronchospasm and cough can investigate reflux as a possible cause of
result in chest pain, epigastric discomfort, poorly controlled asthma (in adults), includ-
and nausea indistinguishable from GERD. ing documenting reflux with pH probe
Increased secretions promote triggering of studies, if indicated.41,42
the gag reflex and nausea, adding to the There is some evidence that GER is a pos-
diagnostic difficulties. In practical terms, sible trigger or aggravating factor in a sub-
the possibility of GERD-aggravated asthma group of patients with severe asthma. In
is considered when response to appropriate patients who have frequent exacerbations,
therapy is inadequate, and when asthma nocturnal attacks or cough, frequent need
symptoms seem to worsen at night or recur for steroids, or steroid dependence, a trial
without obvious explanation. Steroid de- of aggressive acid suppression (preferably
pendence and difficulties in maintaining with a proton pump inhibitor) and lifestyle
airway quiescence while receiving anti- modifications for at least 3 months can be
inflammatory and bronchodilator therapy beneficial and should be recommended.
should be a “red flag” pointing to GERD For patients without any GER symptoms,
as a possible contributor to the refractory but with a positive pH study or a clinical
nature of asthma. A positive pH probe is profile that includes recurrent pneumonia,
more likely in patients with severe asthma nighttime wheezing, and steroid dependence,
than in patients without severe asthma. 40 the same recommendations apply.
In 2001, the North American Society for
Pediatric Gastroenterology and Nutrition Apparent Life-Threatening Events
published clinical practice guidelines for eval-
uation and treatment of GER in infants and In the spectrum of pulmonary complications
children.30 In this evidence-based review, a related to reflux disease, ALTEs hold a special
meta-analysis of 13 case series involving 668 place, given the high anxiety generated
106 Pulmonary Manifestations of Pediatric Diseases

by the episodes and the costly evaluation to first hour postprandially, and if the infant
which many of these infants are subjected was awake (or semiawake) and supine.44
when they are admitted to the hospital Changes in position are known to pro-
for investigation of the episode.43 ALTEs mote relaxation of the lower esophageal
are defined as frightening events affecting sphincter, and the presence of a full stom-
infants who, during the episode, appear to ach in the recumbent position favors
require resuscitation (usually mouth-to- regurgitation.
mouth breathing for perceived apnea) and
look cyanotic (or pale) and lifeless, and Clinical Management
who were sometimes observed to have had Management of ALTEs associated with
a preceding gasping, choking, or gagging reflux focuses on measures geared to
trigger.44 In the typical case, an otherwise decrease the likelihood of reflux; avoidance
healthy infant has an ALTE episode when of the supine position within 1 hour of feed-
placed supine on a changing table soon after ings and thickened feedings have been
a feed or a bottle. It is not unusual to elicit a recommended. If there is a history of symp-
history of finding formula in the infant’s tomatic reflux, acid suppression and
mouth, or noticing the infant cough just improvement in the degree of esophagitis
as the airway clears and the long episode would optimize sphincter function. Diag-
(15 to 40 seconds) subsides. Characteristi- nostically, a pH monitoring study rarely is
cally, by the time emergency personnel helpful because the ALTEs are so random
arrive at the home and bring the infant to that capturing a whole GER-obstruction-
the emergency department, there is little to apnea sequence is seldom successful or
support the parents’ concerns about a life- worth the effort. Conservative treatment is
threatening event. recommended for most infants with ALTEs.
In addition to certain infections (e.g., respi- This recommendation represents a signifi-
ratory syncytial virus in premature infants), cant change in the indication for surgery
the differential diagnosis of ALTEs includes (fundoplication), which used to be the stan-
cardiac arrhythmias, central nervous system dard of care in some centers for manage-
disorders (including seizures), and metabolic ment of GERD-related ALTEs.46
derangements. It is important to consider All parents, and especially parents whose
defects of fatty acid oxidation and other, less infants have had an ALTE, should be
common entities because they can be diffi- instructed on back to sleep, the recommenda-
cult to diagnose unless there is a high index tion to encourage sleeping in the supine
of suspicion and specific tests are obtained position. This recommendation has been
shortly after the event.45,131,132 associated with a major reduction in the inci-
GER plays a role in a large proportion of dence of sudden infant death syndrome.
children with ALTEs (80% can have abnor- Severe GERD has been considered a special
mal pH monitoring studies, although they circumstance, however, in which a semi-
seldom are found to correlate with ALTE epi- prone position can be allowed, provided that
sodes). Frequent regurgitation is elicited the infant is carefully observed and moni-
in the history of 60% to 70% of infants tored, and the infant’s face rests against a
presenting with ALTEs.43 firm mattress. In addition, bottle propping
The understanding of the sequence of or bottle in bed is recognized as a risk factor
events leading to apnea in this setting is for ALTE and aspiration and chronic bronchi-
that the activation of protective reflexes in tis from aspiration as the infant falls asleep
the upper airway leads to airway obstruction with the bottle in the mouth.
when refluxate reaches the upper larynx or
is about to penetrate the airway. Vagally
mediated reflexes can explain the vasomo- Heiner Syndrome
tor and cardiorespiratory changes after the
obstructive episode. The likelihood of GER Heiner syndrome is a very rare form of pul-
being responsible for the ALTE episode monary hemosiderosis, believed to be due
increases if the event occurred within the to cow’s milk allergy because in the initial
Chapter 5—Pulmonary Manifestations of Gastrointestinal Diseases 107

report all infants had precipitins to cow’s milk presents with recurrent or chronic respira-
proteins in their serum.47 The symptoms tory symptoms. A history of chronic cough,
in these children were not the symptoms nor- pneumonia, bronchitis, and bronchiolitis
mally expected in idiopathic pulmonary is often elicited, and a history of frequent
hemosiderosis48 (recurrent hemoptysis or visits to the emergency department for
intermittent blood-streaked sputum, varying wheezing and a suspected diagnosis of
degrees of anemia, and radiographic find- asthma. Hemoptysis can occur when the in-
ings of symmetric diffuse alveolar infiltrates flammation and alveolar damage progress to
predominant in perihilar regions and lower intrapulmonary bleeding.48,51 Some children
zones), and all had nonspecific complaints can have transient hives and other urticarial
of chronic lung disease and upper respiratory rashes, periorbital edema, and allergic shin-
tract disease. These patients apparently im- ers. As a result of the chronic nature of the
proved on a milk-free diet. pulmonary involvement, many children are
In more recent decades, enthusiasm for debilitated and have poor weight gain and
cow’s milk allergy as the cause of idiopathic failure to thrive.52 Gastrointestinal manifes-
pulmonary hemosiderosis has waned. In a tations are nonspecific and include vomiting
very large series of patients with idiopathic and abdominal pain. Diarrhea is more com-
pulmonary hemosiderosis, no such associa- mon than constipation, although in some
tion was present. Some patients with pul- cases, both may be present.
monary hemosiderosis did not have milk
precipitins, whereas many children with
milk precipitins did not have pulmonary Diagnostic Approach
hemosiderosis. Because of the reported asso-
ciation between cow’s milk allergy and pul- The chest x-ray findings are nonspecific and
monary hemosiderosis, many children reflect the underlying interstitial changes
with idiopathic pulmonary hemosiderosis and air trapping caused by small and large
are placed on milk-free diets, but unless airway obstruction. Diffuse and variable
there is unequivocal evidence of true milk infiltrates, patchy pneumonia, interstitial
allergy, this approach is unjustified.49,50 lung disease, and fibrosis can be document-
The possible role played by exposure to ed at various times during the course and
foreign food proteins should be actively progression of the condition. Chronic intra-
elicited during the history. The onset of pulmonary bleeding results in a microcytic,
symptoms depends on the time of introduc- hypochromic anemia and iron deficiency
tion of milk and solid foods and varies in that can be severe and debilitating.
different geographic areas and cultural back- The precipitins against cow’s milk protein
grounds. As mentioned, cow’s milk seems fractions can be identified by the micro-
to be the major offender, but individual Ouchterlony technique; their appearance
experiences suggest soy, eggs, and pork also and concentration can vary depending on
can play a role.47 the state of sensitization and the temporal
The reported clinical improvement that proximity of the exposure to the offending
results from withdrawal of the offending protein.50 These circulating IgG antibodies
protein seems to be marked. It also is fol- are not pathognomonic, however, because,
lowed by radiologic improvement, which as mentioned previously, they have been
can lag behind symptomatic relief. Demon- reported in children who do not manifest
stration of the causal relationship with pulmonary hemosiderosis. Identification of
cow’s milk protein exposure is not always iron-laden alveolar macrophages in bron-
feasible because parents might be reluctant choalveolar lavage is good evidence that
to allow re-exposure after they have wit- bleeding has occurred recently, and that
nessed the dramatic resolution of chronic the disease process is still active. The finding
symptoms and the resumption of normal of hemosiderin in macrophages from gastric
weight gain and growth. aspirates also is suggestive of the diagnosis,
Heiner syndrome may be considered in but is less direct than bronchoalveo-
any atopic infant or young child who lar lavage. Nevertheless, their presence—
108 Pulmonary Manifestations of Pediatric Diseases

notwithstanding the suspected specific pro- Inflammatory Bowel Disease

tein exposure trigger—should raise the
possibility of other entities responsible Inflammatory bowel disease (IBD) refers to
for pulmonary hemorrhage/hemoptysis in the two most common forms of chronic,
children (Fig. 5-5).49,53,54 idiopathic inflammation affecting the intes-
Heiner syndrome remains a controversial tinal tract: Crohn disease and ulcerative coli-
entity because circulating precipitins, al- tis. These conditions presently are believed
though necessary, are insufficient to pre- to be due to the intersection of predisposing
dict clinical symptoms. The role of genetic genetic factors, environmental triggers, and
and environmental factors has not been a dysregulation of immune control resulting
elucidated in most reported cases of pulmo- in varying degrees of damage.57 In the case
nary hemosiderosis, but it is important to of Crohn disease, the inflammation is trans-
consider alternative, or concurrent, triggers mural and segmental, involving any portion
resulting in iron deposition in the lungs.55,56 of the small or large bowel, and often
progressing to cicatricial stricture. In con-
trast, the involvement in ulcerative colitis is
limited to the large bowel. The inflammation
is mucosal, begins at the rectum, and is
contiguous, without skip lesions. At worst,
ulcerative colitis affects the whole colon
(universal colitis), but sometimes only the
rectum (proctitis) or left colon is affected.
The clinical manifestations depend on
the severity and location of the inflamma-
R L tion and range from mild, intermittent
abdominal pain to severe bloody diarrhea
with or without extraintestinal involve-
A ment. In a quarter of children, the gastro-
intestinal manifestations can be subtle;
delayed growth and pubertal development
is more prominent.58 Fatigue, low-grade
fever, and night sweats sometimes can be
confused for hematologic or oncologic etiol-
ogies; rheumatologic manifestations also are

Pulmonary Manifestations

The multisystemic involvement in IBD has

long been recognized, and the extraintes-
tinal manifestations are believed to reflect
the effects of deranged immunologic regula-
tion.60 Changes in intestinal permeability
B that allow translocation of bacteria, fungal,
Figure 5-5. A, Chest CT scan of a 2-year-old patient or viral products (including endotoxin)
with hemosiderin-laden macrophages in bronchoalveolar can stimulate the formation of antibodies
lavage shows multiple nodular masses involving the upper targeting similar epitopes. Also, a common
and lower lobe fields. B, Chest x-ray shows bilateral nodu-
lar masses of varying sizes. The appearance of the chest embryologic origin (as is the case with the
radiographs improved between attacks of febrile respira- gut and the lung or with elements of the
tory distress. Although this patient was initially diagnosed eye or the joints) can result in distant
with idiopathic pulmonary hemosiderosis, her subsequent
benign course suggests that she might have had Heiner inflammation in conjunction with or inde-
syndrome. pendent of the bowel disease.61
Chapter 5—Pulmonary Manifestations of Gastrointestinal Diseases 109

The involvement of the lung is perhaps the most commonly as the development of bron-
least recognized of the extraintestinal mani- chiectasis and suppurative bronchitis.63,67
festations of IBD, and there are no reliable fig- The spectrum of involvement includes bron-
ures to describe true incidence and prevalence chial and bronchiolar inflammation, bron-
rates.133 It is possible that a systematic study chiolitis obliterans organizing pneumonia,67
would bring to light many cases that are mild and severe upper airway stenosis.69,70 In
and subclinical, or that would be identifiable Crohn disease, metastatic granulomatous
only by abnormalities in PFTs, including the involvement of the larynx, trachea, and bron-
diffusing capacity for carbon monoxide, or chi has been reported.69 Most of the published
by increased lung permeability as identified series involve adults, although single case
by Tc 99m DTPA clearance.62 It is believed that reports have shown that children also can
as a whole, extraintestinal manifestations are develop these complications.71 In the spec-
more common in Crohn disease than in ulcer- trum of extraintestinal manifestations, pul-
ative colitis, although pulmonary complica- monary disease is much less common than
tions in particular seem to be more common joint, skin, or eye involvement.
in ulcerative colitis.63 Also, when a patient The presence of lymphocytes in the
has one extraintestinal complication, gener- bronchoalveolar lavage of some patients
ally there is a higher likelihood of involve- with Crohn disease suggests an immune-
ment in another organ. mediated damage. Along these same lines,
Parenchymal and Pleural Disease the changes observed histologically in
Ascribing an etiologic role to the immune instances of small airway disease have been
mechanisms that underlie IBD may be similar to those found in patients with a
difficult because reactions to drugs used in its graft-versus-host disease after bone marrow
management can confound the picture. or lung transplantation. In patients with
Hypersensitivity pneumonitis with eosino- ulcerative colitis, pulmonary complications
philia is a known complication of exposure to can occur 1 to 2 years after colectomy
certain drugs, including sulfa and some of its (Fig. 5-6). One study suggests that colec-
derivatives—a class of drugs that is commonly tomy might represent an independent risk
used in the long-term treatment of IBD factor for the onset of the lung disease.72
patients.64,65 Clinical manifestations of drug- In some patients, there is no correlation
related pneumonitis are nonspecific and between the degree of inflammatory activity
include fever, dyspnea, chest pain, and produc- in the bowel and the timing of appearance
tive cough. A mixed obstructive-restrictive of the respiratory disease.63
lung disease pattern is often shown on PFTs.
Confirming the presence of eosinophilic
pleural effusions or alveolar fibrosis and res-
olution of clinical symptoms and signs or
radiologic findings is sometimes the only
way that a presumptive diagnosis of a
drug-induced complication can be consid-
ered. Response to drug withdrawal and ster-
oids can be lifesaving, particularly in cases
in which the inflammation potentially
could progress to pulmonary fibrosis.65 For
the most part, the offending agent is
believed to be the sulfapyridine moiety of
sulfasalazine, although there have been
isolated reports of eosinophilic pneumonia Figure 5-6. A 16-year-old patient, who underwent
in patients receiving only mesalamine.66-68 colectomy for ulcerative colitis, developed bronchiectasis
in the right mid-lung field 1 year later. Clinical manifesta-
Airway Disease tions included recurrent fever, productive cough, and dys-
pnea on exertion. Management included antibiotics for
Airway damage in IBD has been document- acute exacerbations and prophylactically, postural drain-
ed at all levels of the tracheobronchial tree, age, and inhaled bronchodilator.
110 Pulmonary Manifestations of Pediatric Diseases

Clinical Manifestations

The most common manifestations of pul-

monary disease in IBD are cough and dys-
pnea. In bronchiectasis, the cough is
productive, and the secretions are copious
and thick—although there are reports of
well-documented bronchiectasis with nei-
ther cough nor sputum production. In B
patients with few (if any) symptoms, pul-
monary disease can only be surmised on
the basis of abnormal radiologic findings or
abnormal PFTs. In more severe cases of sup-
purative disease, dyspnea and hypoxemia
can be significant.73

Diagnostic Approach

The airway and interstitial changes that

occur as a result of the immune-mediated A
damage are not always accompanied by
identifiable radiologic changes in plain
chest films, even when the clinical situation
has progressed, and the patient is clearly Figure 5-7. “Tree in bud” pattern on high-resolution
CT. (From Mahadeva R, et al: Clinical and radiological char-
symptomatic.63 A more representative pic- acteristics of lung disease in inflammatory bowel disease. Eur
ture is obtained through the use of high- Resp J 15:41-48, 2000.)
resolution CT, particularly if care is exercised
in obtaining full inspiration and expiration
views.74 The presence of bronchiectasis is
identified by the discrepant caliber of the in bud” pattern (Fig. 5-7).75 Air trapping
bronchus in relation to its corresponding can be prominent and can be reversible
artery. The bronchus appears of a homoge- with steroid treatment. Pathophysiologi-
neous diameter even in images that extend cally, this pattern often seems to be asso-
to the periphery, where the size would be ciated with more severe coughing, much as
expected to diminish. The presence of secre- bronchiectasis is often accompanied by pro-
tions in the dilated bronchial tree reflects ductive cough.
the stasis and suppuration occurring during
the inflammatory process.
Changes in the diameter of the larger air- Clinical Management
ways have been described in isolated instances
of glottis and tracheal stenosis in patients Systemic steroids are the mainstay of treat-
with ulcerative colitis. In these instances, the ment for inflammatory lung disease when
trachea can appear as a long, rigid channel. it occurs in the context of IBD. The inflam-
Mucosal swelling can be identified promi- matory changes in the lungs do not always
nently in magnetic resonance imaging scans parallel the degree of activity of the under-
with gadolinium enhancement.71 lying intestinal disease and need to be man-
Parenchymal characteristics on high-reso- aged in their own right, regardless of
lution CT reflect the inflammatory exudates whether the intestine is quiescent or not.
present in various portions of the lung and In some instances of suppurative bronchial
appear in a ground-glass pattern. Centrilob- or bronchiolar disease, the response to ster-
ular nodules and branching linear opacities oids can be dramatic and has been the indi-
can give what has been described as a “tree cation for recurrent courses of treatment
Chapter 5—Pulmonary Manifestations of Gastrointestinal Diseases 111

during the course of the illness. Similarly, pulmonary vasoconstriction leads to compro-
patients with stenosing airway presen- mised oxygenation in the presence of portal
tations, in which airway wall edema is hypertension.82
prominent, have benefited greatly from HPS is found in 30% to 40% of patients
steroids. In some instances of interstitial with chronic liver disease (range 13% to
pneumonia, methylprednisolone has been 47%).83 PPHTN is much less common, diag-
administered directly in the form of bron- nosed in about 5% of patients with chronic
chial lavages.76 In this respect, the thera- liver disease. The symptoms of PPHTN are
peutic response is similar to what is seen in those of hemodynamic compromise, with
immune-mediated lung disorders, including right ventricular dysfunction and cor pul-
autoimmune and vasculitic syndromes, or in monale. PPHTN is associated with mortality
graft-versus-host disease. rates of 40% within 15 months of diagno-
sis.80 In contrast to HPS, PPHTN is much
less likely to reverse after successful liver
Hepatopulmonary Syndrome transplantation.

HPS is a recognized complication of cirrhotic

and noncirrhotic liver disease that is accom- Clinical Manifestations
panied by portal hypertension. HPS is charac-
Initially, patients with HPS can be asymp-
terized by the clinical triad of (1) chronic liver
tomatic, although as the alveolar-arterial
disease, (2) arterial hypoxemia, and (3) for-
gradient increases, dyspnea and cyanosis
mation of abnormal intrapulmonary vascular
inevitably ensue. In addition, digital club-
dilations.77 The initial description of HPS
bing can be prominent. In some patients,
dates to the turn of the 19th century, but the
orthodeoxia—the decrease in arterial oxyge-
pathophysiologic processes underscoring the
nation caused by pooling of blood in the
intrapulmonary shunting, and the molecular
dilated capillary vasculature when a patient
mechanisms responsible for those changes,
stands up (as blood moves with gravity to
have begun to be appreciated only in the past
the lower lobes of the lungs)—develops.84
2 decades.78
Patients also have clinical signs of the
HPS has a profound impact on the sur-
underlying chronic liver disease, most com-
vival of patients who develop it. It raises
monly hyperbilirubinemia, spider angio-
the Model End-Stage Liver Disease score
mas, splenomegaly, and other signs of
for patients awaiting liver transplantation
portal hypertension.
because orthotopic liver transplantation
remains the only proven therapy at this
time.79 Liver transplantation brings about a Pathophysiology
resolution of the pulmonary findings in
greater than 80% of patients. The reversibil- New insights into the possible mechanisms
ity of the syndrome reinforces the notion of development of HPS have been gained
that HPS is secondary to functional abnor- from detailed studies in a mouse model of
malities occurring in the endothelium of common bile duct ligation. After ligation
the pulmonary vasculature.80 These abnor- of the common bile duct, progressive
malities seem to be mediated by various changes in the pulmonary vasculature are
key circulating molecular species released consistent with the changes shown in the
into the venous circulation, particularly concentrations of nitric oxide in the lung:
nitric oxide and carbon monoxide, which hypoxia results.81 The postulated mecha-
contribute to the vasodilation and subse- nism is a chain reaction triggered by produc-
quent microvascular changes.81 tion of the mediator endothelin-1 (ET-1) by
It is important to distinguish between HPS cholangiocytes, which become hypertro-
and portopulmonary hypertension (PPHTN) phic after the ligation. Overexpression of
because these two entities are pathophysio- endothelial endothelin B (ETB) receptor pro-
logically distinct. Their underlying mechani- moted by the shear stress in the pulmonary
sms are diametrically opposed. In PPHTN, circulation increases the production of nitric
112 Pulmonary Manifestations of Pediatric Diseases

oxide in the lung. This cascade possibly is

initiated by absorption of bacterial endo-
toxin in the gut, triggering tumor necrosis
factor-a release, which upregulates cyclic
adenosine monophosphate and the intrin-
sic nitric oxide synthesis pathway.85
Factors playing a role in the formation of
pulmonary arteriovenous shunts and dilated
microcapillaries differ from the factors that
are involved in the hyperdynamic circulation
most characteristic of patients with cirrhotic
liver disease. In all patients with cirrhosis,
systemic vasodilation occurs uniformly as a
function of time, whereas HPS is seen in only
about one third of this population, pointing
to other mechanisms involved in the patho-
genesis.86 It also has become clear that, in
rare instances, HPS can develop even when
cirrhosis is not firmly established, suggesting
that activation of nitric oxide–mediated
pathways can occur in the presence of pre-
served hepatic synthetic function84 or tran-
siently, in the setting of acute or chronic
In the above-described experimental Figure 5-8. Patient with cystic fibrosis, established bili-
model of common bile duct ligation, ET-1 ary cirrhosis, and portal hypertension shows arteriovenous
shunting by right and left selective pulmonary arterio-
plays an important role in producing an grams. Findings are characteristic of the hepatopulmonary
overexpression of the ETB receptor, which syndrome and resulted in hypoxemia and orthodeoxia
brings about vascular dilation.85 It is para- (see text).
doxical that ET-1, a well-recognized vaso-
constrictor, would result in vasodilation in
the pulmonary circulation. The explanation of the capillary bed interrupts the normal
seems to lie in selective activation of ETB physiologic steady state characterized by
receptors on the luminal surface of the vas- the movement of single red blood cells
cular endothelial cells in the lung by ET-1, through the capillary bed with highly effi-
which is the final mediator of vasodilation. cient oxygen transfer to hemoglobin. This
ETB receptor expression was found to be transfer cannot occur when four or five
significantly increased in the presence of red blood cells are traversing the capillary
portal hypertension secondary to biliary or bed simultaneously, as has been shown in
nonbiliary cirrhosis. The increase in ETB pathologic preparations.82 Depending on
receptor concentration mediates the sensiti- the extent of the phenomenon, a pressure
zation of the pulmonary vasculature to the difference between the oxygen in the
vasodilating effects of ET-1, with activation alveoli and the arteries can result in either
of the endothelial nitric oxide synthase no symptoms or in severe dyspnea, with
pathway.81 consequent hypoxemia.
One consequence of this vasodilation is
the development of a perfusion/ventilation
mismatch, owing in part to increased perfu- Diagnostic Approach
sion in under ventilated areas where the
abnormal dilation has developed. In addi- The diagnosis of HPS depends on identifica-
tion, there are direct shunts between the tion of dilated capillary channels in the
arterial and venous plexuses creating a periphery of the lung. Four common methods
bypass physiology (Fig. 5-8).86 The dilation of identifying this process are (1) contrast-
Chapter 5—Pulmonary Manifestations of Gastrointestinal Diseases 113

enhanced echocardiography, (2) Tc 99m– From a structural point of view, high-reso-

labeled macroaggregated albumin (MAA) lution CT may facilitate determining the
scan, (3) pulmonary angiography, and (4) ratio of the pulmonary artery (main pulmo-
high-resolution CT. nary trunk, right and left main pulmonary
In contrast-enhanced echocardiography, arteries) and the diameter of pulmonary vas-
indocyanine green or normal saline is culature. These changes can be shown best
injected intravenously while a transthoracic on the “parenchymal” windows on the
echocardiogram is performed. In the pres- CT scan, in contrast to the “mediastinal”
ence of a dilated capillary bed in the lungs, windows, which seem better suited for the
the 8 to 15mm bubbles are noted to appear vascular measurements. The ratio of the
in the heart after five or six cardiac cycles diameter of the right lower lobe basal seg-
owing to the “escape” of the microbubbles mental pulmonary artery to the diameter
through the dilated channels, which may of the lumen of the accompanying bron-
be 500 mm in diameter.89 The delayed opaci- chus, known as the pulmonary artery/
fication seen after three to six cardiac cycles bronchus ratio, can be calculated. In high-
is a reflection of the time it takes for the resolution chest CT, there is a correlation
microbubbles to permeate through the pul- between the diameter of the right lower lobe
monary capillaries, and is a specific sign of basal segmental artery and the partial pres-
the intrapulmonary shunting that is taking sure of oxygen in HPS. An increased pulmo-
place. The presence of a positive contrast- nary artery/bronchus ratio may be helpful
enhanced echocardiography study is not in diagnosing HPS in patients with liver dis-
enough, however, to ensure a diagnosis of ease and hypoxemia. High-resolution CT
HPS. In some instances, some patients have also can identify the presence of pleural or
been found to have a positive contrast- direct arteriovenous communications in
enhanced echocardiography study, but nor- dilated channels, and provide information
mal alveolar-arterial gradient. These patients on the lung parenchyma.92 More experience
would not technically qualify for a diagnosis with this technique is needed because these
of HPS. findings have been inconsistent.93
A similar principle applies to the passage of The appearance of the chest x-ray in HPS is
Tc 99m MAA molecules through the dilated usually nonspecific. Some chest radiographs
channels in a Tc 99m MAA study. The sen- might show “mottled” shadows bilaterally,
sitivity of these tests is not high, but they are which have been suspicious enough to war-
specific in the absence of intracardiac shunt- rant treatment for suspected tuberculosis.
ing.90 The oxygenation in the pulmonary Increased bilateral interstitial markings also
artery when 100% oxygen is inspired has been have been described. It is believed that these
shown to be significantly worse in HPS when markings are a result of the intrapulmonary
pulmonary nonvascular comorbidities are vascular dilations.
present. This finding is of clinical significance
because mortality is increased when decreased
oxygenation is present while breathing room Clinical Management
air and when there is an increase in the shift
of Tc 99m MAA to the brain. The presence of HPS is associated with
Echocardiography, especially if the trans- increased mortality in patients with liver
esophageal approach is used, has better disease. It is important to evaluate periodi-
sensitivity for distinguishing between intra- cally the presence and progression of the
pulmonary and intracardiac shunting than gradient and the presence of hypoxemia in
the regular transthoracic echocardiogram. any patient with chronic liver disease.
Because it requires anesthesia, however, trans- Because HPS is reversible only by trans-
esophageal echocardiography poses practical plantation, it constitutes at present an
risks in the setting of compromised liver func- indication for early liver transplantation.
tion and the possible presence of esophageal Transplantation results have been positive;
varices.91 greater than 80% of transplant recipients
114 Pulmonary Manifestations of Pediatric Diseases

have near-complete resolution of pathologic

Table 5-3 Etiology of Pancreatitis in Children
changes.94 The return to normal occurs over
months in patients surviving the transplant. Idiopathic (20%-30% of cases)
As mentioned, it is important to ensure Trauma (including child abuse)
beforehand that no pulmonary comorbid- Drugs*
ities are present, particularly the presence Thiazides
of PPHTN. Azathioprine
Pancreatitis Valproic acid
Infections (congenital and acquired)
Acute pancreatitis is often a self-limited Viral/bacterial—mumps, rubella, coxsackievirus,
influenza, hepatitis A and B, Mycoplasma
condition characterized by abdominal pain pneumoniae
and elevation in the serum concentrations Parasitic—Ascaris, Echinococcus, Clonorchis sinensis
of amylase and lipase. Inflammation of the Metabolic disorders
pancreas is the result of activation of Hyperparathyroidism
the digestive enzymes normally maintained Hyperlipidemia types I, IV, V
in an inactive proform in the exocrine Hypercalcemia
portion (the acini) of the gland. Autodiges- Vitamin D deficiency
tion is potentially a serious consequence, Hereditary conditions
although self-limited mild inflammation is Cystic fibrosis
more common than fulminant, necrotizing Shwachman-Diamond syndrome
pancreatitis.95 Familial recurrent pancreatitis
The hallmarks of pancreatitis include Collagen vascular disorders
abdominal pain and abnormalities in the Systemic lupus erythematosus
measured circulating pancreatic enzymes, Periarteritis nodosa
principally amylase and lipase.96 The abdom- Congenital anatomic abnormalities
inal pain—typically referring to pain in the Choledochal cyst
back and epigastrium—can be excruciating, Enteric duplications
requiring narcotics for management. Nausea, Cholelithiasis
vomiting, and the sensation of bloating
often accompany the pain. In many cases, *List is not comprehensive.

pancreatitis can be asymptomatic, however,

and can be suspected only from the presence
of biochemical abnormalities.
handlebar injuries are notorious in this
regard,99 but the possibility of child abuse
Etiology needs to be considered.100
The most common triggers for pancreatitis
in adults are gallstones and alcohol inges- Pulmonary Manifestations
tion. In children, the etiology often remains
elusive or idiopathic; Table 5-3 lists the Lung involvement in the course of acute
broad categories to be considered in the dif- pancreatitis has long been recognized as a
ferential diagnosis. In addition to infections potentially extremely serious complication,
and medications, some metabolic disorders manifesting in 5% of cases as acute respira-
and hereditary forms of recurrent pancre- tory distress syndrome (ARDS) with high
atitis are now being increasingly recog- mortality rates of 50% to 75%. In adults,
nized as possible causes, with mutations in the incidence of lung complications has
genes involved in the stability of trypsino- been reported to be 15% to 55%.101 Data
gen and other protective mechanisms.97,98 for pediatric patients are unavailable, and
An important cause of pancreatitis in chil- only anecdotal case reports have been
dren is blunt abdominal trauma; bicycle published.102,103
Chapter 5—Pulmonary Manifestations of Gastrointestinal Diseases 115

The changes leading to pleural effusions Damaged acini release the powerful mem-
and to alveolar damage are not fully under- brane and cellular digestive enzymes nor-
stood, but intensive work in several animal mally kept in their proenzyme granular
models of pancreatitis has helped expand storage form. Elastase and phospholipase A
understanding of the pathophysiologic are considered key players in this process.110
steps involved in the process. Cystic fibrosis When the inflammatory cascade is trig-
also can manifest as recurrent pancreatitis. gered, upregulation of the genes encoding
These patients often have similar CFTR gene for nuclear factor kB and tumor necrosis fac-
mutations, class IV (abnormal conductance) tor-a has been shown.111
and class V (reduced synthesis or traffick- Important changes occur in the pulmo-
ing). In these two classes, lung dysfunction nary capillary bed, resulting from recruit-
is often recognized only after complete ment of neutrophils and translocation of
genetic evaluation.134 serum proteins into the lung interstitium
Early in the course of the attack of acute (this can be shown with the use of chro-
pancreatitis, changes can occur in the lung mium-labeled albumin or transferrin). Pul-
ranging from asymptomatic hypoxemia to monary infiltrates are seen radiologically.
fulminant respiratory failure. The degree of Thickening of basement membranes and
hypoxemia is not correlated to the severity lysis of the surfactant proteins and phos-
of the underlying pancreatic involvement. pholipids results in the clinical picture of
Tachypnea, dyspnea, and shallow breathing ARDS and profound hypoxemia.112
can be present, with the last-mentioned Various adhesion molecules, such as intra-
reflecting the presence of diaphragmatic irri- cellular adhesion molecule-1, are synthe-
tation secondary to accumulated pleural effu- sized in higher quantities in the presence
sions. Effusions have been shown in more of inflammation.111 They play a role in the
than 15% of patients and are preferentially activation of lymphocytes, macrophages,
left-sided, for unclear reasons, but perhaps and neutrophils; they further contribute to
related to direct irritation of the dia- the endothelial damage and the leaking of
phragm.101 The effusion fluid is usually rich proteins into the lung parenchyma. The role
in amylase, and the enzyme concentrations of endotoxemia is strongly suspected as
can remain elevated even after the circulating another important promoter of progressive
pancreatic enzymes have normalized.104 damage and multiorgan failure because
severe pancreatitis is frequently associated
with infection of the necrotic gland; the
Pathophysiology most common organisms are enteropatho-
gens believed to have translocated as a result
Experimental pancreatitis, induced in rats of the above-described diffuse capillary per-
either by intraperitoneal injections of cerulein meability changes.113
(an analogue of cholecystokinin) or by intra- Structural changes in the alveolar integ-
biliary ductal injection of the bile acid tauro- rity parallel severe impairment in oxygen
cholate, has allowed identification of several diffusing capacity and bronchial reactivity.
important mechanisms participating in the Vital capacity piratory volume in 1 second
observed multiorgan dysfunction.105,106 are diminished, although the functional
As autodigestion of the gland occurs, che- residual capacity does not seem as
mokines and cytokines are released into the affected.114 On the basis of results provided
circulation, resulting in recruitment of acti- by labeled transferrin studies, it has been
vated cellular mediators capable of producing established that the main drive for the patho-
intense changes in the alveolar endothelium physiologic changes in the lung results from
and the pulmonary vasculature.105 Among the changes in vascular permeability
the cellular mediators, mast cells and macro- and protein exudation into the peribronch-
phages are believed to play central roles, iolar and parenchymal space.115 After this
whereas activated trypsinogen generates tryp- process takes place, mortality increases
sin, a potent protease.107-109 significantly.116
116 Pulmonary Manifestations of Pediatric Diseases

The most dreaded complication of pan- infiltrates, and atelectasis all can be present
creatitis is the progression to fulminant nec- during the evolution of the pulmonary de-
rotizing destruction of the gland. As noted, terioration. High-resolution CT can help
this occurs via autodigestion and activation demarcate the alveolar damage and the exu-
of inflammatory pathways by virtue of a dative process that ultimately result in the
wide variety of mediators capable of affect- picture of ARDS.125 The pulmonary picture
ing the circulation in profound ways, with is similar to the one observed in shock, or in
rapid progression to systemic inflammatory what is now termed “systemic inflammatory
syndrome, capillary leak, and irreversible response syndrome.”
shock. The pulmonary changes are mani-
fested by subclinical hypoxia or by frank
ARDS, with serious implications for the Clinical Management
patient’s prognosis.117
Management of pancreatitis is conservative,
addressing the following factors: (1) support
Diagnostic Approach of cardiovascular homeostasis, (2) judicious
use of antibiotics when infected collections
In addition to the biochemical abnormal- or peritonitis is believed to be imminent or
ities, pancreatitis is characterized by radio- established, and (3) nutritional support.
logically identifiable changes in the gland, More recent evidence suggests improved
best documented by abdominal CT with survival with early introduction of enteral
oral and intravenous contrast enhance- feedings (intragastric or transpyloric) and
ment. The presence of glandular edema avoiding reliance on intravenous alimenta-
and peripancreatic fluid accumulation are tion, which carries a high risk for serious
common in the acute phase of the process, bacteremia and fungemia.126-128 Patients
whereas calcifications, fat necrosis, and scar- benefit from the expertise of tertiary centers
ring are sequelae of chronic pancreatitis.118 with excellent intensive care units and
Ultrasonography is useful in identifying access to important ancillary services such
concomitant gallbladder pathology, bile as intervention radiology, gastroenterology,
duct dilation, and cholelithiasis, but the and surgery.
presence of intraluminal gas makes it an Experimental approaches aimed at inhib-
unreliable examination to visualize the pan- iting the inflammatory cascade triggered by
creas.119 Newer techniques using magnetic noxious cytokines have not changed the
resonance (magnetic resonance cholangio- natural course of the disease, and much
pancreatography [MRCP]) can accurately work continues in this field of clinical
visualize the pancreatic and biliary tree, research. The interruption of systemic ab-
often obviating the need for the more inva- sorption and widespread distribution of
sive endoscopic retrograde cholangiopan- toxic vasoactive and proteolytic substances
creatography (ERCP).120,121 ERCP is more by ligation or external draining of the tho-
commonly used in adults, but advances in racic duct has been promising, but has not
equipment design and miniaturization of been confirmed by additional studies.101 In
video processors have made ERCP applica- an attempt to decrease pancreatic secretion,
ble in infants and children.122,123 Concur- the somatostatin analogue octreotide and
rent improvements in the magnetic signal the platelet-activating factor antagonist lexi-
acquisition and processing have reduced pafant have been tried with mixed results,
the resolution of MRCP and expanded its although the exact mechanism of the pur-
usefulness for pediatric patients.120,121,124 ported beneficial effect could not be deter-
Radiologically, the lung changes during mined with certainty. In addition to its
acute pancreatitis are nonspecific and are effects on exocrine and endocrine pancreatic
often mild or unappreciated, even when secretion, it is believed that somatostatin
pulmonary function abnormalities are pres- has a direct immunomodulator effect, which
ent. The presence of effusions already has could play a part in the observed decreased
been alluded to, and increased markings, progression to ARDS.129,130
Chapter 5—Pulmonary Manifestations of Gastrointestinal Diseases 117

The complexity of the processes at play, 10. Herve P, et al: Intraesophageal perfusion of acid
increases the bronchomotor response to methacho-
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87. Regev A, et al: Transient hepatopulmonary syn- 108. Leindler L, et al: Importance of cytokines, nitric
drome in a patient with acute hepatitis A. J Viral oxide, and apoptosis in the pathological process
Hepat 8:83-86, 2001. of necrotizing pancreatitis in rats. Pancreas
88. Tzovaras N, et al: Reversion of severe hepatopul- 29:157-161, 2004.
monary syndrome in a non cirrhotic patient after 109. Hartwig W, et al: Trypsin and activation of circu-
corticosteroid treatment for granulomatous hepa- lating trypsinogen contribute to pancreatitis-
titis: A case report and review of the literature. associated lung injury. Am J Physiol Gastrointest
World J Gastroenterol 12:336-339, 2006. Liver Physiol 277(5 Pt 1):G1008-G1016, 1999.
89. Santamaria F, et al: Noninvasive investigation of 110. Lungarella G, et al: Pulmonary vascular injury in
hepatopulmonary syndrome in children and ado- pancreatitis: Evidence for a major role played by
lescents with chronic cholestasis. Pediatr Pulmo- pancreatic elastase. Exp Mol Pathol 42:44-59,
nol 33:374-379, 2002. 1985.
90. Abrams GA, et al: Use of macroaggregated albumin 111. Hartwig W, et al: Membrane-bound ICAM-1 is up-
lung perfusion scan to diagnose hepatopulmonary regulated by trypsin and contributes to leukocyte
syndrome: A new approach. Gastroenterology migration in acute pancreatitis. Am J Physiol Gastro-
114:305-310, 1998. intest Liver Physiol 287:G1194-G1199, 2004.
91. Aller R, et al: Diagnosis of hepatopulmonary syn- 112. Frossard J-L: Pathophysiology of acute pancreati-
drome with contrast transesophageal echocardi- tis: A multistep disease. Acta Gastroenterol Belg
ography: Advantages over contrast transthoracic 66:166-173, 2003.
echocardiography. Dig Dis Sci 44:1243-1248, 113. Pastor CM, et al: Role of Toll-like receptor 4 on
1999. pancreatic and pulmonary injury in a mice model
92. Lee KN, et al: Hypoxemia and liver cirrhosis of acute pancreatitis associated with endotoxemia.
(hepatopulmonary syndrome) in eight patients: Crit Care Med 32:1759-1763, 2004.
120 Pulmonary Manifestations of Pediatric Diseases

114. Ates F, Hacievliyagil SS, Karincaoglu M: Clinical sig- 125. Puneet P, Moochhala S, Bhatia M: Chemokines in
nificance of pulmonary function tests in patients acute respiratory distress syndrome. Am J Physiol
with acute pancreatitis. Dig Dis Sci 51:7-10, 2006. Lung Cell Mol Physiol 288:L3-L15, 2005.
115. Foitzik T, et al: Persistent multiple organ microcir- 126. Kaushik N, et al: Enteral feeding without pancre-
culatory disorders in severe acute pancreatitis: atic stimulation. Pancreas 31:353-359, 2005.
Experimental findings and clinical implications. 127. O’Keefe SJD, McClave SA: Feeding the injured
Dig Dis Sci 47:130-138, 2002. pancreas. Gastroenterology 129:1129-1130, 2005.
116. Steer ML: Relationship between pancreatitis and 128. Eatock FC, et al: A randomized study of early naso-
lung diseases. Resp Physiol 128:13-16, 2001. gastric versus nasojejunal feeding in severe acute
117. Bhatia M, et al: Pathophysiology of acute pancrea- pancreatitis. Am J Gastroenterol 100:432-439,
titis. Pancreatology 5(2-3):132-144, 2005. 2005.
118. Graziani R, et al: The various imaging aspects of 129. Heinrich S, et al: Evidence-based treatment of
chronic pancreatitis. J Pancreas 6(1 Suppl):73-88, acute pancreatitis: A look at established para-
2005. digms. Ann Surg 243:154-168, 2006.
119. Gupta V, Toskes PP: Diagnosis and management of 130. Hoogerwerf WA: Pharmacological management of
chronic pancreatitis. Postgrad Med J 81:491-497, pancreatitis. Curr Opin Pharmacol 5:578-582,
2005. 2005.
120. Pamuklar E, Semelka RC: MR imaging of the pan- 131. McGovern MC, Smith MBH: Causes of apparent
creas. Magn Reson Imaging Clin N Am 13:313-330, life threatening events in infants: A systematic
2005. review. Arch Dis Child 89:1043-1048, 2004.
121. Arcement CM, et al: MRCP in the evaluation of 132. Kozzi DA, et al: Pathogenesis of ALTE in infants
pancreaticobiliary disease in children. Pediatr with esophageal atresia. Pediatr Pulmonol
Radiol 31:92-97, 2001. 41:488-493, 2001.
122. Cheng C-L, et al: Diagnostic and therapeutic 133. Black H, Mendoza M, Murin S: Thoracic manifes-
endoscopic retrograde cholangiopancreatography tations of inflammatory bowel disease. Chest
in children: A large series report. J Pediatr Gastro- 131:524-532, 2007.
enterol Nutr 41:445-453, 2005. 134. DeBoeck K, et al: Pancreatitis among patients with
123. Rocca R, et al: Therapeutic ERCP in paediatric cystic fibrosis: Correlation with pancreatic status
patients. Dig Liver Dis 37:357-362, 2005. and genotype. Pediatrics 115:463-469, 2005.
124. Hamada Y, et al: Magnetic resonance cholangio-
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children with choledochal cysts. Pediatr Surg Int
20:43-46, 2004.

Pulmonary Manifestations of
Renal Diseases

Role of the Kidney in Fetal Lung Pulmonary Calcifications 126

Growth 121 Urinothorax 126
Physiologic Connections Between the Sleep Apnea 127
Lungs and the Kidneys 121 Anemia 127
Diseases That Affect Lungs and Pulmonary Embolism 128
Kidneys 123 Hemodialysis-Related Hypoxemia 129
Wegener Granulomatosis 123 Respiratory Effects of Acute Renal
Systemic Lupus Erythematosus 124 Failure 130
Goodpasture Syndrome 124 How Critical Illness and Mechanical
Respiratory Effects of Chronic Renal Ventilation Can Damage the
Failure 124 Kidneys 131
Pulmonary Edema 125 Summary 132
Fibrinous Pleuritis 125 References 132
Tuberculosis 125

The relationships between the kidneys and Role of the Kidney in Fetal
the lungs are clinically important ones in Lung Growth
health and disease. This chapter first reviews
the role of the kidney in fetal lung develop- Lung development continues during the
ment and the interactions between respiratory middle trimester with branching morpho-
and renal function under normal conditions. genesis and is completed postnatally with
Then a brief overview is provided of the large the development of alveoli. Fetal urine is an
group of diseases that affect the lungs and the important component of the amniotic fluid
kidneys. Most of these conditions are uncom- during late gestation and contributes to lung
mon in pediatric patients, although three of growth. During fetal development, the kid-
them—Wegener granulomatosis, systemic ney also is a major source of proline. Proline
lupus erythematosus, and Goodpasture syn- aids in the formation of collagen and mesen-
drome—may be encountered frequently by chyme in the lung, explaining the severe pul-
clinicians. They are discussed in detail else- monary hypoplasia secondary to prolonged
where in this book. This chapter describes or severe oligohydramnios (amniotic fluid
how chronic renal failure may affect res- index <4 for >2 weeks) seen in fetal renal
piratory function and the intrathoracic agenesis, urinary tract obstruction, bilateral
structures, and provides a brief review of renal dysplasia, and bilateral cystic kidneys.
the corresponding manifestations of acute
renal failure and the ways in which they
affect respiratory care in children. The phe- Physiologic Connections
nomenon of dialysis-related hypoxemia is Between the Lungs and the
described and explained. Finally, the ways Kidneys
in which critical illness and its manage-
ment may adversely affect kidney function Lung and kidney function are intimately
are summarized. related in health and disease.1 Respiratory

122 Pulmonary Manifestations of Pediatric Diseases

changes help modulate the systemic effects of thought of as respiratory compensation for
renal acid-base disturbances, and the reverse is metabolic acidosis. The stimulus to increase
also true, although renal compensation oc- the ventilation is chiefly the action of Hþ
curs more slowly than its respiratory counter- ions on the peripheral chemoreceptors.
part. Under normal circumstances, the lungs An increase in HCO3 concentration
and kidneys work together to maintain acid- (metabolic alkalosis)5 causes an increase in
base balance in the body, according to the arterial pH (alkalemia), which tends to
relationship described by the Henderson- decrease alveolar ventilation (respiratory
Hasselbalch equation1,2: acidosis).6 In this instance, respiratory com-
pensation is usually less vigorous, however,
pH ¼ pK þ log ðbase concentration= because the respiratory stimulant effect of
acid concentrationÞ hypercapnia is much stronger than the
According to this equation, the overall respiratory depressant effect of alkalemia.
acidity or alkalinity of the blood, which is The familiar clinical presentation of diabetic
quantified by the negative logarithm of the ketoacidosis is an example of respiratory
hydrogen ion concentration (or pH), is compensation for severe metabolic acidosis.
determined by the relationship between Patients with this disorder may hyperventi-
the amount of base and the amount of acid late to PaCO2 levels of 10 mm Hg or less,
present, also expressed logarithmically, as which diminishes (but does not completely
modified by a mathematical constant (pK) correct) their severe acidemia. In both
for the particular acid involved. The bicar- instances, the respiratory changes are imme-
bonate-carbonic acid system is the major diate (within a few minutes) because of the
buffering system of the extracellular fluid. rapidity of equilibration between alveolar
Bicarbonate (HCO3) dissociates into CO2 gas and pulmonary capillary blood.
and water in the presence of the enzyme In the less frequent situation of primary
carbonic anhydrase, so that the acid-base metabolic alkalosis, as is seen with pro-
quotient in the previous equation can be tracted vomiting or the ingestion of excess
thought of as the HCO3 concentration alkali, patients typically present with only
divided by the CO2 concentration. The modest hypercapnia (e.g., PaCO2 48 to 50
CO2 concentration is related to the partial mm Hg) despite pH greater than 7.60.
pressure of CO2 (PaCO2) in the arterial An increase in PaCO2 stimulates the kidneys
blood by the solubility constant 0.03, so to retain HCO3, producing metabolic al-
the Henderson-Hasselbalch equation can kalosis, which tends to normalize arterial
be rewritten in terms of what clinicians typ- pH. Conversely, hypocapnia prompts an
ically measure: increased loss of HCO3, causing a compen-
satory metabolic acidosis that decreases arte-
pH ¼ 6:1 þ log ½HCO
3 concentration= rial pH. The renal responses to respiratory
ðPaco2  0:03Þ
acid-base disturbances occur much more
Because the kidneys normally determine slowly, however—over a few days—than do
the concentration of the HCO3, and the respiratory adjustments to metabolic distur-
alveolar ventilation regulates the PaCO2, bances. As a result, because carbonic acid/
the relationship also can be rewritten con- HCO3 buffering acts immediately, but is
ceptually as: relatively weak, sudden alterations in respi-
ratory acid-base status cause more sudden
pH ¼ pK þ ðkidneys=lungsÞ
and severe changes in arterial pH than do
A decrease in HCO3 concentration (met- their primary metabolic counterparts. An
abolic acidosis),3 whether from an increase example of the more gradual adjustment of
in acids in the blood or an overall loss of metabolic status with changes in ventilatory
HCO3, provokes an increase in alveolar status is respiratory acidosis in patients
ventilation (respiratory alkalosis),4 which with cystic fibrosis. When such patients
tends to restore the balance between the present with a severe exacerbation, they
two and bring the low arterial pH (acidemia) may be severely acidemic if hypercapnia
back toward normal. This process may be has developed rapidly, whereas the same
Chapter 6 — Pulmonary Manifestations of Renal Diseases 123

Table 6-1 Renal Compensation for Respiratory Acidosis

Normal Acute Respiratory Acidosis* Chronic Respiratory Acidosis{
pH 7.40 7.24 7.38
PaCO2 (mm Hg) 40 56 56
HCO3 (mEq/L) 24 25 33

*Minutes to hours; no renal compensation.

Days to weeks; renal compensation present.
Adapted from Pierson DJ: Respiratory considerations in the patient with renal failure. Respir Care 51:413-422, 2006.

PaCO2 in a clinically stable patient tends to

Diseases That Affect Lungs
be associated with a much more normal pH Table 6-2 and Kidneys
(Table 6-1).
A more comprehensive discussion of the Diseases that cause alveolar hemorrhage in the
presence of pulmonary capillaritis
different types of acid-base disturbance, Wegener granulomatosis
their effects on respiratory and renal func-
Henoch-Schönlein purpura
tion, and their management is beyond the
Microscopic polyangiitis
scope of this brief review. More recent
Immune complex–associated glomerulonephritis
reviews of these topics are available, how-
Pauci-immune glomerulonephritis
ever.3-8 The kidneys also regulate fluid bal-
Mixed cryoglobulinemia
ance in the body,1 and derangements in
Diseases that cause alveolar hemorrhage with
overall volume status can affect pulmonary pulmonary capillaritis variably present
function, as discussed subsequently. Systemic lupus erythematosus
Other connective tissue diseases
Goodpasture syndrome
Diseases That Affect Lungs Diseases that cause alveolar hemorrhage without
pulmonary capillaritis
and Kidneys
Thrombotic thrombocytopenic purpura
Drug-induced (e.g., penicillamine)
There are many “pulmonary-renal syn-
Diseases in which alveolar hemorrhage is not a
dromes” that affect the lungs and the typical feature
kidneys.1,9-11 These disorders most com- Churg-Strauss syndrome
monly manifest with hemoptysis from dif-
fuse alveolar hemorrhage, along with renal Adapted from Pierson DJ: Respiratory considerations in the
patient with renal failure. Respir Care 51:413-422, 2006.
failure associated with either acute glomeru-
lonephritis or other vasculitis. Patients may
develop pulmonary hemorrhage without evi- distinction difficult.14 Three of the most
dence of renal involvement, however, with familiar diseases with pulmonary and renal
the latter appearing only later in the clinical manifestations are Wegener granulomatosis,
course. The reverse sequence may also occur. systemic lupus erythematosus, and Goodpas-
Many of these diseases have overlapping and ture syndrome (see Chapter 11).
variable features, prompting investigators to
classify them in various ways. Schwarz and Wegener Granulomatosis
colleagues12,13 have used the presence or
absence of pulmonary capillaritis as a means Wegener granulomatosis is a clinical syndrome
of categorizing these diseases (Table 6-2). consisting mainly of necrotizing granuloma-
Another classification of patients with pul- tous vasculitis of the upper and lower respira-
monary hemorrhage and nephritis uses the tory tract, along with glomerulonephritis.9,15
presence or absence of anti–glomerular base- The eyes, ears, heart, skin, joints, and central
ment membrane antibody; antineutrophil nervous system also may be involved. It is the
cytoplasmic antibody; or small, medium, or most common vasculitis involving the lungs
large vessel vasculitis, although overlapping and most frequently affects school-age chil-
features in different cases often make clear dren and adolescents. Sinusitis is the most
124 Pulmonary Manifestations of Pediatric Diseases

common clinical manifestation, followed by Goodpasture Syndrome

fever, arthralgias, cough, rhinitis, hemoptysis,
otitis media, epistaxis, and ocular inflamma- Goodpasture syndrome is a disorder of
tion.9,15 Although Wegener granulomatosis unknown etiology, manifested by diffuse alve-
may be confined to the kidneys, the lungs are olar hemorrhage and glomerulonephritis. It is
involved in more than 80% of all patients with also known as anti–glomerular basement
the disease. Likewise, some patients have pul- membrane antibody disease because the pres-
monary but not renal involvement. The pul- ence of such antibodies is characteristic and
monary involvement varies, but localized believed to account for at least some of its
infiltrates or nodules or both, either bilateral manifestations. It is most common in young
or unilateral, are most common. men, particularly in the fourth decade of life,
Cavitations may occur in 10% to 20% of and manifests with cough, hemoptysis, and
cases. The cause of the disease is unknown, fatigue. Alveolar hemorrhage seems to be
but it is characterized by the presence of pos- more common among patients who smoke.
itive tests for antineutrophil cytoplasmic Although either pulmonary or renal involve-
antibody in at least 90% of affected patients. ment may be present in isolation, at least at
Wegener granulomatosis was almost always the time of presentation, most patients with
fatal within a few months before the advent Goodpasture syndrome have both. The diag-
of combination therapy with corticosteroids nosis is typically made with renal biopsy. The
and cytotoxic agents, but today more than disease is treated with plasmapheresis, corti-
three quarters of all patients achieve com- costeroids, and cytotoxic drugs, but the prog-
plete remission, with long-term survival.11,15 nosis is guarded at best, and dialysis or renal
transplantation is often necessary.

Systemic Lupus Erythematosus

Respiratory Effects of
Systemic lupus erythematosus is a multisys- Chronic Renal Failure
tem inflammatory disorder of unknown
cause, which is most common in young Numerous complications related to the respi-
women.16 It is characterized by the presence ratory system occur in patients with chronic
of antinuclear antibodies. Its many manifes- renal disease (Table 6-3).1,18-20 Some of these
tations include a characteristic but highly are related to alterations in volume status,
variable malar rash, photosensitivity, ar- plasma oncotic pressure, bone and mineral
thritis, various neuropsychiatric problems, metabolism, concomitant heart failure, and
and hematologic and immune defects. Pul- altered immune function in such patients,
monary and renal involvements are very although in other instances the precise
common. Thoracic manifestations include mechanisms are not well understood.
pleuritis, acute lupus pneumonitis, intersti-
tial pulmonary fibrosis, pulmonary vasculi-
tis, diffuse alveolar hemorrhage, pulmonary Respiratory Complications
Table 6-3 of Chronic Renal Failure
hypertension, organizing pneumonia, and
the “shrinking lung syndrome.”17 Pleuritis, Pulmonary edema
with pleuritic pain and effusions, is com- Fibrinous pleuritis
mon, as is acute pneumonitis. Although Tuberculosis
these usually occur in patients with an Pulmonary calcification
established diagnosis of lupus, either of Urinothorax
them, and any of the other intrathoracic Sleep apnea
processes listed, may be the initial manifes- Anemia
tation of the disease. Systemic lupus erythe- Pulmonary embolism
matosus has a highly variable course, and Dialysis-associated hypoxemia
the response to treatment and the overall Adapted from Pierson DJ: Respiratory considerations in the
prognosis may be difficult to predict. patient with renal failure. Respir Care 51:413-422, 2006.
Chapter 6 — Pulmonary Manifestations of Renal Diseases 125

Pulmonary Edema in inflammatory conditions such as acute

respiratory distress syndrome (ARDS).
Pulmonary edema (Fig. 6-1) is a common Left ventricular failure is common in
complication in acute and chronic renal fail- chronic renal failure, further complicating
ure.1 Its pathogenesis is not fully understood. attempts to clarify the nature of pulmonary
Uremia may be associated with pulmonary edema in patients with this condition. Pul-
edema as the result of overhydration, expan- monary congestion in patients with chronic
sion of the blood volume, and elevation of renal failure is associated with a restrictive
the pulmonary microvascular pressures, pattern on pulmonary function testing,
compounded by anemia and reduced colloid and reduced airflow rates can be observed
osmotic pressures. Hypoalbuminemia, char- on spirometry. These abnormalities have
acteristic of chronic renal failure, decreases been shown to improve or resolve with
plasma oncotic pressure and promotes move- hemodialysis.23-25 This observation would
ment of fluid out of the pulmonary capil- seem to strengthen the argument that
laries. The increased hydrostatic pressure increased lung water results primarily from
that occurs may result from the altered vascu- overall hypervolemia in the presence of low
lar permeability caused by the increased serum albumin levels in this condition, and
metabolic products of uremia, which also fos- accounts for the symptoms and signs tradi-
ters such movement. One would assume tionally associated with “uremic lung.”19
that the edema fluid resulting from these
processes would be low in protein, as is
characteristic of cardiogenic or hydrostatic Fibrinous Pleuritis
pulmonary edema. The finding of increased
protein concentrations in the edema fluid Pleural disease is common in patients with
of patients with renal failure21 suggests, chronic renal failure, being present in as many
however, that capillary permeability also is as 20% to 40% of autopsies on adult patients
altered. Such a suggestion is supported by with this condition.1,26,27 The most common
the occurrence of pulmonary edema in manifestation encountered clinically is pleu-
patients who are clinically normovolemic ral effusion, which was present in 3% of all
and do not have other features of heart fail- patients with end-stage renal disease in one
ure. Other studies of the edema fluid in series.28 The effusion is typically an exudate
patients with chronic renal failure22 have and may be hemorrhagic.27,29 Effusions are
found low protein levels, however, more con- typically unilateral and can be quite large.
sistent with those found in heart failure than Most patients with fibrinous pleuritis are
asymptomatic. Dyspnea is the most common
symptom, but this condition also can be asso-
ciated with fever and pleuritic chest pain,
sometimes with an audible friction rub on
auscultation. Fibrothorax also can occur.


The incidence of tuberculosis is increasing

worldwide. Compared with the general pop-
ulation, patients with chronic renal failure
and patients on long-term dialysis have at
least a several-fold greater risk of developing
tuberculosis.30 Patients with chronic renal
failure are immunocompromised. Because
of an impairment of cellular immunity,
patients with chronic renal failure are sus-
Figure 6-1. Pulmonary edema as seen in a chest x-ray of ceptible to reactivation of tuberculosis. Sev-
a 4-year-old child with nephrotic syndrome. enty patients were treated by continuous
126 Pulmonary Manifestations of Pediatric Diseases

ambulatory peritoneal dialysis in a pediatric implicated as causes of ischemic necrosis, car-

nephrology department during an 8-year diac arrhythmias, and respiratory failure. Soft
period.31 Tuberculosis was diagnosed in four tissue calcification has been regarded as rare,
patients, representing 5.7% of all continu- however, in pediatric renal patients. In a retro-
ous ambulatory peritoneal dialysis patients spective review of clinical, biochemical, and
in that study. One patient had extrapul- autopsy data of 120 patients with uremia, on
monary tuberculosis (tuberculosis osteomy- dialysis, or after renal transplantation,33 soft
elitis), and the others had pulmonary tissue calcification was found in 72 patients
tuberculosis. All patients were treated with (60%). Forty-three patients (36%) had sys-
antituberculous drugs. Two patients with temic calcinosis; the lung was the most fre-
pulmonary tuberculosis were cured. Symp- quent site of mineral deposition. By multiple
toms improved in the other two patients, logistic regression analysis, the use of vitamin
but they died at home of unknown causes. D or its analogues, the form of vitamin D med-
An 8-year-old boy receiving maintenance ication prescribed, the peak calcium  phos-
hemodialysis for chronic renal failure devel- phorus product, the age at onset of renal
oped mediastinal lymph node tuberculosis. failure, and male sex were together associated
He showed only intermittent fever, recurring with calcinosis. Vitamin D therapy showed
every 2 weeks, with no other symptoms sug- the strongest independent association with
gesting tuberculosis. Although tuberculosis calcinosis, and the probability of calcinosis
skin test was negative, and staining and culture was greater in patients receiving calcitriol com-
of gastric aspirate specimens failed to provide pared with dihydrotachysterol and vitamin D2
evidence of tuberculosis, a lymph node biopsy or D3. The duration of renal failure, peak serum
specimen showed caseating granulomas. Anti- calcium, serum calcium and phosphorus at
tuberculous therapy with isoniazid, rifampin, death, and primary renal diagnosis were not
pyrazinamide, and ethambutol was given for statistically associated with calcinosis.
12 months, resulting in complete resolution The rapid administration of sodium bicar-
of the tuberculosis, with no subsequent recur- bonate to correct severe metabolic acidosis has
rence.32 It is recommended that all children been associated with soft tissue calcification.
with chronic renal failure in regions of high Acidosis increases while alkalosis decreases the
prevalence of tuberculosis should be investi- proportion of ionized calcium, and calcium
gated for tuberculosis, especially if they have deposition in soft tissues may occur during
a cough or fever of unknown etiology. the rapid correction or overcorrection of aci-
Renal insufficiency complicates the man- dosis or with alkalosis. Alkalinization or over-
agement of tuberculosis because the kidneys correction of an acidosis may facilitate the
clear some antituberculosis medications. development of ectopic calcification.34
Management may be complicated further When calcification occurs in the lungs, it is
by the removal of some antituberculosis frequently asymptomatic. Although some-
agents via hemodialysis. Some adjustment times not apparent on chest radiography,
in dosing is commonly necessary in patients pulmonary calcification usually can be de-
with renal insufficiency and end-stage renal tected on computed tomography (CT), or,
disease receiving hemodialysis. Increasing more specifically, on Tc 99m diphosphonate
the dosing interval, instead of decreasing scanning.35 When visible on the standard
the dose of the antituberculosis agent, is chest radiograph, pulmonary calcification
recommended and either estimating or mea- most often produces small nodular opacities,
suring creatinine clearance.30 which occasionally may coalesce into larger
infiltrates (Fig. 6-2).36,37

Pulmonary Calcifications
Calcifications occur as a complication of
chronic renal failure in adult patients and Urinothorax, or collection of urine in the
may be found in various visceral organs and pleural space, is a very rare complication of
soft tissues. Calcifications have been obstructive uropathy.38 Most patients who
Chapter 6 — Pulmonary Manifestations of Renal Diseases 127

as restless legs syndrome and periodic limb

movement disorder, also are common in this
population.44 Several potential explanations
have been proposed, but the mechanism
remains unknown. There seems to be a strong
link between sleep apnea and nocturnal hy-
poxemia and cardiovascular complications in
patients with chronic renal failure.45,46 Hemo-
dialysis during the night is said to have an
ameliorating effect on sleep apnea,43,47,48
although the reason for this also remains
unclear. As in obstructive sleep apnea unasso-
ciated with renal disease, treatment with con-
tinuous positive airway pressure is effective.
Breathing disorders during sleep complicating
chronic renal failure in children is an area that
warrants investigation.

Figure 6-2. Pulmonary calcifications on a chest x-ray of Normochromic normocytic anemia is a
a 4-year-old child with chronic renal failure.
common and important manifestation in
children with chronic renal failure when
their glomerular filtration rate is less than
are found to have urinothorax also have a 35 mL/min/1.73 m2 body surface area, but it
urine collection (urinoma) in the abdominal may develop earlier in some forms of renal
cavity or retroperitoneal space.39 Leakage disease. An inadequate erythropoiesis due
from the urinary tract may cause urinoma, to insufficient erythropoietin synthesis in
which can lead to urinothorax. The urino- the kidneys is the main cause of renal ane-
thorax usually disappears within a few days mia. Other reasons include reduced red blood
after adequate urinary drainage has been cell life span, chronic blood loss, iron
established. Reported underlying causes deficiency, inhibitors of erythropoiesis, and
include posterior urethral valves, nephro- malnutrition. The presence of anemia con-
lithiasis, blunt renal trauma, ureteral instru- tributes to many of the symptoms of uremia,
mentation, or ureteral surgery.39 The pleural including decreased appetite, decreased
fluid in urinothorax is a transudate, although energy, poor cardiac function, and poor
the lactate dehydrogenase level can be high, school performance.49,50
causing misclassification as an exudate.38 If the anemia is untreated, hemoglobin
The pH and glucose levels tend to be low. An concentrations typically decrease to less
elevated pleural fluid-to-serum creatinine than 10 g/dL, and frequently to half or less
ratio (which should be about 1, but may be of the normal value. With blood oxygen car-
10 in urinothorax) confirms the diagnosis. rying capacity markedly diminished, cardiac
output must increase to maintain normal
Sleep Apnea tissue oxygen delivery, and even in the
absence of pulmonary disease, patients are
Sleep apnea is common in adults with chronic vulnerable to tissue hypoxia during exertion
renal failure.1,40-42 Its prevalence is said to be and at times of acute illness. Correction of
10-fold higher in adults with end-stage renal anemia dramatically improves the quality
disease than in the general population,43 and of life of a child with chronic renal failure.
studies have found that at least 60% of Presently, the goal of anemia management is
patients on long-term hemodialysis have the to maintain hematocrit concentrations at
disorder.18,44 Other sleep disturbances, such 33% to 36% and a hemoglobin concentration
128 Pulmonary Manifestations of Pediatric Diseases

of at least 11 g/L. This objective can be ac- increase. Right ventricular dilatation leads to
complished by weekly intravenous or sub- tricuspid regurgitation and may eventually
cutaneous administration of recombinant compromise the filling of the left ventricle.
erythropoietin and iron preparations. If ade- In addition, right ventricular enlargement
quate iron stores cannot be maintained with causes leftward shift of the interventricular
oral therapy, intravenous iron should be con- septum, resulting in an impaired left ventricu-
sidered. Treatment with recombinant human lar filling during diastole. Cardiac output
erythropoietin corrects anemia, avoids the decreases, and the patient becomes hypoten-
requirement for blood transfusions, and sive. The increased right ventricular pressure
improves quality of life and exercise toler- compresses the right coronary artery, decreas-
ance.51 To optimize anemia management in ing subendocardial perfusion, and as a conse-
children with chronic renal failure, future quence, cardiac ischemia may develop.
research should concentrate on the normali- The clinical manifestations of pulmonary
zation of hemoglobin early in the course of embolism vary, and no group of physical
chronic renal failure, and the long-term findings yields a high positive predictive
effects on the child’s development. value. Pleuritic chest pain, dyspnea, appre-
hension, and cough are the most common
complaints, and tachypnea is the most
Pulmonary Embolism common physical finding. Other potential
findings include crackles, increased inten-
Pulmonary embolism is an uncommon sity of the pulmonary component of the
complication in children with renal dis- second heart sound, tachycardia, diapho-
eases, but a potentially serious and fatal resis, wheezing, and hemoptysis. Patients
disease. Children with nephrotic syndrome with severe pulmonary embolism can even
are at increased risk of thromboembolic present with hemodynamic instability, cor
events. The incidence of this complication pulmonale, and shock. Fever, chest pain,
in children is 2% to 5%, which represents and respiratory manifestations may suggest
a much lower risk than that of adults with heart disease, or masquerade as pneumonia;
nephrotic syndrome.72 Nephrotic syndrome however, significant hypoalbuminemia may
is primarily a pediatric disease. The charac- raise the index of suspicion.
teristic features of nephrotic syndrome are Because the clinical diagnosis lacks sensi-
heavy proteinuria (>40 mg/m2/hr), hypoal- tivity and specificity, objective diagnostic
buminemia (<2.5 g/dL), edema, and hy- imaging is necessary to establish or rule
percholesterolemia.73 Most children (90%) out the presence of pulmonary embolism.
with nephrotic syndrome have a form of An electrocardiogram and arterial blood
idiopathic nephrotic syndrome.74 The risk of gases are useful in ruling out other diseases.
thrombosis is related to increased prothrom- The measurement of the breakdown prod-
botic factors (fibrinogen, thrombocytosis, uct of cross-linked fibrin (D-dimer) in
hemoconcentration, relative immobilization) plasma is a sensitive but nonspecific test
and decreased fibrinolytic factors (urinary for suspected venous thrombosis. In adults,
losses of antithrombin III, proteins C and S).75 studies showed that it is safe to exclude pul-
The effects of pulmonary embolism depend monary embolism in patients with a normal
on the extent to which it obstructs the pulmo- D-dimer level. Chest radiographs are often
nary circulation, coexistent cardiopulmonary normal in patients with pulmonary embo-
disease, and vasoactive mediators. Acute pul- lism. Ventilation/perfusion imaging displays
monary embolism, obstructing more than regional blood flow and ventilation defects
50% of the pulmonary circulation, increases by noninvasive means and is safe and inex-
right ventricular afterload. Because the thin- pensive. A normal ventilation/perfusion
walled right ventricle is not accustomed to scan does not exclude a pulmonary embo-
working against a sudden obstruction, right lism, however. Helical (spiral) CT is becom-
ventricular dilatation occurs, and the right ing the first-choice diagnostic test for
ventricular and pulmonary artery pressures pulmonary embolism in many centers. An
Chapter 6 — Pulmonary Manifestations of Renal Diseases 129

iodinated contrast agent that is injected in a There are several techniques. Effective frag-
peripheral vessel visualizes the pulmonary mentation of central emboli and dislocation
vessels. Pulmonary embolism is seen as par- of the fragments to the periphery has been
tial or complete filling defects in pulmonary reported in children.
arteries. This scan is particularly useful in
patients with concomitant lung disease. Pul- Hemodialysis-Related Hypoxemia
monary angiography is the gold standard
diagnostic test for pulmonary embolism.76 Shortly after it was introduced in the treat-
The optimal treatment of hypercoagulabil- ment of renal failure, most patients un-
ity in nephrotic syndrome has not been dergoing hemodialysis were discovered to
prospectively investigated, and randomized develop hypoxemia while connected to the
trials to guide the therapy are lacking. Prophy- dialysis apparatus.1 This phenomenon has
lactic anticoagulation is not recommended in generated much interest among renal and
children unless they have had a previous respiratory clinicians as to its possible mech-
thromboembolic event. Overaggressive diure- anisms. Proposed explanations included a
sis should be avoided, and use of indwelling shift in the oxyhemoglobin dissociation curve
catheters should be limited because these because of the increased pH during dialysis,
factors may increase the likelihood of clot- depression of central ventilatory drive, im-
ting complications. Unfractionated heparin pairment of oxygen diffusion, leukostasis in
should be used in the initial phase of anticoag- small pulmonary vessels leading to mismatch-
ulation.76,77 It functions as an antithrombotic ing of ventilation and perfusion, and alveolar
agent by binding to and potentiating the hypoventilation because of diffusion of CO2
activity of antithrombin. Careful monitoring into the dialysate.18
of the activated partial thromboplastin time Studies in animals and humans showed
and platelets is important. Low-molecular- that leukocytes did accumulate in the lungs
weight heparin is an equally effective alterna- during hemodialysis, with activation of com-
tive to unfractionated heparin.76,77 Similar to plement and other events associated with
unfractionated heparin, the anticoagulant inflammation.54,55 For several years, “dialysis
activity of low-molecular-weight heparin lung” was a subject of intense interest at the
results from catalyzing the ability of anti- bedside and in the laboratory. It was shown
thrombin to inactivate coagulation factors. that PaO2 decreases within a few minutes of
Monitoring of the anti–factor Xa assay should the initiation of hemodialysis, usually by 10
be done. Warfarin (Coumadin), which sup- to 15 mm Hg, but sometimes considerably
presses vitamin K–dependent clotting factors, more, reaching a nadir after 30 to 60 minutes
should be started 24 to 48 hours after heparin and then returning to predialysis levels on ter-
therapy is begun. Generally, anticoagulation mination of the procedure.18,56 The magni-
therapy for a minimum of 6 to 12 months is tude of the decrease in PaO2 varies according
recommended.77 Some authors have sug- to the chemical composition of the dialysate
gested continuing anticoagulation for as long and the type of membrane used.57 Current
as the patient is nephrotic.77 understanding of dialysis-related hypoxemia
Thrombolytic agents such as plasminogen is based on the fundamentals of alveolar ven-
activators, including urokinase, streptoki- tilation, as taught in physiology class. Leuko-
nase, and tissue plasminogen activator, also stasis and complement activation do occur
are useful. In most centers, tissue plasmino- during dialysis, but they are almost certainly
gen activator is favored over the other throm- unrelated to the observed changes in PaO2.
bolytic agents because of fibrin specificity The hypoxemia is explained by decreased
and affinity and low immunogenicity.76 alveolar ventilation in response to diffusion
Thrombolytic therapy causes faster resolu- of CO2 into the dialysate (Fig. 6-3).
tion of the embolus than heparin therapy. As CO2 diffuses into the dialysate, the CO2
Open surgical embolectomy can be benefi- content in venous blood decreases. Because
cial in hemodynamically unstable patients ventilation is tightly controlled by the periph-
for whom thrombolysis is contraindicated.76 eral and central chemoreceptors in response
130 Pulmonary Manifestations of Pediatric Diseases

Diffusion of CO2 into dialysate decreased plasma oncotic pressure from

hypoalbuminemia and hemodilution pro-
motes leakage of fluid from pulmonary
↓CO2 content in venous blood capillaries. The restrictive effects of pulmo-
nary interstitial and alveolar edema, pleural
effusion, and chest wall edema increase the
↓Hypercapnic ventilatory drive work of spontaneous breathing and may
contribute to the development of acute ven-
tilatory failure. In addition, the metabolic
↓Minute ventilation to acidosis present in most instances of acute
maintain constant PaCO2 renal failure increases the demand for venti-
lation through compensatory respiratory
alkalosis, further disrupting the relationship
↓PaO2 secondary to between the patient’s ventilatory needs and
alveolar hypoventilation
capabilities. Pulmonary edema and ventila-
tion at low lung volumes can cause or
worsen hypoxemia.
Acute renal failure may necessitate num-
Figure 6-3. Pathogenesis of dialysis-associated hypoxemia. erous adjustments to the management of
mechanical ventilation (Table 6-4). Higher
airway pressure is required to maintain the
to changes in PaCO2, this decrease in blood same level of ventilation in the presence of
CO2 content diminishes central ventilatory
drive and decreases minute ventilation.
Because some of the body’s CO2 production is Ways in Which Acute Renal Failure
being eliminated through dialysis, to maintain Table 6-4 Affects Ventilator Management
a normal PaCO2, less CO2 must be eliminated
Decreased Respiratory System Compliance
via the lungs. As alveolar ventilation falls and
Intrapulmonary causes
oxygen extraction remains the same, alveolar
Pulmonary edema
PO2 (PaO2) decreases, and PaO2 decreases.
Airway edema
That this basic physiologic sequence is
Extrapulmonary causes
responsible for dialysis-associated hypox-
Pleural effusion
emia was finally shown by a series of studies
Pericardial effusion
of ventilation and perfusion in several
Chest wall edema
laboratories.56,58,59 This mechanism is an
Clinical implication
example of alveolar hypoventilation with-
Requirement for higher airway pressure
out hypercapnia,60 something that is possi-
Increased Airway Resistance
ble only if CO2 is being removed from the
body by some route other than the lungs.
Airway edema
Decreased lung volumes
Clinical implication
Respiratory Effects of Acute
Increased likelihood of hyperinflation and auto-
Renal Failure PEEP
Metabolic Acidosis
Acute renal failure is common in the intensive Cause
care unit (ICU).1 An observational study of Impaired excretion of acid and metabolic products
nearly 30,000 adults admitted to the ICUs of Clinical implications
54 hospitals in 23 countries found that 5.7% Need for compensatory hyperventilation
of all patients had acute respiratory failure Worse acidemia with lung protective ventilation
during their stay, and that nearly 75% of these Increased minute ventilation requirement may
required some form of renal replacement ther- interfere with weaning
apy.52 Development of acute renal failure pre- Adapted from Pierson DJ: Respiratory considerations in the
disposes patients to overall fluid overload, and patient with renal failure. Respir Care 51:413-422, 2006.
Chapter 6 — Pulmonary Manifestations of Renal Diseases 131

pulmonary edema, pleural effusion, or total

Mechanisms by Which Critical
body fluid overload. Airway mucosal edema Table 6-5 Illness and Its Management Can
can reduce effective airway diameter, predis- Damage the Kidneys
posing to air trapping and endogenous posi- Systemic effects of sepsis
tive end-expiratory pressure, which can Intensive care unit–acquired urinary tract infection
reduce venous return, compromising cardiac Drug toxicity
function further and increasing the risk of Abdominal compartment syndrome
alveolar rupture.53 Ventilator-induced renal injury
The management of acute lung injury Adverse effects of permissive hypercapnia
(ALI) and ARDS using lung protective venti- and hypoxia on renal blood flow
lation is made more difficult in the presence Renal hypoperfusion owing to decreased cardiac
of metabolic acidosis, which increases venti- output (increased intrathoracic pressure)
latory drive and worsens acidemia related to Effects of systemic inflammatory mediators released
in response to mechanical ventilation
permissive hypercapnia. Because low tidal
volume, lung protective ventilation sub- Adapted from Pierson DJ: Respiratory considerations in the
stantially improves survival in ALI and patient with renal failure. Respir Care 51:413-422, 2006.

ARDS, its use should not be abandoned

because of acidemia in the face of acute renal failure, particularly in patients with
renal failure. Using a dialysate solution with underlying renal disease. A host of drugs used
a higher concentration of bicarbonate can in the ICU can cause or aggravate renal failure.
facilitate “compensation” for hypercapnia Shock from any cause is a known precipitant
and permit renal replacement therapy and of acute renal failure, as are conditions that
lung protective ventilation to be main- predispose to diminished renal perfusion.
tained. Weaning in the face of a metabolic One of the latter conditions that has
acidosis is challenging because of the received increasing attention in recent years
requirement that the patient be able to is abdominal compartment syndrome.62-64
maintain higher than usual minute ventila- In this syndrome, increased intra-abdominal
tion. Otherwise healthy patients may have pressure impairs venous return to the heart,
no trouble with this requirement, but in diminishes cardiac output, and causes venous
patients with severe obstructive lung disease congestion of the abdominal organs, includ-
or ARDS, weaning may have to be deferred ing the kidneys. Clinically, the abdominal
until either ventilatory function improves compartment syndrome is characterized by
or the required hyperpnea diminishes. hypotension, increased airway pressure, and
oliguria. In this clinical setting, its presence is
confirmed by measurement of pressure in
the urinary bladder. Although some authors
How Critical Illness and consider intravesical pressures greater than
Mechanical Ventilation Can 12 mm Hg to be associated with adverse
Damage the Kidneys effects,64 others use a pressure of 30 cm H2O
or greater to diagnose the syndrome.65
Patients may be admitted to the ICU because Although ventilator-induced lung injury is
of illness or injury causing acute renal failure. now a widely accepted entity and a much-
There are several ways, however, in which crit- investigated subject,66-68 until more recently,
ical illness not initially involving the kidneys, much less attention was focused on the poten-
and the management of that illness in the tial association between mechanical ventila-
ICU, can precipitate iatrogenic renal damage tion and renal injury. An increasing body of
(Table 6-5).1 Just as acute processes that precip- experimental evidence supports the concept
itate the systemic inflammatory response syn- that ventilatory support, particularly with high
drome predispose patients to ALI and ARDS, airway pressure and distending volume, can
these same processes are associated with the damage the kidneys and the lungs.69-71 In addi-
development of acute renal failure in the tion, permissive hypercapnia and permissive
ICU.61 Urinary tract infection, the most com- hypoxemia, although potentially protecting
mon hospital-acquired infection, can lead to the lungs from mechanical and biochemical
132 Pulmonary Manifestations of Pediatric Diseases

damage, may be associated with adverse effects 4. Foster GT, Vaziri ND, Sassoon CS: Respiratory alka-
losis. Respir Care 46:384-391, 2001.
on renal perfusion and excretory function.69 5. Khanna A, Kurtzman NA: Metabolic alkalosis.
The emerging concept of biotrauma,68 Respir Care 46:354-365, 2001.
through which mechanical events in the lungs 6. Epstein SK, Singh N: Respiratory acidosis. Respir
Care 46:366-383, 2001.
and airways initiate systemic processes that 7. Kraut JA, Madias NE: Approach to patients with
adversely affect other tissues and organs, may acid-base disorders. Respir Care 46:392-403, 2001.
apply to the kidneys and to the lungs.69 8. Madias NE, Adrogue HJ: Cross-talk between two
organs: How the kidney responds to disruption of
acid-base balance by the lung. Nephron Physiol
93:61-66, 2003.
Summary 9. Akikusa JD, et al: Clinical features and outcomes of
pediatric Wegener’s syndrome. Arthritis Rheum
57:837-844, 2007.
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and renal function is important in managing in children. Pediatr Pulmonol 37:476-484, 2004.
11. von Vigier RO, et al: Pulmonary renal syndrome in
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kidneys. Among the disease processes with of the literature. Pediatr Pulmonol 29:382-388, 2000.
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lar hemorrhage and other rare infiltrative disorders.
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16. Gutiérrez-Suárez R, et al: A proposal for a pediatric
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Pulmonary Manifestations of
Hematologic and Oncologic Diseases

Oncologic Diseases 135 Complications of Treatment of

Complications Related to Disease and Acute Hematologic and Oncologic
Treatment 135 Disorders 154
Solid Tumors 141 Hematopoietic Stem Cell
Primary Lung Neoplasms 146 Transplantation 154
Inflammatory Pseudotumor 147 Transfusion-Related Acute Lung Injury 156
Hematologic Disorders 147 Chemotherapy-Induced Lung Toxicity 158
Sickle Cell Disease 147 Radiation Therapy 162
Histiocytic Disorders of the Lung 152 Acknowledgments 163
References 163

Pulmonary complications are a common side (erythroid, myeloid, lymphoid, and megakar-
effect of pediatric hematologic and oncologic yocytic) that result from the transformation
disorders and their treatment. Respiratory of immature progenitor cells of these hemato-
signs and symptoms can be the presenting poietic lineages. These disorders are grouped
manifestations of several types of pediatric in four broad categories: acute lymphoblastic
malignancies. The anatomic structures typi- leukemia (ALL), acute myeloid leukemia
cally affected by this group of disorders are (AML), non-Hodgkin lymphoma (NHL), and
the mediastinum, airways (trachea and bron- Hodgkin disease (HD). They are classified
chus), alveolocapillary units, lung paren- further by the type of specific progenitor
chyma, pleura, diaphragm, and chest wall. cells involved in the process.1 Because the
Many of these thoracic structures, as exem- hematopoietic system is functionally diverse
plified by the thymus, continue to develop and has a wide anatomic distribution, the
intensively after birth and are common tar- clinical and biologic characteristics of leuke-
gets of malignant transformation. This chap- mias and lymphomas in young patients vary
ter describes the pulmonary symptoms and substantially.
management of pediatric hematologic and In the United States, of the approximately
oncologic disorders that directly or indirectly 13,000 new cases of cancer diagnosed per
affect the respiratory system. year in children, adolescents, and adults
younger than 20 years old, 18.7% are ALL,
Oncologic Diseases 8.8% are HD, 6.5% are NHL, and 3.5% are
AML.2,3 Of the neoplasias in children and
Complications Related to Disease adolescents, 50% are hematologic malig-
and Acute Treatment nancies. The incidence of leukemias and
lymphomas varies with age. ALL represents
Pediatric acute leukemias and lymphomas are 17% of all cases of pediatric cancer in neo-
clonal disorders of the blood-forming cells nates and infants, 46% of cases of cancer

*This work was supported in part by Cancer Center Support (CORE) grant P30 CA-21765 from the National Insti-
tutes of Health, by a Center of Excellence Grant from the State of Tennessee, and by the American
Lebanese Syrian Associated Charities (ALSAC)

136 Pulmonary Manifestations of Pediatric Diseases

in children 2 to 3 years old, and 9% of cases vena cava (SVC) syndrome, or both. The
of cancer in individuals 15 to 20 years old. most common tumors in this area are HD
Although the incidence of AML also varies and NHL. Tracheal compression may cause
with age, the rates are highest in the first cough, stridor, dyspnea, or orthopnea. In
2 years of life, after which they decrease to these cases, chest radiograph may reveal an
a nadir at the end of the first decade, and anterior mediastinal mass, prominent hilar
then gradually increase during the second lymph nodes, posterior tracheal deviation,
decade of life. Conversely, the rates of NHL atelectasis, and pleural effusion. Tracheal
and HD increase with age. The incidence compression is not always obvious, how-
of HD increases with age, with 43.2 cases ever, from the physical examination or
per 1 million for individuals 19 years old. chest radiograph. It may become apparent
The pattern of age distribution among leu- when a patient is unable to lie supine
kemia and lymphomas suggests that etiologic because of increased dyspnea; the patient
factors differ in these diseases. Generally, the should be considered at high risk for com-
process of malignant transformation of a spe- plete tracheal obstruction.11,12 The SVC
cific hematopoietic progenitor cell is believed is particularly susceptible to compression
to occur during fetal development in acute because it is surrounded by lymph nodes
leukemias4 and postnatally in lympho- and is in direct contact with rigid anatomic
mas5—hence, the incidence of lymphomas is structures. It has a delicate vessel wall and
greatly affected by environmental factors. In low intraluminal pressure.
some areas of Africa, Burkitt lymphoma and Symptoms resulting from moderate to
Kaposi sarcoma are two common types of severe SVC compression include headache,
pediatric malignancy.6 dizziness, syncope, and cardiovascular col-
The intrathoracic cavity harbors primary lapse secondary to decreased venous return
(thymus) and secondary (lymph nodes and (Fig. 7-1).13 Physical examination may be
mucosa-associated lymphatic aggregates) unremarkable or may show facial and peri-
lymphoid organs; thoracic lymphoid struc- orbital edema, cyanosis, plethora, neck and
tures are commonly affected in lymphoid leu- chest vein distention, papilledema, and
kemias and lymphomas. Enlargement of the edema of the upper extremities. The severity
thymus or its associated lymph nodes is very of the clinical manifestations of SVC syn-
common in T cell ALL, lymphoblastic NHL, drome depends on how rapidly the obstruc-
and HD.7-9 Mediastinal involvement is tion arises, and whether sufficient time has
extremely rare in AML. Chest radiography is elapsed for new collateral blood vessels to
an effective screening tool to identify children develop.
with mediastinal mass and should be Children with tracheal compression or
obtained in any patient newly diagnosed with SVC syndrome are often anxious and dia-
leukemia or lymphoma. A large mediastinal phoretic. They resist efforts to be placed
mass in a child should be considered a medical in the supine position and should not be
emergency and managed in a tertiary care forced into this position. Assessment of air-
hospital by a multidisciplinary team. Depend- way patency with computed tomography
ing on the size, location, organ compression, (CT) scan or flexible bronchoscopy is ill-
and progression time, a particular constella- advised because patients do not tolerate
tion of clinical signs and symptoms indicates these procedures well and may be very
whether the airways, great vessels, or both difficult to resuscitate if they experience
are predominantly affected.10,11 A detailed cardiorespiratory collapse. Total airway
assessment of the patient’s medical history occlusion has been reported during the
and results of the physical examination can induction of general anesthesia, tracheal
provide clues regarding whether the compres- intubation or extubation, movement of a
sion is affecting the airways, great vessels, patient to a supine or flexed position (for
heart, or more than one of these structures. lumbar puncture), and conscious seda-
tion.14 Flow-volume loops have been used
Tracheal Compression and Superior to indicate the degree of central airway
Vena Cava Syndrome obstruction and may be helpful in distin-
Large tumors in the anterior mediastinum guishing fixed from variable intrathoracic
can cause tracheal compression, superior airway lesions.15
Chapter 7—Pulmonary Manifestations of Hematologic and Oncologic Diseases 137

Figure 7-1. An 11-year-old boy with lymphoblastic lymphoma. A, Posteroanterior chest radiograph shows large ante-
rior mediastinal mass and pleural effusion. B and C, Cytocentrifuge examination of the pleural effusion shows FAB L1 lym-
phoblasts (B) (Wright-Giemsa) of T cell origin (C) (anti-CD3 staining).

Whole-body positron emission tomogra- lower extremities because most of the venous
phy (PET) has been increasingly used to deter- return proceeds through the inferior vena
mine the extent of disease and response to cava. Although SVC syndrome per se does
therapy. NHL and HD are metabolically active, not represent a medical emergency, most
and so they can be detected with this method. children with SVC syndrome experience
Although PET/CT (Fig. 7-2) is still considered a some degree of airway compression. Therapy
research tool in disease staging and prognosis, with radiation to the mid-plane or cortico-
some studies have shown the superiority of steroids (hydrocortisone, 2 mg/kg every 6
PET/CT to PET or CT alone in the manage- hours) or both usually alleviates symptoms.
ment of NHL and HD.15 The least invasive Most mediastinal masses in children and
technique is used to obtain tissue for diagno- adolescents are highly sensitive to chemo-
sis. The diagnosis often can be made from therapy. These patients are at high risk of uric
bone marrow aspirate or peripheral lymph acid nephropathy and consequently kidney
node biopsy, which can be obtained with top- dysfunction.17,18 Hyperhydration and alka-
ical anesthesia. Similarly, if pleural effusion is linization used for patients at high risk of
present, thoracentesis can be used in making tumor lysis syndrome (hyperuricemia)17
a diagnosis (Fig. 7-3). should be avoided in patients with SVC
A proper regimen of chemotherapy should syndrome, however, because of the risk of
be started as soon as a diagnosis is established. respiratory insufficiency and worsening of
Intravenous access should be started in the existent pleural effusion. Rasburicase is very
138 Pulmonary Manifestations of Pediatric Diseases

Figure 7-2. A, A 14-year-old boy with

lymphoblastic lymphoma complicated
by vena cava compression syndrome.
The compression was predominantly
vascular; the patient had no signs of
respiratory distress. B, A 10-year-old
boy with lymphoblastic lymphoma,
superior vena cava syndrome, and tra-
cheal compression. In addition to having
increased collateral circulation in the
frontal and cervical regions, the patient
was plethoric and was experiencing A B
respiratory distress.



Figure 7-3. PET/CT images of a 15-year-old boy with non-Hodgkin lymphoma. A, CT image, transverse plane, shows large
mediastinal mass (top arrow) and large pleural effusion (bottom arrow). Collapse of the right lung and mediastinal shift to the
right are evident. B, PET image at same anatomic level as A shows irregularly increased uptake of fludeoxyglucose F 18
(FDG) in mediastinal mass (top arrow). The pleural effusion (bottom arrow) shows no uptake of FDG. Increased uptake of
FDG, which represents pleural involvement, is evident along the periphery of the effusion, however. C, Fused image of A
and B overlies the anatomic image in A and the functional image in B.

effective in rapidly decreasing plasma urate, for primary malignancy should be instituted
avoiding the need for hyperhydration and as soon as the diagnosis is established.
Doppler ultrasonography and echocardi- Pulmonary Leukostasis Syndrome
ography may be indicated for evaluating Approximately 50% of children with ALL
flow through the great vessels and myocar- and AML present with an abnormally ele-
dial function. If thrombosis is detected, use vated blood leukocyte count. Severe leuko-
of unfractionated or low-molecular-weight cytosis (defined as peripheral leukocytes
heparin should be considered to prevent 100,000/mm3) occurs in approximately
propagation of the thrombus. In rare cases, 20% of children with ALL and 15% of chil-
catheter-directed thrombolysis has been dren with AML.21,22 Most of these patients
performed to relieve obstruction.20 Most have no pulmonary signs or symptoms asso-
importantly, prompt specific chemotherapy ciated with this abnormality. Depending on
Chapter 7—Pulmonary Manifestations of Hematologic and Oncologic Diseases 139

the number of leukocytes and the type of can lead to the misdiagnosis of pulmonary
leukemia, however, a constellation of signs embolism. Imaging studies are nonspecific
and symptoms, known as pulmonary leu- for pulmonary leukostasis.37
kostasis syndrome, may occur.23 Leukostasis Hypoxemia in patients with hyperleuko-
can affect any organ, but it most commonly cytosis can be a true or false finding. Causes
involves brain and lungs. Clinically, pulmo- of true hypoxemia in these patients include
nary involvement is characterized by short- infection, hemorrhage, pulmonary embo-
ness of breath, tachypnea, dyspnea on lism, pulmonary alveolar proteinosis (PAP),
exertion, and pleuritic chest pain. Mortality and occlusion of the pulmonary vasculature
in patients with leukostasis is approximately by leukocyte thrombi. False hypoxemia can
20%, usually secondary to pulmonary or result from technical inaccuracies in the
intracranial hemorrhage.24 measurement of PaO2, and often may reflect
Patients with AML tend to develop symp- that leukemic cells are metabolically active
tomatic leukostasis at much lower leukocyte in vitro.38-41 In this situation, low levels of
counts than do patients with ALL.25 Post- PaO2 reflect consumption of dissolved oxy-
mortem evidence of leukostasis in AML, gen by leukocytes or platelets after the
including extensive leukemic infiltration of arterial blood specimen is obtained, a phe-
the alveoli and parenchyma, and occlusion nomenon called “oxygen steal.”42 Consis-
of small pulmonary vessels, has been found tent with this concept is the observation
in patients presenting with a wide range of that PaO2 values are negatively correlated
leukocyte counts.26,27 Symptomatic pulmo- with the number of circulating leukocytes.
nary leukostasis occurs almost exclusively Because pulse oximetry measures capillary
in children with AML.28 oxygen instead of whole-blood oxygen
Respiratory distress and early death result- saturation, this method is considered the
ing from hyperleukocytosis (defined as leu- most accurate way to assess oxygenation in
kocyte counts 200,000/mm3) is more patients with hyperleukocytosis.43
common in children with AML, occurring Acute leukemia complicated by severe
in 6% of patients. A high initial white blood hyperleukocytosis should be considered a
cell count seems to be the only marker asso- medical emergency. Admission of the patient
ciated with the development of respiratory to an intensive care unit and proper manage-
complications.29 In addition, because myelo- ment of aggravating factors, such as dehydra-
blasts express adhesion molecules that attach tion, electrolyte or metabolic imbalances,
to the pulmonary vascular endothelium, infection, thrombocytopenia, and coagulop-
they are more tissue-invasive than lympho- athy, should be initiated immediately. Fluid
blasts. These factors apparently are more rele- balance is required to avoid excessive fluid
vant to the severity of pulmonary leukostasis retention. Transfusion of platelet concen-
syndrome than the number of leukemia cells. trate or fresh frozen plasma is used to reduce
The adverse interactions between leukemic the risk of bleeding. Prophylaxis of thrombo-
cells and organs such as lungs, brain, and embolic phenomena with heparin is not
kidneys seem to be worsened further in M5 indicated. Transfusion of packed red blood
AML and M4 AML because these subtypes of cells should be withheld or be given with
AML31-34 release many proinflammatory caution to prevent an increase in blood
cytokines and lysozymes.30,35 viscosity before the reduction of the leuko-
Chest radiographs can be normal, or they cyte count.44 Anemia in patients with hyper-
may reveal variable degrees of diffuse alveo- leukocytosis can be seen as an adaptive
lar-interstitial infiltrates and pulmonary ves- mechanism. Inhaled nitric oxide to produce
sel enlargement. Findings of chest CT scans pulmonary vasodilation and ventilation/
include bilateral thickening of the interlob- perfusion mismatch reduction has been used
ular septa with patchy areas of ground-glass by some investigators.45-47 Leukapheresis or
opacity that resemble that of interstitial exchange transfusion (for young children)
edema. A ventilation/perfusion lung scan is commonly considered as a temporary mea-
can show mismatched defects,36 but is not sure until specific antileukemia treatment is
specific for leukostasis, and reliance on it initiated.48-53 The efficacy of leukapheresis in
140 Pulmonary Manifestations of Pediatric Diseases

reducing mortality or life-threatening compli- evidence suggest that abnormality of the

cations has not been evaluated in controlled GM-CSF signaling in the lung is associated
clinical trials. with PAP pathogenesis. First, histologically
similar PAP lung changes occur in mice
Pulmonary Alveolar Proteinosis genetically deficient in GM-CSF or its
PAP can rarely be a cause of respiratory fail- receptor.76,77 Abnormal clearance of surfac-
ure in patients with acute leukemia, partic- tant lipids is impaired in GM-CSF–deficient
ularly AML.54 PAP is characterized by the mice, providing an explanation for the
intra-alveolar accumulation of surfactant intra-alveolar accumulation of PAS-positive
proteinaceous material, resulting in impaired material. PAP in GM-CSF–deficient mice
alveolocapillary gas exchange (Fig. 7-4).55-57 can be corrected by the local expression of
Three types of PAP have been recognized: GM-CSF in the lungs,78,79,84 or by bone
congenital,58-62 associated with or secondary marrow transplantation from a wild-type
to systemic disease,63-65 and idiopathic. The mouse.80 Second, PAP occurs in individuals
last-mentioned is the most common form harboring constitutional mutations in the
of PAP and believed to have an autoimmune genes encoding surfactant proteins B or C or
basis.66-68 the bc chain of the GM-CSF receptor.58-62
The mechanism of PAP has not been firmly Finally, autoantibodies that bind and neu-
established, although surfactant homeostasis tralize GM-CSF are found in broncho-
apparently is impaired in this disease.69 alveolar lavage (BAL) of patients with the
Although only 10% of surfactant comprises idiopathic form of PAP.66
proteins, denominated A, B, C, and D, they Imaging studies of the lungs suggest PAP.85
are crucial to surfactant metabolism, opsoni- The chest radiograph usually shows bilateral
zation of microorganisms, and stimulation airspace disease characterized as ground-glass
of alveolar macrophage.70-72 Alveolar type II opacities suggestive of pulmonary edema,
epithelial cells and alveolar macrophage con- but without other signs of left-sided heart dys-
trol surfactant synthesis, storage, and ca- function. There is no relationship between
tabolism. Alveolar macrophages, which are clinical and radiographic findings, with the
produced by bone marrow hematopoietic latter being disproportionately more severe.85
cells, internalize and catabolize surfactant High-resolution CT scans reveal a pattern
by a process believed to depend on granulo- referred to as “crazy-paving,” which is charac-
cyte-macrophage colony-stimulating factor terized by ground-glass opacifications with
(GM-CSF) signaling.73-75 Several lines of superimposed interlobular septal and intra-
lobular thickening.86
BAL specimens can be used to establish
the diagnosis.87 Lung biopsy is the gold
standard for the diagnosis of PAP, but it
sometimes can yield false-negative results.
The incidence of PAP associated with leu-
kemia is unknown, but a study by Cordon-
nier and colleagues63 suggested that it can
be 10% in patients with leukemia and respi-
ratory failure. Treatment of PAP consists of
overall supportive care because many of
these patients have severe neutropenia from
previous chemotherapy, and whole-lung
lavage for patients with severe respiratory
distress.88-93 Most cases of chemotherapy-
induced PAP usually improve with the reso-
Figure 7-4. Pulmonary alveolar proteinosis (accumula- lution of neutropenia.
tion of amorphous, eosinophilic, periodic acid-Schiff-posi- Because the mechanism of PAP has been
tive material) in pulmonary alveolar lumens. (Hematoxylin
and eosin, 40 original magnification.) Inset shows PAS associated with GM-CSF deficiency, adminis-
stain counterstained with hematoxylin. tration of GM-CSF has been proposed as a
Chapter 7—Pulmonary Manifestations of Hematologic and Oncologic Diseases 141

treatment of PAP. In a study of 25 patients of diagnosis.95-98 Approximately 5% of all

with idiopathic PAP, subcutaneous adminis- osteosarcomas are multifocal (i.e., involving
tration of GM-CSF improved oxygenation two or more bones at the time of diagnosis).
and decreased alveolar-arterial oxygen gradi- Multifocal osteosarcoma has a more aggres-
ent in approximately 50% of the patients.94 sive clinical behavior, a higher incidence of
Whether GM-CSF has a therapeutic value pulmonary metastases, and a very poor
in children with leukemia and respiratory dis- prognosis.99
tress associated with clinical and laboratory When osteosarcoma is diagnosed, even the
features of PAP remains to be determined. most accurate staging procedures detect
Defective expression of GM-CSF/interleukin- metastases in only a few patients. Without
3/interleukin-5 receptor common b chain adequate treatment, however, most patients
has been shown to occur in children with with seemingly localized disease develop sec-
AML associated with respiratory failure.95 ondary metastases within 1 year.100 This
finding implies that micrometastases are
already present at diagnosis in most patients.
Solid Tumors With appropriate treatment, 60% to 70%
of patients with localized disease are ex-
Solid malignancies in children differ mark- pected to be cured. The outcome of pa-
edly from such tumors in adults; biology tients with clinically detectable metastatic
and histology define a very distinct group of disease at diagnosis is usually very poor; less
neoplasms, most of them of dysontogenetic than 30% of patients are expected to sur-
origin, with unique clinical manifestations vive.94,101-103 Care of these patients needs
and natural history. Epithelial malignancies to combine a multimodal approach, with
are extremely rare in children; sarcomas and intensive preoperative and postoperative
dysontogenetic tumors constitute most solid chemotherapy and resection of the primary
cancers. Generally, these groups of malignan- tumor and all the metastatic lesions.102-105
cies are aggressive, and systemic dissemina- Using these guidelines, more recent research
tion (microscopic or macroscopic) is present reports 2- to 5-year, progression-free survival
at the time of diagnosis. For this reason, an rates of 25% to 45%.102,106-108 Factors that
extensive metastatic work-up is necessary, affect outcome include number of metas-
and most malignancies require systemic ther- tases, laterality, and the ability to perform a
apy regardless of the local stage. complete resection.102,105
The lungs also are the most common sites
Osteosarcoma of treatment failure in patients with osteo-
Osteosarcoma, a malignant neoplasm derived sarcoma. For patients with recurrent disease,
from primitive mesenchymal cells and char- a surgical approach is recommended; the
acterized by the presence of osteoid-produc- 5-year postrelapse survival of patients in
ing spindle cell stroma, is the most common whom a complete resection of all macro-
malignant bone tumor in pediatric patients.92 scopic disease can be achieved is almost
Osteosarcoma accounts for 2.6% of all neo- 40%, whereas it is 0% for patients with unre-
plasms in children, with an estimated annual sectable disease.104,109 Prognostic factors for
incidence of 3.9 per 1 million in white survival after recurrence include isolated
children and 4.5 per 1 million in African- lung metastases, late (>24 months) recur-
American children.93 Most osteosarcomas rences, and small number of pulmonary
occur during the first 2 decades of life, a nodules.105,109,110
period characterized by rapid skeletal growth. Plain chest radiographs detect lung metas-
Overt macroscopic metastatic disease is seen tases in most cases. High-resolution CT of
in a significant proportion of patients, and the chest is the procedure of choice, how-
has a grave prognosis when present.94 The ever. False-positive results occur, particularly
most common site for metastatic spread with smaller lesions, and biopsy confirma-
is the lung; 14% to 24% of patients have tion of the lung disease is usually required.
macroscopic pulmonary disease at the time Osteoid matrix produced by osteosarcoma
142 Pulmonary Manifestations of Pediatric Diseases

cells forms bone and causes calcification in nodule in the site of a scar was malignant
pulmonary nodules. Seventy-five percent was 82%.111
of metastatic osteosarcoma nodules lack cal- The ability to control the pulmonary micro-
cification, however. Conversely, only 50% metastatic disease after completion of therapy
of calcified nodules in newly diagnosed would result in a significant improvement
patients with osteosarcoma are malignant, in outcome. Muramyl tripeptide phospha-
whereas 65% of noncalcified lesions are tidylethanolamine (MTP-PE), a synthetic lipo-
found to be metastatic osteosarcoma.111 philic analogue of muramyl dipeptide (a
Mediastinal adenopathies are very rare in component of the cell wall of bacille Calm-
patients newly diagnosed with osteosar- ette-Guérin), has been encapsulated in lipo-
coma, and their presence in the context of somes to deliver the agent selectively to
lung nodules favors the diagnosis of a non- monocytes and macrophages to activate their
malignant condition; 60% of patients with tumoricidal properties. In an animal model,
benign nodules have mediastinal disease the administration of liposome-encapsulated
compared with less than 20% of patients muramyl tripeptide (L-MTP-PE) resulted in
with metastases.111 activation of pulmonary macrophages and
CT is often unable to distinguish benign eradication of pulmonary micrometastases.113
from malignant pulmonary disease, and a In the cooperative Children’s Cancer Group
surgical procedure is often required for con- and Pediatric Oncology Group intergroup
firmation. CT can miss 40% to 50% of the INT0133 clinical trial, patients with localized
lesions that are found later during the surgi- osteosarcoma received standard treatment
cal procedure.112 This finding highlights the with methotrexate-cisplatin-doxorubicin reg-
importance of manual palpation during imen. Patients were first randomly assigned
open thoracotomy; minimal access proce- to receive ifosfamide, L-MTP-E, or a combi-
dures such as thoracoscopy should not be nation of both. Adding a combination ther-
the approach if the goal is resection. apy with ifosfamide and L-MTP-PE to the
In patients who have undergone thoracot- standard regimen resulted in a significantly
omy for metastatic disease, new nodules are better outcome than the other three regi-
likely to be metastatic, and surgical interven- mens.114 This improved outcome could be
tion is warranted. Surgical scarring often due to the synergistic effect of L-MTP-PE
makes the diagnosis of recurrent disease diffi- and ifosfamide.115
cult, however. McCarville and associates111 It also is possible to induce activation of
evaluated the imaging patterns of recurrent alveolar macrophages by nebulization of
nodules after thoracotomy in patients with GM-CSF. Based on encouraging preliminary
osteosarcoma. Pulmonary nodules recurred data, the Children’s Oncology Group is cur-
in 90% of patients who underwent thoracot- rently evaluating this approach in patients
omy, and metastatic disease was found in with metastatic osteosarcoma. Another simi-
90% of patients who underwent another sur- lar approach is the interleukin-12 gene trans-
gical procedure. Only one third of the fer by aerosol using a nonviral vector, such as
nodules appeared to be calcified on CT scans. polyethylenimine, a polycationic DNA car-
A consistent pattern suggestive of malig- rier. Interleukin-12 has a well-known activity
nancy was the presence of progressive pleural against various tumors. The systemic admin-
thickening. In contrast to newly diagnosed istration of interleukin-12 is limited by its
patients, in most patients who had under- toxicity. In animal models, aerosol therapy
gone thoracotomy, recurrent pulmonary dis- resulted in a significant decrease in the size
ease was associated with the presence of and number of metastatic nodules.116,117
mediastinal adenopathies. With subsequent Interleukin-12 also has been shown to
recurrence, the proportion of malignant enhance the sensitivity of osteosarcoma cells
lesions and the incidence of malignant medi- in vitro to 4-hydroxy-cyclophosphamide by
astinal disease increased.111 Also, half of the a mechanism involving the Fas pathway,
new lesions occurred in previous scars, and which suggests that this approach may act
the estimated probability that a recurrent synergistically with ifosfamide.115 The same
Chapter 7—Pulmonary Manifestations of Hematologic and Oncologic Diseases 143

polyethylenimine transfer technology has metastases; most (50% to 60%) have extrapul-
been shown to provide an antitumor effect monary disease (usually of the bone and bone
using p53 transfection.117 marrow).122,125-127,131 Overall, approximately
Aerosolized technology also has been devel- 10% of patients have lung metastases at the
oped to deliver chemotherapeutic agents time of diagnosis (Fig. 7-5).129
directly to the lungs. In an animal model, The most important prognostic factor is
aerosolized 9-nitrocamptothecin liposome the presence of metastatic disease at diagno-
was administered to mice that had subcutane- sis.122 Advances in the treatment of ESFT
ous xenografts of various human cancers and have resulted in only a very modest improve-
to mice with lung metastases of osteosar- ment in the survival of patients with metas-
coma. The results were encouraging; a signi- tases.122,126,132 Even among patients with
ficant antitumor effect was noted in the metastatic disease, however, there is some
xenografts and in the pulmonary disease, heterogeneity. Patients with isolated lung
suggesting not only a local, but also a sys- metastases may have a better prognosis than
temic effect.118 Clinical trials to assess this patients with extrapulmonary metastases,
form of therapy are under way.119 with long-term survival rates approaching
40% to 45%.125,130,131 Among patients with
Ewing Sarcoma Family of Tumors lung metastases, patients with unilateral
The term “Ewing sarcoma family of tumors” disease130 and patients with good histologic
(ESFT) refers to a group of small round cell response to induction chemotherapy129
neoplasms of neuroectodermal origin. Ewing seem to have a survival advantage.
sarcoma of the bone is the least differentiated In approximately 50% of patients with
form, and primitive neuroectodermal tumor isolated lung metastases, treatment fail-
and peripheral neuroepithelioma are the ures occur as isolated pulmonary disease
most differentiated forms. Of all types of pedi- again,129,130 suggesting that further response
atric malignancy, 3% are ESFT; these tumors consolidation might improve the outcome
are rare in nonwhites.120 Approximately of these patients. In contrast to osteosar-
40% of all bone cancers in children are ESFT coma cells, ESFT cells are very sensitive to
of the bone, the second most common type radiation therapy, and lung radiation is an
of bone malignancy in children after osteo- alternative to lung surgery. In the first Amer-
sarcoma.120 Patients with ESFT commonly ican Intergroup Ewing Sarcoma Study, lung
present with symptoms during the second radiation was associated with a lower inci-
decade of life; 80% of patients with EFST are dence of lung (and distant) recurrences.133
younger than 18 years, and the median age With the development of more intensive
at diagnosis is 14 years.120-122 ESFT has a chemotherapeutic regimens, lung radiation
tendency to involve the shaft of long tubular of localized disease was abandoned. It
bones, the pelvis, and the ribs, but almost remains a therapeutic option, however, for
every bone can be affected. More than 50%
of the tumors arise from axial bones, with
the pelvis being the most commonly
involved (23% to 27%). Primary ESFT of the
chest wall, previously known as Askin tumor,
occurs in 12% of patients with ESFT.120-123
ESFT are aggressive neoplasms; systemic
manifestations including fever and anemia
are present in 10% to 15% of patients,124 and
approximately 20% to 25% of cases have clini-
cally apparent metastatic disease at the time
of diagnosis.125-127 Metastatic disease seems
to be associated with older age128 and large
tumors128-130 or with pelvic primary
tumors.125,126,129 Isolated lung disease, usually Figure 7-5. Chest CT scan shows multiple pulmonary
bilateral, occurs in 25% to 45% of patients with metastases (arrows) in a patient with Ewing sarcoma.
144 Pulmonary Manifestations of Pediatric Diseases

patients with metastatic disease. In this Approximately 10% to 15% of patients

regard, whole-lung radiation seems to pro- with RMS have metastatic disease at the
vide a modest survival advantage in patients time of diagnosis. The incidence of meta-
with metastatic disease.129 Preliminary data static disease is higher in patients with alve-
of the European Bone Marrow Transplant olar RMS (25% to 30%) than in patients
Registry134 suggest that an alternative ap- with embryonal RMS (5% to 10%).137-139
proach to the treatment of patients with Most cases of alveolar RMS are characterized
isolated lung metastases may be high-dose by the presence of the t(2;13)(q35;q14) or,
chemotherapy using a busulfan-based regi- less frequently, t(1;13)(p36;q14) transloca-
men and autologous stem cell rescue. tions, which result in the PAX3-FKHR or
Patients with primary ESFT of the chest PAX7-FKHR chimeric genes. Patients with
wall represent a distinct group. Many of these the PAX3 translocation have more wide-
patients have infiltration of the pleura, have spread metastatic disease and a worse out-
pleural effusion, or may develop intraopera- come. The PAX7 translocation seems to be
tive contamination of the pleural space. They associated with a lower incidence of lung
may be at high risk of disease relapse within metastases.140
the pleural compartment, and many groups Approximately 5% of patients with RMS
have used hemothorax radiation covering have lung metastases at the time of diagno-
the entire pleural space. The use of hemi- sis.138 Only 15% to 25% of patients with
thorax radiation seems to reduce systemic metastatic disease have isolated lung metas-
relapse rates (mainly in lung metastases) tases; in most cases, the presence of lung
and to provide a survival advantage.135 disease is a sign of more widespread meta-
static RMS.141,142 The presence of isolated
Soft Tissue Sarcomas lung metastases is associated with favorable
Pediatric soft tissue sarcomas (STS) are broadly features, such as embryonal histology and
divided into rhabdomyosarcoma (RMS) (40% negative nodal involvement. Patients with
to 45%) and non-RMS soft tissue sarcomas metastatic disease have a generally poor
(NRSTS) (55% to 60%), which include several prognosis, with long-term survival estimates
histologic subtypes, each one of which con- of less than 30%. Patients with isolated lung
stitutes less than 5% to 10% of STS. Alto- metastases seem to benefit from lung radia-
gether, STS represent approximately 6% to tion, however, and have a slightly better
7% of the cases of malignancy in individuals outcome, with 4-year overall survival rates
younger than 20 years. The incidence of of 40%.142
RMS is highest in infancy and during the first NRSTS comprise a very heterogeneous
years of life, and it decreases and levels out at group of neoplasms of mesenchymal origin.
later ages, whereas NRSTS have their highest The most common subtypes in children are
incidence in adolescence, although a peak is dermatofibrosarcoma protuberans, synovial
observed in infants.136 sarcoma, malignant fibrous histiocytoma,
RMS recapitulates the phenotypic and bio- fibrosarcoma, and malignant peripheral nerve
logic features of developing skeletal muscle. sheath tumor. Because each tumor is individu-
Two broad categories are identified: Embry- ally rare in pediatric patients, little is known
onal RMS with its botryoid and spindle cell about their biology and natural history in
variants accounts for two thirds of the cases, children. Most have clinical behavior similar
and alveolar RMS and undifferentiated RMS to tumors in adults; however, there are nota-
account for the remaining cases. RMS is clini- ble exceptions, such as infantile fibrosar-
cally heterogeneous; it can arise anywhere in coma and infantile hemangiopericytoma,
the body where mesenchymal tissue is found. neoplasms that are associated with character-
One third of the cases arise in the head and istically good prognosis despite aggressive
neck region (orbit, parameningeal, and non- histologic features.
parameningeal sites); 25% arise in the genito- Lung metastases are present in 5% to 10% of
urinary tracts, primarily bladder and prostate; the cases at diagnosis.143,144 Only 12% of chil-
and 18% arise in the extremities. RMS occur dren who have undergone gross tumor resec-
much less frequently in the trunk and pelvis. tion experience metastatic tumor recurrence.
Chapter 7—Pulmonary Manifestations of Hematologic and Oncologic Diseases 145

Patients with large (5 cm), invasive, or high- lesions identified on CT only are not malig-
grade tumors have a significantly higher (25% nant.156 For these reasons, the role of lung
to 35%) risk of distant disease recurrence, radiation in this group of patients with CT-
however, usually in the lungs.145-147 If pa- only lung nodules is unclear. In such patients
tients are at high risk of distant metastases treated on the National Wilms Tumor Studies
after local control or have unresectable or met- 3 and 4, the 4-year event-free survival esti-
astatic tumors at presentation, chemotherapy mates were 89% for patients receiving radia-
must be considered. tion and 80% for patients treated with
Among all the histologic subtypes of chemotherapy only.157 Similarly, results of a
NRSTS, alveolar STS warrants special men- study by the International Society of Pediatric
tion. This rare tumor accounts for only 1% Oncology showed that patients with lung
of all STS. Of patients with this form of sar- nodules identified only on CT and who
coma, 65% have lung metastases at the time achieved a complete response to chemo-
of diagnosis, however. This sarcoma has a therapy had a 5-year overall survival esti-
very indolent course, and even in the pres- mate of 83%.158 These results contrast
ence of metastases, 5-year overall survival with the findings of the United Kingdom
rates exceed 70% to 80%.148 Children’s Cancer Study Group, which
indicated much lower (65%) survival rates
Wilms Tumor if no radiation was used.159
Wilms tumor is the most common childhood Because this issue remains unresolved,
renal tumor, accounting for approximately future trials by investigators in the Chil-
6% of all pediatric malignant disease. The most dren’s Oncology Group are expected to
common presentation is an asymptomatic assess the necessity of lung radiation for
abdominal mass in a young child (typically patients whose tumors have favorable bio-
<5 years old), although approximately one logic and histologic features and show rapid
third of such patients present with abdominal response to chemotherapy. It is possible that
pain, anorexia, and malaise. Hypertension is some children with stage IV favorable his-
present in 25% of the cases, and congenital tology Wilms tumor may be treated success-
anomalies, such as aniridia, genitourinary mal- fully without lung radiation.152 Finally, an
formations, or hemihypertrophy, are present important consideration is the frequent
in 10% to 20% of children.149 Histologic char- extension of Wilms tumor into the renal
acteristics are the most important prognostic vein and proximal inferior vena cava, which
indicators; anaplasia (which occurs in 10% of is sometimes associated with pulmonary
cases) is associated with an adverse outcome. embolism.160 In most cases, tumor throm-
Lung metastases are present in approximately bus can be removed en bloc with the kid-
10% of patients with favorable histology and ney. If the tumor extends to the hepatic
in 20% of patients with anaplasia.150,151 In level or into the atrium, however, the risk
contrast to most other types of pediatric malig- of operative morbidity is very high, and pre-
nancy, Wilms tumor with lung metastases operative chemotherapy is recommended.
has a good outcome, with 5-year overall sur-
vival estimates exceeding 80% for patients Neuroblastoma
with favorable histology.152 Lung radiation is Neuroblastoma is the most common extra-
an integral component in the management cranial solid tumor in children, accounting for
of these patients with lung metastases. 10% of all childhood cancers. Approximately
Plain chest radiographs have been used to two thirds of patients with neuroblastoma
define the presence of metastatic disease in have metastatic disease at diagnosis, typically
patients with Wilms tumor. In approximately of the bone or bone marrow, and their prog-
10% of patients with lung nodules, plain chest nosis is very poor, although it varies accord-
x-rays are normal, however, and the lesions ing to many clinical and biologic risk
are visible only on CT scan.153 Nonmalignant factors.161 Pulmonary involvement at diag-
nodular lesions are frequently identified on nosis is extremely rare, occurring in less than
chest CT scans, but not on plain radiographs 1% of patients.162 In patients with metastatic
in children.154,155 In adults, 50% to 60% of disease, lung metastases may be present in
146 Pulmonary Manifestations of Pediatric Diseases

4% of patients, are never isolated, and are

always found in the context of a very aggres-
sive clinical and biologic behavior. On radio-
graphs, these lesions appear as multiple,
small, bilateral, noncalcified nodules.163

Hepatoblastoma is a very rare malignancy in
the overall population, but it accounts for
75% of all liver cancers in children. Lung A
metastases are very common; 20% of pediat-
ric patients have pulmonary disease at diag-
nosis, and the lungs are the most common
site of recurrence.164-166 Metastatic hepato-
blastoma is curable if the tumor responds
to chemotherapy and the lung metastases
are resected. With this aggressive approach,
the 5-year overall survival estimates are
approximately 50%.164,166

Imaging Considerations
Multiple studies have shown that even in
children with tumors known to metastasize
to the lungs, a significant proportion of Figure 7-6. A and B, Chest CT scans show single pul-
lesions found on chest CT scans are monary nodules (arrows) of similar characteristics in
two patients with osteosarcoma. Both patients under-
benign.167,168 Although granulomas develop went a thoracotomy. Examination of a tissue specimen
less frequently in children than in adults, helped establish a diagnosis of histoplasmosis in the
several other benign conditions may develop patient shown in A and metastatic osteosarcoma in
the patient shown in B.
in the lungs of children, including the
growth of normal intrapulmonary lymph
nodes, hamartoma, round pneumonia, atel-
as PET/CT may allow us to assess more accu-
ectasis (particularly in children requiring
rately and noninvasively the metabolic activ-
sedation or anesthesia), and inflammatory
ity of pulmonary nodules.
pseudotumor. Distinguishing benign from
malignant pulmonary nodules may be diffi-
cult (Fig. 7-6). Primary Lung Neoplasms
The availability of helical CT has improved
the quality of the chest images by diminish- Pleuropulmonary blastoma (PPB) is a unique
ing the effect of breathing and cardiac dysontogenetic neoplasm of childhood that
motion on the readability of the scan. appears as a pulmonary or pleural-based mass,
McCarville and associates169 investigated with a primitive, histologically variable mixed
the imaging features of 81 pulmonary blastomatous and sarcomatous appearance. It
nodules in 41 patients with solid tumors usually manifests in the first 3 to 4 years of life
who had undergone a thoracotomy. The with respiratory distress, fever, cough, or chest
new chest CT scans were able to detect 75% pain. Cystic changes and pneumothorax are
of the nodules found at surgery; 44% of the common on CT scans. The lower lobes are
patients had benign lesions only. Sharply more commonly involved, and pleural inva-
defined nodules were more likely to be malig- sion and effusion are typical. PPB can be
nant in children than in adults.169 Although divided into three morphologic types or sub-
node size was not always a predictor of malig- types based on the cystic, cystic and solid, or
nancy, small (<5 mm) nodules were less solid appearance of the tumor, as determined
likely to be malignant, particularly small sol- by the gross and microscopic examination.
itary nodules.169,170 New technologies such The exclusively cystic or type I PPB is the least
Chapter 7—Pulmonary Manifestations of Hematologic and Oncologic Diseases 147

complex, manifests at an earlier age than the Hematologic Disorders

other two forms, and is more readily resect-
able. The rhabdomyosarcomatous compo- Sickle Cell Disease
nent is a prominent feature of type II and
type III PPB, and it is the exclusive malignant Sickle cell disease (SCD) comprises a group
element in type I. PPB is an aggressive malig- of inherited hemoglobinopathies character-
nancy, and metastases to the brain are ized by a predominance of hemoglobin
common. (Hb) S. Included in SCD are sickle cell ane-
Type I PPB usually has a good prognosis mia (Hb SS, the homozygous state for the b
if complete resection is achieved. The out- S globin gene), Hb SC (Hb S and Hb C),
come associated with type II and type III sickle b-thalassemia syndrome (either Hb
PPB is much worse, with 5-year survival rates b0 thalassemia or Hb bþ thalassemia in com-
of less than 50%. These patients need a very bination with Hb S), and other combina-
aggressive treatment approach, with wide tions of Hb S and abnormal hemoglobins.
resection and systemic chemotherapy.171 These hemoglobinopathies result from the
Other, less common primary malignancies substitution of valine for glutamic acid at
of the lungs include carcinoid and primary position 6 of the b globin chain, which
sarcomas such as malignant peripheral nerve alters the quaternary structure of hemoglo-
sheath tumor and fibrosarcoma. bin and reduces the solubility of deoxyhe-
moglobin S to approximately 10% of that
of the normal deoxyhemoglobin A. After
Inflammatory Pseudotumor deoxygenation of the erythrocyte, Hb S
undergoes intracellular polymerization. As
Inflammatory pseudotumor (plasma cell the concentration of Hb S increases, the ery-
granuloma, inflammatory myofibroblastic throcytes collapse into a sickle shape, either
tumor) is a rare benign neoplasm consisting reversibly or irreversibly. Repeated cycles of
of histiocytes, myofibroblasts, plasma cells, polymerization induce a series of erythro-
and spindle-shaped mesenchymal cells. cyte abnormalities, including cytoplasmic
Inflammatory pseudotumor most often and membrane rigidity and cellular dehydra-
affects children and young adults, and it tion. Elevated blood viscosity and microvas-
can be found in pulmonary and extrapul- cular occlusion then develop. The clinical
monary locations, most commonly the features of the sickle cell syndromes include
abdomen. Despite its benign nature, it may chronic hemolytic anemia, frequent infec-
be difficult to differentiate from a malig- tions owing to loss of splenic function, and
nancy because of its local invasiveness and microvascular obstruction producing acute
its tendency to recur. Pulmonary pseudotu- and chronic anemia and organ damage from
mor is often encountered as an incidental infarction and fibrosis.174
finding in a chest radiograph. Patients with sickle cell anemia frequently
When a pseudotumor is symptomatic, experience acute pulmonary complications,
patients may present with nonspecific respi- such as asthma, thromboembolism, and acute
ratory symptoms, such as cough, shortness chest syndrome (ACS). Results of several
of breath, chest pain, hemoptysis, and club- studies suggest that asthma is a significant
bing. Laboratory findings consistent with contributing factor for acute pulmonary com-
inflammation are common. The etiologic plications, and 35% of children with SCD have
factors are not clearly established, although obstructive lung disease.175 Individuals with
an infectious cause is suspected. Although SCD seem to be at risk of thromboembolism
there are some anecdotal cases of spontane- because of a hypercoagulable state. The term
ous regression, the treatment of pulmonary “acute chest syndrome” reflects the difficulty
inflammatory pseudotumor is surgical. Local of establishing a definitive cause for these
recurrences are well described; for this rea- acute pulmonary episodes, particularly in dis-
son, an aggressive surgical resection at diag- tinguishing infection from pulmonary infarc-
nosis is always recommended.172,173 tion by microvascular occlusion (Fig. 7-7).
148 Pulmonary Manifestations of Pediatric Diseases


Figure 7-7. An 18-month-old

girl with hemoglobin SS disease
and respiratory distress. A-C, Rad-
iographs reflect the rapid pro-
gression typical of acute chest
syndrome at the time of admission
(A), 24 hours later (B), and 72 C
hours later (C).

Acute Chest Syndrome vated steady-state white blood cell counts.

Definition. ACS is a clinical pulmonary Patients with Hb SC disease also are at risk,
exacerbation of SCD manifested by fever; a although the incidence and frequency of
new infiltrate on chest radiograph; and one vaso-occlusive episodes, including ACS, is
or more pulmonary signs or symptoms, lower.178
such as cough, dyspnea, and chest pain.177 Etiology. The etiology of ACS is complex
As with pneumonias in children without and heterogeneous. In addition to the
SCD, the initial radiograph may not show expected intravascular pulmonary thrombo-
a new infiltrate. The most common present- sis, ACS is marked by the co-occurrence of
ing signs are fever, cough, tachypnea, infection, fat embolism (presumably from
crackles, and hypoxemia. Fever is more bone infarcts), hypoventilation, edema, and
common in children with ACS, and pain is reactive airway disease, and by secondary
more common in adults. ACS is the second problems of mucus hypersecretion and atelec-
leading reason for hospitalization (after tasis. Pulmonary infarction is the presumed
vaso-occlusive painful crisis) and the lead- cause in 16% of cases, and fat embolism is
ing cause of death in patients with SCD.176 the presumed cause in 9%. Because multiple
Sudden death in the setting of ACS may be etiologic factors are usually involved, the diag-
associated with acute exacerbations of pul- nostic label of ACS is strongly preferred to
monary hypertension. pneumonia. A specific cause of ACS can be
Epidemiology. Vaso-occlusive painful identified in 50% of the cases.
crisis and ACS are the most common sickle In children with SCD, infections are more
cell–related events during the first decade commonly documented, as are associated
of life. The risk of vaso-occlusive painful cri- bacteremias. An infectious etiology can be
sis and ACS begins in the first year and identified in one third of the patients; the
increases steadily; ACS is experienced by most common agents are viruses, such as
half of all patients with Hb SS disease by 6 respiratory syncytial virus, parvovirus, and
years of age. Of patients with sickle cell ane- rhinovirus, particularly during winter
mia (Hb SS) experiencing a first ACS, 25% months. These can be diagnosed through
have a recurrent event in 6 months. The risk the immunofluorescent assessment of nasal
is decreased with greater levels of fetal secretions or by serial measurements of spe-
hemoglobin (Hb F) and is increased with cific antibody titers. Atypical bacteria, such
the magnitude of the anemia and with ele- as Mycoplasma pneumoniae and Chlamydia
Chapter 7—Pulmonary Manifestations of Hematologic and Oncologic Diseases 149

pneumoniae, mostly cause bacterial infec- decrease after diagnosis, despite aggressive
tions. Pneumonia from these agents is more intervention. Hypoxia is common, but
severe in SCD than in normal children. In younger patients are less likely to require
the era of long-term antibiotic prophylaxis oxygen.174,177
and immunizations for Streptococcus pneu- Bronchoscopy and BAL provide adequate
moniae and Haemophilus influenzae, these material, and the diagnostic yield is high,
bacteria are less commonly responsible for but it is associated with risk of complica-
ACS than previously, and other causes such tions. The mean hospital stay is 10 days.
as community-acquired pneumonia have Adults are more likely to have complications
arisen.178 In 45% of the cases, an etiology during hospitalization; neurologic events
cannot be identified.177 occur in 10% of patients. The most com-
The vasculopathy of SCD progresses in mon is altered mental status, although cere-
the first years of life to render the spleen brovascular accidents also are common.177
incapable of performing its immune func- Pathogenesis. The pathogenesis of ACS
tions, including the generation of antibodies is the result of a complex series of reactions
to encapsulated organisms. In addition to involving activation of the endothelium,
this “functional asplenia,” there are abnor- often caused by an infection, and subsequent
malities of the complement defense system. adherence of sickle erythrocytes. This
Together, these deficits predispose patients, sequence of events leads to a partial obstruc-
especially children, to blood-borne infections tion of microcirculatory flow; prolonged
with encapsulated organisms. Antimicrobial transit allows extensive polymerization of
prophylaxis with penicillin and immuniza- Hb S with its resultant erythrocyte rigidity.
tion against these organisms (S. pneumoniae Trapping of poorly deformable sickle erythro-
and H. influenzae) are important strategies cytes results in transient or prolonged
to reduce episodes of bacterial sepsis and obstruction, ischemia, and further endothe-
recurrences of ACS. After age 6 months, lial activation.174 Various adhesive proteins
annual immunizations against influenza are expressed on the sickle erythrocyte mem-
recommended. brane interact with the corresponding mole-
Clinical Presentation. Nearly half of cules on the endothelial cell and are
patients with SCD are usually admitted with mediated by plasma ligands, such as throm-
a diagnosis other than ACS, usually a vaso- bospondin and von Willebrand factor.174
occlusive crisis; pain is a prodrome of ACS. Hb S polymerization generates reactive oxy-
The clinical presentation of ACS is similar to gen species, which activates the transcription
that of pneumonia. Cardinal features com- factor nuclear factor-kB, which upregulates
prise fever; a new infiltrate on radiograph; expression of the adhesion molecule
symptoms including cough, shortness of VCAM-1 on the endothelium, facilitating
breath, and chest pain; signs including erythrocyte adhesion.
tachypnea, crackles, and hypoxia; and pain, Granulocytes and monocytes also play an
including a greater frequency of chest, rib, important role in microvascular occlusion.
and abdominal pain in children, and a Additional vasoactive components also
greater frequency of extremity pain in adoles- may play a role in the ACS process.
cents and adults. The presenting chest ra- Endothelin is a potent vasoconstrictor of
diograph may be normal, as it may be with the pulmonary vascular bed, and its levels
clinical pneumonia, so a second radiograph are increased with hypoxemia. In patients
should be obtained as indicated by clinical with SCD, endothelin-1 levels are increased
suspicion. Multilobar involvement, espe- during the steady state, and increase sharply
cially of the lower lobes, and effusion are during the ACS. Nitric oxide, in addition to
present in two thirds of patients. Upper and providing vasodilation of the pulmonary
middle lobe involvement is more common vasculature, downregulates VCAM-1 and
in children, and isolated lower lobe involve- inhibits the adherence of normal sickle ery-
ment is more common in adults.177,178 throcytes to vascular endothelium.174
Abnormalities seen on radiographs tend Treatment. In the management of ACS,
to progress. Oxygenation and hemoglobin clinicians need to consider the evolving
150 Pulmonary Manifestations of Pediatric Diseases

nature of the ACS. Most patients present development of ACS and pulmonary hyper-
with pain or develop pain during admission, tension.181 The concurrent association of
and in many instances, chest pain may reactive airway disease and ACS is associated
result in hypoventilation, atelectasis, or with more severe exacerbation and prolonged
pneumonia. Incentive spirometry must be hospitalization. Reactive airway disease is
started early and be aggressively imple- associated with the release of a wider variety
mented. A judicious use of opioid analgesics of inflammatory mediators and cytokines
must be implemented early in management. than with ACS alone, and is associated with
Dehydration predisposes to vaso-occlusive airway edema and mucus hypersecretion, fac-
painful crisis and ACS, and commonly fol- tors known to worsen the course of ACS.
lows episodes of fever, tachypnea, or Treatment of reactive airway disease
anorexia. Aggressive rehydration is always exacerbations in the context of ACS is simi-
indicated in the management of vaso-occlu- lar to standard acute asthma care. There is a
sive crises. Rehydration is often accom- theoretical basis for steroid use because acti-
plished by the administration of fluids at a vation of the inflammatory cascade plays a
rate of 1.5 times maintenance, which is central role in ACS; however, its role is still
reduced to maintenance when the patient is unclear. A short course of steroids may
normovolemic. Overhydration should be reduce the length of hospitalization in chil-
avoided because pulmonary edema and wors- dren and the need for analgesics and oxygen
ening of the disease process might ensue. supplementation, but a rebound effect may
Empiric antibiotic therapy always must occur.179 Bronchoscopy is recommended
include a combination of a macrolide and a when patients do not respond to initial ther-
second-generation cephalosporin. Vancomy- apy. Aggressive mechanical ventilatory sup-
cin also is recommended if fever persists, and port, including extracorporeal membrane
there is history of infection with penicillin- oxygenation, may be necessary; nitric oxide
resistant S. pneumoniae, or if the patient resides also may be used.174,176,180
in an area with a high prevalence of resistance Secondary Complications. As with
of this organism. Oxygen supplementation community-acquired pneumonias, ACS is
also is indicated for decreases in pulse oxime- frequently associated with atelectasis or
try greater than 4% over baseline, or for values pleural effusions or both. The pleural fluid
less than 92%. is usually sterile and exudative, but may
Oxygenation significantly improves with develop empyema. The atelectasis may or
simple blood transfusion and exchange trans- may not be associated with retained airway
fusion. Early transfusions are indicated for mucus secretions. In some cases, the mucus
patients at high risk of complications; patients strings are extensive and dehydrated and
presenting with severe anemia, thrombocyto- may form bronchial casts. Because of their
penia, and multilobar pneumonia should firmness, the syndrome has been referred
receive a transfusion even before respiratory to as plastic bronchitis. In these cases, fiber-
distress develops. A post-transfusion increase optic bronchoscopy with washes of saline,
in hemoglobin levels greater than 11 g/dL DNase, or N-acetyl cysteine may be useful
must be avoided, however, because of the risk in clearing the airway obstruction and expe-
of sudden increase in blood viscosity that diting the resolution of the atelectasis.
could lead to thrombosis and ischemic epi-
sodes. Exchange transfusion is indicated if Chronic Sickle Cell Lung Disease
the patient’s baseline hemoglobin is elevated, Chronic sickle lung disease is a progressive dis-
or the patient has more severe disease, wors- order that is insidious in onset during child-
ening hypoxemia, neurologic abnormalities, hood and may be asymptomatic in the
or multiorgan failure. absence of frequent exacerbations of ACS.
Evidence is mounting that reactive airway The end stage of progression is characterized
disease may play a role as a cause and as a con- by persistent hypoxemia, radiographic evi-
sequence of ACS.174 Reactive airway disease dence of interstitial fibrosis, restrictive lung
may occur in almost half of SCD patients, disease on pulmonary function testing, pul-
and seems to be a risk factor for the monary hypertension, and cor pulmonale.
Chapter 7—Pulmonary Manifestations of Hematologic and Oncologic Diseases 151

Pulmonary hypertension in patients with Much of the improved quality of life and
SCD has been associated with worsened sur- survival of patients with SCD is attributed
vival. Close pulmonary and cardiac follow- to the details of preventive health care.
up are essential to monitor the progression of Because the spleen is a victim of sickle cell
chronic sickle lung disease. vasculopathy in the first few years of life
(functional asplenia), functional immunity
Pulmonary Hypertension to encapsulated organisms is impaired, and
The obliterative vasculopathy of pulmonary the risk for sepsis from these organisms is
hypertension is evident in one third of post- increased. Protective strategies include peni-
mortem studies of patients with SCD, but cillin prophylaxis and immunizations to
the true prevalence is unknown. This disor- S. pneumoniae and H. influenzae. Penicillin
der is most frequently recognized in adults, (or erythromycin) is administered twice
but almost certainly originates earlier in daily from early infancy to age 5 years in
childhood. Although a worsened prognosis children with the more severe hemoglobi-
for chronic sickle lung disease and pulmo- nopathies (Hb SS and Hb S/b0 thalassemia)
nary hypertension is associated with recur- and through age 3 years in children with
rent episodes of ACS, the prevalence of less severe variants of SCD, such as Hb SC.
pulmonary hypertension also is high in Prophylactic antibiotics are given perma-
patients without a history of ACS. nently to patients who have undergone
This pathophysiologic predisposition is splenectomy or have experienced pneumo-
related to the combination of hemolytic ane- coccal sepsis. The 7-valent pneumococcal
mia and “functional asplenia.”181 Hemolysis vaccine is administered to infants beginning
in combination with inadequate splenic clear- at 2 months of age with four doses adminis-
ance results in the accumulation of iron-rich tered by the age of 15 months, and the
hemoglobin, which functions as a scavenger 23-valent vaccine is administered at ages
of nitric oxide and catalyzes the formation of 2 and 5 years and then every 5 to 7 years
oxygen radical species. Arginase is simulta- thereafter. The usual childhood schedule is
neously released from erythrocytes and serves followed for H. influenzae type B immuniza-
to limit the supply of arginine to nitric oxide tions. Immunizations to influenza virus are
synthase, limiting the synthesis of nitric administered annually after age 6 months.
oxide. The nitric oxide serves a crucial func- The usual childhood immunization sched-
tion in promoting pulmonary vasodilation ule for hepatitis B is emphasized to prevent
and limiting the impact of many factors this potential complication of recurrent red
contributing to the vascular remodeling of blood cell transfusions.
pulmonary hypertension. The functional Therapies to correct the basic genetic or b
asplenia contributes to the remodeling by globin protein defect of SCD and therapies
the failure to clear platelet-derived mediators to prevent the progression of SCD do not
and cytokines that promote adherence of ery- yet exist. The major current therapeutic
throcytes to the endothelium and cause strategies are designed to reduce the propor-
microthrombosis. tion of erythrocytes carrying predominantly
The diagnosis of pulmonary hypertension sickle hemoglobin (Hb S) and to delay the
in SCD is ominous, with a 10-fold increase in progression of pulmonary hypertension.
the risk for death and survival less than 50% Of all the new therapies for treating SCD,
within 4 years. The more recent validation of hydroxyurea is the most promising. Several
echocardiography as a diagnostic tool for pul- pediatric and adult trials have reported
monary hypertension in SCD should promote decreases in pain, the incidence of ACS,
earlier detection. Several studies have sug- and overall mortality.181 Hydroxyurea ther-
gested the potential role for oxygen therapy, apy was initiated because of the drug’s abil-
red blood cell transfusions, inhaled nitric ity to increase Hb F production. This
oxide, intravenous arginine, prostacyclin, increase in Hb F and a concomitant increase
and the newer vasodilators. Controlled long- in red blood cell volume effectively reduce
term studies are needed to determine the the intracellular concentration of Hb S and
effectiveness of these and other therapies.183 result in decreased sickling. Hydroxyurea
152 Pulmonary Manifestations of Pediatric Diseases

has other beneficial effects, including a Histiocytic Disorders of the Lung

decrease in neutrophils and monocytes
(intervening in the inflammatory cascade), The histiocytoses are a group of rare hemato-
an increase in red blood cell deformability, poietic disorders characterized by the clonal
and a decrease in the adhesive receptors in proliferation and pathologic accumulation
the erythrocyte membrane.181 Trials of of cells of the mononuclear-phagocyte system
increasing length of hydroxyurea therapy in tissues. The mononuclear-phagocyte sys-
in adults and children have shown safety tem is a system of cells whose primary func-
and clinical efficacy, including a reduction tions consist of phagocytosis of foreign
in the incidence of ACS.181 material, antigen processing, and antigen
Other options include therapy with eryth- presentation to lymphocytes. Mononuclear
ropoietin to increase Hb F, but its effective- phagocytes are subclassified into two major
ness has been suboptimal. Because of this classes, macrophages and dendritic cells,
and its substantial expense, use of erythro- based on morphologic and functional charac-
poietin has been limited. Its primary use is teristics. The most common pulmonary
as adjunctive therapy for patients whose phagocytes are the alveolar and the airway
response to hydroxyurea is suboptimal or macrophages. They are indistinguishable
for patients with religious objections to except for their location within the respira-
blood transfusions. tory tract. These cells are primarily responsible
Transfusion therapy of normal erythro- for the sequestering and disposal of inhaled
cytes serves to depress the bone marrow pro- particles and pulmonary surfactant. They play
duction of erythrocytes expressing sickle an active role in the maintenance and remod-
hemoglobin.182 The timing of transfusion eling of the extracellular connective tissue
may be acute, intermittent, or chronic. matrix through the secretion of cytokines that
Adverse effects of recurrent transfusions regulate matrix production and degradation.
include iron overload, blood-borne infec- Interstitial macrophages are the second group
tions, and alloimmunization, complications of pulmonary macrophages with an improved
that can be reduced by erythrocytopheresis, antigen-presenting capability. The second
highly specific crossmatching, and the class of mononuclear phagocytes, the den-
newer iron-chelating agents. Current indica- dritic cells, consist of dendritic cells of the
tions for red blood cell transfusion therapy lymphoid follicle and Langerhans cells of the
in SCD include severe cases of vaso-occlu- skin and other organs.
sive painful crisis, recurrent or severe ACS, The histiocytic disorders can be classified
severe or worsening anemia, and primary into three classes based on the pathologic cells
and secondary stroke prevention in patients present within the lesions: class I, dendritic
at increased risk. cell histiocytosis; class II, non-dendritic cell
Because of the potentially serious complica- histiocytosis, and class III, malignant histiocy-
tions of bone marrow transplantation, in the tosis. The rest of this discussion is dedicated to
United States it is offered primarily to patients the pathophysiology, clinical presentation,
who have had serious complications, such as diagnosis, and treatment of Langerhans cell
stroke or recurrent ACS, and to patients with histiocytosis (LCH) and histiocytic disorders
HLA-matched sibling donors. Its greatest involving the lung.
benefit is, however, to patients who have nei- LCH is the most common of the dendritic
ther experienced significant complications cell histiocytoses. It is a proliferative disorder
nor developed significant chronic sickle lung of activated Langerhans cells and is character-
disease. ized by variable biologic behavior and a spec-
Efforts to develop effective gene therapy trum of distinct clinical presentations.184 The
or b globin substitution have failed so far. pathogenesis of LCH is poorly understood.
The primary impediment has been the Because LCH has been shown to be a mono-
development of a vector suitable for the clonal condition, it has been considered a
delivery of the replacement of b globin neoplastic disorder.185,186 Different patterns
DNA to bone marrow precursors. of clinical involvement indicate other
Chapter 7—Pulmonary Manifestations of Hematologic and Oncologic Diseases 153

pathogenetic mechanisms, however. The

benign histopathologic appearance of the
lesions, the occurrence of spontaneous remis-
sions,187 and the ability to respond to immu-
nomodulation188 suggest a reactive clonal
disorder, rather than a malignant process, at
least in some cases. Langerhans cells, similar
to other dendritic cells, have a crucial role in
the immune system, and it has been suggested
that LCH could be the result of immune dys-
regulation. Although no consistent immuno-
logic abnormalities have been described,
there is increasing evidence that LCH may be A
the result of an uncontrolled and abnormal
proliferation of Langerhans cells secondary
to immune dysregulation or after exposure
to an as-yet-undetermined stimulus.189,190
The diagnosis of LCH requires a biopsy
with the specimen showing typical patho-
logic features of Langerhans cell infiltrates
and confirmatory positive staining for
CD1a and S-100. Alternatively, the demon-
stration of Birbeck granules by electron
microscopy has been used for confirmation
of this diagnosis. The diagnosis of pulmo-
nary LCH in children with multisystem dis-
ease is usually clinical because the histologic
diagnosis is usually made from extrapul- Figure 7-8. Pulmonary involvement in Langerhans cell
monary lesions. In the rare cases of isolated histiocytosis (LCH). A, CT scan shows acute changes in an
infant with newly diagnosed LCH and multisystem involve-
lung disease, a morphologic confirmation ment. Multiple small nodular opacities and cystic changes
is required, and it can be obtained by lung are seen. Also note enlarged thymus with calcifications. B,
biopsy or by BAL. In the latter case, the pres- CT scan of a 6-year-old boy shows chronic fibrosis, air
trapping, and bullous disease. This child received treatment
ence of greater than 5% of CD1a-positive for LCH and had lung involvement during infancy.
cells in the BAL fluid is very suggestive of
LCH. BAL also is a good tool for monitoring LCH includes diffuse skin involvement and
response and follow-up.191 involvement of multiple bones. The oral cav-
The histopathology of the lesion is ity; lymph nodes; and, to a lesser extent,
uniform, regardless of the clinical severity lungs, liver, and brain are common sites of
of the disease. It consists of collections of involvement in this disease. Lung involve-
Langerhans cells, interdigitating cells, and ment has been reported to occur in 20% to
macrophages, accompanied by T lympho- 50% of patients with multisystem disease.
cytes with variable numbers of multinucle- Radiographic changes consistent with past
ated giant histiocytes and eosinophils.192 lung involvement are present in 15% to
In light of the pathologic basis of the diag- 20% of long-term survivors (Fig. 7-8A).193,194
nosis of LCH and the variable nature of clini-
cal presentations, LCH is now subclassified Primary Pulmonary Langerhans Cell
by the degree of organ involvement: loca- Histiocytosis
lized single-system disease, multifocal sin- Primary pulmonary LCH is a disorder that
gle-system disease, and multisystem disease. most frequently affects young white adults
Localized LCH, involving skin, lymph node, with an equal sex distribution. LCH in this
or bones, usually has a good prognosis. The age group is epidemiologically associated with
most common presentation of multifocal cigarette smoking; greater than 90% of patients
154 Pulmonary Manifestations of Pediatric Diseases

have a history of smoking, and the disease usu- involving the middle and upper lobes, sym-
ally responds to smoking cessation, although metrically. As the disease progresses, nodular
systemic chemotherapy also may be needed. lesions are less frequent, and cystic changes
An important defining factor is that, in adult are much more prominent, progressing to
cases, Langerhans cell proliferation in primary the appearance of honeycombing and
pulmonary LCH is usually not clonal; this advanced emphysema. Early changes are best
finding is in contrast to that associated with seen in high-resolution CT scans. The combi-
childhood LCH.195 Although primary pulmo- nation of diffuse cystic changes with small
nary LCH can occur at any age, it is rarely seen peribronchial nodular opacities on CT is
in patients younger than 15 years. Pulmonary highly suggestive of LCH.193-195
involvement as part of systemic LCH is a com- Treatment of pulmonary LCH in children
mon feature of multisystem LCH, however, needs to be discussed in the context of the
seen in one third of patients. degree of involvement of other organs. Lung
The pathogenesis underlying primary pul- involvement is considered a poor prognostic
monary LCH, similar to systemic LCH, is feature, however, so these patients need to be
not well defined, but thought to be the treated aggressively, usually with combina-
result of an abnormal immune reaction to tion chemotherapy, for approximately 12
an irritant (i.e., smoke). Primary pulmonary months. Different regimens have proven to
LCH is mostly seen in the third or fourth be effective, and different combinations of
decade of life. Twenty percent to 25% of prednisone, vinblastine, etoposide, mercap-
patients are asymptomatic at the time of topurine, and methotrexate have been
diagnosis, with the disease being detected used.193,194 The optimal therapy for primary
on a screening chest radiograph. Respiratory pulmonary LCH remains undefined. Smoking
symptoms may include chronic cough and cessation is the most important component of
dyspnea and, more rarely, hemoptysis or therapy. Successful smoking cessation, com-
chest pain. Chest pain may be due to pneu- bined with use of oral corticosteroids, usually
mothoraces or rib lesions. results in remission. In cases refractory to cor-
Histopathologically, primary pulmonary ticosteroids, systemic chemotherapy may be
LCH begins as a proliferation of Langerhans required.195
cells along the small airways. These cellular
lesions expand to form nodules that can mea-
sure 1.5 cm. These nodules include a mixed Complications of Treatment
population of cells with variable numbers of of Hematologic and
CD1a-positive Langerhans cells, eosinophils, Oncologic Disorders
lymphocytes, plasma cells, and fibroblasts.
There is progression from cellular nodules to Hematopoietic Stem Cell
fibrosis, leading to a distinctive honeycomb- Transplantation
like pattern and hyperinflation (Fig. 7-8B).
In later stages, fibrosis is the predominant Hematopoietic stem cell transplantation
feature, and Langerhans cells are absent from (HSCT) has been used as a lifesaving proce-
the lesions.195 dure in children who have many malignant
Clinically, acute lung involvement occurs hematologic, immunologic, and inherited
in the context of multisystem disease. Patients metabolic diseases. Allogeneic and autolo-
usually present during the first 2 years of life, gous HSCTs are increasingly used. Pulmonary
with involvement of multiple systems, such complications depend on various factors,
as the bones, skin, lymph nodes, liver, spleen, including pretransplant intensive chemo-
and hematopoietic system.193 Children most therapy combined with radiation therapy,
commonly develop nonproductive cough and post-transplant infectious and noninfec-
and dyspnea. Early in the disease, the chest tious complications. These complications
radiograph shows micronodular or reticulo- have been well studied in adults. The pediat-
nodular and interstitial infiltrates, with su- ric experience is limited, but includes the
perimposed cystic changes predominantly same respiratory complications.
Chapter 7—Pulmonary Manifestations of Hematologic and Oncologic Diseases 155

In one retrospective analysis, severe pul- microbiologic results that exclude pulmonary
monary complications occurred in 17 of infection. Risk factors for the development of
138 patients, leading to death in 8 (7%) DAH include intensive conditioning chemo-
patients.196 Three important post-HSCT therapy, radiation toxicity, solid malignancy,
periods can be identified for lung compli- and age older than 40 years. Early diagnosis
cations: the first month post-transplant, of DAH and prompt intervention are crucial.
which is characterized by neutropenia; the High doses of corticosteroids may improve
second month, in which idiopathic pneu- survival and reduce the development of
monia syndrome can develop; and the late subsequent respiratory failure201; however,
phase, after the third month, which is the prognosis for DAH is very poor.
characterized by late-onset noninfectious
pulmonary complications. Second Phase
Between the first and third months post-
First Phase transplant, as the neutropenia resolves, idio-
The phase that precedes engraftment is typi- pathic pneumonitis syndrome (IPS) may
cally characterized by prolonged neutropenia develop. The diagnosis of IPS is made by
and disruption of the mucosal barrier. The exclusion of other causes, including infec-
combination of neutropenia and mucositis tious.202 The incidence of IPS after allogeneic
predisposes patients to infectious pulmonary HSCT in adult patients is approximately 10%
complications. Noninfectious complications to 15%, and the median time from trans-
(pulmonary edema, diffuse alveolar hemor- plantation is approximately 45 days.203 The
rhage) also may occur. histologic patterns of IPS are interstitial pneu-
Pulmonary edema usually occurs in the sec- monitis and diffuse alveolar damage.203 The
ond or third week after HSCT.197 The exact usual presenting symptoms include dyspnea,
incidence is unknown, but it is a common nonproductive cough, fever, hypoxemia, and
problem. Patients present with acute onset of diffuse pulmonary infiltrates. The risk factor
dyspnea and clinical findings that include for the development of IPS includes allogeneic
weight gain of rapid onset, bilateral pulmo- HSCT, high-dose radiation, increasing age,
nary crackles, and hypoxemia. The chest chronic myelogenous leukemia, previous
radiograph shows mild to severe vascular splenectomy, and graft-versus-host disease
redistribution and bilateral interstitial infil- (GVHD). There is no proven effective treat-
trates, with or without pleural effusion. These ment for IPS after HSCT, although corticoster-
findings are indistinguishable from other oids may be helpful in some patients. The
causes of cardiogenic and noncardiogenic pul- prognosis is poor.
monary edema. Overzealous hydration, blood Pulmonary complications occurring after
transfusion, and renal and cardiac insuffi- the third month post-transplant are usually
ciency from chemotherapy can contribute to due to chronic GVHD.205 The incidence of
the development of pulmonary edema.198 late-onset noninfectious pulmonary compli-
The management of post-HSCT pulmonary cations after HSCT has been reported to be
edema is similar to the management of pul- 10% to 23%.206,207 The only significant vari-
monary edema resulting from other causes. ables associated with such complications
Diffuse alveolar hemorrhage (DAH), a seri- were chronic GVHD and complications of
ous post-HSCT complication, usually occurs GVHD therapy. These obstructive or restric-
in the second and third week after transplan- tive pulmonary complications include bron-
tation.199 DAH has been reported in 5% of all chiolitis obliterans, cryptogenic organizing
patients who have undergone HSCT, and is pneumonia (COP), and toxicity syndrome.
more frequent in autologous HSCT recipi- Bronchiolitis obliterans, an obstructive
ents.200 DAH is characterized by dyspnea of pulmonary disease, affects the small airways
sudden onset, nonproductive cough, fever, and was first described as a late complica-
and hypoxemia; hemoptysis is rare. Chest tion of allogeneic HSCT, mostly in long-
radiograph abnormalities include bilateral term survivors who have chronic GVHD,
interstitial infiltrates. The diagnosis is made although it can occur at any time. The inci-
by BAL that shows a hemorrhagic fluid and dence of bronchiolitis obliterans has been
156 Pulmonary Manifestations of Pediatric Diseases

reported to be 2% to 14% in allogeneic HSCT radiographs are characterized by the presence

recipients who survive longer than 3 months of patchy pulmonary infiltrates in multiple
post-transplant.208 The cause is unknown. lobes. Bronchiolitis obliterans manifests with
An immunologic mechanism that includes hyperlucency. High-resolution CT shows
injury of the bronchial epithelia has been patchy consolidation, particularly with peri-
suggested, but other causes, such as viral in- bronchovascular or peripheral distribution
fections, also have been postulated. The in immunocompetent patients, in whom
pathogenesis is likely to be multifactorial.209 ground-glass attenuation and nodules are
Patients generally present with dyspnea, more frequent.211 Risk factors for COP
wheezing, and nonproductive cough. Chest include being the recipient of an allogeneic
radiograph findings may be minimal with HSCT and the development of GVHD. Corti-
occasional evidence of hyperinflation. High- costeroids are effective in 60% of patients
resolution CT scan of the chest shows bron- with COP, but infections should be carefully
chial wall thickening, peripheral vascular ruled out before initiating treatment with
pruning, and mosaic lung attenuation with corticosteroids.206
air trapping on expiratory scan.210 Recipients of autologous transplants who
Airflow obstruction is the hallmark of receive high-dose chemotherapy or radiother-
bronchiolitis obliterans. A reduction in the apy as conditioning for HSCT may experience
ratio of forced expiratory volume in 1 second pulmonary toxicity months to years after the
to forced vital capacity is commonly present transplantation procedure.212 Drug-induced
in patients with GVHD. An obstructive lung and radiation-induced lung toxicity is de-
disease pattern and the lack of response to scribed in greater detail subsequently. Pulmo-
bronchodilators form a sufficient basis for nary complications are important causes of
making a diagnosis of bronchiolitis obliter- morbidity and mortality. Chest radiographic
ans. Although open lung biopsy is required changes are nonspecific. High-resolution CT
to confirm the diagnosis of bronchiolitis of the chest increases the detection of pulmo-
obliterans, it is seldom needed in practice. nary abnormalities, even when results of chest
The diagnosis of bronchiolitis obliterans can radiographs are normal, and it can help in
be made based on clinical criteria, pulmonary establishing the diagnosis. It also is helpful
function test abnormalities, and high-resolu- in guiding lung biopsy.
tion CT scan without open lung biopsy. The
treatment consists of increasing immuno-
suppression, usually with prednisone and Transfusion-Related Acute Lung
other agents such as cyclosporine or azathio- Injury
prine. Bronchiolitis obliterans is often pro-
gressive and unresponsive to therapy. A Although uncommon, transfusion-related
rapid deterioration, as shown on pulmonary acute lung injury (TRALI) has been increas-
function test, and severe obstruction (forced ingly recognized as the leading cause of trans-
expiratory volume in 1 second <45%) are fusion-related death in the United States; its
associated with poor prognosis. development is associated with 1 in 5000 U
COP is a common late complication; in of transfused blood products.213 Patients in
most cases, the exact etiology is unknown. whom acute onset of bilateral chest infiltrates
COP was formerly known as “bronchiolitis develops during or within 6 hours of the com-
obliterans with organizing pneumonia.” This pletion of transfusion of plasma-containing
condition differs from that of bronchiolitis blood products should be evaluated for this
obliterans. The histologic changes associated condition. In most cases, signs of respiratory
with COP are proliferative bronchiolitis and distress develop within the first 1 to 2 hours
alveolitis, which affect the distal airways. after the transfusion is started. Affected
Patients with COP have a characteristically patients usually have hypoxemia (PaO2/FIO2
restrictive pattern on pulmonary function <300 mm Hg) and diffuse lung infiltrates on
tests. Patients with COP have nonproductive the chest x-ray suggestive of noncardiogenic
cough, low-grade fever, and dyspnea. Chest pulmonary edema.214,215
Chapter 7—Pulmonary Manifestations of Hematologic and Oncologic Diseases 157

Blood products implicated in TRALI include normal or decreased pulmonary artery wedge
whole blood, red blood cells, platelet transfu- pressure and left atrial pressure, although these
sions (including platelet concentrates and are rarely measured in children.
plateletpheresis), fresh frozen plasma, and The pathophysiology of TRALI is not well
cryoprecipitate.216 Although less common, understood. Two hypotheses have been postu-
intravenous immunoglobulin preparations lated. The first one tries to explain TRALI as an
also have been implicated in TRALI.216 The antibody-mediated event.221 These antibodies
condition has been reported predominantly may bind to the corresponding HLA epitopes
in patients with cancer or other hematologic on the lung endothelium, resulting in capil-
diseases such as SCD and in patients under- lary leak and cell damage.222 Alternatively,
going solid organ or stem cell transplanta- some authors hypothesize that a two-event
tion.214 Other, less common settings where model may explain the occurrence of TRALI.
this adverse transfusion reaction may occur The first event would be host-related predis-
are complement-mediated hemolysis in par- posing factors, such as the ones described pre-
oxysmal nocturnal hemoglobinuria and lung viously, leading to lung sequestration of
damage associated with granulocyte transfu- polymorphonuclear neutrophils.222 The sec-
sions.214 Because pulmonary infiltrates may ond event includes the infusion of chemical
result from various causes, establishing the mediators, including antibodies against poly-
diagnosis of TRALI may be difficult. The differ- morphonuclear neutrophils, HLA, or cyto-
ential diagnosis includes ACS in sickle cell kines.222 Soluble CD40 (a member of the
anemia, infections, diffuse alveolar damage tumor necrosis factor family of receptors)
after bone marrow recovery, and lung hemor- ligands have been reported to accumulate in
rhage. Patients with TRALI often improve stored blood components, leading to priming
within 48 to 72 hours of onset, but occasional of CD40-dependent granulocyte activation,
patients die of acute respiratory failure. which ultimately may cause lung injury.223
TRALI is more common in adults; however, The management of TRALI is largely sup-
several well-documented pediatric cases have portive.214 Oxygen supplementation and
been reported. Neonates, who seem to be pro- occasional mechanical ventilation should be
tected from TRALI, may develop leukopenia provided. It is important that clinicians be
as a complication of transfusion, but not pul- aware of this potential complication because
monary problems.214,217,218 Pediatric oncol- patients usually do well without long-term
ogy patients require frequent and repeated sequelae, if they survive the initial insult.
transfusions, so it is not surprising that TRALI The blood bank also should be informed of
has been more frequently reported in this this complication to avoid repeated exposure
population.217 of the recipient to the same donor-derived
No single test can reliably help make the blood products, and if possible, the blood
diagnosis of TRALI, but some clinical clues bank can perform anti-HLA antibody detec-
may be helpful. Patients with TRALI often tion. These tests are expensive, however, and
present with fever, chills, and hypotension. are not available in many blood banks. If
Such patients often have transient leukopenia respiratory distress occurs during transfusion,
that resolves within a few hours; this condition the transfusion should be stopped immedi-
may be helpful in making a diagnosis.219 A ately. Preventing TRALI is a challenge because
complete blood cell count should be obtained no test is reliable enough to predict this poten-
in every case in which TRALI is suspected. In tial complication.
patients requiring ventilatory support, a bron- An increased awareness of this complica-
chial sample to measure the protein level tion may improve the knowledge of its clinical
should be obtained within 15 minutes of intu- and pathophysiologic features. At present,
bation to be reliable.220 An edema fluid pro- TRALI can be diagnosed only by excluding
tein-to-plasma protein ratio greater than 0.6 other causes, however. TRALI should be in-
is highly suggestive of TRALI. Ratios less than cluded in the differential diagnosis of acute
0.6 may indicate a cardiac source of pulmonary pulmonary problems in pediatric oncology
edema.220 Patients with TRALI also have patients.
158 Pulmonary Manifestations of Pediatric Diseases

Chemotherapy-Induced Lung nervous system-mediated mechanisms seem

Toxicity to play a role in the toxicity of certain agents.
Identified risk factors include patient age,
Numerous drugs can cause pulmonary or cumulative dose, prior or concurrent radia-
pleural reactions in children. The most com- tion, oxygen therapy, and use of other toxic
mon offenders are certain chemotherapeutic drugs. Most reactions to noncytotoxic drugs
agents used in pediatric oncology (Table 7-1). seem to develop idiosyncratically. When
Other agents with lung toxicity are increas- patients are treated with several potentially
ingly reported (Table 7-2). Diffuse interstitial toxic drugs or with a toxic drug plus irradia-
pneumonitis and fibrosis constitute the most tion to the chest or high oxygen concentra-
frequent clinical presentation. Hypersensi- tion, specific offenders cannot be identified.
tivity lung disease, noncardiogenic pulmo- There is little, if any, evidence that children
nary edema, pleural effusion, bronchiolitis are more susceptible to drug-related lung
obliterans, and alveolar hemorrhage also are injury, and they may be less susceptible to
encountered. some agents, such as bleomycin.
Although some drug-induced pulmonary Although better identification of chemo-
damage is reversible, persistent and even fatal therapy-induced lung toxicity has led to a
dysfunction may occur. Lung reactions occa- more judicious use of agents that might
sionally are temporarily remote from expo- cause lung toxicity, the widespread use of
sure to chemotherapeutic agents. Depending higher dose chemotherapy regimens preced-
on the agent involved, the reaction may or ing stem cell rescue has improved the
not be dose-related. The mechanism of toxic- chances of survival of high-risk patients
ity is thought to be direct injury to lung cells who receive a high cumulative dose of che-
in most cases, but immunologic and central motherapy and radiotherapy, and who have

Table 7-1 Lung Toxicity Associated with Chemotherapeutic Agents Used in Pediatric Oncology

Bleomycin Hodgkin disease Oxidative effect Most common cause of pulmonary
Germ cell tumors Release of proteases Dose-related acute and chronic
lung toxicity
Busulfan Bone marrow Direct toxicity Late-onset pulmonary fibrosis
transplantation Radiation may increase toxicity
Carmustine Bone marrow Oxidative damage Same as bleomycin
Cyclophosphamide Widely used in several Oxidative damage Lung toxicity is uncommon
malignancies Usually subacute
Methotrexate Hematologic Hypersensitivity Mild and reversible
malignancies or direct effect hypersensitivity lung toxicity
Osteogenic sarcoma Not related to cumulative dose
Cytarabine Hematologic Not well studied Capillary leak syndrome
malignancies BO associated with higher doses
Melphalan Bone marrow Similar to busulfan Similar to busulfan
Fludarabine Acute myelogenous Not well studied Interstitial pneumonia reported
leukemia in adults
Bone marrow

BO, bronchiolitis obliterans.

Data from references 224-229, 237, 238, 242.
Chapter 7—Pulmonary Manifestations of Hematologic and Oncologic Diseases 159

Table 7-2 Newer Agents Used in Pediatric Cancer Treatment Associated with Lung Toxicity


Rituximab Lymphoma, post-transplant Acute-onset interstitial pneumonia, lung fibrosis
lymphoproliferative disease
Imatinib Chronic myelogenous leukemia Rare cases of interstitial pneumonia
Filgrastim Various diseases, bone marrow Pleural effusion and noncardiogenic pulmonary
(G-CSF) transplantation edema and ARDS
Trans- Acute promyelocytic leukemia Diffuse pulmonary infiltrates in the setting
retinoic of retinoic acid syndrome

ARDS, acute respiratory distress syndrome; G-CSF, granulocyte colony-stimulating factor.

Data from references 224, 226, 242-245.

a history of opportunistic infection. This These include (1) no other likely cause of
new generation of heavily pretreated survi- lung disease, (2) symptoms consistent with
vors constitutes a high-risk population for the suspected drug, (3) time course compat-
long-term toxicity, including lung toxicity. ible with drug-induced lung disease, (4)
The clinical manifestations of drug-induced compatible tissue or BAL findings, and (5)
lung disease include fever, malaise, dyspnea, improvement after the drug is discontinued.
and a nonproductive cough. Radiologic stud-
ies almost always show diffuse alveolar or Cytotoxic Drugs
interstitial infiltrates, or both. Segmental or Antibiotics—Bleomycin. Bleomycin has
lobar disease, particularly if unilateral, should been consistently associated with lung tox-
suggest another diagnosis. A restrictive lung icity, especially lung fibrosis, in children
pattern in pulmonary function testing may and adults.227 Although the drug is active
be found before the appearance of radio- against squamous cell carcinoma and germ
graphic lesions. CT of the chest also may reveal cell tumors, its major use in children is in
early evidence of parenchymal abnormalities. the treatment of HD and other lympho-
Hypoxemia is an early and clinically im- mas.231,232 Because of the high frequency
portant functional manifestation. Patho- of lung reactions and the utility of bleomy-
logic changes do not distinguish among most cin for generating animal models of lung
drugs and most often consist of interstitial fibrosis,230 this drug has been studied more
thickening with chronic inflammatory cell thoroughly than others. Bleomycin can
infiltrate in the interstitial or alveolar compart- cause early-onset and late-onset lung
ment, fibroblast proliferation, fibrosis, and injury.227 Late-onset lung injury, which is
hyperplasia of type II pneumocytes. With initially characterized by interstitial pneu-
hypersensitivity reactions, the interstitial infil- monitis potentially leading to pulmonary
trate includes numerous eosinophils. fibrosis, is the most common effect and
The manifestations of drug-induced lung may occur several months or years after
toxicity are usually nonspecific, and so estab- exposure to the drug. Early bleomycin toxic-
lishing a definitive diagnosis may be difficult. ity usually manifests as an acute hypersensi-
Other diagnoses, such as infection, pulmo- tivity reaction.227
nary hemorrhage, lung disease related to an Lung injury secondary to bleomycin
underlying disorder, and radiation damage, occurs in approximately 4% to 7% of all
must be considered in the differential diagno- patients receiving the drug,227 although the
sis. BAL is being increasingly done to provide reported incidence is 40%. The frequency of
microbiologic and cytologic information rea