ERS Handbook of Paediatric Respiratory Medicine - E. Eber, F Midulla

handbook
handbook Paediatric Respiratory Medicine

The 18 chapters of the ERS Handbook of Paediatric
Respiratory Medicine cover the whole spectrum
of paediatric respiratory medicine, from anatomy
and development to disease, rehabilitation and Paediatric
treatment. The Editors have brought together
leading clinicians to produce a thorough and easy-
to-read reference tool. The Handbook is structured
to accompany the paediatric HERMES syllabus,
Respiratory
making it an essential resource for anyone
interested in this field and an ideal educational
training guide.
Medicine
Ernst Eber is a Professor of Paediatrics and Head
of the Respiratory and Allergic Disease Division in
Editors
the Department of Paediatrics and Adolescence Ernst Eber
Medicine at the Medical University of Graz, and is
also Head of the ERS Paediatric Assembly. Fabio Midulla
Fabio Midulla is an Assistant Professor and
Director of the Paediatric Emergency Department,
Policlinico Umberto I. Sapienza University of
Rome, and is Secretary of the ERS Paediatric
Assembly.
handbook
Paediatric
Respiratory
Medicine
1st Edition
Editors
Ernst Eber
and Fabio Midulla
PUBLISHED BY
THE EUROPEAN RESPIRATORY SOCIETY
CHIEF EDITORS
Ernst Eber (Graz, Austria)
Fabio Midulla (Rome, Italy)
ERS STAFF
Matt Broadhead, Alyson Cann, Jonathan Hansen, Sarah Hill,
Elin Reeves, Claire Turner
2013 European Respiratory Society
Design by Claire Turner, ERS

Typeset in China by Charlesworth Group
Printed by Charlesworth Press
All material is copyright to the European Respiratory Society.

It may not be reproduced in any way including electronically without the express
permission of the society.
CONTACT, PERMISSIONS AND SALES REQUESTS:

European Respiratory Society, 442 Glossop Road, Sheffield, S10 2PX, UK
Tel: +44 114 2672860 Fax: +44 114 2665064 e-mail: info@ersj.org.uk
ISBN 978-1-84984-038-5
Table of contents
Contributors xii
Preface xvii
Get more from this Handbook xviii
List of abbreviations xxix
Chapter 1 Structure and function of the respiratory system
Anatomy and development of the respiratory system 1

Robert Dinwiddie
Applied respiratory physiology 11

Caroline Beardsmore and Monika Gappa
Immunology and defence mechanisms 19

Diana Rdler and Bianca Schaub
Environmental determinants of childhood respiratory health 29

and disease
Erik Meln and Matthew S. Perzanowski
Chapter 2 Respiratory signs and symptoms
History and physical examination 33

Michael B. Anthracopoulos, Kostas Douros and Kostas N. Priftis
Cough 44
Ahmad Kantar, Michael Shields, Fabio Cardinale and Anne B. Chang
Tachypnoea, dyspnoea, respiratory distress and chest pain 50

Josef Riedler
Snoring, hoarseness, stridor and wheezing 57

Kostas N. Priftis, Kostas Douros and Michael B. Anthracopoulos
Exercise intolerance 65
Kai-Hkon Carlsen
Chapter 3 Pulmonary function testing and other diagnostic tests
Static and dynamic lung volumes 70

Oliver Fuchs
Respiratory mechanics 77
Oliver Fuchs
Reversibility, bronchial provocation testing and exercise testing 83

Kai-Hkon Carlsen
Blood gas assessment and oximetry 93

Paola Papoff, Fabio Midulla and Corrado Moretti
Exhaled nitric oxide, induced sputum and exhaled breath analysis 100
Johan C. de Jongste
Pulmonary function testing in infants and preschool children 107

Enrico Lombardi, Graham L. Hall and Claudia Calogero
Single- and multiple-breath washout techniques 113

Sophie Yammine and Philipp Latzin
Forced oscillation techniques 118

Shannon J. Simpson and Graham L. Hall
Polysomnography 122
Sedat Oktem and Refika Ersu
Chapter 4 Airway endoscopy
Flexible bronchoscopy 132

Jacques de Blic
Bronchoalveolar lavage 140

Fabio Midulla, Raffaella Nenna and Ernst Eber
Bronchial brushing and bronchial and transbronchial biopsies 146

Petr Pohunek and Tamara Svobodov
Rigid and interventional endoscopy 151

Thomas Nicolai
General anaesthesia, conscious sedation and local anaesthesia 156

Jacques de Blic and Caroline Telion
Chapter 5 Lung imaging
Conventional radiography 161

Meinrad Beer
Computed tomography 166

Harm A.W.M. Tiddens, Marcel van Straten and Pierluigi Ciet
Magnetic resonance imaging 176

Lucia Manganaro and Silvia Bernardo
Ultrasonography 183
Carolina Casini, Vincenzo Basile, Mariano Manzionna and
Roberto Copetti
Isotope imaging methods 189

Georg Berding
Interventional radiology 193

Efthymia Alexopoulou, Argyro Mazioti and Dimitrios Filippiadis
Chapter 6 Inhalation therapy
Aerosol therapy 198

Hettie M. Janssens
Chapter 7 Acute and chronic lung infections
Epidemiology 207
Steve Turner
Microbiology testing and interpretation 214

Elpis Hatziagorou, Emmanuel Roilides and John Tsanakas
Immunisation against respiratory pathogens 221

Horst von Bernuth and Philippe Stock
Upper respiratory tract infections 227

Rossa Brugha, Chinedu Nwokoro and Jonathan Grigg
Community-acquired pneumonia 233

Mark L. Everard, Vanessa Craven and Patricia Fenton
Hospital-acquired pneumonia 242
Vanessa Craven, Patricia Fenton and Mark L. Everard
Lung involvement in immunodeficiency disorders 248

Rifat Chaudry and Paul Aurora
Non-CF bronchiectasis 253

Elif Dagli
Pleural infection, necrotising pneumonia and lung abscess 258

Fernando M. de Benedictis, Chiara Azzari and Filippo Bernardi
Bacterial bronchitis with chronic wet lung 266

Petr Pohunek and Tamara Svobodov
Chapter 8 Tuberculosis
Pulmonary TB, latent TB, and in vivo and in vitro tests 270
Zorica Zivkovic and James Paton
Extrapulmonary TB and TB in the immunocompromised host 284

Toyin Togun, Uzor Egere and Beate Kampmann
Chapter 9 Bronchial asthma and wheezing disorders
Epidemiology and phenotypes of bronchial asthma and 293

wheezing disorders
Franca Rusconi, Ben D. Spycher and Claudia E. Kuehni
Genetic and environmental factors in bronchial asthma and 298

wheezing disorders
Oliver Fuchs and Erika von Mutius
Acute viral bronchiolitis 305

Fabio Midulla, Ambra Nicolai and Corrado Moretti
Preschool wheezing 310

Paul L.P. Brand, Annemie M. Boehmer, Anja A.P.H. Vaessen-Verberne
Bronchial asthma 316

Marille Pijnenburg and Karin C. Ldrup Carlsen
Emerging therapeutic strategies 328
Giorgio Piacentini and Laura Tenero
Differential diagnosis of bronchial asthma 334

Chapter 10 Allergic disorders
Pathophysiology and epidemiology of allergic disorders 339

Karin C. Ldrup Carlsen
In vivo and in vitro diagnostic tests in allergic disorders 345

Gunilla Hedlin
Anaphylaxis 349
Antonella Muraro
Allergic rhinitis 354

Michele Miraglia Del Giudice, Francesca Galdo and Salvatore Leonardi
Atopic dermatitis 363

Paolo Meglio, Elena Galli and Nunzia Maiello
Food allergy 370

Alessandro Fiocchi, Lamia Dahdah and Luigi Terracciano
Allergic bronchopulmonary aspergillosis 376

Andrew Bush
Specific immunotherapy, prevention measures and alternative treatment 383

Susanne Halken and Gunilla Hedlin
Chapter 11 Cystic fibrosis
Genetics, pathophysiology and epidemiology of CF 390

Sabina Gallati
Screening and diagnosis of CF 397

Jrg Barben and Kevin Southern
CF lung disease 402

Nicolas Regamey and Jrg Barben
Extrapulmonary manifestations of CF 410
Anne Munck, Manfred Ballmann and Anders Lindblad
Emerging treatment strategies in CF 421

Melinda Solomon and Felix Ratjen
Prognosis, management and indications for lung transplantation in CF 427

Helen Spencer and Andrew Bush
Chapter 12 Congenital malformations
Airway malformations 435

Ernst Eber and Andreas Pfleger
Thoracic malformations 445

Ashok Daya Ram, Jennifer Calvert and Sailesh Kotecha
Vascular malformations 452

Oliviero Sacco, Serena Panigada, Nicoletta Solari, Elena Ribera,
Chiara Gardella, Silvia Rosina, Michele Ghezzi and Francesca Rizzo
Chapter 13 Bronchopulmonary dysplasia and chronic lung disease
Aetiology, pathogenesis, prevention and evidence-based 461

medical management
Robert I. Ross-Russell
Nutritional care 466

Kajsa Bohlin
Neurodevelopmental assessment and outcomes 469

Charles C. Roehr, Lex W. Doyle and Peter G. Davis
Long-term respiratory outcomes 472

Manuela Fortuna, Marco Filippone and Eugenio Baraldi
Chapter 14 Pleural, mediastinal and chest wall diseases
Pleural effusion, chylothorax, haemothorax and mediastinitis 477

Juan Antn-Pacheco, Carmen Lucas-Paredes and
Antonio Martinez-Gimeno
Pneumothorax and pneumomediastinum 485

Nicolaus Schwerk, Folke Brinkmann and Hartmut Grasemann
Neuromuscular disorders 492
Anita K. Simonds
Chest wall disorders 497

Daniel Trachsel, Carol-Claudius Hasler and Jrg Hammer
Chapter 15 Sleep-related disorders
Physiology and pathophysiology of sleep 503

OSAS and upper respiratory airway resistance syndrome 514

Maria Pia Villa and Silvia Miano
Central sleep apnoea and hypoventilation syndromes 521

Malin Rohdin and Hugo Lagercrantz
Impact of obesity on respiratory function 528

Andrea Bon, Martina Tubaro and Mario Canciani
Chapter 16 Lung injury and respiratory failure
Lung injury 533

Andreas Schibler
Acute and chronic respiratory failure 538

Robert I. Ross-Russell and Colin Wallis
Home oxygen therapy, invasive ventilation and NIV, and home 545
ventilatory support
Brigitte Fauroux, Adriana Ramirez and Sonia Khirani
Chapter 17 Other respiratory diseases
Primary ciliary dyskinesia 551

Deborah Snijders, Serena Calgaro, Massimo Pifferi, Giovanni Rossi
and Angelo Barbato
Gastro-oesophageal reflux-associated lung disease and 559

aspiration syndrome
Osvaldo Borelli, Efstratios Saliakellis, Fernanda Cristofori and
Keith J. Lindley
Foreign body aspiration 566
Iolo Doull
Bronchiolitis obliterans 570

Francesca Santamaria, Silvia Montella and Salvatore Cazzato
Plastic bronchitis 577

Bruce K. Rubin and William B. Moskowitz
Haemangiomas, lymphangiomas and papillomatosis 582

Thomas Nicolai
Interstitial lung diseases 587

Annick Clement, Guillaume Thouvenin, Harriet Corvol and Nadia Nathan
Surfactant dysfunction and alveolar proteinosis 596

Armin Irnstetter, Carolin Krner, Ralf Zarbock and Matthias Griese
Pulmonary vascular disorders 601

Andrea McKee and Andrew Bush
Eosinophilic lung diseases and hypersensitivity pneumonitis 610

Carlo Capristo, Giuseppina Campana, Francesca Galdo, Emilia Alterio
and Laura Perrone
Pulmonary haemorrhage 619

Robert Dinwiddie
Sickle cell disease 625

Tobias Ankermann
Lung and mediastinal tumours 630

Amalia Schiavetti
Systemic disorders with lung involvement 636

Andrew Bush
Lung transplantation and management of post-lung transplant patients 647

Paul Robinson and Paul Aurora
Chapter 18 Rehabilitation in chronic respiratory diseases
Rehabilitation programmes and nutritional management 656

Andreas Jung
Prevention of indoor and outdoor pollution 662

Giuliana Ferrante, Velia Malizia, Roberta Antona and Stefania La Grutta
Respiratory physiotherapy 665

Beatrice Oberwaldner
Fitness-to-fly testing 670

Mary J. Sharp and Graham L. Hall
Sports medicine 673

Giancarlo Tancredi, Giovanna De Castro and Anna Maria Zicari
Contributors
Chief Editors
Ernst Eber Fabio Midulla

Respiratory and Allergic Disease Division, Department of Paediatrics,
Department of Paediatrics Sapienza University of Rome,
and Adolescence, Medical University Rome, Italy.
of Graz, Graz, Austria. midulla@uniroma1.it
ernst.eber@medunigraz.at
Authors
Emilia Alterio Paul Aurora
Department of Pediatrics, Second Great Ormond Street Hospital for
University of Naples, Naples, Italy. Children, London, UK.
p.aurora@ucl.ac.uk
Efthtymia Alexopoulou
2nd Department of Radiology, Chiara Azzari
University Hospital ATTIKON, Department of Pediatrics, University
Athens, Greece. of Florence, Mayer Childrens
ealex64@hotmail.com Hospital, Florence, Italy.
c.azzari@meyer.it
Tobias Ankermann
Klinik fr Allgemeine Pdiatrie Manfred Ballmann
Universittsklinikum Schleswig- Department of Pediatric
Holstein (UKSH), Kiel, Germany. Pulmonology, Ruhr-University
ankermann@pediatrics.uni-kiel.de Bochum, Bochum, Germany.
m.ballmann@klinikum-bochum.de
Michael B. Anthracopoulos
Respiratory Unit, Department of Eugenio Baraldi
Paediatrics, University of Patras, Pediatric Pneumonolgy, University of
Patras, Greece. Padova, Padova, Italy.
manthra@otenet.gr baraldi@pediatria.unipd.it
Roberta Antona Angelo Barbato

Consiglio Nazionale delle Ricerche, Department of Pediatrics, University
Istituto di Biomedicina e Immunolo- of Padova, Italy.
gia Molecolare, Palermo, Italy. barbato@pediatria.unipd.it
roberta.antona@ibim.cnr.it
Jrg Barben
Juan L. Antn-Pacheco Division of Respiratory Medicine,
Pediatric Surgery, Hospital Universi- Childrens Hospital St. Gallen,
tario 12 de Octubre, Madrid, Spain. St Gallen, Switzerland.
janton.hdoc@salud.madrid.org juerg.barben@kispisg.ch
xii
Vincenzo Basile Kajsa Bohlin
Pediatric Department, Monopoli Neonatal intensive Care,
Hospital, Bari, Italy. Karolinska Institutet, Karolinska
vinbasile67@libero.it University Hospital
Huddinge, Stockholm, Sweden.
Caroline Beardsmore kajsa.bohlin@ki.se
Department of Infection, Immunity
and Inflammation (Child Health), Andrea Bon
University of Leicester, Leicester, UK. Pediatric Department, University of
csb@le.ac.uk Udine, Udine, Italy.
gandale@gmail.com
Meinrad Beer
Department of Pediatric Osvaldo Borrelli
Radiology, Medical University Graz, Department of Paediatric
Graz, Austria. Gastroenterology, Division of
meinrad.beer@medunigraz.at Neurogastroenterology and Motility,
Great Ormond Street Hospital for
Georg Berding Children, ICH University College of
Department of Nuclear Medicine, London, London, UK.
Hannover Medical School, Hannover, osvaldo.borrelli@gosh.nhs.uk
Germany.
berding.georg@mh-hannover.de Paul L.P. Brand
Princess Amalia Childrens Clinic,
Filippo Bernardi Isala Klinieken, Zwolle,
Department of Pediatrics, University The Netherlands.
of Bologna, S. Orsola-Malpighi p.l.p.brand@isala.nl
Hospital, Bologna, Italy.
filippo.bernardi@unibo.it Folke Brinkmann
Department of Pediatrics, Pediatric
Silvia Bernardo Pneumology, Allergology and
Radiological Oncological and Neonatology, Hannover Medical
Pathological Sciences, Umberto I School, Hannover, Germany.
Hospital, Sapienza University of brinkmann.folke@mh-hannover.de
Rome, Rome, Italy.
silviabernardo@live.it Rossa Brugha
Centre for Paediatrics, Blizard
Annemie M. Boehmer Institute, Barts and the London
Department of Paediatrics, Maasstad School of Medicine and Dentistry,
Hospital, Rotterdam, Queen Mary University of London,
The Netherlands. London, UK.
BoehmerA@maasstadziekenhuis.nl r.brugha@qmul.ac.uk
xiii
Andrew Bush Fabio Cardinale
Department of Paediatric Respiratory Department of Pediatric Allergy and
Medicine, Royal Brompton Hospital, Pulmonology, Paediatric Hospital
London, UK. Giovanni XXIII, University of Bari,
A.Bush@rbht.nhs.uk Bari, Italy.
fabiocardinale@libero.it
Claudia Calogero
Respiratory Medicine, Anna Meyer, Kai-Hkon Carlsen
University Hospital for Children, Institute of Clinical Medicine,
Florence, Italy. University of Oslo, Oslo, Norway.
c.calogero@meyer.it k.h.carlsen@medisin.uio.no
Serena Calgaro Carolina Casini

Department of Pediatrics, University Pediatric Department, SantAndrea
of Padova, Padova, Italy. Hospital, Rome, Italy.
serena.calgaro@studenti.unipd.it carolinacasini@libero.it
Jennifer Calvert Salvatore Cazzato

Department of Neonatal Medicine, Dept of Pediatrics, University of
University Hospital of Wales, Cardiff Bologna, S. Orsola-Malpighi
and Vale LHB, Cardiff, UK. Hospital, Bologna, Italy.
salvatore_cazzato@aosp.bo.it
Giuseppina Campana
Department of Pediatrics, Second Anne B. Chang
University of Naples, Naples, Italy. Respiratory Medicine, Royal
Childrens Hospital, Brisbane,
Mario Canciani Australia.
Pediatric Department, Azienda annechang@ausdoctors.net
Ospedaliero, Universitaria di Udine,
Udine, Italy. Rifat Chaudry
canciani.mario@aoud.sanita.fvg.it Great Ormond Street Hospital for
Children, London, UK.
Carlo Capristo r.chaudry@gosh.nhs.uk
Department of Pediatrics, Second
University of Naples, Naples, Italy. Pierluigi Ciet
carlo.capristo@unina2.it Radiology and Pediatric
Pulmonology, Erasmus Medical
Center, Sophia Childrens Hospital,
Rotterdam, The Netherlands.
p.ciet@erasmusmc.nl
xiv
Annick Clement Peter G. Davis
Paediatric Pulmonary Department, Department of Newborn Research,
Reference Centre for Rare Lung The Royal Womens Hospital,
Diseases, AP-HP, Hpital Trousseau, Melbourne, Australia.
INSERM UMR S-938, Universit pgd@unimelb.edu.au
Pierre et Marie Curie, Paris, France.
annick.clement@trs.aphp.fr Ashok Daya Ram
Department of Paediatric Surgery,
Roberto Copetti Birmingham Childrens Hospital,
Latisana General Hospital, Latisana, Birmingham, UK.
Italy. ashokdram@hotmail.com
robcopet@tin.it
Fernando M. de Benedictis
Harriet Corvol Department of Mother and Child
Paediatric Pulmonary Department, Health, Salesi University Childrens
Reference Centre for Rare Lung Hospital, Ancona, Italy.
Diseases, AP-HP, Hpital Trousseau, debenedictis@ospedaliriuniti.
INSERM UMR S-938, Universit marche.it
Pierre et Marie Curie, Paris, France.
harriet.corvol@trs.aphp.fr Jacques de Blic
Universit Paris Descartes,
Vanessa Craven Assistance Publique des Hpitaux
Department of Respiratory Medicine de Paris, Hpital Necker Enfants
and Microbiology, Sheffield Malades, Service de Pneumologie
Childrens Hospital, Sheffield, UK. et Allergologie Pdiatriques Paris,
valgar@doctors.org.uk France.
j.deblic@nck.aphp.fr
Fernanda Cristofori
Pediatrics Department, University of Giovanna De Castro
Bari, Bari, Italy. Department of Paediatrics,
fernandacristofori@gmail.com Sapienza University of Rome,
Rome, Italy.
Elif Dagli giovanna.decastro@uniroma1.it
Pediatric Pulmonology, Marmara
University, Istanbul, Turkey. Johan C. de Jongste
elifzdagli@gmail.com Dept of Pediatrics/Respiratory
Medicine, Erasmus Medical Center,
Lamia Dahdah Sophia Childrens Hospital,
Division of Allergy, Department Rotterdam, The Netherlands.
of Pediatrics, Pediatric Hospital j.c.dejongste@erasmusmc.nl
Bambino Ges, Rome, Italy.
lamia.dahdah@opbg.net
xv
Robert Dinwiddie Brigitte Fauroux
Portex Unit, Institute of Child Health, AP-HP, Hopital Armand Trousseau,
London, UK. Pediatric Pulmonary Department,
rdinwiddie@doctors.org.uk INSERM U 955, Universit Pierre et
Marie Curie, Paris, France.
Iolo Doull brigitte.fauroux@trs.aphp.fr
Department of Paediatric Respiratory
Medicine, Childrens Hospital for Patricia Fenton
Wales, Cardiff, UK. Department of Respiratory Medicine
doullij@cf.ac.uk and Microbiology, Sheffield
Childrens Hospital, Sheffield, UK.
Kostas Douros patricia.fenton@sch.nhs.uk
Respiratory Unit, 3rd Department of
Paediatrics, Attikon Hospital, Giuliana Ferrante
University of Athens, Athens, Greece. Consiglio Nazionale delle Ricerche,
costasdouros@gmail.com Dipartimento di Scienze per la
Promozione della Salute e Materno
Lex W. Doyle Infantile, University of Palermo,
Department of Obstetrics and Palermo, Italy.
Gynaecology, The University of giuliana.ferrante@unipa.it
Melbourne, Melbourne, Australia.
lwd@unimelb.edu.au Dimitrios Filippiadis
2nd Deaprtment of Radiology,
Uzor Egere University Hospital ATTIKON,
Vaccinology Theme, Medical Athens, Greece.
Research Council (MRC) Unit, The dfilippiadis@yahoo.gr
Gambia, Africa.
uegere@mrc.gm Marco Filippone
Department of Pediatrics, University
Refika Ersu of Padova, Padova, Italy.
Division of Pediatric Pulmonology, filippone@pediatria.unipd.it
Marmara University, Istanbul, Turkey.
rersu@yahoo.com Alessandro Fiocchi
Division of Allergy, Dept of
Mark L. Everard Pediatrics, Pediatric Hospital
School of Paediatrics and Child Bambino Ges, Rome, Italy.
Health, University of Western allerg@tin.it
Australia, Princess Margaret
Hospital, Subiaco, Australia.
mark.everard@uwa.edu.au
xvi
Manuela Fortuna Chiara Gardella
Pediatric Pneumonolgy, University of Dept of Pulmonary Disease, G.
Padova, Padova, Italy. Gaslini Institute, Genoa, Italy.
fortuna.manuela@alice.it chiaragardella@hotmail.com
Oliver Fuchs Michele Ghezzi

Division of Paediatric Allergology, Pulmonary Disease Department,
University Childrens Hospital, G. Gaslini Institute, Genoa, Italy.
Ludwig-Maximilians-University,
Munich, Germany. Hartmut Grasemann
oliver.fuchs@med.lmu.de Division of Respiratory Medicine,
Department of Pediatrics, The
Francesca Galdo Hospital for Sick Children, Toronto,
Department of Pediatrics, Second Canada.
University of Naples, Naples, Italy. hartmut.grasemann@sickkids.ca
Sabina Gallati Matthias Griese

Division of Human Genetics, Hauner Childrens Hospital,
Departments of Paediatrics and University of Munich, Germany.
Clinical Research, Inselspital, matthias.griese@med.uni-
University of Bern, Bern, Switzerland. muenchen.de
sabina.gallati@insel.ch
Jonathan Grigg
Elena Galli Paediatric Respiratory and
Department of Pediatric Allergy, Environmental Medicine Blizard
Research Centre, San Pietro Hospital Institute, Barts and the London
- Fatebenefratelli, Rome, Italy. School of Medicine and Dentistry,
galli.elena@fbfrm.it Queen Mary University of London,
London, UK.
Monica Gappa j.grigg@qmul.ac.uk
Childrens Hospital and Research
Insitute for the Prevention of Susanne Halken
Allergies and Respiratory Diseases in Hans Christian Andersen Childrens
Children, Marien-Hospital Wesel Hospital, Odense University
GmbH, Wesel, Germany. Hospital, Odense,
Monika.gappa@prohomine.de Denmark.
Susanne.Halken@rsyd.dk
xvii
Graham L. Hall Hettie M. Janssens
Paediatric Respiratory Physiology , Department of Paediatric Respiratory
Telethon Institute for Child Health Medicine, Erasmus Medical Center,
Research, Perth, Australia. Sophia Childrens Hospital,
grahamh@ichr.uwa.edu.au Rotterdam, The Netherlands.
H.Janssens@erasmusmc.nl
Jrg Hammer
Paediatric Intensive Care and Andreas Jung
Pulmonology, University-Childrens Children`s University Hospital
Hospital Basel, Basel, Germany. Zurich, Division of Respiratory
juerg.hammer@unibas.ch Medicine, Zurich, Switzerland.
andreas.jung@kipsi.uzh.ch
Carol-Claudius Hasler
Paediatric Orthopaedics, University Beate Kampmann
Childrens Hospital UKBB, Basel, Vaccinology Theme, Medical
Switzerland. Research Council (MRC) Unit, The
carolclaudius.hasler@ukbb.ch Gambia, Africa.
bkampmann@mrc.gm
Elpis Hatziagorou
Peadiatric Respiratory Unit, 3rd Ahmad Kantar
Paediatric Dept, Aristotle University Department of Paediatrics, Institutes
of Thessaloniki, Hippokration of Bergamo Hospitals, Bergamo,
Hospital, Thessaloniki, Greece. Italy.
elpcon@otenet.gr kantar@tin.it
Gunilla Hedlin Sonia Khirani

Astrid Lindgren Childrens A.A.O. Ospedali Riuniti di Bergamo,
Hospital, Department of Womens U.S.C. Pneumologia, Bergamo, Italy.
and Childrens Health and Centre for sonia_khirani@yahoo.fr
Allergy Research, Karolinska
Institutet, Stockholm, Sweden. Sailesh Kotecha
Gunilla.Hedlin@ki.se Department of Child Health, School
of Medicine, Cardiff University,
Armin Irnstetter University Hospital of Wales, Cardiff,
Pneumology Dept, University of UK.
Munich, Dr. von Haunersches kotechas@cardiff.ac.uk
Kinderspital, Munich, Germany.
armin.irnstetter@med.uni- Carolin Krner
muenchen.de Pediatrics Dept, University of
Munich, Munich, Germany.
Carolin.Kroener@med.uni-
muenchen.de
xviii
Claudia E. Kuehni Keith J. Lindley
Division of International and Great Ormond Street Hospital,
Environmental Health, Institute of London, UK.
Social and Preventive Medicine, k.lindley@ucl.ac.uk
University of Bern, Switzerland.
kuehni@ispm.unibe.ch Karin C. Ldrup Carlsen
Department of Paediatrics, Women
Stefania La Grutta and Childrens Division, Oslo
Consiglio Nazionale delle Ricerche, University Hospital, Oslo, Norway.
Istituto di Biomedicina e k.c.l.carlsen@medisin.uio.no
Immunologia Molecolare, Palermo,
Italy. Enrico Lombardi
stefania.lagrutta@ibim.cnr.it Paediatric Pulmonary Unit, Anna
Meyer Paediatric University Hospital,
Hugo Lagercrantz Florence, Italy.
Neonatal Research Unit, Department e.lombardi@meyer.it
of Woman and Child Health,
Karolinska Institutet, Astrid Lindgren Carmen Luna-Paredes
Childrens Hospital, Karolinska Hospital Universitario 12 de Octubre,
University Hospital, Stockholm, Madrid, Spain.
Sweden. lunalavin1@yahoo.es
hugo.lagercrantz@ki.se
Nunzia Maiello
Philipp Latzin Department of Women, Children
Division of Respiratory Medicine, and General and Specialized Surgery,
Department of Paediatrics, University Second University of Naples, Naples,
Childrens Hospital of Bern, Bern, Italy.
Switzerland. nunzia.maiello@unina2.it
philipp.latzin@insel.ch
Velia Malizia
Salvatore Leonardi Consiglio Nazionale delle Ricerche,
Department of Pediatrics, University Istituto di Biomedicina e
of Catania, Catania, Italy. Immunologia Molecolare, Palermo,
leonardi@unict.it Italy.
velia.malizia@ibim.cnr.it
Anders Lindblad
Dept of Pediatrics, Queen Silvias Lucia Manganaro
Hospital, Gothenburg University, Department of Radiological Sciences,
Gothenburg, Sweden. Umberto I Hospital, Sapienza
anders.lindblad@vgregion.se University of Rome, Rome, Italy.
lucia.manganaro@uniroma1.it
xix
Mariano Manzionna Silvia Montella
Pediatric Department, Monopoli Department of Pediatrics, Federico II
Hospital, Bari, Italy. University, Naples, Italy.
mariano.manzionna@alice.it amina2004@virgilio.it
Antonio Martinez-Gimeno Corrado Moretti

Division of Respiratory Medicine, Department of Paediatrics Emer-
Hospital Universitario 12 de Octubre, gency and Intensive Care, Sapienza
Madrid, Spain. University of Rome, Rome, Italy.
amgimeno@gmail.com corrado.moretti@uniroma1.it
Argyro Mazioti William B. Moskowitz

Department of Radiology, General Department of Pediatrics, The
Hospital of Larissa, Larissa, Greece. Childrens Hospital of Richmond at
argyromazioti@yahoo.gr VCU, Richmond, VA, USA.
moskowit@hsc.vcu.edu
Andrea Mckee
Paediatric Respiratory Medicine, Anne Munck
Royal Brompton Hospital, London, Paediatric CF Centre Gastrointesti-
UK. nal and Pulmonology Department,
a.mckee@rbht.nhs.uk Robert Debr University Hospital,
Paris-Diderot AP-HP, Paris, France.
Paolo Meglio anne.munck@rdb.ap-hop-paris.fr
Department of Pediatric Allergy,
Research Centre, San Pietro Hospital Antonella Muraro
- Fatebenefratelli, Rome, Italy. Food Allergy Centre, Department of
paolo.meglio@tiscali.it Women and Child Health, University
of Padua, Padua, Italy.
Erik Meln muraro@pediatria.unipd.it
Institute of Environmental Medicine,
Karolinska Institutet, Stockholm, Nadia Nathan
Sweden. Paediatric Pulmonary Department,
erik.melen@ki.se Reference Centre for Rare Lung
Diseases, AP-HP, Hpital Trousseau,
Silvia Miano INSERM UMR S-938, Universit
Sapienza University of Rome, Pierre et Marie Curie, Paris, France.
Rome, Italy. nadia.nathan@trs.aphp.fr
silvia.miano@gmail.com
Raffaella Nenna
Michele Miraglia del Giudice Department of Paediatrics,
Department of Pediatrics, Second Sapienza University of Rome,
University of Naples, Naples, Italy. Rome, Italy.
michele.miraglia@unina2.it raffaella.nenna@uniroma1.it
xx
Ambra Nicolai Paola Papoff
Department of Paediatrics, University PICU, Policlinico Umberto I,
of Rome, Rome, Italy. Sapienza University of Rome,
ambra10.nic@gmail.com Rome, Italy.
p.papoff@libero.it
Thomas Nicolai
University Kinderklinik, Munich, James Paton
Germany. Royal Hospital for Sick Children,
tnicolai@med.uni-muenchen.de Glasgow, UK.
james.paton@glasgow.ac.uk
Chinedu Nwokoro
Centre for Paediatrics, Blizard Laura Perrone
Institute, Barts and the London Department of Pediatrics, Second
School of Medicine and Dentistry, University of Naples, Naples, Italy.
Queen Mary University of London, laura.perrone@unina2.it
London, UK.
c.nwokoro@qmul.ac.uk Matthew S. Perzanowski
Department of Environmental Health
Beatrice Oberwaldner Sciences, Mailman School of Public
Klinische Abteilung fr Health, Columbia University, New
Pulmonologie und Allergologie,Univ. York, NY, USA.
Klinik fr Kinder-und mp2217@columbia.edu
Jugendheilkunde, Graz, Austria.
beatrice.oberwaldner@klinikum- Andreas Pfleger
graz.at Respiratory and Allergic Disease
Division, Department of Paediatrics
Sedat Oktem and Adolescence Medicine, Medical
Istanbul Medipol University, Division University of Graz, Graz, Austria.
of Pediatric Pulmonology, Istanbul, andreas.pfleger@meduni-graz.at
Turkey.
sedatoktem@hotmail.com Maria Pia Villa
Dept of Pediatrics, University
Serena Panigada Hospital, Rome, Italy.
Pediatric Pulmonary and Allergy Unit, mariapia.villa@uniroma1.it
Istituto Giannina Gaslini, Genoa,
Italy. Giorgio Piacentini
serenapanigada@ospedale-gaslini. Department of Pediatrics, University
ge.it of Verona, Verona, Italy.
giorgio.piacentini@univr.it
xxi
Massimo Pifferi Nicolas Regamey
Department of Pediatrics, University Division of Respiratory Medicine,
of Pisa, Pisa, Italy. Department of Paediatrics, Inselspital
m.pifferi@med.unipi.it and University of Bern, Bern,
Switzerland
Marille Pijnenburg Nicolas.Regamey@insel.ch
Department of Paediatrics/Paediatric
Respiratory Medicine, Rotterdam Elena Ribera
The Netherlands. Pulmonary Disease Department,
m.pijnenburg@erasmusmc.nl G. Galini Institute, Genoa, Italy.
Petr Pohunek Josef Riedler

Paediatric Pulmonology, Childrens Hospital Schwarzach,
University Hospital Motol, Prague, Salzburg, Austria.
Czech Republic. josef.riedler@kh-schwarzach.at
petr.pohunek@LFMotol.cuni.cz
Francesca Rizzo
Kostas N. Priftis Pulmonary Disease Department,
Respiratory Unit, 3rd Department of G. Galini Institute, Genoa, Italy.
Paediatrics, Attikon Hospital,
University of Athens, Athens, Greece. Paul Robinson
kpriftis@otenet.gr Dept of Respiratory Medicine,
Childrens Hospital at Westmead,
Diana Rdler Westmead, Australia.
Pulmonary Dept, University Childrens paul.robinson1@health.nsw.gov.au
Hospital, Munich,
Germany. Charles C. Roehr
diana.raedler@med.uni-muenchen.de Dept of Neonatology, Charit Berlin,
Berlin, Germany.
Adriana Ramirez christoph.roehr@charite.de
ADEP ASSISTANCE, Suresnes, France.
a.ramirez@adepassistance.fr Malin Rohdin
Neonatal Research Unit, Department
Felix Ratjen of Woman and Child Health,
Hospital for Sick Children, Toronto, Karolinska Institutet, Astrid Lindgren
Canada. Childrens Hospital, Karolinska
felix.ratjen@sickkids.ca University Hospital, Stockholm,
Sweden.
malin.rohdin@ki.se
xxii
Emmanuel Roilides Francesca Santamaria
Peadiatric Respiratory Unit, 3rd Department of Paediatrics, Federico
Paediatric Dept, Aristotle University of II University, Naples, Italy.
Thessaloniki, Hippokration santamar@unina.it
Hospital, Thessaloniki, Greece.
roilides@gmail.com Bianca Schaub
Silvia Rosina University Childrens Hospital
Munich, Munich, Germany.
Giovanni Rossi Bianca.Schaub@med.uni-muenchen.de
Pulmonary and Allergy Units,
Giannina Gaslini Institute, Genova, Amalia Schiavetti
Italy. Department of Paediatrics,
giovannirossi@ospedale-gaslini.ge.it Sapienza University of Rome,
Rome, Italy.
Robert I. Ross-Russell amalia.schiavetti@uniroma1.it
Department of Paediatrics,
Addenbrookes Hospital, Cambridge, Andreas Schibler
UK. Paediatric Critical Care Research
robert.ross-russell@addenbrookes. Group, Paediatric Intensive Care
nhs.uk Unit, Mater Childrens Hospital,
Brisbane, Australia.
Bruce K. Rubin andreas.schibler@mater.org.au
Childrens Hospital of Richmond at
VCU, Richmond, VA, USA. Nicolaus Schwerk
brubin@vcu.edu Department of Pediatrics , Pediatric
Pneumology, Allergology and
Franca Rusconi Neonatology, Hannover Medical
Epidemiology Unit, Anna Meyer, School, Hannover, Germany.
Childrens Hospital, Florence, Italy. schwerk.nicolaus@mh-hannover.de
f.rusconi@meyer.it
Mary Sharp
Oliviero Sacco Neonatology Clinical Care Unit,
Pulmonary Disease Department, King Edward Memorial Hospital for
G. Gaslini Institute, Genoa, Italy. Women, Perth, Australia.
olivierosacco@ospedale-gaslini.ge.it Mary.Sharp@health.wa.gov.au
Efstratios Saliakellis Michael Shields

Great Ormond Street Hospital, Department of Child Health, Queens
London, UK. University of Belfast, Belfast, UK.
efstratios.saliakellis@gosh.nhs.uk m.shields@qub.ac.uk
xxiii
Anita K. Simonds Ben D. Spycher
NIHR Respiratory Biomedical Division of International and
Research Unit, Royal Brompton & Environmental Health, Institute of
Harefield NHS Foundation Trust, Social and Preventive Medicine,
London UK. University of Bern, Bern, Switzerland.
A.Simonds@rbht.nhs.uk bspycher@ispm.unibe.ch
Shannon J. Simpson Philippe Stock

Paediatric Respiratory Physiology, Charit Kinderklinik mit Schwerpunkt
Telethon Institute for Child Health Pneumologie und Immunologie
Research, University of Western Labor Berlin Fachbereich
Australia, Perth, Australia. Allergologie, Berlin, Germany.
shannons@ichr.uwa.edu.au philippe.stock@charite.de
Deborah Snijders Tamara Svobodov

Department of Pediatrics, University Paediatric Respiratory Division,
of Padova, Padova, Italy. University Hospital Motol, Prague,
olanda76@gmail.com Czech Republic.
tamara.svobodova@lfmotol.cuni.cz
Nicoletta Solari
Pulmonary Disease Department, Giancarlo Tancredi
G. Gaslini Institute, Genoa, Italy. Department of Paediatrics,
Sapienza University of Rome,
Rome, Italy.
Melinda Solomon giancarlo.tancredi@uniroma1.it
Hospital for Sick Children, Toronto,
Canada. Caroline Telion
melinda.solomon@sickkids.ca Dpartement danesthesie,
Assistance Publique des Hpitaux de
Kevin Southern Paris, Hpital Universitaire Necker
Institute of Child Health, University Enfants Malades, Paris, France.
of Liverpool, Alder Hey Childrens caroline.telion@nck.aphp.fr
NHS Foundation Trust, Liverpool,
UK. Laura Tenero
kwsouth@liverpool.ac.uk Clinica Pediatrica,
Pediatria Verona, Verona, Italy.
Helen Spencer lauratenero@hotmail.com
Great Ormond Street Hospital,
London, UK. Luigi Terracciano
helen.spencer@gosh.nhs.uk Melloni Paediatria, Melloni University
Hospital, Milan, Italy. terrycom1957@
gmail.com
xxiv
Guillaume Thouvenin Steve Turner
Paediatric Pulmonary Department, Child Health, Royal Aberdeen
Reference Centre for Rare Lung Childrens Hospital, Aberdeen, UK.
Diseases, AP-HP, Hpital Trousseau, s.w.turner@abdn.ac.uk
INSERM UMR S-938, Universit
Pierre et Marie Curie, Paris, France. Anja A.P.H. Vaessen-Verberne
guillaume.thouvenin@trs.aphp.fr Department of Paediatrics, Amphia
Hospital, Breda, The Netherlands.
Harm A.W.M. Tiddens AVaessen-Verberne@amphia.nl
Pediatric pulmonology, Erasmus
Medical Center, Sophia Childrens Horst von Bernuth
Hospital, Rotterdam, Pediatric Pneumology and
The Netherlands. Immunology, Charit Berlin, Berlin,
h.tiddens@erasmusmc.nl Germany.
Horst.von-Bernuth@charite.de
Toyin Togun
Vaccinology Theme, Medical Marcel van Straten
Research Council (MRC) Unit, The Department of Radiology, Erasmus
Gambia, Africa. MC, Rotterdam, The Netherlands.
ttogun@mrc.gm marcel.vanstraten@erasmusmc.nl
Daniel Trachsel Erika von Mutius

Paediatric Intensive Care and University Childrens Hospital,
Pulmonology, University-Childrens Ludwig Maximilians-University,
Hospital Basel, Basel, Switzerland. Munich, Germany.
daniel.trachsel@ukbb.ch erika.von.mutius@med.uni-
muenchen.de
JohnTsanakas
Peadiatric Respiratory Unit, 3rd Colin Wallis
Paediatric Dept, Aristotle University Respiratory Unit, Great Ormond
of Thessaloniki, Hippokration Street Hospital, London, UK.
Hospital, Thessaloniki, Greece. Colin.Wallis@gosh.nhs.uk
tsanakasj@ath.forhnet.gr
Sophie Yammine
Martina Tubaro Pediatric Pulmonology Dept,
Pediatric Department, University of University of Bern, Bern, Switzerland.
Trieste, Trieste, Italy. sophie.yammine@insel.ch
martina.tubaro@gmail.com
xxv
Ralf Zarbock Zorica Zivkovic
Pediatrics Dept, University of Medical Center Dr Dragisa Misovic,
Munich, Munich, Germany. Hospital for Lung Diseases and
Ralf.Zarbock@med.uni-muenchen.de Tuberculosis, Belgrade,
Serbia.
Anna Maria Zicari zoricazivkovic@beotel.net
Department of Paediatrics,
Sapienza University of Rome,
Rome, Italy.
annamaria.zicari@uniroma1.it
xxvi
Preface Tell me and I forget.
Teach me and I remember.
Involve me and I learn.
Benjamin Franklin
The dissemination of knowledge, and medical and public education constitute a

fundamental objective of the ERS mission; and the ERS School aims to provide
excellence in respiratory medicine education. In 2005, the ERS School started
the very ambitious HERMES (Harmonised Education in Respiratory Medicine
for European Specialists) project. Since then, seven HERMES Task Forces
have formed to standardise training and education within different specialties
of respiratory medicine. To support the implementation of various educational
activities, the ERS has produced a series of Handbooks as educational tools, with
the ERS Handbook of Respiratory Medicine being the first textbook to be launched
in 2010.
Starting in 2007, the Paediatric Respiratory Medicine Task Force, using a formal
consensus process and working with numerous experts throughout Europe,
developed a HERMES syllabus (description of the competencies required) and
a HERMES curriculum (description of how competencies should be taught,
learned and assessed), as well as a voluntary European examination in paediatric
respiratory medicine. With the paediatric HERMES project now well underway,
it is an opportune time to publish an ERS Handbook of Paediatric Respiratory
Medicine to provide a comprehensive update for specialists within this field of
respiratory medicine. The content of this Handbook follows the HERMES syllabus
and curriculum to provide a compact, state-of-the-art textbook, with each of the
sections prepared by senior specialists and clinical experts in the field.
We hope that this Handbook will not only inform our trainees but also provide an
easily accessible and comprehensive update for colleagues at all levels of seniority
across paediatric respiratory medicine. Thus, this educational tool is intended
to make a significant contribution to increasing the standards of training in
paediatric respiratory medicine throughout Europe and, ultimately, to improving
the care of children with respiratory disease.
We are indebted to the ERS School Committee and to the ERS staff who so
thoroughly and thoughtfully curated this Handbook, and last, but not least, to
all the contributors who have shared their knowledge and experience with the
readers.
Ernst Eber and Fabio Midulla

Chief Editors
xxvii
Get more from this Handbook
By buying the ERS Handbook of Paediatric Medicine, you also gain access to the
electronic version of the book, as well as an accredited online CME test.
To log in, simply visit www.ersnet.org/handbook and enter the unique code
printed on the inside of the front cover. Once logged in, youll be able to
download the entire book in PDF or EPUB format, to read on your computer or
mobile device.
Youll also be able to take the online CME test. This Handbook has been
accredited by the European Board for Accreditation in Pneumology
(EBAP) for 18 CME credits.
Also available from the ERS

EUROPEAN RESPIRATORY MONOGRAPH
Monograph 47, March 2010
NUMBER 56 / JUNE 2012
Paediatric
Lung Function
Paediatric Asthma Edited by
U. Frey and P.J.F.M. Merkus
Edited by Kai-Hkon Carlsen and

Jorrit Gerritsen
EUROPEAN
RESPIRATORY
EUROPEAN
RESPIRATORY
SOCIETY
EUROPEAN RESPIRATORY
European Respiratory Monograph 56: European Respiratory Monograph

Paediatric Asthma covers all aspects of 47: Paediatric Lung Function offers
paediatric asthma from birth through a comprehensive review of the lung
to the start of adulthood. It considers function techniques that are currently
diagnostic problems in relation to the available in paediatric pulmonology.
many phenotypes of asthma, covers the This field is developing rapidly and
treatment of both mild-to-moderate and equipment and software can tell us
severe asthma, and discusses asthma more than ever about respiratory
exacerbations as well as exercise- physiology in health and disease in
induced asthma. The issue provides children with various lung disorders.
an update on the pathophysiology The issue provides a state-of-the-art
of asthma, the role of bacterial and review of the techniques, with a special
viral infections, and the impact of focus on the clinical applications and
environmental factors, allergy, genetics usefulness in diagnosing and treating
and epigenetics. children with chronic lung disease.
Go to erm.erjsournals.com to view the table of contents for each Monograph
To buy a copy of these Monographs please visit ersbookshop.com
xxviii
List of abbreviations
(C)HF (Congestive) heart failure
AHI Apnoeahypopnoea index
AIDS Acquired immunodeficiency syndrome
BMI Body mass index
CF Cystic fibrosis
COPD Chronic obstructive pulmonary disease
CPAP Continuous positive airway pressure
CT Computed tomography
ECG Electrocardiogram
ENT Ear, nose and throat
FEV1 Forced expiratory volume in 1 s
FVC Forced vital capacity
Hb Haemoglobin
HIV Human immunodeficiency virus
HRCT High-resolution computed tomography
KCO Transfer coefficient of the lung for carbon monoxide
MRI Magnetic resonance imaging
NIV Noninvasive ventilation
OSA(S) Obstructive sleep apnoea (syndrome)
PaCO2 Arterial carbon dioxide tension
PaO2 Arterial oxygen tension
PCR Polymerase chain reaction
PtcCO2 Transcutaneous carbon dioxide tension
SaO2 Arterial oxygen saturation
SpO2 Arterial oxygen saturation measured by pulse oximetry
TB Tuberculosis
TLC Total lung capacity
TLCO Transfer factor for the lung for carbon monoxide
V'E Minute ventilation
xxix
Anatomy and development
of the respiratory system
Robert Dinwiddie
Anatomy of the lower respiratory tract Larynx The larynx can be divided into three
areas (fig. 1):
The lower respiratory tract consists of the
trachea, hila of the lungs, large bronchial N supraglottis,
airways, small airways and alveoli. The larynx N glottis,
lies at the junction of the upper and lower N subglottis.
respiratory tract and since it is a frequent
source of pathology in children its anatomy It extends from the tip of the epiglottis to the
will also be described. The mediastinum lower border of the cricoid cartilage. In the
contains the heart and its related cardiac neonatal period it lies at the level of cervical
structures: vertebrae C2C3 and in adults at the level of
C3C6. It contains major cartilaginous
N thymus, structures including the epiglottic, thyroid
N trachea, and cricoid cartilages, and the paired
N thoracic lymph nodes, arytenoid cartilages. The vocal apparatus is
N thoracic duct, muscular and consists of the false vocal
N vagus nerves, cords (vestibular folds) and the true vocal
N recurrent laryngeal nerves, cords (folds). The true vocal cords are drawn
N autonomic nerve plexus. together by adduction of the arytenoid
cartilages. The larynx is bounded on each
Another important structure which passes side by the aryepiglottic folds. These lie
through the thorax via the mediastinum is between the lateral borders of the epiglottis
the oesophagus. anteriorly and the upper edge of the
arytenoid cartilages, which join posteriorly
to form the interarytenoid cartilage. The
Key points larynx is chiefly innervated by branches of
the vagus nerves. The subglottic area is
supplied by the recurrent laryngeal nerves
N The anatomy of the thorax can be
which also arise from the vagal nervous
divided into the lungs, heart,
system. These supply the vocal cords and
mediastinum, pleura, diaphragm and
damage to them can result in unilateral or
chest wall.
bilateral vocal cord paralysis.
N The lungs can be further subdivided
Hila Each hilum forms the root of the lung
into the trachea, bronchi, hila, lobes
and preacinar and acinar regions. joining it to the heart and the trachea.
Structures that pass through this area on
N The mediastinum contains the each side include the major bronchus,
thymus, the heart and its associated pulmonary artery, superior and inferior
structures, thoracic lymphatics, pulmonary veins, bronchial artery and vein,
sympathetic and parasympathetic vagus nerves, pulmonary autonomic nerves
nerves and the oesophagus. and lymphatic vessels. Lymph nodes within
each hilum are often directly involved in
ERS Handbook: Paediatric Respiratory Medicine 1

Epiglottis become bronchioles before finally
becoming a terminal bronchiole (table 1).
Vocal cord (fold) The portion of the respiratory tree from the
Vestibular fold trachea down to the terminal bronchioles is
(false cord)
known as the preacinar region. The acinar
Aryepiglottic fold
region comprises the gas exchanging units
Trachea and includes seven further branches of the
distal lung made up of the respiratory
Interarytenoid
cartilage bronchioles, alveolar ducts and the
alveolar sacs.
Figure 1. Laryngeal anatomy as seen from above. The blood supply to the trachea and
bronchi is principally via the bronchial
disease processes spreading systemically arteries and the intercostal arteries, which
from the lung parenchyme. arise via the systemic circulation from the
aorta. The upper trachea is supplied by
Trachea and bronchi The trachea is made up
branches of the inferior thyroid arteries.
of anterolateral cartilaginous rings and a
The venous drainage from the trachea
fibro-muscular posterior wall. The trachea
returns via the inferior thyroid venous
divides into the right and left main bronchi
plexus. The tracheal nerve supply is via
(fig. 2). The right main bronchus is more
the vagus nerves, the recurrent laryngeal
vertically orientated than the left resulting in
nerves, supplying parasympathetic
a greater percentage of inhaled foreign
fibres and sympathetic nerves arising
bodies entering that side. The right main
from the upper ganglia of the
bronchus gives off the right upper lobe
sympathetic trunks.
bronchus and continues as the bronchus
intermedius. This divides into the right
middle and lower lobe bronchi. The right
upper lobe bronchus divides into three
segmental bronchi: apical, posterior and
anterior. The right middle lobe bronchus
divides into two: the medial and lateral
segments of the middle lobe. The right lower
lobe bronchus gives off a superior
segmental branch and then medial, lateral,
anterior and posterior segments. Segmental
bronchi are particularly important to
recognise during bronchoscopy. The left
main bronchus divides into the left upper
and lower lobe bronchi. The left upper lobe
bronchus gives off the superior division
supplying the apical, anterior and posterior
branches of the left upper lobe. The inferior
division of the left upper lobe supplies the
superior and inferior segments of the lingua.
The left lower lobe bronchus then descends
laterally to give off a posteriorly located
apical segment of the left lower lobe and
then the antero-medial, lateral and posterior
basal segmental bronchi. After dividing into
segmental bronchi the airways further
subdivide into subsegmental bronchi and
then, from generation seventeen onwards, Figure 2. The trachea and bronchi. P.L. Shah.
2 ERS Handbook: Paediatric Respiratory Medicine

Table 1. Anatomical subdivisions of the lung
Trachea
Right main bronchus Left main bronchus
Segmental bronchi right Segmental bronchi left
Right upper lobe: Left upper lobe:
Apical Apical
Posterior Posterior
Anterior Anterior
Right middle lobe: Left middle lobe:
Lateral Superior
Medial Inferior
Right lower lobe: Left lower lobe:
Superior (apical) Apical
Medial basal Antero-medial basal
Anterior basal Lateral basal
Lateral basal Posterior basal
Posterior basal
Pulmonary vasculature and lymphatic aorta, subsequently crossing to the left side
drainage The pulmonary artery carries and runs alongside the oesophagus. It ends
deoxygenated blood to the lungs, thereafter in the neck where it enters the left internal
subdividing and eventually becoming jugular vein. The right bronchomediastinal
alveolar capillaries. Oxygenated blood then lymphatic trunk joins the right lymphatic
returns via the pulmonary capillary and duct and enters the venous circulation at the
venous circulation to the left atrium. The junction of the subclavian and internal
pulmonary arteries lie anterior to the carina jugular veins. Leakage of fluid from the
and main bronchi. Each artery then enters thoracic duct is the primary cause of
the lung via the hilum. There are two chylothorax in the paediatric age group.
pulmonary veins on each side (superior and
inferior) that pass in front of and below the Mediastinum The mediastinum is divided
adjacent pulmonary artery and major into superior, anterior, middle and posterior
bronchus. portions. It contains the thymus, which
develops from the third branchial pouch and
The lymphatic drainage of the lungs, pleurae has two lobes located in the superior and
and mediastinum is via visceral lymph anterior mediastinum. Its principle function
nodes. These are arranged along the is the programming of thymocytes.
bifurcation of the trachea, major bronchi Thymocytes, which originate from bone
and peripheral bronchi. Further nodes are marrow, mature into T-lymphocytes and
situated in the mediastinum. The output of have major immune functions, especially in
most of these vessels is into a relation to resistance to infection and the
bronchomediastinal trunk on each side of development of atopic status and allergy. T-
the trachea. Another major lymphatic vessel helper (Th)-1 lymphocytes form part of the
in the chest is the thoracic duct. This starts cellular immune system and are principally
in the abdomen and enters the chest on the involved in the response to infection. Th-2
right side through the aortic hiatus of the lymphocytes are part of the humoral
diaphragm. It then ascends close to the immune system mainly involved in allergic

responses resulting in atopy and allergy- especially in preterm infants. Intercostal
related diseases including anaphylaxis, muscles are also less active during rapid eye
asthma and allergic rhinitis. movement (REM) sleep which lasts twice as
long in infancy as in later life. As the child
The thymus gland is proportionately largest matures and spends more time awake and
in infancy and early childhood; by in the vertical position, gravity acts on the
adolescence it has begun to atrophy and ribs and intercostal muscles pulling them
greatly decreases in size. downwards. The chest also becomes less
circular in shape and more ovoid,
Mediastinal lymph nodes are located in the particularly in the preschool years. The rib
pre-tracheal, paratracheal and subcarinal cage becomes increasingly calcified with age
areas, as well as adjacent to the and consequently stiffer which improves its
oesophagus. mechanical efficiency.
Diaphragm The diaphragm is the principal Development of the lungs
muscle of respiration in childhood. It
consists of a fibro-muscular sheet of tissue Lung development starts very early in fetal
that separates the thorax from the abdomen. life, just before 28 days of gestation, as an
It is comprised of a central membranous endodermal outgrowth of the fetal gut called
tendon to which the muscles of the the ventral diverticulum. Although almost all
diaphragm are attached. These comprise of the lung structure is in place by the time
muscles arising from the xiphoid process of of birth the process continues throughout
the lower sternum, the lower six costal childhood into adolescence.
cartilages and the upper two to three lumbar
Intrauterine lung development Lung
vertebrae. Diaphragmatic muscles are more
development in utero is divided into four
easily fatigued in infancy because they
periods.
contain a smaller proportion of fatigue-
resistant muscle fibres than in later life. The N Embryonic: 3rd to 7th week of gestation.
diaphragm is perforated by a number of N Pseudoglandular: 7th to 17th week.
hiatal openings through which important N Canalicular: 17th to 27th week.
structures pass from the thorax to the N Alveolar period: from 27th week to term.
abdomen. These include the oesophagus
(oesophageal hiatus), the aorta (aortic Embryonic period (37 weeks): During this
hiatus) and the inferior vena cava (vena period the initial lung bud develops as an
caval hiatus). The diaphragm is supplied by endodermal groove from the fetal foregut
the right and left phrenic nerves arising (respiratory diverticulum). The lining of the
through the cervical vertebrae C3, C4 and C5. larynx, trachea, major airways and alveoli is
endodermal in origin. The thyroid, cricoid
Chest wall The chest wall includes the ribs and arytenoid cartilages and their associated
and the intercostal muscles. The ribs initially muscles, originating from the mesoderm of
develop as cartilage. The chest wall the fourth and sixth branchial arches, also
functions as a pump which performs the develop during this period. The developing
respiratory movements driving respiration tracheobronchial tree then subdivides into
itself. In the fetus the ribs are almost at right the major bronchi, lobar bronchi and
angles to the vertebral column and the peripheral airways. Other locally developing
muscles of the diaphragm are arranged mesodermal tissues influence this
more horizontally than in later life. Chest branching pattern. At the end of this period
movements are therefore less efficient in the major subdivisions of lung anatomy
early life than later life when the child adopts have already formed and although the
a more upright posture. The cartilaginous associated blood supply is not fully
nature of the ribs also makes the chest wall developed each lung bud is supplied via the
less stiff, thus, resulting in the potential for pulmonary trunk, which appears at 5 weeks
paradoxical movements and indrawing of gestation from the sixth bronchial arch and
the thoracic cage during inspiration, divides into right and left branches. Each

Trachea Major Segmental/ Bronchioli
Alveoli
bronchi subsegmental Terminal Respiratory Ducts Sac
Airway bronchi
generations 3 1015 810 1 3 3 1
Preacinus# Acinus
Figure 3. Anatomy of the tracheobronchial tree. #: this region comprises the conducting portion including
trachea, bronchi and bronchioli to terminal bronchioles; ": this region comprises a gas exchanging unit
(with alveoli) and includes respiratory bronchioli, alveolar ducts and alveolar sacs. Reproduced from
Dinwiddie (1997), with permission from the publisher.
lung bud is also connected to the evolving as the arterial duct (ductus arteriosus) and
left atrium by a pulmonary vein. The remains patent until the early period of
associated capillaries begin their adaptation to post-natal life. Bronchial
development in the adjacent mesenchyme. arteries also develop directly from the aorta.
The more distal preacinar arteries develop
Pseudoglandular period (717 weeks): During and are fully present by 16 weeks.
this period there is further rapid branching
of the airways. By 16 weeks the terminal Canalicular period (1727 weeks): At this
bronchioles have developed and airway stage the lungs develop their distal
columnar and cuboidal lining cells have architecture. The peripheral airways elongate
appeared. Fetal lung fluid develops and is and the epithelial lining cells become
propelled through the airways by fetal cuboidal in shape in the lower airway
breathing movements first seen at around generations. Mesodermal tissue thins out
10 weeks of gestation with important and the pulmonary microcirculation
consequences for volume expansion of the matures. Terminal bronchioles, respiratory
fluid-filled lungs. Other specialised tissues bronchioles and distal alveolar sacs develop
develop including the cilia from 6 weeks, rapidly. The acinus, which forms the distal
which becomes fully developed, including in gas exchange unit of the lung, develops its
the trachea, by 18 weeks. Cartilage and final structure by 24 weeks; immediately
before this time thin-walled saccules appear
lymph vessels develop from 10 weeks
to develop into individual alveoli. The most
onwards. These spread peripherally through
peripheral pulmonary vascular structures
the developing lungs. Goblet cells, mucus
develop as intimately associated alveolar
glands and airway muscles also first appear
capillary units to form a bloodgas barrier
at this time and continue their development
sufficient to maintain extrauterine life even
throughout prenatal and post-natal life. The
at this gestation (fig. 3).
main pulmonary arteries and veins develop
further; the right pulmonary artery arises The alveolar lining cells subdivide into two
from the proximal part of the sixth right types: Type I and Type II. Each is
branchial arch following which the distal histologically distinguished by 24 weeks
part degenerates. The left pulmonary artery gestation. Type I (gas exchanging) cells
arises from the sixth left aortic arch which occupy 95% of the alveolar lining. Primary
gives off the main artery and then continues surfactant production occurs in Type II cells.

Signalling pathways Overall, lung Table 2. Components of surfactant
morphogenesis is under the control of a
number of signalling pathways. These are Phospholipids 78%
primarily controlled by genetic factors, Dipalmitoylphosphatidylcholine 66%
especially for the development of lung Phosphatidylglycerol 4%
lobulation and the first 16 airway
Phosphatidylethanol 5%
generations. These activities are mediated
through a number of peptide growth factors Sphingomyelin 3%
and more distally by similar substances Cholesterol, glycerides and 12%
modified by local physical factors that fatty acids
regulate distal airway branching, Surfactant proteins A, B, C and D 10%
development of the pulmonary vasculature
and, ultimately, the alveoli. A number of
polypeptides are known to be involved in soluble and acts mainly by decreasing
this process including transforming growth protein-related inhibition of surfactant
factor (TGF)-b, bone morphogenic protein activity. It also has an important role in lung
(BMP)-4, fibroblast growth factors (FGFs), inflammation where it acts as part of the
platelet-derived growth factor (PDGF), host defence mechanism. SP-A levels are
epidermal growth factors (EGF)/TGFs, sonic responsive to pre-natal corticosteroid
hedgehog (SHH), vascular endothelial therapy. SP-B, which is hydrophobic, is an
growth factor (VEGF), insulin-like growth important component of lamellar bodies. It
factors (IGFs) and granulocyte-macrophage facilitates the reduction of alveolar surface
colony-stimulating factor (GM-CSF), as well tension when alveolar volume is reduced
as thyroid transcription factor (TTF)-1 during expiration. SP-C, also hydrophobic, is
protein. another important protein component of
Surfactant lamellar bodies. It appears to function
closely with SP-B in the spreading of
Surfactant is produced in the Type II alveolar surfactant onto the alveolar surface, thus,
lining cells. It has a number of important facilitating its surface tension reducing
functions. The primary role of surfactant is properties. SP-D is water soluble and not
to promote and maintain lung volume and directly associated with the function of
prevent alveolar collapse during expiration. surfactant phospholipids. Its principal role
Thus, surfactant decreases the mechanical appears to be as an innate immune system
work and energy expenditure of breathing, protein that acts as part of the host defence
especially at birth. Surfactant also has an against infections, e.g. with common
important role in host defence of the lungs respiratory tract bacteria and viruses.
against infection and in their response to
tissue insults, such as barotrauma during ABCA3 is another important substance
treatment. Genetic defects in surfactant related to surfactant function. It is an ATP
production are now known to be major binding cassette protein. Its precise function
aetiological factors in several chronic and is not yet fully known but it has been shown
potentially lethal lung diseases of infancy to be widely present in Type II alveolar
and childhood (table 2). epithelial lining cells. Its most likely action is
in the inward transport of lipids for
Type II alveolar lining cells are principally surfactant production.
involved in the production, storage,
secretion and recirculation of surfactant Surfactant secretion occurs by a process in
through the intracellular lamellar bodies. which lamellar bodies are released from
The principal surface active lipid in Type II lining cells within the alveoli.
surfactant is phosphatidylcholine. Phospholipids combine with SP-A, SP-B and
SP-C. Secretion is stimulated by stretching
Four surfactant proteins have been of the lung parenchyma, as well as by
identified. Surfactant protein (SP)-A is water extrinsically administered b-adrenergic

agonists. Surfactant lasts for approximately stimulates neutrophilic destruction of
5 h before being broken down. bacteria, including Staphylococcus aureus,
Approximately 50% of active surfactant is Streptococcus pneumoniae and Escherichia coli.
recycled through the lamellar bodies before
being reused. When secreted into the alveoli Exogenous surfactant is not only used in the
and distal small airways, mature surfactant treatment of preterm infants but also in a
forms a structure (tubular myelin) that, variety of diseases in older children.
along with other compounds, lines the
During this pseudoglandular period the
alveolar surface. Fully functional surfactant
lungs reach a liquid-filled volume similar to
secreted in normal amounts into the alveoli
the air filled FRC after birth of ,25
results in decreasing surface tension as the
30 mL?kg-1. Fetal breathing movements at
alveoli shrink in volume, preventing their
this gestation are especially important in the
collapse at the end of expiration. On
maintenance of the developing lung
inspiration surface tension rises.
volumes.
At birth, even in the presence of surfactant,
In summary:
an initial opening pressure is required to
establish a stable functional residual N Surfactant is predominantly composed of
capacity (FRC) of ,30 mL?kg-1. This is in the phospholipids, principally
order of 15 cmH2O. In the surfactant- phosphatidylcholine.
deficient pre-term infant, pressures twice as N Surfactant contains four proteins A, B, C,
great may be needed just to initially open and D.
the alveoli with a tendency for recurrent N Surfactant proteins have important
collapse at end expiration. The presence of surface tension lowering functions and
adequate amounts of active surfactant also innate immune modulating properties.
results in the achievement of significantly N Genetic deficiencies of surfactant
greater lung volumes at full inspiration. proteins cause serious, and potentially
Several potentially severe conditions occur lethal, lung disease in neonates and
in young infants and children if infants.
abnormalities exist in the surfactant Alveolar sac period (27 weeks to term)
production or breakdown pathways. These
include potentially lethal or severe lung This is the final stage of fetal lung
disease in early life if there are genetic development. It is at this stage of fetal life
mutations of SP-B, SP-C, ABCA3 and TTF-1. that the lungs are able to sustain
These conditions are important causes of independent breathing. The epithelial lining
respiratory distress syndrome in full term, cells further differentiate and establish their
otherwise normal, babies. Another condition intimate inter-relationship with the epithelial
of variable severity, alveolar proteinosis, lining surface of the alveoli. Distal lung
occurs in older children and adults when growth continues as the respiratory
there is deficiency of GM-CSF, a substance bronchioles subdivide into saccules, which
which is vital for the breakdown of then form their final specialised structure
surfactant. becoming alveoli. Alveoli are lined by two
distinct types of cell. Type I alveolar lining
Surfactant proteins have important cells cover 95% of the alveolar surface and
immunological functions. SP-A increases have a thickness of 0.10.01 mm. Type II
macrophage activity in the lung. It also alveolar lining cells are thicker, with a
facilitates the destruction of various diameter of 10 mm. Although covering only
microorganisms by other immune- 5% of the alveolar surface, they play a vital
modulated cells within the lung. The roles of role in surfactant production and
SP-B and SP-C in lung inflammation have not metabolism.
yet been fully evaluated. SP-D stimulates
the phagocytosis of several types of micro- During this period the pulmonary
organisms by alveolar macrophages. It also vasculature develops rapidly. The arterial

Length from
Age
TB to pleura
16 weeks 0.1 mm TB Pleura

gestation
0.1 mm
RB3
19 weeks 0.2 mm TB
gestation RB1
RB3 TD S3
28 weeks 0.6 mm TB S1
gestation RB1 S2
TS
Birth 1.1 mm TB S3
RB1 S1 S2
TS
2 months 1.75 mm TB
RB1 RB2
AS
At
AD2 AD6
7 years 4 mm TB RB1 At
RB2 RB3
Figure 4. Development of the acinus. Stages of acinar development in fetal and post-natal life. TB:
terminal bronchiole, RB: respiratory bronchiole; TD: terminal duct; S: saccule; AD: alveolar duct; At:
atrium; AS: alveolar sac. Reproduced from Hislop (1974) with permission from the publisher.
muscle coat is proportionately thicker than childhood. This is covered in detail in this
in later life. This allows for intense Handbook in the Sleep-related Disorders
vasoconstriction during periods of section. Important reflexes that originate in
intrauterine hypoxia but is a major the chest wall are the HeringBreuer reflex
contributory factor to persistent pulmonary and the Heads paradoxical reflex. The
hypertension in the neonatal period (fig. 4). HeringBreuer reflex is an inspiratory
Control of breathing inhibitory response mediated through the
vagal nerves. It is particularly active in the
The development of control of breathing is a control of the rate and depth of breathing in
complex process beginning early in fetal life the neonatal period and during the first
and is continuously changing throughout 2 months of life. The Heads paradoxical

reflex is initiated by rapid lung inflation and Table 3 Factors affecting lung growth and development
precipitates an increase in respiratory effort.
The increased compliance of the ribcage in Abnormal embryonic and fetal development
the neonatal period can lead to distortion Genetics
during REM sleep, resulting in respiratory Hormones
irregularity and, in some cases, apnoea.
Maternal and fetal malnutrition
Post-natal lung development Reduced fetal breathing movements
After birth the alveoli become multilocular Reduced fetal lung fluid volumes
and progressively increase in size and Inadequate size of thoracic cage
numbers with further out budding of the
Impaired adaptation to post-natal life
alveolar saccules. By term, approximately
one-third to one half of the adult alveolar Preterm birth and its treatment
numbers is present. Thereafter, alveoli Maternal smoking in pregnancy
continue to increase in number, especially
Pre- and post-natal infection
during the first 2 years of life reaching
100250 million by the end of this period.
Adult numbers of alveoli, 300400 million,
are already present by the age of 23 years. malformations, e.g. diaphragmatic hernia,
Boys have more alveoli than girls. Alveolar can have profound effects on the growth and
multiplication continues at a reduced rate development of both the affected and also
and is finally completed by 810 years of the contralateral lung, especially if it arises
age. After this there is a continuing increase during the pseudoglandular period when
in diameter of the large airways and further airway generation is occurring at its
remodelling of the alveoli until physical maximum rate. Reduced alveolarisation is
growth is complete. The peripheral airways another associated complication. Genetic
increase in relative size and proportion factors are particularly important and play a
compared to the central airways until the significant role in controlling various
age of 5 years. Lung volumes increase hormone-related influences, including
throughout childhood. A final growth spurt thyroid hormones (TTF-1), FGF, PDGF,
occurs in adolescence associated with a IGF-1 and TGF-b, as well as steroid
parallel increase in lung volumes which lasts hormones, specifically oestrogen a and b
longer in boys than in girls. TLC at birth in a and androgen receptor hormones which are
3-kg newborn infant is, on average, 150 mL expressed in developing lung tissue.
(50 mL?kg-1) increasing to 6.0 L Maternal malnutrition results in low birth-
(75 mL?kg-1) in adult males and 4.2 L weight babies as does placental
(60 mL?kg-1) in adult females. During the insufficiency. These factors can lead to
first 10 years of life the rib cage gradually reduced lung growth for gestation. Severe
changes from a horizontal orientation to the maternal malnutrition, studied at the end of
downward (caudal) slope of the adult. World War II, has been shown to result in an
Ossification of the ribs also progresses increase in COPD in adult life in affected
throughout childhood into early adult life offspring. Fetal breathing movements are
reaching completion in the early 20s. first seen at 10 weeks gestation and are
important for lung growth because of their
Factors affecting lung growth and role in the development and maintenance of
development lung volume. Lung cell proliferation is
A number of factors can adversely affect inhibited if fetal breathing movements are
lung growth and development throughout diminished. Absence of fetal breathing
both fetal and post-natal life; these are results in pulmonary hypoplasia including a
shown in table 3. decrease in distal lung airspaces.
Hypoplastic lungs secondary to reduced
Abnormalities of embryonic and fetal fetal breathing movements have impaired
development, including congenital synthesis and secretion of pulmonary

surfactants resulting in abnormal lung Thus, the growth and development of the
mechanics at birth. Reduced amniotic fluid lungs is a continuous process from early
volumes during pregnancy due to early fetal life, throughout childhood and into
rupture of the membranes or secondary to early adulthood. The most important
abnormal renal function, which results in changes occur before birth and in early
oligohydramnios, can result in pulmonary childhood. It is at these times that other
hypoplasia. Intrauterine pleural effusions, adverse events, such as severe intercurrent
such as congenital chylothorax, can result in infections, are most likely to have profound
inhibition of lung growth. Syndromes effects on future structure and function.
involving reduced thoracic cage
development, for example Jeunes Further reading
asphyxiating thoracic dystrophy, are
associated with pulmonary hypoplasia and N Dinwiddie R. Development of the Lungs.
impaired surfactant secretion. Another In: Dinwiddie R, ed. Diagnosis and
Management of Paediatric Respiratory
cause of pulmonary hypoplasia relates to
Disease. 2nd Edn. Edinburgh, Churchill
respiratory muscle weakness, such as Livingstone, 1997; pp. 18.
occurs in congenital myopathies and N Gaultier C. Developmental Anatomy and
neuropathies. Impaired adaptation to Physiology of the Respiratory System. In:
extrauterine life leading to chronic hypoxia Taussig LM, et al., eds. Pediatric
or treatment-induced hyperoxia, with or Respiratory Medicine. 1st Edn. St Louis,
without long-term ventilation resulting in Mosby, 1999; pp. 1837.
barotrauma-induced lung injury, can also N Hislop A, et al. (1974). Development of
impair age-related lung growth and the acinus in the human lung. Thorax; 29:
development. Maternal smoking in 9094.
pregnancy is a well-described cause of N Inanlou MR, et al. (2005). The role of fetal
breathing-like movements in lung orga-
impairment of small airway development
nogenesis. Histol Histopathol; 20: 1261
with immediate and long-term
1266.
consequences on small airway development N LeVine AM, et al. The Surfactant System.
and resultant hyperresponsiveness. Severe In: Chernick V, et al., eds. Kendigs
infections in early life, such as with Disorders of the Respiratory Tract in
adenovirus, can lead to obliterative Children. 7th Edn. Philadelphia,
bronchiolitis and impaired post-natal lung Saunders Elsevier, 2006; pp. 1722.
development.

Applied respiratory
physiology
Caroline Beardsmore and Monika Gappa
Knowledge of respiratory physiology is considering the applications of these

essential for understanding the pathological measurements in a clinical context the
changes in disease, and the application and underlying principles of the most
interpretation of respiratory function tests. commonly used measurements will be
Pathological changes in lung physiology will summarised.
vary according to disease or condition, but
Spirometry and the flowvolume loop
common patterns can be observed
according to whether the condition is Spirometry is the means of recording the
primarily obstructive or restrictive in nature. volumes of inspired and expired air, and the
This dichotomy may be overly simplistic for maximum flows during the respiratory
describing some of the conditions that the manoeuvres.
respiratory paediatrician will have to
manage, but can serve as a useful starting Equipment and procedure The original
point (fig. 1). Whatever condition is under spirometers used from the inception of the
technique until the 1980s were mechanical
consideration, spirometry remains a
devices with a chamber from which the
cornerstone of assessment, and
subject breathed in and out. The chamber
measurement of lung volume is also vital
incorporated a low-resistance movable
for interpretation. This section will briefly
section that accommodated the change in
summarise the underlying measurement
volume without any appreciable pressure
principles and discuss how to approach
change, and the movement was translated
clinical questions by applying available
into a recording, either directly via a pen on
respiratory function tests. Before a chart or via a transformer into a digital
recording (fig. 2). These mechanical
spirometers measured changes in volume
Key points directly, and flow was calculated secondarily.
The historical devices have been superseded
N Distinguishing obstructive and by electronic spirometers which have the
restrictive disorders is simplistic but a advantages of portability, simplicity of
helpful starting point. cleaning and ease of use. The electronic
spirometers usually incorporate a
N A combination of spirometry and body
pneumotachograph or an ultrasonic flow-
plethysmography is most useful.
meter to measure flow, with volume
N Visual inspection of the flowvolume subsequently being obtained by
loop, including the inspiratory limb, is differentiation.
essential.
Children who are able to cooperate with
N Assessment of inflammation is testing will be asked to make an airtight seal
becoming increasingly recognised as around the mouthpiece, breathe steadily
an important part of the overall and then make maximum inspiratory and
evaluation. expiratory manoeuvres. The recordings of
volume change showing tidal breathing and

a maximum (slow) respiratory manoeuvre Measurements of lung volume
are shown in figure 2. In addition to a slow
manoeuvre, a full forced manoeuvre is The principal means of measuring absolute
generally recorded. The derivation of a flow lung volumes are gas dilution (usually
volume loop from the volumetime helium dilution), plethysmography and
recording (the spirogram) is shown (fig. 3). nitrogen washout, all of which measure
The manoeuvres are repeated several times functional residual capacity (FRC) and
in order to achieve the best (highest) values derived lung volumes (refer to the
and assess repeatability. Internationally Pulmonary function testing and other
accepted guidelines exist for the technical diagnostic tests section in this Handbook).
specifications and performance of The underlying principle for
spirometers, the conduct of the test, and plethysmography differs from the gas
quality control. Some modifications may be dilution or washout techniques, and this
necessary for children, and the use of may be utilised to characterise the
incentive spirometry may be particularly pathophysiology in different disease states.
helpful in younger children. Equipment and procedure Whole body
plethysmography is used to measure
(intra)thoracic gas volume. The principle of
Restrictive conditions: Obstructive conditions: the measurement is such that it includes the
lnterstitial lung disease, e.g. asthma, including volume of all the air in the chest, whether in
neuromuscular disease extrathoracic airway
(e.g. Duchennnes obstruction communication with the airway and
muscular dystrophy)and ventilated, or not. In contrast, FRC is
skeletal abnormalities generally taken to include the volume of the
(e.g. scoliosis) lungs in free communication with the airway
opening and therefore ventilated.
Spirometry (principally The pattern of the
Nevertheless, the abbreviation FRCp (FRC by
VC) shows the flowvolume loop obtained plethysmography) has gained popularity and
extent of restriction and through spirometry can will be used hereafter. The measurement of
is helpful for regular indicate the site of FRCp is based on Boyles law. The subject is
monitoring. obstruction (intrathoracic
Lung volume or extrathoracic) and
enclosed in a cabin, which is almost airtight,
measurements will whether it is fixed or and breathes through a pneumotachograph
show the extent of the variable. that measures airflow. A shutter is closed in
deficit at either end of Changes in FEV1,FVC and the device through which the subject is
the VC range. expiratory flows can
Measurements of quantify the extent of
breathing, transiently occluding the external
compliance and gas intrathoracic obstruction,
transfer may be helpful and perform a similar
a) b)
where the underlying function for extrathoracic
condition is pulmonary obstruction. 4.0
in origin. Lung volume
3.0 TLC
Tests of respiratory measurements can show
Volume L
muscle strength can the extent of any 2.0

help in the evaluation hyperinflation or gas VC
of neuromuscular trapping. 1.0
disease. Other investigations (e.g.
gas mixing) may show 0.0 FRC
abnormal function before RV
spirometry becomes
abnormal and may be
helpful in monitoring Time h
individuals and in research.
Figure 2. a) Original type of mechanical
Figure 1. Consideration of abnormalities as either spirometer and b) associated recording of changes
restrictive or obstructive in nature. These are not in volume. The recording shows three tidal breaths
mutually exclusive and individuals frequently show at FRC followed by inspiration to TLC, and
elements of both. expiration of VC to RV.

a) b) is switched to breathe 100% oxygen from
3.0 TLC 3.0
PEF PEF
either a reservoir or a bias flow. The expired
nitrogen is quantified and the lung volume
1.5 1.5 FEF50 calculated. In simple terms, if the alveolar
Volume L
50% VC concentration of nitrogen was 80% and 2 L

0.0 0.0 of nitrogen was exhaled during the test, the
FEV1
FEV1
lung volume would be 26100/80 L, or 2.5 L.
RV The measurement is usually continued until
1.5 1.5
the expired nitrogen is ,2.5%; continuation
0 1 2 3 4 0 5 10
Time s Flow L.s-1
beyond this point results in significant
amounts of nitrogen dissolved in the blood
Figure 3. Relationship between a) spirogram and coming out of solution in the lungs and
b) expiratory flowvolume curve, showing resulting in an artefactually high estimation
inspiration to TLC followed by forced expiration to of lung volume.
RV. PEF occurs early in the manoeuvre, followed
The principle behind the test is not
by smooth decline in flow to RV. Note that FEV1
restricted to nitrogen, and it is possible to
can only be derived from the spirogram.
use other tracer gases. These are first
washed in to the lungs by giving the
airway. The subject makes a respiratory subject a pre-set concentration of inert,
effort against the shutter and the alveolar nonsoluble gas to breathe until alveolar
pressure change is measured directly from (end-tidal) concentration is equal to the
the mouthpiece. The change in thoracic inspired concentration. One advantage of
volume as the subject compresses or other gases can be the avoidance of
expands the chest is measured indirectly breathing 100% oxygen, which can have
from the cabin pressure and used in the undesired effects on pulmonary blood flow
calculation. in certain patients (see chapter 3).
Once FRCp has been measured during the Helium dilution Measurement of lung
transient period of airway occlusion the volume by helium dilution requires a
subject continues to breathe through the mechanical spirometer which, at the start of
mouthpiece and, after one or two breaths, the measurement, is set to a known volume
makes a full inspiration and expiration so and contains a known concentration of
that the TLC and residual volume (RV) can helium (typically 10%). The subject is
be determined (refer to the Pulmonary connected to breathe tidally from the
function testing and other diagnostic tests spirometer, with carbon dioxide being
section in this Handbook). absorbed in order not to provoke
hyperventilation. Oxygen is titrated into the
Nitrogen washout The principle behind this system in order to maintain a stable
technique is to quantify the volume of baseline volume and prevent onset of
nitrogen within the lungs and then, knowing hypoxia. As the air in the lungs mixes and
the alveolar concentration of nitrogen, equilibrates with that in the spirometer, a
calculate lung volume. Therefore, the new, lower concentration of helium is
equipment combines a means of measuring established. When this is stable, the FRC can
volume, usually a pneumotachograph, and a be calculated as follows:
nitrogen analyser or equivalent. The
technical issues associated with nitrogen V1C15V2C2
analysers mean that nitrogen is usually
where C1 and C2 are the initial and final
measured either by mass spectrometry or by concentrations of helium, V1 is the starting
quantification of other gases (oxygen and volume of the spirometer and V2 is the final
carbon dioxide) and subtracting these from volume, i.e. spirometer and lung volume
100%. The procedure requires the subject to combined. Rearranging:
breathe through a mouthpiece and, when
steady respiration is established, the subject V25V1C1/C2

and early changes within the small airways than
parameters obtained using full forced
FRC5V2-V1 expiratory manoeuvres.
The calculated value of FRC is likely to need Assessment of obstruction
some small adjustment for the dead space of
the mouthpiece and any connections to the Patients with obstructive disorders form the
spirometer. The spirometer will be at room largest component of the workload of the
temperature, but (by convention) lung respiratory paediatrician, with diseases
volume is expressed at BTPS (body involving the small airways (mainly asthma
temperature, ambient pressure, saturated and CF) being the most common.
with water vapour). Most modern equipment Spirometry continues to be an essential part
will have the corrections within the software of assessment and monitoring,
so that the measurement shown will be demonstrating deviation from predicted
accurate. Usually three determinations are values and changes over time or in response
made and a mean value reported. to treatment. The typical patient with
obstructive respiratory disease will have an
Which measurement of lung volume is most expiratory flowvolume loop that shows a
appropriate? The measurement of choice distinct concave shape, such that flows at
will depend on why the measurement is high lung volumes (peak expiratory flow
being taken, i.e. what is the question to be (PEF) and forced expiratory flow at 25% of
answered. Measurements based on dilution FVC (FEF25)) will be relatively spared and
or washout measure the volume of lung that those at lower lung volumes (FEF50 and
is being ventilated, i.e. functional, available FEF75) will show a greater reduction. Visual
for gas exchange. Trapped gas will not be inspection of the flowvolume loop is an
included. Plethysmography measures essential part of the evaluation. During the
trapped gas in addition to the ventilated course of expiration, the site of flow
portions of the lung, because all the air in limitation moves progressively down the
the thorax (whether trapped or not) is bronchial tree into ever smaller airways,
subjected to changes in pressure and where the extent of any airway narrowing
volume that are used in the calculation. In (e.g. caused by oedema of the airway
healthy individuals the differences in FRC epithelium mucosa) has a greater effect.
may be slight but in others they can differ
considerably, and the size of the difference When FEV1 and FVC are compared with
may be informative. Therefore, in some predicted values both indices may be within
patients with complex conditions, it may be normal limits, but in obstructive airway
helpful to include different methods to disease the FEV1/FVC ratio is usually
assess lung volumes in the evaluation. reduced and this can be helpful in
Measurements based on dilution or interpreting spirometry. However, FEV1/FVC
washouts have the advantage that the time should not be considered in isolation,
taken to complete the measurements can be because it cannot convey whether either or
informative. Where pulmonary function is both component parts are within normal
good, equilibration of gas or the ease with limits or not. For example, when assessing
which a gas is washed out is rapid. More response to bronchodilator in an asthmatic
accurately, the amount of ventilation patient, there may be a significant
required to achieve equilibration or washout improvement in both FEV1 and FVC, but
is less in a healthy individual than in a little change in FEV1/FVC. When assessing
subject with deranged function, and changes in response to treatment it is
assessment of this adds valuable helpful to take account of changes in the
information. This change in ventilation can shape of the flowvolume curve, since it is
be quantified by parameters of ventilation not uncommon to measure a significant
inhomogeneity such as the Lung Clearance improvement in FEV1 (usually an increase of
Index (LCI) and other indices which have o12%), but for the patient to still have a
been shown to be much more sensitive to significant degree of obstruction so that the

expiratory flowvolume curve continues to dilate the extrathoracic airway, so the
show marked concavity. Vice versa, a change abnormality will not be evident. During
in the flowvolume loop from concave to inspiration the pressure gradient will be
linear or convex may be the sole indicator of reversed and the tendency may be for
bronchial reversibility in patients with unstable regions of the extrathoracic airway
asthma, even if the parameters are within to be sucked inwards. The inspiratory flow
the normal range. will be low and may be variable. During
performance of the test it may be noticeable
The shape of the flowvolume loop can also that the patient takes a long time to inspire
help with the diagnosis of obstruction in the fully to TLC; a technician or physiologist with
large airways. With a fixed obstruction, such experience of observing and coaching
as a subglottic stenosis, the maximum flow children can confirm whether the test is
that can be achieved will be determined by indicative of extrathoracic obstruction or not.
the physical dimensions of the airway at its
narrowest point. Depending on the In cases where there is severe obstruction of
underlying cause of the obstruction, this the small airways (e.g. an exacerbation of
may change little as the child grows, so that asthma or advanced CF), the distribution of
the absolute peak inspiratory and expiratory lung volumes may become abnormal.
flows remain fairly constant from one year During the course of expiration the airways
to the next, with progressive worsening of become narrower as lung volume decreases,
the flows as related to predicted values. The and when the airways are abnormally
flowvolume curve will appear flattened on narrowed (e.g. due to oedema, excessive
both the inspiratory and expiratory limbs, mucus or contraction of the smooth
with a loss of a well-defined peak flow and muscles within the airway wall) they may
no significant response to bronchodilator close completely at an early stage in the
(fig. 4). manoeuvre. When this happens, RV is
increased and vital capacity (VC) is reduced.
Where there is an extrathoracic variable Since the range of prediction for RV is fairly
obstruction, the abnormality will be evident wide, the RV/TLC ratio is a useful indicator
on the inspiratory limb of the flowvolume of early airway closure. If airway narrowing
loop (fig. 4), and expiration may be becomes more marked, so that airway
unaffected. During expiration the positive- closure begins within the normal tidal
pressure gradient extending from the lung breathing range, the patient will adopt a
down to the airway opening will tend to pattern of breathing which involves
breathing at an elevated FRC in order to
a) 12 Baseline b) 4 maintain airway patency. If this becomes a
Predicted
8 3 frequent or extended event, such that the
2 inspiratory muscles become trained, it is
Flow L.s-1
Flow L.s-1
4
1 possible that the TLC (which is dependent,
0 0
in part, on respiratory muscle strength) may
1
increase. A reduction in VC should be an
4 indicator for measurement of absolute lung
2
4 8 1 2 3 4 volumes in such patients. The technique of
Volume L Volume L
choice for this should be plethysmography,
since this technique can quantify trapped
Figure 4. a) Fixed obstruction (tracheal stenosis), gas. In the most extreme cases, where
with flattening of both inspiratory and expiratory patients have extensive airflow obstruction
curves. On expiration, flow is reduced primarily at and uneven distribution of pressure changes
high lung volume, with normal flow in the last within the chest, the assumptions
quarter of VC. b) Variable upper airway underpinning plethysmography may no
obstruction (laryngeal polyp), illustrating reduced longer be valid but in these individuals there
flow through inspiration but normal pattern to is usually clear clinical evidence of
expiratory curve. hyperinflation.

Assessment of restriction predicted loop, and almost invariably the
loops will be aligned at TLC (fig. 5). To the
Restrictive diseases are characterised by a uninitiated, this will give the erroneous
reduction in TLC, leading to restriction in impression that the reduction in VC occurs
lung expansion. Usually, reduced VC in the due to elevation of RV and not by a
forced expiratory manoeuvre will prompt reduction in TLC. Flows at high lung
further assessment of lung function to volumes (PEF and FEF25) are reduced in
diagnose or exclude true restrictive restrictive disease, not because of airway
respiratory disease. The subject may report obstruction but because the volumes at
shortness of breath on exertion with poor which they are measured are constrained.
exercise tolerance, or in severe cases Alignment of the recorded flowvolume loop
shortness of breath on mild exertion or at with the predicted loop at TLC will further
rest. Where the underlying condition is compound the impression that flows are
known, such as a skeletal or neuromuscular reduced; alignment at RV may be helpful in
disorder, spirometry will be part of the these cases.
assessment, usually on a regular basis. A
single assessment is usually of limited Measurement of absolute lung volumes will
value, since the range of predicted value is confirm whether the deficit in VC is
wide. Serial measurements are more exclusively at the upper end (i.e. reduction in
informative, for example in the early stages TLC only) or whether RV is also increased,
of GuillainBarre syndrome as a pointer to as may happen in skeletal abnormalities. RV
probable need for mechanical ventilation, or may also be elevated in severe obstructive
to monitor the progression of scoliosis. disease, but changes in spirometry will
usually distinguish between the two.
The shape of the expiratory flowvolume Measurements of absolute lung volumes are
loop in pure restrictive disorders in children all based on determination of FRC, which
will generally show a linear or even a convex may be influenced by the posture of the
descending portion, in contrast to that subject. The number of individual
observed in obstructive disorders. Most measurements performed may also affect
spirometers will display the flowvolume the accuracy, and is generally higher for
loop together with a schematic of the plethysmography than other techniques
where a maximum of three determinations
a) b) is usual. In contrast, the within-test
6 Predicted 6 Predicted
4 4 repeatability of spirometry is generally good,

2 2 making VC the index of choice for
Flow L.s-1
Flow L.s-1
0 0 monitoring changes in restrictive disease.

2 2 Where the restriction is due to a
4 4
neuromuscular condition, spirometry may
6 6
be more variable and the flowvolume loop
0.5
1.0
1.5
2.0
2.5
3.0
0.5
1.0
1.5
2.0
2.5
3.0
can give the impression of inconsistency of

Volume L Volume L
effort; in these cases the operator must be
alert to the tiring effect of repeated forced
Figure 5. Flowvolume loop from a child with
restrictive disorder, including a schematic of the manoeuvres and avoid too many
predicted expiratory flowvolume loop with a VC unnecessary and fruitless attempts at
of 3.0 L predicted. a) The actual flowvolume loop achieving higher values of VC.
aligned with the schematic at TLC. It appears as if
the expiratory flows are substantially below the When the restrictive pattern results from a
predicted flows. b) The actual flowvolume loop muscular condition, such as muscular
aligned at RV, showing that measured expiratory dystrophy, if the diaphragm is involved the
flows coincide with predicted flows over much of VC may be further reduced when the
the VC. Note that the precise positioning of the patient lies supine when compared to an
actual loop on the schematic requires upright posture. If the diaphragm is weak
measurement of absolute lung volumes. or incompetent, the abdominal contents

move up into the thorax when the patient oximetry at rest and during exercise is easy
lies down, whereas when the subject is to apply and informative when abnormal; a
upright the gravitational force prevents this finding of normal saturation is reassuring
from happening. Assessing the posture- but can disguise the presence of significant
related change may therefore be relevant if lung disease.
surgery is contemplated. Although
sequential measurements of VC are Assessment of inflammation
undoubtedly helpful in monitoring changes Applied respiratory physiology has
in the function of patients with muscle historically been mainly limited to studies of
disease, it may be difficult to interpret pulmonary mechanics and gas exchange,
them if it is impossible to make an but should properly be extended to
accurate measurement of body height, as is peripheral lung function. In the clinical
often the case in nonambulant patients setting this should include an assessment of
who may also have developed scoliosis. A the degree of inflammation, particularly in
measurement of VC may have increased in asthma. The most common means of
absolute terms from one annual review to assessment is measurement of the exhaled
the next, but the net effect may yet be nitric oxide fraction (FeNO). Measurement of
deterioration if the increase in VC has not nitric oxide is also relevant in screening for
kept up with linear growth. An alternative primary ciliary dyskinesia, because levels of
approach is to measure maximum nasal FeNO are lower than in healthy
inspiratory and expiratory pressures individuals. Equipment for measuring FeNO
directly, which has the advantage that ranges from laboratory-based analysers
predicted values can be related to age using a chemiluminescence technique to
rather than height. hand-held, portable devices that incorporate
an electrochemical sensor. The
Interstitial lung diseases are rare in children
measurement of FeNO requires that the
but also result in a restrictive pattern with a
subject maintains a steady expiratory flow
reduction in TLC, although FRC and RV may
for a minimum period of 4 s, which is
be normal. In these children the ability of usually achieved by having the subject
gases to diffuse from the alveoli into the breathe out against a resistance, with the
blood may be reduced, a situation that can value of FeNO (expressed in parts per billion)
also arise in children treated with certain being available within approximately 2 min.
medications for cancer. Assessment of A detailed review of the technical aspects
TLCO, from its components KCO and alveolar and clinical applications is available (see
volume (VA), can be informative in children chapter 3). The measurement of FeNO may
able to perform the necessary manoeuvre. contribute to confirming a diagnosis of
The most common technique is the single- asthma, but has a greater role in assessing
breath method. In brief, the subject breathes response to steroids. Failure of high levels of
out to RV, then takes a full inspiration of a FeNO to respond to steroids may alert the
gas mix that includes 0.3% carbon clinician to poor adherence on the part of
monoxide and a proportion of an inert, the child with asthma or the parents.
insoluble gas (usually helium or neon),
followed by a 10-s breath-hold and a slow, Measurement of FeNO can be considered a
steady exhalation. The rate at which carbon marker of inflammation, but in this regard it
monoxide is transferred out of the lungs and may be of most help in asthma. In CF
into the blood can be calculated and related (where airway inflammation is a feature)
to the volume of the lungs, determined from values of FeNO are normal or even low. In
the dilution of the inert gas. The cooperation situations where FeNO may not be useful,
required for successful measurements looking at the profile of inflammatory cells
means that the transfer factor cannot be or other biomarkers in sputum may be
measured in very young children, but it may informative (see chapter 3) but the value of
be possible in some as young as 6 years of various biomarkers is still being evaluated.
age. From a practical perspective, pulse Sputum may be produced spontaneously,

particularly in patients with CF, but can be N Horstman M, et al. (2005). Transfer
otherwise obtained by sputum induction factor for carbon monoxide. Eur Respir
with hypertonic saline. In children where this Monogr; 31: 127145.
is not possible, bronchoalveolar lavage can N Miller MR, et al. (2005). Standardisation
be used to obtain the sample in those of spirometry. Eur Respir J; 26: 319338.
individuals where the importance of the N Quanjer PH, et al. (2012). Multi-ethnic
reference values for spirometry for the 3-
sample merits the invasiveness of the
95-yr age range: the global lung function
procedure.
2012 equations. Eur Respir J; 40: 1324
1343.
Further reading N Quanjer PH, et al. (1994). [Lung volumes
and forced ventilatory flows. Work Group
N Beydon N, et al. (2007). An official on Standardization of Respiratory
American Thoracic Society/European Function Tests. European Community
Respiratory Society statement: pulmonary for Coal and Steel. Official position of
function testing in preschool children. the European Respiratory Society]. Rev
Am J Respir Crit Care Med; 175: 13041345. Mal Respir; 11: Suppl. 3, 540.
N Goldman MD, et al. (2005). Whole-body N Troosters T, et al. (2005). Respiratory
plethysmography. Eur Respir Monogr; 31: muscle assessment. Eur Respir Monogr;
1543. 31: 5771.

Immunology and defence
mechanisms
Diana Radler and Bianca Schaub
The immune system is a system of itself, but also in closely connected

interdependent cell types that collectively regulation with the adaptive system.
protect the body from various diseases with
increasing specificity of immune regulation. Innate defence mechanisms
In general, it is composed of two major Innate immunity of the lung The lung is
parts of immune defence, namely the innate exposed to a multitude of airborne
and the adaptive immune system, also pathogens while only very few cause
designated as the first- and second-line of respiratory infections. This observation is
defence, respectively. In order to keep a proof of the efficiency of the lungs defence
healthy immune balance, the innate defence system. The innate immune system is
system needs to be regulated efficiently by composed of a mechanical, physical and
chemical barrier, which act together in the
defence against invading microorganisms
(fig. 1).
Key points
The first defence mechanism of the lung is
N Innate immune mechanisms an initial mechanical barrier to avoid the
comprise a mechanical, physical and invasion of particles .5 mm into the upper
chemical barrier, which act together in airways. This barrier comprises the:
the defence against invading
microorganisms. N nasal hairs,
N The airway epithelium forms a N nasopharynx channels,
physical barrier against inhaled N glottis,
substances and contributes to host N trachea,
defence by producing mediators of N small branches of the bronchi and
the chemical barrier, including bronchioles.
chemokines, cytokines, antimicrobial
The surface of the airways is covered with
peptides, proteinase inhibitors and
mucins and glycoproteins which trap
surfactant proteins.
microorganisms. This complex is then
N Adaptive immune mechanisms cleared by cilliary movement of the mucus to
include T-cell-mediated responses of the oropharynx.
different subpopulations and
components of the humoral and Cell types participating in innate immunity
mucosal immune system. Several cell types participate in initiating and
maintaining the innate immune response
N Interaction of innate and adaptive and link the innate and adaptive part of the
immune regulation is required for immune defence (fig. 1). Macrophages
specific defence against respiratory engulf and digest pathogens by
diseases, involving prenatal and post- phagocytosis and initiate the adaptive
natal factors. immune system. Dendritic cells are a link
between the innate and adaptive immunity,

Allergens, microorganisms, pollutants
Mucins
Recognition of pathogens Chemical barrier Mechanical barrier Glycoproteins
Collections AMPs (defensins, LL-37)
Cilia
NOD1 and NOD2 Lysozyme
TLRs Lactoferrin
Physical barrier
Innate Airway epithelium Adaptive
IL-10 Mast cell T-cell CD4+ Nave
IL-12 Prostaglandins Th9 cell Th22 cell IL-17 CD8+
IFN- T-cell
G-CSF Histamine CD8+
TNF- IL-9 IL-22
IL-8 Th17 cell
Macrophage MHC II CTL
DC TCR IFN-
Cytotoxins
Granulocytes NK cell
B-cell
Th0 cell Th1 cell
Basophil Eosinophil Neutrophil (PMN) TLR
IL-4
IL-13
IFN- Th2 cell Ig
TNF- Treg
Chloramines
Histamine Toxic granule proteins TGF-
Leukotrienes IL-10 Plasma cell
Prostaglandin derivates
ion
gulat
Dysre
Respiratory diseases
Figure 1. Overview of the initiation and interaction of the innate and adaptive immune system. LL-37:
cathelicidin; IL: interleukin; G-CSF: granulocyte colony-stimulating factor; DC: dendritic cell; NK: natural
killer cell; Th: T-helper cell; TGF-b: transforming growth factor-b; CTL: cytotoxic T-cell.
as they ingest, process and present antigens histocompatibility complexes (MHCs) on

to further cell types of the immune system. their surface. The cdT-cells are a small
Granulocytes are a group of white blood subset of T-cells which have a T-cell receptor
cells containing cytoplasmatic granules. (TCR) composed of a c- and d-chain instead
They are divided into three types, namely of the more frequent occurring a- and b-
neutrophils, eosinophils and basophils. chain. These cells are thought to play an
Neutrophils participate in phagocytosis and important role in the recognition of lipid
immediate killing of microorganisms, antigens. Due to their complex biology, i.e.
independent of previous exposure, whereas exhibiting characteristics of the innate and
basophils are highly specialised in the the adaptive immune system, they are
synthesis and secretion of several thought to be involved in both systems.
pharmacologically active products such as
Mast cells participate in inflammatory
histamine, proteases, leukotrienes or
processes by releasing characteristic
prostaglandin derivates. Eosinophils are
granules and hormonal mediators upon
recruited to the site of inflammation during
activation. For example, they produce
a T-helper (Th)-2 type immune response,
histamine and prostaglandins.
where they produce a variety of cytokines
and lipid mediators and release their toxic Thrombocytes primarily act in blood clotting
granule proteins. but also initiate innate immune functions by
secretion of pro-inflammatory molecules.
Additionally, natural killer cells are a type of
cytotoxic lymphocyte, which are involved in Recognition of pathogens by the airway
a fast immune reaction and killing of cells in epithelium The airway epithelium is the
the absence of antibodies and major point of contact for smaller inhaled

substances like allergens, microorganisms adequate response following microbial
or pollutants. It presents the interface exposure, and are involved in the regulation
between external environment and internal of cytokine, chemokine and AMP expression
milieu. This epithelium forms a physical and the production of reactive oxygen
barrier and, moreover, contributes to the species (ROS). The different TLRs can detect
host defence in several ways, including a variety of bacterial, viral and fungal
production of chemokines, cytokines and products, as well as damage-associated
antimicrobial peptides (AMPs), as well as molecular patterns (DAMPs) that are
proteinase inhibitors and surfactant proteins released by cells undergoing necrosis. The
as chemical barrier. TLR signalling pathway is divided into two
main signalling cascades, the myeloid
As a response to pathogenic exposure, the differentiation primary response gene 88
innate immune system releases (MyD88)-dependent and -independent
antimicrobial peptides into the lumen of the pathways. In the MyD88-dependent
airways and chemokines, as well as pathway, all TLRs except TLR3 recruit the
cytokines into the submucosa. These adaptor molecule MyD88 upon stimulation
mediators initiate inflammatory reactions and induce nuclear factor (NF)-kB and
accompanied by the recruitment of mitogen-activated protein kinase (MAPK)
phagocytes, dendritic cells and lymphocytes, through interleukin (IL)-1 receptor-associated
which in turn help to initiate adaptive kinases (IRAK)1 and IRAK4 and the tumour
immune responses. In order to introduce necrosis factor (TNF) receptor-associated
the aforementioned cascade, factor (TRAF)-6. This leads to activation of
microorganisms need to be recognised first. NF-kB and MAPK (JNK and p38), followed by
Microorganisms have characteristic the translocation of NF-kB and activator
conserved molecules on their surface, the protein 1 to the nucleus and the upregulation
pathogen-associated molecular patterns of proinflammatory genes. Additionally, TLR2
(PAMPs), which can be recognised by and TLR4 require the adaptor molecule
pattern recognition receptors (PRR). These TIRAP (TIR domain-containing adaptor
receptors comprise soluble forms, such as protein), which acts as a bridging molecule
collectins. Eight collectins have been between the receptor and MyD88.
identified so far, including the mannan-
binding lectin (MBL) or the surfactant The MyD88-independent signalling pathway,
proteins (SP)-A and SP-D. Collectins play a which depends on the adaptor molecule
key role in the first line of defence by binding TRIF (TIR domain-containing adaptor
to invading microorganisms and thereby inducing interferon (IFN)-c), is utilised by
enhancing phagocytosis by macrophages. TLR3 and TLR4. TRIF forms a complex with
The other groups of PRRs are the TRAF-3 and subsequently activates the
intracellular nucleotide-binding interferon regulatory factors (IRF)-3 and
oligomerisation domain (NOD) proteins IRF7, which locate to the nucleus and
NOD1 and NOD2, which are involved in activate IFN-inducible genes. The adaptor
peptidoglycan recognition, and the molecule TRAM (TRIF-related adaptor
transmembrane molecules, such as Toll-like molecule) is solely involved in TLR4 MyD88-
receptors (TLRs), which directly mediate a independent signalling, where it recruits
cellular response after microbial exposure. TRIF to the TLR4 complex.
The TLR signalling cascade is shown in
figure 2. TLRs are the homolog to the Toll TLRs can also form homo- or heterodimers,
receptor in Drosophila flies. In total, 13 TLRs such as TLR2 with TLR1 and TLR6,
have been identified in mammals so far and respectively. The dimers have different
10 of these have been shown to be ligand specificity. Moreover, additional co-
expressed in humans. receptor molecules increase ligand
sensitivity. Four different adaptor molecules
TLRs are abundant on nearly all cells of the exist: MyD88, TIRAP, TRIF and TRAM. This
body. They are responsible for initiating an variety of adaptor molecules might allow

Triacyl Diacyl
Bacterial Flagellin lipopeptide lipopeptide
CpG DNA MD-2
Bacteria T T T
T T L L T T
Viral LPS L
L L R R L L
ssRNA R
R R R R
CD14
Viral
dsRNA 4 4 MyD88
5 MyD88 2 1 MyD88 2 6
8 TIRAP
MyD8 TIRAP
A P Cytoplasm
TIR TRAM
FADD
IRAK
Endosome
CASP8
8
T
TRAF6
D8
L
My
R
T
T T T T L Apoptosis
7
L L L
L R
R
R R
R 88
TR yD MAPK NF-B
IF 3 9 M
3 9
8
88
MyD IRAK IFN-
TRAF3 IFN- Nucleus IL-
IKK IL-6
IRF7 IRF3 IRF7 IL-12
TBK1 IL-8
TNF-
IRF3 AP-1 NF-B RANTES
CD40
CD80
CD86
T-cell Inflammation
stimulation
Antiviral
immune response
Figure 2. TLR signalling cascade. The myeloid differentiation primary response gene 88 (MyD88)-
dependent pathway can be used by all TLRs except TLR3 (black arrows). The MyD88-independent
pathway is utilised by TLR3 and TLR4 (blue arrows). RANTES: regulated on activation, normal T-Cell
expressed and secreted; IRF: interferon regulatory factors; AP-1: activator protein-1; MAPK: mitogen-
activated protein kinase; IKKe: IkB kinase-e; TBK: TANK-binding kinase; FADD: Fas-associated death
domain; CASP: caspase 8, apoptosis-related cysteine peptidase.
them to recruit different transducers, in TLRs, such as TLR2 and TLR4, have been
resulting in specific downstream signalling. shown to play an important role in the
For TLR4 signalling, CD14 faciliates the development of immune-mediated lung
presentation of lipopolysaccharide (LPS) to diseases in childhood.
MD-2, a co-receptor required for LPS
recognition by TLR4. Antimicrobial factors Airway epithelial cells
secrete large numbers of different
The most studied TLR, TLR4, is the central molecules, which are involved in
component in response to LPS, a unit of the inflammatory processes. These molecules
outer membrane of Gram-negative bacteria. kill microorganisms, induce wound healing
TLR2 recognises a wide array of bacterial and angiogenesis, and orchestrate the
and fungal substances. Recently, TLR2 was adaptive immune response (fig. 1). The term
described to also be expressed on regulatory AMP summarises a class of innate effector
T-cells (Tregs), a type of T-cell that molecules of the lung, with a broad
suppresses the activity of pathogenic T-cells spectrum of activity against bacteria, fungi
and prevents the development of and enveloped viruses. AMPs are classified
autoimmune responses and allergic lung according to their size, predominant amino
diseases. TLR2 stimulation is thought to acids or conformational structure, whereas
reduce the suppressive function of Tregs. defensins and cathelicidins are the principal
Moreover, single-nucleotide polymorphisms families found in the respiratory tract.

Defensins are highly structured compact The communication of alveolar
peptides, classified into a- and b- subgroups macrophages with other immune cells is of
depending on their folding. The a-defensin great importance in order to launch an
human neutrophil peptides (HNP)-1 to efficient immune response (fig. 1).
HNP4 are present on neutrophils and have a Cytokines play a major role in pulmonary
non-oxidative microbicidal activity. The b- host defence, especially IL-10, IL-12, IFN-c,
defensins are widely expressed throughout granulocyte colony-stimulating factor (G-
the epithelia in order to avoid microbial CSF) and TNF-a, the key mediator in
colonisation. In general, defensins induce recruiting polymorphonuclear leukocytes
proliferation of the airway epithelial cells and (PMLs) into the lung. Microorganisms that
are involved in wound repair. Cathelicidin, are resistant to the microbicidal activity
also called LL-37, displays a similar activity require cell-mediated immunity associated
as defensins and attracts neutrophils, with the recruitment of large numbers of
monocytes, activated mast cells and CD4+ PMLs into the alveolar space by generating
T-cells. These AMPs also show a synergistic mediators, such as the arachidonic acid
activity with other host defence molecules, metabolite leukotriene B4, and complement
such as the large antimicrobial proteins or chemotactic peptides, such as IL-8.
lysozyme and lactoferrin, which are present
in airway fluids. Lysozyme acts as a lytic to Neutrophil recruitment and enhancement of
bacterial membranes whereas the phagocytic defence The PMLs represent the
antibacterial activity of lactoferrin is largest population of intravascular
mediated by their iron-binding property. It phagocytes with greater phagocytic activity
holds iron, an element necessary for growth, than alveolar macrophages. In response to
away from the bacterial metabolism. The inflammatory stimuli like tissue-released
function of these antimicrobial substances mediators and microbial-derived
in host defence has been proven in several compounds, they migrate into the infected
animal experiments. For example, mice tissue site. Following phagocytosis, fusion
deleted in the LL-37 homologue CRAMP of the phagosome and lysosome and add-on
(cathelicidin antimicrobial peptide) showed fusion of azurophil granules with the
an impaired defence against invasive phagolysosome generates highly toxic
bacterial infections. Moreover, AMPs play an antimicrobial compounds like chloramines
important role in several lung diseases, such and defensins, lysozyme and other
as pneumonia, chronic bronchitis or CF. In proteases. During pulmonary infection and
CF patients, AMPs might become inflammation, PMLs also participate in the
inactivated as a result of the high salt regulation of local host responses by
concentration in the epithelial lining fluid. secreting TNF-a, IL-1b, IL-6 and macrophage
Moreover, AMPs show a concentration- inflammatory protein (MIP)-2.
dependent toxicity towards eukaryotic cells. In summary, the innate immune system is
In high concentrations, which have been crucial for an immediate defence against
described in CF and chronic bronchitis infection. However, this part of the immune
patients, AMPs contribute to exuberant system does not contain an immunological
inflammation, potentially through lysis of memory, which allows a fast and specific
lung epithelial cells, induction of IL-8 response in the case of a reinfection with
production and restriction of defensin- familiar agents. This immunological
induced cytotoxicity. memory is a key feature of the second,
Alveolar macrophages represent the first-line adaptive, part of the immune defence.
of phagocytic defence against particles that Adaptive defence mechanisms
evade the mechanical defence. These cells
combine important phagocytic, microbicidal Basic principles of adaptive immune defence
and secretory functions and initiate The adaptive immune system requires a
inflammation and further immune couple of days for an efficient, specific
responses. immune defence. This system gets switched

on when the innate defence mechanisms are anti-parasitic and allergic immune
not sufficient. The adaptive immune system responses.
is induced by different cellular processes
and activation of the innate immune Tregs are relevant for keeping the balance of
response. While some infections can be different T-cell populations (Th1/Th2) and,
controlled through activation of the innate thus, for a healthy immune balance. Th17
immune system, the adaptive immune and Th22 cells operate in a pro-
system is essential for several respiratory inflammatory fashion, as far as hitherto
tract infections. Besides T-cell mediated known, and are essential for acute
immune responses, the humoral and the inflammatory processes through activating
mucosal immune system play a prominent or recruiting neutrophils to the local
role in the adaptive immune defence. infection. Th9 cells, previously grouped in
the Th2 subpopulation, constitute a new
T-cell mediated immune response After T-cell subpopulation and produce the cytokine
development in the thymus, T-cells reach IL-9. The different T-cell populations secrete
the blood circulation, migrate through a more or less specific cytokine pattern
peripheral lymphatic tissue, circulate (fig. 1). The cytotoxic CD8 T-cells recognise
through the blood and tissue and return via and eliminate virus-infected cells by
the lymphatic system to the blood secreting cytotoxins such as perforin,
circulation. Migration is supported by CCR7, granulysin and granzymes.
a chemokine receptor, which binds CCL21
(ligand) and is produced by stroma cells in The humoral immune system response to
the T-cell zone of the peripheral lymphoid infections consists of production of
organs. After rolling of T-cells, adhesion, antibodies through plasma cells, which
diapedesis and migration into the T-cell derive from B-lymphocytes, binding of the
zone, antigen presentation takes place. antibody to the pathogen and elimination
through phagocytosis and molecules of the
To complete the adaptive immune response,
humoral immune system. For production of
nave T-cells need contact with a specific
the antibodies, antigen-specific Th cells are
antigen. After presenting the processed
important. B-cell proliferation and
antigen peptides via MHCII (to the TCR),
the co-stimulatory cascade is initiated, differentiation takes place in the T-/B-cell
which consists of complex interactions of periphery in the secondary lymphatic tissue,
several T-cells and antigen-presenting cells followed by the T-cell periphery and the
(APCs). The most potent APCs are dendritic germinal centre. IgM is produced by mature
cells; their interaction with T-cells is a key B-cells. IgM in the blood circulation is
factor for the induction of efficient immune essential for protection against infections,
responses. Subsequently, T-cell whereas the IgG-isotype diffuses into the
differentiation into effector T-cells and tissue. Overall, the humoral defence system
proliferation takes place. These effector cells operates through the production of specific
operate with other cells, not with the antibodies. Effector cell mechanisms are
pathogen itself. determined through the heavy chains of
the isotype and antibody classes.
T-cells can be roughly classified into the
subpopulations of CD4+ and CD8+ T-cells. The secretory Ig, i.e. IgA and IgM, are
The CD4+ T-cells consists of Th1, Th2, Tregs secreted by epithelial cells of the mucus
and the recently described subgroups Th17, gland into the lumen, while IgG and IgE
Th22 and Th9 (fig. 1). Th1 effector cells diffuse passively. During an immune
support activation of macrophages and response, different functions and amounts
express cytokines, which induce a class of Ig can be detected. Newborns already
switching to specific antibody classes. Th2 have a large amount of secretory (s)IgM and
cells express B-cell activating effector sIgA, directed against bacterial and viral
proteins and secrete cytokines, regulating pathogens and also against antigens, e.g. for
the class-switching which is responsible for anti-casein.

This antigen sensitisation takes place during the breast during lactation. Due to its
intrauterine development, as there is no physiological function (e.g. gas exchange in
passage over the placenta. sIgA is the main the lungs), surfaces are thin and barriers are
Ig in the respiratory tract, while sIgM permeable. Its main role is an efficient
decreases during maturation. While IgM can defence against invading infectious agents.
efficiently agglutinate particulated antigens Thus, it is not surprising that the majority of
and make microbes more susceptible to severe infections worldwide are caused by
phagocytosis, IgA is essential for binding of invasion of pathogens through the mucosa.
antigens without activating an inflammatory Approximately 4 million people worldwide
response. IgA (two subclasses: IgA1 (80% in die of acute respiratory infections every year.
the respiratory tract) and IgA2) protects Besides pathogens, foreign, non-pathogenic
against viruses and bacteria by inhibiting antigens can invade, e.g. food proteins in the
bacterial adherence, blocking toxins and gastrointestinal tract.
neutralising viruses. The former is sensitive
The mucosal immune system probably
to bacterial proteases (Streptococcus
contains 75% of all lymphocytes of the body
pneumoniae, Haemophilus influenzae and
and produces the majority of Ig in healthy
Neisseria meningitidis). By binding IgA to
individuals. Specific features of the mucosal
antigens before transcytosis, it can
immune systems are as follows.
additionally activate cells through binding to
the Fc receptors. Two major mechanisms of N Anatomical: the interaction between
IgA response exist, an innate, T cell- mucosa-epithelium and lymphatic tissue,
independent mechanism, which provides a particularly components of the lymphatic
first line of protection, and a T cell- tissue.
dependent adaptive response, which takes N Modulated effector-cell mechanisms:
longer to develop the high affinity activated or memory-cells exist also
antibodies. IgG is locally produced, binds without prior infection and nonspecific
subephithelial antigens and leads to local natural effector T-cells and Tregs are
inflammation after complement fixation. It present.
also exists in the bronchial lumen. N Immune regulation: an actively
downregulated immune response,
The adaptive immune response requires at
inhibitory macrophages and tolerance-
least 96100 h to establish antigen contact
inducing dendritic cells are present.
for T- and B-cells and differentiation and
proliferation of effector cells. After activation Some immune responses to antigen
of adaptive immune responses, antibodies overload occur in the mucosa, induced by
and effector T-cells are distributed via the particular compartments of the mucosal
circulation and recruited to the relevant immune system. Antigen intake and
tissue, in this case the lung. An effective presentation, Microfold cells and especially
adaptive immune response is characterised dendritic cells are involved, while special
through protection and immunological homing receptors are relevant.
memory. This manifests itself via an
improved chance to react against familiar Pathogenic microorganisms use different
pathogens and to eliminate them strategies to invade the body, e.g. inclusion
successfully. Memory T- and B-cells are of antibodies, inflammatory mechanisms
developed. This protection can be generated and modulation of different components of
artificially by vaccination. the immune system. The immune system of
the mucosa has to distinguish between
The mucosal immune system is of potentially harmful and harmless antigens.
considerable size and includes the Accordingly, it can induce an efficient
gastrointestinal tract, the lower respiratory effector response to pathogens and will not
tract, the genitourinary tract and other respond to colonisation of common airway
exocrine glands such as the pancreas, microorganisms. As bacterial colonisation
conjunctiva, eye glands, salivary gland and generally exerts a positive effect on humans,

there has to be coexisting, non-harmful chronic airway diseases. This seems to
immune regulation. In the mucosal immune depend on the specific pathogen. Exposure
system, antigen presentation to the T-cell is to environmental pollution during
the main component for the decision pregnancy is an example of an exogenous
between tolerance and defence. In the risk factor that changes structural processes
absence of inflammation, antigen of the lung and has an impact on early
presentation occurs without complete co- immune maturation. This multifaceted field
stimulation. Mostly, differentiation of Tregs of research demonstrates that many
occurs, which guarantees a healthy immune complex interactions of innate and adaptive
regulation. If pathogens invade, an immune regulation are required to induce
inflammatory response is induced, an effective immune response.
activation of antigen presentation and co-
stimulation occurs and a protective T-cell Development of defence mechanism Defence
response is initiated. against potentially harmful substances and
pathogens is crucial for healthy
Relevance of interaction of innate and adaptive development. As the development of the
immune regulation for specific defence against immune system occurs during the prenatal
respiratory diseases While exogenous and stage, the specific defence mechanisms of
environmental factors can influence the lung are most probably already
susceptibility to pulmonary diseases, developed.
modulation and interaction of innate and
adaptive immune responses play a Prenatal period Prenatal immune regulation
prominent role in the defence and regulation is complex and it is probable that immune
of a healthy immune response. programming occurs at this early stage.
Various studies suggest that exposure to
For asthma, one of the most common different components of the environment
chronic diseases in childhood, a close can interfere with early programming. These
interaction of the innate and the adaptive include infections, smoke exposure or
immune system early in life, often in the first certain maternal dietary habits. Bidirectional
year or during intrauterine development, is interactions between the mother and the
responsible for whether a child develops fetus seem to be key for post-natal immune
asthma or transient wheezing or stays maturation; however, this field of research is
healthy. still evolving. Besides genetic factors, in
particular epigenetics, the environment and
The most convincing results originate from their interactions seem to influence this
epidemiological studies. Multiple cross- early immune response.
sectional and longitudinal studies have
replicated the finding that prenatal exposure Regarding modulatory mechanisms of
(during pregnancy) to an environment rich intrauterine immune regulation, there may
in microbial substances can decrease the be different explanations. Potential exposure
risk for asthma, hay fever and atopy for the of fetal cells to allergens can occur through
offspring. It has been shown that activation the transfer of amniotic fluid via the
of the innate immune system via TLRs placental tissue starting at 20 weeks of
modulates the adaptive immune response, gestational age. Furthermore, indirect
which can subsequently be protective modulation through influences on the
against the development of Th2-mediated maternal immune system is likely, as the
immune diseases such as asthma. Besides fetalplacental transfer occurs via an active
activation of the innate TLR-receptors, motherchild regulation. Immune cells in
activation of Tregs seems to be essential as decidual tissue of the mother (e.g.
an important adaptive defence mechanism. macrophages, CD8+ and cd-T-cells and large
granulated lymphocytes) can induce
A further example is respiratory infections rejection of paternal histocompatibility
early in life, which can lead to subsequent antigens. Additionally, novel data indicate
protection or, conversely, a higher risk for that maternalfetal tolerance to paternal

allo-antigens is an active process in which which local part of the airway (upper/lower
peripheral Tregs specifically respond to respiratory tract) are relevant besides
paternal antigens to induce tolerance. genetics, epigenetics and other
Overall, maturation of the infant adaptive environmental triggers.
immune system probably starts between the
15th and 20th week of gestation and can be A multifaceted influence on early immune
antigen specific. development of a child is most likely critical
for the development of allergic airway
Post-natal period During this period, similar disease or, vice versa, for potential protection
influences as during the prenatal period are against childhood asthma, for example. All
present in addition to ongoing immune these influences can occur prenatally and
maturation. Contact with environmental are the key for later immune and, potentially,
factors such as smoke exposure or disease development.
respiratory pathogens probably directly
Taken together, the innate and adaptive
change the development of immune
immune system need to work efficiently
regulation in the airways. Airway APCs seem
individually, being closely connected to each
to be important during the late phase of
other in order to provide successful defence
inflammation. They are most likely involved
against invading pathogens or inflammation
in the local damage during inflammatory
in general. In the case of default regulation
processes of the airways and are, therefore,
in any part of the system, either partial or
also important for programming of T-cell
absent defence can result in different forms
responses after their migration in the lymph
of immune-mediated disease such as
nodes.
infections or more chronic diseases like
Regarding dendritic cells, age-dependent allergies.
immaturity is associated with a decreased
ability to react to inflammatory conditions. Further reading
In children during the first year of life, no
dendritic cells are present in the airways if N Akira S, et al. (2004). Toll-like receptor
no inflammation occurs. In the case of signalling. Nat Rev Immunol; 4: 499511.
severe respiratory infection, some mature N Braun-Fahrlander C, et al. (2002).
dendritic cells are present. Thus, local Environmental exposure to endotoxin
impacts on lung structures, such as and its relation to asthma in school-age
children. N Engl J Med; 347: 869877.
infectious processes, seem to affect
N Huh JC, et al. (2003). Bidirectional
dendritic cell maturation and, subsequently,
interactions between antigen-bearing
T-cell activation.
respiratory tract dendritic cells (DCs)
Early infections of the respiratory tract, e.g. and T cells precede the late phase
reaction in experimental asthma: DC
rhinovirus, are associated with allergic
activation occurs in the airway mucosa
inflammation later in childhood. However,
but not in the lung parenchyma. J Exp
this early priming of the airways seems to Med; 198: 1930.
occur depending on the type of infection, as N Lauener RP, et al. (2002). Expression of
other infections are rather protective against CD14 and Toll-like receptor 2 in farmers
development of allergic airway and non-farmers children. Lancet; 360:
inflammation. 465466.
N Liu J, et al. (2011). TLR2 polymorphisms
In summary, early exposure to infections influence neonatal regulatory T cells
seems to influence maturation of local depending on maternal atopy. Allergy;
immune networks, which can switch on Th1- 66: 10201029.
mediated immune responses and are, in N Nizet V, et al. (2001). Innate antimicro-
turn, relevant for efficient defence, while bial peptide protects the skin from
Th2-related immune responses are most invasive bacterial infection. Nature; 414:
likely decreased. However, more studies are 454457.
needed to elucidate which infections at

N Nyirenda MH, et al. (2011). TLR2 stimula- N Schaub B, et al. (2009). Maternal farm
tion drives human naive and effector exposure modulates neonatal immune
regulatory T cells into a Th17-like pheno- mechanisms through regulatory T cells.
type with reduced suppressive function. J J Allergy Clin Immunol; 123: 774782.
Immunol; 187: 22782290. N Strachan DP (1989). Hay fever, hygiene,
N Riedler J, et al. (2001). Exposure to and household size. BMJ; 299: 12591260.
farming in early life and development of N Tschernig T, et al. (2001). Dendritic cells
asthma and allergy: a cross-sectional in the mucosa of the human trachea are
survey. Lancet; 358: 11291133. not regularly found in the first year of life.
N Schaub B, et al. (2006). Immunology and Thorax; 56: 427431.
defence mechanism of the developing N Williams Z (2012). Inducing tolerance to
lung. Eur Respir Monogr; 37: 6078. pregnancy. N Engl J Med; 367: 11591161.

Environmental determinants
of childhood respiratory
health and disease
Erik Melen and Matthew S. Perzanowski
Worldwide, exposure to second-hand smoke environmental factors have also been

is one of the most common indoor identified, such as farming and rural
pollutants and as many as 40% of children environments. Large individual variability in
are regularly exposed. Adverse effects of response to environmental factors exists,
long-term exposure to anthropogenic especially for allergen exposure, and genetic
ambient air pollution on childrens susceptibility may partly account for this
respiratory health are also well described, (termed geneenvironment interaction).
particularly in relation to asthma and lung This chapter will discuss the role of these
function. In developing countries, biomass major environmental determinants of
smoke from domestic fires for cooking and respiratory health in children.
warmth constitutes a major source of air
Adverse effects of environmental exposures
pollutants. Children are known to be more
susceptible to hazardous airborne Environmental tobacco smoke (ETS) There is
substances compared to adults, possibly ample evidence from both epidemiological
because of their growing organs and tissues. and experimental studies that ETS has many
In addition, children have higher ventilation negative effects on several organs in the
per minute in relation to body size and often body, including the respiratory system,
have higher physical activity compared to through induction of oxidative stress,
adults, which leads to relatively higher inflammation and tissue damage. If a childs
exposure. However, protective mother smokes during pregnancy, the fetus
is exposed to nicotine, carcinogens and
other toxic substances that pass the
Key points placental barrier. Solely prenatal exposure,
without subsequent post-natal exposure, is
N Exposure to ETS, ambient air associated with a 6070% increased risk of
pollutants and biomass smoke asthma in pre-school children, which under-
increases the risk of respiratory lines the importance of targeted preventive
disease (e.g. asthma and pneumonia) efforts. Post-natal ETS exposure has been
in children. convincingly associated with asthma and
N Protective effects of certain exposures, lung function deterioration in many
such as farming lifestyle and some studies.
microbes, on asthma and allergy have
Data from the World Health Organization
been observed.
(WHO) show that, on average, 40% of
N Genetic susceptibility and children aged 014 years are regularly
co-exposure to several environmental exposed to ETS, with the lowest exposure in
factors contribute to an overall central and southern Africa (12%) and
complex relationship between highest exposure in East Asia (67%).
inhalant allergens and disease Children are considered to be at increased
development. vulnerability to ETS-related health effects
relative to adults because of heavy exposure

in the home by family members that is children living .1500 m from the motorway.
difficult to avoid. The global disease burden Whether this growth deficit persists into
of ETS exposure in children is immense and later adulthood is not known. Exposure in
the importance of preventive measures to utero and during infancy appears particularly
reduce this exposure cannot be stressed harmful and studies report negative effects
enough. It has been estimated that 165 000 on lung function in infants, as well as in
children aged ,5 years die every year from school-age children. Also in areas with
lower respiratory infections caused by ETS relatively low air pollution levels such as
exposure. Stockholm, Sweden, remarkably strong
effects are seen in that children with the
Anthropogenic air pollution Combustion of
highest exposure during the first year of life
fossil fuels contributes both particulate
matter (PM) (e.g. soot, non-volatile are four to five times more likely to have
polycyclic aromatic hydrocarbons (PAHs)) poor lung function at school-age compared
and gases (primarily NO, NO2, CO2, SO2, to low-exposed children, further supporting
ozone, volatile PAHs) to indoor and outdoor the relevance of air pollution to impaired
air. PM10 and PM2.5 (particles with a 50% lung development.
cut-off aerodynamic diameter of 10 and Biomass smoke Open domestic fires for
2.5 mm, respectively) constitute inhalable biomass burning (wood, charcoal, crop
particulates and these are commonly residues, etc.) for cooking and heating are
measured in studies on respiratory effects main sources of air pollutants in certain
from pollutants. Automobile exhaust (gases parts of the world (fig. 1). More than 2
in particular), combustion processes and billion people live in households in which
road dust (particulates) are the main biomass fuels are used regularly. Several
sources of pollutants of interest for the
studies show positive associations between
respiratory system. Other chemical agents,
asthma prevalence and biomass cooking
such as phthalates commonly used in
indoors, but a recent meta-analysis did not
consumer products, can evaporate into food
provide reliable evidence of overall increased
or the air and exposure to these agents has
risk of asthma in children. However, many
also been associated with respiratory
studies on biomass smoke effects suffer
symptoms.
from limitations in study design,
Similar to ETS, ambient air pollutants may confounding control and low power, and
induce airway inflammation, increased further research in this area is warranted.
airway responsiveness and lung damage,
partly due to oxidative stress mechanisms.
Both short- and long-term exposure has
been associated with an increasing range of
adverse respiratory outcomes, and air
pollutants are well-known triggers for
asthma exacerbations. Exposure to particles
from diesel exhaust have also been linked to
atopy, and experimental data support
adjuvant effects of particles on IgE
synthesis. However, conflicting evidence for
air pollution being causative in the
development of asthma and allergy persists.
There is evidence that adverse long-term

effects of air pollution occur on lung
function growth. A US study from California Figure 1. Open domestic fire for cooking and
showed that children who lived within heating (image courtesy of J. Thacher, Institute of
500 m of a motorway had ,3% lower lung Environmental Medicine, Karolinska Institutet,
function, measured as FEV1, compared to Stockholm, Sweden; personal communication).

In contrast to effects on asthma, there is Presence of older siblings in the home, day
rather strong evidence that exposure to care attendance and certain infections (e.g.
indoor air pollutants from cooking or heating herpes or EpsteinBarr virus) early in life
is associated with pneumonia and acute were reported to protect against the
lower respiratory infections in young development of asthma in school-age
children. A recent WHO meta-analysis children. From an immunological point of
concluded that indoor exposure increased view, reduced activity of T-regulatory cells,
the risk of pneumonia almost two-fold. From which may lead to reduced immune
a population point of view, this is of utmost suppression, has been emphasised as a
importance since pneumonias can be basis for the mechanisms behind the
attributed to around half of all deaths occurr- hypothesis. As of today, recent data
ing worldwide in children ,5 years of age. indicate, however, that the hygiene
hypothesis only partly holds true, and that
Allergens The role of inhalant allergen aetiological mechanisms are, after all,
exposure in the aetiology of asthma and rather unclear.
allergic sensitisation is complex, and our
understanding of these processes has Farming lifestyle One key component of the
changed markedly during the last 30 years. hygiene hypothesis, farming lifestyle, has
It is now acknowledged that asthma and consistently been associated with low
allergy are heterogeneous diseases and that prevalence of asthma and allergy in both
overall, wide-spread generalisation about low-income and high-income countries.
allergen exposure and disease development Early animal contact at the farm and
cannot be made. It is likely that genetics, consumption of unpasteurised milk seem to
phenotype diversity and large variations in be particularly important for the protective
the intensity and pattern of allergen effect. In addition, children living on farms
exposure contribute to this complex picture. are exposed to a greater variety of
Nevertheless, sensitisation remains an environmental microorganisms (certain
important risk factor for asthma bacteria and fungi) compared to non-
exacerbations and development of severe farming children and this diversity is
symptoms. In combination with an upper inversely related to the risk of asthma.
respiratory infection, exposure to a certain Visible mould and dampness in the home
allergen in sensitised individuals may have are, however, associated with increased
detrimental effects. Asthma is rather risks of asthma and allergy.
common in urban, low socioeconomic
The link between environmental exposure
families, and for inner-city asthma,
and genetic factors
exposure to cockroach and dust mite
allergens have more convincingly been Although smoking and exposure to certain
associated with disease. A recent trial of air pollutants are established risk factors for
anti-IgE among inner-city children in the respiratory diseases, not all individuals who
USA found a decrease in seasonal are highly exposed develop diseases such as
exacerbation peaks (autumn and winter) asthma. Thus, large individual variability in
typically associated with viruses, suggesting response to environmental factors exists,
a complex relationship between allergic and genetic susceptibility (and epigenetics)
sensitisation, viruses and asthma may partly account for this. In this context,
exacerbations. genes involved in the anti-oxidative system,
Role of protective environmental factors inflammation and innate immunity have
been a particular focus in studies of
The hygiene hypothesis Almost 25 years ago, respiratory diseases. Variants in IL13, GSTP1
the so called hygiene hypothesis was and TNF have been shown to modulate the
introduced suggesting that the decrease in adverse effects of ETS on asthma risk and
infectious burden and microbial exposure pulmonary function, and CD14 variants are
during early life may have led to increased related to the risk for allergy related to
predisposition to allergy and asthma. domestic dust mite allergen exposure.

In addition, geneenvironment interactions N Dherani M, et al. (2008). Indoor air
have been reported with both protective and pollution from unprocessed solid fuel
adverse effects observed. For example, the use and pneumonia risk in children aged
dose-response to developing sensitisation under five years: a systematic review and
to cockroach with increasing cockroach meta-analysis. Bull World Health Organ;
allergen exposure was observed to be 86: 390398.
greatest among children exposed to higher N Ege MJ, et al. (2011). Exposure to
levels of PAHs and those with a deletion of environmental microorganisms and
childhood asthma. N Engl J Med; 364:
GSTM1 (involved in detoxification of PAH).
701709.
However, convincing and reproducible
N Gauderman WJ, et al. (2007). Effect of
interaction effects have been difficult to exposure to traffic on lung development
identify in large, well-characterised data sets, from 10 to 18 years of age: a cohort study.
especially if genome-wide association study Lancet; 369: 571577.
(GWAS) data were used. Further research is N Laumbach RJ, et al. (2012). Respiratory
warranted in this area before we better health effects of air pollution: update on
understand the complex interplay between biomass smoke and traffic pollution.
genes and the environment and certainly J Allergy Clin Immunol; 129: 311.
before clinical applications can be N Melen, E., et al. (2012). Pathophysiology
implemented. of asthma: lessons from genetic research
with particular focus on severe asthma.
Conclusion J Intern Med; 272: 108120.
N Neuman A, et al. (2012). Maternal smok-
There is good evidence that exposure to ing in pregnancy and asthma in preschool
pollutants such as ETS, ambient air children: a pooled analysis of eight birth
pollutants and biomass smoke increase the cohorts. Am J Respir Crit Care Med; 186:
risk of respiratory disease in children. 10371043.
Protective effects of certain exposures, such N Oberg M, et al. (2011). Worldwide burden
as farming lifestyle and microbes, on of disease from exposure to second-hand
asthma and allergy are also well described. smoke: a retrospective analysis of data
Genetic susceptibility and co-exposure to from 192 countries. Lancet; 377: 139146.
N Olmedo O, et al. (2011). Neighborhood
several environmental factors contribute to
differences in exposure and sensitization
an overall complex relationship between
to cockroach, mouse, dust mite, cat, and
inhalant allergen exposure and disease dog allergens in New York City. J Allergy
development. Clin Immunol; 128: 284292.
N Perzanowski MS, et al. (2013). Early-life
Further reading cockroach allergen and polycyclic aro-
matic hydrocarbon exposures predict
N Brooks C, et al. (2013). The hygiene cockroach sensitization among inner-city
hypothesis in allergy and asthma: an children. J Allergy Clin Immunol; 131: 886
update. Curr Opin Allergy Clin Immunol; 893.
13: 7077. N Schultz, ES., et al. (2012). Traffic-related
N Bruin, JE., et al. (2010). Long-term con- air pollution and lung function in children
sequences of fetal and neonatal nicotine at 8 years of age: a birth cohort study. Am
exposure: a critical review. Toxicol Sci; 116: J Respir Crit Care Med; 186: 12861291.
364374. N Strachan DP. (1989). Hay fever, hygiene,
N Busse WW, et al. (2011). Randomized trial and household size. BMJ; 299: 1259
of omalizumab (anti-IgE) for asthma in 1260.
inner-city children. N Engl J Med; 364: N Tischer C, et al. (2011). Association
10051015. between domestic mould and mould
N Carlsten C, et al. (2012). Air pollution, components, and asthma and allergy in
genetics, and allergy: an update. Curr children: a systematic review. Eur Respir J;
Opin Allergy Clin Immunol; 12: 455461. 38: 812824.

History and physical
examination
Michael B. Anthracopoulos, Kostas Douros and Kostas N. Priftis
Respiratory medicine, particularly in young

children, relies much more on clinical Key points
information than on precise laboratory
results. Even in todays world of technological N Patient history is focused on the
wonders, there is no substitute for a proper respiratory system and is adapted to
history and physical examination. This patient circumstances (emergency
section discusses basic issues of paediatric situation, chief complaint, chronic
medical history and physical examination of problem, age, etc.); however, other
the respiratory system, and briefly addresses pertinent organ systems should not
the pathogenesis of physical findings. Lung be neglected and structure is
sounds and specific signs and symptoms are important in order to avoid missing
addressed in separate sections of this helpful clues.
chapter. N Respiratory physical examination of
Medical history the chest includes inspection,
palpation, percussion and
Patient history in respiratory consultation is auscultation. Nomenclature of lung
governed by the same principles as any sounds is a subject of considerable
other medical history. The childs parents confusion.
are the primary source or, at the very least, N A structured physical examination of
important contributors to the history. the chest, applied with flexibility in
However, when obtained by proxy, the paediatric patients, including the
subjective nature of the information can be upper respiratory system, evaluation
further obscured. The chaotic use of terms of cyanosis, the digits and other
for respiratory signs and symptoms, such as pertinent organ systems, is
wheezing, adds to the confusion. fundamental to the evaluation of the
Nevertheless, useful information may be respiratory patient.
obtained from children as young as 3 years
of age and from the age of 8 years, the child
should be the principal source of the history.
Privacy of older children and adolescents and a chronological description of the
must be respected (Bickley et al., 2013). problem. Clarification of its onset,
frequency, timing, duration and severity,
The physician should ask open-ended relation to specific circumstances, and
questions and, depending on the complaint, response to medication already used should
further questioning will focus on and expand be sought. Other relevant signs and
specific points. Still, a general structure of symptoms need to be investigated and
the required information needs to be kept in previous assessments and laboratory results
mind in order to cover all the issues relevant reviewed. Past medical history, especially
to the presenting illness. Such structure that of the respiratory system, is important.
should include the major concern that Recurring or persistent respiratory
prompted consultation (chief complaint) problems, emergency visits,

hospitalisations, surgery, vaccination status, (coryza) or a sudden episode of choking
and pre-, peri- and neonatal circumstances while eating or playing with small objects,
including prematurity, mode of delivery, thus suggestive of aspiration?
birth weight, etc. need to be assessed.
Family and social history are not to be Viral infections in young children are the
neglected, and review of other organ most common cause/trigger of such
systems is no less important in paediatric symptoms; six to eight colds per year,
patients than it is in adults. The all too mostly during the colder months, are not
common presentation of a young child who unusual at a young age. However, an
appears chesty all the time and excessive number of severe infections,
continuously coughing and wheezing recalcitrant nappy rash and oral candidiasis
exemplifies the aforementioned issues. beyond 612 months of age may indicate
immunodeficiency.
Chief complaint and past medical history It is
important to discern from the beginning Careful questioning should attempt to
what a parent means by wheezing: is it a discern whether the current episode is
whistling expiratory sound or is it actually different from previous ones and, if
reminiscent of rattling of the chest? The so, in what respect. In addition, what is its
proverbial expression not all that wheezes duration and that of similar previous
is asthma holds true, but then again, not episodes? Are they only triggered by colds
all that wheezes is a wheeze. Regarding (viral wheeze) or are there other triggers
cough, it is important to clarify whether it is such as laughter, exercise, strong odours,
dry and irritating, or whether it sounds wet aeroallergens, etc. (multiple-trigger
(or productive, if the child can produce wheeze)?
sputum); also, if it is often accompanied by
wheeze. Cough-variant asthma, if existent, is Cough and wheeze after exercise are
unusual and chronic (.4 weeks duration) associated with airway hyperresponsiveness;
intolerance to exercise, poor feeding and
wet cough is the most common
presentation of persistent (protracted) oedema are consistent with CHF.
bacterial bronchitis, an out-of-fashion Do the episodes occur during night sleep
paediatric diagnosis revisited that may and, if so, do they wake up the child?
require more extensive investigation. Seasonality of symptoms (viral or pollen
season) and evidence of eczema, allergic
In the case of diagnosed asthma, a
rhinitis and/or allergic sensitisation should
questionnaire-based clinical scoring system
be addressed.
such as the Childrens Asthma Control Test
(C-ACT), which has been validated for Does the child vomit and does vomiting
children aged 411 years, is useful in the always come after coughing, or is it related
evaluation of asthma control. C-ACT uses to meals and the recumbent position (i.e.
information from the child (four questions, reminiscent of gastro-oesophageal reflux)?
including a visual scale) and the parents
(three questions); the score is based on Have inhaled medications been used and
daytime asthma symptoms such as cough does any medical (or other) intervention
and wheeze (also during exercise and play), appear helpful? If the patient is already on
night awakenings due to asthma, and medications, their compliance should be
parental report of disease activity during the evaluated. History of hospitalisations or
last 4 weeks. emergency department visits and
physicians diagnoses should be obtained.
If a diagnosis of asthma cannot be made
with reasonable certainty, further probing What was the age of onset of symptoms? If
may be in order. What was the reason that close to birth, congenital malformations or
prompted specialist consultation? Was the genetic inheritance should be considered.
onset of wheeze and/or cough acute or Weight and height graphs need to be
progressive? Was it related to viral cold reviewed and adequate growth ascertained;

if the weight lags behind these, information management choices and compliance
on stool consistency should be sought and expectations.
the diagnosis of CF considered.
Physical examination
Knowledge of the duration of pregnancy is
important, as are the circumstances at birth Upper airways The upper respiratory tract
(including birth weight and Apgar scores) should be examined and facial (e.g.
and during the neonatal period. History of micrognathia, retrognathia, asymmetry or
prematurity, intubation, mechanical depressed nasal bridge) or buccal (e.g. cleft
ventilation, or prolonged oxygen lip and/or palate, bifid or long uvula, texture
dependence and corrected oesophageal of the oropharynx, and presence and size of
atresia with or without a tracheo- tonsils) deformities should be noted.
oesophageal fistula is crucial for interpreting Examination of the nasal passages can be
the childs respiratory symptoms in later performed with a nasal or a large ear
years; the diagnoses of chronic lung disease speculum. It may reveal mucosa that is
of prematurity, subglottic stenosis, acutely inflamed and bright red (consistent
tracheomalacia and gastro-oesophageal with infectious rhinitis), or pale and boggy
reflux need to be considered accordingly. (consistent with allergic rhinitis). The
History and duration of breastfeeding, presence of nasal polyps before age 12 years
gastro-oesophageal reflux, and problems of should prompt investigation for CF, while in
poor feeding or failure to thrive should be older adolescents, they are often the result
addressed. of allergic rhinitis or chronic sinusitis.
Chief complaints such as cyanotic episodes, The issue of allergy often arises in the
hoarseness, stridor, snoring and/or apnoea, presence of airway disease (e.g. asthma).
haemoptysis, chest pain, etc. will require The frequent upward rubbing of the nose
further specific probing by the respiratory due to itching (allergic salute) and the
specialist (see the relevant sections of this resultant crease across the front of the nose
chapter). are signs of allergic rhinitis. The patient may
use the facial muscles in order to relieve
Family, environmental and social history nasal itching (rabbit nose or the
Family history of asthma, allergies or CF is
Bewitched sign). Skin creases on the
very helpful. It is important to investigate for
lower eyelids are also consistent with allergy
consanguinity of parents, miscarriages and
(allergic crease). Erythematous, itchy
childhood deaths (including sudden infant
conjunctivae and nasal symptoms are
death of a sibling) in the family, as well as
characteristic of hay fever. The classic signs
history of HIV positivity or TB.
of dark circles under the eyes, a constantly
Environmental history can be quite open mouth often associated with a
revealing. Exposure to indoor tobacco history of snoring and, in more severe cases,
smoke, wood stove heating or gas cooking with sleep apnoea and a high arched
can trigger asthma exacerbations and palate identify children with upper airway
predispose to poor respiratory health. obstruction (rhinitis and enlarged lymphoid
Questions should address exposure to other tissue) but not necessarily of allergic
inhaled irritants and the presence of pets aetiology. Evidence or history of eczema is
and indoor plants. Wall-to-wall carpets, an also helpful.
aged dwelling environment or renovation
Chest The patients chest should be exposed
may be important contributors to the childs
symptoms. This also holds true for exposure and inspected for congenital or acquired
to outdoor air pollution. deformities (e.g. pectus excavatum, pectus
carinatum, kyphoscoliosis). During
Social history may help to determine the inspection indeed, throughout the entire
quality of historical information and the physical examination the two sides of the
patients household circumstances, and aids chest are compared. Hyperinflation of the
the physician in forming realistic thorax (e.g. air trapping due to asthma or

chronic lung disease) or asymmetry of the difficult to realise in children due to the
two hemithoraces (e.g. due to higher frequency of their voice. Low-pitch,
pneumothorax or cardiomegaly) should be high-amplitude sounds, such as repeating
sought; asymmetrical excursion of the ninety-nine or one-one-one (equivalent
hemithoraces due to paralysis of the vocalisations should be used in other
hemidiaphragm may also occur. languages), rather loudly will result in
increased tactile fremitus in the case of
Chest expansion, respiratory rate and parenchymal consolidation (e.g.
pattern of breathing should be noted, and pneumonia) and attenuation of the tactile
increased work of breathing as evidenced fremitus in the case of pneumothorax and
by tachypnoea, retractions, use of accessory pulmonary distension (air trapping). Pleural
respiratory muscles and paradoxical friction rubs may also be noted.
respiration should be assessed (see
Tachypnoea, dyspnoea, respiratory distress Since its initial description two and a half
and chest pain). In chronic obstruction, the centuries ago, dedicated teachers have
Hoover sign may be observed. It consists of taught the art of percussion to medical
(untoward) indrawing of the lateral chest students. The method is based on the match
during inspiration at the level where the (or mismatch) of the vibratory
diaphragm attaches to the ribcage. It is characteristics of adjoining materials such
associated with an outward movement of as tissues. Thus, by interpreting the acoustic
the lateral ribs caudally to this level and is result of an impulse, one can draw
caused by the reduction of the zone of conclusions about the bordering tissues.
diaphragmchest wall apposition. It may be When there is great mismatch (e.g. chest
associated with the loss of the bucket- wall overlying a pneumothorax), there will be
handle movement of the ribs of the barrel- resonance and the sound is perceived as
shaped chest and with the exaggeration of tympanic. Conversely, when there is small
pump-handle movement about the acoustic difference between the bordering
longitudinal axis of the body. However, it tissues (e.g. pleural fluid underneath the
does not reliably reflect the degree of chest wall), the energy of the impulse
obstruction. propagates quickly and the sound is dull.
Between these two extremes are the
Palpation of the chest usually follows that of
characteristics of the sound produced by
the head and neck. It is mainly used to
chest percussion over normal lung
confirm the findings of inspection. Areas of
tenderness and masses (e.g. lymph nodes) parenchyma. Most paediatricians use the
may be identified. The position of the indirect method of percussion, whereby they
trachea, i.e. the tracheal tug, is more tap lightly, vertical to the surface, with the
easily felt than observed. long finger of one hand (plexor), two or
three times in each position, on the terminal
Chest excursion can be evaluated and phalanx of the middle finger of their other
asymmetrical movement can be identified hand (pleximeter), which is placed over an
by placing the palms of both (warm) hands intercostal space. The chest is percussed
in a manner wrapping the childs chest symmetrically.
symmetrically, with the thumbs placed
posteriorly and the rest of the fingers Since the respiratory system is the most
anterior. The physician follows the chest frequently affected organ system in
excursions during breathing with his hands, paediatric practice, respiratory sounds heard
comparing the two sides by observing the at a distance or auscultated over the chest
movement of the thumbs away from the may provide valuable clues. The stethoscope
midline. has practical and symbolic value for the
general physician and the pulmonologist
Vibrations generated by the voice and felt alike. Auscultation provides the most
with the palm of the hands or the base of the detailed information of the entire physical
fingers, i.e. tactile fremitus, are more examination. The binaural stethoscope is

favoured by most physicians and can over the chest during inspiration and
adequately serve the specialist. The hardly audible during normal expiration.
diaphragm of the head piece, when pressed N Bronchial sound is auscultated over the
firmly on the skin, filters out the lower upper anterior chest wall, of higher
frequencies and allows for better perception frequency and intensity than vesicular
of the high-pitched sounds. Conversely, the sound and of approximately equal
bell should be applied lightly (to avoid duration in inspiration and expiration.
stretching the skin) in order to select for
lower frequencies. Appropriately sized chest Normal breath sounds are characterised by
pieces for different chest sizes should be a broad frequency spectrum that ranges
selected. according to the location of auscultation.
Tracheal sounds are heard over the
To have infants assume a straight position extrathoracic trachea. They are broad-
and young children cooperate for proper spectrum noises with frequency spectra
auscultation is an art; still, it may not always from ,100 to .1500 Hz and a rapid power
be possible to listen adequately over all lung decrease at ,800 Hz. They have a short
segments. The upper lobes are best inspiratory and long expiratory duration.
auscultated over the upper anterior chest, Muscle sounds are low-frequency (,20 Hz),
lower lobe sounds are best heard over the low-intensity sounds related to the
posterior lower chest, and the middle lobe contraction force of thoracic skeletal
and lingula are best represented on the muscles that mesh into the normal breath
respective sides of the lower third of the sound spectrum. Often, the terms
sternum. Over the lateral chest, in the respiratory sounds, breath sounds and
axillae, all lobes can be auscultated. lung sounds are used interchangeably.
This is also the case with the terms
To date there is no definitive nomenclature
vesicular sound and normal breath
of lung sounds. In this section, the
sound, and with the terms bronchial
terminology of the CORSA (Computerized
sound and tracheal sound. In fact, the
Respiratory Sound Analysis) guidelines is
sound described here as bronchial is
adopted (Sovijarvi et al., 2000); terms used
termed bronchovesicular (intermediate
by other authorities or popular among
between tracheal and vesicular) in certain
physicians are also mentioned.
textbooks (Brown et al. 2008; Bickley et al.,
Respiratory sounds are related to chest air 2013), while the terms tracheal sound and
movement, either normal or adventitious, bronchial sound are used
heard at the mouth, the trachea and the interchangeably.
chest; they include sounds produced by
cough, snoring, sneezing or respiratory Adventitious sounds are additional sounds
muscle contraction, but exclude voiced superimposed on normal breath sounds;
sounds. Lung sounds are the respiratory they are usually associated with pulmonary
sounds heard (or otherwise detected) over disorders. Adventitious sounds are primarily
the chest. divided into continuous (musical or
wheezes) and discontinuous (nonmusical or
(Normal) breath sounds are respiratory crackle) sounds.
sounds that arise from breathing, excluding
adventitious sounds. They consist of the Wheeze is the respiratory sound term most
following. widely used by physicians and the general
public, albeit with dismal specificity. It is
N Vesicular breath sound (a misnomer, as characterised by periodic waveforms
it does not originate in vesicles, i.e. the (continuous, of musical quality) with a
alveoli) is a quiet, low-frequency, dominant frequency .100 Hz (range ,100
nonmusical sound. Its energy peaks to .1000 Hz) and duration o100 ms.
below 100 Hz and decreases rapidly However, the term usually implies a
between 100 and 200 Hz, but is still dominant frequency of .300 to 400 Hz.
audible above 1000 Hz. It is auscultated Lower-frequency wheezes have different

pathogenesis and are often termed rhonchi or bubbling sounds originating in the large
(see later). In general, wheezes are louder airways (i.e. what most authorities would
than breath sounds and may be audible at term coarse expiratory crackles, see
the patients mouth or at a distance. They below).
are better transmitted through the airways
rather than through the lung to the thoracic Crackles (other terms in use are
surface and their higher frequencies crepitations or rales) are adventitious,
(approximately .700 Hz) are better or discontinuous (nonmusical) sounds, usually
solely transmitted over the trachea. Wheeze auscultated during inspiration, that
is of great clinical value as it is usually represent local phenomena. Crackles are
associated with airway obstruction classified according to their waveform,
due to various mechanisms (e.g. duration and timing in the respiratory cycle.
bronchoconstriction, airway wall oedema, Fine crackles (subcrepitant crackles) are
intraluminal obstruction such as a foreign characterised by high pitch, low intensity
body, external compression or dynamic and short duration (two-cycle duration
airway collapse). Prediction models (the (2CD) ,10 ms). They are caused by the
fluid dynamic flutter theory) have shown explosive opening of small airways collapsed
that expiratory wheeze always signifies flow by surface forces (increased elastic lung
limitation, while its absence does not recoil pressure or inflammation/oedema in
preclude flow limitation (Grotberg et al., the lung); they are gravity dependent and the
1989). Healthy subjects can wheeze during sound is rarely transmitted to the mouth.
forced expiration, probably due to the Fine, late inspiratory crackles are typical of
aforementioned mechanism. However, the interstitial/fibrotic lung disease. However,
mechanism of generation of inspiratory they may also be present in normal subjects
wheezes, which are often associated with who inhale slowly from their residual lung
more pronounced obstruction, is not clear. volume, which can be explained by the
In addition, wheeze may be produced by mechanism already described. Coarse
turbulent flow-induced airway wall vibration, crackles (crepitant crackles) are low-pitched,
without flow limitation (Pasterkamp et al., higher intensity and longer duration sounds
1997). Notably, there is a loose correlation (2CD .10 ms); they are more scant, gravity
between the proportion of wheeze detected independent and usually audible at the
throughout the respiratory cycle and the mouth. They are generated by a different
severity of obstruction, but there is no mechanism to that of fine crackles, i.e.
correlation between wheeze intensity and movement of thin secretions in the bronchi
the degree of obstruction. It should be or the bronchioles. They start early and
remembered that wheezing is not a continue until mid-inspiration but may be
parameter of the clinical scores of asthma, heard during expiration. A typical example of
croup or bronchiolitis. The classification of coarse crackles can be heard in
wheeze into mono- and polyphonic is bronchiectasis and chronic airway
addressed in a separate section of this obstruction (e.g. CF). Similar auscultatory
chapter, as is stridor, which is a loud, usually findings can be found focally early in
inspiratory, continuous sound that, other pneumonia but shift into more end-
than being heard at the mouth or at a inspiratory crackles of variable duration that
distance, can be auscultated over the chest progress to fine crackles during recovery.
wall. Acoustic analysis has characterised the
crackles of cardiac failure as coarse, of long
Rhonchus (plural: rhonchi) is a low-pitched, duration during inspiration and appearing
continuous (musical) sound that consists of late in the course of the disease (Brown et
rapidly dampened sinusoids (frequency al., 2008; Pasterkamp et al., 2012).
,300 Hz, duration .100 ms). Rhonchi are
generated by intraluminal secretions and Other adventitious sounds are squawk and
collapse of large airways. However, the term the pleural friction sound. A squawk
has also been used for expiratory gurgling (sometimes classified as a type of wheeze)

is a composite, short (50400 ms), environment. The peripheral perfusion of
inspiratory adventitious sound with a the patient should be taken into account.
musical character (short inspiratory wheeze) The detection of cyanosis is influenced by
that is preceded by a crackle. It is not various factors such as type and intensity of
associated with airway obstruction but light, skin pigmentation, and ambient
rather with pulmonary fibrosing (restrictive) temperature. Central cyanosis is sought at
disease. It is thought to result from the the ear lobes, the mucous membranes
vibrations set in motion by the sudden (buccal, tongue and nasal) and the retina. It
opening of a collapsed airway. Pleural is considered to be reliable evidence of
friction sound (or friction rub) is coarse hypoxaemia. Peripheral cyanosis or
crackles (often described as leathery) acrocyanosis (circumoral, or in the distal
produced by inflamed parietal and visceral phalanges of fingers and toes) is more
pleura that cause vibration of the chest wall common and, especially in case of cold
and local pulmonary parenchyma. It can be extremities, does not necessarily imply
auscultated during inspiration or in both hypoxaemia. Tissues with increased oxygen
phases of breathing. Pleural friction consumption or reduced blood flow
precedes pleural effusion and disappears (increased arteriovenous oxygen difference)
when fluid is formed. The rub is are prone to high concentrations of reduced
synchronous with breathing and does not Hb; hence, the poor clinical value of
disappear with cough, but is modified by the peripheral cyanosis in evaluating arterial
breathing pattern and posture (Brown et al., oxygen content (Stack, 2005).
2008; Bickley et al., 2013).
The value of reduced Hb in the capillary bed
Voice transmission is filtered by normal lung required for cyanosis is 46 g?dL-1, which
parenchyma so that speech becomes corresponds to 3 g?dL-1 of reduced Hb in
indistinct (i.e. perceived as an arterial blood. Capillary blood oxygen
incomprehensible mumble) when content is postulated to be halfway between
auscultating the chest. When there is the arterial and the venous values.
underlying consolidation or compression, Depending on the Hb content, cyanosis will
higher frequencies are effectively occur at different levels of SaO2: for Hb 8
transmitted. Thus, normally spoken syllables (anaemia), 14 (normal) and 20 g?dL-1
become distinct during auscultation; this is (polycythaemia), the respective SaO2 that is
termed bronchophony. Aegophony is a necessary for cyanosis is 65%, 78% and
similar change in transmission but has a 85%. In the newborn, fetal Hb (HbF) shifts
nasal quality with a change of E sounds to
the oxygen dissociation curve to the left,
A. Whispered pectoriloquy is an unusually
thus preventing cyanosis in the neonate. The
clear transmission of whispered sounds
opposite is true for sickle Hb (HbS) in sickle
during auscultation in the case of severe
cell disease (West, 2008). Differential
consolidation or compression.
cyanosis may be observed in congenital
Cyanosis and clubbing Examination of organ heart disease (e.g. cyanosis of the lower part
systems beyond the respiratory system of the body in preductal coarctation of the
should be performed as deemed necessary. aorta, and of the upper part of the body in
Inspection of the skin and mucosa for transposition of the great arteries).
cyanosis is obviously important, and the
fingers should be evaluated for digital The sensitivity of cyanosis in the evaluation
clubbing. of hypoxaemia is poor. Therefore,
hypoxaemia should be assessed by
Cyanosis is the bluish-purple discoloration measuring PaO2 or, more readily, SpO2. Pulse
of the skin or the mucosa caused by high oximetry is an invaluable clinical tool,
concentrations of reduced Hb in the considered by some as the fifth vital sign.
capillary bed and the subcapillary venous Nevertheless, the possibility of abnormal Hb
plexus. Ideally, cyanosis should be evaluated (e.g. carboxyhaemoglobin or
in daylight in a comfortably warm methaemoglobin) should be taken into

Table 1. Differential diagnosis of cyanosis
Severe decrease of air entry
Congenital malformations (may present as Choanal atresia
emergencies in the neonate) Supraglottic fusion of the larynx
Complete laryngeal web
Laryngeal cyst
Cricoid ring dysplasia
Vocal cord paralysis
Vascular ring (usually presents later)
Mediastinal cyst/mass
Oesophageal atresia tracheo-oesophageal
fistula
Large bronchogenic cyst
Congenital cyst adenomatoid malformation
Congenital lobar emphysema
Lung hypoplasia/agenesis
Pneumothorax (due to rupture of cyst)
Lymphangiectasia/chylothorax
Congenital diaphragmatic hernia
Severe thoracic dysplasia
Airway obstruction Severe croup
Foreign body
Angio-oedema
Retro-, parapharyngeal abscess
Neck mass
Asthma
Bronchiolitis
Chronic lung disease of prematurity
CF
Severe aspiration
Lung compression Large pneumothorax (especial under tension)
Pneumomediastinum
Haemothorax
Large space occupying lesion (congenital or
acquired)
Pleural effusion
Prominent abdominal distention
Anatomical or functional abnormalities of Severe chest wall deformity
the thoracic cage Flail chest
Diaphragmatic paralysis
Neuromuscular disease (GuillainBarre
syndrome, botulism, poliomyelitis,
diaphragmatic paralysis)
Myopathy (muscular dystrophy, myasthenia
gravis, Werding-Hoffman)
Hypokalaemia
Organophosphate poisoning

Table 1. Continued
Disorders of gas exchange (V9/Q9 mismatch,
dead space ventilation, alveolar-capillary block)
Peripheral airway obstruction Bronchitis
Bronchiolitis
Pneumonia
Chronic lung disease of prematurity
CF
Exacerbation of severe bronchiectasis
ARDS
Aspiration (from above or below) Gastro-oesophageal reflux
Swallowing dysfunction
Congenital anomalies (laryngeal cleft, tracheo-
oesophageal fistula)
Meconium aspiration
Atelectasis
Interstitial lung disease/pulmonary fibrosis
Pulmonary oedema CHF
Smoke inhalation
Chemical pneumonia
High altitude
Idiopathic pulmonary haemosiderosis/
Heiner syndrome
Pulmonary embolus Rare in children (dyspnoea/respiratory distress
and hypoxaemia are disproportionately
severe to the auscultatory and chest
radiography findings)
Cardiovascular disorders
Cyanotic congenital heart disease Transposition of the great arteries (variations)
Tetralogy of Fallot
Pulmonary atresia with ventricular septal
defect
Double-outlet right ventricle (variations)
Total anomalous pulmonary venous return
Tricuspid atresia
Ebstein anomaly of the tricuspid valve
Truncus arteriosus
CHF (cardiogenic shock) Cardiovascular pump failure (myocarditis,
arrhythmia, post-operative complication,
metabolic disorder, drugs)
Right heart failure/pulmonary hypertension/
PPHN
Restrictive pericarditis/myocarditis/ Pneumo- and haemopericardium (tamponade)
endocardial fibroelastosis/atrial myxoma are emergent situations
Inefficient tissue oxygenation
Polycythaemia/HbF Favour cyanosis

Table 1. Continued
Methaemoglobinaemia Hereditary (HbM, Hb reductase deficiency)
Acquired (aniline dyes, nitrites, nitrates, drugs:
dapsone, nitroglycerine, benzocain,
sulfonamides, etc.)
Shock Haemorrhage
Sepsis
Cardiogenic
Adrenal insufficiency
CNS irritation or depression
Seizures
Meningitis/encephalitis
Cerebral oedema
Haemorrhage Intracerebral
Subdural
Subarachnoid
Drugs/toxins Anaesthetics
Narcotics
Sedatives
Spasmolytics
Peripheral cyanosis
Vasoconstriction Exposure to cold
Drugs
Autonomic nervous system disturbances
(Raynaud phenomenon etc.)
Hypoperfusion Clot
Post-traumatic
Vasculitis
DIC
Venous blood stasis
Skin colour
Blue hues
Blue-tinged skin lesions Extended ectasia of the subcapillary
venous bed
Venous stasis
Blood extravasation
Drugs Amiodarone
Silver toxicity
Other causes
Breath hold Infants and young children
Cry
Hypoglycaemia Infants
Familial dysautonomia
V9: ventilation; Q9: perfusion; ARDS: acute respiratory distress syndrome; PPHN: primary pulmonary
hypertension of the newborn; CNS: central nervous system; DIC: diffuse intravascular coagulation.

account in the interpretation of the pulse Further reading
oximetry reading (Fouzas et al., 2011).
N Bickley LS, et al. Bates Guide to Physical
Table 1 presents the differential diagnosis of
Examination and History Taking. 11th
cyanosis/hypoxaemia.
Edn. Philadelphia, Wolters Kluwer
Clubbing is the thickening of the connective Health/Lippincott Williams & Wilkins,
tissue in the distal phalanges of the fingers 2013.
and toes. It can be detected clinically in N Brown MA, et al. Clinical assessment and
three ways (Pasterkamp, 2012): diagnostic approach to common pro-
blems. In: Taussig LM, et al., eds.
N the Schamroth sign, which is the Pediat-ric Respiratory Medicine. 2nd
obliteration of the diamond shaped Edn. Philadelphia, Mosby-Elsevier, 2008;
opening at the base of the nail beds that pp. 101133.
is normally created by precisely opposing N DeGowin EL, ed. Bedside Diagnostic
the dorsal surface of the distal phalanges Examination: a Comprehensive Pocket
of similar (right-left) fingers; Textbook. 5th Edn. New York,
Macmillan, 1987.
N the inversion of the phalangeal depth
N Fouzas S, et al. (2011). Pulse oximetry in
ratio, i.e. the ratio of the distal phalangeal
pediatric practice. Pediatrics; 128: 740
diameter (measured most accurately by
752.
calliper at the level of the eruption of the N Grotberg JB, et al. (1989). Flutter in
nail) over the interphalangeal diameter collapsible tubes: a theoretical model of
(measured at the crease between the two wheezes. J Appl Physiol; 66: 22622273.
distal phalanges) is .1 in clubbing N Pasterkamp H, et al. (1997). Respiratory
instead of the normal ,1 ratio; sounds. Advances beyond the stetho-
N the increase of the hyponychial angle scope. Am J Respir Crit Care Med; 156:
(defined by the plane of the nail and that 974987.
of the adjacent skin at the eruption of the N Pasterkamp H. The history and physical
nail) to .180u as compared to the normal examination. In: Wilmott RW, et al., eds.
,180u value. Kendig & Chernicks Disorders of the
Respiratory Tract in Children. 8th Edn.
Clubbing is an important indicator of lung Philadelphia, Saunders Elsevier, 2012;
disease more commonly seen in CF and pp. 110130.
non-CF bronchiectasis, empyema, or lung N Sovijarvi AR, et al. (2000). Definition of
abscess, but it may also occur in association terms for applications of respiratory
with heart (congenital or endocarditis), liver sounds. Eur Respir Rev; 10: 597610.
or other gastrointestinal disease. It may N Stack AM. Cyanosis. In: Davis MA, et al,
reflect the course of disease over time. It eds. Signs and Symptoms in Pediatrics.
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periostosis in the context of hypertrophic Elsevier-Mosby, 2005; pp. 5865.
osteoarthropathy.

Cough
Ahmad Kantar, Michael Shields, Fabio Cardinale and Anne B. Chang
Cough is the most common symptom of atelectasis or collapse from retained

airway lung disease. It is also a frequent secretions and recurrent pneumonia occur
reason for which medical advice is sought. frequently. As a symptom, it is nonspecific
Cough is an important physiological and many of the potential causes in children
protective reflex that clears airways of are different from those in adults (Gibson et
secretions and inhaled or aspirated material. al., 2010; Chang et al., 2007).
The importance of cough in maintaining
The cough reflex pathway involves cough
respiratory health is evident in clinical
receptors, mediators of sensory nerves and
situations where the cough is ineffective
an afferent pathway, the vagus nerve, the
(e.g. generalised muscular weakness, cough centre, an efferent pathway, and the
tracheobronchomalacia and laryngeal effectors. Cough has three defining features:
disorders). When these conditions exist,
N an initial deep breath,
N a brief, powerful expiratory effort against
Key points a closed glottis, and
N opening of the glottis with closure of the
N Cough has different major nasopharynx and vigorous expiration
overlapping constructs based on through the mouth.
duration, inflammation type,
Within this definition, there are several
phenotype or clinical syndromes.
variants. The act may be: a single deep
N It is not logical to try to suppress a inspiration followed by a single glottic
cough that has a protective role. closure interrupting an almost complete
expiration near to residual volume; the same
N It is important to try to make a
as this but with multiple glottic closures
diagnosis and treat the underlying
during the single expiration; or a bout of
cause of cough. Potential causes in
coughing, with each expiratory effort either
children are different from those in
completed or partial. Other acts, such as the
adults.
huff of clearing the throat and the
N There is little evidence that either expiratory effort with glottis closure due to
nonspecific isolated cough or post- touching the vocal folds or trachea (the
infectious coughing respond to any expiration reflex) are, by definition, not
currently available treatment. cough but may be fragments of a cough
(Widdicombe, 2003).
N There is good evidence that children
with protracted (persistent) Cough can be initiated from the larynx,
productive (moist or wet) cough including its supraglottal part, from the
benefit from treatment with trachea and from the larger bronchi.
antibiotics to cover the organisms Irritation of the smaller bronchi, the
associated with protracted bacterial bronchioles and the alveoli does not seem to
bronchitis. cause effective cough because the luminal
airflows and velocities would be too low to

have shear forces adequate to clear airway many factors including the duration of cough
mucus and debris. Cough sound is due to (acute versus chronic), the setting (e.g.
vibration of larger airways and laryngeal affluent versus less developed), selection
structures during turbulent flow in criteria of the children studied (e.g. general
expiration. Rheological properties of mucus practice versus specialist clinics), follow-up
and shearing of the secretions from the rate, depth of clinical history, examination
airways influence cough sound. and investigations performed (Chang, 2011).
For example, bronchiectasis (a condition
Causes
causing susceptibility to airway infection) is
Cough has different major overlapping more common in places like Turkey than in
constructs based on: Italy, and a child with bronchiectasis may be
not correctly diagnosed unless followed up
N duration (acute, subacute or chronic), with a chest CT scan.
N inflammation type (neutrophilic,
eosinophilic, lymphocytic or neurogenic) The common causes of acute and chronic
or cough in children are presented in tables 1
N clinical syndromes (e.g. acute bronchitis, and 2. In addition to the many aetiologies of
laryngotracheobronchitis, protracted cough, there are also exacerbation factors,
bacterial bronchitis or aspiration such as air pollution. The ascribed possible
bronchitis). underlying aetiologies of chronic cough have
a very wide spectrum that ranges from acute
Although the inflammation classification cough related to a viral infection, to chronic
may be useful in defining treatment cough from nonspecific cough (that is more
(especially in eosinophilic bronchitis), likely to resolve spontaneously), to serious
phenotypic descriptions and clinical causes such as foreign bodies in the airways
syndromes are usually used in the clinical and bronchiectasis. Not surprisingly,
arena. The characterisation of these clinical different centres report highly variable
syndromes related to cough is dependent on aetiologies (Chang, 2008) that are probably
Table 1. Common causes of acute cough (,2 weeks duration)

Associations or characteristic Additional comments
Infection related
Upper respiratory dominant A large number of viruses can cause acute bronchitis
May be associated with common cold, otitis media,
sinusitis or pharyngitis
Croup Stridor
Pertussis Usually paroxysmal post-tussive vomiting
In younger children, whoop may be present
Pneumonia Tachypnoea dyspnoea and fever
Environmental
Acute exposure to toxicants For example, exposure to burning debris and other
chemical pollutants
Others
Foreign body inhalation History of choking
Acute asthma History and symptoms of asthma
This is not an exhaustive list. Any pathogen that infects the respiratory tract can cause bronchitis and this includes
opportunistic pathogens, fungi and helminths. All the causes of chronic cough in table 2 can present as acute
cough. Nonpulmonary conditions (e.g. acute leukaemia or cardiac failure) can also present with acute cough.

Table 2. Common causes of chronic cough (.4 weeks duration)
Associations or characteristic Additional comments
Conditions where other symptoms and signs
are mostly absent (nonspecific cough)
Mycoplasma
Pertussis In the acute phase, cough is usually
paroxysmal post-tussive vomiting
In younger children, whoop may be present
Post-infectious cough Cough that naturally resolves without
treatment
Habitual tic (psychological)
Early phase of specific cough
Wet or productive cough
Protracted bacterial bronchitis Chest radiographs usually show only
peribronchial thickening
Tracheomalacia may co-exist especially if
recurrent
Chronic suppurative lung disease or
bronchiectasis
Recurrent small volume aspiration Many children have a neurodevelopmental
problem as well but its absence does not
indicate absence of recurrent aspiration
Other conditions where other symptoms and
signs are mostly present (specific cough)
Asthma Dyspnoea with exertion
Wheeze
Foreign body inhalation History of choking
This is not an exhaustive list. Other less common conditions include the entire spectrum of lung disease,
such as interstitial lung disease and plastic bronchitis, and other conditions external to the respiratory tract,
such as cardiac disease, ear disease, gastro-oesophageal reflux and OSA; in the last two conditions, debates
still exist as to cause and effect. Both the US (Chang et al., 2006b) and Australia/New Zealand (Chang et al.,
2006a) guidelines classify chronic cough as duration .4 weeks but the British Thoracic Society (Shields et al.
2008) uses a duration of .8 weeks. The duration used in other European countries varies. For example, the
Belgian guideline defines prolonged cough as a daily cough lasting for .3 weeks (Leconte et al., 2008).
(at least in part) related to inherent as well as indirectly, such as through the
difficulties in studying chronic cough (Chang, immune system and neural pathways.
2011). Some of these are outlined here. However, irrespective of exposure, cough
should not be simply ascribed to pollutants
The most clinically important air pollutant in such as environmental tobacco smoke (ETS)
childhood bronchitis is tobacco smoke. exposure. Cohort studies on children with
Systematic reviews have described the link chronic cough have shown that cough
between cough and air pollution, both resolution was still achieved in children
indoors and outdoors (Laumbach, 2010). It exposed to ETS (including a cohort with
is increasingly appreciated, in human and high exposure rates (56%)) (Asilsoy et al.,
animal studies, that environmental 2008; Marchant et al., 2006b). This
pollutants may have additive effects and suggests that, while ETS is undoubtedly
influence the respiratory apparatus directly associated with increased coughing

illnesses and an important contributing more than 23 weeks in 10% of normal
factor, ETS alone is not the sole aetiology. children. Provided the child is otherwise well
with no pyrexia, tachypnoea or crackles, it is
Defining causes and ascribing aetiologies In likely best to wait for resolution as aetiology
the interpretation of studies that describe is most often viral. There is limited evidence
cough aetiology, clinicians need to be that any therapy is beneficial.
cognisant of several key points. Firstly,
clinicians should be aware of the time- N Erythromycin is useful for early pertussis
period effect. The time-period effect, cases.
described Evald et al. (1989), refers to the N Honey medications and vapour rub may
spontaneous resolution of cough with time. reduce the severity of acute cough.
Secondly, the placebo effect is as high as N Antibiotics may be beneficial for acute
80% in cough studies (Eccles, 2002). bacterial bronchitis but most bacterial
Hutton et al. (1991) described that parents cases resolve naturally anyway.
who wanted medicine at the initial visit
reported more improvement at follow-up, An inhaled foreign body is a possibility when
regardless of whether the child received there is a sudden onset of cough with no
drug, placebo, or no treatment. Thus, in upper respiratory tract infection or after a
non-randomised controlled trial cough choking episode; bronchoscopy is needed to
studies, the time factor and a priori remove the foreign body. In allergic rhinitis
definition of what constitutes an and post-nasal drip syndrome (throat-
improvement in cough needs to be clearing type cough), intranasal steroids
predetermined. Studies that do not and/or antihistamines may be beneficial.
predefine these have limited validity. Just by
10% of normal children with acute cough due
seeing a doctor who takes an interest in the
to upper respiratory tract infections are still
childs cough, the cough score and quality of
coughing 34 weeks later. Some children with
life improves before treatment (Marchant et
a post-infectious cough (prolonged acute
al., 2006a). Thirdly, studies that do not use
coughing after an obvious upper respiratory
validated outcome measures for cough
infection) cough for much longer and this is
research require scrutiny in light of the
especially true for those with pertussis (Hay
above. A small reduction in cough scores in
et al., 2005). Providing the child is otherwise
association with a medication given does
well, waiting for a period of time allows
not mean that the treatment for the
natural resolution of post-infectious
assumed aetiology is the true cause of the
coughing and pertussis to occur.
cough. The small change may be related to
the variability of the test itself. Also, Do not use a wait-and-see approach if there
paediatric cough-related issues, like most is:
other conditions, particularly in young
children, share similarities but also have N weight loss,
substantial important differences when N night sweats,
compared to adults. Thus, publications on N haemoptysis,
clinical issues of cough in adults may not be N sudden-onset cough or cough after a
applicable in children (Chang, 2011). choking episode,
Management
N coughing is relentlessly progressive (e.g.
TB, expanding intrathoracic mass,
It is not logical to try to suppress a cough retained foreign body, collapsed lobe or
that has a protective role (see earlier). It is pertussis), or
important to try to make a diagnosis and N the child has a clinical history of
treat the underlying cause (e.g. asthma, CF symptoms or signs (or are at risk) of
and non-CF bronchiectasis). underlying chronic lung disease (e.g.
finger clubbing, barrel-shaped chest,
Acute cough In upper respiratory tract Harrisons sulci, recurrent pneumonia
infection with bronchitis, cough usually lasts and immunodeficiency).

Chronic cough The underlying principle for appropriate antibiotic and the child
the management of chronic cough is to returning to completely good health
make the correct diagnosis and manage the confirms the diagnosis. Failure to respond
underlying condition. Remove child from or other features of chronic disease should
ETS or other pollutant exposure. Children trigger further investigations as to an
started on ACE inhibitors may have a dry underlying cause, such as:
cough, which stops with medication
withdrawal. N persistent bacterial bronchitis,
N CF,
Chronic cough is very common and often N immune deficiencies,
there are no pointers to a specific diagnosis N primary ciliary disorders,
(e.g. normal chest radiograph, normal lung N recurrent pulmonary aspiration, or
function and dry isolated cough in otherwise N retained inhaled foreign body.
well child). In such cases often a trial of
treatment is used to confirm a diagnosis as Care needs to be taken, especially in
it is neither feasible nor desirable to children with neurological or neuromuscular
extensively investigate all such children. disabilities, to ensure dysfunction of
However, it is important to realise that swallowing and gastro-oesophageal reflux is
natural resolution typically occurs with the treated to prevent recurrent pulmonary
passage of time and, therefore, a response aspiration.
to treatment must not be taken as
confirming a diagnosis. Children responding Psychogenic or habit coughing can be
to a trial of therapy should have the difficult to treat if there is some secondary
treatment stopped and only a second clear- gain associated with an underlying stressor
cut response should be used to suggest a and psychotherapy may be needed. More
diagnosis. often behavioural therapies can be
employed to empower the child to be able to
There is little evidence that either resist the urge to cough on his/her own (e.g.
nonspecific isolated cough or post- the child takes a sip of hot lemon drink with
infectious coughing responds to any each urge to cough)
currently available treatment (inhaled
corticosteroids (ICS), b2-agonists, Conclusion
leukotriene antagonists, anti-gastro-
oesophageal reflux therapy, cromones and The approach to a child with problem
environmental modification). Most of these coughing involves firstly trying to arrive at a
coughs resolve naturally but over a specific diagnosis (after taking history,
considerable period of time. Ultra-high-dose examination and performing relevant tests)
ICS may have a small benefit but the side- and using targeted treatments. Nonspecific
effects seem to outweigh the benefits. isolated coughing in an otherwise well child
may not need treating if natural resolution is
There is good evidence that children with occurring. In some, a trial of antiasthma
protracted or persistent productive (moist therapy may help diagnose cough-
or wet) cough benefit from treatment with predominant asthma but it is important to
antibiotics to cover the organisms keep at the back of ones mind that the
associated with protracted bacterial response to a trial of treatment may simply
bronchitis (e.g. Haemophilus influenzae, be natural resolution. Chronic wet cough
Pneumococcus and Moraxella), such as co- suggests excessive mucus in the airways
amoxiclav (Chang et al., 2008). It is and may indicate potentially a serious lung
important that a full 14-day course is given condition. Protracted bacterial bronchitis
and, sometimes, a prolonged course is seems to be the most common cause, which
needed for 46 weeks along with intensive responds by definition to a full course of
physiotherapy before the persistent antibiotics. Care needs to be taken because
endobronchial infection is eradicated. A these children, if not adequately treated,
positive response to a full course of an may develop bronchiectasis.

Further reading N Gibson PG, et al. (2010). CICADA: Cough in
children and adults: diagnosis and assess-
N Asilsoy S, et al. (2008). Evaluation of
ment. Australian Cough Guidelines sum-
chronic cough in children. Chest; 134: mary statement. Med J Aust; 192: 265271.
11221128. N Hay AD, et al. (2005). The natural history
N Chang AB (2008). ACCP cough guidelines of acute cough in children aged 04 years
for children: can its use improve out- in primary care: a systematic review. Br J
comes? Chest; 134: 11111112. Gen Pract; 52: 401409.
N Chang AB (2011). Therapy for cough: N Hutton N, et al. (1991). Effectiveness of
where does it fall short? Expert Rev an antihistamine-decongestant combina-
Respir Med; 5: 503513. tion for young children with the common
N Chang AB, et al. (2006a). The Thoracic cold: a randomized, controlled clinical
Society of Australia and New Zealand. trial. J Pediatr; 118: 125130.
Position statement. Cough in children: N Laumbach RJ (2010). Outdoor air pollu-
definitions and clinical evaluation. Med J tants and patient health. Am Fam
Aust; 184: 398403. Physician; 81: 175180.
N Chang AB, et al. (2006b). Guidelines for N Leconte S, et al. (2008). Prolonged cough
evaluating chronic cough in pediatrics: in children: a summary of the Belgian
ACCP evidence-based clinical practice primary care clinical guideline. Prim Care
guidelines. Chest; 129: 260S283S. Respir J; 17: 206211.
N Chang AB, et al. (2007). Cough through- N Marchant JM, et al. (2006a). Utility of
out life: children, adults and the senile. signs and symptoms of chronic cough in
Pulm Pharmacol Ther; 20: 371382. predicting specific cause in children.
N Chang AB, et al. (2008). Chronic wet Thorax; 61: 694698.
cough: protracted bronchitis, chronic N Marchant JM, et al. (2006b). Evaluation
suppurative lung disease and bronchiec- and outcome of young children with
tasis. Pediatr Pulmonol; 43: 519531. chronic cough. Chest; 129: 11321141.
N Chang AB, et al. (2012). A multi-centre N Shields MD, et al. (2008). British
study on chronic cough in children: Thoracic Society Guidelines recommen-
burden and etiologies based on a stan- dations for the assessment and manage-
dardized management pathway. Chest; ment of cough in children. Thorax; 63:
142: 943950. Suppl. 3, iii1iii15.
N Eccles R (2002). The powerful placebo in N Weir K, et al. (2011). Oropharyngeal
cough studies? Pulm Pharmacol Ther; 15: aspiration and silent aspiration in chil-
303308. dren. Chest; 140: 589597.
N Evald T, et al. (1989). Chronic non- N Widdicombe JG. A brief review of the
asthmatic cough is not affected by mechanisms of cough. In: Chung KF, et
inhaled beclomethasone dipropionate. A al., eds. Cough: Causes, Mechanisms and
controlled double blind clinical trial. Therapy. Oxford, Blackwell Publishing
Allergy; 44: 510514. Ltd, 2003; pp. 1723.

Tachypnoea, dyspnoea,
respiratory distress and
chest pain
Josef Riedler
Definition sternocleidomastoid muscle, head bobbing

and a seesaw type of thoracoabdominal
Tachypnoea describes abnormally high movements. Various diseases of the
breathing frequencies and often airways, lung parenchyma, rib cage and
accompanies dyspnoea. The normal diaphragm, as well other organs, can cause
respiratory rate decreases with age and can dyspnoea and respiratory distress (table 1).
be quite variable, particularly in newborns
and young infants. The mean values range The following are abnormal patterns of
from 25 to 35 breaths?min-1 in the first years breathing with changes in breathing
of life and decrease to 15 to 20 breaths?min-1 frequency, rhythm or respiratory effort.
in the adolescent. Tachypnoea without
dyspnoea is seen in young infants with a N Apnoea: no breathing (central apnoea or
compliant rib cage and in children with obstructive apnoea).
fever, anaemia and intoxication, and as a N Hypopnoea: shallow breathing without
result of psychogenic causes. the production of hypercarbia.
N Hyperpnoea: deep breathing without the
The term dyspnoea refers to an abnormal production of hypocarbia.
breathing pattern usually with increased N Bradypnoea: slow respiratory rate
respiratory effort. Dyspnoea can be caused (metabolic alkalosis, increased brain
by different objective factors and is a very pressure and respiratory muscle fatigue).
subjective feeling of difficult or painful N Tachypnoea: high respiratory rate.
breathing and often air hunger. Objective N Hypoventilation: decreased alveolar
signs of respiratory distress are ventilation, which usually leads to
suprasternal, intercostal or subcostal chest hypercarbia.
wall retractions, flaring of the alae nasi, use N Hyperventilation: increased alveolar
of accessory muscles such as the ventilation, which usually leads to
hypocarbia.
N Biot breathing: irregular respiration at
Key points variable tidal volumes interrupted by
apnoea (sign of brain damage).
N Dyspnoea can be caused by N CheyneStokes breathing: cycles of
respiratory, cardiac, metabolic, increasing and decreasing tidal volumes
neuromuscular or psychogenic interrupted by apnoea (sign of brain
conditions. damage).
N History taking and physical examination N Kussmaul breathing: deep respiration
are cornerstones of a proper (metabolic acidosis).
assessment of a child with dyspnoea,
Chest pain is rather common in children.
tachypnoea or respiratory distress.
Whereas the most likely cause is
N A clear diagnosis is mandatory for musculoskeletal, functional or psychogenic,
correct treatment. benign and self-limited in older children,
serious conditions have to be excluded,

Table 1. Causes of dyspnoea
Respiratory
Extrathoracic obstruction (croup, epiglottitis, laryngospasm and foreign body)
Intrathoracic obstruction (asthma, obstructive bronchitis, bronchiolitis, foreign body
aspiration and tracheomalacia)
Pneumonia, atelectasis, pneumothorax, pleural effusion, trauma, pulmonary embolus,
pulmonary hypertension
Cardiac
Myocarditis, acute myocardial infarction, CHF, acute pulmonary oedema
Cardiac arrhythmias
Metabolic
Metabolic acidosis (diabetes mellitus, inborn error of metabolism)
Metabolic alkalosis (CF, hypertrophic stenosis of pylorus)
Neuromuscular and central
Defects or dysfunction of diaphragm
Myopathy and neuropathy
Poisoning, drugs, trauma and anaemia
Psychogenic
Hyperventilation
Anxiety and trauma
Vocal cord dysfunction
particularly in younger children (table 2). A the child increases the respiratory effort to
thorough history often helps to find the overcome the narrowing. This leads to an
cause and avoids unnecessary diagnostic increase of the negative intratracheal/
steps. The following aspects of pain should intrabronchial pressure distal to the
be assessed: obstructive site during inspiration which
often results in airway collapse. At the same
N intermittent versus persistent pain, time the intrapleural pressure becomes more
N short lasting (hours or days) versus longer negative (up to -40 cmH2O) leading to
lasting (months), retraction of the compliant parts of the chest
N localised, sharp, superficial versus diffuse, wall and of suprasternal and substernal
deep, visceral, tissue. This can be seen particularly in infants
N occurrence of cough, dyspnoea or fever, with floppy airways and the more quadratic
N prevalent during sleep, shape of the thorax with horizontally lined
N related to swallowing or heart burn, ribs. Nasal flaring may be present and helps
N association with posture, motion and to reduce upper airway resistance and to
exercise. stabilise the upper airways by reducing the
negative pharyngeal pressure. Flaring of the
In most situations a multidisciplinary
alae can also help reduce the inhalation time
approach including a paediatric
and respiratory muscle activities in situations
pulmonologist, cardiologist, orthopaedics
of chest or abdominal pain.
and psychologist should be attempted.
Pathophysiology In normal inspiration, the diaphragm
contracts and moves downwards leading to
In case of obstruction or dynamic outward motion of the thorax and the
compression of the extrathoracic airways, abdomen. Paradoxical breathing refers to

Table 2. Causes of chest pain
Musculoskeletal disorders (myositis, myalgia, costochondritis, Tietze syndrome and deformities
of vertebral column)
Trauma
Herpes zoster
Mastitis and gynaecomastia
Pulmonary infarction
Sickle cell anaemia
Pneumothorax, pleuritis, atelectasis and foreign body aspiration
Mediastinitis
Chemical pneumonitis
Gastro-oesophageal reflux, hiatus hernia and diaphragmatic irritation
Pericarditis, myocarditits, coronary disease, idiopathic hypertrophic subaortic stenosis and
arrhythmia
Pancreatitis and cholecystitis
Psychogenic
inward movement of the chest wall during case, the time course of the symptoms, i.e.
inspiration, mostly due to paralysis of the sudden onset or longer lasting, is essential.
intercostal muscles or the diaphragm. This A past history of asthma or recurrent
breathing pattern with seesaw type of obstructive bronchitis helps in determining
thoracoabdominal motion can also be seen the cause of acute intrathoracic airway
in preterm babies and newborns with a very obstruction. Possible foreign body
compliant thorax. In older children, however, inhalation needs to be excluded in a young
the most likely cause is respiratory muscle child with unilateral wheezing or diminished
fatigue and impending respiratory failure. breath sounds on one side of the thorax.
Risk factors such as known allergies, a
The more distal the obstruction, the more positive family history, underlying
effort is needed to get the air out of the lung. cardiovascular conditions, psychological
The elastic recoil pressure of the lung disorders, drugs or recent infections should
tissue is no longer sufficient as a driving be assessed. In patients with long lasting or
force in expiration and this usually passive recurrent episodes of dyspnoea, normal
process becomes an active one. In this growth and normal physical fitness point
situation, the usually negative intrapleural towards a more benign course. Dyspnoea
pressure becomes positive during expiration due to functional or psychological
leading to bulging of intercostal spaces. conditions usually disappear during sleep
Physiological triggers in the various causes of (fig. 1).
dyspnoea are changes in carbon dioxide and Inspection Correct observation is one of the
oxygen tension (PCO2 and PO2, respectively) most important parts of the physical
and in blood pH, as well as irritation of pain examination in a child with dyspnoea.
and thermo receptors and direct damage of Tachypnoea at rest, particularly during
neuronal receptors of breathing. sleep, is suggestive of increased effort in
Assessment of the patient and differential breathing. In a child with pneumonia,
diagnosis respiratory rate increases to improve
oxygenation. Thus, visible tachypnoea is one
History In a patient with severe respiratory of the most sensitive signs of restrictive lung
distress, history taking will be limited. In any disease, such as pneumonia, atelectasis,

Acute dyspnoea,
respiratory rate or
Inspection,
auscultation,
percussion
No intra- or extrathoracic
obstruction, crackles or No intra- or extrathoracic Normal inspiration, expiratory Inspiratory stridor, normal or
diminished lung sounds obstruction, normal lung wheeze (one or both sides) obstructive expiration
present sounds
Intrathoracic
Respiratory: blood
Metabolic: blood gases, obstruction: blood gases, Extrathoracic
gases, ultrasound,
electrolytes, blood bronchodilator test obstruction: blood
chest radiograph,
glucose (both sides), fluoroscopy gases
thoracic CT
(one-sided)
Neuromuscular or
Cardiac: blood gases, central: blood gases,
ECG, Echo, chest fluoroscopy, brain
radiograph imaging, liquor puncture
electromyogram
Psychogenic or
functional
Figure 1. Assessment of acute dyspnoea.
alveolitis, or pleural effusion and trachea usually can be heard without a

pneumothorax. In airway obstruction of the stethoscope. The noise either comes from
younger child, indrawing of the suprasternal vibrations of the aryepiglottic folds or vocal
fossa or subcostal and intercostal tissue and cords (vocal cord dysfunction) or from
nasal flaring is usually present. In unilateral dynamic compression of the extrathoracic
diseases of the lungs, the rib cage or part of the trachea just below the
diaphragm are seen as asymmetric obstruction of the subglottic or proximal
breathing motion. Chronic airway trachea (subglottic stenosis or croup). The
obstruction may result in a barrel-shaped sound may vary in pitch and intensity due to
chest with increased anteroposterior the site of obstruction. A more coarse
diameter. A bilateral skin fold below and a character indicates pharygolaryngeal site
bluish coloration of the lower eyelid may be (epiglottitis), whereas a sharp high-pitched
seen in atopy. Digital clubbing may tone may come from the subglottic region
accompany long lasting respiratory disease (croup). An additional expiratory stridor
like CF, and can be found rarely in lung suggests involvement of the intrathoracic
abscess and empyema. Peripheral or central part of the trachea. Stridor of a baby that
cyanosis occurs when the absolute diminishes or even disappears in the prone
concentration of reduced haemoglobin in position is very suggestive of a benign
the arterial blood exceeds 3 g per100 mL. infantile floppy larynx.
Auscultation and percussion Inspiratory Wheeze due to intrathoracic airway
stridor indicating narrowing of the larynx or obstruction refers to polyphonic continuous

musical lung sounds, in some languages children with hypothermia and peripheral
called asthma concert and is present in vasoconstriction, pulse oximetry cannot be
expiration and sometimes inspiration. relied on. In these situations arterial blood
Narrowing of a single central bronchus gas tests are mandatory. Besides this
results in a unilateral monophonic wheeze indication, assessing blood gases is crucial
often heard in a foreign body aspiration into for information on PCO2 and acid/base
a main bronchus. Crackles are non-musical, constellation. In a dyspnoeic child the rapid
discontinuous sounds indicating air increase in PCO2 (.5 mmHg per hour) is of
movements through secretions (bronchitis) great concern because this can be the first
or sudden opening or closing of airways or sign of impending respiratory failure and the
alveoli (pneumonia). They are coarse when need for ventilation. Hypocarbia and
they come from the bronchi and fine from respiratory alkalosis is indicative of
bronchioli or alveoli. A dyspnoeic child with hyperventilation seen in psychogenic
unilateral fine crackles most probably suffers disorders or hyperventilation tetany.
from pneumonia, whereas bilateral fine Hypocarbia and respiratory alkalosis also
crackles might be indicative of alveolitis, occur as compensation for metabolic
bronchiolitis or lung oedema. In acidosis. In ventilated children PCO2 values
pneumonia, the normally present are assessed and are necessary for
bronchovesicular breath sounds are monitoring ventilation parameters. PCO2
replaced by bronchial sounds because the measurement is essential for evaluating
bronchioli and alveoli component is lacking chronic lung disease (CF, chronic neonatal
due to congestion and secretions. lung disease or severe restrictive lung
Unilaterally diminished lung sounds with disease) and assessment of possible long-
dull percussion notes suggests atelectasis, term oxygen supplementation.
tumour or pleural effusion. Less breath
sounds and hypersonic/tympanic Respiratory imaging A very thorough and
percussion on one side of the thorax might skilled physical examination with proper
be a sign of pneumothorax. auscultation and percussion often leads to a
definitive diagnosis without the need for
Pulse oximetry and blood gases Pulse further imaging in a child with dyspnoea.
oximetry is a noninvasive means for This is the case in most patients with
measuring the bodys SaO2. A slight decrease obstruction due to asthma or typical viral
in oxygen saturation cannot readily be bronchiolitis. A chest radiograph helps to
detected by simple inspection of the skin or rule out pneumonia, atelectasis or
the mucous membranes. Pulse oximetry is pneumothorax. Children with lung TB are
an essential tool in any child with dyspnoea rarely dyspnoeic or in respiratory distress,
or respiratory distress. Causes for only in the case of miliary TB.
desaturation are similar to those for
cyanosis. By far the most likely cause is Usually, a radiograph sufficiently detects
ventilation/perfusion mismatch (V9/Q9) due lung bleeding in haemosiderosis or chest
to viral or bacterial infections of the lung. trauma. However, in the work-up of lung,
Sepsis, inhalation of toxic fumes, acute mediastinal or rib cage tumours, CT or MRI
respiratory distress syndrome (ARDS) or will be necessary. CT is diagnostic in
pulmonary oedema may lead to oxygen bronchiectasis and mandatory in suspected
diffusion impairment. In preterm babies, interstitial lung disease. Chest radiographs
respiratory distress syndrome is caused by are hardly ever useful in the assessment of
insufficient production of surfactant. Target dyspnoea due to upper respiratory tract
values for oxygen saturation in these babies pathology. In preterm babies a chest
are in the range of 8488% to avoid radiograph confirms clinical respiratory
detrimental effects of oxygen on the eyes. distress syndrome due to surfactant
Later in life, 92% is the lower limit of deficiency or suggests different pathology,
normal. In severe dyspnoeic children with such as lobar emphysema, cysts or other
signs of cardiorespiratory failure or in causes of congenital airway malformation.

In these cases CT or MRI will follow. In a patients and parents of the non-organic, and
dyspnoeic child with pleural effusion, usually benign, course of the disease. In
sonography can be used to monitor the vocal cord dysfunction, the inspiratory and
amount and consistency of the fluid and to expiratory part of the flowvolume loop
guide tapping. Many centres now use often shows saw-tooth like changes. In
interventional radiologists to insert chest patients with neuromuscular or skeletal
drains under ultrasonic guidance. problems, lung function measurement is
helpful in predicting potential limitations for
Lung function measurement In most patients surgery and anaesthesia.
with acute dyspnoea, history taking, physical
examinations, lab tests and imaging lead to Bronchoscopy and bronchoalveolar lavage In
diagnosis and lung function measurements an acutely dyspnoeic child with unilateral
are not necessary. Response to an anti- diminished lung sounds and a possible
obstructive treatment of lower or upper history of foreign body aspiration, rigid
airways is assessed clinically. However, in bronchoscopy should be performed. Apart
case of reported episodes of dyspnoea or from removal of a foreign body there is
limitations in physical activities and virtually no indication for rigid
uneventful actual physical examination, lung bronchoscopy. However, the use of flexible
function measurements may confirm or rule bronchoscopy has substantially increased
out obstructive or restrictive airway disease. in the last 20 years and one of the most
In the diagnosis of obstruction, spirometry prevalent indications is dyspnoea with
and flowvolume loop are essential whereas inspiratory stridor. Infantile larynx,
in suspected restriction vital capacity and congenital or acquired subglottic stenosis,
TLC need to be assessed. Carbon monoxide subglottic haemangioma, or a vascular
diffusion is measured when an impairment ring can be found. Bronchoalveolar lavage
of the alveolarcapillary diffusion capacity is is warranted in a child in whom lung
suspected as a cause for dyspnoea. bleeding, gastric content aspiration,
Impairment of diffusion can also be surfactant deficiency or certain infections
investigated by the means of pulse oximetry (Pneumocystis jirovecii, Aspergillus,
under physical stress. Standardised Cytomegalovirus), particularly in
protocols for treadmill tests and bicycle immunosuppression, are thought to cause
ergometry are available. A drop in FEV1 of dyspnoea. The role of transbronchial or
.10% after standardised physical activity open lung biopsies is particularly in
suggests exercise-induced severely sick patients with longer lasting or
bronchoconstriction. In functional or chronic dyspnoea in whom no diagnosis
psychogenic dyspnoea, a normal lung could have been made by investigations
function may be useful for reassuring so far.
Acute
dyspnoea
Respiratory rate Intrathoracic Diffusion impairment Potential

Extrathoracic Psychogenic or
or , PCO2 ,PO2 , obstruction (respiratory or cardiac) foreign body
obstruction functional
O2 saturation (both sides) (one-sided)
Repeated 2- O2, diuretics, Rule out Rule out epiglottitis, Psychogenical

O2, intensive care, agonists, possibly pneumothorax intervention,
steroids orally or
ventilation corticosteroid i.v. catecholamines, or effusion biofeedback
i.v. inhalation of
possibly antibiotics adrenalin
Rigid
bronchoscopy and
removal, no
2-agonists
Figure 2. Management of acute dyspnoea. PCO2: carbon dioxide tension; PO2: oxygen tension.

Evaluation of non-respiratory causes of administered intravenously. Inadequate
dyspnoea As seen in table 1, conditions release of antidiuretic hormone often
other than respiratory ones also need to be accompanies severe respiratory distress and
considered in a child with dyspnoea. If a warrants reduction in fluid administration.
respiratory cause is unlikely, a cardiac
assessment including electrocardiogram In a toxic dyspnoeic child with typical
and echocardiography should be performed. symptoms of epiglottitis, rapid intubation
Abnormalities in blood gases, blood and administration of antibiotics is
glucose, lactate, pyruvate or ammonia necessary. Systemically applied steroids
suggest defects in metabolism. In some and, in selected cases, inhalation of
cases a detailed neurologic or psychological adrenaline are cornerstones of the treatment
evaluation will be necessary. of a child with inspiratory stridor and
suspected croup. 4001000 mg of
General management salbutamol is inhaled in airway obstruction
due to asthma or obstructive bronchitis. In
A clear diagnosis is essential before
these diseases the obstruction is reversible
management can start in a dyspnoeic
and wheezing and respiratory distress will
patient. Figure 2 depicts the different
diminish after application. If this is not the
diagnostic paths and corresponding
case, irreversible airway obstruction due to a
treatment modalities. However, some
foreign body or mechanical narrowing must
general management steps apply for most
be suspected. The later situation warrants
situations. Cardiopulmonary resuscitation is
bronchoscopy and further evaluation or
obligatory in any unconscious child with
treatment.
cardiac or respiratory arrest. As a general
rule, children in respiratory distress should
not be investigated or transported in a lying Further reading
position but with upper body elevated. To
find out whether oxygen needs to be N Pasterkamp H. The history and physical
examination. In: Chernick V, et al., eds.
supplemented, pulse oximetry has to be
Kendigs Disorders of the Respiratory
performed. Repeated checks of blood gases
Tract in Children. 7th Edn. Philadelphia,
help to detect increases in PCO2 and
Saunders Elsevier, 2006; pp. 7593.
potential impending respiratory failure with N Riedler J. Symptome haufiger respirator-
the need of invasive or noninvasive ischer Krankheiten. In: Lentze MJ, et al.,
ventilation. Nasogastric tubes should be eds. Padiatrie Grundlagen und Praxis. 3.
avoided, particularly in infants with Auflage. Heidelberg, Springer, 2007;
respiratory distress, because they pp. 10411045.
substantially increase airway resistance and N Thomas P (2005). I cant breathe.
respiratory work load. Usually, enteral Assessment and emergency management
feeding is reduced to ,50% in these infants of acute dyspnoea. Aust Fam Physician;
to avoid compression of lungs by abdominal 34: 523529.
distension. The necessary fluids are

Snoring, hoarseness, stridor
and wheezing
Kostas N. Priftis, Kostas Douros and Michael B. Anthracopoulos
Wheezing, stridor and snoring are common

Key points causes of noisy breathing, particularly in
infants and young children, and their
N Wheeze is a continuous, usually high- presence indicates a degree of airway
pitched whistling sound that is obstruction. The term noisy breathing is
accompanied by prolongation of the used to describe respiratory sounds that are
expiratory phase; it is believed to audible to the naked ear without the use
originate from oscillation of large of a stethoscope. Although the evaluation of
airways in response to turbulent noisy breathing is not always
airflow in partially blocked straightforward, the proper identification of
intrathoracic airways. these noises is of major clinical importance,
N Stridor is a musical, monophonic, as it can assist in localising the site of an
high-pitched sound that can be heard obstruction and, thus, in the differential
without a stethoscope, and it is diagnosis of the potential underlying causes
caused by narrowed large, (table 1).
extrathoracic airways; its presence The cause is often obvious from the history
suggests significant obstruction of and clinical examination, and the final
airflow in the larynx and proximal diagnosis can be reached with a minimum
trachea. of diagnostic procedures. However, an
N Snoring is produced during sleep interventional approach may sometimes be
and is due to obstructed air necessary to effectively diagnose the cause,
movement in the naso- and especially if a lower airway lesion is
oropharynx; children who snore tend suspected.
to have more collapsible airways and/
or increased size of adenotonsillar The difficulty in correctly recognising these
tissue. abnormal sounds arises from the different
types that may be present in the same
N Rattle is created by the movement of patient at the same time or at different
excessive secretions during normal points in time, and from the fact that they
airflow in the central and extrathoracic are frequently intermittent and not heard
airways; it has a rattling, during the clinical examination, making the
noncontinuous quality, but quite clinician rely only on the parents
commonly is mislabelled by parents description. Parents descriptions are often
as wheezing. inaccurate, and their use of terms to
N Hoarseness (or dysphonia) is a describe a noise can be quite misleading;
disorder of phonation and is used to this can also be the case among physicians,
describe a change in the quality of the as there is still ambiguity in the terminology
voice; it is not usually associated with used for respiratory noises in the medical
airway obstruction. literature, highlighting the need for a
common nomenclature in each language.
Nevertheless, a detailed history by the

Table 1. Different kinds of noisy breathing, site of origin and usual potential causes
Noise Site of origin Common causes
Wheezing Intrathoracic airways Asthma
(wheeze) (primarily expiratory) Viral wheeze
Bronchiolitis
Foreign body
Protracted bacterial bronchitis
Tracheo/bronchomalacia
Stridor Extrathoracic airways Croup
(primarily inspiratory) Epiglottitis
Laryngomalacia
Tracheomalacia
Vocal cord paralysis
VCD
Snoring Oro/nasopharyngeal airway Collapsible airways with increased size of
adenotonsillar tissue
Obesity
Craniofacial disorders
Rattle Intra- and extrathoracic Acute viral bronchitis
airways Protracted bacterial bronchitis
Neurologic disorders with swallowing
dysfunction and/or chronic aspiration
Grunting Glottis Respiratory distress syndrome (neonates)
Pneumonia
Bacterial infection
Snuffles Blocked nasal passages Upper respiratory tract infections
Allergic rhinitis
parents on the exact nature of the In this section, wheezing, stridor and
respiratory noise, with special attention to snoring will be discussed, and there will be a
whether it occurs during inspiration, brief reference to some other quite common
expiration or both, whether it is low or high types of noisy breathing, namely rattle,
pitched, or has a musical quality and is grunting and snuffle. Hoarseness (or
accompanied by vibrations of the chest wall, dysphonia), which is a disorder of phonation
and perhaps the imitation of the various and is not usually associated with airway
sounds by the physician, will undoubtedly obstruction, will also be discussed.
assist in differentiating between the various
noises. Wheezing
Computerised acoustic analysis technology Wheeze is a continuous, usually high-

has been used to evaluate the properties of pitched whistling sound with a musical
sounds and, in the future, may provide an quality. It can be heard throughout the
objective clinical tool for correctly respiratory cycle but is more common
characterising respiratory sounds and during expiration and is accompanied by
assessing disease activity through the serial prolongation of the expiratory phase. It
recording and quantification of these originates from turbulent airflow, caused by
sounds. However, for the time being, this partially blocked intrathoracic airways, that
technology is used only for research oscillates the airway wall and gives rise to
purposes. the sound.

Although, in theory, wheezing can arise from The absence of a choking event is not
throughout the conducting airways, it requires reassuring, as ,15% of cases are not
sufficient airflow that, practically, it is associated with a clear history of a choking
restricted to the large and medium-sized episode. Monophonic progressive wheeze
airways. Still, it is common experience that implies either a focal endobronchial lesion
wheezing is audible in cases of extensive small (endobronchial TB or adenoma) or
airway narrowing, as is the case with asthma extraluminal compression of central airways
and with bronchiolitis. This could be due to air by a growing lymph node or other mass and
trapping in the lung periphery and the higher should always prompt further investigation.
pleural pressures required to overcome the In general, monophonic wheeze needs a
narrowing. Thus, the wheeze is thought to be thorough investigation with chest
produced by the resultant external radiography, flexible bronchoscopy and/or
compression of the larger airways, especially CT. If foreign body aspiration is a strong
during infancy when the walls of the more possibility, urgent rigid bronchoscopy
central bronchi are more collapsible. Since the should be carried out, while mere suspicion
noise is produced by a multitude of airways should prompt investigation of the airways
throughout the lungs the wheeze consists of a with a flexible bronchoscope.
multitude of distinct harmonics (differing
acoustic characteristics) and is therefore Stridor
polyphonic. Conversely, when the sound is Stridor is a musical, monophonic, high-
generated by one (e.g. stenosis, foreign body) pitched sound, albeit much more harsh
or few, at the most, large airways, it consists of (oligophonic) than wheeze, which can be
a much more limited number of harmonics heard without a stethoscope, especially
and is termed monophonic (perhaps more during inspiration. It is caused by
precisely, oligophonic). The focal nature oscillations of narrowed large, extrathoracic
of the generation of the monophonic wheeze airways, and its presence suggests
may explain the decrease of its loudness with significant obstruction of airflow in the
the increase in the distance of the site of larynx and extrathoracic trachea. The
auscultation from the sound source generation of stridor can be explained by the
(obstruction). dynamics of inspirationexpiration
Assessment The most common cause of (particularly when forced) and Bernoullis
intermittent episodes of polyphonic wheeze principle, which, simply put, states that the
in children is asthma. A prompt response of pressure (dynamic energy) exerted by a
wheeze to a trial of bronchodilator is of great moving fluid (or gas) on a surface decreases
importance, as it strongly supports the as the velocity (kinetic energy) of the fluid
diagnosis of asthma. In infants, especially if increases. Inhalation generates negative
crepitations predominate on auscultation (relative to that of the atmosphere)
and particularly if it is the first episode of intrapleural pressure, which, in turn, is
diffuse airway obstruction, bronchiolitis is applied to the trachea. In normal
the most likely diagnosis, although asthma individuals, this results in minimal collapse,
cannot be excluded. The response to which is not clinically relevant. However, if
bronchodilators, the presence and/or a the airway is partially obstructed, there is a
family history of atopy may all help to disproportionally large drop in the
differentiate bronchiolitis or viral wheeze intraluminal pressure, which is created by
from asthma. Although simple the respiratory muscles in order to
noninterventional studies like chest overcome the obstruction. This pressure
radiography, allergy testing and spirometry drop is further augmented by the turbulent
may be useful in older children, more flow through the constricted laryngeal/
elaborate studies are usually not necessary. tracheal tube due to Bernoullis principle,
which further deteriorates the narrowing (a
Acute onset of monophonic wheeze raises floppy extrathoracic airway will deteriorate
the possibility of foreign body aspiration. the collapse even further). The Bernoulli

effect, which creates high-frequency .90% of all cases of stridor in children. It is
fluctuations of intraluminal pressure, is also unlikely to occur before 6 months of age.
probably primarily responsible for the Most episodes are mild and only a minority
vibrations of the airway wall that are of children need hospital admission. The
responsible for the creation of stridor. obstruction is due to subglottic oedema
Conversely, exhalation induces a positive and, in most cases, stridor occurs during
intraluminal pressure of the extrathoracic inspiration, although it can be biphasic in
airway, which tends to distend the severe disease. Other quite exceptional
extrathoracic trachea, alleviate the tracheal infectious causes of acute stridor are
obstruction and reduce expiratory flow epiglottitis, and bacterial tracheitis.
resistance. These mechanisms explain why
stridor is predominantly inspiratory, Foreign body aspiration should always be
although it can also be present during suspected whenever the beginning of stridor
expiration if the obstruction is severe is abrupt and accompanied by severe
enough (fig. 1). respiratory distress. Rigid bronchoscopy
constitutes the definitive procedure in this
Assessment The history and physical case, as it not only allows for the
examination provides information on the visualisation of the airways but also for the
persistence of stridor (chronic versus acute), removal of the foreign body.
acuity of onset (abrupt versus gradual),
timing during the respiratory cycle The most common cause of chronic stridor
(inspiratory, expiratory or biphasic), in infancy is laryngomalacia. It usually
accompanying symptoms (fever or coryza), manifests days or weeks after birth and
hoarse and/or weak cry, cyanotic episodes, symptoms usually resolve by 1218 months.
positional differences in the intensity of The noise varies in intensity depending on
noise, interval symptoms between episodes the respiratory effort and varies with the
and severity of respiratory distress. position of the patient. The obstruction is
due to prolapse of the epiglottis or the loose
The most common cause of acute stridor is mucosal tissue overlying the arytenoid
viral croup, which is quite common and cartilages into the laryngeal inlet. Laryngeal
presents with stridor accompanied by walls collapse due to the subatmospheric
hoarseness, dry barking cough and pressure generated during inspiration. On
respiratory distress. Croup is usually expiration, the positive luminal pressure
preceded by coryzal symptoms and overcomes the obstruction, thus keeping the
improves within a few days. It accounts for airway open; therefore, if there is expiratory
Extrathoracic airway
C7
T1
Intrathoracic airway
Inspiratory phase Expiratory phase
Figure 1. During inhalation, a negative (relative to that of the atmosphere) intrapleural pressure in
extrathoracic airways is generated, which in turn is applied to the trachea. This results in minimal collapse,
which, in normal individuals, is not clinically relevant. Exhalation induces a positive intraluminal pressure
of the extrathoracic airway, which tends to distend the extrathoracic trachea.

stridor, an alternative diagnosis needs to be can be set only with direct visualisation of
sought. the cords with laryngoscopy, during an
episode.
Intermittent, sudden-onset, daytime
episodes of stridor in school-aged children Snoring
or adolescents may indicate vocal cord
dysfunction (VCD). In this condition, which Snoring is a sound that is produced during
may coexist with asthma, the vocal cords are sleep from the increase in resistance to the
held in a paradoxical adducted position. airflow in the upper airways and, more
Patients present with significant inspiratory specifically, in the region of the naso- and
stridor and respiratory distress. Symptoms oropharynx. Children who snore tend to
usually appear during exercise, especially in have more collapsible airways and increased
highly competitive young athletes, but may size of adenotonsillar tissue. During rapid
also appear without any identifiable cause. eye movement (REM) sleep, the tone in
pharyngeal muscles is reduced, resulting in
Rare causes of chronic stridor include vocal an increase in the frequency and severity of
cord paralysis (congenital or acquired), obstruction. Snoring is more pronounced on
laryngeal clefts, subglottic stenosis inspiration but it can also be audible during
(congenital or acquired), haemangiomas, expiration. It is considered to be common in
laryngeal cysts and laryngeal webs. children, with the reported prevalence
For acute episodes of stridor that are typical ranging from 5% to 20%. Its severity ranges
of croup, there is no need for investigations from the so-called primary snoring with no
other than clinical evaluation. However, evidence of ventilation abnormalities to
children who have unusually prolonged or severe OSAS. The latter is characterised by
recurrent episodes, or are not completely episodes of complete or partial upper airway
asymptomatic between episodes, and obstruction leading to hypoxaemia and/or
children ,6 months of age require hypercapnia, and frequent nocturnal
endoscopic evaluation. arousals. The spectrum of disorders from
primary snoring to OSAS is characterised as
In infants with chronic inspiratory stridor sleep disordered breathing (SDB).
who are thriving and do not have significant
respiratory distress, cyanotic episodes, Assessment The main concern in the
chronic cough, hoarseness or weak cry, the evaluation of snoring is to define the
most likely diagnosis is laryngomalacia and children who may suffer health
there is no need for further investigations. consequences related to the pathology
However, if any of the above characteristics underlying this breath sound; this may prove
are present, a more thorough investigation to be difficult. OSAS cannot be diagnosed
is in order. If an endoscopic evaluation is simply on the grounds of a history of
decided upon, it is preferable to perform snoring since not all children who snore
both rigid laryngotracheoscopy and flexible have OSAS, nor is the absence of snoring is
bronchoscopy. Rigid instruments allow a sufficient to exclude OSAS, as parents may
much better view of the posterior aspect of not have noticed the snoring of their child.
the larynx and upper trachea, whereas Furthermore, there is some evidence
flexible bronchoscopy is superior in suggesting that primary snoring may not be
evaluating airway dynamics. The entire completely benign.
airway should always be examined, despite
the finding of a lesion in the larynx that can A detailed history is helpful. Children who
explain the stridor, since in ,15% of suffer from OSAS snore almost every night,
patients, an additional lesion will coexist in snoring usually persists throughout the
the lower airways. night and there are frequent apnoeic
episodes followed by loud snorts and
If VCD is suspected, spirometry may show changes in position. They may suffer from
truncated inspiratory and expiratory flow daytime tiredness, poor concentration and
volume loops. However, definite diagnosis enuresis. Behaviour and learning problems

(including attention deficit hyperactivity created by excessive secretions which are
disorder) are not unusual. Clinical moving during normal airflow in the central
examination may reveal adenoidal facies, and extrathoracic airways. The mislabelling
enlarged tonsils or hyponasal speech. of a rattle as wheeze may result in
Obesity, prematurity, family history and overdiagnosis (and overtreatment) of
craniofacial anomalies are all well-known asthma in children.
risk factors for OSAS. However, history and
clinical examination are not sufficient to The most common cause of rattle is acute
reliably identify OSAS and the definitive viral bronchitis and, in preschoolers, upper
diagnosis has to rely on polysomnography airway viral infections. A rattle can be heard
(PSG), which is considered the gold for a few days or weeks and subsides after
standard for evaluating children for SDB. the removal of secretions from cough and
Still, this method is complex, expensive and mucociliary clearance. Chronic rattling
time-consuming; these drawbacks restrict sound is often related to chronic aspiration
its usefulness to a limited number of in children with various neurological
specialised centres. A simplified alternative conditions.
method is the continuous recording of
Grunting
oxygen saturations overnight with pulse
oximetry. Furthermore, there are a number Grunting is a short, hoarse, moaning or
of other devices that monitor pulse oximetry crying-like expiratory sound that occurs
with a combination of one or more when a partially closed glottis halts the
parameters, like chest wall movement, body expiratory flow of air. This mechanism may
movement and airflow. Due to their low be considered as a self-administered form of
cost, simplicity and portability, they can be peak end-expiratory pressure, since the
used for unattended studies at home. In slowing of expiratory flow increases the
general, these methods have high positive functional residual capacity and alveolar
and low negative predictive values, which pressure, and prevents alveolar collapse.
imply that patients with negative results However, the underlying pathophysiology is
require a full PSG for definitive diagnosis. not yet fully elucidated. In neonates, the
noise is commonly associated with
Adenotonsillectomy is the treatment of
respiratory distress syndrome. In older,
choice for the vast majority of children with
previously healthy children, it is a sign of
OSAS. When surgery is not an option or if
pneumonia, whereas in children with
resolution of symptoms is not achieved
underlying chronic disease, it is considered
following surgery, nasal CPAP is usually
as a sign of serious bacterial infection.
effective.
Snuffles
Rattle
The term snuffles (or snorts) is used to
Parents tend to use wheeze as a generic
describe noisy breathing coming from
term to describe a variety of abnormal
blocked nasal passages. It is also used to
respiratory sounds. One of the commonest
describe the common cold or simply a runny
errors is the misuse of the word wheeze to
nose. The noise is audible throughout the
describe a coarse respiratory sound known
respiratory cycle and is associated with
as rattle. Rattle is characterised by a much
visible secretions from the nares. Apart from
lower pitch than wheeze, it has a rattling,
upper respiratory tract infections, snuffles
noncontinuous quality, is usually
may also indicate allergic rhinitis or, on rare
accompanied by chest wall vibrations that
occasions, primary ciliary dyskinesia and
are easily detectable by parents, and it can
be heard during both inspiration and nasal polyps as in CF.
expiration. It is found quite often in infants Hoarseness
and toddlers and, although there is a paucity
of data in the literature regarding the The term hoarseness (or dysphonia) is used to
underlying mechanism, it is believed to be describe a change in the quality of the voice.

It can be caused by any pathological or Vocal cord paralysis is rare in children. It can
behavioural condition that affects the be bilateral or unilateral. The former is
function or the structure of the larynx. The mostly caused by central nervous system
problem appears to be common in children, anomalies like ArnoldChiari malformation,
with a reported incidence ranging from 6% to whereas the latter mainly results from
23%. However, these numbers are derived damage to the left recurrent laryngeal nerve
from small epidemiological studies that have because of birth trauma, heart anomalies or
used a variety of definitions for dysphonia/ cardiac surgery. However, bilateral and
hoarseness or no definition at all. unilateral vocal cord palsy can be idiopathic
without any identifiable cause. In bilateral
Hoarseness usually evolves gradually, which palsy, there is almost always severe airways
may result in delayed diagnosis and obstruction and stridor, whereas in
treatment. Fortunately, in most children, it is unilateral stridor, it may be absent and the
due to benign or self-limited causes that lesion may manifest as a husky, weak cry.
require no intervention or can be managed Bilateral vocal cord paralysis is a
with voice therapy techniques. predisposing cause of chronic or recurrent
aspiration pneumonitis. About half of these
Assessment A detailed history and clinical
palsies recover spontaneously, largely
examination are essential for the evaluation
irrespective of their cause.
of hoarseness. The persistence and
evolution of hoarseness, i.e. if it is acute In general, history and physical examination
versus chronic, or intermittent versus may help to distinguish between many of the
continuous progressive, is of pivotal pathological conditions causing hoarseness.
importance. Acute hoarseness is usually due However, direct inspection of the larynx by
to injury of the mucosa overlying the vocal laryngoscopy is usually necessary for a
chords after vocal abuse but may also definitive diagnosis. If the hoarseness is
result from infectious or inflammatory rapidly progressive and/or is accompanied
processes. Chronic problems typically by stridor or respiratory distress,
indicate structural abnormalities. If laryngoscopy is mandatory.
hoarseness is intermittent and worsens in
the morning, then gastro-oesophageal reflux Conclusion
is a distinct possibility. Conversely, if it is
Distinguishing the various respiratory
worse in the evening following prolonged
noises can, at times, be quite challenging.
use of the voice, it may be related to
The terminology is confusing and there is no
anatomical problems such as vocal nodules.
gold standard for the definition of the
Persistent, progressive dysphonia that different sounds. Things are more
fluctuates from day to day may suggest the complicated when the clinician has to rely
presence of papillomatosis. The presence of only on the parents description and
stridor or any other form of noisy breathing interpret their terms for the breathing noise
and/or respiratory distress indicates a that they are referring to. Acoustic analysis
serious and potentially life-threatening of respiratory sounds may improve
condition that must be evaluated and communication among clinicians and
treated promptly. The presence of dysphagia audiovideo recordings demonstrating the
implies either a neurological problem various sounds may prove quite useful in
affecting both the laryngeal and order to improve the accuracy of the
hypopharyngeal area, or a mass lesion information that is obtained.
affecting both swallowing and vocalisation.
It is imperative to ask whether there are The clinical usefulness of respiratory noises
potential iatrogenic causes, including could be improved by technology, such as
previous endotracheal intubation or video recording and sound analysis, but
nasogastric tube insertion, that may have although these techniques would clearly
contributed to the emergence of the improve uncertainty regarding the
problem. estimation of each specific noise, they are

not suitable for everyday clinical practice N Elphick HE, et al. (2004). Validity and
and their use remains confined to research reliability of acoustic analysis of respira-
projects. tory sounds in infants. Arch Dis Child; 89:
10591063.
N Fakhoury K. Approach to wheezing in
Further reading children. www.uptodate.com/contents/
approach-to-wheezing-in-children.
N Au CT, et al. (2009). Obstructive sleep N McMurray JS (2003). Disorders of phona-
breathing disorders. Pediatr Clin North tion in children. Pediatr Clin North Am;
Am; 56: 243259. 50: 363380.
N Bilavsky E, et al. (2008). Are grunting N Mellis C (2009). Respiratory noises: how
respirations a sign of serious bacterial useful are they clinically? Pediatr Clin
infection in children? Acta Paediatr; 97: North Am; 56: 117.
10861089. N Witmans M, et al. (2011). Update on
N Boudewyns A, et al. (2010). Clinical pediatric sleep-disordered breathing.
practice: an approach to stridor in infants Pediatr Clin North Am; 58: 571589.
and children. Eur J Pediatr; 169: 135141. N Zalvan C, et al. Etiology and management
N Chang JI, et al. (2012). Evidence-based of hoarseness in children. www.uptodate.
practice: management of hoarseness/ com/contents/etiology-and-management-
dysphonia. Otolaryngol Clin North Am; of-hoarseness-in-children.
45: 11091126.
N Elphick HE, et al. (2001). Survey of Further listening
respiratory sounds in infants. Arch Dis
Child; 84: 3539. N The R.A.L.E. Repository. www.rale.ca.

Exercise intolerance
Kai-Hakon Carlsen
Exercise intolerance or the lack of ability to

participate in physical activity and exercise Key points
together with peers may have many causes.
Some of the most common causes of N Participating in and mastering physical
exercise intolerance are of respiratory origin exercise is extremely important in
and will be briefly dealt with here (table 1). children and adolescents.
Participating in physical activity is important N Participation in physical activity

for children, for their growth, their long-term improves quality of life, fitness and life
development and future health. In asthmatic expectancy in many respiratory
children, physical fitness has been disorders.
associated with psychological functioning. N Treatment of childhood asthma
should aim at mastering physical
One of the most common respiratory causes activity and exercise-induced asthma.
of exercise intolerance is exercise-induced
asthma (EIA), a frequent manifestation of N Several chronic respiratory disorders
childhood and adolescent asthma. In the of childhood may influence the ability
Oslo birth cohort, the Environment and to participate in physical activity.
Childhood Asthma study, exercise-induced Assessment of the ability to
bronchoconstriction (EIB) was found in participate in physical activity and
8.6% of all 10-year-old children and in 36.7% setting up therapeutic procedures to
of children with current asthma, whereas in counteract exercise intolerance should
a Danish population-based study of 494 be part of the diagnostic assessment
children aged 716 years, EIB with a o10% of children with respiratory disease.
reduction in FEV1 after exercise was found in
16% of the subjects.
programme in children and adolescents
When participating in systematic physical (mean age 13.4 years), but they found a
training, the fitness and quality of life of an reduction in total IgE and specific IgE to
asthmatic adolescent or child improves, as house dust mite in the actively training
confirmed by a Cochrane-based meta- group. Fanelli et al. (2007) conducted a 16-
analysis of eight training studies including week training programme of 90 min twice a
226 asthmatics aged o6 years of age. week in two groups (index and control) of
Similar results were also reported when later children with moderate-to-severe persistent
studies were also included. Counil et al. asthma. In the training group they found
(2003) confirmed improvement in aerobic improved fitness (peak oxygen uptake
and anaerobic fitness in asthmatic (V9O2peak), work rate and oxygen pulse
adolescents (mean age 13 years), but no during submaximal and maximal work),
improvement in lung function after 6 weeks improved quality of life, reduction in exercise
of training with high-intensive bouts. bronchoconstriction and reduced dose of
Moreira et al. (2008) found no changes in inhaled steroids in 11 out of 21 subjects in the
asthma control after a 3-month training training group compared to four out of 17

Table 1. Causes of exercise intolerance in children and adolescents
Cause of exercise Clinical characteristics Diagnostic procedure
intolerance
EIA Expiratory dyspnoea occurring Exercise test for exercise-
shortly after end maximal or induced bronchoconstriction
sub-maximal exercise
Clinical airways obstruction
EIVCD Inspiratory stridor occurring Continuous laryngoscopic
during maximal exercise exercise test
Exercise-induced Anaphylaxis occurring during Food allergy evaluation
anaphylaxis or immediately after exercise, Simultaneous food provocation
most often with food intake and exercise test under safe
(allergenic) within the last 2 h emergency precautions
prior to exercise
Other chronic respiratory Chronic respiratory disorder, CPET with recording of breath to
disorders with reduced which can be of different kind breath V9O2max and
baseline lung function (CF, primary ciliary dyskinesia simultaneous tidal flow
and bronchiectasis) volume loops every minute
Reduced baseline lung function Detection of flow limitation and
measure EELV
Dysfunctional breathing in Chronic or recurrent changes in Nijmegen questionnaire
asthma breathing patterns causing
respiratory (and non-
respiratory) complaints
Symptoms include dyspnoea
with normal lung function,
deep sighing, chest pain, chest
tightness, frequent yawning,
hyperventilation and
breathlessness during exercise
Poor physical fitness Breathlessness during exercise CPET (maximum work capacity
before ordinarily anticipated and/or V9O2max)
Muscle stiffness
Obesity As for poor physical fitness
Other chronic disabling Varying clinical picture Clinical assessment
disorders
CPET: cardiopulmonary exercise test; EELV; end-expiratory lung volume; V9O2max: maximal oxygen uptake.
in the control group. Thus, the training physically active as healthy children, whereas
subjects improved their exercise tolerance other studies have demonstrated that
through physical training. physical activity and fitness are related to
asthma control and improve with optimal
Subjects with higher physical activity levels treatment and asthma control. Therefore, to
were found in a review of longitudinal studies master EIA is considered one of the main
to have a lower incidence of asthma (OR objectives of treating childhood asthma.
0.87, 95% CI 0.770.99), thus indicating a
potential for protection of developing asthma Exercise-induced vocal cord dysfunction
by being physically active.
Exercise-induced vocal cord dysfunction
Some studies demonstrate that asthmatic (EIVCD) is caused by airways obstruction
children are as physically fit and as during exercise due to airflow limitation in

the laryngeal area. This was first described in specific IgE to tri V-gliadin. Other food
1983. This condition occurs frequently allergens may also be responsible. Usually,
during adolescence, and is almost as it is sufficient to secure removal of the
frequent as EIB, especially among girls causative food allergen from the food, with
active in sport with high fitness levels. The the patient then tolerating exercise.
symptoms consist of inspiratory stridor as However, as a precaution the patient should
the exercise load increases. When reaching a still carry an Epi-pen. Diagnosis may be
submaximal or maximal level, stridor usually secured by simultaneous administration of
appears. The laryngeal area represents the the suspected food allergen and an exercise
smallest orifice for the air to pass through test with safe emergency precautions being
during inspiration, and in well-trained taken.
youths, especially girls, the orifice becomes
Chronic lung diseases other than asthma
too small to allow entry of the required
amount of air without the appearance of These may also cause exercise intolerance,
stridor and reduction of V9O2peak. Several but through other mechanisms. Whereas
laryngeal structures can participate in the baseline lung function is usually normal or
airflow limitation, and the treatment may vary close to normal in asthma, exercise causes
depending on this. Treatment may be bronchoconstriction, which limits the ability
surgical or conservative. Lung function of participating in physical exercise. In other
during exercise will, in many cases, be chronic lung disorders, exercise usually does
characterised by reduced inspiratory flow. not cause bronchoconstriction, but reduced
This condition has often been misinterpreted baseline lung function may represent a
as EIA, but with no effect of asthma pulmonary limitation for participating in
treatment. Inspiratory stridor during maximal physical exercise similar to other children.
exercise may be observed during testing for This includes CF, primary ciliary dyskinesia,
EIB, but an exact diagnosis requires a other causes of bronchiectasis, secondary
continuous laryngoscopic exercise test. lung disease to immunodeficiency and other
chronic lung diseases with reduced baseline
Exercise-induced anaphylaxis
lung function. The reduced lung function
Exercise-induced anaphylaxis is a condition will represent a flow limitation during
with anaphylaxis provoked by physical exercise, which limits the possibility of
exercise. This is a rare, but dramatic increasing oxygen uptake with the increasing
disorder in which the anaphylaxis occurs demands for oxygen during exercise, thus
during or immediately after exercise. It may giving rise to an anaerobic metabolism. The
be life threatening and is most often food resulting dyspnoea is due to reaching the
dependent (food-dependent exercise- limits of airflow and not due to obstruction
induced anaphylaxis (FDEIA)), but may also of the airways due to the exercise, as in
be due to exercise alone. Usually there is an asthma. The patient will have an anaerobic
associated food allergy, but this may be metabolism during exercise at a much
unknown to the patient as food allergy earlier time-point (fig. 1).
symptoms may not occur without Some other causes of exercise intolerance
simultaneous exercise. Most often both are specific for athletes, such as exercise-
exercise and the specific food are induced arterial hypoxaemia and swimming-
independently tolerated in FDEIA, induced pulmonary oedema; therefore,
simultaneous exposure to both are usually these are only mentioned for completeness.
required for the symptoms of anaphylaxis to
occur. Wheat proteins have often been One condition that has received little focus
found to be the causative food in FDEIA, in children is dysfunctional breathing. This
most often due to the major component condition is defined by chronic or recurrent
allergen, tri V-gliadin. One should be aware changes in breathing patterns. Symptoms
that, in some cases, negative specific IgE include dyspnoea with normal lung function,
may be found to wheat even with increased deep sighing, chest pain, chest tightness,

Early exercise Mid exercise End exercise
a)
b)
Figure 1. Tidal breathing during exercise in a) a patient with asthma and b) a patient with chronic lung
disease (bronchiectasis). The patient with asthma demonstrated normal baseline lung function at early,
mid and end exercise. The patient with chronic lung disease had reduced baseline lung function during
early, mid and end exercise, demonstrating flow limitation and increased end-expiratory lung volume.
There was no flow limitation in the patient with asthma.
frequent yawning, hyperventilation and the opposite, to focus on mastering of

breathlessness during exercise. A diagnosis is physical activity and training, would
based on the Nijmegen questionnaire. A represent a positive starting point. The
recent study demonstrated that this condition patients presenting with exercise
occurred in 5.7% of asthmatic children intolerance should be encouraged to
followed at a hospital outpatient clinic. participate in exercise to improve physical
fitness and muscular strength. Physical
There are other non-respiratory causes of
training has been shown to prolong life
exercise intolerance that are not included in
expectancy in patients with CF, and
the above review. These often appear with
systematic training in children with and
breathlessness and muscular weakness as
without pulmonary disorders will improve
the most prominent symptoms. These
fitness, quality of life and life expectancy.
include general physical illnesses such as
In children with chronic lung disease focus
cardiac disease and other general disabling
should be on optimal treatment of their
diseases. Other causes are poor physical
fitness, when the physical activity level does respiratory disease in combination with a
not meet expectations in the absence of any systematic training programme focusing
illness, and obesity with its limitations to on upper girdle muscles and fitness in
physical activity (table 1). order to enable them to master physical
activity and to participate on an equal level
To focus on exercise intolerance may with their peers in sports and outdoor
represent a negative point of view. Rather, living.

Further reading N Ram FS, et al. (2000). Effects of physical
training in asthma: a systematic review.
N Backer V, et al. (1992). Bronchial respon-
Br J Sports Med; 34: 162167.
siveness to exercise in a random sample of
N Ram FS, et al. (2005). Physical training
494 children and adolescents from
for asthma. Cochrane Database Syst Rev;
Copenhagen. Clin Exp Allergy; 22: 741747.
4: CD001116.
N Berntsen S, et al. (2009). Norwegian
N Refsum HE, et al. Exercise-associated
adolescents with asthma are physical
ventilatory insufficiency in adolescent
active and fit. Allergy; 64: 421426.
athletes. In: Oseid S, et al. The
N Counil FP, et al. (2003). Training of
Asthmatic Child in Play And Sports.
aerobic and anaerobic fitness in children
London, Pitmann Books Limited, 1983;
with asthma. J Pediatr; 142: 179184.
N de Groot EP, et al. (2013). Dysfunctional pp. 128139.
breathing in children with asthma: a rare N Roksund OD, et al. (2009). Exercise
but relevant comorbidity. Eur Respir J; 41: induced dyspnea in the young. Larynx as
10681073. the bottleneck of the airways. Respir Med;
N Del Giacco SR, et al. (2012). Allergy and 103: 19111918.
sports in children. Pediatr Allergy Immunol; N Scheett TP, et al. (2002). The effect of
23: 1120. endurance-type exercise training on
N Eijkemans M, et al. (2012). Physical growth mediators and inflammatory
activity and asthma: a systematic review cytokines in pre-pubertal and early
and meta-analysis. PLoS One; 7: e50775. pubertal males. Pediatr Res; 52: 491
N Fanelli A, et al. (2007). Exercise training 497.
on disease control and quality of life in N Stanghelle JK, et al. (1992). . Eight-year
asthmatic children. Med Sci Sports Exerc; follow-up of pulmonary function and
39: 14741480. oxygen uptake during exercise in 16-year-
N Lee TH, et al. (1985). Heterogeneity of old males with cystic fibrosis. Acta
mechanisms in exercise-induced asthma. Paediatrica; 81: 527531.
Thorax; 40: 481487. N Strunk RC, et al. (1989). Cardiovascular
N Lodrup Carlsen KC, et al. (2006). Asthma fitness in children with asthma correlates
in every fifth child in Oslo, Norway: a 10- with psychologic functioning of the child.
year follow up of a birth cohort study. Pediatrics; 84: 460464.
Allergy; 61: 454460. N Vahlkvist S, et al. (2010). Effect of asthma
N Maat RC, et al. (2007). Surgical treatment treatment on fitness, daily activity and
of exercise-induced laryngeal dysfunction. body composition in children with
Eur Arch Otorhinolaryngol; 264: 401407. asthma. Allergy; 65: 14641471.
N Moreira A, et al. (2008). Physical training N Varjonen E, et al. (1997). Life-threatening,
does not increase allergic inflammation recurrent anaphylaxis caused by allergy to
in asthmatic children. Eur Respir J; 32: gliadin and exercise. Clin Exp Allergy; 27:
15701575. 162166.

Static and dynamic lung
volumes
Oliver Fuchs
This section begins with a short review on measured with slow breathing
static and dynamic lung volumes. Then, manoeuvres: tidal volume (VT), inspiratory
physiological principles underlying forced reserve volume (IRV), expiratory reserve
expiration and especially flow limitation will volume (ERV), inspiratory capacity (IC), and
be highlighted. Lastly, the reader will be vital capacity (VC), the latter being the
introduced to the field of lung function, and volume exhaled from full inspiration to full
relevant literature in relation to current expiration, or inhaled from full expiration to
guidelines for those measurements in full inspiration. This explains the limitations
children as well as normative data will be especially of a VC manoeuvre in unco-
pointed out. operative subjects, particularly during early
childhood and preschool age.
Static lung volumes
Using additional techniques such as body
Lung volumes that are not affected by air plethysmography and gas dilution
flow are termed static lung volumes and techniques, it is also possible to measure
consist of specific volumes and capacities the residual volume (RV), which is
(sums of specific volumes). All static important for maintaining continuous gas
volumes are age-dependent and increase exchange during profound expiration. It
with age during childhood. In contrast to a cannot be exhaled and has thus to be
forced expiration (see later), the following measured indirectly. With these
static lung volumes can be directly measurements, it is also possible to
calculate the TLC and the functional residual
capacity (FRC). The FRC is the volume of air
Key points in the lung after a normal expiration during
tidal breathing. It is dependent on standing
N Lung volumes that are not affected by height, age, posture, compliance and tone of
air flow are termed static lung the diaphragm and represents the volume at
volumes and consist of volumes and which the elastic recoil pressures of the lung
capacities (sum of specific volumes). and of the chest wall are in balance. Static
N The total lung capacity and the lung volumes that can be measured either
functional residual capacity include a directly or indirectly as well as capacities
volume of gas that cannot be exhaled are displayed in the table 1 and figure 1
(residual volume) and which is together with their respective
important for maintaining continuous acronyms.
gas exchange during profound Dynamic lung volumes
expiration.
N Lung volumes that are affected by air Lung volumes that are affected by air flow,
flow are termed dynamic lung are termed dynamic lung volumes and they
volumes and are measured during are measured during spirometry with a
forced expiration. forced expiration. Dynamic lung volumes, as
well as expiratory flows that can be

Table 1. Static lung volumes
Parameter Acronym Explanation
Volumes Tidal volume VT Normal volume of air moved between in- and
expiration during quiet tidal breathing when no
additional effort is applied
Inspiratory IRV Volume of air that can additionally be inhaled in
reserve volume maximal inspiration
Expiratory ERV Volume of air that can additionally be exhaled in
reserve volume maximal expiration
Residual volume RV Volume of air that remains in the lung after
maximal expiration
Capacities: Functional FRC RV + ERV: volume of air that remains in the lung
sums of residual capacity after normal expiration during quiet tidal
volumes breathing when no additional effort is applied
Inspiratory IC VT + IRV: volume of air that can be inhaled in
capacity maximal inspiration
Vital capacity VC ERV + VT + IRV: volume of air moved between
combined maximal in- and expiration
Total lung TLC RV + ERV + VT + IRV: maximal total volume of air
capacity in the lung including volume of air moved
between combined maximal in- and expiration
and volume of air that remains in the lung after
maximal expiration
Volumes Capacities
IRV
Inspiration IC
VC
TLC
VT
ERV
Expiration
FRC
RV
Time
Figure 1. Spirogram with lung volumes (left) and capacities (right) and with expiratory (left) and
inspiratory (right) vital capacity manoeuvres.

measured during spirometry, are displayed needs to be familiar with the mechanics of
in table 2 and figures 2 and 3 together with the airways and also with respiratory
their respective acronyms. Forced expiration mechanics, as well as the physiological
rarely occurs under physiological conditions principles underlying forced expiration in
in everyday life, and it requires collaboration spirometry.
with inhalation to TLC and then exhalation
down to the RV, both as long and as quickly As described elsewhere in this Handbook,
as possible, thus provoking flow limitation the airways are interconnected by sur-
without any further effort dependence. This rounding lung tissue leading to pulmonary
measurement displays limitations in non- tethering. During inspiration, the lung
cooperative subjects, which is why a forced expands and the airway calibres increase
expiratory manoeuvre is usually possible due to this tissue network. During
only from late preschool age onward. In expiration, the lung deflates and the airway
order to better understand the performance diameter decreases concurrently, reflecting
of such a manoeuvre, and its results, one breathing-dependent changes in airway
Table 2. Dynamic lung volumes and expiratory flows that can be measured during spirometry
Parameter Acronym Explanation
Volumes Forced vital capacity FVC Volume of air that can be exhaled during
forced expiration after maximal
inspiration to TLC
Forced expiratory FEV1 Volume of air that can be exhaled during
volume in 1 s 1 s in forced expiration after maximal
inspiration to TLC
Forced expiratory FEVx Volume of air that can be exhaled during
volume in x second(s) x second(s) in forced expiration after
maximal inspiration to TLC. Preschool
children may not be able to expire for
1 s. Here, FEV0.5 or FEV0.75 are useful
parameters.
Tiffeneau index FEV1/FVC Ratio of volume of air that can be
exhaled during 1 s in forced expiration
after maximal inspiration to TLC over
total volume of air that can be exhaled
during forced expiration after maximal
inspiration to TLC.
Flows Peak expiratory flow PEF Maximal expiratory flow during forced
expiration
Forced expiratory flow FEFx Maximal expiratory flow at 75%, 50% or
at x% of FVC (already (FEF75, FEF50, 25% of FVC already exhaled, primarily
exhaled) FEF25) used in English language
Maximal expiratory MEFx Maximal expiratory flow at 25%, 50% or
flow at x% of FVC (to (MEF75, MEF50, 75% of FVC to be exhaled, primarily used
be exhaled) MEF25) in German language
Maximal midexpiratory MMEF or Maximal mean expiratory flow between
flow FEF2575 or 25% and 75% of FVC expired (FEF2575)
MEF2575 or, equally, 75% and 25% of FVC to be
expired (MEF2575), is highly correlated
with, but not equal to, FEF50 or MEF50,
respectively

Volume
1s TLC
FEV1
RV
Time
Figure 2. Volumetime relationship during forced expiration. The solid line represents measurement in a
healthy subject; the broken line represents measurement in a subject with obstruction and a lower value of
FEV1.
resistance. Thus, the airways do not The consequent driving force of expiratory
resemble a system of rigid, but still an flow (the resulting pressure drop from the
oversimplification of compliant and alveoli along the airways to the airway
moreover also compressible tubes building opening) the transairway pressure (Pta) can
up resistance to air flow. This air flow results be calculated as:
from a pressure difference between the ends
of the tube system, the airway opening Pta 5 Palv Pm (1)
(mouth), usually the barometric pressure where Palv is the sum of pure static (volume
(Pm) and the pressure in the alveoli (Palv), dependent) pressure made up by elastic
with the latter being below Pm during recoil (Pst) and of the additional positive
inspiration and above Pm during expiration. pressure in the pleural space (Ppl)
While expiration during quiet tidal breathing
usually happens passively, this is not the Palv 5 Pst + Ppl (2)
case during forced expiration which is
additionally supported by active muscular This results in expiratory flow (V9) which can
contraction. Active expiration results in a be calculated as:
reduced transversal and sagittal diameter of V9 5 Pta / RAW 5 [(Pst + Ppl) Pm] / RAW (3)
the thorax (due to activity of the internal
intercostal muscles), elevation of the Hence, any change in V9 is dependent on
diaphragm and, as the main contributor of both resulting pressure Pta and resulting
the expiratory driving force, increased resistance RAW. By measuring flow during
intraabdominal pressure (activity of rectus spirometry, one cannot know whether any
abdominis, transversus abdominis and change in flow is due to a change in
external as well as internal oblique muscles). pressure or in resistance. Under the

Flow PEF Expiration
FEF25 = MEF75
FEF50 = MEF50
FEF75 = MEF25
Volume
FVC
Inspiration
Figure 3. Flowvolume loops before and during forced expiration. Flowvolume loops during inspiration
(below) and expiration (above) before (dotted line, light grey) and during forced expiration. The solid line
represents measurement in a healthy subject and the broken line represents measurement in a subject with
obstruction.
condition of flow limitation with maximal point in the airway tree where intrabronchial
muscular activity, however, flow is and extrabronchial pressures are equal, i.e.
independent of any further increase in where Pintrabronch5Ppl. This point is termed
driving force and thus representative of the equal pressure point (EPP). According to
airway calibre. The following section depicts equation (4), the pressure drop along the
why this is the case during forced expiration. airway equals Pst at the site of EPP, with Pst
as highlighted above being volume-
Dynamic airway compression As highlighted dependent. This has an important
above, inhaling deeply and then exhaling implication. During expiration, lung volume
with maximum effort increases Ppl and Palv decreases and consequently so does Pst.
well above Pm, thus creating the driving Hence, the EPP will be closer to the alveoli
force for airflow in forced expiration. The with small lung volumes (e.g. towards the
positive Ppl results in pressure on the whole end of expiration) as compared to the start
lung tissue and importantly, also on airways. of forced expiration, where it is located near
Accordingly, not only Palv but also pressure the upper thoracic aperture. One can
in the airway lumen (Pintrabronch) increase as imagine the EPP entering the trachea during
a result of Pst and positive Ppl. expiration and then splitting up into several
EPPs in segmental, more compliant bronchi
Pintrabronch 5 Pst + Ppl (4) making up an EPP wave front.
Pintrabronch slowly decreases from the alveoli The movement of the EPP during forced
(5Palv) towards the airway opening (5Pm). expiration is the reason why this airway
Under the condition of maximum forced compression is called dynamic. Upstream of
expiration and flow limitation, there will be a the EPP, towards the alveoli, airways are not

compressed as Pintrabronch . Ppl. than Ppl at this position before reaching the
Downstream, however, there will be airway above anatomical impediment. This results
compression, creating a check valve, the in airway closure and increased residual
flow through which is effort-independent. volume resembling hyperinflation.
Why is this so? If one pictures the airway as
a compressible tube, airway compression Measurement of static and dynamic lung
results in an increased resistance to flow. volumes
Likewise, the intraluminal gas pressure As highlighted above, the static lung
upstream of the compressed airway is volumes VT, IRV, ERV, IC, and VC can be
increased. Despite this, the speed of air directly measured during spirometry, while
through this airway segment can never others (RV, FRC and TLC) require body
exceed the velocity by which a pressure wave plethysmography or gas dilution techniques
propagates through the wall of this airway such as multiple-breath washouts (MBW).
segment (this is called wave-speed Importantly, body plethysmography and
limitation). This is alike to a loud sound MBW do not measure exactly the same. In
which cannot travel any faster than a quiet short, body plethysmography is a measure
sound, the speed of both being limited to of compressibility of thoracic gas volume
that of sound in air. based on Boyles law. The measured volume
includes non- or poorly ventilated lung
Limiting maximum expiratory flow in
regions. This in contrast to the
addition to increased airway resistance,
measurement of FRC by MBW (FRC-MBW),
airway compression at the site of the check
which reflects a volume that communicates
valve depends on several factors: airway wall
with larger airways. FRC-MBW can be
thickness and tone of bronchial muscles.
computed by either mass spectrometry or
This has important implications. More
devices based on ultrasonic flow meters
compliant airways will give rise to lower flow
which are also able to measure molar mass
rates than stiffer airways in the case of
of gas. Here, FRC-MBW is calculated on the
airway compression. Consequently,
basis of conservation of mass. This means
maximum expiratory flow is smaller at low that any amount of gas within the lung may
than at high lung volume, explaining the be computed after measuring the con-
descending portion of the flowvolume centration of this gas in expired air as well as
curve during forced expiration. Moreover, in the total volume of expired air if one washes
the case of both abnormally compliant this gas out of the lung, such as by inhaling
airways (e.g. in the case of bronchomalacia) pure oxygen to measure washout of
and of airways with increased resistance nitrogen. With MBW it is also possible to
such as in asthmatic airway obstruction, the calculate parameters that allow assessment
EPP and the site of airway compression will of ventilation homogeneity, such as the lung
be located more downstream (towards the clearance index (LCI), which is important in
larger airways). In a healthy subject, all these small airway diseases such as CF but also in
EPPs can be pictured at the same relative asthma.
position at the same time and the same
airway generation. In case of airway Detailing all the guidelines for lung function
obstruction, however, the EPP front measurements in children would be clearly
becomes inhomogeneous, the EPPs attain beyond the scope of this chapter.
different relative positions and the flow Measurements during quiet tidal breathing
volume curve becomes concave instead of a are possible even in infants, and if sedation
straight downward line (fig. 3). The end of is used also in toddlers. Due to lack of
the forced expiratory manoeuvre results cooperation, early childhood may impose
from the thoracic structure itself, which difficulties for any lung function
imposes an insurmountable impediment to measurements. From preschool age on,
any further expiration, resulting in the RV. In measurements during tidal breathing and
case of airway obstruction with a more especially those requiring either forced
downstream EPP, Pintrabronch will be smaller expiration or a VC manoeuvre are once again

feasible, especially in experienced N Hammer J, et al., eds (2005). Paediatric
paediatric centres. For guidelines and Pulmonary Function Testing. Progr Respir
recommendations as well as peculiarities Res. Basel, Karger.
of paediatric lung function testing across N Hyatt RE (1983). Expiratory flow limita-
age groups, the interested reader is tion. J Appl Physiol; 55: 17.
referred to the respective chapters in this N Mead J, et al. (1967). Significance of the
Handbook and to the relevant literature. relationship between lung recoil and
For recent advances relating to normative maximum expiratory flow. J Appl Physiol;
data for spirometry covering large age 22: 95108.
N Quanjer P, et al. (2012). Multi-ethnic
ranges and also early childhood, the author
reference values for spirometry for the 3
would also like to refer to the relevant
95 year age range: the global lung function
literature (Stanojevic et al., 2007; Quanjer
2012 equations. Eur Respir J; 40: 13241343.
et al., 2012) as well as to www. N Stanojevic S, et al. (2007). Reference
growinglungs.org.uk. ranges for spirometry across all ages: a
new approach. Am J Respir Crit Care Med;
Further reading 177: 253260.
N West JB, ed. Pulmonary Pathophysio-
N Dawson SV, et al. (1977). Wave speed logy. The Essentials. Philadelphia,
limitation of expiratory flow a unifying Lipincott Williams & Wilkins, 2008.
concept. J Appl Physiol; 43: 498515. N West JB, ed. Respiratory Physiology.
N Frey U, et al., eds. Paediatric Lung The Essentials. Philadelphia, Lippincott
Function. Eur Respir Monogr 2010; 4. Williams & Wilkins, 2008.

Respiratory mechanics
Oliver Fuchs
Breathing is the movement of air along overcome elastic or static forces and is
pressure differences in the lung and airways. stored as potential energy. Any force
A simple model of the respiratory tract is necessary to overcome resistance is lost as
that of a stiff tube (airways) connected in heat due to friction; its contribution to
series to an elastic balloon (lung). The physical work is very small.
following formula describes how much
pressure (P) is needed for a certain volume In the healthy subject, expiration happens
(V), dependent on the compliance (C), the passively along elastic retraction forces.
During inspiration, however, a negative
resistance (R) related to a certain flow (V9),
intrapleural (Ppleur) and secondly intra-
and the acceleration (V99) necessary to
alveolar pressure (PA) is created by
overcome the systems inertia to changes in
respiratory muscles in relation to the
flow (impedance; I):
surrounding atmospheric pressure (Patm).
P 5 V/C + RV9 + IV99 PA and Ppleur can be used to calculate the
resulting transpulmonary pressure
Respiratory mechanics are determined by (Ptranspulm):
elastic properties of the respiratory system
(C), reflecting changes in volume without Ptranspulm 5 PA - Ppleur
any change in flow (static forces). Another Strain and static properties of the respiratory
factor is represented by non-elastic forces system change constantly during pulmonary
(RV9), which are dynamic forces due to their development. During breathing, PA equals
dependency on flow. The third factor, Patm at the end of inspiration and expiration.
impedance, plays only a minor role. The For Ppleur, this is only the case during
major part of physical work is necessary to infancy. Even earlier, i.e. during the first
breaths after birth and then again from
childhood when elastic retraction forces
Key points increase during growth, Ppleur is always
negative in relation to Patm both during
N Respiratory mechanics are helpful in inspiration and expiration.
understanding the cyclic changes in
airflow due to pressure differences Elastic properties of the respiratory system:
during breathing and the influence of compliance
elastic (compliance) and dynamic
properties of the respiratory system Elastic properties of thorax and lungs act in
(resistance). opposite directions. While the thorax is
predisposed to expand due to its structure,
N Both compliance and resistance are lungs tend to collapse because of their
volume dependent and display content of elastic fibres and surface tension
influence of age due to growth and at the alveolar gaswater interface.
development from infancy throughout Adhesion forces in the pleural space, which
childhood to adulthood. make the lung tissue follow any change in
thoracic diameter during inspiration and

expiration, prevent lung collapse. Pulmonary Depending on where pressure changes are
tethering transmits these forces throughout measured at zero flow at the end of
the lung tissue; pressure differences (PA inspiration and expiration, it is possible to
Patm) are built up and enable airflow calculate CCW (PpleurPatm), CL
towards alveoli. (PA-Ppleur5Ptranspulm) or CRS (PA-Patm).
Ppleur and its relative changes are measured
Law of Laplace, alveolar gaswater phases and using an oesophageal pressure probe.
surfactant Alveolar physical properties can
be compared to those of soap bubbles. Compliance is volume dependent There is a
Surface tension minimises the area between direct relationship between compliance and
the gaswater phases. Resulting forces the ratio of volume over pressure gradients.
follow the law of Laplace, describing the Accordingly, compliance is volume
pressure (P) in relation to surface tension dependent, visualised in a pressurevolume
(T) and radius (r): curve (fig. 1). The pressurevolume curve
for CRS has a characteristic S-shape with
P 5 2T/r inflection points. The slope reflects CRS,
which is largest in the steep middle part of
The higher the surface tension and the
the curve. Thus, the physical work needed
smaller the radius, the higher the resulting for inflation during inspiration is lowest in
pressure and the more probable alveolar this range. Beyond inflection points physical
collapse is. Surfactant (surface active agent) work is increasing and respiration becomes
reduces surface tension directly proportional less efficacious. The lower part of the curve
to its alveolar concentration. Thus, reducing results from closure of smaller airways and
surface tension becomes more efficacious in alveoli below a specific lung volume, the so-
case of smaller radii and concomitant called closing volume. The upper part
increases in concentration, the opposite results from exhaustion of elastic properties
being the case during pulmonary in the lung structure due to distension of
hyperinflation. As a net effect, alveolar elastic fibres, thorax and alveolar septa.
radius is stabilised and the coexistence of Thus, mechanical ventilation beyond the
neighbouring smaller and larger alveoli is upper inflection point may carry the risk of
possible. Without surfactant, smaller alveoli volutrauma or barotrauma. As the
would collapse and empty into larger alveoli compliance is volume dependent, its value
in direct contact. is standardised by relating it to a certain
Compliance measurement Compliance is a lung volume, usually the functional residual
measure for elastic properties of the capacity (FRC), resulting in the specific
respiratory system; it describes how much compliance. Interestingly, volume decreases
change in pressure (DP) is necessary for a less in relation to pressure during expiration
specific change in volume (DV). Its than inspiration. The pressurevolume
reciprocal counterpart is the elastance (E), curves for inspiration and expiration are not
describing how much change in volume is identical, which is known as hysteresis. This
necessary for a specific change in pressure. is possibly due to reorganisation of
surfactant molecules during expiration with
C [L?kPa-1 or cmH2O] 5 DV/DP 5 1/E complex folding processes, the creation of
several surfactant layers and perhaps even
The compliance of the whole respiratory partitioning into different surfactant sub-
system (CRS) is made up by the compliance compartments.
of the thoracic wall (Ccw) and that of the
lung (CL). These add up like electrical Influence of age on CL, CCW and CRS FRC
resistances connected in series, hence, by reflects the intrapulmonary volume at which
the addition of their reciprocal units elastic properties of both CCW and CL equal
(individual elastance values): each other. Here, tendencies towards
expansion and collapse are in balance.
1/CRS [kPa or cmH2O/L] 5 1/CCW + 1/CL Generally, this is the case for a higher FRC in

100 100
Upper
inflection point

80
Throracic wall
tendency
all
75
to expand = 0
cw
raci
60 V
ic wall
tho
and
Thorac P
Lun
TLC
VC %
40
50
%
Resting

breathing FRC
position
20
Lung
Lower 25
RV
inflection point
0
0
20 10 0 +10 +20 +30
Pressure cmH2O
Figure 1. Inspiratory pressurevolume curves for CCW, CL and CRS. The dashed lines represent CCW
(thoracic wall) and CL (lung). The solid line represents CRS (whole respiratory system, i.e. lung and
thoracic wall). The different states of the respiratory system and resulting forces are shown on the left of
the graph (red arrows). VC: vital capacity; RV: residual volume; DP: pressure gradient, DV: volume
gradient.
older children and in adults than it is for regard to their tendency for airway collapse
newborns or toddlers. In addition to below the closing volume which is,
surfactant, elastic properties of the therefore, itself age-dependent. This is also
pulmonary system also depend on lung the reason for the higher amount of
structure, especially elastic fibres. Owing to functional shunts early in life and the
ageing, elastic retraction forces increase increasing incidence of shunts among older
from birth through adolescence, but then people. In order to circumvent airway
decrease again. Thus, in both newborns and collapse in dependent lung areas the
in older people, FRC can be below the newborn has several mechanisms available
closing volume. Accordingly, the newborn to dynamically upregulate FRC, leading to
and the aged lung are very similar with either a shorter duration of expiration or to a

decrease in expiratory flow (expiratory (Pao) over airflow, which is itself measured
braking). at airway opening (V9):
N Increasing the respiratory rate reduces RRS [kPa?L?s-1] 5 (PA Pao)/V9

the time for passive expiration (tE) in
comparison to the duration of active RRS can be subdivided into the resistance of
inspiration (tI). the airways (RAW) and the resistance due to
N During expiration, vocal cords are either friction between chest and lung tissue.
actively moved towards each other Resistance due to friction is only minor
(adduction) or there is a loss of laryngeal compared to RAW, which itself accounts for
abductor activity, thus, resistance approximately 90% of RRS.
increases on the vocal cord level. Due to
RAW is influenced by both airway diameter
reduced expiratory flow, lung emptying is
and fluid flow behaviour of air. Depending
slowed down. While this is noiseless in
on airway generation and pathological
the healthy newborn, it may become
conditions, such as airway obstruction,
audible in the sick infant as expiratory
airways may demonstrate different shares of
grunting.
laminar and turbulent flow. The Hagen
N During expiration, the activity of
Poiseuille equation describes laminar flow.
respiratory muscles is adapted in such a
According to this equation, airway resistance
way that passive expiration is decelerated
is proportional to airway length (l) and
or even terminated through tonic
dynamic gas viscosity (g) and inversely
muscular activity of the diaphragm. In
proportional to the fourth power of the
addition, inspiration starts earlier than in
airway radius (r) and p:
older children or adults.
Dynamic upregulation of FRC lasts R [kPa?L?s-1] 5 8lg/r 4p
approximately until the end of the first year Under the condition of turbulent flow,
of life, when elastic retraction forces of the movement of gas molecules seems more
thoracic skeleton increase due to random and mathematically describing this
progressing ossification, i.e. when CCW state is more complex. In case of turbulent
slowly decreases. At the end of the second flow, resistance increases with flow rate and
year of life CL equals CCW in resting is proportional to gas density and viscosity
expiratory position without any necessary but inversely related to the fifth power of the
regulatory measures. CRS changes airway radius. Pressure differences are thus
predominantly due to increasing numbers of much higher than with laminar flow. The
alveoli during childhood, further influenced Reynolds number (Re) helps to predict when
by the development of upright walking. laminar flow changes into a turbulent one.
Dynamic properties of the respiratory This is again dependent on gas density (r)
system: resistance and dynamic gas viscosity (g), as well as
airway length (l) but also flow (V9).
Respiratory mechanics are not only
influenced by elastic properties of the Re 5 V9Lr/g
respiratory system but also by its dynamic
properties, which are by definition Above a critical value of Re (.1500) laminar
dependent on flow. These non-elastic, flow passes on to turbulent flow. Pure
viscous resistances are made up by airway laminar flow can be found for smaller Re of
resistance to flow, non-elastic tissue ,1000, usually in small peripheral airways,
resistance and resistance due to inertia. while flow in larger airways is predominantly
turbulent. Airway branching and bending, as
Resistance of the whole respiratory system In well as abrupt changes in airway diameter,
analogy to Ohms law, the resistance of the as in the case of airway obstruction, play a
whole respiratory system (RRS) is defined as role. Hence, peripheral airways only account
the ratio of difference between pressure in for ,1020% of RRS despite their total share
alveoli (PA) and pressure at airway opening in airway diameter, of ,95%. The biggest

portion of RRS results from airway resistance
secondary to turbulent flow in larger, more
Resistance/conductance
central airways.
Time constant of the whole respiratory system
Airways and lung tissue are considered
separately regarding their influence on
respiratory mechanics. This is an
oversimplification as they are both
interdependent on each other. The time
constant (t) of the respiratory system is a
parameter taking both into consideration. In
general, t describes the duration during
which an exponential process decreases to FRC TLC
1/e (Eulers constant; e), i.e. ,36.8% of the
Lung volume
default value. In case of the respiratory tract,
t is defined by the product of CRS and RRS
Figure 2. Volume dependency of resistance and
and represents the time in seconds that is conductance; pulmonary tethering. The boxes
needed for the respiratory system to expire represent elastic fibres stabilising airway diameter
63.2% of the lung volume in air due to in relation to lung volume (tethering). The solid
passive retraction forces. For a full line represents resistance, and the dashed line
expiration, the respiratory system will need represents conductance in relation to lung volume.
approximately three to five time constants.
Any decrease in RRS is associated with an
increase in CRS and vice versa.
higher (C2C3) in newborns and infants than
Resistance is volume dependent Due to in adults (C3C6), favouring breathing
pulmonary tethering and resulting elastic through the nose and making simultaneous
retraction forces that stabilise airway breathing and drinking possible. Accordingly,
diameter, as well as concurrent bronchiolar due to the laryngeal anatomy breathing
distension during deep inspiration, resistance through the mouth is rather disadvantageous
is also volume dependent. In contrast, radial early in life. This explains the significant
tension is decreased with lower lung volumes nuisance of infants and, to the lesser extent,
(fig 2). This volume dependency is taken into of toddlers in case of upper airway infections
account when calculating the specific with nasal obstruction.
resistance and specific conductance (inverse
Resistance of the lower airways
of resistance) by relating both values to the
FRC. Below FRC there is a steep increase in In contrast to their small individual
resistance. There is a hyperbolic relationship diameter, the total share of the small
between resistance and lung volume, on one peripheral airways is high in relation to that
hand, and a linear relationship of the of other airways. In older children and
conductance (inverse of resistance) and lung adults, the portion of RRS formed by small
volume, on the other hand (fig. 2). airways is, nevertheless, 1020%.
Resistance of the upper airways Consequently, measuring resistance is not
very sensitive with regards to quantifying
In infants, the nasopharyngeal space can obstruction of small airways in these
account for up to 40% of RRS, and in adults subjects. In infants, however, small
up to 60%. The larynx is the narrowest part of peripheral airways may account for up to
the upper airways; in infants and toddlers this 50% of RRS. Thus, as with nasal
is due to the anatomy of the cricoid, owing to obstructions, even minor peripheral airway
growth it is the glottis in older children and in obstructions may be associated with
adults. Before it descends during growth, the significant impairment in this age group.
larynx is initially located further forward and Furthermore, in dyspnoeic infants airways

are more prone to collapse due to their N Hughes GM, et al. (1978). Static
relatively high compliance during forced pressure-volume curves for the lung of
inspiration and due to increased transmural the frog (Rana pipiens). J Exp Biol; 76:
pressure in the case of crying. This is the 149165.
reason why measures of calming down N Lucangelo U, et al. (2007). Lung
agitated infants or even the use of sedatives mechanics at the bedside: make it
simple. Curr Opin Crit Care; 13: 6472.
may help to reduce resistance and thus to
N Mansell A, et al. (1972). Airway closure in
improve the clinical status. children. J Appl Physiol; 33: 711714.
N West JB, ed. Pulmonary Pathophysiology.
Further reading The Essentials. Philadelphia, Lipincott
Williams & Wilkins, 2008.
N Agostoni E (1959). Volume-pressure rela- N West JB, ed. Respiratory Physiology. The
tionships of the thorax and lung in the Essentials. Philadelphia, Lippincott
newborn. J Appl Physiol; 14: 909913. Williams & Wilkins, 2008.

Reversibility, bronchial
provocation testing and
exercise testing
Kai-Hakon Carlsen
The variability in bronchial smooth muscle

tone is an important characteristic of
Key points bronchial asthma and is probably related to
the presence of airway inflammation. As
N Bronchodilator reversibility early as 1859, Sir Henry Hyde Salter
demonstrates reversible bronchial described bronchial sensibility in patients
obstruction and is a diagnostic with asthma. This variability in bronchial
marker of active asthma. smooth muscle tone may go in two
N Bronchial challenge with directions:
methacholine/histamine is a sensitive
measure of asthma, but is not so
N towards exaggerated bronchodilation
upon a bronchodilator stimulus, also
specific.
called bronchodilator reversibility; or
N Indirect measures of bronchial N towards increased bronchial constriction
responsiveness (exercise, inhaled and obstruction after exposure to a
adenosine monophosphate, bronchoconstrictor stimulus, often called
hypertonic saline and mannitol, and bronchial hyperresponsiveness (BHR).
EVH) are specific, but not sensitive,
measures of asthma. This variability in bronchial tone is assessed
both in diagnosis and in monitoring of
N Indirect measures of bronchial asthma.
responsiveness (exercise, etc.)
respond rapidly (over 13 weeks) to Reversibility: bronchodilator responsiveness
inhaled steroids. The reversibility to bronchodilator drugs is
N Direct measures of bronchial usually measured in a standardised way by
responsiveness (methacholine and first measuring lung function, usually FEV1,
histamine) respond slowly to inhaled then inhaling a bronchodilator drug and
steroids (over 3 months). then again measuring FEV1 after a suitable
time, enabling the bronchodilator drug to
N Direct measures of bronchial have an effect upon bronchial smooth
responsiveness (methacholine and muscle. In addition, other measures of lung
histamine) are presently the function may be used. The procedure has
most exact monitoring tool for been standardised by a joint Task Force of
asthma and reflect airway European Respiratory Society (ERS) and
remodelling. American Thoracic Society (ATS), and an
N Indirect measures of bronchial increase in FEV1 of 12% or o200 mL after
responsiveness reflect airway inhaled bronchodilator has been selected as
inflammation. a significant increase in lung function and as
a criterion for a positive reversibility test
N BHR in childhood may predict later (Pellegrino et al., 2005). Either salbutamol
asthma. or another bronchodilator, such as
ipratropium bromide, may be used. Inhaled

salbutamol at a dose of 100 mg given four Baseline lung function
times from a metered-dose inhaler through 15 mins after salbutamol

a suitable inhalation chamber with a 6 Predicted lung function
mouthpiece is the recommended dose in

adults and in children/adolescents from

12 years; in younger children, half the dose 4
should be used. Alternatively, ipratropium
bromide 160 mg (4640 mg) may be used. If
2
Flow Ls-1
preferred, inhalation may be given by
nebuliser or powder inhaler but it is

important to know the delivery of drug from
the device in order to ascertain that 0

1 2 3 4 5
sufficient drug has reached the patient. Lung
Volume L
function is measured 15 min after
salbutamol inhalation or 30 min after 2
ipratropium bromide inhalation (Pellegrino
et al., 2005). In order to assess the full
reversibility, the patient should not be under 4
the influence of any other bronchodilator.
The following recommendations are given
by the ERS/ATS Task Force (Miller et al., Figure 1. Lung function in a 13-year-old boy
showing maximal flowvolume loops before and
2005). Short-acting inhaled drugs, such as
after inhalation of nebulised salbutamol
the b2-agonist salbutamol or the
(5 mg?mL-1, 0.5 mL in 2 mL isotonic saline
anticholinergic agent ipratropium bromide, nebulised by a CR 60 nebuliser). Baseline FEV1
should be withheld for o4 h; long-acting b2- was 2.09 L?s-1 (66% predicted); 15 min after
agonists (salmeterol and formoterol), and inhalation of salbutamol, it had risen to 2.46 L?s-1
oral therapy with aminophylline and slow (78% predicted), presenting an increase of 18%
release b2-agonists should be withheld for and demonstrating a positive reversibility test. The
12 h prior to the test. It is also recommended baseline lung function test was performed without
that smoking should be avoided for o1 h the influence of any bronchodilator.
before the procedure.
Figure 1 shows lung function from a 13-year- persistently reduced FEV1 may possibly
old boy as maximal flowvolume curves indicate the presence of airway remodelling
before and 15 min after inhalation of (Goleva et al., 2007).
salbutamol.
In addition, in preschool children,
In the Childhood Asthma Management assessment of reversibility has been made
Program (CAMP) study, the consistent by assessment of airway resistance by use of
presence of a positive bronchodilator the interrupter technique (Rint), setting the
response over a 4-year period in asthmatic limit for a positive response to a decrease in
children was associated with persistently Rint at 32% of baseline or a decrease in Z-
lower baseline FEV1 values as well as a lack score of 1.25 (Mele et al., 2010), as well as
of use of inhaled steroids, thus using tidal breathing parameters (time taken
demonstrating the usefulness of to achieve peak tidal expiratory flow (tPTEF)/
bronchodilator reversibility in the expiratory time (tE) ratio), which was found
monitoring of childhood asthma (Sharma et to discriminate between children with
al., 2008). In severe, steroid-resistant asthma and healthy children. An increase in
asthma, FEV1 was persistently reduced tPTEF/tE of at least two standard deviations
together with a reduced bronchodilator of intrasubject variation was used as a
response in spite of therapeutic trials with criterion for a positive response to
prednisolone. The combination of a lack of bronchodilator, and a highly significant
bronchodilator response in the presence of correlation between reversibility and a

marker of eosinophil inflammation, serum reduction in lung function, is brought about
eosinophil cationic protein, was reported indirectly through an effect of mediator
(Ldrup Carlsen et al., 1995). Other lung release.
function techniques have also been used to
assess reversibility to bronchodilators in Methods of measuring bronchial
preschool children, such as the forced responsiveness
oscillation technique. A change of 32% (and Originally, direct bronchial responsiveness
z-score change of -1.85) from baseline values was measured qualitatively through a BPT by
has been suggested as a significant relative inhaling the test substance in 10-fold
bronchodilator response for the resistance increasing concentrations (Aas, 1970),
of the respiratory system (Rrs) at 8 Hz whereas during the last 25 years, quantitative
(Calogero et al., 2013). None of these assessment has been performed by
techniques require sedation of the child. doubling the concentration/dose of the test
Classification of BHR substance (Cockcroft et al., 1977a).
Bronchial responsiveness, which reflects the Figure 2 shows the doseresponse curve
variability in bronchial tone in asthma, may obtained in a BPT, with a reduction in FEV1
be described as subjective, as demonstrated caused by inhaling doubling concentrations
by the symptoms experienced by the of methacholine and interpolation to
asthmatic child and adolescent, or objective, determine provocative concentration
as measured by procedures in the pulmonary causing a 20% fall in FEV1 (PC20) (Cockcroft
physiological laboratory. BHR is defined as et al., 1977a). Later, a simplification of the
an increase in the ease and degree of airflow test was introduced, inhaling single
limitations in response to bronchoconstrictor doubling doses of methacholine,
stimuli in vivo (Sterk, 1996). determining the provocative dose causing a
20% fall in FEV1 (PD20) (Yan et al., 1983).
The specific bronchial responsiveness, the
bronchial responsiveness to specific inhaled The test is performed under standardised
allergens, may be measured by the allergen conditions (Hargreave et al., 1981; Cockcroft
bronchial provocation test (BPT) (Aas, 1970). et al., 1977b), with specified nebulisation
rates for the tidal breathing method (PC20),
The non-specific BHR may be measured in inhaling the test agent for 2 min, then
several ways. According to the mechanisms measuring FEV1, and then inhaling the
of bringing about the bronchial response, doubled concentration. The test is stopped
the methods can be classified as direct and when FEV1 is reduced by o20% and the
indirect (Pauwels et al., 1988). Direct
bronchial responsiveness is measured by
bronchial provocation with the transmitter
methacholine (Hargreave et al., 1981) or the 110
mediator histamine (Cockcroft et al., 1977a),
acting directly upon the bronchial and 100
vascular smooth muscle. Examples of 90
FEV1 %
indirect methods of measurement of the

nonspecific BHR are by measuring exercise- 80
induced bronchoconstriction (EIB) (Jones et
al., 1963) or the reaction brought about by 70
inhalation of dry cold air (Zach et al., 1987),
hyperventilation caused by dry air 60
(Rosenthal, 1984), or inhalation of other Saline 0.03 0.06 0.125 0.25
substances, such as adenosine mono- Methacholine mgmL-1
phosphate (AMP) or the hyperosmolar
agent mannitol (Avital et al., 1995; Brannan Figure 2. Determination of PC20 by interpolation
et al., 2005). The reaction, measured as a on the logarithmic x-axis.

PC20 or PD20 is determined by interpolating marathon runners) are thought to
on the semilogarithmic doseresponse contribute. Endurance training has
curve (fig. 2). specifically been demonstrated to increase
parasympathetic tone. Thus, several factors
When determining bronchial responsiveness probably contribute in the development of
by measuring PD20, the cumulated dose athletes asthma (Carlsen, 2012).
inhaled is determined. An inspiration-
triggered nebuliser is most often used as the Exercise testing
delivery device, such as the Spira nebuliser
Most guidelines for treating childhood
(Spira Respiratory Care Centre,
asthma have control of EIB as one of their
Hameenlinna, Finland) (Nieminen et al.,
main aims due to the appreciation of the
1988) or the Aerosol Provocation System
importance for children of being able to
(Jaeger, Wurzburg, Germany), enabling
participate in physical activity and play
inhalation by controlled tidal ventilation.
together with their peers.
Alternatively, a handheld DeVilbiss
(Mannheim, Germany) nebuliser has been Testing for EIB also represents a measure of
used (Yan et al., 1983). bronchial responsiveness, and is an example
of an indirect test (Pauwels et al., 1988).
Recommendations for the measurements of Different types of exercise have been
bronchial responsiveness were given by an standardised for testing EIB: running is
ERS/ATS Task Force (Crapo et al., 2000). more provocative in children than cycling
(Anderson et al., 1971) and a duration of 6
Determination of PC20 or PD20 are used
8 min gives a greater decrease in post-
both for BPT with methacholine, histamine
exercise FEV1 than shorter or longer exercise
and AMP, and may be used for allergen BPT.
periods (Godfrey et al., 1975). It is common
A mannitol BPT was recently developed and
to employ a treadmill incline of 5.5% (3u)
launched commercially; it is performed by
with rapidly increasing speed until a steady
inhaling cumulative doses of mannitol
heart rate of approximately 9095% of the
through a powder inhaler, with a 15%
calculated maximum is reached within the
reduction in FEV1 (PD15) as the cut-off
first 2 min of running and then maintained
(Brannan et al., 2005).
for 46 min (Crapo et al., 2000; Carlsen et
Eucapnic voluntary hyperpnoea (EVH) is al., 2000). In children, heart rate should be
another BPT. In this test, the subject inhales followed electronically, whereas in adults it
dry air with 4.9% carbon dioxide for 6 min at should be followed by ECG. The running test
a preferred ventilation rate of 85% of their should preferably be performed at room
maximal voluntary ventilation (MVV), often temperature (2022uC) and a relative
calculated as 306FEV1, but tolerating a humidity of ,40%. Lung function is
ventilation rate down to 65% MVV measured before, immediately after, and 3,
(226FEV1) (Rosenthal, 1984). A reduction 6, 10, 15 and 20 min after running. FEV1 is
in FEV1 o10% is taken as a positive test. the most common lung function parameter
EVH tests have been shown to be employed, with a 10% fall in FEV1 most
particularly sensitive for asthmatic athletes, frequently used for diagnosis of EIB.
in particular endurance athletes (Rosenthal, Sensitivity of the test can be markedly
1984; Stadelmann et al., 2011). Endurance increased while maintaining specificity by
athletes are particularly prone to developing adding an extra stimulus to the exercise test,
BHR. This has been suggested to be due such as running on a treadmill with
primarily to epithelial damage caused by the inhalation of cold (-20uC) or dry air (Carlsen
frequent high-ventilation periods during et al., 1998).
training and competition, leading to airway
inflammation and BHR. Environmental There are several differential diagnoses to
factors (chlorine exposure in swimmers, exercise-induced asthma (EIA), including
cold air exposure in winter athletes, and exercise-induced vocal cord dysfunction as
environmental pollution in cyclists and the most frequent (Landwehr et al., 1996;

Refsum et al., 1983). The exercise test may response after allergen bronchial
help to discriminate between EIB and provocation increased direct BHR and that
exercise-induced vocal cord dysfunction. nonspecific BHR increased through
With EIB, the dyspnoea is expiratory and exposure to seasonal allergens. Thus, a
occurs after exercise with a simultaneous seasonal allergic sensitisation may
decrease in FEV1, whereas for vocal cord contribute to a perennial asthma by
dysfunction, the dyspnoea is inspiratory, increasing the nonspecific BHR through
usually audible and occurs during maximum seasonal allergen exposure. Clough et al.
exercise intensity. Vocal cord dysfunction is (1991) reported that the presence of atopy
best diagnosed by continuous laryngoscopy had an impact both on lung function and
during exercise testing. BHR in asthmatic 78-year-old children.
Safety precautions during bronchial Respiratory virus infections, particularly
challenges and patient preparations rhinovirus infections, are the main
environmental factor provoking acute
Bronchial challenges with
asthma during childhood (Carlsen et al.,
bronchoconstrictive agents as well as with
1984; Johnston et al., 1995). Respiratory
indirect measures, like exercise and EVH
virus infections increase bronchial
testing, require that the laboratory has the
responsiveness to histamine in healthy
necessary competence and equipment for
subjects (Empey et al., 1976), asthmatic and
treating severe bronchoconstriction,
atopic individuals (Bardin et al., 1995), and
including the preparedness for treating
animals (Nakazawa et al., 1994).
anaphylaxis. A physician should be present
during testing and equipment for Air pollution has also been reported to
cardiopulmonary resuscitation immediately increase BHR (Forastiere et al., 1994a),
available. Whereas progressive including exposure to diesel exhaust
pharmacological challenge testing with (Nordenhall et al., 2001), and living in an
interval spirometry gradually builds up a industrially polluted area during the first
bronchoconstriction, an exercise or EVH test 2 years of life was found to be related to BHR
represents a maximal or near-to maximal to methacholine at school age (Soyseth et
stimulus for bronchoconstriction, requiring al., 1995). Although not a consistent finding
special awareness. Preferably, oxygen (Gehring et al., 2010), assessment of BHR in
saturation should be monitored during relationship to traffic air pollution has
exercise or EVH testing. FEV1 should be at shown that children with BHR is particularly
baseline or o75% pred before exercise and sensitive to traffic-related air pollution
EVH testing. (Janssen et al., 2003).
The patient should be without the influence Second-hand smoke is among the most
of bronchodilators during testing unless the important air pollutants, and an effect upon
exercise test is performed to assess BHR in children has been reported, although
protection by the bronchodilator. Inhaled the results are not unequivocal. Forastiere et
corticosteroids should not be used on the al. (1994b) reported a doseresponse
day of the test (Thio et al., 2001). relationship between the number of
cigarettes smoked by mothers and BHR in
Vigorous exercise should be avoided for 6 h
daughters of school age.
before testing, as exercise may cause a
refractory period for eliciting EIB of up to 4 h Exercise and physical training have been
(Edmunds et al., 1978; Stearns et al., 1981). reported to influence bronchial
Effect of environmental conditions on BHR responsiveness. Short-term intensive
exercise increases direct bronchial
Several environmental conditions influence responsiveness both in asthmatic and
BHR. Cockcroft and co-workers (1977, 1983) healthy children (Carlsen et al., 1989).
documented the link with atopy and allergen Intensive physical endurance training and
exposure by reporting that the late allergic competition increase bronchial

responsiveness in actively training young population-based birth cohort (Riiser et al.,
skiers (Heir, 1994; Heir et al., 1995a), and a 2012a), but in the same birth cohort, BHR to
combination of respiratory virus infections methacholine at 10 years of age in children
and heavy training induce an increase in without asthma was a significant though
bronchial responsiveness for 46 weeks modest predictor of asthma at 16 years of
(Heir et al., 1995b). In addition, adolescent age (Riiser et al., 2012b), suggesting that
competitive swimmers have very frequent BHR may develop before active asthma
BHR measured both by methacholine symptoms appear.
bronchial challenge and EVH (Stadelmann
et al., 2011). The environment is important Diagnostic significance of BHR
in this regard, as chlorine products affect the As BHR may be found both in children with
swimming environment and cold air and without asthma, and asthmatic children
inhalation is an important part of daily may not demonstrate BHR, measurement of
exposure in winter athletes.
BHR cannot be a conclusive tool for the
Thus, several environmental factors may diagnosis of asthma. In a study of 500
increase BHR in susceptible subjects and young university students, Cockcroft et al.
individuals with BHR may be particularly (1992) reported a sensitivity of 100% for
sensitive to environmental exposures. histamine PC20 f8 mg?mL-1 for current
Conversely, for asthmatic subjects, staying symptomatic asthma, a specificity of 93%, a
in the mountains, with low allergen exposure negative predictive value of 100% and a
and low air pollution, improves both in positive predictive value of current
respiratory symptoms and bronchial asthmatic symptoms of only 29%. While a
responsiveness as measured by PC20 .8 mg?mL-1 ruled out current asthma,
methacholine provocation (Peroni et al., a PC20 of 1 mg?mL-1 was almost diagnostic
1994). Measuring bronchial responsiveness, for current asthma. Studies comparing
either by direct or indirect means, may thus direct and indirect measurements of BHR in
assess the effect of environmental exposure asthmatic children and children with other
upon respiratory health. chronic lung diseases show that direct
measurements by histamine or
Relationship of BHR to respiratory methacholine challenge are sensitive tools
symptoms and variation with age to identify asthmatic children, but with a
rather low specificity towards other chronic
Tiffeneau (1955) suggested that BHR was the lung diseases. However, indirect
most important characteristic of asthma. measurements by exercise tests or by
Later studies have shown that BHR is not inhalation of cold, dry air have low sensitivity
obligatory for asthma and that different ways but high specificity (Godfrey et al., 1991).
of measuring BHR may relate differently to When combining exercise testing with
asthma severity. Hargreave et al. (1981) found inhalation of cold, dry air, the sensitivity of
a distinct relationship with asthmatic the test increases while maintaining a high
symptoms and severity in asthmatic sensitivity for comparing asthma and other
subjects, whereas Salome et al. (1987), in a chronic lung disorders (Carlsen et al., 1998).
population-based study, found that a number A positive diagnosis by an exercise test thus
of asthmatic children did not have BHR and favours the diagnosis of asthma.
some children with BHR were not asthmatic. Furthermore, by use of exercise tests in
In addition, children with mild recurrent children, information about physical skill,
wheeze were found to include children both fitness and motor development are obtained
with and without BHR (Roizin et al., 1996). by an experienced observer.
Hopp et al. (1985) reported that bronchial Effect of therapy on BHR
responsiveness to methacholine varied
markedly throughout the lifespan. Bronchial Anti-inflammatory therapy by inhaled
responsiveness to methacholine decreased steroids improves BHR in asthma. This may
significantly from 10 to 16 years of age in a be assessed by repeated measurements of

both direct and indirect BHR. However, it epidemiological studies as objective
has been demonstrated that inhaled measures. Tests of BHR are valuable tools,
steroids improve direct and indirect BHR to particularly in assessing severe asthma, but
a different degree and with different speed. they cannot replace careful clinical
No effect on BHR was found from a single examination and assessment of children
dose of inhaled steroid (van Essen-Zandvliet with asthma.
et al., 1993). However, after 1 week of inhaled
steroids, protection against EIB has already
occurred, further increasing over the next Further reading
4 weeks (Henriksen et al., 1983). This was N Aas K (1970). Bronchial provocation tests
confirmed by Waalkens et al. (1993), who in asthma. Arch Dis Child; 45: 221228.
showed that the effect on EIB reached a N Anderson SD, et al. (1971). Specificity of
plateau effect within 2 months. However, exercise in exercise-induced asthma. Br
improvement of methacholine PC20 did not Med J; 4: 814815.
occur until after 23 months of treatment N Avital A, et al. (1995). Adenosine, metha-
with inhaled budesonide, but then choline, and exercise challenges in chil-
continued throughout a 22-month study by dren with asthma or paediatric chronic
van Essen-Zandvliet et al. (1993). Thus, the obstructive pulmonary disease. Thorax;
direct and indirect tests of BHR may reflect 50: 511516.
different properties of nonspecific bronchial N Bardin PG, et al. (1995). Increased
responsiveness in asthmatic children. sensitivity to the consequences of rhino-
viral infection in atopic subjects. Chest;
BPT measurements may thus be used to 107: 157S.
monitor treatment effects in asthma. By N Brannan JD, et al. (2005). The safety and
assessment of airway inflammation and efficacy of inhaled dry powder mannitol
airway remodelling (reticular layer of the as a bronchial provocation test for airway
epithelial basement membrane) in bronchial hyperresponsiveness: a phase 3 compar-
biopsies, it has been shown that ison study with hypertonic (4.5%) saline.
Respir Res; 6: 144.
methacholine BPT is superior to clinical
N Calogero C, et al. (2013). Respiratory
assessment and lung function
impedance and bronchodilator respon-
measurements in the follow-up of asthma
siveness in healthy children aged 2
patients (Sont et al., 1999). Based upon the 13 years. Pediatr Pulmonol; 48: 707715.
rapid response to inhaled steroids and the N Carlsen KH, et al. (1984). Respiratory
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Blood gas assessment
and oximetry
Paola Papoff, Fabio Midulla and Corrado Moretti
In clinical practice, arterial blood gas (ABG) PaCO2 and pH are measured directly, other
analysis is needed to assess patients with variables, such as bicarbonates (actual and
respiratory diseases and those with other standard) and SaO2, are calculated using
disorders influencing pulmonary gas well-defined equations.
exchange and acidbase disturbances. ABG
analysis is also needed to establish the A systematic approach to ABG
diagnosis of respiratory failure. interpretation is demonstrated in table 1.
ABG analysis helps to evaluate the following: Compensation for respiratory or metabolic
disorders
N acidbase equilibrium (pH)
N respiratory function (PaCO2, PaO2 and Because the body attempts to maintain
SaO2) blood pH at 7.4, respiratory or metabolic
N metabolic function (bicarbonate, base disorders normally trigger an equal
excess and anion gap). counterbalancing effect in the other
systems. Table 2 summarises the formulas
The principles underlying traditional ABG
used for estimating the compensation level.
measurement are based on the
electrochemical interaction between Under these circumstances the respiratory
respiratory gases and selected metals within and metabolic components are both
electrodes (Clark, 1956). Whereas PaO2, abnormal, but pH is almost normal
(table 1). The body never overcompensates,
and may even fail to reach complete
Key points compensation (Carmody et al., 2012).
Failure to reach the predicted compensation
N Acidbase disturbances can be level should lead the clinician to suspect a
classified using a three step mixed disorder.
systematic approach: pH, PaCO2,
Mixed disorders
bicarbonate.
N If pH is abnormal, determine if Mixed acidbase disorders can be simply
acidaemia or alkalaemia. defined as a condition in which two or more
acidbase imbalances exist. Some of the
N If the measured pH and PaCO2 are more common mixed acidbase imbalances
both abnormal, assess the direction of include those that have an additive effect on
change; if they change in opposite
the change in pH (respiratory acidosis and
directions the primary acidbase
metabolic acidosis, or metabolic alkalosis
abnormality is respiratory, otherwise it
and respiratory alkalosis). The other set of
is metabolic.
imbalances will have opposite effects on pH,
N When an acidbase imbalance is resulting in apparent overcompensation
diagnosed look for compensation or (metabolic acidosis and respiratory
mixed disorders. alkalosis, or metabolic alkalosis and
respiratory acidosis).

Table 1. Interpretation of acidbase disorders: examine the pH, determine the primary disorder and look for
compensation
Normal pH 7.357.45
Acidaemia: decreased pH ,7.35
Respiratory acidosis: decreased pH, increased PaCO2
Renal compensation:
Kidneys reabsorb bicarbonate
pH <, increased bicarbonate
Metabolic acidosis: decreased pH, decreased bicarbonate
Pulmonary compensation:
Hyperventilation releases CO2
pH <, decreased PaCO2
Alkalaemia: increased pH .7.45
Respiratory alkalosis: increased pH, increased PaCO2
Renal compensation:
Kidneys excrete bicarbonate
pH <, decreased bicarbonate
Metabolic alkalosis: increased pH, increased bicarbonate
Pulmonary compensation:
Hypoventilation retaining CO2
pH <, increased PaCO2
pH acidaemic, if it is .7.45 the patient is

alkalaemic. Acidosis and alkalosis, the
pH is a scale for measuring acidity or processes leading to these states, are either
alkalinity. Normally, blood is slightly alkaline respiratory or metabolic (Carmody et al.,
(pH 7.4) with an acceptable range of 7.35 2012). Significant deviations in pH from
7.45. If the pH is ,7.35 the patient is normal ranges rapidly become
Table 2. Compensatory response of a metabolic or respiratory disorder

Disorder Expected compensation
Metabolic acidosis PaCO2 5 1.5 (bicarbonate) + 82 (Winters formula)
Metabolic alkalosis PaCO2 5 0.7 (bicarbonate) + 201.5
Acute respiratory acidosis Bicarbonate will increase by 1 mEq?L-1 for each 10 mmHg rise
in PaCO2 above 40 mmHg
Chronic respiratory acidosis Bicarbonate will increase by 34 mEq?L-1 for each 10 mmHg
rise in PaCO2 above 40 mmHg
Acute respiratory alkalosis Bicarbonate will decrease by 2 mEq?L-1 for each 10 mmHg
decrease in PaCO2 below 40 mmHg
Chronic respiratory alkalosis Bicarbonate will decrease by 5 mEq?L-1 for each 10 mmHg
decrease in PaCO2 below 40 mmHg
Reproduced from Dzierba et al. (2011), with permission from the publisher.

life-threatening; Marieb et al. (2007) acidosis. Metabolic compensation of
suggested absolute blood pH limits for respiratory acidosis takes time to reverse.
life are 7.07.8, although patients may Rapidly correcting chronic respiratory
survive if isolated samples exceed this acidosis will, therefore, result in a self-
range. Both carbon dioxide and bicarbonate resolving metabolic alkalosis.
affect pH. To better quantify the relationship
between pH, carbon dioxide and Measures/indices that assess adequacy of
bicarbonate, Henderson (1913) developed oxygenation
the following formula demonstrating that PaO2: blood oxygen measurement serves as a
the ratio of bicarbonate and carbon dioxide, surrogate for tissue oxygen measurement.
not the absolute values, determines pH: Tissue oxygen is far lower than blood
oxygen. Oxygen in the arterial blood is
pH 5 6.1 + log ([HCO3-]/[0.03 6 PaCO2]) present as PaO2 (dissolved oxygen) and SaO2
(oxygen bound to haemoglobin). As long as
Normal pH can be found under normal the PaO2 is .60 mmHg, SaO2 remains above
conditions, in a compensated state or in 90%. If PaO2 is ,60 mmHg, this may lead
mixed acidbase abnormalities. to a significant reduction in SaO2 and
Respiratory disorders impaired oxygen delivery to tissues (fig. 1).
Measures that assess adequacy of ventilation PaO2/inspiratory oxygen fraction (FiO2): this
Air normally contains almost no carbon ratio can be used to compare arterial
dioxide (0.04%); blood carbon dioxide is a oxygenation in patients breathing different
normal metabolic waste product. Normal FIO2 values. A patient who has a normal PaO2
PaCO2 ranges from 35 to 45 mmHg. Blood of ,100 mmHg while breathing room air
levels depend on clearance, which, in turn, should have a PaO2/FiO2 ratio of 100/
depends on ventilation. 0.215500. The normal range for the PaO2/
FiO2 ratio is 300500. Values of less than
Small tidal volumes, low frequencies or 250 imply a significant problem in the lung
obstructed airways lead to reduced carbon gas exchange mechanisms. For this
dioxide clearance and, therefore, high blood calculation the percentage of oxygen being
carbon dioxide (respiratory acidosis). For administered must be entered in the blood
every increase in PaCO2 of 20 mmHg above gas analyser.
normal the pH falls by 0.1. For every
decrease in PaCO2 of 10 mmHg below Alveolararterial oxygen tension difference
normal the pH rises by 0.1. Any change in (PAaO2): is the difference between the
pH outside these ranges suggests a mixed alveolar oxygen pressure (PAO2) and PaO2.
disorder. PaCO2 may also be elevated in PaO2 is derived from the ABG analysis,
compensated metabolic alkalosis (table 2). whereas PAO2 may be calculated from the
simplified alveolar gas equation:
Hyperventilation leads to increased carbon
dioxide removal and then to a decreased
PaCO2 and an elevated pH (respiratory 100
90
alkalosis). Low PaCO2 levels can be also
by O2 %
80
Haemoglobin
found in compensated metabolic acidosis 70

(table 2). 60
50
saturated
40

Mechanisms for metabolic compensation in a

30
respiratory disorder When respiratory 20
acidosis persists beyond 612 h, the kidneys 10
generate bicarbonate by excreting 0
0 20 40 60 80 100
ammonium with chloride in the urine and, in
this process, bicarbonate is added to the PaO2 mmHg
plasma leading to the hypochloraemic
alkalosis typically seen in chronic respiratory Figure 1. The oxyhaemoglobin dissociation curve.

PAO2 5 (Patm - 47 mmHg) 6 FIO2 - PaCO2/0.8 5 g?dL-1 (i.e. blood that is approximately one-
third of the extracellular fluid).
47 mmHg is the water vapour added by the
airways and 0.8 is the respiratory quotient. Metabolic acidosis
In normal lungs, the PAaO2 is Metabolic acidosis is defined as a serum

,1215 mmHg in room air and ,70 mmHg bicarbonate ,22 mEq?L-1 and a pH ,7.35.
in 100% oxygen. A high PAaO2 gradient Metabolic acidosis may be caused either by
implies a defect in oxygen diffusion across adding acid or removing buffer. Help in
the alveolarcapillary membrane or a defect distinguishing these two conditions comes
in ventilation/perfusion ratio or right-to-left from calculating the anion gap. With the
shunting. Conversely, if the PAaO2 gradient onset of metabolic acidosis a certain
is not increased, lack of oxygenation is due amount of respiratory compensation takes
to low respiratory effort. For example, a place in the form of hyperventilation
healthy person who hypoventilates would (table 2). When the carbon dioxide tension
have hypoxia, but a normal PAaO2 gradient (PCO2) is outside the expected range for a
(Carmody et al., 2012). given bicarbonate concentration, a
superimposed respiratory acidbase
PaO2/PAO2 ratio: this offers better accuracy disturbance is present.
over a broader FIO2 range than the PaO2/FIO2
Anion gap
ratio. It is considered a somewhat better
index of oxygenation. When the PaO2/PAO2 Organisms exist in a state of electro-
ratio is very low, high FIO2 values obviously neutrality with major and minor cations
do not translate into improved blood balanced by similar anions (fig. 1). The
oxygenation: in such situations, a high shunt major extracellular cation is sodium, while
fraction can be expected. the other minor cations (potassium,
calcium, magnesium, etc.) are grouped as
Metabolic disorders unmeasured cations. Similarly, the major
Metabolic disorders will initially cause commonly measured anions are chloride
alterations in the serum bicarbonate and bicarbonate, whereas other anions (e.g.
concentrations and, thus, pH. The base albumin, phosphates and sulfates) are
grouped as unmeasured anions (Carmody et
excess/deficit is a calculation that estimates
al., 2012). In normal conditions, a small
the metabolic component in the acidbase.
unmeasured anion excess represents the
Whereas a positive base excess may indicate
anion gap (fig. 2).
metabolic alkalosis, a negative base excess
usually suggests metabolic acidosis. Blood Anion gap 5 unmeasured anion -
with a pH 7.4 and PaCO2 40 mmHg at 100% unmeasured cations 5 1014 mEq?L-1
oxygen saturation has a base excess of zero.
Most blood gas analysers offer the option of or indirectly
calculating either the base excess of the
Anion gap 5 Na+ - (Cl- + HCO3-)
blood sample, also called standard base
5 1014 mEq?L-1
excess, or the base excess of the
extracellular fluid, also called actual base In low albumin states, 2.5 mEq?L-1 should be
excess. The blood base excess does not truly added to the calculated anion gap for every
indicate the base excess of all extracellular 1 g?dL-1 of albumin below the usual normal
fluids, as buffering capacities (i.e. value (Oh, 2010). Metabolic acidosis with
haemoglobin concentration) differ between a normal anion gap occurs when the
the intravascular and the extravascular bicarbonate concentration falls and the
compartments. Therefore, to be chloride concentration increases
representative of the whole extracellular proportionately to maintain electrical
compartment (intravascular and neutrality. This happens when bicarbonate is
extravascular), the blood base excess value lost either in the gastrointestinal tract, as in
is calculated on a haemoglobin level of diarrhoea, or in urine (renal tubular acidosis).

Total cations = Total anions Metabolic alkalosis is classically delineated
into two types: chloride responsive and
chloride unresponsive. A helpful way to
Unmeasured
differentiate between the two is to evaluate
cations
Unmeasured urine chloride. Patients with a low urine
Anion anions chloride (,10 mEq?L-1) are those who have
gap chloride responsive alkalosis (e.g. loss of
acids from the gastrointestinal tract and
diuretics), whereas patients who have a
Sodium Chloride normal or high urine chloride (.10 mEq?L-1)
have chloride unresponsive alkalosis. In
most patients with chloride unresponsive
Bicarbonate alkalosis, urine potassium will also be
elevated (.30 mEq?L-1), indicating
significant renal losses of potassium. The
pathophysiology of chloride unresponsive
Figure 2. Schematic representation of the metabolic alkalosis involves potassium
concentration of plasma cations, mainly depletion along with excessive
represented by sodium, plasma anions mineralocorticoid activity (e.g.
(bicarbonate and chloride), and the anion gap. hyperaldosteronism, Cushings disease or
Bartters syndrome) (Carmody et al., 2012;
Ayers et al., 2012).
An abnormally large anion gap indicates that Specific issues

the metabolic acidosis depends on
Type of blood sample for blood gas Although
accumulation of acids not normally found in
blood gas has historically been analysed in
significant quantities in the body (e.g.
arterial blood, obtaining arterial samples
ketoacids, lactic acid and salicylic acid).
may be difficult and lead to complications.
Metabolic alkalosis Capillary blood is routinely used in neonates
or other patients when an arterial sample is
Metabolic alkalosis is defined as a serum not easy to collect. Capillary blood is a mix
bicarbonate .26 mEq?L-1 and a pH .7.45. of arteriolar, capillary and venous blood with
Compensatory hypoventilation may cause a a small contribution of interstitial and
slight rise in PaCO2 (table 2), but this is intracellular fluid. Although the relative
typically minor. The development of higher pressure on the arterial side of the
alkalosis is usually due to excessive loss of circulation increases the proportion of
hydrogen ions either from the stomach arterial blood in the capillary sample, only
(vomiting) or the kidney (when excess pH and PCO2 are acceptable because of their
aldosterone increases the activity of a low arteriovenous gradient; on the
sodiumhydrogen exchange), which results contrary, PO2, which exhibits a relatively high
in regeneration of the titrated plasma arteriovenous difference, is less likely to
bicarbonate. Important to the pathogenesis show good agreement between capillary and
of the alkalosis is chloride and potassium arterial blood (Sauty et al., 1996). Increasing
depletion, which also leads to bicarbonate local blood flow by the so-called
reabsorption. This leads to further arterialisation of capillary blood
reabsorption of bicarbonate. Chloride and (warming) does not show significant
potassium depletion can be induced in a difference of pH and blood gas compared to
number of ways by: the non-warmed capillary blood. Another
acceptable alternative for the initial
N corticosteroid medication, assessment of a patient with mild
N diuretic therapy, respiratory problems is peripheral venous
N gastric suction. sampling (table 3). Arterial and venous pH,

Table 3. Arterial and venous blood gas reference values
Arterial blood Venous blood Capillary blood
pH 7.40 (7.357.45) 7.36 (7.317.41) 7.357.45
PaCO2 mmHg 40 (3545) 4255 3645
PaO2 mmHg 95 (80100) 3050 5080
Bicarbonate mEq?L-1 24 (2230) 2428 2227
Base excess mEq?L-1 -33 -33 -33
O2 saturation % .90 6085
Data from Dzierba et al. (2011).
bicarbonate and base excess yield Each degree above or below 37uC will result
acceptable agreement in patients with in a 5 mmHg change in PaO2 and a
normal peripheral circulation. The mean 2 mmHg change in PaCO2. All blood gas
arteriovenous difference in pH is ,0.035 machines have the option of analysing the
pH units, for PCO2 is 5.7 mmHg, and for blood at an actual temperature but this
bicarbonate is -1.41 mmol?L-1 (Kelly, 2010). is rarely carried out. When blood gases are
Owing to the wide variations in venous measured at 37uC, PaO2 and PaCO2 increase;
PCO2, a venous sample can be used only to therefore, the normal range for blood
screen for arterial hypercarbia or to monitor gases should be increased (Thoresen,
trends in PCO2 for selected patients, but not 2008).
to establish the diagnosis of respiratory
failure.
Further reading
Pitfalls in ABG interpretation ABG samples
must be collected, handled and analysed N Ayers P, et al. (2012). Simple acid-base
properly for accurate results. Every sample tutorial. JPEN J Parenter Enteral Nutr; 36:
must be obtained anaerobically and be 1823.
anticoagulated. After collection, the sample N Carmody JB, et al. (2012). A clinical
approach to paediatric acid-base disor-
should be immediately analysed or properly
ders. Postgrad Med J; 88: 143151.
chilled and analysed within 30 min.
N Clark LC (1956). Monitor and control of
Supplemental oxygen should be entered in
blood and tissue oxygen tensions. Trans
the blood gas machine to obtain Am Soc Artif Intern Organs; 2: 4148.
oxygenation indices. Factors influencing the N Dzierba AL, et al. (2011). A practical
results of ABG analysis include: approach to understanding acid-base
abnormalities in critical illness. J Pharm
N the type of syringe used for collection Pract; 24: 1726.
(unless the sample is analysed within N Essin DJ (1984). The application of the
15 min), extracellular base excess to children.
N the presence of air bubbles (causing an Biochem Med; 32: 6778.
artificially high PaO2 and underestimating N Hasan A, ed. Understanding Mechanical
the true PaCO2), Ventilation: A Practical Handbook. 2nd
N using too much heparin as an Edn. New York, Springer, 2010.
anticoagulant (decreased PaCO2). N Henderson LJ (1913). The regulation of
neutrality in the animal body. Science; 37:
Blood gas analysis values during systemic 389395.
hypothermia Physical laws determine that N Kelly AM (2010). Can venous blood gas
gas solubility within a liquid decreases analysis replace arterial in emergency
when the temperature diminishes. During medical care. Emerg Med Australas; 22:
therapeutic hypothermia, arterial PaCO2 493498.
therefore decreases and pH increases.

N Marieb EN, et al. eds. Human Anatomy and N Sauty A, et al. (1996). Differences in PO2
Physiology. 7th Edn. San Francisco, and PCO2 between arterial and arterialized
Pearson/Benjamin/Cummings, 2007. earlobe samples. Eur Respir J; 9: 186189.
N Oh YK (2010). Acid-base disorders in ICU N Thoresen M (2008). Supportive care
patients. Electrolyte Blood Press; 8: 6671. during neuroprotective hypothermia in
N Reeves EL, et al. (2011). Respiratory sleep the term newborn: adverse effects
medicine: instructions for authors. J Inst and their prevention. Clin Perinatol; 35:
Auth; 12: 4549. 749763.

Exhaled nitric oxide,
induced sputum and
exhaled breath analysis
Johan C. de Jongste
Noninvasive tests to assess the presence

and nature of airway inflammation in Key points
children are particularly relevant for the
diagnosis and treatment of asthma, and N At present, FeNO is the only biomarker
may also be valuable for other inflammatory in exhaled air that has been
conditions of the airways. Other standardised, developed and
applications include the diagnosis and validated for clinical application.
monitoring of respiratory infections and of N Increased FeNO is suggestive of
certain nonrespiratory metabolic conditions. eosinophilic airway inflammation and
This chapter will focus on the use of FeNO has a role in the diagnosis and
noninvasive markers of airway inflammation management of asthma after
in childhood asthma. preschool age. Low FeNO is seen in
Exhaled nitric oxide fraction suppurative airways disease,
including CF, and low nasal nitric
Exhaled nitric oxide fraction (FeNO) is the oxide is typical for primary ciliary
best studied and validated noninvasive dyskinesia or sinusitis.
marker of airway inflammation, and is the
only inflammation marker that has widely N Dose titration of inhaled steroids on
gained acceptance in routine patient care. the basis of induced sputum
Nitric oxide is a free radical gas that is eosinophilia has been shown to
produced from L-arginine, involving reduce exacerbations in adult
constitutively expressed nitric oxide asthmatics, but studies in children are
synthases (NOS). One of the isoforms of few and inconclusive. The
methodology of sputum induction in
NOS, inducible NOS, also called type 2 NOS
children is demanding and unlikely to
or iNOS, is present on airway epithelial cells,
become useful in clinical routine.
where it is upregulated by proinflammatory
cytokines and then produces relatively high N A large number of other potential
amounts of nitric oxide into the airway biomarkers in exhaled air, or in EBC,
lumen. This nitric oxide can be measured at await further standardisation. Careful
the mouth during exhalation, and with evaluation is needed before these can
appropriately standardised methodology the be applied in clinical practice.
FeNO is highly reproducible. Exhaled nitric
oxide levels are measured in parts per billion
(ppb), and hence extremely sensitive
analysers are needed. FeNO analysers for
clinical purposes are commercially available, different devices do not necessarily produce
and have evolved from bulky, expensive, the same results, and the smaller hand-held
delicate chemoluminescence analysers into analysers cannot be adjusted. Hence,
hand-held, user-friendly devices using a different equipment cannot be used
more robust electrochemical cell-based interchangeably unless formal comparisons
technology (fig. 1). Unfortunately, the have shown equivalence.

various, often complicated approaches, that
require an academic setting and dedication.
Such methods have not been well
standardised and are not suitable for clinical
practice.
Several factors can affect FeNO, and should

be taken into account when FeNO is
interpreted. Maximal forced breathing
manoeuvres, including spirometry, should
be avoided as these reduce FeNO for several
minutes. Inhaling nitric-oxide-free air before
the measurement is desirable as high
ambient values may increase FeNO. For this
purpose, a nitric oxide scrubber can be used
that removes ambient nitric oxide from the
inhaled airstream.
Figure 1. Measurement of FeNO in a child using a
Cigarette smoke reduces FeNO, whereas
hand-held device with an electrochemical sensor.
Maintaining a low, constant expiratory flow is nitrate- or arginine-rich foods, such as
facilitated by optical, auditory and visual feedback vegetables, may slightly increase the levels.
signals. The result is immediately available. However, the impact of food is limited and
does not need to be taken into account.
Airway infections have been reported to
Methodology of FeNO The recommended
either slightly increase or reduce FeNO.
technique to assess FeNO is an on-line
measurement during a constant expiratory Assessing FeNO at different expiratory flows
flow of 50 mL?s-1, for at least 10 s (children makes it possible to calculate bronchial and
with vital capacity ,3 L: 6 s), through a alveolar components of FeNO. It is unclear
mouthpiece. Contamination with air from how this information could be clinically
the nose should be avoided, as the nose and useful, and such measurements are still
paranasal sinuses produce nitric oxide in limited to research.
much higher amounts than the lower
airways. This is accomplished by exhaling Clinical applications of FeNO in children
against a positive pressure that ensures Normative values of FeNO in children have
closing of the soft palate, thus closing the been published, and show an age-dependent
nose off from the lower airways. increase during childhood (fig. 2). The
upper level of normal ranges from 15 ppb in
Ideally, the equipment provides one or more early childhood to 25 ppb in adolescence,
biofeedback signals to help the patient to and is slightly higher in males than in
standardise the expiration flow and females. Higher normal levels are also seen
duration, and accepts only attempts that in atopic individuals and in certain non-
fulfil quality criteria. The recommended Caucasian ethnic groups. In asthma, FeNO
procedure is feasible in children from the shows daily fluctuations and the minimal
age of 67 years; in younger children the change that may be clinically relevant has
success rate falls rapidly. For preschool been proposed as 10 ppb if FeNO is
children, a number of offline methods have ,50 ppb or 20% with higher values.
been described, which make use of
collection devices where exhaled air is High FeNO, especially above 4050 ppb, is
stored and analysed, with or without tidal strongly associated with eosinophilic airway
flow control. In infants, FeNO measurements inflammation. An abnormally low FeNO may
have been performed by collecting mixed be seen during suppurative airway infection,
nasal-oral exhaled air samples in a nitric e.g. in CF, and is of some diagnostic value in
oxide inert collection bag, or online using primary ciliary dyskinesia. For the latter

40 reflects eosinophilic inflammation, but not
other types of inflammation. FeNO may be
35 low in neutrophilic inflammation, which
occurs in a considerable proportion of
30 asthmatic children, and this may alternate
with eosinophilic patterns.
25
FeNO ppb
Inhaled corticosteroids (ICS) reduce FeNO,

20
an effect that occurs within a few days of
15 daily treatment. The diagnostic value of
FeNO is, therefore, limited in subjects who
10 are already on ICS treatment. The effect of
ICS on FeNO may be used to alert for
5 nonadherence if a child with a documented
FeNO response on ICS exhibits high FeNO
0 levels. Elevated FeNO is predictive of
0 5 10 15 20
successful treatment with ICS, and an
Age years increase in FeNO has been shown to precede
loss of control in children who stop or taper
Figure 2. Normative values of FeNO in children. their ICS dose while in clinical remission.
Black lines show mean and upper 95% FeNO FeNO above 4050 ppb is associated with an
(n5405). Orange lines show mean and upper increased risk of exacerbation and loss of
95% FeNO excluding outliers and atopics (n5332). control. In an individual, the predictive value
Reproduced with modification from Buchvald et
is, however, limited and the benefits of
al. (2005) with permission from the publisher.
regular FeNO assessment to prevent loss of
control remain to be shown.
purpose, nasal nitric oxide measurements
have better specificity and sensitivity. Studies in adults with difficult-to-treat
asthma indicated that FeNO monitoring may
A large number of clinical studies, both in be helpful to identify patients who have an
adults and in children, support the clinical accelerated decline in lung function, and to
use of FeNO. Firm evidence of added benefit identify subjects who might benefit from
as compared to conventional practise is higher doses of ICS. Similar studies in
often lacking. In practice, FeNO should be children are lacking.
considered as one of the many pieces of
information that clinicians may want to use Several studies in children and adults have
when making a diagnosis or for treatment tried to improve asthma management by
decisions. titrating the dose of ICS in FeNO. Although
most of these studies report some
FeNO can be of help in the diagnosis of significant benefit of FeNO monitoring on
atopic asthma, especially if symptoms are secondary end-points, only a few found an
indeterminate. Most published studies on effect on the primary end-point that differed
the diagnostic value of FeNO in asthma between studies. These studies had
compared clear asthma cases with normal important methodological flaws, and
patients, thus providing a strong contrast differed in many other aspects as well, in
that is often lacking in daily practice. Hence, particular how often and to what degree
the diagnostic value will be lower in less FeNO could indeed influence treatment
clearly defined populations of children. In decisions. The dosing algorithm is entirely
contrast to spirometry, which is often responsible for this, and had to be defined
normal in children with asthma, elevated on arbitrary grounds. Unfortunately, the
FeNO commonly persists in asymptomatic heterogeneity of dose titration studies
episodes and, as a diagnostic test, FeNO impairs meta-analysis and, therefore, the
performs better than FEV1 or other tests of issue of whether tailoring the ICS treatment
airway patency. A limitation of FeNO is that it in asthma on FeNO is beneficial is still

unresolved, and the use of FeNO for ICS Induced sputum may be valuable for the
dose titration can not, at present, be diagnosis of airway infections in children
recommended for clinical routine. who do not expectorate, and has been used
as a diagnostic, e.g. in CF and for the
An important observation was that among diagnosis of pulmonary TB.
adult asthma patients, there are subjects in
whom FeNO and symptoms are concordant Inhalation of hypertonic saline may cause
while in others there is discordancy, with bronchoconstriction, especially in
high symptom scores and normal FeNO, or asthmatics, and pre-treatment with an
vice versa. Clearly, any added benefit of FeNO inhaled b-agonist is therefore needed. There
monitoring compared to classical symptom is some risk of microbial contamination of
monitoring cannot be expected if there is a laboratory personnel due to the induced
perfect concordance of FeNO and symptoms, coughing, and appropriate protective
and none of the paediatric ICS dose titration measures need to be taken.
studies has taken this aspect into account.
In experienced hands, sputum induction in
The potential benefit of FeNO as a school-age children has been reported with
monitoring tool in asthma treatment still success rates of 6085%, occasionally even
requires more study, focussing on well- higher, while much lower proportions have
defined subgroups and exploring the effects been reported for younger children, in whom
of different algorithms. voluntary expectoration is often problematic
Induced sputum and specimens may be only obtained by
using a suction cannula. The success rate
Several studies in adults with asthma have will depend on subject selection and on the
examined the potential of incorporating experience and skills of the laboratory
sputum eosinophilia as a marker of airway technician. The success of repeated
inflammation in asthma management. The procedures is lower, and this is a significant
first proof-of-concept study in adults showed problem if sputum is to be used for regular
benefits of a treatment strategy that was monitoring purposes. Paediatric normal
aimed at reducing sputum eosinophilia. values of differential cell counts in sputum
These included a substantial reduction of have been published previously.
the number of exacerbations and hospital
admissions, with no concomitant need for Clinical application of sputum induction in
higher doses of anti-inflammatory children The only paediatric study to date
medication. that incorporated sputum eosinophils in the
management of asthma showed no benefits
Methodology of sputum induction Most in terms of improved asthma control or
children with asthma will not spontaneously overall exacerbation rates. This study
expectorate sputum. This makes it difficult included a highly selected population of
to use sputum for regular assessment of children with severe problematic asthma
airway inflammation. The procedures to from a third-line reference centre, using
induce sputum have been standardised by a relatively high doses of ICS. Hence, the
European Respiratory Society Task Force findings may not be applicable to other
and are suitable for use from the age of populations of children with more common
8 years. Commonly, sputum is induced by forms of asthma. There are no paediatric
inhaling hypertonic saline, and whole studies on the clinical application of soluble
expectorated samples, or selected sputum components in sputum.
plugs, are pre-treated with a mucolytic
before examination. Reported characteristics In summary, induced sputum as a means to
include total differential cell counts and diagnose or monitor children with
contamination with epithelial squamous inflammatory airway disease is still a
cells in cytospin preparations, soluble research tool and, until now, no clear benefit
components in the supernatant, and of measuring any sputum component in
cytokines and mediators of inflammation. children has been documented.

The methodology is demanding and time- Unfortunately, the methods employed in
consuming, and requires considerable EBC research to date have the inherent
expertise, which makes the place for induced difficulty that the air from the lower airways
sputum in paediatric clinical practice a passes through the pharynx and mouth,
limited one. where contamination may easily occur.
Saliva is an important potential source of
Exhaled breath analysis contamination as it contains molecules of
interest in vastly higher quantities than EBC.
Exhaled breath condensate (EBC) has been
In addition, the equipment itself may be a
studied for many years as an attractive
source of contamination and either rigorous
vehicle for soluble components from the
cleaning of all parts of the equipment that
lower airways that can be obtained in a
come into contact with the airstream or
noninvasive way. A large number of
disposable tubing and containers are
measurements have been described in
needed to avoid contamination.
exhaled air condensate, including
inflammatory mediators and cytokines, pH, Clinical application of EBC in children A lot of
hydrogen peroxide and other markers of studies have reported associations of
oxidative stress, and molecules derived from molecules in EBC and clinical disease in
microorganisms. Substances in breath children and adults. Examples include:
condensate are generally present in trace
amounts, which are near or well below the N pH, which tends to be lower in severe or
detection limits of most routine analytical acute asthma but not in mild and stable
techniques, and require extremely sensitive disease;
detection methods. The reproducibility of N hydrogen peroxide and nitric oxide
the measurements remains an issue of metabolites that are elevated in asthma;
concern. N hydrogen cyanide, which is produced by
Pseudomonas and detectable in EBC of CF
A promising new approach is the study of patients;
metabolomics in EBC, which makes use N 8-isoprostane, a marker of oxidative
of spectrometric techniques and detects stress in CF and asthma;
thousands of components, separated on the N a large number of inflammatory
basis of molecular mass and/or charge, mediators and proinflammatory cytokines
which can be associated with a clinical trait in relation to wheezing or asthma.
of interest in a hypothesis-free manner. An
What is lacking for most potential
excellent overview of the present state-of-
biomarkers in EBC are studies into the
the-art regarding biomarkers in EBC is
clinical methodology, especially short- and
provided in a recent European Respiratory
long-term reproducibility studies and
Monograph.
studies associating meaningful changes in
Methodology of EBC Various methods have disease activity to changes in biomarkers. In
been recommended to collect EBC samples, general, the overlap with findings in healthy
and equipment for EBC collection is subjects has been considerable, and studies
commercially available. The methodology for that did assess reproducibility have been
EBC collection was reviewed and disappointing. No paediatric studies have
recommendations provided in an American been published that showed clinical benefit
Thoracic Society Task Force report. The of measuring components in EBC in
techniques vary from a simple tube system individual patients.
to be cooled in a refrigerator before use, to Conclusion
more sophisticated devices that use cooled
containers through which the exhalate Noninvasive biomarkers of airway
passes and in which EBC is retained. A nose inflammation in exhaled air are of great
clip and saliva trap are recommended, and interest as they may provide information on
the material of tubing and condenser should an important aspect of disease that is
be inert for substances of interest. otherwise difficult to assess in children.

In theory, a reliable marker of airway N Buchvald F, et al. (2005). Measurements
inflammation would allow for better of exhaled nitric oxide in healthy subjects
diagnosis and selecting the appropriate age 4 to 17 years. J Allergy Clin Immunol;
treatment in the lowest possible dose that 115: 11301136.
suppresses airway inflammation. In practice, N Carraro S, et al. (2010). Exhaled nitric
it has proven exceedingly difficult to oxide measurements. Eur Respir Monogr;
substantiate these expectations. Of all 47: 137154.
noninvasive biomarkers of airway N Deykin A, et al. (2002). Exhaled nitric
oxide as a diagnostic test for asthma.
inflammation, only FeNO has developed into
Am J Respir Crit Care Med; 165: 1597
a useful clinical tool with many applications,
1601.
but also with limitations and pitfalls that one N Dweik RA, et al. (2011). An official ATS
should be aware of. Induced sputum clinical practice guideline: interpretation
requires more time and effort, and has of exhaled nitric oxide levels (FENO) for
limited feasibility and repeatability in clinical applications. Am J Respir Crit Care
children, especially at a younger age. As Med; 184: 602615.
adult studies have clearly demonstrated N Fleming L, et al. (2012). Use of sputum
benefits of induced sputum-based eosinophil counts to guide management
monitoring of asthma, it remains desirable in children with severe asthma. Thorax;
to pursue sputum induction further for 67: 193198.
application in children. At present, induced N Haldar P, et al. (2008). Cluster analysis
sputum mainly seems useful for obtaining and clinical asthma phenotypes. Am J
Respir Crit Care Med; 178: 218224.
microbiological specimens in suspected
N Horvath I, et al. Exhaled Biomarkers. Eur
airway infection, but also the evidence for
Respir Monogr 2010; 49: 1249.
added value is scanty. Assessing biomarkers N Kovesi T, et al. (2008). Exhaled nitric
of inflammation in EBC has been an exciting oxide and respiratory symptoms in a
and promising development for many years community sample of school aged
now. Despite a growing number of studies, children. Pediatr Pulmonol; 43: 1198
development into clinical practise is 1205.
hampered by methodological difficulties N Leung TF, et al. (2006). Clinical and
related to the extremely low concentrations technical factors affecting pH and other
of potential markers in EBC, a low biomarkers in exhaled breath condensate.
reproducibility and a high risk of Pediatr Pulmonol; 41: 8794.
contamination in the upper airway. Sensitive N Li AM, et al. (2006). Sputum induction in
and robust detection methods and better children with asthma: a tertiary-center
experience. Pediatr Pulmonol; 41: 720
equipment for collection, all well
725.
standardised, may sooner or later reveal the
N Nicolaou NC, et al. (2006). Exhaled
true clinical potency of EBC biomarkers. breath condensate pH and childhood
asthma. Unselected birth cohort study.
Further reading Am J Respir Crit Care Med; 174; 254259.
N Perez-de-Llano LA, et al. (2010). Exhaled
N Baraldi E, et al. (2002). ERS/ATS state- nitric oxide predicts control in patients
ment: measurement of exhaled nitric with difficult-to-treat asthma. Eur Respir J;
oxide in children, 2001. Eur Respir J; 20: 35: 12211227.
223237. N Petsky HL, et al. (2012). A systematic
N Baraldi E, et al. (2006). 3-Nitrotyrosine, a review and meta-analysis: tailoring
marker of nitrosative stress, is increased asthma treatment on eosinophilic mar-
in breath condensate of allergic asthmatic kers (exhaled nitric oxide or sputum
children. Allergy; 61: 9096. eosinophils). Thorax; 67: 199208.
N Beck-Ripp J, et al. (2002). Changes of N Pijnenburg MW, et al. (2005). Titrating
exhaled nitric oxide during steroid treat- steroids on exhaled nitric oxide in chil-
ment of childhood asthma. Eur Respir J; dren with asthma. Am J Respir Crit Care
19: 10151019. Med; 172: 831836.

N Pijnenburg MW, et al. (2005). Exhaled N Szefler SJ, et al. (2008). Management of
nitric oxide predicts asthma relapse in asthma based on exhaled nitric oxide in
children with clinical asthma remission. addition to guideline-based treatment for
Thorax; 60: 215218. inner-city adolescents and young adults:
N Rosias PP, et al. (2008). Biomarker a randomised controlled trial. Lancet; 372:
reproducibility in exhaled breath conden- 10651072.
sate collected with different condensers. N Van Jagwitz M, et al. (2011). Reduced
Eur Respir J; 31: 934942. breath condensate pH in asymptomatic
N Shaw DE, et al. (2007). The use of children with prior wheezing as a risk factor
exhaled nitric oxide to guide asthma for asthma. J Allergy Clin Imunol; 128: 5055.
management. Am J Respir Crit Care Med; N Van Veen IH, et al. (2008). Exhaled nitric
176: 231237. oxide predicts lung function decline in
N Sivan Y, et al. (2009). The use of exhaled difficult-to-treat asthma. Eur Respir J; 32:
nitric oxide in the diagnosis of asthma in 344349.
school children. J Pediatr; 155: 211216. N Wilson NM, et al. (2000). Induced
N Smith AD, et al. (2004). Diagnosing sputum in children: feasibility, repeatabil-
asthma. Comparisons between exhaled ity, and relation of findings to asthma
nitric oxide measurements and conven- severity. Thorax; 55: 768774.
tional tests. Am J Respir Crit Care Med; N Zacharasiewicz A, et al. (2005). Clinical
169: 473478. use of noninvasive measurements of
N Smith AD, et al. (2005). Exhaled nitric airway inflammation in steroid reduction
oxide. A predictor of steroid response. in children. Am J Respir Crit Care Med; 171:
Am J Respir Crit Care Med; 172: 453459. 10771082.

Pulmonary function testing
in infants and preschool
children
Enrico Lombardi, Graham L. Hall and Claudia Calogero
Measuring lung function in infants (first during tidal breathing (such as tidal
year of life) and preschool children (2 breathing measurements and the multiple
5 years old) represents a major challenge in breath washout) are more readily used
paediatric respiratory medicine. Infants without sedation, although test success
cannot voluntarily perform the manoeuvres rates will decrease with increasing age.
required for pulmonary function tests While PFTs in this age group are possible
(PFTs) used in older children and adults. and equipment is commercially available,
The majority of lung function tests in infant PFTs are less suitable for routine
infants and young children up to 2 years of clinical testing. A recent survey cited the
age require sedation to ensure acceptable need for sedation and the uncertainty
and repeatable results. The most about how data actually impacts patient
commonly used sedative is chloral hydrate care as limitations for the use of
(80100 mg?kg-1, maximum 1 g); however, infant PFTs. Infant PFTs have been
this sedative is no longer available in the standardised by the American Thoracic
USA. Infant lung function tests performed Society (ATS) and European Respiratory
Society (ERS).
Preschool children can be more challenging

Key points
than infants as far as lung function testing is
concerned. They are too old to sedate, have
N Measuring lung function in infants
a very short attention span and the success
and preschool children is possible
of lung function testing in this age group
because of standardised techniques
depends on the capability of the operator of
that require minimal cooperation
initiating a good relationship with the child.
from the child.
Several techniques are now available that are
N Sedation is usually required in infants performed during tidal breathing, thus only
and young children up to 2 years of requiring passive collaboration in preschool
age (generally chloral hydrate children. International recommendations for
80100 mg?kg-1, maximum 1 g) for most PFTs in preschool children have been
most PFTs, limiting the use of infant recently published and the evidence for the
PFTs in routine clinical care. clinical utility of the tests has been recently
N In preschool children, the feasibility of reviewed.
the interruptor technique and
This section will describe some of the most
plethysmographic sRaw, which are
frequently used PFTs in infants and
performed during tidal breathing, is
preschool children. Other fundamental PFTs
usually .80%.
for infants and preschool children, such as
N Spirometry is also feasible in the washout techniques and the forced
preschool children when appropriate oscillation technique, are described in great
criteria are used. detail separately in this section of the
Handbook.

PFTs in infants (ISIS) demonstrated a significant adjusted
treatment effect in FEV0.5 of 38 mL
Raised volume rapid thoracic compression The suggesting that RVRTC outcomes may be a
measurement of forced expiratory flow and valid choice for clinical trials in early CF lung
volumes in infants is obtained using the disease. In infants with recurrent wheeze/
raised volume rapid thoracic compression infantile asthma, evidence of airway
(RVRTC) technique and international testing obstruction and improvements following
guidelines that are available. The RVRTC treatment with montelukast or inhaled
technique is demanding in terms of staffing corticosteroids have been reported. The
and equipment resources, as well as the RVRTC technique has been combined with
training required to ensure high-quality inhaled challenge tests for the assessment
measurements are obtained. Briefly, the of airway hyperresponsiveness (AHR)
technique involves applying repeated although these are limited to highly
inflation breaths to the sedated infant, via a experienced centres.
facemask, to a pressure of 30 cmH2O. An
inflatable jacket is used to rapidly compress In summary, the RVRTC technique is
the infants thorax and abdomen to produce becoming more readily available and has a
the forced expiratory flowvolume curves. role in research studies with emerging
The jacket inflation pressure is increased evidence of its utility in clinical trials. The
progressively until there are no further role of the technique in the clinical
increases in forced expiratory flow (FEF), management of infants and young children
suggesting flow limitation has been with lung disease is less clear and further
achieved. The reported RVRTC outcomes are studies defining normal reference ranges
FVC, FEV0.5 and FEF at a defined proportion and clinically meaningful differences are
of FVC. Technically acceptable and required.
repeatable outcomes are influenced by
laboratory experience. The most commonly Infant plethysmography The use of body
used reference equations may no longer be plethysmography in infants to measure
suitable for the current generation of functional residual capacity (FRCpleth)
commercially available equipment and it is operates on the same principles as
not clear what changes in RVRTC outcomes plethysmography in older children and
constitute a clinically meaningful difference, adults. The primary difference is that the
primarily due to the difficulties associated infant or young child is sedated, lying supine
with repeated sedation and changes with and breathing through a facemask that is
lung growth over time. These place further sealed over the nose and mouth using
limitations on the use of RVRTC for the silicon putty. Infant plethysmography
management of lung disease in individual measurement guidelines have been
patients. published. The success in obtaining FRCpleth
is generally high and is influenced by
The RVRTC technique has been applied in a sedation success and experience of the
range of patient populations including CF, personnel. Reference data in healthy infants
recurrent wheezing, infants born preterm are available; however, the validity of these
and in infants with chest wall and data in using currently available equipment
parenchymal lung disorders. The majority of has been questioned. There are very few
studies reported in the literature are in data on the repeatability of FRCpleth over
infants with CF and infants with recurrent time and a clinically meaningful change in
wheeze. In infants and young children with response to treatments (such as
CF diagnosed following newborn screening, bronchodilators) or deterioration in clinical
FEV0.5 is normal or near normal in the first status is not known. Considered together
months of life, declines over the first 12 these limit the ability of infant
24 months of life and is reduced in infants plethysmography to be used in a meaningful
with pulmonary infection. The recent Infant way in individual infants with chronic lung
Study of Inhaled Saline in Cystic Fibrosis diseases.

The use of infant plethysmography in infants as 21%) has been found in children
with CF, bronchopulmonary dysplasia (BPD) aged f4 years and in those with
and recurrent wheeze has been recently neurodevelopmental disabilities (such as
reviewed. Considering that equipment has children with BPD).
been commercially available for a number of
years there are relatively few published Standardisation of spirometry for adults and
studies with sample sizes that allow for children aged o6 years requires that
meaningful conclusions to be drawn. In subjects inhale up to TLC and forcefully
general, studies in infants with CF have exhale for at least 3 s (for children ,10 years
demonstrated an elevated FRCpleth and, of age) or at least 6 s (for children
recently, this has been reported to be .10 years of age) until residual volume (RV)
associated with pulmonary infections. In is reached, so that FEV1 and FVC can be
contrast to FEV0.5, there was no change in accurately measured. The manoeuvre
FRCpleth in the ISIS trial. The few studies in should also have a good start, meaning an
infants with recurrent wheeze suggest the extrapolated volume ,5% of FVC or
presence of air trapping, probably secondary ,0.150 L. This manoeuvre needs to be
to airway obstruction, which improves repeated until at least three manoeuvres are
following bronchodilation. In infants born obtained with the two largest values of FVC
preterm (with or without BPD) the majority and FEV1 within 0.150 L of each other.
of studies have reported reduced FRC
Several studies have shown that preschool
obtained with gas dilution techniques
children have difficulty in meeting such
related to the decreased alveolar complexity
acceptability criteria for spirometry.
occurring as a result of altered lung
Preschool children are physiologically
development. FRC using infant
different from older children and adults: they
plethysmography is reported to be elevated
have smaller lung volumes and larger
in infants with BPD and may suggest the
airways with respect to lung volume when
presence of trapped gas.
compared with older children. Therefore,
In summary, the limited information on spirometric manoeuvres in preschool
healthy reference ranges for both the infant children are completed more quickly than in
RVRTC and plethysmography techniques, older children, sometimes even in ,1 s. As a
and a limited understanding on a clinically result, FEV1 is not always measurable and
meaningful change have impacted on the indices such as FEV0.75 or FEV0.5 are more
ability of these lung function tests to reasonable in this age group. It has been
contribute to the clinical management of shown that extrapolated volume is lower and
infants with respiratory disease. The extrapolated volume/FVC is higher in
application of lung function testing in preschool children than in older children
sedated infants and young children is likely and adults. For these reasons, acceptability
to require a combination of tests and careful criteria for spirometry in preschool children
consideration of pathophysiological changes are different from those used in older
and the most appropriate PFT are required. children and adults.
PFTs in preschool children Figure 1 shows a preschool child performing

spirometry. The ATS/ERS statement for lung
Preschool spirometry In individuals .5 years function testing in preschool children has
of age, spirometry is the most commonly provided appropriate recommendations for
used lung function technique, while it is spirometry in this age group, which can be
thought that preschool children are not able summarised as follows:
to perform acceptable spirometry
manoeuvres. Recent studies have N the child should have time to familiarise
highlighted that spirometry in preschool themselves with the equipment and
children has a good feasibility (between 47% operator,
and 92%), especially when an incentive N incentive software may be used, although
software is used. A lower feasibility (as low this is not mandatory,

N the childs posture (seating or standing) It requires little collaboration and can be
and the use of a nose clip should be performed in children as young as 2 years.
reported, The interruptor resistance (Rint) reflects the
N if the extrapolated volume is .80 mL or resistance of the respiratory system
12.5% of FVC, the curve should be (airways, lung tissue and chest wall) and
inspected again but not necessarily equipment is commercially available. It is
rejected, assumed that during a sudden flow
N in case of early termination of expiration, interruption at the mouth:
it may be possible to record FEV0.5,
FEV0.75 and FEV1, but not FVC, N mouth pressure will equilibrate with
N a minimum of two acceptable alveolar pressure,
manoeuvres should ideally be obtained, N the valve closure time will minimise leak,
where the second largest FVC and FEV N compliance of the upper airway is
values are within 0.1 L or 10% of the negligible.
highest value; however, poor repeatability
should not be a reason for automatic The interruption time is usually ,100 ms.
Rint can be calculated by dividing the change
rejection of data.
in mouth pressure at the beginning of the
Several reference values for spirometry in interruption by the flow measured
preschool children have been reported and immediately before the interruption
these data are now included in the recently (classical technique) or dividing mouth
published reference values of the ERS Global pressure at the end of the interruption by
Lung Function Initiative. Clinical data on the flow measured immediately after the
usefulness of spirometry in preschool interruption (opening technique). The
children have also been published. results obtained with the two different
techniques cannot be used interchangeably.
Interrupter technique The interrupter
technique is a suitable method to measure The test procedure, technical aspects and
lung function in preschool children. data analysis for the classical interruptor
technique have been fully described
previously. The child should be seated,
breathing quietly through a mouthpiece and
bacterial filter, wearing a nose clip and with
the cheeks supported (fig. 2). Each occlusion
Figure 1. Preschool child performing spirometry. Figure 2. Preschool child performing Rint.

should be triggered during expiration by a points of inspiratory and expiratory
flow set to coincide with peak expiratory flow pressure;
and 10 interruptions should be recorded, with N resistance at the peak of flow (sRaw,peak);
the aim of obtaining a minimum of five N effective specific resistance (sReff), which
acceptable manoeuvres. At the end of the test is the least-squared regression of
the median value of all technically acceptable pressure and flow throughout the
interruptions should be reported. breathing cycle.
International reference equations for males Being a product of a volume and a

and females have been recently published. resistance, an abnormal value can indicate
Measurements of Rint have been shown to changes in both components. It has been
have a good intra-measurement and recently recommended that sReff should be
between-test repeatability. calculated since it measures sRaw over the
entire breathing cycle.
The feasibility of Rint in preschool children is
.80% in most studies. The sensitivity and Preliminary reference equations for sRaw have
specificity for different bronchodilator been recently published; however, the authors
response (BDR) cut-off levels to highlight that those reference values can only
discriminate between healthy and asthmatic be used when similar measurement
children are available. conditions are applied. In a recent study
conducted in the UK, statistically significant
In the clinical setting, Rint can be used to differences were reported for sRaw measured
measure lung function in children with in three different centres, suggesting that
different respiratory diseases such as even after a methodological standardisation
wheezing, CF or BPD. BDR assessed using reference values cannot be used inter-
Rint is probably more useful for asthma changeably between different laboratories.
diagnosis than for excluding asthma.
The repeatability of measuring sRaw in
However, as the definitions of different
preschool children has shown intra-subject
phenotypes of preschool wheezing are
coefficients of variation of ,913%.
complex, recent recommendations suggest
Feasibility is also good, being ,80% in
that in the individual patient measuring lung
36 year olds.
function, including BDR, can help to
differentiate common wheezing disorders In preschool children, sRaw has been shown
from other diseases. to be able to detect airway calibre changes
after bronchodilation. Preschool children
Plethysmographic specific airway resistance In
with asthma were found to have higher sRaw
cooperating children, airway resistance
than healthy children and, in a longitudinal
(Raw) can be measured with whole body
cohort study, high sRaw at 3 years of age was
plethysmography, where the subject is asked
found to predict the persistence of recurrent
to breathe against a closed shutter to obtain
wheezing at 5 years of age. In preschool
thoracic gas volume (TGV). In preschool
children with CF, sRaw was also found to be
children the measurement of specific Raw
higher than in healthy children and was
(sRaw), only requiring minimal collaboration
shown to be more sensitive than spirometry
during tidal breathing, has been proposed.
in detecting early lung disease, although less
sRaw is defined as the product of Raw sensitive than the lung clearance index from
multiplied by FRCpleth and its calculation multiple-breath washout.
avoids the need to perform breathing
manoeuvres against a closed shutter. Conclusion
Several indices for sRaw have been The optimal lung function test to be used in
proposed, such as: infants and preschool children depends on
the clinical or research questions that need
N total specific resistance (sRaw,tot), which to be answered. In preschool children with
is the slope of the line between the two wheezing the interruptor technique,

plethysmographic sRaw and forced N Frey U, et al. (2000). Specifications for
oscillation technique appear to be the most equipment used for infant pulmonary
suitable to provide information on the function testing. Eur Resp J; 16: 731740.
change in airway calibre. However, N Kirkby J, et al. (2010). Reference equa-
techniques that are able to detect more tions for specific airway resistance in
peripheral changes (such as the washout children: the Asthma UK initiative. Eur
techniques and, potentially, forced Respir J; 36: 622629.
oscillation technique) appear more suitable N Lowe LA, et al. (2005). Wheeze pheno-
in studying diseases such as CF or BPD. types and lung function in preschool
children. Am J Respir Crit Care Med; 171:
In conclusion, measuring lung function in 231237.
infants and preschool children is possible N Mele L, et al. (2010). Assessment and
thanks to standardised techniques that validation of bronchodilation using the
require minimal cooperation from the child. interrupter technique in preschool chil-
dren. Pediatr Pulmonol; 45: 633638.
Further studies will need to highlight the
N Merkus PJ, et al. (2010). Reference ranges
role of single tests in the clinical
for interrupter resistance technique: the
management of infants and preschool Asthma UK Initiative. Eur Respir J; 36:
children with respiratory illness. 157163.
N Miller MR, et al. (2005). Standardisation
Further reading of spirometry. Eur Respir J; 26: 319338.
N Pillarisetti N, et al. (2011). Infection,
N ATS/ERS statement (2005). Raised inflammation, and lung function decline
volume forced expirations in infants: in infants with cystic fibrosis. Am J Respir
guidelines for current practice 2005. Am Crit Care Med; 184: 7581.
J Respir Crit Care Med; 172: 14631471. N Quanjer PH, et al. (2012). Multi-ethnic
N Aurora P, et al. (2005). Multiple-breath reference values for spirometry for the 3
washout as a marker of lung disease in 95 year age range: the global lung
preschool children with cystic fibrosis. function 2012 equations. Eur Respir J;
Am J Respir Crit Care Med; 171: 249256. 40: 13241343.
N Beydon N, et al. (2007). An official N Rosenfeld M, et al. (2013). An official ATS
American Thoracic Society/European workshop report: Optimal lung function
Respiratory Society statement: pulmonary tests for monitoring cystic fibrosis,
function testing in preschool children. bronchopulmonary dysplasia and recur-
Am J Respir Crit Care Med; 175: 13041345. rent wheezing in children less than 6
N Bisgaard H, et al. (2005). Plethy- years of age. Ann Am Thorac Soc; 10: S1
smographic measurements of specific S11.
airway resistance in young children. N Sonnappa S, et al. (2010). Symptom-
Chest; 128: 355362. pattern phenotype and pulmonary func-
N Brand PL, et al. (2008). Definition, tion in preschool wheezers. J Allergy Clin
assessment and treatment of wheezing Immunol; 126: 519526.
disorders in preschool children: an N Stocks J, et al. (2001). Plethysmographic
evidence-based approach. Eur Respir J; measurements of lung volume and airway
32: 10961110. resistance. Eur Respir J; 17: 302312.

Single- and multiple-breath
washout techniques
Sophie Yammine and Philipp Latzin
Inert-gas washout (IGW) has been re- Anatomical and physiological background
established in recent years as one of the
most sensitive lung function tests for The dichotomous branching structure of the
assessing small-airway function. It can be lung, resulting in .100 m2 of lung surface,
performed over a single tidal breath, termed has evolved to facilitate gas exchange. In the
single-breath washout (SBW), or over a conducting airways (generations 016), gas
series of tidal breaths, termed multiple- transport mainly occurs by convection, and
breath washout (MBW). Recent in the intra-acinar airways (generations 17
developments have led to commercially 23), mainly by diffusion. In the transition
available and user-friendly washout zone at the entry to the acinus, both
equipment, mirroring the increasing interest mechanisms show a similar contribution.
in a transition of IGW tests from research The definition of small airways is derived
into clinical routine. from post mortem adult data and includes all
airways with a luminal diameter of ,2 mm
(corresponding to generations 823).
Pathological processes such as mucus
Key points impaction, hyperinflation, obstruction and
bronchiectasis affect these gas transport
N IGW is based on washing in and out mechanisms and lead to inefficient gas
inert tracer gases to assess the gas mixing, which can be detected and
mixing efficiency of the lung. quantified using IGW.
N The most important outcome Evolution of IGW
parameter of MBW is the LCI,
calculated as the cumulative expired The IGW technique was introduced in the
volume needed to clear the lungs of 1950s. Most data from the last 15 years have
the tracer gas divided by the lung size been obtained using sulfur hexafluoride as
(FRC). the inert tracer gas. However, because of its
potent greenhouse gas effect, in many
N IGW seems most sensitive in children
countries, sulfur hexafluoride is no longer
with CF for detecting early lung
available. Furthermore, bulky and expensive
disease; its role in other disease
mass spectrometers, the gold standard for
groups is currently less well examined.
sulfur hexafluoride analysis, are not suited
N After early studies demonstrating the to routine clinical use. This has led to a
feasibility and usefulness of washout renaissance of nitrogen washout using
measurements in children, 100% oxygen, which had previously been
commercially available equipment, abandoned, for observing alterations in
and new guidelines for infant breathing patterns. An ultrasonic flow
standardisation will now enable the meter nitrogen MBW setup is now
implementation of MBW in routine commercially available. It is based on the
clinical practice. measurement of oxygen, carbon dioxide and
molar mass with indirect calculation of the

nitrogen concentration. Nitrogen MBW breathing pattern. After reaching
measurement has been demonstrated to be equilibration of the exogenous washed-in
safe and feasible at school and preschool gas, the gas is switched off and the washout
age, whereas in infants, sulfur hexafluoride is started. For nitrogen MBW, the test starts
is currently still standard. directly with the washout by switching into
100% oxygen (fig. 2). The washout is
SBW technique and parameters terminated when the end-tidal gas
SBW is classically performed using a vital concentration reaches values below 1/40 of
capacity (VC) manoeuvre (fig. 1) but can also its starting concentration. The current
standard requires at least two, ideally three,
be done during tidal breathing, which has
valid test runs. New guidelines for IGW
the advantage of being feasible even in
measurement extended for all age groups
children younger than 1012 years. The SBW
have just been published.
expirogram shows the tracer gas
concentration over expired volume, where The main outcome parameter of MBW,
phase III represents the expired gas from the reflecting overall ventilation inhomogeneity,
alveolar zone (fig. 1). The main outcome is the lung clearance index (LCI), calculated
parameter of SBW is the slope of phase III as the cumulative expired volume needed to
(SIII), representing the efficiency of gas clear the lungs of the tracer gas divided by
mixing in the small airways. the functional residual capacity (FRC).
MBW technique and parameters Based on SIII analysis of washout breaths,
more specific indices have been developed
MBW is better established than SBW. As a reflecting the convection-dependent
tidal breathing test, it is easy to perform in inhomogeneity (Scond) and diffusion
children. It requires an adequate convection-dependent inhomogeneity
mouthpiece/facemask seal and a regular (Sacin). Abnormalities in these indices allow
assignment of ventilation inhomogeneity to
proximal, conducting (increase in Scond) or
30
Closing volume phase IV distal, intra-acinar (Sacin) airways.
Phase III slope Clinical application of inert gas washout

Normative data The advantage of LCI as an
20 outcome parameter of MBW is an intrinsic
Nitrogen %
Alveolar phase III correction for variations in lung size, with

FRC as the denominator. This is reflected in
the consistency of LCI normative data
10 ranges across wide age groups. The normal
Bronchial phase II range is surprisingly constant, with LCI
values ,8. The availability of commercial
nitrogen MBW equipment and the effort for
Dead space phase I standardised operating procedures will
0 contribute to a more uniform normative
0.0 0.5 1.0 1.5 2.0 data set for LCI.
Tidal volume L
In a tidal breathing test, it is important to
Figure 1. Classical VC nitrogen SBW in a normal appraise the range of normal variability as a
subject. The four sequential phases of the prerequisite to distinguishing pathological
expirogram are: phase I, representing the absolute values. Within-test repeatability is well
dead space; phase II, the bronchial phase; phase documented for LCI, with reported
III, the alveolar phase; and phase IV, delimiting coefficients of variation between 3% and 8%
the closing volume (in tidal-breath SBW, phase IV in health and disease. Current guidelines
is missing). The slope of phase III is calculated by recommend FRC/LCI variability ideally be
linear regression over phase III (%?L-1). ,10% for the three test runs with acceptable

Flow mL.s-1
0
N2 %
100
O2 %
5
CO2 vol %
0
0 20 40 60 80 100 120 140 160
Time s
Figure 2. A nitrogen MBW test in a healthy adolescent. The raw signals flow (black), oxygen (blue) and
carbon dioxide (green) are plotted against time. The nitrogen concentration (brown) is calculated
indirectly as 100-([O2]+[CO2]+[Ar]).
FRC variability up to 25% if technical airways is still debated. Regarding the clinical
reasons are ruled out. Data on utility of LCI, longitudinal tracking could be
reproducibility over longer time periods are demonstrated throughout childhood. Most
scarce and show variability comparable to importantly for future studies, two
the within-test repeatability. This is randomised controlled trials studying
important to consider for reliable clinical use mucociliary clearance regimens in subjects
of LCI as an outcome parameter and for with mild CF lung disease have shown that
longitudinal tracking. LCI was a sensitive study end-point and
superior to spirometry outcomes.
Clinical utility The majority of paediatric
MBW studies have focused on CF. Few Few promising results exist in children with
paediatric studies exist in other disease CF using both VC and tidal SBW of tracer
groups, such as asthma or gases. Those methods still represent
bronchopulmonary dysplasia (BPD). research tools requiring further
development.
Airway involvement without clinical
symptoms is an early component in children In adult asthmatics, SIII analysis from MBW
with CF due to infectious and inflammatory and SBW has shown promising results with
lung disease. Compared to HRCT, it has been regards to predicting the response to dose
shown that MBW is sensitive to early changes titration of inhaled corticosteroid and
in children with CF, with clear superiority over demonstrated that different
spirometry and other lung function tests. In bronchoprovocative agents exhibit their
all cross-sectional studies, LCI was signifi- effects at different sites in the airways. In
cantly higher in the CF group compared children, only a few studies exist, yielding
to healthy controls, with increasing less clear results. Future findings will help to
differences with age. Whether this better understand the physiological
reflects changes in small or medium-sized processes of different phenotypes in asthma

and might provide new insights into specific N Beydon N, et al. (2007). An official
diagnostic and therapeutic effects. American Thoracic Society/European
Respiratory Society statement: pulmon-
Data in infants with BPD are controversial. ary function testing in preschool chil-
On one hand, a pattern of increased dren. Am J Respir Crit Care Med; 175:
ventilation inhomogeneity and decreased 13041345.
FRC was described in a group of infants at N Crawford AB, et al. (1985). . Convection-
term using nitrogen MBW. On the other and diffusion-dependent ventilation mal-
hand, in two larger groups of infants at later distribution in normal subjects. J Appl
gestational age, no effect of BPD was found Physiol; 59: 838846.
on LCI or FRC using sulfur hexafluoride N Estenne M, et al. (2000). Detection of
MBW. Several points may explain these obliterative bronchiolitis after lung trans-
different findings: differences in washout plantation by indexes of ventilation dis-
equipment and gases, especially the tribution. Am J Respir Crit Care Med; 162:
imprecision of the older nitrogen analysers; 10471051.
the use of sedation; and changes in the N Farah CS, et al. (2012). Ventilation
pathophysiology of BPD over time. The heterogeneity predicts asthma control in
adults following inhaled corticosteroid
utility of MBW in BPD thus remains unclear
dose titration. J Allergy Clin Immunol;
and needs further study as well as
130: 6168.
longitudinal follow-up. N Gustafsson PM, et al. (2008). Multiple-
In adults, parameters of IGW (SIII of SBW breath inert gas washout and spirometry
and MBW) showed a high sensitivity in versus structural lung disease in cystic
detecting the early stages of bronchiolitis fibrosis. Thorax; 63: 129134.
N Kieninger E, et al. (2011). Long-term
obliterans syndrome, a well-known
course of lung clearance index between
complication after haematopoietic stem cell
infancy and school-age in cystic fibrosis
transplantation. Preliminary data in children subjects. J Cyst Fibros; 10: 487490.
confirm these findings. N Latzin P, et al. (2009). Lung volume,
Future directions and open questions breathing pattern and ventilation inho-
mogeneity in preterm and term infants.
The widespread application of IGW has the PLoS ONE; 4: e4635.
potential for early detection of diseases and N Ljungberg HK, et al. (2003). Peripheral
more specific monitoring in children. MBW airway function in childhood asthma,
is on the verge of being implemented in CF assessed by single-breath He and SF6
clinics, opening the field for investigation of washout. Pediatr Pulmonol; 36: 339
the immediate and long-term benefits of its 347.
application. One important question will be N Owens CM, et al. (2011). Lung clearance
index and HRCT are complementary
whether LCI-directed treatment can change
markers of lung abnormalities in young
disease outcome in patients with CF. SBW
children with CF. Thorax; 66: 481488.
in children still represents a research tool N Paiva M (1973). Gas transport in the
and needs further development regarding human lung. J Appl Physiol; 35: 401410.
robustness and standardisation. N Ratjen F (2012). Cystic fibrosis: the role of
the small airways. J Aerosol Med Pulm
Further reading Drug Deliv; 25: 261264.
N Robinson PD, et al. (2013). Guidelines for
N Amin R, et al. (2010). Hypertonic saline inert gas washout measurement using
improves the LCI in paediatric patients multiple and single breath tests. Eur
with CF with normal lung function. Respir J; 41: 507522.
Thorax; 65: 379383. N Singer F, et al. Practicability of nitrogen
N Aurora P, et al. (2004). Multiple breath multiple-breath washout measurements
inert gas washout as a measure of in a pediatric cystic fibrosis outpatient
ventilation distribution in children with setting. Pediatr Pulmonol 2012 [In press
cystic fibrosis. Thorax; 59: 10681073. DOI: 10.1002/ppul.22651].

N Singer F, et al. (2013). A new double- alteration of respiratory bronchioles. Am
tracer gas single-breath washout to Rev Respir Dis; 146: 11671172.
assess early cystic fibrosis lung disease. N Van Muylem A, et al. (1995). Inert gas
Eur Respir J; 41: 339345. single-breath washout after heartlung
N Tiddens HA, et al. (2010). Cystic fibrosis transplantation. Am J Respir Crit Care
lung disease starts in the small airways: Med; 152: 947952.
can we treat it more effectively? Pediatr N Van Muylem, et al. (2000). Overall and
Pulmonol; 45: 107117. peripheral inhomogeneity of ventilation in
N Van Muylem A, et al. (1992). Inert gas patients with stable cystic fibrosis. Pediatr
single-breath washout and structural Pulmonol; 30: 39.

Forced oscillation techniques
Shannon J. Simpson and Graham L. Hall
Theoretical background respiratory system (Rrs), and an imaginary

part, respiratory system reactance (Xrs).
The forced oscillation technique (FOT) was
first introduced by Du Bois in 1956 as a The majority of FOT studies in humans have
method capable of informing physicians been conducted using medium frequency
about the mechanical behaviour of the ranges (450 Hz), with oscillations
respiratory system. In short, time-varying superimposed over spontaneous breathing.
pressures (or flows) are generated from a However, low frequency oscillations have
loudspeaker at one or more frequencies, been applied during apnoea, particularly
which in the modern day environment is during infancy, allowing the assessment of
generally several sinusoidal wave forms airway and tissue contributions to
(pseudorandom noise) or a rectangular impedance via mathematical partitioning. In
wave, as with the impulse oscillation system the medium frequency range, Xrs is
(IOS). This signal is applied at the airway dominated by the tissue elastic properties at
opening and the resulting flow (or pressure) frequencies below the resonant frequency
response of the respiratory system is (fres; where Xrs 5 0) and the inertial
measured in addition to the phase shift properties of the gas in the airways at higher
frequencies. In younger children, Rrs also
between these signals. This pressure to flow
exhibits some frequency dependence in the
ratio is defined as the mechanical input
medium frequency range which decreases in
respiratory system impedance (Zrs). As Zrs
older children and adults. Typical
is a complex function of frequency, it is
impedance spectra across the medium
comprised of a real part, resistance of the
frequency range in young children are shown
in figure 1.
Use of the FOT in young children
Key points
The FOT is ideal for use in young children
N The FOT can be used to measure who are unable to adequately cooperate
respiratory mechanics with oscillatory during traditional lung function tests and
signals superimposed over tidal has been applied in children as young as
breathing in awake children as young 2 years of age with success rates .80% in
as 2 years of age. young children. Commercially available FOT
devices are currently available and
N Alterations in respiratory mechanics
guidelines have been established for the use
have been evaluated in several
of FOT in young children.
commonly encountered paediatric
diseases including asthma, CF and Data collection and repeatability The child
BPD; however, further work is should be seated in the upright position with
required to cement a place for the a neutral head position, a nose clip in place
FOT in the routine clinical and a good seal around the mouthpiece. The
management of such diseases. cheeks and floor of the mouth must be firmly
supported to minimise the upper airway

20 signal and the frequencies of reported
Healthy
CF
outcomes can make a comparison difficult.
Asthma In addition, much of the available reference
15 BPD
data has been collected in Caucasian
populations. The majority of published
10 reference equations use height as the only
Zrs hPa. s-1.L-1
predictor of FOT outcomes, although sex

5 was shown to contribute to Rrs, Xrs and the
area under the Xrs curve (integrated area of
reactance below the resonant frequency
0
(AX)) in a recently published large study.
-5 Generally, Rrs is reported at frequencies of 5

10 Hz, which is believed to approximate
values of airway resistance. However,
-10
10 20 30 40 resistances at higher frequencies are also, at
Frequency Hz least theoretically, valuable and therefore the
resistance and reactance curves should be
Figure 1. Impedance spectra in a healthy child and considered as a function of the whole
in young children with lung disease. The frequency range in clinical applications of the
components of respiratory system impedance, FOT. For example, the frequency dependence
resistance (top) and reactance (bottom) are shown (fdep) defined as the slope of the resistance
across the medium frequency range. An average of frequency curve or the AX, which has been
three impedance measurements were obtained proposed as an index of respiratory system
from four boys aged 4.4 years and 105 cm tall for elastance, may be particularly appropriate.
comparison between disease states. Differences in Recently published normative data for these
Rrs, Xrs, AX, fres and fdep are evident, to varying FOT outcomes will facilitate further
extents, in commonly encountered paediatric information on their clinical utility.
diseases when compared to a typical healthy child.
Clinical utility
shunting of input flows. Measurements
should be obtained over several breathing Alterations in respiratory mechanics have
cycles with no leak, vocalisation, swallowing, been evaluated in respiratory diseases
glottic closure or movement and the average commonly encountered in the paediatric
of three to five acceptable measurements setting using the FOT. However, it is
should be reported. reasonable to speculate that the FOT would
be most clinically useful in paediatric
Within a testing session, the coefficient of diseases with pathophysiology in the distal
variation for Rrs has generally been reported lung. Although the FOT is able to detect
as ,10%, while the coefficient of changes in airway calibre after therapeutic
repeatability (twice the standard deviation of interventions, to date, its role in the
the difference between two measurements management of individual patients remains
taken 15 min apart) ranges between 1.1 and unclear. Examples of impedance
2.6 hPa?s-1?L-1 for Rrs and equates to a measurements in children with commonly
relative change of 1230% with similar encountered respiratory diseases in the
repeatability reported over a 2-week period paediatric clinic are given in figure 1.
and in children with CF and
bronchopulmonary dysplasia (BPD). The Asthma and wheeze The majority of research
repeatability of Xrs is reported as absolute using the FOT has been performed in young
values and ranges from 1.2 to 2.0 hPa?s-1?L-1. children with recurrent wheeze. The ability of
the FOT to sensitively distinguish between
Reporting of outcomes and normative data healthy and wheezy preschool children
The upper and lower limits of normal are before or after the administration of
defined, although differences in oscillatory bronchodilator remains unclear.

Some studies have shown no difference in the FOT has been used less extensively in
baseline lung function and bronchodilator young children born preterm. Further
responsiveness between healthy and wheezy studies to examine the changes to FOT
children, while others have shown outcomes during development following
significant differences, even between preterm birth would be particularly
different wheezing phenotypes. Several beneficial.
studies have defined the response to
bronchodilators in healthy populations with Other/potential clinical utility The FOT has
relative cut-off values (derived from the 5th also been used to examine the temporal
to 95th centiles) in the range of -33 -42% changes in respiratory mechanics, although
for Rrs, 6170% for Xrs and 81% for AX, primarily as a research tool rather than in
regardless of the salbutamol dose; although clinical practice. Such studies have
most studies administered 200 mg of examined temporal changes over the normal
salbutamol. breathing cycle as a method of detecting
expiratory flow limitation, the effect of deep
The FOT has been used to assess bronchial inspiration on respiratory mechanics and
hyperresponsiveness in young children, with the monitoring of upper airway patency
significant increases in Rrs and decreases in during sleep. The technique also has
Xrs reported during both direct and indirect potential for the noninvasive assessment of
bronchial challenge tests. The FOT respiratory mechanics in patients receiving
outcome most useful for monitoring mechanical ventilation for acute respiratory
bronchoconstriction during bronchial failure. While perhaps underutilised in this
provocation is yet to be defined. The area, the FOT is able to detect and quantify
respiratory system admittance, the upper or central airway diseases including
reciprocal of Zrs, is more sensitive to tracheal stenosis, tracheo-oesophageal
bronchoconstriction than the commonly fistula, laryngeal obstruction and vocal cord
used Rrs due to the elimination of the upper dysfunction; although separation of
airway artefact. Previous studies have used inspiratory and expiratory impedances to
various changes in Rrs to define a positive examine the flow dependence during each
response to bronchial provocation and the phase of the respiratory cycle would likely
most appropriate cut-off for a positive yield most information in this group of
response is yet to be validated. The patients.
development of shortened protocols for
Future directions
challenge tests using the FOT, such as for
adenosine 59-monophosphate, may help to The measurement of respiratory system
overcome the shorter attention span of impedance has the potential to provide a
young children. great deal of information on a variety of
Cystic fibrosis CF begins in the peripheral conditions during the early years of life;
airways and lung function tests sensitive to however, further work is required if the FOT
small airway dysfunction are likely to be best is to reach its full clinical potential. In the
at monitoring early CF lung disease. The role short term it is important to explore other
of the FOT in monitoring CF lung disease is FOT outcomes in addition to the
unclear with some studies reporting that the traditionally reported Rrs at a single
FOT fails to adequately identify airway frequency with the knowledge that the
obstruction in young children with CF. In pathophysiological mechanisms of many
contrast, increased Rrs and decreased Xrs respiratory diseases exhibit strong
have been reported in young children with peripheral lung involvement during early life.
CF particularly in the presence of respiratory For example, measures of Xrs or AX may be
symptoms. more sensitive at monitoring the course of
those respiratory disorders. We must also
Bronchopulmonary dysplasia Despite the work towards understanding which FOT
observation that Rrs, Xrs, fres and fdep are outcomes are most relevant for particular
frequently abnormal in children with BPD, pathologies as one outcome for all disease

approach may not be appropriate. In the in asthmatic children and cystic fibrosis
longer term it is important to gain an patients. Eur Respir J; 10: 891895.
understanding of how respiratory mechanics N Nielsen KG, et al. (2004). Serial lung
alter longitudinally during development and function and responsiveness in cystic
what kind of deviation from this path fibrosis during early childhood. Am J
requires intervention. Respir Crit Care Med; 169: 12091216.
N Oostveen E, et al. (2010). Lung function
and bronchodilator response in 4-year-old
Further reading children with different wheezing pheno-
types. Eur Respir J; 35: 865872.
N Bates JHT, et al. (2011). Oscillation N Oostveen E, et al. (2003). The forced
mechanics of the respiratory system. oscillation technique in clinical practice:
Compr Physiol; 1: 12331272. methodology, recommendations and
N Beydon N, et al. (2007). An official future developments. Eur Respir J; 22:
American Thoracic Society/European 10261041.
Respiratory Society statement: pulmonary N Rigau J, et al. (2004). Oscillometric
function testing in preschool children. assessment of airway obstruction in a
Am J Respir Crit Care Med; 175: 13041345. mechanical model of vocal cord dysfunc-
N Calogero C, et al. (2013). Respiratory tion. J Biomech; 37: 3743.
impedance and bronchodilator respon- N Rosenfeld M, et al. (2013). An Official
siveness in healthy children aged 2 to 13 American Thoracic Society Workshop
years. Pediatr Pulmonol; 48: 707715. Report: Optimal lung function tests for
N Gangell CL, et al. (2007). Respiratory monitoring cystic fibrosis, bronchopul-
impedance in children with cystic fibrosis monary dysplasia and recurrent wheezing
using forced oscillations in clinic. Eur in children ,6 years of age. Ann Am
Respir J; 30: 892897. Thorac Soc; 10: S1S11.
N Hall GL, et al. (2009). Application of a N Simpson SJ, et al. (2012). Clinical inves-
shortened inhaled adenosine-5-mono- tigation of respiratory system admittance
phosphate challenge in young children in preschool children. Pediatr Pulmonol;
using the forced oscillation technique. 47: 5358.
Chest; 136: 184189. N Sly PD, et al. (1996). Measurement of
N Hellinckx J, et al. (1998). No paradoxical low-frequency respiratory impedance in
bronchodilator response with forced infants. Am J Respir Crit Care Med; 154:
oscillation technique in children with 161166.
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N Hoijer U, et al. (1991). The ability of bronchodilator responsiveness in pre-
noninvasive methods to detect and school children using forced oscillations.
quantify laryngeal obstruction. Eur Respir Thorax; 62: 814819.
J; 4: 109114. N Udomittipong K, et al. (2008). Forced
N Klug B, et al. (1998). Specific airway oscillations in the clinical setting in young
resistance, interrupter resistance, and children with neonatal lung disease. Eur
respiratory impedance in healthy children Respir J; 31: 12921299.
aged 2-7 years. Pediatr Pulmonol; 25: 322 N Vrijlandt EJ, et al. (2007). Respiratory
331. health in prematurely born preschool
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stance by the forced oscillation technique monary dysplasia. J Pediatr; 150: 256261.

Polysomnography
Evaluation of children with suspected sleep

disorders is primarily based on a thorough Key points
history. In appropriate cases the diagnostic
process includes performance of N Clinicians should enquire whether the
polysomnography (PSG), most commonly child or adolescent snores and, if so,
for characterisation of breathing during obtain a PSG.
sleep. Because PSG is a relatively expensive N PSG is the gold standard for the
procedure requiring significant time and diagnosis of sleep-disordered
healthcare resources, understanding the breathing in children.
strengths, limitations, and clinical utility of
PSG is necessary to ensure optimal
N If PSG is not available, then clinicians
may order alternative diagnostic tests,
utilisation.
such as nocturnal video recording,
Respiratory indications for PSG in children nocturnal oximetry, daytime nap PSG
or ambulatory PSG.
Diagnosis for sleep-related breathing disorders
PSG is indicated when: N Paediatric PSG should be performed
in a sleep laboratory equipped for
N the clinical assessment suggests a children and staffed by qualified
diagnosis of OSAS in children; personnel following the American
N the clinical assessment suggests a Thoracic Society standards for testing.
diagnosis of congenital central alveolar N Age-adjusted rules for the scoring and
hypoventilation syndrome or sleep- interpretation of PSGs should be used
related hypoventilation due to for children.
neuromuscular disorders or chest wall
deformities (it is indicated in selected
cases of primary sleep apnoea in infancy);
PSG is indicated following
N there is clinical evidence of a sleep-
adenotonsillectomy to assess for residual
related breathing disorder in infants who
sleep-related breathing disorder in children
have experienced an apparent life-
with pre-operative evidence for moderate-
threatening event.
to-severe OSAS, obesity, craniofacial
Pre-operative PSG is indicated in children anomalies that obstruct the upper airway
being considered for adenotonsillectomy to and neurological disorders (e.g. Down
treat OSAS. syndrome, PraderWilli syndrome and
myelomeningocele). It is also indicated
Assess response to treatment Children with after treatment of children for OSAS with
mild OSAS pre-operatively should undergo rapid maxillary expansion to assess for the
clinical evaluation following level of residual disease and to determine
adenotonsillectomy to assess for residual whether additional treatment is necessary.
symptoms. If there are residual symptoms Children with OSAS treated with an oral
of OSAS then PSG should be performed. appliance should have clinical follow-up

and PSG to assess response to Polysomnography
treatment.
PSG in children should be performed in the
PSG is indicated for positive airway pressure proper setting. In young children, this will
titration in children with OSAS and for mean that the study has to be attended
noninvasive positive pressure ventilation during the whole night by a trained
titration in children with other sleep-related technician to ensure the quality of the study.
breathing disorders. It is equally important to note that none of
the current polysomnographic systems can
Follow-up PSG in children on chronic generate accurate automated reports on
positive airway pressure support is indicated paediatric polysomnographic studies. An
to determine whether pressure requirements automated report can both underestimate
have changed as a result of the childs and overestimate the clinical condition. For
growth and development, if symptoms recur this reason, paediatric polysomnographic
while on positive airway pressure, or if studies should be reviewed manually using
additional or alternative treatment is the raw data by trained physicians with
required. knowledge on paediatric polysomnographic
studies. The accuracy and agreement of
Children treated with mechanical ventilation manual scoring is dependent on the training
may benefit from periodic evaluation with background and the experience of the
PSG to adjust ventilator settings. PSG for physicians. In the best hands, an interscorer
the management of oxygen therapy is not agreement of at least 7080% is expected.
routinely required in children treated with
supplemental oxygen. Children treated with In general, the result from a single nights
tracheostomy for sleep-related breathing study is sufficient for the diagnostic purpose
disorders benefit from PSG as part of the of children with suspected OSAS. A first
evaluation prior to decannulation. These night effect has been described in adults,
children should be followed clinically after whereby sleep differs during the first night in
decannulation to assess for recurrence of a sleep laboratory compared to subsequent
nights. Two studies assessing first night
symptoms of sleep-related breathing
effect in children have shown that the
disorders.
parameters are no different between the first
Respiratory diseases PSG is indicated in the and second nights.
following respiratory disorders, but only if
Technique Standard PSG consists of
there is clinical suspicion of an
electroencephalogram, electromyogram
accompanying sleep-related breathing
(submental and tibial), electrooculogram
disorder:
(right/left), oximetry, end-tidal carbon
dioxide tension (PetCO2), oronasal airflow
N chronic asthma,
(thermistor), nasal pressure sensor,
N CF,
respiratory inductance plethysmography,
N pulmonary hypertension,
electrocardiography and a body position
N bronchopulmonary dysplasia,
sensor. Children are also monitored and
N chest wall abnormalities, such as recorded on an audio/videotape using an
kyphoscoliosis. infrared video camera. Each child is
continuously observed by a technician
Clinical evaluation alone does not have
trained in paediatric PSG who also records
sufficient sensitivity or specificity to
sleep behaviour and respiratory events
establish a diagnosis of OSAS. Clinical
(table 1 and fig. 1).
parameters such as history, physical
examination, audio or visual recordings, and Electroencephalogram The international 10
standardised questionnaires do not 20 system of electrode placement is used to
consistently identify the presence or absence determine surface electrode placement. The
of OSAS when compared with PSG. American Academy of Sleep Medicine (AASM)

EEG EOG

Nasal PETCO2
Airflow
Chin EMG (2)
Microphone

ECG
SpO2
Video camera to
Respiratory record behaviour
effort
Technicians note
Leg EMG (2)

Figure 1. Components of PSG in children.
Table 1. Components of PSG in children

Electroencephalogram activity: current AASM recommendations are F4-M1, C4-M1 and O2-M1
with backup (F3-M2, C3-M2 and O1-M2), and are a change from the previous recommendation of
C3 or C4 referenced to A1 or A2
Eye movements (electrooculogram) from electrodes placed near the outer canthus of each eye
Submental electromyographic activity from electrodes placed over the mentalis, submentalis
muscle and/or masseter regions
Rhythm ECG with one lead II electrode or more chest leads at the discretion of the provider
Respiratory effort by chest-wall and abdominal movement via strain gauges, piezoelectric belts,
inductive plethysmography, impedance or inductance pneumography and endo-oesophageal
pressure
(Note: the AASM does not recommend strain gauges or piezoelectric belts)
Nasaloral airflow via a thermistor, nasal pressure transducer or pneumotachograph, or
inductance plethysmography
SpO2 including waveform with an averaging time of f3 s
PetCO2 or PtcCO2
Body position via sensor and direct observation
Limb movements (right and left legs) via electromyogram
Snoring recording or vibration (frequency and/or volume)
Audio/video recording by infrared or low-light equipment

recommends F4-M1, C4-M1 and O2-M1. Nasal-oral airflow This is best measured
Since children frequently displace leads and/or monitored by nasal pressure
during sleep, contralateral leads are transduction and continuous monitoring of
typically applied as well (F3-M2, C3-M2 the capnography waveform. Thermistor
and O1-M2). Children have high-amplitude application has been the standard technique
brain waves; thus, electroencephalogram in adult laboratories but might not be as
recordings may need a sensitivity of 10 sensitive a measure of airflow as pressure is
15 mV?mm-1, as compared to 5 mV?mm-1 in in children.
adults.
Oxygen saturation The sensor is
Electrooculogram Eye movements are incorporated into a soft cuff that fits around
detected by placing surface electrodes near a finger or toe or clips to an ear lobe.
the outer canthus of each eye. The Children tend to move frequently during
electrooculogram electrodes should be sleep, so the monitoring of the pulse
offset from horizontal, one slightly above waveform in addition to the saturation value
and one slightly below the horizontal plane is helpful in distinguishing motion artifact
to detect both horizontal and vertical eye from true desaturation. This output can also
movements. As infants and young children be used for more sophisticated analyses,
have smaller heads than adults, such as the measurement of pulse transit
electrooculographic leads may need to be time.
placed 0.5 cm from the outer canthi.
Carbon dioxide Measurements of carbon
Electromyogram Two surface electrodes are dioxide have been used in two contexts
placed either on the mentalis or submentalis during PSG:
to detect muscle activity. Again, as infants
and young children have smaller heads than N PetCO2 as an indicator of airflow
adults, chin electromyogram electrodes may obstruction and, hence, apnoea;
need to be placed 1 cm apart rather than N measurement of end-tidal or
2 cm apart. transcutaneous carbon dioxide (PtcCO2)
as a quantitative measure of
Rhythm electrocardiogram A simple single
hypoventilation during sleep.
lead ECG should be used to monitor cardiac
rate and rhythm to enable cardiac Monitoring carbon dioxide has also been
arrhythmias and changes resulting from considered of potential value in diagnosing
respiratory disturbances to be assessed. sleep hypoventilation syndrome. In addition,
Respiratory effort Chest and abdominal wall the measurement of carbon dioxide is useful
motion can be measured in a number of in children with chronic lung disease or
ways. Respiratory inductance those receiving ventilatory support. It is
plethysmography is the preferred method. especially important to measure carbon
Other sensors that have been used include dioxide when supplemental oxygen is
piezoelectric belts, which are provided with initiated in the sleep laboratory, as some
many commercial PSG systems, intercostal patients may be dependent on their hypoxic
electromyogram and oesophageal pressure drive to breathe. Adding oxygen without
monitoring. In one nonrandomised study of monitoring carbon dioxide may lead to
normal children, paradoxical breathing was worsening hypoventilation, and clinical
seen much more commonly with deterioration of the patient.
piezoelectric belts than with respiratory
inductance plethysmography. PetCO2 can be measured directly from a
tracheostomy or endotracheal tube, or as a
Oesophageal pressure monitoring is rarely side-stream measure from a nasal cannula.
used as it is invasive, and the nasal pressure PetCO2 values maybe inaccurate in patients
flow signal is often used as a surrogate when with obstructive lung disease with long time
the upper airway resistance syndrome is constants, such as in patients with
suspected. advanced CF.

An alternative measurement option for electromyogram from a leg muscle
evaluating hypoventilation is PtcCO2.The (conventionally tibialis anterior) is a useful
transcutaneous electrode warms the skin, measure of peripheral skeletal muscle tone
thereby arteriolising the capillary blood flow. and allows assessments of gross body
The sensor must be moved during the night movements and arousals during sleep.
to prevent skin burns. Transcutaneous
measurements may be preferable to end- Interpretation of the PSG in children
tidal measurements in children with Standard duration of the study A study of the
advanced obstructive lung disease, infants whole night is the recommended
with rapid respiratory rates, children who investigation to assess sleep-disordered
breathe through their mouth and children breathing. A minimum of 6 h sleep is
receiving CPAP, in whom the CPAP airflow desirable. The timing of the studies is also
may interfere with end-tidal measurements. important. The study timing should be set to
Although most studies comparing PetCO2 mimic the childs bedtime as closely as
and PtcCO2 to arterial samples have been possible. The sleep study should then be
performed in the intensive care unit or conducted during the late evening and early
during anaesthesia, these studies show a morning.
good correlation. Sleep stage analysis It is helpful to quickly
Body position is frequently measured during review the patients sleep architecture by
PSG, although the measurement of body viewing the hypnogram. A hypnogram is a
position is less important in young children graphical summary of the different sleep
than in adults, as OSAS is less positional. stages achieved (fig. 2). It is important to
review the sleep architecture in terms of
Oesophageal pH is occasionally measured what is to be expected for the patients age.
to determine whether gastro-oesophageal
reflux is contributing to night wakenings, Components of sleep architecture should be
apnoea or desaturation. pH probe insertion assessed including percentage of total sleep
is more invasive than the rest of the leads on time (TST) spent in stage I/II, stage III, rapid
a polysomnogram and takes specialised eye movement (REM) stage and
skill; placement must be confirmed by wakefulness. These percentages should be
radiography. The percentage of total sleep compared with age-appropriate normals.
time with pH ,4 and the number and Stage I sleep occupies 47.7% of TST, and
length of pH drops ,4 can be quantified, stage II occupies 3649% of TST, with the
and reviewed for an association with combination of stage I and II in each study
respiratory disturbances. ranging from 41% to 53% of the TST. Slow
wave sleep occupies 1432% of the TST,
Video and sound recording Good quality whereas stage REM occupies 17.421.1% of
video recordings are an important
the TST. Timing of sleep stages can be
component of a clinical sleep study, and can
be made using infra-red or low-light cameras
and appropriate microphones. Video and Wake
sound recordings can provide useful
REM
information on sleep behaviour, snoring,
Sleep stages
sleep disturbance and breathing patterns. 1

2
Limb movements Gross body movements
3
and limb movements may be assessed from
direct observation, a video recording or from 4
a peripheral electromyogram recording.
1 2 3 4 5 6 7 8
These may be of use in detecting the extent
of sleep disturbance or arousal frequency, Sleep hours
and are necessary for assessment of sleep
state in infants. Monitoring the Figure 2. Hypnogram.

noted by review of the hypnogram. Children Leg movements The scoring technician will
usually have a short period of stage I/II after score leg movements that meet criteria for
sleep onset, and then enter stage III (slow periodic leg movement. Criteria for periodic
wave sleep). Stage III sleep will predominate leg movements include leg movements
early in the night, with regular cycling noted in either or both legs that are at least
between the stages I/II, stages III and REM. one quarter of the amplitude noted during
REM sleep will usually cycle every 60 the biocalibration lasting 0.55 s. Leg
120 min, with a wide range of timing movements must be separated by at least
between REM periods. Sleep latency, the 5 s, but not .90 s, and must occur in
time after lights out until sleep is achieved, clusters of at least four to be considered
should also be noted. Sleep latency is periodic leg movements. These leg
generally ,25 min. It may be prolonged if movements should not be related to other
the child has recently had a nap, and it may events, such as respiratory events or
be shortened in certain sleep disorders. arousals. The periodic leg movement index
is calculated by dividing the total number of
Sleep efficiency is a measurement of the periodic leg movements by the number of
amount of the total time in bed that the hours of sleep. A periodic leg movement
patient spends asleep, and should also be index of o5 is considered abnormal.
noted. Sleep efficiency in children is usually
.89%. Gas exchange should be reviewed carefully
for the entire tracing. The pulse oximetry
REM latency, the time from onset of sleep to tracing should be reviewed for desaturation,
the first epoch of REM sleep, is also noted. with careful attention to whether the
REM latency can be prolonged if the first desaturation is associated with a respiratory
REM period is difficult to detect by the event, arousal or leg movement. In general,
scoring technician. Length of time spent in oxygen saturation should be .92% in normal
REM is short earlier in the night, with studies. Median baseline SpO2 at preterm,
lengthening of REM episodes as the night term and infancy was approximately 98%,
progresses. 98% and 96% respectively.
Arousal summary Arousals are scored by In children outside infancy a normal

the scoring technician based on the oximetry recording should have:
appearance of the electroencephalogram
tracing. An arousal is scored when
N a median SpO2 level o 95%,
there is an abrupt change in the
N no more than four desaturations of o4%
per hour,
electroencephalogram lasting 3 s, following
at least 10 s of continuous sleep. Arousals
N no abnormal clusters of desaturation.
can be attributed to preceding events, Carbon dioxide tracing should be reviewed as
including respiratory events, leg well. Baseline carbon dioxide levels before
movements, snore events or technician sleep onset should be noted. Children may
presence in the room, or may occur without have a pattern of obstructive hypoventilation
an obvious trigger. Arousals are reported with OSAS, resulting in increases of carbon
using the arousal index, which is the dioxide without significant oxygen
number of arousals divided by the hours of desaturation. Abnormal levels of carbon
sleep. Studies of normal children have dioxide vary, with some studies reporting
found mean arousal indices of 8.89.5. .25% of TST being spent with carbon dioxide
.50 Torr as abnormal, and some reporting
Heart rate/rhythm The ECG should be
that in normal children 2.811.3% of TST was
reviewed for evidence of brady or tachy
spent with carbon dioxide o50 Torr.
rhythms, as well as abnormal ECG rhythms.
Respiratory events may be associated with a Respiratory events Respiratory scoring in
decrease in heart rate, with subsequent children is different from that in adults.
increase in heart rate after the event has Paediatric scoring must be used for children
resolved or in association with arousals. f12 years of age. Small studies indicate

Table 2. Description of respiratory events
Obstructive apnoea Drop in thermal sensor amplitude by o90% baseline
o2 missed breaths
o90% duration meets amplitude reduction criteria
Continued or increased inspiratory effort during reduced airflow
Central apnoea Drop in thermal sensor amplitude by o90% baseline
Either duration o20 s OR o2 missed breaths and associated with
arousal, awakening or o3% desaturation
Absent inspiratory effort
Mixed apnoea Drop in thermal sensor amplitude by o90% baseline
o2 missed breaths
o90% duration meets amplitude reduction criteria
Absent inspiratory effort initially, then resumption of effort during
latter part of event
Hypopnoea Drop in nasal air pressure transducer amplitude by o50%
o2 missed breaths
o90% of duration meets amplitude criteria
Associated with arousal, awakening or o3% desaturation
RERA o2 missed breaths
Flattening of nasal air pressure transducer waveform
Increased work of breathing
Sequence leads to arousal
Drop in amplitude ,50%
Periodic breathing .3 episodes of central apnoea lasting .3 s separated by f20 s of
normal breathing
Apnoea index Number of obstructive and/or central apnoeic events per hour of
sleep
Obstructive apnoea index Number of obstructive apnoeic events per hour of sleep
Hypopnoea index Number of hypopnoeas per hour of sleep
AHI Sum of the apnoea index and hypopnoea index
Obstructive AHI Sum of obstructive apnoeic events and hypopnoeic events per hour
of sleep
that adolescents have breathing patterns children. Table 3 shows normative data for
similar to those of younger children and the the different polysomnographic variables.
use of paediatric scoring criteria would be These are statistical norms rather than
appropriate for adolescents. Adult criteria clinical criteria upon which to base
are used for patients aged o18 years. treatment decisions. It is generally accepted
Respiratory related arousals (RERA) are not that OSA is mild if the obstructive AHI is
scored in all laboratories. Definitions of f5 events?h-1, and moderate if it is
respiratory events are summarised in .5 events?h-1 but ,10 events?h-1, and
severe if it is .10 events?h-1. It is generally
table 2. Examples of snoring, central
accepted that if the snoring child has
apnoea, obstructive apnoea and hypopnea
moderate or severe OSA they should be
are shown in figures 36.
treated. Treatment indications for children
Normal values of PSG and treatment with mild OSA are less clear. One review
indications suggested that treatment should be
considered if the child is at increased risk of
There are very few studies assessing the having OSA and fulfils at least one of the
polysomnographic predictors of morbidity in following criteria.

LEOG
REOG
C3M2
C4M1
O1M2
O2M1
F3M2
F4M1
Chin EMG
Thermist
THO
ABD
Micro
ECGI
SpO 2
97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97
Pleth
RLEGEMG
LLEGEMG
Body R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R
Stage N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3 N3
78 78
5 10 15 20 25 30
Figure 3. Snoring.
LEOG
REOG
C3M2
C4M1
O1M2
O2M1
F3M2
F4M1
Chin EMG
Thermist
THO
ABD
Micro
ECGI
SpO2
97 97 98 98 98 98 99 99 99 99 98 98 98 98 98 97 95 95 96 98
Pleth
RLEGEMG
LLEGEMG
Body S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S
Stage N3N3N3 N3N3N3N3 N3N3N3 N3N3 N3

157 N3N3
158 N3N3 N3N3 N3N3 N3N3N3N3 N3N3 N3N3N3 N3 N3N3N3 N3N3N3 N3N3 N3N3N3 N3 N3N3N3N3N3N3 N3N3N3N3N3N3 N3N3N3N3 N3
158 159
10 20 30 40 50 60
Figure 4. Central apnoea.
LEOG
REOG
C3M2
C4M1
O1M2
O2M1
F3M2
F4M1
Chin EMG
Thermist
THO
ABD
Micro
SpO 2
96 96 96 97 97 96 96 96 96 96 97 96 96 96 96 96 95 94 93 93
Pleth
RLEGEMG
LLEGEMG
657 657 658 658
10 20 30 40 50 60
Figure 5. Obstructive apnoea.

LEOG
REOG
C3M2
C4M1
O1M2
O2M1
F3M2
F4M1
Chin EMG
Flow
Thermist
THO
ABD
Micro
SpO 2 98 97 96 96 96 98 99 98 97 96 96 97 96 94 94 94 95 97 99 99
Pleth
RLEGEMG
LLEGEMG
Stage R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R
80 81 81 82
10 20 30 40 50 60
Figure 6. Hypopnoea.
N AHI 15 events?h-1 and systolic or N AHI 15 events?h-1 and morbidity from

diastolic blood pressure consistently the central nervous system (excessive
.95th percentile for sex, age and height, daytime sleepiness, hyperactivity,
or documented pulmonary hypertension. inattention and academic difficulties).
Table 3. PSG values in normal children

Montgomery-Downs Verhulst Uliel Traeger
(2006) (2007) (2004) (2005)
Subjects n 542 60 70 66
# "
Age range years 35 o6 616 115 2.59.4
Sleep latency min 24.125.6 2325.3 45.629.4
Sleep efficiency % 907 89.37.5 80.58.5 90.86.5 89 8
Arousals events?h-1 9.34.8 6.11.8 8.83.8
RERA events?h-1 0.922.0 1.21.0
Hypopnoea index+ events?h-1 0.030.07 0.100.18 0.30.5
Apnoea index events?h-1 0.860.75 0.50.52
Obstructive apnoea index 0.030.10 0.050.11 0.060.16 0.020.1 0.10.03
events?h-1
AHI events?h-1 0.90.78 0.680.75 1.981.39 0.40.6
Obstructive AHI events?h-1 0.080.16 0.140.22 0.080.17
% TST SpO2 .95% 99.60.95
SpO2 nadir % 92.74.5 92.63.6 91.82.7 94.62.2 923
SpO2 lower limit % 84 85 86 90 86
ODI events?h-1 0.290.35 0.470.96 0.80.9
PetCO2 % TST .50 mmHg 4.015.3 2.07.1 0.290.24
Data are presented as meanSD, unless otherwise stated. ODI: oxygen desaturation index. #: n5173;
"
: n5369; +: with desaturation (34%) and/or arousal.

N AHI 15 events?h-1 and inadequate N Aurora RN, et al. (2011). Practice parameters
somatic growth. for the respiratory indications for polysom-
N AHI 15 events?h-1 and nocturnal nography in children. Sleep; 34: 379388.
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N AHI 15 events?h-1 and presence of risk Scoring of Sleep and Associated Events:
factor(s) for persistence of OSA in Rules, Terminology and Technical
adolescence. Specifications. Westchester, AASM, 2007.
N AHI 15 events?h-1 and diagnosis of N Kaditis A, et al. (2012). Algorithm for the
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(e.g. Duchenne muscular dystrophy or
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mechanisms (e.g. Down syndrome). N Katz ES, et al. (2003). Pulse transit time
N Nocturnal pulse oximetry with three or as a measure of arousal and respiratory
more SpO2 decreases ,90% and three or effort in children with sleep-disordered
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In conclusion, paediatric PSG is the gold N Montgomery-Downs HE, et al. (2006).
standard for evaluation of children with Polysomnographic characteristics in nor-
chronic snoring both for diagnosing and mal preschool and early school-aged
assessing severity of OSA. Response to children. Pediatrics; 117: 741753.
various treatment modalities are also N Royal College of Paediatric and Child
objectively evaluated by PSG. It is also used Health Working Party on Sleep Physiology
to evaluate cardiorespiratory function in and Respiratory Control Disorders in
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Children with Disorders of Sleep
hypoventilation, chronic lung disease or
Physiology Report. London, Royal College
neuromuscular disease when indicated.
of Paediatric and Child Health, 2009.
Paediatric PSG should be performed in a
N Schechter MS, et al. (2002). Technical
child-friendly environment and should be report: Diagnosis and management of
evaluated according to the paediatric rules. childhood obstructive sleep apnea syn-
drome. Pediatrics; 109: e69.
Further reading N Scholle S, et al. (2001). Arousals and
obstructive sleep apnea syndrome in
N Clinical practice guideline (2002). diag- children. Clin Neurophysiol; 112: 984991.
nosis and management of childhood N Tapia IE, et al. (2008). Polysomnographic
obstructive sleep apnea syndrome 2002. values in children undergoing puberty:
Pediatrics; 109: 704712. pediatric vs. adult respiratory rules in
N American Academy of Sleep Medicine. adolescents. Sleep; 31: 17371744.
International Classification of Sleep N Traeger N, et al. (2005). Poly-
Disorders. 2nd Edn. Westchester, AASM, somnographic values in children 29
2005. years old: additional data and review of
N Indications for Polysomnography Task the literature. Pediatr Pulmonol; 40: 2230.
Force (1997). Practice parameters for N Uliel S, et al. (2004). Normal polysomno-
the indications for polysomnography graphic respiratory values in children and
and related procedures 1997. Sleep; 20: adolescents. Chest; 125: 872878.
406422. N Verhulst SL, et al. (2007). Reference values
N Standards and indications for cardiopul- for sleep-related respiratory variables in
monary studies in children (1996). Am J asymptomatic European children and ado-
Respir Crit Care Med 1996; 153: 866878. lescents. Pediatr Pulmonol; 42: 159167.

Flexible bronchoscopy
Jacques de Blic
Bronchoscopy has become an invaluable

tool for the diagnosis and treatment of many Key points
lung disorders in infants and children
(Midulla et al., 2003; Schellhase, 2002; N Cleaning and disinfection of flexible
Wood, 1984). Since its introduction in the bronchoscopes are a major concern to
mid-1970s, an increasing number of flexible prevent cross infection and
bronchoscopies are performed each year. contamination.
The diagnostic value of flexible N Stridor is a common indication for
bronchoscopy is now widely accepted; it can flexible bronchoscopy in infants and
be used to visualise the lower airways laryngomalacia is the most frequent
directly and to take samples, particularly of observed abnormality. Direct
bronchoalveolar lavage (BAL). Its visualisation of the airways is
indications are not limited to exploring necessary in all children with
stridor, persistent atelectasis or recurrent persistent stridor because lower
pneumonia in ambulatory patients; more airway lesions are frequently
severely ill children, who are in an unstable associated with upper airway lesions.
respiratory status, may require
bronchoscopy, sometimes under N In older children all pathological
mechanical ventilation, in neonatal or respiratory situations, especially
paediatric intensive care units (ICUs). persistent or recurrent clinical
symptoms and/or radiological
Equipment abnormalities, should lead to
endoscopic airway exploration.
Bronchoscopes Two technologies are used to
transmit light and images: glass fibres and N Measures to prevent complications
charge-coupled devices (CCD). include: detection of high-risk
children; nebulisation of b2-agonists if
N The classic fibreoptic bronchoscope uses there is pre-existing bronchial
fine filaments of flexible glass fibres. With hyperresponsiveness; careful local
this technology, the larger the anaesthesia to prevent laryngospasm;
bronchoscope, the better the image large oxygen supplementation; use of
obtained because of the higher number of the lowest flexible bronchoscope
fibres. diameter; appropriate anaesthesia;
N In a bronchovideoscope, the CCD is and training.
incorporated into the distal extremity of
the instrument; it doesnt contain an
N Post-BAL fever may occur in up to
50% of cases.
eyepiece, needs a video screen and allows
for a very high image quality.
N The hybrid bronchofibrevideoscope
combines these two technologies. A CCD Table 1 summarises the main characteristics of
is located in the body of the instrument, the different instruments available for children.
which improves the quality of images. External diameter determines the presence

(and size) or absence of a working channel. N an operating table;
The 2.2-mm flexible bronchoscope does not N a workstation, including a bright light
have a working channel and is limited to source (some equipment uses a battery-
visualisation of airways in ventilated operated system), a video system centre
neonates. The 3.43.6-mm flexible (with adaptor for older broncho-
bronchoscopes have a 1.2-mm working fibrescopes), a flat-screen LCD monitor, a
channel, which allows suction and BAL to keyboard and recording equipment;
be performed, and is wide enough to allow N a trolley containing room temperature
the use of instruments such as a cytology saline, a syringe, cytology brushes and
brush or biopsy forceps (but the procedure biopsy forceps, trap for BAL, etc.;
is more difficult and the specimen very N monitoring equipment (ECG, pulse
small). The 4-mm and 4.9-mm flexible oximeter and blood pressure monitor);
bronchoscopes have a 2-mm working N an oxygen supply system;
channel, which allows excellent quality N high-power suction sources;
biopsies and transbronchial biopsy. N equipment and drugs for intubation and
resuscitation.
The choice of the flexible bronchoscope is
made according to the age of the patient Cleaning, disinfection and storage After each
and the diameter of the cricoid, but also use, flexible bronchoscopes must be cleaned
according to the procedures that are to be and disinfected to prevent cross infection
performed. In general, the smallest and contamination. Disinfection may be
instrument available should be used to performed by immersion in an appropriate
minimise obstruction of the airways. It is disinfectant (2% alkaline glutaraldehyde) or
assumed that there must be at least a 2-mm in a washing machine. Checks for
difference between the external diameter of microorganism colonisation should be
the flexible bronchoscope and the diameter performed once a week with a culture of
of the narrowest point of larynx, the cricoid saline solution used for rinsing the flexible
cartilage. In paediatric and neonatal ICUs, it bronchoscopes. Flexible bronchoscopes
may be necessary to pass the flexible should always be stored in a dedicated
bronchoscope through the endotracheal storage cabinet, hanging in a straight vertical
tube, and the recommended difference in position to prevent development of
diameter is at least 1 mm. unwanted curves. Finally, flexible
bronchoscopes should be regularly tested for
Endoscopy room It needs to be fully leaks before cleaning to prevent permeation
equipped with: of any fluids into the optical system.
Table 1. Available bronchoscopes

External Imaging Age Working BAL Biopsy TBB Brushing
diameter mm technique years channel mm
2.2 BF Neonate No No No No No
2.72.8 BF/HFV 02 1.2 Yes Yes No Yes
(not easy)
3.43.6 BF/BV 25 1.2 Yes Yes No Yes
(not easy)
4 HFV 25 2 Yes Yes Yes Yes
4.95.1 BF/BV .5 2.22 Yes Yes Yes Yes
5.96 BF/BV .15 2.22.8 Yes Yes Yes Yes
TBB: transbronchial biopsy; BF: bronchofibrescope; HFV: hybrid bronchofibrevideoscope;

BV: bronchovideoscope.

Procedure In children, the main indications are the
search of airway obstruction. Stridor is one
N The procedure may be performed under of the most common indications, especially
conscious sedation or general in neonates and infants. Inspiratory stridor
anaesthesia. is indicative of narrowing of the larynx, while
N Endoscopy is performed either at the biphasic, inspiratory and expiratory stridor
head or at the bedside of the child. suggests tracheal obstruction. In older
N The flexible bronchoscope is usually children all pathological respiratory
passed through the nose. situations, especially persistent or recurrent
clinical symptoms and/or radiological
Once the bronchoscope is inserted into the abnormalities, should lead to endoscopic
upper airway, the vocal cords are inspected. airway exploration.
The instrument is advanced to the trachea
and further down into the bronchial system Information
and each area is inspected as the
Upper airways At the upper airways level,
bronchoscope passes (fig. 1).
laryngomalacia is the most frequent
Indications observed abnormality. Endoscopy identifies
collapse of the epiglottis and/or aryepiglottic
Airway endoscopy provides two different folds and/or arytenoids into the glottis.
types of information, one by direct Direct visualisation of the airways is
anatomical observation and the other necessary in all children with persistent
through the samples taken during the stridor; lower airway lesions are frequently
procedure (mainly BAL, brushing and associated with upper airway lesions. The
biopsies). Indications for bronchoscopy in examination must be carried out carefully,
children are listed in table 2. and the airways should be monitored during
Right lung Left lung
Apical
Apical
Posterior
Upper Posterior
lobe Upper
Anterior lobe
Anterior
Lateral Lingula
Middle Apical
lobe Medial lower
Anterior
Anterior basal
Lower basal Lower
lobe Posterior Lateral
Lateral lobe
basal basal
basal
Figure 1. Segmentation of the tracheobronchial tree.

Table 2. Main indications for endoscopy in children
Airway obstruction
Suspected foreign body aspiration
Stridor (inspiratory and/or expiratory), noisy breathing
Severe recurrent/persistent wheezy bronchitis
Severe unexplained chronic cough that is unresponsive to therapy
Persistent/chronic productive cough
Recurrent bronchopneumonia
Recurrent/persistent consolidation
Localised hyperinflation
Bronchiectasis
Mediastinal adenopathies
Chronic interstitial pneumonitis
Infectious diseases
Immunocompetent children
TB
Severe acute pneumonia, severe acute interstitial pneumonia (that does not respond to
standard broad-spectrum antibiotic therapy within 48 h)
Immunocompromised children
Acute onset of diffuse interstitial pulmonary infiltrates
Acute focal infiltrates (that do not respond to standard broad-spectrum antibiotic therapy
within 48 h)
Chronic interstitial pneumonitis
Chronic recurrent bronchopneumonia in HIV-infected children (if organisms are not found
by less invasive techniques)
In association with TBB in lung transplant recipients, as part of a routine surveillance
programme and/or for the diagnosis of suspected lung disease
Haemoptysis
TBB: transbronchial biopsy.
the various stages of sedation. Local N Haemangioma presenting as an

anaesthesia may worsen laryngomalacia asymmetrical subglottic mass.
(Nielson et al. 2000). Other abnormalities N Laryngeal cysts, laryngeal papillomatosis,
include the following. laryngeal web or laryngeal cleft.
N Vocal cord dysfunction characterised by
N Subglottic stenosis: this may be paradoxidal adduction of the vocal cord
congenital with membranous (or during inspiration, or both inspiration
diaphragmatic) stenosis and symmetrical and expiration: diagnosis may be difficult
narrowing, or acquired after prolonged even during endoscopy of the upper
endotracheal intubation and appear airways without sedation.
irregular with granulation tissue,
ulcerations and cysts. Lower airways At the lower airway level,
N Vocal cord paralysis (unilateral or endoscopy provides information on airway
bilateral): this must be evaluated when distribution, mechanical or dynamic
the child is awake or under light sedation. obstruction, inflammation and secretions.

Proximal airway pattern is usually stable in shape of comma or drop, with the narrowest
humans. Most of the abnormal bronchi are part directed to the right. Pulmonary sling
variant and supply normal lung obstructs the distal trachea and the origin of
parenchyma. Tracheal bronchus, which is the right main stem bronchus. Pulmonary
observed in 1% of flexible bronchoscopes, is sling is strongly associated with congenital
the most common. In this case, the tracheal stenosis. Congenital heart disease
bronchus originates from the right lateral with left to right shunt and enlarged
wall of the trachea, above the carina. It may pulmonary arteries may compress the right
supply the entire right upper lobe or only the main stem and right middle lobe bronchus.
apical segments. Abnormal airway Left main stem bronchus may be
distribution includes situs inversus compressed by heart enlargement. The left
(associated with primary ciliary dyskinesia), main stem bronchus may also be
left or right isomerism (two right or two left compressed between right pulmonary artery
bronchial patterns, frequently associated and descending aorta. Absent pulmonary
with congenital heart cardiopathy), and lung valves is associated with enlarged
agenesis/aplasia. In the latter a more or less pulmonary arteries, which compress distal
rudimentary bronchus is observed at the trachea, both the main stem bronchi and
main carina. Finally, opening of a tracheo- troncus intermedius. Significant anterior
oesophageal fistula can be found on the compression by anomalous innominate
posterior tracheal wall. Fistula can be artery associated with tracheomalacia is
confirmed by injecting methylene blue into rare. Likewise, posterior tracheal
the fistula and detecting its presence in the compression of an aberrant subclavian
oesophagus (the same results is obtained artery is usually not clinically relevant.
when injecting methylene into the
oesophagus to view the trachea). In dynamical obstruction, tracheomalacia
and bronchomalacia are defined as an
During mechanical and dynamical airway abnormal collapse (.50%) of the trachea or
obstruction, airway patency may be affected the main bronchi during spontaneous
by intrinsic or extrinsic lesions. breathing, expiration or cough, due to a
localised or generalised weakness of the
Intrinsic obstructions include inhaled
airwall (Boogaard et al., 2005). They may be
foreign bodies, stenosis (may be congenital
congenital or acquired, and are mainly seen
with complete tracheal rings or acquired
in children with vascular malformation and
post-intubation), diaphragm, granuloma,
oesophageal atresia and/or tracheo-
endobronchial tumour or bronchial cast
oesophageal fistula.
(also known as plastic bronchitis).
Inflammation and secretions In children, the
Extrinsic obstructions include compression
bronchial mucosa appears thicker than in
by congenital malformation (such as
adults and the mucosa is salmon pink. The
bronchogenic cyst or duplication),
mucosa can be pale, erythemic, thinned or
adenopathies (e.g. malignancy or TB),
thickened. Endoscopy can also identify
tumour or vascular compression. The most
granulations, for example in swallowing
frequent vascular compression is vascular
disorders or sarcoidosis. Secretions should
ring (right-sided aortic arch and double
be characterised as moderate or abundant,
aortic arch) (Chapotte et al., 1998; McLaren
localised or diffuse, being renewed or not
et al., 2008). A double aortic arch causes
after aspiration, mucous, muco-purulent,
obstruction of the distal trachea and left
purulent or haemorrhagic.
main stem bronchus. A right-sided aortic
arch with an aberrant left subclavian artery Bronchoscopy in paediatric ICUs
and enlargement of the Kommerell
diverticulum appears with an anterior and Children in paediatric ICUs may require a
posterior compression of the right wall of bronchoscopy for a primary airway problem
the distal trachea and the right main stem or a secondary complication (Bar-Zohar et al.,
bronchus. The trachea is distorted in the 2004; Efrati et al., 2009; Koumbourlis, 2010,

Manna et al. 2006). These children are In spontaneously breathing infants, classic
unstable and/or ventilator dependent. In flexible bronchoscopy carries the risk of
these situations, sedation should be inducing respiratory failure, particularly in
increased appropriately, the procedure small patients (f2500 g) or those with a
should be fast, and should be performed by borderline respiratory status. A 2.2-mm
an experienced bronchoscopist, assisted by flexible bronchoscope can be passed
an intensivist. Flexible bronchoscopes are through a 2.5 mm endotracheal tube in
useful for diagnosing and assessing therapy intubated infants, but it has no working
in very sick children. Adverse effects of channel. A 2.8-mm flexible bronchoscope
bronchoscopy in paediatric ICUs include can be passed through a 3.5 mm
hypoxia, hypercapnia, inadvertent positive endotracheal tube and has a working
end-expiratory pressure, hypotension, raised channel for bronchoaspiration and BAL.
intracranial pressure and prolonged Similar to paediatric ICUs, an experienced
hypoxaemia following BAL (Morrow et al., paediatric bronchoscopist must perform the
2001). Main contraindications are severe procedure quickly in an ICU; the heart rate,
hypoxaemia, bleeding diathesis, severe blood pressure, oxygen saturation and
pulmonary hypertension, cardiac failure, temperature should be constantly
cardiac instability/hypotension and monitored throughout the procedure. The
procedures that provide no additional absence of an operator channel with the
information. Indications for bronchoscopy ultra-thin flexible bronchoscope prevents the
use in paediatric ICUs are listed in table 3. suctioning of secretions, and the
administration of anaesthesia or normal
Bronchoscopy in neonatal ICUs saline. However, careful suctioning prior to
ultra-thin flexible bronchoscopy adequately
Persistent radiological airway obstruction is prepares the airways for the procedure.
a constant concern in the neonatal ICU and Risks of complication are increased,
the rapid evaluation of the airways is a major including the risks of hypothermia,
requirement for determining whether flexible hypotension, hypoxia, apnoea, bradycardia
bronchoscopy is needed or not. Sudden and intra-cranial haemorrhage.
unexplained deteriorations in the respiratory
status also provide reasons for endoscopic Flexible bronchoscopy may reveal
evaluation. endoluminal abnormalities (e.g. granuloma
and inflammatory stenosis), malformation
(tracheal bronchus), severe extrinsic
Table 3. Main indications of endoscopy in paediatric compression, or severe tracheo and/or
and neonatal ICUs bronchomalacia (de Blic et al., 1991;
Koumbourlis, 2010). These airway
Paediatric ICU
anomalies can exist simultaneously, and
Endobronchial toilet their correct diagnosis is paramount to the
Assessment of lobar collapse management of these patients, also
Ventilator-associated pneumonia providing information for possible surgical
intervention.
Difficult intubation
Selective intubation Tolerance and complications
Failure to extubate Data show that flexible bronchoscopes are well
Airway stent assessment tolerated in most cases and that the risk of
major complications remains low (de Blic
Neonatal ICU
et al., 2002). However, the potentially
Unexplained cyanotic spells dangerous nature of these complications
Failure to wean from mechanical necessitates careful analysis of indications
ventilation and clinical status for each patient and proper
Persistent atelectasis/hyperinflation monitoring during the procedure. Moreover,
the skill of the bronchoscopist and

anaesthesiologist may also decrease the Anaesthetic complications The most life
incidence of complications, demonstrating threatening adverse events during flexible
the value of training. These complications can bronchoscopy involve drug overdose,
be divided into physiological, mechanical, inadequate monitoring or inappropriate
infectious, anaesthetic and post-BAL fever. sedation.
Physiological complications These represent The following will reduce the risk of
the most frequent complications and include complications:
hypoxaemia, with or without hypercapnia,
laryngospasm and bronchospasm, as well as N detection of high-risk children (aged
cardiac arrhythmia and bradycardia. ,2 years, with known or suspected
Respiratory depression is the most laryngotracheal abnormalities);
concerning adverse effect of sedation. Partial N nebulisation of b2-agonists, if there is pre-
or total airway obstruction by the existing bronchial hyperresponsiveness,
bronchoscope and depression of respiratory to avoid bronchospasm;
drive due to sedation are the most frequent N careful local anaesthesia to prevent
causes of oxygen desaturation during flexible excessive cough and laryngospasm;
bronchoscope in children, and may worsen N large oxygen supplementation;
pre-existing hypoxaemia. Upper airway N using the lowest flexible bronchoscope
pathology, persistent radiographic changes, diameter;
oxygen dependency, weight ,10 kg and age N use of appropriate anaesthesia;
,23 years are significantly associated with N training.
increased risk of adverse events. Oxygen
desaturation may also be a consequence of Post-BAL complications Fever is observed in
laryngospasm or bronchospasm. In children up to 52% of cases (Fonseca et al., 2007;
undergoing bronchoscopy, when the airways Picard et al., 2000; Schellhase et al., 1999).
are compromised by both the underlying Post-BAL fever usually begins a few hours
condition and the procedure itself, any after the examination, with spontaneous
depressant effect of sedation is likely to be defervescence occurring within 24 h. It has
poorly tolerated. Oxygen supplementation been attributed to the release of biologically
may delay detection of reduced ventilation active mediators, such as cytokines, and to
but this should be sought by close transient bacteraemia. Factors such as
observation of the child, and capnography young age, a positive bacterial culture and
when appropriate. If desaturation episodes abnormal bronchoscopic findings, including
are moderate and transient (no decrease in whether a topical anaesthetic and saline are
oxygen saturation to ,90%, episodes lasting administered, are related to a higher risk of
,1 min) they do not affect or preclude developing post-BAL fever. A recent study
completion of the procedure. However, if showed that the use of intramuscular
desaturation decreases to ,90%, dexamethasone in immunocompetent
intervention is required and, if needed, the children prior to the procedure caused a
procedure should be terminated. significantly greater reduction in the
Mechanical complications These include incidence of fever than placebo, favouring
epistaxis, haemoptysis (which may be inflammatory cytokine-induced fever (Picard
favoured if coagulopathy is present or if the et al., 2007).
platelet count is ,20 000 cells?mm-3),
pneumothorax and post-flexible
bronchoscope subglottic oedema. Further reading
Infectious complications These complications N Bar-Zohar D, et al. (2004). The yield of
are rare and, by default, are related to the flexible fiberoptic bronchoscopy in pedia-
cleaning of the bronchoscope. The spread of tric intensive care patients. Chest; 126:
infection appears to be a very rare 13531359.
complication.

N Boogaard R, et al. (2005). Tracheomalacia N McLaren CA, et al. (2008). Vascular
and bronchomalacia in children: incidence compression of the airway in children.
and patient characteristics. Chest; 128: Paediatr Respir Rev; 9: 8594.
33913397. N Midulla F, et al. (2003). Flexible endo-
N Chapotte C, et al. (1998). Airway compres- scopy of paediatric airways. Eur Respir J;
sion in children due to congenital heart 22: 698708.
disease: value of flexible fiberoptic broncho- N Morrow B, et al. (2001). Risks and compli-
scopic assessment. J Cardiothorac Vasc cations of nonbronchoscopic bronchoal-
Anesth; 12: 145152. veolar lavage in a pediatric intensive care
N Daniel SJ (2006). The upper airway: unit. Pediatr Pulmonol; 32: 378384.
congenital malformations. Paediatr N Nielson DW, et al. (2000). Topical
Respir Rev; 7: Suppl. 1, S260S263. lidocaine exaggerates laryngomalacia dur-
N de Blic J, et al. (1991). Ultrathin flexible ing flexible bronchoscopy. Am J Respir Crit
bronchoscopy in neonatal intensive Care Med; 161: 147151.
care units. Arch Dis Child; 66: 1383 N Picard E, et al. (2000). A prospective
1385. study of fever and bacteremia after
N de Blic J, et al. (2002). Complications of flexible fiberoptic bronchoscopy in chil-
flexible bronchoscopy in children: pro- dren. Chest; 117: 573577.
spective study of 1,328 procedures. Eur N Picard E, et al. (2007). A single dose of
Respir J; 20: 12711276. dexamethasone to prevent postbroncho-
N Efrati O, et al. (2009). Flexible bronchoscopy fever in children: a randomized
scopy and bronchoalveolar lavage in placebo-controlled trial. Chest; 131: 201205.
pediatric patients with lung disease. N Schellhase DE (2002). Pediatric flexible
Pediatr Crit Care Med; 10: 8084. airway endoscopy. Curr Opin Pediatr; 14:
N Fonseca MT, et al. (2007). Incidence rate 327333.
and factors related to post-bronchoalveo- N Schellhase DE, et al. (1999). High fever
lar lavage fever in children. Respiration; after flexible bronchoscopy and bronch-
74: 653658. oalveolar lavage in noncritically ill immu-
N Koumbourlis AC. Flexible fibre-optic nocompetent children. Pediatr Pulmonol;
bronchoscopy in the intensive-care unit. 28: 139144.
In: Paediatric bronchoscopy. Priftis KN, N Wood RE (1984). Spelunking in the
et al., ed. Basel, Karger, 2010; pp. 54 pediatric airways: explorations with the
63. flexible fiberoptic bronchoscope. Pediatr
N Manna SS, et al. (2006). Retrospective Clin North Am; 31: 785799.
evaluation of a paediatric intensivist-led N Wood RE (2008). Evaluation of the upper
flexible bronchoscopy service. Intensive airway in children. Curr Opin Pediatr; 20:
Care Med; 32: 20262033. 266271.

Bronchoalveolar lavage
Fabio Midulla, Raffaella Nenna and Ernst Eber
Definition
Key points
Bronchoalveolar lavage (BAL) is a procedure
used to recover cellular and noncellular N BAL is a procedure used to recover
components of the epithelial lining fluid cellular and noncellular components
from the alveolar and bronchial airspaces. from the alveolar and bronchial
Techniques airspaces.
Bronchoscopic BAL involves the instillation

N Clinical applications involve
microbiological studies and/or
and immediate withdrawal of pre-warmed
evaluation of cellular components.
sterile 0.9% saline solution through the
working channel of a flexible bronchoscope, N BAL is performed for diagnostic and
which has been wedged into a bronchus therapeutic indications.
with a matching diameter. Generally,
paediatric bronchoscopes with external
diameters of 2.8, 3.5 or 3.7 mm and a Two methods are used for calculating the
working channel of 1.2 mm are used in amount of sterile saline for lavage and the
children ,6 years of age, whereas number of aliquots required to obtain
instruments with external diameters of 4.6 samples that are representative of the
4.9 mm and a working channel of 2.0 mm alveolar compartment. Some authors
are used in children .6 years of age. The choose to use two to four aliquots of equal
preferred sites for bronchoscopic BAL are volume (10 mL per aliquot for children
the middle lobe or the lingula because, ,6 years of age and 20 mL per aliquot
being the smallest lobes of the respective for children .6 years of age), irrespective
lungs, they offer better fluid recovery. When of the patients body weight. Others
lung disease is localised, BAL must target suggest the use of three aliquots, each
the radiological or endoscopically identified consisting of 1 mL?kg-1 body weight for
involved lobe or segment. In patients with children weighing up to 20 kg, and three
CF, samples from multiple sites should be 20-mL aliquots for heavier children.
obtained in order to avoid underestimation While maintaining the tip of the
of the extent of infection. bronchoscope wedged at the selected
Alternatively, a nonbronchoscopic BAL can site, gentle manual or mechanical
be performed by inserting a catheter through suction (3.313.3 kPa, i.e. 25100 mmHg)
an endotracheal tube. Unfortunately, this is applied in order to collect the lavage
method does not allow visualisation of the specimen in a syringe or in a dedicated
lavage site, although turning the childs collection trap. BAL is considered
head to the left predictably directs the technically acceptable if .40% of the
catheter into the right lung. total saline instilled is recovered and
the lavage fluid (except for the first
To avoid contamination, BAL must precede sample) contains few epithelial
any other planned bronchoscopic procedure. cells.

Processing cellular and noncellular components
(table 1). The mean BAL fluid total cell count
BAL specimens should be processed as ranges from 10.3 to 59.96104 cells?mL-1,
soon as possible. To optimise cell viability, with a range of 81.290% for macrophages,
BAL fluid must be kept at 4uC until analysed. 8.716.2% for lymphocytes, 1.25.5% for
The first unfiltered BAL aliquot is usually neutrophils and 0.20.4% for eosinophils.
processed separately for microbiological The BAL fluid neutrophil percentage appears
studies. Bacteria, fungi, protozoa and to be higher in children aged ,12 months as
viruses are detected by direct light compared to children aged 1336 months.
microscopy after centrifugation or Normal values of BAL fluid lymphocyte
alternatively by smears. Special stains such subsets in children resemble those found in
as Gram, Papanicolaou, Gomori-Grocott or healthy adults, except for the CD4/CD8 ratio,
tolouidine blue are used in air-dried which is lower in children. Establishing
preparations. In addition, the samples that reference values for noncellular components
are to be cultured for fungi, protozoa and
is a complex task owing to the absence of
viruses are centrifuged first, whereas those
valid BAL fluid dilution markers. Studies
for bacterial cultures are processed without
designed to investigate noncellular BAL fluid
centrifugation. The rest of the aliquots are
components have few clinical indications
filtered through sterile gauze to remove
and are more important in the research
mucus; then they are pooled and submitted
setting.
for cytological studies and analysis of BAL
solutes. Indications
BAL fluid can be prepared in two ways by: BAL is performed for diagnostic and
therapeutic indications. Clinical indications
N obtaining cytospin preparations of the
for BAL include nonspecific chronic
whole BAL fluid,
respiratory symptoms, nonspecific
N re-suspension of the cells pellet in a small
radiological findings and clinical signs and
amount of medium.
symptoms suggestive of chronic DPLD.
At least three to four slides should be Clinical applications involve microbiological
prepared for each patient. The number of studies and/or evaluation of cellular
cells per mL of the recovered BAL fluid is components.
counted with a cytometer on whole BAL
Microbiology BAL is an important tool in the
specimens stained with trypan blue or with a
diagnosis of lung infection in both
cytoscan. Slides can be stained with May
Grunwald, Giemsa or Diff-Quick stains for immunocompromised and
differential cell counts and the evaluation of immunocompetent patients, including
cellular morphological features. In particular children with chronic pneumonia, CF and
situations, slides can also be prepared with suspected TB. BAL is diagnostic when
specific stains, e.g. oil red O stain to detect pathogens not usually found in the lung are
lipid-laden macrophages, iron stain to recovered, such as Pneumocystis jirovecii,
identify iron-positive macrophages in Toxoplasma gondii, Legionella pneumophila,
patients with alveolar haemorrhage, and Histoplasma capsulatum, Mycobacterium
periodic acidSchiff (PAS) to identify tuberculosis, Mycoplasma pneumoniae and
glycogen. Immunocytochemical staining of respiratory viruses. Other infectious
lymphocyte surface markers is used to diseases, in which isolation of the infectious
differentiate lymphocyte subsets in specific agent from BAL fluid is not diagnostic, but
clinical situations, such as chronic diffuse may contribute to their diagnosis and
parenchymal lung disease (DPLD). management, include infections with herpes
simplex virus, cytomegalovirus, Aspergillus,
The parameters measured include the Candida albicans, Cryptococcus and atypical
percentage of the instilled normal saline that mycobacteria. The presence of .104 colony-
is recovered (as compared to the amount of forming units per mL BAL fluid will identify
saline instilled), as well as various BAL fluid patients with bacterial pneumonia with

Table 1. Total and differential cell counts in BAL fluid from control children
Clement Ratjen Riedler Midulla Tessier
(1987) (1994) (1995) (1995) (1996)
Alveolar macrophages
Mean SD 89.75.2 81.212.7 NR 867.8 89.95.5
Median 89 84 91 87 92.5
Range 8299 34.694 8494# 7198 7798
Lymphocytes
Mean SD 8.74.6 16.212.4 NR 8.75.8 8.95.6
Median 10 12.5 7.5 7 8
Range 117 261 4.712.8# 222 222
Neutrophils
Mean SD 1.30.9 1.92.9 NR 5.54.8 1.21.2
Median 1 0.9 1.7 3.5 1
Range 03 017 0.63.5# 017 03
Eosinophils
Mean SD NR 0.40.6 NR 0.20.3 NR
Median NR 0.2 0.2 0 NR
#
Range NR 03.6 00.3 01 NR
NR: not reported. #: first interquartile to third interquartile.
reasonable accuracy. Hence, the physician Findings from BAL may help in providing a
must consider this cut-off together with the specific diagnosis in children with alveolar
underlying disease and the overall clinical proteinosis, pulmonary haemorrhage,
picture. Furthermore, in children who pulmonary Langerhans cell histiocytosis,
present with chronic wet cough, a positive chronic lipoid pneumonia and pulmonary
culture with .104 colony-forming units per alveolar microlithiasis.
mL is indicative of a protracted bacterial
bronchitis. Because BAL fluid recovered from infants
with alveolar proteinosis contains PAS-
Cellular components The evaluation of BAL positive, diastase-resistant, basophilic and
fluid cellular components may have mucin-negative amorphous material it
important clinical indications in children typically appears milky. Electron microscopy
with chronic DPLD, a group of disorders of the BAL fluid sediment discloses
that are characterised by alveolitis, tissue abundant extracellular, multilamellar bodies
remodelling, fibrosis or a combination and tubular myelin structures consistent
thereof. In these patients BAL may be a with abnormal surfactant forms. Differential
useful tool for characterising the alveolitis cell counts predominantly show
and for monitoring the patient during lymphocytes with alveolar macrophages,
treatment, follow-up and in reaching or which, on electron microscopy, have an
confirming a specific diagnosis (table 2). enlarged foamy cytoplasm containing
Three different forms of alveolitis can be numerous extracellular, concentrically
identified (fig. 1): lamellar surfactant bodies (lamellar bodies).
N lymphocytic, When the BAL fluid appears bloody or orange
N neutrophilic, pink in children with anaemia and infiltrates
N eosinophilic. on chest radiographs the suspected

Table 2. Forms of alveolitis in children with respiratory disorders
Lymphocytic alveolitis Neutrophilic alveolitis Eosinophilic alveolitis
Prevalence of CD4 cells IPF Eosinophilic pneumonia
Diffuse parenchymal lung
Sarcoidosis BOOP
diseases
Crohns disease Wheezy bronchitis Asthma
Prevalence of CD8 cells
Exogenous allergic alveolitis
(hypersensitivity pneumonitis)
Histiocytosis X
Diffuse parenchymal lung
diseases associated with
collagen diseases
BOOP
BOOP: bronchiolitis obliterans organising pneumonia; IPF: idiopathic pulmonary fibrosis.
diagnosis is alveolar haemorrhage. The BAL

fluid characteristically becomes progressively
bloodier with each sequential sample.
Specific haemosiderin staining detects
haemosiderin in alveolar macrophages
(fig. 2). When haemosiderin-laden alveolar
macrophage percentages exceed 20%, the
diagnosis of diffuse alveolar haemorrhage is
usually confirmed. The diagnosis can
sometimes be delayed because
haemosiderin-laden macrophages may take
.48 h to appear after bleeding.
Figure 1. BAL fluid cytology features in eosinophilic
In patients with pulmonary Langerhans cell alveolitis (MayGrunwald Giemsa stain, 6100
histiocytosis, Langerhans cells can be magnification).
identified in BAL fluid through
immunostaining for S-100, CD1a and
langerin. The threshold of 5% CD1a-positive
cells in BAL fluid used for diagnosing
pulmonary Langerhans cell histiocytosis has
excellent specificity, but low sensitivity.
BAL has also been used to document the
diagnosis of pulmonary alveolar micro-
lithiasis by demonstrating microliths in the
BAL fluid, which stain pink with PAS stain.
Well-formed microliths stain black with von
Kossa stain because they have a high
calcium content.
Figure 2. Haemosiderinladen alveolar
A cytological examination showing vacuo- macrophages in the BAL fluid of a patient with
lated alveolar macrophages indicates chronic alveolar haemorrhage (Prussian blue stain, 6100
lipoid pneumonia (fig. 3). The diagnosis magnification).

can be confirmed by specific staining with oil Therapeutic BAL BAL has a major role in the
red O. Lipid-laden macrophages can be therapy of certain lung diseases, in the form
quantified with the lipid-laden macrophages of total lung lavage (alveolar proteinosis) or
index assigning to each lipid-laden mucus plug removal (persistent atelectasis).
macrophage a score ranging from 0 to 4 In particular, children with persistent and
according to the amount of cytoplasmic lipid. massive atelectasis, especially CF patients,
A lipid-laden macrophage index .100 has seem to successfully undergo selective
100% sensitivity, 57% specificity, a negative lavage with DNase or surfactant.
predictive value of 100% and a false-negative
Complications and contraindications
rate of zero.
BAL is a well-tolerated and safe procedure;
BAL remains the procedure of choice to however, on occasion fever, cough, transient
diagnose chronic pulmonary aspiration by wheezing and pulmonary infiltrates have been
determining the lipid-laden macrophage observed, which usually resolve within 24 h.
index and/or by measuring gastric pepsin
concentrations. A lipid-laden macrophage The most frequent complication, usually
index .100 is considered positive for lasting ,24 h, is fever; the only
aspiration. With respect to other potential treatment needed is antipyretics. In
biomarkers, tracheal pepsin has been used immunocompromised patients antibiotic
as a marker of reflux aspiration. Pepsin therapy must be performed for at least 48 h.
detection in the BAL fluid has been shown to
BAL may cause hypoxaemia, hypercapnia, or
have high sensitivity and specificity for
both. Severe bleeding, bronchial perforation,
reflux-related pulmonary aspiration.
mediastinal emphysema, pneumothorax
and cardiac arrest are extremely rare.
a) Contraindications to the procedure include
bleeding disorders, severe haemoptysis and
severe hypoxaemia that persists despite
oxygen treatment.
Further reading
N Braun J, et al. (1997). Different protein
composition of BALF in normal children
and adults. Respiration; 64: 350357.
N Castellana G, et al. (2003). Pulmonary
alveolar microlithiasis. World cases and
review of the literature. Respiration; 70:
549555.
b)
N Clement A, et al. (1987). A controlled
study of oxygen metabolite release by
alveolar macrophages from children with
interstitial lung disease. Am Rev Respir
Dis; 136: 14241428.
N Corwin RW, et al. (1985). The lipid-laden
alveolar macrophage as a marker of
aspiration in parenchymal lung disease.
Am Rev Respir Dis; 132: 576581.
N Costabel U, et al. (2007). Bronchoalveolar
lavage in other interstitial lung diseases.
Figure 3. Lipoid pneumonia. a) Contrast-enhanced Semin Respir Crit Care Med; 28: 514524.
CT scan of the chest showing lipoid material in the N de Blic J, et al. (2000). ERS Task Force on
lungs. b) BAL fluid cytology showing vacuolated bronchoalveolar lavage in children. Eur
alveolar macrophages (MayGrunwald Giemsa Respir J; 15: 217231.
stain, 6100 magnification).

N Farrell S, et al. (2006). Pepsin in bronch- N Ratjen F, et al. (1994). Differential cytol-
oalveolar lavage fluid: a specific and ogy of bronchoalveolar lavage fluid in
sensitive method of diagnosing gastro- normal children. Eur Resp J; 7: 18651870.
oesophageal reflux-related pulmonary N Ratjen F, et al. (1995). Lymphocyte subsets
aspiration. J Pediatr Surg; 41: 289293. in bronchoalveolar lavage fluid of children
N Gutierrez JP, et al. (2001). Interlobar without bronchopulmonary disease. Am J
differences in bronchoalveolar lavage Respir Crit Care Med; 152: 174178.
fluid from children with cystic fibrosis. N Ratjen F, et al. (1996). Adjustment of
Eur Respir J; 17: 281286. bronchoalveolar lavage volume to body
N Krishnan U, et al. (2002). Assay of weight in children. Pediatr Pulmonol; 21:
tracheal pepsin as a marker of reflux 184188.
aspiration. J Pediatr Gastroenterol Nutr; 35: N Ratjen F, et al. (1996). Immunoglobulin
303308. and b2-microglobulin concentrations in
N Midulla F, et al. (1998). Bronchoalveolar bronchoalveolar lavage of children and
lavage cell analysis in a child with adults. Lung; 174: 383391.
chronic lipid pneumonia. Eur Respir J; N Riedler J, et al. (1995). Bronchoalveolar
11: 239242. lavage cellularity in healthy children. Am J
N Midulla F, et al. (1995). Bronchoalveolar Respir Crit Care Med; 152: 163168.
lavage studies in children without par- N Ronchetti R, et al. (1999). Bronch-
enchymal lung disease: cellular constitu- oalveolar lavage in children with chronic
ents and protein levels. Pediatr Pulmonol; diffuse parenchymal lung disease. Pediatr
20: 112118. Pulmonol; 27: 18.
N Milman N, et al. (1998). Idiopathic pulmon- N Tessier V, et al. (1996). A controlled study
ary haemosiderosis. Epidemiology, patho- of differential cytology and cytokine expres-
genic aspects and diagnosis. Respir Med; 92: sion profiles by alveolar cells in pediatric
902907. sarcoidosis. Chest; 109: 14301438.

Bronchial brushing and
bronchial and transbronchial
biopsies
Petr Pohunek and Tamara Svobodova
Flexible bronchoscopy allows detailed Bronchial brushing

examination of the bronchial tree down to,
at least, the segmental and subsegmental Bronchial brushing is a method used for
bronchi. Visual examination is the main sampling superficial samples of bronchial
part of the examination; it provides mucosa. Basically, two methods can be
information about the anatomy and used. A protected brush is a brush enclosed
intraluminal lesions, and allows in a plastic tube that covers the brush and
assessment of airway stability and patency. prevents unwanted contamination during
Visual assessment of the bronchial mucosa passage of the brush through the working
gives some basic information about channel (fig. 1). Only after the brush is fully
possible inflammation, swelling or atrophy. passed through the channel is it pushed out
If we want to examine the processes of the cover. It is then used for sampling of
occurring in bronchial mucosa in more the desired area before being withdrawn
detail, visual information alone is not back into the covering tube. The whole
sufficient. For detailed information about instrument is then pulled back out of the
the inflammatory or structural changes in channel, the brush is pushed out of the
the mucosa some additional methods are cover and sampled cellular material washed
needed. For sampling of bronchial mucosa in appropriate medium or smeared on a
tools are available that can be passed slide for further examination. The use of a
through the working channel of the protected brush is limited by the size of the
bronchoscope. working channel. The minimum channel
diameter needed for protected brushing is
2.0 mm. When using a smaller paediatric
bronchoscope (3.6 mm or 2.8 mm) we are
Key points left with a small working channel with a
diameter of 1.2 mm. Only a thin unprotected
N Bronchial brushing is a useful brush can be passed through this channel.
complementary method for assessing Unprotected brushing is usually performed
cytological changes in the superficial as a final method before the end of the
mucosal layer. bronchoscopy. An unprotected brush is
passed through the channel and then, under
N Endobronchial biopsy allows more
visual control, the mucosal surface is
detailed evaluation of inflammation
sampled by gently scratching the surface
and structural damage of the
with the brush. The main difference to
bronchial wall. It also allows direct
protected brushing is that the unprotected
histological analysis of an
brush is then withdrawn into only the tip of
endobronchial lesion, e.g. a tumour.
the bronchoscope just to be hidden in the
N TBLB samples lung parenchyma channel. Then, with the brush left in place,
without the need for thoracoscopy or the whole bronchoscope is withdrawn from
thoracotomy. the patient, The brush is then pushed out of
the channel and either cut and dropped into

a vial containing the appropriate medium, Bronchial brushing is generally safe, as it is
washed in the medium or smeared on a limited just to the mucosal surface. Minor
slide. This method allows proper sampling superficial self-limited bleeding can be seen.
with minimum contamination or loss of In a deep blind sondage there is a possible
collected material during the passage of the risk of pneumothorax and the patient should
brush through the working channel. be properly monitored post-procedure with
this possibility in mind. Routine follow-up
Bronchial brushing is a useful method of chest radiography is not necessary after a
sampling mucosa for cytology and has been bronchoscopy with bronchial brushing.
successfully used both for clinical and
research purposes. Bronchial biopsy
Main indications Usually, bronchial brushing Bronchial (or endobronchial) biopsy is a

is performed from mucosa within the visual method allowing sampling of a small piece
reach of the bronchoscope and sampling is of bronchial mucosa for histological
performed from the visible lesion or from examination.
the unselected mucosal surface in expected
Main indications Targeted biopsy is essential
general pathologies. Cytology from visible
for histological diagnosis in focal
lesions may provide a specific diagnosis;
intraluminal processes, such as tumours,
cellularity of mucosa in general conditions
mucosal nodules, granulation tissue, etc.
can be evaluated with an assessment of
Biopsy is also often indicated as a
possible mucosal dysplasia or metaplasia,
supplementary method for the evaluation of
providing contributory information about diffuse pathological processes in the
the intensity and type of inflammation. bronchial wall (e.g. asthma, CF, chronic
Bronchial brushing is also used for sampling bronchitis and primary ciliary dyskinesia).
epithelial cells for an evaluation of ciliary Bronchial biopsy only provides information
function or structure in suspected primary about processes occurring in the superficial
ciliary dyskinesia. In selected situations, layer of the bronchial wall; however, a
blind sampling can be performed, such as a properly obtained biopsy usually comprises
deep sondage for cytology or culture from a all the relevant structures involved in most
peripheral lesion. Sampling into culture pathological processes. In a bronchial
media allows collection of material under biopsy, bronchial epithelium, basement
visual control for targeted culture. membrane, the subepithelial layer with
mucus glands and vessels, and, usually also,
the smooth muscle bundles are visible.
Various staining methods can be used to
increase yield of the method, including
immunohistochemistry and specific staining
for structural proteins (e.g. trichrome)
The size of bronchial biopsy depends on the

size of biopsy forceps. Larger paediatric
bronchoscopes, with a diameter of 4.9 mm,
or hybrid flexible bronchoscopes, with a
diameter of 4.0 mm, have a 2.0 mm
working channel. This allows most standard
biopsy instruments to be used. Biopsy
forceps are available in different sizes and
shapes. The most commonly used type for a
standard bronchial biopsy is an oval
fenestrated cup forceps (fig. 2). This forceps
allows appropriate embedding in bronchial
Figure 1. Protected bronchial brush. mucosa and sampling without undesired

damage to the sample. Various other types
are available, including alligator shape
forceps. These are usually not used for
standard biopsy as more damage to the
sample might occur. For a standard
paediatric bronchoscope with a diameter of
3.6 mm or 2.8 mm with a 1.2-mm channel
only limited types of biopsy forceps are
available (fig. 2). These are usually provided
as an oval non-fenestrated cup with or
without a rat tooth. These small instruments
are generally much less efficient in obtaining
a proper sample of bronchial mucosa and
their use, and especially handling of the tiny
samples, requires experience.
Bronchial biopsies in general processes are Figure 3. Position of the biopsy forceps for
usually taken from some secondary or sampling from a secondary carina.
tertiary carina. It is not recommended to sample off the forceps branches. Depending
sample from the main carina as the mucosa on a visual assessment of the sample size
at this level could carry some nonspecific
and quality, biopsy is repeated to guarantee
changes. Sampling from the carina is
a sufficient sample for further diagnostic
technically rather easy as there is good
evaluation.
possibility to position the forceps, close and
grab, and then withdraw the closed forceps If the focal pathology is located in the
carrying the sample between the closed bronchial wall and therefore sampling from
branches (fig. 3). The forceps are then a carina would not be helpful, a different
pulled out of the channel and handed to an technique must be used. Using the flexion of
assistant who places the sample into a vial the tip of the bronchoscope, the forceps
containing appropriate fixation medium. must be pressed against the wall with the
The sample can usually be liberated from branches open parallel to the wall and the
the branches by vigorous shaking of the pathological structure kept between the
forceps in the medium. Sometimes a small branches. The forceps are then closed and
needle might need to be used to get the the mucosa grabbed between the branches.
If this is not successful, the positioning
must be retried and sampling repeated.
Bronchial biopsy is generally a very safe

method. As it samples only a superficial
layer of bronchial wall, bleeding is negligible
in most cases and a risk of pneumothorax is
almost zero. It has been shown to be safe
even in children with CF whose bronchial
mucosa is generally inflamed and
hyperaemic. Even in very young children
evaluated for recurrent wheezing bronchial
biopsy has been shown to be safe and
effective. There was one case of
pneumothorax as a complication of
bronchial biopsy in a large series (de Blic et
Figure 2. Left: oval cup forceps for a thin paediatric al., 2002). In this case, the biopsy was taken
bronchoscope (1.2-mm working channel). Right: from an existing pathology that may have
oval fenestrated cup forceps. caused some pre-existing lesion of the

bronchial wall. It is recommended to take monitoring of the whole procedure,
bronchial biopsies from one lung only to including possible immediate
avoid theoretical risk of a bilateral complications, such as pneumothorax
pneumothorax. (fig. 4). Once the closed forceps are wedged
with an elastic resistance, the forceps are
Logically, any supplemental procedure
withdrawn ,10 mm, opened and pushed
prolongs the time required to perform
down with the aim to break the bronchial
bronchoscopy. Sampling of three adequate
wall and accumulate adjacent lung
biopsy samples requires ,5 min and this
parenchyma between the branches. The
should be taken into account when planning
forceps are then closed and withdrawn back
a procedure.
through the channel. A marked elastic
Transbronchial lung biopsy resistance should be felt, which signals a
good position of the forceps and predicts an
Transbronchial lung biopsy (TBLB) is a adequate sample. A quick release of the
special procedure that allows sampling of resistance occurs when the sample is
pulmonary tissue via endobronchial detached from the lung and the whole
approach. closed forceps can then be withdrawn
Main indications A main and well- through the channel. Three to six samples
established indication for TBLB is evaluation from one side are usually taken to ensure
of rejection in patients with transplanted sufficient tissue to evaluate. Sampling from
lungs. Less often, TBLB has been used for both sides may lead to bilateral
diagnostic evaluation of diffuse pneumothorax and severe respiratory
parenchymal lung diseases or for evaluation compromise and should, therefore, be
of infection. Successful diagnostic TBLB has avoided. Any bleeding from the area should
been documented mainly in homogeneous be carefully monitored using the
pathologies, such as pulmonary sarcoidosis bronchoscope, which should be left in place
and hypersensitive pneumonitis. The main for ,3 min after the last sampling to ensure
advantage of TBLB is its repeatability as that no major haemorrhage has occurred. If
there is no need for video-assisted significant bleeding occurs the
thoracoscopy or open thoracic surgery (now bronchoscope can be wedged into the
used much less often). It has been relevant sub-segmental bronchus to help to
recommended to target the TBLB using stop the bleeding.
preceding HRCT. This helps to increase yield
especially in non-homogenous pathologies. Compared to endobronchial biopsy, TBLB
carries higher risk of complications. The
The technique of TBLB is relatively simple; most frequent are bleeding and
however, it needs experience and practice.
TBLB is performed using standard biopsy
forceps, preferably with an oval fenestrated
cup. Use of alligator forceps is generally not
recommended as it may cause more
complications. Use of larger instruments
through the 2.0-mm channel has better
yield; however, successful TBLB can be
obtained even with thin forceps used
through a small paediatric bronchoscope.
For TBLB, the bronchoscope is positioned
into a relevant segmental or sub-segmental
bronchus. Biopsy forceps are then inserted
through the working channel and gently
pushed into the periphery beyond direct
vision. Fluoroscopy is mandatory as it helps Figure 4. Biopsy forceps during TBLB as shown on
to position the forceps and allows the fluoroscopy.

pneumothorax. Overall, the frequency of any Further reading
complications has been shown to be ,10%.
N de Blic J, et al. (2002). Complications of
Conclusion flexible bronchoscopy in children: pro-
spective study of 1,328 procedures. Eur
Sampling of bronchial mucosa and Respir J; 20: 12711276.
pulmonary parenchyma is now a well- N Greene CL, et al. (2008). Role of clinically
established part of a diagnostic process in indicated transbronchial lung biopsies in
many respiratory diseases. Cytology and, the management of pediatric post-lung
mainly, histology significantly contribute to transplant patients. Ann Thorac Surg; 86:
diagnosis and therapeutic decision. Biopsy 198203.
is generally safe but every procedure N Looi K, et al. (2011). Bronchial brushings
should be properly planned in advance for investigating airway inflammation and
remodelling. Respirology; 16: 725737.
with possible risks kept in mind and with a
N Molina-Teran A, et al. (2006). Safety of
decision as to what samples are required
endobronchial biopsy in children with
for diagnostic evaluation. As cystic fibrosis. Pediatr Pulmonol; 41:
endobronchial biopsies contribute 10211024.
significantly not only to immediate N Regamey N, et al. (2009). Time required
diagnosis but also to general to obtain endobronchial biopsies in
understanding of pathological processes, children during fiberoptic bronchoscopy.
it is now considered ethically acceptable to Pediatr Pulmonol; 44: 7679.
use part of the biopsy material for N Romagnoli M, et al. (1999). Safety and
research. Of course this must be based on cellular assessment of bronchial brushing
an appropriate protocol, informed consent in airway diseases. Respir Med; 93: 461
of legal representatives of the patient and 466.
approval by the Institutional Review Board. N Saglani S, et al. (2005). Airway remodel-
ing and inflammation in symptomatic
Acknowledgements infants with reversible airflow obstruc-
tion. Am J Respir Crit Care Med; 171: 722
This work was supported by the Ministry of 727.
Health, Czech Republic (conceptual N Visner GA, et al. (2004). Role of trans-
development of research organisation, bronchial biopsies in pediatric lung dis-
University Hospital Motol, Prague, Czech eases. Chest; 126: 273280.
Republic; grant number 00064203).

Rigid and interventional
endoscopy
Thomas Nicolai
Rigid bronchoscopy was the first method

described to visualise the lower human Key points
airway. In 1897, Kilian removed an airway
foreign body using rigid bronchoscopy. The N Rigid bronchoscopy is indicated for
technique was simple and has, in principle, foreign body retrieval and pre-
remained unchanged. A rigid hollow tube is operative diagnostic workup of
used to intubate the trachea or a bronchus. subglottic lesions.
Ventilation can be maintained through this
tube, and direct vision was used initially to
N With the necessary precautions the
procedure is quite safe.
inspect the airway. The tube was
illuminated internally with a prism. Later N Teaching the necessary skills to future
improvements included a rigid telescope generations of paediatric
introduced into the hollow bronchoscope bonchoscopists is a challenge.
tube (table 1). These telescopes are
fibreglass rods protected by a metallic
covering, with a lens at the distal and an eye
are used to intubate differently sized airways
piece at the proximal end. Light is
to achieve a reasonable seal and allow
transmitted through this instrument with a
ventilation of the patient. The rigid
coupling device from an external light
endoscope has smooth edges at the distal
source. Today, the eye piece at the proximal
end but could still potentially damage the
end can be connected to a charge-coupled
airway. Therefore, the rigid tube can only be
device camera; thus, the image can be
advanced safely if its distal edge is visible
converted to a digital signal and displayed
during its movement. If this principle is
on a video screen.
adhered to, rigid bronchoscopy is a very safe
Technical considerations procedure.
The use of the rigid endoscope for the If the rigid tube is advanced into the lower
trachea and bronchi is only possible if the airways, care must be taken to smoothly
larynx can be exposed and the bronchoscopy align the long axis of the rigid tube with the
tube can then be advanced into the airway. airway. This is achieved by turning the head
In children with difficult airways, such as in to the right when intubating the left
Pierre Robin sequence and other bronchial system, and conversely on the
malformations, this may sometimes be right side.
impossible.
The bronchoscope tubes have small lateral
As the introduction of a rigid tube into the slits that allow the passage of air into the
airways is very irritating, full anaesthetic is more proximal airways, even when the tip of
always necessary. Because the ventilation of the bronchoscope has been advanced into
the patient has to be performed through the the distal bronchi or when it may be
rigid tube, appropriate connectors are occluded by a foreign body during an
necessary and different sizes of rigid tubes extraction procedure. So-called

Table 1. Rigid bronchoscopes for children
Tubes: internal diameter mm Telescopes: outer diameter mm
3.0 1.8
3.5 2.0
4.0 2.7
4.5 3.4
5.0 4.0
5.5
6.0
These are typical examples, exact actual sizes may vary for different manufacturers; typical lengths are 28, 30
and 35 cm.
tracheoscopes are rigid tubes with the same procedure and the possibility to introduce
diameter as the bronchoscopes but without various instruments. In particular, if a large
lateral openings to avoid a loss of ventilation and potentially occluding foreign body has
pressure when the tip of the tracheoscope is to be extracted, the rigid technique allows
placed in the trachea, when, the lateral the bronchoscopist to reposition or push
openings of a bronchoscope would still be the foreign body if it is lost during the
proximal to the larynx. procedure, giving more safety to a
potentially life-threatening operation. In
The rigid bronchoscope allows for the use of
addition, bleeding or secretions can be
various instruments through its lumen
controlled or suctioned. This is often
(fig. 1); these can be:
impossible when a foreign body retrieval
N forceps, basket has been advanced through the thin
N suction catheters, suction channel of a flexible scope. Also,
N special magnets, with a flexible bronchoscope, ventilation
N biopsy needles. through a mask or laryngeal mask is
necessary while the bronchoscope
Specialised bronchoscopes even allow the obstructs part of the airway. The possible
transmission of a carbon dioxide laser ventilation pressure is limited to 20
through a set of mirrors and make laser 25 cmH2O with this technique. If the
surgical procedures in the lower airways foreign body or bodies cause increased
possible with no deeper or transmural tissue airway resistance, sufficient ventilation
damage. pressure may not reach the lung, leading to
dangerous hypoventilation and respiratory
Indications
instability. However, small distally
Today, most diagnostic indications are positioned foreign bodies may be more
covered by the use of a flexible easily extracted with a combination of both
bronchoscope. However, a few clear methods (flexible through rigid).
indications for rigid bronchoscopy remain,
and foreign body removal is the most Other indications include the recanalisation
frequent (fig. 2). The guidelines of the of airways, e.g. in TB, the use of a carbon
American Thoracic Society clearly advocate dioxide laser for surgical interventions and,
rigid bronchoscopy for foreign body removal rarely, the placement of silicone stents. The
in children. removal of bronchial casts in plastic
bronchitis or solidified airway secretions in
Even today the advantage of rigid severe bacterial tracheobronchitis are also
bronchoscopy is a secure airway during the best performed with a rigid bronchoscope.

Figure 1. Instrument tray for rigid bronchoscopy in children, including bronchoscopy tubes, telescopes and
suction tubes.
Bronchoscopy using only a rigid telescope table with a special device, thereby freeing
the left hand of the bronchoscopist
A variant of rigid laryngo-tracheo- (suspension laryngoscopy) (fig. 3). During
bronchoscopy that is quite useful in children
a period of apnoea, the rigid telescope is
consists of the use of a rigid telescope alone
then advanced through the level of the
(without a rigid bronchoscopy tube) to
vocal folds into the lower airways. Great
intubate and inspect the airways.
care is taken not to touch the airway
The technique involves exposing the larynx surface. This technique gives extremely
with a laryngoscope. If a more complicated detailed pictures of the glottis, subglottic
examination or intervention is planned, the region and trachea and can be used for
laryngoscope can be fixed to the operating preoperative documentation and
instrumentation if laryngeal or subglottic
surgery is planned. It also allows for the
use of instruments, apart from the
telescope, without the limitations of space
within the rigid bronchoscopy tube.
Measurements of distances can be made
with great accuracy. This method is
particularly suited to directly inspect the
subglottic region, even in cases such as
laryngitis, without touching the airway
surface. This is useful to exclude a foreign
body in the diagnostic workup of atypical or
persistent cases of croup. The procedure
lasts only seconds and can be performed
under short anaesthetic such as for an
Figure 2. Rigid bronchoscopy for the removal of a intubation procedure, even in a respiratory-
foreign body. unstable patient.

Future developments
It will be necessary to keep teaching future

generations of bronchoscopists rigid
bronchoscopy to ensure airway foreign body
extraction remains a safe procedure. This
poses a real challenge to paediatric
bronchoscopists because almost all
diagnostic bronchoscopies will be flexible,
with few indications remaining for rigid
endoscopy except foreign body removal.
Usually, ENT surgeons have the necessary
Figure 3. Rigid laryngoscopy with a telescope and skills and a paediatric bronchoscopist who
laryngoscope blade fixed to the operating table wants to learn this technique would be
(suspension laryngoscopy). advised to participate in (at least adult) rigid
bronchoscopies, followed by a hands-on
This method may also be used to inspect the simulation course in paediatric rigid
damage to the larynx in children with bronchoscopy and supervised foreign body
intubation stenosis or glottic inflammation extractions.
by retracting the endotracheal tube,
inspecting the subglottic region and Further reading
immediately reintroducing the tube. This
technique allows optimal diagnosis and N Ansley JF, et al. (1999). Rigid tracheo-
even local therapies, such as laser resection bronchoscopy induced bacteraemia
or infiltration of laryngeal papillomas with in the paediatric population. Arch
substances like cidofovir. Otolaryngol Head Neck Surg; 125: 774
776.
Contraindications and difficulties N Barbato A, et al. The bronchoscope
flexible and rigid - in children. Treviso,
Contraindications to rigid bronchoscopy Arcari Editore, 1995.
obviously include an airway that cannot be N Garabedian EN, et al. (1989). The carbon
intubated with a rigid bronchoscopy tube dioxide laser in tracheobronchial diseases
without excessive force or when the use of in children. A prospective study of 11
laryngoscope exposing the larynx is con- cases. Ann Otolaryngol Chir Cervicofac;
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N Handler SD (1995). Direct laryngoscopy
A bleeding diathesis or severe in children: rigid and flexible fiberoptic.
thrombocytopenia makes the use of a rigid Ear Nose Throat J; 74: 100104.
endoscope more dangerous, without being N Helmers RA, et al. (1995). Rigid broncho-
scopy. The forgotten art. Clin Chest Med;
an absolute contraindication. Bacteraemia
16: 393399.
may ensue with rigid bronchoscopy and,
N Holinger LD, et al., eds. Pediatric
therefore, the recommendations for Laryngology and Bronchoesophagology.
antibiotic coverage in children with Philadelphia, Lippincott, Williams and
congenital heart disease must be followed. Wilkins, 1996.
N Martinot A, et al. (1997). Indications for
Rigid laryngoscopy and bronchoscopy will not flexible versus rigid bronchoscopy in
allow the diagnosis of any dynamic or children with suspected foreign-body
functional features such as airway malacia, aspiration. Am J Respir Crit Care Med;
vocal cord paralysis or pharyngeal instability 155: 16761679.
and may, therefore, be insufficient in the N Nicolai T (2001). Pediatric bronchoscopy.
diagnosis of stridor. In these cases, it may be Pediatr Pulmonol; 31: 150164.
combined with flexible endoscopy as indicated.

N Nicolai T, et al. (2005). Subglottic N Pransky SM, et al. (1999). Intralesional
hemangioma: a comparison of CO(2) cidofovir for recurrent respiratory papillo-
laser, Neodym-Yag laser, and tra- matosis in children. Arch Otolaryngol
cheostomy. Pediatr Pulmonol; 39: 233 Head Neck Surg; 125: 11431148.
237. N Thomas R, et al. (1995). Post intubation
N Nicolai T, et al., eds. Praktische laryngeal sequelae in an intensive care
Pneumologie in der Padiatrie unit. J Laryngol Otol; 109: 313316.
Diagnostik. Stuttgart, Thieme, 2011; N Wood RE (1996).Pediatric bronchoscopy.
pp. 3455. Chest Surg Clin North Am; 6: 237251.

General anaesthesia,
conscious sedation and
local anaesthesia
Jacques de Blic and Caroline Telion
The diagnostic value of bronchoscopy is techniques are general anaesthesia for

now widely accepted to directly visualise the babies or young children and moderate
lower airways and obtain samples, sedation for children, teenagers or patients
particularly by performing bronchoalveolar with ASA IIIV status, according to the
lavage. Performing a safe and successful American Society of Anesthesiology
examination and sampling of the airways classification.
depend on the experience and skill of the
Pre-bronchoscopic procedures
operator and on the comfort of the child.
Bronchoscopy, like any invasive technique, A detailed history and a complete physical
may induce anxiety, fear, pain and examination should be performed. Pre-
unpleasant memory of the experience. operative assessment of the child is
Paediatric patients should almost always be essential, including:
sedated for bronchoscopy. The available
N general history,
N allergies and previous adverse drug
reactions,
Key points
N current medications,
N Appropriate sedation is important for
N sedation/anaesthesia history with focus
on complications and airway problems,
a well-tolerated bronchoscopic N history of upper airway problems and
procedure; available techniques sleep-disordered breathing or snoring,
include general anaesthesia and N major medical illnesses,
moderate sedation.
N physical abnormalities and neurological
N Various protocols may be used during problems,
flexible bronchoscopy that involve the N recent acute illnesses (e.g. upper
administration of a single drug or respiratory infection, fever, etc.).
drug combination (midazolam, N written fully informed consent.
meperidine, propofol, ketamine,
remifentanil, etc.), or inhalation Minimum fasting periods prior to the
agents (premixed 50% nitrous oxide procedure are usually 2 h for clear liquids,
and oxygen or sevoflurane). 4 h for breast milk, 6 h for formula or light
meals and 8 h for full meals.
N Rigid bronchoscopy should always be
performed under general anaesthesia. The need for premedication is at the
discretion of the anaesthetist. In general it is
N Whatever the choice of sedation and
unnecessary; however, if the child is
technique of oxygen delivery (nasal
distressed or unable to cooperate then
prongs, face mask, laryngeal mask or
premedication is advisable.
endotracheal intubation) it is
essential to maintain and preserve Oral atropine (0.010.02 mg?kg-1)
spontaneous ventilation. minimises bradycardia induced by vasovagal
stimulation and also decreases airway

secretions. The utility and safety of oral or ventilation. When using inhalational agents,
intramuscular atropine premedication has the preferred technique for administration is
yielded conflicting results usually via a face mask with the
bronchoscope being passed through a port
Appropriate equipment in a dedicated on the mask while the anaesthetic gas is
bronchoscopy suite including pulse delivered. An alternative technique is the use
oximeter, blood pressure measuring device, of a laryngeal mask.
electrocardiograhy, capnography, suction
apparatus and, if possible, a temperature Moderate sedation
monitor is necessary.
There is no unique protocol for inducing
General anaesthesia conscious sedation. As for general
anaesthesia, conscious sedation may be
General anaesthesia may be achieved either achieved either by an intravenous drug (e.g.
by an intravenous drug (propofol, ketamine midazolam or meperidine) (table 1) or a
or remifentanil) (table 1) or a volatile agent volatile agent (inhalation of premixed 50%
(halothane or sevoflurane). They can be nitrous oxide and oxygen). Combinations of
used alone or in combination. The presence agents are more effective than single agents.
of a trained anaesthesiologist is necessary. Sedation should be given in small
N Propofol is an intravenous sedative incremental doses until the desired effect is
hypnotic agent administered in a dose of obtained.
25 mg?kg-1. It has a rapid onset and a Midazolam is a water soluble
short duration of action. The level of benzodiazepine. It reduces anxiety and
sedation and that of respiratory causes amnesia of the procedure.
depression are dose dependent. Flumazemil is used as an antagonist.
N The use of ketamine as an anaesthetic Midazolam is not intended as a sole agent
agent is less common in children. for paediatric sedation, but should be
Ketamine has been associated with administered in association with an opioid
laryngospasm and bronchospasm. It or nitrous oxide via a face mask.
should be used in combination with
atropine and benzodiazepine in Meperidine is a synthetic opiate that
premedication. Ketamine can be used produces both sedation and analgesia; it has
successfully, but requires attention to the advantage of rapid onset of action and is
topical anaesthesia of the airway in order easily reversible (naloxone). Mepiridine is
to reduce the risk of laryngospasm; the preferably administered intravenously by
addition of a benzodiazepine is also fractional doses to achieve the desired effect
recommended to prevent the emergence with the minimum drug dose. The use of a
of hallucinations. benzodiazepine reduces the required dosage
N Remifentanil is a synthetic opioid agent of meperidine. Known adverse effects
which is a strong analgesic. It has a short include:
duration of action and a short half-life. Its
adverse effects include respiratory N respiratory depression that may last
depression, hypotension, vomiting and longer than other clinical effects,
rigid chest syndrome. It is rarely used in N transient urticaria due to release of
anaesthesia for flexible bronchoscopy, histamine,
but it is used in rigid endoscopy. N transient hypotension,
N nausea,
Inhalational agents are commonly used. N vomiting.
Sevoflurane has a rapid onset of action, its
effects quickly resolve after the Anxiolysis and analgesia may also be
discontinuation of drug administration, it achieved with inhalation of premixed 50%
has minimal cardiovascular and no nitrous oxide and oxygen administered via a
bronchoconstrictive effects. It allows deep face mask. Onset of action is 3 min and
sedation with preservation of spontaneous duration of action is 5 min. Side-effects,

Table 1. Main drugs used for sedation in paediatric flexible bronchoscopy
Drug Actions Dose Onset of Duration Antagonist
action of action
Midazolam Anxiolysis i.v. (bolus): 15 min 90 min Flumazemil
Amnesia 75300 mg?kg-1 0.01 mg?kg-1
Meperidine Analgesia i.v. (bolus): 5 min 34 h Naloxone
0.52 mg?kg-1 0.01 mg?kg-1
Ketamine Analgesia i.v. (intermittent bolus): 24 min 10
Anaesthesia 0.250.5 mg?kg-1 20 min
Amnesia
Propofol Anaesthesia i.v. (intermittent bolus): ,1 min 30 min
0.51 mg?kg-1
i.v. (continuous
infusion):
100 mg?kg-1?min-1
Remifentanil Anaesthesia i.v. (intermittent bolus) 25 min 23 min
Analgesia 0.25-0.1 mg?kg-1?min-1
Continuous infusion
0.05 mg?kg-1?min-1
especially nausea, may occur when it is Nasopharyngeal prongs are easy to pass
administered for more than 15 min. down one nostril while the bronchoscope is
passed through the other. They allow
Local anaesthesia inspection of most of the upper airway and
Local anaesthesia is of particular assessment of the airway dynamics.
importance when conscious sedation is Face masks allow the inspection of the entire
used. 25% lidocaine is applied on the nose airway and the assessment of its dynamics.
and the larynx and 0.51% below the larynx. This method permits application of positive
Lidocaine may be instilled directly, sprayed end-expiratory pressure. The bronchoscope
or nebulised (15 mL of 24% lidocaine is passed through an adaptor on the face
according to the childs weight). The total mask. Problems may arise if a complication
dose should not exceed 57 mg?kg-1, but the occurs as the airway is shared during the
exact amount applied is difficult to assess as entire process between the bronchoscopist
most of the lidocaine is removed by suction, and the anaesthesiologist (fig. 1).
spitting or swallowing. Insufficient topical
anaesthesia will result in pain, cough, Laryngeal masks allow a larger
laryngospasm and/or bronchospasm due to bronchoscope to be introduced, avoid
vagal stimulation. Topical lidocaine may tracheal intubation and are well tolerated.
worsen layngomalacia. Airway control is better achieved than with
the use of a face mask. Disadvantages are
Techniques to ensure adequate ventilation that the upper airways and vocal cord
during flexible bronchoscopy movement cannot be assessed (fig. 2).
Whatever the combination of drugs and the Endotracheal intubation allows the
technique utilised to deliver oxygen, it is bronchoscope to be re-passed easily and
essential to maintain and preserve quickly when necessary. Disadvantages are
spontaneous ventilation. The techniques that upper airways, vocal cord movement
available include nasopharyngeal prongs, and airway dynamics cannot be assessed
face or laryngeal mask, and endotracheal and that the endotracheal tube may limit the
intubation. size of the bronchoscope.

Sedation and anaesthesia in rigid
bronchoscopy
Rigid bronchoscopy should always be

performed under deep sedation. Induction
of anaesthesia is similar to that of flexible
bronchoscopy. Inhalational anaesthesia and
oxygen delivery are maintained through a T-
piece connected to the side arm of the rigid
bronchoscope. Two modes of ventilation are
routinely used: spontaneous ventilation or
Figure 1. Face mask.
(preferably) positive pressure-controlled
ventilation. The use of jet ventilation has
Moderate sedation or general anaesthesia also been reported. The use of a muscle
for flexible bronchoscopy relaxant (e.g. suxamethonium 1.5 mg?kg-1)
The technique of sedation used depends on: has been proposed for cases when
interventional endoscopy is performed;
N respiratory status, however, it appears to be less useful in
N psychological and emotional status of the children than in adults.
patient, Recovery and post-procedural care
N underlying disease,
N available drugs, Upon completion of the procedure, the child
N availability of an anaesthetist, must remain in the recovery area until
N procedures to be performed. cardiovascular and respiratory stability are
assured and the child is awake and
The principal objective of moderate sedation orientated. An intravenous line should be
is to maintain spontaneous ventilation, but left in situ until the child is completely awake
fibroscope insertion may induce cough and tolerating oral fluids.
reflex, laryngospasm or ventilatory
depression. For these reasons if, in the past,
most flexible bronchoscopies were Further reading
performed under moderate sedation, most N American Academy of Paediatrics, et al.
units have currently moved to general (2006). Guidelines for monitoring and
anaesthesia, which appears to be more management of pediatric patients during
comfortable for both the child and the and after sedation for diagnostic and
medical team. therapeutic procedures: an update.
Pediatrics; 118: 25872602.
When sedation is used, the most frequent N American Academy of Paediatrics, et al.
agents used are sevoflurane and propofol (2008). Guidelines for monitoring and
alone or in combination. management of pediatric patients during
and after sedation for diagnostic and
therapeutic procedures: an update.
Paediatr Anaesth; 18: 910.
N Amitai Y, et al. (1990). Serum lidocaine
concentrations in children during
bronchoscopy with topical anesthesia.
Chest; 98: 13701373.
N Antonelli M, et al. (1996). Noninvasive
positive-pressure ventilation via face
mask during bronchoscopy with BAL in
high-risk hypoxemic patients. Chest; 110:
724728.
Figure 2. Laryngeal mask.

N Berkenbosch JW, et al. (2004). Use of a N Malviya S, et al. (1997). Adverse events
remifentanil-propofol mixture for pedia- and risk factors associated with the
tric flexible fiberoptic bronchoscopy seda- sedation of children by nonanesthesiolo-
tion. Paediatr Anaesth; 14: 941946. gists. Anesth Analg; 85: 12071213.
N de Blic J, et al. (2002). Complications of N Mason DG, et al. (1990). The laryngeal
flexible bronchoscopy in children: pro- mask airway in children. Anaesthesia.; 45:
spective study of 1,328 procedures. Eur 760763.
Respir J; 20: 12711276. N Midulla F, et al. (2003). Flexible endo-
N Erb T, et al. (1999). Fibreoptic bronchoscopy of paediatric airways. Eur Respir J;
scopy in sedated infants facilitated by an 22: 698708.
airway endoscopy mask. Paediatr Anaesth; N Naguib ML, et al. (2005). Use of laryngeal
9: 4752. mask airway in flexible bronchoscopy in
N Farrell PT (2004). Rigid bronchoscopy for infants and children. Pediatr Pulmonol; 39:
foreign body removal: anaesthesia and 5663.
ventilation. Paediatr Anaesth; 14: 8489. N Nielson DW, et al. (2000). Topical
N Fauroux B, et al. (2004). The efficacy of lidocaine exaggerates laryngomalacia dur-
premixed nitrous oxide and oxygen for ing flexible bronchoscopy. Am J Respir Crit
fiberoptic bronchoscopy in pediatric Care Med; 161: 147151.
patients: a randomized, double-blind, N Nussbaum E, et al. (2001). Pediatric
controlled study. Chest; 125: 315321. fiberoptic bronchoscopy with a laryngeal
N Hasan RA, et al. (2009). Sedation with mask airway. Chest; 120: 614616.
propofol for flexible bronchoscopy in N Shaw CA, et al. (2000). Comparison of
children. Pediatr Pulmonol; 44: 373378. the incidence of complications at induc-
N Jaggar SI, et al. (2002). Sedation, anaes- tion and emergence in infants receiving
thesia and monitoring for bronchoscopy. oral atropine vs no premedication. Br J
Paediatr Respir Rev; 3: 321327. Anaesth; 84: 174178.
N Larsen R, et al. (2009). Safety of propofol N Slonim AD, et al. (1999). Amnestic agents
sedation for pediatric outpatient proce- in pediatric bronchoscopy. Chest; 116:
dures. Clin Pediatr (Phila); 48: 819823. 18021808.

Conventional radiography
Meinrad Beer
The role of chest radiography includes: preterm babies and polytrauma children)
demands a well-equipped radiological unit
N primary diagnosis, and well-trained personal.
N monitoring of patients progress, and
N assessment for interventional Chest radiography
procedures.
Technique For newborns and infants, the
Thorough consideration of radiation anteriorposterior (AP) view in supine and,
protection based on optimised equipment later, the upright/sitting position is the
includes the protection of relatives and accepted standard for conventional chest
medical staff. Fluoroscopy allows the radiography, as the time-point for deep
generation of functional information and inspiration is better detectable. For
should be available as an advanced newborns, specially designed holder
diagnostic modality in special systems are available, which allow the
circumstances. Typical indications for chest optimal positioning of the field of view
radiography and fluoroscopy for different (properly centred) and radiation protection.
age groups are listed in table 1. Digital Moreover, movements of the children are
imaging has revolutionised chest minimised. The AP projection is also used in
radiography in the last decade. The critically ill children at the paediatric
increasing number of severely ill children intensive care unit (PICU) for bedside
(stem cell transplantation, very low weight imaging. However, the technical capabilities
of the bedside Xray machines are limited,
leading to decreased spatial resolution of
Key points images. Moreover, as in adults, heart size is
increased and pleural effusions are more
N Chest radiography is the backbone of difficult to quantify.
the radiological diagnosis of chest
diseases. The use of fluoroscopy is The posterioranterior (PA) projection is
restricted to special clinical the accepted standard for conventional
indications. chest radiography in older children.
Historically, this was the position that
N The advent of digital imaging and
allowed the most exact judgement of the
pulsed fluoroscopy significantly
size of the heart. Moreover, the radiation
improved the imaging quality of chest
dose is about one-third higher at the site of
radiography and allowed a
entry. Most radiosensitive structures and
tremendous reduction of radiation
dose. organs, such as eyes, thyroid glands,
thymus and mammae, are on the far side
N Careful attention is necessary for from the X-ray machine, i.e. anterior. In rare
consideration of radiation protection conditions (exact location of basal
and necessity of imaging (role of pneumonias, oncological follow-up and
routine follow-up examinations). scoring of CF), the PA projection may be
combined with the lateral projection.

Table 1. Typical indications for chest radiography and fluoroscopy for different age groups
Age years Radiography Fluoroscopy
02 IRDS Oesophageal atresia
CLD
Lines and wires
Pneumonia
Dysplasia
25 Pneumonia Foreign body aspiration
Aspiration
Lines and wires
510 Pneumonia Gastric reflux
Asthma
CF
Lines and wires
1018 Pneumonia Gastric reflux
Asthma
CF
Lines and wires
IRDS: infant respiratory distress syndrome; CLD: chronic lung disease.
However, the radiation dose of these lateral A direct readout matrix (conversion of X-ray
views is about two to three times as high as intensity into electrical signals) is the
a standard PA view. hallmark of digital radiography. Direct
(selenium based) are distinguished from
Table 2. Criteria for image quality and technical indirect (scintillator/photodiode) systems.
parameters Both systems provide high-quality images
Size of focus o0.6 to f1.3 mm
with a resolution of ,10 pixels per
millimetre (corresponding to 5 line pairs per
Additional 1 mm aluminium + 0.1 millimetre) and allow a significant reduction
filtering 0.2 mm copper of radiation dose of up to 50% (depending
Anti-scatter grid None on the desired resolution). With the advent
Distance focus 100120 cm (AP, children of dual-reading systems, the spatial
detector without the chance to resolution is now comparable to the older
cooperate) conventional radiographic systems. An
140160 cm (AP, children individual optimisation of the software for
with the possibility to image calculation is essential. Nevertheless,
cooperate) artefacts from extrafocal radiation may be
Tube voltage 6080 kV exaggerated by the digital systems.
Automatic Should not be used in Criteria for image quality and technical
exposure infants; if used, then with parameters are listed in table 2. Correct
control both lateral detectors adaption of tube voltage and current to age
Time of f20 ms and to weight is an essential prerequisite for
exposition dose reduction as well as the age adapted
Radiation Wrapped around, use of filters. The distance between the child
protection including the gonads and tube should be not to narrow. Dose
(lead) reference values allow an estimation of the
correctness of the radiologists own dose
Chest radiography in the AP/PA projection from values. Most European national guidelines
the newborn stage up to 10 years is shown as an
recommend a range for the radiation dose of
example.
chest X-rays from 0.3 (preterm child) to

whether chest radiography allows the
differentiation between viral and bacterial
infections. Moreover, some authors doubt the
necessity of routine chest radiography in the
assessment of ambulatory acute lower
respiratory tract infection. Figure 1 shows the
value of chest radiography in detecting
complicated pneumonia with relevant pleural
effusion in a young child. Ultrasound may be
used as follow-up modality to reduce
radiation dose.
For PICUs, the value of chest imaging is less

debated. In critically ill newborns, it is used
Figure 1. A 15-month-old girl with fever, coughing to assess the correct position of different
and wheezing. Pneumonia on both paracardial lines and wires, such as tracheal and gastric
sides with pleural effusion on the left side.
tubes, temperature sensors, and central
venous lines (fig. 2).
4 cGy?cm-2 (10-year-old child). Whenever
possible, shielding (of at least the gonads) Conventional chest imaging plays an
should be adopted with appropriate important role in the detection of the salient
materials. In addition, radiation protection radiographic features of CF. Different scoring
of parents and/or medical staff and/or other systems, such as the Brasfield or Crispin
children (e.g. in the PICU) are important. Norman (CN) scores, have been developed to
provide objective parameters for longitudinal
Besides the exact positioning of the X-ray on assessment of potential disease progression.
the child, deep inspiration and minimal These scoring systems allow an objective
rotation are important quality factors. A assessment of disease severity with low interob-
straight run of the trachea is an indicator of server variability. Included criteria encompass
a properly inspired X-ray image in newborns structural changes of the lung parenchyma/
and infants. For older children, the scapulae tracheobronchial system itself as well as
should be rotated so that they are projected secondary changes in thorax shape and
outside the lung parenchyma. The exposure displacement of adjacent organ systems (fig. 3).
to the X-ray generator should be as short as
possible to reduce radiation exposure and
minimise potential distortion caused by
movements of the child.
Nowadays, special training programmes for

chest imaging in infants and small children
are available. Thus, even nonspecialist
medical staff can learn a high standard of
data acquisition prior to primary patient
contact. This is especially important for low
birth weight infants.
Clinical examples Most chest radiographs are Figure 2. Newborn child at the PICU with fever.
taken for assessment of children with Opacities are seen centrally (pneumonia on both
suspected infectious diseases of the lung, paracardial sides). The patient is intubated (closed
focusing on exclusion/verification of asterisk), and has a gastric tube inserted too high
pulmonary opacities and pleural effusions, (arrow), a correctly inserted temperature sensor
sometimes also of pulmonary hyperinflation (dotted arrow) and central venous catheter from
(obstruction). There is lively discussion of the right jugular vein (open asterisk).

Figure 3. A 22-year-old male patient with CF. Increased lung volumes (obstruction) with a low diaphragm,
increased retrosternal space and kyphotic thoracic spine are seen. Marked pulmonary round, linear and
confluent opacities are also evident (CN score 27).
Complications of advanced CF such as aspergillosis, ABPA). MRI is unique in the

atelectasis, mucous impaction, assessment of functional pulmonary
pneumothorax, pulmonary haemorrhage parameters such as perfusion and
and cor pulmonale can be detected. ventilation.
However, CT is superior in detection of
extent of bronchiectasis or special kinds of Chest radiography also constitutes the first
infections (e.g. allergic bronchopulmonary step in the radiological diagnosis of
Figure 4. A boy with suspected aspiration of a foreign body. Fluoroscopy detected regional
hypertransparency/hyperinflation in the left lower lobe, mostly due to a valve mechanism (increased
volume on the left side in end-expiratory (right) compared to end-inspiratory (left) ventilation).

noninfectious chest diseases like tumours, N De Lange C (2011). Radiology in paedia-
trauma, malformation and foreign bodies. tric non-traumatic thoracic emergencies.
Insights Imaging; 2: 585598.
Fluoroscopy N European Commission. Radiation
Technique The last decade also brought Protection No. 162. Criteria for
Acceptability of Medical Radiological
significant technical improvements for
Equipment used in Diagnostic Radiology,
fluoroscopy. The most important was the
Nuclear Medicine and Radiotherapy.
advent of pulsed imaging. State-of-the-art Brussels, European Commission, 2012.
fluoroscopy allows the option of different N Grum CM, et al. (1992). Chest radio-
extents of pulse rates. Thus, functional graphic findings in cystic fibrosis. Semin
imaging affording high (e.g. motility Respir Infect; 7: 193209.
disorders of the oesophagus) and low N Hammer GP, et al. (2011). Childhood
temporal resolution (e.g. slow breathing) is cancer risk from conventional radio-
possible with a reduction in radiation graphic examinations for selected referral
exposure of up to 70% (low temporal criteria: results from a large cohort study.
resolution and low pulse rate). However, Am J Radiol; 197: 217223.
functional radiography by fluoroscopy is only N European Commission. Radiation
rarely used for post-operative complications Protection No. 109. Guidance on
or detection of fistulas. Diagnostic Reference Levels (DRLs) for
medical exposures. Brussels, European
Clinical example Determination of regional Commission, 1999.
hyperinflation is one possible indication for N Langen HJ, et al. (2009).
chest fluoroscopy. Fluoroscopy allows the Trainingsprogramm fur MTRA zur
storage of a series of digitally acquired Anfertigung von Thoraxubersichtsau-
images (cine-loop and extended last fnahmen in Inspiration bei unkooperativen
image hold). Retrospectively, images in Kindern [Training program for radiologic
maximum end-inspiratory and end-expiratory technologists for performing chest X-rays
phases can be selected to judge or rule out at inspiration in uncooperative children.].
Rofo; 181: 237241.
aspiration of foreign bodies (fig. 4).
N Schneider K, et al. (2001). Paediatric
fluoroscopy a survey of childrens
Further reading hospitals in Europe. I. Staffing, frequency
of fluoroscopic procedures and investiga-
N American College of Radiology. ACR tion technique. Pediatr Radiol; 31: 238246.
standard for performance of pediatric N Swingler GH, et al. (1998). Randomised
and adult bedside chest radiography controlled trial of clinical outcome after
(portable chest radiography). In: chest radiograph in ambulatory acute
Standards. Reston, American College of lower-respiratory infection in children.
Radiology, 2011; pp. 3134. Lancet; 351: 404408.
N Brenner DJ, et al. (2001). Estimated N Trinh AM, et al. (2010). Scatter radiation
risks of radiation-induced fatal cancer from chest radiographs: is there a risk to
from pediatric CT. Am J Radiol; 176: infants in a typical NICU? Pediatr Radiol;
289296. 40: 704707.
N Calder A, et al. (2009). Imaging of N Valk JW, et al. (2001). The value of routine
parapneumonic pleural effusions and chest radiographs in a paediatric inten-
empyema in children. Pediatr Radiol; 39: sive care unit: a prospective study. Pediatr
527537. Radiol; 31: 343347.

Computed tomography
Harm A.W.M. Tiddens, Marcel van Straten and Pierluigi Ciet
A wide spectrum of lung function tests has of chest CT in children. This information will
been developed to detect and monitor be helpful both to fill in relevant information
structural lung abnormalities+ in children. on the chest CT order form and to discuss
Over the past decade, chest computed the selection of the best protocol for the
tomography (CT) has gained importance as chest CT for children more efficiently with
a more sensitive modality for diagnosing the paediatric radiologist.
and monitoring such abnormalities. The
radiation exposure needed for a volumetric CT technology
chest CT has fallen substantially, which has Since their introduction in 1972, CT scanners
lowered the threshold for its usage in and reconstruction algorithms have
children. In addition, CT scanners have improved greatly. The time needed to obtain
become much faster making it feasible to the information for reconstructing a cross-
perform a chest examination within a single
section has been reduced to the order of
breath-hold or even in free breathing. This
one second, and the spatial resolution has
section of the Handbook focuses on key
improved substantially. Most CT scanners
issues needed for the optimal and safe use
use so-called fan beam geometry, meaning
that the X-ray tube rotates around the
Key points patient and attenuation measurements are
obtained with an array of detectors, which
also rotates. Early scanners acquired data
N Use of chest CT in children requires
during full rotation of the X-ray tube, before
special expertise of the radiologist to
the scanner table moved to scan the next
follow the As Low As Reasonably
longitudinal position (fig. 1a). This
Achievable (ALARA) principle.
technique, called sequential scanning, was
N A chest CT investigation requires a used for nearly two decades
well-defined clinical question, detailed
patient history, and deliberation with In the late 1980s, a new technique, called
the radiologist prior to the spiral or volumetric CT, was introduced by
investigation to maximise diagnostic the German physicist Willi Kalender. The
yield and minimise radiation patient moves through the CT scanner while
exposure. simultaneously projection data are acquired
from the continuously rotating X-ray source
N Careful instruction of the child prior to and detector array (fig. 1b). The
the investigation is important to performance of the spiral CT scanner was
reduce anxiety, optimise volume further improved by the introduction of
control during the procedure and scanners which measured multiple fans
reduce movement artefacts. simultaneously. With multi-slice spiral CT,
N Volume control during the chest CT multiple fan measurements are made and
should be considered whenever an arbitrary number of slices can be
possible. reconstructed. (In the literature, a number of
alternative terms can be found for this

a) by sequentially acquiring thin (0.51.5 mm)
slices at intervals of 0.52 cm (fig. 1a).
These are usually obtained in inspiration
from the apex of the lung to the diaphragm.
A disadvantage of this procedure is that
acquisition time will be longer, requiring a
longer breath-hold and thus more
cooperation by the child. Furthermore,
relevant information between the slices can
b)
be missed. Finally, for longitudinal follow-up
it is unlikely that slices will be taken at the
same anatomical levels, making comparison
difficult. The only advantage of
noncontiguous sequential scanning is a
lower radiation exposure than volumetric
scanning, which might be considered
preeminent in specific cases. Using a
Figure 1. a) Noncontiguous sequential CT. Data volumetric acquisition mode the complete
are acquired during full rotation of the X-ray tube, lung is scanned (fig. 1b). An important
and then the scanner table moves to scan the next advantage of this mode is that the scanning
longitudinal position. Typically thin (0.5 procedure is faster. With modern scanners,
1.5 mm) slices at intervals of 0.52 cm are
the entire lung can be scanned in less than
acquired using this technique. b) Volumetric or
one second or only a few seconds,
Spiral CT. The patient moves through the CT
depending on the size of the child and the
scanner while simultaneously projection data are
acquired from the continuously rotating X-ray speed of the scanner. Scanning usually
source and detector array. begins at the lung apices and works toward
the diaphragm. In case of long breath-hold
times, movement artefacts near the level of
technique, such as multi-section, multi- the diaphragm can be observed. When
channel, and volumetric CT). The coverage breath-hold times are critical, it can be
in the longitudinal direction per fan considered to scan the lung starting at the
measurement is given by the total beam level of the diaphragm up to the apices of
collimation, i.e. the width of a single the lung to reduce movement artefacts.
detector row times the total number of rows.
Currently available CT scanners allow The major advantages of volumetric CT
acquisition of 256320 fans simultaneously include comprehensive assessment of the lung
with a beam collimation of up to 320 6 structure, allowing reconstruction into multiple
0.5 mm 5 16 cm. Thanks to multi-slice CT, planes and of three-dimensional images. In
the time needed for a chest CT scan has addition it enables matching and sensitive
been reduced dramatically, without comparison of slices at identical anatomical
decreasing the spatial resolution. More positions for longitudinal follow-up.
recently, scanners have been introduced
with two X-ray tubes and two detector arrays Resolution
rotating simultaneously. These dual-source
The achievable spatial resolution of a scan
scanners are capable of scanning the whole
depends on the scan speed and indirectly on
chest of a child in less than one second.
the radiation dose. The scan speed is
Volumetric or sequential scan determined by the speed of table movement
and the speed of rotation of the X-ray tube.
Multi-detector CT (MDCT) scanners allow The speed of table movement mainly
imaging of the chest using either depends on the pitch value. The pitch is
noncontiguous sequential CT scans or by defined as table feed per full rotation of the
continuous volumetric acquisition. X-ray tube divided by the total width of the
Sequential CT techniques sample the lung collimated X-ray beam. The lower pitch

value, the more information is collected per low-dose chest CT protocols are considered
unit length. Young children have small to be low. Radiation exposures for a
airway diameters, hence for detailed combined inspiratory and expiratory chest
information of the lung a low pitch is CT protocol are in the order of 0.51 year of
required. When scanning is performed with the annual background radiation in the USA.
a low pitch, thin slices can be reconstructed For an expiratory scan, a lower radiation
without interpolation artefacts. When dose protocol should be used than for an
scanning is done with a high pitch, inspiratory scan. The required radiation
reconstruction artefacts will appear. Spatial dose can be in the order of half to one third
resolution will generally also improve when of that for the inspiratory scan. An expiratory
the rotation speed of the X-ray tube is scan should only be requested when small
lowered, because this allows for the airways disease and/or perfusion defects
acquisition of more detailed measurements. are suspected.
The level of detail needed will primarily Contrast media

depend on the clinical question. For
example, for CT angiography, high In order to image the vascular system of the
resolution is needed to allow the lungs, administration of contrast is needed.
reconstruction of vessels in great detail. Several issues complicate the
When trapped air on an expiratory scan is administration of i.v. contrast media to
evaluated, a low resolution is often neonates and children, including the use of
sufficient. High-resolution images have small volumes of contrast medium, the use
more image noise. This image noise can of small-gauge angiocatheters (for example,
affect the visibility of the structures of 24-gauge), and unusual vascular access sites
interest despite the resolution improvement. (hand or foot). Ideally, angiocatheters should
Therefore more detailed information can be inserted 0.51 hour prior to the chest CT
only be acquired at the cost of higher so the child is not too upset to lie down
exposure to ionising radiation. High- quietly in the CT scanner. The dose of
resolution volumetric datasets are required contrast media varies between 24 mL?kg-1
for (semi-) automated image analysis of body weight, with very small volumes of
lung parenchyma and airways. contrast media typically administered to
neonates and infants (typically 2 mL?kg-1).
Radiation Since contrast media are cleared through the
kidneys, a normal kidney function is required.
A disadvantage of chest CT scanning is the In case of suboptimal renal function, the
relatively high doses of ionising radiation dose of contrast needs to be adjusted.
needed compared to, for example,
conventional chest radiography. It is Adverse reactions to iodinated contrast
assumed that exposure to ionising radiation media are classed as acute or late. The
in CT increases lifetime risk of cancer. This former occur within 1 hour of contrast
risk is higher in paediatric patients, who medium injection and are further classified
have a higher number of active dividing cells as mild, moderate or severe (table 1). For
than adults. Hence, radiation dose should this reason, resuscitation equipment, a
be justified and minimised to a level as low paediatric resuscitation protocol and
as reasonably achievable (ALARA qualified personal should be close at hand in
principle). Since the effects of radiation are case a severe allergic reaction occurs. Late
assumed to be cumulative, the number of adverse reactions occur 1 hour to 1 week
CTs should be kept within acceptable limits. after contrast medium injection and are
Care should be taken to tailor the CT represented by a variety of late symptoms
protocol to the size of the patient and to use (nausea, vomiting, headache,
the minimum radiation dose that will musculoskeletal pain, fever) or by skin
produce images of diagnostic quality and reactions, which are usually mild and self-
allow sensitive image analysis. The risks limited. While most minor physiological
related to exposure levels of state-of-the-art side-effects of i.v. contrast medium

Table 1. Classification of adverse reactions to on the level of inflation of the lung. When
intravenously administered contrast media the lung is well inflated, lung parenchyma is
positioned between the heart and sternum.
Mild Nausea, mild
In addition the trachea has a round
vomiting
appearance and the contour of the
Urticaria
Itching
diaphragm is flattened. For an optimal
diagnostic result, volume control is
Moderate Severe vomiting important and should be aimed for
Marked urticaria whenever possible. Furthermore, it is
Bronchospasm
important that movement of the subject and
Facial/laryngeal
of the lungs is minimised. However, most
oedema
Vasovagal attack young children below the age of 4 years are
not able to perform a voluntary breath-hold
Severe Hypotensive shock at the correct volume level and at the correct
Respiratory moment. There are two methods available to
arrest
scan the lungs in these young children.
Cardiac arrest
Convulsion The first technique is the noninvasive
pressure-controlled ventilation (PCV)
technique under general anaesthesia or
administration in adults are of minimal
sedation. The PCV technique starts off by
significance, such events are often of
hyperventilating the child by giving a short
increased importance in children. For
series of augmented breaths using high
example, local warmth at the injection site
positive pressure applied via a facemask,
and nausea, generally regarded to be
laryngeal mask, or tube to recruit all lung
physiological side-effects to contrast medium
areas and to allow for a respiratory pause.
administration, may cause a child to move or
Next, for inspiratory images, the lung is
cry. Such a response to contrast medium
inflated to a positive transpulmonary
injection may result in the acquisition of a
pressure of 25 cmH2O and the lungs are
nondiagnostic imaging study, necessitating
imaged while pressure is maintained. For
repeat imaging and additional exposure to
expiratory images, no pressure is applied,
contrast medium and radiation.
hence the lung will deflate to a volume level
There are several difficulties in interpreting near functional residual capacity. PCV
the available literature on the incidence of techniques have been shown to be highly
allergic-like reactions to i.v. iodinated reproducible. A disadvantage, however, is
contrast media in children. Many studies fail that atelectasis can develop within minutes
to discriminate between physiological side- in children under general anaesthesia.
effects and allergic-like reactions. In addition, Atelectatic regions of the lung cannot be
these studies lack agreement on what evaluated for the presence of bronchiectasis
constitutes mild, moderate, or severe or other structural abnormalities. When
reactions. Finally, there is a lack of controlled high-resolution images are required, for
prospective paediatric studies on the topic. example when interstitial lung abnormalities
Therefore, not surprisingly, the reported are suspected, PCV should be selected as
incidence of paediatric allergic-like reactions the technique of choice.
to contrast media is variable, and ranges The second technique to acquire a CT scan
0.180.46%. It is generally agreed, however, in children below the age of 4 years is to use
that the incidence of allergic-like reactions in an ultra-fast CT scanner that can obtain
children is lower than that in adults. motion-free images of the lung in free-
Volume control breathing children even without sedation or
general anesthesia. A disadvantage of this
Lung volume, and configuration and method is that there is no strict control of
orientation of airways, is highly dependent lung volume. Spontaneous breathing will be

in a volume range between functional the evaluation of lung parenchyma and for
residual capacity and functional residual the detection of bronchiectasis (fig. 2ac).
capacity plus tidal volume. Scans acquired
during tidal breathing are less sensitive than To diagnose bronchiectasis, the diameter
those acquired using PCV in detecting of the airway is compared to the diameter
bronchiectasis. However, the specificity of of the adjacent or nearby pulmonary artery.
bronchiectasis detection is good. For When the bronchoarterial ratio exceeds 1.0,
children aged o4 years, chest CT can be it is considered bronchiectasis. It has been
carried out mostly without sedation or shown that the airway:artery ratio is
anaesthesia. Breath-hold instructions during dependent on the inspiration level. The
the in- and expiratory CT scan are routinely current consensus is that the diagnosis of
given by a CT technician, often resulting in bronchiectasis can best be made on an
suboptimal volume levels. The inspiratory inspiratory CT near TLC. At lower lung
volume level of these radiographer-guided volumes, the diameter of the airway is
scans results in a lung volume in the range reduced more relative to that of the
of 80% of TLC. The expiratory volume level adjacent artery. Hence, at lower lung
of such scans is in most subjects near volumes the bronchoarterial ratio can be
functional residual capacity, which is well less than 1.0 even for a bronchiectatic
above residual volume. For many years, it airway. In addition, at low lung volumes
has been recognised that spirometer- the orientation of airways is different
controlled breathing manoeuvres during the relative to that at inspiration, and airway
CT scan result in improved standardisation length is reduced as well, making
of in- and expiratory volume levels and identification of abnormal widened airways
fewer movement artefacts and thus cut in cross-section more difficult. Finally,
improve the diagnostic yield substantially. at low lung volumes, a lower number of
In this case, the patient can be trained by a airways can be evaluated relative to an
lung function technician 3060 minutes inspiratory scan. Similarly, to measure
prior to the CT scan to perform the airway wall thickness a standardised
requested breathing manoeuvres in supine volume level near total lung volume is
position using a spirometer. The same needed. At lower lung volumes, the inner
technician instructs the patient during the wall of the airway will fold into the lumen,
CT scan. The spirometer operated by the which will appear as a thickened airway
patient is connected to a monitor wall on a chest CT.
positioned in front of the window of the CT Expiratory scans can be important when
control room, and the lung function perfusion defects and/or small airways
technician focuses on the patient during the disease are suspected (fig. 2df). While
CT scan while the CT technician can focus airways ,1 mm in diameter are in general
on operating the scanner. The lung function not visible on CT scans, small airway disease
technician indicates when the CT can be detected indirectly as lucent regions
acquisition can be started, taking into on expiratory scans. These lucent regions
account the delay (14 s) between pushing can be the result of trapped air with or
the start button of the CT scanner and start without hypoperfusion. Trapped air areas
of the actual acquisition. The sensitivity for can be distinct to the adjacent healthier
the detection of trapped air of spirometer- deflated and normally perfused or
controlled expiratory scans is superior to hyperperfused dense parenchyma. When
that of uncontrolled scans. multiple lucent areas are present in the lung
Inspiration and/or expiration scan combined with normal or hyperperfused
dense areas, the term mosaic attenuation
For many chest CT scan indications, pattern is used. Areas of trapped air can be
acquisition of both inspiratory and differentiated from hypoperfused areas by
expiratory chest CTs is relevant. An comparing their density in inspiratory and
inspiratory CT scan near TLC is needed for expiratory scans. Trapped air areas without

a) b) c)
d) e) f)
Figure 2. ac) A spirometer-controlled inspiratory chest CT reconstructed in the axial (a), coronal (b) and
sagittal (c) planes. Note that the lung is positioned between the heart and the sternum and that the lung
is protruding between the ribs. df) A spirometer-controlled expiratory chest CT reconstructed in the axial
(d), coronal (e) and sagittal (f) plane. Arrows indicate lucent regions of the lung caused by hypoperfusion
and/or trapped air. The lucent areas are adjacent to normal dense regions, representing a mosaic pattern.
hypoperfusion appear lucent only on the method can be used as an alternative

expiratory scan. Optimal expiration to a method to bronchoscopy to diagnose
volume level near residual volume increases tracheomalacia. Unfortunately, dynamic
the contrast between lucent regions and information requires exposure to ionising
normal or hyperperfused healthier lung radiation for the duration of the scan, which
regions. However, lucent regions can be will increase the total radiation dose needed
considered as trapped air areas only when for the study. MRI is an alternative
they follow the distribution of a secondary technique in development to acquire
pulmonary lobule (defined as the smallest dynamic information. Hence, further
unit of lung surrounded by fibrous septa). research is needed to define whether cine-
When up to five secondary lobules are multidetector CT or MRI will become a
involved, especially if positioned in the competing technique for bronchoscopy in
dependent regions of the lung (superior the near future.
segments of the lower lobes, anterior parts
of middle lobe and lingula), areas of trapped Image processing
air are still considered physiological. Generated images need to be reconstructed
However, reference studies to support this and stored in the correct way. After a chest
are lacking. CT has been performed, the raw data are
Dynamic versus static imaging post-processed to generate relevant series
and specific reconstructions. The generated
Dynamic cine-multidetector CT has been images are stored in the Picture Archiving
used to study the dynamic behaviour of and Communication System (PACS) system.
central airways in adult patients. This Raw data are in general automatically

a) b)
c) d)
Figure 3. The effect of administration of an intravenous contrast medium. a) A slice (3 mm) in the axial plane
acquired before the administration of a contrast medium. b) The same patient scanned after the administration
of a contrast medium. Note that the contrast-enhanced image appears slightly sharper and noisier as compared
to the native image because of a small change in reconstruction kernel and windowing. c and d) The lung
reconstructed in the coronal (c) and sagittal (d) plane using a maximum intensity projection. Note that the
contrast-enhanced blood vessels contrast clearly with the surrounding lung tissue.
deleted 12 weeks after the scan. Hence, it speaking, there is a tradeoff between spatial
is important that all relevant series are resolution and noise for each kernel. A
reconstructed and stored before the raw smooth kernel generates images with lower
data are deleted. The radiologist will noise but with reduced spatial resolution
determine scan protocol and reconstruction (fig. 3a). A sharp kernel generates images
series needed based upon the clinical data with higher spatial resolution, but increases
and questions as defined on the order form. the image noise (fig. 3b). Other important
Reconstruction protocols define reconstruction algorithms are maximum
reconstruction planes (axial, coronal, intensity projection (MIP) (fig. 3cd) and
sagittal), slice thickness (for example 0.65, 1, minimum intensity projection (MinIP)
1.25, 3, or 5 mm), windowing (parenchyma (fig. 4). MIP consists of projecting the voxel
or mediastinum) and definition of with the highest attenuation value on every
reconstruction kernels (soft or hard). The view throughout the volume onto a two-
reconstruction kernel, also referred to as dimensional image. This technique is
filter or algorithm by some CT vendors, normally used to detect lung nodules or in
is one of the most important parameters scans with contrast to improve vessel
that affect the image quality. Generally depiction. MinIP is a data visualisation

method that enables detection of low- be performed both for the inspiratory and
density structures in a given volume. The the expiratory CT scan. Slice-by-slice
MinIP algorithm is particularly useful for comparison enables determination of
analysing the airways, which are hypodense whether observed structural changes on the
compared the surrounding tissue. It is often baseline CT have progressed, are stable, or
worthwhile to discuss with the radiologist have improved on the follow-up CT or
the case before the scan is made, especially whether new abnormalities have developed.
for non-routine patients. At least one series Ideally, structural changes on chest CT, such
of thin-slice images (f1 mm) in the axial as bronchiectasis or trapped air, should be
plane should be stored using an appropriate quantified when possible. To date for chest
predefined reconstruction kernel. These thin CT in CF, the method of choice has been
slices are needed to evaluate the airways and scoring. A CT scoring system is a tool to
this series allows additional post-processing describe the abnormalities that can be
for example reconstruction of thicker slices observed on the slices obtained from a
in the axial, coronal or sagittal plane or for a single CT investigation in a semi-
three-dimensional reconstruction. quantitative way. Several scoring systems
Furthermore, thin slices are mostly required have been developed (see de Jong et al.,
for commercially available image analysis 2004). For all these systems, the reader
platforms. identifies various abnormalities on the CT
scans and assesses their severity. Important
Image analysis abnormalities that are included in most of
the scoring systems are bronchiectasis,
For clinical use, it is possible to monitor
mucous plugging, airway wall thickening
progression of structural lung changes on
and parenchymal opacities. Other
chest CTs. This can best be examined by
abnormalities such as small nodules,
comparing slice by slice the follow-up to the
mosaic attenuation, sacculations and air
baseline examination in the axial or other
trapping on expiratory images are included
planes. Most PACS viewers enable coupling
only in some of the systems. An advantage
of two examinations in a single window, with
of scoring systems is that they are relatively
scrolling down through the lung from the
insensitive to the CT scanner technique and
apices to base. These comparisons should protocol being used. Recently the CFCT
scoring system was developed. The CFCT
scoring training module includes clear
definitions and reference images for the
structural abnormalities that have to be
scored and provides training sets. It has
been used successfully in a number of
studies. To date there are no validated
automated image analysis systems available
to quantify bronchiectasis, trapped air or
emphysema on paediatric chest CT. It is
likely that in the near future commercially
available (semi-) automated systems will
come to market and replace visual scoring.
The use of such systems will require volume
standardisation of the chest CT protocol.
Semi-automated systems to compare
airway:vessel ratios have been used in CF
studies. In addition, programs to segment
Figure 4. A slice of the lung reconstructed in the the lung parenchyma and the bronchial tree
coronal plane using a MinIP algorithm which have been developed. These systems will be
enables detection of low-density structures in a used in the near future to detect and
given volume. quantify CF and non-CF bronchiectasis.

Furthermore, systems have been developed N Ciet P, et al. Spirometer controlled cine-
to visualise and quantify trapped air. Ideally magnetic resonance imaging to diagnose
such a system should be able to compute tracheobronchomalacia in pediatric
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N Contrast media in children. In: ACR Manual
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Conclusion
puted tomography for patients with cystic
Chest CT technology has been developed to fibrosis. Am J Respir Crit Care Med; 176:
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tool for the diagnosis and monitoring of
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graphy scans of children with cystic
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question. Furthermore, the referring for CT in children with cystic fibrosis: is it
clinician should carefully describe relevant feasible to reduce the number of images
clinical details and the clinical questions. per scan. Pediatr Radiol; 36: 5053.
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importance to optimise the diagnostic yield cancer mortality associated with repeti-
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trending in the right direction. Radiology; value of bronchial and arterial dimension
261: 58. measurements. Radiology; 231: 434439.
N Bankier AA, et al. (2012). Through the N Dillman JR, et al. (2007). Incidence and
Looking Glass revisited: the need for severity of acute allergic-like reactions to
more meaning and less drama in the i.v. nonionic iodinated contrast material
reporting of dose and dose reduction in in children. AJR Am J Roentgenology; 188:
CT. Radiology; 265: 48. 164316477.
N Bonnel AS, et al. (2004). Quantitative air- N Goris ML, et al. (2003). An automated
trapping analysis in children with mild approach to quantitative air trapping
cystic fibrosis lung disease. Pediatr measurements in mild cystic fibrosis.
Pulmonol; 38: 396405. Chest; 123: 16551663.
N Callahan MJ, et al. (2009). Nonionic N Hansell DM, et al. Fleischner Society:
iodinated intravenous contrast material- glossary of terms for thoracic imaging.
related reactions: incidence in large urban Radiology 2008; 246: 697722.
childrens hospital retrospective analy- N Huda W (2007). Radiation doses. risks in
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N Kalender WA. Computed Tomography. N McDermott S, et al. (2009).
3rd edn. New York, Wiley, 2011. Tracheomalacia in adults with cystic
N Kirpalani H, et al. (2008). Radiation risk fibrosis: determination of prevalence
to children from computed tomography. and severity with dynamic cine CT.
Pediatrics; 121: 449450. Radiology; 252: 327329.
N Lee KS, et al. (2007). Comparison of N Mott LS, et al. Assessment of early
dynamic expiratory CT with bronchoscopy bronchiectasis in young children with
for diagnosing airway malacia: a pilot cystic fibrosis is dependent on lung
evaluation. Chest; 131: 758764. volume. Chest 2013 [in press DOI:
N Lever S, et al. (2009). Feasibility of 10.1378/chest.12-2589].
spirometry-controlled chest CT in chil- N Mott LS, et al. (2012). Progression of early
dren. Eur Respir J; 34: Suppl. 53, A344. structural lung disease in young children
N Loeve M, et al. (2009). The spectrum of with cystic fibrosis assessed using CT.
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from CF patients with severe advanced N OConnor OJ, et al. (2010). Development
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ment of airway disease in infants N Robinson TE, et al. (1999). Standardized
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Radiol; 31: 413422. to know. Insights Imaging; 3: 229246.

Magnetic resonance imaging
Lucia Manganaro and Silvia Bernardo
MRI of the chest is a new technique in the the diagnosis can be obtained by other
imaging of the lung. The lack of ionising means. CT is the gold standard in:
radiation makes MRI an attractive alternative
to CT in paediatric applications, in which N the evaluation of congenital anomalies,
repeated or serial scanning is required. N parenchymal pathologies,
N the case of chronic airway disease for a
Paediatric lung imaging morphological study,
N the assessment of the complications of
Diseases of the respiratory system are of inflammatory process,
great importance in paediatrics. Imaging of N the staging of tumoural masses.
the chest has led to improvements in the
diagnosis and treatment of numerous MRI is a radiation-free technique and offers
medical conditions in children. alternative solutions to routine diagnostic
challenges for the imaging of the lung. It is
The first, and most widely used, modality is especially relevant to young patients and
represented by radiographic imaging. It is pregnant patients, as well as subjects who
fast and inexpensive and provides a good need to undergo multiple investigations.
overview of anatomy and pathology. However, in the approach of lung diseases,
the feasibility of MRI investigation is limited
For most paediatric pulmonary pathologies by several technical problems. Despite this,
a plain film is the first, and only, step in the in recent years many efforts have been made
absence of complications and when the and there have been significant advances.
clinical course is regular. The best case is to
avoid additional imaging, especially CT, if MRI techniques For many years MRI
imaging was considered useful in the
evaluation of mediastinal abnormalities and
Key points not the lung parenchyma. However, the lack
of radiation exposure makes MRI of the lung
N MRI techniques allow for fast and particularly attractive for paediatric
reliable assessment of pulmonary radiology.
diseases in children. The subordinate role of MRI in the
N Thoracic MRI is a radiation-free evaluation of lung is caused by different
method and can be performed technical problems, especially:
frequently without contrast media
application. N artefacts related to cardiac and breathing
motion,
N The diagnostic value of MRI is shown N the low signal-to-noise ratio because of
in patients with infectious diseases, low proton density of the lung,
immunodeficiency, anatomic N the susceptibility of artefacts because of
abnormalities, acquired chronic airsoft tissue transition,
diseases and pulmonary tumours. N the low-spatial resolution in comparison
to CT.

In addition, it is important to remember the Contrast media use (gadolinium chelates)
heterogeneity of the paediatric population allows for:
and that the time of acquisition of an MRI
examination is longer than for CT. N better characterisation and extension of
disease,
More so than in radiography or CT, the N evaluation of the process activity,
image quality in MRI depends on patient N studies of cardiovascular and perfusion
compliance. It can be expected that some performance.
sequences may produce unsatisfactory
results in very young patients. A drawback of As work in progress, MRI can assess various
MRI is that, in general, it requires a longer aspects of pulmonary function, including
scan time than CT, something that is not lung perfusion, blood flow, respiratory
much of an issue with older children but mechanics and, using an inhaled contrast
may preclude its use in non-sedated younger agent, pulmonary ventilation. Thus, MRI is
children. Lung MRI is generally performed emerging as a versatile modality for
with a high-field magnet system using ultra- morphological and functional imaging of the
short acquisition. Different types of lung.
sequences can be used.
MRI perfusion imaging can be performed
The spoiled gradient echo (three-dimensional using two different techniques: contrast-
gradient-echo) sequence has multiple enhanced MRI perfusion and noncontrast-
applications in lung MRI. For anatomical enhanced MRI perfusion. In patients with
imaging, it can be used for two- or three- pulmonary embolism MRI perfusion
dimensional acquisitions with or without fat provides additional information about
suppression pre- and post-contrast perfusion defects. Perfusion scintigraphy
administration. has been replaced by ultrafast CT (multiple-
detector or volume CT with special child
The balanced steady-state free precession programmes) in the imaging of pulmonary
(bSSFP) sequence has many applications, in embolism in children. Using CT as the gold
particular in cardiac MRI, but it can also be standard, MRI perfusion shows a
applied to anatomical lung imaging. comparable high sensitivity and specificity
The single-shot fast spin echo (SSFSE) for the detection of perfusion defects. In
sequence is advantageous for lung imaging patients affected by pneumonia, MRI
for fast acquisition. perfusion contributes important information
for the differential diagnosis of pulmonary
Diffusion-weighted imaging (DWI) provides embolism.
qualitative and quantitative assessment of
water diffusivity within tissues. In the MRI ventilation Because of the low proton
thoracic field, DWI is more challenging due density and high susceptibility of lung
to respiratory and cardiac motion. tissue, conventional proton MRI is not
Nevertheless, DWI can be used to evaluate suitable for visualising lung ventilation, and
pre-treatment cellularity and treatment alternative contrast mechanisms have to be
responses of focal thoracic lesions. used. Oxygen-enhanced MRI has been
investigated for lung ventilation imaging
Control of respiratory phase Respiratory and has a unique feature in which perfusion
motion of the diaphragm and chest wall can and diffusion also contribute to the oxygen
be reduced by respiratory triggering using a enhanced MRI signals. An inhaled contrast
pressure-sensing belt. Recently, respiratory agent, either oxygen or a hyperpolarised
gating using a navigator echo has been noble gas (hyperpolarised helium-3 is a
widely used for the same purpose. Other gaseous MRI contrast agent that, when
motion-reducing methods, such as inhaled, provides a very high MRI signal
saturation bands, signal averaging and from the airspaces), is required for MRI lung
motion-insensitive pulse sequences, may be ventilation imaging. In clinical studies, MRI
used in children. is able to differentiate between diseases with

a) b)
c) d)
Figure 1. A CT scan from a 9-year-old boy with cough and dyspnoea of b) the coronal and d) the axial
plane showed bronchiectatic areas and bronchial wall thickening next to the heart (white arrows). a, c)
The same findings are visible on MRI sequences, confirming sensitivity of these protocols for bronchiectasis
is at least similar to CT.
a) b) c)
d) e)
Figure 2. A 12-year-old boy with dyspnoea following lung transplantation. a) The chest radiograph showed
an opacity in the right lung (#). b, d) T2-weighted fat saturation images clearly demonstrate a pneumonic
infiltrate (arrows), e) confirmed with a particularly high signal in diffusion weighted imaging (arrow),
associated with posterior hyperintensity in T2-weighted imaging (arrowheads) and c) hypointensity in T1-
weighted imaging (arrowhead) indicating pleural effusion.

a) b) c)
Figure 3. A CT scan, performed after a chest radiograph, in a 10-year-old girl with a history of progressive
difficulty in breathing and chest pain. a) A dishomogeneous space-occupying lesion in the mediastinum
(arrow) associated with pleural effusion (short arrow) from the upper mediastinal area, in front of the
aorta and pulmonary artery, is visible. b, c) MRI confirmed the mediastinal mass causing a compressive
effect on pulmonary vessels and parenchyma with almost total collapse of the left lung (arrow) and pleural
effusion (short arrow). The signal intensity demonstrated the presence of water intensity cystic spaces with
fat-fluid levels (specific for teratoma).
and without ventilation/perfusion mismatch ratio (the difference in signal intensity between
(V9/Q9) and has shown high sensibility in the area of interest and the background) and
comparison to gold standard references such difficulties in performing the examination.
as scintigraphy. However, its clinical Further clinical studies in children are
application is limited by a low signal-to-noise necessary to prove its great potential.
a) b)
c) d)
Figure 4. An 11-year-old girl with a history of fever and cough. Acute phase dorsal consolidations on the left
are well represented as hyperintense focus in a) diffusion weighted imaging sequence b600 (arrow) and b)
turbo spin echo (arrow). After 3 weeks of therapy the focus appears less hyperintense in c) diffusion
weighted imaging sequence b600 (arrow) and d) turbo spin echo (arrow) showing a response to therapy
(image courtesy of G. Morana, Department of Radiology, Ca Foncello Hospital, Treviso, Italy; personal
communication).

a) b) c)
d) e) f)
Figure 5. A fetus at 23 months +4 days of gestation. ae) Hyperinflation of the left lung (arrows)
associated with trans mediastinal hernia (arrowheads) and right medistinal shift (#). Many centimetric
lesions are present in the pulmonary parenchyma (black arrows). f) These lesions are hyperintense in T2-
and hypointense in T1-weighted fat saturation images, indicating cystic lesions suggestive of a Type II
CPAM (Stocker classification).
Paediatric lung MRI: indications and empyema or lung abscess. In these cases
features MRI allows the complications and the
extension of pleural empyema to be
Major clinical indications for MRI arise from evaluated; it can also be repeated to
three major fields: evaluate the development and to monitor
N lung infections, CF, asthma and the response to treatment (fig. 4).
pulmonary hypertension (fig. 1), Some authors emphasise the role of MRI in
N regular imaging in patients in whom the characterisation of pulmonary infiltrates,
radiation exposure should be avoided especially in patients suffering from
(fig. 2), neutropenic fever, although cost-efficiency
N mediastinal masses (fig. 3). has not been proven for this indication.
Lung infections The diagnostic value of MRI CF is the most common indication for MRI.
is shown in patients with infectious diseases. By using common proton-MRI sequences it
MRI detects pulmonary infiltrates, hilar is possible to visualise the structural
changes and pleural or pericardial effusions changes of CF lung disease such as:
as well as, or better than, chest radiography.
The predominant MRI findings are alveolar N bronchial wall thickening,
or interstitial parenchymal changes, pleural N mucus plugging,
thickening and fluid and lymph node N bronchiectasis,
enlargement. It is very important to N airfluid levels,
highlight the role of MRI in complicated N consolidation,
pneumonia when there is the suspicion of N segmental/lobar destruction.

In patients with CF, bronchial wall MRI plays a key role in the accurate
thickening of the small airways enhances diagnosis of congenital chest masses,
their detectability by MRI so that small allowing for accurate prediction of outcome,
airways with thick walls can be visualised in parental counselling, planning of pregnancy
the lung periphery. Mucus plugging is also and newborn management.
well visualised by MRI due to the high T2-
weighted signal of its fluid content and is Congenital bronchopulmonary
associated, in most cases, with malformations (BPMs) represent a wide
spectrum of lung anomalies, including
bronchiectasis. The MRI appearance of
congenital pulmonary airways malformation
bronchiectasis is dependent on bronchial
(CPAM) (fig. 5), bronchopulmonary
level, bronchial diameter, wall thickness,
sequestration (BPS) and congenital lobar
wall signal and the signal within the
overinflation.
bronchial lumen.
The normal fetal lungs demonstrate
Another sign is consolidation, which is increasing relative signal intensity on fluid-
mainly caused by alveolar filling with sensitive sequences as the pregnancy
inflammatory fluid. The visualisation of progresses, secondary to the accumulation
consolidation in MRI is based on the high of fluid within the developing lungs.
T2-weighted signal from the inflammatory
fluid. A developmental role of MRI in the A BPM can present with different features
patients affected by CF maybe related to and can appear as solid, cystic or mixed
follow-up after transplantation because it is lesions. Masses may appear as iso-signal or
radiation free. lower signal compared to normal lung tissue
in the third trimester of pregnancy. A high-
Neoplasm Although not used routinely, MRI signal solid mass on MRI is not diagnostic
may be sensitive in the detection of for a specific type of BPM. The identification
pulmonary metastases. The sensitivity will of a macroscopic cyst or systemic arterial
depend on lesion size; the sensitivity in blood supply to the mass improves
smaller nodules (,5 mm) remains to be specificity. MRI provides alternative or
established. Much work is needed to additional diagnoses compared with
establish the role of MRI and its relationship ultrasound in 3850% of fetuses.
with CT.
In conclusion, although spatial resolution is
Other important indications are anatomic lower than CT, MRI has the advantage of
abnormalities such as pulmonary being able to:
sequestration, acquired chronic diseases,
pulmonary arteriovenous malformations N evaluate different aspects of tissue,
(PAVMs), vascular malformations and fetal N improve the characterisation of a
malformations. pathological process,
N combine the morphological and
Fetal lung MRI functional findings in one study.
Prenatal diagnosis of congenital lung The absence of ionising radiation is the
anomalies has increased in recent years as strength of MRI. For all these reasons, MRI
imaging methods have benefitted from in paediatrics is a major acquisition.
technical improvements. Fetal MRI offers
several technical advantages over
ultrasound, including: Further reading
N Bauman G, et al. (2009). Non-contrast-
N a larger field of view, enhanced perfusion and ventilation
N fewer limitations due to maternal assessment of the human lung by means
habitus, of Fourier decomposition in proton MRI.
N the ability to visualise fetal anatomy Magn Reson Med; 62: 656664.
regardless of fetal presentation.

N Goo HW (2013). Advanced functional N Levine D, et al. (2003). Fetal thoracic
thoracic imaging in children: from basic abnormalities: MR imaging. Radiology;
concepts to clinical applications. Pediatr 228: 379388.
Radiol; 43: 262268. N Puderbach M, et al. (2008). Can lung MR
N Henzler T, et al. (2010). Diffusion and replace lung CT? Pediatr Radiol; 38: Suppl.
perfusion MRI of the lung and mediasti- 3, S439S451.
num. Eur J Radiol; 76: 329336. N Puderbach M, et al. (2007). Proton MRI
N Hubbard AM, et al. (1999). Congenital appearance of cystic fibrosis: comparison
chest lesions: diagnosis and characteriza- to CT. Eur Radiol; 17: 716724.
tion with prenatal MR imaging. Radiology; N Rupprecht T, et al. (2002). Steady-state
212: 4348. free precession projection MRI as a
N Kauczor H, et al. (2009). Imaging of potential alternative to the conventional
pulmonary pathologies: focus on mag- chest X-ray in pediatric patients with
netic resonance imaging. Proc Am Thorac suspected pneumonia. Eur Radiol; 12:
Soc; 6: 458463. 27522756.
N Levin DL, et al. (2001). Evaluation of N Wagner M, et al. (2001). A fast magnetic
regional pulmonary perfusion using ultra- resonance imaging technique for children
fast magnetic resonance imaging. Magn with mediastinal lymphoma: work in
Reson Med; 46: 166171. progress. Med Pediatr Oncol; 37: 532536.

Ultrasonography
Carolina Casini, Vincenzo Basile, Mariano Manzionna and Roberto Copetti
Newborns, infants and children present a Technique and ultrasound anatomy

similar clinical picture on lung ultrasound
examination as adults. A high-resolution The examination is performed with the child
linear probe (7.512 MHz) is used for lung in a supine position. The probe is placed
examination through longitudinal and perpendicular, oblique and parallel to the
transverse sections of the anterior, lateral ribs in the anterior, lateral and posterior
and posterior wall of the chest. (lower and upper) thorax. Posterior areas
may be better viewed in lateral recumbence.
Precocious exposure of infants and The position with an erect trunk is practically
children to radiation may lead to a higher never necessary.
risk of developing malignancies later in
life due to both the latency of the effect of The normal lung of the newborn does not
radiation exposure on the cells and the differ substantially from that of adults. The
fact that growing children are inherently pleural line is easily visualised beneath the
more radiosensitive, because they have a ribs and it is easy to highlight the sliding
larger proportion of dividing cells. movement of the pleural layers (sliding sign)
Ultrasound avoids the use of ionising (Lichtenstein et al., 1995).
radiation. The presence of horizontal reverberation
The interest of the neonatal and paediatric artefacts of the pleural line (A lines) that are
community in lung ultrasound is growing repeated at constant intervals below the
very slowly. However, the use of ultrasound pleural line is normal (fig. 1) (Lichtenstein et
in respiratory diseases of the newborn and al., 1995).
the child needs to be encouraged not just as At birth, is possible to observed vertical
a valid diagnostic alternative but as a artefacts (B lines) pathognomonic of
necessary ethical choice (Cattarossi et al., interstitial syndrome in adults
2011). (Lichtenstein et al., 1995, 1997; Reissig
et al., 2003; Soldati et al., 2009), even in
newborns who are absolutely healthy
Key points (Copetti et al., 2007) (fig. 2). The fetal lung
is very rich in fluids and, therefore, B lines
N A high-resolution linear probe is also can be seen in healthy term newborns
employed for lung ultrasound born either vaginally or by caesarean
examination in children and infants. section, but more frequently in the latter.
This is due, in large part, to the greater
N Lung ultrasound avoids the use of
quantity of liquid contained in the lung to
ionising radiation.
prevent squeezing of the rib cage during
N Lung ultrasound demonstrates very passage through the birth canal. It can be
good accuracy in several respiratory more often seen on the right side without a
diseases. typical localisation and disappears
completely within 2436 h.

a) b)
Pleural line
Pleural line
Rib
A lines
A lines
Acoustic shadowing
Figure 1. Normal lung. a) Longitudinal scan showing the ribs and their acoustic shadowing, the pleural line
and A lines. b) Transverse scan showing the pleural line and A lines.
Transient tachypnoea of the newborn in both lungs, though not always

symmetrically. The boundary between the
Transient tachypnoea of the newborn (TTN) inferior pulmonary fields, where the artefacts
is a common cause of neonatal respiratory are coalescent, and the superior fields is so
distress, which has a similar frequency all sharp that the lung picture is specific. It is
over the world. TTN has low morbidity but it important to note that the pleural line is
can be severe and should be differentiated normal in the areas of white lung. This
from other pulmonary or cardiac diseases ultrasound finding was named double lung
(such as pneumothorax, pneumonia, sepsis, point because it looks like two different
respiratory distress syndrome (RDS) and contiguous lungs in the same patient (fig. 3).
congenital heart disease).
Respiratory distress syndrome
All infants with TTN show, on the first
ultrasound examination, bilateral coalescent RDS, also known as hyaline membrane
B lines on the lung base (echographic disease, is due, at least in part, to
white lung) and a normal or near-normal
appearance of the lung in the superior fields
(Copetti et al., 2007). This finding is evident
Pleural line Double lung point
Normal lung White lung
B lines
Figure 3. Longitudinal scan showing a clear sharp

Figure 2. Transverse scan in a healthy newborn at difference between the upper and lower lung fields
birth. There is evidence of numerous B lines. (double lung point).

a) b)
Coalescent B lines
Figure 4. a) Superior and b) inferior field of the lung in a newborn with RDS. In both areas, there is
evidence of coalescent B lines (white lung). The pleural line is poorly defined and coarse.
insufficiency of pulmonary surfactant and is defined and coarse. Multiple subpleural

mainly confined to preterm infants. All hypoechoic areas, which are generally small,
infants show B lines, which are coalescent, are observed mainly in the posterior and
diffuse and symmetrically distributed in lateral scans, indicating lung consolidations.
both lungs. This pattern is echographic Larger consolidations with a tissular pattern
white lung. The pleural line is always and with evidence of air or fluid
extensively thickened, irregular, poorly bronchograms may be observed more
a) b)
Coalescent B lines
White lung
Spared area
c) d)
Subpleural
consolidations
Muitiple B lines
Figure 5. a) Evidence of a spared area in infant affected by BPD. b) Area of white lung in BPD.
c) Area of interstitial syndrome in BPD. d) Subpleural consolidations in BPD.

Lung consolidation
Air bronchograms
Lung hepatisation
Air bronchograms
Figure 6. Liver-like appearance of the lung and

Figure 8. Typical ultrasound appearance of
parallel course of air bronchograms in pulmonary
pneumonia in children.
atelectasis.
frequently in the posterior fields. These Bronchopulmonary dysplasia

findings are immediately present at birth
before clinical deterioration (Copetti et al., Bronchopulmonary dysplasia (BPD) is a
2008a). Scans of the anterior thoracic wall form of chronic lung disease that develops
are sufficient for the diagnosis. The three in preterm neonates treated with oxygen and
most important signs for ultrasound positive pressure ventilation. The diagnosis
diagnosis are: is made on the basis of oxygen requirement
at 36 weeks gestation.
N bilateral coalescent B lines involving all of
the lung (white lung); In infants with BPD, there is evidence of
N absence of spared areas (areas of lung multiple B lines that have a
with a normal appearance); and nonhomogeneous distribution and diffuse
N pleural line abnormalities (fig. 4). changes in the pleural line, which is
thickened with multiple small subpleural
consolidations. Generally, there is evidence
of spared areas and interstitial syndrome,
Small subpleural and pleural line changes correlate to
consolidation disease severity (fig. 5) (Copetti et al.,
2008a).
Pleural effusion
Coalescent B lines Liver
Normal lung
Lung consolidation
Air bronchograms
Figure 7. Typical picture of bronchiolitis with

evidence of a small subpleural consolidations and
an area of coalescent B lines near an area of
normal lung. Figure 9. Lobar pneumonia in a child.

Bronchiolitis
Small pleural effusion
Bronchiolitis is an acute, infectious,
inflammatory disease of the upper and lower
respiratory tract that may result in
obstruction of the small airways. Diagnosis
Lung consolidation is made based on age and seasonal
occurrence, tachypnoea, and the presence of
Spleen
profuse coryza and fine rales, wheezes or
both upon auscultation of the lungs.
In our experience, the ultrasound findings

Air bronchograms are peculiar and this is important because in
some patients with more severe symptoms,
chest radiography may be avoided. In
patients with bronchiolitis, we have
Figure 10. Left basal pneumonia in a child. consistently observed bilateral involvement
of the lungs. Typically, areas of normal lung
Pulmonary atelectasis adjacent to areas with subpleural
consolidations (13 cm) are observed, due
Pulmonary atelectasis is frequent in to small atelectasis. These consolidations
ventilated newborns. Often, chest are surrounded by B lines that can also
radiographic diagnosis is difficult due to the appear coalescent (fig. 7). Larger
underlying respiratory disease. The dynamic consolidations are less frequent and
ultrasound signs are very useful for diagnosis generally observed in more severe disease.
and may be monitored at the bedside. Small pleural effusions can also be seen.
The ultrasound appearance of atelectasis is Recently, Caiulo et al. (2011) confirmed our
characterised by a liver-like appearance of observations and demonstrated that
the lung with lung pulse (Lichtenstein et ultrasound can avoid the need for chest
al., 2003), absence of lung sliding and a radiography.
parallel course of air bronchograms, as
described in adult patients (fig. 6). The Finally, unpublished observations made by
evidence of dynamic air bronchograms rules V. Basile and P. Comes (San Giacomo
out obstructive atelectasis (Lichtenstein et General Hospital, Monopoli, Italy) showed
al., 2009). This is very important because, that early, pulmonary paravertebral areas are
often, lung consolidation may be caused by affected by the appearance of B lines and
alveolar collapse (i.e. pulmonary small subpleural consolidations. These
haemorrhage and RDS) and, in ventilated findings often anticipate the involvement of
newborns, by hypoventilation due to low anterior areas.
ventilatory pressure.
Pneumonia
Pneumothorax
Children and infants with pneumonia may
Pneumothorax is frequent in newborns. present with a number of clinical symptoms
Chest radiography has the same diagnostic and signs such as fever, cough and
limitation as in adults. Transillumination is tachypnoea. A minority of children present
the bedside procedure used by with fever of unknown origin and may have
neonatologists. Ultrasound signs are the no respiratory symptoms or signs. Chest
same as described in adults: radiography is still considered to be the first
imaging step for diagnosing pneumonia in
N absence of lung sliding; children.
N absence of B lines; and
N presence of lung point without massive In children, pneumonia appears as a
pneumothorax (Lichtenstein et al., 1995). hypoechogenic area with poorly defined

borders and compact underlying B lines. N Copetti R, et al. (2007). The double lung
Vertical artefacts are often seen in varying point: an ultrasound sign dagnostic of
numbers, in areas adjacent to the transient tachypnea of the newborn.
consolidation. The pleural line is less Neonatology; 91: 203209.
echogenic in the area affected by lung N Copetti R, et al. (2008a). Lung ultrasound
consolidation. Lung sliding is reduced or in respiratory distress syndrome: a useful
absent. In the case of large consolidations, tool for early diagnosis. Neonatology; 94:
5259.
branching echogenic structures
N Copetti R, et al. (2008b). Ultrasound
representing air bronchograms, are seen in
diagnosis of pneumonia in children.
the infected area. Dynamic air Radiol Med; 113: 190198.
bronchograms can be observed. This N Lichtenstein DA, et al. (1995). A bedside
finding rules out atelectasis. Multiple ultrasound sign ruling out pneumothorax
lenticular echoes, representing air trapping in the critically ill. Lung sliding. Chest;
in the smaller airways, are also frequently 108: 13451348.
present. Fluid bronchograms, described in N Lichtenstein D, et al. (1997). The comet-
post-obstructive pneumonia, are identified tail artefact. An ultrasound sign of
as anechoic tubular structures with alveolar-interstitial syndrome. Am J
hyperechoic walls, without a colour-Doppler Respir Crit Care Med; 156: 16401646.
signal. Pleural effusion is easily detected N Lichtenstein DA, et al. (2003). The lung
pulse: an early ultrasound sign of
and appears as an anechoic area in the
complete atelectasis. Intensive Care Med;
pleural space (fig. 810) (Copetti et al.,
29: 21872192.
2008b). N Lichtenstein D, et al. (2009). The dynamic
air bronchogram. A lung ultrasound sign
In paediatric patients, as in adults, lung
of alveolar consolidation ruling out atelec-
ultrasound demonstrates a diagnostic
tasis. Chest; 135: 14211425.
accuracy higher, or at least not inferior to, N Reissig A, et al. (2003). Transthoracic
chest radiography (Volpicelli et al., 2012). sonography of diffuse parenchymal lung
disease: the role of comet tail artefacts. J
Further reading Ultrasound Med; 22: 173180.
N Soldati G, et al. (2009). Sonographic
N Caiulo VA, et al. (2011). Lung ultrasound interstitial syndrome. The sound of lung
in bronchiolitis: comparison with chest X- water. J Ultrasound Med; 28: 163174.
ray. Eur J Pediatr; 170: 14271433. N Volpicelli G, et al. (2012). International
N Cattarossi L, et al. (2011). Radiation evidence-based recommendations for
exposure early in life can be reduced by point-of-care lung ultrasound. Intensive
lung ultrasound. Chest; 139: 730731. Care Med; 38: 577591.

Isotope imaging methods
Georg Berding
Background can be studied using aerosols of larger

particles (.2 mm), or alveolar capillary
Radiotracer methods allow physiological membrane integrity which can be measured
processes in the lungs to be visualised and with water-soluble radiotracers. A more
the regional pathologic changes due to recent approach focuses on the detection of
disease, resulting into functional florid inflammation or vital malignant tissue
impairment, to be detected. Most in the lungs/thorax using fluorodeoxyglucose
frequently, ventilation and perfusion of the (18F-FDG) and positron emission
lungs are investigated. Inhaled nuclides of tomography (PET).
inert gases that emit gamma rays or
aerosols of fine particles (,1 mm) Indications
containing Technetium-99m (99mTc) are
used to display the ventilated volume of the In children, ventilation/perfusion (V9/Q9)
lungs. When injected intravenously, 99mTc- scintigraphy is used to characterise primary/
labelled albumin aggregates are retained in congenital abnormalities of the lungs and
the capillary bed of the lungs and thereby pulmonary vessels, as well as the heart and
visualise arterial perfusion of the large vessels (fig. 1). Generally, V9/Q9
parenchyma (via vasa publica). Other scintigraphy can be used to quantify lung
processes are less frequently investigated, function pre- and post-intervention. In
e.g. mucociliary clearance function, which particular, essential information can be
provided by perfusion scintigraphy before
and after:
Key points
N pulmonary arterioplasty,
N The use of radiopharmaceuticals N intravascular stent placement,
enables information on ventilated N coil occlusion of unwanted vascular
volume and regional perfusion of the communications,
lungs to be obtained. N surgical creation of a shunt.
N V9/Q9 scintigraphy enables accurate Notable per cent fractions of V9 and Q9in the
diagnosis of congenital abnormalities left and right lung can be determined. In the
of the lungs, vessels and heart, as well case of right-to-left shunts, these can be
as in patients with bronchiectasis or measured semi-quantitatively based on
CF. kidney and brain uptake during the lung
N V9/Q9 scintigraphy is easy to perform, perfusion scan. These measurements can be
typically without sedation, and causes valuable in the assessment and treatment of
only low-radiation exposure. patients with cyanosis, e.g. due to the
tetralogy of Fallot or arteriovenous
N A more recent method, 18F-FDG PET/ malformations. Assessment of suspected
CT, contributes to the diagnosis of pulmonary embolism in children is, in
malignancies and inflammation. contrast to adults, a rare indication. Damage
to lung tissue due to infection can be

% %
100 100
0 0
% %
100 100
0 0
Figure 1. V9/Q9 scintigraphy in a 6-year-old boy with decreased physical capacity and recurring pneumonia
of the right lung. Planar 99mTc-Technegas scintigraphy showed hypoplasia of the right lung (30% versus
70%; upper row). A subsequent 99mTc-MAA scan revealed a complete lack of perfusion (from vasa
publica) in the right lung (lower row). In angiographic CT the pulmonary veins could not be detected.
Angiography showed an outflow of the contrast medium from the right to the left pulmonary artery. V9/Q9
scintigraphy helped to identify noninvasively congenital abnormality of the pulmonary vessels.
assessed. Regional lung function (V9/Q9) in the literature so far suggests that 18F-
can be evaluated in children with FDG-PET can be useful for the detection of
bronchiectasis as well as CF. Beyond which active infective foci in children with chronic
delayed mucociliary clearance can been seen granulomatous disease and monitoring of
in both diseases; however, this is still an disease activity in children with CF.
experimental indication. Effects of foreign
Patient preparation
body aspiration (e.g. air trapping) can be
demonstrated using V9/Q9 scanning. In There is no specific preparation that is
paediatric oncology with respect to thoracic necessary for children before V9/Q9scanning.
masses, 18F-FDG-PET is used specifically in However, mucus secretions should be
children with lymphoma for staging, removed with mucolytics and chest
treatment response assessment and physiotherapy to facilitate ventilation
planning of radiation therapy. In scanning. Patients must avoid moving
inflammatory diseases, evidence provided during acquisition. In children who are old

enough this might be achieved by careful perfusion imaging would add 1.56 mSv.
explanation of the procedure together with Together both scans would cause
the parents. Neonates and infants are 2.03 mSv, which is below the natural
conveniently studied when they have fallen annual radiation exposure in Germany.
asleep after feeding. Medicinal sedation
should be the exception. If unavoidable, at Imaging equipment/acquisition
o7 months of age the benzodiazepine Lung scintigraphy is normally acquired with
midazolam can be given intravenously at a a dual-head large-field gamma camera from
dose of 0.1 mg?kg-1. Nevertheless this has to standard projection angles (anterior,
be agreed upon with the referring physician oblique, lateral, etc.). The use of single-
and the risk of hypoventilation has to be photon emission computed tomography
taken into account. (SPECT) offers the advantage of avoiding
Radiopharmaceuticals super-imposition and thereby creating the
possibility of finer (sub-segmental)
Nowadays, ventilation studies are most assessment. However, SPECT requires more
frequently performed using 99mTc- patient co-operation or anaesthesia.
Technegas. This is a pseudo-gas produced Furthermore, SPECT/CT allows correlation
using a dedicated generator containing a of functional and morphological findings,
graphite crucible filled with 99mTc which can provide unique diagnostic
pertechnetate in a chamber, which is information, but specifically in children the
heated to a high temperature. Thereby an additional radiation exposure has to be
ultrafine aerosol of solid graphite particles balanced against it. Regarding paediatric
with a 530 nm diameter is produced oncology, 18F-FDG-PET/CT can be performed
which, when inhaled, shows a static using specific CT-parameters for children to
alveolar deposition. Due to the much reduce radiation exposure (ultralow-dose
simpler logistics, Technegas has largely CT) or, in the case when a diagnostic CT
replaced the use of inert gases such as investigation is required, this can be
xenon-133 (133Xe) or krypton-81m. performed in one session with PET obviating
Nevertheless, 133Xe allows sequential data the inconvenience of two single
acquisitions and thereby identification of examinations.
air trapping as a hallmark of regional
obstructive airway disease. However, 133Xe
Further reading
application to the lungs requires a bag-box
spirometer system, which is rarely N Bajc M, et al. (2010). Methodology for
available. With respect to producing ventilation/perfusion SPECT. Semin Nucl
aerosols of larger particles for mucociliary Med; 40: 415425.
clearance a nebuliser is required. For N Charron M (2006). Application of PET/
perfusion studies 99mTc-MAA CT in children. Paediatr Respir Rev; 7:
(macroaggregated albumin) is injected Suppl. 1, S41S43.
intravenously. It embolises a small N Ciofetta G, et al. (2007). Guidelines for
proportion of (pre)capillary vessels in the lung scintigraphy in children. Eur J Nucl
lung. Since the number of these vessels is Med Mol Imaging; 34: 15181526.
N Gelfand MJ, et al. Nuclear studies of the
lower in children compared to adults the
heart and great vessels. In: Miller JH, et
number of injected particles has to be
al., eds. Pediatric Nuclear Imaging. 1st
decreased. The radiation exposure induced Edn. Philadelphia, Saunders, 1994;
by lung scintigraphy is generally relatively pp. 83101.
low. For example, in a 5-year-old child N Krasnow AZ, et al. Diagnostic applica-
weighing 20 kg, adapted application of tions of radioaerosols in nuclear medi-
,10 MBq 99mTc-Technegas for ventilation cine. In: Freeman LM, ed. Nuclear
scintigraphy would result in an effective Medicine Annual. New York Raven
dose of 0.47 mSv. In addition, the Press, 1993; 123194.
application of 46 MBq 99mTc-MAA for

N Magnant J, et al. (2006). Comparative N Sanchez-Crespo A, et al. (2008). A
analysis of different scintigraphic technique for lung ventilation-perfusion
approaches to assess pulmonary ventila- SPECT in neonates and infants. Nucl Med
tion. J Aerosol Med; 19: 148159. Commun; 29: 173177.
N Parker JA, et al. (1996). Procedure guide- N Stauss J, et al. (2008). Guidelines for 18F-
line for lung scintigraphy: 1.0. Society of FDG PET and PET-CT imaging in paedia-
Nuclear Medicine. J Nucl Med; 37: 1906 tric oncology. Eur J Nucl Med Mol
1910. Imaging; 35: 15811588.
N Roach PJ, et al. (2010). SPECT/CT in V/Q N Trevis ST, et al. Lungs. In: Trevis ST, ed.
scanning. Semin Nucl Med; 40: 455 Pediatric Nuclear Medicine. 2nd Edn.
466. New York, Springer, 1995; pp. 159198.

Interventional radiology
Efthymia Alexopoulou, Argyro Mazioti and Dimitrios Filippiadis
The improvement of anaesthesiology interventional radiology in the treatment of

techniques, imaging guidance and paediatric patients.
instrumentation has contributed to the
evolution of several image-guided, Proper and adequate training of an
minimally invasive, percutaneous diagnostic interventional radiologist in paediatric
and therapeutic techniques, thus patients along with strict local sterility
dramatically changing the role of measures are prerequisites. Prophylactic
antibiotics are recommended in some of the
techniques, but are not needed in most of
the chest interventions. Although local
Key points anaesthesia would be fine for the majority of
the procedures, deep sedation or general
N Proper and adequate training of the anaesthesia is required in order to ensure
operator along with extensive local maximum cooperation and a safe
sterility measures and environment for technique performance.
anaesthesiology control are Occasionally, in older children or young
prerequisites for safe and effectively adults, local anaesthesia might be sufficient
performed interventional radiology. in certain techniques; however, this is not
recommended.
N In cases where determining a lesions
nature will alter a patients Parents, and older children, should be
management and benefits outweigh informed about the invasive procedure, as
risks, a percutaneous biopsy is well as the benefits and potential risks of
indicated; core biopsy is preferred the technique. Written consent from
over fine-needle aspiration. parents is required before beginning any
N Image-guided percutaneous drainage procedure. Pre-procedural planning
is a safe and efficacious technique for includes evaluation of the patients medical
the treatment of pleural effusions, record (including laboratory and imaging
abscesses and empyemas; in the case studies), control of renal function (in
of complex effusion, abscess or relation to intravascularly administered
empyema drainage can be combined contrast), cardiac function and coagulation
to fibrinolytic therapy. profile. Separate anaesthesiology evaluation
should be performed as well. Post-
N Tumour localisation or
procedural follow-up includes patient
thermoablation can be performed in
monitoring, control for any delayed
selected cases of paediatric patients.
complications and evaluation of the overall
N Transcatheter embolisation seems to clinical condition of the patient. As the
be a first-line therapy for the treatment patient is admitted for medical therapy,
of pulmonary AVM or major most of these interventional radiology
haemoptysis in patients with CF. techniques are not performed on an
outpatient basis.

Image-guided percutaneous biopsy Tumour localisation
Percutaneous biopsy in paediatric patients The technique of localisation can be used in

is most commonly performed for diagnosis cases of a small lung nodule under the
of a focal lesion rather than for evaluation of pleural surface, which will not be felt during
diffuse parenchymal disease. Especially in thoracoscopic surgery. Localisation can be
the immunosuppressed paediatric performed by means of image-guided
population, lung biopsy can be performed in percutaneous introduction of a hooked wire
cases where invasive pulmonary or needle and intralesional injection of
aspergillosis cannot be diagnosed with methylene blue dye.
imaging studies alone. Core biopsy is Tumour ablation
preferred over fine-needle aspiration.
Absolute indication for biopsy is the case Image-guided percutaneous thermoablation
where the management of a child will be in the lung is most commonly performed in
altered according to the lesions nature and secondary lesions that do not respond to
characterisation. Furthermore, benefits radiotherapy (metastatic lesions from
should outweigh the risks. osteosarcoma, Ewings sarcoma and
Contraindications of image-guided hepatoblastoma). In most of the described
percutaneous biopsy in the chest include series in the literature, radiofrequency
non-correctable coagulopathy, lack of safe ablation seems to be the most popular, as
trajectory and other comorbidities which opposed to the other ablative techniques.
might, for example, prohibit safe Concerning paediatric ablation, all sessions
anaesthesia. Alternatives to percutaneous are performed under general aesthesia and
biopsy include bronchoalveolar lavage or for the first 24 h a patient-controlled
transbronchial biopsy. analgesia is administered. Ablation
protocols in the lung are shorter when
Percutaneous biopsy is performed under compared to procedures in the liver due to a
local sterility measures and anaesthesiology lower vasculature. Complications include
control (generally intubation is required in pneumothorax, haemorrhage and air
order to control breathing). Whenever a embolism.
lesion is in contact with the pleural surface,
ultrasound can serve as a guiding modality Image-guided percutaneous drainage
of choice; advantages for this include the Occasionally, childhood pneumonias are
lack of ionising radiation, low cost and wide complicated by pleural effusions, abscesses
availability. In cases where a lesion is and empyemas which require drainage.
surrounded by lung parenchyma, CT is the Image-guided drainage of such collections is
guiding modality of choice. The shortest governed by high success (7499%) with a
trajectory that avoids fissures and blood suggested threshold of 95%, and low
vessels is chosen (fig. 1). Biopsy can be complication rates (110%) with a
performed with direct or coaxial technique. suggested threshold of 220%. Diagnosis of
Once the needle is at the lesions periphery such collections is performed with chest
the biopsy system (semi-automatic or radiographs, ultrasound or CT.
automatic depending upon operators
choice) is fired, thus obtaining the sample Indications for drainage include fluid
within the trocar. sampling, the presence of large or complex
collection (with pus or septae), and any
Success rates of image-guided percutaneous collection (of fluid or pus) with symptoms
biopsy in children are ,85%, whilst warranting drainage. Whenever culture and
complications include pneumothorax (10 laboratory testing is required a sample is
15%, usually not clinically significant) and obtained by needle aspiration. Sedation or
mild haemoptysis. Erect chest radiography general aesthesia is a prerequisite.
is performed 2 h post-biopsy for evaluation Ultrasound is preferred as a guiding
of delayed pneumothorax (figs 13). modality due to the lack of ionising

a) b) c)
Figure 1. A 7-year-old girl with LouisBarr syndrome, fever and cough. a) Initial chest radiograph and b)
subsequent CT scan revealed left lower lobe consolidation (black arrow, a). Consolidation was not resolved
after persistent appropriate treatment (antibiotics) and bronchoalveolar lavage was negative for common
bacteria, mycobacteria and fungi. An additional PCR test was negative for Cryptococcus aspergillus,
Candida and Pneumocystis carinii, whereas cytology was negative for malignancy. c) The child was
referred to our department for lung biopsy, which was performed under ultrasound guidance. The white
arrow indicates the needle inside the lesion. Histology proved lymphoproliferative syndrome. #: the spleen.
radiation, low cost and wide availability. a)

Under extended local sterility measures, a
tube (614 F in diameter) is introduced,
usually at the level of the midaxillary line
using a direct or seldinger technique, and
then connected to a water seal. Output
monitoring and catheter flushing (310 mL
of sterile 0.9% saline solution every 812 h)
are performed in order to keep the tube
patent. It must always be remembered that
the catheter should be placed at the superior b)
rib margin in the pleural space in order to
avoid intercostal vessels located at the lower
margin of the rib.
The technique for draining abscess or

empyema is similar; however, the need for
CT guidance is higher in these indications.
In any case, passage of the tube through
lung parenchyma or fissures must be
avoided (fig. 2).
In case of complex effusions, drainage of Figure 2. a) A 5-year-old boy with necrotic

abscesses and empyemas can be combined pneumonia and complicated right pleural effusion. A
to fibrinolytic therapy with tissue 10F pigtail catheter was placed under CT guidance
for drainage and adjuvant fibrinolytic therapy. A 10-
plasminogen activator (usual dose is
mm multiplanar reconstruction CT image in the
0.1 mg?kg-1, maximum 3 mg injected). axial plane displays the position of the catheter. b) A
Injection is performed through the tube which 10-year-old boy with necrotic pneumonia and right
then remains closed for 1 h and then suction pleural effusion. An 8F pigtail catheter was placed
is resumed. Fibrinolytic therapy is performed under ultrasound guidance for drainage. The arrow
with three doses injected every 12 h. indicates the catheter inside the effusion.

a) b) c)
Post embo
Figure 3. A teenager with CF and massive haemoptysis. a) Angiography after selective right bronchial
artery catheterisation shows hyperaemia with dilated and tortuous vessels at the right upper lobe. b)
Superselective catheterisation with a microcatheter was performed and subsequent embolisation with
polyvinyl alcohol particles followed. c) Final post-embolisation (post embo) angiography revealed complete
vessel obstruction.
Drainage complications include septic The majority of pulmonary AVMs are simple,
shock, bacteraemia, bleeding, multiple and located on lower lobes of the
superinfection, bowel or pleural lungs. Complications of transcatheter
transgression, bronchopleural fistula and embolisation include pleurisy, transient
complications associated with sedation or angina, severe perioral pain or leg pain,
general anaesthesia. brachial plexus injury or deployment
complications.
Transcatheter embolisation
Due to the decreased incidence of TB and
Transcatheter embolisation is mainly
bronchiectasis, CF has become the major
indicated for treatment of pulmonary
cause of haemoptysis in childhood. Minor
arteriovenous malformations (AVM) or in
bleeding in the form of blood streaking is
cases of major haemoptysis. Embolic
more common whilst major haemoptysis
materials include coils, particles, gel foam
occurs in ,1% of children with CF. The term
and detachable balloons, as well as others
major haemoptysis implies the presence of
depending upon pathological substrate,
acute bleeding (.240 mL?day-1) or recurrent
vessel size/location and material availability.
bleeding of small volumes (.100 mL?day-1
Scarce data are found in the literature over several days or weeks).
concerning pulmonary AVM in children and Pathophysiology of haemoptysis in CF
no data are found for the same pathological includes erosion of enlarged thin-walled
entity in infants. There is a clear association tortuous neovasculature of the
between pulmonary AVM and hereditary bronchovascular net, which are located in
haemorrhagic telangiectasia. Transcatheter bronchiectatic areas secondary to chronic
embolotherapy seems to be an attractive infection. Cases of minor bleeding are
alternative for these patients. Since this usually self-limited. However, cases of major
technique is governed by a 15% reperfusion haemoptysis can be self-limited or require
rate of the AVM it should be reserved for treatment, either conservative (bed rest,
symptomatic children. However, pulmonary intravenous antibiotics, blood transfusion,
AVMs are often embolised when they are vitamin K administration, temporarily
o3 mm due to the risk of paradoxical postpone positive pressure chest physio-
embolisation and stroke. Symptoms include therapy) or transcatheter embolisation
exercise intolerance, cyanosis or clubbing, of bronchial arteries (fig. 3). It is noteworthy
neurological or haemorrhagic complications that both therapeutic arms are governed
(which mainly occur in cyanotic patients). by similar success and recurrence rates.

Complications of transcatheter bronchial lesions in children. Pediatr Radiol; 36:
artery embolisation include post-embolic 491497.
syndrome (fever, thoracic pain and potential N Hoffer FA (2003). Biopsy, needle localiza-
dysphagia), iatrogenic ischaemic necrosis of tion, and radiofrequency ablation for
other organs and, very rare but severe, cases pediatric patients. Tech Vasc Interv
of spinal cord ischaemia. Radiol; 6: 192196.
N Hogan MJ, et al. (2012). Quality improve-
ment guidelines for pediatric abscess and
Further reading fluid drainage. Pediatr Radiol; 42: 1527
1535.
N American Association of Pediatrics N McConnell P, et al. (2002). Methylene
(1992). Guidelines for monitoring and blue-stained autologous blood for needle
management of pediatric patients during localization and thoracoscopic resection
and after sedation for diagnostic and of deep pulmonary nodules in children.
therapeutic procedures. Pediatrics; 89: J Pediatr Surg; 7: 17291731.
11101115. N Nanthakumar K, et al. (2001). Contrast
N Barben JU, et al. (2003). Major haemop- echocardiography for detection of pul-
tysis in children with cystic fibrosis: a 20- monary arteriovenous malformations.
year retrospective study. J Cyst Fibros; 2: Am Heart J; 141: 243246.
105111. N Roebuck DJ, et al. (2011). Interventions in
N Cahill AM, et al. (2004). CT-guided the chest in children. Tech Vasc Interv
percutaneous lung biopsy in children. Radiol; 14: 815.
J Vasc Interv Radiol; 15: 955960. N Schidlow DV, et al. (1993). Cystic fibrosis
N Faughnan ME, et al. (2004). Pulmonary foundation consensus conference report
arteriovenous malformations in children: on pulmonary complications of cystic
outcomes of transcatheter embolother- fibrosis. Pediatr Pulmonol; 15: 187198.
apy. J Pediatr; 145: 826831. N Spies JB, et al. (1988). Antibiotic prophy-
N Feola GP, et al. (2003). Management of laxis in vascular and interventional radi-
complicated parapneumonic effusions in ology: a rational approach. Radiology; 166:
children. Tech Vasc Interv Radiol; 6: 197 381387.
204. N Wood RE (1992). Hemoptysis in cystic
N Fontalvo LF, et al. (2006). Percutaneous US- fibrosis. Pediatr Pulmonol; 3: Suppl. 8,
guided biopsies of peripheral pulmonary 8284.

Aerosol therapy
Hettie M. Janssens
Aerosol therapy has gained importance in croup (Rittichier, 2004), and atelectasis
the treatment of paediatric respiratory (Hendriks et al., 2005). Aerosol therapy is
disorders over the last few decades. It is now considerably more complex than oral
the mainstay of asthma management in therapy, as drugs must be delivered to an
children (GINA, 2012) and is increasingly organ that has mechanisms to exclude
important for the treatment of other foreign material.
respiratory disorders, such as CF
(Heijerman et al., 2009) and broncho- As a rule of thumb, one needs to consider
pulmonary dysplasia (Tin et al., 2008). the five Ds for prescribing optimal aerosol
Other indications are impaired mucociliary therapy:
clearance such as in primary ciliary
dyskinesia (PCD), neuromuscular diseases,
N disease,
tracheobronchomalacia and non-CF
N drug,
bronchiectasis (Boogaard et al., 2007),
N deposition,
N device,
N disability of the patient.
Key points
One needs to be informed about the
pathophysiology and the severity of the lung
N To match the correct aerosol delivery
disease, the pharmacological aspects of the
device to a patient, a clinician should
various drugs, and how the disease, drug,
be informed about the disease, drug,
device and patients characteristics will
deposition and device characteristics,
influence the deposition of the aerosol into
and the ability or disability of the
the lungs. This information and the
patient to perform an inhalation
technical qualities of the aerosol delivery
manoeuvre.
devices are needed to be able to match the
N A pMDI/VHC with an attached device to the patient. Last but not least, the
facemask is the first choice in asthma abilities and disabilities of the child and
maintenance treatment in young parents should be known in order to use the
children. device correctly. Available inhaled drugs
include steroids, bronchodilators,
N DPIs are convenient for older children,
mucolytics, inhaled antibiotics,
who can perform a fast, deep
prostaglandins, antiproteases, analgesia,
inhalation.
anticarcinoid therapy, proteins and
N New (smart) nebulisers are promising surfactant. Many more inhaled therapies are
but monitoring of safety and efficacy in development. For the treatment and
is important. choice of drugs of the different diseases,
please see the sections relating to those
N Correct inhalation technique and
diseases elsewhere in this Handbook.
adherence are mandatory for
successful aerosol therapy. This section will discuss some basic
principles of aerosol technology and the

different delivery devices with information Smaller particles have a higher probability of
on choosing the right device. For detailed being deposited in the smaller airways and
background information on all available alveoli, or being exhaled. It is important to
aerosol delivery devices, please refer to the realize that this 15 mm range is mostly
recently published European Respiratory derived from studies with healthy adult
Society (ERS)/International Society of subjects. In the case of severe airway
Aerosols in Medicine (ISAM) Task Force obstruction, like in CF, the deposition
consensus statement on inhaled therapies pattern is inhomogeneous and will move
(Laube et al., 2011). from the periphery of the lung to more
central airways. Little is known about
Basic aerosol technology particle size deposition relation for young
An aerosol is best described as a cloud of children. However, it is likely that the
fine particles that are small enough to respirable fraction is in the smaller particle
remain suspended in the air for a range. It has been shown in models and
considerable length of time. The probability deposition studies that smaller particles
of inhaled particles being deposited in the more effectively bypass the upper airways
respiratory tract and their distribution and reach the periphery of the lungs, even in
pattern depends on: the particle young children or in CF patients with airflow
characteristics, such as size, density and obstruction (Schuepp et al., 2005; Janssens
shape; the anatomy of the respiratory tract; et al., 2003; Laube BL et al., 1998; Roller et
and the breathing pattern. Particles are al., 2007).
deposited by three mechanisms: Most aerosol delivery devices used for the
N impaction, treatment of children are suboptimal, as
N sedimentation, they were primarily designed for adults and,
N diffusion. therefore, do not take into account the
special characteristics needed for children.
Large particles and/or particles with high
velocity tend to be deposited by impaction Aerosol delivery devices: match the device
in the upper and central airways at airway to the patient
bifurcations. Smaller particles have a higher The current methods to deliver therapeutic
probability of reaching the peripheral aerosols can be classified in four categories:
airways where they are deposited by
sedimentation under the influence of N nebulisers;
gravitational forces. The smallest particles N pressurised metered-dose inhalers
can make it all the way to the alveoli. The (pMDIs), which can be used with a press-
most important deposition mechanism of and-breathe technique, as a breath-
these particles is by diffusion through actuated device, or in combination with a
Brownian movements of the molecules. spacer or valved holding chamber (VHC);
The size distribution of aerosol particles is
N dry-powder inhalers (DPIs);
usually described as the mass median
N soft-mist inhalers.
aerodynamic diameter (MMAD), which The choice of device for children depends on
refers to the droplet diameter above and the availability of the specific drug and the
below which 50% of the mass of the drug is ability of the child to perform an inhalation
contained. The geometric standard manoeuvre (fig. 1). In addition, not all
deviation (GSD) is a measure of the devices are available in worldwide (Laube et
distribution in size of the aerosol particles. al., 2011). Firstly, it should be known for
Aerosol particles between 1 and 5 mm are which device the intended drug is available.
thought to have a high probability of being Secondly, one needs to determine whether
deposited in bronchi and, therefore, are the patient can perform an inhalation
often referred to as respirable particles. manoeuvre and whether they can achieve an
Large particles have a higher probability of inspiratory flow of around 3060 L?min-1
being deposited in the upper airways. reproducibly. The latter is necessary for

performing the right technique to use a DPI. Nebulisers convert a liquid medication into a
Most DPIs give the best particle size and mist for inhalation and can deliver a wide
dose with a flow of 60 L?min-1. Particle size range of drug formulations. The traditional
increases and dose decreases with lower view of nebulisers is that they are expensive
inspiratory flows (Ross et al., 1996). Young and bulky as well as inconvenient to handle
children and dyspnoeic patients are often and maintain. Therefore, they are relegated
not able to achieve an inspiratory flow of to third place in the market. However,
60 L?min-1 (Amirav et al., 2005). For a perhaps as a direct consequence of a lack of
breath-actuated pMDI, an inspiratory flow of pharmaceutical vested interest, nebulisers
30 L?min-1 is required. For children under the remain poorly researched and understood
age of 78 years, it is generally by many clinicians.
recommended to use a pMDI in
The use of nebulisers should be restricted to
combination with a VHC and to use an
delivering drugs that are only available as
additional face mask if the child cannot
liquids or that cannot be delivered by a
breath consciously through the mouth
pMDI with a VHC or autohaler, or DPI.
(usually below 34 years). In addition, it is
Examples of such drugs are recombinant
not recommended to use the pMDI directly
human deoxyribonuclease (rhDNase),
in the mouth for children of all ages because
tobramycin inhalation solution (TSI),
the press-and-breath technique requires
colomycin and hypertonic saline. Drugs
careful handmouth coordination, which is
such as rhDNase or TSI are registered for
often not correctly performed. This leads to
delivery by well-defined nebulizer
inefficient deposition with high oro-
compressor combinations.
pharyngeal and low lung deposition. For
young children, a pMDI/VHC with a face A child should be switched from a mask to a
mask is now the mainstay of asthma home mouthpiece as soon as they are old enough
treatment. Nebulisers are used when a child to inhale through the mouth voluntarily, as it
refuses to use a VHC, the medication is not will increase the efficiency of aerosol delivery
available in other forms, large doses need to (Chua et al., 1994). An optimal seal between
be given or aerosol inhalation needs to be the face and mask is important to maxi-
combined with oxygen suppletion. mise the efficiency of aerosol delivery
Drug available in pMDI or DPI Drug available in fluid only
Inhalation through Inhalation through

mouth possible? mouth not possible
(>4 years) (<4 years)
Nebuliser
(+ mask,
Sufficient Insufficient
<4 years)
inspiratory flow# inspiratory flow#
>78 years <78 years
pMDI spacer
pMDI spacer + mask
Breath-actuated pMDI spacer (nebuliser + mask)
pMDI (nebuliser)
DPI
(nebuliser)
Figure 1. How to choose the right aerosol delivery device for a child. #: sufficient inspiratory flow depends
on the intended inhaler; it is usually .30 L?min-1 but for some inhalers (DPIs) is o60 L?min-1.

(Everard et al., 1992). Bronchodilators and advantages of using a nebuliser over using a
inhaled steroids can be delivered faster, more pMDI/VHC or DPI are that oxygen can be
efficiently and more safely by pMDI/VHC, given during inhalation and that high doses
breath-actuated pMDI or DPI. Even in acute can be administered over a prolonged time.
asthma attacks, delivery of bronchodilators Furthermore, only tidal breathing is required
by pMDI/VHC is equally as effective as so nebulisers can be used in patients
nebulisers (Cates et al., 2006). If a child is of all ages and disease severities. The
very distressed during administration of disadvantaged are numerous. For the home
aerosols by pMDI/VHC, a nebuliser can be a setting, the equipment is expensive,
more acceptable alternative. cumbersome and noisy, and needs a power
supply. The administration time can be as
There are different types of nebulisers, which long as 2030 min several times a day. This
differ in the way the aerosol is generated. is not beneficial for patient compliance.
The differences in the delivered aerosol Furthermore, it requires regular cleaning,
between currently available nebuliser with a high risk of contamination if the
systems are significant. There are the jet, cleaning instructions are not followed
ultrasonic and vibrating-mesh nebulisers, correctly (Vassal et al., 2000). Jet nebulisers
with or without smart nebuliser technology. use an electric compressor or compressed
Advancement in nebuliser and inhalation gas source (oxygen or air) to create the
technology has developed modern smart aerosol. There are numerous technical
nebulisers that are more effective than other factors that can affect aerosol output and
devices. Nebulised drug delivery is possibly particle size distribution of a jet nebuliser.
the most confused area of clinical practice, These may result in highly variable doses
largely as a result of there being little or no and poor reproducibility of particle size.
regulatory control. In the European These technical factors include the fill
guidelines for nebulisers (Boe et al., 2001), it volume, the operational flow, the viscosity,
is recommended that an inhaled drug is concentration and temperature of the
registered for use with a specified nebuliser. solution or suspension, the nebuliser
So, a pharmaceutical company should have design, and breathing pattern (OCallaghan,
tested the drug with a certain nebuliser in 1997). It is important that the correct
order to have recommendations for its use operational flow or compressor is used
and guarantees for efficacy when used while nebulising. This is mentioned in the
properly. This is, however, still not obligatory users instructions. Usually, a flow of 6
when a new nebuliser is introduced to the 8 L?min-1 is the optimal operational flow. A
market. Using an alternative system can lower flow leads to larger particles and
have an unpredictable effect both in terms of prolonged nebulisation time. The fill volume
efficacy and toxicity, especially for potentially determines the concentration, particle size
toxic drugs like inhaled antibiotics. If there is and nebulised dose. For each nebuliser and
a good reason to choose another device drug, there is a recommended fill volume. If
than the recommended, the efficacy and a smaller volume is used, there might be
toxicity should be closely monitored. New less drug delivered, largely because there is
nebuliser technology offers greater a residual volume of 11.5 mL that remains
convenience and portability and a significant in the nebuliser. There are different types of
increase in aerosol delivery. On one hand, jet nebulisers. The most widely used
this new, more efficient technology offers unvented nebulisers, with continuous
obvious benefit to patients. On the other output of aerosol, are inefficient, as there is
hand, adoption of this new and improved loss of aerosol during exhalation or when a
nebuliser technology without due patient is not breathing through the
consideration of the consequences of nebuliser. More efficient systems have been
increased dosing presents potential risk. developed, such as open-vent and breath-
enhanced nebulisers with in- and exhalation
The jet nebulisers are the oldest, and most valves. The latest technology uses breath-
well-known and widely used nebulisers. The actuated systems, which only deliver during

inspiration, either by using a mechanism that controlled (slow and deep) and aerosol is
opens when an inspiratory flow threshold is delivered only during the first 50% of
reached, or electronically by following the inspiration: the deeper the inhalation, the
patients breathing pattern and giving a shorter the nebulising time (Nikander et al.,
precise dose during inhalation (Laube et al., 2010). Almost no drug is lost during
2011; Geller, 2008). The use of breath- exhalation. Smart nebulisers can achieve a
actuated systems results in improved lung lung deposition of 6080% (Bakker et al.,
deposition, dose reproducibility and reduced 2011), compared with 515% with the
loss by exhalation. Breath-actuated devices traditional jet nebulisers (Laube et al., 2011).
are suitable for children from 4 years of age. Furthermore, more peripheral lung
deposition can be achieved, which may
Ultrasonic nebulisers use a piezoelectric result in improvement in peripheral airway
crystal to convert fluid into a fine mist. The obstruction, as in CF (Bakker et al., 2011).
output of ultrasonic nebulisers is faster than Another advantage is that adherence is
that of jet nebulisers, which is useful for logged electronically and the data can be
administration of large volumes. However, downloaded afterwards (Dhand, 2010). This
ultrasonic nebulisers are not suitable for can be a useful tool to get insight into the
nebulising suspensions, such as steroids, adherence to aerosol therapy and discuss
and viscous fluids, such as antibiotics. this with the patient, in order to improve the
Furthermore, the fluid may become too efficacy of the treatment.
warm in the ultrasonic nebuliser because
the crystal produces heat by vibrating in high Although they have many advantages,
speed. This may inactivate certain drugs, vibrating mesh and smart nebulisers have
like rhDNase. Ultrasonic nebulisers are not still not been extensively tested in children
widely used because they are expensive and and there is little clinical information
produce relatively large particles compared available. Lung deposition is improved but
with jet nebulisers (Laube et al., 2011). dose recommendations are lacking or based
on in vitro or adult data. There might be
The recently introduced mesh nebulisers use indications that, especially in young children,
either a vibrating or fixed membrane with a higher lung deposition of aerosols can lead to
piezoelectric element with microscopic holes toxic side-effects (Guy et al., 2010). Therefore,
to generate an aerosol. Vibrating-mesh clinicians should be cautious when using
devices have a number of advantages over these new devices, especially in children.
other nebuliser systems. They are very There are many good arguments to use one
efficient and quiet, and are generally portable, of the new-generation nebulisers but efficacy
as they operate as effectively when using and toxicity should be carefully monitored,
batteries as mains electricity. Lung especially when using potentially toxic drugs,
deposition is substantially increased, varying such as inhaled antibiotics.
between 30% and 80%, depending on the
device. However, they also are significantly pMDI, pMDI/VHC and breath-actuated
more expensive than other types of pMDI Almost all drugs available for aerosol
nebulisers, and require a significant amount therapy of asthma are available in pMDIs. In
of maintenance and cleaning after each use a pMDI, the drug is present in a solution or
to prevent build-up of deposit and blockage suspension with propellants and surfactants.
of the apertures (especially when In the case of a suspension, the pMDI should
suspensions are aerosolised), and to prevent be shaken before use to mix the drug with the
colonisation by pathogens (Geller, 2008; propellant. When the pMDI is fired, an
Rottier et al., 2009). They are most widely accurately metered dose is released at a high
used for the treatment of patients with CF. velocity. The mass of drug and its aerosol
characteristics are largely independent of the
There are breath-enhanced mesh nebulisers inspiratory effort made by the patient.
and those with dosimetric aerosol delivery,
the so-called smart nebulisers. In smart Inhalation from a pMDI should be precisely
nebulisers, the breathing pattern is timed with a press-and-breath manoeuvre.

Most patients are not able to coordinate (Pierart et al., 1999; Wildhaber et al., 2000).
actuation of the pMDI with the breathing Anti-static VHCs have been developed to
manoeuvre, causing high oropharyngeal and overcome this problem (Laube et al., 2011). In
low lung deposition. This coordination a model study, it was shown that when
problem can be resolved by using a breath- electrostatic charge is minimised, the
actuated pMDI (Newman et al., 1991) or a deposition in the lung is dependent on the
pMDI/VHC. Breath-actuated pMDIs pMDI, and relatively independent of the VHC,
automatically release the drug when a patient used (Janssens et al., 2004). The differences
is inhaling. A patient should be able to in aerosol deposition of the different pMDIs
perform a maximal exhalation followed with a were explained by the particle size of the
slow inhalation with a breath hold. Lung aerosol cloud. In general, it was shown that
deposition is improved using a breath- the smaller the particles, the higher the dose
actuated pMDI but oropharyngeal deposition delivered to the lungs, and the lower the
is still high. VHCs are used to facilitate oropharyngeal deposition. In particular, a
inhalation from a pMDI with normal tidal hydrofluoroalkane (HFA)beclomethasone
breathing and decrease the oropharyngeal pMDI with a high proportion of extra-fine
deposition. The use of a VHC is particles (MMAD 1.1 mm) resulted in a
recommended for all patients in principle, considerably higher lung dose (Janssens et al.,
especially using inhaled corticosteroids, but 2003). These in vitro data were confirmed by
particularly for those who have difficulties an in vivo lung deposition study with the same
with the press-and-breath technique with the breath-actuated pMDI in children aged
pMDI, such as children. For children with o5 years (Devadason et al., 2003). The higher
asthma below the age of 7 years, the pMDI/ lung deposition translates to a reduction by
VHC is the system of first choice. A VHC with half of the effective dose in inhaled steroids if
a mouthpiece should be used whenever extra-fine particles are used (GINA, 2012;
possible. In children below the age of 3 Busse et al., 1999) but randomised controlled
4 years, a face mask should be added to the trials failed to show a superior clinical effect
VHC. In children younger than 2 years, it can (Boluyt et al., 2012). Even when an anti-static
be very difficult to obtain a proper seal VHC and a pMDI with small particles is used,
between the face and mask (Amirav et al., cooperation remains the most important
1999; Janssens et al., 2000). Even a small leak determinant for the efficiency of dose delivery
of 0.2 cm will dramatically reduce the output (Janssens et al., 2000). Furthermore, if there
of the pMDI/VHCmask combination is a suboptimal facemask seal, the increase
(Esposito-Festen et al., 2004). Each VHC in dose obtained by minimising the
comes with its own face mask. There are electrostatic charge of a VHC by detergent
substantial differences in the efficiency of coating is almost completely lost (Smaldone
achieving a good facemask seal with the et al., 2005). Parents of young children should
different designs (Amirav et al., 2001; be carefully instructed about the importance
Esposito-Festen et al., 2005). After the face of an optimal mask seal, good administration
mask is positioned on the face, one puff of the technique and good cooperation during the
pMDI needs to be fired into the VHC. As soon administration procedure.
as the aerosol cloud is released from the
pMDI, aerosol particles start to sediment DPI Most anti-asthma drugs are available
onto the VHC wall as a result of gravitational as DPIs. DPIs are small, portable, handheld
forces. This effect is stronger when a plastic devices. There are numerous different
VHC is used, due to electrostatic charge. devices available, each with its own
Therefore, any delay between the moment the directions for use. Older children and adults
dose is fired and the moment of effective prefer DPIs because they are easy to use
inhalation will reduce the inhaled dose in daily life, which may help adherence. In a
substantially (Wildhaber et al., 1996). DPI, the drug is present in single or multiple
However when a plastic VHC is coated with dosing chamber. DPIs are formulated with
detergent, electrostatic charge is minimised their drug particles either attached to a carrier
and lung deposition will increase substantially or as agglomerates in the form of pellets.

To facilitate deposition in the lungs, drug diameter. For this DPI, a slow, deep
particles are de-agglomerated during inhalation manoeuvre is needed. The
inhalation. Airflow through a DPI combines colistimethate is a micronised dry powder in
with its internal resistance to create turbulent a low-resistance inhaler. For this DPI, a fast,
energy inside the DPI. This internal energy is deep inhalation is required.
required to de-agglomerate the particles and
aerosolise the dose. The turbulent energy In recent years, many different types of DPI
created during inhalation is the product of have been introduced. They differ in the
inhalator resistance and particle size. The
the patients inspiratory flow multiplied by
newest technology uses feedback mech-
the DPIs resistance (Laube et al., 2011). Thus,
anisms and dose counters to check
for a set energy, a DPI with a high resistance
compliance and stimulate good inhalation.
will require a lower inspiratory flow than a
The clinician needs to be informed on which
DPI with a lower resistance. The mass of drug
drugs are available in the different devices.
and the MMAD and GSD of the released
In addition, most of the new DPIs are not
aerosol cloud depends on the inspiratory flow
well studied in children.
of the patient. When there is insufficient
inspiratory flow through the DPI Soft-mist inhalers Currently, there is only
(,60 L?min-1 for most DPIs), the mass of one commercially available soft-mist
drug that is released is reduced and the inhaler. This inhaler is available for the
MMAD is increased. Sufficiently high and delivery of fenoterol 50 mg/ipratropium
reproducible inspiratory flows through a DPI bromide, and tiotropium bromide. The
can be obtained in asthmatic children aged soft-mist inhaler atomises the drug
o7 years (Amirav et al., 2005). Clearly, such solution using mechanical energy imparted
devices can only be used when a patient is by a spring. When the spring is released,
able to generate sufficient flow for optimal the solution is forced through an extremely
drug dispersion. Careful inhalation fine nozzle system. This produces a fine
instructions are important for correct use and mist that is slow moving, giving the patient
effective aerosol delivery of DPIs. Mistakes in time to inhale after a press-and breath,
dose preparation, no maximal exhalation leading to lower deposition in the mouth
before inhalation, insufficient inspiratory and throat, and relatively high lung
effort and storage in a humid environment deposition (,39%) (Laube et al., 2011).
can lead to decreased lung deposition or Soft mist-inhalers have not been tested in
even none at all (Laube et al., 2011). The children.
recommended inhalation manoeuvre for a
DPI is to inhale as quickly and deeply as Inhalation instructions and adherence
possible for optimal de-agglomeration of the For optimal effect of aerosol therapy, correct
particles. Consequently, this causes high use of the aerosol delivery device is crucial.
impaction of particles in the oropharynx, Any mistake during the inhalation procedure
which may increase local side-effects. The can influence the delivered dose sub-
high inspiratory flow also causes the aerosol stantially. It is known that inhalation
to be deposited mainly in the larger airways instruction needs to be repeated several
rather than the periphery. This may vary times before the inhalation is performed
between different DPIs depending on particle correctly (Kamps et al., 2000). For detailed
size and internal resistance. inhalation instructions for each device,
please see the ERS/ISAM Task Force
Recently, DPIs were introduced for inhaled consensus statement on inhalation therapy
tobramycin (Konstan et al., 2011) and (Laube et al., 2011).
colistimethate (Schuster et al., 2012).
Tobramycin inhalation powder uses a new If the correct device is chosen for the patient
spray drying technique (Geller et al., 2011). and inhalation instructions have been given,
This results in hollow porous particles that the patient still needs to use the device daily
behave like small particles because a lower at home. It is known that adherence to
density decreases the aerodynamic inhalation therapy is generally low, which

can lead to more severe disease and hos- N Bakker EM, et al. (2011). Improved
pital admissions (Murphy et al., 2012). In a treatment response to dornase alfa in
good partnership with patients, parents and cystic fibrosis patients using controlled
the doctor, the treatment needs to be inhalation. Eur Respir J; 38: 13281335.
discussed and explained. N Boe J, et al. (2001). European Respiratory
Society Guidelines on the use of nebuli-
Conclusion zers. Eur Respir J; 18: 228242.
N Boluyt N, et al. (2012). Assessment of
There are many different types of aerosol controversial pediatric asthma manage-
delivery devices. In the last few years, many ment options using GRADE. Pediatrics;
new devices have been introduced. Aerosol 130: e658e668.
delivery devices can be divided in four N Boogaard R, et al. (2007). Pharma-
groups: nebulisers (jet, ultrasonic, mesh cotherapy of impaired mucociliary clear-
and smart); pMDIs (combined with a VHC ance in non-CF pediatric lung disease. A
or breath actuated); DPIs; and soft-mist review of the literature. Pediatr Pulmonol;
inhalers. The prescribing physician needs 42: 9891001.
detailed knowledge about: N Busse WW, et al. (1999). Efficacy
response of inhaled beclomethasone
N aerosol and deposition characteristics of dipropionate in asthma is proportional
the various aerosol delivery systems; to dose and is improved by formulation
N availability of drugs in the different with a new propellant. J Allergy Clin
devices; Immunol; 104: 12151222.
N Cates CJ, et al. (2006). Holding chambers
N advantages and disadvantages of the
(spacers) versus nebulisers for b-agonist
devices;
treatment of acute asthma. Cochrane
N the pathophysiology of the lung disease;
Database Syst Rev; 2: CD000052.
N the skills of the patient in various age N Chua HL, et al. (1994). The influence of
groups. age on aerosol deposition in children with
cystic fibrosis. Eur Respir J; 7: 21852191.
Only when this knowledge is available can N Devadason SG, et al. (2003). Distribution
the appropriate delivery device for the of 99mTc-labelled Qvar delivered using an
patient be selected. In addition, optimal AutohalerTM device in children. Eur Respir J;
aerosol therapy is only possible with 21: 10071011.
repeated inhalation instructions and well- N Dhand R (2010). Intelligent nebulizers in
informed patients and parents, which will the age of the Internet: the I-neb Adaptive
encourage adherence. Aerosol Delivery (AAD) system. J Aerosol
Med Pulm Drug Deliv; 23: Suppl 1, iiiv.
N Esposito-Festen JE, et al. (2004). Effect of a
Further reading facemask leak on aerosol delivery from a
N Amirav I, et al. (1999). Delivery of pMDI-spacer system. J Aerosol Med; 17: 16.
aerosols to children with MDI and hold- N Esposito-Festen J, et al. (2005). Aerosol
ing chambers (MHC) is critically depen- delivery to young children by pMDI-
dent on the facemask seal. Am J Respir spacer: is facemask design important?
Crit Care Med; 159: A142. Pediatr Allergy Immunol; 16: 348353.
N Amirav I, et al. (2001). Aerosol therapy N Everard ML, et al. (1992). Drug delivery
with valved holding chambers in young from holding chambers with attached
children: importance of the facemask facemask. Arch Dis Child; 67: 580585.
seal. Pediatrics; 108: 389394. N Geller DE, et al. (2011). Development of an
N Amirav I, et al. (2005). Measurement of inhaled dry-powder formulation of tobra-
peak inspiratory flow with in-check dial mycin using PulmoSphere technology. J
device to simulate low-resistance (Diskus) Aerosol Med Pulm Drug Deliv; 24: 175182.
and high-resistance (Turbohaler) dry pow- N Geller DE (2008). The science of aerosol
der inhalers in children with asthma. delivery in cystic fibrosis. Pediatr
Pediatr Pulmonol; 39: 447451. Pulmonol; 49: Suppl. 9, S5S17.

N Global Initiative for Asthma. Global strat- the I-neb Adaptive Aerosol Delivery
egy for asthma management and preven- (AAD) system affects lung deposition of
99m
tion 2012. www.ginasthma.org Tc-DTPA. J Aerosol Med Pulm Drug
N Guy EL, et al. (2010). Serum tobramycin Deliv; 23: Suppl. 1, S37S43.
levels following delivery of tobramycin N OCallaghan C (1997). Delivery systems:
(Tobi) via eFlow advanced nebuliser in the science. Pediatr Pulm; 15: 5154.
children with cystic fibrosis. J Cyst Fibros; N Pierart F, et al. (1999). Washing plastic
9: 292295. spacers in household detergent reduces
N Heijerman H, et al. (2009). Inhaled electrostatic charge and greatly improves
medication and inhalation devices for delivery. Eur Respir J; 13: 673678.
lung disease in patients with cystic N Rittichier KK (2004). The role of corti-
fibrosis: a European consensus. J Cyst costeroids in the treatment of croup.
Fibros; 8: 295315. Treat Respir Med; 3: 139145.
N Hendriks T, et al. (2005). DNase and N Roller CM, et al. (2007). Spacer inhalation
atelectasis in non-cystic fibrosis pediatric technique and deposition of extrafine
patients. Crit Care; 9: R351R356. aerosol in asthmatic children. Eur Respir
N Janssens HM, et al. (2000). Aerosol J; 29: 299306.
delivery from spacers in wheezy infants: N Ross DL, et al. (1996). Effect of inhalation
a daily life study. Eur Respir J; 16: 850856. flow rate on the dosing characteristics of
N Janssens HM, et al. (2003). Extra-fine dry powder inhaler (DPI) and metered
particles improve lung delivery of inhaled dose inhaler (MDI) products. J Aerosol
steroids in infants: a study in an upper Med; 9: 215226.
airway model. Chest; 123: 20832088. N Rottier BL, et al. (2009). Changes in perfor-
N Janssens HM, et al. (2004). Determining
mance of the Pari eFlow rapid and Pari LC
factors of aerosol deposition for four pMDI-
Plus during 6 months use by CF patients.
spacer combinations in an infant upper
J Aerosol Med Pulm Drug Deliv; 22: 263269.
airway model. J Aerosol Med; 17: 5161.
N Schuepp KG, et al. (2005). In vitro
N Kamps AW, et al. (2000). Poor inhalation
determination of the optimal particle size
technique, even after inhalation instruc-
tions, in children with asthma. Pediatr for nebulized aerosol delivery to infants.
Pulmonol; 29: 3942. J Aerosol Med; 18: 225235.
N Konstan MW, et al. (2011). Safety, efficacy N Schuster A, et al. (2013). Safety, efficacy
and convenience of tobramycin inhala- and convenience of colistimethate sodium
tion powder in cystic fibrosis patients: dry powder for inhalation (Colobreathe
The EAGER trial. J Cyst Fibros; 10: 5461. DPI) in patients with cystic fibrosis: a
N Laube BL, et al. (1998). The efficacy of randomised study. Thorax; 68: 344350.
slow versus faster inhalation of cromolyn N Smaldone GC, et al. (2005). Variation in
sodium in protecting against allergen pediatric aerosol delivery: importance of
challenge in patients with asthma. facemask. J Aerosol Med; 18: 354363.
J Allerg Clin Immunol; 101: 475483. N Tin W, et al. (2008). Adjunctive therapies in
N Laube BL, et al. (2011). What the chronic lung disease: examining the evi-
pulmonary specialist should know about dence. Semin Fetal Neonatal Med; 13: 4452.
the new inhalation therapies. Eur Respir J; N Vassal S, et al. (2000). Microbiologic
37: 13081331. contamination study of nebulizers after
N Murphy AC, et al. (2012). The relationship aerosol therapy in patients with cystic
between clinical outcomes and medica- fibrosis. Am J Infect Control; 28: 347351.
tion adherence in difficult-to-control N Wildhaber JH, et al. (1996). Effect of
asthma. Thorax; 67: 751753. electrostatic charge, flow, delay and multi-
N Newman SP, et al. (1991). Improvement ple actuations on the in vitro delivery of
of drug delivery with a breath actuated salbutamol from different small volume
pressurised aerosol for patients with spacers for infants. Thorax; 51: 985988.
poor inhaler technique. Thorax; 46: 712 N Wildhaber JH, et al. (2000). High-percen-
716. tage lung delivery in children from
N Nikander K, et al. (2010). Mode of detergent-treated spacers. Pediatr
breathing-tidal or slow and deep-through Pulmonol; 29: 389393.

Epidemiology
Steve Turner
The childs respiratory system is constantly associated with CF (refer to relevant

exposed to infective agents and acute lower sections in the Handbook). Infectivity,
respiratory tract infections are normal in diagnosis, investigation, management and
children. The global burden of acute pharmacology are covered elsewhere.
respiratory infections in children is huge and
Acute infections
the World Health Organization (WHO)
estimates that approximately one-third of all Bronchiolitis
deaths in children are due to acute Definition. Bronchiolitis is a clinical
respiratory infections. In contrast, chronic diagnosis based on history and examination,
respiratory infection (arbitrarily defined here which has been defined by a Delphi
as symptoms lasting for more than 4 weeks) consensus in the UK as a seasonal viral
is never normal and is usually associated illness characterised by fever, nasal
with bacterial infection. Bacteria causing discharge and dry, wheezy cough. On
chronic infection are usually part of the examination there are fine inspiratory
normal upper airway flora and what is not crackles and/or high pitched expiratory
well understood is what transforms them wheeze.
from commensal to pathogenic. This
Infective agents. Approximately 75% of cases
section will describe the epidemiology and
are associated with respiratory syncytial
microbiology of acute and chronic lung
virus (RSV) infection and the remainder are
infection. For the purpose of this section,
associated with other viruses, including
croup, epiglottitis and tracheitis are
parainfluenza virus type 3, human
considered airway infections and are not metapneumovirus and adenovirus. Infection
covered, and neither are TB nor infections with more than one virus is increasingly
recognised with the advent of more sensitive
PCR testing.
Key points
Incidence. Approximately 20% of all infants
N Acute lung infections have a very high develop bronchiolitis and 3% of all infants in
incidence in children. Europe are admitted to hospital with
bronchiolitis. The median age of admitted
N Chronic lung infections (i.e. lasting infants is 23 months, the age range is not
more than 4 weeks) are also common normally distributed and very young infants
in children. are much more commonly admitted than
N Sex, age, geography and vaccinations older infants. Figure 1 demonstrates the
are important determinants of lung seasonality of RSV infections. In many
infection incidence. European countries there is evidence of
alternating years of higher and lower
N The incidence of many infections incidence. An RSV vaccine is not widely
changes over time and this reflects available at present but may be introduced
changes in pathogen and/or host. in the near future, and this is likely to change
the epidemiology of bronchiolitis.

800
<1 year
14 years
514 years
600
1544 years
4564 years
Reports n
65+ years
400
200
0
40
41
42
43
44
45
46
47
48
49
50
51
52
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Time week
Figure 1. Laboratory reports of respiratory syncytial virus by week of specimen and age in 20092010.
Reproduced from Salisbury et al. (2013) with permission from the publisher.
Risk factors. Young age, male sex, exposure bronchiolitis suggest that RSV does not
to tobacco smoke and reduced lung function cause asthma.
prior to onset of symptoms are associated
Pneumonia
with increased risk for bronchiolitis. More
Definition. There are a number of definitions
serious features of bronchiolitis are
of pneumonia but no single gold standard
associated with prematurity (with or without
definition. Pneumonia is a clinical diagnosis
bronchopulmonary dysplasia),
which is defined by the WHO as the
haemodynamically significant heart disease
presence of cough, fever and tachypnoea.
and infection with RSV (compared with
Community-acquired pneumonia (CAP) is
other viruses). defined as the presence of signs and
Prognosis. Approximately 20% of infants symptoms of pneumonia in a previously
with bronchiolitis have respiratory healthy child due to an infection which has
symptoms for more than 1 month during been acquired outside hospital. Crackles
convalescence. An association with may be heard with a stethoscope in up to
two-thirds of cases. A chest radiograph is
increased risk for later asthma symptoms
not required for the diagnosis of
has been described but this relationship is
uncomplicated pneumonia. Among infants,
not straightforward. The association is seen
there is some overlap between bronchiolitis
more clearly in those who were hospitalised
and pneumonia in clinical presentation. A
for bronchiolitis rather than cared for in the
broader term acute lower respiratory tract
community. The association usually
infection includes pneumonia and for the
becomes weaker as the children become purpose of this chapter is considered
older. One explanation for these synonymous.
observations is that a common airway
abnormality or genetic predisposition may There are a number of classifications of
lead an individual to develop bronchiolitis pneumonia. Different infective agents may
in infancy and asthma in later childhood. be associated with different classifications
Observations that infants with RSV so there is clinical merit in distinguishing
bronchiolitis are less likely to develop between categories. Typical CAP is by far the
asthma compared to those with non-RSV most common presentation.

Table 1. Infective agents commonly associated with acute and chronic respiratory infection in children
Bronchiolitis Pneumonia Empyema Chronic bronchitis
Respiratory viruses
Respiratory syncytial virus ++++ ++
Parainfluenza ++ ++
Influenza + ++
Human metapneumovirus ++ ++
Bacteria
Streptococcus pneumoniae +++ +++ ++
Haemophilus influenzae ++ + ++
Streptococcus pyogenes ++ +
Moraxella catarrhalis ++ ++
Mycoplasma pneumoniae ++ +
Staphylococcus aureus + +
+++: very common pathogen; ++: moderately common pathogen; +: not an uncommon pathogen; : not
thought to be a pathogen.
N Typical/atypical. Atypical pneumonia is 85% of cases. Pneumonia can be caused by

characterised by respiratory distress and a number of bacteria and viruses (table 1)
hypoxia, sometimes associated with and approximately one-third of hospitalised
headache, vomiting or diarrhoea, with children have both viral and bacterial
essentially normal findings on infections identified. Viral identification is
auscultation but marked diffuse chest more common in younger children and is
radiograph changes. present in 80% of infants and 60% of 1
N CAP/hospital-acquired/tracheostomy- or 2 year-olds. Wheezing and conjunctivitis are
ventilator-associated pneumonia. CAP is more commonly associated with viral
defined as the signs and symptoms of pneumonia compared to bacterial
pneumonia in a previously healthy child. pneumonia. Typical pneumonias are usually
Hospital-acquired pneumonia infection is caused by Streptococcus pneumoniae,
defined (in adults) as pneumonia that is Haemophilus influenzae and Moraxella
acquired after at least 48 h of admission catarrhalis, whilst the most common agents
to hospital and is not incubating at the causing atypical pneumonia in children are
time of admission. Tracheostomy or Mycoplasma pneumoniae and respiratory
ventilator-associated pneumonia are self- viruses. Chlamydophila pneumoniae may also
descriptive. cause atypical pneumonia but Legionella
N Radiological. Chest radiographs (if taken) pneumophila is rarely seen in immune-
show patchy pneumonic changes in competent children. Children with influenza
approximately 60% of cases, lobar infection are at increased risk for
consolidation in approximately 20% and Staphylococcus aureus co-infection including
perihilar changes in a further 20%. pneumonia. Hospital-acquired and
tracheostomy-/ventilator-associated
Infective agents. The challenge in obtaining a pneumonias are often associated with
sample of lower airway secretions in a small methicillin resistant S. aureus and
and often unwell child means that until Pseudomonas species.
recently an infective agent was not identified
in most cases of pneumonia. Recent Incidence. Age and geography are major
introduction of PCR testing now means that determinants of the annual incidence of
infective agents can be identified in up to pneumonia in children. In Western

countries, the annual incidence ranges from Empyema thoracis
approximately 600 cases per 100 000 in the Definition. Empyema is thought to
neonatal period to 10 cases per 100 000 in complicate 1% of childhood bacterial
1014 year-olds. In contrast, the WHO cites pneumonias and can be defined as a
a median annual incidence for developing parapneumonic effusion, i.e. a collection of
countries of 0.28 episodes per child-year fluid within the pleural cavity. There is a
(fig. 2). Widespread introduction of continuum of parapneumonic effusion from
pneumococcal vaccination reduced the a reactive (exudative) effusion to purulent
incidence of pneumonia by approximately effusion (empyema) to organised effusion
one-third. (rind). Diagnosis requires imaging with
ultrasound plus pleural aspirate. Clinically,
Risk factors. Pneumonia is a seasonal
disease with peak presentations occurring at the child will present with a prolonged
the same time as bronchiolitis, i.e. pneumonic illness where the fever fails to
December and January in the Northern settle and pleuritic pain develops. There is
hemisphere. Boys are at increased risk for often an acquired scoliosis towards the
pneumonia compared to girls. Abnormal affected side. Bilateral empyema is very
lung function in early infancy and exposure uncommon. Rarely, an empyema may be
to tobacco smoke are associated with higher associated with no preceding febrile illness
risk of later radiologically confirmed and a lack of elevated inflammatory markers
pneumonia. The risk for pneumonia is and this should raise suspicion of
reduced in cases who consult with their underlying malignancy. In these cases a CT
primary care physician early in the illness scan with contrast of the chest and
and in those who have the pneumococcal mediastinum should be taken and reviewed
vaccine. before considering drainage and/or
anaesthetics.
Prognosis. Complete resolution is the usual
outcome for childhood pneumonia although Infective agents. The same infective agents
a small proportion (,1%) of children associated with bacterial pneumonia are
develop bronchiectasis. implicated in empyema causation (table 1).
Episodes per child-year

0.10
0.110.20
0.210.30
0.310.40
0.410.50
Figure 2. Incidence of childhood clinical pneumonia at the country level. Reproduced from the World
Health Organization (2008) with permission from the publisher.

Bacteria are identified in pleural fluid and/or Boys account for 70% of cases. Prior
blood culture in approximately five times as treatment with antibiotics and
many cases when PCR is used compared to pneumococcal vaccination are associated
standard bacterial culture, but even with with a reduced risk for empyema.
PCR no infective agent is identified in at
Prognosis. Empyema is a serious and
least 25% of cases. Where bacteria are
potentially life-threatening infection but
identified, S. pneumoniae is present in 50
most children survive the initial illness and
70% of cases and a recent study from
their long-term prognosis is usually
Australia reported that 97% of S.
excellent. Chest radiograph changes may
pneumoniae were non-vaccine related
persist for at least 12 months and there is a
serotypes; this demonstrates the efficacy of
risk of bronchiectasis.
pneumococcal vaccination but also the
ability for new serotypes to fill the void left Chronic infections
by vaccination.
Chronic bronchitis
Incidence. This is currently approximately Definition. This condition is not described in
three cases per 100 000. Figure 3 many text books and is not universally
demonstrates how incidence increased in accepted as a diagnosis at present, but can
Scotland, UK, during the early 2000s. be defined as a productive (i.e. wet) cough
which lasts for more than 3 weeks or
Risk factors. The mean age of children 1 month in an otherwise well child. An
presenting with empyema is 45 years alternative term is protracted bacterial
which is unexpected given the higher burden bronchitis, which includes an additional
of pneumonia among infants compared to caveat that the symptoms should respond to
older children; a lower threshold for a 1014 day course of treatment with
treatment with antibiotics in younger antibiotics. Chronic bronchitis is often
children may partly explain this apparent associated with coarse, loud rattly
inconsistency. There is evidence that the respiratory sounds that can be wrongly
prevalence in 14 year-olds is increasing. interpreted as wheeze and the child is
wrongly diagnosed with asthma. The
40 reluctance in parts of the clinical community
for accepting chronic bronchitis as an entity

35 is the potential for misdiagnosis in serious
Empyema admissions per million
conditions, such as foreign body aspiration,

30 CF, immune deficiency and pertussis. It is
possible that bacterial bronchitis and non-
25 CF bronchiectasis are at opposite ends of
the same disease spectrum.
20
Infective agents. Bacteria are identified in
15 approximately 70% of cases where
prolonged productive cough is reported and
10 bronchoscopy is performed; H. influenzae is

present in 3040% of cases, S. pneumoniae
5
in 2025% and M. catarrhalis in 1510%.

Respiratory viruses are likely to be important
0
in some cases but their role is not currently
1980 1985 1990 1995 2000 2005
understood.
Year
Incidence. Different definitions of chronic
Figure 3. Empyema admissions per million per bronchitis (or cough) have been used in
year in Scottish children between January 1981 epidemiological studies making the
and December 2005. Reproduced from Roxburgh incidence difficult to estimate. The incidence
(2008) with permission from the publisher. of chronic bronchitis is highest in children

aged 12 years. As many as 20% of Infective agent. Bordetella pertussis usually
preschool children may have a cough which causes pertussis but B. parapertussis and
lasts for more than 1 month. RSV can cause a pertussis-like illness.
Risk factors. Assuming that other alternative Incidence. There are approximately 200
diagnoses for chronic cough are excluded, million cases of pertussis each year and
the main risk factor is young age. There is no there are peaks (epidemics) every 4 years.
evidence of an immune deficiency but As in all respiratory infections, incidence is
absence of evidence is not the same as age-dependent; a survey of cases across
evidence of absence. Europe reported an overall incidence of 10
cases per 100 000 children but this was 100
Prognosis. This is uncertain but is probably cases per 100 000 among infants and one
very good for most cases. There is a case per 100 000 among older teenagers.
possibility that recurrent infection leads to
progressive airway damage (a vicious cycle Risk factors. The major risk factor for
hypothesis) and, in some cases, to pertussis is not being vaccinated (i.e. very
bronchiectasis. young infants and older children who have
not been vaccinated). Prior vaccination does
Pertussis not protect all individuals against pertussis
Definition. Pertussis (or whooping cough) is but is associated with less severe symptoms
characterised by paroxysms of coughing if these develop.
which can last for up to 4 months. There are
three stages to the infection: Prognosis. Pertussis remains a serious
condition on a world-wide scale and is
N the initial catarrhal phase lasts for 1 week associated with 200 000 deaths,
and is characterised by runny nose and predominantly in infants. Once paroxysms
nonspecific cough; fully resolve most children have made a
N the subsequent paroxysmal phase lasts complete recovery although some may
for 1 month and is characterised by develop bronchiectasis.
paroxysmal cough and often also an
inspiratory whoop and vomit at the end of Conclusion
paroxysms;
Acute lung infections are extremely common
N the convalescent phase lasts for up to
in children and chronic infections are also
3 months and is characterised by
common. The epidemiology of acute and
paroxysms of shorter and less frequent
chronic infections is a dynamic field where
duration.
incidence changes over time due to variation
The catarrhal and early paroxysmal phases in both pathogen and host.
are when the individual is highly infectious.
Inspiratory whoop and post-tussive Further reading
vomiting are not necessarily specific for
pertussis. In one community study of N Celentano LP, et al. (2005). Resurgence of
children aged less than 3 years, these pertussis in Europe. Pediatr Infect Dis J;
symptoms were present in 50% and 70%, 24: 761765.
N Chang AB, et al. (2008). Chronic wet
respectively, of cases of pertussis and 25%
cough: protracted bronchitis, chronic
and 40%, respectively, of cases with
suppurative lung disease and bronchiec-
chronic cough but not pertussis. In older tasis. Pediatr Pulmonol; 43: 519531.
children with pertussis who had been N Crocker JC, et al. (2012). Paediatric
vaccinated, less than 15% of cases had pneumonia or empyema and prior anti-
whoop or vomiting and generally, those biotic use in primary care: a case-control
children who have been vaccinated study. J Antimicrob Chemother; 67:
and have pertussis have a less severe 478487.
illness.

N Harnden A, et al. (2006). Whooping N Rudan I, et al. Epidemiology and etiology
cough in school age children with persis- of childhood pneumonia. Bulletin of the
tent cough: prospective cohort study in World Health Organisation. Vol 86,
primary care. Br Med J; 333: 174177. Number 5. 2008. www.who.int/bulletin/
N Harris M, et al. (2011). British Thoracic volumes/86/5/07-048769/en/index.html
Society. Guidelines for the management N 27a. Respiratory syncytial virus. In:
of community acquired pneumonia in Salisbury D. et al., eds. Immunisation
children: update 2011. Thorax; 66: Suppl. against infectious disease. London,
2, ii1ii23. Department of Health, 2013.
N Kuehni CE, et al. (2009). Causal links N Scottish Intercollegiate Guidelines
between RSV infection and asthma: no Network. Guideline 91. Bronchiolitis in
clear answers to an old question. Am J children: a national clinical guideline.
Respir Crit Care Med; 179: 10791080. 2006. www.sign.ac.uk/pdf/sign91.pdf.
N McIntosh K (2002). Community-acquired N Strachan RE, et al. (2011). Bacterial causes
pneumonia in children. N Engl J Med; of empyema in children, Australia, 2007
346: 429437. 2009. Emerg Infect Dis; 17: 18391845.
N Roxburgh CS, et al. (2008). Trends in N Yaari E, et al. (1999). Clinical manifesta-
pneumonia and empyema in Scottish tions of Bordetella pertussis infection in
children in the past 25 years. Arch Dis immunized children and young adults.
Child; 93: 316318. Chest; 115: 12541258.

Microbiology testing and
interpretation
Elpis Hatziagorou, Emmanuel Roilides and John Tsanakas
Respiratory tract infections constitute a the severity of lower respiratory tract

major health problem, with significant cost symptoms are more pronounced in
and mortality worldwide. These infections patients with asthma.
are mainly caused by viruses, bacteria, N Respiratory syncytial virus (RSV) follows a
mycobacteria and fungi. well-characterised epidemiologic pattern,
with annual outbreaks occurring between
Viral infections October and May in temperature
climates. At least half of the infant
The majority of childhood lower respiratory
population becomes infected during their
illnesses are caused by viral agents.
first RSV epidemic and almost all children
Technological developments in molecular
have been infected by 2 years of age.
biology show that known respiratory viruses
are more prevalent than previously thought
N Three type of influenza virus have been
identified; they are designated A, B and C.
across the childhood age range.
N Parainfluenza virus (PIV)1 and PIV2 are
N Rhinoviruses or common cold viruses generally associated with
are the most prevalent, usually causing laryngotracheobronchitis (croup), URT
mild disease. Although the severity of illness and pharyngitis, whereas PIV3 is a
upper respiratory tract symptoms after major cause of infant bronchiolitis and is
rhinoviral infection does not differ associated with the development of
pneumonia in susceptible subjects.
between patients with asthma and
normal subjects, both the duration and N Adenoviruses may cause pneumonia,
bronchiolitis or conjunctivitis.
N Human coronaviruses may cause milder
lower respiratory tract symptoms than
Key points
other viruses.
N Rapid antigen detection and
N Human metapneumovirus (MPV) causes
symptoms ranging from URT disease to
molecular tests are the methods of
severe bronchiolitis and pneumonia.
choice for the identification of viral
MPV is an important cause of RSV-like
infections.
illness.
N Blood culture is positive in ,10% of N Human bocavirus accounts for 13% of
paediatric patients with bacterial lower respiratory tract infection (LRTI) in
LRTIs. infants.
N IGRAs are the method of choice
N Viruses may be copathogens and this
creates difficulties in the case of positive
for discrimination between
results. More recent studies using nucleic
M. tuberculosis, M. bovis and
acid technologies have identified multiple
nontuberculous mycobacteria.
viruses in up to 27% of hospitalised
N BAL GM is a reliable test for the children with LRTI. The presence of more
diagnosis of invasive aspergillosis. than one virus may result in more severe
or prolonged infection.

It is difficult to determine the optimal children. Identification can be with either
method for virus detection. Although cell culture or a rapid antigen detection test,
culture remains the gold standard, it is time- after a throat swab. Retropharyngeal,
consuming and thus it has been replaced by parapharyngeal and peritonsillar abscesses
antigen-detecting methods and molecular have similar microbiology; most are
techniques. Their commercial availability, polymicrobial infections. In acute otitis
ease of performance and rapidity have made media, there is acute inflammation with 5%
antigen-based methods increasingly viral, 75% bacterial and, 20% mixed bacterial
popular. They can be performed within and viral aetiology. The most common
15 min to a few hours. Antigens of the organism is Streptococcus pneumoniae. The
common respiratory viruses can be detected most common causes of sinusitis are S.
by direct immunofluorescence or by pneumoniae, Haemophilus influenzae and
commercially available enzyme Moraxella catarrhalis. These organisms,
immunoassays. The sensitivities of these along with Staphylococcus aureus and S.
tests vary from 50% to 90%. Serological pyogenes, account for .90% of sinusitis in
methods attempt to detect viruses in the children. Since the introduction of vaccines
host by assessing the presence of specific that protect against H. influenzae type b
antibodies in blood, sputum and urine infection, epiglottitis has become a rare
samples. Identification of the pathogen disease. Other causative organisms include
responsible for a recent infection may be nontypable H. influenzae, Haemophilus
achieved through detection of specific IgM parainfluenzae, S. aureus and S. pneumoniae.
in serum 1 week after symptoms begin, or a S. aureus is the most common bacterium
four-fold or greater increase in IgG. causing tracheitis. A significant proportion
However, PCR has been widely used during of infections are polymicrobial.
the last decade and its clinical use is steadily
increasing. PCR methods allow specific Fresh pus, fluid or tissue from the sinuses
amplification of defined DNA sequences to (obtained by washing, aspiration, biopsy,
a level at which they can subsequently be scraping or debridement), and pharyngeal
detected and these tests can be applied to swabs from the tonsils and/or the posterior
any virus for which part of the genome pharynx are the main upper respiratory tract
sequence is known. Recent developments of biological specimens.
this method include semiquantitation of
Microscopy following Gram staining is
results with the use of specialised
useful for the examination of paranasal
equipment and primers specific for
sinus smears (which are normally sterile),
additional viral and bacterial species,
pharyngeal smears or material from
allowing for the detection of as many as 19
the oral cavity for the detection of
different microorganisms in a clinical
polymorphonuclear neutrophils (PMNs) and
sample. PCR may give quantitative, as well
some microbes (e.g. corynebacteria
as semiquantitative, results. In clinical
(diphtheroids)), and nasopharyngeal smears
practice, we may use any of these tests, for Bordetella pertussis. Following the
according to their feasibility in the particular isolation of the pathogen, serologic typing
laboratory. and antibiotic susceptibility testing are
Bacterial infections usually performed.
Specimens for bacteriological culture should Lower respiratory tract infections are the third
be collected as soon as possible after the most important cause of mortality globally
onset of disease and before the initiation of and are responsible for .4 million deaths
antimicrobial therapy. annually. The aetiology of pneumonia varies
based on patient age, vaccination status,
Upper respiratory tract infections Pharyngitis immunological status and the clinical
includes tonsillitis, tonsillopharyngitis and setting in which the causative agent was
nasopharyngitis. Streptococcus pyogenes acquired. Determining the aetiology of
causes 1530% of acute pharyngitis in pneumonia is difficult and the choice of

antimicrobial therapy is often empirical. In initial antibiotic treatment,
the neonate, the most common causes of immunocompromised cases or CF.
bacterial pneumonia are group B b-
haemolytic streptococci (GBS) and Gram- Recovery of ,104 bacteria per millilitre of
negative enteric bacilli, such as Escherichia BAL is most likely to represent
coli and Klebsiella pneumoniae. S. contamination, while .105 bacteria per
pneumoniae is the most common bacterial millilitre is indicative of active infection.
aetiology of community-acquired Antigen detection in blood and urine has a
pneumonia in all age groups, including limited role in the diagnosis of bacterial
children. H. influenzae type b was an pneumonia. The reported sensitivity for the
important cause in the pre-vaccination era detection of group A streptococci is 6095%
but is now rare. S. aureus pneumonia is also but can be as low as 31%. Urine detection of
infrequent but may progress rapidly. In the polysaccharide antigen C, which is
hospital-acquired pneumonia, Gram- present in all pneumococcal serotypes, is
negative organisms, such as K. pneumoniae, performed with the use of an
Pseudomonas and Serratia, and Gram- immunochromatographic method (Binax,
positive organisms, such as S. aureus, occur Portland, ME, USA) and has high sensitivity
most frequently. among children with documented invasive
pneumococcal infection. However, the
N There are .100 pathogens that may
capability of this method to discriminate
infect the lower respiratory tract and
between true pneumococcal disease and
produce secondary bacteraemia.
rhinopharyngeal carriage is questionable
However, blood cultures are positive in
and is not recommended in the recent
only ,10% of paediatric respiratory tract
guidelines for diagnosis of community-
infections.
acquired pneumonia.
N Urine specimens may be used for the
detection of antigens from S. pneumoniae Serological methods are also used for the
and Legionella. diagnosis of pathogens responsible for
N Candidate lower respiratory tract atypical pneumonias but are rarely used in
specimens for processing include clinical practice for the diagnosis of bacterial
sputum (noninvasive), bronchoalveolar pneumonia. A four-fold rise in titre or a titre
lavage (BAL) (invasive) and pleural fluid greater than 1:32 in convalescent serum is
(via thoracentesis) (invasive). diagnostic (sensitivity 8095% and 60%,
respectively). ELISA for IgM detection may
Macroscopic and microscopic examination diagnose infection using only one sample if
of a lower respiratory tract specimen (i.e. this is collected after the 10th day of illness.
sputum or BAL fluid) gives valuable
information. The appearance, colour, Nucleic acid persists in specimens after the
consistency (e.g. purulent, mucoid, serous initiation of treatment, and may be detected
or bloody), quantity, odour and presence of in smaller and noninvasive specimens. PCR
visible formations in lower respiratory tract using blood or pleural fluid specimens is
specimens should all be considered. Direct mainly applied for the detection of S.
examination of the specimen with Gram pneumoniae and H. influenzae, with the
staining along with compatible sensitivity and specificity of the method
symptomatology is sensitive in only 10% of depending on the specimen. Detection of
cases but has a specificity of 7080%. As it bacterial antigens in pleural fluid is
is an easy, cheap and fast method that potentially useful in the diagnosis of
provides information within 1 h, microscopy empyema.
allows proper diagnosis and treatment of
LRTI. A variety of nonspecific laboratory
evaluations have been used to support the
Culture for the identification of the diagnosis of bacterial pneumonia; these
responsible organism and susceptibility include an increased serum concentration of
testing are useful in the case of resistance to C-reactive protein, an increased erythrocyte

sedimentation rate and an increased blood later). In general, the TST should be
leukocyte count with a predominance of interpreted in the same way for patients who
polymorphonuclear leukocytes. However, all have or have not received a BCG
these techniques suffer from poor sensitivity vaccination; however, this will lead to some
and positive predictive values. children with false-positive TST results being
treated.
The diagnosis of empyema is strongly
supported by the presence of thick pus with IFN-c release assays The identification of
bacteria demonstrable by Gram staining, a genes in the M. tuberculosis genome that are
pH ,7.3 or a glucose concentration absent from those of the Mycobacterium
,60 mg?dL-1. The average white blood count bovis BCG vaccine and most nontuberculous
in empyema fluid is 19 000 cells per cubic mycobacteria has supported the
millimetre. These findings may be variably development of more specific and sensitive
present and must be interpreted in their tests for detection of M. tuberculosis. IGRAs
clinical context. are designed to measure the host immune
response to M. tuberculosis rather than the
Mycobacterial infections presence of the organism itself. In persons
with M. tuberculosis infection, sensitised
TB is the most prevalent chronic infection in memory/effector T-cells produce IFN-c in
the world, with two-thirds of the global response to M. tuberculosis antigens, which
population infected. Most infection is is the biological basis for IGRAs. Available
asymptomatic (latent TB infection (LTBI)). data suggest that the TST and IGRAs have
In adults and older children, reactivation of similar accuracy for the detection of M.
LTBI causes active pulmonary TB disease in tuberculosis infection or the diagnosis of
,10% of individuals. A variety of specimens active TB in children. Use of M. tuberculosis-
can be collected, including sputum, specific antigens leads to greater specificity
induced sputum, gastric aspirate, BAL, (.90%), which decreases the probability of
transbronchial biopsy, urine, blood, false-positive responses, particularly in
cerebrospinal fluid, tissue and other body young, BCG-vaccinated children. Although
fluids. Gastric aspirates are frequently the direct cost of IGRAs is greater than that
obtained, as children cannot easily produce of the TST, IGRAs may be cost effective in
sputum. Mycobacterium tuberculosis may be cases where there is difficulty in interpreting
recovered from gastric aspirates in almost a TST or where the clinical index of
40% of children with radiographic evidence suspicion is high but the TST is negative.
of significant pulmonary TB. The culture
yields are as high as 70% in infants with TB. Tests for the detection of M. tuberculosis
infection, such as IGRAs and the TST, are
Tuberculin skin test The tuberculin skin test
most helpful as adjunctive tests to confirm
(TST) remains the most widely employed
disease in a patient with a high probability of
test for the diagnosis of TB and LTBI in
active disease. The likelihood that a positive
children. The sensitivity and specificity of
TST represents true infection (positive
the TST are significantly affected by a predictive value) increases as the prevalence
number of factors. The tuberculin reaction of infection with M. tuberculosis increases in
should be read 4872 h following injection. that population. The same is true for IGRAs.
A number of factors have been associated Interpretation of the TST reaction is based
with false-positive tuberculin reactions and on risk of infection.
decreased TST specificity. The TST has the
lowest sensitivity in younger children. There Staining and microscopic examination of
is no reliable method of distinguishing sputum or BAL fluid Acid-fast staining using
bacille CalmetteGuerin (BCG)-induced TST the ZiehlNeelsen technique and
cross-reactivity from TST reactivity microscopic examination are the easiest,
secondary to mycobacterial infection; quickest and least expensive diagnostic
interferon (IFN)-c release assays (IGRAs) procedures. There must be 500010 000
have the ability to make this distinction (see bacilli present per millilitre of specimen to

allow detection of the bacteria in stained N a positive TST or IGRA result; and
smears, resulting in low sensitivity rates in N a history of contact with an infectious TB
children. case within the past year.
Culture for mycobacteria, identification and Fungal infections
susceptibility testing Culture is the most
important laboratory test for the diagnosis Filamentous fungi of the genus Aspergillus
and management of TB. Mycobacterial may cause transient asymptomatic
culture from gastric aspirates has provided a colonisation, pulmonary hypersensitivity
more useful method of diagnosis in children reactions, saprophytic colonisation of
with suspected pulmonary TB. The role of pathological airway structures, and life-
bronchoscopy in evaluating children with threatening tissue invasive infections
pulmonary TB is controversial. Cultures predominantly of the lung with or without
from BAL fluid in children with suspected dissemination in patients with congenital or
pulmonary TB has a low yield and does acquired deficiencies in host defences. Most
not significantly aid bacteriological cases of human disease are caused by
confirmation. In three studies evaluating the Aspergillus fumigatus, followed by Aspergillus
role of bronchoscopy, only 1362% of flavus and, less commonly, Aspergillus
cultures in children with pulmonary TB were nidulans, Aspergillus niger and Aspergillus
positive. Bronchoscopy can be useful to terreus. Hypersensitivity reactions caused by
define anatomy, bronchial obstruction or Aspergillus spp. mainly include allergic
clarify the diagnosis but it cannot be bronchopulmonary aspergillosis (ABPA).
recommended solely to collect culture Bronchopulmonary colonisation occurs in
specimens in children. In high-risk groups, patients with asthma, bronchiectasis, CF
such as those patients with and primary ciliary dyskinesia syndrome.
immunodeficiency, where a positive Invasive pulmonary aspergillosis is the
diagnosis is needed and TSTs are often most frequent entity. In severely
falsely negative, bronchoscopy can be immunocompromised patients, a variety of
useful. fungi can cause invasive sinopulmonary
disease, including the zygomycetes,
Detection of mycobacterial nucleic acid Direct Fusarium spp. and Pseudallescheria boydii.
detection of the DNA of M. tuberculosis in
clinical samples has been performed using Routine methods for rapid specific
nucleic acid amplification, most often by identification of Aspergillus spp. are generally
PCR. When compared with the clinical not available. The current diagnostic
diagnosis of pulmonary TB in children, the markers for invasive aspergillosis include
sensitivity of PCR for sputum or gastric conventional and more recent methods
aspirates has varied from 25% to 83% and under evaluation. Recently, more rapid and
the specificity from 80% to 100%. A sensitive methods have been developed, for
negative PCR never eliminates TB as a example, the detection of antigenic markers,
diagnostic possibility, nor does a positive such as galactomannan and b-1,3-D-glucan,
result completely confirm it. The major use and the detection of molecular markers of
for PCR in children may be when the Aspergillus DNA by PCR.
diagnosis of TB is not readily established on
clinical and epidemiological grounds, and Staining and microscopic examination of
perhaps for children with HIV infection for sputum or BAL fluid, and culture for fungi and
whom a greater variety of causes of identification Conventional methods of
pulmonary disease must be considered. diagnosis include direct microscopy and
histology, and culture of respiratory and
The gold standard for diagnosis of various fluids and tissues. While microscopy
childhood tuberculosis is a triad of: and culture obtained from the clinically
affected site remain the gold standard,
N abnormal chest radiograph and/or clinical technical problems in obtaining an
findings consistent with TB; appropriate specimen, the time of culture

and negative results all limit an efficient and consecutive positive samples were 0.75
rapid diagnosis; similarly, the diagnostic (95% CI 0.540.88) and 0.87 (95% CI 0.78
yield of histology is unsatisfactory, with an 0.93), respectively. A similar meta-analysis
approximate sensitivity of 50%. Histological evaluating PCR with BAL fluid revealed a
diagnosis requires invasive methods that are sensitivity of 0.91 (95% CI 0.790.96) and
often difficult in children and are nonspecific specificity of 0.92 (95% CI 0.870.96). For
for speciation. Although Aspergillus can paediatric patients, data concerning DNA
colonise the respiratory tract, its isolation detection of Aspergillus spp. with different
from sputum of BAL fluid in an PCR techniques are lacking.
immunocompromised patient with
pneumonia is highly suggestive of invasive The galactomannan test can be used in
disease. children with caution. Molecular markers
such as PCR present the same problems and
Given this background, detection of fungal difficulties as in adults. While progress has
cell wall antigens and DNA in blood and been achieved in terms of galactomannan
other tissues may enhance the diagnosis of and certain recommendations have been
invasive aspergillosis. made, further research is needed for the
validation of newer diagnostic procedures in
Galactomannan assay in serum and BAL fluid paediatric patients.
A serologic assay to detect galactomannan,
a molecule found in the Aspergillus cell wall,
is commercially available for diagnosing Further reading
invasive disease but most data refer to N Balfour-Lynn IM, et al. (2005). BTS guide-
adults. The galactomannan assay also has lines for the management of pleural
high diagnostic utility for analysis of BAL infection in children. Thorax; 60: Suppl.
fluid of paediatric patients with suspected 1, i1i21.
pulmonary aspergillosis. The presence of N Bradley JS, et al. (2011). Executive sum-
galactomannan in BAL fluid (BAL GM) is an mary: the management of community-
alternative serological diagnostic marker, acquired pneumonia in infants and chil-
especially for invasive pulmonary dren older than 3 months of age: clinical
aspergillosis, which constitutes the most practice guidelines by the Pediatric
common presentation of invasive Infectious Diseases Society and the
aspergillosis. False-positive tests occur Infectious Diseases Society of America.
more commonly in children than adults and Clin Infect Dis; 53: 617630.
a negative test does not exclude the N Chi XS, et al. (2007). Semiquantitative
one-step RT-PCR for simultaneous identi-
diagnosis. The reported sensitivity of BAL
fication of human influenza and respira-
GM is in general higher than that in serum
tory syncytial viruses. J Virol Methods; 139:
due to the increased fungal burden in the
9092.
bronchi of patients with pulmonary invasive N de Mol M, et al. (2012). Diagnosis of
aspergillosis. However, the role of BAL GM invasive pulmonary aspergillosis in chil-
in paediatric invasive aspergillosis has not dren with bronchoalveolar lavage galac-
been extensively evaluated. A recent tomannan. Pediatr Pulmonol [In press
retrospective study conducted by Desai et al. DOI: 10.1002/ppul.22670].
(2009) suggests that BAL GM is a valuable N Desai R, et al. (2009). The role of
adjunctive diagnostic tool. bronchoalveolar lavage galactomannan
in the diagnosis of pediatric invasive
Detection of fungal nucleic acid PCR aspergillosis. Pediatr Infect Dis; 28: 283
represents one of the most investigated 286.
rapid diagnostic methods with clinical utility N Deuffic-Burban S, et al. (2010). Cost-
for invasive aspergillosis. A recent meta- effectiveness of QuantiFERON-TB test
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or plasma samples for the detection of of latent tuberculosis infection. Int J
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N Doan Q, et al. (2012). Rapid viral diagnosis N Harris M, et al. (2011). British Thoracic
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Cochrane Database Syst Rev; 5: CD006452. dren: update 2011. Thorax; 66: Suppl. 2,
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Immunisation against
respiratory pathogens
Horst von Bernuth and Philippe Stock
Acute lower respiratory tract infection (ALRI)

is still the leading cause of global child Key points
mortality. ALRI caused by Streptococcus
pneumoniae, a Gram-positive bacterium, and N The natural course of RSV infection
respiratory syncytial virus (RSV), an can be modified by passive
enveloped single-stranded RNA immunisation with neutralising
paramyxovirus, and their prevention by antibodies by monthly intramuscular
vaccination will be addressed here. administrations of Palivizumab, a
humanised monoclonal IgG1 antibody
RSV infection directed against the F-protein of RSV.
Epidemiology and risk factors RSV infects N There is broad agreement that
99% of all children by the age of 2 years, prematurely born children with
with an estimate of 66 000199 000 deaths chronic lung disease in infancy and
being associated with RSV worldwide, 99% children with haemodynamically
of these occurring in developing countries. relevant heart disease during the first
Generally accepted independent risk factors 2 years of life may benefit from
for severe RSV infection requiring passive immunisation against RSV.
hospitalisation are 1) prematurity and 2) age N Serious (in particular invasive)
,6 months at the start of RSV season pneumococcal diseases can be
(ranging from October to March or avoided by active immunisation with
November to April). Other risk factors are: either polysaccharide-protein
male sex, haemodynamically significant conjugate vaccines during the first 2
congenital heart defects, chronic lung years of life or with 23-valent
disease (CLD) of prematurity (formerly pneumococcal polysaccharide vaccine
called bronchopulmonary dysplasia), Down after the first 2 years of life.
syndrome, presence of elder siblings/
residential crowding and exposure to N Active immunisation against
environmental tobacco smoke. Additional S. pneumoniae serotypes is highly
risk factors for RSV infection are recommended.
malformations, neuromuscular disease, liver
disease, chromosomal abnormalities,
congenital immunodeficiencies and inborn
required, or live attenuated vaccines even
errors of metabolism. For a comprehensive
led to vaccine-primed disease enhancement,
review of risk factors predisposing to RSV
which is unacceptable for children at risk.
infection, see Sommer et al. (2011).
However, the natural course of RSV infection
Immunisation The development of RSV can be modified by passive immunisation
vaccines to actively immunise the host has with neutralising antibodies by monthly
not yet led to satisfying results. In summary, intramuscular administrations of Palivizu-
either the immune responses were weak or mab, a humanised monoclonal IgG1 antibody
short lasting, repetitive immunisation was directed against the F-protein of RSV.

Palivizumab was originally approved for the Palivizumab is recommended only for
prophylactic treatment of infants born infants younger than 12 months with severe
prematurely (before 35 weeks of gestation) CLD or with haemodynamically significant
and for the prophylactic treatment of children heart disease and additional risk factors. In
up to 2 years of age treated for CLD of contrast, the Austrian guidelines
prematurity ,6 months before the recommend the use of Palivizumab for all
anticipated RSV season. This children 1) born prematurely below the age
recommendation was based on a double- of 24 months with CLD, 2) born prematurely
blind, placebo-controlled, multicentre, at ,28 weeks plus 6 days of gestation below
multinational trial mainly conducted in the age of 12 months, 3) born prematurely at
northern America in which 10% of children 2932 weeks plus 6 days of gestation and
with RSV infection born before the 35 weeks with certain risk factors, 4) born prematurely
of gestation were hospitalised. Approval was at 3335 weeks plus 6 days of gestation
later extended to children ,2 years of age below the age of 3 months at the beginning
with pulmonary hypertension, relevant left of the RSV season and with certain other risk
right or rightleft shunting, and pulmonary factors, 5) with haemodynamically
venous congestion. significant heart disease below the age of
24 months, 6) with diseases of the
Given the high costs of passive respiratory tract below 24 months (e.g. CF),
immunisation with Palivizumab, and the 7) with floppy infant syndrome below the
fact that Palivizumab never proved to lower age of 24 months, 8) with inborn or acquired
RSV-associated mortality but only protects a immunodeficiencies below the age of
subpopulation of patients from 24 months. Given the lack of evidence for
rehospitalisation, passive immunisation the effectiveness of passive immunisation
against RSV remains a highly debated public against RSV for many conditions, recent
health issue, as the costs of passive recommendations of the American Academy
vaccination of large populations should be of Pediatrics (AAP) seek an optimal balance
lower than the costs of rehospitalisation of of benefit and cost for this intervention. In
patients with RSV infection. The number of general, three major groups of infants that
patients needed to treat (NNT) to avoid may benefit from Palivizumab are
rehospitalisation depends on the baseline addressed. In infants and children younger
rehospitalisation rate without RSV than 24 months with CLD who receive
prophylaxis, a number that depends strongly medical therapy and infants born before
on the proportion of children developing 32 weeks of gestation, a maximum of five
CLD. If the basal proportion of prematurely doses of Palivizumab (15 mg?kg-1?month-1
born children with CLD is lower, the during the RSV season) is recommended for
rehospitalisation rate due to RSV is lower infants within these two groups. A third
than published by the Impact trial in 1999 major group is defined as infants born at 32
(mainly the USA and Canada) and the NNT to ,35 weeks of gestation. The usefulness of
will be higher than originally proposed in Palivizumab in this group strongly depends
1999 for a cohort comprising almost 50% on the presence of additional risk factors. If
prematurely born children with CLD. two of these risk factors are present, a
Notably, national guidelines for prophylaxis maximum of three doses of Palivizumab
with Palivizumab differ substantially. This should be administered. For details, see the
can be exemplified by comparing the Swiss AAP recommendations.
and Austrian recommendations. Although it
is rather unlikely that the Swiss and Austrian In summary, almost 15 years after approval
populations differ significantly in 1) ethnic or of passive immunisation against RSV,
genetic background, 2) risk factors for recommendations are still mainly based on
severe RSV infections, or 3) rehospitalisation a single multinational, randomised, placebo-
rates due to RSV infection, the Swiss controlled trial for prematurely born children
recommendations are more restrictive than and on a single multinational, randomised,
the Austrian guidelines. In Switzerland, placebo-controlled trial for children with

congenital heart disease. According to individual disease and infections of others.
medical as well as economic criteria, there is As pneumococcal resistance to
broad agreement that prematurely born antimicrobial agents is a growing problem in
children with CLD in infancy and children all age groups, active vaccination is the
with haemodynamically relevant heart most promising strategy to prevent
disease during the first 2 years of life may pneumococcal diseases worldwide.
benefit from passive immunisation against
RSV. Still, many guidelines recommend the Immunisation Current vaccines use bacterial
use of Palivizumab for children born capsular polysaccharides. These induce
,28 weeks of gestation regardless of serotype-specific antibodies that activate
additional risk factors an approach that is and fix complement, and promote bacterial
at least debated, if not highly controversial. opsonisation and phagocytosis. The 23-
valent pneumococcal polysaccharide
Conclusion Given the aforementioned vaccine (PPV23) is based on purified
unresolved public health issue on who will polysaccharide and was introduced in 1983.
best benefit from passive vaccination The heptavalent polysaccharideprotein
against RSV, we consider the conjugate vaccine (PCV7) is based on seven
recommendations of the AAP as an capsular polysaccharides covalently
acceptable compromise. conjugated to a protein carrier and was
introduced in 2000. Recently, two further
Pneumococcal pneumonia
PCVs were introduced, PCV10 and PCV13.
Epidemiology and risk factors S. pneumoniae
leads to substantial morbidity and mortality PPV23 elicits antibody responses in 6080%
in children with an estimated 10 million of children older than 2 years after a single
deaths per year worldwide, particularly in intramuscular injection. PPV23 is not
developing countries. The most common sufficiently immunogenic in children
form of the disease is bacteraemic ,2 years of age: it does not prevent mucosal
pneumococcal pneumonia, which shows colonisation and does not elicit
peaks of incidence below 2 years of age and immunological memory. The clinical
above 65 years of age. In developed effectiveness of PPV23 in children between 6
countries, S. pneumoniae in adults is a and 24 months of age for the prevention of
common cause of community-acquired pneumococcal diseases is limited. PCVs, in
pneumonia, while in children in developed contrast, are sufficiently immunogenic in
countries, S. pneumoniae is a leading cause children ,2 years of age after three or four
of invasive bacterial diseases (IPDs) intramuscular injections. PCVs elicit
(notably meningitis and sepsis). The annual immunological memory and prevent
overall European incidence of IPD in nasopharyngeal colonisation, thus
children aged ,2 years is estimated to be 44 promoting herd immunity. This has
cases per 100 000 population. Children with probably led to an even more substantial
an increased risk of pneumococcal diseases decrease in pneumococcal diseases in the
are those born prematurely, and those with elderly than in the vaccinees. Since the
sickle cell disease, cochlear implants and introduction of PCVs in 2000, vaccine
cerebrospinal fistulae, HIV infection, efficacy has been shown to be 7797% for
secondary loss of the spleen, or primary the avoidance of IPD and 1937% for the
immunodeficiencies due to either a defect in avoidance of pneumococcal pneumonia.
opsonisation, phagocytosis of opsonised PCVs also proved beneficial in HIV-infected
bacteria or in Toll-like receptor signalling. children for both the prevention of IPD and
There are 40 serogroups and 91 serotypes of pneumococcal pneumonia. Active
S. pneumoniae, and 20 of these account for vaccination against S. pneumoniae is
.70% of IPD occurring in all age groups. beneficial not only from the individual,
The only natural reservoir of S. pneumoniae medical point of view but also from the
is the human nasopharynx, and colonisation socioeconomic point of view. The saved
of the nasopharynx is a prerequisite for both costs by reduced morbidity and mortality

outweigh the costs of vaccination, N American Academy of Pediatrics
regardless of the epidemiological Committee on Infectious Diseases, et al.
background and the price of the vaccine. The (2003). Revised indications for the use of
socioeconomic benefit will most likely be palivizumab and respiratory syncytial
even higher if PCV13 is directly introduced, virus immune globulin intravenous for
whereas the benefit may be less obvious if the prevention of respiratory syncytial
PCV13 replaces PCV7. The obvious current virus infections. Pediatrics; 112: 1442
success of PCV7 has been shadowed by 1446.
N Black S, et al. (2000). Efficacy, safety and
concerns about serotype replacement.
immunogenicity of heptavalent pneumo-
Recent studies confirmed that serotypes not
coccal conjugate vaccine in children.
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also cause pneumococcal diseases (e.g. Infect Dis J; 19: 187195.
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replacement has partly been met by the using conjugate vaccines to protect HIV-
introduction of PCV10 and PCV13 vaccines infected children against pneumococcal
comprising more serotypes. However, the disease. Lancet Infect Dis; 8: 6780.
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replacement by introducing more and more drome: a novel risk factor for respiratory
serotypes in one vaccine is limited syncytial virus bronchiolitis a prospec-
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immunisation against S. pneumoniae
born during two consecutive seasons.
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Upper respiratory tract
infections
Rossa Brugha, Chinedu Nwokoro and Jonathan Grigg
The upper respiratory tract (URT) lies cranial due to respiratory infections. URTIs make up
to the thoracic inlet and comprises the nose 95% of these infections. Preschool children
(in continuity with the sinuses and the have six to eight URTIs per year. The vast
lacrimal sac) and nasopharynx, the mouth majority of URTIs are self-limiting viral
and oropharynx (in continuity with the infections. Human rhinovirus is the most
middle ear via the Eustachian tube), and the common causative organism (,40% of
larynx and laryngopharynx. The respiratory infections), and respiratory syncytial virus,
role of the URT is three-fold. influenza, parainfluenza and adenovirus are
among the numerous (,200) viruses
N To warm inspired air before it reaches the associated with infections throughout the
lungs. URT (table 1).
N To trap and remove inhaled particles that
may irritate the respiratory epithelium This chapter will outline clinical features and
(dust, smoke or organic matter such as the management of common URTIs,
pollen). alongside important rarer infections, rare
N To perform innate and adaptive immune complications of common infections, and
responses against inhaled pathogens. important differential diagnoses.
The URT is also responsible for phonation Common cold or viral rhinitis
and for preparing food and fluids for
digestion. URT infections (URTIs) are the Common colds are self-limiting viral
most common human malady (Johnston, illnesses involving the nasal mucosa, and
2005). For example, in the UK, one quarter are experienced annually by the majority of
of the population visit their doctor every year individuals.
Clinical features Inflammation of the nasal
Key points epithelium (rhinitis) leads to a mucous or
muco-purulent discharge (coryza). There
may be associated sneezing, cough and/or
N The majority of upper respiratory tract
fever. A cold is a diagnosis of exclusion: if
infections are viral in aetiology and
there are symptoms associated with
self limiting.
adjacent structures (such as sore throat or
N Consider epiglottitis or bacterial mid-facial sinus pain) then the diagnosis will
tracheitis in a child with stridor who be ascribed to inflammation at that site
looks unwell. (tonsillitis/pharyngitis or rhinosinusitis) as a
matter of convention.
N Decisions regarding antibiotics for
otitis media and tonsillitis are difficult Management Treatment is support
and involve pros and cons for the (antipyretics) and reassurance, once
patients and for society; these should relevant negatives have been excluded. A
be openly discussed when making meta-analysis of the use of antibiotics for
treatment choices. the treatment of common colds has been
published by Arroll et al. (2005). It shows no

Table 1. Common viruses in upper respiratory tract most episodes are self-limiting and will
infections resolve. Antibiotics should, therefore, be
reserved for those children at risk of
Rhinovirus
complications. In young adults intranasal
Respiratory syncytial virus corticosteroids may be of use as an adjunct
Influenza virus A and B to antibiotic therapy (Fokkens et al., 2012).
Metapneumovirus Foul-smelling or bloody discharge should
prompt consideration of a foreign body high
Parainfluenza virus in the nasal cavity.
Adenovirus
Chronic rhinosinusitis is less common in
Coronavirus
children and management may require input
from an Ear, Nose and Throat surgeon, as
benefit in comparison with placebo and an there may be an indication for
increase in adverse events when antibiotics adenoidectomy. A chronic sinus infection
were prescribed in children and adults for should lead the treating physician to
acute purulent rhinitis (relative risk 1.46, consider an underlying diagnosis; gastro-
95% CI 1.101.94). oesophageal reflux, asthma,
immunodeficiency, cystic fibrosis and
Rhinosinusitis primary ciliary dyskinesia are all associated
with chronic rhinosinusitis in children. The
Rhinosinusitis is the term encompassing presence of significant central nervous
infection and inflammation of the sinuses as
system symptoms should prompt
the process involves the nasal passages
consideration of a subdural empyema.
both for route of infection and drainage.
One in every 10 colds in children will go on Acute otitis media
to cause sinus inflammation. The infections
are initially viral in aetiology, but the Acute otitis media (AOM) is extremely
anatomy of the drainage means that bacteria common in childhood, with a peak
may cause secondary infections in the incidence between 6 and 15 months of age.
sinuses. Acute rhinosinusitis should be Viral infections are commonest, although
considered when URTI symptoms have secondary bacterial infection may coexist or
exceeded 710 days, and is defined as subsequently occur.
lasting up to 30 days by the Cochrane group.
Clinical features Younger children will
Clinical features These are similar to the display nonspecific features of illness; fever,
common cold (coryza, cough and fever), vomiting, minor irritability and poor feeding
and in younger children (where the sinuses are all common, and young children with
are still developing and the child may not these symptoms should always have their
communicate symptoms) sinusitis may be ears examined. Older children may complain
missed. The frontal sinuses can be of dizziness and pain in the ear or pain when
demonstrated on plain radiographs in 20 eating. Examination of the ear should
30% of children by 6 years of age. Older demonstrate an inflamed erythematous
children and young adults may experience bulging tympanic membrane. The tympanic
facial congestion or heaviness membrane may rupture and there may be
alongside focal pains. The sinuses may be pus in the ear canal on examination. Lymph
tender if gently percussed. nodes draining the area may be inflamed.
Management In acute rhinosinusitis in Treatment should be to:
children there is no evidence for the use of
nasal decongestants or saline irrigation. N give adequate analgesia and antipyretics,
There is modest evidence for treatment with N ensure parents administer sufficient
antibiotics (amoxicillin/clavulanic acid or an doses of paracetamol and a nonsteroidal
appropriate substitute if allergic), although anti-inflammatory.

Acute otitis media is usually a self-limiting Chronic suppurative otitis media
viral infection. Bacterial infection may rarely
be followed by spread to the mastoid air Chronic suppurative otitis media is present
cells with associated risk of intracranial when otitis media with effusion is
infection and/or venous thrombosis. This associated with tympanic perforation and
risk has to be balanced against adverse persistent (usually bacterial) discharge
occurs. In children this may be a sign of
consequences of antibiotic use both for the
underlying disease, such as
individual and the wider population. Other
immunodeficiency or primary ciliary
complications include middle ear effusions
dyskinesia.
and hearing impairment.
Pharyngitis and tonsillitis
A meta-analysis by Glasziou et al. (2004) of
10 trials using antibiotic versus placebo in Inflammation of the pharynx is
AOM in children (using pain as an predominantly viral in aetiology and may
outcome measure) demonstrated no coexist as a common pathology in many
benefit at 24 hours, but some benefit at 2 URTIs (such as a cold and a sore throat).
and 7 days: however most childrens Posterior pharyngeal wall inflammation is
symptoms (78%) are improved at this readily observed on depression of the
point. There was one case of mastoiditis in tongue. Treatment is supportive with
almost 3000 trial subjects (in a child analgesia (oral syrups and topical local
treated with penicillin). The number anaesthetic sprays) and antipyretics.
needed to treat to prevent one child
Acute tonsillitis Waldeyers ring of lymphoid
experiencing ear pain was 16. The number
tissue includes the tonsils, adenoids and
needed to harm due to antibiotic side-
lymphoid aggregates in the pharynx, at the
effects (vomiting, diarrhoea or rash) was
base of the tongue and in the pharyngeal
24. The authors conclude that antibiotics
walls. Tonsillitis is inflammation of the
should be given to children with AOM who
palatine tonsils, and is most common in
are ,2 years old, and children with children between the ages of 3 to 9 years,
bilateral AOM or with AOM plus otorrhoea. after which age tonsillar regression occurs.
Ventilation tubes (grommets) can be Tonsillitis may occur secondary to both viral
inserted into the tympanic membrane and and bacterial infections. The common
one study from the early 1980s has bacterial pathogens include group A
demonstrated that they decrease the rate of Streptococcus, Staphylococcus aureus and
subsequent episodes of AOM. Streptococcus pneumoniae.
Otitis media with effusion Clinical features: Younger children may have
Otitis media with effusion or glue ear nonspecific features of fever, poor feeding,
occurs when there is serous fluid in the coryza, irritability and they may have a rash
middle ear without symptoms of acute (either a viral exanthema, or a rash secondary
infection. It occurs in association with to Streptococcal infection in scarlet fever).
There may also be vomiting and diarrhoea.
Eustachian tube dysfunction, which may in
Older children and young adults may have
turn be secondary to AOM. Over time this
similar symptoms plus localising throat pain,
fluid can become tenacious. One in three
especially on eating or drinking. Local lymph
affected children has culture positive
nodes may be enlarged.
effusions. Otitis media with effusion can
lead to impaired hearing (conductive Complications of tonsillitis include the
deafness) and antibiotics have been trialled following.
to aid its resolution. A meta-analysis of 23
studies did not demonstrate any substantial N A peritonsillar abscess: a unilateral
improvement in hearing or need for purulent collection in the peritonsillar
grommets following antibiotic fossa. Presents with pyrexia, ipsilateral
administration (van Zon et al., 2012). otalgia (ear pain), odynophagia (pain on

swallowing) and often trismus (pain on for 57 days and exposes a child to the risk
opening the jaw). Examination shows a of anaesthetic and surgical complications
deviated uvula and swelling of the soft (infection and haemorrhage) despite
palate. uncertainty over the likelihood of recurrence
N A retropharyngeal abscess should be without surgery. A meta-analysis of
considered in children who present with tonsillectomy or adenotonsillectomy for
fever, stiff neck, dysphagia and other recurrent or chronic tonsillitis in childhood
symptoms related to inflammation or found that severely affected children benefit
obstruction of the upper aerodigestive from fewer episodes of sore throat in the
tract. first year following surgery (3.3 episodes
N Rheumatic fever and glomerulonephritis versus 1.8 episodes plus one surgery-
were previously associated with associated episode) (Burton et al., 2009). In
streptococcal tonsillitis but are now rare less severely affected children the review
outside the developing world. concluded that surgery will mean having an
average of two rather than three
Treatment: Acute management options unpredictable episodes of any type of sore
include analgesia, antipyretics and in some
throat. The cost of this reduction is one
cases antibiotics. As with AOM conflict
inevitable and predictable episode of
exists between the risks of antibiotic
postoperative pain. Children and families
resistance and side-effects on the one hand,
should be invited to consider the relative
and acute and subacute post-infectious
risks and benefits of intervention in
complications and morbidity on the other.
comparison to a wait and see approach
Clinical scores have been developed for
when considering surgery for recurrent sore
assessing the probability of Streptococcal
throats.
infections. Of these, the Centor score is
most widely used, although it was not Diphtheria Diphtheria is a bacterial
developed in a paediatric setting. The pharyngitis caused by Cornyebacterium
McIsaac score (table 2) adjusts the Centor diphtheriae. Mortality varies between 5% and
score for patient age. 10%. Affected children will have a fever and
sore throat; additionally there may be neck
b-lactam antibiotics are first-line drugs
swelling and a characteristic posterior
against bacteria that commonly cause
pharyngeal grey, adherent pseudomembrane
tonsillitis. Amoxicillin may cause rashes in
that may progress to airway obstruction in
children who have sore throats due to
which case urgent expert paediatric airway
EpsteinBarr virus (infectious
management is required. Diphtheria is
mononucleosis and glandular fever).
prevented by mass immunisation;
Tonsillectomy Tonsillectomy prevents suggestive symptoms in an area of low
recurrent tonsillitis, but does not prevent immunisation should prompt consideration
recurrent sore throats as only the tonsillar or of diphtheria in the differential diagnosis.
adeno-tonsillar lymphoid aggregates are Russia, North Africa, the Middle East and
removed. Tonsillectomy causes a sore throat East Asia all experienced diphtheria
Table 2. Centor score and McIsaac adjustment for assessing the likelihood of streptococcal infection in tonsillitis/
pharyngitis
Centor score (1 point for each) Guidance
Fever Score 01: do not prescribe antibiotics
Absence of cough Score 2: treat if the rapid antigen test is positive
Tonsillar exudates Score 3: treat if the test is positive or treat empirically
Anterior cervical lymphadenopathy Score 4: treat empirically
Aged ,15 years (McIsaac adjustment)

outbreaks in the 1990s. Treatment is Whooping cough (pertussis), caused by
isolation, airway management, antitoxin and Bordetella pertussis, occurs in all countries
systemic penicillins or erythromycin. and increased nine-fold in incidence in the
USA between 1980 and 2010. The increase is
Laryngeal infections thought to be multifactorial; but improved
Infection of the larynx causes characteristic diagnosis (using PCR techniques) and a
changes in cough and phonation. change to acellular vaccines (DTaP) are
implicated (Cherry, 2012). Infants aged
Croup (laryngotracheobronchitis) is a viral ,2 months are most at risk from severe
infection of the larynx and adjacent infection as there is little transplacental
structures; the common causative transfer of immunity. Recent anti-pertussis
organisms are rhinovirus, respiratory strategies include maternal vaccination with
syncytial virus and parainfluenza 1 and 2. DTaP during pregnancy.
Clinical features: The illness often begins with Clinical features: Children present with a
rhinitis as the upper airway is infected first. coryzal, feverish illness which mimics a self-
Distal progression irritates the larynx, limiting URTI. At this stage the coryzal
resulting in a cough. With subsequent vocal infant is highly infectious to non-immune
cord oedema the cough becomes harsh or close contacts. The classic, paroxysmal
barking and inspiratory stridor will cough follows this stage and lasts for weeks
develop. Airway obstruction is progressive or months; in China, whooping cough is
with limitation of airflow until the condition known as the hundred-day cough. The
begins to resolve or anti-inflammatory cough has a characteristic rise in pitch and
measures are instigated. The onset of may or may not be followed by a whoop or
stridor usually occurs over 612 hours. episodes of vomiting in younger infants.
Sudden onset of stridor should prompt There may also be episodes of cyanosis,
consideration of an inhaled foreign body or apnoea or bradycardia in infants. The cough
anaphylaxis. may occasionally result in petechiae,
subconjunctival haemorrhages, rib fractures
Treatment: Management should be aimed at and pneumothoraces.
maximising airflow through the larynx. Risk
factors for significant hypoxia include Treatment: Accurate diagnosis with
diffusion limitation (e.g. chronic lung pernasal swab or PCR of nasopharyngeal
disease of prematurity) or pre-existing aspirate is key; although cultures take up to
airway compromise (e.g. subglottal 1 week and decline in sensitivity the longer
stenosis). It is imperative to keep the child the illness continues. Children requiring
as relaxed as possible as anxiety (e.g. from hospitalisation should be isolated and
unwelcome or unwarranted interventions) subject to barrier nursing. A macrolide
may worsen airflow. Steroids reduce vocal antibiotic (conventionally 14 days of
cord oedema, facilitating respiration. They erythromycin) is first-line treatment,
can be nebulised or delivered orally. More although shorter courses of newer
severely affected children may gain macrolides may be considered (these may
temporary benefit from nebulised improve adherence). Supportive treatment
epinephrine, with doses repeated as including mechanical ventilation may
necessary due to the short half-life. be required.
Supplemental oxygen (which can be Epiglottitis
administered by a parent with the child on
their lap) may be required and analgesia Haemophilus influenzae type b (Hib) causes
should be offered to all children. Decreasing epiglottitis, a severe swelling of the
the viscosity of inhaled gases results in epiglottis that leads to airway obstruction.
improved large airway flow, and in severe Since the introduction of the conjugate Hib
cases a heliumoxygen mixture may be vaccine, the incidence of epiglottitis has
helpful. fallen considerably.

Clinical features Features of infectious Diagnosis is usually made at bronchoscopy
airway obstruction (fever, cough, stridor and where the differential includes severe croup
recessions) occur rapidly (onset over hours) or epiglottitis.
in a toxic-appearing child, without a clear
viral prodrome. The child sits upright with Treatment The majority of children require
the head held forwards to extend the neck admission to intensive care, intubation and
and hold the larynx open. As airflow systemic antibiotic therapy. Aspiration of
obstruction progresses, breathing becomes exudates and breakdown of membranes may
quieter and the child may become cyanosed be performed at bronchoscopy.
with decreasing consciousness.
Further reading
Treatment Suspected epiglottitis is an
airway emergency and children should be N Arroll B, et al. (2005). Antibiotics for the
managed in co-operation with anaesthetic common cold and acute purulent rhinitis.
and otolaryngology teams. Examination of Cochrane Database Syst Rev; 3: CD000247.
the throat may precipitate acute obstruction N Burton MJ, et al. (2009). Tonsillectomy or
(via distress causing laryngospasm) and adeno-tonsillectomy versus non-surgical
should be avoided until measures are in treatment for chronic/recurrent acute
place to secure a definitive airway at the tonsillitis. Cochrane Database Syst Rev; 1:
point an intervention is required. The CD001802.
epiglottis typically appears swollen and N Cherry JD (2012). Epidemic pertussis in
cherry-red in appearance. There may be 2012 the resurgence of a vaccine-
systemic features of sepsis and treatment preventable disease. N Engl J Med; 367:
includes fluid resuscitation and a third or 785787.
N Fokkens WJ, et al. (2012). European
fourth generation cephalosporin.
Position Paper on Rhinosinusitis and
Intravenous access should only be obtained
Nasal Polyps 2012. A summary for
once the airway is secure.
otorhinolaryngologists. Rhinology; 50:
Bacterial tracheitis Suppl. 23, 1298.
N Glasziou PP, et al. (2004). Antibiotics for
As a result of the Hib vaccine and acute otitis media in children. Cochrane
widespread use of steroids for croup, Database Syst Rev; 1: CD000219.
bacterial tracheitis is now the most N Hopkins A, et al. (2006). Changing
common, although still rare, URTI cause of epidemiology of life-threatening upper
respiratory failure in children (Hopkins et al., airway infections: the reemergence of
2006). Bacterial infection of the trachea with bacterial tracheitis. Pediatrics; 118: 1418
S. aureus, S. pneumoniae and Streptococcus 1421.
pyogenes can result in erythema, oedema N Johnston SL (2005). Impact of viruses on
and purulent exudates in the trachea. There airway diseases. Eur Respir Rev; 14: 5761.
may be pseudomembrane formation. Viral N van Zon A, et al. (2012). Antibiotics for
tracheal infection may co-exist. otitis media with effusion in children.
Cochrane Database Syst Rev; 9:
Clinical features Children present with fever, CD009163.
cough, hoarseness, stridor and recessions.

Community-acquired
pneumonia
Mark L. Everard, Vanessa Craven and Patricia Fenton
Pneumonia and lower respiratory tract inflammation primarily in the terminal and
infections respiratory bronchioles with exudate
spreading to surrounding peri-
Pneumonia is defined as an inflammatory bronchoalveolae often resulting in a number
disorder of the lung characterised by of discreet foci. A wide range of organisms
consolidation due to presence of exudate in including viruses, bacteria, atypical
the alveolar spaces. There is, inevitably, organisms and fungi are capable of
associated inflammation in the surrounding creating a pneumonic illness.
interstitial tissues. In classic lobar
pneumonia, watery exudates and pus filling The limited response repertoire of the lungs
the alveoli flow directly into adjacent zones, ensures that many of the clinical features of
which extend to create a confluent and pneumonia, such as fever, cough,
confined area of infection generally within respiratory distress and tachypnoea, are also
the affected lobe; spread of infection features of other clinical entities, such as
predominantly occurs via the lumen of the acute bronchiolitis, wheezy bronchitis and
airways (fig. 1). Invasive disease inevitably indeed viral exacerbations of asthma.
involves organisms penetrating into the Diagnosis remains largely clinical with most
interstitial tissues and, more importantly, community-acquired pneumonia (CAP)
adjacent capillaries leading to bacteraemia. guidelines recommending that chest
Bronchopneumonia is characterised by radiographs are only undertaken in those
with a more severe or atypical clinical
course. This inevitably leads to over
Key points diagnosis of pneumonia and this reality is
reflected in the use of the significantly less
N Around 2 million children ,5 years of specific term lower respiratory tract
age die from pneumonia each year. infection (LRTI) in certain guidelines,
which includes pneumonia and other clinical
N While Streptococcus pneumoniae is the entities.
classic organism it probably
accounts for less than half of the Importance of CAP
cases of pneumonia.
CAP usually refers to a pneumonia
N Many guidelines do not recommend developing in a generally well individual who
the use of chest radiographs to make has acquired the organism outside of a
a diagnosis on pragmatic grounds but healthcare setting.
this is associated with over and under
diagnosis. Worldwide, CAP remains the biggest killer of
children and, thus, is a major health issue. It
N Most children can be treated with oral has been estimated that approximately 2
antibiotics unless they have severe million deaths per year in children ,5 years
and/or atypical disease or cannot of age are attributable to pneumonia, a fifth
tolerate oral therapy. of all deaths in this age group. This is likely
to be an underestimate as most deaths

significantly over estimate the true incidence
of pneumonia the catch all approach is
based on the high levels of mortality seen in
those with community-acquired bacterial
pneumonia if not treated with antibiotics.
Worldwide, under treatment is a much
greater problem than over use of antibiotics
for significant LRTIs.
Aetiology of CAP
Studies aimed at determining the causative
organisms in children with CAP have been
hampered by difficulties in obtaining
samples from the site of infection in the
distal lung as:
N young children rarely expectorate

Figure 1. Lobar pneumonia. sputum,
N positive blood cultures resulting from
invasive disease occur in a minority of
probably occur without interaction with
bacterial infections,
healthcare professionals. Epidemiological
studies would indicate that the prevalence
N rapid antigen tests can be misleading due
to false-positive results,
of CAP is significantly higher in developing
countries, which would account, in part,
N sampling of the upper airways for viruses
and bacteria may not be directly relevant
for the higher mortality in these countries.
to the organisms replicating in the
However, the true incidence of pneumonia
alveoli.
is difficult to define without confirmation
of the diagnosis being confirmed by chest It is believed that most episodes of
radiography with many LRTIs being pneumonia commence with colonisation of
labelled as pneumonia on clinical the mucosa of the nasopharynx with
grounds. Studies assessing the accuracy of subsequent spread to the lower respiratory
a clinical diagnosis of pneumonias when tract. Less commonly, a persistent bacterial
compared with chest radiographs bronchitis may precede an acute
have confirmed that there is significant exacerbation with associated pneumonic
over diagnosis, as well as under changes.
diagnosis.
A wide range of organisms including
UK and Scandinavian studies would suggest bacteria, viruses and so-called atypical
that incidence of chest radiograph- organisms cause CAP. Mixed viral and
confirmed pneumonia is in the region of 15 bacterial infections are very common.
cases per 10 000 children with high Streptococcus pneumoniae is the most
incidence in those aged 02 years (42 out of commonly identified bacteria and is
10 000) and 05 years (33 out of 10 000). frequently considered to be responsible for
Higher incidences in excess of 100 per the classic pneumonic illness. However,
10 000 have been suggested in European studies have indicated that it accounts for
studies that did not include chest less than half of all cases of paediatric CAP
radiographs and/or did not exclude infants and indeed may account for as little as 5% of
with acute bronchiolitis. Much higher levels cases, although this will be influenced by
are reported in the developing world, definitions of disease and techniques
particularly sub-Saharan Africa and south- available for diagnosis. The advent of
east Asia with estimates suggesting that conjugated vaccines has reduced the
75% of the 150 million cases a year occur in incidence of pneumonia although the
just 15 countries. While figures may magnitude of the impact varies depending

Table 1. Bacteria and CAP
Organism Predisposing factors Suggested first-line Comments
treatment
Streptococcus Previously well Amoxicillin (oral) 13-valent vaccine in use in
pneumoniae Benzylpenicillin if i.v. empyema?
therapy is required Add clindamycin to
treatment
Streptococcus Chicken pox Benzylpenicillin and Invasive group A
pyogenes clindamycin Streptococcus is notifiable to
the CCDC in the UK
Contact tracing indicated
Mycoplasma Outbreaks every Clarithromycin Often mild
pneumoniae 57 years Organism has no cell wall so
cannot be treated with
penicillin
Staphylococcus Influenza A, Linezolid, clindamycin Health Protection Agency
aureus PVL toxin and rifampicin guidelines in UK
Contact tracing indicated
Haemophilus Immune defect if Co-amoxiclav or Rare
influenzae HiB isolated from cefotaxime/ceftriaxone
vaccinated individual
PVL: panton valentine leukocidin; HiB: Haemophilus influenzae type B; CCDC: consultant in communicable
disease control.
of the definition of pneumonia used. Using a pneumoccocal disease or an atypical

broad definition based on clinical criteria a organism rather than a virus, it should be
study in the Gambia found that clinical remembered that severe pneumococcal
pneumonia was reduced by 7%, increasing disease and invasive disease, in particular, is
to 37% in patients with radiologically proven most common in infants and pre-school
lobar pneumonia. Again this emphasises children.
that clinically suspected pneumonia
overestimates the true incidence of Other bacteria that cause pneumonia
pneumonia and the fact that pneumococci include:
are responsible for a minority of all N Haemophilus influenzae type B (HiB) and
pneumonias although it remains the target nontypable species, although HiB is now
organism for empirical antimicrobial very rare in developed countries and
treatment in the hospitalised child with when it occurs in a vaccinated child it is
pneumonia. S. pneumoniae is the an indication to look for an immune
commonest bacteria found in analysis of defect;
parapneumonic effusion/empyema, N group A streptococci, commonly
although any organism, including viruses, associated with a history of recent
may be associated with a parapneumonic chickenpox infection;
effusion. Associated invasive disease, such N Staphylococcus aureus, especially during
as bacteraemia and meningitis, contributes influenza A epidemics or if the strain
to the poor outcome in untreated children. produces panton valentine leukocidin
The current conjugated vaccines have toxin.
targeted the serotypes most likely to cause
invasive disease. While it is often remarked In addition to these bacteria atypical
that most pneumonias in infants are viral organisms such as Mycoplasma pneumoniae
and that an older child is more likely to have and Chlamydia pneumoniae may account for

20% of cases. Again they are classically development of the pneumonia or to the
considered to be causes of pneumonia in severity of the episode.
school-age children but are both capable of
causing a severe pneumonia in younger Diagnosis The World Health Organizations
children (table 1). (WHO) recommendations are aimed at
resource-poor countries and are based on
A wide range of respiratory viruses can simple clinical criteria. They suggest that
cause pneumonia, particularly in infants pneumonia should be suspected in children
and, to a lesser extent, pre-school children. with a cough and/or difficulty breathing with
As with any clinical syndrome from rhinitis age-adjusted tachypnoea:
through to bronchitis and bronchiolitis to
pneumonia, any of the respiratory viruses N .50 breaths?min-1 for infants aged 2
may be responsible. In general they cause 11 months of age,
less severe illnesses than bacteria but N .40 breaths?min-1 for preschool children
remain an important cause of severe disease aged 15 years,
and indeed death. Viral LRTIs tend to affect N .20 breaths?min-1 for children aged
the airways more diffusely than bacterial .5 years.
pneumonias and it is not uncommon for
One study found that this approach had the
infants with clinical acute bronchiolitis
highest sensitivity (74%) and specificity
characterised by widespread crackles to
(67%) for radiographically defined
have evidence of collapse and/or
pneumonia. Associated factors are used to
consolidation on a chest radiograph.
determine severity with recession, grunting
Moreover, with increasingly sensitive
and nasal flaring being indicative of severe
diagnostic techniques it is clear that many pneumonia while cyanosis, persistent
cases of bacterial pneumonia are preceded vomiting, severe respiratory distress and
or accompanied by infection by one or more confusion suggest a very severe illness. This
of these viruses. pragmatic approach serves the needs of
In general, studies have found that the more healthcare systems faced with a huge
severe illnesses are associated with bacterial burden of disease and associated morbidity
infection but this is not necessarily the case where clear, unambiguous direction in
and this is already changing with the relationship to management is required in
widespread introduction of vaccines to S. order to optimise outcomes. This approach
has been incorporated into the WHO
pneumoniae and HiB. However, it should be
integrated management of childhood illness
remembered that the mortality of patients
programme which has been proven to have
with viral LRTIs, such as acute bronchiolitis
had a significant impact on childhood
due to respiratory syncytial virus and other
mortality. It is widely recognised that the
viruses in the absence of good supportive
features above are not specific, with
care and oxygen therapy, in particular, is very
tachypnoea and fever being associated with
significant.
many other conditions.
While it is widely stated that most
Interestingly, a very similar approach is
pneumonias in very young children are viral
observed in several developed countries as
this is also the peak age for severe bacterial
highlighted by the British Thoracic Society
infections and death due to organisms such
(BTS) guidelines which again advocate a
as pneumococcus. Mixed viral and bacterial
clinical approach to diagnosis. The
infections are very common.
guidelines do not have clear
Clinical assessment and diagnosis recommendations regarding making a
definitive diagnosis but state that bacterial
When assessing a child who may have pneumonia should be considered in children
pneumonia it is important to make a when there is persistent or repetitive fever
diagnosis, assess the severity and consider .38.5uC together with chest recession and a
comorbidities which may contribute to the raised respiratory rate. They make no

recommendation regarding the use of chest pneumonias may cause abdominal pain and
radiographs other than to state that they should be considered in the differential of
should not be a considered to be a routine the acute abdomen even in the absence of
investigation in children thought to have coughing. Organisms such as S.
CAP. Once again this is likely to be pneumoniae and HiB may cause serious
associated with misdiagnosis; both false invasive disease such as septicaemia and
positive and false negative. It is known that meningitis with or without an obvious
chest radiograph changes lag behind the pulmonary focus.
clinical picture and an early chest radiograph
Comorbidities While CAP is generally
may miss a developing pneumonia. In
considered to be those pneumonias that
contrast, other guidelines recommend the
develop in the community in previously well
use of chest radiographs to make a
children, it is important to obtain a full
definitive diagnosis and to assist with
history in order to try and determine whether
antibiotic stewardship. Clinical judgement
there may be predisposing factors. These
was shown to be associated with both over
would include possible chronic aspiration
and under diagnosis in a recent Dutch study
associated with neuromuscular or other
comparing general practitioner assessment conditions and protracted bacterial
with chest radiographs. bronchitis, both of which may be
Cough is not a key feature and it is known accompanied by a chronic cough, as well as
that for classic bacterial lobar pneumonia a more acute episode such inhalation of a
cough may be infrequent until lysis occurs foreign body, influenza and recent
as there are few, if any, cough receptors in chickenpox.
the distal lung. Of other symptoms that Severity Features reflecting the severity of
might be present the most predictive is the pneumonic illness have been outlined by
wheeze which has a very strong negative the WHO as noted previously. These provide
predictive value. Conversely, the absence of a guide to a step-wise approach to
wheeze in a known asthmatic with treatment, escalating from oral antibiotics to
respiratory distress and fever may indicate intravenous antibiotics in severe disease. In
bacterial pneumonia which generally does Europe, determination of apparent severity
not cause an exacerbation of the asthma. influences both the decision to admit to
Other auscultatory findings are considered hospital and the route of administration of
to be unreliable but if localised crackles are therapy. The BTS guidelines suggest that
present they increase the likelihood of a any of the following would indicate that
lobar consolidation and dullness to admission to hospital is indicated:
percussion is a good predictor of an
associated effusion/empyema. Widespread N children with an oxygen saturation of
crackles in an infant are consistent with a f92% in air,
diagnosis of bronchiolitis rather than N apnoea or grunting,
pneumonia. While tachypnoea is perhaps N significant difficulty in breathing,
the most important symptom this is less N poor feeding or dehydration,
specific and sensitive than noted above N concerns regarding appropriate
during the first few days of the pneumonia. supervision.
It is likely that many children with
pneumonia are treated inadvertently in Pulse oximetry is an important parameter
influencing the use of oxygen therapy and,
primary care with antibiotics prescribed for
indeed, antibiotic therapy.
conditions such as tonsillitis or ear
infections. Investigations
Extrapulmonary symptoms are not Chest radiographs Current guidelines have
uncommon. These may be nonspecific concluded that for most cases of pneumonia
symptoms such as diarrhoea and vomiting, a presumptive diagnosis can be made on
headaches and myalgia. Of note is that the basis of clinical criteria outlined above

and that treatment can be initiated Samples can be obtained from the
empirically. A definitive diagnosis would nasopharynx and oropharynx and may reflect
require a chest radiograph with changes the cause of infection in the distal airways,
consistent with consolidation, although it but inevitably there are false positives and
should be remembered that the chest false negatives. This is particularly true for
radiograph changes may lag behind the bacteria that are frequently present as
clinical picture, both during the evolution of transient commensals in the upper
infection and the resolution. WHO and respiratory tract of infants and young
North American and European guidelines children and, hence, bacterial culture of the
do not recommend the use of chest upper airways is not recommended. Viral
radiographs in the majority of cases for a PCR may be helpful but a positive result
number of reasons. These include the does not exclude a bacterial pathogen and it
apparent inability to distinguish bacterial is increasingly recognised that more than
and viral infections on the basis of the chest one organism may be involved. Paired
radiograph appearances and studies which serology is useful in epidemiological studies
suggest that while in those with a clinical but contributes little to the clinical care and
diagnosis obtaining a chest radiograph only outcomes. The value of rapid antigen tests
leads to a change in management in a for pneumococcus is compromised by
minority of case, this does not influence relatively low sensitivity and specificity
outcomes in the vast majority of cases. especially in young children when false
Furthermore, interobserver agreement positives are common. A negative test in
regarding interpretation of chest radiograph older children may be valuable.
changes is poor, even with clear guidance.
There is certainly a consensus that they are For all these reasons it is widely
not required in the vast majority of recommended that no investigations are
ambulatory patients treated in the required in those ambulatory patients with
community. The BTS guidelines suggest suspected pneumonia treated in the
that a chest radiograph could be considered community. In those admitted to hospital,
in those with fever .39uC, children aged blood cultures, viral PCR on nasopharyngeal
,5 years, and in those not responding aspirates or nasal swabs and paired serology
rapidly and in whom complications, such as for atypical organisms may all be of value.
an effusion, may have developed. Where pleural fluid is obtained culture PCR
for pneumococcus and other organisms and
Microbiology Making a positive pneumococcal antigen detection should be
identification of the causative organism(s) is undertaken.
clearly desirable as therapy could then be
tailored more accurately. However, Other investigations Evidence would suggest
obtaining microbiological samples from the that acute-phase reactants are not helpful in
site of infections (the distal airways) is distinguishing viral infection from bacterial
challenging, and invasive investigations infection and, hence, are not indicated in the
such as bronchoscopy or lung aspirates are management of uncomplicated pneumonia.
rarely indicated. Sputum cultures may be Clinical experience, however, would suggest
helpful if present but most young children that they can contribute to the management
do not expectorate sputum. Blood cultures of children who do not follow the expected
are positive in a minority of patients, in part, clinical course.
because many clinical pneumonias are not Treatment
due to bacteria and, in part, because
bacteraemia is often not present or Treatment involves both supportive and
intermittently present. The likelihood of therapeutic components. There is no
conventional microbiological approaches question that children with hypoxia should be
identifying bacteria in such samples is treated with supplemental oxygen although
significantly reduced in the presence of prior there is some debate as to whether a
antibiotic use. saturation of 90% or 92% is the appropriate

cut-off and altitude may need to be taken into intubation an anti-psuedomonal agent (such
account. Studies in Zambia and other as piperacillin/tazobactam) is a good
countries have indicated the importance of empiric choice.
oxygen therapy in reducing mortality. General
supportive care including fluids, possibly Prevention
restricted to 80% of maintenance, is Vaccines against HiB and S. pneumoniae
indicated in those who are vomiting or have had a significant impact in these
unable to tolerate oral fluids. In the most specific diseases. While the HiB vaccine has
severe cases intensive care may be required. largely eliminated this organism from the
list of likely pathogens, the limited cover of
Specific treatment in the form of antibiotics
conjugate pneumococcal vaccines means
should be given to all of those with a clinical
that the organism continues to cause
diagnosis of pneumonia since there is no
pneumonia. Current vaccines cover up to 13
reliable means of distinguishing viral and
of the more than 80 serotypes and, hence,
bacterial infections. It is clear that this
disease resulting from infection with other
approach will result in many children with
serotypes continues; this may, in part, be
viral LRTIs being treated with antibiotics but
due to serotype replacement. The impact of
the risk of mortality and adverse outcomes
the conjugate vaccines on the incidence of
in untreated bacterial pneumonia is such
pneumonia depends upon the rigor of
that this is indicated. There is clear evidence
diagnosis ranging from a ,15% reduction in
that the oral route is appropriate for the vast
those meeting the WHO definition of
majority of children with pneumonia.
probable pneumonia to a .35% reduction in
Intravenous therapy should generally be
confirmed lobar pneumonia. One benefit of
reserved for those with a severe illness or
the widespread introduction of the
those not tolerating oral administration.
conjugate vaccines is that they are effective
Amoxicillin is generally the antibiotic of against both antibiotic-susceptible and -
choice as it is effective against the majority of resistant strains while the herd effect has
bacterial pathogens. In older children where led to an impact on the incidence in the
an atypical infection is suspected or there is elderly as well as the very young.
poor response to therapy, a macrolide maybe
In the developing world, factors such as
used or added. Current recommendations
improved nutrition are associated with
are that co-amoxiclav is appropriate for
reduced morbidity and mortality.
influenza A-associated bacterial pneumonia.
The optimal duration of treatment is Complications
unknown, with most courses consisting of 5
7 days of antibiotics. For streptococcal The most common complication with CAP is
pneumonia in the presence of lysis and fever, development of pleural effusions and
shorter courses may be appropriate but empyemas (fig. 2). Small uncomplicated
evidence is lacking. Benzyl penicillin is effusions do not need draining. Ultrasound
generally appropriate for intravenous therapy is a valuable modality in determining the
although co-amoxiclav or a second- or third- size and distribution of the collection and its
generation cephalosporin may be used in consistency. Current evidence suggests that
severe disease. in those developing an empyema, drainage
with a small calibre catheter and intrapleural
Antibiotic resistance patterns vary from fibrinolytics is as effective as other
country to country and within countries. approaches (fig. 3), although mini
Hence the choice of antibiotics should be thoracotomy and video-assisted thoracic
based on local guidelines developed as part surgery (VATS) have their advocates. All of
of a multi-disciplinary approach involving these approaches appear to shorten the
microbiologists, those specialising in duration of hospitalisation by a similar
infectious diseases, pharmacists and amount as compared with drainage and
paediatricians. In children with antibiotics alone. Some 1015% of
neurodisability or a history of recent empyemas resolve relatively quickly with

Figure 3. Empyema with a chest drain with
Figure 2. Ultrasound showing empyema with urokinase.
septations secondary to pneumonia.
tachypnoea is associated with improved
antibiotic therapy alone and hence drainage clinical outcomes, particularly in the
on the basis of chest radiograph appearance developing world, but inevitably results in
alone is inappropriate. Whichever approach large numbers of patients receiving
is used, outcomes are generally good. Up to antibiotics for non-bacterial infections. While
15% of patients treated with drainage and the majority of pneumonias in infants and
fibrinolytic therapy might subsequently young children are viral this is also the peak
require further intervention, such as VATS or age for serious life-threatening bacterial
decortication, although fever alone is not an infections. Most pneumonias can be treated
indication of failed therapy. effectively with appropriate oral antibiotics,
with intravenous antibiotics being reserved
Pneumatoceles are most commonly seen in for those with severe infections or who are
those with S. aureus infection but may not tolerating oral therapy. Supportive care
develop in pneumonia due to almost any of remains a vital aspect of care for those with
the common bacteria (fig 4). The vast severe infection.
majority regress spontaneously and surgical
management is rarely required. Lung
abscesses developing in the course of
necrotising pneumonia are often associated
with an empyema and are most commonly
treated with a prolonged course of
intravenous antibiotics, although
radiological placement of a drain has been
suggested as a way of more rapid resolution.
Surgical resection should be avoided.
Broncho-pleural fistulae may also develop in
necrotising pneumonia. They are usually
peripheral and usually resolve with
continuous chest drainage.
Conclusion
CAP remains a major healthcare issue

despite the development of vaccines directed
against two of the major bacterial pathogens. Figure 4. Pneumatocele developing during
A clinical diagnosis based on fever and pneumonia.

Further reading seven-valent pneumococcal conjugate
vaccination in England and Wales: an
N Bradley JS, et al. (2011). The management
observational cohort study. Lancet Infect
of community-acquired pneumonia in
Dis; 11: 760768.
infants and children older than 3 months
N Nair H, et al. (2010). Global burden of
of age: clinical practice guidelines by the
acute lower respiratory infections due to
Pediatric Infectious Diseases Society and
respiratory syncytial virus in young chil-
the Infectious Diseases Society of
dren: a systematic review and meta-
America. Clin Infect Dis; 53: e25e76.
analysis. Lancet; 375: 15451555.
N Cherian T, et al. (2005). Standardized
N Palafox M, et al. (2000). Diagnostic value
interpretation of paediatric chest radio-
of tachypnoea in pneumonia defined
graphs for the diagnosis of pneumonia in
radiologically. Arch Dis Child; 82: 4145.
epidemiological studies. Bull World
N Ranganathan SC, et al. (2009).
Health Organ; 83: 353359.
Pneumonia and other respiratory infec-
N Cutts FT, et al. (2005). Efficacy of nine-
valent pneumococcal conjugate vaccine tions. Pediatr Clin North Am; 56: 135156.
against pneumonia and invasive pneu- N Sawicki GS, et al. (2008). Necrotising
mococcal disease in The Gambia: rando- pneumonia is an increasingly detected
mised, double-blind, placebo-controlled complication of pneumonia in children.
trial. Lancet; 365: 11391146. Eur Respir J; 31: 12851291.
N Hardie WD, et al. (1998). Complicated N Scott JA, et al. (2012). The definition of
parapneumonic effusions in children pneumonia, the assessment of severity,
caused by penicillin-nonsusceptible and clinical standardization in the
Streptococcus pneumoniae. Pediatrics; 101: Pneumonia Etiology Research for Child
388392. Health study. Clin Infect Dis; 54: Suppl. 2,
N Harris M, et al. (2011). British Thoracic S109S116.
Society guidelines for the management of N Society for Healthcare Epidemiology of
community acquired pneumonia in chil- America, et al. (2012). Policy statement
dren: update 2011. Thorax; 66: Suppl. 2, on antimicrobial stewardship by the
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Hospital-acquired pneumonia
Vanessa Craven, Patricia Fenton and Mark L. Everard
Hospital-acquired infections, also known as (Foglia et al., 2007). In the 2011 English Net
nosocomial infections, are infections that Point Study, HAP in neonates and children
are not present and that lack evidence of was the second most common cause of
incubation at the time of admission to nosocomial infection after clinical sepsis,
hospital. Pneumonia and other lower accounting for 15.9% of cases and occurring
respiratory tract infections (LRTIs) account most commonly in those aged ,2 years old.
for a large proportion of these potentially
serious complications of hospitalisation. HAP poses greatest risk to those
Such infections can be transmitted to the undergoing mechanical ventilation in which
case it is termed ventilator-associated
patient from another source or may be due
pneumonia (VAP). VAP is generally defined
to an organism already carried by the
as development of a pneumonia .48 h after
patient. Interventions, such as endotrachel
intubation. Many publications have
intubation or use of broad-spectrum
addressed the issue of VAP although it
antibiotics, may compromise host defences
should be remembered that most HAPs
increasing the patients predisposition to
occur outside the intensive care unit (ICU).
infection. Hospital-acquired pneumonia
Attempting to define HAP and VAP has been
(HAP) is generally defined as one that challenging for those designing
presents with signs and symptoms that epidemiological and intervention studies.
occur after, and not originating before, 48 h Variations in definition probably contribute
to differing reports of incidence, with a
recent UK paediatric ICU (PICU) review of
Key points ventilated patients reporting an incidence of
5.6%, accounting for 9.2 per 1000 ventilator
N Hospital-acquired LRTIs are days (Hunter, 2012), while US data indicates
associated with significant mortality, rates of 2.9 to 8.1 per 1000 ventilator days
morbidity and prolonged (Bingham et al., 2009). Differing rates are
hospitalisation. likely to reflect variation in the case mix of
different units.
N Risk factors include intensive care,
immunosuppression and admission HAP in neonatal ICUs (NICU) poses an even
of infants to paediatric wards greater challenge as it is difficult to
containing patients with LRTIs. distinguish between hospital-acquired and
N Organisms may be part of the vertically transmitted infections. This
patients normal flora or maybe uncertainty is compounded by usual NICU
transmitted from another patient or practices being early intervention in
healthcare provider. suspected sepsis, often prior to chest
radiograph changes, a feature usually
N Following recommended infection, integral to the definition of VAP, in addition
control policies significantly reduces to endotracheal secretions that can often
rates of nosocomial infection. yield positive growth in which colonisers and
pathogens are difficult to distinguish.

Hospital-acquired LRTIs are also relatively However, of all the adverse factors in this
common amongst infants admitted to setting, it appears that intubation poses the
hospital in whom viral LRTIs acquired in greatest risk to the establishment of HAP. By
hospital contribute to increased mortality, providing a continuous foreign object
morbidity and duration of stay. Other at risk extending through the upper airway into the
groups include patients with trachea, the endotracheal tube permits
immunodeficiencies such as those organisms from the upper airway to reach
undergoing chemotherapy, patients with the trachea more easily. Current evidence
neuromuscular disease and post-surgical suggests that oral tubes have a lower rate of
patients. infective complication than nasal tubes.
Endotracheal tubes also impair mucocillary
There is an extensive literature transport while trauma from the
demonstrating the effectiveness of careful endotracheal tube and suctioning may also
preventative strategies in greatly reducing impair host defences. Tracheostomies have
the rates of nosocomial infection in both the an even greater effect (Bigham et al., 2009)
ICU and paediatric wards. and in this population, nosocomial infection
Risk factors rates are greater still. Neuromuscular
blockade in all groups has a negative impact
HAP can be thought of as endogenous, in on rates of pneumonia.
which auto-infection occurs when ones own
microbes breach the usual protective In addition to the use of endotracheal tubes,
barriers and become pathogenic, or intensive care patients frequently have a
exogenous in which external factors lead to nasogastric tube which is likely to facilitate
the acquiring of new pathogens that proceed reflux and lead to aspiration of gastric
to cause infection. Certain factors in the contents into an artificially patent airway.
host lead to this becoming more or less The risk of infection appears to be increased
likely to occur and it is these risk factors that by the use of drugs, such as H2 receptor
form the basis for interventions to limit antagonists, that are used to prevent gastric
nosocomial pneumonias. stress ulceration as they increase gastric pH
which contributes to an increase in bacterial
Paediatric intensive care Mechanical growth which may, in turn, contribute
ventilation poses the biggest risk in this directly to the establishment of pneumonia
setting as it is generally used in those with in the presence of aspiration (Kollef et al.,
the greatest illness severity and is an 2013). The risk-benefit of adding a H2
invasive intervention that circumvents the receptor to agents such as sucralfate
normal upper and lower pulmonary continues to be debated.
antimicrobial defences. In this group,
nosocomial pneumonia is usually Neonatal intensive care In addition to the
synonymous with VAP and this has been risks addressed in the PICU setting, in NICU
linked to a prolongation of mechanical the population has its own unique factors
ventilation, as well as an increase in that predispose to nosocomial pneumonia.
mortality and morbidity (Bigham et al., Low birth weight, poor nutrition, a greater
2009). permeability of skin and mucous
membranes, and hypogammaglobulinaemia
Patients can become colonised with new due to a restriction in the time available for
organisms during hospitalisation, in the placental translocation of maternal IgG
particular those who are severely unwell and all contribute to a greater risk of infection. In
thus require PICU admission. These newly the NICU, as in the PICU, the effect of hand
colonising organisms tend to differ between hygiene, local equipment practices and ward
institutions and the rate of their design also all impact on infection rates.
establishment increases with acidosis,
intubation, hypotension, broad-spectrum Post-surgical patients The post-operative
antibiotic use and those at risk of clinical or period, with the risk of ventilation and the
sub-clinical aspiration (Elward et al., 2003). impact of pain or sedation predispose to

nosocomial pneumonia, in particular influenza and parainfluenza viruses, with
thoracic and abdominal surgery in which RSV, by virtue of its high infectivity, being
coughing may be painful and adequate most common. Other implicated viruses
mucous clearance difficult. include cytomegalovirus (CMV), Epstein
Barr virus (EBV) and adenovirus, although
Chronic disease Immunodeficiency (primary they occur less often and tend to be of most
and secondary), CF, cardiac disease, low
importance in the immunocompromised
birth weight and malnutrition all contribute
(Hall).
to increasing rates of nosocomial
pneumonia. In addition, those with gastro- Bacteria Gram-negative organisms
oesophageal reflux, swallowing difficulties, including Pseudomonas aeruginosa, Klebsiella
trachea-oesophageal fistulae and sp., Enterobacter sp. and nontypable
neurological disorders are at risk of Haemophilus influenzae are the most
aspiration and subsequent nosocomial common Gram-negative isolates.
pneumonia (Zar et al., 2002). Streptococcus pneumoniae and Staphylococcus
aureus are the most common Gram-positive
Hospital factors Nosocomial infection rates
isolates (Bradley, 2010).
vary among institutions and the impact of
staffing, ward design, local hygiene practices Antimicrobial resistance poses a great
among staff and the management of problem in exogenous bacterial HAP and
equipment have been shown to have a will differ between institutions according to
significant effect on infection rates, local resistance patterns. Although one of
including pneumonias. The impact of the rarer causes, methicillin-resistant S.
acquiring an organism, such as the aureus (MRSA) infections do cause a
respiratory syncytial virus (RSV), in hospital therapeutic challenge, and third-generation
is frequently overlooked in discussions cephalosporin resistance and extended
about HAP, but studies have reported that spectrum b-lactamase producing organisms
ICU patients who acquire the virus after can cause significant morbidity and
admission may have a mortality rate mortality.
approaching 25%, while acquisition during
an admission to the paediatric ward for an Fungi The immunocompromised are at
unrelated problem is associated with highest risk of fungal lung infections,
substantial increases in the duration of stay particularly if exposed to broad-spectrum
and readmission rates, as well as significant antibiotics for suspected bacterial sepsis.
morbidity. Building work is quoted as a risk factor for
the acquisition of Aspergillus species whilst
Antibiotic usage Sensitivity results vary
endogenous Candida and Aspergillus are a
markedly between different healthcare
particular risk to neutropenic patients. It is
establishments and even within the same
due to this risk that in those with
hospital on different wards. Empiric
neutropenic sepsis, anti-fungal agents tend
guidelines are usually available but results
to be used early in those not responding to
should always be kept under review.
first-line antibacterial agents. High-efficiency
Antimicrobial stewardship guidelines should
particulate air-filtered positive pressure air
be followed by all prescribers.
supply to single rooms is recommended for
Aetiology children in the period immediately after
bone marrow transplant.
Viruses Viruses are responsible for the
majority of nosocomial pneumonias, being Pneumocystis jirovecii This organism,
highly contagious and having the ability to classified as a protozoan, is an
infect relatively well children in addition to opportunistic organism with a high mortality
those who are deemed high risk. The that should increase the suspicion of an
epidemiology of these nosocomial underlying immunodeficiency. This, as well
pneumonias reflect epidemic patterns and as infections with CMV, EBV and adenovirus
are, in the most part, attributable to RSV, in this vulnerable population, tend to reflect

Table 1. Antimicrobial treatment for HAP in children#
Clinical setting Likely organisms Appropriate first Comments
guess treatment
Post-operative, Streptococcus Co-amoxiclav" OR If genuine penicillin
previously healthy pneumoniae cefuroxime allergy discuss oral
Haemophilus switch with
influenzae microbiologist
Moraxella catarrhalis Maximise physiotherapy
Post-viral, e.g. Streptococcus Co-amoxiclav" OR If genuine penicillin
deterioration in pneumoniae cefuroxime allergy discuss oral
bronchiolitis Haemophilus switch with
influenzae microbiologist
Moraxella catarrhalis
Staphylococcus aureus
Ventilator-acquired Pseudomonas Piperacillin/ Usually requires full i.v.
pneumonia aeruginosa tazobactam" OR course
Staphylococcus aureus ceftazidime plus
teicoplanin
Neutropenic/post- Wide variety of Follow local Discuss with
transplant/immune potential organisms; protocols microbiology, infectious
deficient bacterial, fungal and Consider anti-fungal diseases, radiology and
viral and anti-viral oncology
Consider possibility of treatment in addition May need invasive
Mycobacterium to antibacterial diagnostic tests
tuberculosis
Be guided by local protocols and sensitivity patterns. #: consider i.v. to oral switch as soon as clinically
appropriate; ": these agents are penicillins and should be avoided in cases of genuine penicillin allergy.
endogenous rather than exogenous ICU and in paediatric wards. Attention to

acquisition and can be life-threatening. detail is the key to implementing well-known
infection control measures, including
Mycobacterium Mycobacterium tuberculosis rigorous hand hygiene, the use of disposable
should not be overlooked in the search for aprons and gloves, and isolating infectious
aetiology in HAP. Although all children are patients. Ensuring that healthcare workers
highly susceptible to M. tuberculosis, the are immunised against influenza and
immunosuppressed child is at increased ensuring those with respiratory viral
risk of nosocomial infection with possible illnesses do not look after at-risk patients are
spread from undiagnosed adults posing a also important aspects of preventing
threat in the ward setting. nosocomial infection. Care bundles,
Prevention including the previously mentioned
precautions, together with
Prevention of hospital-acquired infection, recommendations such as nursing
including HAP, should be at the forefront of ventilated patients with their head elevated
the clinicians approach to the care of where possible, minimising changes in
patients. There is a substantial body of ventilator circuits unless contaminated;
evidence that HAP is associated with using oral rather than nasal tubes, and
increased morbidity, mortality and avoiding re-intubation where possible, in
healthcare utilisation and a similar body of addition to ongoing education of staff
evidence that the implementation of have been shown to have a significant
programmes designed to prevent such impact in lowering rates of VAP (Brierley
infections can be very effective both in the et al., 2012).

Not only does attention to detail approach involving microbiologists
significantly improve clinical outcomes for specialising in infectious diseases,
the patient, but it also reduces healthcare pharmacists, intensivists and paediatricians.
costs and leads to much lower use of broad- A suggested approach is outlined in table 1.
spectrum antibiotics.
Diagnosis and surveillance Further reading
As noted above, the diagnosis of HAP and N American Thoracic Society, et al. (2005).
indeed VAP can be problematic. Common to Guidelines for the management of adults
all definitions is deterioration in respiratory with hospital-acquired, ventilator-asso-
status more than 2 days after admission or ciated, and healthcare-associated pneu-
intubation that does not appear to be monia. Am J Respir Crit Care Med; 171:
attributable to infection apparent at the point of 388416.
admission/intubation. New chest radiograph N Apperley J, et al., eds. EBMT-ESH
changes associated with fever and leukocytosis Handbook on Haemopoietic Stem Cell
Transplantation. Barcelona, EBMT, 2012.
or leukopenia, together with clinical features
N Bigham MT, et al. (2009). Ventilator-
such as increased cough or airway secretions
associated pneumonia in the pediatric
on suctioning, strongly support the diagnosis
intensive care unit: characterizing the
though it is clear from post mortem and other problem and implementing a sustainable
studies that over and under diagnosis occurs, solution. J Pediatr; 154: 582587.
as is the case with community-acquired N Bradley JS (2010). Considerations unique
pneumonia. Hospital-acquired LRTIs, due to to pediatrics for clinical trial design in
viruses such as rhinovirus or respiratory hospital-acquired pneumonia and
syncytial virus, are often not classified as HAP ventilator-associated pneumonia. Clin
as they develop after discharge and if the Infect Dis; 51: Suppl. 1, S136S143.
patient is re-admitted are frequently assumed N Brierley J, et al. (2012). Reducing VAP by
to be community acquired. instituting a care bundle using improve-
ment methodology in a UK paediatric
Diagnostic approaches include sampling the intensive care unit. Eur J Pediatr; 171: 323
lower airways in those being ventilated with 330.
simple endotracheal aspirates, blind N Elward AM (2003). Pediatric ventilator-
protected brushings, and blind and associated pneumonia. Pediatr Infect Dis
bronchoscopic lavage. Identifying the bacteria J; 22: 445446.
responsible requires more focused antibiotic N FayonMJ, et al. (1997). Nosocomial pneu-
prescribing and reduces the use of broad- monia and tracheitis in a pediatric
spectrum antibiotics. None of the sampling intensive care unit: a prospective study.
techniques are ideal, in terms of sensitivity Am J Respir Crit Care Med; 155: 162169.
and specificity, with the sensitivity increasing N Foglia EE, et al. (2007). Effect of nosoco-
with combinations of techniques. For non- mial infections due to antibiotic-resistant
ventilated patients, obtaining samples from organisms on length of stay and mortality
the lower airway is rarely undertaken other in the pediatric intensive care unit. Infect
than in immunosuppressed patients, Control Hosp Epidemiol; 28: 299306.
although upper airways sampling for N Gauvin F, et al. (2003). Ventilator-asso-
respiratory viruses can be very valuable. ciated pneumonia in intubated children:
comparison of different diagnostic meth-
Treatment ods. Pediatr Crit Care Med; 4: 437443.
N Healthcare Infection Control Practices
Ideally treatment should be tailored to the Advisory Committee, et al. (2004).
specific organism. As noted previously this is Guidelines for preventing health-care-
not possible for many patients with HAP and associated pneumonia, 2003 recommen-
empirical treatment is frequently used based dations of the CDC and the Healthcare
on likely organisms. The choice of antibiotics Infection Control Practices Advisory
should be based on local guidelines Committee. Respir Care; 49: 926939.
developed as part of a multi-disciplinary

N Health Protection Agency. English N Niederman MS, et al. (2011). Treatment
National Point Prevalence Survey on of hospital-acquired pneumonia. Lancet
Healthcare-associated Infections and Infect Dis; 11: 728.
Antimicrobial Use, 2011. Preliminary data. N Rello J (2013). Antibiotic stewardship in
London, Health Protection Agency, 201. hospital-acquired pneumonia. Chest; 143:
N Hunter JD (2012). Ventilator associated 11951196.
pneumonia. BMJ; 344: e3325. N Rutledge-Taylor K, et al. (2012). A point
N Jansson M, et al. (2013). Critical care prevalence survey of health care-asso-
nurses knowledge of, adherence to and ciated infections in Canadian pediatric
barriers towards evidence-based guide- inpatients. Am J Infect Control; 40: 491
lines for the prevention of ventilator- 496.
associated pneumonia a survery study. N Srinivasan R, et al. (2009). A prospec-
Intensive Crit Care Nurs; 29: 216227. tive study of ventilator-associated pneu-
N Kollef MH (2013). Ventilator-associated monia in children. Pediatrics; 123: 1108
complications, including infection-related 1115.
complications: the way forward. Crit Care N Thorburn K, et al. (2012). Mortality and
Clin; 29: 3350. morbidity of nosocomial respiratory syn-
N Langley JM, et al. (2005). Defining cytial virus (RSV) infection in ventilated
pneumonia in critically ill infants and children a ten year perspective. Minerva
children. Pediatr Crit Care Med; 6: Suppl. Anestesiol; 78: 782.
3, S9S13. N Venkatachalam V, et al. (2011). The
N Masterton RG, et al. (2008). Guidelines for diagnostic dilemma of ventilator-asso-
the management of hospital-acquired ciated pneumonia in critically ill children.
pneumonia in the UK: report of the work- Pediatr Crit Care Med; 12: 286296.
ing party on hospital-acquired pneumonia N Zar HJ, et al. (2002). Nosocomial pneu-
of the British Society for Antimicrobial monia in pediatric patients: practical
Chemotherapy. J Antimicrob Chemother; problems and rational solutions.
62: 534. Paediatr Drugs; 4: 7383.

Lung involvement in
immunodeficiency disorders
Rifat Chaudry and Paul Aurora
Overview of clinical approach N Open-lung biopsy may be useful and

should be considered if other causes of
N Immunocompromise may be suspected lung damage (e.g. interstitial lung disease
in children experiencing recurrent or toxic damage) are high on the
infections. differential diagnosis.
N Differential diagnosis of lung disease is N Additional advice from infectious
dependent on the underlying primary diseases, microbiology and immunology
diagnosis. For example, in children who specialists can be helpful.
are immunosuppressed due to
chemotherapy for malignancy, the Immune defences in the lungs and points
possibility of toxic lung damage from of compromise
chemotherapeutic agents must also be
Natural barriers and immunological
considered.
defences exist in order to protect our lungs
N An appreciation of the types of organisms
from infection. Primarily, these are:
immunodeficient children are susceptible
to and their presenting features is N hair within the nasal passages;
necessary. N lymphatic tissue within the pharynx
N Detailed history taking and examination (adenoids and tonsils);
remain crucial in providing diagnostic N mucociliary clearance of lower airway
clues. secretions; and
N Radiology and bronchoscopy are N an effective cough with swallow.
extremely useful in diagnosis.
If these mechanical barriers are breached,
then the risk of recurrent respiratory
Key points
infection increases. Specific deficiencies in
cellular defence pathways increase
N Immunocompromise/
susceptibility to particular organisms.
immunodeficiency can be broadly
Although when screening for infection, a
divided into congenital (primary
broad investigative approach should be
immunodeficiency) or acquired
used in order not to miss causal agents, an
(through immunosuppression or
understanding of the different components
infection such as HIV).
of the immune response can help to focus a
N Preventative measures such as diagnosis (table 1).
antibiotic prophylaxis along with swift
diagnosis and treatment can Features, diagnosis and treatment of
effectively reduce lung morbidity. opportunistic infections
N Long-term sequelae vary from mild The most important pathogens causing
restrictive or obstructive defects to disease in immunocompromised children
end-stage respiratory failure. are listed here. It should be noted that this
list is certainly not exhaustive.

Table 1. Components of the immune response
Component Mechanism of Examples Increased susceptibility to
compromise
Neutrophils Reduced CGD Bacteria
numbers or Children with leukaemia Staphylococcus aureus
function Children after cytotoxic therapy Pseudomonas aeruginosa
Pancytopenia, either primary or Klebsiella
in response to infection (e.g. Escherichia coli
parvovirus infection in children Haemophilus influenzae
with sickle cell disease) Nocardia
More rare genetic conditions Fungi
Candida
Aspergillus
Mucormycosis
Complement Reduced Mannose-binding lectin Bacteria
production or deficiency Streptococcus
dysfunction Early classical pathway (C2, C4, pneumoniae
C1qrs) deficiency Neisseria meningitidis
Alternate pathway deficiency
Late lytic deficiency
B-lymphocytes Reduced Common variable Bacteria
production or immunodeficiency Streptococcus
dysfunction X-linked agammaglobulinaemia pneumoniae
IgG subclass deficiency Haemophilus influenzae
SCID
Acute lymphoblastic leukaemia,
chronic lymphoblastic
leukaemia, and lymphomas
pre- and post-treatment
T-lymphocytes Reduced SCID Bacteria
production or After chemotherapy for Listeria
dysfunction malignancy or organ Mycobacterium
transplantation including M. tuberculosis
Lymphoma Nocardia
Secondary to use of chronic Legionella
high-dose corticosteroids Viruses
HIV/AIDS VZV
CMV
HSV
Fungi
Candida
Aspergillus
Cryptosporidium
Pneumocystis jiroveci
Parasites
Toxoplasma gondii
VZV: varicella zoster virus; HSV: herpes simplex virus.
Aspergillus and Candida are highly These organisms rarely cause disease in
prevalent in our normal environment, in soil healthy individuals, but can do in the
and as part of the skin flora, respectively. immunocompromised.

Diagnosis is made as follows. Cytomegalovirus (CMV) can be transmitted
vertically from mother to fetus but also
N History and examination findings: high- through infected blood products or organs
risk patients include those with primary post-transplantation. In children with
or secondary neutropenia, chronic normal immune function, CMV infection is
granulomatous disease (CGD) or hyper- often asymptomatic. In the
IgE syndrome, and those receiving high- immunocompromised host, there is a wide
dose broad-spectrum antibiotics. Chronic range of nonspecific presenting symptoms
or high-dose corticosteroid use also including fever, malaise, arthralgia, pyrexia
increases risk. Pleuritic chest pain is and macular rash. Patients post-
characteristic of invasive disease in transplantation are at particular risk.
conjunction with cough, dyspnoea,
hypoxaemia and haemoptysis. CMV pneumonitis presents with insidious
N Chest radiography may reveal new increase in dyspnoea, nonproductive cough
infiltrates or round focal opacity; and evolving oxygen requirement. Fulminant
however, CT is extremely useful for respiratory failure requiring ventilator
diagnosis as there are several support due to CMV alone is rare; and, more
commonly, results from dual pathology or
characteristic features, including
multiple pulmonary infectious agents for
cavitations, air crescents and halo signs,
example secondary bacterial pneumonia
all suggestive of fungal parenchymal
with or without septicaemia.
erosion.
N Contamination of the upper airway with Diagnosis is made by:
fungus is common in children with
mucositis so sputum samples may give N history and examination findings, and
false-positive results; therefore, exclusion of other infections;
bronchoscopy with bronchoalveolar N typical chest radiography changes of
lavage (BAL) is helpful in confirming the bilateral diffuse infiltrates;
diagnosis. It should be noted that yield N CT showing patchy bilateral consolidation
can be poor and false-negative results are and nodular shadowing;
common. N detection of CMV antigen in peripheral
N Examine other organ systems for signs of blood mononuclear cells;
infection. Oncomycosis is particularly N possibly, the presence of giant cells in
common in immunodeficient individuals. BAL;
N Open-lung biopsy may be the only means N PCR from blood, urine and or BAL
of diagnosis, but be cautious as, in CGD specimens; and
in particular, the fungal load in the lung N transbronchial or open-lung biopsy
may be very low. specimens can be stained and cultured
for CMV.
Several antifungal agents are available but
In children with established CMV
those with broadest cover, greatest tissue
pneumonitis, intravenous ganciclovir is the
penetrance and lowest toxicity are liposomal
treatment of choice. If ganciclovir resistance
amphotericin (Ambisome; Gilead, Foster
is suspected or if there is no clinical
City, CA, USA) and caspofungin. Azoles, for
response, then foscarnet or cidofovir can be
example voriconazole, are commonly used
used as alternatives.
for prophylaxis; however, they are less
effective for treatment of Candida infection. Neutrophil suppression by treatment drugs
Duration of treatment is titrated to response increases susceptibility to fungal infections;
and must be discussed with specialist therefore, fungal prophylaxis should be
teams. Treatment is often commenced considered. Children receiving stem cell or
empirically, as confirmation of the diagnosis solid-organ transplantation who are at high
may be difficult without biopsy. If such a risk of CMV infection (e.g. a CMV-negative
decision is taken, then a full treatment child receiving a CMV-positive graft) may
course should still be completed. benefit from ganciclovir prophylaxis.

Protocols vary between centres, and by Tuberculosis All children in high-risk groups
clinical situation. are susceptible to pulmonary TB infection
and subsequent disease. Risk factors
Pneumocystis jiroveci , formerly known as include: close domiciliary contacts with
Pneumocystis carinii, was originally others who have open disease; travel to or
misclassified as a fungus but is now known from areas of high TB incidence; children
to be a protozoan; although the ,2 years with relatively nave immune
nomenclature has changed, the term memory; and those infants of HIV-infected
P. carinii pneumonia (PCP) is still used. It mothers or those with some congenital
is highly prevalent in the environment and immunodeficiencies (particularly SCID,
infection is caused by inhalation of airborne CGD and defects of innate immunity).
cysts. In immunocompromised children, Patients with these primary
manifestations of infection can be slow and immunodeficiencies and infants with
subtle with increasing signs and symptoms confirmed HIV should not be vaccinated
over several weeks. Patients with T-cell with bacille CalmetteGuerin (BCG).
deficiency are particularly at risk (e.g. post-
transplantation, severe combined Diagnosis is made as follows.
immunodeficiency (SCID) and HIV
infection). N History and examination findings:
suspected contact with index case, weight
Diagnosis is made as follows. loss, chronic cough, lethargy, pyrexia,
night sweats and peripheral
N History and examination findings are lymphadenopathy. History of BCG
intermittent fever, dry cough and vaccination and scar should be noted.
dyspnoea with weight loss. Hypoxia is a N Gastric aspirates, and Mantoux and
classic feature of P. jiroveci pneumonitis QuantiFERON (Qiagen, Hilden,
along with tachypnoea. Poor adherence Germany) tests can all be used to focus
to or prescription failure of prophylactic the diagnosis. Use local age-appropriate
co-trimoxazole should always raise PCP guidelines.
as a differential diagnosis. N Bronchoscopy with BAL permits staining
N Chest radiography findings include and culture for alcohol- and acid-fast
increased bilateral interstitial and alveolar bacilli.
markings. HRCT may only add a picture N Complications include: endobronchial
of ground-glass opacification and lesions causing airway obstruction,
therefore is not always necessary, given pleural effusion, miliary disease with
the increased radiation exposure. haematogenous spread, spinal lesions
N Bronchoscopy with BAL if often and meningitis.
diagnostic: cytology reveals characteristic N Typical chest radiography changes are
foamy macrophages and casts with low hilar lymphadenopathy, calcification of
neutrophilia suggestive of minimal lymph nodes, consolidation, atelectasis,
inflammation. Lung biopsy is rarely effusions and miliary shadows. All of the
required unless there is treatment failure. changes noted on chest radiography,
including cavitations in reactivation or
High-dose intravenous co-trimoxazole is more advanced disease in adolescents,
recommended and the treatment course will can be seen by HRCT.
depend on clinical response. Pentamidine is
an alternative should co-trimoxazole fail. Diagnostic and treatment guidelines will
Concomitant use of pulsed high-dose differ geographically depending on strains
corticosteroids can expedite recovery as and population mix. Four oral drugs are
seen in adults with HIV; however, they can conventionally used for uncomplicated TB
cause deterioration if there is co-infection treatment: rifampicin, isoniazid,
with CMV. Milder disease may respond to pyrazinamide and ethambutol. Adherence
treatment with combined oral antimicrobials can be problematic as treatment courses
such as clindamycin with primaquine. generally last for 6 months (all four drugs for

the first 2 months followed by rifampicin and are malnourished or have been on long-term
isoniazid for the remaining 4 months). corticosteroids should also be considered.
Support from specialist nursing teams in the
community with regular outpatient follow-up Examples of long-term sequelae are:
is vital to ensure correct and complete N scoliosis, thoracic growth arrest and
eradication. A diagnosis of multidrug crush fractures of the vertebrae;
resistance to rifampicin and isoniazid N restrictive lung function defects;
(multidrug-resistant TB) requires specialist N obliterative bronchiolitis;
advice on treatment. Ethambutol can rarely N pulmonary fibrosis and traction
cause reversible ocular toxicity; therefore, bronchiectasis;
ophthalmology screening and titration of N pulmonary hypertension;
drug doses is recommended. N pulmonary veno-occlusive disease; and
Differential diagnosis N pulmonary infarcts after recurrent acute
chest syndrome in sickle cell disease.
This will depend upon primary diagnosis,
Conclusion
but the following must be considered.
Paediatric pulmonologists should have a
N Infiltration by disease process, as in good understanding of the systemic and
lymphoma and leukaemia pulmonary manifestations of both infectious
N Radiation pneumonitis and noninfectious disease processes in the
N Drug-induced inflammation and fibrosis immunocompromised child. Consultation
N Adult respiratory distress syndrome with specialist colleagues in related
N Lymphoid interstitial pneumonitis in HIV disciplines will permit a holistic and effective
infection approach to each individual patients needs.
N Pulmonary embolism
N Alveolar haemorrhage
N Graft-versus-host disease Further reading
N Post-transplant lymphoproliferative N Bellanti JA. Immunology IV: Clinical
disease Applications in Health and Disease.
N Alveolar proteinosis Bethesda, I Care Press, 2011.
N Acute chest syndrome in sickle cell N Chapman S, et al. Pulmonary disease in
disease the immunocompromised (non-HIV). In:
Oxford Handbook of Respiratory
Long-term sequelae and follow-up Medicine. 2nd Edn. Oxford, Oxford
University Press, 2009; pp. 6777.
Immunocompromised children are
N Chernick V, et al., eds. Kendigs Disorders
susceptible to chronic, progressive damage of
of the Respiratory Tract in Children. 7th
the lung parenchyma and airways from both
Edn. Philadelphia, Saunders, 2006.
infectious and noninfectious factors. N Hull J, et al. The immunocompromised
Physiological monitoring (i.e. spirometry), child. In: Oxford Specialist Handbook of
bronchodilator reversibility, transfer factor Paediatric Respiratory Medicine. Oxford,
measurement and polysomnography can Oxford University Press, 2007; pp. 5558.
provide objective information about the N Hull J, et al. Primary immuno-deficiency.
clinical course and guide supportive In: Oxford Specialist Handbook of
management. Echocardiography to assess Paediatric Respiratory Medicine. Oxford,
pulmonary hypertension and dual-energy Oxford University Press, 2007; pp.
X-ray absorptiometry (DEXA) scans for 425444.
measurement of bone density in children who

Non-CF bronchiectasis
Elif Dagli
In 1819, Laennec first described the finding nutrition, vaccination and use of early
of ectatic bronchi in pathological specimens. antibiotics. However, the ability to recognise
Since then, bronchiectasis has been a bronchiectasis improved with novel imaging
morphological term used to describe techniques has renewed the interest in this
dilatation of the airways, supported by clinical condition globally.
radiological and clinical evidence. Dilated
Pathophysiology
airways are often manifested with a
thickened wall, bacterial colonisation and Bronchiectasis is categorised into three
destruction of the surrounding tissue due to main phenotypes according to the shape of
excessive inflammation. the dilatation:
Epidemiology N tubular,
Non-CF bronchiectasis (NCFB) is still an
N varicose,
important cause of chronic suppurative lung
N cystic.
disease in low-income countries and among This classification describes the progression
disadvantaged populations of high-income of the disease without providing information
countries. A decline in prevalence has been about aetiology. The aetiology of NCFB is
noted since the 1950s in high-income variable, but the common
countries with improved sanitation, pathophysiological mechanism contains
infection, inflammation and tissue damage.
Key points The airway excessive inflammatory response

triggered by bacterial burden may result in
N The diagnosis of non-CF an increased production of proinflammatory
bronchiectasis may be delayed as cytokines and uncontrolled activation of
chronic wet cough can be effector cells.
misdiagnosed as other respiratory Aetiology
diseases.
An underlying cause for bronchiectasis
N HRCT scanning is necessary as chest
cannot be determined in all patients.
radiography is not sensitive for
Improvements in diagnostic techniques, and
detecting early disease.
facilities for more subtle immunological
N Prognosis has been related to the abnormalities and primary ciliary dyskinesia
extent of disease and the type of have decreased the proportion of idiopathic
bronchiectasis. patients. Nevertheless, the prevalence of
idiopathic cases in different series ranges
N Treatment is based on optimising
from 17% to 40% depending on the
airway clearance techniques and
facilities.
intermittent courses of antibiotics
for pulmonary exacerbations. The period between the first symptom and
diagnosis is usually too long to prove

causality in most clinical series. Among the Symptoms
identified aetiologies, severe childhood
infections (measles, pertussis, adenovirus Cough is the primary presenting symptom
and TB), primary ciliary dyskenesia, a1-anti- followed by sputum production, dyspnoea
trypsin (AAT) deficiency, atypical CF, and wheeze. The most common reason for
immune deficiencies and congenital referral was reported as recurrent chest
anomalies have been recognised. Missed infection. Recurrent otitis media, failure to
opportunities such as undertreated asthma thrive, gastro-oesophageal reflux, rhinitis
and undiagnosed foreign body aspirations from neonatal period, exercise intolerance
may commonly be reported. Aspiration and and haemoptysis were among other reasons
gastro-oesophageal reflux, collagen vascular for admission to a special care centre.
disorders and other conditions, such as The distribution of bronchiectasis within the
sarcoidosis, Young syndrome, Mounier- lung fields was not found to be correlated
Kuhn syndrome, Ehler-Danlos syndrome, with the underlying aetiology. However, in
Marfan syndrome and yellow nail syndrome, most series localisation was in the middle
are less frequently reported aetiologies. and lower lobes.
In affluent countries, primary Microbiology
immunodeficiency remains the most
common cause accounting for 2039% of Sputum culture is standard in evaluating
paediatric bronchiectasis (table 1), whereas airway colonisation and infection in NCFB. If
in non-affluent countries bronchiectasis as a sputum cannot be produced spontaneously,
result of past infection is much more sputum induction could be used as an
common. alternative. The most common bacterial
isolates are non-typeable Haemophilus
Missed diagnosis CF may be an underlying influenzae, Pseudomonas aeruginosa,
cause. 20% of patients with NCFB had Streptococcus pneumoniae, Staphylococcus
diagnosis of CF after a comprehensive aureus and Moraxella catarrhalis.
analysis in a clinical series. All patients with Colonisation with P. aeruginosa is associated
apparent NCFB should have comprehensive with more severe bronchiectasis and a
analysis to detect cystic fibrosis worse prognosis as demonstrated by
transmenbrane conductance regulator physiological and radiographical studies.
(CFTR) mutations.
Diagnosis
The possibility of bronchiectasis must be

Table 1. Immunodeficiencies usually identified in considered under the following clinical
patients with bronchiectasis conditions:
Agammaglobulinaemia
Common variable immunodeficiency N chronic moist or productive cough,
lasting longer than 8 weeks,
IgA deficiency N asthma unresponsive to treatment,
Selective antibody deficiency N incomplete resolution of pneumonia after
Severe combined immunodeficiency treatment or recurrent pneumonia,
TAP deficiency
N persistent and unexplained lung crackles,
N respiratory symptoms in children with
Ataxia telangiectasia structural or functional disorders of the
Hyper-IgE syndrome oesophagus and upper respiratory tract,
Cartilage-hair hypoplasia N haemoptysis.
Chronic granulomatous disease Imaging
TAP: transporter associated with antigen
As chest radiograph findings and HRCT
presentation.
scans of the chest show poor agreement,

a normal chest radiograph cannot exclude progression; however, it is not sensitive at
bronchiectasis in a symptomatic child. detecting early bronchiectatic structural lung
damage.
Before the development of HRCT scans,
diagnosis was made by bronchograms using A study that investigated clinical,
contrast material to map the airways. When radiological and laboratory features of
CT appeared as a diagnostic tool it replaced children with NCFB reported a significant
bronchography as the gold standard for correlation between HRCT severity scores
the diagnosis of bronchiectasis. At present, and symptoms, FEV1, sputum interleukin
chest HRCT is the gold standard for (IL)-8 and tumour necrosis factor-a levels
diagnosis with a sensitivity of 97%. Most proving ongoing inflammation.
paediatric studies report bronchiectasis as a
multilobar disease. The pulmonary function of children with
NCFB declines significantly over time,
The Bhalla scoring system is generally used despite treatment. Aetiology has a
for evaluation of the severity of significant impact on severity which may
bronchiectasis by CT. Bronchiectasis is indicate an opportunity to target screening
present when the internal luminal diameter and treatments.
is slightly greater than the adjacent blood
vessel. Peribronchial thickening is present Treatment
when the wall thickness is equal to or larger There is no evidence-based consensus on
than the diameter of the adjacent vessel. the treatment of NCFB. Management
Evaluating the extent of mucus plugging, recommendations are mostly based on
bronchiectasis, the presence of abscesses or evidence extrapolated from trials in CF in
sacculation, the generation of bronchial high-income countries.
divisions, the presence of emphysema, There are some general therapeutic
collapse, and/or consolidation can be made recommendations for NCFB patients as
during further assessment. follows.
MRI is a new method used in the diagnosis of
NCFB. Chest MRI was found to be equivalent
N Chest physiotherapy and exercise are
essential for airway clearance.
to HRCT in determining the extent of lung
disease in children with non-CF lung disease. N Annual influenza and 5-yearly
The findings support the use of chest MRI as pneumococcal vaccinations should be
an alternative to HRCT in diagnostic pathways given.
for paediatric chronic lung disorders. N The use of inhaled steroids remains
controversial, however, cessation of
A sweat test must be performed in all inhaled steroids with bronchial
patients with bronchiectasis and repeated in hyperreactivity was reported to increase
the case of doubt. Immune function test, bronchial hyperresponsiveness and
such as serum Ig, IgG subclasses, specific decrease in neutrophil apoptosis.
antibody levels to vaccinations, T- and B-cell N Prompt and effective antibiotic use is
lymphocyte subsets, a Mantoux test and essential in acute infectious
HIV detection, tests for primary ciliary exacerbations, increase in wheeze,
dyskinesia in the form of nasal brushing to breathlessness and sputum purulence.
examine cilial motility under light Antibiotic therapy should be prescribed
microscopy and ultrastructure under based on bacterial cultures and
electron microscopy, tests for aspiration sensitivity.
contrast study of swallowing, and
oesophageal pH studies may be performed There is no evidence for the use of
to investigate underlying aetiology. carbocysteine, mannitol, leukotriene
receptor antagonists, anti-inflammatory
Spirometry does not provide diagnostic drugs and methylxanthines. However, some
information but may serve as a marker of beneficial effects on lung function were

reported of long-term, oral, low-dose Prognosis
azithromycin use. Azithromycin also
reduced bronchoalveolar lavage neutrophilia Long-term consequences of childhood
and interleukin-8 mRNA. bronchiectasis have been recently
documented. Many reports, regardless of
Children with NCFB will require inpatient analysis strategy, have shown that children
treatment for the following: with bronchiectasis have significant airway
obstruction which deteriorates over time. In
N increased respiratory rate and increased one study, FEV1 was reported to have
work of breathing, declined by a mean of 1.6% predicted per
N circulatory or respiratory failure, year.
N fever (a body temperature .38uC),
Patients with NCFB may have complications
N no oral intake,
of the disease which may contribute
N infection not controlled with oral
negatively to the prognosis.
antibiotics.
NCFB patients have been found to have
Surgery
disturbed sleep associated with severity of
Surgery is indicated in patients with mild disease. Night-time symptoms and
bronchiectasis confined to resectable limits hypoxaemia during sleep may affect sleep
who are unresponsive to medical treatment, quality in children with bronchiectasis. Poor
or in patients with severe tissue damage sleep quality may impair growth, learning
causing threat to the intact part of the lung. and emotional development of children.
Surgery has been performed in fewer cases Patients with bronchiectasis who snored had
as the diagnosis is made earlier and the poorer sleep quality and patients with
medical treatment improves. wheezing had a significantly higher rate of
snoring.
There are few data about long-term results
Other long-term outcomes of childhood
of medical and surgical treatment.
bronchiectasis include impaired left
Nevertheless, correctly chosen cases may
ventricular diastolic functions and
benefit from surgery. A study on 19 cases of
osteopenia. Osteopenia is reported to be
bilateral surgical resection, six cases of
more common in children with NCFB
complete pneumonectomy, 165 cases of
compared to controls and the risk of
complete resection and 11 cases of
osteoporosis and osteopenia increases with
incomplete resection, with mean age of
age.
12.3 years, reported a perfect outcome in
73.3% of patients.
Further reading
Lung transplantation
N Al Subie H, et al. (2012). Non-cystic
N Lung transplantation might only be an fibrosis bronchiectasis. J Paediatr Child
option in patients with advanced lung Health; 48: 382388.
disease and declining lung function. N Barker AF, et al. (1988). Bronchiectasis:
N Comorbidities of advanced update of an orphan disease. Am Rev
bronchiectasis should be detected and Respir Dis; 137: 969978.
treated before referral for transplantation, N Bhalla M, et al. (1991). Cystic fibrosis:
scoring system with thin-section CT.
as the underlying disease may cause
Radiology; 179: 783788.
morbidity after surgery.
N Dagli E (2000). Non cystic fibrosis
N Patients with CF and NCFB generally bronchiectasis. Paediatr Respir Rev; 1:
have a good outcome following lung 6470.
transplantation. N Eastham KM, et al. (2004). The need to
N Management of infection is a key redefine non-cystic fibrosis bronchiecta-
issue both pre- and post-lung sis in childhood. Thorax; 59: 324327.
transplantation.

N Goeminne P, et al. (2010). Non-cystic N Karadag B, et al. (2005). Non-cystic-
fibrosis bronchiectasis: diagnosis and fibrosis bronchiectasis in children: a
management in 21st century. Postgrad persisting problem in developing coun-
Med J; 86: 493201. tries.. Respiration; 72: 233238.
N Hilla AT, et al. (2011). Primary care N Li AM, et al. (2005). Non-CF bronchiectasis:
summary of the British Thoracic Society does knowing the aetiology lead to changes
Guideline on the management of non- in management? Eur Respir J; 26: 814.
cystic fibrosis bronchiectasis. Prim Care N Montella S (2012). Magnetic resonance
Respir J; 20: 135140. imaging is an accurate and reliable method
N Kapur N, et al. (2011). Differences and to evaluate non-cystic fibrosis paediatric
similarities in non-cystic fibrosis lung disease. Respirology; 17: 8791.
bronchiectasis between developing and N Sirmali M, et al. (2007). Surgical manage-
affluent countries. Paediatr Respir Rev; ment of bronchiectasis in childhood. Eur J
12: 9196. Cardiothorac Surg; 31: 758.

Pleural infection, necrotising
pneumonia and lung abscess
Fernando M. de Benedictis, Chiara Azzari and Filippo Bernardi
Pleural infection, necrotising pneumonia continuum, but classically it has been

and lung abscess are serious conditions in divided into three stages according to the
children and deserve a systematic, evolution of the inflammatory process:
multidisciplinary approach. exudative (simple parapneumonic effusion),
fibropurulent (complicated parapneumonic
Pleural infection effusion) and, eventually, overt pus in the
In children, the presence of pleural fluid pleural space (empyema). A simple
collection is usually the consequence of parapneumonic effusion (PPE) is present in
underlying pneumonia. Pleural infection is a up to 40% of community-acquired
pneumonia (CAP) and more than half of
cases may complicate further. In our setting,
Key points the term of empyema is used generically to
describe an advanced stage of PPE.
N The incidence of pleural empyema is Evidence suggests that the incidence of
increasing in many countries. pleural empyema has increased in many
N The most common pathogens countries over the past few years. The
associated with empyema, necrotising reasons for this dramatic increase are not
pneumonia and lung abscess are known, but possibilities include changing
S. pneumoniae and S. aureus. bacterial resistance and virulence,
introduction of the pneumococcal
N Chest CT is unnecessary for most vaccination, adjustments to primary care
cases of complicated pneumonia and antibiotic prescribing practices and referral
should be considered in selected patterns.
cases.
Diagnosis
N Therapeutic choices should be Clinical features of empyema can closely
evaluated individually and shared in a resemble those of an uncomplicated
multidisciplinary team. pneumonia, but the possibility of a pleural
N Antibiotics remain the mainstay of complication should be considered
treatment. especially in children who remain pyrexial or
unwell 48 h after starting antibiotic therapy.
N Chest drain with fibrinolysis is the Judicious use of appropriate investigations
preferred primary therapy in can clarify what is often a difficult clinical
empyema; VATS should be reserved diagnosis.
for use in patients refractory to
medical treatment. Imaging studies may help to confirm the
clinical suspicion and to better follow the
N The long-term outcome for children
evolution of the infectious process.
with complicated pneumonia and no
predisposing conditions is usually Chest radiographs are usually the first
good. investigation to confirm the presence of
PPE. Early signs include blunting of the

costophrenic angle and a rim of fluid
ascending the lateral chest wall (meniscus
sign) (fig. 1). Large effusions may appear as
complete white out of the lung field,
making it impossible to differentiate
between pleural fluid and consolidated lung.
Lateral chest radiographs are not necessary
in most cases.
Chest ultrasound scans are critical in the

diagnosis of PPE, especially as they do not
involve radiation and sedation is not
necessary. Although it cannot reliably
establish the stage of pleural infection, it can Figure 2. Empyema: consistent amount of infected
differentiate pleural fluid from consolidated fluid in the right pleural space and a totally
lung in children with complete white out of collapsed right lung.
the lung field, estimate the size of the
effusion, reveal fibrinous septations and before surgical intervention in order to
assess loculation of fluid. It can also be used delineate the anatomy further.
to guide chest drain insertion and assess
treatment response. Laboratory
Blood Acute reactants such as white cell
Chest CT scans do not appear able to reliably count, C-reactive protein, erythrocyte
distinguish the stage of pleural collection sedimentation rate and procalcitonin are
and predict the outcome of empyema. While unhelpful in distinguishing bacterial from
unnecessary for most cases of paediatric viral pneumonia. However, an initial
empyema, CT scans should be considered evaluation of acute reactants should be
when there is concern that infection is not obtained to provide supportive evidence for
the underlying cause (i.e. blood-stained an infective aetiology of PPE. Serial
pleural fluid or tumours) or when clinical measurements can be helpful in monitoring
improvement is not obtained with the progress.
appropriate treatment (fig. 2). Many
surgeons will require that a CT be performed Blood cultures should be obtained despite
the low isolation rate in PPE (1022%), as
they may be positive when pleural fluid
culture proves sterile.
Real-time PCR analysis of blood and

respiratory specimens has become more
widely available over the past years, enabling
rapid identification of potential pathogens.
This molecular technique appears to add
diagnostic value and should always be
considered for specific pathogens, if
available, especially when cultures are
negative.
Sputum Any available sputum should be

sent for culture, as microbiology isolation is
likely to represent the infecting organism
from the lower airways. However, the low
Figure 1. Pleural effusion: blunting of the right quality of specimens often obtained from
costophrenic angle and a rim of fluid ascending children, and the inability to distinguish
the lateral chest wall. colonisation from infection of the respiratory

tract limit the usefulness of this analysis, the Indeed, most small PPE will respond to
results of which should always be antibiotics without the need for further
interpreted with caution. intervention. Decisions on empirical
antibiotic therapy should be based on
Pleural fluid Although frequently sterile due pneumonia treatment guidelines and take
to prior administration of antibiotics, any into consideration whether the infection was
pleural fluid that is available should undergo community or hospital acquired, local
biochemical, cytological and microbiological antibiotic resistance patterns, and whether
analysis including Gram stain, acid-fast the child has any underlying medical
bacilli stain, culture and antibiotic sensitivity problems (i.e. CF or immunodeficiency). The
testing. Molecular analysis by PCR of pleural choice of antibiotics should be modified
fluid more than doubled the detection of accordingly once the causative pathogens
pathogens causing empyema. and sensitivities are known. If culture results
Other analysis In children, the are negative, the adjustment may depend on
immunochromatographic membrane test the response of clinical and radiography
(Binax Now) for rapid detection of parameters.
pneumococcal C polysaccharide antigens in Given evidence from epidemiological
urine showed false-positive results which studies, it is imperative that initial
make this test unhelpful for diagnostic antibiotics provide good Streptococcus
purposes. Mantoux testing and pneumoniae cover pending culture results. If
microbiology for Mycobacterium tuberculosis there is radiological evidence of
should be performed if there is a pneumatocoeles, adequate staphylococcal
predominance of lymphocytes in the pleural cover is required. Anaerobic cover should be
fluid or risk factors for TB are present. added if the child is at risk of aspiration. A
Management second- or third-generation cephalosporin
Despite the fact that empyema has been (cefuroxime, cefotaxime or ceftriaxone), or
recognised for over 2000 years, its amoxicillin-clavulanate are often used
management in childhood remains empirically intravenously. In areas where
controversial, mainly because of the paucity there is a high prevalence of methicillin-
of evidence-based studies at this age. This resistant S. aureus, clindamycin or a
has led to treatment being determined by glycopeptide can be used as additional first-
personal experience and local availability of line agent. In children with known allergy to
different therapeutic options. penicillin, clindamycin should be considered
as the first-line antibiotic treatment.
The goals of treatment are sterilisation of
the pleural cavity and drainage of excessive Intravenous antibiotic therapy is usually
pleural fluid, in order to allow re-expansion continued until there is definite evidence of
of the lung and restoration of normal pleural clinical improvement and resolving fever, or
fluid circulation. Since management is at least until the chest drain is removed.
harder in those with an advanced organised While there is no evidence to guide the
empyema, prompt recognition and duration of treatment, oral antibiotics, such
treatment remains important. Preferably, as amoxicillin-clavulanate or a second-
children with PPE should be transferred to a generation cephalosporin, are generally
tertiary paediatric respiratory unit, continued for 23 weeks following
particularly if the effusion is large or the discharge.
child is unwell. The therapeutic choices
should be evaluated individually and shared Routine diagnostic thoracentesis is not
in a multidisciplinary team. recommended in children, unless there is a
suspicion of a noninfectious aetiology.
Treatment Unlike adults, biochemical analyses of
Antibiotics There is undoubtedly a role for pleural fluid (pH, glucose levels, proteins or
antibiotic treatment alone in children with lactate dehydrogenase) has not been shown
mild PPE and no respiratory compromise. to be of any value in the practical

management of children with pleural Surgery The role of surgery in the
effusions. In addition, obtaining a sample of management of childhood empyema is
pleural fluid is technically challenging in controversial. While surgery was previously
children, requires sedation and results in a reserved for cases of failed medical therapy,
significantly higher re-intervention rate when the advent of less invasive techniques has
compared to insertion of a pigtail catheter led to an increasing interest in surgerys
as a primary procedure. potential role in primary treatment.
Chest drain alone Following the introduction Video-assisted thoracoscopic surgery (VATS)
of appropriate antibiotics, the decision to achieves debridement of fibrinous material,
proceed to drainage should take into breakdown of loculations and drainage of
consideration a number of factors including pus from the pleural cavity under direct
clinical and laboratory response to antibiotic vision. The more controversial area is the
therapy at 4872 h and evidence of role of VATS versus chest drainage with
enlarging effusion on repeated ultrasound. intrapleural fibrinolysis in the primary
management of empyema. In a systematic
Development of respiratory compromise is review of 67 studies published over a period
an indication for drainage. While chest drain of .20 years, primary operative therapy was
insertion alone can be effective in children associated with a lower LOS, time of
with empyema, the length of stay (LOS) in drainage, time of antibiotic therapy, re-
hospital is prolonged (20 versus 10.7 days) intervention rate and mortality rate
and there is a higher failure rate (23.6% compared with nonoperative treatment.
versus 9.4%) compared to chest drain with However, the majority of these studies did
intrapleural fibrinolytics. not include treatment with fibrinolytics in
addition to chest drainage.
Chest drain plus intrapleural fibrinolytic agent
The aim of instilling a fibrinolytic agent in Two prospective randomised trials have
the pleural cavity is to break down fibrin compared primary VATS to chest drain with
strands in order to improve drainage and re- intrapleural fibrinolysis, either urokinase or
establish pleural circulation. Numerous case tissue plasminogen activator, in children.
series and a few randomised controlled No difference between treatment groups
trials on the use of intrapleural fibrinolytic was found in the main outcomes, but VATS
therapy in childhood empyema have been cost significantly more. Current evidence
published to date. They have used different suggests that chest drain with fibrinolysis is
agents, dosage schedules and treatment the preferred primary therapy in empyema,
protocols, and there was a great diversity in and that VATS should be reserved for failure
the stage at which treatment was started. of medical management. In clinical practice,
Not surprisingly, outcomes varied greatly. the choice of one of these options is often
conditioned by local experience and
Urokinase is actually the preferred fibrinolytic
tradition.
agent for the treatment of empyema. The
most widely used dosage regimen is 40 000 Open thoracotomy enables removal of the
units of urokinase in 40 mL of normal saline, thickened pleural rind and irrigation of the
or 10 000 units in 10 mL of normal saline for pleural cavity. Potential drawbacks include a
children ,1 year of age, which is large scar and the risk of wound infection,
administered twice daily for 3 days. After persistent air leaks and bleeding. Mini-
instillation, the chest drain is clamped for 4 h thoracotomy involves a similar procedure
and the child is encouraged to mobilise. The through a small incision.
drain is then left on a suction pressure of -
20 cmH2O until the next dose. There is some A number of retrospective studies have
evidence to suggest a potential advantage for compared VATS to open thoracotomy for
smaller catheters in reducing the time of rescue treatment demonstrating less post-
drainage, time until the patient became operative pain, a better cosmetic result and,
afebrile, and LOS. in some cases, a shorter LOS.

Open thoracotomy procedures should, occurs as a result of inflammatory response
therefore, only be reserved for late due to toxins produced by the invasive
presenting empyema with significant pleural pathogen or the associated vasculitis with
fibrous rind. thrombotic occlusion of alveolar capillaries.
The process may rapidly progress to tissue
Prognosis The prognosis in children with destruction and intraparenchymal bullae,
empyema is usually very good. Unlike even in the presence of proper antibiotic
adults, empyema in childhood is associated therapy. At such stage, the process may
with a low mortality (,0.5%) with the further extend to the pleural space and
majority of children eventually making a create a bronchopleural fistula, especially
complete recovery. Follow-up studies have when the necrotic segment is adjacent to the
shown that chest radiography returns to pleural surface. When multiple necrotic foci
normal in almost all patients by 6 months
are involved, they may coalesce and a large
and that lung function returns to normal or
cavity can result.
shows only minor abnormalities long-term.
Clinical features Children with necrotising
Pneumatoceles are generally complications pneumonia usually present with symptoms
of a staphylococcal pneumonic process and of severe pneumonia, such as high fever,
may be associated with empyema. They are
cough, and tachypnoea, lasting for several
more common in infants and young
days. Necrotising pneumonia should be
children. They usually regress spontaneously
suspected when a patient with pneumonia
with the improvement of the pneumonic
develops progressive respiratory distress,
process, but sometimes they require
haemoptysis or septic shock despite
surgical intervention when they become taut
appropriate antibiotic treatment. Pleural
or infected, or when they break in the pleural
effusion is often detectable at physical
cavity, thus inducing pneumothorax or
examination.
pyopneumothorax.
Imaging The diagnosis of necrotising
Necrotising pneumonia
pneumonia can be detected by chest
Necrotising pneumonia is a severe radiography, but the presence of pleural
complication of CAP and is characterised by effusion may obscure the underlying lung
liquefaction and cavitation of lung tissue. In process. Chest radiography underestimates
the last few years, increasing cases of the degree of parenchymal destruction,
necrotising pneumonia in previously healthy therefore contrast-enhanced CT may be
children have been reported with special needed for a more definitive diagnosis when
emphasis on laboratory, pathology, necrotising pneumonia is suspected.
radiology and clinical aspects. This Radiographic criteria for necrotising
increased incidence is probably due to a pneumonia include the loss of the normal
combination of improved recognition of lung architecture and the presence of areas
necrotising pneumonia as a specific entity of decreased parenchymal enhancement,
and heightened detection resulting from the representing liquefaction, that are
use of CT scans in the evaluation of children progressively replaced by multiple small air
with complicated pneumonia. However, the or fluid filled cavities. Transition from
observed increase of necrotising pneumonia liquefaction to cavitation may progress
parallels that of complicated PPE observed rapidly within 48 h. Although CT offers the
in several nations over the past years. The advantage of being able to identify
necrotic process can occur at any lobe of the parenchymal complications over chest
lung, but involvement of lower lobes is more radiography (fig. 3), clinical management is
frequent. The affected extent may be patchy, not changed in the majority of cases and
segmental, lobar or even an entire lung. routine use of CT is therefore not justified.
The pathogenetic mechanisms of Abnormal laboratory findings of increased

necrotising pneumonia are not clear, but it acute reactants, low haemoglobin level and
is commonly believed that tissue necrosis hypoalbuminaemia are observed in many

do not warrant specific intervention
strategies beyond a prolonged course of
antibiotics.
Antibiotics Unlike adults, exclusive treatment

with high-dose antibiotics is frequently
successful in children, with unexpected
parenchymal conservation and lung re-
expansion over time, even in cases of severe
pulmonary involvement. As for empyema,
the choice of initial antibiotics should be
directed at broad coverage of commonly
implicated pathogens and modified
Figure 3. Necrotising pneumonia: multiple accordingly once the causative agent and
cavitary lesions and air bronchogram in the
sensitivities are known. Penicillins or
consolidated right upper lobe.
cephalosporins may be administered
initially, while clyndamycin or metronidazole
patients. The pleural fluid characteristics can be added to cover possibly involved S.
associated with necrotising pneumonia aureus or anaerobes.
reflect those usually found in PPE.
A chest drain may be mandatory in cases of
Microbiology Like empyema, S. pneumoniae concomitant pleural effusion. Intrapleural
is the more frequent aetiological agent of fybrinolysis may potentially result in a risk in
necrotising pneumonia. Mycoplasma necrotising pneumonia, since the
pneumoniae and S. aureus strains, often breakdown of the fibrinous seal in the pleura
methicillin-resistant, producing cytotoxin may favour the lack of air from necrotic
Panton-Valentine leukocidin have been also peripheral areas of the lung.
involved in the genesis of necrotising
pneumonia. Other bacteria less frequently Surgery VATS has been used successfully in
reported include S. pyogenes, S. viridans, children with necrotising pneumonia. It
Pseudomonas aeruginosa and anaerobes. should be reserved for patients with
Almost 50% of the cases of necrotising associated empyema or to resolve
pneumonia have no identified aetiological bronchopleural fistulae that do not close
cause with common microbiological with conservative treatment. Surgical
methods. However, new methods, such as resection of the lung should be reserved to
PCR analysis, could potentially increase the particularly severe cases, bearing in mind
diagnostic yield in necrotising pneumonia. potential complications of surgical
intervention and the possible long-term
Treatment There is not a general agreement impairment of pulmonary function.
on the best therapeutic strategy for
necrotising pneumonia, mainly because the Prognosis Long-term outcome for children
frequent coexistence of empyema prevents with necrotising pneumonia is usually good.
uncoupling of the two conditions and the Follow-up chest radiography and, in a few
separate evaluation of their respective cases, CT scan have shown almost complete
contribution to overall morbidity. Studies normalisation of pulmonary parenchyma
comparing the effect of different within months of hospitalisation. This pattern
interventions (i.e. conservative versus of improvement suggests that the lung
surgical) on the evolution of necrotising damage caused by necrotising pneumonia in
pneumonia are unfortunately lacking, and children is transient and that no or minimal
there is an urgent need for these to be functional sequelae are expected.
addressed. However, it should be borne in Lung abscess
mind that, in children, parenchymal
complications of pneumonia do not carry a A lung abscess is a thick walled cavity
particularly adverse prognosis and usually containing purulent material resulting from

suppuration and necrosis of the lung
parenchyma. It is an uncommon paediatric
condition, with a paucity of quality data in
the literature.
Lung abscesses may be single or multiple
and are classically divided into primary and
secondary according with their appearance
in previously well children or in those with
predisposing comorbidities, such as
significant neurocognitive disability,
immunodeficiency, CF or congenital lung
malformation (i.e. pulmonary
sequestration). Lung abscesses may develop
in any area of the lung, but are more
frequent in the lower lobes.
A lung abscess may arise from the
aspiration of infected fluid, aspiration of
noninfected fluid which triggers a chemical
reaction (i.e. gastric content), a primary
bacterial infection of the lung,
Figure 4. Lung abscess: well-circumscribed shadow
haematogenous spread of bacteria or spread
containing an airfluid level in the left upper lobe.
of infection from a contiguous organ. The
time course for progression from initial
involvement to abscess formation is usually improved microbiological diagnostic
slow. techniques, such as PCR, have increased the
yield of pathogens identified from abscess
Clinical features Children may present for fluid samples. S. aureus, group B
several days with a low grade cough and Streptococci, Escherichia coli and Klebsiella
mild fever. Less commonly, chest pain, pneumoniae are the more common
dyspnoea, sputum production and pathogens in primary abscesses and in
haemoptysis may be seen suddenly. The young children. In older children, the
clinical history is important in revealing likelihood of aspiration increases, and oral
predisposing conditions, such as recurrent anaerobic bacteria (Peptostreptococcus,
pulmonary aspiration of airway secretions, Fusobacterium spp., etc.) or mixed flora may
neurocognitive disability, immunodeficiency
be found. More rarely, fungi such as Candida
and proximal airway structural
albicans or Aspergillus spp. can cause lung
abnormalities. Physical examination may
abscess in children.
reveal normal chest auscultation or signs of
consolidation. Treatment
Antibiotics Treatment with a course of
Imaging Typically, the diagnosis of lung
systemic antibiotics will usually successfully
abscess is based on the chest radiograph,
treat a lung abscess. The choice and
which will reveal a well circumscribed
duration of antibiotic therapy will be guided
shadow containing an airfluid level (fig. 4).
by local experience, the type of abscess
Less frequently, multiple abscesses may be
(primary or secondary), and the ability to
present. Distinction between parenchymal
isolate pathogenic organisms. At baseline
abnormalities and pleural collections is
therapy, antibiotics will cover S. aureus,
normally possible by ultrasound, but CT may
be reserved for the occasional cases where streptococcal species and Gram-negative
there is unresolved doubt. bacilli that are usually found in the upper
respiratory tract. Treatment may include
Microbiology More invasive procedures, cephalosporins, vancomycin, clindamycin,
aspiration and drainage, together with aminoglycosides, quinolones and

carbapenems. In patients where anaerobic N Calder A, et al. (2009). Imaging of para-
infection is suspected, metronidazole pneumonic pleural effusions and empyema
should be considered. Generally, a 23 week in children. Pediatr Radiol; 39: 527537.
course of intravenous antibiotics is N de Benedictis FM, et al. (2009).
sufficient to induce clinical and radiological Aspiration lung disease. Pediatr Clin
improvement of the lesion. Once the child North Am; 56: 173190.
has improved, the intravenous route may be N Grijalva CG, et al. (2010). Increasing
replaced by oral antibiotics to complete a 4- incidence of empyema complicating
week treatment course. childhood community-acquired pneumo-
nia in the United States. Clin Infect Dis;
Interventional procedures and surgery Many 50: 805813.
centres will use ultrasound or a CT scan for N Hoffer FA, et al. (1999). Lung abscess
interventional, image-guided aspiration and versus necrotizing pneumonia: implica-
drainage of the abscess cavity with a tions for interventional therapy. Pediatr
percutaneously placed pigtail catheter for Radiol; 29: 8791.
both diagnostic and therapeutic purposes. N Hsieh Y-C, et al. (2006). Necrotizing
Thoracoscopic drainage of lung abscesses pneumococcal pneumonia in children:
may be obtained concurrently with the role of pulmonary gangrene. Pediatr
treatment of empyema. In children, the role Pulmonol; 41: 623629.
N Islam S, et al. (2012). The diagnosis and
of surgical therapy for lung abscess should
management of empyema in children: a
be limited to a minority of patients who are
comprehensive review from the APSA
refractory to medical treatment or who
Outcomes and Clinical Trials
develop complications such as Committee. J Pediatr Surg; 47: 21012110.
bronchopleural fistula. N Nagasawea KK, et al. (2010).
Prognosis Complications of a lung abscess Thoracoscopic treatment of pediatric lung
may include pneumothorax, bronchopleural abscesses. J Pediatr Surg; 45: 574578.
fistula, lung compression and mediastinal N Resti M, et al. (2010). Community-
acquired bacteremic pneumococcal pneu-
shift with progressive respiratory
monia in children: diagnosis and serotyp-
compromise. The existence of underlying
ing by real-time polymerase chain
conditions will influence the prognosis. The
reaction using blood samples. Clin Infect
long-term outcome of lung abscesses in Dis; 51: 10421049.
immunocompetent children is favourable. N Sawicki GS, et al. (2008). Necrotising
Mortality rate is estimated about 5%, pneumonia is an increasingly detected
predominantly in children with predisposing complication of pneumonia in children.
conditions. Eur Respir J; 31: 12851291.
N Sonnappa S, et al. (2006). Comparison of
Further reading urokinase and video-assisted thoraco-
scopic surgery for treatment of childhood
N Alsubi H, et al. (2009). Lung abscesses in empyema. Am J Respir Crit Care Med; 174:
children. J Pediatr Inf Dis; 4: 2735. 221227.
N Avansino JR, et al. (2005). Primary N St Peter SD, et al. (2009). Thoracoscopic
operative versus nonoperative therapy for decortication vs tube thoracostomy with
pediatric empyema: a meta-analysis. fibrinolysis for empyema in children: a
Pediatrics; 115: 16521659. prospective, randomized trial. J Pediatr
N Balfour-Lynn IM, et al. (2005). BTS guide- Surg; 44: 106111.
lines for the management of pleural N Walker W, et al. (2011). Update on the
infection in children. Thorax; 60: 121. causes, investigation and management of
N Blaschke AJ, et al. (2011). Molecular empyema in childhood. Arch Dis Child;
analysis improves pathogen identification 96: 482488.
and epidemiologic study of pediatric N Yen CC, et al. (2004). Pediatric lung
parapneumonic empyema. Pediatr Infect abscess: a retrospective review of 23 cases.
Dis; 30: 289294. J Microbiol Immunol Infect; 37: 4549.

Bacterial bronchitis with
chronic wet cough
Petr Pohunek and Tamara Svobodova
Protracted bacterial bronchitis (PBB) is a

clinical condition characterised by isolated Key points
wet cough lasting for .4 weeks with
absence of pointers suggestive of an N Bacterial bronchitis should be
alternative specific cause of cough, which suspected in a child with protracted
resolves fully following appropriate wet cough.
prolonged antibiotic treatment. It should be N Detailed differential diagnostic
differentiated from bronchiectasis and protocol aims to exclude other
chronic suppurative lung disease (CSLD), underlying causative factors.
which presents with excessively prolonged
moist cough with persistent purulent N Treatment should target the most
secretions. frequent pathogens.
Epidemiology N Protracted bacterial bronchitis can be

a precursor of chronic suppurative
The general epidemiology of PBB is not lung disease and bronchiectasis, if left
known. In a study of 108 children with untreated.
chronic wet cough PBB was the final
diagnosis in 39.8% of patients. In a recent N If detected early and adequately
study analysing 197 children with protracted treated, prognosis of protracted
wet coughing, bacterial cultures were bacterial bronchitis is good.
positive in 91 (46%) children. More than half
of the study patients (55%) were aged 0
3 years, 36% were aged 37 years and only presence of serotypes not included in the
9% were .7 years of age. vaccine. Infection by Pseudomonas
aeruginosa or other more difficult pathogens
Aetiology
does not occur in PBB. When these
Among the positive bacterial cultures the pathogens are found in a child with chronic
leading pathogen is usually nontypable cough, the search for underlying aetiology
Haemophilus influenzae (,50%), followed by should be actively undertaken (e.g. CF,
Streptococcus pneumoniae and Moraxella primary ciliary dyskinesia and
catarrhalis (,20% each). Staphylococcus immunodeficiency).
aureus is less common with a frequency of
Risk factors
,12%. Combinations of more than one
pathogen at the same time have been The main risk factors for developing PBB are
described. A recent study that compared as follows.
serotypes of S. pneumoniae in children with
bacterial bronchitis from the UK with those Impaired mucociliary clearance after viral
from Greece found an important impact of respiratory infections Lack of convalescence
vaccination. In children vaccinated with a after viral bronchitis may lead to impaired
pneumococcal vaccine they found a trend to airway clearance (secondary disorders of
serotype replacement with more frequent ciliary epithelium and persistent

inflammation of airway mucosa) and mucosal barrier. With some risk factors this
facilitation of bacterial infection. may start gradually and be based on
continuous damage of the mucosa (e.g.
Airway malacia Tracheomalacia/ recurrent aspiration, environmental triggers
bronchomalacia has been detected in or gastro-oesophageal reflux) with no
children with PBB more frequently than in apparent initial acute event. Additionally,
the general population. In one study
high presence of neutrophils with their
evaluating children with PBB aged
enzymatic activity enhances the process. In
,60 months the authors found
various studies the fraction of neutrophils in
laryngomalacia or tracheomalacia in 74%.
differential count from bronchoalveolar
Another study found tracheomalacia in 30%
lavage fluid (BALF) was as high as 90%.
of young children with PBB. How far the
Uncontrolled bacterial infection, mucus
malacia is a causative factor or to what
retention and high proteolytic activity of the
extent instability of the airways may be
neutrophils can lead to CSLD, damage to
secondary to prolonged infection and
the bronchial wall and gradual development
protracted coughing remains to be
of bronchiectasis. If diagnosed early, this
speculated.
can be interrupted by appropriate treatment
Immunodeficiency Disorders of humoral and even the development of mild
immunity can be associated with insufficient bronchiectasis can be reversed. Changes in
protection and may facilitate bacterial the properties of some of the pathogens also
growth in the airways. contribute to chronicity. Microbes can
regulate their gene expression based on the
Environmental burden An important environment and signalling within the
environmental risk for the development of bacterial population and develop protective
PBB is environmental tobacco smoke (ETS). mechanisms that suppress host defence
In many countries the frequency of smoking mechanisms. Biofilm formation by some
in families with children is as high as 40 pathogens (e.g. nontypable H. influenzae and
50%. Local heating by burning wood or coal P. aeruginosa) is well documented. Bacteria
has been described as a significant risk can also cleave Ig and, thus, suppress
factor for the paediatric airways. specific immune response.
Industrial pollution Industrial pollution has Symptoms
been found to be a risk factor for respiratory
infections in children. The most important The leading symptom of bacterial bronchitis
part of industrial emissions is particulate is wet cough with or without sputum
matter (PM). The concentration of PM may production. Generally, the wet sound of the
increase under local adverse climatic coughing suggests an intrabronchial content
conditions. For respiratory health, particles of secretions of various quality and
with a 50% cut-off aerodynamic diameter of consistency. The ability to produce sputum
10 mm (PM10) or smaller play a major role is age and training dependent. Infants and
as these particles are respirable and can very young children are generally not able to
easily reach the lower airways. A correlation spit out sputum; however, this can be
of PM exposure with increased respiratory successfully trained by a physiotherapist as
symptoms has been repeatedly early as in the third year of life. Coughing is
documented. usually present both during the day and the
Pathogenesis night, which is often more pronounced in
the mornings as secretions tend to
PBB usually develops as a result of an insult accumulate during the night. Physical
that suppresses the local mechanism of the exercise can also exacerbate coughing.
airway defence. There may be initial acute Wheezing is not a typical symptom. In
viral bronchitis followed by inappropriate bacterial bronchitis the patient may wheeze
regrowth of damaged cilia, healing of airway on occasion based on obstruction by
mucosa, and re-establishment of a proper mucus; this is usually only transient and

variable and changes after coughing. The most reliable method of
Recurrent wheeze may signal bronchial microbiological sampling with high yield is
hyperresponsiveness and should raise bronchoscopy. It is not indicated in
suspicion of asthma. children with a single episode of PBB. Even
in children with recurrent PBB it is usually
Fever is generally absent in PBB. The not necessary if they expectorate
infection is mostly limited to the bronchial sufficiently. Bronchoscopy may be
tree and does not trigger general systemic considered in cases with inadequate
inflammatory response. Fever and elevation expectoration or in those with other
of acute phase proteins may signal an acute suspected underlying pathology. Flexible
exacerbation or more severe affection of bronchoscopy is best performed with
lung parenchyma. preserved spontaneous breathing. It allows
visual assessment of airways anatomy,
Diagnosis
excluding aspirated foreign body. It also
The main task in early detection of PBB lies helps to assess the level of mucosal
with a general practitioner (GP). Children inflammation, observe stability of the
with protracted wet cough should be noticed airways during breathing and coughing and
early in the general practice. An important find possible tracheomalacia/
initial task for the GP is to map and properly bronchomalacia. Removing mucus plugs,
characterise the symptoms. Basic providing appropriate bronchial toilette
differential blood count, C-reactive protein and direct sampling of mucus specimens
and erythrocyte sedimentation rate belong are essential. In addition, a standardised
to standard first-line investigations. GPs bronchoalveolar lavage should be
should also trace possible environmental performed and a specimen of BALF sent for
risk, such as smoking, local heating or other microbiology, differential cytology and
local risk in the household. staining for lipid-laden macrophages.
Anaerobic and mycotic cultures should also
Detailed investigation is needed, mainly in be considered.
children with repeated episodes of PBB. In
further investigation algorithm, a plain chest Additional examinations must include
radiograph is mandatory. A sweat test detailed ENT assessment to exclude focal
excludes CF and assessment of clinical risks infection in the upper airways area
for primary ciliary dyskinesia helps to (adenoids and sinuses).
exclude this condition. Pulmonary function Immunological testing should mainly
testing using basic forced expiration test, include testing of humoral immunity,
with recordings of flowvolume loop, is then including concentration of vaccination-
performed. Forced expiration testing can specific antibodies and total serum IgE.
even be performed with children as young as Allergic sensitisation should be tested in
3 years of age if properly trained. context with symptoms and history either by
Reversibility testing should be performed skin prick tests or specific IgE antibodies.
using an inhaled rapid acting b2-agonist.
When there is suspicion of a development of
Microbiological testing of sputum is a bronchiectasis, the diagnostic method of
crucial step. If the child is able to properly choice is HRCT. Current protocols are fast
expectorate, the sputum should be sent for and use low-dose techniques. Therefore,
cultures and microscopic evaluation. This they are considered safe and can even be
should be done before any antibiotics are used in young children.
administered. If the child is already treated,
the antibiotics should be stopped for at least Testing of older school children and
48 h. In a child not able to expectorate, deep adolescents for active smoking using
suctioning from the pyriforms in the cotinine in urine or carbon monoxide in
morning or after physiotherapy or the cough exhaled breath can reveal another
swab may help. contributing factor.

Management and prognosis of severe sequelae, such as chronic
suppurative lung disease or bronchiectasis.
Uncomplicated PBB is easily treated;
however, untreated persistent bacterial Acknowledgements
infection and accompanying inflammation is This work was supported by the Ministry of
associated with development of chronic Health, Czech Republic (conceptual
suppurative lung disease and development of research organisation,
bronchiectasis. In most cases the treatment University Hospital Motol, Prague, Czech
is based on expected or confirmed microbial Republic; grant number 00064203).
aetiology and broad-spectrum antibiotics
targeted against Haemophillus spp.,
Pneumococcus spp. or Moraxella spp. are
used. As Haemophillus spp. and M. Further reading
catarrhalis usually produce penicilinase, this
should be respected in the selection of N Bialy L, et al. (2006). The Cochrane Library
antibiotics. Generally, there is an agreement and chronic cough in children: an
that uncomplicated PBB should resolve after umbrella review. Evid-Based Child Health;
a 2-week course of an appropriate antibiotic. 1: 736742.
This was also shown in a randomised N Chang AB, et al. (2008). Chronic wet
controlled trial analysing a 2-week course of cough: protracted bronchitis, chronic
amoxycillineclavulanate against placebo. suppurative lung disease and bronchiec-
Children in the active arm showed a tasis. Pediatr Pulmonol; 43: 519531.
N Chang AB, et al. (2011). Diagnosing and
significantly higher resolution rate (48%)
preventing chronic suppurative lung dis-
than children in the placebo arm.
ease (CSLD) and bronchiectasis. Paediatr
The benefit of antibiotics has also been Respir Rev; 12: 97103.
N Hoek G, et al. (2012). PM10, and chil-
shown in a systematic review that found the
drens respiratory symptoms and lung
use of inhaled corticosteroids to be justified
function in the PATY study. Eur Respir J;
in limited situations. There are no consistent 40: 538547.
data available on the effect of physiotherapy N Kompare M, et al. (2012). Protracted
in PBB. It is certainly reasonable to employ bacterial bronchitis in young children:
at least some basic techniques of airway association with airway malacia. J Pediatr;
clearance, especially in young children. 160: 8892.
N Marchant JM, et al. (2006). Evaluation
Even though the effect of antibiotic and outcome of young children with
treatment is usually very good, a rather high chronic cough. Chest; 129: 11321141.
frequency of relapse (up to 70%) has been N Marchant J, et al. (2012). Randomised
described, with good effect when the controlled trial of amoxycillin clavulanate
antibiotic course is repeated. In a child with in children with chronic wet cough.
high frequency of recurrence, a prolonged Thorax; 67: 689693.
course of antibiotics may be considered. If N Priftis KN, et al. (2013). Bacterial bron-
an underlying condition is found, it is critical chitis caused by Streptococcus pneumo-
to treat this pathology together with the niae and nontypable Haemophilus
treatment of infection. influenzae in children: the impact of
vaccination. Chest; 143: 152157.
Conclusion N Qian Z, et al. (2007). Respiratory
responses to diverse indoor combustion
PBB with chronic wet cough is a diagnosis air pollution sources. Indoor Air; 17: 135
that requires attention and should be 142.
suspected in children with protracted N Zgherea D, et al. (2012). Bronchoscopic
coughing. Appropriate diagnosis and early findings in children with chronic wet
institution of proper management should cough. Pediatrics; 129: e364e369.
lead to complete resolution and prevention

Pulmonary TB, latent TB, and
in vivo and in vitro tests
Zorica Zivkovic and James Paton
Burden of disease in children concentration of organisms in children,

,30% of paediatric cases will have
TB in children has been called a hidden bacteriological confirmation of TB;
epidemic. Poor ascertainment and N lack of awareness of multidrug-resistant
reporting of cases in children have hindered (MDR)-TB in adults and, more especially,
accurate estimates of the global burden of in children.
TB in children, but in 2011 the World Health
Organization (WHO) estimated there were In Europe, overall TB rates in children have
490 000 cases of TB in children aged been declining, and were 4.2 per 100 000 in
,15 years with 64 000 deaths. Children are 2009 although there is wide variation in
also susceptible to the dual epidemics of rates both within and between countries.
TB/HIV with HIV-infected children at 20
Natural history in children
times greater risk of TB disease than HIV-
uninfected children. The natural history and presentation of
Mycobacterium tuberculosis infection in
The reasons for underestimating TB in children is different from adults, being
children include: strongly influenced by age and immune
status. Children aged ,4 years have a
N children with TB are generally not greater risk of developing clinical and
infectious: at ,10 years of age children radiographic complications shortly after
develop pauci-bacillary types of TB and infection, but will rarely present with
are usually not infectious compared to reactivation of disease in adulthood.
adults with caseating pulmonary TB; Teenagers develop forms of the disease
N difficulties in confirming a case of more typical of adults.
childhood TB: because of the inability to
produce sputum and the low M. tuberculosis infects almost all children via
inhalation by the respiratory tract, usually
from an infectious adult in their close
Key points environment. A number of factors influence
the likelihood of infection including:
N TB remains a major, but often
unrecognised, cause of disease and N intensity and duration of exposure to the
death in children. infectious case,
N ability of the infectious case to cough and
N Children with TB are generally not generate an infectious aerosol,
infectious. N virulence of the organism,
N TB in children generally reflects active N age,
disease in the adult population. N innate and acquired immune defences of
the child exposed.
N Treating TB in children is not
straightforward. In the pulmonary alveoli, M. tuberculosis
organisms are ingested by alveolar

Acid-fast bacilli
Alveolar macrophage
15
organisms
Alveolus
3050%
No infection: Infection:
alveolar macrophage release of acid-fast bacilli
kills acid-fast bacilli into extracellular space;
recruitment of additional
mononuclear cells
Granuloma formation:
spread to lymph nodes, blood stream Exogenous
and other organs reinfection
90% 10%
Latent: Active:
strong cellular immunity, poor cellular immunity,
containment progressive disease
Reactivation
Senescence
Exogenous steroids
Malnutrition
Figure 1. Outcomes following exposure to Mycobacterium tuberculosis. The percentages in red are
typical of outcomes in older children and adults. Reproduced from Manabe et al. (2000) with permission
from the publisher.

macrophages and may be killed without Enlarged mediastinal lymph nodes do not
causing further problems (fig. 1). usually cause problems but they can
compress the airways producing ventilation
The organisms that survive initiate a disturbances and, occasionally, complete
localised granulomatous inflammatory bronchial obstruction and distal atelectatic
process in the mid to upper zones of the changes in the affected segment. If
lung, the Gohn focus. In most cases, the caseating lymph nodes liquefy, there may be
centre of this focus undergoes caseous local extension and distant haematogenous
necrosis. M. tuberculosis bacilli, either free or spread of M. tuberculosis organisms. If the
within phagocytes, drain to the main lymph nodes are sub-carinal, infection can
regional, mediastinal lymph nodes (hilar, spread to adjacent structures such as the
para-tracheal and sub-carinal), which also heart, causing pericarditis, or the
often caseate. Enlarged regional lymph oesophagus resulting in a tracheo-
nodes along with the Gohn focus and the oesophageal fistula. Haematogenous
local tuberculous lymphangitis constitute spread seeds M. tuberculosis in others
the primary complex. The enlarged regional tissues and organs. Disseminated TB
lymph nodes can be seen in 5070% of appears when multiple foci develop in the
children on good quality plain radiographs. lungs or other organs.
From the regional lymph nodes, bacilli can The natural history of primary TB in children
enter the systemic circulation. Occult follows a typical time-course. In the vast
haematogenous spread can occur before the majority, disease occurs within 2 years of
immune response contains the disease. The primary exposure infection with the very
disseminated bacilli can then survive in young (04 year) and the
target organs for long periods of time. immunocompromised being most at risk.
The immune response, marked by the Massive lympho-haematogenous
development of a positive tuberculin skin dissemination leading to miliary or other
test (TST), develops about 38 weeks after disseminated disease is uncommon and
primary infection and it usually stops the occurs in 0.52% of cases usually between 3
multiplication of M. tuberculosis. The end of and 39 months after lymph node
the asymptomatic incubation period and the involvement. Bone and joint TB develop
development of an immune response may later, usually a few years after infection.
be marked by immune hypersensitivity Only a small proportion of children with TB
reactions. These include nonspecific, self- develop post-primary TB, either due to
limiting viral-like symptoms such as fever, reactivation or re-infection. Adult-type
or, more rarely, florid reactions such as disease can follow recent primary infection
erythema nodosum. In most cases the child in children aged .10 years, particularly girls
will have no symptoms. around the age of menarche.
In the majority of children, the primary Age and risk of progression The risk of TB
complex heals completely and the organisms after infection in children varies with age
are contained by the cell-mediated immune (table 1). In children aged ,2 years, the risk
response within the tissues. In up to 50% of is as high as 50% with most disease
children, the regional lymph nodes calcify occurring within 6 months of infection. With
within 1224 months indicating the disease the onset of puberty, the risk rises again and
is quiescent. But M. tuberculosis can persist in there is a switch in disease phenotype to
calcified lymph nodes and dormant orga- adult-type cavitary disease.
nisms may reactivate to cause TB later in life.
Sites of disease Pulmonary TB Most children
Sometimes, following primary infection, a with TB have pulmonary TB (fig. 2).
parenchymal lesion continues to enlarge
and spread resulting in focal pneumonitis More than half of children with TB will have
and pleural involvement (primary chest radiographic changes with no
progressive TB). symptoms or clinical signs of disease and

Table 1. Age-specific risk of progress after primary infection in immunocompetent children
Age years Risk of disease progression following exposure
,1 No disease: 50%
Pulmonary disease (Ghon focus, lymph node or bronchial): 3040%
Tuberculous meningitis or miliary disease: 1020%
12 No disease: 7080%
Pulmonary disease (Ghon focus, lymph node or bronchial): 1020%
Tuberculous meningitis or miliary disease: 25%
25 No disease: 95%
Pulmonary disease (lymph node or bronchial): 5%
Tuberculous meningitis or miliary disease: 0.5%
510 No disease: 98%
Pulmonary disease (lymph node, bronchial effusion or adult type): 2%
Tuberculous meningitis or miliary disease: ,0.5%
.10 No disease: 8090%
Pulmonary disease: 1020%
Tuberculous meningitis or miliary disease: 0.5%
Reproduced from Marais et al. (2004) with permission from the publisher.
are identified only through contact tracing. Extra-pulmonary TB in children develops by

Infants have more intensive symptoms of dissemination of M. tuberculosis through
TB, while school age children may have lymphatic and haematogenous spread with
disease that is not clinically apparent. the development of foci in various organs.
Adolescents develop adult-type TB and can
present with parenchymal destruction and Miliary TB characteristically occurs in
cavity formation. Such children will be immunocompromised and malnourished
sputum-smear positive and are able to children with infants being the most
transmit infection. Pleural effusions are rare vulnerable. Typical miliary changes on chest
in children aged ,5 years and are most radiographs take 13 weeks to develop. The
common in adolescent boys. illness can progress rapidly and the
prognosis is poor. TB meningitis is the most
200 serious complication in childhood with a
risk of significant long-term neurological
150
seqeulae and death if diagnosis is delayed or
Cases n
100 treatment inadequate. Bone and joint TB is

mainly mono-articular involving the spine,
50 hip or knee.
0 Congenital TB: M. tuberculosis infection may

Abdomen
be acquired before birth during intrauterine

Pleural
Bone
Lung
CNS
Peripheral
lymph nodes
Intrathoracic
lymph nodes
life, perinatally or post-natally. In a pregnant

female with active TB, M. tuberculosis can be
transmitted transplacentally from the blood
stream of the mother to fetal blood. Once in
Site of infection the fetal circulation, the organisms spread
by the umbilical veins to tissues and organs,
Figure 2. The different sites of infection in children mainly to the liver and spleen. Symptoms
with TB in the UK from 19881998. Orange bars (failure to thrive, jaundice and
signify pulmonary disease. CNS: central nervous hepatosplenomegaly) develop within a
system. Information from Balasegaram et al. (2003). couple of weeks after birth.

A newborn infant may also acquire M. onset were highly sensitive and specific
tuberculosis infection during delivery or soon markers of TB. A persistent non-remitting
after through the close contact with an cough in childhood was almost exclusively
infectious case, e.g. breast feeding mother. associated with TB (table 2). As a result, in
In this situation, nonspecific respiratory this setting clinical follow-up was a useful
symptoms develop after 34 weeks. Chest diagnostic tool because a non-remitting
radiography is not diagnostic and a TST may cough persisting beyond 24 weeks was
be negative. uncommon other than with TB, and no child
whose symptoms spontaneously resolved
Diagnosing TB was diagnosed with TB in the following
History and examination Children are usually 6 months.
evaluated for TB either after presenting with
There are no specific identifying physical
symptoms or signs suggestive of TB
signs that unequivocally establish that a
(passive case finding) or, most commonly,
child has TB. Some signs are highly
as a result of contact investigation or routine
suggestive of extrapulmonary TB (e.g.
new entrant immigrant screening (active
gibbus of recent onset and painless cervical
case finding). The clinical presentation is
adenopathy with fistula) while other signs
different between these two groups with
children detected through active case require investigation to exclude
finding often having either TB infection or extrapulmonary TB (e.g. pleural effusion,
TB disease in a very early phase. phlyctenular conjunctivitis and erythema
nodosum).
History of contact Since children generally
acquire TB following exposure to a sputum- Tests of adaptive immunity
positive case of pulmonary TB, a key piece of For more than 100 years, the TST was the
diagnostic information is a history of close only test available to detect infection with M.
contact with an infectious source case. The tuberculosis. The test involves the
WHO defines close contact as living in the intradermal injection of purified protein
same household as or being in frequent derivatives derived from M. tuberculosis.
contact with sputum smear-positive There are a number of TSTs available but the
pulmonary TB cases. Cases of smear- WHO recommends using the Mantoux test.
negative TB that are sputum culture positive Interpretation of the TST test depends on
are also infectious but to a much lesser the clinical situation. In children identified
degree. by active case finding, or in those where TB
The infection risk from close household is suspected clinically, induration of .5 mm
contact is greatest for infants and young in children who have not had a Bacillus
children ,5 years of age (table 1). Apart CalmetteGuerin (BCG) vaccination or are
from age, other important risk factors for TB at high risk, or induration of .10 mm
include HIV infection and severe (according to WHO or .15 mm in other
malnutrition. countries) in all other children (whether they
have had a BCG vaccination or not) should
Symptoms and signs In children identified be considered to indicate infection.
through active case finding who have
radiographic changes of TB, more than half Unfortunately, the TST has problems with
will have no symptoms or signs of disease. both false-positive and false-negative
results. This has led to the development of
For children with symptoms, well-defined peripheral blood T-cell-based interferon
symptoms of recent onset that are (IFN)-c assays. Two are commercially
persistent and non-remitting are typical of available:
TB. The frequency of the five most relevant
symptoms from a community study in South N whole blood IFN-c release assay (IGRA)
Africa is shown in table 2. Both persistent (QuantiFERON Gold; Cellestis Ltd,
cough and/or persistent fatigue of recent Victoria, Australia);

Table 2. Persisting non-remitting symptoms in children aged ,13 years in Cape Town, South Africa, presenting to the
local community clinic with a cough .2 weeks duration
Symptom No TB# TB" Odds ratio
Cough 2 (1.6) 15 (93.8) 2010.0
Chest pain 0 (0) 4 (25) NA
Weight loss 3 (2.6) 6 (37.5) 25.0
Fatigue 1 (0.8) 13 (81.3) 580.7
Fever 0 (0) 4 (25) NA
# "
Data are presented as n (%), unless otherwise stated. NA: not available. : n5135; : n516. Reproduced from
the International Union Against Tuberculosis and Lung Disease; Copyright The Union (Marais et al., 2005)
with permission.
N an enzyme linked immunospot assay (T- typically hilar and mediastinal

SPOT.TB; Oxford Immunotec, Oxford, lymphadenopathy (figs 3 and 4).
UK). Extraluminal compression of the enlarged
lymph nodes may cause partial luminal
IGRAs measure IFN-c production ex vivo by obstruction of the airway leading to
circulating T-lymphocytes when incubated in radiographic signs of hyperinflation and
the presence of highly specific M. air-trapping. Caseous lymph node may
tuberculosis antigens (early secreted ulcerate into the airway closing the lumen
antigenic target (ESTA)-6 and culture filtrate completely and causing distal atelectasis.
protein (CFP)-10). IGRAs are more specific Persistent pulmonary opacification,
than the TST and can distinguish a positive especially if there is no improvement with
TST due to BCG vaccination or to
antibiotics, along with prominent hilar or
environmental atypical mycobacterial
subcarinal adenopathy is highly suggestive
(NTM) infection from a positive TST test
of TB.
due to infection with M. tuberculosis.
However, despite their greater specificity, A chest CT may be very useful in
IGRAs cannot differentiate between active demonstrating early cavitation and
and latent TB, and a negative IGRA test does bronchiectasis. However, while HRCT offers
not exclude TB. excellent visualisation of mediastinal lymph
Neither the TST nor the IGRA test can nodes, treatment algorithms for latent TB
differentiate latent infection from active and pulmonary TB in children have been
disease and neither test should be used for
the diagnosis of active TB. The place of
IGRA tests in children, particularly young
children aged ,5 years, is still being
evaluated. The TST and IGRA tests may be
complementary, improving the sensitivity
and specificity of the assessment in specific
clinical circumstances. At present, the WHO
recommends that for children in low- and
middle-income countries IGRA tests should
not be used in place of the TST for the
diagnosis of latent TB infection (LTBI).
Radiography and other imaging techniques
The majority of children with pulmonary TB Figure 3. Right mediastinal lymphadenopathy in a

will have chest radiography changes, child with TB.

Figure 6. Chest radiograph from a 15-year-old boy
Figure 4. Right upper lobe atelectasis and hilar with TB with right lower lobe atelectasis and
adenopathy in a child with TB. pleural effusion.
based on plain radiographs. Accordingly, diagnosis of TB more difficult than in adults.

chest CT is usually reserved for more Microbiological confirmation is commonly
complex cases. not achieved, and in many cases is not even
attempted. The European Centre for Disease
Bronchoscopy may be useful in children with Prevention and Control estimated between
areas of atelectasis where compression by 2000 and 2009 that less than one in six
lymph nodes or caseating material children had their diagnosis confirmed by
ulcerating through an airway can be TB culture. Nevertheless, a positive culture
visualised (fig. 5). for M. tuberculosis remains the gold standard
for the diagnosis of TB. Microbiological
Ultrasound can identify and guide drainage confirmation is increasingly important
of pleural, pericardial or abdominal because of the increase in drug-resistant TB.
effusions (fig. 6) and can help in guiding The WHO recommends that bacteriological
fine-needle aspiration of lymph nodes. confirmation should be sought wherever
Microbiological confirmation possible. Appropriate samples from
suspected sites of involvement should be
Children generally have pauci-bacillary obtained for microscopy and culture and, if
disease, which makes microbiological appropriate, histopathology. However,
culture can take weeks and is consequently
unavailable to inform clinical decisions at
the start of treatment.
Collecting samples Sputum samples from
spontaneous coughing may be obtainable in
older children (.10 years). In younger
children, particularly those ,5 years,
sputum is more difficult to obtain. Smaller
amounts of sputum are produced and are
swallowed rather than expectorated.
Consequently, most children are sputum-
smear negative even when optimised
techniques are used. Bacteriological
samples can be collected by three early
Figure 5. Extramural compression demonstrated morning gastric washings via nasogastric
on bronchoscopy with broadening of main carinal tube, following an overnight fast. More
bifurcation due to subcarinal lymphadenopathy. recently, sputum induction following

nebulisation with hypertonic saline (35%) sputum and was not affected by whether a
has been shown to be safe and effective in child had HIV or not.
children of all ages with bacterial yields as
good, or better than, for gastric aspirate. HIV testing In high prevalence areas where
One induced sputum specimen provides a TB and HIV are likely to coexist, or in low
similar microbiological yield to three gastric prevalence areas where risk factors are
lavage specimens in children admitted to identified for HIV, HIV counselling and
hospital with pulmonary TB. However, the testing is indicated.
technique requires training and equipment Making the diagnosis: putting it altogether In
and staff need to follow effective infection children, because microbiological
control procedures appropriate for
confirmation is commonly not available, the
infectious aerosol exposure. At least two
diagnosis of TB is often based on a careful
samples should be collected.
assessment of the available evidence and a
TB lymphadenitis is a common form of high index of suspicion. TB can mimic many
extrapulmonary TB. Fine-needle aspiration common childhood diseases. However, a
of accessible enlarged lymph glands has combination of clinical, radiological and
been shown to be useful with a high laboratory findings along with a history of
bacteriological yield. Aspiration of TB exposure and immunological evidence of
cerebrospinal fluid, pleural or other fluids M. tuberculosis allows an accurate diagnosis
may also provide material for microscopy in most cases.
and culture in appropriate situations.
Treatment of TB
Molecular testing Molecular testing
Management of active TB Because large
techniques are being developed for TB. One
system, the Xpert MTB/RIF (Cepheid, studies in children are generally lacking, the
Sunnyvale, CA, USA) has been endorsed by principles of drug treatment and
the WHO as an initial diagnostic test in recommended drug regimens are the same
people suspected of having drug-resistant or as for adults. TB should never be treated
HIV-associated TB. This system combines with a single drug; a single drug should
integrated sample processing and a nucleic never be added to a failing regime because
acid amplification test for the detection of of the risk of developing drug resistance.
M. tuberculosis and rifampicin resistance.
Although every effort should be made to
The test can detect resistance to rifampicin
with a high degree of sensitivity and attain a microbiological diagnosis, the
specificity. Results are available much more threshold for starting treatment therapy
quickly than culture results, often within empirically is lower for children, especially
1 day of testing. for young children where potentially life-
threatening conditions such as TB
In one large South African study in children, meningitis or miliary TB can develop quickly.
when two induced sputum samples were Fortunately, drug-related adverse events are
used, the MTB/RIF tests were shown to rare in young children treated with first-line
detect three-quarters of culture confirmed drugs and they are at low risk for acquiring
cases of pulmonary TB with a very high or transmitting drug-resistant disease.
specificity. The test had a lower sensitivity in
smear negative cases with two tests The goals of treatment are to cure the
detecting ,60% of cases. Thus a negative individual and prevent late complications, as
MTB/RIF test cannot rule out TB and has to well as to decrease transmission to others and
be interpreted in the context of other clinical prevent the development of drug resistance.
and radiological findings. MTB/RIF testing Successful TB treatment requires more than
was more sensitive than smear microscopy just anti-TB chemotherapy medicines.
detecting twice as many cases. It worked Medications need be provided within an
well with gastric lavage aspirate samples appropriate clinical and social framework if an
with an accuracy similar to testing induced effective cure is to be achieved.

Combination anti-tuberculous regimens Recommended treatment regimens are listed
Combination regimens are used to treat in table 3.
active disease. The aim is to eliminate both
actively replicating and dormant or near- Recommended drug doses The WHO has
dormant mycobacteria by using a recently recommended revising the doses of
combination of drugs with different anti- the main first-line anti-TB drugs for HIV-
mycobacterial actions while minimising uninfected children (table 4). At present,
toxicity and preventing the emergence of HIV-infected children should receive the
drug-resistant organisms. same dosages of anti-TB therapy as HIV-
uninfected children.
Bactericidal drugs are used to kill actively
metabolising and replicating organisms. Treatment should be given daily. Thrice
They bring about a rapid reduction in weekly regimens should only be considered
microbial load leading to clinical during the continuation phase for children
improvement, preventing disease known to be HIV uninfected living in
progression and stopping transmission. settings with well-established directly
Isoniazid (H) and rifampicin (R) are the observed therapy (DOT) programmes.
most important first-line drugs with Adherence Ensuring adherence to the long
isonizaid having the most important courses of treatment used for treating TB is
bactericidal activity. a major problem. Poor adherence is an
important factor in the emergence of
Sterilising drugs aim to eradicate organisms
resistance to TB therapy and in treatment
that are less metabolically active in order to
failure. The WHO recommends that all
prevent relapse. Rifampicin (R) and
children should receive TB drugs free of
pyrazinamide (Z) are important first-line
charge irrespective of whether the child is
sterilising agents. Protection against the
smear positive at diagnosis or not. Fixed-
emergence of drug-resistant organism is
dose combinations of drugs should be used
achieved through the combination of
whenever possible. These simplify
effective bactericidal activity with effective
adherence and minimise the risk of
sterilising activity and is strengthened by the
developing drug resistance. However, this is
addition of ethambutol (E).
often not possible in children because of a
Treatment regimens The drugs and lack of suitable drug combinations. In
treatment regimens for TB in children are addition, there is a lack of drug formulations
the same as those used in adults. suitable for children, e.g. liquids.
Recommended regimens are based on
national programmes recommended for a Children, parents and families should be
particular country (if one exists), or by the educated about TB and the importance of
WHO. completing treatment. Providing anti-TB
medications directly to the patient and
In Europe, the most frequent scenario is that watching them take them is termed DOT
the M. tuberculosis is sensitive to all first-line and is recommended for all patients
agents. Consequently, for new cases of diagnosed with TB. As a minimum, all
pulmonary TB in children (smear positive or children and families should be assessed for
negative), the current WHO recommenda- the risk that adherence is likely to be poor
tions for Europe are treatment with the four and DOT should be used for those at high
first-line drugs (HRZE) for 2 months as an risk of non-adherence. A healthcare worker
initial bactericidal regimen. After 2 months, or a trained community worker can
treatment is continued with a prolonged administer DOT. In some settings, children
sterilising regime of H and R for a further with severe disease, such as TB meningitis,
4 months. In some less developed countries, or with severe side-effects may need
the initial 2 months of treatment is given in prolonged hospitalisation during the first
hospital to ensure administration. In children, 2 months of treatment to ensure that
TB relapse or reactivation occurs rarely. treatment is successfully delivered.

Table 3. Treatment regimens for children with TB as recommended by the World Health Organization (WHO)
TB cases and diagnostic criteria Anti-TB drug regimen
Intensive phase Continuation phase
New smear-positive pulmonary TB 2 months HRZE 4 months HR
Smear-negative pulmonary TB 2 months HRZE 4 months HR
with extensive parenchymal
involvement
Extrapulmonary TB-peripheral 2 months HRZE 4 months HR
adenitis
Tuberculous meningitis 2 months HRZE 10 months HR
TB osteoarthritis 2 months HRZE 10 months HR
MDR-TB Individualised regimens
H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol.
Side-effects Hepatotoxicity is the major childhood. Screening for visual related side-
drug-related adverse event, with case effects is not required.
reports of hepatic failure even when
recommended doses of anti-tuberculous Other drugs Corticosteroids may be used for
therapies are used. However, extensive the management of some specific cardio-
experience has demonstrated that the first- respiratory complications of TB, e.g. airway
line drugs used in treating TB are well obstruction and atelectasis secondary to TB
tolerated in children with a low risk of side- mediastinal lymph gland enlargement, or
effects. Indeed, the drugs are better pericardial TB. Corticosteroids have been
tolerated in children than adults perhaps used in advanced pulmonary disease with
because of the lower peak serum levels clinical and radiological benefits. They are
achieved in children when using the same recommended for all children with TB
dose per kg as adults. meningitis. Prednisolone (12 mg?kg-1 daily
for 34 weeks and then tapered) has been
Hepatotoxicity may be detected more the most commonly used drug. Rifampicin
frequently in children who are malnourished, induces hepatic enzymes that catabolise
immunocompromised, e.g. with HIV corticosteroids and reduce effective
infection, or who present with extensive and bioavailability by ,50%.
serious TB disease. If signs of hepato-
toxicity develop (vomiting, jaundice, liver Corticosteroids are also used in the
tenderness and hepatomegaly) all drugs management of the immune reconstitution
should be stopped and levels of hepatic syndrome (also known as paradoxical
enzymes monitored. Reintroduction of anti- reaction). In this, a temporary deterioration
TB therapy should not be tried until liver occurs after the start of anti-tuberculous
function is normal and should then proceed treatment due to restitution of the capacity
on a step-wise basis with one drug to mount an inflammatory immune
reintroduced at a time. response. It may cause fever, increased
lymph node size and tuberculomas. It can
Ethambutol is now recommended for use in occur after the start of anti-TB treatment,
children of all ages including those aged e.g. commonly as the enlargement of the
,5 years. At the recommended doses and mediastinal lymph node on chest
durations, a review of the evidence radiographs, after improved nutrition or
suggested that ethambutol is safe with a following the initiation of antiretroviral
negligible risk of toxicity throughout therapy in children with HIV infection.

Table 4. Recommended doses for first-line anti-TB drugs for the treatment of TB in children aged .3 months
Drug Daily dose (range) mg?kg-1
Isoniazid 10 (1015), maximum 300 mg daily
Rifampicin 15 (1020), maximum 600 mg daily
Pyrazinamide 35 (3040)
Ethambutol 20 (1525)
Management of drug-resistant TB in Children with TB who are co-infected with

children HIV
Rates of resistant TB are increasing. Drug Children with TB should be screened for
resistance originates in adults with TB who HIV. Similarly, children newly diagnosed for
have a high bacillary load and who receive HIV should be screened for TB by history
inadequate anti-tuberculous therapy or are and chest radiograph. Drug interactions
poorly compliant. Acquisition of resistance between HIV antiretroviral therapy and the
is rare in the pauci-bacillary disease that similar side-effect profiles of the drugs
occurs in children. involved in treating the two diseases make
managing the two treatments challenging.
Resistance to isoniazid and/or rifampicin is Rifampicin, in particular, reduces the
most important because these two drugs are concentrations of many HIV drugs. For
the mainstay of current first line treatment. children with significant
In MDR-TB, the organism is resistant to immunosuppression, treatment for HIV
both rifampicin and isoniazid with or should be delayed for 28 weeks once anti-
without resistance to other anti-TB drugs. tuberculous treatment is started. For those
Infection is usually the result of with mild or no immunosuppression,
transmission of a strain of MDR-TB from an treatment for HIV may be deferred until
adult index case. treatment of TB is completed.
Treatment is often complex and specialist Guidelines recommend that TB in HIV-
advice should be sought. There is infected children should be treated with a 6-
uncertainty about activity and safety of the month regimen as for uninfected children.
available second line drugs. Suitable The WHO recommends that rifampicin
formulations for children are often not should be used for the entire duration of
available. If an isolate from the child is not treatment. In children, intermittent
available, the best guide to treatment is the regimens (twice or thrice weekly) should not
susceptibility pattern of the adult source be used in areas with high HIV prevalence
case. In general, at least four drugs certain for the treatment of pulmonary TB or TB
to be effective (and to which the child is lymphadenitis.
nave), including an injectable and a
fluorquinolone, are given on a daily basis Immune recovery in children with HIV after
using DOT for an extended initial period of initiation of antiretroviral therapy, nutritional
6 months followed by at least three of the rehabilitation or sometimes just beginning
most active and best tolerated drugs for a anti-TB therapy may unmask subclinical
further period of 1218 months. disease or induce a paradoxical temporary
deterioration despite adequate therapy for
Current recommendations are to avoid TB, the so-called immune response
using primary chemoprophylaxis or inflammatory syndrome (IRIS). This can
treatment for latent TB in cases of close simulate worsening TB disease with fever
contact with a case of MDR-TB if the child is and increased size of lymph nodes or
clinically well, and to observe for 2 years. tuberculomas. Treatment for TB should not

be interrupted. A course of steroids may be For the last 20 years, WHO guidelines have
required for severe IRIS. recommended that all children aged
,5 years (irrespective of BCG status) in
In adults with HIV-infection in endemic areas, close contact with an infectious (usually
the use of secondary isoniazid preventive smear positive) case of TB receive 6
therapy after completion of TB therapy 9 months isoniazid therapy. However,
significantly reduces the risk of recurrent TB. screening is frequently not provided in
The WHO has therefore recommended 6 endemic areas. Treatment with isoniazid for
36 months isoniazid therapy in all patients 9 months has been established to reduce
with HIV infection including children living in the risk in exposed children by .90% if
high-prevalence areas of TB. adherence is good. A shorter 3-month
course of rifampicin and isoniazid has been
The WHO has recently published updated
shown to be equally effective and may
policy guidelines for the collaborative
improve treatment compliance. Before
management of TB and HIV.
treating latent TB it is important to exclude
TB control and prevention active TB by a chest radiograph and/or
symptom review.
Preventive chemotherapy TB preventive
therapy is important in two broad categories Unfortunately, the implementation of
of children: preventive strategies has been poor because
parents are often reluctant to provide
1. children who have been recently preventive treatment to a well child and
exposed to M. tuberculosis, e.g. following because of the long duration of treatment
close contact with an infected case; required.
2. children at increased risk of progression
Treatment for TB exposed children with HIV
of M. tuberculosis infection to TB
In HIV-infected children the value of post-TB
because of age or other clinical
exposure prophylaxis and the need for
conditions, such as HIV.
careful ongoing screening is clear. Isoniazid
Controlled trials have focused on preventing preventive therapy is indicated following
progression from latent infection to active every documented exposure to TB,
disease by providing a limited course of particularly for the young and the
treatment (either in duration or number of immunosuppressed. The value of pre-
drugs) to sterilise existing subclinical exposure routine chemoprophylaxis in
lesions and prevent future progression to TB children with HIV remains uncertain.
disease (treatment of LTBI). Genuine BCG vaccination is a live attenuated vaccine
primary prevention (primary derived from Mycobacterium bovis prepared
chemoprophylaxis) is used to prevent as a freeze-dried powder for suspension
primary infections from becoming prior to injection. It was first used in
established during/after a period of contact humans in 1921 and is one of the most
with an infectious case. Preventing widely used of all vaccines.
recurrence of TB may be targeted by
secondary chemoprophylaxis provided The BCG vaccination is given intradermally
after successful completion of therapy. normally into the lateral aspect of the left
upper arm at the level of the insertion of the
Treatment of children recently infected deltoid muscle (the left arm is
Treating recently infected children and recommended by the WHO).
preventing progression to active TB
(treatment of LTBI) eliminates reservoirs of Vaccination soon after birth is
M. tuberculosis and prevents later recommended in high-prevalence countries.
reactivation disease. Such treatment is Low-prevalence countries use risk-based
particularly important in young children strategies targeting neonatal BCG
because of the higher risks of disease vaccination to protect those children most
progression. at risk from exposure to TB. Targeted

approaches require careful ongoing audit to New developments Intensive research is
ensure that high proportions of those at-risk underway to develop more effective TB
continue to be vaccinated. vaccines and has followed two basic
approaches. The first aims at replacing BCG
Effectiveness in preventing progression to by either improved recombinant (r)BCG or
disease Studies of the effectiveness of BCG in by genetically attenuated M. tuberculosis. The
protecting against TB have given widely second approach focuses on subunit
varying results, ranging from no protection vaccines, which may be used as booster
in some studies in India to 7080% vaccines on top of BCG-, recombinant BCG-
protection in UK school children. The or attenuated M. tuberculosis-priming
reasons for the variation in efficacy in vaccines. Around 12 candidate vaccines are
different regions of the world are not well currently in clinical testing.
understood.
Importance of well-functioning TB control
BCG vaccination has been shown programmes
consistently to be 7080% effective in
preventing against TB meningitis and Children are generally infected with TB by
miliary TB, the more severe forms of close contact with an infectious adult,
disseminated disease that occur in young therefore, early diagnosis and treatment of
children. Recent studies combining IGRA adult infectious cases is the best way to stop
and TST have suggested that BCG may also children from becoming infected. A well-
protect against TB infection reducing the functioning TB control system, which
risk of primary TB infection and the ensures the early diagnosis and treatment of
development of latent TB infection by up to infectious adults with TB, has a key role in
50%. However, BCG offers no consistent preventing TB in children.
protection against adult-type TB with the
most limited protection in geographical Within hospitals and clinics, the risk of
areas such as India where TB is most infection to healthcare workers from
prevalent. paediatric patients with primary TB
appears to be minimal, and most children
Levels of protection from the BCG fall with with TB do not need isolation. However, it
time with the best estimates of suggesting is important to remember that
protection for around 10 years. BCG is not symptomatic parents or caregivers may
protective if given to those already infected have TB and pose an infection risk.
and revaccination does not seem to offer Infection control efforts should, therefore,
substantial re-protection. be focused on accompanying adults and
adult visitors.
Side-effects BCG is the one of the most
widely administered vaccines worldwide and
only a small number of children (12%) Further reading
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However, individuals with genetic defects in with standard therapy with isoniazid, for
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Extrapulmonary TB and TB in
the immunocompromised
host
Toyin Togun, Uzor Egere and Beate Kampmann
Globally, an estimated 11% of the nearly 10 The risk of disease progression and
million new cases of active TB diagnosed extrapulmonary dissemination is highest in
annually occur in the paediatric population, the first 2 years of life, with risk of disease
but the true burden of TB in children progression estimated at 4050% in the
remains underestimated. absence of Bacille CalmetteGuerin (BCG)
vaccination or prophylactic therapy. The
Extrapulmonary TB is common in children majority of disease occurs within 2
and refers to the isolated occurrence of 12 months of initial infection with
active TB at body sites other than the lung. pulmonary TB accounting for 6080% of all
The exact mechanisms that determine the cases.
clinical outcomes following infection in
children are not completely understood, but Extrapulmonary TB usually originates from
include: lymphohaematogenous spread of TB bacilli
from a primary pulmonary focus,
N age, contiguous spread from infected lymph
N nutritional status, nodes or direct inoculation of bacilli.
N underlying immunity, Generally, superficial lymphadenopathy is
N vaccination status, the most common form followed by central
nervous system (CNS) disease, pleural,
N genetic susceptibility,
miliary/disseminated and skeletal TB. Less
N microbial virulence.
common forms include abdominal,
pericardial, renal and cutaneous TB.
Key points The role of age-related immune responses
in clinical manifestations of TB in children
N Young children are more likely to
It is well established that less mature or
develop extrapulmonary
impaired immune responses contribute to
manifestations of TB, associated with
the disseminated forms of TB seen in
age-related impairment of cellular
children and immunocompromised hosts.
immune responses.
N Extrapulmonary TB can have very A number of studies have reported an age-
severe consequences and thorough related functional impairment of both innate
investigations and prolonged therapy and adaptive immune responses in children.
are required. The current paradigm in TB immunology is
the crucial importance of Mycobacterium
N Conditions of immunosuppression, in tuberculosis-specific CD4+ T-cells and the key
particular HIV, are more likely to lead cytokines such as interferon gamma (IFN)-c
to extrapulmonary severe produced in the protection against M.
manifestations. This is proportionate tuberculosis. However, M. tuberculosis-
to the level of suppression of T-cell specific IFN-c responses alone are not an
function. absolute correlate of protection against the
development of TB.

Following inhalation of M. tuberculosis in increase the risk of TB disease progression
infected aerosols into the terminal alveoli, it in children.
is immediately engulfed by resident
Genetic susceptibility to TB
phagocytes including the alveolar
macrophages and dendritic cells. Activated Mendelian susceptibility to mycobacterial
macrophages infected with M. tuberculosis diseases (MSMD) Additional evidence of the
induce the synthesis and secretion of importance of cell-mediated immune
chemokines and cytokines which recruit response and Th-1 IFN-c response in the
other inflammatory cells to the site of protection against M. tuberculosis infection
infection. The dendritic cells, which are the has come from genetic studies reporting an
major antigen presenting cells in the lung, increased risk of progressive disease in
migrate to regional lymph nodes where they specific genetic defects affecting the IL-12/
present processed M. tuberculosis antigens IFN-c pathway.
to nave CD4+ T-cells via major
histocompatibility complex (MHC)-class II MSMD is a familial inherited disorder
molecules. The antigen presentation by associated particularly with an increased
dendritic cells with the aid of co-stimulatory susceptibility to severe disseminated
molecules such as CD80 and synthesis of mycobacterial diseases that often manifest
polarising cytokine such as interleukin (IL)- in childhood. Affected children have a
12 promotes the priming, proliferation and diminished ability to induce activation and
upregulation of the killing mechanism of M.
differentiation of nave CD4+ T-cells into M.
tuberculosis-infected macrophages because
tuberculosis-specific CD4 T-cells with T-
of a number of specific mutations in the
helper (Th)-type 1 effector function, which
genes encoding major components of the
produces classical Th-1 cytokines including
IL-12/IL-23 IFN-c axis of the Th-1 cytokine
IFN-c, tumour necrosis factor (TNF)-a and
pathway. A number of mutations have been
IL-2. IFN-c produced by the M. tuberculosis-
identified in the autosomal genes including
specific CD4+ T-cells is critical for the
IFNGR1 (encoding IFN-gR1), IFNGR2
optimal activation of infected macrophages (encoding IFN-gR2), STAT-1 (encoding
to become microbicidal, promoting killing of signal transducer and activator of
the phagocytosed bacilli and thus protection transcription-1), IL12P40 (encoding IL-12p40
against TB. subunit), IL12RB1 (encoding IL-12Rbeta1
Specifically, it has been reported that the chain), TYK2 (encoding tyrosine kinase 2)
and NEMO (encoding nuclear factor-kB-
alveolar macrophages in children show
essential modulator).
diminished phagocytosis, cellular
recruitment and microbial killing when Acquired susceptibility to TB
compared with adults, which could promote
delayed initiation of antigen-specific T-cell HIV infection The most compelling evidence
responses and disease progression. Further for the crucial role of CD4+ T-cells in
studies are needed to define the role and protection against human mycobacterial
importance of CD8 T-cells in immune infection is the increased risk of infection,
responses to TB in children. reactivation and progression to TB disease
in individuals with HIV co-infection. A
These immunological differences described number of studies have reported a higher
above could largely be a reflection of risk of TB and poorer survival among HIV-
immaturity of the immune response and infected children when compared with HIV-
explain the high rate of progressive TB seen negative children with TB, while the reported
in young children. risk of disseminated BCG disease (called
BCG-osis) in HIV-infected children has
Apart from the intrinsic deficiencies in cell- prompted the World Health Organization
mediated immune responses in children, (WHO) to recommend avoiding BCG
there are other primary and acquired causes vaccination in newborns with known HIV-
of immune suppression which could further positive status.

Although the attributable effect of the HIV transplant recipients due to compounded
epidemic on the burden of TB in children is immunosuppression. Therefore, efficient
less well defined than in adults, the HIV pre-transplant risk assessment and
epidemic has resulted in a shift of TB screening of both the transplant recipient
disease burden to younger adults resulting and the donor/donor organ is an important
in an increased exposure of both HIV- part of the management of recipients which
infected and -uninfected children at a very will allow for preventive intervention in the
young age. While HIV is known to be a pre- and/or post-transplant period.
strong risk factor for TB, this risk is further
increased in HIV-infected children by Helminth infestation, nutritional deficiencies
younger age and underlying immune status and vitamin D Several studies have
as defined by the CD4 count and viral suggested that helminth infection could
loads. The incidence of TB has been downmodulate the protective immune
reported to be four times higher in children response against M. tuberculosis thereby
with a CD4 count ,15% and 30 times facilitating progression to active TB disease.
higher in children with viral load .5 log10 Heavy helminth infection in humans has
copies per mL when compared with been shown to be associated with a
other children. generalised state of immune
hyporesponsiveness, probably facilitated
The diagnostic difficulties in childhood TB through immunoregulatory pathways
are further compounded in HIV/TB co- involved in mycobacterial control.
infection, as the clinical presentations in
both diseases are similar and radiological The association between malnutrition and
features are nonspecific. The tuberculin risk of TB is largely derived from
skin test (TST), which is the most widely observational studies in humans,
used immunological test supporting the experimental studies in animal models and
diagnosis of TB, is frequently false in vitro studies. However, it is still unclear
negative because of HIV-associated whether malnutrition facilitates TB or TB
anergy in delayed-type hypersensitivity leads to malnutrition. Similarly the effect of
to purified protein derivatives. Thus, different forms and degrees of malnutrition
diagnosis of TB in children, especially in and the population attributable risk due to
resource-limited settings, relies on malnutrition in communities where both TB
practical algorithms, which lack standard and malnutrition are endemic remain to be
symptoms definitions and adequate defined.
validations, with HIV co-infection Vitamin D deficiency is associated with TB
aggravating these shortcomings.
among children and immigrants in low-
Transplant-related immune suppression endemic settings, as well as in people in
Impairment of immune control of M. TB-endemic settings regardless of HIV
tuberculosis can also result from the status. A seasonal variation in the notified
immunosuppression, either due to disease cases of TB related to exposure to UV light
and/or treatment in solid organ transplant and vitamin D deficiency has also been
and/or haematopoietic stem cell transplant reported from several populations. Vitamin
(HSCT). Lung transplantation has the D, through its active metabolite 1-alpha-25-
highest risk of such donor-derived dihydroxy-vitamin-D, contributes to the
transmission and of post-transplant TB. As host immune protection against TB
such, the incidence of TB and its associated through non-classical mechanisms
mortality is higher in transplant recipients including upregulation and activation of
than in the general population and the antimicrobial peptides such as
incidence is directly proportional to cathelicidins, promoting IFN-c induced
endemicity of M. tuberculosis infection in the activation of M. tuberculosis-infected
general population. These risks are further macrophages as well as the maturation and
heightened or amplified in paediatric activation of dendritic cells.

Clinical manifestations of extra- bacteria into the subarachnoid space causes
pulmonary TB meningitis. In some individuals, Rich foci
enlarge to form tuberculomas.
Lymph node TB Superficial tuberculous
lymphadenitis involves mainly cervical Clinical features TBM can manifest in
lymph nodes and is the most common form progressive phases. The first stage (stage 1)
of extrapulmonary TB in children from TB- presents with nonspecific symptoms such
endemic areas. Environmental factors and as headache, nausea and fever, and vague
other mycobacteria can also cause cervical CNS symptoms, such as behaviour changes,
lymphadenitis depending on their irritability, drowsiness and vomiting. Stage 2
prevalence in a given setting. is marked by signs of meningeal irritation
and cranial nerve palsies involving mainly
Clinical features Lymphadenitis presents 6 nerves III, VI and VII. Stage 3 is
12 months after initial TB infection as non- characterised by raised intracranial pressure
tender, non-erythematous solid masses 2 and altered sensorium. Some stage 3
4 cm in size. They may become matted patients present in a coma. Seizures may
together and develop a chronic discharging occur at any stage. Late presentation is
sinus. Constitutional symptoms such as common in developing countries;
fever, fatigue and failure to thrive are tuberculomas are more common in the
observed in .50% of the children. Anterior older child, present with focal seizures or
cervical lymph nodes are more commonly with symptoms and signs of raised
involved; posterior cervical, supraclavicular intracranial pressure and may coexist with
and submandibular nodes are less involved. meningitis in up to 10% of cases (fig. 1).
Infants are rarely affected.
Diagnosis Lumbar puncture is mandatory.
Diagnosis Fine-needle aspiration for acid-fast The cerebrospinal fluid (CSF) shows a clear
bacilli, cytology and culture are usually hyper-concentrated fluid with high protein
adequate for accurate diagnosis. Lymph (.0.4 g?L-1), low glucose (,60 mg?dL-1)
node biopsy confirms diagnosis and and a high white cell count of 100
excludes other causes of lymphadenopathy 1000 cells?mL-1 of which at least 80% are
such as malignancy. Histology shows the lymphocytes. Acid-fast bacilli staining and
typical features of necrosis and epitheloid culture of CSF rarely yield mycobacteria.
granulomata. Partially treated bacterial meningitis, and
CNS TB constitutes around 13% of all cases viral and fungal meningitis (especially
of extrapulmonary TB in children and
complicates the clinical course of TB in 0.5
2% of cases. Tuberculous meningitis (TBM)
is the most common form (,95% of cases);
tuberculomas and abscesses are less
common. The spinal cord is rarely involved.
CNS TB develops 36 months after primary
infection, usually in children ,2 years of
age. TBM is a devastating illness. It may
develop acutely or more commonly evolve
slower than other forms of bacterial
meningitis. Serious neurological sequelae
develop in almost 50% of cases and overall
mortality is ,13%. TBM is very rare in low-
TB prevalence countries. Seeding of TB
bacilli in the CNS leads to formation of
small subpial and subependymal foci in the
brain and spinal cord referred to as Rich Figure 1. A transverse section of the brain showing
foci. Rupture of Rich foci and release of dilated ventricles in a child who died of TBM.

cryptococcal meningitis in HIV-positive
children) should be ruled out.
Complications include hydrocephalus,

seizures and cranial nerve palsies. Learning
difficulties, deafness, blindness and
hemiplegia may persist in the long term.
Imaging in CNS TB MRI with gadolinium
enhancement is the most sensitive test for
detecting the extent of leptomeningeal
disease and is superior to CT scanning in
detecting parenchymal abnormalities
such as tuberculomas, abscesses and
infarctions.
A CT scan with contrast enhancement can

show meningeal enhancement,
hydrocephalus and focal infarcts from
Figure 2. Miliary TB. Chest radiograph of a 2-year-
vasculitis. Tuberculomas appear as hyper
old boy showing bilateral distribution of miliary
dense, rim-enhancing lesions 15 cm in
nodules.
dimension. Neurocysticercosis has a similar
appearance and needs to be differentiated
from tuberculomas, especially in developing
countries. acid-fast bacilli and culture should be
performed; culture might be positive in up
Miliary TB Classic miliary TB refers to to 50% of cases.
millet-like (15 mm) seeding of TB bacilli in
the lung as evidenced by radiography. Very Chest CT has a higher sensitivity and
young and/or immunocompromised specificity compared to radiography in
children, such as HIV infected or severely displaying the nodules. It is useful in
malnourished children, are usually affected resolving suggestive but inconclusive chest
and miliary TB tends to develop soon radiography findings. Ultrasonography may
after primary infection from an adult reveal diffuse liver disease, splenomegaly
source case. and para-aortic lymph nodes. A head CT
scan or MRI scan may show involvement of
Clinical features Progressive symptoms the CNS. Echocardiography helps to exclude
similar to other forms of pulmonary TB pericardial involvements.
develop over days or weeks and the
diagnosis is then apparent on the Pleural TB Pleural TB occurs in 238% of
pathognomonic chest radiograph (fig. 2). cases of pleural TB in children and may be a
manifestation of primary or reactivation
Diagnosis Chest radiographs show the disease. Primary pleural TB results from a
typical, bilaterally distributed, miliary hypersensitivity reaction to bacilli in the
nodules in the majority of cases. pleural space. The effusion usually develops
Lymphocytic interstitial pneumonitis (LIP) 612 weeks after infection.
and opportunistic infections such as
Pneumocystis jirovecii may present with a Clinical features Pleural TB is more common in
similar picture in HIV-infected children. adolescents. It presents with chest pain,
cough, shortness of breath, weight loss,
The TST may be negative in miliary TB as fatigue and anorexia. Examination reveals
disseminated disease may cause TST wasting, pyrexia, respiratory distress, dullness
anergy. This should never rule out TB. to percussion and reduced breath sounds,
Fundoscopy may identify retinal tubercles. mimicking pneumonia. Effusion is usually
Gastric washings or induced sputum for unilateral and more common on the right.

Diagnosis Radiological examination reveals 3060 Units?L-1 indicate disease and aid
effusion, mediastinal shift, parenchymal therapeutic decisions. Acid-fast bacilli in
consolidation, bulging lung fissures and pericardial fluid or pericardial tissue
hilar or mediastinal adenopathies. Pleural histology establish the definitive diagnosis.
aspiration and analysis shows straw Myocardial TB is very rare and remains
coloured fluid, an exudative lymphocytic mainly a post mortem diagnosis. It presents
effusion with 10006000 white blood cells with arrhythmias, conduction blocks,
per mL, protein .4 g?dL-1 and glucose level valvular insufficiency and CHF.
,70 g?dL-1. Elevated pleural fluid ADA levels
(.4060 Units?L-1) can support the Skeletal TB is seen in 12% of all childhood
diagnosis. Sputum acid-fast bacilli and TB cases. TB bacilli get deposited at the
culture should be performed on sputum, bone site forming a caseating focus, which
pleural fluid and pleural biopsy specimen; then causes bone trabecular destruction.
however, pleural fluid is rarely acid-fast 50% of children have concurrent active
bacilli positive. Culture may be positive in pulmonary TB at the time of diagnosis. Most
4060% of cases. Histopathological affected children are in their second decade
examination of pleural tissue demonstrates of life except for TB dactylitis, which is
granulomata with or without caseous common among children ,5 years of age.
necrosis. Symptoms often begin 13 years after
primary TB infection and diagnosis is often
Pericardial TB TB can involve the delayed because of lack of exposure history,
pericardium in ,12 % of cases and causes nonspecific symptoms and lack of systemic
,70% of all cases of large pericardial illness. The most common manifestations
effusions. Most cases of constrictive are spondylitis (TB of the spine), arthritis
pericarditis in developing countries and and osteomyelitis.
,4% of cases in industrialised countries are
due to TB. Spinal TB constitutes ,50% of skeletal TB
cases and mostly involves the
Clinical features Common presenting thoracolumbar spine (Potts disease). The
symptoms include shortness of breath, infection spreads to involve the adjacent
cough, fever and weight loss. Chest pain is tissues initially and intervertebral disc later
less common. Hepatomegaly and jugular on in the process. Contiguous spread to the
venous distension are common. Cardiac paraspinal muscles results in abscesses.
tamponade has been noted in up to 90% of Swelling, pain and tenderness at the site are
cases. Pulsus paradoxus and pericardial the most common presenting symptoms.
rubs are occasionally demonstrated. Gibbus (swelling and angulation along the
spine) may be observed on clinical
Diagnosis Chest radiograph shows examination. Features of paraparesis or
cardiomegaly in .90% of cases and may quadriparesis due to spinal cord
also demonstrate features of active TB. ECG compression may be observed.
shows nonspecific ST and T-wave
abnormalities. Echocardiography shows Diagnosis MRI is the imaging modality of
non-TB specific features; effusion with choice and determines the extent of soft
fibrinous strands on the visceral tissue involvement and the level of cord
pericardium. CT scans show pericardial compression. Radiography of the spine later
effusion and thickening. Typical changes in in the disease progression shows loss of
mediastinal lymph nodes are seen in almost height of vertebral bodies, bony erosions,
100% of cases. periosteal reaction, sequestra and vertebral
collapse. Chest radiograph may
Pericardiocentesis is both diagnostic and demonstrate active pulmonary disease in
therapeutic and shows blood-stained 50% of cases. CT scans demonstrate bony
exudative fluid with high protein and high sclerosis and destruction. Histopathological
leukocyte count, with lymphocyte and examination of bone biopsy specimen
monocyte predominance. ADA levels of showing granulomatous lesions confirms

Table 1. Extrapulmonary TB treatment regimen
Manifestation Drug regimen Dosage Duration of
treatment
Intensive phase
All forms of extrapulmonary TB HRZE H 10 mg?kg-1?day-1 2 months
R 15 mg?kg-1?day-1
Z 35 mg?kg-1?day-1
E 20 mg?kg-1?day-1
Continuation phase#
Pleural, pericardial, HR H 10 mg?kg-1?day-1 6 months
abdominal and renal R 15 mg?kg-1?day-1
CNS TB HR HR as above 10 months
Skeletal TB HR HR as above 10 months
H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol. #: a thrice weekly regimen is used in the
continuation phase but this is not recommended in high HIV prevalence settings, except where the child is
HIV negative and DOTS (directly observed treatment, short-course) is well established.
the diagnosis. Acid-fast bacilli stains of bone ribs with forearm bones and clavicles often
specimen are often negative but culture may involved. Short bones of the hands and feet
be positive in up to 75% of cases. may be affected in younger children (TB
dactylitis). Systemic symptoms may be
TB arthritis is usually a monoarticular
observed.
disease affecting the large weight-bearing
joints; the hips or knees are involved in Diagnosis Radiography shows soft tissue
,30% of cases. swelling, osteoporosis, cystic bone changes
and sequestrum. An infiltrative pattern
Clinical features resemble those of spinal TB.
resembling Ewings sarcoma, fungal
The diagnosis is established through
radiography of the affected joint and reveals infection and chronic pyogenic osteomyelitis
joint effusion, periarticular osteopenia, may sometimes be seen. Cyst-like cavities
irregularity of the bone cortex, lytic lesions with expansion of the diaphysis, the so-
and periosteal new bone formation. called Spina ventosa, may be seen. BCG
Decreased joint space and widening of the osteomyelitis presents similarly and can
intercondylar notch in the knee are observed occur a few months to 5 years post-BCG
in advanced disease. Marked joint vaccination. Culture of the BCG strain
destruction and fibrous or bony ankylosis establishes this differential diagnosis.
are seen in end-stage disease. An ultrasound Abdominal TB is generally less common in
scan demonstrates joint effusion and aids children. It may complicate untreated
the aspiration for acid-fast bacilli and pulmonary TB in ,638% of cases.
culture. MRI demonstrates marrow changes, Abdominal TB due to M. bovis can result
joint effusions and cartilage and bone
when unpasteurised milk is ingested, but
erosions. Joint fluid aspiration or synovial
this is now rare.
biopsy is necessary for confirmation of
diagnosis. Clinical features Abdominal TB is more
Tuberculous osteomyelitis is a very rare form common in older children and adolescents,
of skeletal TB in children. Lesions are either and usually presents as enteritis or
solitary or multifocal. peritonitis. Patients suffer with chronic
abdominal symptoms over several months:
Clinical features are local pain, swelling and vague abdominal pain, abdominal mass,
tenderness of the skull vault, hands, feet and anorexia and vomiting in association with

weight loss. Physical examination shows a therapy, requires ongoing support for
distended abdomen that feels doughy on parents and children and regular clinical
palpation. Abdominal TB could present reviews to assess response to treatment,
acutely with intestinal obstruction, adherence and possible side-effects/
perforation and peritonitis as a complication interference of medication. Drug dosage
of adhesions. should be adjusted according to the
patients weight. Children with proven or
Diagnosis CT scans show bowel wall
suspected multidrug-resistant (MDR)-TB
thickness, ascites and the abdominal viscera
should be treated by experts and within the
and detect para-aortic and mesenteric
context of a well-functioning MDR-TB
lymphadenopathy and calcifications, which
are often also visible on ultrasound. Chest control programme. Hospitalisation is
radiography may reveal abnormality in 50 mandatory during the initial phase for
70% of patients. Evaluation of ascitic fluid disseminated forms of TB.
shows lymphocytic exudates; acid-fast bacilli
and culture are positive in up to one-third of Further reading
patients.
N Allen JE, et al. (2011). Diversity and
Other forms of disseminated TB include dialogue in immunity to helminths. Nat
renal TB and cutaneous TB. Both are Rev Immunol; 11: 375388.
extremely rare in children. N Bumbacea D, et al. (2012). The risk of
tuberculosis in transplant candidates and
Treatment of extrapulmonary TB recipients: a TBNET consensus state-
ment. Eur Respir J; 40: 9901013.
The treatment of EPTB follows the same
N Cottle LE (2011). Mendelian susceptibility
basic principles as for pulmonary TB. to mycobacterial disease. Clin Genet; 79:
Treatment is divided into intensive and 1722.
continuation phases. The intensive phase N Geldmacher C, et al. (2012). Interaction
rapidly eliminates the majority of TB bacilli between HIV and Mycobacterium tubercu-
and prevents the emergence of drug losis: HIV-1-induced CD4 T-cell depletion
resistance. The continuation phase and the development of active tubercu-
eradicates dormant organisms. The losis. Curr Opin HIV AIDS; 7: 268275.
recommended drug regimen is shown in N Hewison M (2012). Vitamin D and
table 1. immune function: an overview. Proc
Nutr Soc; 71: 5061.
Corticosteroids N Jones C, et al. (2011). Immunology and
Corticosteroids are indicated in children pathogenesis of childhood TB. Paediatr
with TB meningitis, TB pericarditis and Respir Rev; 12: 38.
N Marais B, et al. (2006). The spectrum of
possibly also in severely ill children with
disease in children treated for tuberculo-
disseminated TB (miliary). The
sis in a highly endemic area. Int J Tuberc
recommended treatment is prednisone 1
Lung Dis; 10: 732.
2 mg?kg-1 daily orally for 46 weeks in N Marais BJ, et al. (2011). TB and HIV in
addition to TB drugs. The dose can be children advances in prevention and
tapered to stop over 24 weeks, depending management. Paediatr Respir Rev; 12: 39
on resolution of symptoms. 45.
General considerations N Mwachaka PM, et al. (2011). Spinal
tuberculosis among human immunodefi-
Any child presenting with disseminated ciency virus-negative patients in a Kenyan
forms of TB should be screened for HIV or tertiary hospital: a 5-year synopsis. Spine
other forms of immunodeficiencies, if J; 11: 265269.
known to be HIV negative. N Newton SM, et al. (2008). Paediatric
tuberculosis. Lancet Infect Dis; 8: 498
Prolonged treatment with several drugs, 510.
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Society guidelines for the diagnosis and World Health Organization, 2012.

Epidemiology and phenotypes
of bronchial asthma and
wheezing disorders
Franca Rusconi, Ben D. Spycher and Claudia E. Kuehni
Studies of the epidemiology of asthma have diagnosis, which cannot be made by a single
flourished in the last 30 years, reflecting the measurement or test. Physicians diagnose
fact that the disease is common in asthma on the basis of medical history,
developed and developing countries, the physical examination and assessment of
aetiology still largely unknown, and costs are reversibility of airway obstruction. In
high. This section explains how asthma is epidemiological studies, the most common
assessed in epidemiological surveys, approach uses questionnaires to ascertain
describes time trends and prevalence whether subjects have had symptoms of
differences by age and sex, explains the asthma or have ever received a diagnosis of
concept of asthma phenotypes, and asthma from a physician.
summarises the current knowledge on
The prevalence of asthma diagnosis and
natural history and long-term outcome.
symptoms is dependent on the awareness of
Assessment of asthma in epidemiologic the disease in the populations studied and
studies and time trends on diagnostic labels. The same child might
be diagnosed with asthma by one doctor
Paediatric asthma guidelines emphasise and with wheezy bronchitis by another.
that asthma remains a complex clinical Thus, the preferred approach to assessing
asthma prevalence in epidemiological
studies is based on symptoms, particularly
Key points current wheeze (wheeze during the past
12 months).
N Asthma and wheezing disorders are
heterogeneous conditions in terms of The International Study of Asthma and
risk factors, age of onset, clinical Allergies in Childhood (ISAAC) is a major
phenotype, severity, response to initiative involving nearly 2 million
treatment and long-term course. schoolchildren aged 67 and 1314 years
from .100 countries. It was designed to
N Despite a large body of research, the compare prevalence of asthma, rhinitis and
factors explaining time trends and eczema between countries (phase I, 1994
international disparities in asthma 1995) and their trends over time (phase III,
prevalence remain largely unknown. 510 years later) using standardised
N Both severity of asthma and lung questionnaires (Asher et al., 2006). Key
function show a track from early findings included the high prevalence of
childhood to adulthood. asthma symptoms and asthma diagnosis in
English-speaking countries and Latin
N It is important to study phenotype and America (.20% in most centres),
clinical course of wheezing illness intermediate prevalence in Western Europe,
early in life when it might still be and low prevalence (,5%) in Eastern
possible to modify the natural history Europe, with a clear northwestsoutheast
of the disease. gradient. The lowest prevalence is found in
Africa and Asia with the exception of affluent

countries such as Singapore and Japan. In Prevalence by age and sex
most high-prevalence regions, particularly
English-speaking countries, prevalence of Only a few cohort and cross-sectional
current wheeze changed little between studies have described changes in asthma
phase I and III, and even declined in some symptoms from infancy to adulthood.
Existing studies suggest that the prevalence
cases, while most countries with low and
of current wheeze is highest in infants and
intermediate prevalence reported increases.
toddlers, then decreases slightly to remain
Other recent reports of time trends in
relatively stable throughout the school years.
Western countries, outside of ISAAC, also
However, the relevance of different trigger
suggest that prevalence of wheeze might
factors changes strongly with age: while
have reached a peak (Patel et al., 2008).
virally induced wheeze decreases, wheezing
Virtually all countries reported increases in
episodes triggered by pollen or exercise
the lifetime prevalence of an asthma
become more common with age.
diagnosis, irrespective of the prevalence of
wheeze. This might indicate better Sex differences in asthma also change with
recognition and diagnosis of the disease, age. In many (but not all) surveys, young
and more frequent use of the diagnostic boys are reported to have more wheeze and
label, which is considered less stigmatising asthma than girls. In adolescence, the
today than it has been in previous years. pattern changes and new-onset wheeze
becomes more frequent in females.
Wide variations of asthma prevalence were Explanations for this include age-related
found within genetically similar groups; differences in the growth of the airways and
therefore, environmental and cultural factors lung parenchyma, sex-specific differences in
are likely to play a role in explaining regional environmental exposures and exercise,
and temporal variations. However, the hormonal changes occurring during puberty,
asthma risk factors studied (e.g. infant changes in symptom reporting, and sex-
feeding, diet, maternal smoking, related underdiagnosis and under-treatment
immunisations, allergens and air pollution) in female adolescents (Almqvist et al.,
explain only a small part of the regional 2008).
variability and time trends (Asher et al.,
2010). Asthma phenotypes
Studies in migrants also point to the Wheezing disorders might comprise several
distinct phenotypes, possibly representing
importance of socio-cultural and
different disease entities (Silverman et al.,
environmental factors. These studies
1997). If this is true, early distinction of
generally found a steep increase in
phenotypes would allow more focused
prevalence among groups migrating from
research into aetiology and pathophysiology,
low- to high-prevalence areas, particularly
prescription of treatments and preventive
among those who were born in the host
measures targeted to the phenotypes, and
country or migrated during the first years of
improvement in the prediction of long-term
life. Unfortunately, numerous changes occur
outcome. Classical approaches for
simultaneously in migrants, so it is difficult
distinguishing asthma phenotypes have
to disentangle the role of environmental
relied on trigger factors or time course. A
factors (e.g. climate and allergens),
distinction by the main triggers led to the
behaviours (diet and smoking) and social definitions of:
factors that might affect their interaction
with the healthcare system; for example, the N episodic viral wheeze (wheeze occurring
likelihood of being diagnosed and treated episodically only during viral infections);
(Kuehni 2011). Asthma risk factors are N multiple-trigger wheeze (wheeze also
described in detail in the Genetic and occurring in response to other factors
environmental factors in bronchial asthma such as crying, laughter, exercise or
and wheezing disorders section in this allergens, and often associated with
Handbook. atopy).

While the prevalence of the former defined by these methods have confirmed
decreases during the first years of life, the some of the previously suggested patterns
latter becomes relatively more frequent, is such as transient viral wheeze and
more persistent and more likely to be persistent atopic wheeze. Currently,
diagnosed as asthma (Brand et al., 2008). phenotype research is thriving, and it is
However, these phenotypes, based on important to keep in mind that phenotype
triggers of wheeze only, show limited definitions only have value if they improve
stability through early childhood, suggesting patient care or lead to a better
that triggers of wheeze alone are not understanding of disease processes.
sufficient to distinguish underlying disease
processes or that the disease processes Natural history and long-term prognosis
change in some children throughout this
Childhood asthma is characterised by a
period (Spycher et al., 2012).
highly variable time course differing by age
An alternative approach distinguishes of onset, duration of symptomatic periods,
children based purely on the time course of and remissions and relapses. This
wheezing episodes during childhood. A complicates the study of the natural history
common distinction is between: of asthma. Nevertheless, long-term
prospective studies have revealed important
N early transient wheeze (wheezing only aspects of the disease.
during the first 23 years of life);
N persistent wheeze (wheezing beginning In one of the oldest cohort studies, the
in early life and persisting up to school Melbourne Asthma Study (Australia), a
age); population-based sample of 7-year-old
N late-onset wheeze (beginning to wheeze children with a history of wheeze and an
after the age of 3 years) (Martinez et al., asymptomatic control group were followed
1995). over several decades (Phelan et al., 2002).
The study found consistent associations
Novel statistical approaches in large cohorts between severity of symptoms in childhood,
have distinguished more temporal patterns defined by frequency of wheeze, and
(Henderson et al., 2008). Classifications by persistence of asthma up to the age of
time course, however, have the 42 years: children with frequent episodes in
disadvantage that they can only be applied childhood had more severe asthma and a
retrospectively, once a child has reached a lower FEV1/FVC throughout adolescence and
certain age. Therefore, they cannot be used adulthood. Eczema, hay fever or allergic
to decide how to treat a preschool child or sensitisation in childhood also tended to
inform parents about the likely prognosis. result in more severe asthma later in life.
Recently, multidimensional approaches In the Dunedin birth cohort (New Zealand)

have been used whereby phenotypes are (Sears et al., 2003), children with persistent
defined based on a wider range of wheeze throughout follow-up were more
concurrently assessed features using likely to be sensitised to common allergens
statistical methods such as latent class and had lower FEV1/FVC ratios at 26 years of
analysis (Spycher et al., 2010). These age than nonwheezers. In both the
analyses can include different asthma- Melbourne and Dunedin studies, the lung
related symptoms and measurements such function deficit was already established by
as lung function, bronchial responsiveness, school age, suggesting an early loss of lung
atopy or exhaled nitric oxide simultaneously, function in some asthmatic children and
and identify groups that are relatively that lung function tracks over time into
homogeneous with respect to these adulthood. These and other studies show
features. Such phenotypes are closer to the that a considerable proportion (2030%) of
clinical situation, where a number of patient children with asthma at school age continue
characteristics are evaluated by the to have symptoms as adults, although some
physician simultaneously. The phenotypes experience long asymptomatic periods.

A limitation of these older cohort studies is Further reading
that respiratory symptoms and lung function
N Almqvist C, et al. (2008). Impact of
were first assessed at school age. Thus,
gender on asthma in childhood and
information on the first years of life was
adolescence: a GA2LEN review. Allergy;
lacking. More recent cohort studies that 63: 4757.
have followed children prospectively from N Asher MI, et al. (2006). Worldwide time
fetal life or birth and have assessed lung trends in the prevalence of symptoms of
function in infancy, before the onset of asthma, allergic rhinoconjunctivitis, and
disease, can shed more light on this critical eczema in childhood: ISAAC Phases One
period (www.birthcohorts.net). Importantly, and Three repeat multicountry cross-
it was suggested that lung function deficits sectional surveys. Lancet; 368: 733743.
might be congenital in some children, while N Asher MI, et al. (2010). Which population
in others they are probably a consequence of level environmental factors are associated
severe asthma. These hypotheses must be with asthma, rhinoconjunctivitis and
tested using repeated measurements of eczema? Review of the ecological analyses
lung function from birth to late childhood. of ISAAC Phase One. Respir Res; 11: 8.
Long-term follow-up of these cohorts will N Brand PLP, et al. (2008). Definition, assess-
clarify which children with persistent asthma ment and treatment of wheezing disorders
in preschool children: an evidence-based
are at risk of developing irreversible airway
approach. Eur Respir J; 32: 10961110.
obstruction, the clinical hallmark of COPD
N Henderson J, et al. (2008). Associations
(Martinez, 2009). of wheezing phenotypes in the first
6 years of life with atopy, lung function
Several approaches have been taken to
and airway responsiveness in mid-child-
predict the long-term prognosis of young
hood. Thorax; 63: 974980.
children with wheezing illness based on risk N ISAAC. The International Study of Asthma
factors such as symptom severity, markers and Allergies in Childhood. http://isaac.
of atopy, parental history of asthma and auckland.ac.nz/
environmental exposures (Savenije et al., N Kuehni CE (2011). Do migrant studies
2012). However, the ability of currently help to identify causes of asthma? Clin
available prediction scores to identify Exp Allergy; 41: 10541058.
children who go on to have asthma in later N Leonardi NA, et al. (2011). Validation of
childhood has been disappointing. The most the Asthma Predictive Index and compar-
important commonly assessed predictor of ison with simpler clinical prediction rules.
future asthma is severity of current J Allergy Clin Immunol; 127: 14661472.
symptoms (frequency and severity of N Martinez F (2009). The origins of asthma
wheezing episodes) (Leonardi et al., 2011). and chronic obstructive pulmonary dis-
The additional prognostic value of ease in early life. Proc Am Thorac Soc; 6:
investigations such as blood eosinophils or 272277.
N Martinez FD, et al. (1995). Asthma and
exhaled nitric oxide remains to be shown. In
wheezing in the first six years of life. The
addition, currently proposed prediction
Group Health Medical Associates. N Engl
models have been developed for specific age J Med; 332: 133138.
groups, and might not be generalisable to N Patel SP, et al. (2008). Systematic review
older or younger children. of worldwide variations of the prevalence
of wheezing symptoms in children.
In summary, the concept of an early window Environmental Health; 7: 57.
of susceptibility, beginning in fetal life, and N Phelan PD, et al. (2002). The Melbourne
the tracking of certain characteristics of Asthma Study: 19641999. J Allergy Clin
asthma from childhood to adulthood, Immunol; 109: 189194.
including severity and impairment of lung N Savenije OE, et al. (2012). Predicting who
function, stress the importance of will have asthma at school age among
characterising the clinical course of the preschool children. J Allergy Clin Immunol;
disease early in life, when, in principle, it is 130: 325331.
still possible to modify natural history.

N Sears MR, et al. (2003). A longitudinal, N Spycher BD, et al. (2010). Phenotypes of
population-based, cohort study of child- childhood asthma: are they real? Clin Exp
hood asthma followed to adulthood. N Allergy; 40: 11301141.
Engl J Med; 349: 14141422. N Spycher BD, et al. (2012). Multiple trigger
N Silverman M, et al. (1997). Asthma time and episodic viral wheeze in early child-
for a change of name? Arch Dis Child; 77: hood: are these phenotypes stable over
6264. time? Eur Respir J; 40: Suppl. 56, 517s518s.

Genetic and environmental
factors in bronchial asthma
and wheezing disorders
Oliver Fuchs and Erika von Mutius
Asthma is a disease with a strong genetic pathways or aetiologies of asthma-related

background. Asthma heritability, i.e. the traits and intermediate phenotypes such as
variance caused by genetic factors, has been allergic rhinitis, atopic eczema, IgE levels or
estimated to be between 35% and 95%. lung function parameters, e.g. bronchial
Asthma heritability can be explained by hyperresponsiveness (BHR). So far, there is
genetic or by epigenetic effects. evidence for both common and distinct
Understanding the genetic disease aetiological pathways. For the latter, loci
background is important, as it offers the identified to be associated with lung
opportunity of new therapies or even function were not related to asthma,
preventive measures. Moreover, it helps to implying that causal pathways are distinct. It
understand the overlap between pathogenic is still unclear whether these reflect diverse
pathways or whether some phenotypes
share a number of them, at least partly.
Key points Historically, different methods have been
used to assess genetic associations with
N For childhood asthma and wheezing asthma-related traits. Table 1 displays all
disorders both genes and the existing approaches, their concepts as well
environment play a role, which is why as their individual benefits and downsides
they are complex diseases. relating to study design, sample size
N Genetic studies have identified requirements and need for replication. The
numerous risk loci for childhood first studies were genome-wide family-
asthma, in particular the GSDMB- based linkage studies and subsequent
ORMDL3 locus on 17q21, which has positional cloning. Generating hypotheses
replicated numerous times and has to be tested in subsequent analyses, they
the strongest effect on childhood- led to the discovery of various genetic loci
onset asthma found to date. and genes related to asthma, e.g. ADAM33
(potential role in airway remodelling),
N Epidemiological observations have SPINK5 (role in integrity of airway
identified both protective
epithelium), or STAT3 (IgE level). Based
environments and risk factors
on the hypothesis that they were
associated with childhood asthma
asthma-related due to biological,
and wheezing disorders. The most
pathophysiological or functional relevance,
robust and consistent finding relating
the majority of genetic variants associated
to risk is ETS exposure, particularly
with asthma, however, were discovered by
maternal smoking during pregnancy.
candidate-gene approaches. Within these
N Geneenvironment interactions, for studies, numerous genetic variants, such as
example ETS, and the association of CD14 (involved in innate immunity), TGFB1,
the 17q21 locus could be established ADRB2, NOS13 (roles in lung function,
in relation to childhood asthma. lung growth and development, allergic
airway inflammation) have been identified.

Emerging high-throughput techniques childhood-onset asthma could be explained
helped to detect asthma-related genetic loci by the seven identified genetic loci. Figure 1
in large populations. Genome-wide displays the genetic loci discovered in
association studies (GWAS) included asthma GWAS until the end of 2012.
several hundred thousand single-nucleotide
polymorphisms (SNPs) across the whole What is the best approach to identify genetic
human genome. Due to decreasing costs, variants conferring risk for development of
their number is steadily increasing. Until the childhood wheeze and asthma? As all
end of 2012, 1489 GWAS, 22 thereof on methods have their advantages and
asthma, were listed on www.genome.gov/ disadvantages, they may play a role
gwastudies. The first asthma GWAS altogether and consequently, there will be
described the GSDMB-ORMDL3 locus on trade-offs for their benefits and downsides.
chromosome 17q21. This locus was Moreover, careful disease phenotyping is
replicated in independent populations and necessary as childhood asthma is not one
has the strongest effect on childhood-onset disease entity but many. If one is interested
asthma. Being involved in intracellular Ca2+ in discovery and analysis of genes conferring
flux and possibly contributing to airway only modest effect sizes, GWAS and
remodelling, there is also a plausible candidate gene approach would be
mechanism related to ORMDL3. The favourable. If one is interested in rare
GABRIEL Consortium performed the largest variants, sequencing might be the best
GWAS for childhood asthma to date. Seven approach, perhaps even family-based
loci, IL18R1, HLA-DQ, IL33, SMAD33, IL2RB, linkage studies (table 1).
GSDMA, and GSDMB-ORMDL3, were The epigenome
identified. More recently, it has become
possible to apply extensive sequencing of In addition, alterations in gene expression
whole genomes for the discovery of by activation and deactivation of genes
mutations associated with childhood without any changes in the underlying DNA
wheeze and asthma. As whole-genome sequence may influence the risk of
sequencing is still overly expensive, whole- childhood asthma and wheezing disorders.
exome sequencing, i.e. analysing enriched This is called the epigenetic effect. It can be
coding sequences (exons) of the human mediated by methylation of cytosine to
genome, may be a way to go until whole- 5-methylcytosine and vice versa mostly at
genome sequencing, including other but sites with a cytosine in linear sequence with
putatively nonetheless important non- a guanine base on the same DNA strand,
coding sequences such as introns, will leading to gene silencing. Epigenetic effects
become affordable in large studies. can also be mediated by non-coding RNA
species (such as miRNAs) and through
Unfortunately, the genetic basis of asthma is alterations of chromatin by histone
as yet unknown. Instead of discovering modification (methylation, acetylation,
the asthma gene or a few genes with ubiquitinylation, phosphorylation and
strong effect sizes, analyses to date sumoylation).
discovered several loci each with small
effects. With relatively low positive The possible role of epigenetics in asthma is
predictive values even for highly associated highlighted by several findings. So far, pure
risk alleles, the utility of genetic data in genetics explain only limited heritability.
personalised medicine for diagnostic or Moreover, affected mothers transmit
even predictive testing of asthma in the asthma more often to their offspring than
individual is still science fiction. affected fathers, i.e. there is a clear parent-of-
Nevertheless, current evidence has origin effect for asthma, possibly due to
promoted the field on a population level. An maternofetal immune-interactions or to
example for this is the population under imprinting. However, epigenetic studies in
study in the GABRIEL Consortium asthma are complex and their possible use
mentioned above. Here, at least 38% of is still unclear. First of all, unlike genetic

Table 1. Methods to assess genetic associations with asthma-related traits
Best for Approach Concept Comparisons Advantages Disadvantages
Study of Currently Hypothesis driven Frequency of alleles Cheap Limited as it relies
common done: Includes genes a priori in gene of interest of Results can be on existing evidence
variants candidate- thought to be asthma- individuals with rapidly interpreted Does not lead to
gene related due to asthma versus healthy Straight-forward discovery of genes
approach biological, controls because hypothesis or SNPs
pathophysiological or Risk of asthma can be driven
functional relevance or computed depending
known to be on study design (case
associated with control: OR;
asthma prospective: RR).
SNP analysis within
genes or regions of
interest, targeted SNP
analysis possible,
tagging of non-
represented SNPs by
analysis of SNPs in LD
Currently Hypothesis free, can SNPs of whole Is becoming Limited to common
done: GWAS be hypothesis genomes of cheaper, several SNPs (usual MAFs
generating individuals with platforms available are 15%) and to
SNP analysis covering asthma versus healthy May lead to SNPs represented
the whole genome, controls discovery of genes on platform or that
tagging of non- Risk of asthma can be or SNPs can be tagged
represented SNPs by computed depending High resolution due (needs LD)
analysis of SNPs in LD on study design (case to proceeding SNP Large sample sizes
control: OR; discovery and replication in at
prospective: RR) Imputation of least one
additional SNPs in independent
LD to covered population are
variants possible needed
Study of rare Currently Can be both Gene of interest or May reveal rare Expensive
variants done: hypothesis free exomes as well as variants (MAFs Can be difficult to
sequencing, (exome or whole whole genomes of below thresholds of interpret,
either genes, genome) or individuals with GWASs) computational and
exomes or hypothesis driven asthma versus healthy Enables fine- bioinformatic
whole (gene), may generate controls mapping of ROIs analysis is
genomes, new hypotheses Risk of asthma can be demanding
so-called Enables analysis of computed depending Large sample sizes
next- DNA sequence and on study design and replication in at
generation thus of all sequence (case-control: OR; least one
sequencing variation prospective: RR) independent
population are
needed
Historically Hypothesis free, can Studied in families May lead to Relatively expensive
and currently be hypothesis (usually with two discovery of new Laborious and time
done: generating affected siblings and ROI or gene, intensive
linkage study Gene identified by unaffected parents) perhaps SNP of Needs families
followed by genome-wide linkage Risk of asthma interest Needs several steps
positional study computed as log of May also lead to for discovery of gene
cloning Genomes screened odds in favor of discovery of rare of interest
study with genetic markers linkage (LOD score) variants Limited resolution
evenly dispersed over Identification of Requires relatively
whole genome genes or SNPs by few markers
Linkage: marker is fine-mapping
inherited together with (positional cloning)
disease more often is possible
than expected by Further analyses are
chance needed to define
gene function
LD: linkage dysequilibrium; OR: odds ratio; RR: relative risk; MAF: minor allele frequency; ROI: region of interest.

36.3
36.2
36.1 25
35 24
34.2 23
33
32 ATPAF1* 22
26 IL5RA*
21 25
31 16 24
16 15.3
14 22 15.3
22 13 15.1 25 NOTCH4*
21 15.1 24
21 12 14 14 23 PBX2*
11.2 C6orf10*
13 13 22 HLA-DQA1*
13 GNAI3* 14 12
11.2 IL1RL1*,*** 12 21 HLA-DQB1* 23 24 IL33*,***
12 12 13 12 HLA-DPB1*
13 IL18R1* 11.2 22 23
14.1 DPP10* 12 13 21 HLA-DRA*
12 12 PDE4D* 12 HLA-DOA* 21 21 ACO1*
IL6R*
14.3 21 13 BTNL2* 12
21 FLG***** 21 11. AGER-PPT2**** 11.2 13
22 FAM13A*** 12 12
22 CRCT1* 22 13. 14 13
23 PYHIN1* 24 GSTCD**** 14 11.2
23 13. INTS12**** 15 15 12 12
24 FCER1A** 21
25 24 21 GATA2*** 26 TSLP* 16 13 13
22 27 22 WDR36*** 21.2
31 DENND1B* 31 23 21 21 TLE4-
23 SLC22A5* CHCHD9*
CRB1* 32.1 24 28 HHIP**** 21.3
32.3 RAD50*,** 22 MYB***
32 CHI3L1* 25 31 LOC729675* 31 IL13*,IL5*** 22 22 PTCH1****
33 SPATS2L*,**** 26. 31
GAB1* HTR4**** 23
34 IKZF2*** 32 C5orf56* 23 31
41 35 TNS1**** 26. 32 24 GPR126**** 32
27 33 33 NDFIP1* 33
42 36 PID1**** 34 TNIP1* 25 24 SLC30A8
43 28 34 26 34
37 29 35 35 ADRA1B* 27 GAPDHP72-T*
44 C1orf100* ADAM19**** 24.3
1 2 3 4 5 6 8 9
15
14 LOC338591* 15 13
13 13
12 14 12
12 13
11.2 13 11.2 11.2
12 12
11.2 12 11.2
11.2 PRKG1* IKZF4 12 13
13 CDK2* 13 DCLK1* 12 12 HS3ST3A1-
21 12 STAT6** 14 CDRT15P1*
LRRC32* 14 14 11.2
13 15 15 13 KIAA1271*
C11orf30***** 11.2 13
22
14 21 21 PCDH20* 21 SCG3* 12 PERLD1* 12 PRNP* 12
11.2
23 21 RORA* 21 GSDMA* 11.2
22 22 22 SMAD3*
22 23 THSD4**** 22 GSDMB* 11.2
24 23 31 ORMDL3*
24 23 11.2 12
25 23 C11orf71* 24.1 SH2B3*** 24 12
24.2 32 25 13.1
26 24 KIRPEL3- 33 26 25 13 IL2RB*
25 ETS1* 24.3 34 13.3
10 11 CRTAM*
12 13 15 17 20 22
Figure 1. Genetic loci discovered in GWASs until the end of 2012 on asthma (*) and related traits: IgE
levels (**), eosinophil count (***), lung function (****) and atopic dermatitis (*****). Locus positions
are shown down to chromosome, region and bands. Arrows represent partly sub-bands. Short arms of
chromosomes (p) face upwards and long arms (q) face downwards. Data courtesy of D. Vercelli (Arizona
Respiratory Center, Tucson, AZ, USA; personal communication). Image courtesy of M. Rocchi (University
of Bari, Bari, Italy; personal communication).
variants, epigenetic modifications may be in and of FOXP3 for regulatory T-cells (Treg)).
a constant state of flux. It is difficult to Thus, epigenetic modification may possibly
decide when to measure and what cell types impact asthma with Th2-skewing, as it is
or tissue to analyse. Likewise, their relative known that such immune responses
contribution to gene expression and contribute to asthma development. Here,
especially their heritability across human studies have demonstrated the
generations is unknown. impact of air pollution as an environmental
factor on FOXP3 methylation and Treg cell
There is evidence from both animal and function in asthmatic children. Furthermore,
human studies for epigenetic regulation in epigenetic effects on more intermediate
asthma and wheezing disorders. Mouse outcomes such as atopy and allergic airway
studies demonstrated an influence of inflammation, lung function and on
maternal methyl-donor rich diet on BHR, childhood wheeze subtypes are also
airway inflammation and serum IgE levels in supported by data derived from human
offspring. Also exposure to environmental studies. Due to ethical constraints, human
microbes can act by epigenetic regulation as studies have examined epigenetic effects in
shown by a study in mice where prenatal cells outside the lung, mostly peripheral
administration of the farm-related bacterial blood cells, but also in possibly more
species Acinetobacter lwoffii F87A prevented relevant buccal and nasal cells or in cells
an asthmatic phenotype in the offspring. In from sputum. Such easily obtained material
immunology, epigenetic mechanisms are might be useful for markers of childhood
known to be involved in T-cell differentiation asthma as demonstrated by the fact that
(e.g. by modification of the IFNG promoter hypo-methylation in Alox12 even in
for T-helper (Th)-1 cells, as well as for Th2, peripheral blood cells was associated with

persistent wheeze. For exhaled nitric oxide compounds (VOCs) and PM), VOCs and
as a marker of allergic airway inflammation formaldehyde from new furniture, for
data are conflicting. example, have been related to childhood
asthma. Moisture damage, as well as
The environment mouldy spots indoors, has been shown to
There is evidence that the environment plays increase the risk of childhood asthma and
a significant role as populations with very wheezing disorders.
similar genetic backgrounds show different
Importantly, viral infections in early life have
rates of childhood asthma and wheezing
been related not only to asthma
disorders. Epidemiological observations
exacerbations but also to the development
have identified protective environments and
of childhood wheeze and asthma, especially
risk factors associated with the development
if they occur against a background of early
of childhood asthma and wheezing
atopic sensitisation. In turn, the role of
disorders. The most robust and consistent
allergen exposure has been highly debated.
finding conferring risk is environmental
There is evidence that indoor allergen
tobacco smoke (ETS) exposure, particularly
exposure is a determinant for the
maternal smoking during pregnancy. In
development of allergic sensitisation
numerous studies, these exposures have
been shown to be associated with an towards this particular allergen. In contrast,
increased risk of wheezing and childhood allergen exposure has not convincingly been
asthma. Passive smoke exposure through associated with the development of
other family members also increases the risk childhood asthma and wheezing disorders.
of wheeze and childhood asthma in many Avoidance of house dust mite exposure has
studies. Interestingly, the ban on tobacco not achieved a reduction in asthma risk.
smoking in public places established in However, carers of children who are already
Scotland in 2001 significantly decreased the sensitised and allergic to indoor allergens
rates of hospitalisation for asthma by ,15%. such as house dust mite, cat or dog dander
Moreover, active smoking in children and should clear indoor environments of these
adolescents has been related to increased allergens as they may trigger symptoms.
risk for new-onset or progression of asthma Lifestyle factors have also been shown to
in this age group. play a role. These include maternal diet
during pregnancy as well as diet in early and
With respect to outdoor air pollution, later childhood, in particular breastfeeding,
studies relating to the density of car traffic, a Mediterranean diet and vitamin intake.
in particular truck traffic on roads in close BMI and obesity have been debated for a
proximity to the childs residence, have been number of years. These might be related to a
most conclusive. Here, particles with changed inflammatory state, especially due
aerodynamic diameters between 2.5 mm to central obesity, increased insulin
(PM2.5, able to enter the alveoli) and 10 mm resistance and further metabolic alterations,
(PM10, too large to enter the alveoli), ozone which may lead to asthma. Furthermore,
and nitrogen dioxide were demonstrated to there is evidence that, particularly in
affect lung growth and to be associated with adolescent females, an increase in body
reduced lung function and airway weight, which may be related to early
inflammation in children, even prenatally. menarche, is a determinant for new onset of
This underlines the importance of adverse asthma in these subjects. The role of
effects during the most vulnerable phases of physical activity remains unclear. Reduced
lung development early in life and it is not physical activity may be a consequence of
limited to outdoor air pollution. Indoor asthma and wheeze rather than a causal
parameters in addition to ETS may play a factor for the new onset of disease.
role. Besides pollutants resulting from
indoor heaters and fireplaces (carbon In the context of protective environments,
monoxide, nitrogen dioxide, polycyclic studies have consistently shown that
aromatic hydrocarbons, volatile organic growing up on a traditional farm reduces the

risk for asthma and hay fever. These studies clear need for similar stringent quality
have consistently been reproduced in many control and replication and the same
countries worldwide. The important necessities in study design and careful
exposures relate to contact with farm phenotyping as discussed previously.
animals, their fodder and unprocessed
cows milk which have been identified in a There are examples for geneenvironment
number of studies. The protective farm interactions in the field of asthma and
effect on asthma is, at least in part, wheezing disorders on different levels of
attributable to environmental bacteria and analytical approach. The first level is that of
fungi, which are highly prevalent in these a known candidate gene and a well-defined
environments. Experimental studies using environmental exposure with suspected
microbes cultured from farming geneenvironment interactions, such as in
environments confirm the preventive effect the interaction of endotoxin (a component
of exposure for the development of allergic of the cell wall of Gram-negative bacteria)
asthma in mice. with the gene for its receptor CD14 for the
risk of asthma and/or atopy. Another
The role of geneenvironment interaction example is ETS exposure and the 17q21
locus. Here it has been shown that the
Given the high prevalence of asthma, it is of
increased risk for childhood-onset asthma is
major public health relevance to elucidate
further increased by ETS exposure in early
the effects of genes and the environment in
life, itself known to confer a risk for early-
the study of pathological pathways in
onset disease. The first GEWIS for asthma
asthma. By fixing one parameter in the
assessed geneenvironment interactions in
equation, it is possible to disentangle their
the field of the protective farm effect on
individual impacts. As highlighted above,
asthma in children. Neither significant
one may identify genetic factors by studying
interaction of farm-related exposures with
populations sharing similar environments;
common SNPs nor with previously
by studying populations sharing the same
published genetic markers of asthma was
genetic background but living under
found.
different environmental conditions, one can
identify relevant environmental impacts. Thus, in the field of asthma and wheezing
However, asthma and wheezing disorders disorders, few geneenvironment
probably result from a joint effect of genes interaction mechanisms have been
and the environment and their interaction, established although epidemiological
i.e. the dependence of effects by one factor studies have demonstrated numerous
on the presence or absence of another environmental exposures associated with
factor. Technological progress has advanced asthma and studies to date on the genetic
the field of geneenvironment interactions background have identified a number of
in asthma, as the analysis of gene asthma-associated loci. Future research will
environment interactions on a genome-wide have to take into account windows of
level, i.e. geneenvironment-wide interaction opportunity for exposures under study as
studies (GEWIS) have been introduced well as better characterised wheezing
recently. This poses a challenge to even phenotypes.
highly advanced computational systems. In
addition to what has been mentioned for the
study of genetic and epigenetic effects, there Further reading
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N Moffatt MF, et al. (2010). A large-scale, N von Mutius E, et al. (2010). Farm living:
consortium based genomewide associa- effects on childhood asthma and allergy.
tion study of asthma. N Engl J Med; 363: Nat Rev Immunol; 10: 8688.
12111221. N Yang IV, et al. (2012). Epigenetic mechan-
N Ober C, et al. (2011). The genetics of isms and the development of asthma. J
asthma and allergic disease: a 21st Allergy Clin Immunol; 130: 12431255.

Acute viral bronchiolitis
Fabio Midulla, Ambra Nicolai and Corrado Moretti
Definition North American definition, in particular,

might engender an overlap between
Bronchiolitis is an acute viral respiratory bronchiolitis and early wheezy bronchitis.
infection involving the terminal and
respiratory bronchioli in infants, resulting in Epidemiology
small airways obstruction. Bronchiolitis is a
Bronchiolitis is the most frequent infectious
clinical diagnosis but, despite its high
disease in children ,1 year of age (90% of
frequency, its definition is still controversial.
patients are 19 months of age), and is the
The American Academy of Pediatrics
leading cause of hospitalisation in this
subcommittee defines bronchiolitis as a
group of infants. Bronchiolitis is epidemic
disorder in infants ,24 months of age that
between November and April. Annually, 11
is most commonly caused by a viral lower
out of every 100 infants have bronchiolitis
respiratory tract infection characterised by and 1113% of patients require
wheezing. In contrast, European guidelines hospitalisation. Each year 150 million new
define bronchiolitis as a seasonal viral cases of bronchiolitis are reported
illness in infants ,12 months of age worldwide. Only 13% of infants require
characterised by nasal discharge, cough, admission to intensive care, particularly
tachypnoea, retractions and bilateral those in whom risk factors are present.
crackles. These definitions reflect differences
in how the disease is interpreted and the Aetiology/risk factors
Bronchiolitis is caused by viruses. The most
Key points common viruses responsible are respiratory
syncytial virus (RSV), human bocavirus,
N Bronchiolitis is the first episode of rhinovirus, human metapneumovirus,
acute viral infection of terminal and influenza A and B, and parainfluenza viruses
respiratory bronchioli in infants 13.
,1 year of age. Risk factors for severe bronchiolitis are age
N Symptoms of bronchiolitis are ,3 months, male sex, low socioeconomic
moderate-to-severe respiratory conditions, maternal smoking and RSV
distress with rales at auscultation. infection. Other risk factors for severe
bronchopulmonary are prematurity with
N Supportive therapies aim to keep the bronchopulmonary dysplasia and coexisting
upper airways clear, and the infant co-morbidities, such as cardiovascular
oxygenated and hydrated. diseases, immunodeficiency and chronic
N A bronchodilator mixed with 3% respiratory diseases. The only protective
hypertonic saline might be tried and factor is maternal breastfeeding.
this combination should be continued
Pathophysiology
only if it achieves a documentable
clinical benefit. Viral respiratory infection results in
respiratory epithelium necrosis, loss of

epithelial cilia, collection of desquamated blood tests are required only if suggested by
airway epithelial cells, lymphocyte and clinical indications; blood gas analysis is
neutrophil infiltration within terminal and recommended only in more severe cases.
respiratory bronchioli, and oedema around Rapid virus detection could reduce
the airway. Cellular debris, inflammatory antibiotic use.
cells and fibrin cause airway obstruction.
Mucus plugs can partially or totally occlude Symptoms
the bronchioli. When the bronchioli are
The natural history of bronchiolitis is of a
completely occluded, atelectasis develops; if
self-limited disease that usually lasts for 3
bronchioli are only partially occluded, diffuse
7 days with an average duration of
air trapping occurs (fig. 1).
hospitalisation of 3.9 days. A small minority
The increase in airway resistance and of infants, especially those with associated
decrease in dynamic lung compliance comorbidities, may require intensive care
increase the work of breathing. Atelectasis and mechanical ventilation.
and air trapping result in hypoxaemia and
increased carbon dioxide due to an altered The initial symptoms of bronchiolitis are
ventilation/perfusion ratio. Tachypnoea, rhinorrhoea and cough, sometimes
increased work of breathing and reduced accompanied by a low-grade fever. The first
feeding can cause dehydration with clinical symptom could also be episodes of
metabolic acidosis. apnoea, especially in preterm infants, but
most infants with bronchiolitis manifest
Diagnosis tachypnoea, retractions, nasal flaring, rales
at auscultation and hypoxaemia. Other
Bronchiolitis is commonly diagnosed on
symptoms might include dehydration with
clinical grounds alone without help from
metabolic acidosis. SIADH (syndrome of
diagnostic tests. The criteria for the
inappropriate secretion of antidiuretic
diagnosis of bronchiolitis include exposure
hormone) is common in infants with severe
to other children or adults with respiratory
respiratory distress and can cause
viral infection, age ,12 months, preceding
upper respiratory illness and signs of acute hyponatraemia and accidental fluid
lower respiratory illness (respiratory overload. Bronchiolitis is a dynamic
distress, low oxygen saturation, rales and, disease and its clinical characteristics can
rarely, wheezing). Chest radiographs and quickly change.
Admission criteria include respiratory

distress, apnoea, tachypnoea, oxygen
requirement, poor feeding, dehydration,
continuous clinical assessment of airway
clearance requirement, underlying chronic
disease, and inappropriate social and family
conditions.
The major discharge criteria are oxygen

saturation that stably remains .9094% in
room air in the absence of respiratory
distress, and adequate daily oral intake
(.75% of usual intake) at a level to prevent
dehydration followed by adequate parental
care and family education about the
potential duration of acute symptoms.
Figure 1. Chest radiograph of an infant with severe Indications for intensive care unit
acute bronchiolitis showing diffuse air trapping consultation and admission include failure
and peribronchial thickening. to maintain SpO2 .92% with oxygen

therapy, deteriorating respiratory status with in preventing mechanical ventilation could
exhaustion, and recurrent apnoea. not be evaluated.
Supportive therapy Pharmacological therapy
General management includes therapies Current clinical evidence shows that
intended to reduce the work of breathing bronchodilators produce small short-term
(keep upper airways clear by using improvements in clinical scores. A trial with
vasoconstrictors and nasal suction), and to salbutamol is justified in infants with severe
restore clinical stability (oxygenation and respiratory distress. Inhaled salbutamol
hydration). Heart rate, respiratory rate and should be continued only if clinical
SpO2 should be monitored for at least the first examination documents a significant clinical
24 h. A small minority of patients with severe response (e.g. decreased respiratory rate or
bronchiolitis need airway support either via an improvement in SpO2).
CPAP or mechanical ventilation (fig. 2).
Nebulised racemic adrenalin provides better
In infants with mild bronchiolitis, breast short-term improvement in the clinical score
feeding should be supported and small than placebo, particularly in the first 24 h.
volume and frequent feeding should be Clinical trials have shown adrenaline to be
encouraged. Nasogastric feeding should be superior to placebo and salbutamol. Inhaled
considered in infants with severe adrenalin should be continued only if clinical
bronchiolitis and intravenous hydration examination documents a significant clinical
should be given only if nasogastric feeding response.
is not possible or in infants with severe
dehydration. Intravenous fluid should be A recent Cochrane Review of seven trials
administered carefully to avoid fluid showed that nebulised 3% hypertonic saline
overload (SIADH). alone or together with a bronchodilator
effectively reduces the length of
According to the American Academy of hospitalisation among infants with
Pediatrics oxygen should be administered nonsevere acute viral bronchiolitis, and
only when saturation at room air is ,90% in improves clinical severity scores in
the absence of respiratory distress, while the outpatient and inpatient populations.
Scottish Intercollegiate Guideline Network Hypertonic saline, through osmosis, causes
guidelines recommend the use of oxygen water to move from the interstitium into the
until oxygen saturation remains permanently airway thereby decreasing interstitial
.95%. Oxygen is usually administered via oedema and mucosal viscosity.
nasal cannula or a head box. Recent
evidence shows that oxygen can be given Current evidence provides no support for a
efficaciously with heated humidified high- clinically beneficial effect of systemic or
flow nasal cannula; its presumed role is inhaled glucocorticoids.
reduction of the work of breathing,
prevention of dynamic airways collapse and No evidence justifies using antibiotics in
improvement of gas exchange. bronchiolitis because it is a viral disease and
affected infants rarely undergo bacterial
Indications for CPAP include severe superinfection. Antibiotic treatment should
respiratory distress, a need for an inspiratory be recommended only in infants with severe
oxygen fraction (FIO2) .0.5 or the presence bronchiolitis requiring intubation, a group in
of apnoea. It is hypothesised that the whom bacterial superinfection is more
addition of heliox to CPAP, transforming common.
turbulent gas flow into laminar gas flow,
could improve the washout of carbon Nebulised DNase and montelukast are not
dioxide as well as oxygenation in the newly indicated in the treatment of bronchiolitis.
recruited airways with a consequent In infants with a history of prematurity with
decrease of the work of breathing. episodes of apnoea, caffeine appears to be a
Unfortunately, the potential benefit of CPAP rational choice of treatment.

History, physical and risk-
factor assessment
YES Toxic or in severe

Admission to PICU
respiratory distress?
NO
Nasal suction
Assess respiratory status
Start oxygen if SpO2 consistently 9094%
Manage without Single administration trial with 3%

medications Improvement of
hypertonic saline + adrenaline or
clinical status?
salbutamol (consider
YES
bronchodilators if family history of
Consider repeat allergy, asthma or atopy)
inhalation
treatment(s) Admit
NO Respiratory care
Nasal suction prior to
feeding as needed
Period of observation Monitor
Heart rate,respiratory
NO rate and SpO2 during
the first 24 h
Stable and/or Meets admit Frequent clinical
improving? NO criteria? assessment of
YES
respiratory status
NO YES Spot checks for SpO2
If on oxygen, consider
YES weaning when SpO2
Meets discharge Discharge with parent education consistently higher than
criteria? PCP follow-up 9095%
YES
Meets discharge
criteria?
NO
Continue observation
Figure 2. An algorithm for the management of bronchiolitis in the emergency department. PICU:
paediatric intensive care unit; PCP: primary care physician.

Prevention and prophylaxis N Chowdhury MM, et al. (2013). Heliox
terapy in bronchiolitis: phase III multi-
Preventative measures include adequate center double-blind randomized con-
healthcare professional education about trolled trial. Pediatrics; 131: 66669.
epidemiology and control of viral infection, N Donlan M, et al. (2011). Use of contin-
such as washing the hands before and after uous positive airway pressure (CPAP) in
caring for patients with viral respiratory acute viral bronchiolitis: a systematic
symptoms and single rooms for infected review. Pediatr Pulmunol; 46: 736746.
patients. Equally important, adequate local N Fernandes RM, et al. (2010).
policies should restrict hospital visiting by Glucocorticoids for acute viral bronchio-
those with symptoms of respiratory infections. litis in infants and young children.
Cochrane Database Syst Rev; 10:
Palivizumab is a humanised monoclonal RSV CD004878.
antibody licensed for preventing the N Gadomski AM, et al. (2010).
development of severe diseases arising from Bronchodilators for bronchiolitis.
an RSV infection. Palivizumab prevents Cochrane Database Syst Rev; 12:
hospital admission for RSV infections, but CD001266.
does not decrease length of stay or oxygen N Hartling L, et al. (2011). Epinephrine for
requirements for those who are hospitalised. bronchiolitis. Cochrane Database Syst Rev;
Palivizumab is a useful therapeutic option in 6: CD003123.
infants ,12 months who have severe N Kennedy N, et al. (2005). Is nasogastric
comorbidity (extreme prematurity, congenital fluid therapy a safe alternative to the
or acquired lung diseases, congenital heart intravenous route in infants with bronch-
disease and immune deficiency). iolitis? Arch Dis Child; 90: 320321.
N Martino`n-Torres F (2012). Non invasive
Prognosis and follow-up ventilation with helium-oxygen in chil-
dren. J Crit Care; 27: e1e9.
Mild respiratory symptoms may last for
N McKiernan C, et al. (2010).
,3 weeks after bronchiolitis. About 50% of
High flow nasal cannulae therapy in
children with bronchiolitis may have infants with bronchiolitis. J Pediatr; 156:
episodes of wheezing in later years. The 634638.
most important risk factors for recurrent N Midulla F, et al. (2010). Respiratory
and persistent wheezing after bronchiolitis syncytial virus, human bocavirus and
are rhinovirus infection and a positive family rhinovirus bronchiolitis in infants. Arch
history for atopy. Dis Child; 95: 3541.
N Plint AC, et al. (2009). Epinephrine and
dexamethasone in children with bronch-
Further reading
iolitis. N Engl J Med; 360: 20792089.
N Andabaka T, et al. (2013). Monoclonal N Scottish Intercollegiate Guideline
antibody for reducing the risk of respira- Network (SIGN). Bronchiolitis in chil-
tory syncytial virus infection in children. dren. A national clinical guideline.
Cochrane Database Syst Rev; 4: CD006602. Guideline no. 91. Edinburgh, SIGN, 2006.
N Blom DJ, et al. (2007). Inhaled corticoster- N Spurling GK, et al. (2011). Antibiotics for
oids during acute bronchiolitis in the bronchiolitis in children. Cochrane
prevention of post-bronchiolitis wheezing. Database Syst Rev; 6: CD005189.
Cochrane Database Syst Rev; 1: CD004881. N American Academy of Pediatrics
N Bronchiolitis Guideline Team, Cincinnati Subcommittee on Diagnosis and
Childrens Hospital Medical Center. Management of Bronchiolitis. (2006).
Evidence-based care guidelines for manage- Diagnosis and management of bronchio-
ment of bronchiolitis in infants 1 year of age litis. Pediatrics; 118: 17741793.
or less with a first time episode. Bronchiolitis N Zhang L, et al. (2008). Nebulized hyper-
Pediatric Evidence-Based Care Guidelines, tonic saline solution for acute bronchio-
Cincinnati Childrens Hospital Medical litis in infants. Cochrane Database Syst
Center. Guideline 1, 2010, pages 116. Rev; 4: CD006458.

Preschool wheezing
Paul L.P. Brand, Annemie M. Boehmer, Anja A.P.H. Vaessen-Verberne
Wheezing and dyspnoea in preschool have at least one episode of wheeze before
children are among the most common their third birthday. There is much clinical
presenting symptoms in paediatric practice. heterogeneity in phenotypes of children with
Approximately one in three children will preschool wheeze, which appears to be
similar between populations. Due to this
heterogeneity, and despite its common
occurrence, relatively little evidence is
Key points available on the pathophysiology and
treatment of wheezing in preschool children.
N Despite the favourable natural history Therefore, considerable controversy exists in
in the majority of children with the literature about the classification and the
wheeze during preschool years, treatment of preschool wheezing disorders.
symptoms in this age range can be To end this controversy, the underlying
severe or frequent, justifying pathophysiology and aetiology of preschool
maintenance treatment. wheezing disorders need to be properly
N Limited information is available on understood.
the pathophysiology of recurrent
Epidemiology
wheeze in preschool children, which is
likely to be complex and Much of the knowledge on recurrent wheeze
multifactorial. As a result, one- and dyspnoea in preschool children comes
dimensional classification systems from a series of well-designed, large-scale
(e.g. episodic viral versus multiple- birth cohort studies. The most well-known of
trigger wheeze) are of limited value in these was conducted in Tucson, AZ, USA.
diagnosis and management. The main results of this landmark study, the
N ICS are recommended as first choice Tucson Childrens Respiratory Study, are as
maintenance therapy in children with follows:
frequent or severe symptoms
irrespective of phenotype.
N 826 infants were followed from birth;
Montelukast is an alternative
N during the first 3 years of life 30% of
children had had at least one episode of
maintenance treatment option,
wheeze and half of these children had
although it is less effective than ICS.
wheezed more than once;
N If symptoms persist despite N 60% of wheezy preschool children ceased
maintenance treatment ongoing to wheeze before the age of 6 years
exposure to relevant inhalant (transient wheeze associated with
allergens and tobacco smoke, poor maternal smoking and with wheeze
adherence or inhalation technique, occurring only during viral colds);
alternative diagnoses and relevant N 40% continued to wheeze after their sixth
comorbidity should be excluded birthday (persistent wheeze associated
before stepping up therapy. with eczema, maternal asthma and
elevated cord blood IgE).

In contrast with asthma in school-aged episodes, with numerous triggering factors
children, which is more likely to persist including viral colds, mist, exercise, etc.
throughout childhood, many wheezy (table 1). Based on the evidence available at
preschool children outgrow their symptoms that time, this distinction was considered to
by school age. This prompted efforts to be both clinically plausible (most experts in
identify factors that could predict the ERS Task Force felt they could
persistence of preschool wheeze into school distinguish these phenotypes reliably based
age, and to classify preschool wheezing on the patients history) and meaningful,
disorders into different phenotypes with because the few published studies appeared
different treatment response or outcome. to support the view that inhaled
corticosteroids (ICS) were the treatment of
Predicting the outcome of preschool choice for MTW, and that EVW might
wheeze respond more favourably to maintenance
Despite differences between studies, atopy treatment with montelukast. The ERS Task
during early childhood has consistently been Force acknowledged that these
identified as the most important risk factor recommendations were likely to change with
for wheeze persisting beyond the sixth new evidence becoming available.
birthday, in a doseeffect relationship: the Limitations of the EVWMTW phenotype
more allergens the child is sensitised to, and distinction
the stronger the degree of sensitisation, the
greater the likelihood the childs wheeze is Although the ERS Task Force classification
going to be persistent. Although asthma risk system has been widely adopted, it has been
indices constructed of different risk factors criticised as being too simple to capture the
are significantly associated with persistent multidimensional nature of preschool
wheeze in groups of children in birth cohort wheezing, and it has been suggested that
studies, they have not been validated EVW and MTW do not represent different
prospectively, and the predictive value of phenotypes, but rather different degrees of
these indices is too poor to allow severity of the same disease. In addition, the
meaningful prediction of outcome of classification system is hampered by the fact
preschool wheeze in individual cases. that viral colds are the main cause of
exacerbations, both in EVW and in MTW.
Classification of preschool wheeze
Evidence from a range of recent studies
The finding in the Tucson study that wheeze suggests that the ERS classification system
occurring only during viral colds was should be reconsidered.
associated with transient wheeze suggested
that exclusive viral-induced wheeze in early First, prospective studies have shown that
childhood might be an innocuous disease, these phenotypes are not stable over time;
which is likely to disappear when children get when repeatedly taking a history from
older. However, this hypothesis is not parents about their preschool childs wheeze
supported by follow-up studies, which showed symptoms, the symptom pattern changes
that the majority of children with episodic viral over time from EVW to MTW and vice versa.
wheeze (EVW) seen in secondary care Secondly, the distinction between EVW and
continue to wheeze beyond the age of 6 years. MTW does not take the severity and
frequency of episodes of wheeze into
In 2008, a European Respiratory Society account, while in clinical practice these
(ERS) Task Force report proposed to factors are more important in determining
distinguish two wheezing phenotypes in the initiation and choice of maintenance
preschool children. 1) EVW: wheezing in therapy than the temporal pattern of
discrete episodes associated with viral symptoms. Thirdly, although statistically
upper respiratory tract infections (URTIs) significant differences in physiology and
and no symptoms between episodes; and 2) pathology between the two phenotypes have
multiple-trigger wheeze (MTW): wheeze been demonstrated, the two phenotypes
both in discrete episodes and between also show considerable clinical overlap.

Table 1. Different classification systems for preschool wheeze
Atopic versus non-atopic wheeze
Atopic wheeze (or allergic asthma): three or more episodes of wheeze and dyspnoea AND
demonstrated sensitisation to inhalant or food allergens
Non-atopic (or viral) wheeze: three or more episodes of wheeze and dyspnoea, only occurring
during URTIs, AND no evidence of allergic sensitisation to inhalant or food allergens
EVW versus MTW
EVW: wheezing during discrete time-periods, often in association with clinical evidence of a
viral cold, with absence of wheeze between episodes
MTW: wheezing that shows discrete episodes, but also symptoms between episodes
Mild and infrequent wheeze versus severe or frequent wheeze
Mild and infrequent wheeze: wheeze with little impact on daily life of affected children, and
with a low frequency of episodes (less than one episode per month)
Severe or frequent wheeze: wheeze with considerable impact on daily life of affected children
(requiring hospital admission or emergency room visit), or with a high frequency of episodes
(two or more per month)
Data from Brand et al. (2008), Pedersen et al. (2011), and Schultz et al. (2011).
With respect to inhaled steroid treatment, a conditions. The initial diagnostic approach
systematic review showed that ICS are to a preschool child with wheeze is aimed at
effective in reducing preschool wheeze, excluding serious underlying conditions,
irrespective of the reported symptom pattern which usually present in the form of
(EVW or MTW). A recent large trial in the USA atypical wheeze (table 2). A detailed
showed that daily nebulised low-dose history and thorough physical examination
budesonide was no more effective in reducing when the child is symptomatic are usually
the number and severity of wheezing sufficient to exclude atypical wheeze. If
episodes in preschool children than history and physical examination suggest
intermittent use only during symptomatic the possibility of atypical wheeze, specific
episodes. While episodic nebulised further diagnostic testing is indicated.
budesonide was no more effective than
episodic use of montelukast in preschool The majority of preschool children
children with viral-induced wheeze, daily use presenting with troublesome wheeze and
of nebulised budesonide was more effective dyspnoea will have typical wheeze, after
than daily montelukast in children aged 2 exclusion of the unlikely causes listed in
8 years with mild persistent wheezing. table 1. Because parents differ from
physicians in their understanding of the
Different ways to classify preschool wheeze term wheeze, confirmation of the
Based on the available evidence, several presence of wheeze by a physician is
classification systems of preschool wheeze recommended before initiating therapy. In
have been proposed (table 1). None of these children with confirmed typical wheeze, the
systems is universally accepted, which is not only potentially useful diagnostic test is a
surprising given the limited evidence on test of allergic sensitisation (either skin-
which they are based. There is no consensus prick test or measurement of specific IgE to
on the preferred terminology. a panel of allergens in blood) for
classification purposes (table 1).
Diagnostic approach to preschool children
with recurrent wheeze and dyspnoea Treatment of acute episodes
Wheeze is a nonspecific symptom, which The initial treatment of choice in episodes of

may be caused by a range of clinical acute wheeze is an inhaled bronchodilator

Table 2. Atypical wheeze: warning signs and possible underlying conditions
Warning sign Possible underlying causes
Persistent symptoms from birth Tracheobronchomalacia and PCD
Productive wet cough as a main symptom PCD, CF, immune deficiency and TB
Never completely symptom free Tracheobronchomalacia, vascular ring, foreign
body aspiration and neonatal chronic lung
disease
Failure to thrive CF and immune deficiency
Recurrent pneumonia CF and immune deficiency
PCD: primary ciliary dyskinesia.
such as salbutamol, preferably by metered- their child. If sensitisation to aeroallergens

dose inhaler-spacer combination because has been demonstrated, reducing the
this is more effective than treatment exposure to these allergens is likely to be
delivered by a nebuliser. Oral corticosteroids effective, although evidence in this area is
are less effective in preschool children with lacking.
an episode of acute wheeze than in older
children with asthma, and are only Because wheezing in preschool children
recommended in children who require largely occurs in discrete episodes with
hospitalisation and supplemental oxygen for sometimes relatively long symptom-free
a severe exacerbation, or those with atopic intervals, parents should understand that
wheeze. Pre-emptive high-dose ICS for viral the effect of maintenance therapy can only
induced wheeze, at the start of a viral upper be judged after the child had one or more
airway infection and continued until this is subsequent URTIs. This may require
resolved, although effective, is not prolonged continuation of medication,
recommended because of its effect on which parents will be more likely to provide
growth. when they trust, and can collaborate
constructively with, their childs physician.
Maintenance treatment
The choice of whether or not to initiate
Principles of maintenance treatment are maintenance therapy in preschool children
outlined in table 3, and these are in line with with wheeze depends primarily on the
asthma guidelines in older children and severity and frequency of episodes. After a
adolescents. Based on the realisation that systematic review of all available studies
parental cooperation is necessary to ensure using the GRADE (Grading of
optimal effects of therapy, the first, and Recommendations Assessment,
perhaps most important, step of Development and Evaluation) methodology,
maintenance therapy is to achieve and the Dutch Paediatric Respiratory Society, in
maintain a therapeutic alliance with patients collaboration with the Dutch Cochrane
and parents. Tailored self-management Centre, recommended ICS as maintenance
education is needed to ensure that parents treatment in preschool children with
understand how and why treatment works. A troublesome wheeze, irrespective of
recommendation to reduce exposure to wheezing phenotype. Although inhaled
tobacco smoke can only be achieved if this steroids do not alter the long-term outcome
is discussed with parents in a constructive or persistence of wheeze, they are effective
and non-judgmental fashion. Tailored self- in controlling symptoms, which is why their
management education is most effective use in preschool children with troublesome
when it is delivered repeatedly, addresses wheezing symptoms is justified. There is no
parental concerns and cognitions, and preference for any specific inhaled steroid
incorporates parents treatment goals for preparation. The assumed superiority of

Table 3. Principles of maintenance treatment of preschool children with recurrent wheeze
Therapeutic alliance with parents and patient
Non-pharmacological therapy
Self-management education
Maximal reduction of passive smoke exposure
When sensitised to aeroallergens reduce aeroallergen exposure
Repeated scheduled follow-up
Pharmacological therapy
Inhaled salbutamol on demand
Train and maintain correct inhalation technique
If repeated troublesome symptoms and parents motivated for maintenance therapy then start
low-dose ICS or montelukast
If low-dose ICS do not control symptoms
Check inhalation technique and adherence to treatment
Exclude relevant comorbidity or alternative diagnosis
Add additional controller (inhaled steroid, montelukast or long-acting b-agonist)
inhaled steroid preparations with ultrafine be controlled effectively by inhaled steroids

particles is theoretical, with no evidence or montelukast alone, or by a combination
from randomised trials to support their use. of controller medications.
Although data on side-effects of long-term
use are lacking, inhaled steroids in this age Because of preschool wheezings favourable
group appear to be safe. natural history, maintenance treatment
should be tapered off when the child is
Montelukast is a reasonable alternative as a completely symptom free for 36 months,
controller therapy, although it is less or for 12 months in children who have had a
effective than ICS in children with recurrent serious exacerbation requiring long-term
wheeze. hospitalisation or admission to intensive
care.
If symptoms fail to improve sufficiently
during inhaled steroid or montelukast Conclusion
maintenance treatment, physicians should
exclude reasons for failure of such therapy Recurrent wheeze in preschool children is
before starting additional medication. common. Due to the limited amount of
Treatment failure can often be explained by evidence on its complex and multifactorial
insufficient adherence to medication, poor pathophysiology, different classification
inhalation technique, an alternative systems with associated treatment
diagnosis such as bronchomalacia, or recommendations have been proposed,
relevant comorbidity such as allergic none of which can be recommended for
rhinitis. If these are properly addressed and universal use at present. After excluding
treated, and symptoms remain problematic, cases with atypical features, most patients
addition of other controllers (montelukast, with severe recurrent wheeze in this age
ICS or long-acting b-agonists) can be range can be managed effectively by ICS or
considered. There is no evidence from montelukast, either alone or in a
randomised trials to prefer any add-on combination regimen. Mild intermittent
treatment schedule over another. Most wheeze can be treated with an inhaled
cases of troublesome preschool wheeze can bronchodilator only.

Further reading N Panickar J, et al. (2009). Oral predniso-
lone for preschool children with acute
N Bacharier LB, et al. (2008). Episodic use
virus-induced wheezing. N Engl J Med;
of an inhaled corticosteroid or leukotriene 360: 329338.
receptor antagonist in preschool children N Pedersen SE, et al. (2011). Global strategy
with moderate-to-severe intermittent for the diagnosis and management of
wheezing. J Allergy Clin Immunol; 122: asthma in children 5 years and younger.
11271135. Pediatr Pulmonol; 46: 117.
N Boluyt N, et al. (2012). Assessment of N Savenije OE, et al. (2011). Comparison of
controversial pediatric asthma manage- childhood wheezing phenotypes in 2 birth
ment options using GRADE. Pediatrics; cohorts: ALSPAC and PIAMA. J Allergy
130: e658e668. Clin Immunol; 127: 15051512.
N Brand PL, et al. (2008). Definition, N Savenije OE, et al. (2012). Predicting who
assessment and treatment of wheezing will have asthma at school age among
disorders in preschool children: an preschool children. J Allergy Clin Immunol;
evidence-based approach. Eur Respir J; 130: 325331.
32: 10961110. N Schultz A, et al. (2010). The transient
N Castro-Rodriguez JA, et al. (2009). value of classifying preschool wheeze into
Efficacy of inhaled corticosteroids in episodic viral wheeze and multiple trigger
infants and preschoolers with recurrent wheeze. Acta Paediatr; 99: 5660.
wheezing and asthma: a systematic N Schultz A, et al. (2011). Episodic viral
review with meta-analysis. Pediatrics; 123: wheeze and multiple trigger wheeze in
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Bronchial asthma
Marielle Pijnenburg and Karin C. Ldrup Carlsen
Asthma is the leading chronic disease in

children in the Western world, affecting 5 Key points
20% of school-age children in Europe.
Asthma prevalence has increased during the N There is no universally accepted
last two decades, although this trend seems definition of asthma, although
to being levelling off, at least in high-income reversible airway obstruction, airway
countries. Childhood asthma is a serious hyperresponsiveness and chronic
public health problem for several reasons. inflammation are key features.
First, asthma causes considerable morbidity N There is accumulating evidence that
and healthcare utilisation. High frequencies the interaction between respiratory
of sleep disturbances due to asthma (up to viral infections and atopy is important
34%), absence from school (2351%) and in the cause and pathogenesis of
limitation of activities (47%) have been atopic asthma.
reported in several studies. Asthma is the
third-ranking course of hospitalisation in N Airway remodelling is a common
children and the major cause of school feature in adult severe asthma but this
absenteeism due to chronic disease among is less clear in childhood, particularly
as to when it starts and what elicits
children in the USA (www.afaa.org). In
the process.
Europe, unscheduled emergency visits to
healthcare accounted for 47% of total asthma N The ultimate goal of asthma
costs in infants and 45% in children; 7% of all treatment is to achieve and maintain
children reported at least one hospitalisation. clinical control with a minimum of
Secondly, as asthma is associated with side-effects and to reduce future risks
reduced growth of lung function and lung to the patient.
function at a young age is a determinant of
lung function in adult life, optimal treatment
N There is no uniform definition of
severe childhood asthma and several
is of major concern for long-term prognosis. criteria are used such as the need for
The main characteristics of asthma are or use of high-dose corticosteroids,
reversible airway obstruction and airway severe and/or frequent exacerbations,
hyperresponsiveness; chronic inflammation chronic asthma symptoms, or
of the airways plays a central role in the reduced lung function.
pathogenesis of asthma and anti- N Severe childhood asthma should be
inflammatory treatment with inhaled referred to and managed in
corticosteroids (ICS) is the treatment of specialised paediatric units.
choice. A stepwise approach to asthma
management has been suggested by all
international guidelines, and the ultimate The underlying mechanisms of asthma are
goal of asthma treatment is to achieve and poorly understood. However, there is
maintain clinical control with the least accumulating evidence that the interaction
possible unwanted effects. between respiratory viral infections,

against a background of atopy, is The main features, therefore, for diagnosing
important in the cause and pathogenesis asthma are:
of atopic asthma.
N history taking,
Diagnosis N objective documentation of reversible
Diagnosing asthma may be challenging, bronchial obstruction,
particularly in infants and pre-school N allergy and bronchial
children, and no universally accepted hyperresponsiveness (BHR) testing,
definition of asthma exists that embraces N assessing airway inflammation whenever
children from infancy to post-puberty. possible.
Difficulty in studying asthma arises from the
fact that asthma is not a single disease but a The medical history should focus on
compilation of diseases presenting as a symptoms of bronchial obstruction or
syndrome or a collection of symptoms. cough, triggers of these symptoms, and
Particularly in childhood, reversible should include all items in figure 1, with
bronchial obstruction may be a final attention to the age-specific questions.
common feature of a number of different Furthermore, triggers of symptoms are
diseases with distinct aetiologies, and distinct from inciters of asthma
different environmental and genetic development, mechanisms of the latter
associations. However, most cases of being less clear. Common triggers of
asthma start in childhood and early-life symptoms are viral infections, exercise,
asthma, particularly in boys, is a significant allergen exposure and irritants such as
risk factor for later COPD, and the severity tobacco smoke.
and number of obstructive episodes in early
childhood appear to be reasonable Pathophysiology
predictors for later on-going childhood
Asthma is a chronic inflammatory airway
asthma.
disease characterised by reversible airway
Several phenotypes of asthma have been obstruction and BHR. However, there is no
described and are being identified, current consensus on the underlying
commonly based upon the time of pathophysiology of asthma throughout
presentation of wheeze within the first childhood. This said, the underlying chronic
part of childhood. However, phenotypes inflammation is often characterised by
based on the presence or absence of allergic eosinophilic activity and allergic
sensitisation, eosinophilic or inflammation, but nonallergic asthma is not
noneosinophilic inflammation, or response uncommon in childhood.
to treatment are also recognised. The
asthma-like clinical presentations often Bronchial obstruction is a result of bronchial
referred to as wheezy disorders in children muscle constriction, acting particularly
are common prior to signs or through the b-receptors, as well as mucosal
documentation of allergic markers, although oedema and increased airway secretions
nonallergic childhood asthma is common in resulting from airway inflammation. All
many areas. contribute to reduced airway flow, which is
reflected in reduced lung function and
With this background, various definitions are classical symptoms such as wheezing,
used, and common to them all are reversible dyspnoea and coughing. Reversibility of the
airway obstruction and chronic airway
bronchial obstruction may occur
inflammation. Thus, a descriptive and
spontaneously or with bronchodilators
pragmatic approach is necessary in the clinic,
(particularly b2-agonists), whereas anti-
as the diagnosis will elicit targeted treatment.
inflammatory medications, such as
Classical symptoms of asthma are wheeze, corticosteroids, are necessary to reduce the
cough (particularly at night or during underlying pathophysiological causes of
exertion), dyspnoea and chest tightness. bronchoconstriction (see later).

In all children, ask about:
Wheezing, cough
Specific triggers, e.g. passive smoker, pets, humidity, mould and dampness, respiratory
infections, cold air exposure, exercise/activity, cough after laughing/crying
Altered sleep patterns: awakening, night cough, sleep apnoea
Exacerbations in the past year
Nasal symptoms: running, itching, sneezing, blocking
Additionally
In infants (<2 years) In children (>2 years)

Noisy breathing, vomiting associated Shortness of breath (day or night)
with cough Fatigue (decrease in playing compared to peer
Retractions (sucking in of the chest) group, increased irritability)
Difficulty with feeding (grunting Complaints about "not feeling well"
sounds, poor sucking) Poor school performance or school absence
Changes in respiratory rate Reduced frequency or intensity of physical
activity, e.g. in sports, PE classes
Avoidance of other activities, e.g. sleepovers,
visits to friends with pets
Specific triggers: sports, classes, exercise/activity
Figure 1. Specific symptoms that should be asked in assessing asthma diagnosis. PE: physical education.
Informaton from Bacharier et al. (2008).
Airway inflammation The underlying airway cells (APCs) that facilitate presentation to
inflammation in asthma is generally the T-cells. IgE is synthesised in the
considered to be eosinophilic. However, the presence of interleukins (ILs) (e.g. IL-4 and
strength of the association between atopic IL-13) and other cytokines. The allergic
sensitisation and asthma varies, and most inflammation is characterised by a T-helper
sensitised subjects do not have asthma. cell (Th) type 2 cascade involving Th2
Allergen exposure may, in some, lead to a cytokines and other immune mediators. It is
break in natural tolerance, triggering allergic currently believed that directing nave T-cells
inflammation, and an allergen-specific to Th1 versus Th2 immunity involves
immune response involving T- and B- regulatory T-cells (Tregs), a process which is
lymphocytes. The innate immune system is, important in tolerance development and
in effect, the barrier between the organism suppression of allergic inflammation.
and external environment, being the
important first line of defence against In addition, dendritic cells in the airway
infections and intruders. The adaptive epithelium facilitate uptake of allergens
immune system, however, classically bound to FceRI. Such mechanisms are
involves (T-)cellular responses to antigens probably propagated through defects in
(or allergens), typically with production of barrier function that have recently been
specific IgE antibodies from B-cells, and shown in the airway epithelium of asthmatic
adapts to environmental challenges. subjects.
The allergic response is initiated when an Viral infections are important triggers of
allergen binds to the high-affinity receptor symptoms and exacerbations of asthma in
for IgE (FceRI) on the antigen-presenting childhood, whereas many children with

viral wheeze may later not have asthma. entirely clear. There is no doubt that asthma
Recent studies suggest that respiratory is associated with reduced lung function as
viruses, possibly (subtypes of) human well as a more rapid decline in lung function
rhinovirus in particular, may play a role in compared to healthy individuals. In a few
triggering the immune system. The birth cohorts, reduced lung function has
mechanisms are currently not known, been found to precede asthma in some, but
although several hypotheses exist, including not all children with asthma.
an immune circle in asthma development in
which repeated airborne irritant stimuli Airway remodelling, being a common
(such as allergens or viruses) evoke cycles of feature in adult asthma, is less clear in
inflammation, giving intermittent childhood, particularly as to when it starts
inflammation resulting in episodic and what elicits the process. Nevertheless,
symptoms at first. However, with repeated lung function reductions in older children
insults, the inflammatory resolution are likely to reflect structural changes in the
becomes less complete, leading to tissue airways such as subepithelial reticular
repair and regeneration that may set off basement layer thickening, epithelial cell
prolonged periods of pathological changes. disruption, imbalance of proteases and
These periods may progress to deterioration antiproteases, and neoangiogenesis
in respiratory function and, perhaps, to (remodelling).
remodelling. Management
A potential causal association between Several guidelines address asthma
allergic sensitisation and viral infection is treatment in adults and children.
currently the focus of research, and is has
been suggested that allergic sensitisation This section discusses management of
precedes rhinovirus-induced wheezing. asthma in children aged o5 years. For
Another aspect of the damaged epithelium children under the age of 5 years, please see
in asthma is the reduced ability to handle the section on Pre-school wheezing in this
viruses in an optimal way. It appears that Handbook. Details on aerosols, delivery of
reduced ability of airway epithelial cells to drugs to the lung, inhaler devices and
produce interferon-c may lead to cytotoxic instructions on optimal inhaler technique
cell death and subsequent dissemination of can be found in the Aerosol therapy section
viruses, rather than apoptosis, possibly in this Handbook.
explaining the prolonged symptomatic viral
infection observed in asthmatics. Nonpharmacological management Most
nonpharmacological interventions in
BHR is a common, but not obligate, feature asthma have limited effect and often lack
of childhood asthma. It typically presents as sufficient evidence, except for avoidance of
a general liability to develop symptoms by active or passive smoking. Exposure to
exposure to various physiological or environmental tobacco smoke (ETS) is
environmental stimuli, exercise being a associated with decreased lung function
classical childhood asthma symptom from birth, increases the risk of asthma
trigger. The underlying mechanisms for BHR development, increases the frequency and
development are not clear but may involve severity of asthma symptoms, decreases
barrier dysfunction as well as possibly neural asthma related quality of life and is
parasympathetic mechanisms involving heat associated with persistent asthma in adults.
and fluid exchange over the epithelium. BHR Smoking cessation by parents/caregivers or
is a modest, but significant, risk factor for children themselves should be vigorously
later asthma and tends to decrease through encouraged and supported.
childhood.
In obese patients, weight reduction may
The role of lung function reductions in the increase general health and improve asthma
development of asthma in contrast to lung control, although this has not been proven
function decline with chronic asthma is not for children. It has been suggested that

rapid weight gain during early life is treatment, there is an absolute need to
associated with increased risk of developing check adherence to treatment, inhaler
asthma. technique and ongoing exposure to
triggers (table 2). In a patient unresponsive
Single measures are unlikely to reduce to treatment, one should confirm that the
exposure to house dust mite (HDM) symptoms are due to asthma and consider
allergens and have not been effective in comorbidity like untreated allergic rhinitis,
reducing asthma symptoms. An integrated obesity or gastro-oesophageal reflux
approach aimed at reduction of HDM disease. Step down should be considered
allergens may have some clinical benefit in if patients are well controlled for
selected children but has not been 36 months, and the lowest step and dose
recommended for all HDM-allergic of treatment that maintains control should
asthmatic children. be sought.
In general, in pet-allergic children, removal
At each step, short-acting b2-agonists
of these animals from the home is advised
(SABA) should be provided for quick relief of
to gain adequate asthma control, although
symptoms (step 1).
this has been questioned.
There are no dietary interventions that have If children have symptoms and/or need
been proven beneficial in asthma, although rescue SABA more than twice a week, wake
regular intake of fruits and vegetables have up at least one night a week or have had any
been associated with reduced risk of asthma exacerbation during the last year,
developing asthma. maintenance treatment with ICS should be
started (step 2). ICS at a lowmoderate dose
Aim of asthma treatment The ultimate goal are the recommended controller treatment
of asthma treatment is to achieve and for patients of all ages in step 2. The starting
maintain clinical control and to reduce dose of ICS may depend on severity of disease
future risks to the patient. The level of and will usually be 200400 mg?day-1 for chlo-
clinical control is defined as the extent to rofluorocarbon (CFC)-containing beclome-
which asthma manifestations, like daytime thasone dipropionate (BDP) and budesonide
symptoms, night waking, the use of reliever preparations, and 200250 mg?day-1
medication and the ability to carry out daily for fluticasone, mometasone and ultra-fine
activities including exercise, have been CFC-free beclomethasone preparations. The
reduced by treatment. The future risk to the advised starting dose of ciclesonide in
patient includes loss of control, children 12 years and older is 160 mg?day-1.
exacerbations, accelerated decline in lung One should be aware that although ICS are
function and side-effects of treatment. highly effective in reducing asthma symptoms,
Ideally, treating patients with asthma should improving lung function and reducing airway
take into account both aspects. The Global hyperresponsiveness, these effects do not
Initiative for Asthma (GINA) guidelines persist when discontinuing treatment.
suggest discerning three asthma control
levels (controlled, partly controlled and Alternative controller medications are
uncontrolled), which guide step-up or step- leukotriene modifiers, which may be
down asthma treatment (table 1). Although appropriate for patients who are unable or
this is a working schema and has not been unwilling to inhale ICS.
validated, it enables physicians to assess
asthma control systematically and adjust If children are uncontrolled at lowmoderate
treatment accordingly. doses of ICS, there are three treatment
options: add inhaled long-acting b2-agonists
A stepwise treatment approach for asthma (LABA), increase the dose of ICS or add a
has been proposed by all international leukotriene receptor antagonist (LTRA).
guidelines (fig. 2). In patients with Presently, there is no evidence for
uncontrolled asthma, step-up treatment superiority of one of the strategies over the
should be considered. Before stepping up other. While the interindividual response

Table 1. Levels of asthma control
Assessment of current clinical control (preferably over 4 weeks)
Characteristic Controlled (all of the Partly controlled (any Uncontrolled
following) measure present in any
week)
Daytime symptoms None (twice or less More than twice per Three or more
per week) week features of partly
Limitation of activities None Any controlled asthma
present in any week+,1
Nocturnal symptoms/ None Any
awakening
Need for reliever/ None (twice or less More than twice per
rescue treatment per week) week
Lung function (PEF or Normal ,80% predicted or
FEV1)#," personal best (if
known)
Assessment of future risk (risk of exacerbations, instability, rapid decline in lung function, side-
effects)
Features that are associated with increased risk of adverse effects in the future include: poor
clinical control, frequent exacerbations in the past year+, admission to critical care for asthma,
low FEV1, exposure to cigarette smoke, high-dose medications
#
: not reliable for children aged f5 years; ": without administration of a bronchodilator; +: any exacerbation should
prompt a review of maintenance treatment to ensure it is adequate; 1: by definition, an exacerbation in any week
makes that an uncontrolled week. Reproduced and modified from GINA (2012) with permission from the publisher.
may vary significantly, no predictors of children, the convenience of their use,

response to one of the three options has individual patient preferences and costs may
been identified, highlighting the need to guide treatment choices in individual
regularly monitor and appropriately adjust patients.
each childs asthma therapy.
Although healthcare varies between and
The British Thoracic Society (BTS) and within countries, it should be emphasised
GINA guidelines favour the addition of that children who are not controlled on
inhaled LABA in step 3 treatment. LABA step 3 treatments should be referred to a
should always be an add-on treatment to ICS paediatrician specialised in asthma care.
therapy and should never be used as single Assessment of a possible wrong diagnosis,
agents. If effective, LABA should be lack of treatment adherence or persistent
continued, and if ineffective, LABA should exposure to untoward environmental factors
be stopped and the dose of ICS should be should be considered. In step 4, ICS dose
increased. If this treatment is (partly) should be optimised to 800 mg?day-1 BPD or
ineffective, LTRA could be added. It is equivalent together with LABA and/or LTRA.
important to note that individual variations Low-dose, sustained-release theophylline
in the susceptibility to side-effects of may provide some benefit in addition to
steroids may render some children, even mediumhigh dose ICS and LABA, although
those on low doses, at risk of adrenal axis generally the clinical effects have been small.
suppression.
Step 5 treatment should be confined to
National guidelines may differ from the BTS paediatric specialists in asthma
and GINA guidelines and should be management. Regular systemic
consulted on a local level. In addition, corticosteroids might be considered in step
considerations of the safety of LABA in 5, although side-effects severely limit their

Patients should start treatment at the step most appropriate to the
initial severity of their asthma. Check concordance and reconsider
diagnosis if response to treatment is unexpectedly poor
Use daily steroid

Increase inhaled
1. Add inhaled LABA tablet in lowest dose
steroid up to
2. Assess control of proviving adequate
800 gday-1#
asthma: control
Add inhaled steroid
200400 gday-1# good response to
Inhaled SABA LABA - contiue LABA Maintain high dose
(other preventer drug
as required benefit from LABA inhaled steroid at
if inhaled steroid
but control still 800 gday-1#
cannot be used)
200 g is an inadequate - continue
appropriate starting LABA and increase
inhaled steroid dose Refer to respiratory
dose for many paediatritican
patients to 400 gday-1# (if
not already on this
Start at dose of dose)
inhaled steroid no response to LABA
appropriate to - stop LABA and
severity of disease increase inhaled
steroid to 400
gday-1# if control
still inadequate,
institute trial of other
Step 5
therapies, leukotriene
receptor antagonist Continuous or frequent
Step 4
or SR theophylline use of oral steroids
Persistent poor
Step 2 control
Initial add-on
Step 2 therapy
Regular preventer
Step 1
therapy
Mild intermittent
asthma
versus
Symptoms Treatment
Figure 2. Stepwise management of asthma treatment in children aged 512 years. #: BDP or equivalent.
Reproduced and modified from BTS et al. (2012) with permission from the publisher.
use. Monoclonal antibody therapy is an Other options that might be considered in

option in children from the age of 6 years step 5 are intramuscular triamcinolone and
with elevated total IgE between 76 experimental therapies like macrolide
3000 IU?mL-1. Omalizumab reduces asthma antibiotics, cyclosporine, methotrexate and
exacerbations and ICS dose, and improves subcutaneous terbutaline, and other, rare
asthma-related quality of life; however, its treatment options.
long-term safety and efficacy are not clear.
Treatment of asthma exacerbations For
treatment of asthma exacerbations,
Table 2. Factors to be assessed in poorly controlled consultation of (inter)national guidelines is
asthma, before step-up treatment highly recommended as local policies may
differ between countries and settings, and
Adherence to treatment guidelines are not uniform on all points.
Inhaler technique Most mildmoderate exacerbations might
Exposure to triggers (tobacco smoke, be treated in a community setting, whereas
allergens) moderatesevere exacerbations should be
treated in acute care settings.
Allergic rhinitis
Is it asthma? The severity of the asthma exacerbation is
Comorbidity assessed by a brief history and physical
examination. Important signs and

symptoms are the ability to talk in Severe or life-threatening exacerbations
sentences, pulse rate, respiratory rate, should be treated with nebulised salbutamol
breath sounds, use of accessory muscles, 5 mg or terbutaline 10 mg at intervals of 10
retractions, oxygen saturation, degree of 20 min. Some countries use subcutaneous
agitation, conscious level and (if possible) injections of adrenaline.
peak expiratory flow (PEF) or FEV1 (table 3).
Systemic steroids should be given in all but
With moderate or severe exacerbations, the mildest exacerbations. After starting
treatment should be initiated immediately. inhalation therapy, oral prednisolone is
equally effective as parenteral prednisolone;
Children with an asthma exacerbation who do however, in children with altered
not respond adequately to b2-agonists and/or consciousness or who vomit, intravenous
are in need of supplemental oxygen and/or corticosteroids are preferred. In children, the
have severe asthma should be admitted to advised dose is 12 mg?kg-1 prednisolone for
hospital. A follow-up visit within a short time 35 days up to a maximum of 4060 mg.
after discharge by a general practitioner or
asthma specialist should be arranged. Intravenous magnesium sulphate in a dose
of 40 mg?kg-1 (maximum 2 g) administered
There is no absolute limit at which oxygen over 15 min may be considered in children
therapy should be instituted. However, unresponsive to 1 h of adequate treatment.
oxygen via a facemask or nasal cannulae
should be administered if oxygen saturation If the response to intensive nebulised
is ,94%, although the BTS guidelines treatment and prednisolone is poor,
accept a lower limit of 92%. children should be referred to a paediatric
intensive care unit (PICU). Intravenous
In children with mildmoderate
salbutamol or terbutaline may be considered
exacerbations, b2-agonists delivered via a
even before transport to the PICU under
pressurised metered-dose inhaler (pMDI)
close monitoring of heart rate, arterial blood
spacer combination are usually sufficiently
gases and serum potassium. The starting
effective. Two to four puffs of b2-agonists
dose is 0.1 mg?kg-1?min-1 continuously.
should be administered one at a time and
inhaled via tidal breathing, and repeated at Monitoring
1020-min intervals for the first hour as
needed. However, nebulised b2-agonists Asthma is a chronic disorder with a variable
should be considered in moderatesevere course, which makes regular follow-up of
exacerbations if there is insufficient effect asthmatic children necessary. Traditionally,
from pMDIspacer administration. Addition subjective parameters like symptoms, and
of an inhaled anticholinergic, like more objective measures such as
ipratropium bromide 0.5 mg, may be spirometry, PEF and BHR, are used to
beneficial. assess asthma control and disease activity.
Table 3. Assessment of severity of asthma exacerbation in children aged .5 years

Moderate exacerbation Severe exacerbation Life threatening exacerbation
Able to talk Too breathless to talk Agitation
SpO2 o92% SpO2 ,92% drowsiness, confusion
Heart rate f120 beats?min-1 Heart rate .120 beats?min-1 risk factors for near fatal
Respiratory rate Respiratory rate asthma
f30 breaths?min-1 .30 breaths?min-1 Silent chest
PEF o50% best or predicted PEF ,50% best or predicted PEF ,30%
Use of accessory muscles PCO2 .45 mmHg
Chest retractions PO2 ,60 mmHg
PCO2: carbon dioxide tension; PO2: oxygen tension.

In daily practice, parents, children and their assessing lung function and bronchodilator
physicians usually estimate asthma control response at least yearly.
and make therapeutic decisions on
subjective symptom assessments. Validated Contrary to adults, in children, adjusting the
dose of ICS to symptoms and BHR did not
questionnaires may be of help in the
result in more symptom-free days compared
standardised assessment of asthma control
to titrating treatment to symptoms only.
in the clinic and for research purposes.
However, in a subgroup of children with few
There are several questionnaires available,
symptoms but hyperreactive airways,
such as the Asthma Control Questionnaire
monitoring BHR resulted in improved lung
(ACQ), the Asthma Control Test (ACT) and
function.
the Childhood Asthma Control Test (C-ACT),
the Asthma Therapy Assessment Recently, much attention has been paid to
Questionnaire (ATAQ) and the three-item markers of inflammation, like the exhaled
Royal College of Physicians (RCP3) nitric oxide fraction (FeNO) and eosinophils
questionnaire. The C-ACT has been in induced sputum, as objective tests to
developed for detecting uncontrolled monitor asthmatic patients. However,
asthma in children aged 411 years; the ACT titrating ICS based on FeNO levels or on
and ACQ have been validated for children sputum eosinophils has not been shown to
aged o12 years. The seven-item version of be effective in improving asthma outcomes
the ACQ has five questions on symptoms in children. Whether FeNO may be of help in
and additionally includes FEV1 and use of diagnosis, phenotype-specific treatment,
rescue b2-agonists. Standardised decisions on starting and stopping ICS, or
questionnaires seem attractive in measuring monitoring adherence remains to be shown.
asthma control as they are cheap, easy to
use and interpret, and give a quick At every visit, use of rescue b2-agonists,
impression on asthma control. They provide exacerbations, asthma symptoms and
a reproducible, objective measure that may limitations in physical activity, oral
corticosteroid use, school absenteeism,
be repeated over time and may improve
inhaler technique, and adherence to
communication between the patient/parent
treatment should be checked.
and physician. However, no data are
available on the potential of such Before stepping up treatment, one should
questionnaires to improve asthma outcome consider low adherence, poor inhaler
in children. technique, adequate avoidance of risk
factors, allergic rhinitis, (passive) smoking,
The GINA guidelines suggest the use of other aggravating factors and comorbidities.
symptoms and lung function to assess
asthma control, and make a difference Self-management Although self-
between controlled, partly controlled and management education including written
poorly controlled asthma (table 1). action plans clearly leads to improved
Subsequently, the level of asthma control outcomes in asthmatic adults, this has not
guides medication adjustments. been shown for children. To date, there is a
lack of studies comparing the effect of
In patients older than 56 years, spirometry providing a written action plan versus no
or PEF should be measured during clinic written action plan in children and
visits to assess asthma control and detect adolescents. However, symptom-based
possible decline in lung function. FEV1 is action plans seem superior to peak flow-
preferred over PEF, as PEF may be based action plans for preventing acute care
completely normal while severe airway visits in children. There is some evidence
obstruction is present. The presence and that combined interventions aimed at self-
degree of airway obstruction has short- and management (e.g. information, self-
long-term prognostic value for asthmatic monitoring and action plan, or educational
children, and is an independent predictor of and environmental measures) may reduce
future risk. Guidelines recommend asthma exacerbations in children who

Table 4. Particular features that contribute to severity of asthma by age group
Infancy Underlying pathophysiology and clinical characteristics poorly understood
Viruses are the most common precipitating factors
Many conditions to be considered in the differential diagnosis
Difficulty in objective documentation of bronchial obstruction
Many with problems in the first year of life remit long term in the second year
Preschool age Viruses are the most common precipitating factors
Compliance with management largely depending upon carers
Some difficulty in objective documentation of bronchial obstruction or airway
inflammation
School age Allergy is frequent
Symptoms often precipitated by exercise
Compliance with management still depending upon carers
Evaluation of lung function easy
Indirect evaluation of airway inflammation relatively easy
Adolescence Clinical expression is variable
Tendency to deny symptoms
Risk-taking behaviour common
Low compliance
Psychological problems
Treatment may be difficult
Reproduced and modified from Hedlin et al. (2010).
visited the emergency room for asthma. The and irritants that worsen the disease,
optimum setting and content for such nonadherence to therapy, psychosocial
educational interventions and relative issues, or true severe asthma that is
effectiveness of the various components are resistant to therapy.
largely unknown.
Each age group has particular features that
In general, a written personal action plan is contribute to the severity of asthma, as
recommended for all children with asthma outlined in table 4.
and, in particular, for children with poorly
controlled asthma. Furthermore, parental In contrast to adults, children with severe
education in asthma is recommended to asthma may not yet have developed
improve assessment of the childs disease remodelling, although increases in smooth
as well as adherence to treatment. muscle and evidence of reticular membrane
layer are frequently found. Furthermore, the
Problematic, difficult or severe asthma inflammation in childhood severe asthma
may appear to be eosinophilic without the
Severe asthma is relatively rare, occurring in classical Th2 inflammation, in contrast to
approximately 45% of children with asthma the more commonly neutrophilic
and 0.5% of the general child population. inflammation in adults.
However, there is no uniform or generally
accepted definition of severe childhood Managing children with severe asthma
asthma, and several criteria are used, such requires a systematic approach to assess
as the need for or use of high-dose diagnosis, airway inflammation and
corticosteroids, severe and/or frequent therapeutic responses to corticosteroids.
exacerbations, chronic asthma symptoms, This should enable further differentiation of
or reduced lung function. Thus, severe or those children who have a true severe,
difficult asthma may be related to wrong therapy-resistant asthma, from those with
diagnosis, exposure to environmental the wrong diagnosis, those with asthma with
factors such as allergens, tobacco smoking significant comorbidities that need to be

addressed, and those with asthma that is N Ducharme FM, et al. (2011). Addition to
not responding to treatment because of inhaled corticosteroids of long-acting b2-
factors other than medication response. agonists versus anti-leukotrienes for
Only in those with severe therapy-resistant chronic asthma. Cochrane Database Syst
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Treating severe asthma is challenging and clinical applications. Am J Respir Crit Care
includes medication that is not well Med; 184: 602615.
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of symptoms on assessment in pedia-
particular expertise in diagnosis and
tric asthma. Pediatrics; 118: 619
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and Prevention. www.ginasthma.org
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treatment of asthma in childhood: a function at birth and the risk of asthma at
PRACTALL consensus report. Allergy; 63: 10 years of age. N Engl J Med; 355: 1682
534. 1689.
N Baena-Cagnani C, et al. (2007). Airway N Hedlin G, et al. (2010). Problematic
remodelling in children: when does it severe asthma in children, not one
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196200. Eur Respir J; 36: 196201.
N Bhogal S, et al. (2006). Written action N Holgate ST (2012). Innate and adaptive
plans for asthma in children. Cochrane immune responses in asthma. Nat Med;
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N Bossley CJ, et al. (2012). Pediatric severe N Holt PG, et al. (2012). Viral infections and
asthma is characterized by eosinophilia atopy in asthma pathogenesis: new ratio-
and remodeling without TH2 cyto- nales for asthma prevention and treat-
kines. J Allergy Clin Immunol; 129: ment. Nat Med; 18: 726735.
974982. N Ldrup Carlsen KC, et al. (2011).
N Boyd M, et al. (2009). Interventions for Assessment of problematic severe
educating children who are at risk of asthma in children. Eur Respir J; 37:
asthma-related emergency department 432440.
attendance. Cochrane Database Syst Rev; N National Asthma Elimination and
2: CD001290. Prevention Panel (2007). Expert Panel
N BTS/SIGN British Guideline on the Report 3 (EPR-3): guidelines for the
Management of Asthma. 2008. www.sign. diagnosis and management of asthma
ac.uk/guidelines/fulltext/101/index.html summary report 2007. J Allergy Clin
N Burke H, et al. (2012). Prenatal and passive Immunol; 120: S94S138.
smoke exposure and incidence of asthma N Papadopoulos NG, et al. (2012).
and wheeze: systematic review and meta- International consensus on (ICON)
analysis. Pediatrics; 129: 735744. pediatric asthma. Allergy; 67: 976997.
N Castro-Rodriguez JA (2011). The Asthma N Petsky HL, et al. (2012). A systematic
Predictive Index: early diagnosis of review and meta-analysis: tailoring
asthma. Curr Opin Allergy Clin Immunol; asthma treatment on eosinophilic mar-
11: 157161. kers (exhaled nitric oxide or sputum
N Custovic A, et al. (1994). Exercise testing eosinophils). Thorax; 67: 199208.
revisited. The response to exercise in N Saglani S, et al. (2007). The early-life
normal and atopic children. Chest; 105: origins of asthma. Curr Opin Allergy Clin
11271132. Immunol; 7: 8390.

N Saglani S, et al. (2008). Asthma, atopy, N Strunk RC, et al. (2009). Long-term
and airway inflammation: what does it budesonide or nedocromil treatment, once
mean in practice? Am J Respir Crit Care discontinued, does not alter the course of
Med; 178: 437438. mild to moderate asthma in children and
N Savenije OE, et al. (2011). Comparison adolescents. J Pediatr; 154: 682687.
of childhood wheezing phenotypes in N Szefler SJ, et al. (2002). Significant
2 birth cohorts: ALSPAC and PIAMA. variability in response to inhaled corti-
J Allergy Clin Immunol; 127: 1505 costeroids for persistent asthma. J Allergy
1512. Clin Immunol; 109: 410418.

Emerging therapeutic
strategies
Asthma is the most common chronic patients presents ongoing chronic

childhood disease and the major cause of symptoms or severe exacerbations despite
hospitalisation for children. It is a chronic high-dose medication may benefit from new
disease with repeated attacks of airways treatment strategies.
obstruction and intermittent symptoms of
responsiveness to triggering factors, such as Pharmacotherapy
allergens, smoke, exercise or viral infection. Guidelines on paediatric management of
In the majority of asthmatic patients, asthma aim for control of symptoms,
symptoms can be controlled with a stepwise reduction of exacerbations, hospitalisation
approach according to guidelines and emergency department visits, and
(Papadopoulos et al., 2012; Global Initiative improvement of quality of life.
for Asthma, 2011) with inhaled steroids,
Currently, after an initial classification of
long-acting b2-agonists (LABAs) and and
severity into the categories of mild,
leukotriene receptor antagonists.
moderate and severe at the time of
However, the prevalence of severe and diagnosis, most guidelines propose that the
therapy-resistant asthma in a general level of treatment be considered on the
paediatric population is 0.5% (4.5% of basis of the evaluation of symptoms
children with asthma). This group of according to their presentation as
intermittent or persistent, controlled or
uncontrolled. Therapy is based on an
Key points increasing or decreasing stepwise approach
according to the level of disease control.
N New treatments based on
Inhalation therapy, which facilitates
interventions in the
immunopathogenesis of asthma are administration of drugs directly into the
currently under development and airways, is currently the preferred route for
evaluation, especially in subjects most patients. The delivery of the drug
whose symptoms are not controlled directly to the site of disease results in a
by current therapy. powerful therapeutic effect and minimises
the occurrence of systemic side-effects.
N Omalizumab is a monoclonal human
antibody which can antagonise the Inhaled corticosteroids (ICS) are the most
role of IgE in the pathogenesis of effective controller medications currently
allergic asthma. available. Their regular use reduces the
severity of symptoms, decreases
N IL-5 plays an important role in exacerbations and hospital admission,
eosinophil activation and airway improves lung function and reduces
hyperresponsiveness and is involved hyperesponsiveness.
in the induction of Th2 responses in
the asthmatic airway. Critical issues regarding asthma treatment
in children are the necessity of delivering

drugs at the site of the inflamed distal control, reduce exacerbations during
airway, the potential side-effects of long- corticosteroid therapy and allow a reduction
term treatment with ICS and the difficulty of of ICS dose. In 2009, the licence for the use
controlling symptoms. The ongoing need to of omaluzimab was extended to include
solve these issues warrants research into children aged 612 years as an add-on
new therapeutic strategies. treatment for poorly controlled asthma in
patients with severe persistent allergic
New strategies for asthma treatment disease.
Various new treatments based on
Though the treatment needs to be
interventions in the immunopathogenesis of
administered in a controlled clinical setting
the disease are currently under development
with a period of observation after injection,
and evaluation to improve asthma control.
this therapy has become increasingly
T-helper type 2 (Th2) inflammation, popular in the past few years. It can be
mediated by interleukin (IL)-4, IL-5, IL-9 and considered as an option in children with IgE-
IL-13, plays a central role in the pathway of mediated sensitisation to one or more
allergic asthma. Two different phenotypes of allergen, with chronic symptoms, recurrent
asthma patients based on high or low Th2- severe asthma exacerbations and resistance
cytokine gene expression have been to high doses of ICS and LABAs.
identified. Th2 high asthma patients
Omaluzimab has been shown to be safe and
present with elevated IL-5 and IL-13
beneficial in children through 1-year trial, but
expression in bronchial biopsies, serum IgE
long-term safety and efficacy have not yet
and blood and airway eosinophilia. These
been demonstrated.
patients are those for whom the best
response to ICS is expected, whereas Children and adolescents with severe
subjects with Th2 low asthma phenotype persistent asthma with positive skin prick
represent a subgroup with clinical test for allergen and with reduction of FEV1
manifestations that are poorly controlled by (,80% predicted) who are treated with ICS
current therapies since the disease is mostly have been shown to benefit from improved
related to nonallergic, steroid-unresponsive, quality of live with when treated with
mechanisms. omalizumab.
A number of alternative potential therapies Analysis of a subgroup of subjects from a
have been proposed to prevent T-cell study evaluating the effect of omalizumab as
activation, to modulate Th1/Th2 add-on treatment in inadequately controlled
differentiation, to inhibit Th2-related severe asthmatics suggests that patients
cytokines and to inhibit downstream with IgE levels below 76 IU?mL-1 are less
mediators. In paediatric patients the likely to benefit.
inhibition of downstream mediators using
anti-IgE has been shown to be an interesting Although free IgE is extensively and rapidly
emerging approach of practical application. suppressed after commencing treatment
with omalizumab, it may take up to
Omalizumab Omalizumab is a monoclonal 3 months before clinical symptoms
human antibody that can antagonize the equilibrate at a new level.
role of IgE in the pathogenesis of allergic
asthma. A number of studies, mainly in Although omalizumab brings clinical
adults, have demonstrated that omalizumab benefits, treatment costs are high, and while
can reduce serum levels of free IgE, some authors have concluded that
expression of IgE receptors on basophils omalizumab produces sufficient
and antigen stimulated histamine release. improvement in clinical outcomes in
Studies performed with this new therapeutic difficult-to-treat, persistent allergic asthma
strategy show that the treatment can reduce to justify the cost, other studies have
both early and late response as well as suggested that the clinical benefits may not
bronchial reactivity, improve asthma offset the high cost of treatment. The UK

National Institute for Health and Clinical IgE levels, eosinophil counts and lower
Excellence has recommended that mean FEV1, the strength of this evidence
omalizumab should not be routinely used needs to be further investigated. Clinical
for the treatment of severe persistent trials with vitamin D supplementation in
allergic asthma in children aged 611 years. children with asthma are warranted.
TNFa blockers Some studies in adults have Macrolides Macrolides are commonly used
suggested that tumour necrosis factor as antimicrobial agents but they have been
(TNF)a may be a marker of severity in also demonstrated to have
asthma and a target for biological therapy. immunomodulatory and anti-inflammatory
TNFa is a cytokine produced by different cell properties in the airway. Clinical trials have
types which plays a role in the innate shown benefits of macrolides in the
immune response. It has been suggested treatment of a spectrum of chronic
that TNFa can contribute to the inflammatory respiratory diseases.
inflammatory response in asthmatic airways.
The mechanism of action remains partially
Studies evaluating the efficacy of the use of unexplained but it may be possibly due to
anti-TNFa therapy in asthma refractory to their antibacterial and/or anti-inflammatory
ICS have been published, and a significant actions, which include reductions in IL-8
improvement in methacholine airway production and neutrophil migration and/or
hyperresponsiveness, as well as function.
improvements in FEV1 and in quality of life
in patients with severe asthma treated with Clarithromycin and azithromycin have been
etanercept (a TNFa receptor IgG Fc fusion shown to exert an effect in reducing airway
protein) have been reported. However, these inflammation, with decreased airway
studies have been carried out in adult oedema and TNFa, IL-1, and IL-10
patients; no evidence in children is currently concentrations. Furthermore, azithromycin
available. Therefore, further investigations has been demonstrated to reduce IL-5
are needed in order to evaluate the benefits production in children with atopic asthma,
and the risks of this treatment in the and to have a beneficial effect on the
paediatric population. pathogenesis of asthma.
Vitamin D Recent research has shown that Nevertheless, positive effects of macrolides
vitamin D has an important role in the have not yet been fully demonstrated in
modulation of the immune system clinical trials in asthma and recent studies
response, especially through the inhibition have presented conflicting conclusions on
of Th1 response and T-cell proliferation. the use of macrolides in routine clinical
practice in patients with uncontrolled
An epidemiological study suggested that asthma. Further studies investigating the
low concentration of vitamin D in children effects of macrolides in asthma
with asthma is associated with more severe management are, therefore, required.
symptoms, frequent exacerbations,
reduction in lung function and an increase Theophylline Theophylline may act through
in medication use. Vitamin D has been different molecular mechanisms to inhibit
postulated to play an important role in the phosphodiesterase and adenosine receptor
modulation of inflammatory response and antagonism at therapeutic concentrations.
maintenance of airway homeostasis as well Some studies show that low doses of oral
as to have a role in the improvement of the theophylline increase histone deacetylase-2
anti-inflammatory action of glucocorticoids (HDAC2) expression in alveolar
in patients with refractory asthma. macrophages in patients with COPD and it
also downregulates inflammatory gene
Though some observational studies show expression via effects on histone acetylases
lower plasma levels of vitamin D in (HATs) and histone deacetylases (HDACs).
asthmatic patients as well as inverse In asthma, HAT levels are increased while
associations between vitamin D and total HDACs are reduced; this is inverted by

glucocorticoids as well as by theophylline, These studies, performed in adult patients,
with a reduction in IL-8, TNF-a and demonstrate the utility of anti-IL5 but the
granulocyte-macrophage colony-stimulating general applicability of the studies is still
factor (GM-CSF) in response to under debate because of the the strict
lipopolysaccharide. Moreover, theophylline selection criteria used and the low numbers
may prevent downregulation of the b- of participating patients. However, these
receptors by b2-agonists. studies explore a very attractive rationale for
the modulation of eosinophils activity in
Through these mechanisms, theophylline asthma and demonstrate that anti-IL-5
has been demonstrated to re-establish antibodies represent a promising avenue for
steroid responsiveness, thus representing a asthma therapy.
potential new approach in steroid-resistant
patients. At present, no study on IL-5 in children has
been published.
Anti-IL antibodies Eosinophils are major
actors in airway inflammation and Conclusion
remodelling mechanisms in asthma. They
Different guidelines and consensus
release a wide range of mediators which can
documents are currently available for
promote airway inflammation, induce
asthma treatment. They all agree regarding
epithelial damage and cause airway
the main objective of the treatment
hyperresponsiveness.
intervention, which is to achieve and
The complex networks of cytokines and cells maintain control of the disease, including
involved in the pathology of asthma provide reduction of exacerbations, need for
scope for intervention with monoclonal emergency visits and hospitalisation.
antibodies that block cytokine or The stepwise therapeutic model, with step-
chemokinereceptor interactions, to deplete up of treatment in case of poor control is
cells expressing a specific receptor or to not always adequate to achieve control of
block cellcell interactions. symptoms and exacerbations in patients
Though, at present, anti-IgE is the only with severe asthma.
monoclonal antibody approved for asthma New strategies to improve asthma control
treatment in children, other antibodies have have been proposed in recent years and are
been clinically tested in asthma, including currently under development and
anti-IL-5, anti-IL-4, anti-IL-13, anti-TNFa, evaluation.
anti-CCR3, anti-CCR4 and anti-OX40L.
New drugs are involved in the modulation of
In particular, IL-5 plays an important role in Th1/Th2 differentiation, inhibition of Th2-
eosinophil activation and airway related cytokines and inhibition of the
hyperresponsiveness and it is involved in the downstream mediators.
induction of Th2 responses in the asthmatic
airway. IL-5 also plays a role in the migration While omalizumab is currently approved for
of eosinophils from the bone marrow to the the treatment of severe persistent allergic
blood circulation and subsequently to the asthma unresponsive to traditional theapy
sites of inflammation and it is also active in in children aged 611 years, other drugs are
promoting the survival of eosinophils at the under evaluation to improve the control of
site of airway inflammation by preventing the disease in clinical practice.
apoptosis.
Further reading
The compelling evidence linking IL-5 to
asthma pathology led to the development of N Bacharier LB, et al. (2008). Diagnosis and
therapies targeting IL-5 and a few studies treatment of asthma in childhood: a
have been performed in patients with severe PRACTALL consensus report. Allergy; 63:
asthma and sputum eosinophilia and 534.
hypereosinophilic syndromes.

N Barnes PJ (2006). Theophylline for N European Medicines Agency. Summary of
COPD. Thorax; 61: 742743. the European public assessment report
N Barnes PJ (2012). Severe asthma: (EPAR) for Xolair. 2009. www.ema.europa.
advances in current management and eu/ema/index.jsp?curl5pages/medicines/
future therapy. J Allergy Clin Immunol; human/medicines/000606/human_med_
129: 4859. 001162.jsp&mid5WC0b01ac058001d124
N Brehm JM, et al. (2010). Serum vitamin D &jsenabled5true.
levels and severe asthma exacerbations in N Fonseca-Aten M, et al. (2006). Effect of
the Childhood Asthma Management clarithromycin on cytokines and chemo-
Program study. J Allergy Clin Immunol; kines in children with an acute exacerba-
126: 5258. tion of recurrent wheezing: a double-blind,
N Brightling C, et al. (2008). Targeting randomized, placebo-controlled trial. Ann
TNFa: a novel therapeutic approach for Allergy Asthma Immunol; 97: 457463.
asthma. J Allergy Clin Immunol; 121: N Freishtat RJ, et al. (2010). High preva-
510. lence of vitamin D deficiency among
N Brusselle GG, et al. (2013). Azithromycin inner-city African American youth with
for prevention of exacerbations in severe asthma in Washington, DC. J Pediatr; 156:
asthma (AZISAST): a multicentre rando- 948952.
mised double-blind placebo-controlled N Gjurow D, et al. (2009). Tumor necrosis
trial. Thorax; 68: 322329. factor inhibitors in pediatric asthma.
N Burch J, et al. (2012). Omalizumab for the Recent Pat Inflamm Allergy Drug Discov;
treatment of severe persistent allergic 3: 143148.
asthma in children aged 6-11 years: a N Global Initiative for Asthma (GINA).
NICE single technology appraisal. Global Strategy for Asthma Management
Pharmacoeconomics; 30: 9911004. and Prevention 2011. www.ginasthma.org.
N Bush A, et al. (2011). Pharmacological N Good JT Jr, et al. (2012). Macrolides in the
treatment of severe, therapy-resistant treatment of asthma. Curr Opin Pulm
asthma in children: what can we learn Med; 18: 7684.
from where? Eur Respir J; 38: 947958. N Gupta A, et al. (2012). Vitamin D and
N Cameron EJ, et al. (2012). Long-term asthma in children. Paediatr Respir Rev;
macrolide treatment of chronic inflam- 13: 236243.
matory airway diseases: risks, benefits N Hedlin G, et al. (2010). Problematic
and future developments. Clin Exp Allergy; severe asthma in children, not one
42: 13021312. problem but many: a GA2LEN initiative.
N Carr TF, et al. (2012). Asthma: principles Eur Respir J; 36: 196201.
and treatment. Allergy and Asthma Proc; N Howarth PH, et al. (2005). Tumour necro-
33: S39S43. sis factor (TNFa) as a novel therapeutic
N Catley MC, et al. (2011). Monoclonal target in symptomatic corticosteroid
antibodies for the treatment of asthma. dependent asthma. Thorax; 60: 10121018.
Pharmacol Ther; 132: 333351. N Humbert M, et al. (2005). Benefits of
N Chang TW (2000). The pharmacological omalizumab as add-on therapy in patients
basis of anti-IgE therapy. Nat Biotechnol; with severe persistent asthma who are
18: 157162. inadequately controlled despite best avail-
N Corren J (2011). Anti-interleukin-5 anti- able therapy (GINA 2002 step 4 treat-
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Opin Allergy Clin Immunol; 11: 565570. N Lanier B, et al. (2009). Omalizumab for
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and steroid responses in COPD macro- mediated) asthma. J Allergy Clin Immunol;
phages. J Exp Med; 200: 689695. 124: 12101216.
N Dal Negro RW, et al. (2011). Cost-utility of N Lin SJ, et al. (2011). Azithromycin inhibits
addon omalizumab in difficult-to-treat IL-5 production of T helper type 2 cells
allergic asthma in Italy. Eur Ann Allergy from asthmatic children. Int Arch Allergy
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N Lowe J, et al. (2009). Relationship N Shi HZ, et al. (1998). Effect of inhaled
between omalizumab pharmacokinetics, interleukin-5 on airway hyperreactivity and
IgE pharmacodynamics and symptoms in eosinophilia in asthmatics. Am J Respir
patients with severe persistent allergic Crit Care Med; 157: 204209.
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Differential diagnosis
of bronchial asthma
Epidemiology of objective lung function measurements and

biomarkers. Differential diagnosis may also
Although asthma is considered the most be challenging in older children, due to
common condition presenting with conditions which may mimic asthma, such as
wheezing, not all children who wheeze are dysfunctional breathing.
affected by asthma. Wheezing can be an
isolated symptom or it may be accompanied Childhood asthma and wheezing are not
by cough, chest tightness, shortness of synonymous, these terms characterise a
breath and dyspnoea in different clinical number of conditions that may have different
conditions. Recurrent wheezing is common outcomes. Some children present with
in young children and population studies transient wheezing and have a reduction in
have shown that one third of children have pulmonary function at birth but do not go on
had at least one episode of wheezing before to develop asthma, whereas other children
the age of 3 years and 50% of children have have persistent wheezing and have an
had at least one episode by the age of increased risk of developing asthma.
6 years. Recurrent wheezing is, therefore, a
Definition of wheezing
common condition in paediatric practice and
the differential diagnosis represents a Wheezing is noisy breathing that can be
challenging clinical procedure for classically defined as a musical, high-
paediatricians. The main issue is to correctly pitched, airway-derived noise detectable
distinguish between the different phenotypes during exhalation. Wheeze results from
of wheezing in pre-schoolers, for whom the narrowing of the intrathoracic airways,
diagnosis is further complicated by the lack which produces expiratory flow turbulence.
Therefore, a number of different conditions,
including airways narrowing, airways
Key points abnormalities, cystic fibrosis and
bronchomalacia, may cause a child to
N Although asthma is considered the wheeze. Although this definition is well
most common condition presenting known to medical personnel, parents and
with wheezing, not all the children patients, it is often improperly used to
who wheeze are affected by asthma. describe respiratory symptoms that are not
Recurrent wheezing is a common really wheezes. It is important to clearly
condition in paediatric practice and define the features of the sound in order to
the differential diagnosis represents a confirm or reject wheezing as the
challenge for paediatricians. appropriate descriptor of the symptom
N The diagnosis of asthma is more under consideration. Stridor, which is an
difficult in preschoolers. inspiratory noise associated with
extrathoracic or upper airway obstruction, is
N The symptoms of asthma can be often confused with wheezing; however, its
associated with other diseases. presence prompts consideration of an
alternative differential diagnosis.

Clinical conditions presenting with to adequate inhaled corticosteroid
wheezing treatment, viral and bacterial infections are
frequent. The main pathogens involved are
Alternative conditions must be taken into Mycoplasma pneumoniae, Chlamydia
account before a diagnosis of asthma is pneumoniae, Moraxella catarrhalis and
defined permanently. Alternative causes of Streptococcus pneumoniae. The chronic
recurrent episodes of wheezing, especially in inflammatory response to infection may be
early childhood, are shown in table 1. The related to persistent wheezing despite
main differential diagnoses are respiratory therapy. Antimicrobial therapy should be
infections, congenital and structural considered in these patients. Chronic cough
problems, foreign bodies, and gastro- is also a frequent symptom in young
oesophageal reflux. In children with severe, children that could be confused with
recurrent wheezing that is nonresponsive to asthma. In sinusitis, purulent rhinorrhea,
inhaled corticosteroids, leukotriene receptor sneezing and post-nasal drip are related to
antagonists and/or bronchodilators, other chronic cough, but sinusitis is often
diagnoses should be considered. misdiagnosed especially if it persists for
Major causes of wheezing to consider longer than 4 weeks. Chronic sinusitis
during diagnosis requires a long course of antibiotics (10
15 days). Other respiratory infections
Respiratory infections In children with causing wheezing and cough in children that
persistent wheezing that does not respond could be confused with asthma are
Table 1. Differential diagnosis in bronchial asthma

Symptoms and history Medical findings
Respiratory infections Fever Wheezing
Cough with respiratory distress Rales
Relatives with the same symptoms Rhonchi
GORD Frequent regurgitation Failure to thrive
Post-prandial vomiting Loss of weight
Crying in supine position
Nocturnal symptoms
Foreign body aspiration Cough/suffocation with sudden Bronchial breathing
onset
Sudden cough
Vocal cord dysfunction (VCD) Shortness of breath, wheezing, Inspiratory flowvolume
stridor, or cough loop
Laryngomalacia Inspiratory stridor present from The volume loop is
birth characterised by a
tooth deflection in the
inspiratory phase
Cardiovascular causes of airway Recurrent respiratory difficulty, Wheezing
compression dyspnoea, dysphagia, wheezing
and stridor
Present from birth
Genetic disease Recurrent dyspnoea Wheezing and dyspnoea
Recurrent infections
Congenital malformations Respiratory symptoms at birth, but Malformations on
can remain asymptomatic for long radiological
periods investigation

pertussis, bronchiolitis and epiglottitis. or cough, which may be interpreted as
Cough and upper respiratory symptoms uncontrolled or worsening asthma, leading
could also be related to tuberculosis, which to unnecessary therapy or step up in
may manifest without the typical symptoms medication. The diagnosis could be
(night sweats, haemoptysis, weight loss and suspected when there is a truncation of the
fatigue). In this case it is necessary to inspiratory flowvolume loop. Direct
perform chest radiography, which may show visualisation during an attack permits
upper lobar infiltrates, cavitary infiltrates or definitive diagnosis. In these children the
adenopathy. exhaled nitric oxide fraction (FeNO) is
expected to be normal.
Gastro-oesophageal reflux disease (GORD)
Infant wheezing that is unresponsive to Cardiovascular causes of airway compression
bronchodilator therapy may be related to Compression of the airways is a relatively
GORD or silent aspiration. GORD has been common complication of congenital
shown to be associated with chronic upper vascular malformation in children. The main
airway respiratory symptoms, including symptoms are recurrent respiratory
reactive airways disease, recurrent stridor, difficulty, dyspnoea, dysphagia, wheezing
chronic cough and recurrent pneumonia in and stridor without other causes. The
infants who do not respond to common differential diagnosis may start from
anti-asthma medications (Bhatia et al. spirometric evaluation, but confirmation
2009).The gold standard for investigation of requires chest radiography, eventually with
this problem is 24-h pH monitoring. barium contrast, echocardiography, MRI, CT
and bronchoscopy.
Foreign body aspiration In children with
sudden cough and wheezing, the risk of Genetic diseases Genetic conditions such as
inhalation of a foreign body should be primary ciliary dyskinesia and CF may be
considered. In this case, it is important to relevant in the differential diagnosis in
analyse the history and look for temporal children presenting with recurrent dyspnoea.
relationships with onset of symptoms.
Though chest radiography could be helpful if Congenital abnormalities Congenital
the foreign body is radiopaque or if indirect malformations of the lower airways are rare
signs, such as peribronchial inflammation of anomalies and include a wide spectrum of
mediastinal dislocation, develop, the conditions with a broadly varying clinical
diagnostic and therapeutic gold standard is presentation. Individuals with congenital
bronchoscopy. lung malformations can present with
respiratory symptoms at birth or can remain
Airway abnormalities Laryngomalacia is the asymptomatic for long periods. Usually, the
most common congenital abnormality and diagnosis requires an imaging evaluation.
cause of stridor in children. The Depending on the pathophysiological
manifestations can vary from mild noisy mechanisms and structures involved, lung
breathing with feeding to life-threatening malformations can be divided into several
airway obstruction to failure to thrive. categories: bronchopulmonary anomalies;
Stridor is inspiratory for the collapse of combined lung and vascular abnormalities;
supraglottic airway structures. The volume and vascular anomalies.
loop is characterised by a tooth deflection
in the inspiratory phase. Vocal cord Pulmonary sequestration is characterised by
dysfunction is a disorder characterised by an normal, nonfunctioning lung tissue that has
upper episodic and involuntary airway no connection with the bronchial tree and
obstruction caused by adduction of the receives its blood supply from the systemic
vocal cords, primarily on inspiration, circulation. Pulmonary sequestrations can
inducing paroxysms of the glottis. This be classified as extralobar or intralobar
disease is often confused with refractory depending on their location in relation to the
asthma as symptoms are intermittent adjacent normal lung and on their visceral
shortness of breath, wheezing, stridor, pleural covering.

Congenital cystic adenomatoid malformations Further reading
are hamartomatous lesions, with focal
N Amimoto Y (2012). Lung sound analysis
dysplasia and anomalous development, and
in a patient with vocal cord dysfunction
are characterised by a cystic mass of lung bronchial asthma. J Asthma; 49: 227229.
tissue with proliferation of bronchial N Andrade CF, et al. (2011). Congenital lung
structures and lung tissue showing aberrant, malformations. J Bras Pneumol; 37: 259
differentiated architecture, with various 271.
degrees of cyst formation. The most N Bhatia J, et al. (2009). GERD or not
common symptoms are recurrent infections, GERD: the fussy infant. J Perinatol; 29:
and there have been reports of malignant Suppl. 2, S7S11.
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asthma-like symptoms in young children.
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infantile lobar hyperinflation, is a rare lung N Brand P, et al. (2008). Definition, assess-
malformation. Entrapment of air in the ment and treatment of wheezing disor-
affected lobe during the expiratory phase ders in preschool children: an evidence-
results in progressive distension and a based approach. Eur Respir J; 32: 1096
1110.
consequent effect on lung structures and
N Brown SC, et al. (2012). Treatment
adjacent mediastinal mass. All this leads to strategies for pulmonary sequestration
breathing problems due to alteration of in childhood: resection, embolization,
normal gaseous exchange. observation? Acta Cardiol; 67: 629634.
N Epelman M, et al. (2010). Current ima-
Various terms have been used to designate ging of prenatally diagnosed congenital
arteriovenous malformations, including lung lesions. Semin Ultrasound CT MR; 31:
arteriovenous fistula, pulmonary 141157.
arteriovenous aneurysm, pulmonary N Guilbert TW, et al. Approach to infants
haemangioma, pulmonary cavernous and children with asthma. In: Adkinson
angioma, and pulmonary telangiectasia. NF Jr, et al., eds. Middletons Allergy:
Principles and Practice. 7th Edn.
Another differential diagnosis that should be Philadelphia, Mosby, 2008; pp. 1319133.
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(BPD). It is an important cause of morbidity natural history, assessment, and treat-
and mortality in preterm infants. Its ment. Mt Sinai J Med.; 78: 645660.
incidence in infants with birth weight N Hsu CC, et al. (2012). Embolisation for
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the presence of oxygen dependence to Cochrane Database Syst Rev; 8: CD008017.
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36 weeks of post-conceptional age or at
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Conclusion postnatal management of congenital cys-
tic adenomatoid malformation. Paediatr
The symptoms of asthma, not always
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specific, can be associated with other N Kussman BD, et al. (2004).
diseases, and differential diagnosis should Cardiovascular causes of airway compres-
always be considered to confirm or exclude a sion. Paediatr Anaesth; 14: 6074.
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attention should be considered in preschool outcomes of the National Institute of Child
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phenotype of wheezing.

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through December 1996. Pediatrics; 107: E1. phageal reflux in pediatric patients with
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N Morton RL, et al. (2001). Evaluation of the N Tenenbaum T, et al. (2012). Clinical
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N Ramanuja S, et al. (2010). The approach on the carriage of specific pathogens in
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Immunol.; 105: 38. Allergy.; 5: 2732.

Pathophysiology and
epidemiology of allergic
disorders
Karin C. Ldrup Carlsen
Allergic disorders include asthma, allergic

rhinitis, allergic rhinoconjunctivits, atopic Key points
eczema, urticaria, food allergy and
anaphylaxis. Allergic diseases are chronic N Manifestations of allergic diseases
and often complex diseases with may appear at any age, but most
environmental, as well as genetic, commonly occur in childhood.
influences. With the recent asthma and N The so-called allergic march
allergy epidemic in the Western world, it portrays a succession from atopic
has been suggested that environmental eczema, through food allergy to
factors play a more important role in disease inhalant allergy, often accompanied
development than previously thought. In by asthma and subsequently allergic
addition, more than 100 different genes are rhinitis, all of which commonly occur
implicated in allergic diseases to some by school age.
extent; however, there is no clear specific
gene, suggesting a less prominent role of N Viral infections are important triggers
genes in the current epidemic of allergic of symptoms and exacerbations of
diseases. Whether this is related to more asthma in childhood; however,
abundant risk factors or the loss of allergic sensitisation appears to
potentially protective factors is not known. precede viral infection in children with
Current research is investigating whether viral wheeze and allergic sensitisation
environmental effects on genes causing who develop asthma.
epigenetic changes are involved in disease N The observed increase in allergic
modification. However, neither the factor(s) diseases is particularly worrying since
nor the timing of triggers that off-set the it not only affects the subjects with the
immune system from normal development diseases, but is likely to increase the
into an allergic inflammatory pathway are burden of allergic disease in the
known. offspring of the current younger
Pathophysiology generation.
Manifestations of allergic diseases may

appear at any age, but most commonly subsequent female predominance after
occur in childhood. The so-called allergic puberty. The causes of this change are not
march portrays a succession from atopic known, but hormonal changes with
eczema, through food allergy to inhalant increasing allergic manifestation in females
allergy, often accompanied by asthma and during puberty are considered a probable
subsequently allergic rhinitis, all of which cause of the changing sex predominance.
commonly occur by school age. Puberty is
the second life-phase with major changes in Allergic sensitisation, particularly to mites,
allergic disease, and is when the male cockroaches, pollen and pet allergens, are
predominance of allergic diseases seen in among the strongest risk factors for asthma.
childhood gradually changes into a However, allergic diseases may also occur in

individuals without detectable serum IgE or cytokines and other immune mediators
positive skin prick tests to allergens. leading to:
Children with atopic eczema, asthma or
asthma-like symptoms often lack detectable N survival of the Th2 cell;
serum IgE antibodies, suggesting that there N mast cell differentiation and maturation;
are alternative mechanisms for initiating the N B-cell isotype switching to IgE synthesis;
underlying inflammation. This is commonly N maturation and survival of eosinophils;
seen as differing phenotypes of allergic N recruitment of basophils.
diseases, with allergic sensitisation being a
pivotal phenotypic criterion. This view is It is not known what triggers T-cells and how
currently challenged, as allergy is probably the nave T-cells mature into Th2 immune-
not an all-or-nothing phenomenon, but active cells. However, it is believed that
rather a continuum of immunological directing nave T-cells to Th1 versus Th2
mechanisms underlying allergic disease immunity involves regulatory T-cells (Tregs),
presentations. However, some common a process that is important in tolerance
underlying pathophysiological mechanisms development and suppressing allergic
inflammation.
within and between allergic diseases are
probable in view of the frequent comorbidity The innate immune system is, in effect:
of allergic diseases, typically allergic rhinitis
and asthma, or atopic eczema preceding N the barrier between the organism and the
asthma and allergic rhinitis. external environment;
N an important defence against infections;
In general, most individuals do not respond N the first line of defence against intruders.
adversely to allergens. However, in some,
allergen exposure leads to a break in natural Innate immune cells (such as mast cells),
tolerance triggering allergic inflammation granulocytes, mononuclear phagocytes,
(fig. 1), and an allergen-specific immune lymphocytes and epithelial cells, express
response that is maintained by host T- and surface and internal receptors, including
B-cells. The allergic inflammation typically Toll-like receptors and those involved in
involves the production of specific serum recognising and removing microbial
IgE antibodies against allergens (allergic substances.
sensitisation). Allergic inflammation
However, the adaptive immune system
involves local, as well as systemic, immune classically involves T-cell responses to
cells and biomarkers of the innate and antigens (or allergens), typically with
adaptive immune system (fig. 1). The production of serum IgE-antibodies from B-
allergic response is initiated when an cells adapting to environmental challenges.
allergen binds to the high-affinity receptor In addition, dendritic cells (APCs in the
for IgE (FCeRI) on the antigen presenting airway and gut epithelium) (fig. 2) are not
cell (APC). The APC will then process the present at birth, but move from the bone
allergen into small peptides that will be marrow to the epithelium, possibly as a
presented via the major histocompatibility result of damage to the airway epithelium,
complex (MHC) class II molecules for like viral infections in asthmatic subjects. In
recognition by the T-cells. The immediate subjects with established allergic
allergic response involves isotype switching sensitisation, the dendritic cells, which
of a B-cell into IgE synthesis, a process that contain receptors that are able to attach to
requires the presence of several interleukins allergens, engulf the intruding allergen,
(IL; such as, IL-4 and IL-13) and cytokines, processing them to form peptides that can
resulting in a cascade of immunological be presented to the T-cell receptors as
events. In contrast to normal immune host complexes formed with the MHC. The
responses to microbial products involving T- dendritic cell uptake of allergens is
helper type 1 (Th1) lymphocytes, the allergic facilitated by allergens bound to FceRI
inflammatory cascade involves Th2 (fig. 1), which may be particularly abundant

lgE-specific
FcRl antibody
IL-9-specific
antibody
Mast cell
Eosinophil IL-9 lgE
IL-4-specific IL-4
antibody IL-13 IL-4- and
IL-13-specific
Allergen MHC IL-4 antibodies
class ll molecule IL-4 TH2 cell
TCR IL-5
IL-5-specific
antibody Eosinophil
TH0 cell
APC
IL-12 IFN-
rhIL-12 TH1 cell rhIFN-
Figure 1. Schematic diagram showing the interplay between local, as well as systemic, immune cells and
biomarkers of the innate and adaptive immune system in allergic inflammation. TCR: T-cell receptor;
rhIL: recombinant human IL; IFN: interferon; rhIFN: recombinant IFN. Reproduced from Holgate
(2008), with permission from the publisher.
as the cells move from the bone marrow to cycle in asthma development suggests that
the mucosal lining. repeated airborne irritant stimuli (such as
allergens or viruses) evoke cycles of
Such mechanisms are probably propagated inflammation leading to intermittent
through defects in barrier function, and have inflammation and initially resulting in
recently been demonstrated in the airway episodic symptoms. However, with repeated
epithelium of asthmatic subjects and the insults the inflammatory resolution becomes
skin of subjects with atopic eczema, as well less complete leading to tissue repair and
as in other allergic diseases. A link has been regeneration, which may trigger prolonged
reported through a common genetic variant
periods of pathological changes. These
of filaggrin.
periods may progress to deterioration in
Viral infections are important triggers of respiratory function and perhaps to
symptoms and exacerbations of asthma in remodelling. A commonly asked question,
childhood, whereas many children with viral the answer to which is not clear at present, is
wheeze will not go on to develop asthma. what is the role and potential interaction
Recent studies suggest that respiratory between allergic sensitisation and viral
viruses, possibly (sub-types of) human infections in eliciting disease development,
rhinovirus in particular, may play a role in in contrast to both viruses and allergens
triggering the immune system. The being potential triggers of disease
mechanisms are not known, but a series of exacerbations? However, it was recently
interactions between antiviral and atopic deduced that allergic sensitisation appears to
inflammatory pathways mediated by local precede viral infections in children who have
activation of myeloid cell populations are both conditions. Another aspect of the
probable in the airways, as well as in the bone damaged epithelium in asthma is the
marrow. A recently hypothesised immune reduced ability to handle viruses in an

Eosinophil
Mast cell
GM-CSF Basophil
IL-4 IL-5 IL-3
IL-9 IL-5 GM-CSF
IL-13 IL-3
IL-13 IL-4
Mucus Mucocyte TH2
IL-13
Mucus
IL-9
IL-33 IL-4
IL-25
NKT Thymus TH9 IL-9

IL-21 IL-4
IL-15 TGF-
TH0
IL-10
IL-10 TGF-
TGF-
IL-6 TGF-
IL-12
IL-18
IL-17A TH17 iTreg
Smooth muscle
IFN-
IL-17A
TH1
IL-17A
IL-17F
IL-22
TNF-
IFN-
Neutrophil
Figure 2. Different T-cell subtypes are involved in the pathogenesis of asthma. Cytokines and contact
signals, together with dendritic cells and the thymic epithelium, drive the inflammatory process into
various cell lines (blue circle), maintaining inflammatory responses involved in asthma and airway
hyperreactivity. GM-CSF: granulocyte-macrophage colony-stimulating factor; TNF: tumour necrosis
factor; IFN: interferon; NKT: natural killer T-cell; Th: T-helper; iTreg: inducible regulatory T-cell.
Reproduced and modified from Holgate (2012), with permission from the publisher.
optimal way. It appears that the reduced parasympathetic mechanisms involving heat
ability of airway epithelial cells to produce and fluid exchange over the epithelium. BHR
interferon-c may lead to cytotoxic cell death is a modest, but significant, risk factor for
and subsequent dissemination of viruses, later onset of asthma and tends to decrease
rather than apoptosis, possibly explaining the throughout childhood.
prolonged symptomatic viral infection
The role of lung function reductions in the
observed in asthmatics.
development of asthma, in contrast to lung
function decline with chronic asthma, is not
Bronchial hyperresponsiveness (BHR) is a
entirely clear. There is no doubt that asthma
common, but not necessary, feature of
is associated with reduced lung function as
childhood asthma. BHR typically presents as
well as a more rapid decline in lung function
a general tendency to develop symptoms via
compared to healthy individuals. In a few
exposure to various physiological or
birth cohorts, reduced lung function has
environmental stimuli, with exercise being a
been found to precede asthma in some, but
classical childhood asthma symptom trigger.
not all, children with asthma.
The underlying mechanisms for BHR
development are not clear, but may involve Airway remodelling is a common feature in
barrier dysfunction, as well as possibly neural adult asthma but this is not as clear in

childhood, particularly with reference to between perceived and documented (usually
when it starts and what elicits the process. by food challenges) symptoms of food allergy.
Nevertheless, lung function reductions in However, in a recent study in Australia, 13% of
older children are likely to reflect structural 1-year-old children with atopic mothers were
changes in the airways, such as subepithelial found to have a food allergy whereas 4% of
reticular basement layer thickening, those with a non-atopic mother had
epithelial cell disruption, imbalance of confirmed a food allergy. However, cows milk
proteases and anti-proteases, as well as allergy has been reported in up to 40% of 5
neoangiogenesis (remodelling). 16-year-olds, but was only confirmed in 5%.
Anaphylaxis is increasing, and although there
Epidemiology
are shortcomings in definitions and
Allergic diseases in children have increased methodology, an annual incidence rate of
over the past decades to epidemic 0.49% has been reported, with peanuts and
proportions. In a recent Swedish birth tree-nuts being the most common triggers. In
cohort study from 1994, .50% of 12-year- a recent Swedish study the population
old children had at least one allergic disease, incidence was found to be 32 per 100 000
and 7.5 % had at least two diseases out of person, with food involved in 92% of the
atopic eczema, asthma or allergic rhinitis. episodes.
In the International Study of Asthma and The observed increase in allergic diseases is
Allergy phases IIII, asthma prevalence particularly worrying since it not only affects
varied up to 15-fold in the .50 included the subjects with the diseases, but is likely
countries and almost 200 000 67-year-old to increase the burden of allergic disease in
children and 300 000 1314-year-old the offspring of the current younger
children. In 20012003, the prevalence of generation.
current asthma symptoms in 67-year-olds
ranged from 5.0% (Nigeria) to 37.6% (Costa
Further reading
Rica) with respective figures in 1314-year-
olds ranging from of 5.1% (Georgia) to N Annamalay AA, et al. (2012). Prevalence
31.2% (Isle of Man). The corresponding of and risk factors for human rhinovirus
figures for allergic rhinitis were 2.2% (Iran) infection in healthy aboriginal and non-
to 24.2% (Taiwan) for 67-year-olds and aboriginal Western Australian children.
4.5% (Baltic countries) to 45.1% (Paraguay) Pediatr Infect Dis J; 31: 673679.
in 1314-year-olds, and for atopic eczema N Ballardini N, et al. (2012). Development
were 2.0% (Iran) to 22.3% (Sweden) and and comorbidity of eczema, asthma and
1.8% (Georgia) to 21.8% (Morocco), rhinitis to age 12: data from the BAMSE
birth cohort. Allergy; 67: 537544.
respectively. Overall, since the mid-1990s,
N Bousquet J, et al. (2012). Severe chronic
an increase in allergic disease prevalence
allergic (and related) diseases: a uniform
has been found more often than a decrease,
approach a MeDALL/GA2LEN/ARIA
most often in the younger age group and position paper. Int Arch Allergy Immunol;
particularly for atopic eczema. In Europe, 158: 216231.
pooled data from 11 birth cohorts (.14 000 N Carlsen KH (2012). Sports in extreme
children) demonstrated a mean prevalence conditions: the impact of exercise in cold
of current asthma in children aged 6 temperatures on asthma and bronchial
10 years of 8.1%; approximately half of the hyper-responsiveness in athletes. Br J
children had concomitant allergic Sports Med; 46: 796799.
sensitisation, 7.7% had current allergic N Haland G, et al. (2006). Reduced lung
rhinitis and 29.5% had allergic sensitisation, function at birth and the risk of asthma at
demonstrating large variations between 10 years of age. N Engl J Med; 355: 16821689.
countries and cohorts. N Holgate, et al. (2008). Treatment strate-
gies for allergy and asthma. Nat Rev
The prevalence of food allergy is more difficult Immunol; 8: 218230.
to assess due to the relatively large difference

N Holgate ST (2012). Innate and adaptive N Minnicozzi M, et al. (2011). Innate
immune responses in asthma. Nat Med; immunity in allergic disease. Immunol
18: 673683. Rev; 242: 106127.
N Holt PG, et al. (2012). Viral infections and N Palmer CN, et al. (2006). Common loss-
atopy in asthma pathogenesis: new ratio- of-function variants of the epidermal
nales for asthma prevention and treat- barrier protein filaggrin are a major
ment. Nat Med; 18: 726735. predisposing factor for atopic dermatitis.
N Jackson DJ, et al. (2012). Evidence for a Nat Genet; 38: 441446.
causal relationship between allergic sensi- N Prescott S, et al. (2011). Food allergy:
tization and rhinovirus wheezing in early riding the second wave of the allergy
life. Am J Respir Crit Care Med; 185: 281285. epidemic. Pediatr Allergy Immunol; 22:
N Lodrup Carlsen KC, et al. (2012). Does pet 1551560.
ownership in infancy lead to asthma or N Riiser A, et al. (2012a). Does bronchial
allergy at school age? Pooled analysis of hyperresponsiveness in childhood predict
individual participant data from 11 active asthma in adolescence? Am J
European birth cohorts. PLoS One; 7: Respir Crit Care Med.; 186: 493500.
e43214. N von Hertzen L, et al. (2006).
N Martinez FD, et al. (1988). Diminished Disconnection of man and the soil:
lung function as a predisposing factor for reason for the asthma and atopy epi-
wheezing respiratory illness in infants. N demic? J Allergy Clin Immunol; 117: 334
Engl J Med; 319: 11121117. 344.

In vivo and in vitro diagnostic
tests in allergic disorders
Gunilla Hedlin
Many children who start to wheeze during is also a clear relationship between exposure
airway infections in early life will improve and allergic symptoms, yet this may not
with age when infections become less always be the case. Exposure to dander
frequent and the airways grow. There is, present on clothes, hair or on surfaces at
however, a large group of children who start home and school or in other public places
with viral wheeze and continue to develop constitutes an invisible source of allergen.
persistent asthma. In many of these Under these and other circumstances it can
children, IgE-mediated allergy will play an be difficult to evaluate the impact of allergy
important role as a trigger of symptoms. In on a childs symptoms. These examples
some, allergy testing will confirm an IgE- highlight the importance of performing a
mediated sensitisation sometimes careful, thorough, diagnosis of allergy before
preceding the clinically relevant allergy. In the decision is made to take action on
others, asthma symptoms at allergen allergen avoidance and/or initiate
exposure will appear before sensitisation immunotherapy. The allergens responsible
can be confirmed. Thus, although allergy is a for causing asthma symptoms have to be
common cause of symptoms of asthma and confirmed.
often of asthma exacerbations, it is not Prevalence of allergic sensitisation
always clear what role a specific allergen
plays in the severity of the disease. This is Allergic sensitisation can start at any age
particularly obvious when the relationship and is a common phenomenon. In the US
between exposure and symptoms is not National Health and Nutrition Survey 54%
clear. In pollen allergy, the relationship of 10 500 participants had one or more
between exposure and symptoms is easy to positive SPT to one or more of 10 allergens.
assess using pollen count reports. There is The sensitisation rate had more than
usually no need to confirm a relationship doubled between the tests performed during
between sensitisation, exposure and 19761980 and 19881994. Similar trends
symptoms by any other means than taking a have been seen in European longitudinal
history and performing a skin prick test and/or cross-sectional population-based
(SPT) and/or an analysis of allergen-specific studies. In a Swedish study of the
IgE in serum. In animal dander allergy there sensitisation rate in schoolchildren the
prevalence of one or more positive SPT
increased from 2130% between 1996 and
Key points 2006.
Diagnosis of allergy
N Allergy is a common trigger of
asthma. History The first and foremost step in the
N Allergy can start at any age. evaluation of children with asthma is a
careful detailed history. Important questions
N Allergy testing should be performed in include family history of allergic disease,
all children with asthma. known triggers of symptoms, frequency and
severity of symptoms, other signs of atopic

Table 1. Advantages of allergy testing
SPT Serum IgE
No blood sample needed No need to withhold antihistamines
Reliable with good extracts Reliable with validated methods
Immediate results Always available
Visible results Can be used when skin is impaired
disease like rhinitis without relation to colds, has developed tolerance. A SPT can be
atopic dermatitis and adverse reactions to performed at any age but skin reactions tend
food. In some children allergic rhinitis may to be smaller in young children (table 2).
precede asthma and act as a predictor of an
increased risk of asthma. Early development IgE in serum can be analysed for:
of eczema and/or food allergies can also be N single allergens,
signs of risk of later allergic asthma in N allergenic molecules (components) of
children. single allergens,
Allergy sensitisation testing: practice and N a mix of allergens (mix of rodents,
interpretation The most common mode of moulds and dust mites),
allergy testing is in vivo testing by the SPT; N for screening purposes by a multi-
usually the test of choice. The alternative is allergen test, including the common SPT
in vitro testing, which is analysis of allergen- panel of allergens (table 3).
specific IgE antibodies in serum. Both tests The in vitro IgE measurement and the SPT
have advantages and disadvantages result usually agree, but not always. If the
(table 1). SPT does not agree with the history IgE in
SPTs should be performed with well- serum should be measured before rolling
standardised extracts. Usually a panel of out a suspected allergy. Analysis of serum
aeroallergens are used. The test is applied IgE can be performed at any age or any time;
by drops of allergen extract on the volar side current pharmacotherapy does not
of the forearm. The drops are then interfere with the test result. Negative test
punctured by a needle-like device (fig. 1). results in young children should be
After 1520 min any wheal and skin flare interpreted with caution. Low specific-IgE
reactions are recorded and the longest levels (0.10.35 kUa?L-1) can indicate
diameter of each wheal is measured. A sensitisation. There are a number of
wheal diameter o3 mm is considered a companies that provide assays for the in vitro
significant skin reaction. A false-negative IgE antibody tests. Most commonly, a solid
test result can be seen when the patient has phase matrix with allergen extract is used.
ongoing antihistamine therapy, ongoing
dermatitis and/or when a topical
corticosteroid has recently been applied on
the skin. A false-negative result can also be
seen at an early stage of sensitisation or if
sensitisation is weak. A false-positive SPT
can be seen if the child suffers from
dermographism or when sensitisation does
not reflect clinical allergy; in the latter case
the history is more important than the test
result, although a positive test can precede
the clinical allergy. In food allergy that
subsides, such as egg and milk allergy, the
skin sensitivity can remain after the child Figure 1. Performance of a SPT.

Table 2. Interpreting allergy test results
Allergy can be an asthma trigger in spite of a negative allergy test
Allergic sensitisation may not have any relation to asthma symptoms
The degree of sensitisation (e.g. wheal size and antibody level) may or may not reflect disease
severity
SPT and in vitro IgE tests often agree but sometimes both tests are needed
When allergy testing and history disagree there can be a need for an allergen challenge test, if
allergy needs to be confirmed or excluded
After adding the patients serum an anti-IgE whose symptoms are mainly caused by
antibody is added and the amount of bound other factors in spite of confirmed allergen
allergen-specific IgE in the patients serum sensitisations.
is analysed. The result is usually expressed
Food challenges, open or double-blind, are
in arbitrary mass units (kUa?L-1).
sometimes warranted to confirm an allergy
Allergen challenge tests While in vitro tests or but also to support development of
SPTs are good enough for confirming pollen tolerance, which is common in children
and animal dander allergy, it may be with, for instance, milk and egg allergy.
necessary to perform allergen provocation
Total IgE measurements in serum are mainly
tests in the eyes and/or the nose to confirm
needed when treatment with anti-IgE
a dust mite or mould allergy. Bronchial (omalizumab) is considered, an injection
allergen challenge is rarely indicated. It can therapy with monoclonal anti-IgE
be dangerous in children with asthma, antibodies. Dosing is based on the patients
inducing a severe asthmatic reaction, and age, weight and level of total IgE.
should be avoided.
Molecular diagnosis in allergy is usually
Nasal and conjunctival allergen challenges performed by measuring IgE antibodies
can be important if there is doubt about the towards individual allergenic components.
impact of the specific allergy on the severity An alternative is microarray-based testing
of symptoms. This may be the case when against multiple recombinant or purified
allergen immunotherapy is considered. natural allergen components. This has
The rationale is to avoid treating a child made it possible to analyse IgE antibodies
to numerous allergen components of many
common allergens simultaneously in small
Table 3. Common panels of allergens included in SPT samples of serum (20 uL). The allergen
and/or IgE antibody screening components can be classified by protein
Tree pollen (relevant for geographical area) families. This detailed analysis improves
Grass pollen (relevant for geographical area) the possibility to identify antibodies to
proteins that cross-react between different
Weed pollen (relevant for geographical area)
allergens from a sensitisation that is
Animal dander species specific. Currently, the only
Cat commercially available component
resolved microarray diagnostic method is
Dog
the Immuno Solid phase Allergen Chip
Horse microarray (Phadia, Uppsala, Sweden).
Dust mite
Allergy diagnostics is an important part of
Mould the evaluation and management of children
Alternaria with preschool wheeze and asthma.
Cladosporium Together with a careful history it is one of
the first steps in identifying possible triggers

in children of all ages. Allergy becomes more N Hoest A, et al. (2003). Allergy testing in
common as a trigger in children with children: why, who, when and how?
recurrent wheeze and is a major cause of Allergy; 58: 559569.
symptoms and exacerbations in children N Platts-Mills TA, et al. (2011). Allergens
with persistent and/or seasonal asthma. and their role in the allergic immune
response. Immunol Rev; 242: 5168.
N Sastre J (2010). Molecular diagnosis in
Further reading allergy. Clin Exp Allergy; 40: 14421460.
N Sicherer SH, et al. (2012). Allergy testing
N Bousquet J, et al. (2012). Practical guide in childhood: using allergen-specific IgE
to skin prick tests in allergy to aeroaller- tests. Pediatrics; 129: 193197.
gens. Allergy; 67: 1824. N Zuberbier T, et al. (2010). GA2LEN/EAACI
N Cox L (2011). Overview of serological- pocket guide for allergen-specific immu-
specific IgE antibody testing in children. notherapy for allergic rhinitis and asthma.
Curr Allergy Asthma Rep; 11: 447453. Allergy; 65: 15251530.

Anaphylaxis
Antonella Muraro
Anaphylaxis is a serious allergic reaction anaphylaxis can be triggered by physical

that is rapid in onset and may result in exercise, aeroallergens and contact with
death. The epidemiology of the disease is latex, radiocontrast media and ethanol.
hindered by difficulties in timely Almost all episodes are IgE-mediated
assessment of symptoms and in the lack of reactions, although sometimes other, non
proper coding according to the IgE-mediated, immunological mechanisms
International Classification of Disease. In might be involved, or there may be direct
addition, anaphylaxis in infants and mast cell activation such as in physical
children might be even more difficult to exercise. Idiopathic anaphylaxis, i.e. when
recognise and needs a high degree of the cause is unknown, is also relatively
suspicion. However, although no exact common.
incidence can be established, based on In contrast with older patients, in which
current data it is reasonable to assume that drugs and hymenoptera venom are the main
12% of the population may be affected, causes, food allergens are the most
with food and drugs being the most common trigger of anaphylaxis in children.
common cause of anaphylaxis. Among them, cows milk, egg, peanuts, tree
Triggers nuts and seafood are most frequently
reported.
The most common causes of anaphylaxis
Clinical manifestation and diagnosis
are food allergens, medications and
hymenoptera venoms. Less frequently, The diagnosis of anaphylaxis is primarily
based on clinical symptoms and signs, as
well as a detailed description of acute
Key points episodes, including antecedent activities
and events occurring within the preceding
N Anaphylaxis is a serious allergic minutes to hours.
reaction that is rapid in onset and may
result in death. Typically, exposure to a triggering allergen is
followed by rapid development of symptoms
N The most common causes are food over minutes to several hours. Investigation
allergens, medications and is mandatory, especially if exposure to a
hymenoptera venoms. likely allergen is reported. Sudden onset of
N Infants are usually not able to urticaria, swelling of the oropharynx,
describe symptoms; therefore, rhinorrea, cough, breathing difficulties,
physicians need to have a high index vomiting and progressive abdominal pain,
of suspicion in order to diagnose pallor, irritability and sleepiness (i.e.
anaphylaxis. hypotension) should be carefully evaluated
in any allergic child. In infants, anaphylaxis
N Adrenaline is the medication of choice may be even more difficult to recognise
for anaphylactic episodes. because they are usually unable to describe
the symptoms. Moreover, some signs of

anaphylaxis, such as irritability, flushing, Role of laboratory tests
hoarseness, drooling, regurgitation, loose
stools, colicky abdominal pain and The diagnosis is hampered by the lack of
somnolence, may be difficult to interpret reliable markers of the disease. Serum
since they are quite common in this age tryptase, which should be obtained 15 min
group. to 3 h after onset of the symptoms, has low
sensitivity and specificity and its level is
Recently, the National Institute of Allergy typically normal in food anaphylaxis.
and Infectious Disease and the Food Allergy Histamine blood levels obtained 1560 min
and Anaphylaxis Network have established after onset may also be useful. However,
three diagnostic criteria, allowing 95% of both tests are not universally available, not
anaphylaxis events to be diagnosed performed on an emergency basis and not
(table 1). specific for anaphylaxis. A recent report
highlights the possible role of platelet-
In both adults and children, the time course activating factor in the pathogenesis of more
of the reaction may be: severe reactions.
N Uniphasic, occurring immediately after Management

exposure and resolving with or without
The management of anaphylaxis encompasses
treatment in minutes to hours;
both the treatment of acute episodes and the
N Biphasic, recurring after the apparent
preventive strategies in the community to
resolution of initial symptoms, usually
avoid recurrences and new cases.
about 8 h after the first reaction;
N Protracted, persisting for hours or days Basic management As with the treatment of
following the initial reaction. any critical patient, the treatment of
Table 1. Clinical criteria for diagnosing anaphylaxis

Anaphylaxis is highly likely when any one of the following three criteria are fulfilled
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue
or both (e.g. generalised hives, pruritus or flushing and swollen lips-tongue-uvula), and at least
one of the following:
Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, reduced PEF and
hypoxaemia)
Reduced BP or associated symptoms of end-organ dysfunction (e.g. hypotonia (collapse),
syncope and incontinence)
Two or more of the following that occur rapidly after exposure to a likely allergen for that patient
(minutes to several hours):
Involvement of the skin-mucosal tissue (e.g. generalised hives, itch-flush and swollen lips-
tongue-uvula)
Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, reduced PEF and
hypoxaemia)
Reduced BP or associated symptoms (e.g. hypotonia (collapse), syncope and incontinence)
Persistent gastrointestinal symptoms (e.g. cramping abdominal pain and vomiting)
Reduced BP after exposure to known allergen for that patient (minutes to several hours):
Infants and children: low systolic BP# (age specific) or .30% decrease in systolic BP
Adults: systolic BP ,90 mmHg or .30% decrease from that persons baseline
PEF: peak expiratory flow; BP: blood pressure. #: defined as ,70 mmHg at 1 month to 1 year of age,
,70 mmHg+[26age] at 110 years of age and ,90 mmHg at 1117 years of age.

anaphylaxis begins with a rapid assessment
The severity score should be based on the organ system most affected. Bold indicates a mandatory indication for the use of adrenaline. GI: gastrointestinal. #: defined as systolic
Light headedness and
a feeling of impending
Change in activity level
and maintenance of airway, breathing and
Confusion, loss of
consciousness
circulation. Patients experiencing acute
Neurological
plus anxiety
anaphylaxis should be kept in a position of
doom
comfort, which usually involves lying
recumbent or semi-recumbent. This
accomplishes two therapeutic goals:
N preservation of fluid in the circulation

(the central vascular compartment), an
severe bradycardia and/
collapse, dysrhythmia,
Tachycardia (increase
important step in managing distributive

Hypotension# and/or
.15 beats?min-1)
or cardiac arrest shock;

Cardiovascular
blood pressure ,70 mmHg at 1 month to 1 year of age, ,70 mmHg+[26age] at 110 years of age and ,90 mmHg at 1117 years of age.
N
As above
prevention of empty vena cava/empty

ventricle syndrome, which can occur
within seconds when patients with
anaphylaxis suddenly assume or are
placed in an upright position.
Patients with this syndrome are at high risk
Any of the above, cyanosis or
tightness and mild wheezing
for sudden death and unlikely to respond to

Any of above, hoarseness,
Nasal congestion and/or
sneezing, rhinorrhoea,
stridor, dyspnoea and

throat pruritus, throat
difficulty swallowing,
adrenaline, regardless of route of

moderate wheezing
saturation ,92%,
respiratory arrest
barky cough,
administration, because it does not reach

Respiratory
the heart and therefore cannot be circulated

throughout the body.
After removing exposure to the trigger (if
possible), if any of the three criteria of
anaphylaxis outlined in table 1 are fulfilled,
the patient should receive adrenaline
immediately.
Any of the above, cramping
tingling, mild lip swelling,
Any of the above, loss of

nausea or emesis, mild
pain, diarrhoea and
Adrenaline is the medication of choice for

recurrent vomiting
Oral pruritus, oral
abdominal pain
bowel control
anaphylactic episodes; all other medications

abdominal
GI tract
should be regarded as ancillary. Prompt

injection of adrenaline has been associated
with better outcomes. A severity score can
be helpful in the diagnosis and in ensuring
the timely administration of adrenaline
(table 2).
Table 2. Grading of severity of anaphylactic reaction
Sudden itching of eyes and

nose, generalised pruritus,
The intramuscular route is acknowledged as

flushing, urticarial and
the optimal route for adrenaline

Any of the above
Any of the above
administration. Adrenaline in a
angioedema
concentration of 1 mg?mL-1 should be used

Skin
in a dose of 0.01 mg?mL-1 body weight

(maximum single dose 0.5 mg). This
dosage can be repeated at short intervals
(every 510 min) until the patients
condition stabilises.
Although frequently administered, the role
Moderate
and efficacy of antihistamines and

Severe
corticosteroids in anaphylaxis has not yet

Grade
Mild
been clarified. These medications should

not be considered as first-line treatments for

Table 3. Indications for prescribing a self-injectable adrenaline device
Absolute indications Relative indications
A previous cardiovascular or respiratory Any reactions to small amounts of a food
reaction to a food (and to other triggers such including airborne or contact of the food
as insect sting or latex) allergen only via skin
Exercise-induced anaphylaxis (often also History of previous, even mild, reactions to
related to food) peanut or tree nuts
Idiopathic reaction Remoteness of home from medical facilities
Child with food allergy and asthma Food allergy reaction in a teenager
anaphylaxis as they do not act quickly. The Prescription of self-injectable adrenaline The
efficacy of corticosteroids in reducing the decision about whether to prescribe a self-
risk of late-phase reactions has not been injectable adrenaline device involves
proven. High-flow oxygen should be given to analysis of the risks of experiencing
any patient with respiratory symptoms or anaphylaxis, the benefits of a self-injectable
evidence of shock. Volume support with adrenaline device, the risks associated with
crystalloid solution or colloid expander is it and its cost on health services and
mandatory in the case of hypotension. individual families. Absolute and relative
indications about prescribing adrenaline are
Long-term management Identification of
shown in table 3.
triggers In order to identify the allergen,
patients with a history suggestive of an Immunomodulation Venom immunotherapy
anaphylactic reaction need urgent referral to is 95100% and ,80% successful in wasp
an allergy clinic for a diagnostic assessment, and bee sting allergies, respectively.
based on clinical history and in vivo and in Desensitisation protocols have also been
vitro examinations (skin prick test, established for some medications, such as a
intradermal test, prick-by-prick with raw few antibiotics and nonsteroidal anti-
food, IgE for suspected allergens and inflammatory drugs, although they are only
recombinant allergens, and oral challenges recommended in exceptional cases.
for food or drugs).
Food-induced anaphylaxis could
Risk reduction Strategies to avoid the theoretically be modulated by allergen
precipitants should be customised taking desensitisation through immunotherapy,
into consideration factors such as age, similarly to hymenoptera sting anaphylaxis.
occupation, activities, hobbies, living However, food allergen immunotherapy
conditions and access to medical care. As remains experimental and although several
most episodes of anaphylaxis occur in the trials of oral tolerance induction are
community, children and their caregivers underway, this procedure is not yet
must know how to prevent further reactions recommended in routine clinical practice.
and how to promptly recognise and
appropriately manage any anaphylactic
reactions that occur outside the hospital. Further reading
Allergists, emergency physicians and general N Boyle RJ, et al. (2012). Venom-
paediatricians/practitioners, as well as immunotherapy for preventing allergic
teachers and caregivers, need to develop a reactions to insect stings. Cochrane
coordinated approach, including actions for Database Syst Rev; 10: CD008838.
primary and secondary prevention and N Castells M (2006). Desensitization
emergency response, in order to prevent for drug allergy. Curr Opin Allergy Clin
fatalities and improve quality of life of Immunol; 6: 476481.
patients and families.

N Dhami S, et al. (2013). The acute and with suspected food allergy. Allergy; 63:
long-term management of anaphylaxis: 15211528.
protocol for a systematic review. Clin N Panesar SS, et al. (2013). The epidemiology
Transl Allergy; 3: 14. of anaphylaxis in Europe: protocol for a
N Dinakar C (2012). Anaphylaxis in children: systematic review. Clin Transl Allergy; 3: 9.
current understanding and key issues in N Pumphrey RS (2003). Fatal posture in
diagnosis and treatment. Curr Allergy anaphylactic shock. J Allergy Clin
Asthma Rep; 12: 641649. Immunol; 112: 451452.
N Gold MS, et al. (2000). First aid anaphy- N Sampson HA, et al. (2006). Second
laxis management in children who were symposium on the definition and man-
prescribed an epinephrine autoinjector agement of anaphylaxis: summary report
device (EpiPen). J Allergy Clin Immunol; Second National Institute of Allergy and
106: 171176. Infectious Disease/Food Allergy and
N Muraro A, et al. (2007). The management Anaphylaxis Network symposium.
of anaphylaxis in childhood: position J Allergy Clin Immunol; 117: 391397.
paper of the European academy of N Simons FE (2004). First-aid treatment of
allergology and clinical immunology. anaphylaxis to food: focus on epinephr-
Allergy; 62: 857871. ine. J Allergy Clin Immunol; 113: 837844.
N Muraro A, et al. (2008). New visions for N Simons FE (2007). Anaphylaxis in
anaphylaxis: an iPAC summary and future infants: can recognition and management
trends. Pediatr Allergy Immunol; 19: Suppl. be improved? J Allergy Clin Immunol; 120:
19, 4050. 537540.
N Ott H, et al. (2008). Clinical usefulness of N Simons FE (2010). Anaphylaxis. J Allergy
microarray-based IgE detection in children Clin Immunol; 125: S161S181.

Allergic rhinitis
Michele Miraglia Del Giudice, Francesca Galdo and Salvatore Leonardi
The allergic pathologies are frequent and paediatric population and is often
bothersome diseases. In the past 30 years, associated with other allergic diseases.
epidemiological studies have shown that the According to various epidemiological
prevalence of allergic rhinitis continues to studies this disease affects more than 10%
increase worldwide although it is often of children ,14 years of age and 2030% of
underestimated, underdiagnosed and adolescents and young adults.
undertreated. Allergic rhinitis is the most
Definition
frequent allergic, chronic disease in the
Allergic rhinitis is defined as a symptomatic
disorder of the nose characterised by:
Key points N itching,

N nasal discharge,
N Allergic rhinitis is a symptomatic N sneezing,
disorder of the nose characterised by N nasal airway obstruction induced by an
itching, nasal discharge, sneezing and IgE-mediated immune reaction after
nasal airway obstruction induced by allergen exposure.
an IgE-mediated immune reaction
It is accompanied by inflammation of the
after allergen exposure.
nasal mucosa and nasal airway
N According to ARIA guidelines, allergic hyperreactivity. Although it is not life
rhinitis is divided into intermittent or threatening, it can have a significantly
persistent disease and the severity is detrimental effect on a childs quality of life,
classified as mild or moderate/severe and it may exacerbate a number of common
depending on the severity of comorbidities, including asthma and
symptoms and their impact on social sinusitis.
life, school and work.
Mechanisms
N The diagnosis of allergic rhinitis is
based on the concordance between a Allergic rhinitis is the result of IgE-mediated
typical history of allergic symptoms allergy and nasal mucosa inflammation. IgE
and diagnostic tests. is produced in the lymphoid tissues and
locally in the nasal mucosa in response to
N The therapeutic strategies of allergic common environmental allergens. When
rhinitis are patient education, allergens bind to mast-cell-bound IgE, mast-
pharmacotherapy and allergen- cell degranulation occurs. Degranulation of
specific immunotherapy. mast cells results in the release of a myriad
N The inflammation of the nasal of biochemical mediators that regulate and/
mucosa may affect the eye mucosa, or mediate the different aspects of allergic
air sinuses, the ear and the lower inflammation.
airways. Among other preformed mediators,
histamine is released into the surrounding

tissues binding to H1-receptors on various Late-phase allergic reactions and chronic
target cells and eliciting a powerful allergic inflammatory changes involve many cell
response (fig. 1). This response is types including T-cells, mast cells and
characterised by an increase in vascular eosinophils. Eosinophilic inflammation also
permeability and by stimulation of local plays an important role. A T-helper (Th)2
nerve endings and mucus-secreting cells. response ensues with the release of
The clinical manifestations of these interleukin (IL)-4 and IL-5. Eosinophils are
biological activities include sneezing, increased in numbers and activated in the
rhinorrhoea, nasal and ocular itching, and nasal mucosa of symptomatic allergic
red watery eyes. Thus, histamine is the key patients. They release proinflammatory
player in the acute allergic response. mediators, including granule-stored cationic
proteins, newly synthesised eicosanoids and
Other important mediator classes involved in cytokines. The major basic protein (MBP) is
the acute-phase allergic response include highly cationic and lacks enzymatic activity,
prostaglandins (e.g. PGD2) and leukotrienes and toxicity is believed to be mediated by
(e.g. LTC4). Prostaglandins, of which PGD2 enhanced membrane permeability resulting
appears to be the most important, have from interactions of the cationic protein with
vasodilatory and bronchoconstrictive the plasma membrane. After allergen
properties. Prostaglandin D2 produces nasal exposure, rhinitis can persist for several
inflammation in the acute phase, but does not weeks. In the late phase the predominant
appear to play a key role in chronic symptom is nasal congestion. Eosinophils
inflammation. Evidence derived from topical release mediators that can induce tissue
application of cysteinyl leukotrienes (cysLTs) damage, and pre-treatment with topical
in the nose and from the effects of leukotriene glucocorticoids reduces eosinophil
receptor antagonists (LTRAs) indicates that infiltration and cytokine release.
cysLTs contribute to nasal mucous secretion, Classification
congestion, and inflammation. CysLTs
promote allergic inflammation by enhancing The classification of allergic rhinitis was
immune responses and the production, previously based on the time of exposure
adhesion, migration and survival of into seasonal or perennial. Perennial allergic
inflammatory cells such as eosinophils. rhinitis is generally caused by indoor
Preformed & Cytokines

Allergen newly formed
IgE Chemokines
mediators/cytokines
Endothelial Allergen
Mast cell cell activation Dendritic cell
Leukocyte IL-4 T-lymphocyte
infiltration and activation IL-13
(lymphocytes, eosinophils, B-lymphocyte
basophils)
Immediate (early)
response Late-phase
responses
Sneezing
Nasal obstruction Nasal
Pruritus
Rhinorrheoa hyperresponsiveness IgE
Rhinorrhoea
Nasal obstruction To allergens To irritants and to
Ocular symptoms (priming) atmospheric changes
Figure 1. The nasal allergic response. Reproduced from Van Cauwenberger et al. (2003) with permission
from the publisher.

allergens such as dust mites, moulds and reversible either spontaneously or with
animal danders. Seasonal allergic rhinitis is treatment include:
most frequently related to pollens or
moulds. N rhinorrhoea,
N nasal obstruction,
Recently, an expert panel proposed a new N nasal itching,
classification of allergic rhinitis. In this N sneezing.
classification allergic rhinitis was divided
into intermittent or persistent disease Other concurring symptoms may affect the
and the severity of allergic rhinitis was eyes such as:
classified as mild or moderate/severe
depending on the severity of symptoms and N lachrymation,
their impact on social life, school and work N conjunctivae itching,
(fig. 2). N swelling.
This classification was proposed in the Ocular symptoms are common, in

Allergic Rhinitis and its Impact on Asthma particular in patients allergic to outdoor
(ARIA) guidelines, the first ever evidence- allergens. Allergic rhinitis due to pollen
based guidelines for allergic rhinitis. allergy occurs in the relevant seasons and
there are large geographical differences.
Another important aspect of the ARIA Apart from season and pollen exposure,
guidelines was to consider co-morbidities of other factors are also important for severity
allergic rhinitis. The eye, ear and lower of symptoms including the weather: rain
airways are involved in allergic rhinitis. reduces the exposure and mild wind in dry
Interactions between the lower and the weather may increase exposure, in addition
upper airways are well known; over 80% of wind may result in exposure far away from
asthmatics suffer from rhinitis and 1040% the source. Perennial allergens may be
of patients with rhinitis have asthma. house dust mites (HDMs) as well as animal
Diagnosis danders. The major cat allergen (Fel d 1) is
transported in the air by particles ,2.5 mm
The diagnosis of allergic rhinitis is based on and can remain airborne for long periods.
the concordance between a typical history of Fel d 1 is also adherent and can
allergic symptoms and diagnostic tests. contaminate an entire environment for
Typical symptoms of allergic rhinitis that are weeks or months after cessation of allergen
Intermittent Persistent
Symptoms Symptoms
< 4 days / week > 4 days / week
or < 4 week or > 4 week
Mild Moderate severe

Sleep: normal Sleep: disturbed
Daily activities (incl. sports): normal Daily activities: restricted
Work and school activities: normal Work and school activities: disturbed
Severe symptoms: no Severe symptoms: yes
Figure 2. Allergic rhinitis classification. Reproduced from Bousquet et al. (2001).

exposure. HDMs are most often found in extending across the junction of the lower
bedding, especially in humid environments. and middle thirds of the bridge of the nose
Since HDM allergy often induces late named nasal crease.
reactions, these children often experience
nasal congestions and may also have Clinical testing
symptoms during the daytime and seldom Diagnostic tests are based on the
specifically in early morning. Allergic
demonstration of allergen-specific IgE in vivo
rhinitis due to HDM allergy also occurs
or in vitro. A skin prick test (SPT) is
most often in older children, though even
recommended as the gold standard
young children may have allergic rhinitis
method for the diagnosis of IgE-mediated
and allergy to pollen as well as HDMs.
allergies in allergic rhinitis.
The main symptom of allergic rhinitis
It has advantages of relative high sensitivity
caused by perennial allergens is nasal
and specificity, rapid results, low cost and
congestion whereas conjunctival swelling,
good tolerability. However, the quality of the
itching and watery discharge can occur. The
allergens is very important and only
congestion is a consequence of the
standardised extracts should be used.
inflammation that involves all the upper
Moreover, the skin of very young children
airways. Nasal congestion can result in
chronic mouth breathing, associated with may not be as reactive as older children and
the development of a high-arched palate, adults.
upper lip and overbite. As a matter of fact, In children, the number of allergens to be
children often suffer from a sore throat tested is limited. The most important
caused by oral respiration. Other symptoms allergens in early childhood are HDM and
may include: coughing caused by post-nasal animal dander but in older children pollens
drip, cephalalgy caused by oedema of the
and moulds must be investigated.
nasal mucosa, and hearing impairment
caused by tympanic dysfunction. Sudden The measurement of allergen-specific IgE in
night awakening and apnoea can affect serum is available using either radio- or
sleep. Therefore, this alteration of sleep enzyme-labelled anti-IgE. This test has a
phase can affect the child in their everyday diagnostic value similar to SPTs but it is
life and activities. more expensive than the latter. For this
reason the measurement of allergen-specific
In children suffering from allergic rhinitis
IgE in serum is recommended if history of
social problems can occur with
allergic symptoms and SPTs disagree, or in
embarrassing repeated actions, such as
children affected by dermographism or
blowing their nose, grimacing in order to
widespread skin lesions, or during treatment
relieve their nasal itching or producing
by drugs affecting the reactions to SPTs,
strange noises.
such as antihistamines.
Children with allergic rhinitis may have
swelling and dark discolouration under the However, the diagnosis of allergic rhinitis is
eyes due to congestion of small blood based upon the coordination between a
vessels beneath the skin in this area. typical history of allergic symptoms and
diagnostic tests. No diagnosis can be based
In children with persistent allergic rhinitis, solely on responses to SPTs in in vitro tests
the habitual manipulation of the nose due to or nasal challenges. In some cases with a
chronic obstruction and itching is typically very clear history, e.g. with clear seasonal
accomplished by pushing the tip of their symptoms or mild symptoms and the child
nose with the palm of their hand in an being well treated on symptomatic
upward motion: this action is known as the treatment, e.g. antihistamines in normal
nasal salute or the allergic salute. This doses, further diagnosis with SPTs, specific
may result in a persistent transverse IgE or even nasal challenges may not be
hyperpigmented or hypopigmented line necessary.

Recently, the nasal allergen provocation test rhinitis and asthma as well. Patients allergic
has been needed to identify local allergic to furred pets may benefit from allergen
rhinitis. This new entity is a localised nasal avoidance at home, but they may encounter
allergic response in the absence of systemic allergens on public transportation, and in
atopy characterised by local production of schools and public places. A systematic
specific IgE antibodies, a Th2 pattern of review of dust mite allergen avoidance has
mucosal cell infiltration during natural shown that single measures are not effective
exposure to aeroallergens, and a positive in reducing symptoms of allergic rhinitis,
nasal allergen provocation test response although the general consensus is that
with release of inflammatory mediators allergen avoidance should lead to an
(tryptase and eosinophil cationic protein). improvement of symptoms. However,
Several non-allergic conditions can mimic improving air quality by ventilating airtight
allergic rhinitis symptoms, but because homes to prevent a build-up of biological
management differs in each case, it is very pollutants and volatile organic compounds
important to differentiate between allergic (VOCs) may be useful.
rhinitis and non-allergic rhinitis.
Medications used for the treatment of
Management of a child affected by allergic
allergic rhinitis in children are
rhinitis
antihistamines (oral or topical), steroids,
The control of the nasal mucosa allergic chromones and antileukotrienes, which are
inflammation is the goal of all the particularly useful when the allergic rhinitis
therapeutic strategies in the management of is associated with asthma and
allergic rhinitis. The key points of the immunotherapy.
management of allergic rhinitis are patient
Antihistamines Oral H1-antihistamines are
education, pharmacotherapy and allergen-
effective against symptoms mediated by
specific immunotherapy (fig. 3).
histamine (rhinorrhoea, sneezing, nasal
A lot of perennial allergens have been itching and eye symptoms) but have nearly
associated with allergic rhinitis, of which no effect on nasal congestion. Second-
HDM and animal dander are the most generation antihistamines are preferred and
important. Mould spores can provoke they may have some, though usually very
Moderate
Mild severe
Moderate persistent
persistent
severe
Mild intermittent
intermittent
Intranasal steroid
Oral or local nonsedative H1-blocker
Intranasal decongestant (<10 days) or oral decongestant
Leukotriene receptor antagonists

Avoidance of allergens, irritant and pollutants
Immunotherapy
Figure 3. Management of allergic rhinitis: ARIA guidelines. Reproduced from Bousquet et al. (2001).

mild, sedative effect. The possible anti- The newer formulations of topical
inflammatory effect of some antihistamines corticosteroids for allergic rhinitis, such as
is very modest and probably not clinically ciclesonide, fluticasone furoate and
relevant. Oral H1-antihistamines have been mometasone furoate, which have less
shown to be safe and effective in children systemic bioavailability, may be safer for
and also for long-term treatment. Nasal long-term use. Fluticasone furoate nasal
corticosteroids and oral antihistamines also spray is a new topical intranasal
result in an improvement of objective corticosteroid with enhanced affinity for the
measurements of pulmonary function. glucocorticoid receptor and low systemic
Intranasal antihistamines have been found exposure, which has recently been approved
in some adult studies to be as effective as in the USA for the treatment of seasonal or
oral antihistamines, with fewer adverse perennial allergic rhinitis in adults and in
effects but there are few data in children. children aged o2 years. In well-controlled
clinical trials, intranasal fluticasone furoate
Corticosteroids The rationale for using 110 mg once daily for 2 weeks in adults and
intranasal corticosteroids in the treatment of adolescents with seasonal allergic rhinitis
allergic rhinitis is that high drug reduced nasal and ocular symptoms.
concentrations can be achieved at receptor
sites in the nasal mucosa with a minimal The treatment of rhinitis reduces asthma
risk of systemic adverse effects. Topical severity: asthma and allergic rhinitis
corticosteroids stabilise the membranes of commonly occur together, treatments for
mast cells and exert most of their effects via one condition could potentially alleviate the
such membranes and partial blocking of the coexisting condition. The use of nasal
late phase reaction. The current intranasal corticosteroids in patients with rhinitis and
preparations are well tolerated and can be asthma reduces not only rhinitis symptoms
used on a long-term basis without atrophy but also asthma symptoms and airway
of the mucosa. Side-effects are generally reactivity to methacholine challenge.
mild (crusting, dryness and minor
It should be made very clear that systemic
epistaxis).
treatment with corticosteroids for allergic
Due to their mechanism of action, efficacy rhinitis in children is not standard
appears after 78 h of dosing, but maximum treatment, although a short course with low-
efficacy may require up to 2 weeks to dose prednisolone in some severe cases can
develop. They are generally safe, and there is be necessary: patients with severe
little evidence to support suppression of the symptoms who do not respond to other
hypothalamicpituitaryadrenal axis (HPA drugs or those who are intolerance to
axis) with prolonged use. The safety of intranasal drugs may need to be treated with
intranasal corticosteroids is particularly systemic corticosteroids (e.g. prednisolone,
relevant in paediatric and adolescent starting dose 1015 mg?day-1) for a short
period of time.
patients because these agents are widely
used in this population. The effect of Allergen-specific immunotherapy Allergen-
6 weeks of once-daily treatment with specific subcutaneous immunotherapy is
beclomethasone dipropionate (BDP) nasal not usually recommended before the age of
aerosol on HPA-axis function, as measured 5 years. In older children the clinical efficacy
by 24-hour serum cortisol concentrations, in of allergen-specific immunotherapy is well
adolescent and adult subjects with perennial established for both rhinitis and asthma.
allergic rhinitis has been evaluated. The Traditionally, immunotherapy has been
results of this randomised, double-blind, administered by the subcutaneous route but
placebo- and active-controlled study, the sublingual route is now available.
indicated that BDP nasal aerosol was not Subcutaneous specific immunotherapy is
associated with HPA-axis suppression in burdened with a risk of inducing systemic
adolescent and adult subjects with perennial side-effects. When treating rhinitis patients,
allergic rhinitis. the risk of serious anaphylactic reactions is

rather limited compared to treating asthma rhinitis are more prone to middle ear otitis
patients. The sublingual route is safer. and otitis media with effusion. A probable
mechanism is that allergic inflammation in
Allergen-specific immunotherapy is the respiratory epithelium at the entrance to
recommended for the treatment of patients and inside the Eustachian tube can result in
with pollen and mite allergy and it may alter tube dysfunction due to swelling in this
the natural course of allergic diseases. region and possibly cause a secondary
Indeed, administered to patients with inflammation in the middle ear. In some
rhinitis, immunotherapy appears to reduce cases there is a difficulty in the interpretation
the development of asthma (secondary of the symptoms of nasal occlusion caused
prevention of asthma). The duration of by allergy and often these symptoms get
immunotherapy is usually 3 years to show confused by the physical inflammatory cause
long-term efficacy after its cessation. (e.g. dental malocclusion combined with
All these different treatments are to be adenoidal obstruction).
modified or combined together depending Integrated handling of the allergic rhinitis
on the: may require the prevention of
complications, therefore foreseeing the
N single case,
best treatment through the expertise of an
N age of the subject,
otolaryngologist, surgeon or an
N duration of the symptoms,
orthodontist. Referring a patient for
N causal allergens, surgical treatment is the only solution in
N seriousness of the clinical symptoms. order to correct certain anatomical
anomalies of the nasal bones, or removal of
The main goal of the therapy isnt just
enlarged tonsils or adenoids, only in the
ending the symptoms, but preventing and
case in which, along with the allergic
treating all the possible complications that
inflammation, they aggravate nasal
may affect the structures close to the nasal
obstruction and breathing.
cavities and lower air system.
Comorbidities and complications Numerous studies have demonstrated that
allergic rhinitis may be a risk factor for both
Allergic rhinitis cannot be considered as an the onset and the worsening of asthma. The
isolated pathology. The inflammation that nasal and bronchial mucosa are
affects the nasal mucosa will consequently characterised by the same pseudo-stratified
affect the eye mucosa, air sinuses, ear and epithelium and the united airways
lower airways. concept suggests that the respiratory
system functions as an integrated unit.
The chronic exposure to perennial allergens, Support for this concept can be found in
especially in domestic environments, induces studies showing that pathophysiological
a gradual nose occlusion that will be very processes involving the upper airways
subtle in its manifestation, therefore the generally occur in conjunction with lower
subject will physically adapt to the airway diseases and that diffuse
symptoms. Permanent signs found in allergic inflammation often affects the respiratory
rhinitis subjects can be malocclusion or mucosa at different sites simultaneously.
misalignment of teeth and jaws and
adenoidal face (long face syndrome). For Finally, in relation to the close connection
subjects affected by allergic rhinitis the co- between lower and upper airways, the
existence of multiple diverse conditions such physical examination should always
as deviated septum, nasal turbinate carefully investigate the breathing condition
dysfunction, sinusitis and adenoid of the patient and consider lung function
hypertrophy can occur. Moreover, physical testing. Bronchial hyperreactivity (BHR) is
examination of the allergic rhinitis subject characteristic of bronchial asthma. Patients
should also include an otoscopic with allergic rhinitis who do not report
examination. Children affected by allergic symptoms of bronchial asthma on

spirometry may show signs of BHR, which N Bousquet J, et al. (2008). Allergic Rhinitis
could indicate the presence of subclinical and its Impact on Asthma (ARIA) 2008
inflammation of the lower respiratory update (in collaboration with the World
airway. The presence of bronchial Health Organization, GA(2)LEN and
hyperresponsiveness and concomitant AllerGen). Allergy; 63: 8160.
atopic manifestations in childhood N Bousquet J, et al. (2012). Practical guide
increases the risk of developing asthma and to skin prick tests in allergy to aeroaller-
gens. Allergy; 67: 1824.
should be recognised as a marker of
N Ciprandi G, et al. (2011). FEF(2575)
prognostic significance, whereas the
might be a predictive factor for bronchial
absence of these manifestations predicts a inflammation and bronchial hyperreactiv-
very low risk of future asthma. ity in adolescents with allergic rhinitis. Int
Measurement of the exhaled nitric oxide Immunopathol Pharmacol; 24: 1720.
fraction (FeNO) may be considered a N Ciprandi G, et al. (2012a). Rhinitis and
surrogate marker for airway inflammation. lung function in asthmatic children. Clin
Forced expiratory flow at 2575% of FVC Exp Allergy; 42: 481482.
(FEF2575%) has been previously N Ciprandi G, et al. (2012b). Recent devel-
demonstrated to be able to predict BHR and opments in united airways disease.
bronchial reversibility. Allergy Asthma Immunol Res; 4: 171177.
N Ciprandi G, et al. (2012c). Impaired
Patients with allergic rhinitis due to pollen FEF25-75 values may predict bronchial
often display adverse reactions upon the reversibility in allergic children with rhi-
ingestion of plant-derived foods as a result nitis or asthma. J Biol Regul Homeost
of IgE cross-reactive epitopes shared by Agents; 26: Suppl. 1, S19S25.
pollen and food allergen sources. The N Ciprandi G, et al. (2012d). Impaired
symptoms of such pollenfood syndromes FEF25-75 may predict high exhaled nitric
oxide values in children with allergic
range from local oral allergy syndrome to
rhinitis and/or asthma. J Biol Regul
severe systemic anaphylaxis. The best
Homeost Agents; 26: Suppl. 6, S27S33.
known association is between birch pollen N de Benedicitis FM, et al. (2001).
and a series of fruits (including apple), Rhinitis, sinusitis and asthma: one linked
vegetables and nuts. airway disease. Paediatr Respir Rev; 2:
358364.
Allergic rhinitis can often be a debilitating N Kaliner MA, et al. (2011). The efficacy of
condition which, if untreated, can result in intranasal antihistamines in the treat-
considerable health-related and economic ment of allergic rhinitis. Ann Allergy
consequences. For example, numerous Asthma Immunol; 106: Suppl. 2, S6S11.
studies have demonstrated that poorly N La Rosa M, et al. (2011). Specific immu-
controlled symptoms of allergic rhinitis notherapy in children: the evidence. Int J
contribute to decreased health-related Immunopathol Pharmacol; 24: 6978.
quality of life (HRQoL), reduced sleep N Leonardi S, et al. (2012). Function of the
quality, daytime fatigue, impaired learning, airway epithelium in asthma. J Biol Regul
impaired cognitive functioning and Homeost Agents; 26: 4148.
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life: findings from the Nasal Allergy
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Pract; 61: Suppl. 2, S5S10.
N Blaiss MS, et al. (2011). Safety update N Miraglia Del Giudice M, et al. (2011a).
regarding intranasal corticosteroids for Allergic rhinitis and quality of life in
the treatment of allergic rhinitis. Allergy children. Int J Immunopathol Pharmacol;
Asthma Proc; 32: 413418. 24: 2528.

N Miraglia Del Giudice M, et al. (2011b). N Scadding GK, et al. (2008). Fluticasone
Fractional exhaled nitric oxide measure- furoate nasal spray consistently and
ments in rhinitis and asthma in children. significantly improves both the nasal
Int J Immunopathol Pharmacol; 24: 2932. and ocular symptoms of seasonal allergic
N Miraglia del Giudice M, et al. (2013). rhinitis: a review of the clinical data.
Exhaled nitric oxide and atopy in children. Expert Opin Pharmacother; 9:
J Allergy Clin Immunol; 111: 193. 27072715.
N Novembre E, et al. (2004). Co-seasonal N Simons FE, et al. (2004). Advances in H1-
sublingual immunotherapy reduces the antihistamines. N Engl J Med; 351: 2203
development of asthma in children with 2217.
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nasal aerosol does not affect hypothalamic- resources in allergy (GLORIA): allergic
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N Rondon C, et al. (2012). Local allergic N Vitaliti G, et al. (2012). Mucosal immunity
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14601467. Homeost Agents; 26: 8593.

Atopic dermatitis
Paolo Meglio, Elena Galli and Nunzia Maiello
Atopic dermatitis (AD) is a chronic/ responsible for the symptoms. Moreover,

relapsing, inflammatory skin disease that complex interactions between genetic and
can affect 7.5% or more of children and environmental factors make the clinical
about 13% of adults. In children, about spectrum of AD very variable (fig. 1).
70% of cases start before age 5 years. The
Clinical manifestations, diagnosis and
disease is characterised by recurrent, acute
monitoring
flare-ups on skin that often exhibits chronic
eczematous pruritic skin lesions. Frequently, AD can present a broad spectrum of
the platform of these manifestations is dry dermatological manifestations and over
skin. Its impact on the quality of life of time various diagnostic criteria have been
affected children is high. proposed. Those of Hanifin and Rajka
(1980), are the most frequently used and
Since the early attempts to clearly and
consist of four major and 23 minor criteria
comprehensively define diagnostic criteria, it
based on consensus reached by experienced
has been evident that AD is a complex,
dermatologists. Even if such criteria are
multifactorial disease. Due to recent
those used most frequently, they are less
advances, we are now aware that an
suitable for use as a diagnostic tool by
impaired skin barrier and complex immune
nonspecialist or primary care doctors, due
dysregulation, sometimes including IgE-
to their complexity. Moreover, they lack
mediated mechanisms, are largely
clinical validation. The UKs diagnostic
criteria (Williams et al., 1994), introduced
Key points with the aim of perfecting Hanifin and
Rajkas criteria, are the best validated and
indicate the six most useful criteria to use
N AD is a multifactorial disease.
when diagnosing AD for children above
N The environmental factors interact 2 years of age.
with skin and allergic genetic factors
so that the clinical appearance is AD may display three clinical aspects. In the
multifaceted and therapy is complex. acute phase, it manifests itself with vesicular,
weeping and crusting eruptions. In the
N Therapy mainstays are emollients, subacute phase, dry, scaly, erythematous
avoidance of irritants and allergens, papules that may converge into plaques may
topical anti-inflammatory drugs be present. Symptoms of chronic AD are dry,
(mainly corticosteroids) and control lichenified skin with papules and/or nodules
of infections and pruritus. and signs of scratchmarks (excoriations).
N In a subgroup of children, early and Pruritus is almost invariably present in all
severe manifestation of AD has been three phases even if it varies in intensity,
associated with an increased risk of usually worsening in the early evening and at
asthma (the so-called atopic night. Normally, AD involves the large joint
march). flexures (elbow flexure, wrist joint, popliteal
region), forehead, face, eyelids, anterior and

Genetic factors
Loss-of-function Allergic shift

FLG gene predisposition
(and other structural/ (Th2 polarisation)
functional genes)
Der P and other

Epidermal Possible co-existing
aeroallergens
barrier functions food allergy
sensitisation
Direct proteolytic
allergen activity Allergic and
Therapeutic
(Der p, others) immunological
options
inflammation
Irritant/allergen
Irritants, allergens, avoidance
infective agent
Environmental entry Emollients
Atopic
factors Anti-inflammatories
Humidity, Dermatitis
aggressive (TCs, TCIs, others)
substances
Control of infections
Control of pruritus
Figure 1. AD is a multifactorial disease that arises from multiple genetic and environmental interactions.
Genetic factors include complex epidermal barrier and immunological defects. Mutations of filaggrin (FLG)
and other structural genes induce damage to epithelial barrier functions. In this way, cutis may become more
permeable to irritants, allergens and infective agents. If an allergic predisposition also exists (T-helper (Th)2
polarisation), potential allergens that come into contact with the skin can provoke an allergic inflammation.
Irritants can further worsen epithelial barrier functions. Moreover, AD cutis is defective in controlling
infections, and Staphylococcus aureus, in particular, may in turn worsen AD. It is now hypothesised that if
the damaged skin of a potential allergic subject comes into contact with a food allergen this can result in food
allergy. Avoiding irritants/allergens, restoring epithelial barrier functions, fighting inflammation and
controlling infections and pruritus are the mainstays of AD therapy. Der p: Dermatophagoides
pteronyssinus allergen; TCs: topical corticosteroids; TCIs: topical calcineurin inhibitors.
lateral neck and the dorsa of the feet and more extensive, severe forms, with
hands. This distribution can vary from patient widespread erythrodermic rash.
to patient and can differ according to age.
The distribution of lesions and the typology
Moreover, it should be remembered that all and severity of AD may vary according to the
these divisions are artificial and that in any patients age and disease activity. During
individual case, acute relapsing of subacute infancy, AD generally presents more acute
or chronic lesions may occur. Both the lesions mainly affecting the face, scalp, and
extent and severity may vary. Thus, AD extensor surfaces of the extremities.
presents a broad clinical spectrum ranging Bacterial secondary infection
from minor and less severe forms (dry (impetiginisation) is frequent. In older
depigmented skin, hand eczema) to major, children and in those with persisting AD,

symmetrical lichenification and localisation Epidermal barrier dysfunction
of rash to the flexural folds of the
extremities are prominent. The sites of Defects in the epidermal barrier due to
predilection are the face, neck, upper chest genetic and/or functional alterations of
and shoulder girdle, large joint flexures and structural proteins (filaggrin, loricrin,
the back of the hands. Flattened involucrin) and functional proteins
inflammatory infiltrated lesions that may be (proteases and their inhibitors,
hyperpigmented and have a tendency antimicrobial peptides) play a critical role in
to confluence, may be a prominent the pathogenesis of AD. The most
feature. significant genetic factor is loss-of-function
mutation found within the filaggrin (FLG)
A useful method to assess the severity of gene encoding profilaggrin, the ,500-kDa
AD, named SCORAD (from SCORing and precursor for the structural protein FLG. It is
AD), was developed in the 1990s (European detected in about 22% of patients with AD
Task Force on Atopic Dermatitis, 1993) and and is associated with early onset and
has subsequently been validated. To persistence of the disease. FLG gene
calculate the SCORAD index, extension mutations are also implicated in immune
(parameter A), intensity (parameter B) and dysregulation, as they are associated with
subjective symptoms (parameter C) must be increased allergen-specific CD41 T-helper
taken into account. (Th)2 cells. Moreover, epidermal
homeostasis is regulated by proteases,
N Extension is graded up to 100 and it is including kallikreins, which are important for
divided along the entire body according skin desquamation and the activity of which
to the rule of nines. Slight differences is tightly controlled by protease inhibitors.
exist between children under or over
Proteolytic activity from allergens (as well as
2 years of age.
possible IgE-linked activity) has been known
N Intensity is graded up to 18, with a
to play a role in the pathogenesis of AD by
severity score (0: no symptoms; 1: mild
directly affecting the structure and function
symptoms; 2: moderate symptoms, 3: of the epidermal barrier (including the tight
severe symptoms) applied to six items junctions), thereby facilitating further
(erythema, oedema/papules, penetration of allergens. This can possibly
scratchmarks, oozing/crust formation, switch the non-IgE-associated form of AD to
lichenification and dryness). the IgE-associated form by driving dendritic
N Subjective symptoms are itchiness and cells to enhance Th2 polarisation. Moreover,
sleeplessness. They are calculated by in susceptible individuals, allergen-induced
means of two visual analogue scales inflammation promotes Th2 and Th17
graded from 0 to 10, with 20 being the cytokines (interleukin (IL)-17) that in turn
maximum total score. are able to stimulate keratinocytes to
produce other pro-inflammatory cytokines
At this point, an arithmetical formula
and to downregulate FLG expression or the
considering parameters A, B and C (A/5 + 7B/2
proper processing of profilaggrin.
+ C) is applied in order to obtain the SCORAD
index, which ranges 0103. Conventionally, FLG breakdown products, such as urocanic
AD is defined as mild with a SCORAD of ,25, acid and pyrrolidone carboxylic acid, are
moderate with a SCORAD of 2550 and important for maintaining an acidic pH that
severe with a SCORAD of .50. A variant of plays a critical role in regulating epidermal
this method is the Objective-SCORAD (O- permeability, barrier homeostasis,
SCORAD), which excludes subjective epidermal antimicrobial barrier and stratum
symptoms from the evaluation. In this case, corneum integrity/cohesion, by regulating
the maximum score is 83 (A/5 +7B/2) and AD the activity of various enzymes including
is defined as mild with an O-SCORAD of ,15, serine proteases and lipid-processing
moderate with an O-SCORAD of 1540, and enzymes. Disorders in FLG expression and
severe with an O-SCORAD of .40. degradation also result in decreased

expression of the FLG-derived natural plausible explanation for nocturnal
moisturising factor in AD skin. exacerbations.
In the lesions in AD patients, the pH of the Even if histamine is the best-known

skin has been reported to be significantly pruritogen in humans, the histamine
raised. This results in a reduced expression receptor (HR) 1 is unlikely to play a major
of proteins that inhibit colonisation by and role in AD, as the efficacy of non-sedating
growth of Staphylococcus aureus. Indeed, antihistamines in this disease is very
S. aureus colonisation and the resulting limited. Indeed, recent studies showed that
production of toxins are also due to the the HR4 plays a more important role
decreased production of anti-microbial inducing Th2 cell increases and IL-31
peptides (defensins and cathelicidins), production, another important itch inducer
which are downregulated by the in AD, particularly in severe forms.
inflammatory AD micro-milieu. Decreased Moreover, the expression of IL-31s
serum levels of the cathelicidin LL-37 have heterodimeric receptor (IL-31R) can be
been observed in patients with AD, induced or upregulated in keratinocytes,
correlating to decreased vitamin D levels. monocytes, macrophages or dendritic cells
Inflammation is further amplified by S. by microbial factors (S. aureus superantigens
aureus toxins that aggravate the defects in and exotoxins, Toll-like receptor (TLR)
the epidermal barrier (ceramidase) and agonists), as well as endogenous mediators
induce IL-17 production by T-cells. Other of inflammation (proteases, such as trypsin,
negative effects of S. aureus colonisation are tryptase, cathepsins, kallikreins, PAF,
to upregulate the expression of the skin- prostaglandins, opioid peptides), including
homing receptor cutaneous lymphocyte- interferon (IFN)-c.
associated antigen on T-cells (CLA) and Even if skin lesions in AD often result in
induced thymic stromal lymphopoietin increased density of the peripheral nerve
(TSLP) that is able to activate dendritic cells fibres, including substance P-positive nerve
with subsequent proliferation of naive CD4+ fibres, the central sensitisation of itch-
T-cells and their differentiation into Th2 cells signalling systems seems to be a key feature
producing the inflammatory cytokines IL-4, of chronic pruritus in AD because of
IL-5 and IL-13, and Th17/Th22 cells sensitisation of the spinal neurons in the
producing IL-22 that is able to induce dorsal horn, which leads to greater
epithelial proliferation, possibly causing the sensitivity to pruritic input. Two forms of
thickened AD epidermis. Finally, S. aureus- central sensitisation are associated with
specific IgE, generated by the immune pruritus: allokinesis and punctate
system, can bind to FceRI receptors on hyperkinesis. Allokinesis is observed when
dendritic cells and initiate an IgE-mediated touch- or brush-evoked itch occurs around
reaction to this microbe. an itching site. This is commonly seen in
Pruritus children with AD, where sweating, sudden
changes in temperature, contact with fabrics
Pruritus (or itching) is the diagnostic and dressing and undressing induce severe
hallmark of AD and has a significant impact pruritus. Punctuate hyperkinesis consists of
on quality of life including agitation, anxiety, an intense itching sensation in the area
changes in eating habits, poor self-esteem, surrounding histamine induction. Stress
difficulty concentrating, and depression. may also induce or aggravate itch in AD with
Pruritus generally leads to scratching, which a neurogenic mechanism involving
further damages the skin barrier function, so neuropeptides.
worsening inflammation (itch-scratch Immunological dysregulation and link to
cycle). Patients with AD are often unaware allergic diseases
of the extent to which they are scratching,
especially during the night when increased Allergic diseases frequently coexist with AD.
transepidermal water loss may provide a A significant association between early food

sensitisation and AD has been found, of asthma, suggesting that AD can be the
especially at an early age. Food allergy, first step in the so-called atopic march.
which is generally the result of failure to Like AD, asthma is also a complex genetic
develop tolerance, or the loss of pre-existing and multifactorial disorder with high
tolerance, may be caused by defects in prevalence in the paediatric population,
immune or nonimmune intestinal barriers largely attributable to the interactions
(e.g. a defective digestive process or between multiple genes and the environ-
abnormalities in the development of ment. According to some longitudinal
regulatory T-cells, soluble IgA, Peyers prospective studies, the relationship
plaques, and associated dendritic cells). between AD and the subsequent onset of
Moreover, perturbation of the skin barrier asthma is more evident if children with AD
allows allergen penetration that in turn have a parental history of asthma, have had
triggers the activation of Langerhans cells, a severe, early onset of AD and if atopic
facilitating the subsequent uptake of sensitisations exist. Thus, the atopic march
antigens through the tight junction barrier of is not a general phenomenon as it affects
the epidermis. The Langerhans cells then only a subgroup of children with AD, in
presumably migrate to draining lymph whom it is supposed that an FLG gene null
nodes and activate antigen-specific T-cells. mutation allows the skin to be attacked by a
This can lead to Th2 responses and IgE range of factors (irritants, allergens, house
production by B-cells. In humans, food dust mites or S. aureus proteases) thereby
allergen-specific T-cells have been isolated predisposing such children to developing
from lesional skin in patients with eczema. asthma.
It is proposed that in some individuals, Therapeutic options
allergic sensitisation to food may occur
through low-dose cutaneous sensitisation Treatment of AD is aimed at suppressing
and that early consumption of food protein inflammation, restoring the skin barrier and
induces oral tolerance. The timing and controlling itching. Various strategies and a
balance of cutaneous and oral exposure broad number of treatments are available
determines whether a predisposed child has that can help achieve these goals. Optimal
allergy or tolerance. This suggestion rises management is tailored to the patient and
from studies in which preschool children often involves multimodal strategies. Patient
with low-dose exposure to peanut in the education to maximise compliance is
form of arachis oil applied to inflamed skin essential.
had an increased risk of peanut allergy at
Avoidance of irritants and allergens Irritants
age 5 years. Randomised controlled trials
that worsen eczema should be assessed
supporting this hypothesis are expected
during medical evaluations. Textiles made of
soon. The grounds for this phenomenon
silver-loaded, seaweed-based cellulosic
come from animal models where it has
fibers have been shown to significantly
been shown how sensitisation to ovalbumin
reduce S. aureus colonisation without
(measured by sIgE production) occurs
affecting the normal flora, and to decrease
through epicutaneous exposure, following
trans-epidermal water loss in patients with
the removal of the stratum corneum or if
mild-to-moderate AD. Exposure to passive
the skin barrier is genetically impaired. This
was not seen in mice exposed to ovalbumin smoking, extreme temperatures and bright
via intraperitoneal injection. This sunlight should be avoided. Preventing
assumption is reinforced by the fact that contact with the house dust mite may be
ovalbumin allergy has been demonstrated useful if there is sensitisation, but also to
in a murine model for loss-of-function prevent the proteolytic and irritative
mutations in the FLG gene. properties of mites. In very selected cases,
especially if a certain food has been shown
The atopic march Early manifestation of AD to cause immediate or very severe reactions,
has been associated with an increased risk an elimination diet may be proposed.

Emollients Measures to restore the There is a need to address concerns
dysfunction of the skin barrier should be regarding so-called steroid phobia, which
considered as first-line therapy, essential for constitutes a barrier to TC use. Exaggerated
effective treatment and prevention. For fear and inappropriate withholding of TCs by
patients with mild-to-moderate eczema, patients, pharmacists, caregivers and the
topical therapy may be sufficient to control general community are significant barriers
disease activity. Emollients may contain to successful management of AD.
both occlusive substances that provide a
lipid layer on the surface of the skin to slow Topical calcineurin inhibitors Topical
water loss and increase moisture content in calcineurin inhibitors (TCIs) work by
the skin, and humectants, which are inhibiting the phosphatase activity of
substances introduced into the stratum calcineurin, blocking the expression of
corneum to increase its moisture-retaining cytokines. They act downstream in the
capacity. They may be applied several times glucocorticoid receptor pathway and thus
a day, especially after bathing, and their are thought to represent a more targeted
continued use during quiescence can reduce way to contain inflammation and avoid
the tendency for eczema flares. possible adverse effects of topical
corticosteroids. Tacrolimus and
Topical corticosteroids Topical pimecrolimus may be used either as a
corticosteriods (TCs), of the appropriate monotherapy or as a combination or
potency and duration, remain the sequential therapy. The labelled indication is
cornerstone of AD therapy for acute flare- for application twice daily for up to 6 weeks
ups, insofar as they have anti-inflammatory, as a second-line therapy for adults and
immunosuppressive and vasoconstrictive children aged .2 years of age exhibiting an
properties and inhibit fibroblast activity. TCs inadequate response or adverse effects to
are divided into seven classes based on topical corticosteroids.
potency, where class I is the strongest, and
class VII the weakest. Commonly used Treatment of skin infection Improving
options include low-potency (class VI and eczema with an anti-inflammatory regimen
VII; e.g. hydrocortisone), mid-potency (class (TCs, TCIs) decreases staphylococcal
IIIV; e.g. triamcinolone, mometasone, colonisation, but patients with high
fluticasone) and high-potency (class I and II; numbers of colonising S. aureus may require
e.g. fluocinonide, desoximetasone, a short-term topical treatment with topical
betamethasone dipropionate, clobetasol) antiseptics and/or topical antibiotics. In
TCs. For the management of flare-ups, the severe exacerbations, systemic antibiotic
use of mid-to-high potency TCs once/twice therapy may be helpful. Mycosis,
daily for up to 5 days/2 weeks (on the trunk dermatophytosis, streptococcal or viral
and extremities) is generally recommended. infections should be treated only if present.
Lower-potency steroids are recommended Ancillary therapy Oral sedating and
on the face, in young children or as a nonsedating antihistamines have a limited
maintenance therapy. Steroid potency may role in the treatment of AD. Leukotriene
be increased to control inflammation and receptor antagonists have not been developed
once control is gained, TCs should be for regular therapy of AD. Probiotics have
suspended or used intermittently. Recently been studied extensively to define their role in
this approach has been challenged by the the treatment and prevention of AD in
proactive treatment concept that consists of children. Unfortunately, the results are varied
a combination of predefined, long-term, low- and, to date, inconclusive.
dose, anti-inflammatory treatment applied
to previously affected areas, in combination Complementary and alternative therapies
with liberal use of emollients. Twice-weekly There is evidence of growing interest in the
application of fluticasone has been shown to use of complimentary alternative medicine
significantly reduce the risk of relapses of to treat AD, such as Chinese herbal
eczema in a proactive strategy. medicine, essential fatty acids,

phytotherapy, homoeopathy, acupuncture, N Glazenburg EJ, et al. (2009). Efficacy and
bio-resonance, salt baths, and vitamins safety of fluticasone propionate 0.005%
(especially vitamin D, if a low level/intake is ointment in the long-term maintenance
documented) and minerals. To date, there is treatment of children with atopic derma-
no evidence to support the use of titis: differences between boys and girls?
complementary alternative therapies in Pediatr Allergy Immunol; 20: 5966.
routine treatment. N Hanifin JM, et al. (1980). Diagnostic
features of atopic dermatitis. Acta Derm
Systemic therapies Systemic agents are Venereol; 92s: 4447.
generally reserved for persistent, widespread N Kanda N, et al. (2012). Decreased serum
and severe AD that is unresponsive to other LL-37 and vitamin D3 levels in atopic
therapies. Such patients should be treated dermatitis: relationship between IL-31 and
by experienced specialists and therapies oncostatin M. Allergy; 67: 804812.
include corticosteroids, cyclosporine, N Krakowski AC, et al. (2008). Management
methotrexate, azathioprine, mycophenolate of atopic dermatitis in the pediatric
mofetil and, more recently, biological agents population. Pediatrics; 122: 812824.
(soluble receptors, monoclonal antibodies, N Kubo A, et al. (2012). Epidermal barrier
intravenous immunoglobulin and cytokines dysfunction and cutaneous sensitization in
such as recombinant interferon, TNF and atopic diseases. J Clin Invest; 122: 440447.
IgE/IL-5 pathway inhibitors). N McPherson T, et al. (2010). Filaggrin null
mutations associate with increased fre-
quencies of allergen-specific CD41 T-
Phototherapy Ultraviolet therapy can be a helper 2 cells in patients with atopic
useful treatment for recalcitrant AD. eczema. Br J Dermatol; 163: 544549.
N Oranje AP, et al. (2007). Practical issues
on interpretation of scoring atopic der-
Further reading
matitis: the SCORAD index, objective
N Barker JN, et al. (2007). Null mutations in SCORAD and the three-item severity
the filaggrin gene (FLG) determine major score. Br J Dermatol; 157: 645648.
susceptibility to early-onset atopic der- N Ring J, et al. (2012). Guidelines for
matitis that persists into adulthood. J treatment of atopic eczema. Part I. J Eur
Invest Dermatol; 127: 564567. Acad Dermatol Venereol; 26: 10451060.
N Chahine BG, et al. (2010). The role of the N Rubel D, et al. (2013). Consensus guide-
gut mucosal immunity in the develop- lines for management of atopic dermatitis:
ment of tolerance versus development of An Asia-Pacific perspective. J Dermatol;
allergy to food. Curr Opin Allergy Clin 40: 160171.
Immunol; 10: 394399. N Schneider L, et al. (2013). Atopic derma-
N Denby KS, et al. (2012). Update on systemic titis: A practice parameter update 2012.
therapies for atopic dermatitis. Curr Opin J Allergy Clin Immunol; 131: 295299.
Allergy Clin Immunol; 12: 421426. N Spergel JM (2010). From atopic derma-
N Dirven-Meijer PC, et al. (2008). titis to asthma: the atopic march. Ann
Prevalence of atopic dermatitis in chil- Allergy Asthma Immunol; 105: 99106.
dren younger than 4 years in a demar- N Valdman-Grinshpoun Y, et al. (2012).
cated area in central Netherlands: the Barrier-restoring therapies in atopic derma-
West Veluwe Study Group. Br J Dermatol; titis: current approaches and future per-
158: 846847. spectives. Dermatol Res Pract; 2012: 923134.
N Elias PM, et al. (2008). Basis for the barrier N Williams HC, et al. (1994). The U.K.
abnormality in atopic dermatitis: Outside- Working Partys Diagnostic Criteria for
inside-outside pathogenic mechanisms. J Atopic Dermatitis. I. Derivation of a
Allergy Clin Immunol; 121: 13371343. minimum set of discriminators for
N European Task Force on Atopic atopic dermatitis. Br J Dermatol; 131:
Dermatitis (1993). Severity scoring of 383396.
atopic dermatitis: the SCORAD Index. N Yosipovitch G, et al. (2003). Itch. Lancet;
Dermatology; 186: 2331. 361: 690694.

Food allergy
Alessandro Fiocchi, Lamia Dahdah and Luigi Terracciano
Food allergy is an adverse health effect foods cause the majority of allergic
arising from a specific immune response reactions: peanuts, tree nuts, eggs, milk,
that occurs reproducibly on exposure to a fish, crustacean shellfish, wheat and soy
given food (Boyce et al., 2010). This (Boyce et al., 2010).
definition of food allergy includes IgE-
Symptoms of food allergy (table 2) can occur
mediated and non-IgE-mediated immune
within minutes to hours of ingesting the
responses, or a combination of both, and is
trigger food and can vary in severity from
in agreement with recent international
mild to life threatening. Co-factors of
guidelines (Urisu et al., 2011; Fiocchi et al.,
severe allergic reactions include co-
2010a; Sackeyfio et al., 2011) and statements ingestion of other foods, exercise and
(Burks et al., 2012). Table 1 shows specific comorbid conditions. Food-induced
food-induced allergic conditions on the anaphylaxis is the most serious, potentially
basis of pathophysiology, with particular lethal allergic reaction. Fatalities are
emphasis on respiratory manifestations. primarily reported from allergic reactions to
peanuts and tree nuts.
Food allergens can cause reactions when
ingested, touched or inhaled. Cross- The natural history of food allergy resolution
reactivity can occur when a food allergen has is variable and some patients reach
structural or sequence similarity with a tolerance (i.e. they develop a specific
different food allergen or aeroallergen. More nonreactivity to the food). The time courses
than 170 foods have been reported to cause appear to be influenced by several factors.
IgE-mediated reactions but a minority of
N Age of development: food allergy that
starts in adulthood often persists.
Key points N Type of food: allergy to milk, eggs, soy or
wheat is more likely to be outgrown than
N Food allergy is on the rise especially in allergy to fish, shellfish, tree nuts or
children. peanuts.
N Level of IgE: patient with high specific IgE
N Its symptoms may include respiratory level by ImmunoCAP assay (Quest
complaints. Diagnostics, Madison, NJ, USA) are at
N The presence of asthma is a negative risk of persistence (Fiocchi et al., 2008).
prognostic factor for anaphylactic N Size of skin-prick test (SPT) wheal: but in
reactions. some cases, SPT responses remain
positive long after tolerance has
N Severe asthma may be associated with developed.
food allergy. N IgE patterns: the epitope-binding profile
N Currently, the treatment for food of IgE might help to predict the clinical
allergy treatment is avoidance, but course of food allergy (Wang et al., 2010).
OIT is a promising new approach. Prevalence determined on the basis of
patient self-report is higher than that

Table 1. Food allergy conditions associated with respiratory complaints
Key features Common triggers
IgE mediated (acute onset)
Anaphylaxis Rapidly progressive, multiple Peanut
organ system reaction up to Tree nuts
cardiovascular collapse Fish
Aggravated by co-existing Shellfish
asthma Milk
Egg
Food-dependent, exercise-induced Food triggers anaphylaxis only if Wheat
anaphylaxis ingestion followed temporally by Shellfish
exercise Celery
May be confused with exercise- Moulds
induced asthma
Combined IgE and cell mediated (delayed/
chronic onset)
Eosinophilic oesophagitis Symptoms may include feeding Multiple
disorders, reflux symptoms
including cough, vomiting,
dysphagia and food impaction.
Food-induced asthma Asthma induced by food Cows milk
ingestion/inhalation (e.g. Wheat
bakers asthma)
Food-induced rhinitis Rhinitis induced by food Cows milk
ingestion/inhalation Tree nuts
Peanut
Cell mediated (delayed/chronic onset)
Heiner syndrome Pulmonary infiltrates Cows milk
Failure to thrive
Iron-deficiency anaemia
determined by clinical testing and medical Prevalence rates of admissions for food
history. In general, food allergy affects more anaphylaxis in Australia increased by 350%
than 12% but ,10% of the population (Keil between 1994 to 2005, and rates of increase
et al., 2010). It seems that prevalence is were greater for children ,4 years of age and
rising: a large population-based study of for peanut and tree nut anaphylaxis, with
challenge-proven food allergy in 12-month- more modest increases noted for older age
old infants in Australia reported prevalences groups and other allergies such as cows
of 3% for peanut allergy, 8.9% for egg allergy milk or egg.
and 0.8% for sesame allergy (Osborne et al.,
2011). The prevalence of food allergy Food allergy symptoms include:
appears to have increased in recent years.
Self-reported survey data in the USA N food refusal in young children,
suggested there has been an 18% increase in N skin symptoms (urticaria, angio-oedema,
food or digestive allergies from 1997 to erythema, itching and eczema),
2007, and Chinese paediatricians reported N gastrointestinal tract symptoms
an increased rate of challenge-confirmed (oropharyngeal tingling and burning, oral
food allergy from 3.5% in 1999 to 7.7% in allergy syndrome, vomiting, and
2009 (p50.017) (Chen et al., 2011). abdominal pain),

Table 2. Symptoms of food-induced allergic reactions
Target organ Immediate symptoms Delayed symptoms
Cutaneous Erythema Erythema
Pruritus Flushing
Urticaria Pruritus
Morbilliform eruption Morbilliform eruption
Angio-oedema Angioedema
Eczematous rash
Ocular Pruritus Pruritus
Conjunctival erythema Conjunctival erythema
Tearing Tearing
Periorbital oedema Periorbital oedema
Upper respiratory Nasal congestion
Pruritus
Rhinorrhoea
Sneezing
Laryngeal oedema
Hoarseness
Dry staccato cough
Lower respiratory Cough Cough
Chest tightness Dyspnoea
Dyspnoea Wheezing
Wheezing
Intercostal retractions
Accessory muscle use
Gastrointestinal (oral) Lip oedema
Tongue swelling
Oral pruritus
Gastrointestinal (lower) Nausea Nausea
Reflux Reflux
Colicky abdominal pain Abdominal pain
Vomiting Haematochezia
Diarrhoea Vomiting
Diarrhoea
Cardiovascular Tachycardia
Hypotension
Dizziness
Loss of consciousness
Reproduced and modified from Boyce et al. (2010) with permission from the publisher.
N airway symptoms (persistent cough, and non-IgE-mediated food allergy

hoarse voice, wheeze, stridor and syndromes present with predominantly
respiratory distress), and abdominal symptoms (vomiting, diarrhoea,
N disturbances of the circulatory system pain and haematochezia) that develop
(pale and floppy infant or young child, several hours after ingestion of the food.
hypotension, or collapse).
Neither medical history alone not physical
IgE-mediated symptoms develop within examination is diagnostic of food allergy
minutes to an hour of ingesting the food. In (Boyce et al., 2010). IgE-mediated food
contrast, non-IgE-mediated and mixed IgE- allergies require the presence of specific IgE

to confirm a diagnosis. These can be of immediate allergic reaction and
identified by SPT or by immunoassays of anaphylaxis is high and cannot be calculated
serum levels of specific IgE. SPT can be a priori. An absolute contraindication to
performed using standardised extracts or, in challenge procedures is a recent
case of fruit and vegetables, fresh products. anaphylactic reaction: if a patient had a
These tests identify sensitisation to foods reaction to a known food, they should not
that may provoke IgE-mediated reactions undergo a challenge with that food.
but neither is directly diagnostic of food
allergy, nor is, despite many attempts, the Food allergy and respiratory disease
patch test with foods. The test results must Children with food allergy have a four-fold
be reviewed against the clinical history increased likelihood of having asthma and
(Boyce et al., 2010; Fiocchi et al., 2010b). For 3.6-fold increased likelihood of respiratory
non-IgE-mediated or mixed IgE-mediated allergies compared with children without
and non-IgE-mediated food allergies, the food allergy (Branum et al., 2009). Allergic
situation is even more complex: in these rhinitis, in particular, has been reported in
cases, no laboratory tests can assist the children allergic to peanuts, tree nuts or
clinician, and the diagnosis relies upon an milk. Food is rarely a trigger for exacerbation
elimination/reintroduction challenge diet of symptoms in asthma (,2% of patients
with the suspected food. with asthma) but may be an important co-
factor in severe asthma (Roberts et al.,
Although serum concentrations of specific
2003). Conversely, the presence of asthma is
IgE and SPT wheal sizes generally correlate
a risk factor for fatal anaphylaxis and longer
with the likelihood of a clinical reaction, they
persistence of food allergy (Fiocchi et al.,
do not correlate with or predict the severity of
2008). It is therefore important to evaluate
allergic reaction to the food (Sampson,
the possible presence of asthma in patients
2001). The availability of recombinant
with food allergy and to keep it under
allergen-specific IgE tests against the major
adequate control. It seems that ongoing
allergens in a food (e.g. Arah2 in peanuts,
airway inflammation (increased exhaled
Bosd8 in cows milk and Gald2 in eggs) has
nitric oxide levels) may persist in children
paved the way for improving the diagnosis of
with food allergy even after asthma is
clinical allergy but the exact use of these tests
thought to have resolved (Kulkarni et al.,
is still to be studied (Fiocchi et al., 2011).
2012). Such persistent airway inflammation
The double-blind, placebo-controlled food might be important in the evolution of
challenge (DBPCFC) is the most specific test respiratory symptoms after food allergen
for identifying a true food allergy. It reliably exposure, even in children whose previously
distinguishes sensitisation from clinical clinically relevant asthma has been
allergy. Ideally, the challenge is performed as apparently quiescent recently.
a double-blind procedure; however, it is Treatment
time- and labour-intensive, and many health
systems do not reimburse it. For these For IgE-mediated, non-IgE-mediated, and
reasons, single-blind or open-food mixed IgE-mediated and non-IgE-mediated
challenges often replace the DBPCFC in food allergy syndromes, the first-choice
everyday clinical practice and may be therapy is avoiding the causal food(s)
considered diagnostic under certain (Boyce et al., 2010). Patients should be
circumstances. They contribute to food instructed on the interpretation of ingredient
allergy diagnosis in young children or in labels to avoid their specific allergens.
presence of objective (rather than However, even in children with severe food
subjective) symptoms. However performed, allergy, avoidance of responsible foods may
a food challenge must be done in a medical be difficult to maintain and accidental
facility with onsite medical supervision and ingestion may occur. Therefore, patients at
appropriate resources for emergency risk for anaphylaxis should be provided with
management of allergic reactions. The risk an emergency action plan indicating signs

and symptoms of mild-to-moderate and to induce immunological tolerance,
severe reactions. These plans can guide however, remains uncertain and the
medical personnel in treatment, including approach is plagued with the risk of severe
how and when to administer adrenaline if an reactions. Given the overall very low quality
autoinjector is prescribed (Simons et al., of the evidence and very imprecise estimates
2012). of the effects, the true effect of OIT in
patients with food allergy is unknown.
Adrenaline is the mainstay of the treatment Consequently, today, patients and clinicians
of anaphylaxis (i.e. acute, severe, systemic willing to avoid possibly serious adverse
allergic reactions). Antihistamines can be effects are likely to continue the elimination
used to manage symptoms of nonsevere diet and re-evaluate the possibility of oral
allergic reactions (Boyce et al., 2012). As immunotherapy when more robust and
biphasic reactions may occur in up to 20% precise data are available. Those determined
of cases, patients who receive adrenaline for to achieve tolerance and who are less
a food-induced anaphylactic reaction should worried about possibly serious adverse
be immediately admitted to an emergency effects may choose to undergo
facility for observation. Systemic immunotherapy with foods (Brozek et al.,
corticosteroids are also often recommended 2012). Thus, OIT is not yet appropriate for
to prevent biphasic or protracted widespread use.
anaphylactic reactions but the evidence
beyond their use is thin (Simons et al., Treatments using modified antigens,
2012). For most patients who have epicutaneous administration of allergens or
experienced anaphylaxis, observation for 4 Chinese herbal therapy could also represent
6 h is in order. Patients with severe or safe and efficient alternatives in the future.
refractory symptoms require prolonged Additionally, treatment with anti-IgE
observation or hospital admission. monoclonal antibodies may increase
threshold doses needed to stimulate an
Food allergy is a quality-of-life disruptor: allergic reaction and provide enhanced
anxiety can arise from the perceived risk of safety profiles for patients. Probiotics, widely
anaphylaxis and the burden of allergen used for food allergy, deserve further
avoidance. The caregivers of these children evaluation (Fiocchi et al., 2012). Recent
are also anxious, and intra- and interfamilial reports about anaphylaxis to
relationships can be heavily influenced by the galactooligosaccharides cast a shadow on
disease (King et al., 2009). Education related the possibility of use of prebiotic fibres in
to managing food allergy may improve the prevention and treatment of food allergy
patient and caregiver self-efficacy, quality of (Chiang et al., 2013).
life, and successful allergen avoidance.
Oral immunotherapy Further reading
Strict avoidance of allergens is not curative N Boyce JA, et al. (2010). Guidelines for the
and the patients remain at risk of accidental diagnosis and management of food
exposure. For this reason, several new allergy in the United States: report of
the NIAID-sponsored expert panel. J
therapeutic approaches are being tested in
Allergy Clin Immunol; 126: S1S58.
clinical trials, but none is ready for clinical
N Branum AM, et al. (2009). Food allergy
care (Nowak-Wegrzyn et al., 2011). Systemic, among children in the United States.
subcutaneous immunotherapy has been Pediatrics; 124: 15491555.
investigated in the past but gave severe N Brozek JL, et al. (2012). Oral immunother-
adverse effects. Newer forms of therapy (e.g. apy for IgE-mediated cows milk allergy: a
immunotherapy) have sought to provide systematic review and meta-analysis. Clin
systemic treatment with reduced risk and Exp Allergy; 42: 363374.
side-effects. For a variety of food allergens, N Burks AW, et al. (2012). ICON: Food allergy.
oral immunotherapy (OIT) is able to reduce J Allergy Clin Immunol; 129: 906920.
clinical reactivity in some patients. Its ability

N Chen J, et al. (2011). The prevalence of food N Kulkarni N, et al. (2012). Eosinophilic
allergy in infants in Chongqing, China. airway inflammation is increased in
Pediatr Allergy Immunol; 22: 356360. children with asthma and food allergies.
N Chiang WC, et al. (2012). Anaphylaxis to Pediatr Allergy Immunol; 23: 2833.
cows milk formula containing short- N Nowak-Wegrzyn A, et al. (2011). Future
chain galacto-oligosaccharide. J Allergy therapies for food allergies. J Allergy Clin
Clin Immunol; 130: 13611367. Immunol; 127: 558557.
N Fiocchi A, et al. (2008). Incremental N Osborne NJ, et al. (2011). Prevalence of
prognostic factors associated with cows challenge-proven IgE-mediated food
milk allergy outcomes in infant and child allergy using population-based sampling
referrals: the Milan Cows Milk Allergy and predetermined challenge criteria in
Cohort study. Ann Allergy Asthma infants. J Allergy Clin Immunol; 127:
Immunol; 101: 166173. 668676.
N Fiocchi A, et al. (2010a). Diagnosis and N Roberts G, et al. (2003). Food allergy as a
Rationale for Action Against Cows Milk risk factor for life-threatening asthma in
Allergy (DRACMA): a summary report. J childhood: a case-controlled study. J
Allergy Clin Immunol; 126: 11191128. Allergy Clin Immunol; 112: 168174.
N Fiocchi A, et al. (2010b). World Allergy N Sackeyfio A, et al. (2011). Diagnosis and
Organization (WAO) Diagnosis and assessment of food allergy in children
Rationale for Action against Cows Milk and young people: summary of NICE
Allergy (DRACMA) guidelines. World guidance. BMJ; 342: d747.
Allergy Organ J; 3: 5761. N Sampson HA (2001). Utility of food-
N Fiocchi A, et al. (2011). The fascinating specific IgE concentrations in predicting
world of molecular diagnosis in the symptomatic food allergy. J Allergy Clin
management of food allergy: nondum Immunol; 107: 891896.
matura est. Curr Opin Allergy Clin N Simons FE, et al. (2012). 2012 Update:
Immunol; 11: 200203. World Allergy Organization Guidelines for
N Fiocchi A, et al. (2012). Clinical Use of the assessment and management of
Probiotics in Pediatric Allergy (CUPPA): a anaphylaxis. Curr Opin Allergy Clin
World Allergy Organization position Immunol; 12: 389399.
paper. World Allergy Organ J; 5: 148167. N Urisu A, et al. (2011). Japanese guideline
N Keil T, et al. (2010). The multinational for food allergy. Allergol Int; 60: 221236.
birth cohort of EuroPrevall: background, N Wang J, et al. (2010). Correlation of IgE/
aims and methods. Allergy; 65: 482490. IgG4 milk epitopes and affinity of milk-
N King RM, et al. (2009). Impact of peanut specific IgE antibodies with different
allergy on quality of life, stress and phenotypes of clinical milk allergy. J
anxiety in the family. Allergy; 64: 461468. Allergy Clin Immunol; 125: 695702.

Allergic bronchopulmonary
aspergillosis
Andrew Bush
Unlike in adults and for reasons which are N Ensure that atypical forms of CF have
not clear, allergic bronchopulmonary been excluded. Even if the sweat test is
aspergillosis (ABPA) in children is virtually unequivocally normal, genetic testing and
always seen in the context of CF. ABPA measurement of transepithelial potential
complicating paediatric asthma has only differences should be considered.
been the subject of isolated case reports. N Consider alternative differential
Other, even more rarely, reported diagnoses, such as mucus plugging and
associations in children include hyper IgE atelectasis, gastro-oesophageal reflux
syndrome, chronic granulomatous disease, disease, eosinophilic or other
bronchocentric granulomatosis, previous TB noninfective pneumonias, and collagen
and treatment of sarcoidosis with infliximab. vascular disease.
In adults, it has been described in N Consider the possibility of the rare
association with COPD. Unsurprisingly, late associations mentioned above.
diagnosis after a prolonged clinical course is
common in this rare setting. If ABPA is Aspergillus fumigatus is ubiquitous in the
suspected in the context of another environment. Two features make it
paediatric respiratory illness, three steps are particularly prone to infect the human lower
essential. airway.
N The spores have a mass median diameter

in the range of 25 mm, meaning that
they are the ideal size for impacting in the
Key points lower airway.
N They grow at 37uC, i.e. body temperature.
N Unlike in adults where asthma with
However, an ABPA-like picture has rarely
ABPA is common, ABPA is rarely seen
in children other than complicating been reported as being caused by other
CF. fungi, for example other strains of
Aspergillus, and non-Aspergillus species such
N In the context of CF, ABPA is difficult as Scedosporium apiospermum. These are not
to diagnose because it mimics CF covered further in this chapter.
lung disease. Manifestations of A. fumigatus lung disease
N The single most useful diagnostic test are summarised in table 1. The rest of this
is an abrupt, four-fold rise in serum chapter discusses ABPA in the context of CF.
IgE.
Definition
N The mainstay of ABPA treatment is
systemic corticosteroids, increasingly ABPA is the clinical manifestation of a T-
pulsed methyl prednisolone rather helper (Th)2 driven hypersensitivity
than oral prednisolone. response within the airway to A. fumigatus
and its exoproducts.

Table 1. Manifestations of Aspergillus fumigatus lung disease
Disease Manifestation
CF ABPA
Positive sputum culture which may be associated with
worse lung function and more pulmonary exacerbations
Allergen provoking wheeze
Large airway plugging
Mycetoma
Invasive aspergillosis
Asthma Isolated positive skin test
Allergen provoking wheeze due to atopic sensitisation
Severe asthma with fungal sensitisation
Immunocompromised host Invasive aspergillosis
(congenital or acquired)
Lung cavity (congenital thoracic Mycetoma
malformation, TB, post pneumonic)
Interstitial lung disease Hypersensitivity pneumonitis
Prevalence of ABPA certainly an underestimate) reported an

increasing prevalence up to 20 years of age,
The prevalence of ABPA is difficult to which thereafter declined. 10% of ABPA
determine due to the different diagnostic patients had a normal FEV1 and .80% did
criteria used, and the different indices of not report wheeze. Infection with
suspicion prevailing in the various clinics. Pseudomonas aeruginosa was common
The latest European CF Society Registry (,70%). The European registry study (967
report (which unfortunately does not yet ABPA patients out of a total of 12 447 CF
contain comprehensive information across patients in the registry) reported a peak
the whole of Europe), using the diagnostic between 1318 years, and ABPA was rare
criteria shown in table 2, reported below 6 years of age. There is no convincing
prevalence that varied from 1.4% (Sweden) sex difference in prevalence when the two
to 17.9% (Switzerland). Whether these databases are combined. ABPA was
differences reflect different levels of associated with a poorer general clinical
diagnostic suspicion, differences in condition (10% lower FEV1, lower weight Z-
diagnostic testing or a genuine geographical score, more commonly infected with P.
variation in disease prevalence is not clear. aeruginosa, Burkholderia cepacia,
The UK CF Trust registry report (7937 Stenotrophomonas maltophilia, and,
patients) reported a total of 725 (prevalence surprisingly, Haemophilus influenzae, but not
9.1%) cases of ABPA in 2010, of which 156 with Staphylococcus aureus infection) and
were new (incidence 2%). Although the there was an association with pneumothorax
incidence of new cases was the same in and massive haemoptysis, presumably
adults and children, the prevalence, perhaps related to the underlying severe lung
surprisingly, was higher in those aged disease. There were no associations with
.16 years (10.8% versus 7.0%). particular genotypes or mutation classes.
There are two other older, but still useful, Pathophysiology
registry studies from the USA and Europe.
The US study (281 (2%) ABPA patients out A. fumigatus may provoke an intense allergic
of 14 210 total registered patients, almost response leading to secondary airway

Table 2. Summary of diagnostic criteria for ABPA used in the European registry
Acute or subacute clinical deterioration, no other aetiology found
Total IgE .500 IU?mL-1
Positive skin prick test (.3 mm) or specific IgE for Aspergillus fumigatus
Either:
IgG precipitins or in vitro demonstration of IgG antibody response to Aspergillus fumigatus
New or recent imaging abnormalities (chest radiograph or CT) not clearing with standard
therapy
damage, but proteolytic and other enzymes patients will have a positive sputum culture
may lead to non-allergic, direct pulmonary for A. fumigatus.
toxicity. ABPA is the result of a skewed
CD4+, Th2 T-cell response to A. fumigatus Confirming the diagnosis of ABPA
leading to interleukin (IL)-4 and IL-5 Making the diagnosis of ABPA in the context
production and, hence, elevation of serum of CF may be difficult; there is no single
IgE and airway eosinophilia. A. fumigatus diagnostic test. The classical case is easy to
may directly lead to the production of pro-
diagnose. However, many of the symptoms
inflammatory cytokines from bronchial
and signs of ABPA are common to the
epithelial cells. The importance of genetics
underlying CF. Furthermore, markers of
has been suggested by the occurrence of
sensitisation to A. fumigatus and positive
familial cases. Important factors include
sputum cultures are frequently seen in
HLA-DR and HLA-DQ (the latter protective),
otherwise uncomplicated CF; and true cases
and polymorphisms in the genes for IL-4RA,
of ABPA may be culture negative for A.
IL-10, surfactant protein A and Toll-like
fumigatus. We found that the single most
receptor 9. Recently, elevated levels of the
useful test is an abrupt, at least four-fold rise
co-stimulatory molecule OX40 ligand
in total IgE to .500 IU?mL-1; IgE may
(OX40L) have been shown to be important
sometimes, but not always, fall with
in driving the Th2 response to A. fumigatus
treatment so serial IgE measurements
in peripheral CD4+ T-lymphocytes. Of
should be used with caution in monitoring
possible therapeutic interest, OX40L levels
response. A high level of IgG precipitating
fell with in vitro addition of vitamin D.
antibodies to A. fumigatus may also be
However, A. fumigatus downregulates the
suggestive (.90 mg?mL-1; ImmunoCap;
vitamin D receptor, which may affect the
Thermo-Fisher Scientific, Uppsala, Sweden);
response to vitamin D therapy.
multiple positive precipitins are more
Presentation suggestive of mycetoma. Major and minor
criteria for ABPA have been proposed, but
ABPA should be at least suspected in CF atypical cases may not meet classical criteria
children with increased respiratory yet still require treatment, which should not
symptoms, particularly if there is wheeze, be delayed if the index of suspicion is high
chest tightness or pleuritic chest pain and but classical criteria are not met. In
an audible pleural rub. Exceptionally, pleural doubtful cases, many would initially give a
effusion and pneumomediastinum have trial of intravenous antibiotics and then treat
been described in ABPA. There may be a for ABPA if there was no response.
sharp decline in spirometry, and the chest
radiograph typically shows one or more new The tables of major and minor criteria are
soft fluffy shadows (fig. 1), with a gloved useful guides to the diagnosis of ABPA, but
finger appearance of mucus impaction in are no more than guides, and atypical cases
the airways, which are very unusual in a CF will continue to be diagnosed on an
pulmonary exacerbation. Less than half the individual clinical basis. The United States

a) b)
Figure 1. Chest radiograph from a CF patient recently diagnosed with ABPA. a) A combination of
widespread indistinct nodular opacities, ring shadows (bronchiectatic airways) in the right mid zone, and
consolidation in the left lower lobe can be seen. b) Several months later, most of the shadowing has
resolved but there is a new elliptical opacity (a plugged bronchiectatic airway) just above the left hilum.
Cystic Fibrosis Foundation (USCFF) studies using targeted allergy testing to

Consensus Conference proposed criteria for specific purified A. fumigatus antigens
classic ABPA, minimal diagnostic criteria including Asp f1, f3, f4 and f6, and serum
and recommendations for screening thymus- and activated-regulated chemokine
(table 3). These are a useful guide to the (TARC) levels looked promising. Only TARC
clinician, and very helpful for ensuring has been studied in a second prospective
uniformity of diagnosis in registries, but cohort, but its measurement currently
cannot be considered definitive under all remains in the research domain.
circumstances.
Lung function testing in ABPA
Novel, more sophisticated, testing has been
proposed. Cytoplasmic A. fumigatus There are no changes specific to ABPA.
antigens may be elevated in ABPA. Initial Characteristically, there is an acute
Table 3. Diagnostic criteria for ABPA in the context of CF

Classical ABPA
Acute or subacute clinical deterioration not attributable to another cause
Serum total IgE .1000 IU?mL-1 in a patient not receiving oral corticosteroids
Positive skin prick test to Aspergillus fumigatus
Positive IgG precipitins to Aspergillus fumigatus
New or recent chest radiograph abnormalities not clearing with conventional therapy, such as
physiotherapy and antibiotics
Minimal diagnostic criteria for ABPA
Acute or subacute clinical deterioration not attributable to another cause
Serum total IgE .500 IU?mL-1 (retest in 13 months if 200500 IU?mL-1)
Positive skin prick test to Aspergillus fumigatus
Either: positive IgG precipitins to Aspergillus fumigatus, or new or recent chest radiograph
abnormalities not clearing with conventional therapy, such as physiotherapy and antibiotics

worsening of pre-existing airflow obstruction would be 2 mg?kg-1 for 2 weeks (maximum
or its de novo development. This is initially, 60 mg), then 1 mg?kg-1 for 2 weeks, then
at least partially, reversible, but becomes 1 mg?kg-1 on alternate days for 2 weeks,
fixed with low lung volumes if the disease followed by a slow taper. The alternative to
progresses. Diffusing capacity may be low in oral corticosteroids is pulsed methyl
an acute exacerbation, and remain low in prednisolone, 500 mg?m-2 on three
end-stage disease. Spirometry is probably successive days every 4 weeks. It is
the most useful marker of response to suggested that there is improved efficacy
treatment, being better than serum IgE or and fewer side-effects. Certainly, the use of
more sophisticated biomarkers. pulsed therapy means that adherence is not
an issue, provided the child is brought to the
Screening
hospital.
An annual measurement of total IgE is
Antifungal therapy: The Cochrane review
recommended, with further investigation if
identified only two trials of antifungal
IgE is .500 IU?mL-1 or 200500 IU?mL-1
therapy in ABPA, neither suitable for
and the index of suspicion is high. The
inclusion here. Itraconazole in combination
possibility of ABPA should be considered in
with steroid treatment is used for two
all pulmonary exacerbations, in particular if
reasons. First, in ABPA complicating asthma
there are fresh chest radiographic infiltrates
there is clear evidence that this is beneficial,
or response to treatment is poor; an
and there is weak retrospective evidence of
admission measurement of total IgE is
benefit in CF. Secondly, rare cases of
routine in our CF unit.
invasive aspergillosis complicating CF have
Management been described and at least, in theory,
itraconazole may prevent this. Oral
Prevention Playing or working in damp absorption of itraconazole is poor, and
places such as stables where A. fumigatus serum levels should be measured and the
spores are in high concentrations must be dose adjusted. Furthermore, at least in
discouraged. Although there is less adults, azole resistance in A. fumigatus is
evidence, it would seem sensible to ensure common. Itraconazole inhibits the
there are no moulds in the house, and to cytochrome p450 enzyme CYP3A, which can
check that that A. fumigatus (or indeed other lead to Cushings syndrome and iatrogenic
organisms) are not cultured from the adrenal suppression in patients also taking
nebuliser by maximising hygiene. Recent inhaled budesonide or fluticasone and oral
immunological work suggests that methyl prednisolone (but not prednisolone).
optimising vitamin D levels may be helpful. Other anti-fungal options include nebulised
Treatment As with much of paediatric
respiratory medicine, there are no
randomised controlled trials to inform
treatment decisions, and no satisfactory
evidence base on which to recommend the
nature and duration of treatment of ABPA. If
there is any doubt about the diagnosis, then
intravenous antibiotics should be given first.
Treatment is aimed at reducing the
inflammatory and tissue-damaging
consequences of fungal infection, and also
reducing the burden of the fungal infection.
Corticosteroids: Conventionally, the mainstay Figure 2. HRCT through the upper lobes showing
of treatment is oral prednisolone, which may bilateral bronchiectasis; the varicose pattern of
need to be given in high dose for a bronchiectasis in the anterior segment of the right
prolonged period of time. A typical regimen upper lobe is typical of APBA.

Table 4. Stages of ABPA
Stage 1: Acute phase
There are acute infiltrates that clear completely with prednisolone
Stage 2: Remission
No prednisone therapy or infiltrates for 6 months
Stage 3:
Recurrent exacerbation similar to stage 1
Stage 4:
Phase of steroid dependent asthma
Stage 5:
Fibrotic disease no longer completely responds to prednisolone therapy
Although frequently described, the clinical utility of this staging is not great.
amphotericin (liposomal if the standard Complications of treatment are generic to

preparation cannot be tolerated) with or the medications used but for CF, loss of
without nebulised budesonide, bone mineral density and precipitation of
voriconazole, posaconazole and intravenous CF-related diabetes are particularly
liposomal amphotericin. The evidence for important.
usage of these agents is minimal.
Prognosis
Other current treatment options: There are
small case series reporting the use of the Mild cases of ABPA may resolve
anti-IgE monoclonal antibody omalizumab spontaneously, but the majority relapse after
(xolair) in ABPA. Inhaled corticosteroids are treatment. Accelerated decline in lung
commonly employed, but there is only the function is reported in patients treated for
most limited evidence that they are ABPA. ABPA has been divided into five
beneficial. There are occasional anecdotal stages with different prognoses (table 4); it
reports of bronchoscopic airway toilet in is arguable whether these are clinically
recalcitrant airway plugging. useful. They are not a chronological
progression in clinical practice. Prolonged
The future: The evidence of Th2 driven and recurrent ABPA is common, so
responses suggests that monoclonal prognosis must be guarded.
antibody-directed signature Th2 cytokines
(IL-4, IL-5 and IL-13), which are already
researched in asthma, may also be useful in Further reading
ABPA
N CF Registry. Cystic Fibrosis Trust Annual
Complications of ABPA Data Report 2010. www.cysticfibrosis.
org.uk/media/108230/CR_Annual_Data_
These are the complications of the disease Report_2010_Dec_11.pdf
itself, and complications of treatment. N Elphick HE, et al. (2012). Antifungal
therapies for allergic bronchopulmonary
Disease-specific complications are severe aspergillosis in people with cystic fibro-
proximal bronchiectasis (fig. 2) and, in sis. Cochrane Database Syst Rev; 6:
some, but not all series, accelerated decline CD002204.
in lung function. ABPA is a risk factor for N European Cystic Fibrosis. ECFS Patient
infection with atypical Mycobacteria Registry Annual Report 20082009. www.
infection, although whether because of ecfs.eu/files/webfm/webfiles/File/ecfs_
steroid therapy rather than the underlying registry/ECFSPR_Report0809_v32012.pdf
disease is not known.

N Hafen GM, et al. (2009). Allergic bronch- N Moss RB (2010). Allergic bronchopul-
opulmonary aspergillosis: the hunt for a monary aspergillosis and aspergillus
diagnostic serological marker in cystic infection in cystic fibrosis. Curr Opin
fibrosis patients. Expert Rev Mol Diagn; 9: Pulm Med; 16: 598603.
N Patterson K, et al. (2010). Allergic bronch-
157164.
opulmonary aspergillosis. Proc Am Thoracic
N Kreindler JL, et al. (2010). Vitamin D3 atten-
Soc; 7: 237244.
uates Th2 responses to Aspergillus fumiga- N Rapaka RR, et al. (2009). Pathogenesis of
tus mounted by CD4+ T cells from cystic allergic bronchopulmonary aspergillosis
fibrosis patients with allergic bronchopul- in cystic fibrosis: current understanding
monary aspergillosis. J Clin Invest; 120: and future directions. Med Mycol; 47:
32423254. Suppl. 1, S331S337.

Specific immunotherapy,
prevention measures and
alternative treatment
Susanne Halken and Gunilla Hedlin
The majority of schoolchildren with asthma associated with chronic inflammation, in

are allergic to airborne allergens and allergy contrast to exposure to pet allergens, which
is a common trigger of asthma symptoms. may induce acute reactions as well.
The allergens associated with allergic airway
disease depend on the age, climatic, Subcutaneous immunotherapy (SCIT) is still
seasonal and social factors, and housing questioned as a safe and efficacious way of
conditions. In temperate and humid treating allergic asthma in children. Children
regions, allergy to house dust mites shows with severe allergic asthma are often
the strongest association with asthma sensitised to multiple allergens, which
followed by allergy to furred pets (especially makes SCIT both complicated and less safe
cats). In arid climates, allergy to the fungus to administer. In a Cochrane review
(Alternaria spp.) is prevalent. published in 2010, however, it was
concluded that SCIT has significant and
Allergic asthma is most often associated beneficial effects on symptoms and
with indoor inhalant allergens, whereas medication use in both children and adults
allergic rhinitis most often is associated with with mostly mild asthma. Only a few studies
outdoor allergens such as pollen. In children have been performed specifically on SCIT in
with allergic asthma, persistent allergen children with moderate and severe asthma.
exposure is associated with airway Sublingual immunotherapy (SLIT) has also
inflammation, bronchial been shown to improve asthma symptoms
hyperresponsiveness, and an increased risk and decrease medication use.
of persistent and severe asthma.
Anti-IgE (omalizumab) is the only
The aerodynamic characteristics of the monoclonal antibody so far with a
allergen-carrying particles vary considerably. documented effect in children with severe
Thus, most house dust mite and cockroach allergic asthma. Although this drug could
allergens are carried on relatively large turn out to be very efficacious in children with
particles, whereas most pet allergens are milder disease, the cost of the treatment is
carried on small particles. Therefore, house one limitation of the use of this therapy
dust mite exposure is most commonly Allergen avoidance
Avoiding exposure to relevant allergens is a
Key points logical way to treat allergic airway diseases,
when the offending allergen can be
N Immunotherapy with seasonal and identified and effective avoidance is feasible.
perennial airborne allergens In the case of allergy to pollen and foods, it
has beneficial effects on allergic is well recognised that avoidance of these
asthma. allergens results in less or no symptoms.
The case of allergy and exposure to
N Anti IgE therapy reduces the risk of
perennial airborne allergens is more
asthma exacerbations on children
complex, as exposure is not restricted to
with severe allergic asthma.
specific situations or environments, but may

occur throughout the community. Moreover, Table 1. Recommendations for children with asthma
many children with allergic asthma are and allergy to house dust mites
allergic to a number of allergens (e.g. both
house dust mites and pets). Pet allergens Ensure sufficient ventilation
are, to a high degree, airborne and Avoid damp housing conditions
ubiquitous. Significant concentrations are Encase mattresses
also found in clothes and places without
Wash pillows, duvets, blankets and bed
direct contact with pets, even several years
pads every 34 months (.55uC)
after removal of a pet.
Wash soft toys and other mite reservoirs
A clinical effect of allergen avoidance was
first suggested by studies in which patients
were removed from their homes to low- measures have been recommended for
allergen, mountain environments, which house dust mite allergen avoidance, most of
resulted in improved lung function and them focusing on the bedding environment
normalised markers of allergic inflammation (table 1).
in children with allergic asthma. Later,
several studies on different measures of A recent update of the Cochrane meta-
environmental control in patients homes analysis concluded that current chemical
indicated a clinical effect of allergen and physical methods aimed at reducing
avoidance. Still, much controversy exists exposure to house dust mite allergens
over the evaluation of results from these cannot be recommended for patients with
studies and from meta-analyses, mainly due asthma and house dust mite allergy
to methodological problems. In order to (table 2). However, this conclusion may
document a causeeffect relationship, have many explanations (e.g. heterogeneity
avoidance measures should be capable both in studies, inclusion criteria and the fact that
of reducing the allergen level sufficiently and some of the allergen avoidance measures
of resulting in a clinical effect. did not sufficiently reduce allergen
exposure).
Most of the previous studies on
environmental allergen avoidance measures Well performed, controlled, randomised
have focused on a single allergen, and the studies with adequate design and methods
measures for exposure have been have demonstrated that some avoidance
concentrations of allergens in dust from measures, such as mattress encasings with
mattresses, floors or furniture. This may not mite allergen-impermeable coverings, have
represent personal exposure to proven effective both in reducing the level of
aeroallergens. Individual differences in house dust mite allergens and in improving
sensitivity to exposure may be important. In disease control in children.
addition, the level of anti-inflammatory
treatment may be important for evaluation There is no evidence that synthetic fillings of
of a possible effect of different bedding (duvets and pillows) are more
environmental measures. beneficial than feather fillings. Some recent
studies indicate that feather fillings result in
House dust mite allergen avoidance House lower exposure to house dust mite allergens.
dust mites are an important and widely
distributed allergen source. House dust
mites require high humidity and a Table 2. No documented effect of allergen avoidance
temperature of ,24uC for their life cycle and Synthetic filling of pillows and duvets
reproduction, and the best conditions are in Foam mattresses
temperate, humid regions. House dust
mites are mainly in our bedding but may Chemical treatment of mattresses
also be detected in, for example, carpets and Special vacuum cleaners
upholstered furniture, although in lower Air filters, ionisers, etc.
concentrations. Many different single

It has also been argued that foam or water demonstrated, and the results are
mattresses should result in lower exposure, encouraging, but further studies are needed.
as compared with spring mattresses, but the
few available data indicate no difference A large trial provided evidence of
except that using a washable bed pad may improvement of asthma control by
reduce exposure from the mattress. multifaceted intervention that was tailored to
the childs sensitisation and exposure
Different floor coverings may have different status. This included several measures, such
effects. Carpeted floors contain different as education, encasing of mattresses and
particles and allergens to which small pillows, high-filtration vacuum cleaners, and
children playing on the floor are especially HEPA filters.
exposed. It has been assumed that hard
floors have a beneficial effect, but available Apart from attempts to reduce the reservoirs
data suggest a complex and small effect. of allergens, it is obvious to try to remove
the conditions for the house dust mites to
Washing of bedding and clothing at .55uC live and reproduce by reducing humidity (to
kills house dust mites and effectively below 4550% relative humidity), avoiding
removes allergens. Washing at low moisture problems and increasing the
temperatures also removes allergens. ventilation of the home, although clinical
However, it is not known whether washing data are limited.
has any clinical effect.
Pet allergen avoidance In the case of asthma
Vacuum cleaners remove allergens and and allergy to pets, repeated exposure is
vacuum cleaning may result in a modest associated with bronchial hyperreactivity
decrease of allergen reservoirs, but it also and eosinophil inflammation, even without
causes a brief increase in personal obvious symptoms. Cat allergens in
aeroallergen exposure while vacuum particular are airborne, and are found at
cleaning and high-efficiency particulate varying levels in houses and public places
arrest (HEPA) filters make only little without cats. Removal of a pet from the
difference. Data on the quantity of a possible
home reduces the allergen level but does
reduction of personal allergen exposure and
not abolish exposure (table 3). Washing of
its clinical effect are lacking.
bedding and clothes might reduce exposure.
The effect of air filtration is still debated and
there is no good evidence for a possible Washing of the pet has been tried in some
effect. studies and it has been shown that it may
reduce the allergen level but only for a short
Acaricides have been included in some time. We lack good data on the clinical
studies but there is no good evidence of effectiveness of different measures to
clinical benefits, and concerns about human reduce pet allergen levels and exposure.
health and environmental toxicity remain.
Pest avoidance Particularly in inner-city
Recently, a clinical effect of a novel concept environments, cockroach allergy is a major
with nocturnal temperature controlled cause of allergic asthma. Approaches
laminar airflow treatment has been include pesticides and sanitation (e.g.
Table 3. Advice for children with asthma and allergy to pets

The only effective method is removal of the pet
General cleaning and vacuum cleaning is advised, although there is no good evidence for this
Even after removal of a pet, it may take many months before the reservoir of allergens is reduced
sufficiently and it may take 612 months before the full benefit is seen
Complete avoidance of pet allergens is impossible as the allergens are ubiquitous and can be
found in many environments outside the home including schools

avoiding making food available to the Immunotherapy for allergic asthma
cockroaches, control of water leaks and
control of entrances). After such elimination Criteria for commencement of
procedures, thorough cleaning is necessary immunotherapy Before considering
for a long period to remove the pesticides immunotherapy, the allergens triggering
and allergens. asthma symptoms must be identified and
the allergic sensitisation confirmed (table 4).
Likewise, mouse exposure, particularly in While in vitro or skin tests are good enough
bedrooms, is prevalent, especially in for confirming pollen and animal dander
inner-city dwellings, and methods for allergy, it may be necessary to perform
effective rodent control have been allergen provocation tests in the eyes and/or
shown to reduce exposure and the nose to confirm other perennial allergies
improve symptoms. However, to date, like dust mite and Alternaria allergy. More
the evidence is limited. information on the relevant procedures can
be found in the position paper published as
Mould avoidance Many studies have shown a Global Allergy and Asthma European
that exposure and allergy to fungi are often Network (GA2LEN)/European Academy of
associated with severe asthma. Some Allergy and Clinical Immunology (EAACI)
fungi (often Aspergillus) may colonise and pocket guide on allergen-specific
even infest the lungs, thereby causing immunotherapy for allergic rhinitis and
severe disease. Many other fungi, most asthma.
often Alternaria but also others such as
Cladosporium or Penicillium, appear to Immunotherapy to improve and/or prevent
play an important role in severe asthma. deterioration of asthma The majority of
There is limited evidence about the role immunotherapy studies in children (and
of fungal allergen avoidance in asthma. adults) with asthma have been performed in
Moisture issues cause most instances those with mild allergic asthma, usually
of fungal growth in the indoor combined with rhinitis. Most of the studies
environment, and control of indoor have been performed using single allergens,
environmental humidity and removal the most predominant perennial allergen
of contaminated material has been being dust mite, and the dominant seasonal
recommended. There are no convincing allergens being birch, olive/Parietaria, grass
trials of avoidance of Alternaria, and ragweed (mostly in the USA). The best
which is primarily an outdoor evidence of efficacy of immunotherapy in
allergen, though it can also be children with asthma emanates from studies
found indoors. of children allergic to pollen and house dust
mites (table 5).
In the case of suspicion of significant
problems with fungal growth in the indoor SCIT with cat allergen extracts has also
environment, it is often necessary to shown beneficial effects both on allergen
investigate which fungus is present, and to sensitivity and bronchial
involve experts and technicians with special hyperresponsiveness, while so far, dog
expertise in this area. allergen extracts have been less efficacious.
A recent study of treatment with Alternaria
Table 4. Indications for allergen immunotherapy
Allergic asthma triggered by allergen
Table 5. Documented effects of immunotherapy
exposure Less severe symptoms on allergen exposure
Confirmed specific allergy Decreased medications use during the
Seasonal allergy to pollens allergy season
Perennial allergy to house dust mite, Quality of life improvements

Alternaria, cat Lasting effect after cessation of therapy

extracts in children has been shown to have adjustments have to be made if the subject
convincing clinical effects, reducing had side-effects like major local swelling
symptoms of asthma. and/or any sign of systemic effects. A
standard procedure for required dose
Few studies have been carried out in adjustments should be followed. After the
children with both seasonal and perennial injection, the subject should stay at the
allergies. One placebo-controlled American clinic for observation for o30 min, as most
study of multi-allergic children SSEs occur within that time. At any sign of a
demonstrated no significant effect of SCIT SSE cough, sneezing, itch or signs of
on medication use and symptom control. A anaphylaxis adrenaline injection(s) should
few other studies have been more be promptly given. Local side-effects can
successful; thus, the possibility remains that usually be treated or prevented by oral
SCIT may alter the severity of asthma by antihistamines. It is mandatory at any clinic
inducing allergen tolerance. More studies that administers SCIT that there is
are needed; however, in the mentioned equipment and trained staff to take
Cochrane report and two recent extensive immediate action in case of a SSE.
reviews conclude that there is evidence for
efficacy of SCIT and SLIT in both children The available guidelines serve an important
and adults with asthma. role in providing standards for the
indications, use and administration of SCIT
Dosing schedules for SCIT and side-effects and SLIT.
Different up-dosing regimens are used for
the stepping up of the dose phase of SCIT SLIT for asthma SLIT has been shown to
treatment. There are rush up-dosing improve asthma symptoms and medication
schedules, cluster regimens and the use. SLIT is safe, although the efficacy
conventional one injection per week compared to SCIT has been very little
regimen. The advantages and disadvantages studied. In one recent paediatric review, the
of immunotherapy have been discussed efficacy of both SCIT and SLIT were
(table 6). reported. In another recent review, SLIT
studies in both children and adults were
The risk of systemic side-effects (SSEs) has reported. In the paediatric review, it is stated
to be considered and the highest risk has that there is good evidence that SLIT has
been reported when a rush regimen is used. effects on asthma in children; this is in
However, none of the schedules is without agreement with the other reviews. However,
risk of SSEs, which is an important reminder dose and dosing are still major issues for
that requires special attention. SLIT. There is, for example, in different SLIT
Implementation of safety measures and studies, a large variation of the cumulative
standardised procedures are mandatory dose of house dust mite administered,
when the injections are administered. ranging from 0.25 to 12 mg Der p. This is an
Precautions are important. Lung function issue that has been discussed and has
should be checked. Injections should not be caused some concern, in that there are still
given if the subject has ongoing allergic few doseresponse studies that have
symptoms or a current infection; asthma confirmed the standard doses that should
symptoms have to be controlled and recent be used for SLIT. The first dose of SLIT
allergen exposure should be checked. Dose should be given at a clinic and followed by
>30 min observation time. The best
documented SLIT to date is for treatment of
Table 6. Problems with allergen immunotherapy pollen and dust mite allergy.
Mostly an injection therapy
Immunotherapy combined with anti-IgE:
Long-term therapy (.3 years) safety and efficacy in children with severe
Loss of school attendance allergic asthma Few studies have addressed
Risk of systemic side-effects this question in children. One of the
paediatric studies was performed in

polysensitised children with seasonal pharmacotherapy. Studies of SCIT for pollen,
rhinitis and included children with birch or house dust mite and cat allergy have shown
grass allergy. Results showed that the convincing effects on the specific allergies. A
combination of omalizumab and pollen couple of recent reviews have confirmed the
SCIT had superior effects on symptom load utility of SCIT and SLIT for asthma and
in both birch- and grass-allergic children. rhinitis in children. The treatment can
Other studies performed in groups of improve the quality of life for the allergic child
children and adults have shown similar but the overall effect on asthma severity, as
results. Pre-treatment with omalizumab in demonstrated by a decreased need for
patients with severe multi-allergic asthma pharmacotherapy for asthma control, has
was the subject of another study of been uncertain in children with multiple and
combined therapy, although omalizumab perennial allergies.
treatment only overlapped at the start of
immunotherapy in symptomatic patients Anti-IgE is a treatment possibility for severe
with asthma. The risk of SSEs was reduced, allergic asthma and, so far, the documented
although severe systemic reactions still effects on risk of exacerbation have been
occurred in the group pre-treated with shown in children needing high-dose
omalizumab. There is a need for more inhaled corticosteroids for symptom control.
studies of this combination before it can be The efficacy increases in those with high
considered an additional therapy in children exhaled nitric oxide fraction (FeNO) and
with asthma and severe allergies. At this other signs of ongoing eosinophilic airway
stage, SCIT alone or in combination with inflammation.
omalizumab should not be used in children
with severe and/or uncontrolled asthma.
Further reading
Conclusion
N Abramson MJ, et al. (2010). Injection
A pragmatic approach in clinical practice allergen immunotherapy for asthma.
should involve interventions tailored to the Cochrane Database Syst Rev; 8: CD001186.
N Bush RK (2011). Does allergen avoidance
patients sensitisation and exposure in a
work? Immunol Allergy Clin N Am; 31:
multifaceted allergen avoidance regime, based
493507.
on removal of the accumulating allergens. The N Busse WW, et al. (2011). Randomized trial
extent of such avoidance measures should of omalizumab (anti-IgE) for asthma in
also be tailored to the severity of the disease, inner-city children. N Engl J Med; 364:
and combined with education and other 10051015.
relevant treatment options. N Cox L, et al. (2011). Allergen immunother-
apy: a practice parameter third update. J
Environmental avoidance measures have Allergy Clin Immunol; 127: 840.
proven effective as a specific treatment of a N Custovic A, et al. (2012). The role of
specific allergy under the right conditions, but inhalant allergens in allergic airways dis-
it requires defining specific sensitivity, ease. J Investig Allergol Clin Immunol; 22:
education and an overall plan to reduce 393401.
exposure in the childs home, and its success N Gtzsche PC, et al. (2008). House dust
depends on the relevance of other allergens mite control measures for asthma.
and exposure outside home. Thus, in children Cochrane Database Syst Rev; 2: CD001187.
with allergic asthma, measures to reduce N Halken S, et al. (2003). Effect of mattress
allergen levels significantly should be included and pillow encasings on children with
in an individual treatment plan as well as an asthma and house dust mite allergy. J
appropriate pharmacological treatment and Allergy Clin Immunol; 111: 169176.
avoidance of exposure to tobacco smoke. N Hedlin G, et al. (2012). The role of
immunotherapy in the management of
If allergen avoidance is not possible, the childhood asthma. Ther Adv Respir Dis; 6:
addition of immunotherapy could be the next 137146.
step, provided it is combined with adequate

N Kennedy JL, et al. (2012). The role of N Lin SY, et al. (2013). Sublingual immunother-
allergy in severe asthma. Clin Exp Allergy; apy for treatment of allergic rhinoconjuncti-
42: 659669. vitis and asthma. JAMA; 309: 12781288.
N Kilburn S, et al. (2003). Pet allergen N Massanari M, et al. (2010). Effect of pretreat-
control measures for allergic asthma in ment with omalizumab on the tolerability of
children and adults. Cochrane Database specific immunotherapy in allergic asthma. J
Syst Rev; 1: CD002989. Allergy Clin Immunol; 125: 383389.
N Kim JM, et al. (2013). Allergen specific N Penagos M, et al. (2008). Meta-analysis
immunotherapy for pediatric asthma and of the efficacy of sublingual immunother-
rhinoconjuctivitis: a systematic review. apy in the treatment of allergic asthma in
Pediatrics; 131: 113. pediatrix patients, 3 to 18 years of age.
N Lanier B, et al. (2009). Omalizumab for Chest; 133: 599609.
the treatment of exacerbations in children N Zuberbier T, et al. (2010). GA2LEN/EAACI
with inadequately controlled allergic (IgE- pocket guide for allergen-specific immu-
mediated) asthma. J Allergy Clin Immunol; notherapy for allergic rhinitis and asthma.
124: 12101216. Allergy; 65: 15251530.

Genetics, pathophysiology
and epidemiology of CF
Sabina Gallati
CF has been recognised as a distinct of the two parental CF mutations and a 25%
inheritable clinical entity for more than chance that the child will inherit two intact
70 years. It is the most common life- genes. Phenotypically healthy siblings of CF
threatening autosomalrecessive disorder patients have a 66% risk of a positive carrier
among Caucasians with an incidence of state.
approximately one in 2500 and a carrier
The CFTR gene and protein
frequency of 4%. Heterozygotes carry one
normal and one mutant CF gene and are The gene causing CF, identified in 1989, is
therefore healthy, but they have a 50% risk located on chromosome 7q31.2 spanning
of passing the defective gene on to their ,200 kb of genomic DNA and containing
offspring. If two partners are carriers they 27 exons. It is transcribed into 6.13 kb
face a 25% risk of having a child with CF, a messenger ribonucleic acids (mRNAs)
50% chance that the child will carry only one encoding a transmembrane protein of 1480
amino acids known as the cystic fibrosis
transmembrane conductance regulator
Key points (CFTR). The CFTR protein is a member of
the ATP-binding cassette (ABC) transporter
N CF is the most common life- superfamily whose proteins transport
threatening autosomal-recessive various molecules across extra- and
disorder in Caucasian populations intracellular membranes. The predicted
with an incidence of 1/2500 and a structure of CFTR includes:
carrier frequency of 1/25.
N CF is caused by mutations in the
N a symmetrical, multi-domain structure
consisting of two membrane-spanning
CFTR gene on chromosome 7. domains (MSD1 and MSD2) with six
N The CF phenotype is very hydrophobic transmembrane helices
heterogeneous and depends on both forming the channel through the
nature and localisation of the membrane;
underlying CFTR mutations, as well as N two nucleotide binding domains (NBD1
genetic background and and NBD2) gating the channel through
environmental influences. ATP-binding and hydrolysis;
N CFTR analysis is indicated for
N a central, highly charged regulatory
domain with multiple consensus sites for
diagnostic purposes in individuals phosphorylation by protein kinase (PK)A
with clinical suspicion of CF or CFTR- and PKC.
related disorders, fetuses with
echogenic bowel or whose parents are The regulatory domain is unique for CFTR as
proven CF carriers, and for carrier it is not present in the other members of the
testing in persons with a positive ABC superfamily. CFTR is mainly located at
family history or in partners of proven the apical membrane of polarised epithelial
CF carriers. tissues. Its main function is that of a cyclic
AMP-regulated chloride channel, which is

expressed in several functionally diverse phenotypes (fig. 1). The second class of
tissues including the lung, sweat ducts, mutations contains many missense
pancreas, gastrointestinal tract and vas mutations as well as in-frame deletions or
deferens. Moreover, CFTR directly mediates insertions, including the F508 deletion. The
secretion of bicarbonate across the apical corresponding proteins fail to be properly
membrane linking ion transport and luminal processed to a mature glycosylated form
pH with mucin secretion, mucus plugging and will not, or only exceptionally, appear at
and retention, the hallmarks of CF the apical membrane. Interestingly, some of
pathology. CFTR-mediated chloride the class II mutations, e.g. F508del, if
secretion across epithelial cells is controlled correctly processed, possess residual
by both modulating channel activity and chloride channel activity and may lead to a
regulating the total number of CFTR milder phenotype. For this reason,
channels in the membrane. mutations in this group are targets of
potential therapies, aimed at correcting the
CFTR mutations processing and delivery of a mutated CFTR
To date, nearly 2000 mutations have been protein to the apical membrane (fig. 1).
reported to the Cystic Fibrosis Genetic Mutations of class III affect the regulation of
Analysis Consortium. The most common CF CFTR function by preventing ATP binding
causing defect is the F508del mutation and hydrolysis at NBF1 and NBF2 required
(c.1521_1523delCTT; p.Phe508del according for channel activation. However, the
to the current standard nomenclature), a missense mutation G551D within NBF1
3 bp deletion in exon 10 (current disrupts not only the binding site through
nomenclature: exon 11) causing the loss of which ATP-dependent gating normally
the amino acid phenylalanine at position occurs, but also allows some ATP-
508 of the protein. There are another 23 independent chloride transport making it a
relatively common mutations (frequency promising candidate for therapeutic
.0.5%) worldwide and a few mutations with approaches using CFTR potentiators (fig. 1).
an unusually high frequency in specific The fourth class of mutations involves
populations indicating founder effect amino acids located within MSD1 and MSD2
genetic drift. The remaining mutations and results in a CFTR channel with defective
represent rare or even individual sequence conductive properties. Mutations (e.g.
changes that are distributed throughout the R117H, R334W, R347H and R347P) in this
entire gene. Mutations (missense, class are typically associated with a milder
nonsense, frame-shift, splice, small and clinical phenotype (fig. 1). Various
large in-frame deletions, and insertions) mutations are associated with reduced
contribute to the phenotype by their nature biosynthesis of fully active CFTR due to
and position in the gene. Therefore, they can partially aberrant splicing (3849+10kbC-.T,
be grouped into different classes based on T5), promotor mutations or inefficient
their known or predicted molecular trafficking (A455E). These mutations,
mechanisms of functional consequences for forming class V, result in reduced amounts
the protein. of functional gene products and, thus, in
milder CF phenotypes (fig. 1). Class VI
Class I mutations include mainly nonsense, includes nonsense and frame-shift
frame-shift and splice site mutations mutations (e.g. Q1412X, 4326delTC and
resulting in premature termination signals 4279insA) causing a 70- to 100-bp
or defective splicing and, as a consequence, truncation of the C-terminus of the CFTR
producing truncated, deleted or elongated that leads to a marked instability of an
protein variants. Such proteins tend to be otherwise fully processed and functional
unstable and rapidly degraded and cleared protein, and as a consequence to a severe
from the cell. In effect, virtually no functional CF presentation (fig. 1). Mutations in any of
CFTR reaches the apical membrane of the classes II to V display a broad range of
epithelial cells and, therefore, class I phenotypic effects making prediction of the
mutations are expected to cause severe clinical course of a patient impossible

Class IV D
CI-
MSD1 MSD2
X
ATP NBD1 NBD2 ATP
X
C
RD
Class III
ATP ATP
Class V
Nucleus
Golgi E
apparatus F
Gene defect
Class VI
A
B X
X Class I
ER
Class II
Figure 1. Class I (A): nonsense, frame-shift and splice site mutations resulting in no functional CFTR
protein. Class II (B): mutations (e.g. F508del) that lead to abnormal processing and trafficking of proteins.
Class III (C): mutations in this group (e.g. G551D) affect the regulation of CFTR and channel gating
activity. Class IV (D): mutations (e.g. R117H, R334W, R347P and R347H) within the MSDs reducing CFTR
channel conductance. Class V (E): mutations associated with reduced biosynthesis of fully active CFTR due
to alternative splicing (e.g. T5). Class VI (F): nonsense and frame-shift mutations causing truncation of the
C-terminus of CFTR and leading to highly unstable proteins. ER: endoplasmic reticulum; RD: regulatory
domain.
simply based on mutation classification. alterations in the synthesis or sequence of

Moreover, the potential of a mutation to the CFTR protein may affect the number of
contribute to the phenotype depends not channels in the plasma membrane and/or
only on its nature, localisation in the gene channel activity and/or intracellular
and molecular mechanism, but also on its trafficking of CFTR. Reduced or missing
interaction with the second mutated CFTR CFTR function leads to a failure of chloride
allele, as well as on disease modifiers. and sodium transport across epithelia. The
defective ion conductance and the
Pathophysiology of the mutated CFTR gene
associated water transport abnormalities
and protein
produce increased viscosity of secretions in
As mentioned before, pathogenic CFTR gene a variety of exocrine epithelia, such as the
mutations can disrupt CFTR protein respiratory tract, pancreas, gastrointestinal
function through a variety of mechanisms tract, urogenital tract and sweat glands and
ranging from complete loss of protein result, as a consequence, in the multi-
synthesis to normal apical membrane organic disease of classic CF. Moreover,
expression of the protein with, however, there is growing recognition of atypical CF
reduced chloride conductance. Furthermore, and CFTR-related disorders including

primary male infertility, isolated idiopathic healthcare provider such that meaningful
pancreatitis, chronic rhinosinusitis, nasal informed consent from the patients may be
polyposis and idiopathic bronchiectasis, obtained. Performing a molecular genetic
presenting in adolescence or adulthood and diagnostic test is a complex process
making diagnosis and prognosis much requiring internal quality control systems
more complex. such as good laboratory practice procedures
or some form of accreditation. A wide range
Based on the considerable technical of mutation testing methods are available
problems in successfully targeting the basic and can be divided into two groups: specific
defects of CF on the one hand, and on the mutation detection based on the well-known
major advances in the understanding of spectrum of CF mutations in a defined
CFTR pathophysiology on the other, the ethnic group or population (e.g. using
focus of treatment strategies has turned commercial kits), and mutation screening
toward pharmacotherapy and the methods (e.g. sequencing of the entire
development of agents that may increase coding region of the CFTR gene) with a high
residual protein synthesis and/or transport detection rate and the ability to identify
to the cell membrane and/or ion novel mutations independent from allele
conductance. Therefore, mutation-specific frequencies and ethnic origin (table 1).
orphan drug therapies are currently the
most favoured strategies. However, they Genotypic and phenotypic heterogeneity
represent a symptomatic treatment option
Although CF is considered a monogenic
rather than a cure and gene therapy may yet
disorder, studies of clinical phenotype in
provide the best solution.
correlation with the genotype have revealed
Genetic testing a very complex relationship. Some
phenotypic features are closely determined
Genetic testing should be performed in the by the genotype in an essentially monogenic
context of appropriate genetic counselling, fashion, whereas others are strongly
and it is the laboratory technicians influenced by both modifying genetic factors
responsibility to explain CF testing to the and the environment. There is a close
Table 1. CFTR analyses indications

CFTR analyses are indicated for:
Diagnostic testing in
Patients with a definite or possible clinical diagnosis of CF
Newborns with positive neonatal screening test
Infants with meconium ileus
Males with proven congenital bilateral absence of vas deferens or suffering from primary
infertility
Patients with idiopathic pancreatitis
Patients with idiopathic bronchiectasis or chronic rhinosinusitis or nasal polyposis
Carrier testing in
Individuals with positive family history
Partners of proven CF carriers
Gamete donors
Prenatal and pre-implantation diagnostic testing
If both parents are proven carriers and both mutations have been identified
In fetuses present with an echogenic bowel during the second trimester

Table 2 Incidence and carrier frequency of CF in different countries
Country Carrier frequency Incidence
Europe
Finland 1/79 (1.3) 1/25 000
Turkey ,1/50 (2.0) ,1/10 000
Sweden 1/43 (2.3) 1/7300
Poland 1/39 (2.6) 1/6000
Russia 1/35 (2.9) 1/4900
Denmark 1/34 (2.9) 1/4700
Norway 1/33 (3.0) 1/4500
Netherlands 1/30 (3.3) 1/3600
Greece 1/30 (3.3) 1/3500
Spain 1/30 (3.3) 1/3500
Germany 1/29 (3.4) 1/3300
Czech Republic 1/27 (3.7) 1/2800
UK 1/26 (3.8) 1/2600
Switzerland 1/25 (4.0) 1/2500
Italy 1/25 (4.0) 1/2500
France 1/24 (4.2) 1/2400
Scotland 1/22 (4.5) 1/2000
Republic of Ireland 1/21 (4.8) 1/1800
North America
USA 1/30 (3.3) 1/3500
Canada 1/27 (3.7) 1/3000
Latin America
Mexico 1/46 (2.2) 1/8500
Brazil 1/41 (2.4) 1/6900
Chile 1/32 (3.1) 1/4000
Cuba 1/31 (3.2) 1/3900
Middle East
United Arab Emirates 1/63 (1.6) 1/15 900
Bahrain 1/38 (2.6) 1/5800
Asia
India 1/1001/158 (1.00.6) 1/40 000100 000
Japan 1/1581/296 (0.60.3) 1/100 000350 000
South Africa 1/42 (2.4) 1/7100
Australia 1/25 (4.0) 1/2500
Data are presented as one case per 6 persons of a population 6 births.

relationship between the CFTR genotype and homologous genotypes and well-defined
the pancreatic phenotype revealing severe phenotypes, as well as on functional
mutations (e.g. F508del, all class 1 consequences, are required to provide
mutations) to be associated with pancreatic clinical utility.
insufficiency and mild mutations with
residual function, such as a series of In complex diseases such as CF,
missense and alternative splice mutations, contribution of epigenetic factors such as
to be associated with pancreatic sufficiency. DNA methylation, chromatin remodelling,
The development of meconium ileus, histone modification and RNA interference
diabetes and liver disease is mainly confined might be substantial. It is well established
to patients with severe mutations without that polymorphisms in a poly-T tract
residual function. However, because of its (c.121012T [5_9]) and a TG repeat (c.1242
35_124212GT [8_13]) in intron 8 (standard
complexity and patient exposure to a
nomenclature: intron 9) of the CFTR gene
multitude of endogenous and exogenous
causes alternative splicing resulting in
factors, pulmonary outcome is clinically the
variable exon 9 (standard nomenclature:
most variable, as well as the most
exon 10) skipping. Moreover, several
unpredictable, component of the CF
polymorphisms have been reported to lead
phenotype. Several studies have shown
to alterations in transcription factor binding
significant correlations between CFTR
and, therefore, to be involved in the
genotypes and pulmonary status concluding
modulation of CFTR transcription. Hence, it
that patients with class I or II mutations on
is very likely that a significant number of
both chromosomes have more rapid
polymorphisms, transcription factors and
deterioration in lung function and lower splicing factors interact to effect the
survival rates than patients with other complex tissue-specific regulation of the
genotypes. Moreover, F508del homozygous CFTR gene.
patients were found to present the most
considerable variation in severity of Epidemiology
pulmonary disease. The broad range of
disease severity, even in patients with the CF causing mutations have existed for more
same genotype (e.g. F508del homozygotes), than 50 000 years and many are strongly
point to the understanding that a CFTR associated with specific European
genotype constitutes only the source or populations. The most common CFTR
potential for CF disease and that the overall mutation, the F508 deletion, accounts for
genetic background, as well as ,60% of all CF chromosomes worldwide
environmental factors, may have a major with considerably variable frequencies
effect on clinical phenotype. depending on populations and
geographical locations. There is a clear
Modifying factors North West to South East gradient in
F508del frequency across Europe with a
A multitude of genetic loci and genes have maximum of 100% in the isolated Faroe
been investigated as modifiers of CF Islands of Denmark and a minimum of
expression at the pulmonary, ,20% in Turkey. Caucasians in Canada and
gastrointestinal and liver levels suggesting North America present with an F508del
that a number of genes could interact in frequency of 6871%, whereas Hispanic
different ways to produce the highly populations and AfricanAmericans show
variegate CF phenotype. Some of the most significantly lower frequencies (4248%).
promising potential modifiers of CF include The overall frequency of non-F508del
mannose-binding lectin (MBL)2, endothelial mutations is low, except for some
receptor type A (EDNRA), transforming population-specific mutations such as
growth factor (TGF)-b1, interleukin (IL)-8, W1282X, which accounts for ,48% of CF
transcription factor 7-like 2 (TCF7L2) and a1- chromosomes in Ashkenazi Jews or
antiprotease (SERPINA1). However, further 621+1G.T accounting for 23% of French
studies on large numbers of cases with Canadian CF chromosomes. Therefore, it is

the presence of the F508del mutation that gene is pathogenic or benign. Am J Hum
increases the frequency of CF in Caucasians Genet; 74: 176179.
compared to other races (table 2). N Kim D, et al. (2009). The role of CFTR in
bicarbonate secretion by pancreatic duct
and airway epithelia. J Med Invest; 56:
Further reading Suppl., 336342.
N Knowles MR, et al. (2012). The influence
N Bombieri C, et al. (2011). of genetics on cystic fibrosis phenotypes.
Recommendations for the classification Cold Spring Harb Perspect Med; 2:
of diseases as CFTR-related disorders. J a009548.
Cyst Fibros; 10: Suppl. 2, S86S102. N Kraemer R, et al. (2009). Long-term gas
N Cystic Fibrosis Genetic Analysis Consortium. exchange characteristics as markers of
Cystic Fibrosis Mutation Database. www. deterioration in patients with cystic fibro-
genet.sickkids.on.ca/cftr/app sis. Respir Res; 10: 106.
N Davies JC, et al. (2010). Gene therapy for cystic N Lubamba B, et al. (2012). Cystic fibrosis:
fibrosis. Proc Am Thorac Soc; 7: 408414. Insight into CFTR pathophysiology and
N Dequeker E, et al. (2009). Best practice pharmacotherapy. Clin Biochem; 45: 1132
guidelines for molecular genetic diagno- 1144.
sis of cystic fibrosis and CFTR-related N MacDonald KD, et al. (2007). Cystic
disorders updated European recom- fibrosis transmembrane regulator protein
mendations. Eur J Hum Genet; 17: 5165. mutations: class opportunity for novel
N Eckford PDW, et al. (2012). Cystic fibrosis drug innovation. Paediatr Drugs; 9: 110.
transmembrane conductance regulator N Pezzulo AA, et al. (2012). Reduced airway
(CFTR) potentiator VX-770 (ivacaftor) surface pH impairs bacterial killing in the
opens the defective channel gate of porcine cystic fibrosis lung. Nature; 487:
mutant CFTR in a phosphorylation- 109113.
dependent but ATP-independent manner. N Quinton PM (2010). Role of epithelial
J Biol Chem; 287: 3663936649. HCO3 transport in mucin secretion:
N Geborek A, et al. (2011). Association lessons from cystic fibrosis. Am J Physiol
between genotype and pulmonary pheno- Cell Physiol; 299: C1222C1233.
type in cystic fibrosis patients with severe N Riordan JR (2008). CFTR function and
mutations. J Cyst Fibros; 10: 187192. prospects for therapy. Annu Rev Biochem;
N Groman JD, et al. (2004). Variation in a 77: 701726.
repeat sequence determines whether a N World Health Organization. The World
common variant of the cystic fibrosis Health Report 2004. Changing History.
transmembrane conductance regulator Geneva, WHO, 2004.

Screening and diagnosis
of CF
Jurg Barben and Kevin Southern
Diagnosis of CF o60 mmol?L-1) should always be

confirmed with a second sweat test and
A diagnosis of CF is based on one or more CFTR mutation analysis. The 40 most
typical phenotypic features (table 1): a frequent disease-associated CFTR
history of CF in a sibling or a positive mutations will detect .90% of affected CF
newborn screening result, and a laboratory patients in most European populations. Up
confirmation of cystic fibrosis to now, more than 1900 CFTR mutations
transmembrane regulator (CFTR) protein have been identified, but only a small
dysfunction and/or identification of two CF percentage (,10%) have been shown to
causing mutations. In most cases, the definitely cause CF.
diagnosis of CF will be confirmed by
measurement of sweat chloride The sweat test comprises three phases:
concentration using quantitative
pilocarpine iontophoresis, which measures N stimulation of the sweat glands
chloride transport through the CFTR (pilocarpine iontophoresis),
channel. A positive result (sweat chloride N sweat collection,
N sweat analysis.
Key points The collection of a sufficient amount of

sweat can sometimes be difficult, especially
N The gold standard confirmation in very young children, but there have been
method for a suspected CF diagnosis many improvements in the sweat collection
is the measurement of sweat chloride method. Newer techniques have reduced the
using pilocarpine iontophoresis. amount of sweat needed, including the
macroduct collection system or the
N A borderline or positive result should nanoduct sweat analysing system (fig. 1).
always be confirmed with a second Sweat testing should always be carried out
sweat test or by CFTR mutation in accordance with the current guidelines
analysis. and by a trained and experienced
N Until recently, the diagnosis has professional. Sweat testing is vulnerable to
usually been made based on clinical many sources of errors. Table 2 lists some
manifestations, but newborn of the common causes of false-negative and
screening for CF has been false-positive sweat test results.
implemented in many European
countries. Sweat chloride concentration increases with
age in people without CF, but a sweat
N Once CF diagnosis has been chloride concentration of o60 mmol?L-1 is
confirmed, other family members usually diagnostic for CF (fig. 2). Values
should be offered screening for the between 30 and 59 mmol?L-1 are
disease using sweat testing, especially intermediate. However, undoubted cases of
all siblings. CF with normal sweat electrolytes have been
described. The measurement of other

Table 1. Age-related signs and symptoms of CF
Age Presentation
Common respiratory Common non-respiratory Less common
General (any) Moist cough with Salty-tasting skin

sputum production
Respiratory infection with
typical CF pathogen (e.g.
Staphylococcus aureus,
Pseudomonas aeruginosa,
Burkholderia cepacia)
Neonatal Diagnosis made by newborn Protracted jaundice
screening (elevated Intestinal atresia
immunoreactive trypsinogen) Intestinal atresia
Meconium ileus (1015% of Fat soluble vitamin deficiency
patients with CF) causing (e.g. bleeding due to
bowel obstruction, partly with vitamin K deficiency)
perforation and peritonitis
Abdominal cramps, fatty stool
Infancy and Recurrent respiratory Failure to thrive due to exocrine Rectal prolapse
childhood symptoms (chronic cough, pancreas insufficiency with Anaemia, oedema and
wheeze and pneumonia) steatorrhoea, diarrhoea and hypoproteinaemia
abdominal distension Dehydration and electrolyte
disturbance (Pseudo-Bartters
syndrome, hypochloraemic
metabolic alkalosis)
Cholestasis
Chronic sinusitis
Adolescence Recurrent respiratory Azoospermia (secondary Acute pancreatitis
and adulthood symptoms (cough and to congenital bilateral absence Liver disease and portal
wheeze) of vas deferens) hypertension
Bronchiectasis Pulmonary infection
Clubbing of fingers and toes with atypical mycobacteria
Chronic pansinusitis Haemoptysis
and nasal polyps Allergic bronchopulmonary
aspergillosis
electrolytes (potassium and sodium) is not Newborn screening

recommended as they are not diagnostic for
CF, but a ratio of sodium/chloride .1 can be Newborn screening for CF, using
supportive for CF. The measurement of immunoreactive trypsinogen (IRT) in dried
conductivity is approved for screening, but a blood spots taken from infants at the third/
value o50 mmol?L-1 should always be fourth day of life, has been implemented in
confirmed with a sweat chloride many European countries (fig. 3). The first
measurement. newborn screening programmes were
based on IRT measurements from a heel
For patients with an unclear diagnosis, there prick test with repeat testing for infants
are two main methods of further with an elevated initial measurement
characterisation of the salt transport defect: 6 weeks later. With the detection of the
CFTR gene in 1989, many countries
N nasal potential difference, introduced DNA analysis as the second
N intestinal current measurement. tier of analysis. To date, more than 30
screening programmes have been
Both are challenging and only available in a developed, with quite marked variation in
few centres. In certain cases, however, they protocol design. All screening algorithms
can provide valuable further information to rely on testing for IRT as the primary
help support or refute a diagnosis of CF. screen for CF. Infants who have an

a) Borderline Borderline
(children) (adults)
Normal CF Error
0 20 40 60 80 100 120 140 160

Sweat chloride concentration mmol.L-1
Figure 2. Sweat chloride measurement.
b) Screen-positive infants are referred to a CF

centre for sweat testing, where the
suspected CF diagnosis will be confirmed or
rejected. The aim of a newborn screening
programme is primarily to detect as many
children with CF and pancreas insufficiency
as possible in order to start treatment as
early as possible, whilst avoiding false-
positive screening results resulting in
unnecessary recalls and sweat tests. The
advantages of early diagnosis include
nutritional benefits, early substitution of
Figure 1. a) A child with a macroduct collection pancreatic enzymes and fat soluble
system. After pilocarpine iontophoresis to vitamins, treatment of CF specific
stimulate sweating, the system is firmly attached pathogens, access to specialised care, a
to the skin of the forearm. Sweat can be seen reduction in the time of diagnostic
entering the tube system (blue rings). Chloride uncertainty and the ability to counsel
analysis can be performed on as little as 1530 mL of parents for prenatal testing. However,
sweat. b) A child with a nanoduct analysing screening programmes also have some
system. After pilocarpine iontophoresis to
negative effects. Newborn screening
stimulate sweating, the system measures sweat
identifies some healthy heterozygote
conductivity while attached to the patient.
Measuring conductivity can be performed on as carriers, which can cause anxiety and
little as 35 mL of sweat depression in affected families. In addition,
some CF-affected individuals will be missed
even in the best newborn screening
programme, depending on the chosen cut-
elevated IRT (usually .99th percentile) off value of the initial IRT measurement
undergo further assessment either by (false negatives in up to 8%). Another
another IRT measurement (IRT/IRT negative impact is the unnecessary
algorithm), genetic testing for the most medicalisation of infants with an equivocal
common CFTR mutations (IRT/DNA diagnosis who turn out not to have CF.
algorithm) or further screening algorithms.
Within these two categories, a variety of Once CF diagnosis has been confirmed,
modifications are used because no single other family members may be offered
algorithm is perfect. The screening screening. All siblings need to be screened
algorithm of each country depends on for the disease (sweat test), which may be
programme resources, and goals including pre-symptomatic or unrecognised.
mechanisms available for sample Asymptomatic adult family members may
collection, regional demographics, the wish to be screened for carrier status to
spectrum of disease phenotype that is to allow them to make informed choices about
be detected and acceptable failure rates. prenatal screening.

Table 2. Causes of false-negative and false-positive sweat test results
False-positive results False-negative results
Evaporation of the sweat sample Dilution of sweat sample
Severe malnutrition Oedema
Anorexia nervosa Dehydration
Atopic dermatitis (eczema) Hypoproteinaemia
Familial hypoparathyroidism Mineralocorticosteroid treatment
Pseudohypoaldosteronism Some CFTR mutations, e.g. R117H, A455E, G551S
Adrenal insufficiency
Glucose-6-phosphatase
Nephrogenic diabetes insipidus
Mauriac syndrome
Fucosidosis
Klinefelters syndrome
Familial cholestatic syndrome
Figure 3. Newborn screening programmes in Europe 2012. Data from Southern (2013).

Further reading N Farrell PM, et al. (2008). Guidelines for
diagnosis of cystic fibrosis in newborns
N Balfour-Lynn IM (2008). Newborn screen-
through older adults: Cystic Fibrosis
ing for cystic fibrosis: evidence for Foundation consensus report. J Pediatr;
benefit. Arch Dis Child; 93: 710. 153: S4S14.
N Castellani C, et al. (2010). European best N Green A, et al. (2007). Guidelines for the
practice guidelines for cystic fibrosis neo- performance of the sweat test for the
natal screening. J Cyst Fibros; 8: 153173. diagnosis of cystic fibrosis. Ann Clin
N Clinical and Laboratory Standards Institute. Biochem; 44: 2534.
Sweat testing: sample collection and quan- N Mayell SJ, et al. (2009). A European
titative chloride analysis; approved guide- consensus for the evaluation and man-
line. 3rd Edn. Wayne, CLSI , 2009. agement of infants with an equivocal
N Comeau AM, et al. (2007). Guidelines for diagnosis following newborn screening
implementation of cystic fibrosis new- for cystic fibrosis. J Cyst Fibros; 8: 7178.
born screening programs: Cystic Fibrosis N Rosenstein BJ, et al. (1998). The diag-
Foundation workshop report. Pediatrics; nosis of cystic fibrosis: A consensus
119: e495e518. statement. J Pediatrics; 132: 589595.
N De Boeck K, et al. (2006). Cystic fibrosis: N Southern KW, et al. (2007). A survey of
terminology and diagnostic algorithms. newborn screening for cystic fibrosis in
Thorax; 61: 627635. Europe. J Cyst Fibros; 6: 5765.

CF lung disease
Nicolas Regamey and Jurg Barben
Lung disease accounts for most of the episodes of acute worsening of respiratory
morbidity and mortality in CF. CF lung symptoms, often referred to as pulmonary
disease begins early in life. It is exacerbations. Tissue damage ultimately
characterised by impaired mucociliary results in lung failure and death in most
clearance and mucus obstruction, as well as people with CF.
chronic pulmonary infection and
Pathophysiology
inflammation, leading to tissue destruction.
Early CF lung disease is characterised by The most commonly accepted
small airways obstruction and the pathophysiological explanation for airway
development of bronchiectasis. There is a disease in CF is the low volume
progressive decline of lung function with hypothesis. This hypothesis postulates that
cystic fibrosis transmembrane conductance
regulator (CFTR) dysfunction leads to a loss
Key points of inhibition of airway epithelial sodium
channels which, in turn, leads to excess
N CF lung disease begins early in life. It sodium and water reabsorption. This results
is characterised by impaired in dehydration of airway surface liquid.
mucociliary clearance and mucus Reduced volume of the airway surface liquid
obstruction, and chronic pulmonary causes failure of mucociliary clearance,
infection and inflammation. which leads to mucus obstruction of the
N There is a progressive decline of lung small airways. The lungs are not able to
function with episodes of acute effectively clear inhaled bacteria, viruses,
worsening of respiratory symptoms, fungi and airborne pollutants. The thickened
referred to as pulmonary mucus on the epithelium forms plaques
exacerbations. with hypoxic areas that can harbour bacteria
and other pathogens.
N Pulmonary effects of CF typically have
the largest impact on morbidity and The lungs of children with CF appear normal
mortality, and account for over 80% at birth but quickly become infected by
of fatalities due to the disease. organisms that are not adequately cleared.
Infants with CF develop persistent
N Current management of CF lung
endobronchial infections early in life due to
disease is predominantly
symptomatic. The cornerstones of CF Staphylococcus aureus, nontypable
respiratory care are airway clearance Haemophilus influenzae and Gram-negative
and treatment of pulmonary bacilli. By the end of the second decade of
infections. life, Pseudomonas aeruginosa is the
predominant pathogen. Chronic bacterial
N Lung transplantation is the final endobronchial infection is associated with
therapeutic option for patients with an intense neutrophilic inflammatory
end-stage lung disease. response that damages the airway, impairs
local host-defence mechanisms and

facilitates further infection. For a given newborn screening. Both infection and
bacterial load, a person with CF will have up inflammation are detected by
to 10-times more inflammation than a bronchoalveolar lavage in CF infants as
person with a lower respiratory tract young as a few weeks of age. CT scans in CF
infection but without the disease. This infants show the presence of structural
vicious cycle of inflammation and infection airway wall changes including thickened
with airway damage results in progressive airway walls, narrowed airway lumens, air
bronchiectasis, gas trapping, impaired gas trapping and bronchiectasis. Once present,
exchange (hypoxaemia and hypercarbia) and bronchiectasis persists and is progressive.
ultimately leads to respiratory failure (fig. 1). Lung function has also been shown to be
diminished in infants with CF, and lung
Airway disease in CF is present early, even in function declines over time throughout life.
asymptomatic infants diagnosed through Pulmonary insufficiency is responsible for at
least 80% of CF-related deaths.
CFTR dysfunction Clinical manifestations
Pulmonary manifestations of the disease

appear throughout life with a great
Dehydrated airway surface liquid variability from patient to patient (table 1;
see also table 1 in the Genetics,
pathophysiology and epidemiology of CF
Impaired mucociliary clearance section in this Handbook).
In the first months of life, respiratory

symptoms can already be present, but
Airway obstruction gastrointestinal symptoms (meconium
ileus, fatty stools and failure to thrive due to
pancreatic insufficiency) are predominant.
Infants with CF do not experience more
Bacterial infection often respiratory virus infections than their
healthy peers but the course of viral
infections can be severe, especially in the
Neutrophilic inflammation case of an infection with respiratory syncytial
virus. Recurrent cough, tachypnoea and
wheeze are the main clinical signs of CF
lung disease in early stages. At first, the
Tissue destruction cough may be dry but eventually it becomes
loose and productive. Some children remain
asymptomatic for long periods or seem to
Bronchiectasis
have only prolonged acute respiratory
infections. Others acquire a chronic cough
within the first weeks of life or have repeated
pneumonias. High energy consumption due
Respiratory failure to an increased work of breathing can
aggravate failure to thrive.
Figure 1. Pathophysiology of CF lung disease.
Steps hypothesised to be relevant in the Older children present with a persistent
progression of CF lung disease are shown. Note moist cough and sputum production.
that the steps do not necessarily occur in the order Expectorated mucus is usually purulent.
presented, for instance, chronic neutrophilic Late clinical findings include increased
inflammation leads to further airway obstruction anteroposterior diameter of the chest,
through the accumulation of dead cells and mucus localised or scattered crackles and digital
in the airway lumen. clubbing. Chest radiograph abnormalities

404
Table 1. Pulmonary manifestations
Stage Manifestation Aim of treatment Management Comments
Early Pre-infection: impaired Mucus clearance, prevent bacterial Airway clearance techniques: Early start of treatment
mucociliary clearance, infection physiotherapy and inhalation with before onset of
virus infections Maintain good lung function hypertonic saline and rhDNase symptoms is
Influenza immunisation recommended
Intermittent isolation of CF Eradication of infection Different protocols with oral, inhaled Eradication can usually be
pathogens and systemic antibiotics achieved, but evidence of
long-term benefit unclear
Intermediate Chronic infection with Sa, Suppression of bacterial load Oral, inhaled and systemic antibiotics Segregation of patients with
Hi, Pa Pa, Bcc, Sm and Ax to
prevent cross infection is
important
Infection with less common CF Eradication if early manifestation; Individual treatment based on Confirmation in a reference
pathogens: Bcc, Sm, Ax suppression of bacterial load antibiotic susceptibility laboratory essential
Allergic bronchopulmonary Reduce allergic response and Oral steroids and antifungal agents Long course over several
aspergillosis fungus load, prevent months required
bronchiectasis
Non-tuberculous Eradication Long-term combination therapy for Treatment started after
mycobacterial infection o12 months repeated detection of the
same isolate with clinical
manifestations
End stage Haemoptysis Prevent bleeding, which may be Intravenous antibiotics, pause airway
fatal clearance therapy for a few days,
bronchial artery embolisation
Pneumothorax Drainage, pleurodesis if recurrent
Respiratory failure Low-flow oxygen therapy, temporarily
CPAP, lung transplantation
rhDNase: recombinant human deoxyribonuclease; Sa: Staphylococcus aureus; Hi: Haemophilus influenzae; Pa: Pseudomonas aeruginosa; Bcc: Burkholderia cepacia complex; Sm:
Stenotrophomonas maltophilia; Ax: Alcaligenes xylosoxidans.
ERS Handbook: Paediatric Respiratory Medicine

(e.g. infiltrates, atelectasis, bronchiectasis) the recovery of Aspergillus fumigatus from
are common pulmonary features of CF sputum, the demonstration of high IgE
(figs 2 and 3). As airways disease persists serum levels or serum antibodies against A.
and worsens, exercise intolerance and fumigatus support the diagnosis. Treatment
shortness of breath are noted. Exacerbations involves antifungals and steroids to control
of pulmonary symptoms eventually require the inflammatory reaction. Airway infection
hospitalisation for effective treatment, but with Burkholderia cepacia may be associated
what constitutes a pulmonary exacerbation with rapid pulmonary deterioration and
of CF is not clearly defined. Increased cough, death. Nontuberculous mycobacteria,
change in sputum colour or quantity, Stenotrophomonas maltophilia and
decreased appetite or weight, change in Alcaligenes xylosoxidans are emerging
respiratory rate and presence of new pathogens in patients with CF. Their clinical
wheezes or crackles on auscultation of the impact is not fully understood but infection
chest are particularly important features. with Mycobacterium abscessus can be a
rapidly progressive process.
With pulmonary disease progression, there
is an increased likelihood of respiratory Haemoptysis and pneumothorax are
complications. Lobar atelectasis may be complications in advanced lung disease.
asymptomatic and noted only at the time of Endobronchial bleeding is the consequence
a routine chest radiograph. Aggressive of airway wall erosion secondary to
antibiotic therapy and increased chest inflammation and infection. Small volume
physiotherapy may be effective. Allergic haemoptysis is relatively common and
bronchopulmonary aspergillosis (ABPA) prompts for intensified antimicrobial
may present with wheezing, increased cough treatment and chest physiotherapy.
and shortness of breath. The presence of Persistent, massive haemoptysis can be
new, focal infiltrates on chest radiograph, controlled by bronchial artery embolisation.
1
2 2 2
3
Figure 2. Chest radiograph of a 15-year-old female CF patient with advanced lung disease a)
posteroanterior view and b) lateral view. The radiograph shows pronounced pulmonary hyperinflation with
sternal bowing, bronchial wall thickening and bilateral bronchiectasis, infiltrates mainly in the right upper
lobe (1) and in the lower lobes on both sides (2) as well as atelectasis of the left lower lobe (3). Note the
central venous access (Port-a-Cath system; Smiths Medical, St Paul, MN, USA). Image courtesy of E.
Stranzinger (Division of Radiology, University Childrens Hospital of Bern, Bern, Switzerland).

#
Figure 3. CT scan of a 15-year-old female CF patient (same patient as in fig. 2) a) coronal plane view and
b) sagittal plane view of the left lung. Bilateral mucus plugging and bronchiectasis, as well as atelectasis of
the left lower lobe (#) is clearly visible. Image courtesy of E. Stranzinger (Division of Radiology, University
Childrens Hospital of Bern, Bern, Switzerland).
Pneumothorax is rarely encountered in A CF team is usually led by a respiratory

children, but may be a life-threatening physician and includes many other
complication in older patients. A small specialists (gastroenterologist,
pneumothorax is managed conservatively, microbiologist, respiratory therapist,
but a large (distance between the apex and dietetician, social worker, psychologist,
cupola .3 cm) pneumothorax or under specialised CF nurse). For patients living a
tension requires rapid treatment with long distance from a CF centre, formalised
drainage. If recurrent, pleurodesis or assisted care with local clinics can be
surgical intervention has to be performed. considered. However, only when the quality
of the assisting team is up to standard.
Acute respiratory failure rarely occurs and is
usually the result of a severe viral illness,
such as influenza. Patients eventually During follow-up outpatients visits, an
progress to chronic respiratory failure from interval history should always be taken and a
slow deterioration of lung function. Chronic physical examination performed. A sputum
right-sided heart failure (cor pulmonale) is a sample should be obtained for
complication seen in CF patients with long- microbiological analysis, or if not available a
standing, advanced pulmonary disease, lower pharyngeal swab taken during or after
especially in those with severe hypoxaemia. a forced cough. Pulmonary function tests
should be performed at regular intervals to
For most patients, lung disease is the major monitor lung disease progression. Chest
health problem in terms of symptoms and radiographs or CT scans are usually
treatment required and because it is the included as part of the annual review. Apart
most likely cause of morbidity and death. from the annual review, chest radiography
Management of lung disease should be considered when atelectasis or a
pneumothorax is considered. In some
Nowadays, most CF patients in Europe centres, yearly bronchoscopy with
receive care on a regular basis every 1- bronchoalveolar lavage is performed for
3 months, coordinated by a team of trained microbiological surveillance in young
and experienced health professionals in a children unable to expectorate, but it is yet
tertiary centre. CF centre care is essential for unclear whether this approach results in
optimal patient management and outcome. better outcomes.

Current management of CF is predominantly airway-oscillating devices positive expiratory
symptomatic. The cornerstones of CF pressure (PEP) devices, active cycles of
respiratory care are clearance of lower airway breathing techniques and autogenic
secretions and treatment of pulmonary drainage (series of respiratory huffs and
infections. Annual influenza vaccination is coughs designed to move mucus from distal
recommended. The goal of therapy is to to proximal airways so it can be coughed
maintain a stable condition and to prevent out). Close supervision by an experienced
any irreversible structural lung changes. physiotherapist and continuity of care is
Much of the clinical practice has evolved essential. There is a divergence of opinion
over decades without being subjected to about specific aspects of therapy, but the
high quality randomised controlled trials, consensus is that this form of therapy is
especially in children ,6 years. highly effective in older subjects, as it
favours clearance of secretions that
Knowledge of the basic CF defect has led to
accumulate in small airways, even before the
the development of new therapeutics aimed
onset of symptoms. Its role is far less clear
at potentiating or even correcting defective
in younger children diagnosed through
CFTR channel function, which also improves
newborn screening, and some forms of
lung function. The first such molecule (VX-
770, Ivacaftor) which potentiates CFTR physical therapy might even be detrimental
function in patients with the G551D (e.g. by inducing gastro-oesophageal reflux).
mutation, has recently been licensed in the Hypertonic saline acts as an hyperosmolar
USA and Europe (see the Emerging agent and presumably rehydrates the airway
treatment strategies in CF section in this surface liquid layer, thus improving
Handbook). mucociliary clearance. It is delivered using a
Treatment modalities small compressor that drives a hand-held
nebuliser. It has been shown to be effective
Treatment aims and modalities for CF lung in older subjects, but its role in young
disease vary according to the disease stage children aged ,5 years is unknown. Saline
(table 1). at a concentration of 67% is usually
Early disease stages So far there have been applied. Whether lower strength saline (3%
hardly any randomised controlled trials on or even 0.9%) is also efficacious has not yet
chronic pulmonary therapies in young been systematically studied. In general,
children with CF. This is, in part, because hypertonic saline is well tolerated. In
appropriate end-points are difficult to patients with reactive airways, salbutamol or
identify, but also because federal regulations other bronchodilators can be added. In the
make inclusion of young in children in light of the current knowledge about the
research studies complicated. Therefore, pathophysiology of the disease, early start
current recommendations for therapies in with a trial and error approach of inhalation
the pre-school age are mainly based on with normal or hypertonic saline seems
studies in older children. Studies including reasonable.
very young patients must be designed and
Early antibiotic treatment of typical CF
undertaken, because it is likely that early
pathogens is recommended. Antibiotics are
therapy, before lung disease is established,
the mainstay of therapy against pulmonary
will provide the most significant and long-
infection. Their goal is to control
term benefits for children with CF.
progression of lung infection and to delay
Preventive therapy with chest physical progressive lung damage. Antibiotic
therapy is recommended. The goal of treatment varies from intermittent short
physiotherapy is to clear secretions from courses of oral antibiotics to continuous
airways. There are many techniques treatment with one or more oral or inhaled
available to augment clearance of tenacious antibiotics. Dosages of oral antibiotics for
airway secretions. These include postural CF patients are often two to three times the
drainage, vibration and percussion, amount recommended for minor infections

in order to achieve effective drug levels in proven successful in the maintenance of
sticky respiratory tract secretions, and lung health.
because CF patients have proportionately
more lean body mass and higher clearance Intermediate disease stages In school-aged
children, treatment with inhaled hypertonic
rates for many antibiotics than do other
saline, dornase alfa (recombinant human
individuals. Whenever possible, in vitro
deoxyribonuclease (rhDNase)) and intensive
sensitivity testing should be performed to
airway clearance is recommended. Exercise
guide the choice of antibiotics, although it
is beneficial for CF patients, as it improves
does not always reflect bacterial
sense of wellbeing, improves quality of life
susceptibility to antimicrobial agents in vivo.
and might stabilise lung function to some
Infection with S. aureus and H. influenzae is degree. Exercise alone should however not
usually treated with oral antibiotics, but be used as an alternative to airway
despite this, chronic infection persist in clearance.
many patients. Anti-staphylococcal
Continuous oral azithromycin treatment,
prophylaxis with oral antibiotics is
which has both antibacterial and anti-
performed in some countries but this
inflammatory effects, is often added to
approach is subject to debate. improve lung function and to reduce
P. aeruginosa initially grows in a non-mucoid exacerbations. Oral high-dose ibuprofen has
form that can be eradicated by aggressive been shown to slow disease progression,
antibiotic treatment. Over time, it builds but it use is hampered by the necessity of
colonies that synthesise an alginate coat and monitoring serum concentrations and
forms biofilms, which are difficult, if not unfavorable side-effects. Systemic
impossible, to clear with antibiotic corticosteroids are useful for the treatment
of ABPA but side-effects (growth
treatment. Patients infected with P.
retardation, cataracts, abnormalities of
aeruginosa have more rapid lung function
glucose tolerance) have limited their use as
decline and diminished survival compared
a standard therapy. Inhaled corticosteroids
to non-infected subjects. Therefore
show no significant benefits in CF lung
heightened surveillance and aggressive
disease, unless the patient has concomitant
treatment of P. aeruginosa is warranted.
asthma. Systemic expectorants such as
First infection with P. aeruginosa is always iodides and guaifenesin are not effective in
treated with antibiotics with the goal to assisting with the removal of secretions
eradicate the germ. Treatment with 1 month from the respiratory tract.
of tobramycin nebulisation is currently the
For CF patients with chronic P. aeruginosa
first line of treatment, and eradication can
infection, long-term treatment with inhaled
be achieved in most cases. Other treatment
antibiotics (tobramycin, colistin or
protocols have been shown to be of similar
aztreonam) is recommended, with the goal
effectiveness and include oral, inhalation of reducing the frequency of pulmonary
and intravenous antibiotics but there are exacerbations and slowing the disease
only few comparative studies available and, progression.
therefore, the optimal antibiotic regimen is
not known. In cases of eradication failure, Intravenous antibiotics are indicated for
repeating antibiotic eradication treatment is patients who have progressive or
recommended. If there is chronic airway unrelenting symptoms (pulmonary
infection with P. aeruginosa, maintenance exacerbation) or a decline in lung function
treatment with chronic suppressive despite intensive home therapy. Intravenous
antibiotics should be initiated. Often used antibiotic therapy is usually initiated in the
regimens are intermittent one month on one hospital but is often completed on an
month off inhalation of tobramycin or ambulatory basis. The usual duration of
continuous administration of inhaled intravenous antibiotic therapy is 14 days,
colistin. These treatment strategies have but this can be extended to several weeks.

In general, a combination therapy is applied. Further reading
Since most patients with pulmonary
N Borowitz D, et al. (2009). Cystic Fibrosis
exacerbations have P. aeruginosa in their
Foundation evidence-based guidelines for
airways, the usual in-hospital treatment is a
management of infants with cystic fibro-
combination of a b-lactam and an
sis. J Pediatr; 155: S73S93.
aminoglycoside. In vitro antibiotic sensitivity N Boucher RC (2007). Airway surface dehy-
tests do unfortunately not predict clinical dration in cystic fibrosis: pathogenesis
outcome in patients with chronic infection and therapy. Annu Rev Med, 58: 157170.
and routine testing of the susceptibility of N Cohen-Cymberknoh M, et al. (2011).
bacteria to combinations of antibiotics Managing cystic fibrosis. Strategies that
(synergy testing) is not recommended. In increase life expectancy and improve
some centres, intravenous antibiotics are quality of life. Am J Respir Crit Care Med;
given on a routine basis independent of 183: 14631471.
pulmonary exacerbations. N Doring G, et al. (2012). Treatment of lung
infection in patients with cystic fibrosis:
Late disease stages Low-flow oxygen therapy current and future strategies. J Cyst Fibros;
at home, especially with sleep, is applied in 11: 461479.
case of chronic respiratory failure. Lung N Flume PA, et al. (2009a). Cystic fibrosis
transplantation is the final therapeutic option pulmonary guidelines: airway clearance
for patients with endstage lung disease. therapies. Respir Care; 54: 522537.
Transplantation has the potential to extend N Flume PA, et al. (2009b). Cystic fibrosis
and substantially improve quality of life in pulmonary guidelines: Treatment of pul-
properly selected patients. How to select monary exacerbations. Am J Respir Crit
patients (especially children) in an optimal Care Med; 180: 802808.
way for this high-risk procedure, is still the N Flume PA, et al. (2010). Cystic fibrosis
subject to debate (see the Prognosis, pulmonary guidelines: pulmonary com-
plications: hemoptysis and pneu-
management of end-stage lung disease and
mothorax. Am J Respir Crit Care Med;
indications for lung transplantation in CF
182: 298306.
section in this Handbook). CF patients with
N Kerem E, et al. (2005). Standards of care
chronic respiratory failure who are on a lung for patients with cystic fibrosis: a
transplant waiting list may be candidates for European consensus. J Cyst Fibros; 4: 7
nocturnal non-invasive ventilatory 26.
assistance. N Mott LS, et al. (2012). Progression of early
structural lung disease in young children
Respiratory treatments represent the with cystic fibrosis assessed using CT.
greatest challenge to patients and families; Thorax; 67: 509516.
proper physiotherapy and inhaling N Mogayzel PJ Jr, et al. (2013). Cystic
hypertonic saline, antibiotics and/or fibrosis pulmonary guidelines. Chronic
rhDNase is very time consuming and takes medications for maintenance of lung
12 h per day during periods of good health health. Am J Respir Crit Care Med; 187:
and much longer during a respiratory 680689.
exacerbation.

Extrapulmonary
manifestations of CF
Anne Munck, Manfred Ballmann and Anders Lindblad
Nutritional approach in patients with CF guidelines provide an invaluable tool in daily

care management. Neonatal screening
Maintaining adequate nutritional status in programmes enabling very early follow-up
terms of lung health and survival is a care, prior to clinical pulmonary
cornerstone of the CF multidisciplinary involvement, offer a unique opportunity for
approach. Consensus-based nutritional nutritional assessment at a crucial period of
rapid growth.
Key points Nutrition When providing nutritional intake

to achieve normal growth in children and
N Nutritional status is strongly maintain adequate weight in adults, sex, age
associated with pulmonary function (rapid growth rate in infants and
and survival in CF. adolescents), specific needs during
pregnancy, nutritional and pancreatic status,
N Nutritional management should be family circumstances, cultural dietary
started as soon as possible after beliefs, and patient food preferences all
diagnosis. must be taken into account.
N Patients height and weight should be
Energy requirements of newly diagnosed
measured at each clinical visit and
BMI calculated (percentile or z-score infants with CF may range from 110% to
in children, absolute BMI in adults). 150% of the recommended daily allowance
(RDA) (Borowitz et al., 2002; Sinaasappel et
N EPI should be confirmed by a al., 2002; Stallings et al., 2008; Munck,
biological test (steatorrhoea or faecal 2010). Infants with CF can be safely
elastase-1) and PERT should be breastfed. Additional calories (carbohydrate
started as soon as possible. content up to 1012 g per 100 mL and fat
N Fat-soluble vitamins need to be given density 5 g per 100 mL) can be added to
in association with pancreatic expressed breast milk and/or infant formula
enzymes in EPI patients. can be concentrated (1.21.5 cal?mL-1) if
weight gain is poor, rather than increasing
N The gastrointestinal tract is a major milk volumes, due to the enhanced risk of
source of comorbidity in CF patients. gastro-oesophageal reflux (GOR). There is
N Entities such as fibrosing no evidence to support the use of protein
colonopathy, appendiceal mucocoele hydrolysate formulas with the exception of
and DIOS are specific to CF. infants undergoing small bowel resection for
meconium ileus, severe failure to thrive or
N In the case of acute abdominal pain, with co-existing cows milk protein
surgical conditions need to be sought; intolerance. Solid food can gradually be
all surgical aetiologies may take on introduced between 4 and 6 months;
the appearance of recurrent pain with parents should seek the dieticians advice on
mild symptoms. the most suitable foods and pancreatic
enzyme dosage. Young children should later

eat three regular meals and two snacks of and textures may help in preventing
high nutrient and calorie density. lassitude. In children, behavioural
interventions have been shown to improve
Protein needs are unknown but may be nutritional outcome.
higher than normal. Dietary fat intake is
considered adequate at 50% of total energy Nocturnal enteral feeding through a
intake at ,6 months, and between 40% and nasogastric tube or gastrostomy, according
50% in older patients. to the patients preference, has to be
considered to provide long-term nutritional
Sodium supplementation is recommended support in patients not gaining (children) or
for all infants, in hot climates, and in the keeping (adults) weight. The majority of
case of fever or sport activities. patients tolerate high-energy polymeric feed
Adolescence is another crucial period, with but a semielemental feed may be beneficial
increased energy requirements related to for some. All feeds need pancreatic enzyme
rapid physical growth. replacement therapy (PERT). Patients may
need up to 70% of RDA by enteral feeding to
Maintaining optimal nutritional status in improve their weight and are encouraged to
adulthood is a challenge, as the prevalence continue with a high-energy diet during the
of malnutrition increases with age-related day. It is important to monitor for glucose
CF complications. Patients height and intolerance and GOR symptoms.
weight should be measured at each clinical
Pancreatic enzyme replacement therapy
visit and BMI calculated (percentile or z-
Exocrine pancreatic insufficiency (EPI)
score in children, absolute BMI in adults).
(Munck, 2010) is present in 8590% of
Patients who develop CF-related diabetes patients. Symptoms include: pale, oily
are encouraged to continue eating a diet rich stools; abdominal pain; and poor weight
in energy and fat (Moran et al., 2010a). A gain. Even if the patients show these
minimal change in the quantity of symptoms, a biological confirmatory test is
carbohydrates is generally advised but required to define pancreatic status. The
distribution may need to be adapted. faecal elastase-1 test is now widely used and
a level of ,200 mg?g-1 is diagnostic of EPI.
Pregnancy is possible in women with CF but Once EPI is confirmed, PERT should start as
the risk of a negative impact on survival may soon as possible. Currently available
increase with more severe disease and, preparations are derived from porcine
therefore, it is not recommended in these pancreas. Enteric-coated preparations
patients. Additional recommended energy dramatically decrease enzyme degradation
requirements for pregnancy vary from 200 by stomach acidity and improve the release
to 300 kcal?day-1 (Edenborough et al., 2008). of enzymes in the duodenum.
Nutritional status before and during
pregnancy influences the evolution of For some patients with poor response to
pregnancy and newborn outcome. PERT needing high doses, H2-receptor
antagonists or proton pump inhibitors may
Careful monitoring of the growth chart at be beneficial.
each consultation is mandatory to prevent
malnutrition. Dietary diary intake with the Following the occurrence of fibrosing
help of a dietician and evaluation of colonopathy in the early 1990s in young
treatment compliance are part of children receiving very high doses of daily
multidisciplinary assessment, and are PERT and despite the rareness of this
needed for early nutritional intervention. If complication, the severity of the condition
the principal cause of poor nutritional status led to consensus guidelines for PERT in
is insufficient food intake despite a high- 2002 recommending not exceeding a daily
energy diet, the use of oral nutritional dose of 10 000 IU lipase per kilogram per
supplements may be of some use at an day (25003000 IU lipase per 120 mL breast
individual level; a large variety of flavours milk or formula, 5002500 IU lipase per

kilogram per meal or 5004000 IU lipase supplementation for all patients might be
per gram of fat) of standard or high beneficial.
strength enzyme preparations. Enzymes
should be given with all fat-containing foods Low plasma 25-hydroxyvitamin D levels have
at the beginning and middle of the meal, often been reported and suboptimal status
with the dose gradually increased. after adjusting for season remains common.
Cholecalciferol (vitamin D3)
Capsules can be opened for infants and supplementation is more effective than
toddlers. In infants, micro- or mini- ergocalciferol (vitamin D2). Recent
microspheres can be mixed with a small improvement in our knowledge of the
amount of breast milk, formula or fruit different roles of fat-soluble vitamins
puree. Microspheres should not be crushed, emphasises the need for optimal
chewed or mixed with the meal. supplementation. Water-miscible
multivitamins formulations with satisfactory
There is insufficient evidence to establish a bioavailability profiles have been developed.
doseresponse association between PERT Current guidelines (Sinaasappel et al., 2002;
and weight gain. Usually, adequacy of PERT Maqbool et al., 2008) on fat-soluble vitamin
is evaluated clinically by growth, weight, prescriptions are old and may require
stool pattern and abdominal pain. In some updating.
cases, it may be helpful to assess the
coefficient of fat absorption (3-day stool Gastrointestinal complications in CF
collection and diet intake). Digestion, absorption and motility In CF, the
three main gastrointestinal functions are
Fat-soluble vitamin supplementation Patients impaired (Borowitz et al., 2005).
with EPI should be supplemented with fat- Maldigestion and malabsorption are
soluble vitamins (table 1) (Maqbool et al., secondary, and the main cause is abnormal
2008) from the time of diagnosis and serum pancreatic function with reduced
levels measured annually. Pancreatic- bicarbonate secretion (thus impairing
sufficient patients should have their serum pancreatic enzyme lipase activity and
fat-soluble vitamin levels checked annually, precipitating bile acids, inhibiting lipid
with doses adjusted accordingly. emulsification) and a dramatic decrease in
enzyme secretion. Other luminal factors are
To ensure satisfactory oral bioavailability, all
excessive mucus production with abnormal
fat-soluble vitamin (A, E, D and K)
composition, impaired gut motility, small
formulations need to be ingested
intestine bacterial overgrowth, chronic gut
concomitantly with pancreatic enzymes
inflammation and gut lumen dehydration
during the meal. Vitamin A is stored in the
closely related to a CF transmembrane
liver. Plasma retinol measurements should
conductance regulator (CFTR) basic ion
be taken during clinical stability. b-carotene,
transport defect (i.e. decreased chloride
a pro-vitamin A antioxidant, is subject to
secretion, and enhanced sodium and water
regulation in its conversion to vitamin A,
absorption from the lumen).
potentially decreasing the risk of
hypervitaminosis A. Vitamin E represents an Physiological and pathological abnormalities A
important, powerful antioxidant. Vitamin E variety of abnormalities have been identified
status can be evaluated by serum level in the gastrointestinal tract but their role in
concentration or serum concentration/lipid clinical syndromes remains poorly
ratio. Vitamin K deficiency is common in understood. Gut histology shows dilated
pancreatic-insufficient patients with mucus glands with inspissated mucus and a
additional risk factors: first year of life, normal enterocyte brush border.
frequent antibiotic use (reduced production Ultrasonography identifies a marked
of menaquinones by the modified gut flora) increase in small and large bowel wall
and cholestasis. Prothrombin time is thickness (Wilschanski et al., 1999).
monitored annually. Routine Recently, duodenal pH studies with wireless

Table 1. Fat-soluble vitamins: current daily intake
Vitamin Age group Intake recommendations mg Monitoring recommendations
(IU)
A 012 months 510 (1500) Serum retinol (deficiency
13 years 1700 (5000) ,20 mg?dL-1)
(RBP zinc level)
48 years 17003400 (500010 000)
.8 years/adults 3400 (10 000)
E 012 months 4050 (4050) Serum a-tocopherol
13 years 80150 (80150)
48 years 100200 (100200)
.8 years/adults 200400 (200400)
K 012 months 0.30.5 Serum prothrombin time
18 years 0.30.5
Adults 2.55 per week
D 012 months 10 (400) Serum 25(OH)D in late autumn
.1 year 1020 (400800) or winter
RBP: retinol binding protein; 25(OH)D: 25-hydroxyvitamin D. Reproduced and modified from Maqbool et al.
(2008).
capsules demonstrated low pH as a presentation includes recurrent acute

consequence of decreased pancreatic abdominal pain, vomiting, increased
bicarbonate secretion. Transit time was also amylase and lipase levels, and pancreatic
evaluated with this technique and identified ultrasonography or CT abnormalities.
delayed small bowel transit without a Amylase and lipase levels may also be
compensatory increase in whole-gut transit normal or only slightly elevated.
(Gelfond et al., 2012). Chronic gut Management consists of pain relief, fasting,
inflammation has been identified in intravascular hydration, use of proton pomp
duodenal biopsies and by increased inhibitors and progressive diet
calprotectin levels in stools and pro- reintroduction (initially lipid-free diet).
inflammatory cytokines in gut lavage (Werlin Because pancreatitis may be a presenting
et al., 2010). feature of CF or CFTR-related disorder
(Munck, 2004), sweat testing and CFTR
Pancreatic exocrine and extrahepatic biliary genetic testing are recommended in
complications Pancreatitis (De Boeck et al., pancreatitis of unknown cause.
2005; Ooi et al., 2012) occurs in up to 20%
of pancreatic-sufficient patients carrying at Extrahepatic biliary manifestation with
least one mild CFTR mutation (class IV or undetectable gallbladder in CF fetuses is
V). It is more common in adolescents and common. Later, gallstones with cholesterol
adults. Patients are at risk of recurrent acute or calcium bilirubinate are frequent and are
or chronic pancreatitis. Progression to EPI a consequence of chronic bile salt loss and
with acinar destruction which may take enhanced unconjugated bilirubin in the
years contributes to the resolution of the colon impairing colonic reabsorption.
pancreatitis. Possible triggering factors Medical treatment with ursodeoxycholic acid
include alcohol, gallstones, abnormalities of (UDCA) is ineffective. In the case of
the pancreaticobiliary junction, dehydration, complications (pain and jaundice), which
modifier genes and specific non-CFTR occur in 410% of patients, surgery is
mutations (Ooi et al., 2012). The typical required.

Gut manifestations GOR is very frequent in is discussed. Meconium ileus is not
CF, even in infants (Vic et al., 1995). It has exclusive to CF patients (although the
been postulated that GOR is a consequence majority have CF) and thus diagnostic tests
of respiratory disease but there is no should be performed as soon as possible to
correlation between GOR and lung disease confirm or refute CF diagnosis. The
severity. The underlying mechanisms are not tendency to express the meconium ileus
completely understood and appear to be phenotype might also be related to non-
multifactorial: the majority of reflux episodes CFTR genetic factors called modifier genes
are caused by transient lower oesophageal (Dorfman et al., 2009). The clinical
relaxation rather than decreased lower presentation of this distal bowel obstruction
oesophageal sphincter pressure (Pauwels et combines distension, bilious vomiting and
al., 2012). Other factors are involved such as failure to pass the meconium within 48 h of
thoracic distension, coughing, malnutrition, birth. Radiography identifies abdominal
delayed gastric emptying, postural drainage distension and dilated loops. Barium enema
head-down and certain drugs. The most shows a microcolon with a soap bubble
common symptoms are heartburn (pyrosis), aspect in the right iliac fossa corresponding
nocturnal cough, vomiting, abdominal to meconium pellets in the distal ileum.
epigastric pain, dysphagia and unexplained Management of uncomplicated meconium
pulmonary deterioration, but GOR may also ileum relies on enema with diluted
remain asymptomatic. GOR may affect both Gastrografin, a hyperosmolar, water-soluble,
respiratory function and nutritional status. It radio-opaque meglumine diatrizoate
is reasonable to start a trial of medical solution containing 0.1% polysorbate 80
therapy based on clinical symptoms. An (Tween 80) slowly infused at low pressure
upper endoscopy is indicated in case of under fluoroscopy control to relieve
dysphagia, haematemesis or suspicion of obstruction. Enema can be repeated and the
peptic ulceration; a 24-h ambulatory success rate is close to 40%. In case of
oesophageal pH probe is useful when there failure, surgery is required. Complicated
is doubt as to whether GOR is the cause of meconium ileus (40%) with peritonitis,
symptoms, prior to starting enteral feeding volvulus and intestinal atresia requires
and when lung transplant is considered. immediate surgery. Depending on the
Standard management combines thickening severity of the newborns clinical condition,
food in infants, raising the head of the bed different surgical approaches can be
and acid suppression with proton pump considered: enterostomy irrigating the distal
inhibitors. Prokinetic drugs are no longer bowel through the stoma, resection of the
available in many countries. For patients compromised bowel with complete proximal
who fail to respond, a surgical and distal meconium evacuation, and either
fundoplication can be discussed and may a primary anastomosis or a temporary
slow pulmonary decline, reduce the number enterostomy (Carlyle et al., 2012). Post-
of exacerbations and improve weight gain operative care and nutritional support by a
(Sheikh et al., 2012). gastroenterology team is part of meconium
ileus management. With early detection,
Meconium ileus is the earliest CF clinical appropriate therapy and nutritional support,
manifestation occurring in up to 20% of CF death is now uncommon, and long-term
newborns. Diagnosis can be made through nutritional and pulmonary outcomes are
ultrasonography in utero during the second equivalent to those of other CF patients.
trimester revealing polyhydramnios with a
dilated, hyperechogenic fetal bowel. The Meconium plug syndrome consists of
distal intestinal obstruction is caused by abnormal meconium accumulation located
accumulation of abnormal viscous in the colon that produces mild abdominal
meconium in the lumen. Careful diagnostic distension and failure to pass meconium.
evaluation and a consultation with a genetic Management relies on contrast enema.
counsellor are recommended, including About 25% of patients present
CFTR gene analysis if pregnancy termination underlying CF.

Distal intestinal obstruction syndrome may be tried before considering resection of
(DIOS) is specific to CF and is a common the ileocaecum. Patients presenting
complication in adolescents and adults (five incomplete DIOS usually respond to oral
to 12 cases per 1000 patients per year) rehydration combined with osmotic laxative
(Houwen et al., 2010; Colombo et al., 2011). lavage containing PEG. Maintenance
It is characterised by the accumulation of therapy with oral PEG for a few months is
viscid faecal material in the terminal ileum recommended and, in cases of a decline in
and/or the right colon. Patients are at high the frequency of bowel movements, this has
risk of recurrence (50%). The been shown to decrease the risk of
physiopathology is not fully understood and recurrence of DIOS episodes in up to 50%.
probably multifactorial, involving Bowel preparation before surgery
gastrointestinal lumen dehydration, (transplantation) has been suggested to
impaired motility and abnormal bile acid prevent DIOS post-operatively.
absorption. Reported risk factors include a
severe genotype, pancreatic insufficiency Fibrosing colonopathy was first described in
(but it does not play a central role because the 1990s (Smyth et al., 1995) in four young
DIOS does not occur in pancreatic children thought to have DIOS. They
insufficiency out of CF and may occur in presented acute abdominal pain, diarrhoea
pancreatic-sufficient CF patients), and partial to complete abdominal
dehydration, poorly controlled fat obstruction. Investigation with contrast
malabsorption, intestinal dysmotility, history enema showed loss of haustral folds and
of myocardial infarction and surgery. DIOS mild to complete occlusion, mainly in the
typically has an acute onset of symptoms. right colon. In most cases, a laparotomy had
Complete DIOS is defined as the to be performed with a right hemicolectomy.
combination of 1) complete intestinal Histology identified submucosal thickness
obstruction with bilious vomiting or fluid due to fibrous connective tissue and an
levels on radiography with 2) a faecal mass intact epithelium border. A casecontrol
in the right iliac fossa and 3) abdominal pain study confirmed a strong association
and/or distension. Incomplete DIOS gathers between fibrosing colonopathy and
the two latter symptoms. A surgical excessive PERT supplementation
aetiology has to be ruled out (appendicitis, (.50 000 IU lipase per kilogram per day).
intussusception, volvulus adhesions, etc.), Thus, European and American guidelines
thus an ultrasonography or an abdominal (Sinaasappel et al., 2002; Borowitz et al.,
CT may be needed. Treatment of DIOS relies 2002) published in 2002 agreed to
on a stepwise approach depending on the recommend restrictions on PERT doses to
severity of the syndrome. Complete DIOS f10 000 IU?kg-1?day-1; since then, cases
with moderate obstruction can be treated have virtually disappeared.
with polyethylene glycol (PEG) lavage; in the
case of more severe presentation with Acute appendicitis is less common in CF
bilious vomiting, hospitalisation with patients (1.55% compared with 7% in
fasting, intravascular hydration and diluted healthy peers). Surveys have shown a high
sodium meglumine diatrizoate rate of perforation and abscesses related to
(Gastrografin) enema under direct vision subacute presentation and delayed
until the terminal ileum is reached may diagnosis probably as a consequence of
achieve resolution of obstruction. Close frequent antibiotic prescriptions for
monitoring of the patient is recommended pulmonary exacerbations (Coughlin et al.,
because Gastrografin enema may cause 1990). Appendiceal mucocoele is a mucoid
major ion and water shifts. In the case of distension of the appendix that can remain
failure, because surgery is a high-risk asymptomatic, or cause chronic pain or
intervention, a colonoscopy with local mimic appendicitis. It can occur at all ages.
instillation of Gastrografin in the caecum Clinical examination of the right iliac fossa
and ileum lavage may be an alternative. If it identifies a small ovoid mass.
fails an attempt of washout, enterostomy Ultrasonography focusing in the right iliac

fossa shows a multilayer mass with an considered in any CF patient presenting with
enlarged appendix (.6 mm) filled with chronic diarrhoea or abdominal pain despite
echogenic material. To rule out other adequate PERT replacement. The presence
aetiologies, CT or contrast enema may be of anti-endomysium and anti-
indicated and may reveal the caecal defect. transglutaminase antibodies has good
In the case of symptoms, appendectomy sensitivity but a duodenal biopsy is required
with resection of the appendix edges and to confirm diagnosis and start the patient on
resection of the caecal tip will avoid the risk a lifelong, strict gluten-free diet.
of recurrence (Munck et al., 2000). At
histology, the appendix is distended with Crohns disease has been reported in CF.
inspissated mucus. Symptoms are difficult to differentiate from
symptoms in CF, including diarrhoea,
The incidence of intussusception is 1%, and abdominal pain, weight loss and
it occurs mainly in children and adolescents. inflammatory parameters. A colonoscopy
It is usually ileocolic, but can also be with multiple biopsies is essential to
ileoileal; it may resolve spontaneously. It is a confirm diagnosis.
consequence of dehydrated mucus and
There is an increased risk of digestive tract
impaired intestinal motility but a starting
cancer, mainly colon, bowel, biliary tract,
point is frequent, such as inspissated
liver and pancreas, but these remain rare
secretions, lymphoid follicles, the appendix
conditions. However, patients with CF have
or polyps (with a malignancy risk in adults).
earlier onset with a markedly increased risk
Clinical presentation combines severe between 20 and 29 years of age (Alexander
colicky abdominal pain, vomiting, bloody et al., 2008).
stools and a palpable mass in the right iliac
fossa. Abdominal radiography may show CF-related liver disease
obstruction, ultrasonography may reveal the
characteristic bulls eye and abdominal CT CF-related liver disease (CFLD) accounts for
can confirm the diagnosis if there is a doubt ,2.5% of overall mortality in CF. 2735% of
concerning the differential diagnosis. patients will develop some sort of liver
Intussusception reduction in children is the involvement while about 510% will develop
first choice unless complicated multilobular cirrhosis (MLC) with portal
(perforation). If it fails or is complicated, hypertension (PHT) (Flass et al., 2012;
immediate surgery is required (Nash et al., Debray et al., 2011). In patients developing
2011). severe liver disease, liver involvement
commonly starts during the first decade of
Rectal prolapse occurs mainly at preschool life and develops to MLC with PHT during
age and usually resolves after adjustment of the second decade of life. Often, the PHT is
PERT, an adequate-fibre diet, stool softeners complicated by variceal bleeding before liver
and advice concerning voiding. Rectal failure develops. The variceal bleeding
prolapse may be also be a presenting feature demands treatment with variceal banding/
of CF. sclerosing and, sometimes, nonselective b-
blockers. The final option is often orthotopic
Comorbid gastrointestinal conditions Milk liver transplantation.
protein intolerance occurs more often in CF.
Infants present nonspecific symptoms such Pathophysiology CFTR is expressed on the
as diarrhoea, constipation, vomiting, failure apical surface of the cholangiocytes, and the
to thrive and eczema. Abnormal biological current belief is that missing CFTR results in
tests, including IgE levels, specific obstruction of the small intrahepatic bile
antibodies and prick tests, are helpful for ducts and retention of toxic substances,
indicating a semielemental diet. leading to the most common histological
feature in CFLD, focal biliary cirrhosis. The
Coeliac disease has a prevalence of 1.2% in reason for its focality is unknown. The focal
CF, which is higher than in the general biliary cirrhosis slowly develops into MLC
population (Pohl et al., 2011). It should be without any symptoms (Debray et al., 2011).

Most commonly, only patients with two ultrasonography may be even more sensitive
severe mutations (class IIII) and than clinical or biochemical abnormalities.
pancreatic insufficiency develop MCL In some situations, liver biopsy can be
(Colombo et al., 2002). No CF mutations indicated (Debray et al., 2011).
have been related to more severe liver
Treatment The liver disease in CF develops
disease and the liver phenotype in patients
slowly, and may remain stable for years and
with the same genotype varies. Modifying
maybe decades. In many cases, liver
genes have been sought but, so far, only the
transplantation is not needed. Based on the
SERPINA1 Z-allele shows an association
hypothesis that the starting event of CFLD is
with MLC and PHT (Bartlett et al., 2009).
bile duct obstruction, UDCA, a bile acid that
Other liver involvement Neonatal has hydrophilic and choleretic properties
hyperbilirubinaemia can be associated with and may act as a cytoprotective agent, is
CF but normally resolves spontaneously used for treatment of CFLD, mostly in
(Shapira et al., 1999). Liver enzymes are Europe. Although evidence of an effect on
often raised during the first year after the level of liver enzymes, biliary drainage,
diagnosis and not related to later severe ultrasound changes and possibly liver
liver disease. Up to 75% have steatosis of histology exist, there is no information
differing degrees, most probably related to about long-term effects of halting the
nutritional deficiencies. Massive steatosis in progression of CFLD. It has been suggested
the early years has become less common, that patients would gain from early
probably due to improved care and treatment when there are less severe
nutrition. Currently, steatosis in CF is pathological changes, although there is no
considered a benign condition not related to evidence to support this. The recom-
the development of MLC. mended starting dose is 20 mg?kg-1?day-1
(Debray et al., 2011). Common
Screening for liver disease Since the recommendations include contraindication
development of MLC with or without PHT is of salicylic acid and nonsteroidal anti-
asymptomatic, screening for CFLD is inflammatory drugs, vaccination against
necessary. At the annual review, liver hepatitis A and B, and special attention to
enzymes and other biochemical markers of nutritional status to ensure adequate caloric
liver disease, including alanine intake (increase energy intake, and enteral
transaminase (ALT), aspartate transaminase nasogastric feeding when awaiting a liver
(AST), serum alkaline phosphatase, c- transplant).
glutamyl transpeptidase (GGT), albumin
and prothrombin time, and a thorough All patients with signs of CFLD should be
physical examination must be included. evaluated by a paediatric gastroenterologist
Regular ultrasound of the liver and the with knowledge of liver disease in CF.
biliary tract are often performed, at least CF-related diabetes
during childhood and adolescence, and are
suggested if the liver enzymes are raised at CF-related diabetes (CFRD) is the most
the annual review. The presence of CFLD frequent comorbidity in CF. Starting with a
should be suspected when the liver enzymes prevalence of ,3% at the age of 10 years, the
(ALT, AST and GGT) are raised three times prevalence increases and peaks at 2530%
over a 12-month period after excluding other at 3540 years. CFRD mimics some aspects
causes of liver disease, and ultrasonography of type 1 and other aspects of type 2 diabetes
shows hepatomegaly/splenomegaly, (Moran et al., 2010a): it is an insulin-
increased/irregular echogenicity or irregular deficient status but with some remaining
margins. Signs of PHT are leukopenia, insulin secretion. CFRD is associated with a
thrombocytopenia and splenomegaly. It is faster decrease in lung function, weight loss
important to emphasise that not all patients and reduced survival compared with age-
developing CFLD display pathologically and sex-matched nondiabetic CF patients. It
increased liver enzymes and is difficult to diagnose CFRD at an early

stage because typical clinical symptoms are patients, including self-managed glucose
often absent. There is no simple laboratory measurements, blood pressure control and
test to screen for CFRD. Glycated 3-monthly HbA1c measurements. The aim is
haemoglobin (HbA1c), as a single laboratory HbA1c ,7% and no hyper- or hypoglycaemic
marker, will miss ,30% of all CF patients situations. The risk of hypoglycaemia is real
with CFRD. The oral glucose tolerance test and must be addressed with education of
(OGTT) is the gold standard for the patient and monitoring of blood glucose
diagnosing CFRD (Moran et al., 2009a). levels. Since ketoacidosis is untypical in
Some specialised centres use continuous CFRD, in these rare cases, type 1 diabetes
glucose monitoring, a more sophisticated must be excluded. In CF centres, treatment
method for early identification of CF patients of CFRD is by a team approach including
with CFRD. Annual OGTTs starting at the pulmonologists, diabetologists, dieticians
age of 10 years are a recommended and psychologists.
screening procedure for CFRD. Screening for
Sinus disease in CF
CFRD is especially important for patients
who are on nocturnal feeding, pregnant, Sinus abnormalities are prevalent in CF and
experiencing a severe acute exacerbation or chronic rhinosinusitis has been shown in up
on systemic steroids. to 74100% of the patients, increasing with
age, but is not always symptomatic. The
It is well accepted to start treatment of
pathophysiology is unclear but is believed to
CFRD independent of fasting
be a combination of increased viscosity of
hyperglycaemia (Moran et al., 2009b).
mucus, decreased clearance and chronic
Clinical studies in the last 15 years have infection (Schraven et al., 2011). Problems
shown positive clinical effects of insulin from the upper airways should be handled in
treatment of CFRD, with an increase in lung close cooperation with an otolaryngologist
function and nutrition, and decreasing risk with experience of CF sinus disease.
of exacerbation. The recommendation is
initially single insulin doses with main meals Common radiological findings are frontal
and adding long-acting insulin as soon as sinus agenesis/hypoplasia and opacification
fasting hyperglycaemia is observed (Moran of the maxilla ethmoid sinus. There is no or
et al., 2009a; UK Cystic Fibrosis Trust only low correlation of CT findings with
Diabetes Working Group, 2004). In general, symptoms. Nasal polyps are common from
nutritional advice differs significantly childhood, increasing with age. Symptoms
between diabetes treatment in general and of the upper airways, like nasal obstruction,
in the case of CFRD. CF patients have to chronic or recurrent headache due to
maintain a high caloric intake not to lose sinusitis and anosmia/hyposmia, are
weight. Management of CFRD must be frequently found when the patient is asked
individualized (UK Cystic Fibrosis Trust and it is important to include these
Diabetes Working Group, 2004). Oral symptoms in the annual assessment.
antidiabetic drugs have been used in the
treatment of CFRD. Up to now, prospective Medical management includes nasal steroids,
randomised controlled clinical studies saline irrigation and antibiotics (adapted to
demonstrating a positive clinical effect of local sampling). The type of bacterial
these drugs in the treatment of CFRD are colonisation of the upper airways may differ
lacking. The use of oral antidiabetic drugs is from the colonisation of the lower airways. Up
therefore not recommended outside clinical to 25% of cases undergo sinus surgery, where
trials. Late complications of CFRD are well endoscopic sinus surgery has been more
described for microvascular (retinopathy, successful than polypectomy alone or
neuropathy and nephropathy) but not for Caldwell Luc procedures (Haworth, 2010).
macrovascular diseases (van den Berg et al., CF-associated osteoporosis
2008). CF patients on insulin should
participate in CFRD education programmes Osteoporosis is a common medical problem
and follow their treatment like other diabetic in adults with CF. Although osteoporosis is

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group, osteopenia/osteoporosis starts outcomes and confounders in cystic
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Emerging treatment
strategies in CF
Melinda Solomon and Felix Ratjen
Traditionally, treatment has included airway

clearance therapies, and inhaled and Key points
systemic antibiotics, as well as strategies to
improve nutritional status. More recent N Despite the successes of CFTR
therapeutic interventions have focused on modulation, treatment of infection
correcting the protein defect or the and inflammation remain important
abnormal ion composition in the CF airway. targets.
The hope is that this form of therapy/ N Therapeutic options in CF are
intervention could change the prognosis of increasing rapidly.
CF patients by altering the disease
progression. N CFTR directed pharmacotherapy is
moving into the clinic.
CFTR pharmacotherapy
Cystic fibrosis transmembrane conductance Ivacaftor (previously VX-770) is an orally

regulator (CFTR) gene mutations result in bioavailable CFTR potentiator with
protein dysfunction by affecting a variety of impressive clinical efficacy and a good safety
different steps in CFTR protein production profile. Studies have focused on CF patients
and function, including synthesis, carrying the most common gating mutation
maturation, intracellular transport, epithelial (G551D), but clinical trials for other
expression and gating function (fig. 1). CF mutations in this class are currently under
drugs are currently being evaluated to way. In patients carrying at least one allele of
improve CFTR protein expression at the cell G551D, ivacaftor was found to improve ion
surface and/or CFTR function. CFTR transport as illustrated by nasal potential
pharmacotherapy affects aspects of difference measurements and to reduce
disturbed intracellular function including sweat chloride concentrations after oral
protein trafficking, CFTR expression or administration of the drug in CF patients.
function of CFTR at the cell membrane. The mean sweat chloride concentrations in
Therapies currently being evaluated target treated patients fell below 60 mmol?L-1; the
class I to III mutations, but it is important to diagnostic threshold for making a CF
recognise that these therapies could diagnosis. This effect has not been observed
potentially also benefit patients with class IV for any other treatment in CF care.
and V mutations as well. Significant clinical effects included a more
than 10% absolute change in FEV1,
CFTR potentiators Class III mutations are reductions in pulmonary exacerbations and
characterised by a reduced opening improvements in symptom scores. This
probability of the CFTR channel, but the medication was approved by the US Food
CFTR expression at the cell surface is not and Drug Administration in 2012 for
altered. Potentiators are pharmaceuticals patients older than 6 years of age with a
that increase the probability of the CFTR G551D mutation and has recently received
channel opening. approval in Canada and Europe as well.

Defect Normal I II III IV V
classification
Defect No synthesis Block in Block in Altered Reduced

result processing regulation conductance synthesis
Types of Nonsense; Missense; Missense; Missense; Missense;

mutation frameshift amino acid amino acid amino acid amino acid
premature deletion change change change
stop codon (F508) (G55ID) (R117H) (A445E)
(G542X) (R347P) alternative
spllcing
Potential Ataluren CFTR corrector Ivacaftor Ivacaftor? Ivacaftor?

therapy (VX-809) (Kalydeco) (Kalydeco) (Kalydeco)
Figure 1. Potential options of CFTR directed therapies. Reproduced from Welsh (2001) with permission
from the publisher.
While these gating mutations are relatively known therapeutics. The lead compound is
rare, this has proven the concept that CFTR currently called VX-809 and has recently
directed pharmacotherapy can have shown some promising results in early
significant beneficial effects in patients that phase clinical studies. In CF patients
exceed the efficacy of any other treatment homozygous for the F508del mutation, oral
previously studied in this disease. application of the compound VX-809 was
well tolerated and there was a dose-
CFTR correctors Class II mutations, such as
dependent effect on sweat chloride levels at
the most common mutation, F508del, result
higher doses, suggesting an effect of this
in misfolded CFTR protein which, when
drug on F508del activity. However, no
expressed at the apical membrane, has
change in lung function was observed.
some chloride conducting ability, but with a
much shorter half-life than wild-type CFTR. It is important to appreciate that CFTR
Most of this misfolded protein will be corrector therapy alone may not be sufficient
recognised as abnormal by the intracellular to induce a clinically meaningful response
quality control machinery and degraded and for this reason VX-809 is currently being
prior to leaving the endoplasmic reticulum. studied in combination with a CFTR
Thus, a potential treatment strategy is potentiator to enhance activity (described
rescue of CFTR (rescue from endoplasmic below).
degradation). Compounds that result in
CFTR rescue are called correctors referring Combining potentiator and corrector While
to their effect on correcting the intracellular VX-809 is designed to move CFTR to the cell
trafficking defect. A number of drugs have surface, ivacaftor is intended to improve the
been identified to potentially improve proteins function once it has reached the
mutated CFTR processing using high- cell surface. A recently completed phase II
throughput assays to screen libraries of clinical trial studying multiple dose

combinations of ivacaftor with VX-809 lower decline in lung function and a lower
showed improvements in lung function in rate of pulmonary exacerbations compared
CF patients with two copies of the F508del with the placebo group. A stronger effect
mutation at higher doses of the drug was seen in patients not receiving inhaled
combination; VX-809 alone did not have any antibiotics as inhaled tobramycin may
effect on lung function and no effect was potentially interfere with the effect of this
seen in a group of patients heterozygeous drug. Therefore, the current evidence for its
for this mutation. The effect size for this efficacy is not convincing and it may be that
drug combination in F508del patients was only a subgroup of patients will respond.
much smaller than the one observed for
ivacaftor alone in G551D patients indicating Many patients carrying stop mutations in
that CFTR pharmacotherapy addressing one allele are also compound heterozygotes
intracellular trafficking is a much more for F508del and potentially a combination of
difficult target. This is not surprising as drug therapy directed toward a PTC could be
intracellular trafficking involves multiple combined with CFTR corrector therapy in
steps; each of which could be a potential the future. Alternatively, an effective therapy
target for therapy. Other correctors are for stop mutations could be combined with
currently in development and future therapy a potentiatior such as ivacaftor thereby
may require the combination of more than maximising the function of any CFTR protein
one corrector plus a potentiator, such as expressed at the cell surface.
ivacaftor. Gene therapy: CFTR replacement therapy The
Suppressors of premature stop codons goal of gene therapy in CF is that delivery of
Premature termination codons (PTCs) are a normal CFTR gene to the lung would result
the cause of CF in only 5% of cases in in expression and restored function of CFTR
countries other than Israel, where class I in the CF airway epithelium. There are
mutations are more frequent. This potential several challenges, including: which vector
treatment strategy will be an option for only to use for gene delivery and the problem of
a small fraction of the CF patient population. short-term gene expression, which would
Aminoglycosides have been shown to require repeated dosing. Viral vectors like
induce read through of PTCs (class I adenovirus seem more efficacious, but more
mutations) in CF. The first drug to have likely to cause side-effects compared to
shown this effect is gentamicin. Ataluren, liposomal vectors which demonstrate lower
previously called PTC 124, has been transfection efficacy. Gene therapy is
developed as a compound sharing the currently not close to clinical use, but a
action on stop codons, but lacking both multi-dose clinical trial conducted by the UK
aminoglycoside antibiotic function and Gene Therapy Consortium using a liposome
vector is currently on its way.
toxicity. It is an oral medication. In vitro
studies have shown that ataluren improves Mucus hydrators
read through of stop codons without
affecting nonsense mediated decay, which is Inhaled hypertonic saline Dysfunction of the
an important cellular mechanism that is CFTR protein results in an imbalance of ion
needed to protect the cell from homeostasis and consequently dehydration
dysfunctional proteins. So far, data from of airway secretions. This leads to disruption
phase II clinical studies in CF patients have of ciliary function and mucociliary clearance.
been variable in terms of treatment A treatment option addressing the depletion
response suggesting that it may not be of airway surface liquid in CF is the
equally effective in all CF patients within a inhalation of hypertonic saline solution. A
given class of mutations. study in Australia showed that inhaled
hypertonic saline improves mucociliary
Recently a phase III clinical trial of ataluren clearance in a dose-dependent fashion up to
has been completed. Study participants who 7% hypertonic saline. A double-blind parallel
received ataluren showed a trend towards a group (7% hypertonic saline versus 0.9%

normal saline) treatment trial showed a Unfortunately, trials of topical
small absolute difference in lung function administration of this short-acting sodium
between the two groups, and significantly channel blocker in CF patients did not show
fewer pulmonary exacerbations for the group any evidence that it improves lung function
treated with 7% hypertonic saline. Inhaled and one study showed that it may even
hypertonic saline is now part of standard of deteriorate lung function. Newer studies are
care in most centres. The beneficial effects looking at novel ENaC blockers that are
are probably multi-factorial including: more potent and less reversible than
amiloride.
N effect on mucus hydration,
N improved mucociliary clearance, Modulators of ion channel function
N increase of airway-surface liquid height,
Chloride channels other than CFTR exist and
N cough induction.
a calcium dependent chloride channel has
Inhaled hypertonic saline is known to be been shown to secrete chloride in epithelial
safe to use in infants with CF. However, a cells. Therefore, increasing the activity of
recent study did not show clear effect of alternative chloride channels in CF airways
treatment on pulmonary exacerbation in could potentially be therapeutic. Two drugs
infants and young children and the role of have been in clinical trials. Lancovutide,
hyertonic saline in this age group is still previously known as Moli 1901, is a chloride
unclear. transport activator that was studied and,
initially, showed some early promising
As hypertonic saline is an irritant for the results. A large trial was completed in
airways, it is recommended to test Europe, but did not show clear evidence of
tolerability in patients in the clinic before efficacy.
initiating long-term therapy. It should be
used only after pre-treatment with a Denufosol, a P2Y2 agonist designed to
bronchodilator, such as salbutamol. restore chloride transport and to increase
mucocilicary clearance, also yielded
Mannitol Mannitol was developed as a dry promising results in early phase studies but
powder formulation as an alternative ultimately showed nonsignificant results
treatment to hypertonic saline. It has been compared with placebo in a large
used as a hyperosmolar agent used to confirmatory trial. Therefore, there is
encourage the flux of water across the lung currently no ion channel modulator that is
surface to improve mucociliary clearance. close to clinical use.
Phase II and III trials show promising
evidence that long-term inhalation of Modulation of airway inflammation
mannitol improves lung function in patients
with CF and decreases the frequency of The beneficial effects in anti-inflammatory
pulmonary exacerbations. The main side- treatments, such as systemic steroids, have
effect is bronchoconstriction and associated been outweighed by the risks, which are
cough. At the present time mannitol is only related to the side-effect profile. In addition,
approved for treatment in CF in Australia the use of non-steroidals has also been
and for adults in Europe, but additional studied, but the side-effects of
studies in children are under way. gastrointestinal bleeds and potential
nephrotoxicity has prevented more extensive
Sodium channel blockers use.
Decreased CFTR-related chloride secretion, Oral N-acetylcysteine Oral N-acetylcysteine
in association with increased sodium and has also been studied and although it is well
water absorption, results in depletion of tolerated and does not cause significant
airway surface liquid. Theoretically, adverse effects, the trials have not shown
amiloride improves mucociliary clearance by significant pulmonary function test
blocking airway epithelial sodium channels improvements or significant clinical benefit.
(ENaC) and expanding airway surface liquid. However, in one study there was marked

post-treatment decrease in elastase activity, in the frequency of pulmonary exacerbations
which needs to be confirmed before and an increase in body weight.
treatment can be recommended.
It is important to assess patients for atypical
Inhaled glutathione Reduced glutathione is mycobacterial infections by sputum culture
known to be decreased in the prior to starting azithromycin, as this could
bronchoalveolar lavage fluid in CF patients. be subtherapeutic/partial treatment for
Glutathione is a major antioxidant and these organisms. In addition, there is some
mediator of cell proliferation. Inhaled recent evidence suggesting that
glutathione has been used as a means to azithromycin may predispose patients to
modify CF respiratory tract oxidative mycobacterial infection.
processes. A few small studies have shown
Antibiotics
mild improvements in the pulmonary
function in CF patients but larger, longer Chronic infection continues to be a
studies are required. At this time there is significant challenge in CF care.
inadequate evidence to recommend inhaled Pseudomonas aeruginosa is one of the major
glutathione as a treatment for CF patients. pathogens in CF lung disease and has been
a major target for antibiotic therapy. The
Anti-protease therapy is currently being reasons for failure of antibiotics to eradicate
evaluated, but the studies are still in early mucoid P. aeruginosa are multiple and may
stages. The most convincing effect to date include:
has been seen with drugs that target both
infection and inflammation, such as N high bacterial loads,
azithromycin. N bioflims,
Azithromycin Azithromycin has both anti-
N poor penetration of antibiotics into the
mucus,
infective and anti-inflammatory properties.
In CF, recurrent airway infections and
N antibiotic resistance.
chronic inflammation result in progressive Recent anti-infective tactics have utilised
airway damage. Treatment with currently available antibiotics in inhaled
azithromycin in subtherapeutic doses for an forms. Inhalation of antibiotics allows higher
antibiotic effect has been shown to improve concentrations at the location of the
lung function and decrease exacerbation infection, while decreasing the potential
rates in CF patients who are chronically systemic side-effects that could occur with
infected with Pseudomonas aeruginosa. oral or parenteral treatment. Early
Furthermore, a randomised, placebo- eradication of P. aeruginosa to delay the
controlled trial of azithromycin in CF establishment of chronic infection is also
patients with P. aeruginosa showed a very important and the use of tobramycin
significant reduction in both oral and inhalation solution alone has been shown to
parenteral antibiotic use and significant be highly effective.
weight gain in the treatment group. The
mechanism of action is still not completely Chronic maintenance therapy for P.
clear. Azithromycin is also used to treat aeruginosa consists of the inhalation of
bronchiolitis obliterans, a condition not antibiotics such as tobramycin and colistin.
associated with chronic infection. This Tobramycin can be administered as a
would support the idea that a major factor of nebulised solution and more recently has
its effect is its anti-inflammatory properties. been introduced as a dry powder
formulation (tobramycin inhalation
A more recent study showed no powder), allowing shorter administration
improvement in pulmonary function in time and greater portability. Aztreonam
children and adolescents with CF uninfected lysinate for inhalation is currently available
with P. aeruginosa, who were treated with and is being utilised as an alternative to
azithromycin for 24 weeks. However, the inhaled tobramycin by either adding it
treatment group had a significant decrease during the off months of cycled tobramycin

or as a replacement for tobramycin changing patients outcomes, it is important
inhalation. to explore new therapies for other targets
including infection and inflammation.
Other inhaled antibiotics being developed
and studied include inhaled liposomal
amikacin, ciprofloxacin inhaled powder, Further reading
inhaled levofloxacin and fosfomycin. N Clancy JP, et al. (2012). Personalized
Conclusion medicine in cystic fibrosis: dawning of a
new era. Am J Respir Crit Care Med.; 186:
Many new therapies are currently in 593597.
development and will probably change our N Flume PA, et al. (2012). State of progress
therapeutic approach in the near future. The in treating cystic fibrosis respiratory
goal for emerging therapies is to find disease. BMC Med; 10: 88.
N Ratjen F, et al. (2012). New therapies in
treatments that slow down the progressive
cystic fibrosis. Curr Pharm Des; 18: 614
decline in lung function, decrease hospital
627.
admissions, and improve quality of life. The N Ramsey BW, et al. (2011). A CFTR
success of ivacaftor, a CFTR potentiator, potentiator in patients with cystic fibrosis
demonstrates that this approach is feasible, and the G551D mutation. N Engl J Med;
but not yet available for many patients. As 365: 16631672.
we learn more about CFTR mutation-specific N Welsh, M, et al. Cystic fibrosis. In: Scriver
abnormalities we can hopefully decrease C, et al., eds. The Molecular and
symptoms, decrease treatment burden, and Metabolic Basis of Inherited Disease.
improve the outcome for CF patients. While McGraw-Hill, New York, 2001; pp. 5121
treatment strategies targeting the basic 5188.
defect have the highest likelihood of

Prognosis, management and
indications for lung
transplantation in CF
Helen Spencer and Andrew Bush
The CF patient with end-stage or rapidly in the 20032004 cohort. In the paediatric
deteriorating lung disease will usually have series all but one of the children had severe
been followed up in a specialist centre for obstructive lung disease, and most were
many years, with intensive therapeutic being actively managed at the time of death;
attempts to improve lung function. Part of most deaths were in the paediatric intensive
the management should be a detailed re- care unit (PICU). A key message from these
evaluation of all aspects of care to ensure two studies and other data is that
that nothing has been missed. spirometry is a poor predictor of prognosis,
although frequently used clinically as such.
The nature of the problem
The combined Royal Brompton Hospital/ Lessons from problematic severe asthma:
Great Ormond Street Hospital (both are the basics right?
London, UK) experience of death and
transplantation in CF in the decade 2000 More than half of all children referred to the
2009 was of 1022 children cared for, there Royal Brompton Hospital quaternary referral
were 11 deaths (median age 14.2 years) and severe asthma service for consideration of
eight transplantations (median age beyond guidelines therapy in fact do not
13 years), with a female predominance for have severe asthma at all, but merely need
both. Of note, spirometry 5 years before to get the basics right for good asthma
death was not predictive. This is in control to be restored. No comparable study
agreement with an adult study which has been performed in CF, but it seems
showed that median survival for patients likely that similar issues are present in what
with an FEV1 ,30% predicted had increased we term challenging CF (table 1). The
from 1.2 years in the 1991 cohort to 5.3 years definition is somewhat arbitrary; it should be
noted that children may become challenging
very quickly (e.g. failure to improve after two
Key points or more courses of intravenous antibiotics
in quick succession) or gradually, with a
N Every effort should be made to series of small, almost subclinical,
optimise standard therapy in patients deteriorations.
with apparently end-stage CF lung
disease. Experience from asthma has identified four
key areas often needing attention as:
N Prediction of prognosis in end-stage
CF lung disease is difficult, and more N medication adherence and
prolonged survival than previously administration;
expected can be anticipated. N adverse environmental circumstances,
N Timely referral for lung transplant particularly environmental tobacco
assessment is essential to maximise smoke;
chances of benefit. N allergen exposure;
N psychosocial factors.

Table 1. Definition of challenging CF
Lung function is o2 Z-scores below normal from the CF-specific charts
At least three courses of i.v. antibiotics annually (whether planned electively or unplanned)
Requirement for home oxygen or nasal mask ventilation
Nutritional failure: BMI f2 Z-scores below the mean; drop in weight or BMI centiles by 10% over
1 year
Any severe CF pulmonary complication, such as massive haemoptysis, pneumothorax, therapy-
resistant ABPA or other causes of oral severe steroid dependency
Any child whose self- or parent-reported symptoms are significantly different to those expected by
a clinician (either overestimated or underestimated)
Any child in whom there is refusal or extreme reluctance to give prescribed treatment by the
carers
Note, that these are arbitrary and not evidence based.
In the context of asthma, a nurse-led home before deploying some of the experimental
visit is often enlightening, and perhaps this therapies described below.
should be used more in CF. Adherence is
notoriously difficult to judge in the clinic; Is the diagnosis really CF?
doctors obtain prescription records This may seem an odd question, but it is
(acknowledging that collecting a important for two reasons. First, if the
prescription does not mean that the diagnosis is wrong it is important to
medication has been administered, but determine whether there is a disease-
failure to collect prescriptions does
specific treatment for what is actually the
guarantee non-adherence) and the nurses
problem, for example bone marrow
assess the availability and accessibility of
transplantation for certain
medications in the home, and whether they
immunodeficiencies. Secondly, innovative
are in date. Obviously inhaler and nebuliser
therapies are increasingly being discovered
techniques are also checked. More objective
that are CF gene mutation or mutation class
data about nebuliser usage can be
specific. It would be ludicrous to try to apply
downloaded from the microchips in some
these therapies to a patient who did not
modern nebulisers. Active and passive
have CF! So, it is essential to make every
tobacco smoke exposure is checked by
effort to establish the genotype of the
measuring urinary or salivary cotinine.
patient with whole gene sequencing if this
Allergic sensitisation and allergen exposure
has not already been done, to check
is less important in CF than in really severe
eligibility for these potential treatments. The
asthma, but should at least be considered in
Clinical and Functional Translation of CFTR
the atopic CF patient. Finally, psychosocial
website (www.cftr2.org) provides current
factors are explored. Most referrals in the
knowledge of the probable disease causing
asthma context are made after discussions
status of rare mutations and should be
in the home, where families are much more
consulted in cases of doubt.
ready to discuss personal matters. It is
suggested that adaptations of this sort of Management of end stage lung disease:
approach may be beneficial in challenging pulmonary aspects
CF. This should include ensuring that all
standard therapies have been trialled, or Our experience is that there are two main
discarded as having not been beneficial, types of end-stage lung disease: the more
including nebulised antibiotics, rhDNAse, common is characterised by severe
hypertonic saline and azithromycin, certainly bronchiectasis, chronic infection and

copious purulent secretions. Less usually, a these very sensitive molecular techniques is
so-called dry and distal lung disease is unclear, and how (if at all) they should be
seen, characterised by distal airway used to guide treatment at any stage of
obstruction and air trapping with no or disease is unknown. In the context of end-
minimal bronchiectasis, and little or no stage lung disease, it might be worth
sputum production. The evidence for the considering molecular studies and intensive
existence of the dry and distal phenotype is treatment of any dominant organism,
based on personal experience and case particularly if frequently detected. Certainly,
reports, although we suspect most an empirical trial of anti-anaerobic
experienced CF physicians will have seen antibiotics should be considered, in
cases. There is little or no evidence base for particular if there is severe bronchiectasis.
the treatment of either phenotype, but
suggested lines of management differ. The Use of antibiotics in end-stage CF lung disease
evidence for most is so scanty that the right Any isolated Gram-negative rods should
approach is to discuss options with the have extended sensitivities performed;
patient and family, and form an occasionally they may be sensitive to
individualised plan on the basis of those unlikely oral antibiotics such as minocycline.
discussions. While accepting that the link between in vitro
sensitivity and clinical efficacy is at best
Are resistant or unusual microorganisms weak, there would seem to be little to be lost
present? Standard sputum culture, if by prescribing an oral antibiotic to which the
available, will identify most of the common organism appears to be sensitive, at least in
pathogens, but other samples should be the laboratory.
considered. Bronchoscopy and
bronchoalveolar lavage is considered the Most, if not all, patients with end-stage lung
gold standard, but there are regional disease, especially those with severe
variations in culture results and not all lobes bronchiectasis, will have been prescribed
are usually sampled. Induced sputum may either inhaled tobramycin or colistin
have a greater yield than spontaneously because of chronic infection with P.
expectorated. Both techniques should be aeruginosa. Particularly in those patients with
used with caution in patients with severe severe bronchiectasis, a trial of nebulised
airway obstruction. Infection with aztreonam lysine should be considered, also
nontuberculous mycobacteria appears to be rotating combinations of nebulised
becoming increasingly common and antibiotics, such as tobramycin, with
Mycobacterium abscessus, in particular, may alternate months of aztreonam. There is
be associated with decline in lung function. some evidence that combined nebulised
A HRCT scan should be considered to look tobramycin and amiloride may be effective
for suggestive features, such as the presence against some genomovars of Burkholderia
of extensive tree-in-bud. If re-evaluation cepacia. Combinations of nebulised
results in the detection of new fosfomycin and tobramycin have also shown
microorganisms, then energetic attempts efficacy against some antibiotic-resistant
should be made to eradicate them. organisms.
Recent molecular microbiology studies have Intravenous antibiotics should be used

shown that CF is a far more polymicrobial liberally. Most would use planned regular
disease than was previously thought and, in (usually 3-monthly) courses, with interval
particular, anaerobes may be as prevalent as courses as needed. The optimal duration of
Pseudomonas aeruginosa. End-stage CF such courses is not known, but it is likely
seems to be characterised by loss of that longer than the conventional 10
bacterial diversity, but it is not known 14 days will be beneficial. Anecdotally, we
whether this is as a reflection of disease have used intravenous colistin for many
progression or as a consequence of multiple consecutive weeks in this situation. Here, as
courses of antibiotics. The interpretation of elsewhere, there are no randomised

controlled trial data to guide the However, there is increasing evidence that
paediatrician. airway infection per se is associated with
worse lung function and an increased rate of
Antibiotic allergy is a frequent problem in exacerbation. In the setting of end-stage
CF. A history of possible allergic reactions
lung disease, we recommend intensive anti-
should be taken and cautious challenge
fungal treatment if A. fumigatus is isolated.
testing should be performed in conjunction
Itraconazole is poorly absorbed, and in this
with an experienced allergist to determine
setting we would use prolonged courses of
which antibiotics truly cannot be used
voriconazole, posaconazole or even
without desensitisation. The transplant
intravenous liposomal amphotericin B.
centre should be contacted to discuss
Anecdotally, nebulised amphotericin
whether desensitisation to particular
(standard or liposomal) has been used, but
antibiotics would be helpful.
again the question of not over-burdening the
Optimising airway clearance A very child with multiple treatments must be
experienced physiotherapist should assess considered.
the patient. There are numerous aids to
sputum clearance, including positive airway Corticosteroids and other standard treatments
pressure and external oscillation, and all We know that the inflammatory response is
options should be reviewed. Anecdotally, protective, and indeed in CF anti-
cough-assist devices have been beneficial in inflammatory therapy with a leukotriene
some patients, despite fears that the (LT)B4 antagonist actually led to more
negative pressure phase might lead to infective exacerbations. Conversely, we know
airway collapse if there is significant that at some stages of CF (those patients
bronchomalacia. chronically infected with P. aeruginosa)
prednisolone improves spirometry, albeit at
Clinically significant expiratory muscle the cost of unacceptable side-effects.
dysfunction is rarely, if ever, seen in CF, so Various anti-inflammatory strategies may be
cough strength should be normal. However, tried especially in dry and distal disease. A
stress incontinence is common in both trial of systemic corticosteroids is the first to
sexes in CF, even in children, and this may be considered, balancing the risks of
lead to reluctance to cough forcefully. worsening CF-related diabetes and reducing
Tactful questioning should elicit whether bone mineral density against possible
this is a problem and, if so, referral for benefit. Dry and distal disease is treated
treatment is mandated. with pulsed intravenous methyl
Pharmacological adjuncts to mucus prednisolone (500 mg?m-2) on 3 successive
clearance include rhDNase, hypertonic days every 4 weeks, to try to reverse the
saline and inhaled mannitol. There is airflow obstruction, combining this with
marked and unpredictable individual high-dose inhaled corticosteroids. A trial of
variation in response to these agents, and all oral prednisolone is indicated in CF patients
should be trialled. Combinations should be with severe bronchiectasis but only in those
considered, with two caveats. The first is who are atopic and have acute
adherence; it is all too easy to overburden bronchodilator reversibility. If neither of
the patient with excessive numbers of these features is present, we would be
nebulised therapies, in particular. The reluctant to risk the side-effects of prolonged
second is the theoretical possibility that steroid therapy.
therapies may be antagonistic, as was found
Should oxygen therapy and NIV be initiated?
in one study when mannitol and rhDNAse
Whereas in hypoxaemic COPD patients
were combined.
there is clear evidence of benefit with oxygen
Anti-fungal therapies It used to be thought supplementation in terms of survival, there
that Aspergillus fumigatus was only a are no such data in CF. Nonetheless, most
significant problem in CF if it caused allergic paediatricians would actively screen for
bronchopulmonary aspergillosis (ABPA). overnight hypoxaemia with saturation

studies, and correct it if present. determining the patients genotype (some of
Assessment by a skilled occupational these nine mutations are not detected on
therapist is mandatory if daytime oxygen is routine testing). CFTR channel opening is a
prescribed, to allow mobility to be function of the number of apical channels,
maintained as far as possible by using their open probability and channel
lightweight portable systems. conductivity. VX-770 may increase channel
opening time in non-gating mutations, and
There is no general consensus as to when there is interest in combining this agent with
and how to initiate NIV. Positive-pressure potentiators such as VX-809 in class II
devices may be used to assist daytime mutations such as DF508. Undoubtedly in
sputum clearance by a skilled these days of internet-based knowledge,
physiotherapist, with due regard to the risk families will want to discuss compassionate
of a pneumothorax. In terms of use during ground use of some of these and other novel
sleep, polysomnography should be part of molecular therapies, such as Ataluren
the work-up of these patients. If there is (PTC124). This is unexplored territory, but
clear cut evidence of nocturnal hypercapnia one that paediatricians will need to tackle in
then we would offer NIV, having excluded the very near future.
any upper airway obstruction (e.g. due to
nasal polyps) as a potential cause of Management of end-stage lung disease:
hypoxaemia. If gas exchange is adequate, extrapulmonary aspects
but work of breathing is high (usually
assessed clinically outside a research Optimising nutrition/other diagnoses A full
context), then we would still consider NIV in dietetic review is mandatory, because most
the hope of improving nutritional status. with end-stage lung disease will be
However, as stated elsewhere in this malnourished. Obviously, additional
chapter, more work is needed. diagnoses which may contribute to
malnutrition, such as coeliac disease,
Innovative therapies are mostly used in the should be excluded, and insulin deficiency
dry and distal form of end-stage CF lung evaluated. Calorie intake must be
disease, and none are evidence based. There maximised, usually via a gastrostomy, and
are anecdotal reports of success. These overnight and daytime bolus high-energy
include monthly infusions of intravenous Ig, feeds, if not already instituted, will be
methotrexate and cyclosporine A. In all required. If a gastrostomy is inserted for the
cases, careful monitoring of response and first time consideration should be given to
alertness for side-effects is mandated. In the performing a laparoscopic or even an
case of cyclosporine, special care should be endoscopic fundoplication at the same time
taken to monitor renal function, which may if gastro-oesophageal reflux is present.
already be impaired by repeated courses of
intravenous aminoglycosides and CF-related Insulin deficiency Many patients will already
diabetes. have been diagnosed with CF-related
diabetes and will be using insulin; in these
Compassionate ground therapies Kalydeco patients, diabetic control must be
(ivacaftor, VX-770) has burst on the scene as optimised. For others, CF-related insulin
a paradigm-shifting molecule addressing the deficiency should be excluded by oral
basic defect in the class III mutation G551D, glucose tolerance testing, random blood
rather than the downstream consequences glucose measurements and continuous
of the cystic fibrosis transmembrane subcutaneous monitoring. There is evidence
conductance regulator (CFTR) dysfunction, that even in those with only occasional
as is the case with the more conventional peaks of blood glucose, insulin therapy can
therapies described above. Although only improve nutrition and lung function.
licensed for G551D, compassionate use
could be considered if the funding obstacles Gastro-oesophageal reflux This has been
can be overcome in the other nine known realised to be increasingly common in end-
gating mutations, hence the importance of stage CF lung disease, and should actively

Table 2. Referral for lung transplant assessment
Referral for lung transplantation should be made when the patient has:
Rapidly declining FEV1 despite maximal medical therapy (particularly females)
FEV1 approaching ,30%
Frequent hospitalisations for exacerbations
Oxygen dependency
Desaturation with exercise
Requirement for NIV
Recurrent or problematic pneumothorax
Recurrent haemoptysis despite embolisation
be excluded. Bile acids can frequently be who are becoming difficult to manage. Early
found in CF sputum and are associated with referral before a patient becomes critically
increased inflammatory markers, suggesting unwell facilitates a number of processes:
that we are underdiagnosing this
complication. There is no gold standard N careful assessment by a multidisciplinary
test, but at the very least 24-h oesophageal transplant team,
pH monitoring should be performed. An N suggestions for further clinical
isotope milk scan is less invasive, but optimisation,
probably a less accurate way of determining N information gathering for the patient,
if reflux is present. The role of impedance family and medical team and education
monitoring is not clear pre-transplant but about the complications,
should be completed post-transplant. N intense follow-up required after
Gastro-oesophageal reflux, including non- transplant.
acid reflux, may be an important factor in
the development of post-transplant Timely referral allows the patient time to
bronchiolitis obliterans syndrome (BOS). reflect on the risks and benefits of both
transplant and the alternative of non-
Bone mineral density Severe osteopenia is a transplant, and also allows the transplant
relative contraindication to transplantation, physician to monitor an individuals clinical
so DEXA scanning and appropriate trajectory over a period of time (table 2).
treatment (calcium supplements, vitamin D
and bisphosphonates) should be instituted When to list for transplant? Deciding when to
early if bone mineral density is decreased. list a patient for transplant is one of the
most difficult decisions. A transplant
Lung transplant Lung transplant is an physicians aim is to list a patient early
accepted therapeutic option for patients enough that they can survive the possible
with end-stage CF lung disease who are wait for an organ but not so early that a
failing maximal medical therapy. Paediatric transplant does not offer a survival benefit.
recipients from the International Society for Most centres aim to list for transplant when
Heart and Lung Transplantation (ISHLT) the predicted chance of surviving 2 years is
international registry had a 5-year survival of ,50%, although this is an increasingly
54% for the era 20022010. difficult time-point to identify.
As previously noted there is no one specific Various survival models have been
clinical or physiological measurement that proposed for CF, all of which are imprecise
portends poor prognosis signifying referral and not particularly useful for an individual.
for transplant assessment. Most paediatric In practice many clinical, physiological,
centres welcome early referral of patients functional and quality of life factors are

taken into account when deciding when the transplant community to transplant
to list. patients only if there is a good chance of a
successful outcome. It is essential to ensure
A controversial paper in 2007 suggested that that there are no major or not too many
only five paediatric CF patients had a survival relative contraindications. Although centre-
benefit with transplant in their US cohort of specific decisions are made in some grey
514 patients listed for transplant. One of the clinical areas there are a number of agreed
main criticisms of this study was that the major contraindications.
5-year waiting list survival was 57% and that
there was a significantly lower post-transplant N Malignancy in the last 2 years (excluding
survival than in other studies of a similar certain skin cancers).
population. The higher waiting list survival N Untreatable dysfunction of another major
reflected the fact that USA priority listing used organ system (although lung/another
to be based on a time accrual basis rather organ transplant can be offered at some
than clinical urgency, suggesting patients centres).
were listed too early. Despite its controversial N Infectious diseases: chronic hepatitis B,
conclusions the paper raises important chronic hepatitis C (biopsy proven),
questions about how we measure the success human immunodeficiency virus.
of transplant, and whether survival benefit is N Active pulmonary TB.
the only valid measure of success or whether N Refractory non-adherence.
quality of life is just as important. N Significant chest wall/spinal deformity.
N Burkholderia cenocepacia (previously BCC
It is important for the CF centre to have an genomovar III) is a contraindication in all
understanding of how the local transplant UK centres.
centre makes decisions about listing and N Absent or unreliable social support
organ allocation. In the UK each transplant system.
centre manages their own waiting list and
will have local knowledge of clinical urgency The relative contraindications are:
of patients and their own average waiting list
times. Other countries have adopted a N critical condition, e.g. mechanical
national waiting list and have used various ventilation, sepsis, extracorporal
lung allocation scores (LAS) incorporating membrane oxygenation (ECMO) and
factors predicting clinical urgency and shock;
probable post-transplant outcome to try and N colonisation with highly resistant
make the best use of available organs. bacteria, nontuberculous mycobacterium
and fungi;
Unfortunately, lack of donor organs continues N severe osteoporosis;
to be a major problem, leading to a waiting N grossly abnormal BMI (high and low).
list mortality of 3040% in the UK. Expansion
of the donor pool is likely in the coming years Although invasive ventilation or ECMO were
with the increasing use of non-heart beating previously felt to be absolute
donors as well the more conventional heart- contraindications to transplant because of
beating donors. EVLP programmes (Ex vivo poor outcomes, recently there have been a
Lung Perfusion; a system for reconditioning number of reports of good short-term
cadaveric lungs deemed untransplantable) outcomes in adults in these scenarios.
are also likely to boost the number of donors Transplant will only be considered in
available, with possible use of upper lobes for patients already known to the transplant
children when the whole lung cannot be used centre if they have no other significant organ
for adult recipients because of lower lobe dysfunction. Invasive support systems
consolidation. should only be instigated in end-stage
irreversible CF lung disease if the transplant
What are the contraindications to transplant? centre feels that the patient has a realistic
To make the best use of the limited and chance of receiving a suitable organ quickly.
precious organ resource it is incumbent on This caveat is likely to rule out most

paediatric patients who have much longer N Dobson L (2002). Clinical improvement
organ wait times. in cystic fibrosis with early insulin treat-
ment. Arch Dis Child; 87: 430431.
Care of the patient referred and waiting for N George PM, et al. (2011). Improved
transplant Adequate preparation, including survival at low lung function in cystic
discussions about prognosis prior to fibrosis: cohort study from 1990 to 2007.
assessment is crucial to give patients and BMJ; 342: d1008.
families a realistic picture of transplant. The N Ho SA, et al. (2004). Clinical value of
transplant journey is stressful and the obtaining sputum and cough swab sam-
patient and family will need support. ples following inhaled hypertonic saline in
Maximal medical therapy should continue children with cystic fibrosis. Pediatr
once listed for transplant with particular Pulmonol; 38: 8287.
attention to nutrition, bone health, diabetic N Kotsimbos T, et al. (2012). Update on
control and psychological input to address lung transplantation: programme,
patients and prospects. Eur Respir Rev;
issues such as adherence and needle
21: 271305.
phobia. Unfortunately, not all patients will
N Liou TG, et al. (2007). Lung transplanta-
receive a transplant and involvement of tion and survival in children with cystic
palliative care should not be delayed fibrosis. N Engl J Med; 357: 21432152.
because a patient is on a transplant waiting N Olivier KN, et al. (2003). Nontuberculous
list. A parallel approach of palliation while mycobacteria. II: nested-cohort study of
waiting for transplant is possible and impact on cystic fibrosis lung disease.
desirable. Some patients may become too Am J Respir Crit Care Med; 167: 835840.
sick to transplant and some families prefer N Pauwels A, et al. (2012). Bile acids in
to come off the list to focus on end of life sputum and increased airway inflamma-
care. A sensitive and individualised tion in patients with cystic fibrosis. Chest;
approach to these difficult issues is 141: 15681574.
essential. N Ramsey BW, et al. (2011). A CFTR
potentiator in patients with cystic fibrosis
and the G551D mutation. N Engl J Med;
Further reading 365: 16631672.
N Rosenthal M (2008). Annual assessment
N Adler FR, et al. (2009). Lung transplanta- spirometry, plethysmography, and gas
tion for cystic fibrosis. Proc Am Thor Soc; transfer in cystic fibrosis: do they predict
6: 619633. death or transplantation. Pediatr
N Benden C, et al. (2012). The Registry of Pulmonol; 43: 945952.
the International Society for Heart and N Trapnell BC, et al. (2012). Fosfomycin/
Lung Transplantation: fifteenth pediatric tobramycin for inhalation in patients with
lung and heart-lung transplantation cystic fibrosis with pseudomonas airway
report 2012. J Heart Lung Transplant; infection. Am J Respir Crit Care Med; 185:
31: 10871095. 171178.
N Bush A (2011). Up the cystic fibrosis N Urquhart DS, et al. (2013). Deaths in
pulmonary creek in a barbed wire canoe. childhood from cystic fibrosis: 10-year
Pediatr Pulmonol Suppl; 34: 118119. analysis from two London specialist
N Collins N, et al. (2011). Survey of the use centres. Arch Dis Child; 98: 123127.
of non-invasive positive pressure ventila- N Yu H, et al. (2012). Ivacaftor potentiation
tion in U.K. and Australasian children of multiple CFTR channels with gating
with cystic fibrosis. Thorax; 66: 538539. mutations. J Cyst Fibros; 11: 237245.

Airway malformations
Ernst Eber and Andreas Pfleger
This chapter cannot cover the complete malformations discovered incidentally. Early
spectrum of congenital airway and accurate diagnosis as well as
malformations but rather gives an overview appropriate management is particularly
of important anomalies (table 1). important in children with severe central
airway stenoses. Flexible airway endoscopy
Most children with airway malformations are is the most important diagnostic procedure.
already symptomatic in the neonatal period In many instances, essential diagnostic
or in infancy; only rarely are airway techniques are MRI and CT, frequently
including angiography (especially
preoperatively and in children with
Key points associated cardiovascular anomalies).
N Many children with airway Depending on the type and severity of the
malformations are already malformation, conservative or surgical
symptomatic in the neonatal period management options may be chosen. With
or in infancy. airway growth, in particular mild to
moderate stenoses in the first years of life
N Airway anomalies are important frequently become less prominent. Thus,
differential diagnoses in children with conservative symptomatic treatment and
many respiratory abnormalities. support is often the preferred approach.
N Airway abnormalities may be part of With adequate management, in most
complex syndromes, and in many patients the long-term prognosis is
cases are associated with other favourable.
congenital anomalies.
Nasopharyngeal airway
N Early, accurate diagnosis and
Choanal stenosis and atresia This
appropriate management is
particularly important in severe malformation represents one of the most
central airway stenosis. common congenital upper airway anomalies
(1 in 8000 births). Most cases are due to
N With airway growth, mild-to-moderate bony occlusion of the airway; some children
stenoses in the first years of life show membranous obstruction. About two-
frequently become less prominent. thirds of patients with choanal atresia have
N Depending on the type and extent of associated congenital anomalies (e.g.
the malformation, conservative or CHARGE association). Unilateral lesions are
surgical management options have to twice as common as bilateral ones.
be chosen on an individual basis.
Bilateral choanal atresia causes immediate
N With adequate management, in most respiratory distress at birth; unilateral
patients the long-term prognosis is lesions are often not detected until later in
favourable. childhood. Some children present with
feeding difficulties and persistent

Table 1. Important congenital airway malformations obstruction is variable. As the mandible
grows forward with age, particularly during
Nasopharyngeal airway the first 6 months of life, airway and feeding
Choanal stenosis and atresia
problems may gradually resolve.
PierreRobin sequence
Craniofacial malformations In severe cases, the anomaly can necessitate
Larynx intubation, especially when associated
Laryngeal atresia airway pathologies (e.g. laryngomalacia,
Laryngeal web tracheomalacia) exist. Prone positional
Subglottic stenosis therapy has proved to be efficient in mild
Laryngomalacia (infantile larynx) cases. Airway obstruction may be relieved by
Laryngeal cyst a nasopharyngeal airway. Noninvasive
Laryngeal (laryngo-tracheo-oesophageal) respiratory support can relieve upper airway
cleft
obstruction, with CPAP ventilation in mild
Trachea and bronchial tree and moderate cases, or with noninvasive
Tracheal agenesis and atresia positive pressure ventilation in severe cases.
Tracheo-oesophageal fistula and Surgical procedures include tonguelip
oesophageal atresia adhesion, mandibular distraction
Isolated tracheo-oesophageal fistula osteogenesis and tracheostomy. Feeding
(H-type fistula)
difficulties can be alleviated by upright
Tracheomalacia
feeding techniques, modification of the
Tracheal stenosis
Tracheal bronchus and other topographic
nipple for bottle feeding, temporary use of
anomalies feeding tubes and the placement of a
Bronchial atresia gastrostomy. Palatal plates such as the pre-
Bronchomalacia epiglottic baton plate with a velar extension
Bronchial stenosis pull the base of the tongue forward. This can
be helpful in the relief of airway obstruction,
facilitates the swallowing mechanism during
rhinorrhoea, especially if the patent nostril is feeds and accelerates mandibular growth.
occluded during respiratory infections.
Other craniofacial anomalies A number of
Flexible nasal endoscopy and CT can syndromic craniofacial anomalies can affect
confirm the diagnosis and delineate the the patency of the upper airways. These
exact site of obstruction and also whether it dysmorphic syndromes are typically
is bony or membranous. characterised by mandibular or maxillary
hypoplasia and include Crouzon, Treacher
A nasal airway should be established as Collins, Apert, Pfeiffer, and Goldenhar
soon as possible. This can be achieved by a syndromes. 36 syndromes with craniofacial
transnasal approach with a dilating anomalies have been found to be associated
instrument and passing airway stents with one or more of 14 laryngotracheal
through the nasal passage to ensure malformations. Several anomalies such as a
continued patency for several weeks. narrowed nasopharynx with associated
Alternatively, repeated choanal dilatation adenotonsillar hypertrophy, midface
may be performed at weekly intervals. In hypoplasia and hypertrophy of the tongue
severe cases, transpalatal surgery may be can cause airway compromise in children
required. with Down syndrome.
PierreRobin sequence This anomaly is Larynx
characterised by micrognathia, glossoptosis,
and resultant (pharyngeal) airway Laryngeal atresia Laryngeal atresia is a life-
obstruction. More than half of affected threatening malformation, and in the past
infants have an associated syndrome, most virtually all affected newborns died.
commonly Stickler syndrome or 22q11.2 Nowadays, antenatal ultrasound
deletion syndrome. The severity of airway examinations allow diagnosis of the

so-called congenital high airway obstruction cricoid cartilage, resulting in circumferential
syndrome (CHAOS), which may be related stenosis of variable appearance. Myer et al.
to intrinsic causes such as atresia of the (1994) proposed a grading system for
larynx or upper trachea or extrinsic subglottic stenosis based on endotracheal
laryngotracheal obstruction caused by large tube sizes (table 2).
masses (e.g. cervical teratoma).
Identification of the condition by The presentation of affected children ranges
sonography and MRI helps facilitate from severe respiratory distress at birth to
management, including the ex utero the development of inspiratory or biphasic
intrapartum treatment (EXIT) procedure. stridor within the first months of life
(recurrent or atypical croup). Signs and
Without antenatal diagnosis, newborns with symptoms clearly depend on the grade of
isolated laryngeal atresia may only survive the stenosis. Children with congenital
when emergency tracheostomy is performed subglottic stenosis are at risk of developing
immediately after birth. Bag-mask additional acquired subglottic stenosis due
ventilation may save the lives of children to airway trauma (mostly iatrogenic such as
with incomplete laryngeal atresia. Laryngeal prolonged endotracheal intubation or
function in survivors is usually abnormal, tracheostomy).
and surgical reconstruction is required later
in life. The prognosis also depends on the Endoscopy is the procedure of choice to
presence of associated malformations (e.g. establish the diagnosis and to differentiate
VACTERL association) or syndromic subglottic stenosis from subglottic
anomalies (e.g. Fraser syndrome). Long- haemangioma. Sonography and MRI may be
term follow-up data after successful EXIT helpful.
procedure are not yet available.
As congenital subglottic stenosis generally
Laryngeal web Laryngeal webs usually are improves with airway growth, a conservative
located at the level of the glottis; supportive approach is recommended
supraglottic and subglottic webs may also whenever possible. Surgery should be
occur. The webs may be complete or reserved for severe forms; treatment options
incomplete, and vary in thickness. include cricoid split, laryngotracheoplasty,
Incomplete laryngeal webs, usually located and long-term tracheostomy.
anteriorly with posterior openings, are
Laryngomalacia (infantile larynx)
strongly associated with the velocardiofacial
Laryngomalacia is the most common
syndrome. Complete laryngeal webs present
congenital laryngeal anomaly (5075%) and
like a laryngeal atresia; symptoms with
the most common cause of persistent stridor
incomplete webs range from (biphasic)
in children (approximately 60%). The term
stridor and hoarseness to aphonia and
laryngomalacia suggests that laryngeal
varying degrees of respiratory distress. The cartilage is abnormally soft. However,
diagnosis is established by endoscopy. whether laryngomalacia is primarily an
Treatment options include (laser) excision anatomic anomaly or is due to delayed
and dilatation. Sometimes endotracheal neuromuscular development, is controversial.
intubation solves the problem, but re-
stenoses are relatively common. The
prognosis mainly depends on the extent of Table 2. Grading system for subglottic stenoses
the malformation. Grade Degree of obstruction of lumen
Subglottic stenosis Congenital subglottic I f50%
stenosis is the second-commonest laryngeal II 5170%
malformation. The more common
membranous form is characterised by III o71% (any detectable lumen)
symmetrical thickening of the soft tissues in IV No detectable lumen
the subglottic area. Cartilaginous subglottic
Adapted from Myer et al. (1994).
stenosis is due to a malformation of the

Table 3. Types of laryngomalacia
Type Characteristics
1 Inward collapse of aryepiglottic folds, primarily the cuneiform cartilages which are
often enlarged
2 Long, tubular epiglottis (pathologic exaggeration of the normal omega shape)
3 Anterior, medial collapse of arytenoid cartilages
4 Posterior inspiratory displacement of epiglottis against the posterior pharyngeal
wall or inferior collapse to the vocal cords
5 Short aryepiglottic folds
Adapted from Holinger et al. (1997).
According to Holinger et al. (1997), five types The diagnosis is suspected based on history
of laryngomalacia can be distinguished (two and physical examination, and confirmed by
or more may occur simultaneously) (table 3). flexible airway endoscopy. Laryngoscopy
Laryngomalacia is frequently associated with demonstrates supraglottic collapse during
other airway lesions and with gastro- inspiration (fig.1). Topical anaesthesia can
oesophageal reflux. potentially exaggerate the findings; thus, the
larynx should be examined before applying
The natural history is characterised by onset topical anaesthesia.
of inspiratory stridor usually within the first
46 weeks of life; cry and cough are normal. In most cases, apart from parental
Stridor varies considerably with posture and reassurance and support, no specific
airflow, is loudest with increased ventilation therapeutic measures are needed. In severe
(e.g. crying, agitation, feeding) and worsens cases (failure to thrive and/or obstructive
during respiratory tract infections. Some apnoeas) surgical treatment (various forms
of supraglottoplasty, rarely tracheostomy) is
patients will have increasing symptoms
needed. In isolated forms prognosis is
during the first few months of life; thereafter,
excellent, with associated malformations
stridor tends to resolve with time. In the very
prognosis usually depends on the latter.
rare severe cases with significant airway
obstruction, serious complications such as Laryngeal cyst Supraglottic cysts, commonly
failure to thrive, pulmonary hypertension located at the aryepiglottic folds or at the
and cor pulmonale may develop. epiglottis, are usually congenital. In contrast,
a) b) c)
Figure 1. Laryngomalacia (infantile larynx). a) Patent airway during expiration; b) prolapse of arytenoids
and aryepiglottic folds into the glottis during mid-inspiration; c) prolapse of arytenoids and aryepiglottic
folds and folding of epiglottis along its long axis (floppy epiglottis) at end-inspiration, resulting in
complete obstruction of the larynx. Reproduced from Eber (2010) with permission from the publisher.

Table 4. Classification system for laryngeal clefts
1 Supraglottic interarytenoid cleft extending inferiorly no further than vocal cord level
2 Cleft with extension below vocal cord level (cricoid cartilage partially involved)
3 Cleft extending through the cricoid cartilage, with or without extension into cervical
trachea
4 Cleft with extension into thoracic trachea (may extend as far as the carina)
Adapted from Benjamin et al. (1989).
subglottic cysts are usually acquired as a A contrast swallow and oesophagogram

result of airway trauma (e.g. endotracheal may be helpful, but airway endoscopy is the
intubation). The appearance of cysts varies diagnostic gold standard (fig. 2). A cleft may
widely; while some are covered by thin be difficult to diagnose with a flexible
mucosa and are easy to recognise, others instrument, as manipulation of the posterior
appear as a submucosal mass. A laryngocele commissure may be necessary to detect the
is a rare special form of a laryngeal cyst, cleft. Rigid bronchoscopy is the ideal
which originates from the laryngeal ventricle, technique for the documentation of
consists of an air-filled saccule and may be pathology of the posterior glottis, subglottis,
difficult to diagnose. Infants commonly and trachea.
present with stridor, hoarseness, weak cry or
In the absence of complicating factors,
aphonia, and sometimes feeding difficulties.
treatment is not required for many type 1
Endoscopy confirms the diagnosis. The
clefts. Treatment of gastro-oesophageal
treatment of choice is resection of the cyst.
reflux, if existing in parallel, is of importance
Laryngeal (laryngo-tracheo-oesophageal) cleft in all patients. Early repair should be sought
A congenital posterior laryngeal cleft is a in children with stable respiratory and
rare lesion. Laryngeal clefts may be familial, nutritional status. Minor clefts (types 1 and
and may be associated with other anomalies 2) may be corrected endoscopically. Surgical
of the trachea or the oesophagus (e.g. repair of type 2, 3 and 4 clefts may be
tracheo-oesophageal fistula) and with performed through anterior and lateral
multiple congenital anomalies of other approaches, often with cardiopulmonary
organ systems. Several types of clefts are bypass or extracorporeal membrane
distinguished (table 4); the most common
(approximately 50%) is type 1 cleft which
should be suspected in infants with
laryngomalacia. Anterior laryngeal clefts (e.g.
bifid epiglottis) are very rare congenital
anomalies. While a bifid epiglottis often is
associated with other malformations, other
anterior clefts appear to be isolated defects.
Aspiration of saliva and food is most likely,

and causes coughing, choking, cyanosis,
respiratory distress and recurrent
pneumonia; stridor results from laryngeal
collapse. While infants with type 1 clefts may
be asymptomatic, newborns with more Figure 2. Type 2 laryngeal cleft extending inferiorly
extensive clefts may show severe respiratory to, but not through, the cricoid plate; nasogastric
distress. Diagnosis is often delayed in tube in the oesophagus. Reproduced from Eber
patients with minor clefts. (2010) with permission from the publisher.

oxygenation (ECMO). Post-operative The newborn is commonly tachypnoeic,
complications are not uncommon and cyanotic, frothing, and choking despite oral
include tracheo-oesophageal fistula suction. An attempt to pass an orogastric
formation and swallowing difficulties. tube should be performed. A chest and
Prognosis depends on the type of the cleft, abdomen radiograph will show the tube in
gestational age, and potentially associated the upper pouch and may identify
anomalies. For patients with type 13 clefts pulmonary anomalies, vertebral and/or rib
it is favourable. anomalies, and the presence or absence of
gas in the stomach, indicating the presence
Trachea and bronchial tree or absence of a tracheo-oesophageal fistula.
Tracheal agenesis and atresia Tracheal
Depending on the anatomical situation,
agenesis and atresia are rare malformations
associated anomalies and the clinical status
ranging from complete tracheal agenesis to
of the patient various surgical techniques
short-segmental atresia, commonly
are recommended. A detailed discussion of
associated with a broncho- or tracheo-
surgical aspects is beyond the scope of this
oesophageal fistula or other anomalies in
chapter.
various organ systems (e.g. VACTERL
association). Similar to laryngeal atresia, The postoperative course may be critical due
these malformations are usually lethal. to various complications, such as
Without antenatal diagnosis affected oesophageal stenosis at the site of
newborns with short-segment atresia of the anastomosis and recurrence of the tracheo-
proximal trachea may only survive when oesophageal fistula. Gastro-oesophageal
emergency tracheostomy is performed reflux and dysphagia are very common and
immediately after birth; in the presence of a contribute to respiratory morbidity.
fistula or a cleft, intubation of the Tracheomalacia may be severe, sometimes
oesophagus may allow temporary even life-threatening (blue spells, dying
ventilation. After antenatal diagnosis an spells). Many children show the typical
EXIT procedure may save the life of the brassy tracheo-oesophageal fistula (TOF)-
affected baby. In those who survive, the cough, which has been reported to be still
short-term prognosis mainly depends on the present in up to 40% of adults. Recurrent
presence of associated malformations. aspiration is frequent and causes bronchitis
Long-term follow up data after successful and pneumonia, causing considerable
EXIT procedure are not yet available. respiratory morbidity. A missed diagnosis of
Tracheo-oesophageal fistula and oesophageal laryngeal (laryngo-tracheo-oesophageal)
atresia A tracheo-oesophageal fistula results cleft or second fistula, or a recurrent fistula
from a defective separation of the should be considered in children with
developing oesophagus from the developing pronounced respiratory symptoms.
lung. Oesophageal atresia is quite common, Survival largely depends on birth weight,
with an incidence of 1 in 3000 (4000) associated malformations, and pulmonary
births. About 30% of affected children are complications. The mortality in children with
born prematurely, and more than 50% have a birth weight above 2500 g and without other
associated anomalies (e.g. VACTERL anomalies today is close to zero. In surviving
association). Various types of oesophageal children, the long-term outcome is good.
atresia can be distinguished. The most
common type (approximately 85%) is Isolated tracheo-oesophageal fistula (H-type
characterised by an upper blind pouch and a fistula) This malformation is much rarer
fistula between the lower trachea and the than a tracheo-oesophageal fistula in
lower oesophagus. Structural anomalies of association with oesophageal atresia, and
the tracheal wall such as abnormally shaped commonly is not associated with other
or hypoplastic tracheal cartilages or a anomalies. Usually, the fistula is located in
widened pars membranacea (i.e. the extrathoracic part of the trachea and has
tracheomalacia) are common. a narrow lumen.

Children present with recurrent coughing innominate artery) or a mediastinal tumour.
and choking, in particular during feedings. After surgical repair (e.g. division of a
The chest x-ray may show pulmonary vascular ring), the tracheomalacia very often
infiltrates or atelectases and a distended continues to cause symptoms. The
stomach or bowel. Contrast injection into prognosis of these anomalies is determined
the oesophagus via a tube may show the by the respiratory tract. Tracheomalacia is
fistula, but may also (repeatedly) be false- frequently misdiagnosed as bronchial
negative. Rigid airway endoscopy is superior asthma or other respiratory conditions.
to flexible endoscopy in establishing the Thus, patients may be treated unnecessarily
diagnosis as the posterior tracheal wall can with inhaled corticosteroids for long periods
be partly distended and visualised better of time, and may be undertreated for
than with the flexible bronchoscope. recurrent or chronic lower airway infections.
Injection of contrast or dye (e.g. methylene
blue) into a suspected fistula with Intrathoracic tracheomalacia leads to
subsequent detection of the material in the dynamic airway compression on expiration,
oesophagus may be useful for establishing in particular during increased respiratory
the diagnosis. Airway endoscopy may also effort (e.g. crying) and coughing, or during
facilitate intraoperative identification by respiratory infections. Tracheal collapse may
cannulating the fistula. result in retention of secretions from the
lower airways, which in turn may cause
Treatment is surgical and consists of bronchopulmonary infections. In contrast,
ligation and division of the fistula, in most malacia of the extrathoracic part of the
cases through a cervical approach. In trachea may result in partial or complete
selected cases, particularly patients with airway collapse on inspiration. Signs and
recurrent fistula, glue injection may be used symptoms include a barking cough, tachy-
for closure of the fistula. Long-term and dyspnoea, retractions, cyanosis,
prognosis is excellent, unless diagnosis is localised monophonic (expiratory)
delayed until late child- or even adulthood, wheezing, and possibly (inspiratory) stridor.
which may result in considerable respiratory Feeding may cause dying spells (food in
morbidity due to recurrent aspiration and the oesophagus may compress the malacic
infection. trachea).
Tracheomalacia This anomaly is caused by With intrathoracic tracheomalacia, a chest

congenital absence, deficiency, X-ray typically reveals bilateral
malformation or softness of tracheal hyperinflation; lateral inspiratory and
cartilage. Congenital tracheomalacia has to expiratory radiographs may show marked
be distinguished from acquired forms; the changes in airway calibre of the malacic part
latter may develop as a result of prolonged of the trachea. The registration of (tidal and)
intubation and mechanical ventilation, maximal flowvolume curves allows
tracheostomy or severe tracheobronchitis. distinction between extra- and intrathoracic
Tracheomalacia can be primary or airway obstruction and between variable
secondary, and may be localised or (tracheomalacia) and fixed (tracheal
generalised. Primary tracheomalacia is stenosis) obstruction. Flexible airway
found in association with oesophageal endoscopy is the diagnostic procedure of
atresia, Down syndrome, EhlersDanlos choice; it can be done with only minimal
syndrome, and with laryngomalacia or mechanical distortion of the airway anatomy
bronchomalacia. Its incidence has been and dynamics, while rigid instruments
reported to be at least 1 in 2100. Localised inevitably distort the airways. It is mandatory
secondary tracheomalacia occurs as a that evaluation of airway dynamics is
consequence of compression from a performed during spontaneous breathing.
vascular malformation (e.g. double aortic CT and MRI with angiography are
arch, right aortic arch variants, left complementary techniques, in particular in
pulmonary artery sling, anomalous patients with localised tracheomalacia

where compression by an extrinsic lesion is left pulmonary artery sling, abnormal
suspected. bronchial arborisation (e.g. tracheal
bronchus), or a single right or left lung. In
Generally, in patients with isolated the past 50 years, various classifications
tracheomalacia airway function improves have been proposed, based on the length of
with increasing age, as the airway grows and stenosis, the severity of symptoms, and
the airway wall stiffens. Thus, most patients recently according to bronchial involvement.
can be managed conservatively, with chest
physiotherapy and antibiotics for secondary Congenital tracheal stenosis may be life-
infections. In particular, infants with threatening or may only be detected
generalised tracheo- and/or bronchomalacia incidentally. Signs and symptoms depend
and significant airway obstruction may on the severity and the site of the stenosis,
benefit from long-term application of CPAP and include localised monophonic
or ventilation with positive end-expiratory (expiratory or biphasic) wheezing or
pressure (PEEP) via tracheal cannula to (inspiratory or biphasic) stridor, tachy- and
splint the airway. In most of these patients, dyspnoea, retractions, cyanosis, and
gradual reduction of positive airway respiratory distress.
pressures and eventual decannulation is
possible. Clinical and radiological Usually, CT or MRI (with three-dimensional
parameters as well as flexible airway reconstruction) is necessary to define the
endoscopy and pulmonary function testing extent of the lesion, and to confirm or rule
enable determination of the individual out compression by an extrinsic lesion
optimal airway pressure. One advantage of (fig. 3). Unless a severe stenosis precludes a
this approach is the avoidance of major complete endoscopic examination, flexible
surgery; disadvantages include long-term bronchoscopy with an ultrathin instrument
tracheostomy and technology dependency. is helpful in defining airway anatomy
Surgical treatment is indicated in children including bronchial arborisation, in
with life-threatening tracheomalacia. detecting possibly associated
Aortopexy is usually effective in localised tracheomalacia, and in planning treatment.
tracheomalacia, but is of limited value in Pulmonary function testing shows evidence
generalised forms. Stents may be effective in of fixed airway obstruction with plateaus in
patients with diffuse tracheomalacia but both the inspiratory and expiratory limb of
severe complications including death have the flowvolume loop.
been reported in a significant proportion of As tracheal stenosis may improve with
children. Thus, today most authors agree airway growth, conservative and
that stents should only be employed in symptomatic treatment (including chest
selected patients when there are no good
alternatives. Treatment and prognosis
depend on the type and severity of the
malacia and on associated anomalies.
Tracheal stenosis Tracheal stenosis occurs
more infrequently than tracheomalacia.
Membraneous stenoses (webs) are less
common than anomalies of the tracheal
cartilages. Complete cartilaginous tracheal
rings (napkin ring cartilages) mainly occur
in the intrathoracic part of the trachea along
a variable length; sometimes the whole
trachea is affected. Stenoses can occur in an
hourglass- or funnel-shape (carrot-shape, Figure 3. Severe, short segment tracheal stenosis
rat-tail trachea). They are frequently (red arrow), and parenchymal lung malformation
associated with other anomalies such as a in the right upper lobe.

physiotherapy and antibiotics) should be problems despite conservative measures,
recommended whenever possible. Surgical resection of the affected segment or lobe
options for more severe stenoses include may be necessary.
tracheostomy to bypass stenosis of the
cervical trachea, resection and primary Topographic anomalies of the whole lung
anastomosis for short segment stenosis, (situs inversus; bronchial isomerism
and, among others, slide tracheoplasty bilateral right or bilateral left lung) are
(including repeated balloon dilation to usually associated with topographic
prevent subsequent recurrence of the anomalies of the heart and/or abdominal
stenosis) for long-segment stenosis. organs (e.g. Ivemark syndrome with
Tracheal surgery should only be exercised in asplenia).
specialised referral centres. In the future, Bronchial atresia This malformation is
tissue-engineered tracheal replacement is frequently associated with congenital lung
expected to play an increasingly important malformations and is seen by many authors
role. Treatment and prognosis depend on as the underlying cause of the latter. In this
the type and severity of the stenosis and on rare anomaly, a lobar or (sub)segmental
associated anomalies. bronchus ends blindly, separated by a short
Tracheal bronchus and other topographic gap from the distally located bronchial tree
anomalies Topographic anomalies, supplying the lobe or (sub)segment. The
representing the most common clinical picture varies widely, from the
malformations of the tracheobronchial tree, neonate with respiratory distress to the
are mostly observed on the right side. A asymptomatic adult. CT or MRI is used to
tracheal bronchus (pig bronchus) may be confirm the diagnosis. Most authors
associated with other anomalies in the recommend resection of the lesion.
tracheobronchial tree or in other organ Bronchomalacia Bronchomalacia is
systems. It supplies either the apical characterised by abnormal weakness of the
segment of the right upper lobe (in this case airway wall. Localised forms are
a normal right upper lobe bronchus supplies distinguished from generalised (e.g.
the other segments), an accessory segment WilliamsCampbell syndrome), and primary
within or separated from the right upper forms from secondary ones; the latter are
lobe, or the whole right upper lobe (in this usually caused by vascular compression.
case the normal right upper lobe bronchus Bronchomalacia is frequently associated
is absent). The tracheal bronchus may also with tracheomalacia, and the left main
originate from the trachea at the level of the bronchus is predominantly affected.
carina (trifurcation). For a detailed
description of the so called bridging Signs and symptoms depend on severity
bronchus in patients with a tracheal and include cough, localised monophonic
bronchus and a left pulmonary artery sling, wheezing and decreased breath sounds.
the reader is referred to relevant literature. Some children only develop symptoms
during respiratory infections. Flexible
These and other lobar or segmental bronchoscopy is the diagnostic procedure of
bronchial anomalies are often asymptomatic choice; echocardiography, CT and MRI are
and thus only incidentally detected. complementary techniques, in particular for
However, if structural anomalies (stenosis, localised bronchomalacia.
malacia) are present the malformation may
result in recurrent or persistent pneumonia Gradual improvement may be expected with
or atelectasis, and later bronchiectasis in the age and thus airway growth. Only a minority
respective segment or lobe. Diagnosis is of patients with significant respiratory
established by bronchoscopy and CT or MRI. problems requires treatment apart from the
Chest physiotherapy and antibiotics are the usual conservative measures (chest
treatment of choice in symptomatic physiotherapy, antibiotics). Prognosis
patients. In patients with persisting mainly depends on associated anomalies.

Bronchial stenosis Bronchial stenosis is rare N Eber E. Congenital and acquired abnorm-
and predominantly occurs in mainstem (left alities of the upper airways. In: Priftis KN,
. right) and lobar bronchi. Retention of et al., eds. Paediatric Bronchoscopy. Progr
secretions may lead to bronchopulmonary Respir Res Vol. 38. Basel, Karger, 2010;
infections and the development of pp. 120129.
bronchiectases. Signs and symptoms are N Holinger LD, et al., eds. Pediatric
the same as with bronchomalacia. Laryngology and Bronchoesophagology.
Diagnosis is confirmed by flexible Philadelphia, Lippincott-Raven, 1997.
bronchoscopy, CT or MRI. As patients tend N Laberge JM, et al. Congenital malforma-
to show improvement with age, conservative tions of the lungs and airways. In: Taussig
LM, et al., eds. Pediatric Respiratory
management is recommended. Resection
Medicine. 2nd Edn. St Louis, Mosby,
and primary anastomosis may be necessary
2008; pp. 907941.
for severe short segment stenosis; localised
N Myer CM 3rd, et al. (1994). Proposed
bronchiectasis may necessitate resection of grading system for subglottic stenosis
the affected segment or lobe. based on endotracheal tube sizes. Ann
Otol Rhinol Laryngol; 103: 319323.
Further reading N Myer CM III, et al., eds. The Pediatric
Airway. Philadelphia, Lippincott, 1995.
N Benjamin B, et al. (1989). Minor con- N Nicolai T (2008). Airway stents in
genital laryngeal clefts: diagnosis and children. Pediatr Pulmonol; 43: 330344.
classification. Ann Otol Rhinol Laryngol; N Pfleger A, et al. (2013). Management of
98: 417420. acute severe upper airway obstruction in
N Boogaard R, et al. (2005). Tracheomalacia children. Paediatr Respir Rev; 14: 7077.
and bronchomalacia in children: inci- N Pohunek P, et al. Congenital and acquired
dence and patient characteristics. Chest; abnormalities of the lower airways. In:
128: 33913397. Priftis KN, et al., eds. Paediatric
N Dinwiddie R (2004). Congenital upper Bronchoscopy. Progr Respir Res Vol. 38.
airway obstruction. Paediatr Respir Rev; 5: Basel, Karger, 2010; pp. 130140.
1724. N Speggiorin S, et al. (2012). A new
N Eber E (2006). Adult outcome of con- morphologic classification of congenital
genital lower respiratory tract malforma- tracheobronchial stenosis. Ann Thorac
tions. Swiss Med Wkly; 136: 233240. Surg; 93: 958961.

Thoracic malformations
Ashok Daya Ram, Jennifer Calvert and Sailesh Kotecha
Congenital thoracic malformations (CTMs) (table 1); however, we will only cover
are a heterogeneous group of rare congenital cystic adenomatoid
congenital developmental anomalies and malformations (CCAMs) and relative
disorders of the lung parenchyma and bronchopulmonary sequestrations (BPS).
airways with an incidence of approximately Close multidisciplinary cooperation between
3.5 per 10 000 live births. The use of routine fetal medicine experts, neonatologists,
antenatal ultrasound scans, post-natal CT paediatric surgeons, geneticists,
and MRI imaging, and advances in neonatal paediatricians and/or paediatric
surgery and intensive care have widened our pulmonologists is crucial to the overall
knowledge of the pathophysiology of CTMs management and outcome of children with
but at the same time have also introduced CTMs.
complexities, especially to the management
of asymptomatic lesions. Many excellent Embryology
recent studies and textbooks of paediatric
respiratory medicine cover all CTMs in detail The lungs develop as an out pouching from
the developing foregut at 3 weeks of
gestation. The respiratory diverticulum
Key points begins to grow caudally and divides at
4 weeks and further subdivides in a
N The routine introduction of antenatal dichotomous fashion. Further lung growth
ultrasound scanning has not only occurs in tightly regulated stages of lung
increased our knowledge of CTMs but development, namely the embryonic,
has resulted in improved antenatal pseudoglandular, cannalicular, saccular and
counselling and management of these alveolar phases. By the end of the sixth
conditions. month of gestation, 17 generations of
N Antenatal resolution of CCAMs is subdivisions have formed. Lung growth and
reported in up to 20% cases but in development continues post-natally until at
most cases there is evidence of their least 2 years of age or beyond. The exact
persistence on post-natal CT images. aetiology for most CTMs remains unknown
but for CCAMs the embryological insults are
N Management of asymptomatic speculated to occur during the
CCAMs is controversial with some pseudoglandular stages of lung
physicians opting for regular follow-up development for Types I to III CCAMs and
and imaging to gauge progress whilst during the late saccular phase of lung
others opt for surgical removal. development for Type IV lesions. It is
N Long-term follow-up studies to assess postulated that transcription and growth
the natural history, including factors, such as homeobox protein Hox-B5
respiratory and neurodevelopmental (HOXb5), thyroid transcription factor 1
outcomes, especially after fetal (TTF) and platelet-derived growth factor
intervention, are required. (PDGF-BB), may play a role in the
pathogenesis of CCAMs.

Table 1. Differential diagnosis of CTMs cysts derived from the primitive foregut
containing viscid, milky mucus and
Tracheobronchial malformations occasionally communicate with the airway.
Tracheal agenesis/atresia/stenosis They present in several ways:
Tracheal bronchus
N on antenatal ultrasound scan,
Oesophageal bronchus/lung N respiratory distress in infancy,
Tracheomalacia/bronchomalacia N recurrent/persistent pneumonia,
Enteric duplication cyst N an incidental finding of a smooth
Neuroenteric cyst
mediastinal mass on chest radiography.
Bronchogenic cyst Treatment is by surgical excision.

Bronchial cyst
Modalities such as antenatal MRI (fig. 1b)
Bronchiolar cyst can accurately delineate and quantify the
Pulmonary parenchymal malformations CTMs providing an excellent method for
Agenesis/aplasia/hypoplasia of the lungs morphological and volumetric evaluation of
the fetal lung, but should be used as an
Congenital lobar emphysema
adjunct to routine antenatal ultrasound
CCAM rather than as a primary investigation.
Bronchopulmonary sequestration
CCAM of the lungs
Vascular malformations
Haemangioma CCAM (also termed congenital pulmonary
airway malformation (CPAM)) is a
Arterio-venous malformations congenital lung anomaly in which abnormal
Scimitar syndrome (congenital venolobar development appears to occur in part of the
syndrome) lung, usually at the lower lobe of either lung.
Congenital pulmonary lymphangiectasia The lesion grows fastest between 20 and
26 weeks of gestation, and then plateaus
Lymphangioma
before decrease in volume relative to foetal
Congenital chylothorax size towards term. The abnormal lung
consists of terminal bronchiolar or acinar
structures that can act as space occupying
Antenatal diagnosis lesions, although it is connected to the
tracheobronchial tree. The lesions usually
The routine introduction of antenatal draw their blood supply from the pulmonary
ultrasound scanning (fig. 1a) has not only circulation but in hybrid lesions, i.e. lesions
increased our knowledge of CTMs but has showing elements of both CCAM and BPS,
resulted in improved antenatal counselling they may have a systemic blood supply.
and management of these conditions. CCAMs can vary in size and consistency,
Improved detection may have resulted in and their continued growth can cause
increased reporting of CTMs. While pressure effects on the remainder of the
antenatal scanning has improved detection, lungs, oesophagus, the mediastinum or the
it has also led to some unique challenges, great vessels. CCAMs are usually isolated
namely the management of lesions with a but Type 2 CCAMs are often associated with
presumed diagnosis and lesions that may other systemic abnormalities.
resolve. A pathological diagnosis would
clearly require tissue for examination, thus, The incidence of CCAM is 0.94 per 10 000
it is important to describe the lesion in live births. Some, but not all, studies report
detail and formulate a differential diagnoses a slight male preponderance with no known
(table 1). Important differential diagnoses genetic or familial association (although
include congenital diaphragmatic hernia and these are increasingly described for specific
bronchogenic cysts, which are congenital lesions).

a) b)
c) d)
Figure 1. a) Antenatal ultrasound and b) MRI scan of an extensive right sided CCAM, which was
symptomatic at birth, with respiratory distress and mediastinal shift as confirmed by c) a chest radiograph
and d) a CT scan. It was surgically removed successfully at 3 days of age.
There have been many classifications for ciliated cuboidal or columnar epithelial
CCAMs but the two by Stocker (2002) and cells.
Langston (2003) are most commonly used N Type 3 are solid lesions without cystic
with significant overlap between the two. components with an excess of acinar
The Langston classification includes lesions structures.
other than CCAMs, including bronchial
atresia and pulmonary hyperplasia. The Other types have subsequently been added
Stocker classification, which focuses on to this classification including Type 0, which
CCAMs, is based on histology and the size is best viewed as describing congenital
of the lesions as follows. acinar dysplasia, and Type 4, which overlaps
with type 1 pleuropulmonary blastoma. Type
N Type 1 where individual cysts are .2 cm 1 is the commonest lesion forming ,50
in diameter and are lined by 70% of all CCAMs and has the best
pseudostratified epithelium. prognosis. Type 2 CCAMs are often
N Type 2 where individual cysts are ,2 cm associated with other malformations, which
in diameter with the cysts resembling should be looked for at antenatal ultrasound
dilated bronchioles; they are lined by screening.

Since Stockers classification is based on sclerosing agent into any feeding vessel.
histological observation, Adzick et al. (1998) Hedrick et al. (2005) reported an 89%
suggested a more clinical classification overall survival in nine patients who
based on antenatal ultrasound underwent the ex utero intrapartum
measurements of the cysts to classify treatment (EXIT) procedure for fetal
CCAMs into two types: hydrops, extensive mediastinal shift or
persistently elevated CVR. Ultrasound-
N macrocystic, where the cyst or cysts are guided intrauterine thoracoamniotic
.5 mm in diameter and constitute 75% shunting for a macrocystic CCAM with a
of all lesions; large cyst has the best outcome with the
N microcystic, where the cyst or cysts are lowest fetal and maternal risk. Out of 23
,5 mm in diameter and constitute 25%
such patients treated with this approach in
of the lesions.
one series, the volume reduction of the
CCAMs act as space occupying lesions with CCAM was 70% and survival throughout the
pressure effects on the: neonatal period was 74%. Open maternal
fetal surgery with pulmonary resection of a
N lungs, which can lead to lung hypoplasia, large CCAM yields a 50% probability of
N oesophagus resulting in polyhydramnios, survival to discharge from the neonatal
N heart, vessels and mediastinum resulting intensive care unit, but given the technical
in pleural effusions or hydrops fetalis. complexity this should only be performed in
Antenatal ultrasound scanning can detect a centre with experience.
these lesions as hyperechoic pulmonary
However, most studies report a small
masses (fig. 1a), as well as features of
number of patients and report success
associated complications (e.g.
although publication bias suggests that
polyhydramnios or hydrops) in .80% of the
those that resulted in failure are unlikely to
cases. Systemic abnormalities including the
reach the wider literature. Furthermore,
cardiovascular, abdominal and mediastinal
most of these interventions have not been
structures should also be investigated.
formally assessed, thus, results need to be
Antenatal resolution of CCAMs is
reported in up to 20% cases but in most interpreted with caution. Longer term
cases there is evidence of their persistence outcomes after fetal intervention have not
on post-natal CT images. 510% of these been reported in any detail but will clearly
lesions can lead to the development of need careful follow-up, especially for
hydrops, which is associated with markedly neurodevelopmental outcomes. Clearly it is
increased fetal demise; thus, this important to counsel the parents with a
association has received great attention for multidisciplinary team offering all available
antenatal fetal surgical intervention. options.
Currently the best available indicator of Post-natally, most CCAMs will have been
prognosis for CCAM is the CCAM volume identified antenatally and infants with large
ratio (CVR). This is the ratio of the lesion lesions may need supportive therapy for
volume compared to the head stabilisation prior to surgical intervention.
circumference. CVR values .1.6 are Planning to deliver in appropriate centres
associated with increased risk of between with the required expertise is a must for
15% and 75% for developing fetal hydrops, these babies. The majority of CCAMs,
i.e. poor prognosis. Due to the increased risk however, are asymptomatic but some may
of developing a complicated course, the CVR present with acute (fig. 1c and d) or chronic
is often used to guide antenatal fetal respiratory distress, recurrent pulmonary
surgical intervention but has limited infections, bronchiectasis, lung abscesses,
sensitivity and specificity. Antenatal haemoptysis, pneumothorax, air embolism,
interventions include steroid administration, haemothorax, pyopneumothorax, steroid-
thoracentesis, thoracoamniotic shunt, laser resistant asthma or high output cardiac
ablation, fetal surgery or injection of a failure (if there is a large systemic arterial

blood supply). They may present it is claimed that the risks of post-natal
asymptomatically on chest radiographs infection for asymptomatic lesions are
obtained for other reasons. exaggerated. Furthermore, these advocates
suggest that the risks of future malignancy
There is little controversy that surgical
are small, there is no evidence for lung
resection of symptomatic lesions is
physiological improvement after early
appropriate in most cases and is relatively
surgery and the post-operative risks for
straightforward with minimal morbidity and
surgery after respiratory infection in a few
mortality in experienced paediatric/neonatal
children do not justify exposing those
surgical centres.
children who may never develop symptoms
Management of asymptomatic lesions is to unnecessary surgery.
more controversial. Possible reasons for
surgical removal of asymptomatic lesions Whichever route is taken for management of
include prevention of chest infections, and asymptomatic CCAMs, it is important to
other rarer complications such as: ensure appropriate counselling of the
parents by a multidisciplinary team and for
N bleeding and pneumothorax; full risk assessment of any surgical
N prevention of future malignancy risk; interventions to be balanced against the
N encourage compensatory lung growth if need for repeated CT scans and risk of loss
performed within 2 years of age; to follow-up of patients. For an
N decrease post-operative complications. asymptomatic child who develops infection,
the surgical risks and complications are
In most cases surgery is performed
marginally higher than those who undergo
between 2 and 12 months. With advances
elective surgery but the absolute risk for
in surgical skills, elective surgery is
development of infection in an
considered relatively safe in expert surgical
asymptomatic child has been poorly
hands with few complications involving a
reported. Newer interventions, such as
short hospital stay but may be associated
thoracoscopic surgery, are being introduced
with poorly delineated longer term
but need to be fully assessed before they
outcomes such as scoliosis. Complete
become routine, especially for
excision of the lesion is usually achieved by
lobectomy but segmentectomy may be asymptomatic CCAMs.
used to preserve parenchyma for small The natural history of CCAMs is not well
lesions or if there is multiple lobe defined. It is unclear what proportion of
involvement. If elective surgery is children with asymptomatic CCAM develop
performed during infancy, there may be symptoms in the future. Although some
potential for compensatory lung growth but reports of limited numbers of children
definitive evidence is lacking. suggests symptoms in up to 10%, the
Thoracoscopic surgery may potentially
duration of follow-up is often short, thus
decrease the risks of traditional open
the true value is likely to be higher.
thoracotomy such as scoliosis, rib
Although tumours such as
crowding, injury to nerves and vessels, etc.,
pleuropulmonary blastoma,
thus may be preferable but needs further
rhabdomyosarcoma and bronchoalveolar
evaluation.
carcinoma are reported to occur with
However, there are proponents of a wait CCAMs, the true risk is unclear and one
and see approach, favouring a conservative report has suggested that risk may not be
approach citing many counter-arguments to reduced after surgery. Studies reporting
surgical intervention. For asymptomatic physiological lung function in surgical
lesions, a recent meta-analysis of 41 series survivors of symptomatic CCAMs are also
with 1070 patients suggests that the rate of conflicting with some reporting normal
infection among asymptomatic infants values whilst others report deficits. There is
beyond the neonatal period is 3.2% a clear need for further studies to evaluate
occurring at a median age of 7 months, thus the natural history of CCAMs.

Bronchopulmonary sequestration planning of intervention, delivery, etc., but
also introduce newer problems particularly
BPS can be extralobar or intralobar with the the management of asymptomatic lesions.
lesions comprising of lung tissue with its Whilst symptomatic lesions are amenable to
own blood supply via an aberrant blood surgical excision, the management of
vessel. They lack continuity with the rest of asymptomatic lesions remains controversial
the respiratory tract. Intralobar BPS and both medical and surgical management
predominantly occurs in the posterior basal needs to be balanced against the risks for
lateral segment of the left lower lobe. It has each approach. New interventions are being
single or multiple systemic arterial supplies increasingly introduced but need careful
arising from the abdominal aorta in 75% of evaluation not only in the short term but
the cases and venous drainage is usually also for long-term outcomes. However
into the pulmonary vein. Extralobar CTMs are dealt with, appropriate
sequestrations are completely separated counselling of the parents with a
from the normal lung, invested by an multidisciplinary team is essential.
individual pleura. The commonest site is the
left lower lobe but it can occur anywhere in
the lungs and even in sub-diaphragmatic
Further reading
areas. In as many as 50% of cases, there are
other associated abnormalities including N Abel RM, et al. Congenital lung diseases. In:
CCAM, congenital cardiac anomalies, Chernick V, et al., eds. Kendigs Disorders
pericardial defects, pectus excavatum, of the Respiratory Tract. 7th Edn.
bronchogenic cysts and vertebral anomalies. Philadelphia, Elsevier, 2006; pp. 280316.
The blood supply is usually from the N Adzick NS, et al. (1998). Fetal lung
systemic circulation. BPS is the commonest lesions: management and outcome. Am
differential diagnosis of CCAM; they both J Obstet Gynecol; 179: 884889.
have distinct radiological, pathological and N Bush A, et al. (2008). Cystic lung lesions
prenatal diagnosis and management.
clinical characteristics. The main distinct
Prenat Diagn; 28: 604611.
characteristics are lack of communication to
N Calvert JK, et al. (2006). Outcome of
the tracheobronchial tree and the aberrant antenatally suspected congenital cystic
blood supply from systemic circulation. In adenomatoid malformation of the lung:
some cases, features of both CCAM and BPS 10 years experience 1991-2001. Arch Dis
coexist in the same lesion, often termed Child Fetal Neonatal Ed; 91: F26F28.
hybrid lesions. N Correia-Pinto J, et al. (2010). Congenital
lung lesions underlying molecular
The treatment for both intralobar and mechanisms. Semin Pediatr Surg; 19:
extralobar BPS is surgical resection because 171179.
of risks of haemorrhage, infection, N Crombleholme TM, et al. (2002). Cystic
arteriovenous shuntings and late adenomatoid malformation volume ratio
malignancy but smaller lesions may be left predicts outcome in prenatally diagnosed
alone or selectively embolised. The most cystic adenomatoid malformation of the
essential step in surgery of these lesions is lung. J Pediatr Surg; 37: 331338.
identification and control of systemic blood N Hedrick HL, et al. (2005). The ex utero
vessels. Unrecognised or uncontrolled intrapartum therapy procedure for high-
bleeding from these vessels can be risk fetal lung lesions. J Pediatr Surg; 40:
associated with serious morbidity or even 10381043.
mortality. N Hsieh CC, et al. (2005). Outcome of
congenital cystic adenomatoid malforma-
Conclusion tion of the lung after antenatal diagnosis.
Int J Gynaecol Obstet; 89: 99102.
Although CTMs are rare, they are important N Joshi S, et al. (2007). Lung growth and
causes of respiratory distress in newborns development. Ear Hum Develop; 83:
and children. They are increasingly 789794.
diagnosed antenatally which allows for

N Knox EM, et al. (2006). In utero pulmon- N Savic B, et al. Pulmonary sequestration.
ary drainage in the management of In: Frick HP, et al., eds. Advances in
primary hydrothorax and congenital cystic Internal Medicine and Paediatrics. New
lung lesion: a systematic review. York, Springer-Verlag, 1979; pp. 5892.
Ultrasound Obstet Gynecol; 28: 726734. N Slade I, et al. (2011). DICER1 syndrome:
N Kotecha S, et al. (2012). Antenatal and clarifying the diagnosis, clinical features
postnatal management of congenital and management implications of a pleio-
cystic adenomatoid malformation. tropic tumour predisposition syndrome.
Paediatr Respir Rev; 13: 162170. J Med Genet; 48: 273278.
N Langston C (2003). New concepts in the N Stanton M, et al. (2009). Systematic
pathology of congenital lung malforma- review and meta-analysis of the postnatal
tions. Semin Paediatr Surg; 12: 1737. management of congenital cystic lung
N Papagiannopoulos KA, et al. (2001). lesions. J Pediatr Surg; 44: 10271033.
Pleuropulmonary blastoma: is prophylac- N Stocker JT (2002). Congenital pulmonary
tic resection of congenital lung cysts airway malformation-a new name for an
effective? Ann Thorac Surg; 72: 604605. expanded classification of congenital
N Roggin KK, et al. (2000). The unpredict- cystic adenomatoid malformation of the
able character of congenital cystic lung lung. Histopathology; 41: Suppl. 2, 424
lesions. J Pediatr Surg; 35: 801805. 458.
N Witlox RS, et al. (2011). Neonatal out- N Wilson RD, et al. (2004). Thoracoa-
come after prenatal interventions for mniotic shunts: fetal treatment of pleural
congenital lung lesions. Early Hum Dev; effusions and congenital cystic adenoma-
87: 611618. toid malformations. Fetal Diagn Ther; 19:
N Salomon LJ, et al. (2003). Fetal thora- 413420.
coamniotic shunting as the only treat- N Wilson RD, et al. (2006). Cystic adeno-
ment for pulmonary sequestration with matoid malformation of the lung: review
hydrops: favorable long-term outcome of genetics, prenatal diagnosis, and in
without postnatal surgery. Ultrasound utero treatment. Am J Med Genet; 140:
Obstet Gynecol; 21: 299301. 151e5.

Vascular malformations
Oliviero Sacco, Serena Panigada, Nicoletta Solari, Elena Ribera, Chiara Gardella,
Silvia Rosina, Michele Ghezzi and Francesca Rizzo
A wide spectrum of congenital anomalies embryonic development of the aortic arch

can occur during the formation of the aortic and related structures is important to
arch, brachiocephalic arteries, pulmonary understand and classify the various form of
arteries and ductus arteriosus, due to the vascular malformation.
failure of embryonic structures to fuse and
regress regularly. Knowledge of the normal During fetal development, six pairs of
primitive aortic arches are sequentially
formed and, as successive arches develop,
the previous arches regress. The major
Key points persistent arches in humans are the fourth
and sixth. The fourth arches contribute to a
N The incidence of vascular portion of the left aortic arch and of the right
malformations is ,1% but the true subclavian artery; the proximal portions of
incidence is difficult to assess if the sixth arches become the mediastinal
less severe abnormalities are segment of the pulmonary arteries, while
included. their distal portions form the ductus
N The most severe forms of vascular arteriosus (Kellemberg, 2010). Abnormal
rings can be detected during the development of the aortic arch complex may
neonatal diagnostic work-up, cause represent an uncommon but potentially
serious symptoms in the newborn serious cause of variable degrees of
period and require surgery within the compression of the trachea, bronchi and/or
first year of life. oesophagus, due to the formation of
vascular ring or sling. Some of these
N The less severe abnormalities are anomalies, such as the double aortic arch
detected in later life, when and the right arch/left ligament, are
unexplained recurrent respiratory anatomically complete rings, while others,
symptoms or occasional mild i.e. anatomically incomplete or partial rings,
dysphagia leads to radiographic or
are called slings, such as the pulmonary
endoscopic evaluation. Symptoms
sling.
such as dyspnoea, wheezing and
cough are often misdiagnosed as
asthma, particularly if they occur in Clinical presentation and classification
older children.
In children with vascular abnormalities, the
N The vascular malformations that most severity of the resulting respiratory disorder
frequently cause symptoms are: does not appear to correlate tightly with the
double aortic arch; right aortic arch degree of anatomical obstruction of the
with a left ligament arising from the airways. Signs and symptoms at
descending aorta; aberrant subclavian presentation are variable, including apnoeic
artery; pulmonary sling; and aberrant spells, recurrent apnoeas, stridor/noisy
innominate artery. breathing, chronic or recurrent cough, a
brassy cough similar to a seals bark,

recurrent respiratory infections and commonly located on the left side of the
dysphagia for solid foods. spine. The ligamentum arteriosum is usually
located between the distal part of the left
The most severe forms of vascular rings can arch and the left pulmonary artery, but may
be detected during the neonatal diagnostic be present on both sides when the aortic
work-up, particularly if associated with arches are both patent (Kellemberg, 2010).
congenital cardiac malformations; they Children with this anomaly usually present
cause serious symptoms in the newborn with severe respiratory symptoms and some
period and require surgery within the first swallowing difficulty early in life. Surgical
year of life. Less severe abnormalities are interruption of the smaller or atretic aortic
detected in later life, when unexplained arch and of the ligament is usually required.
recurrent respiratory symptoms or The most severe case of tight vascular ring
occasional mild dysphagia require can interfere with normal tracheal
radiographic or endoscopic evaluation. development; the tracheal lumen can show
Symptoms such as dyspnoea, wheezing and
segmental stenosis with complete
cough are often misdiagnosed as asthma,
cartilaginous rings (fig. 1e).
particularly if they occur in older children.
Right aortic arch, comprising 1225% of
The true incidence is difficult to assess if we cases of vascular rings, is usually associated
include less severe abnormalities/ with congenital cardiac malformations such
compression. Autopsy studies suggest that as persistent truncus arteriosus, pulmonary
3% of people have a congenital atresia with ventricular septal defect, and
malformation of the aortic arch but about tetralogy of Fallot. In this group of
two-thirds of cases remain undiagnosed abnormalities, the regression of the
(McLaren et al., 2009). In this section, we
embryonic structures involves the left aortic
will focus on the vascular malformations
arch, resulting in the right arch lying to the
that most frequently cause symptoms:
right side of the trachea, passing over the
N double aortic arch, right principal bronchus and generally
N right aortic arch with a left ligament continuing as the right descending aorta,
arising from the descending aorta, located to the right of the spine (fig. 2a and
N aberrant subclavian artery, c). A combination of a right aortic arch and a
persisting left descending aorta results in a
N pulmonary sling, and
circumflex right aortic arch with an
N aberrant innominate artery.
horizontal retro-oesophageal portion of the
Double aortic arch, the most common and dorsal aortic arch, which contributes to the
serious complete type of vascular ring, is compression of trachea and oesophagus
usually an isolated anomaly without from behind (fig. 3). The brachiocephalic
associated cardiac malformation; it is vessels may originate as a mirror image of a
associated with congenital cardiac normal left aortic arch, but many variants
malformations, such as ventricular septal are possible. The association of a right aortic
defect or tetralogy of Fallot, in 20% of cases. arch with a left ligament that passes from
It is due to the persistence of both fourth the left pulmonary artery to the descending
aortic arches encircling the trachea and aorta or to the left subclavian artery,
oesophagus in a tight ring. In 75% of affected coursing to the left of the trachea and
infants, the right-sided arch is dominant oesophagus, describes a complete vascular
(larger and positioned higher than the left ring around these structures. If the left
arch), in 20% the left arch is dominant and in fourth aortic arch regresses proximal to the
5% the arches are equal in size (fig. 1a and b). left subclavian artery, a right aortic arch with
A portion of the left aortic arch can be atretic an aberrant left subclavian artery as the last
and persist only as a fibrous band. Each branch results. The artery passes behind the
aortic arch passes over the ipsilateral oesophagus and forms a complete vascular
principal bronchus and fuses behind into a ring together with the left-sided ligamentum
common descending aorta, which is more arteriosum (Russell et al., 2010).

a) b)
c) d) e)
Figure 1. a) Right-sided dominant double aortic arch (arrow); MDCT axial view. b) Same patient, MDCT
three-dimensional imaging; posterior view. ce) Endoscopic images of double aortic arch compression of
trachea, increasing severity. e) The tracheal rings are complete or circumferential.
The origin of the left subclavian artery from arch and has an oblique course toward the
the descending aorta is frequently dilated, other side, across the superior
forming the so-called Kommerell mediastinum, passing behind the
diverticulum (fig. 2a and c). In patients with oesophagus on its way to the upper
a right aortic arch, the airway compression extremity. An aberrant right subclavian
can be due to different mechanisms: artery as single malformation is rarely
vascular ring due to a left ligamentum symptomatic, although in older children and
arteriosum (fig. 2b), enlargement of the in adults, mild dysphagia may be present
Kommerell diverticulum and/or a midline/ due to compression of the oesophagus.
left descending aorta. However, an aberrant left subclavian artery,
crossing behind the oesophagus as the last
Aberrant subclavian artery, the most common branch of a right aortic arch, forms a
among the aortic arch anomalies, occurs in complete vascular ring together with a left-
nearly 1% of the population and in 25% of sided ligamentum arteriosum, as previously
Down syndrome patients. Originally described, and commonly causes symptoms
described by Bayford in the 18th century as due to compression of both the trachea and
dysphagia lusus naturae (dysphagia freak oesophagus (Kellemberg, 2010).
of nature), this anomaly most commonly
involves the right subclavian artery or, rarely, Pulmonary sling The embryonic origin of
the left subclavian artery when there is a pulmonary artery sling occurs when the
right-sided aortic arch, as previously developing left lung captures its arterial
described. The aberrant subclavian artery supply from the right sixth arch through
originates as the last vessel of the aortic capillaries caudal, rather than cephalad, to

a) c)
b)
Figure 2. a) Right aortic arch, Kommerel diverticulum (arrow); MDCT axial view. b) Right aortic arch, a
rare MDCT imaging of ligamentum arteriosum; axial view. c) Kommerel diverticulum and aberrant left
subclavian artery (arrow), MDCT three-dimensional imaging; posterior view.
the developing tracheobronchial tree. As 50% of pulmonary artery sling cases, most
consequence, the anomalous left pulmonary commonly atrial septal defect, patent ductus
artery arises from an elongated right arteriosus, ventricular septal defect and left
pulmonary artery, turns dorsally encircling superior vena cava.
the right main bronchus, and passes to the
left between the trachea and oesophagus Aberrant innominate artery causes tracheal
before entering the hilum of the left lung compression of various degrees. Why an
(fig. 4a). innominate artery, which arises from the
aortic arch to the left and crosses in front of
The airway may also be compromised by the trachea to the right side, should
associated complete cartilage rings, the so compress the trachea in some cases and not
called ring-sling complex present in 4050% others is not well understood. In innominate
of cases, where the membranous portion of artery compression patients, the artery
the trachea is absent and the tracheal appears to originate somewhat more
cartilages are circumferential or O- posteriorly and leftward on the aortic arch
shaped. Associated tracheobronchial than usual. This condition is more
abnormalities may occur, including frequently symptomatic when associated
tracheomalacia, hypoplasia and stenosis of with tracheomalacia and/or oesophageal
long tracheal segments (fig. 4b and c) (Elliot atresia (fig. 5). Severe compression of the
et al., 2003). Both the right main bronchus trachea results in chronic or recurrent brassy
and the trachea are affected and cough, stridor, tachypnoea and recurrent
compression by the sling can result in respiratory infection (Gardella et al., 2010).
hyperinflation or atelectasis of the right The most severe presentations in infancy
lung. Congenital heart defects are found in include life-threatening events.

including heart malformation and some
a) aortic arch anomalies. As a consequence,
the prenatal diagnosis of some aortic arch
anomalies has become more common in the
last decade due to the widespread use of
fetal sonographic studies sufficient for
delineation of the trachea, aortic arch,
brachiocephalic arteries and ductus
arteriosus (Avni et al., 2007). After birth, the
presence of respiratory distress, wheezing,
stridor, dysphagia and recurrent respiratory
infection may require consideration of a
vascular ring or sling as the underlying
cause.
The historical approach was to perform

chest radiography and barium swallow as
b) the first step to evaluate children with
suspected extrinsic compression of the
airways, while conventional angiography was
reserved for confirmation of the diagnosis.
These studies have now been widely
replaced by MRI and multidetector CT
(MDCT). However, the recent literature
demonstrates variability in the preferred
diagnostic strategies for these conditions.
Chest radiography In symptomatic patients,
evaluation usually begins with frontal and
lateral chest radiograph. On the frontal
projection, the laterality of the aortic arch
can be appreciated by its density and the
side of the descending aorta by the presence
or absence of the aortic stripe on the
respective side. On the lateral projection,
anterior bowing of the trachea and an
increase in the retrotracheal density may
also be appreciated. In pulmonary sling,
chest radiographic findings include
unilateral hyperinflation, tracheal narrowing
and an unusual horizontal course of the left
Figure 3. Vascular ring due to right aortic arch, and right main bronchi, resulting in a T-
aberrant left subclavian artery and left shaped trachea. In any case, chest
ligamentum arteriosum. a) Endoscopic image of radiography can only arouse suspicion of the
tracheal lumen compressed on the right side. b) presence of a major vascular malformation.
Same patient, persistent indentation on barium
Barium oesophagography Upper
oesophagography from behind; lateral view.
Clinically: mild dysphagia.
gastrointestinal study has historically been
reliable and remains an excellent technique
for the diagnosis of a vascular ring, as the
Diagnosis location of the aortic arch in relation to the
oesophagus can be determined (fig. 3b).
Fetal ultrasound may detect malformation of Bilateral persistent indentations on the
several organs during the first trimester, oesophagus on the anteroposterior view

a) b) c)
Figure 4. Pulmonary sling. a) MDCT axial view: the anomalous left pulmonary artery (arrow) arises from
an elongated right pulmonary artery, turns dorsally encircling the right main bronchus, and passes to the
left between the trachea and oesophagus before entering the hilum of the left lung. b) MDCT coronal view
of the associated long-segment tracheal stenosis: two-thirds of the trachea are stenotic and show complete
cartilage rings (line). c) MDCT three-dimensional imaging of the trachea and bronchi: the origin of the
right main bronchus is stenotic due to compression by the anomalous left pulmonary artery.
suggest a double aortic arch, while posterior noninvasive angiography have widely
indentation with an oblique course angled replaced other diagnostic techniques, such
toward the left shoulder suggests an as the now obsolete catheter angiography.
aberrant subclavian artery. Anterior pulsatile The direct multiplanar imaging capability of
indentation of the oesophagus is virtually MRI allows accurate evaluation of vascular
pathognomonic for pulmonary artery sling. malformation and its relationships with
adjacent organs and, possibly, associated
Echocardiography and angiography intracardiac defects in a single sitting,
Echocardiography has the advantage of a without ionising radiation and iodinated
comprehensive assessment of intracardiac contrast material. However, most MRI
anatomy and function. However, it is limited studies for vascular compression are quite
by acoustic windows, a lack of depiction of prolonged (.30 min), the need for absolute
airway/oesophageal involvement and high immobility during image acquisition
interobserver variability. Conventional requires general anaesthesia with controlled
angiography is invasive and is limited by ventilation, and sedation risks are increased
high radiation dose and the need for in children with compromised airways.
iodinated contrast material. Contrast-enhanced MDCT overcomes this
Although the diagnosis of a vascular ring disadvantage by allowing accurate imaging
can be established or suspected with chest in very short scanning times and mild
radiography and oesophagography, the sedation is sufficient in younger,
exact configuration of the vascular uncooperative children. The disadvantages
abnormality cannot be fully defined with of MDCT include ionising radiation and the
conventional radiology alone. The exact need for iodinated contrast material;
anatomy of an aortic arch malformation and however, recent adjustment of specific
its relationship to adjacent structures can be techniques minimises the radiation dose. If
accurately defined only by cross-sectional assessment of the airways is important,
imaging techniques, as MRI and CT MDCT is currently more reliable than MRI
(Hellinger et al., 2011). for the definition of the airway by
multiplanar and three-dimensional image
MRI and MDCT Contrast-enhanced helical reconstruction (figs 1b, 2c and 4c), including
MRI or MDCT imaging allow excellent virtual bronchoscopy, without appreciable
delineation of the aortic arch, its branches respiratory artefacts. For both MRI and
and their spatial arrangement. The MDCT, the major diagnostic limit is that an
multiplanar and three-dimensional imaging obliterated vascular segment (e.g. the
capabilities of magnetic resonance and CT ligamentum arteriosum or an atretic aortic

a) b)
Figure 5. Tracheal compression by aberrant innominate artery in two patients, a) 15 and b) 20 months of
age. a) Endoscopic image of tracheal lumen compressed on the front right side. Good vision of the tracheal
rings is achieved and tracheal compression is visible without tracheomalacia. b) Patient with repaired
oesophageal atresia and less well-delineated tracheal rings. The association of vascular compression and
tracheomalacia caused a severe clinical picture with brassy cough, stridor and life-threatening events.
arch) can be visualised only rarely (fig. 2b). Bronchoscopy and bronchography Despite the
The final decision to image with MRI versus accuracy of both MRI and MDCT in
MDCT should take into consideration evaluating the nature of the vascular
availability of equipment and ease of compression of the airways, current MRI
scheduling, as well as the patients ability to and MDCT techniques do not reliably
cooperate. In practice, the increase in speed distinguish between dynamic or static
and quality of multiplanar reconstruction narrowing of the airways.
provided by MDCT technology means that
CT is used more and more often than MRI in Such distinction can have important clinical
most centres. consequences, as many children with
a) b)
Figure 6. Vascular ring due to right aortic arch, aberrant left subclavian artery and left ligamentum
arteriosum; same patient as in figure 3. Intraoperative view: a) ligamentum arteriosum (arrow) resection;
b) the two ends of the ligamentum (arrows) spontaneously move .1 cm away soon after resection.

vascular malformation can have associated there is a strong association with long-
malacia of the compressed airway. segment congenital tracheal stenosis with
Bronchoscopy and bronchography are still complete tracheal cartilage rings. The
the best techniques to assess the presence surgical procedure is the re-implantation of
of tracheo- or bronchomalacia (fig. 5b). the left pulmonary artery and, at the same
Bronchoscopy and bronchography are time, a slide tracheoplasty to increase the
performed at the same time, injecting tracheal calibre (Fiore et al., 2005). Surgical
isotonic, nonionic contrast down the treatment of patients with an aberrant right
working channel of the flexible subclavian artery is almost never necessary;
bronchoscope. Intraoperative tracheoscopy the artery has to be re-implanted only in the
can be indicated in the aortopexy procedure, rare patients with severe dysphagia.
to evaluate the resolution of the tracheal
collapse during the manoeuvres of Patients with tracheal compression by an
suspension of the aortic arch (Torre et al., aberrant innominate artery may have
2012). Bronchoscopy can be repeated 1 concomitant tracheomalacia rather than
2 years after the surgical procedure to follow pure extrinsic compression and this is
up the airway malacia evolution. particularly frequent in children with
oesophageal atresia. Symptoms tend to
Treatment and outcome
regress, at least partially, with age if
Vascular rings and slings inducing severe tracheomalacia is not associated, and
symptoms usually require prompt surgical tracheoscopy can be useful to assess the
correction. Prolonged severe vascular malacia (fig. 5b). Surgical correction,
compression of the airways is more likely to typically requiring aortopexy, is rarely
induce severe malacia of the compressed needed and is reserved for patients with
airway and interfere with the growth of the severe symptoms, such as apnoeic spells in
trachea or bronchi. In most children, the newborns or recurrent barking cough in
problem is self-limiting and eventually the older children, when the compression
cartilage regains sufficient stiffness for the decreases the tracheal lumen significantly
symptoms to resolve. This clinical (Gardella et al., 2010).
observation suggests that the surgical
procedure should be performed without Further reading
delay in symptomatic patients (Turner et al.,
2005). Children with a double aortic arch N Avni FE, et al. (2007). Evolution of fetal
usually require usually surgical correction by ultrasonography. Eur Radiol; 17: 419431.
N Elliot M, et al. (2003). The management
resection of the nondominant arch. It is
of congenital tracheal stenosis. Int J
important to assess the arch anatomy and
Pediatr Otorhinolar; 67: Suppl. 1, S183
the dominant arch before surgery because
S192.
such assessment determines the operative N Fiore AC, et al. (2005). Surgical treatment
approach. If there is an atretic portion of an of pulmonary artery sling and tracheal
arch, this is the obvious site for arch division. stenosis. Ann Thorac Surg; 79: 3846.
N Gardella C, et al. (2010). Tracheal com-
A right aortic arch with a left ligamentum
pression by aberrant innominate artery:
arteriosum and/or an aberrant left clinical presentation in infants and chil-
subclavian artery is reported even in dren, indication for surgical correction by
asymptomatic children. Relief of symptoms aortopexy, and short- and long-term out-
such as dysphagia can be achieved by come. J Pediatr Surgery; 45: 564573.
resection of the tight ligamentum N Hellinger JC, et al. (2011). Congenital
arteriosum and/or excision of the Kommerell thoracic vascular anomalies: evaluation
diverticulum. The intervention will be with state-of-the-art MR imaging and
adapted to the variant of the anomaly and is MDCT. Radiol Clin N Am; 49: 969996.
aimed at decompressing the upper portion N Kellemberg CJ (2010). Aortic arch mal-
of the gastrointestinal tract or the lower formations. Pediatr Radiol; 40: 876884.
respiratory tract (fig. 6). In pulmonary sling,

N McLaren CA, et al. (2009). Vascular N Torre M, et al. (2012). Aortopexy for the
compression of the airway in children. treatment of tracheomalacia in children:
Pediatr Respir Rev; 9: 8594. review of the literature. Italian J Pediatr;
N Russell HM, et al. (2010). Pediatric thoracic 38: 62.
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Aetiology, pathogenesis,
prevention and evidence-
based medical management
Robert I. Ross-Russell
Bronchopulmonary dysplasia (BPD) is a The disease was first described in 1967 but
chronic lung disease that affects premature the pathophysiology has changed
babies, usually following mechanical significantly since that time. Earlier
ventilation. Over the past 20 years, changes descriptions of fibroproliferation, smooth
in antenatal steroid use, surfactant therapy muscle hyperplasia and decreased
and changes in ventilator strategy have led alveolarisation have changed in the post-
to major improvements in the outcomes of surfactant era. BPD (commonly referred to
very premature infants. However, at the as new BPD) shows less regional
same time, the incidence of BPD has variability, large alveoli and characteristic
changed very little. This has meant that a vascular changes. The features
greater number of affected infants are differentiating old from new BPD are shown
surviving into childhood and beyond. These in table 1.
infants have an increased need for The National Institutes of Health (NIH)
healthcare, with frequent readmissions to diagnostic criteria for bronchopulmonary
hospital in the first 2 years and persistent dysplasia are shown in table 2. All infants
abnormalities of lung function into need to have been in room oxygen for at
adolescence and adulthood. least 4 weeks. For infants born at less than
32 weeks gestation, assessment is made at
36 weeks post-menstrual age or discharge
Key points (whichever comes first), whereas for those
infants born after 32 weeks, assessment is
N BPD remains a significant cause of made at 56 days of age or discharge.
long-term respiratory illness despite Diagnostic criteria remain an important
major advances in the care of the issue, as studies evaluating outcomes have
preterm newborns. historically used varying definitions of BPD,
making comparison difficult. For example,
N The primary pathological process is different units may administer additional
inflammation, driven through the NF- oxygen at varying levels of saturation.
kB pathway, and triggered by a variety
of genetic and environmental factors. The incidence of BPD varies with gestational
age, and particularly birth weight. Infants
N Management is directed at with a birth weight between 500 and 750 g
minimising lung insults, by limiting have a 42% chance of developing BPD
oxygen toxicity and ventilator-induced whereas in infants weighing between 1250
lung trauma. and 1500 g the chance of incidence drops to
N Drugs that may influence 4%.
development of BPD include caffeine
Aetiology and pathogenesis
and vitamin A, although new anti-
inflammatory drugs are in The primary basis of respiratory disease in
development. the preterm infant is a lack of surfactant
leading to the development of respiratory

Table 1. Pathological differences between BPD before (old) and after (new) the introduction of surfactant
Old BPD New BPD
Extensive fibroproliferation Rare proliferative changes
Airway smooth muscle hyperplasia Mild smooth muscle involvement
Areas of atelectasis and hyperinflation More homogeneous lung changes
Reduced alveolarisation Simplified, large alveoli
Pulmonary artery muscularisation Abnormal pulmonary vascularisation
distress syndrome (RDS). Surfactant human leukocyte antigen (HLA)-A2 may

production only starts at around 24 weeks predispose to the condition.
gestation and, coupled with the
underdevelopment of alveoli, gas exchange Inflammation There is no doubt that
in the extremely low birth weight infant is inflammation is a major influence on the
significantly compromised. This leads to a development of BPD. In particular, the role
need for positive-pressure ventilation and of nuclear factor (NF)-kB has been
increased oxygen administration, both of increasingly recognised as a major
which cause lung injury. These and other determinant of inflammation mediated
factors (see later) influence the development injury. NF-kB normally exists in cells bound
of the pulmonary vasculature and alveoli, within the inhibitor of NF-kB (IkB) complex,
both of which are interdependent. Factors but can be released from this by a variety of
that impair vascular growth, such as post- different mechanisms, including hyperoxia,
natal infection, will also have a detrimental trauma and infection. When released, NF-kB
effect on lung development. Endothelial forms several subunits that may each allow
growth factors such as vascular endothelial transcription of different pro-inflammatory
growth factor (VEGF)-A are critical factors mediators. Hyperoxia (through oxidative
for both vascular branching and lung stress) is known to increase expression of
development. Factors affecting expression NF-kB and has been shown to cause injury
of VEGF-A will affect lung development. to the newborn mouse lung. It also affects
Similarly conditions such as pulmonary expression of VEGF-A which directly affects
hypertension are known to worsen the both vascular and alveolar development.
outcome in BPD. Trauma will also increase NF-kB expression.
Volutrauma has been shown to increase the
However, the development of BPD in such incidence of BPD in sheep through NF-kB-
patients is quite variable and may require mediated mechanisms.
several "hits" or insults. Genetic,
inflammatory, infective and traumatic Infection Infection has long been associated
factors may all influence development of with the development of BPD. It has a direct
lung injury. Other factors, such as nutrition effect on the expression of NF-kB, but can
or fluid overload, may also influence the also stimulate inflammatory cytokines
degree of injury seen. directly. Ureaplasma infection has long been
thought to increase the risk of BPD, along
Genetics There is only limited with other genital mycobacteria. Isolation of
understanding of the genetic factors Ureaplasma from the trachea of infants has
influencing the development of BPD. It is been shown to be associated with increased
well recognised that both sex and ethnicity BPD but, more recently, Ureaplasma
can influence the incidence of BPD, and twin infection in preterm lambs has not been
studies have also shown familial shown to affect the incidence of BPD.
associations. Abnormalities in surfactant Similarly to chorioamnionitis, early reports
protein formation can lead to a greater risk of an association with BPD have been
of BPD, and there is a suggestion that followed by less clear data, and there is

Table 2. NIH criteria for the diagnosis of BPD based on gestation
,32 weeks gestation .32 weeks gestation
Mild In room air at 36 weeks post-menstrual age In room air by 56 days post-natal age
Moderate Needing ,30% oxygen at 36 weeks post- Needing ,30% oxygen at 56 days post-
menstrual age natal age
Severe Needing .30% oxygen with or without IPPV Needing .30% oxygen with or without
or CPAP at 36 weeks post-menstrual age IPPV or CPAP at 56 days post-natal age
IPPV: intermittent positive-pressure ventilation. Modified from Jobe et al. (2011).
some suggestion that the combination of Again, however, there is little evidence that
antenatal steroids and chorioamnionitis this approach will have a significant impact
may even be protective for BPD. on the incidence of BPD.
Other factors The role of nutrition in the Post-natally, there are several strategies
pathogenesis of BPD remains unclear. Poor that can help to minimise risk. In the
nutrition is associated with an increased resuscitation room there has been
incidence of BPD but equally there is no considerable interest in minimising lung
evidence that improving nutrition in these trauma and hyperoxia. Recent studies have
infants will reduce the risk of subsequent suggested that normal oxygen saturations
BPD. Tight control of fluid balance in high- in the neonate may well be lower than
risk infants may be beneficial. It is known previously thought and that initial
that infants with a patent ductus arteriosus resuscitation with air, adding in oxygen only
(PDA) have a greater risk of developing when needed, may reduce morbidity. A
subsequent BPD. At the same time, large study (SUPPORT) of 1300 babies
aggressive treatment of a PDA with fluid evaluating CPAP against surfactant, and
restriction, indomethacin or surgery has also high and low oxygen saturation,
been shown to reduce BPD, although the
showed no difference in outcomes
effect may be relatively minor.
(including death, BPD and
Prevention and management neurodevelopment); however, BOOST II
(designed to specifically consider
The ideal approach to the care of preterm oxygenation targets) was terminated early
infants would be to prevent BPD occurring. due to an increase in mortality in the lower
This either requires a reduction in premature oxygenated group. The use of noninvasive
delivery, or a method to prevent or attenuate ventilation (CPAP or noninvasive positive-
BPD in those babies who are born early. pressure ventilation (NIPPV)) has been
However this is difficult in the context of a shown to be safe in neonates and studies
disease that is so multifactorial. suggest that this, used in conjunction with
Prenatally, females who go into premature early surfactant and extubation, is as safe as
labour are routinely treated with oral conventional ventilation. However, this
steroids. It has been shown that this will approach does not result in any significant
increase lung maturity and surfactant reduction in BPD. Ventilation strategies
production and reduce the likelihood of have centred on low-volume ventilation
RDS. Disappointingly, this approach with permissive hypercapnia to minimise
appears to have little impact on the traumatic injury to the lung, and a recent
prevalence of BPD. Similarly, an aggressive Cochrane review has shown reduced deaths
approach to both antenatal and post-natal and chronic lung disease in patients treated
infection would appear to be worthwhile in with volume-targeted ventilation. The use of
view of concerns about their effect on high-frequency oscillation has not shown
inflammation and the development of BPD. any significant impact on BPD.

As suggested earlier, the use of fluid dexamethasone, hydrocortisone or inhaled
restriction may affect the development of steroids, may have significant adverse
BPD although the evidence is somewhat effects and their routine use, especially in
ambiguous. Good nutrition is also the long-term, cannot be recommended.
important as avoidance of BPD is dependent
on lung growth. Infants in the lowest The other medication that has been shown
quartile of growth develop more BPD and to have a beneficial effect on the
high calorie intake is needed for those development of BPD has been caffeine. This
infants who are fluid restricted. came as a coincidental finding in a study on
apnoea of prematurity, when it was found
In terms of drug therapy, a number of that there was a significant reduction in BPD
options have been tried. Given the central at 36 weeks gestation. The study also
role of inflammation there has been suggested that caffeine may provide some
disappointingly poor evidence of a neuroprotection as well.
protective role from anti-inflammatory
treatment. Trials with azithromycin are
Conclusion
ongoing and there may be a small effect.
Similarly, vitamin A appeared to reduce the The complex nature of BPD makes it
incidence of BPD in extremely low birth unlikely that any single approach will
weight infants, but the drug needs to be address all the problems. However, an
administered by intramuscular injection understanding of the basic inflammatory
three times a week and long-term follow-up drivers that cause lung injury will help
studies for up to 2 years following deliver strategies that minimise iatrogenic
treatment show no benefits in respiratory injury and help protect against the long-
or neurological outcome. Consequently its term respiratory morbidity that is
use is not widespread. Nitric oxide has a increasingly seen in ex-preterms.
measurable effect on oxidative stress and
alveolar development in prematurely born
animal models but the evidence in children
Further reading
remains controversial. Results from
studies to date have been ambiguous and N Bland RD (2005). Neonatal chronic lung
the 2011 NIH consensus statement disease in the post-surfactant era. Biol
concludes that current evidence does not Neonate; 88: 181191.
support the use of nitric oxide in the N Carlo WA, et al. (2010). Target ranges of
neonatal period. oxygen saturation in extremely preterm
infants. N Engl J Med; 362: 19591969.
The use of post-natal corticosteroids is also N Cole FS, et al. (2011). NIH Consensus
controversial. It has been known for some Development Conference statement:
time that dexamethasone can facilitate inhaled nitric-oxide therapy for premature
extubation and may reduce BPD, but there infants. Pediatrics; 127: 363369.
have been increasing concerns about N Doyle LW, et al. (2010). Dexamethasone
adverse effects on development. It is likely treatment after the first week of life for
that such adverse effects are more common bronchopulmonary dysplasia in preterm
infants: a systematic review. Neonatology;
in infants treated in the first week of life,
98: 289296.
where the risk/benefit ratio is high whereas
N Finer NN, et al. (2010). Early CPAP versus
the use of steroids for older children who are surfactant in extremely preterm infants. N
proving difficult to wean from ventilation Engl J Med; 362: 19701979.
may be of more value. There is renewed N Hayes D Jr, et al. (2011). Pulmonary
interest in the use of low-dose steroids function outcomes in bronchopulmonary
(dexamethasone 0.05 mg?kg-1?day-1) in this dysplasia through childhood and into
group and early work suggests that this may adulthood: implications for primary care.
be an option. Current advice, however, must Prim Care Respir J; 20: 128133.
remain that post-natal steroids, whether

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at risk for respiratory distress syndrome. dysplasia: can new insights be translated
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Nutritional care
Kajsa Bohlin
Neonatal care has undergone a dramatic interstitial fibroproliferation. Nutrition plays

development during the past decades. an important role in normal lung maturation
Survival rates, particularly for those born and development. Nutritional status may
very preterm, have increased remarkably and directly modulate lung structure as general
there are growing numbers of preterm undernutrition in humans leads to lung
survivors. Despite great progress with emphysema and, in experimental settings,
improved ventilation strategies, antenatal caloric restriction reduces alveolar number.
steroids and surfactant treatment, Thus, sufficient nutrition is necessary for
bronchopulmonary dysplasia (BPD) remains adequate lung growth and undernutrition
the most frequent adverse outcome can compromise repair of ongoing lung
following very low birth weight. However, injury. Nutritional care is therefore to be
the picture of BPD has changed from that of considered a key factor, both in prevention
ventilator-induced lung injury to the so and management of BPD.
called new BPD, characterised by
impaired lung development with reduced Growth failure and BPD
alveolarisation, dysplastic capillaries and
Many preterm infants with BPD become
growth restricted as sufficient nutrition is
often difficult to achieve. Several factors
contribute to the development of growth
Key points failure during the first year of life. Early
challenges in the neonatal intensive care
N BPD is characterised by impaired lung unit (NICU) are as follows:
growth and altered lung structure,
which may be further aggravated by N Delayed time to establish adequate intake
poor nutritional status. following delivery in the small sick infant
and frequent interruptions of enteral
N BPD is associated with increased work feeding because of feeding intolerance
of breathing and a higher resting and clinical concerns.
metabolic state; therefore, energy N Decreased nutritional intake secondary to
expenditure is high, making sufficient fluid restriction.
nutrition a challenge and growth
restriction in preterm infants with
N Dysfunction in other organ systems, such
as heart failure secondary to large patent
BPD a common problem.
ductus arteriosus, renal insufficiency or
N The nutritional challenge continues nerotising enterocolitis.
after discharge, the growth pattern of N Medications, such as methylxanthines
infants with BPD must be closely and b-sympathomimetics, may increase
monitored and, when needed, energy consumption. Post-natal steroids
nutrition should be supplemented to can impair growth and alter the
ensure adequate catch-up growth. composition of weight gain by increasing
fat and decreasing protein accretion.

Later challenges after discharge from the generally indicated in infants that are fed only
NICU are: breast milk to ensure adequate intake for
sustained growth. Analysis of breast milk
N increased energy expenditure secondary content will allow for individualised supple-
to increased work of breathing, mentation and a close collaboration with a
tachypnoea, chronic hypoxia and anaemia paediatric dietician is essential to optimise
of prematurity; nutritional management in the NICU.
N poor feeding related to swallowing
dysfunction, fatigue or gastrointestinal Fluid restrictions High fluid intake during the
reflux as well as oral aversion secondary first days of life is associated with an
to repeated negative stimuli, such as increased risk of developing BPD.
intubation and prolonged tube feeding; Administration of excessive fluid can cause
N undernutrition contributing to an pulmonary oedema through patency of the
increased risk of infections that further ductus arteriousus. Data from the National
interfere with growth. Institute of Child Health and Human
Development demonstrates a strong
In addition, dietary needs are not well correlation of higher fluid intake and lower
established in preterm infants. The post-natal weight loss during the first
fundamental principle is to provide a 10 days of life to BPD. A recent meta-
nutritional intake that meets the needs to analysis also reports an association of
ensure optimal growth and development. restricted fluid volume administration in
Compared with infants without BPD, infants preterm infants with decreased incidence of
with BPD have increased energy expenditure patent ductus and death, and a trend toward
of up to 25% above total caloric needs. This reduced risk of BPD. For preterm infants
is partly explained by increased work of with a birth weight ,1000 g or intrauterine
breathing, but also by a higher resting growth restriction, it is recommended to
metabolic state, and needs to be taken into start fluid administration at 80 mL?kg-1?day-1
account when determining target intake. on the first day of life and then increase by
Nutritional management in BPD 1020 mL?kg-1?day-1 increments to a
maintenance level of 120150 mL?kg-1?day-1.
The overall goal of the nutritional
management of very preterm infants is to Energy, protein and lipid intake As mentioned
support a rate of growth that approximates above, the energy needs of infants with BPD
the intrauterine rate of growth. This may be are higher than those of age-matched healthy
virtually impossible during the first weeks of infants. To date, there are no randomised
life and later the recommended intakes are controlled trials that examine the effects of
based on needs for maintenance and normal increased versus standard energy intake for
growth; no allowance is generally made for preterm infants with developing or
recovery or catch-up. established BPD. The European Society of
Paediatric Gastroenterology, Hepatology and
In clinical practice, very preterm infants are Nutrition (ESPGHAN) have recently
often started on parenteral nutrition and suggested that a reasonable range of energy
enteral feeding is initiated through a intake for healthy growing preterm infants is
nasogastric tube as soon as the infants 110135 kcal?kg-1?day-1. A higher caloric intake
condition is stable. Enteral nutrition may start may be beneficial for children with BPD, but
as trophic feeds of very small volumes: 5 may vary depending on respiratory status,
10 mL?kg-1?day-1. The transition from clinical condition and activity level. Strict
parenteral to full enteral feedings may take monitoring of growth and accordingly
many weeks. No specific feeding regimen has adjusted energy intake is therefore required.
been proven superior in relation to BPD.
Breast milk has benefits over formula feeding Proteins are essential for fetal growth and the
in reducing sepsis and necrotising enetero- goal of post-natal protein administration is to
colitis, but does not affect the incidence of match intrauterine growth and support
BPD. Caloric and protein supplementation is protein accretion. Early intravenous

administration of amino acids is usually well outcome was found. Taken together with the
tolerated and side-effects, such as metabolic need to administer vitamin A as
acidosis and hyperammonaemia, are rarely intramuscular injections three times a week,
seen. However, to avoid amino acid toxicity the use of vitamin A supplementation has not
the right amount of protein should be given at been widely adopted.
the right time. ESPGHAN recommends Catch-up growth and nutrition post-
aiming toward a higher intake for infants discharge
weighing f1000 g (4.04.5 g
protein?kg-1?day-1) and less for infants Despite good efforts, many preterm infants
weighing 10001800 g (3.54.0 g with BPD will grow poorly and accrue
protein?kg-1?day-1). If the growth pattern of the nutritional deficits during their long hospital
infants is adequate, with signs of catch-up stay. Malnutrition leads to reduced brain
growth, protein intake can be reduced size and impaired neurodevelopmental
towards discharge. outcome. A clear relationship exists between
catch-up growth and development, but the
Lipids are necessary to provide energy, time frame within which it needs to occur is
essential fatty acids and improve not well delineated. There is a concern that
bioavailability of fat-soluble vitamins. rapid growth will lead to later development
Moreover, lipid administration limits the of insulin resistance and obesity. The
metabolic conversion of carbohydrates to challenge is to ensure not only weight gain,
lipids, thereby decreasing carbon dioxide but lean mass accretion. Mature human
production, which might be important in breast milk is designed to meet the needs of
BPD. However, the role of lipid the term infant and may not suffice for
administration in the development of BPD catch-up growth of the preterm infant.
remains controversial. The current practice of Therefore, all growth parameters, including
most centres is to initiate lipids at 0.5 length and head circumference, should be
1 g?kg-1?day-1 by the second day of life and closely monitored during the first year of life,
advance by increments of 0.5 to 1 g?kg-1?day-1 preferably in specialist clinics as part of a
up to 34 g?kg-1?day-1. However, ESPGHAN standardised follow-up programme after
states that a reasonable range for most prematurity. In infants with pathological
preterm infants is 4.86.6 g fat?kg-1?day-1, growth patterns, fortification of the breast
corresponding to 4055% of energy intake. milk or supplementation with nutrient-
enriched formula should be considered to
Electrolytes and vitamins Infants with BPD
promote healthy development.
are often treated with diuretics to counteract
a tendency to accumulate interstitial lung
fluid. This, in combination with renal Further reading
immaturity, makes them susceptible to
N Agostoni C, et al. (2010). Enteral nutrient
sodium, potassium and chloride depletion
supply for preterm infants: commentary
and at increased risk for disturbed bone
from the European Society for Paediatric
mineralisation. Calcium, phosphate and Gastroenterology, Hepatology, and
alkaline phosphatase must be closely Nutrition Committee on Nutrition.
monitored and supplementation of vitamin J Pediatr Gastroenterol Nutr; 50: 8591.
D, calcium and phosphate provided through N Biniwale MA, et al. (2006). The role of
premature formula or fortified breast milk. nutrition in the prevention and manage-
ment of bronchopulmonary dysplasia.
Vitamin A is an important antioxidant as well Semin Perinatol; 30: 200208.
as a key nutrient in maintaining lung N Cooke RJ (2011). Nutrition of preterm
epithelial cell integrity. In a recent meta- infants after discharge. Ann Nutr Metab;
analysis, vitamin A has been shown to reduce 58: 3236.
the incidence of death or BPD. The number N Dani C, et al. (2012). Nutrition and
needed to treat was 12 to 13 infants to prevent bronchopulmonary dysplasia. J Maternal
one case of BPD and no long-term positive Fetal Neonatal Med; 25: 3740.
effect on respiratory or neurodevelopmental

Neurodevelopmental
assessment and outcomes
Charles C. Roehr, Lex W. Doyle and Peter G. Davis
The aim of this chapter is to review the with BPD show characteristic radiographic
neurodevelopmental outcome of preterm changes (fig. 1).
infants with bronchopulmonary dysplasia
The clinico-pathological problem of BPD
(BPD). We discuss the influence of neonatal
Despite the many advances, very preterm
intensive care on the development of
infants (defined as ,32 weeks of gestation)
chronic lung disease and neurological
still suffer from BPD, leading to long-term
development in preterm infants.
respiratory morbidity and oxygen
Mechanical ventilation (MV) and its adverse dependency. Sadly, this morbidity is also
effects on the lungs found in survivors of preterm birth who have
never been given MV. Our understanding of
Advances in respiratory support of the preterm the underlying pathophysiology of BPD has
neonate The widespread use of antenatal changed. It is thought that affected infants
corticosteroids and the introduction of with BPD now primarily suffer from a
exogenous surfactant replacement therapy, maturational arrest of alveolar
together with gentler MV, have led to better differentiation (fig. 2).
outcomes for preterm infants. Alongside
these improvements came a change in Classification, incidence and disease burden of
characteristics of NICU patients. Whilst BPD According to the National Institutes of
most NICU patients in the 1960s were more Health consensus definition, BPD is graded as
than 32 weeks of gestation and weighed mild, moderate or severe on the basis of
.1500 g at birth, treatment is now offered oxygen requirements at 28 days and 36 weeks
to many infants ,25 weeks of gestation and of corrected age. Despite many improvements
with a birth weight ,500 g. Lungs of infants in care, BPD still affects approximately 20
40% of very preterm infants. Infants with BPD
are known to have a higher disease burden
than their non-BPD preterm peers. Even after
Key points
initial discharge, they require more adjunct
therapy and have more hospital readmissions
N BPD is a distinct disease entity of in the first 2 years of life.
survivors of preterm birth.
Impact of premature birth and intensive
N The prevalence of BPD among
care treatment on neurodevelopmental
survivors of very preterm birth is
outcome
2040%.
N BPD is associated with a risk for Effects of preterm birth and NICU admission
significant neurodevelopmental delay. on health The disruptive environment of
NICUs per se results in poorer growth and
N Compared with non-BPD peers, impaired neurosensory development.
infants with BPD may exhibit poorer According to a recent meta-analysis, the
academic achievements and impaired incidence of developmental delay or learning
emotional and physical development. difficulties in very preterm infants is 60%,
cerebral palsy is 27%, impaired vision or

Figure 2. A 1-year-old child with severe BPD
receiving respiratory support.
intensity of treatment and will therefore be

at increased risk for iatrogenic effects of
Figure 1. Chest radiograph of a ventilated infant treatment. The post-natal administration of
with severe BPD. corticosteroids has been linked to poorer
neurological outcome, as well as repeated
blindness is 11%, gross motor and fluctuations in arterial oxygen concentration
coordination deficits is 10%, and deafness is and apnoea and bradycardia, both of which
7%. Preterm infants, compared with term- are commonly found in BPD infants.
born infants, are more likely to: Testing the hypothesis that diagnosis of BPD
predicts negative neurological outcome To test
N have poorer overall academic the hypothesis that BPD, defined as
achievement; requirement of supplemental oxygen at
N exhibit specific challenges in 36 weeks of corrected age, predicted poor
mathematical abilities and social neurological outcome, Davis et al. (2002)
relationships; analysed data from 945 preterm infants born
N have impaired emotional and physical with birth weights ,1000 g. The authors
development. found poor neurosensory outcome at follow-
up in 34% of infants. Of these, 77% suffered
In general, the rate of developmental delay cognitive delay, 37% cerebral palsy, 5%
increases with falling gestational age. blindness and 7% severe hearing
Bassler et al. (2009) used severity of illness impairment. However, this definition of BPD
as a predictor of neonatal outcome and had a sensitivity of only 45% for predicting
established that a count of three neonatal poor neurodevelopmental outcomes, and an
morbidities (BPD, brain injury and severe overall accuracy of 63%.
retinopathy of prematurity) strongly predicts
the risk of death or neurosensory Long-term studies on neurodevelopmental
impairment in extremely low birth weight outcome in infants with BPD Long-term
infants. Male sex is increasingly recognised neurodevelopmental impairment can affect:
as a predictor for poor outcome following
prenatal birth. N cognitive development (including visual
spatial perception);
Additive effect of BPD on neurological N hearing;
outcome N speech and language development;
N memory and learning capacity;
Preterm birth and BPD Preterm infants with N gross and fine motor function.
BPD are likely to have been sicker than non-
BPD infants whilst in the NICU. They are The Victorian Infant Collaborative Study
likely to have been subjected to a higher Group has studied large geographical cohorts

of preterm infants since 1979. Data from Further reading
these studies and those of other groups
N Bassler D, et al. (2009). Using a count of
indicate that preterm infants with BPD have
neonatal morbidities to predict poor
poorer outcomes than their non-BPD peers
outcome in extremely low birth weight
infants: added role of neonatal infection.
Prevalence of specific neurological
Pediatrics; 123: 313318.
impairments For general cognitive function,
N Davis PG, et al. (2002). Evaluating
results from different studies suggest that "old" definitions for the "new" broncho-
BPD infants were rated 0.250.66 standard pulmonary dysplasia. J Pediatr; 140:
deviations lower for IQ than their non-BPD 555560.
peers. For behaviour, the rate of attention N Davis PG, et al. (2009). Non-invasive
deficit was 59% for BPD infants compared respiratory support of preterm neonates
with 32% for non-BPD infants. Preterm with respiratory distress: continuous
survivors with BPD performed between 0.51 positive airway pressure and nasal inter-
standard deviations below very low birth mittent positive pressure ventilation.
weight infants (birth weight ,1500 g) Semin Fetal Neonatal Med; 14: 1420.
without BPD or term controls on tests of N Doyle LW, et al. (2004). Neonatal inten-
reading and mathematics. Poor memory sive care at borderline viability is it
worth it? Early Hum Dev; 80: 103113.
performance was significantly more common
N Doyle LW, et al. (2009). Long-term out-
in BPD infants (65%) compared with 29% in
comes of bronchopulmonary dysplasia.
a non-BPD group, and language skills at Semin Fetal Neonatal Med; 14: 391395.
preschool and school age were found to be N Gregoire MC, et al. (1998). Health and
significantly delayed in BPD infants developmental outcomes at 18 months in
compared with non-BPD controls. 49% of the very preterm infants with broncho-
BPD infants tested at preschool age showed pulmonary dysplasia. Pediatrics; 101:
significantly delayed receptive language 856860.
development, and 43% had significantly N Jobe AH (2011). The new bronchopul-
delayed expressive language development. monary dysplasia. Curr Opin Pediatr; 23:
167172.
Conclusion N Morley CJ (2012). Volume-limited and
volume-targeted ventilation. Clin
Preterm birth is strongly associated with Perinatol; 39: 513512.
abnormal neurodevelopmental outcome. N Mwaniki MK, et al. (2012). Long-term
Preterm infants with BPD suffer from poorer neurodevelopmental outcomes after
health and worse neurological outcome than intrauterine and neonatal insults: a sys-
their non-BPD peers. However, the tematic review. Lancet; 379: 445452.
diagnosis of BPD, given at the age of N Peacock JL, et al. (2012). Neonatal and
infant outcome in boys and girls born
36 weeks of corrected gestation, is not a
very prematurely. Pediatr Res; 71: 305310.
highly sensitive predictive measure for
N Saigal S, et al. (2008). An overview of
negative neurological outcome. The mortality and sequelae of preterm birth
increasing survival rates of very preterm from infancy to adulthood. Lancet; 371:
infants and concurrent numbers of children 261269.
with BPD will lead to more children with N Victorian Infant Collaborative Study
neurological problems. Therefore, reducing (VICS). www.vics-infantstudy.org.au Date
the rate of BPD will remain one of the last accessed: December 12, 2012.
biggest challenges in neonatal care.

Long-term respiratory
outcomes
Manuela Fortuna, Marco Filippone and Eugenio Baraldi
Chronic lung disease of infancy (CLDI)

comprises a heterogeneous group of Key points
diseases that evolve as a consequence of a
neonatal respiratory disorder. The most N Survivors of extreme prematurity, and
common form of CLDI is those with BPD in particular,
bronchopulmonary dysplasia (BPD). Due to experience high rates of respiratory
the marked decline in mortality among very symptoms (mainly cough and
immature, extremely low birth weight wheeze) and hospital readmission in
infants in recent decades, there are the early years of life.
increasing numbers of children and adults N Into mid-childhood and adolescence,
who have survived BPD. This means that clinical symptoms become milder and
not only paediatricians, but also adult less frequent, but spirometric studies
physicians, will have to deal more and more show that many of those born very
often with the sequelae. Today, BPD is prematurely have scarcely reversible
defined as the need for supplemental airflow obstruction (mean FEV1 70
oxygen for at least 28 days after birth, and 80% predicted).
its severity is graded according to the
respiratory support required near term. N Although BPD survivors frequently
suffer from asthma-like symptoms,
An important effort has been made to BPD and asthma are distinct clinical
characterise the extent of pulmonary disease entities resulting from different
and assess lung function in infants and pathogenic mechanisms and caution
children born prematurely, generating is needed when recommending
considerable information on the pulmonary asthma treatments to BPD patients.
outcome of BPD into adolescence.
N Due to the natural age-related decline
Less is known about the respiratory health of in respiratory function, it is reasonable
adult survivors of BPD, since few studies are to expect a phenotype resembling
available on this topic. The available data are COPD to develop in some survivors of
based mainly on cohorts born in the late BPD, so these patients should be
1970s and/or 1980s, and often include cases followed up into adulthood and efforts
of old BPD, i.e. patients born before the should be made to prevent them from
introduction of exogenous surfactant and smoking.
antenatal corticosteroids, who usually
required prolonged mechanical ventilation.
Acute lung injury (causing airway
inflammation, bronchial smooth muscle of BPD, which include much more
hypertrophy, emphysema and parenchymal immature, smaller newborns, who are
fibrosis) has a major role in the resulting treated very differently (with less ventilatory
chronic lung disease in such patients, so support). This latter type of so-called new
their functional outcome is not fully BPD is a developmental disease of the
comparable with that of more recent cases terminal airspaces, characterised mainly by

impaired alveolarisation. Although use inhaled asthma medication more
symptoms in the newborn are usually milder frequently than term-born controls.
than those of the old form of BPD, whether
or not patients with this new BPD will Into adolescence, symptoms progressively
ultimately have better respiratory outcomes subside in survivors of BPD too, and most
remains to be seen. of them lead apparently normal lives. The
relationship between clinical symptoms and
Morbidity associated with BPD lung function fades, and even patients with
severe airway obstruction detected by
Infants with BPD may require oxygen spirometry may not have any clinically
supplementation on discharge from significant respiratory symptoms.
neonatal intensive care units. However, very
few remain oxygen dependent beyond 1 year Data on adult respiratory health are limited
of age, reflecting some lung growth. and refer mainly to cases of old BPD in
patients studied in their twenties. These
Upper airway problems (laryngo-tracheal patients seem to complain of more
stenosis, laryngomalacia, tracheomalacia respiratory symptoms (especially shortness
and unilateral vocal cord paralysis) resulting of breath and wheezing on exertion) than
from prolonged or reiterated intubation can healthy controls. The same may not fully
worsen the respiratory course of infants with apply to new BPD cases, however, so a long-
BPD, although the incidence of the more term follow-up of well-characterised cohorts
severe forms of stenosis requiring of children born in the post-surfactant era is
tracheostomy has fortunately declined in the needed to ascertain the respiratory outcome
last decade. after new BPD.
In the first 2 years after birth, infants born Pulmonary arterial hypertension associated
before 33 weeks of gestational age, and with stabilised BPD
survivors of BPD in particular, are very
susceptible to respiratory exacerbations, The clinical course of extremely preterm
with higher rates of recurrent wheezing than infants with BPD can be made worse by
in children born at term. Hospital concomitant pulmonary arterial
readmissions for complications of hypertension (PAH), defined as a mean
respiratory tract infections are also frequent pulmonary artery pressure (Ppa) .25 mmHg
(up to 40% in the first 12 years), with a at rest (measured by cardiac
relevant burden of disease for patients, catheterisation), or an estimated systolic Ppa
parents and the healthcare system. Strict .40 mmHg on echocardiography. PAH
measures to prevent viral infections (e.g. arises from the combination of an altered
prophylaxis against respiratory syncytial vascular development (normal lung
virus with monoclonal antibodies) and to angiogenesis is disrupted by premature
avoid adverse environmental factors (e.g. birth), function (hypoxia-related increases in
passive smoking) are of the utmost vascular tone and reactivity) and structure
importance in this population. (vascular remodelling with smooth muscle
cell proliferation). Although the true
Although respiratory symptoms (cough and prevalence of PAH in infants with stabilised
wheeze) are very common at preschool age, BPD is unknown, it has ranged between 17%
the clinical condition of BPD survivors and 25% in individual studies. Sustained
generally improves with time and their and severe PAH, and the resulting cor
respiratory symptoms become less severe. pulmonale are linked to high mortality rates
By mid-childhood, respiratory exacerbations in infancy (up to 40%), so it is very
become less frequent. During their years of important to detect PAH, not only for the
schooling, most of these children appear to purpose of prognostic considerations, but
live normally, although they experience more also to ensure an appropriate treatment.
chronic coughing and wheezing (and other Echocardiography is recommended as the
asthma-like symptoms), and they need to main screening tool and should be

performed in BPD infants whose clinical N areas of reduced lung attenuation (due to
course is atypical (with high or increasing small airway obstructions leading to
oxygen needs, recurrent cyanotic episodes obstructive emphysema);
and/or a poor growth rate), arousing the N linear and triangular opacities (due to
suspicion of underlying PAH. Cardiac strands of atelectasis extending to the
catheterisation can assess the severity of pleura);
PAH more precisely, but it is usually N multifocal emphysema;
performed only in the more severe cases, N bronchial wall thickening;
when vasodilators other than oxygen (such N bullae and air trapping on expiratory
as phosphodiesterase-5 inhibitors or scanning.
endothelin receptor antagonists) are
needed. Long-term supplemental oxygen These pathological features are more
therapy with a target oxygen saturation in pronounced in cases previously diagnosed
the range of 9195% is considered the with BPD. Some validated scoring systems
standard treatment for PAH associated with are available for assessing the extent of
BPD, because it may reduce pulmonary these structural abnormalities on HRCT;
vascular resistance. Patients should be interestingly, a correlation has recently been
weaned off supplemental oxygen only reported between HRCT scores, duration of
gradually, and monitoring Ppa with serial neonatal oxygen exposure and FEV1 values
echocardiography after it has been in a cohort of children and adolescents
discontinued is mandatory, because the Ppa in surviving extremely preterm birth.
these patients may remain persistently higher
than normal in the early years of life despite Radionuclide imaging is not usually part of
their clinical improvement. By the time they the assessment of BPD patients, but it has
reach school age, pulmonary vascular the potential to add additional information
resistance and Ppa appear to return to normal about lung function. Single photon emission
in survivors, although pulmonary vascular CT has recently been used to assess regional
reactivity to hypoxia may persist into distribution of lung ventilation (V9) and
adolescence and adulthood. A tailored cardiac perfusion (Q9) in a cohort of 30 BPD
and echocardiographic follow-up should then preterm infants at a median post-menstrual
be assured for selected BPD survivors. age of 37 weeks. Interestingly, in this study a
significant proportion of BPD infants (40%)
Long-term imaging anomalies in BPD had an abnormal V9/Q9 distribution, and a
patients correlation between V9/Q9 mismatch and
time spent on mechanical ventilation was
The radiographic pulmonary findings in
detectable.
survivors of BPD have changed. Traditional
chest radiograph findings in survivors of old Lung function studies in BPD patients
BPD during their childhood include fibrosis,
patchy atelectasis and emphysema. Findings Analysing forced expiratory flows (obtained
in new BPD are milder, with the chest with forced expiratory manoeuvres) reveals
radiograph picture improving over time. The substantial airflow limitation in BPD
sensitivity of radiography in diagnosing survivors during the first 3 years of life, with
minor lung abnormalities is limited, no significant improvements on serial
however. Although HRCT of the chest is not measurements. The degree of airflow
performed routinely in BPD survivors, it can limitation in the early years of life seems to
detect abnormalities in up to 80% of predict pulmonary function later on: in a
survivors of extreme prematurity and small group of BPD survivors followed from
provides important information on the birth, forced expiratory flow at 2 years of age
airways and parenchymal structural correlated closely with FEV1 at 8 years of
changes. Significant findings in children and age, indicating a tracking of lung function
adolescents surviving extremely preterm over time and a negligible catch-up in
birth include: lung growth. This finding is suggestive of an

irreversible early airway remodelling of the predicted value, and the well-known
process. natural decline in respiratory reserves with
ageing could mean that these individuals
Spirometric studies have often been used reach a critical threshold for significant
for cross-sectional assessments of lung respiratory symptoms in mid-adulthood.
function in school-age and older BPD Given the lack of longitudinal studies into
survivors. Their findings often refer to adulthood on survivors of prematurity and/
heterogeneous cohorts recruited mainly or BPD, we still do not know whether their
among patients born in the pre-surfactant natural age-related rate of decline in
era, and clearly indicate that BPD children of respiratory function will be normal or
all ages have a significant airflow accelerated, but it is reasonable to expect a
obstruction (generally achieving mean FEV1 new phenotype resembling COPD, but
values between 70% and 80% of the related to premature delivery, to emerge
expected levels) that proves scarcely over the coming years. This risk emphasises
reversible. Patients born prematurely but not the need to follow up BPD survivors into
developing BPD usually fare better, but they adulthood, and to minimise their exposure
too have airflow limitation at school age and to risk factors associated with a faster
later. It is worth noting that recent cohort decline of lung function, such as cigarette
studies on children born extremely smoking.
prematurely in the post-surfactant era report
airflow limitations throughout their years of Other major lung function anomalies
schooling. These studies found a clearly reported in survivors of BPD during their
detectable trend toward an obstructive childhood and adolescence include a higher
spirometric pattern even in very low birth residual volume and a higher residual
weight children who did not develop BPD, volume to TLC ratio, probably due to air
raising concern that premature birth may per trapping. Exercise capacity (e.g. maximal
se impair lung maturation and growth, with oxygen consumption) is also slightly
life-long detrimental effects on pulmonary reduced, and gas exchange (e.g. TLCO) is
function. The benefits associated with better impaired in BPD children. Finally, a
perinatal care may, therefore, be partially significant airway hyperresponsiveness (to
masked by the gradual improvement in the histamine, methacholine or physical
survival rates for the most immature infants. exercise) is detectable in BPD survivors,
These preliminary findings also emphasise although the mechanism(s) behind it is not
the need to develop novel therapies to yet clear.
reduce the long-term pulmonary effects of
extremely premature delivery. Airflow obstruction and asthma-like
symptoms in BPD patients
Only a few studies have been designed to
provide longitudinal lung function data at The real nature of the airflow limitation
multiple time-points in children with a detected in survivors of prematurity and
history of BPD. Data from some of them BPD has yet to be fully elucidated and
indicate that lung function may deteriorate morphologically characterised, since no
throughout childhood and adolescence in information is available on lung pathology in
the more severe cases, suggesting that BPD patients beyond infancy. Airway
some forms of BPD may be progressive in obstruction has often been interpreted as
nature. the result of stable, not progressive,
structural changes in the airways coupled
Persistent airway obstruction with a with a poor or dysmorphic alveolar growth.
significantly lower FEV1/FVC ratio and a In the new form of BPD, in particular,
forced expiratory flow at 2575% of FVC hypoalveolarisation would reduce the
(FEF2575%) than controls is also number of alveolar attachments per airway,
characteristic of BPD survivors in their prompting a more limited airway
twenties. In young adults, a history of BPD is parenchymal coupling and predisposing to
often associated with a maximal FEV1 ,80% airflow obstruction. A relevant question is

whether the long-term pulmonary have been no randomised controlled trials
consequences of prematurity and BPD on these drugs for the treatment of BPD.
depend only on a non-progressive reduction
in airway calibre due to a stabilised airway In conclusion, given the absence of
disease, or whether they also reflect an morphological information and randomised
ongoing active airway disease. A recent therapeutic trials, the pathogenesis of long-
report of higher concentrations of 8- term obstructive symptoms in survivors of
isoprostane (a reliable biomarker of prematurity remains elusive and their
oxidative stress in vivo) in the exhaled breath treatment empirical.
condensate of adolescents born preterm in
comparison with healthy controls born at Further reading
term suggests an ongoing oxidative stress in
the airways of survivors of prematurity. This N Allen J, et al. (2003). Statement on the
issue is important and warrants further care of the child with chronic lung disease
investigation because the presence of of infancy and childhood. Am J Respir Crit
Care Med; 168: 356396.
ongoing airway disease would point to a
N Baraldi E, et al. (2007). Chronic lung
greater risk of an accelerated age-related
disease after premature birth. N Engl J
decline in lung function; however, it opens Med; 357: 19461955.
up the possibility of an active treatment with N Doyle LW, et al. (2006). Broncho-
antioxidants. pulmonary dysplasia in very low birth
Respiratory symptoms and the obstructive weight subjects and lung function in late
adolescence. Pediatrics; 118: 108113.
spirometric pattern encountered in BPD
N Fawke J, et al. (2010). Lung function and
patients are often labelled as asthma, but
respiratory symptoms at 11 years in
caution is needed in dealing with this children born extremely preterm. Am J
problem. Airflow obstruction in BPD Respir Crit Care Med; 182: 237245.
patients is only partially reversed by b2- N Fibrun AG, et al. (2011). Longitudinal
agonists, suggesting a stable remodelled measures of lung function in infants with
airway condition. Moreover, in BPD bronchopulmonary dysplasia. Pediatr
patients, unlike asthma sufferers, there is no Pulmonol; 46: 369375.
evidence of eosinophil-driven airway N Filippone M, et al. (2009). Childhood
inflammation; in fact, exhaled nitric oxide (a course of lung function in survivors of
biomarker of eosinophilic inflammation and bronchopulmonary dysplasia. JAMA; 302:
response to corticosteroid therapy) is 14181420.
reportedly low in BPD survivors. HRCT N Filippone M, et al. (2012). Evidence of
studies have also documented unexpected oxidative stress in airways of
morphological differences in the lungs adolescents born very pre-term. Eur Respir J;
between children with asthma and cases of 40: 12531259.
BPD. Although airway wall thickening and N Gough A, et al. (2012). General and
areas of low attenuation may be seen in both respiratory health outcomes in adult
diseases, scattered parenchymal fibrosis survivors of bronchopulmonary dysplasia.
Chest; 141: 15541567.
(linear opacities facing triangular subpleural
N Kjellberg M, et al. Bronchopulmonary
opacities) and architectural distortion are
dysplasia: clinical grading in relation to
common findings in survivors of BPD but ventilation/perfusion mismatch measure
unusual in children with asthma. Finally, by single photon emission computed
individuals with a history of BPD do not tomography. Pediatr Pulmonol 2013 [in
have a higher than normal prevalence of press DOI: 10.1002/ppul.22751].
atopy (a major risk factor for childhood N Narang I, et al. (2006). Airway function
asthma). So, asthma and BPD are distinct measurement and the long-term follow-
clinical entities resulting from different up of survivors of preterm birth with and
pathogenic mechanisms, and care should be without chronic lung disease. Pediatr
taken when treating BPD children with Pulmonol; 41: 497508.
inhaled asthma medication because there

Pleural effusion, chylothorax,
haemothorax and
mediastinitis
Juan Anton-Pacheco, Carmen Luna-Paredes and Antonio Martinez-Gimeno
Pleural effusion Clinical picture There are two usual patterns

of presentation. In the first, the child has
The pleural space normally contains 0.3 mL classic symptoms of pneumonia (fever,
per kg body weight of pleural fluid. cough, breathlessness, abdominal pain and
Lymphatic vessels can cope with several malaise) but they are usually more unwell
hundred millilitres of extra fluid per 24 h. An than those with simple pneumonia alone,
imbalance between pleural fluid formation with pleuritic chest pain and even cyanosis.
and drainage will result in a pleural effusion. In the other clinical presentation, the child
In a previously well child, pleural effusions has been diagnosed with pneumonia but
are usually secondary to acute bacterial does not respond to 48 h of an appropriate
pneumonia and less often due to chronic treatment. On examination, a pleural
infection such as pulmonary TB. Other effusion is suggested by unilateral signs of
causes usually considered in adults, such as decreased chest expansion and dullness to
malignancies, cardiovascular diseases, or percussion, reduced or absent breath
systemic inflammatory conditions, are sounds, and scoliosis.
uncommon in children.
Diagnosis Contrary to community-acquired
pneumonia (CAP), which may be diagnosed
on clinical grounds only, the diagnosis of
Key points parapneumonic pleural effusion requires an
imaging technique to demonstrate the
N All children with parapneumonic presence of fluid in the pleural space. The
pleural effusion or empyema should first imaging technique should be a
be admitted to hospital and managed posteroanterior chest radiograph. The
following local or national guidelines. earliest sign of a pleural effusion is
obliteration of the costophrenic angle. A rim
N Intravenous antibiotics and careful of fluid may be seen ascending the lateral
consideration of pleural drainage chest wall (meniscus sign). If the film is
procedures are the most important taken in a supine position, the appearance
aspects of parapneumonic effusion/ can be of a homogeneous increase in
empyema management. opacity over the whole lung field without
N Chylothorax is a rare condition in blunting the costophrenic angle, or a classic
children usually caused by injury to pleural-based shadow. A lateral chest
the thoracic duct; simple chest radiograph rarely adds anything extra and
drainage and dietary modifications should not be routinely obtained.
are the mainstay of treatment.
Once pleural effusion has been diagnosed or
N When haemothorax is diagnosed, suspected by a chest radiograph, chest
blood should be promptly drained ultrasonography should be obtained to
from the pleural cavity with a chest confirm the diagnosis, estimate the size of
tube. the effusion, differentiate between free and
loculated pleural fluid and determine its

local threshold, usually 9294%), fluid
therapy if the child is dehydrated or unable/
unwilling to drink, pain control and
antipyretics.
Intravenous empirical antibiotic treatment

should begin as soon as possible. In the
most common setting of a pleural effusion
arising from CAP, empirical treatment must
cover Streptococcus pneumoniae, S. pyogenes
and Staphylococcus aureus. In most cases,
cefotaxime (150 mg?kg-1?dose-1), co-
amoxiclav or cefuroxime are appropriate.
Penicillin allergic patients can be treated
with clindamycin alone. If pneumatoceles
Figure 1. Chest ultrasound showing a loculated are evident, anti-staphylococcal cover is
pleural effusion. mandatory (cloxaciline or flucoxaciline).
However, in cases of hospital-acquired
pneumonia or following surgery, trauma or
echogenicity (fig. 1). It may also be used to aspiration, broader spectrum agents should
guide chest drain insertion or thoracentesis. be used to cover aerobic Gram-negative
rods.
Chest CT scans involve radiation exposure
that can be equivalent to 20400 chest Further blood diagnostic tests should be
radiographs depending on technical factors obtained after diagnosis and before starting
and should not be performed routinely. It antibiotic therapy: full blood count (for
may have a role in complicated cases, anaemia, white cell count with differential
including immunocompromised children and platelet count), electrolytes (to detect
where a CT scan can detect airway or inappropriate anti-diuretic hormone
parenchymal lung abnormalities, such as syndrome), C-reactive protein or other
endobronchial obstruction or a lung acute-phase reactants and blood culture,
abscess, or before surgery to delineate the including anaerobic bottle. If available,
anatomy. sputum culture can also be useful.
Management Once the diagnosis of An important issue is whether to insert a

parapneumonic effusion has been pleural drain or not. It is generally accepted
established, the decisions on additional that isolated pleural taps for diagnostic
diagnostic tests and therapeutic purposes are not recommended in children
interventions should be conducted by with a small, uncomplicated parapneumonic
following local guidelines. Several national pleural effusion, except if there are any
scientific societies have published their own atypical features suggesting the presence of
guidelines and every paediatric centre malignancy, such as the absence of acute
treating children with pleural effusions fever or pneumonia and evidence of an
should have their own protocol adapted to underlying mediastinal mass or
local circumstances. lymphadenopathy. In these uncommon
situations it is important to remember that
All children with parapneumonic effusion large volume aspiration and general
should be admitted to hospital. Initial anaesthesia pose a significant risk of
treatment should focus on general sudden death in children with superior
supportive measures and prompt mediastinal obstruction due to malignancy,
intravenous antibiotic administration. therefore, the volume of aspirated pleural
General measures include assessing the fluid should be small (5 mL) and general
need of supplemental oxygen (SpO2 below anaesthesia should be avoided.

Indications for pleural drain vary in different All chest tubes should be connected to a
guidelines. As a general rule, there is a good unidirectional flow drainage system with an
deal of evidence suggesting that a pleural underwater seal, which must be kept below
drain is not always necessary and that the level of the patients chest at all times.
antibiotics alone can be enough to provide The indications for suction are unclear in the
excellent clinical outcomes when there is not management of pleural effusion but it is
a clear indication for chest drainage. Tube commonly believed that it improves
thoracostomy must be performed if the child drainage. A low suction pressure (5
is in respiratory distress due to lung 10 cmH2O) is usually applied in the
compression by the pleural effusion, or if underwater seal, and it is acceptable to stop
toxic appearance and sepsis is suspected. It suction for short periods (such as for
also may be considered if the effusion size is radiographs or mobilisation). Regular
large (definitions vary from 10 mm flushing of small bore drains to prevent
thickness in ultrasonography or radiography blockage has been recommended. Patients
to one-third of the hemithorax in with chest drains do not need to remain in
radiography) or is enlarging, and the child is the PICU for only this reason and they can
not responding after 48 h of antibiotic be managed on a ward by staff trained in
treatment. chest drain management.
The role of intrapleural fibrinolytics in the
Pleural drainage is rarely an emergency
management of parapneumonic pleural
procedure and must be carefully planned
effusion is not completely clear. Only two
and performed in the most appropriate
fibrinolytics are currently available in most
setting by trained personnel, according to
European countries (urokinase and
local guidelines. Two types of chest drains
alteplase) but only urokinase has been
are usually used. Paediatric surgeons usually
studied in a double-blind placebo-controlled
prefer large bore chest tubes (around 20 FG)
randomised clinical trial in children,
surgically inserted in the operating theatre showing a significantly shorter hospital stay
with general anaesthesia and paravertebral (7.4 versus 9.5 days) compared with placebo.
block with local anaesthetics to provide Urokinase should be given twice daily for
post-operative pain relief. Respiratory 3 days (six doses in total) using 40 000
paediatricians, paediatric intensivists and units in 40 mL 0.9% saline for children aged
interventional paediatric radiologists usually o1 year, and 10 000 units in 10 mL 0.9%
prefer smaller drains (around 10 FG), saline for children aged ,1 year. The
including pigtail catheters, inserted by the summary of product characteristics of
Seldinger technique in paediatric intensive alteplase does not include approval for
care units (PICU) or interventional radiology empyema in adults or children, and only
rooms, with general anaesthesia or case-series have been published.
sedation. These two options are both
appropriate and have the same outcomes, The drain should be removed when there is
so the choice depends on local clinical resolution. An obstructed drain that
circumstances. The drain should be inserted cannot be unblocked should be removed
by well-trained personnel, or trainees under too, but replaced if significant pleural fluid
expert supervision, to minimise the risk of remains. Pain control is extremely important
complications. Ultrasonography guiding is during the time in which the chest drain
mandatory and the appropriate site for chest remains in place.
tube insertion should be marked with an X Another pleural drainage method to be
when this test is being performed. Pleural considered is surgery. Three surgical
fluid must be obtained during the procedure methods are available.
and sent for microbiological and
cytochemical tests, including Gram staining, N Video-assisted thoracoscopic surgery
culture for standard pathogens and (VATS), which achieves debridement of
mycobacteria, PCR, glucose and pH. fibrinous pyogenic material, breakdown

of loculations and drainage of pus from usually caused by an injury to the thoracic
the pleural cavity under direct vision, duct during surgery. The thoracic duct
leaving two or three small scars. collects lymph from the abdomen, lower
N Mini-thoracotomy, which procures limbs, left thorax, head, neck and upper
debridement and evacuation in a similar limbs. Disruption of the duct between the
way to VATS but as it is an open diaphragm and T5 usually yields chylothorax
procedure leaves a small linear scar. on the right side, while a left-sided
N Decortication, which involves an open chylothorax can be seen when damage
posterolateral thoracotomy and excision occurs above T5.
of the thick fibrous pleural rind with
evacuation of pyogenic material. Aetiology Most cases of chylothorax in
children are acquired and of iatrogenic
Early VATS should be considered an origin. According to some studies,
alternative to tube thoracostomy, with or cardiothoracic surgery accounts for 6580%
without fibrinolytics, when a loculated of all paediatric chylous effusions.
effusion is present and its use will largely Congenital presentation represents only a
depend on local availability and expertise. It small percentage in the paediatric age
seems to offer the same clinical outcomes group, although it is the most common type
compared to simple chest tube drainage. of pleural effusion in the neonatal period
Mini-thoracotomy should be reserved for (table 1).
more complex cases, and decortication
should be performed only in symptomatic Diagnosis Antenatal chylothorax can lead to
children with organised empyema not restriction of normal lung development and
responding to previous treatment or in cause lung hypoplasia. For this reason,
cases of lung entrapment. severe respiratory distress can be present in
some cases of congenital chylothorax.
Intravenous antibiotic treatment should Respiratory symptoms depend on the size of
continue until the child is afebrile or the the effusion and most patients will show
chest drain is removed. Oral antibiotics, varying degrees of dyspnoea, cough or chest
such as co-amoxiclav, are then administered discomfort. Large volumes of chyle can lead
for an additional 14 weeks after discharge to significant cardiorespiratory compromise.
or even for a longer period of time if there is
residual disease. A chest radiograph will demonstrate a
unilateral or bilateral pleural effusion
Follow-up and long-term outcome At
(fig. 2). Chylothorax should be suspected
discharge, most children will have abnormal
when an extensive pleural effusion occurs in
chest radiographs and clinical examination
a neonate with a lymphatic malformation,
(diminished breath sounds and some
some genetic syndromes, or after
dullness on the affected area due to pleural
thickening), which must not cause concern. cardiothoracic surgery (table 1).
Most affected children will return to having Although pleural fluid from chylothorax is
normal radiographs and clinical examination typically milky it can appear completely clear
in 36 months and after 1218 months they when fasting. Definite diagnosis relies on
will have a full clinical recovery. Opposite to the biochemical analysis of the fluid drained
what happens in adults, long-term from the pleural space. This study will show
prognosis of parapneumonic pleural
an elevated level of triglycerides
effusion or empyema in children is excellent
.110 mg?dL-1, and the presence of
and significant complications or sequelae
chylomicrons. A high lymphocyte count may
are uncommon.
also be present.
Chylothorax
Diferential diagnosis should be made with
Chylothorax is the accumulation of chyle in empyema and pseudochylothorax, which
the pleural space and is an uncommon develops when an exudative effusion
cause of pleural effusion in children. It is remains in the pleural space for a long

Table 1. Aetiology of chylothorax in children Table 1. Continued
Traumatic Infectious
Iatrogenic TB
Surgical Filariasis
Cardiothoracic surgery Histoplasmosis
Scoliosis or neck surgery Malignancies
Invasive procedures Lymphoma
Subclavian vein catheterisation Teratoma
Non-iatrogenic Sarcoma
Forceful emesis or cough Neuroblastoma
Hyperextension of the neck or thoracic Others
spine Transdiaphragmatic movement of
Mechanism of birth chylous ascites
Blunt trauma Systemic disorders
Penetrating chest trauma Cardiac failure
Non-traumatic Benign tumours
Congenital TORCH: toxoplasmosis, rubella, cytomegalovirus
Abnormalities of the lymphatic system and herpes simplex virus.
Primary or secondary lymphangiectasis
period of time and gradually becomes
Lymphangiomatosis
enriched with cholesterol.
Lymphatic dysplasia syndrome
Management Chest drainage with tube
Genetic syndromes
thoracostomy, together with nutritional
Noonan syndrome modifications, has been the mainstay of
Turner syndrome treatment for many years. More recently, a
dietary approach alone has been suggested
Down syndrome
as the initial treatment option.
Infectious
TORCH infections
Medical therapy Nutritional: the use of
medium chain triglyceride milk formulas
Thoracic duct atresia/agenesia decreases overall lymphatic flow through the
Congenital diaphragmatic hernia thoracic duct, while allowing spontaneous
Congenital cystic malformation of the lung healing of the duct injury. Another option is
total parenteral nutrition with bowel rest,
Congenital heart disease although most reports indicate little
Congenital mediastinal/pleural tumours difference in outcome compared to medium
Hydrops fetalis chain triglyceride enteral nutrition. Chest
drainage cessation with this dietary
Idiopathic
approach ranges from 1 to 4 weeks.
Antenatal primary fetal hydrothorax
Elevated venous pressure in the superior
Medications: somatostatin and synthetic
vena cava analogues (octreotide) have been used in
the treatment of chylothorax resistant to
Secondary to a Fontan-procedure dietary modifications. Although their
Venous thrombosis mechanism of action is not completely
understood, it seems that they reduce the

Pleuroperitoneal shunt: persistent chylothorax
refractory to the standard medical or
surgical therapies can be managed with
pleuroperitoneal shunting. The pleural and
peritoneal cavities are communicated by a
valved catheter placed subcutaneously. Fluid
is pumped from the chest into the abdomen
where it is absorbed by peritoneal vessels.
Possible complications include malfunction
and infection.
If untreated, chylothorax can lead to

nutritional compromise and immunological
problems.
Haemothorax
Figure 2. Chest radiograph of a small infant with Aetiology Haemothorax is a rare condition
bilateral chylothorax. in children in which blood accumulates in
the pleural space. It is usually caused by
intestinal blood flow by vasoconstriction of blunt or penetrating thoracic trauma and
the splachnic circulation with reduction of
may be life threatening if a large-volume
lymphatic fluid output. In addition, they
rapidly developing haemothorax occurs.
decrease gastrointestinal motility, and
Bleeding from lacerated intercostal vessels
gastric, pancreatic and biliary secretions,
or bone surfaces in rib fractures are the
significantly diminishing the lymphatic flow.
most common sources for haemothorax in
Dosage and method of delivery are not
definitely established. Other medications children. Other less frequent lesions such as
such as nitric oxide, etilefrine and pulmonary parenchymal lacerations or lung
corticosteroids have been used in single contusions may cause persistent and
case reports in adults. gradually increasing blood storage inside
the chest. Massive haemothorax with
Surgical therapy The main indication for hypovolaemic shock is indicative of injury to
surgery is persistent chest drainage despite a great vessel or the heart, and has a
nutritional modifications and bowel rest. mortality rate of .60%.
The most frequently used surgical
techniques are described below. Diagnosis Clinical symptoms depend on the
severity of haemothorax; tachypnoea, some
Pleurodesis: can be performed surgically or degree of respiratory distress and decreased
using chemical agents. Sclerosing oxygen saturation are usually observed. In
substances (tetracycline, povidone-iodide those cases with massive bleeding a
and talc) can be administered directly diminished level of consciousness and
through the thoracostomy tube or with the clinical signs of haemodynamic instability
assistance of VATS. Chemical pleurodesis are usually present. On auscultation,
with povidone-iodide has shown good ventilation will be reduced or completely
tolerance and relative success in congenital
absent on the affected side. When two or
idiopathic chylothorax in neonates.
more rib fractures are present there is a high
Thoracic duct ligation: although direct probability of multisystem injury including
surgical ligation of the thoracic duct at the pulmonary contusion and haemothorax. As
rupture site would seem the most definitive in adults, children with lung contusions
treatment, it has yielded variable results with have the same incidence of serious
success rates between 25% and 100% in complications associated to this condition,
different series including a small number of such as pneumonia or acute respiratory
patients. distress syndrome (ARDS).

If haemothorax is suspected a chest clamping of the chest tube may be of some
radiograph is the first image test to be benefit in re-establishing the tamponade
performed. Due to the supine position, fluid effect.
present in the pleural space will be diffusely
distributed across the lung field giving an In most cases, bleeding will stop
image of generalised increased opacity. spontaneously within a short period of time
Ultrasound is a quick and useful test in without requiring any further surgical
demonstrating cardiac or lung injuries and intervention. Drainage of the pleural cavity
haemothorax, but a chest CT scan is the with effective lung expansion is all that is
most valuable diagnostic tool, especially if a needed in this setting. Persistent bleeding in
great vessel injury is suspected (fig. 3). an unstable patient is an indication for
urgent thoracotomy. Guidelines for
Management Management of significant operative intervention are: a bleeding rate of
haemothorax must deal with two crucial 23 mL?kg-1?h-1 in a child over 4 h (200
conditions:
300 mL per hour in an adolescent), or a
N increased intrapleural pressure with return of 2030% of the blood volume in a
secondary lung collapse, child at chest tube placement (1000
N reduced blood volume with possible 1500 mL in an adolescent). As a general
haemodynamic instability. rule, the physiological response of the
patient to volume resuscitation is the best
Both situations can be severe enough to guide in decision making and a prompt and
seriously compromise oxygenation and sustained answer precludes surgical
cardiac output. Initial management exploration. In selected cases of ongoing
measures must be directed to correct both haemothorax, in an otherwise stable patient,
conditions by means of ensuring an thoracoscopy (VATS) may be considered
adequate airway and restoring the
instead of thoracotomy in order to identify
intravascular volume. When diagnosed,
and control the source of the bleeding.
blood should be promptly removed from the
pleural cavity with tube thoracostomy. Large Complications Hypovolaemic shock is the
catheters are preferable although they most frequent complication when massive
should be matched to the patients age and or persistent haemorrhage is present. Renal
size. In some cases, haemodynamic failure, severe acidosis or cardiac ischaemia
collapse may occur with rapid evacuation of may occur in this setting. When blood inside
the blood inside the chest. This is explained the pleural space is not drained promptly it
because it may act as a tamponade reducing may become clotted and organised.
ongoing blood loss from the intravascular Reabsorption may take place in the
space. In this situation, intermittent following weeks or months but in the
meanwhile empyema or fibrothorax may
develop. In order to prevent these
complications, a VATS procedure to
evacuate the retained haemothorax is
recommended within 1 week of injury.
Mediastinitis
Aetiology Mediastinitis is an infection of the
connective tissue of the mediastinum. Most
cases of acute mediastinitis usually occur
after sternotomy for cardiothoracic surgery
but it can also be caused by some
oesophagogastric diseases or injuries and
Figure 3. Chest CT showing bilateral haemothorax from adjacent spread of retropharyngeal or
and lung contusion secondary to blunt trauma. odontogenic infections. In children, an

oesophageal perforation due to a foreign be seen in granulomatous diseases, such as
body should be ruled out. histoplasmosis, or infections like TB, and
after radiation therapy. Treatment remains
Diagnosis Although mediastinitis is a rare controversial.
post-operative complication of median
sternotomy (0.15% of all paediatric
patients undergo this procedure), it Further reading
represents a significant source of morbidity
N Agrawal V, et al. (2008). Lipid pleural
and mortality. Risk factors include: young
effusions. Am J Med Sci; 335: 1620.
age, a high anaesthesiologist score, and a N Al-Sehly AA, et al. (2005). Pediatric
long duration of the surgical procedure. poststernotomy mediastinitis. Ann
Mediastinitis most often presents days to Thorac Surg; 80: 23142320.
weeks after cardiac surgery. Clinical signs N Asensio de la Cruz O, et al. (2001).
are variable, usually in the setting of an [Management of parapneumonic pleural
unfavourable post-operative course. Sepsis, effusions]. An Esp Pediatr; 54: 272282.
N Balfour-Lynn IM, et al. (2005). BTS guide-
pleural effusion, pneumothorax,
lines for the management of pleural
pneumomediastinum, thoracic pain,
infection in children. Thorax; 60: Suppl.
subcutaneous emphysema and
1, i1i21.
odynophagia may be present in a patient N Bradley JS, et al. (2011). The management
with acute mediastinitis. Less frequently, of community-acquired pneumonia in
cardiac arrhythmias may occur. infants and children older than 3 months
The most common organism isolated in of age: clinical practice guidelines by the
children is Staphyloccus spp. but Gram- Pediatric Infectious Diseases Society and
the Infectious Diseases Society of
negative organisms account for up to one
America. Clin Infect Dis; 53: e25e76.
third of cases in some series of post-
N Casero S, et al. (2010). Congenital
operative mediastinitis. The microbiology of chylothorax: from fetal life to adoles-
infection among heart and lung transplant cence. Acta Paediatrica; 99: 15711577.
patients may differ depending on the N Cohen E, et al. (2012). The long-term
underlying condition as well as the use of outcomes of pediatric pleural empyema:
post-transplant immunosuppression. a prospective study. Arch Pediatr Adolesc
Med; 166: 9991004.
Management Treatment for acute
N Crameri J, et al. Blunt thoracic trauma. In:
mediastinitis involves aggressive
Parikh DH, et al., eds. Pediatric Thoracic
intravenous antibiotherapy and surgical Surgery. London, Springer-Verlag, 2009;
management. In post-operative pp. 199212.
mediastinitis the standard surgical approach N Lasko D, et al. Chylothorax. In: Parikh DH,
includes debridement followed by open et al., eds. Pediatric Thoracic Surgery.
wound care with delayed closure. Other London, Springer-Verlag, 2009; pp. 573
surgical alternatives include: closed suction 577.
with antimicrobial irrigation, vacuum- N Sartorelli KH, et al. (2004). The diagnosis
assisted closure and muscle flap closure. and management of children with blunt
These strategies have been initially injury of the chest. Semin Pediatr Surg; 13:
developed for adults and later applied to 98105.
children. Recently, some authors have N Shah SS, et al. (2011). Comparative
suggested treating acute mediastinitis with effectiveness of pleural drainage proce-
debridement and concomitant primary dures for the treatment of complicated
closure without prolonged suction or pneumonia in childhood. J Hosp Med; 6:
irrigation. 256263.
N Soto-Martnez M, et al. (2009).
Chronic mediastinitis is characterised by Chylothorax: diagnosis and management
diffuse fibrosis of the soft tissues of the in children. Paediatr Respir Rev; 10: 199207.
mediastinum. It is a very rare entity that can

Pneumothorax and
pneumomediastinum
Nicolaus Schwerk, Folke Brinkmann and Hartmut Grasemann
Pneumothorax Epidemiology Epidemiological data in

children and adolescents are scarce. PSP in
Pneumothorax is defined as an adults shows male predominance with a
accumulation of air in the pleural cavity. It reported incidence of 1828 cases per
can be classified as primary spontaneous 100 000 in males and 1.26 cases per
pneumothorax (PSP), secondary 100 000 in females. In children, a male
spontaneous pneumothorax (SSP) and predominance is also consistently reported
traumatic or iatrogenic pneumothorax. (6580%), with a mean age at presentation
Whereas PSP occurs in the absence of an of 1416 years. While typically tall, thin boys
underlying disease, SSP is the result of pre- with a below-average BMI are affected, it is
existing lung affection (table 1). important to note that a pneumothorax can
occur in any age group. Smoking is a
Key points recognised risk factor for PSP.
Pathogenesis Apical subpleural blebs and
N The most common cause of bullae are often found in patients with PSP
pneumothorax in paediatric patients (5588% at the ipsilateral side and 1566%
is the rupture of bullae or blebs in the at the contralateral side). Rupture of these
apex of the lung without an underlying lung bullae or blebs that develop without an
predisposing lung disease or history underlying lung disease or history of trauma
of trauma. is generally considered to be the cause of
N When pneumothorax is suspected, PSP. The gradient of negative pleural
standard erect posterior to anterior pressure increases from the lung base to the
chest radiograph in inspiration apex, so that alveoli at the lung apex,
technique represents the diagnostic especially in tall individuals, are subject to
gold standard. significantly greater distending pressures
than those at the lung base. Presumably,
N Patients with pneumothorax who these pressure differences predispose to the
experience symptoms should be development of apical subpleural blebs.
treated with oxygen supplementation
However, the presence of blebs is not a
and needle aspiration or chest
reliable predictor to estimate the recurrence
catheter insertion independent of the
risk in patients suffering from PSP, and
size of the pneumothorax.
apical subpleural blebs and bullae can also
N In the setting of recurrent be found in healthy subjects. In children
pneumothorax, surgical treatment is with PSP and basilar subpleural bullae or
indicated. The preferred technique blebs and a positive family history for PSP,
consists of the resection of the BirtHoggDube syndrome should be
causative bleb or bulla and a considered. Blebs or bullae in the lower
pleurodesis procedure. lobes can be detected in almost all patients
with this autosomal dominant disorder,

Table 1. Causes of secondary and traumatic/iatrogenic pneumothorax
Congenital pulmonary malformations (congenital cystic adenomatoid malformation), congenital
emphysema and lung hypoplasia
Asthma
Bronchiolitis obliterans
CF
Diffuse parenchymal lung diseases
Systemic inflammatory diseases, e.g. rheumatoid arthritis, systemic lupus erythematodes,
polymyositis and dermatomyositis
Sarcoidosis
Connective tissue diseases, e.g. Marfan syndrome and EhlersDanlos syndrome
Foreign body aspiration
Infections, e.g. Pneumocystis jirovecii, TB, parasitic necrotising pneumonia or abscess, and
bronchiolitis
Langerhans cell histiocytosis
Malignancies, e.g. lymphoma, pleuropulmonary blastoma and metastasis
Post-surgical trauma
Sjogren syndrome
Ventilator-associated interstitial emphysema
which is caused by a mutation in the disease. Therefore, following the initial

folliculin gene, and 40% will develop PSP. treatment, patients with SSP should be
transferred to a specialised centre whenever
A special form of pneumothorax is possible.
ventilator-associated interstitial
emphysema. Rupture of alveoli during Symptoms PSP can develop following
mechanical ventilation, especially in manoeuvres that result in increased
neonates, can lead to air entry into intrathoracic pressures (e.g. lifting) but most
perivascular connective tissue. Gas then commonly occurs at rest. Typical symptoms
migrates into the interstitium and becomes are chest pain and dyspnoea. Symptoms can
trapped within the pulmonary perivascular be relatively minor and self-limiting within
sheaths, resulting in interstitial emphysema. 24 h so that a high index of initial diagnostic
Rarely, a pneumothorax results from suspicion is required. In patients with SSP,
infection with gas-producing clinical symptoms are usually more severe
microorganisms, penetrating tumours or than those associated with PSP and may
chest wall defects. Chest wall defects can be include severe breathlessness, even with
traumatic or iatrogenic. SSP constitute a small pneumothoraces. Severity of clinical
threat in patients with pre-existing symptoms is therefore an unreliable
underlying lung diseases and management indicator of pneumothorax size.
in these individuals is potentially more Characteristic signs on physical examination
challenging. SSP in patients with CF is include:
associated with a significantly increased
mortality risk. Treatment for SSP should be N diminished breath sounds,
more aggressive than for PSP (e.g. broad N reduced lung expansion,
indication for a chest drain insertion) and N decreased vocal fremitus,
special consideration may need to be N hyperresonance on percussion at the side
given to the treatment of the underlying of the pneumothorax.

These signs can be subtle or even absent,
especially in neonates or infants. As
pneumothorax in this younger age group is
potentially life threatening, a chest
radiograph in any situation of unexplained
cardiorespiratory symptoms is required to
rule out pneumothorax. At any age, in the
case of cardiorespiratory distress with
tachycardia, hypotension and/or cyanosis, a
tension pneumothorax must be considered
and rapid diagnosis and treatment is
mandatory (fig. 1).
Imaging Standard erect posterior to anterior
chest radiograph in inspiration technique
remains the diagnostic gold standard,
notwithstanding limitations including, for Figure 2. Pneumothorax in CF.
instance, the problem of quantifying the size
of a pneumothorax. Typical radiological justified when confirming the diagnosis is of
signs are displacement of the pleural line clinical and therapeutic relevance.
and an airfluid level visible in the
costophrenic angle (fig. 2). Supine and There are numerous different approaches to
lateral decubitus chest radiographs are calculate the size of a pneumothorax.
alternative options for patients who cannot Commonly the erect radiograph has been
be moved safely. In patients with cystic lung used for these quantifications. According to
lesions, such as congenital pulmonary the British Thoracic Society (BTS) guidelines
malformations or Langerhans cell a large pneumothorax is defined as a 2-cm
histiocytosis (fig. 3), the lesions can lead to gap between the entire lateral lung edge and
diagnostic errors, with potentially fatal the chest wall. In the guidelines of the
consequences for the patient. Therefore, in American College of Chest Physicians
uncertain cases alternative techniques such (ACCP) a large pneumothorax is defined as
as ultrasound or CT can be helpful. It is an apical distance of 3 cm. However, since
important to note that CT scans are only
Figure 3. Pneumothorax in Langerhans cell

Figure 1. Tension pneumothorax. histiocytosis.

pneumothorax size does not closely a single needle aspiration is not inferior to
correlate with its clinical manifestations, a intercostal chest catheter (ICC) insertion
thorough clinical evaluation is probably with respect to success and recurrence
more important for determining the proper rates. Moreover, needle aspiration is less
management strategy than the estimation of invasive, more cost-effective and associated
its actual size. with lower complication rates compared to
ICC. Unfortunately, no randomised
Therapy There are no evidence-based controlled trial comparing needle aspiration
guidelines for the treatment of to ICC has been conducted in paediatric
pneumothorax in children, and patients to date. In the BTS guidelines for
recommendations of different national and adult patients it is recommended that
international guidelines for adult patients aspiration of a maximum of 2.5 L should not
are controversial. Therefore, treatment be exceeded in order to avoid re-expansion
decisions are often made on the basis of oedema. Control radiographs are suggested
institutional guidelines. It is generally after single aspiration to assess the
agreed that a patient with pneumothorax presence of ongoing air leak. ICC insertion
who experiences symptoms should be should be considered in the case of:
treated independently of the size of the
pneumothorax. Asymptomatic children N age ,1 year,
should be observed in hospital for at least N bilateral pneumothorax,
24 h. A repeat chest radiograph should be N tension pneumothorax,
obtained prior to discharge to exclude N evidence for a big air leak (although this
expansion of the pneumothorax. may result in bronchopleural fistula),
Observation only (watch and wait) N pneumothorax recurrence within the first
Conservative treatment with observation hours following aspiration,
only in asymptomatic patients with small N co-existence of a pleural effusion
pneumothoraces has been shown to be safe. especially in the case of haemothorax.
Up to 80% of patients are estimated to have
Furthermore, chest drain insertion should
no active air leak, and recurrence in those
be performed in all children with iatrogenic
managed by observation only is equal or
and traumatic pneumothorax, SSP or co-
even less frequent than in those treated with
existing pneumomediastinum. The success
chest drainage. Nevertheless, a long time to
rates for small-bore ICCs are comparable to
resolution of up to 30 days has to be
large-bore ICCs while being less painful;
considered.
however, large-bore ICCs are indicated when
Supplemental oxygen at high concentrations the rate of air leak exceeds the capacity of a
generates a partial pressure gradient smaller ICC. Needle aspiration or ICC
between the pleural cavity and the capillary insertion should only be performed by, or
blood by decreasing the partial pressure under the supervision of, medical staff
contribution of nitrogen. This accelerates experienced in the procedure. Initial chest
the absorption of gas from the pleural cavity. radiograph imaging should guide the site of
Small case series have shown a four-fold placement. An appropriate approach in the
increase in the rate of pneumothorax majority of cases is the triangle of safety,
resolution in patients treated with which is bordered anteriorly by the lateral
supplemental oxygen compared to patients edge of pectoralis major, laterally by the
managed by observation only. Therefore, lateral edge of latissimus dorsi, inferiorly by
supplemental high-flow oxygen should be the line of the fifth intercostal space and
given to all patients hospitalised for a superiorly by the base of the axilla (fig. 4).
pneumothorax. An alternative approach is the second
intercostal space in the mid-clavicular line.
Needle aspiration and intercostal chest Proper sedation should be given in addition
catheter insertion There is an emerging body to local anaesthetic. After insertion, ICCs
of evidence that, in adult patients with PSP, should be connected to a Heimlich valve or

an underwater seal device. The benefit of
continuous suction is unclear. Since initial a)
suction might increase the risk of re-
expansion pulmonary oedema it is only
recommended if lung re-expansion has not
occurred at 48 h or if there is a persisting air
leak, which may indicate a
bronchopulmonary fistula. Optimal suction
should entail pressures of -10 -20 cmH2O.
Surgical management The primary aim of a

surgical intervention is to prevent recurrence
of pneumothorax. Nevertheless, the
detection of blebs or bullae in patients with
their first PSP normally does not require
surgical intervention. Current indications for b)
surgical intervention include:
N second ipsilateral pneumothorax,

N first contralateral pneumothorax,
N bilateral pneumothorax,
N persistent air leak,
N associated haemothorax,
N following a first episode in professionals
at risk, including pilots and divers.
Surgical treatment consists of the resection
of the causative bulla or bleb associated with Figure 5. Pneumomediastinum. a) Radiograph
some type of pleurodesis procedure, either and b) CT.
pleurectomy or pleural mechanical abrasion.
Chemical pleurodesis is not used in children
because of its potentially severe side-effects. Recurrence Whether children with PSP have
a higher rate of recurrence than adults
The current gold standard in the adult remains unclear. Reported data from small
literature is blebectomy and apical parietal case series range between 20% and 50%
pleurectomy. Newer surgical techniques after first PSP and 115% after surgical
such as video-assisted thoracoscopic treatment. Recurrence risk in paediatric
surgery (VATS) have also been shown to be patients with SSP depends on the course of
safe and effective in children. Advantages of the underlying disease.
VATS are decreased post-operative pain,
reduced length of hospital stay and Pneumomediastinum and subcutaneous
improved lung function. emphysema
Pneumomediastinum is defined as the

presence of free air in the mediastinum.
Epidemiology Currently there are no
epidemiological data in the paediatric
literature, but undoubtedly
pneumomediastinum is an exceedingly rare
condition in this age group.
Pathogenesis Rarely, pneumomediastinum
can occur as spontaneous
Figure 4. Schematic diagram of the triangle of safety. pneumomediastinum (e.g. Hammans

Table 2. Predisposing conditions for pneumomediasti- the underlying cause. While symptoms in
num children with spontaneous
pneumomediastinum can be mild,
Allergic bronchopulmonary aspergillosis pneumomediastinum as a complication of
Asthma exacerbation an underlying disease can be life threatening
Barotrauma with reported mortality rates of up to 40%.
Typical clinical signs are chest pain,
Blunt or penetrating trauma of the chest wall
dyspnoea and cough. In 3040%
Bronchiolitis obliterans pneumomediastinum is associated with
Bronchopulmonary dysplasia/chronic lung subcutaneous emphysema with soft tissue
disease swelling of the neck, the face and sometimes
Central venous or cardiac catheterisation the whole chest wall in conjunction with
characteristic subcutaneous crepitations.
Connective tissue diseases-related
interstitial lung disease Imaging As for pneumothorax the diagnosis
CF of pneumomediastinum is made by
radiography. However, up to 30% of cases of
Diffuse parenchymal lung diseases pneumomediastinum are missed on chest
Endoscopic/bronchoscopic interventions radiographs, therefore CT has become the
Foreign body aspiration gold standard for diagnosis, especially when
the underlying predisposing condition is
Infections, e.g. influenza A/B virus,
unknown.
Mycoplasma pneumoniae, Pneumocystis
jirovecii and Aspergillus fumigatus Therapy In the adult literature, several
Mechanical ventilation surgical techniques have been reported to
Oesophageal perforation treat pneumomediastinum and
subcutaneous emphysema including
Penetrating tumours mediastinal drain insertion, subcutaneous
Pneumothorax (PSP and SSP) pigtail or large-bore drains with or without
Surgical interventions suction. All of these methods are invasive and
have an increased risk of infection. The most
important therapeutic approach is the
syndrome) in the absence of a specific treatment of the underlying cause. In addition
underlying disease. In these cases it is to this, conservative treatment including
thought to be the result of a sudden increase analgesics, bed rest and avoidance of Valsalva
in intrathoracic pressure (e.g. emesis, manoeuvres may be beneficial. Symptoms
cough, physical activity or defecation) and generally improve within 315 days without
subsequent alveolar rupture. Further leakage sequelae. It is not clear whether preventive
of air throughout the interstitium and antibiotic therapy can reduce the risk of
bronchovascular tissue follows a centripetal secondary infections of the mediastinum.
pattern towards the mediastinum. In most Nevertheless, antibiotic treatment should be
cases, however, pneumomediastinum is initiated generously in patients with extended
thought to be a complication of a specific trauma of the bronchial tree, the oesophagus,
underlying disease or the result of a specific or a known infection as the underlying cause
pathological event leading to rupture of lung of pneumomediastinum.
parenchyma or the bronchial tree (fig. 5).
Given the grave clinical consequences of Further reading
pneumomediastinum and the necessity to
institute specific treatment of an underlying N Baumann MH, et al. (2001). Manage-
cause, responsible predisposing conditions ment of spontaneous pneumothorax: an
have to be excluded (table 2). American College of Chest Physicians
Delphi consensus statement. Chest; 119:
Symptoms The severity of symptoms 590602.
depends on pneumomediastinum size and

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thoracic surgery for primary spontaneous spontaneous pneumothorax: British
pneumothorax in children: is there an Thoracic Society pleural disease guide-
optimal technique? J Ped Surg; 43: 21512155. line. Thorax; 65: Suppl. 2, ii18ii31.
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pneumomediastinum: a comparative spontaneous pneumothorax. Br Med J; 4:
study and review of the literature. Ann 8688.
Thorac Surg; 86: 962965. N OLone E, et al. (2008). Spontaneous
N Chan SS (2008). The role of simple pneumothorax in children: when is inva-
aspiration in the management of primary sive treatment indicated? Pediatr
spontaneous pneumothorax. J Emerg Pulmonol; 43: 4146.
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pneumothorax in children: when is invasive reference to the ultrastructure of emphy-
treatment indicated? Ped Pulm; 43: 4146. sematous bullae. Chest; 77: 771776.
N Giuliani S, et al. (2010). Massive sub- N Robinson PD, et al. (2009). Evidence-
cutaneous emphysema, pneumomedias- based management of paediatric primary
tinum, and pneumopericardium in spontaneous pneumothorax. Ped Respir
children. J Ped Surg; 45: 647649. Rev; 10: 110117.
N Guimaraes CV, et al. (2007). CT findings N Toro JR, et al. (2007). Lung cysts,
for blebs and bullae in children with spontaneous pneumothorax, and genetic
spontaneous pneumothorax and compar- associations in 89 families with Birt-
ison with findings in normal age-matched Hogg-Dube syndrome. Am J Respir Crit
controls. Pediatr Radiol; 37: 879884. Care Med; 175: 10441053.
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dures and thoracic ultrasound: British large- and small-bore intercostal cathe-
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line. Thorax; 65: Suppl. 2, ii61ii76. pneumothorax. Intern Med J; 33: 495499.

Neuromuscular disorders
Anita K. Simonds
Prevalence by variable combinations of reduced

inspiratory muscle strength, the presence of
While some neuromuscular diseases are a thoracic scoliosis and reduced chest wall
very rare, as a group the neuromuscular and pulmonary compliance the latter
disorders in childhood are quite common, caused by micro- or macro-atelectasis.
with an overall prevalence of about 1:3000.
Inspiratory and expiratory muscle strength
Most are inherited in origin, the commonest
mostly decrease in parallel, but when
being Duchenne muscular dystrophy, spinal
diaphragm strength is preserved expiratory
muscular atrophy, congenital muscular
muscle weakness may predominate e.g. in
dystrophies and myopathies. The probability
spinal muscular atrophy. Expiratory muscle
of respiratory complications varies
weakness combined with inspiratory muscle
according to diagnosis, genotype and age
weakness leads to poor cough efficacy and
(table 1) and in the past 20 years an
secretion clearance and can be measured by
increasing amount has been learned about
cough peak flow values less than
genotypephenotype correlations and
270 L?min-1 in children aged approximately
respiratory management strategies. In some
10 years and above suggest reduced cough
conditions, the natural history has changed
power, and values less than 160 L?min-1 are
significantly with the introduction of
ventilatory support. associated with increased frequency of chest
infections. A vital capacity of f60%
Assessment of pathophysiology predicted is predictive of the presence of
sleep disordered breathing, which initially
Children with neuromuscular weakness have occurs in REM sleep and then spreads to all
a restrictive pattern of spirometry on sleep stages. Usually this appears as
pulmonary function testing. This is caused nocturnal hypoventilation, but obstructive
hypoventilation may be seen in some
conditions e.g. Duchenne muscular
Key points
dystrophy. Sleep studies should be carried
out routinely in these children or in any with
N Neuromuscular disorders are
sleep-related symptoms or recurrent chest
relatively common, with a prevalence
infections, in those requiring
of 1:3000.
hospitalisation, or in failure to thrive.
N Sleep disordered breathing is likely Scoliosis is common and will occur in
when vital capacity falls to ,60% virtually all children with spinal muscular
predicted. atrophy types 1 and 2, and in 7090% of
N NIV is indicated to control those with Duchenne muscular dystrophy.
symptomatic sleep disordered Scoliosis progresses with the adolescent
breathing. growth spurt and transition to permanent
wheelchair use. Use of steroid therapy and
N Use of NIV in Duchenne muscular preservation of standing using frames may
dystrophy may double life expectancy. reduce scoliosis severity. Scoliosis surgery is
carried out to prevent progression of the

curvature and achieve comfort rather than to occur. In addition, mask rotation and
increase lung volumes. avoidance of tight-fitting interfaces should
be employed to reduce the risk of pressure
Bulbar involvement is inevitable in type 1 over facial structures resulting in mid facial
spinal muscular atrophy and some hypoplasia and pressure sores. Customised
conditions such as myotubular myopathy masks reduce the occurrence of mask-
and myotonic dystrophy, but in others, e.g. related problems in children.
Duchenne muscular dystrophy, it is a late-
stage phenomenon. Assessment of Research has shown that NIV in Duchenne
swallowing function is a key part of muscular dystrophy extends survival pre-
respiratory management in any child with ventilatory support, median survival was
neuromuscular disease weakness is about 18 years; about a third of patients with
suggested by slow feeding, choking, the disease now live into their 30s and 40s.
aspiration and recurrent chest infections. Similarly in type 2 spinal muscular atrophy
Nutritional assessment is also crucial and if and the congenital muscular dystrophies,
adequate nutrition cannot be achieved safely NIV is associated with a reduction in
orally, then percutaneous gastrostomy respiratory tract infections, with improved
placement may significantly improve quality school attendance and quality of life. Type 1
of life and reduce respiratory complications. spinal muscular atrophy comprises a
spectrum of infants ranging from those with
Sleep studies profound floppiness and inability to feed or
smile within weeks of birth and those at the
Overnight oximetry is often used to screen opposite end who are almost able to sit and
for sleep disordered breathing in children have later-onset respiratory problems
with neuromuscular disease. While a normal similar to those with type 2 disease. A
trace in a child who has slept well usually nuanced response to ventilatory support is
excludes a significant problem, values of required in some instances, this may be
arterial oxygen saturation within the normal life saving and extend life by many years,
range can occasionally be seen in children while in others with more severe disease
with mild obstructive sleep apnoea/ NIV may palliate symptoms or respiratory
hypopnea and can be accompanied by distress and allow hospital discharge but is
hypercapnia in children using CPAP or NIV. not intended to extend life expectancy.
If there is a high suspicion of sleep Goalsetting and an anticipatory care plan
disordered breathing, multichannel (see below) are an important part of the care
monitoring including a measure of of any child with neuromuscular weakness.
overnight carbon dioxide tension (e.g.
transcutaneous CO2) is preferred. Chest physiotherapy and cough
augmentation
Long-term assisted ventilation
Standard chest physiotherapy is vital to
Measurement of CO2 control is also successful management and may be
required to assess ventilator efficiency in complemented by manual cough
children started on NIV. NIV is augmentation and breath stacking to
recommended in children with daytime improve lung recruitment, using an ambu-
hypercapnia or symptomatic nocturnal bag. Use of NIV alone may help with
hypoventilation. Noninvasive approaches secretion clearance, and physiotherapy
are preferable providing bulbar function is should be performed while the child uses
adequate. Pressure-preset ventilators are the ventilator. However in those with cough
usually used. Care should be taken to ensure peak flow ,270 L?min-1, and/or poor cough
ventilator performance meets the childs in whom the above simpler techniques are
ventilatory needs: for example, if the not sufficient, a cough inexsufflator device
inspiratory trigger is insensitive, work of may improve cough peak flow and reduce
breathing increases; but if it is too sensitive, pulmonary morbidity. A randomised
auto-triggering resulting in asynchrony may controlled trial in children and adults has

Table 1. Respiratory complications of neuromuscular disorders
Condition Respiratory Secretion Recurrent Progression Disease-specific
failure clearance pneumonia features
difficulty
SMA
Type 1 All by 2 years Marked All Rapid All require full-time
respiratory support
Type 2 ,40% in Early ,25% in first Slow
childhood 5 years
Type 3 Rare in Rare in Rare in Slow
childhood childhood childhood
SMA with respiratory All by Marked All Rapid in first All require full-time
distress type 1 6 months year, then respiratory support
slows
DMD/severe childhood After loss of After loss of Late Cardiomyopathy
onset limb-girdle ambulation ambulation usually occurs after
muscular dystrophy respiratory problems
but may precede
them
Facioscapulohumeral When onset With With Slow Severe infantile
muscular dystrophy ,20 years infantile infantile onset type is
onset onset frequently associated
with sensorineural
deafness
Congenital muscular dystrophy
All types Any age Any age Any age Slow
depending on depending depending
severity on severity on severity
Ullrich 70% in Mild Infrequent Proximal
adolescence contractures with
marked distal laxity
Rigid spine muscular Early while Mild Infrequent Hypoventilation may
dystrophy ambulation occur in ambulant
preserved children with
relatively preserved
vital capacity
Congenital myopathy
Central core Uncommon Uncommon Uncommon Slow Susceptible to
except in malignant
severe hyperthermia
recessive type
Minicore Early while
ambulation
preserved
Nemaline Early in severe In severe In severe Slow
neonatal form, form form
mild later
onset form
may develop
early while
ambulation
preserved
Myotubular 85% in severe In severe In severe Slow Ophthalmoplegia,
X-linked form form form rare coagulopathy
and liver
haemorrhage

Table 1. Continued
Condition Respiratory Secretion Recurrent Progression Disease-specific
failure clearance pneumonia features
difficulty
Fibre type disproportion Depends on Uncommon Uncommon
genotype
Myotonic dystrophy
Myotonic dystrophy 1 Common in Common in Common in Initial Prominent learning
severe severe severe improvement, difficulty,
congenital congenital congenital later slow somnolence, central
onset, usually onset onset deterioration hypoventilation
improves
Myotonic dystrophy 2 Uncommon Uncommon Uncommon
Congenital myasthenic Often in Especially Possible if Weakness may
syndromes neonatal during inter- weakness fluctuate, episodic
period, may current severe and apnoea in some.
occur during illnesses persistent Congenital stridor in
inter-current those with DOK7
illnesses mutations
Mitochondrial myopathy Common Possible Possible Acute
deterioration
possible
CharcotMarieTooth With severe With severe With severe Stridor, especially
early onset, early onset early onset with GDAP1
especially with mutation
GDAP1
mutation
Pompe Infantile Infantile Infantile Infantile rapid, Variable relationship
onset, may be onset onset late onset slow between motor and
early in later respiratory
onset while progression
ambulation
preserved
SMA: spinal muscular atrophy; DMD: Duchenne muscular dystrophy. Reproduced from Hull et al. (2012) with
permission from the publisher.
shown that inexsufflation can increase Acute respiratory complications and

cough peak flow and is well tolerated. intercurrent surgical interventions
Although there are no randomised
controlled trials of long term use, the Chest infections are the commonest cause
combination of NIV and cough in of hospital admissions in those with
exsufflation with or without enteral feeding
may reduce the need for a tracheostomy in
children with mild-to-moderate bulbar/ Table 2. Indications for tracheostomy ventilation
swallowing dysfunction. Severe bulbar weakness leading to
Tracheostomy ventilation aspiration
Upper airway problems limiting delivery of
NIV is usually preferable to tracheostomy, NIV
as it is simpler for child and family, but Failure to control ventilation with
invasive ventilation is indicated in the noninvasive mode
Intractable interface problems
situations listed in table 2. The risk
Near 24-h ventilator dependency,
management of a tracheostomy ventilator-
especially in early infancy
dependent child clearly differs from that of Patient/family preference
a child using NIV.

respiratory muscle weakness. Active steps Oesophageal reflux and feeding problems
should be taken to reduce pulmonary are common and may require supplemental
morbidity with influenza and pneumococcal feeding. In young adults with Duchenne
vaccination, physiotherapy, then active muscular dystrophy, and in patients
secretion clearance techniques and intensive managed on ventilator support for many
NIV if a chest infection develops resulting in years, a new set of problems are emerging
ventilatory compromise. Some children renal and bladder calculi, and intermittent
require NIV only during respiratory tract episodes of bowel pseudo-obstruction
infections. Physiotherapy while using NIV is probably caused by a combination of
less tiring than breathing unsupported, and autonomic dysfunction and reduced
oxygen can be entrained into the ventilator abdominal muscle tone.
circuit to normalise arterial oxygen Palliative care
saturation. A small increase in expiratory
positive airway pressure (EPAP) setting Many children with neuromuscular
e.g. from 5 to 7 cmH2O may be useful if disorders experience muscle, back and joint
there is atelectasis; the inspiratory positive pain; in fact 40% of older Duchenne
airway pressure (IPAP) setting should be muscular dystrophy patients report daily
titrated to control CO2 levels. In addition to pain and fatigue. Good supportive care and
broad-spectrum antibiotics, nebulised symptom palliation are vital and do not
bronchodilators may be useful in children equate with end-of-life care, as symptom
with asthma or bronchial hyperreactivity, but relief may be required for many months or
there is no evidence to support routine years before death. Analgesia should not be
bronchodilator use in neuromuscular stinted for fear of respiratory failure. Careful
disease. up-titration of opioids usually avoids this
problem and ventilatory support can always
The manoeuvres listed above can be useful be added if respiratory insufficiency ensues.
in children in the post-operative period e.g.
following scoliosis correction or other major In all children receiving NIV, an anticipatory
surgical procedures. It should be noted that care plan should be drawn up by joint
consultation between the care team, the
individuals with central core myopathy are at
patient and family. This covers escalation of
risk of malignant hyperthermia during
therapy during acute exacerbations, and the
anaesthesia.
agreed limits to intervention in the face of
Other systems/complications long-term irreversible decline.
A cardiomyopathy is seen in all Duchenne

Further reading
muscular dystrophy patients by the mid-to-
late teenage years and should be treated N Hull J, et al. (2012). British Thoracic
with angiotensin-converting enzyme Society guideline for respiratory manage-
inhibitor and beta blocker. Cardiac ment of children with neuromuscular
involvement is also highly prevalent in weakness. Thorax; 67: Suppl. 1, 140.
Becker muscular dystrophy, myotonic N Wang CH, et al. (2010). Consensus
dystrophy and the lamininopathies such as statement on standard of care for con-
Emery Dreyfuss muscular dystrophy. The genital muscular dystrophies. J Child
Neurol; 25: 15591581.
limb girdle muscular dystrophies are a very
N Bushby K, et al. (2010). Diagnosis and
heterogenous group and cardiac management of Duchenne muscular dys-
surveillance should be adapted to the trophy, part 2: implementation of multi-
underlying disorder for example cardiac disciplinary care. Lancet Neurol; 9: 177
disease is common in the 189.
sarcoglycanopathies (LGMD2C-F), but less N Simonds AK (2006). Risk management of
frequent in the dysferlinopathies (e.g. the home ventilator dependent patient.
LGMD2B) and calpainopathies (e.g. Thorax; 61: 369371.
LGMD2A).

Chest wall disorders
Daniel Trachsel, Carol-Claudius Hasler and Jurg Hammer
Paediatric chest wall disorders include the Pathophysiology of respiratory compromise

congenital structural anomalies of the rib in chest wall disorders and scoliosis
cage, spine, and thoracic musculature, and a
number of acquired chest wall diseases such Long-term respiratory stability requires a
as costal Ewing sarcoma. Congenital chest sufficient ventilatory reserve and the
wall diseases may be apparent at birth or expectoration of accumulating airway
become apparent with time, usually as a secretions. While infants are limited in their
result of disturbed growth and development. respiratory stability by increased chest wall
In this chapter, the most important features compliance and collapsibility of the airways,
of congenital disorders will be highlighted; a older children with thoracovertebral
discussion of acquired chest wall diseases is deformatities are more hindered by
beyond its scope. abnormal stiffness of the chest. The
recruitment of inspiratory reserve to full
expansion of the thoracic cage depends on
Key points the free mobility of the costo-vertebral and
costo-sternal articulations, and on a
N Despite obvious deformations, lung diagonal resting position of the rips on the
function remains surprisingly preserved vertebrocranial to sternocaudal axis, which
in most individuals with adolescent allows widening of the chest by lifting the
idiopathic scoliosis, pectus excavatum ribs into a horizontal position. For this to be
and pectus carinatum. accomplishable with minimal effort, the
N In contrast, severe thoracic restriction alignment of the respiratory muscles must
conveys a high risk of pulmonary provide optimal leverage angles.
morbidity and respiratory failure in
early-onset scoliosis and complex The severity of a thoracovertebral
syndromal thoracovertebral malformation often correlates with the
malformations. degree at which these structural requisites
for respiratory stability are lost in affected
N Surgical correction rarely improves lung children who then become more and more
function but may significantly exclusively dependent of diaphragmatic
deteriorate the natural history if young breathing, which in turn can be hindered by
individuals undergo early fusion of the distortion and flattening of the diaphragm.
thoracic spine.
Congenital chest wall and sternal defects
N Recent developments in orthopaedic
techniques allow timely intervention in Poland syndrome, or Poland sequence,
early-onset scoliosis promoting spinal describes a unilateral hypoplasia or aplasia
and chest wall growth, but the potential of the pectoral muscle which is associated
for improving lung function remains to with a more or less pronounced
be clarified. malformation of the ipsilateral upper
extremity, typically a synbrachydactyly, and

occasionally absence of one or more ribs. The majority of patients, anyhow, seek
Concomitant Moebius syndrome may be correction for aesthetic reasons.
present. Poland syndrome does not usually
affect respiratory function but may have a Sternal clefts Congenital sternal clefts can be
significant psychosocial impact. complete or partial. Partial superior clefts
prevail; partial lower clefts are often
Pectus carinatum The pectus carinatum associated with ectopia cordis or Cantrell
deformity is three times rarer than pectus pentalogy. Other concurrent malformations,
excavatum, occurring sporadically, with a e.g. midline defects, are found in up to three-
familial preponderance in 25% of cases, or quarters of cases, but many individuals with
as part of genetically determined syndromes sternal clefts are asymptomatic. Reported
such as Marfan syndrome, Noonan complaints include exercise intolerance,
syndrome, prune belly syndrome or cough and vulnerability to lower respiratory
homocysteinuria. In most affected tract infections. Early surgical repair is often
individuals, cardiopulmonary function is not recommended, the more theoretical
impaired, but many suffer from the rationale being concerns about chest
psychosocial impact that may justify surgical instability and risk of trauma.
correction.
Cantrell pentalogy Cantrell pentalogy is a
Pectus excavatum The pectus excavatum rare, combined midline defect including the
deformity has a prevalence of 1 in 400 with a pentade supra-umbilical abdominal wall
male preponderance of 35:1. As with the defect with or without evisceration, inferior
carinatum deformity, its occurrence is sternal cleft, pericardial defect or ectopia
sporadic, familial, or syndromic (Marfan or cordis, median diaphragmatic defect, and
Noonan); in addition, it may be seen in congenital heart defect, e.g. ventricular
survivors of congenital diaphragmatic septal defect or tetralogy of Fallot. The
hernia, or secondary to longstanding outcome depends on the extent of the
significant upper airway obstruction. Pectus malformation and the complexity of the
excavatum can become apparent at any age congenital heart defect. Mortality in children
during growth and is not spontaneously with the complete pentalogy is high.
reversible except for the secondary form. Thoracoverebral deformities
Significant pectus excavatum is associated Isolated congenital scoliosis and adolescent
with mild restrictive lung function with a idiopathic scoliosis The period of fastest
decrease in mean vital capacity (VC) to spine growth is from birth to age 5 years
about 8085% predicted. The probability of (T1L5 grows 2.2 cm per year), when spinal
significant restriction is four times higher if length gain is almost 50%. Growth then
the Haller index, defined as the ratio transiently slows to 1.1 cm per year, and re-
between the transverse thoracic diameter accelerates again for the pubertal growth
and the narrowest distance between spurt to 1.8 cm per year, starting at age 10
sternum and vertebra, is .7. Significant 11 years in girls, and 2 years later in boys.
airway obstruction is rare. Although The thoracic volume makes up about 6% of
measurable lung function abnormalities are its adult size at birth, 30% at age 5 years and
usually mild, many affected individuals 50% at age 10 years.
complain about shortness of breath and
reduced exercise tolerance. Early onset scoliosis (EOS) is defined as any
scoliosis manifesting before the age of
Available data report no benefit of corrective 5 years irrespective of its origin, i.e. a
surgery to lung function but a possible congenital (thoraco-)vertebral
favourable effect on exercise capacity, malformation, neuromuscular disease,
independently of the therapeutic approach, specific syndrome or the infantile idiopathic
i.e. treatment with a vacuum bell, an open type. 70% of EOS worsen over time and
surgical procedure, or minimally invasive require treatment, approximately half by
repair of pectus excavatum (MIRPE). surgical intervention. The hallmark of EOS is

its propensity to progressive respiratory leverage vectors of the respiratory muscles,
failure and associated mortality. The overall but likely also reflects a generalised muscle
prognosis is worse in the presence of weakness that has repeatedly been found in
concomitant thoracic cage malformations or AIS patients and might contribute to the
in neurogenic EOS. The best outcome may pathogenesis of scoliosis.
be expected in cases of idiopathic scoliosis
with little rotational deviation (Mehta rib Complex syndromal thoracovertebral
angle difference of ,20u). malformations The complex syndromal
thoracovertebral malformations comprise a
Survival improves dramatically if idiopathic heterogeneous group of combined
scoliosis is diagnosed between 5 and malformations of the spine and thoracic
10 years of age, and is normal in adolescent cage that lead to severe kyphoscoliosis and/
idiopathic scoliosis (AIS) patients. or narrowing and stiffening of the thoracic
cage. Respiratory function of affected
Most individuals with AIS have normal lung children is impaired by the thoracic
function. When scoliosis progresses, restriction, reduced respiratory muscle
however, lung function decreases by the function, weak cough and impaired airway
reduction of both the volume and the clearance. Additional symptoms may arise
compliance of the chest, and by the change from associated malformations, gastro-
of the lever arm vectors of the respiratory oesophageal reflux and heart failure. These
muscles. TLC is preserved longer than VC, malformations not only cause physical
resulting in an extrinsic (asymmetrical) suffering but also enormous psychosocial
overinflation with an increased residual stress from social marginalisation, school
volume/TLC ratio. Ventilation becomes absenteeism and concerns about the future.
increasingly inhomogeneous, but bronchial Medical care, therefore, requires a
obstruction is found in fewer than 20% of multidisciplinary approach. Numerous
cases. The degree of pulmonary restriction syndromes may manifest with complex
is underestimated if height-based reference thoracovertebral malformations, including
values of normal lung function are used. diastrophic dysplasia, infantile Marfan,
KlippelFeil, Jeune, and JarchoLevin
The Cobb angle cannot reliably depict the syndromes.
three-dimensionality of scoliosis, and it
correlates only moderately with the degree Concept of thoracic insufficiency syndrome
of pulmonary limitation. A decrease of the (TIS): The severe thoracic restriction is
FVC below 80% pred may be expected in AIS associated with respiratory failure and lung
from Cobb angles of 70100u onwards, but hypoplasia. This common feature led
the variability of pulmonary restriction Campbell et al. (2003) to propose the
remains significant. Rotation in the concept of TIS in 2003, defined as the
transverse plane is an important feature of inability of the thorax to allow normal
scoliosis, clinically manifesting as rib hump respiration and lung growth. TIS has been
or lumbar hump depending of the height of divided into 4 different types of volume
the scoliosis, and additionally impairs lung depletion deformities (table 1).
function in patients with advanced scoliosis
or concomitant thoracic hypokyphosis. It is Patients with unilateral absent ribs and
estimated that height and length of the associated flail chest have a high mortality in
scoliotic curvature and the presence of the first years of life. Death is usually caused
hypokyphosis (,10u sagittal angulation) by respiratory failure and/or right heart
account for up to 20% of FVC reduction. failure. The unilateral fused ribs type is the
most common form and typically leads to
AIS patients often complain about reduced worsening of scoliosis and pulmonary
exercise tolerance. Maximum inspiratory function with growth. The differentiation
and expiratory pressures (MIPS and MEPS) into the four types of TIS guides the surgical
are about 70% pred on average, which is in management. For the paediatric
part attributable to the disadvantaged pulmonologist, it is important to recognise

Table 1. Types of volume-deficiency deformities causing TIS
I Unilateral absent ribs with scoliosis and hemihypoplasia of the thorax
II Unilateral fused ribs with scoliosis and hemihypoplasia of the thorax
IIIa Vertebral malformation with loss of thoracic height and kyphosis
Bilateral longitudinal restriction of the lungs (e.g. JarchoLevin syndrome)
IIIb Global thoracic hypoplasia with windswept deformity and lateral lung constriction on
both sides (e.g. Jeune syndrome)
that both chest radiography and lung are at risk of developing end-stage renal
function testing do not reliably reflect the disease.
degree of respiratory morbidity. Studies
suggest that sleep studies may be more Spondylocostal and spondylothoracic dysostosis
sensitive to detect respiratory limitation. (JarchoLevin syndrome/LavyMoseley
syndrome): The JarchoLevin syndrome
Asphyxiating thoracic dystrophy is a rare encompasses individuals with a very short
osteochondrodysplasia with autosomal spine and malformed vertebral bodies, and a
recessive inheritance and variable dysplastic rip cage with fused, dysplastic or
expression that occurs in all ethnicities with absent ribs. Various gene mutations have
an estimated incidence of 1 in 130 000. A been found and underlie the phenotypic
narrow, bell-shaped and very stiff thorax with variations. Spondylocostal dysostosis
an almost normal-sized vertebral column is (JarchoLevin syndrome sensu stricto) may
the hallmark of the syndrome. Chest width is be distinguished from spondylothoracic
reduced in both the sagittal and the coronal dysostosis (LavyMoseley syndrome).
plane with shortened ribs typically bowed Severe pulmonary restriction leads to
inwards at the tips, resulting in a cloverleaf chronic respiratory failure, recurrent
appearance of the thoracic cage in the pneumonias, and right heart failure.
transverse plane. Other skeletal features of
Spondylocostal dysostosis occurs both as
the pelvis and extremities are common and
autosomal recessive and autosomal
associated with short stature, and vertebral
dominant trait, and is mainly characterised
malformations of the neck need special
by:
attention for their potential to damage the
cervical medulla. One-third of affected N an abnormal segmentation of at least 10
individuals have renal disease including consecutive vertebral bodies,
cysts, tubular atrophy and renal failure. N a costal malalignment, fused ribs and
Other frequently encountered organ costal bifurcations, or occasionally absent
manifestations involve the liver, the ribs,
pancreas, and the eyes. There is apparently N a mild scoliosis with variable potential for
no correlation between the severity of progression, depending on the
thoracic dystrophy and the extent of asymmetry of the costal malformations
parenchymal involvement. (TIS type II or type IIIa).
More than 120 cases have been described in Multiple associated malformations are
the literature. Mortality is as high as 50%, known. Without early thoracic expansion,
with up to 80% dying within the first 2 years progression of scoliosis occurs in 75% of
due to respiratory failure and cor pulmonale. cases. Mean survival has improved
Most survivors need some sort of ventilatory significantly, but long term prognosis is as
support. Thorax-expansion surgery increases yet unknown.
the transverse cross-sectional area, but its
effect on lung growth remains uncertain. Spondylothoracic dysostosis is an
Jeune patients surviving into adolescence autosomal recessive syndrome seen mostly

in individuals of Puerto Rican descent, small steps and reducing anaesthetic and
characterised by an extremely short spine infection risks.
with posteriorly fused rips giving a crab-like
appearance to the chest radiograph (TIS Whether these interventions stimulate
type IIIa). Among other malformations, it pulmonary catch-up growth is not yet clear.
may be associated with congenital CT scans have revealed a 25 90% increase
diaphragmatic hernia which further worsens of the thoracic cage after VEPTR, likely
the prognosis of these children who are consequent to the enlargement of the
almost exclusively dependent on coronal chest diameter and the stimulation
diaphragmatic breathing. Mortality is very of spinal growth. Reported clinical benefits
high and generally attributable to respiratory of expansion thoracoplasty include
failure, pulmonary arterial hypertension and improved exercise tolerance, reduced
heart failure. ventilatory support, increased body weight,
and reduction of polyglobuly. Whether the
Orthopaedic treatment of scoliosis and improvement of these surrogate markers
thoracovertebral malformations, and impact results from improved breathing mechanics,
on lung function Early multiple-level a larger chest volume or even alveolar catch-
vertebral fusions have been completely up growth is a matter of debate. Preliminary
abandoned because they result in a short longitudinal lung function studies failed to
straight or bent spine and a reduced growth document any significant catch-up growth in
of the ribcage that is associated with children with TIS after repeated thoracic
respiratory compromise and back and chest expansion. It is not known whether an age
pain. Up to 50% or 10 cm of the spine limit exists for possible pulmonary catch-up
length can be lost by spinal fusion before growth, or whether VEPTR halts the
5 years of age, with a corresponding progression of scoliosis and thoracic
significant loss of the thoracic volume. At deformation in children with complex
least 22 cm length of the thoracic spine is thoracovertebral malformations.
deemed necessary as a prerequisite for
Spinal fusion of AIS rarely leads to improved
satisfactory lung function.
lung function. Rib hump resection is even
In contrast, bilaterally implanted spine- accompanied by a 1520% decrease of FVC
based growing rods improve the scoliosis in the first postoperative months that slowly
and stimulate the growth of the vertebral recovers to the preoperative level within
column. They have no direct beneficial 2 years. In contrast, in patients with
impact, however, on chest growth and are neuromuscular disease, specifically in those
therefore standard for treatment for EOS with Duchenne muscular dystrophy, timely
without vertebral or costal malformations. spinal fusion seems to halve the rate of
EOS that is associated with ribcage pulmonary function decline.
malformations tends to progress rapidly and
to end in respiratory failure. The primary Further reading
goal of therapy is thus to partially correct the
deformation and stabilise the correction, N Campbell RM Jr, et al. (2003). The
beginning usually at the age of 1.52 years. characteristics of thoracic insufficiency
syndrome associated with fused ribs
Rib-based implants such as the vertical
and congenital scoliosis. J Bone Joint
expandable prosthetic titanium rib (VEPTR)
Surg Am; 85-A: 399408.
primarily focus on improving the space N Campbell RM Jr, et al. (2007). Thoracic
available for the lungs, thereby allowing lung insufficiency syndrome and exotic scolio-
expansion and, hopefully, stimulating lung sis. J Bone Joint Surg Am; 89: S108S122.
growth. In the near future, new magnetically N Hasler CC, et al. (2010). Efficacy and safety
extensible rods may obviate the need for the of VEPTR instrumentation for progressive
repeated surgical interventions required to spine deformities in young children with
expand current VEPTR devices with growth, rib fusions. Eur Spine J; 19: 400408.
allowing lengthening of the rods in frequent

N Keppler-Noreuil KM, et al. (2011). Clinical N Motoyama EK, et al. (2009). Thoracic
insights gained from eight new cases and malformations with early-onset scoliosis:
review of reported cases with Jeune effect of serial VEPTR expansion thoraco-
syndrome. Am J Med Genet Part A; 155: plasty on lung growth and function in
10211032. children. Paediatr Respir Rev; 10: 1217.
N Kombourlis AC (2009). Pectus excava- N Newton PO, et al. (2005). Results of
tum: pathophysiology and clinical preoperative pulmonary function testing
characteristics. Paediatr Respir Rev; 10: of adolescents with idiopathic scoliosis.
36. J Bone Joint Surg Am; 87-A: 19371946.

Physiology and
pathophysiology of sleep
The two-process model of sleep and overview of basic sleep physiology and
wakefulness predicts the day-to-day pathophysiology, and describes the
synchronisation of an organism with its characteristics of rapid eye movement
environment by the interaction of a circadian (REM) and non-REM (NREM) sleep. Sleep
(process C) and a homeostatic process and circadian-generating systems are also
(process S). This section provides an discussed.
Sleep may be defined as a state of natural

unconsciousness from which a person can
Key points
be aroused. Despite the advances that have
been made in related areas, sleep remains a
N The two-process model of sleep and complicated physiological entity that is not
wakefulness predicts the day-to-day yet fully understood.
synchronisation of an organism to its
environment by the interaction of a For many years, sleep was thought to be a
circadian (C) and a homeostatic purely passive state. However, sleep is an
process (S). active process and the brain is actually quite
N Circadian rhythms are driven by an busy during sleep. It is now known to affect
endogenous circadian pacemaker, both physical and mental health, and is
located in the suprachiasmatic essential for the normal functioning of all
nucleus (SCN) of the hypothalamus. the systems of the body. Since the body is
Circadian sleep rhythm controls the known to require sleep as part of its
sleepwake cycle, modulates physical homeostatic regulatory and repair
activity and food consumption, and mechanisms, it seems logical that the body
over the course of the day, regulates can exert considerable influence on the
body temperature, heart rate, muscle sleep process.
tone and hormone secretion. The physiology of sleep and sleepwake
N The SCN sets the body clock to ,24 h. regulation
The main influence of the SCN on
Sleep is a part of the daily routine for
sleep is due to a series of relays
everyone, even when the normal sleep
through the dorsomedial nucleus of
wake pattern is disrupted by outside factors.
the hypothalamus, which signals to
In humans, the circadian cycle operates in
the sleepwake systems to coordinate
an ,24-h cycle, measured from awakening
their activity with daynight cycles.
after one sleep period to awakening from the
N There are two types of sleep state, next sleep period.
NREM and REM sleep.
The physiological mechanisms of circadian
N NREM sleep is conventionally divided rhythm begin when light strikes special cells
into three or four stages, each with its within the retina of the eye, which, in turn,
own distinguishing characteristics. causes these cells to secrete melatonin,
which causes an area of the brain known as

the suprachiasmatic nucleus (SCN) to None of these theories adequately explain all
signal the pineal body to stop secreting the the facets of sleep as a phenomenon. It is
hormone melatonin, which has been shown also just as likely that a single theory will
to reach its highest levels during sleep. As never be proposed that will incorporate the
the day progresses, adenosine accumulates ever-expanding knowledge base related to
within the brain as the level of melatonin the physiology and function of sleep.
falls.
The two-process model of sleep and
As night falls, the inhibitory effects of the wakefulness predicts the day-to-day
retinal secretions on the pineal body are synchronisation of an organism to its
removed and this allows the pineal to begin environment by the interaction of processes
secreting melatonin once again. It is the C and S.
presence of higher melatonin levels within
certain areas of the brain (e.g. the thalamus Process C Most physiological and
and hypothalamus) that controls the urge to behavioural variables in humans, such as
sleep. heart rate, blood pressure, core body
temperature (CBT), hormone levels, food
Body system changes during sleep are listed consumption, muscle tone, cognitive
in table 1 (NHLBI, 2003; Douglas, 2005). performance, subjective alertness and the
sleepwake rhythm, undergo circadian
There have been several theories advanced rhythms with an ,24-h periodicity.
concerning the biological function of sleep. Circadian rhythms are driven by an
While no one theory can explain all the endogenous circadian pacemaker, located in
observations that have been made regarding the SCN of the hypothalamus. The SCN is
sleep, some are more widely accepted than the master pacemaker in the mammalian
others. brain that synchronises the circadian
oscillators of most neuronal cells and
N The Restorative Theory of sleep holds that peripheral tissues. The SCN sets the body
sleep is a time of growth and repair. clock to ,24 h. Light is the strongest
Some have cited the rise in certain growth zeitgeber for all species, synchronising the
hormones during periods of deeper sleep endogenous circadian clock to the 24-h day
as supporting this hypothesis. However, of the environment. Photobiotic activation is
no one has been able to demonstrate any transmitted to the SCN via the
significant degradation of organ function retinohypothalamic tract. When external
during periods of sleep deprivation. This zeitgebers are absent, the endogenous
theory currently has very little support in circadian clock free-runs with a period
the scientific community. that is slightly different from 24 h in
N The Preservation Theory states that our humans.
sleep cycles are the result of an
evolutionary process that grew from our The circadian profile of melatonin secretion
remote ancestors habits of resting/ and CBT are reliable physiological hands of
sleeping at night, a time when predator the clock and good markers of the
species enjoyed an advantage in vision circadian process in humans. Under
and stealth. Over time, the sleep when entrained conditions, the onset of melatonin
its dark and work in the daylight secretion occurs ,13 h after habitual wake-
behaviors were amplified by natural up time and CBT crests in the afternoon
selection and are present in the brains with a nadir ,2 h before habitual wake time.
neurochemistry. Sleep timing and structure are highly
N The Memory Encoding explanation draws dependent on circadian phase. It has been
upon the large body of evidence shown that the circadian drive for sleep is
demonstrating that learning is facilitated highest in the early morning, whereas the
when the body is well rested and that circadian drive for wakefulness is highest in
memory retention is enhanced by resting the late evening, shortly before bedtime. The
after some new lesson is learned. paradoxical character of these two extremes

Table 1. Physiological changes during sleep
Sleep Physiological changes
periods
Cardiovascular NREM Overall reduction in heart rate, cardiac output and blood
system pressure
REM Variations in blood pressure and heart rate but, overall, the
rates are increased
Respiratory system NREM Slight hypoventilation
REM Slight hypercapnia
Reduction in total ventilation
Reduction in sensitivity to inspired carbon dioxide
Reduction in tidal volume
Increase in respiratory rate
Reduction in rib cage movement
Increase in upper airway resistance
Nervous system NREM Overall, decreased discharge rate, brain metabolism and blood
flow
Active inhibition of the reticular activating system
Increase in parasympathetic activity similar to relaxed
wakefulness
Sympathetic drives remain at about the same level as during
relaxed wakefulness
REM Total blood flow and metabolism in REM sleep are comparable
to wakefulness
Metabolism and blood flow increase in certain brain regions
during REM sleep compared to wakefulness, e.g. limbic system,
visual association areas
During tonic REM sleep, sympathetic activity decreases,
resulting in an overall predominance of parasympathetic activity
During phasic REM sleep, both sympathetic and
parasympathetic activity increase
Sympathetic activation is generally favored
Endocrine system Stage 3 sleep is associated with increased secretion of growth
hormone, thyroid hormone, melatonin and prolactin
Sleep onset inhibits the release of cortisol
Gastrointestinal tract Motility and gastric acid secretion decrease during sleep
Swallowing reflex slows down during sleep.
Kidney Decrease in excretion of Na+, K+, Cl- and Ca2+ during sleep that
allows for more concentrated and reduced urine flow
Secretion of aldosterone increases, as does ADH, both of which
contribute to the decreased production of urine
Decrease in glomerular filtration rate and renal plasma flow
Thermoregulation At sleep onset, body temperature set point is lowered and body
temperature falls
ADH: antidiuretic hormone.
of the circadian system can be explained by homeostatic sleep pressure increases, a

the interaction of process S with process C. stronger wake-promoting signal is needed in
In the course of a normal 16-h day, when the evening than in the morning, when sleep

pressure is low, to counteract upcoming pathways. The first pathway, which
physiological and behavioural decrements. originates from cholinergic neurons in the
In contrast, throughout the night-time sleep upper pons, activates parts of the thalamus
episode, when homeostatic sleep pressure that are responsible for maintaining the
dissipates, a circadian sleep-promoting transmission of sensory information to the
signal is necessary to prevent premature cerebral cortex (Saper et al., 2005). The
waking and to maintain sleep. This concept second pathway, which originates in cell
is drawn from studies with nonhuman groups in the upper brainstem that contain
primates and indicates that one function of the monoamine neurotransmitters
the circadian system is to provide an alerting (norepinephrine, serotonin, etc.), enters the
stimulus, which opposes the accumulating hypothalamus, rather than the thalamus,
homeostatic sleep drive during waking where it picks up inputs from nerve cells
hours. Besides the circadian, there are also that contain peptides (orexin or hypocretin
.24-h and ,24-h processes, which oscillate and melanin-concentrating hormone).
in or out of phase with the endogenous These inputs then traverse the basal
circadian pacemaker and have additional forebrain, where they pick up additional
modulatory influences on sleepwake inputs from cells containing acetylcholine
rhythms in humans (Dijk et al., 1995). and c-aminobutyric acid (GABA).
Ultimately, all of these inputs enter the
Process S Process S was originally assumed cerebral cortex, where they diffusely activate
to be global, and its parameters were mainly
the nerve cells, and prepare them for the
gleaned from central or fronto-central
interpretation and analysis of incoming
derivations. The general view is that the
sensory information.
amount of sleep pressure accumulated
during wake time is reflected in the amount Arousal from sleep could be an important
of slow-wave sleep (SWS) that occurs during defence mechanism against potentially
the following period of sleep. Process S dangerous situations during sleep. Such
depends on prior sleep and wakefulness, situations include severe obstructive
and reflects the need for or pressure of apnoea, oesophageal reflux, cardiac rhythm
sleep. Sleep pressure rises during waking, abnormalities and external suffocation.
declines during sleep and increases with Arousal from sleep that is triggered by
sleep deprivation. The build-up or abnormal levels of carbon dioxide and
dissipation of sleep pressure is usually oxygen is essential for the initiation of
represented by an exponential function. protective airway responses; indeed, head
Slow-wave activity serves as a marker for turning and escape to fresh air are critical
sleep homeostasis and, thus, for modelling for survival from an asphyxial
of process S. Slow-wave activity shows a microenvironment. Arousal involves a
decline in the course of sleep that can be progressive activation of specific
approximated by an exponential decrease subcortical-to-cortical brain structures, and
across NREM sleep episodes (Achermann et consists of ascending and descending
al., 2011). The level of slow-wave activity in components that mediate cortical and
the first NREM sleep episode is dependent subcortical arousal, respectively, with
on the duration of prior waking and is best feedback loops between them. Cortical
described with a saturating exponential arousal involves noradrenergic,
function. serotonergic, dopaminergic, cholinergic and
The central nervous system regulation of histaminergic neurons in the brain stem,
sleep basal forebrain and hypothalamus, which
excite the cerebral cortex and cause cortical
Wakefulness and arousal from sleep Waking activation. Subcortical arousal, however, is
and consciousness depend on the activity mediated mainly by brain-stem pathways
of neurons in the ascending reticular that increase heart rate, blood pressure,
activating system of the brainstem. respiration and postural tone without
Specifically, there are two ascending changes in cortical activity.

NREM and REM sleep The transition catecholamines, acetylcholine, histamine,
between wakefulness and sleep occurs glutamate and aspartate, that are localised
through a process of reciprocal inhibition within the reticular formation and have
between arousal- and sleep-promoting important roles in cortical activation and
neurons by way of a flip-flop switch. arousal.
The switch for sleep is considered to be NREM sleep The thalamus, dorsal raphe,
the ventrolateral pre-optic nucleus (VLPO) nucleus tractus solitarius, anterior
of the anterior hypothalamus. This area hypothalamus and adjacent forebrain areas
becomes active during sleep and uses the are important in producing NREM sleep.
inhibitory neurotransmitters GABA and Neurotransmitters such as serotonin and
galanin to initiate sleep by inhibiting the GABA, which may be important in sleep
arousal regions of the brain. The VLPO mechanisms, are located in these brain
innervates and can inhibit the wake- regions and play an important role in sleep.
promoting regions of the brain including the Serotonin (5-hydroxytryptamine), found in
tuberomammillary nucleus, lateral raphe neurons of the brainstem, may be
hypothalamus, locus coeruleus, dorsal involved in sleep onset. Insomnia occurs
raphe, laterodorsal tegmental nucleus and when serotonergic cells of the dorsal raphe
pedunculopontine tegmental nucleus. The are lesioned. In addition, there is evidence
hypocretin (orexin) neurons in the lateral that substances in the biosynthetic pathway
hypothalamus help stabilise this switch. of serotonin (such as tryptophan and
REM sleep occurs with activation of vitamin B6) may facilitate sleep (Jones,
cholinergic neurons in the laterodorsal and 1989). However, in spite of all the evidence
pedunculopontine tegmental nuclei. This supporting the role of serotonin in sleep
cholinergic activation occurs when onset, there are studies that suggest that the
withdrawal of the aminergic arousal systems role of serotonin in sleep is not clear.
(noradrenergic neurons in the locus
coeruleus and serotonergic neurons in the The inhibitory neurotransmitter GABA is
dorsal raphe nuclei) produces disinhibition. released in its highest concentrations during
This causes the release of acetylcholine, NREM sleep. GABAergic neurons are
which triggers the increased neural activity located throughout the brain, including the
that is a feature of REM sleep. Suppression basal forebrain, hypothalamus, thalamus,
of motor activity, the other marker of REM brainstem and cortex. Hypnotics, such as
sleep, is generated by glutamate-mediated benzodiazepines and barbiturates, tend to
activation of descending medullary reticular work by potentiating GABA-mediated
formation relay neurons. The activity of inhibitory processes. They may shut off
these neurons is inhibitory to spinal motor neurons in the reticular activating system
neurons via the release of glycine, and to a and inhibit transmission and activity of
lesser extent, GABA. neurons that project to the cortex and
thalamus.
Neurochemistry of sleep Sleep results from
the complex interaction of multiple Overall, hypnotics increase total sleep time,
neurotransmitter systems, as well as the decrease sleep latency, decrease the number
influence of other physiological or of awakenings, decrease the amount of time
psychological states. spent in NREM sleep stage 3 and, in some
cases, REM sleep.
Wakefulness Waking and consciousness
depend on the activity of neurons in the REM sleep Acetylcholine is located within
ascending reticular activating system of the neurons in the pontine tegmentum and is
brainstem. These neurons project into the involved in REM sleep generation. REM-
thalamus, hypothalamus and basal on cells are cholinergic cells in the lateral
forebrain, and eventually send projections to pontine and medial medullary reticular areas
the cortex. There are particular that innervate the thalamus, hippocampus
neurotransmitters, such as the and hypothalamus. These cells discharge at

high rates during REM and show little or no standard of 1968. The American Academy of
activity during NREM. Physostigmine, which Sleep Medicine (AASM) has discontinued
inhibits catabolic enzymes, precipitates the the use of stage 4, such that the previous
appearance of REM sleep during NREM. The stages 3 and 4 now are combined as stage 3.
injection of carbachol, a muscarinic agonist, Slow wave sleep usually lasts between 70
into the pontine tegmentum induces REM and 90 min in normal individuals. REM
sleep. Blocking muscarinic receptors will sleep in the first cycle of the night is usually
retard the appearance of REM sleep. short-lived (15 min). Stage 3 sleep occupies
less time in the second cycle, and might
REM-off cells are noradrenergic and disappear altogether from later cycles, as
serotonergic cells found in the locus stage 2 sleep expands to occupy the NREM
coeruleus and raphe. These cells are slow or portion of the cycle. The NREMREM cycles
silent during REM sleep. Affecting levels of vary in length from 70100 min initially to
noradrenaline or serotonin can have an 90120 min later in the night. Across the
effect on REM sleep. In general, night, the average period of the NREMREM
antidepressants have the effect of cycle is approximately 90110 min
decreasing REM sleep, which is elevated in (Carskadon et al., 2011).
human endogenous depression.
The three stages of NREM sleep are each
Sleep architecture
associated with distinct brain activity and
Stages of sleep Sleep is staged in 30-s physiology. As one progresses through
epochs. Sleep begins in NREM and stages 13, sleep gets deeper and waves
progresses through deeper NREM stages become more synchronised.
(stages 13), before the first episode of REM
Stage 1 sleep is a very light stage of sleep with
sleep occurs approximately 80100 min
later. Thereafter, NREM sleep and REM a low arousal threshold. Aside from
sleep cycle with a period of ,90 min. NREM newborns and those with narcolepsy and
other specific neurological disorders, the
and REM sleep alternate cyclically. The
function of alternations between these two average individuals sleep episode begins in
types of sleep states is not yet understood, NREM stage 1. It generally lasts for ,10 min,
but irregular cycling and/or absent sleep constituting 25% of total sleep, and is
easily interrupted by a disruptive noise.
stages are associated with sleep disorders.
Electroencephalography (EEG) is
NREM and REM sleep cycles NREM sleep characterised by low-voltage, mixed-
constitutes about 7580% of the total time frequency activity (47 Hz). Stage 1 is scored
spent asleep and REM sleep constitutes the when ,50% of an epoch contains a-waves
remaining 2025%. REM sleep follows and the criteria for deeper stages of sleep
NREM sleep and occurs four or five times are not met. a-waves are associated with a
during a normal 8-h sleep period. The first wakeful relaxation state and are
REM period of the night may be ,10 min in characterised by a frequency of 813 Hz.
duration, while the last may exceed 60 min. Well-developed a-wave activity is present in
The NREMREM cycles vary in length from most normal children by 8 years of age
70100 min initially to 90120 min later in (fig. 1). Slow rolling eye movements are
the night. often present in the tracings, and the level of
muscle tone is equal or diminished
The first cycle of sleep in the normal young compared to that in the awake state. Vertex
adult begins with stage 1 sleep, which waves are common in stage 1 sleep and are
usually persists for only 17 min at the onset defined by a sharp configuration with a
of sleep. Stage 2 NREM sleep follows this maximum over the central derivations
brief episode of stage 1 sleep and continues (fig. 2).
for approximately 1025 min. Slow-wave
sleep (SWS), often referred to as deep sleep, Stage 2 sleep lasts approximately 1025 min
consists of stages 3 and 4 of NREM sleep, in the initial cycle and lengthens with each
according to the Rechtschaffen and Kales successive cycle, eventually constituting

Left EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Right EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~.C3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~.C4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~.O1M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~.O2M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~.F3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~.F4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chin EMG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Stage W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W
3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
0 5 10 15 20 25 30
Time s
Figure 1. 30-s epoch of wakefulness. During eyes-open wake, the EEG is characterised by high-frequency,
low-voltage activity. Electro-oculography (EOG) shows REM and the chin EMG activity is relatively high.
During eyes-closed wake, the EEG is characterised by prominent a-wave activity. The amplitude of the
channels is 70 mV. W: wake.
between 45% and 55% of the total sleep with durations of 0.51.5 s. The K-complex is
episode. An individual in stage 2 sleep a high-amplitude, biphasic wave of o0.5 s
requires more intense stimuli than in stage 1 duration. A K-complex consists of an initial
to awaken. The EEG during stage 2 sleep sharp, negative voltage (by convention, an
shows relatively low-voltage, mixed- upward deflection) followed by a positive
frequency activity characterised by the deflection (down) slow wave. Spindles are
presence of sleep spindles and K-complexes. frequently superimposed on K-complexes
Sleep spindles are oscillations of 1214 Hz (fig. 3).
Left EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Right EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~C3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~C4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~O1M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~O2M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~.F3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~.F4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chin EMG
107 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
0 5 10 15 20 25 30
Time s
Figure 2. 30-s epoch of stage 1 sleep. EEG is characterised by low-voltage, mixed-frequency activity. Slow
rolling eye movements often are present. Vertex waves are common in stage 1 sleep (arrow). The
amplitude of the channels is 70 mM. EOG: electro-oculogram.

Left EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Right EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~C3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~C4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~O1M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~O2M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~F3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~F4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chin EMG
315 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
0 5 10 15 20 25 30
Time s
Figure 3. 30-s epoch of stage 2 sleep. Stage 2 sleep is characterised by the presence of one or more K-
complexes (arrow) or sleep spindles (arrowheads). The amplitude of the channels is 70 mM. EOG: electro-
oculogram.
During stage 3 sleep (SWS), the EEG is arousal threshold, especially in children
synchronised. Stage 3 lasts approximately (fig. 4).
2040 min in the first cycle and makes up
about 1432% of sleep. This stage is REM sleep is defined by the presence of
characterised by increased amounts of high- desynchronised (low-voltage, mixed-
voltage, slow-wave activity on the EEG. frequency) brain wave activity, muscle
d-wave (slow wave) activity is defined as atonia and bursts of REMs. Sawtooth
waves slower than 2 Hz (.0.5 s duration) wave forms, h-wave activity (37 Hz) and
with a peak-to-peak amplitude .75 mV. slow a-wave activity also characterise REM
During SWS, we see the highest auditory sleep. During the initial cycle, the REM
Left EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Right EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~C3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~C4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~O1M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~O2M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~F3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~F4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chin EMG
208 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
0 5 10 15 20 25 30
Time s
Figure 4. 30-s epoch of stage 3 sleep. Stage 3 NREM sleep is called slow-wave, d-wave or deep sleep. Stage
3 is scored when slow-wave activity (frequency ,2 Hz and amplitude .75 mV peak to peak) is present for
.20% of the epoch. The amplitude of the channels is 70 mM. EOG: electro-oculogram.

period may last only 15 min; however, it the total sleep duration in a day can be 14
becomes progressively prolonged as the 16 h. Over the first several months of life,
sleep episode progresses. REM sleep sleep time decreases; by age 56 months,
generally makes up 2025% of total sleep sleep consolidates into an overnight period
time in adults. In infants, REM sleep may with at least one nap during the day. Total
account for up to 50% of sleep. REM sleep sleep time continues to decrease during
consists of tonic and phasic characteristics. childhood as nap duration and frequency
Tonic characteristics are persistent decrease.
throughout the entire REM sleep period,
while phasic characteristics appear In newborns, sleep can be categorised into
intermittently during the REM sleep period. two main patterns, active sleep (REM
Tonic characteristics include a precursor), and quiet sleep (NREM
desynchronised EEG, muscle atonia and a precursor), but a proportion of sleep time is
lack of thermoregulation. Phasic not attributable to either of these patterns
characteristics include REMs, clitoral and and is accordingly classed as indeterminate.
penile tumescence, and dreams (fig. 5). Non-EEG correlates are very helpful in
recognising NREM and REM sleep in infants
Typically, stage 3 sleep is present more in 6 months post-term or younger. These
the first third of the night, whereas REM correlates in REM sleep include the
sleep predominates in the last third of the presence of irregular respiration, chin
night. This can be clinically helpful, as electromyogram (EMG) atonia and REMs.
NREM parasomnias such as sleep walking In NREM sleep, correlates include regular
typically occur in the first third of the night respiration, no or rare vertical eye
with the presence of stage 3 sleep. This movements and preserved chin EMG tone.
contrasts with REM sleep behaviour REM sleep in infants represents a larger
disorder, which typically occurs in the last percentage of the total sleep (newborn to
half of the night. There are numerous 3 months, 50%; by 35 months, 40%; by the
physiological differences between NREM end of the first year, 30% of total sleep
and REM sleep (table 1). time). After 3 months, NREM sleep begins to
dominate. The percentage of REM sleep is
Important developmental changes occur in reduced to adult levels by 10 years of age.
sleep over an individuals lifetime. In newborns, Until the age of 3 months, newborns
Left EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Right EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~C3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~C4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~O1M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~O2M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~F3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~F4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chin EMG
623 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
0 5 10 15 20 25 30
Time s
Figure 5. 30-s epoch of REM sleep. REM sleep is characterised by a low-voltage, mixed-frequency EEG, the
presence of episodic REMs, and a relatively low-amplitude chin EMG. Sawtooth waves also may occur
in the EEG. The amplitude of the channels is 70 mM. EOG: electro-oculogram.

transition from wake into REM sleep. morning after sleep restriction. In addition,
However, sleep-onset REM may continue up children do not show recovery rebound of
to ,6 months of age. Thereafter, sleep SWS and REM sleep similar to that reported
starts with NREM sleep. At 3 months of age, for adults. Children seem to require more
clear differentiation of NREM sleep states by time to recuperate fully from nocturnal sleep
EEG criteria is quite difficult. By 6 months, restriction than adults. The effect of sleep
NREM sleep can typically be differentiated restriction on daytime sleepiness,
into three distinct states (stages 1 and 2, performance of children in school and
and SWS) (Anders et al., 1995). behaviour is prominent.
Effects of sleep deprivation Sleep disorders
As the function of sleep has not been fully A sleep disorder is loosely defined as any
determined, the absolute number of hours condition or process that alters the patients
necessary to fulfil its function is still previously established sleepwake cycle.
unknown. Some individuals claim full Sleep disorders are divided into two general
effectiveness with only 35 h of sleep per classes: dyssomnias and parasomnias.
night, while others claim to need o8 h of
Dyssomnias are conditions that manifest
sleep per night to perform effectively. Sleep
themselves as either hypersomnia
deprivation is a relative concept. Small
(abnormal sleep cycles causing the urge to
amounts of sleep loss (e.g. 1 h per night over
sleep at times when the circadian cycle
many nights) have subtle cognitive costs,
would suggest that wakefulness was
which appear to go unrecognised by the
appropriate) or insomnia (the inability to
individual experiencing the sleep loss. More
sleep). The dyssomnias can be further
severe restriction of sleep for a week leads to
subdivided into three classes that are
profound cognitive deficits similar to those
dependent on the source of the sleep
seen in some stroke patients. Glucose
interference.
positron emission tomography (PET)
studies in individuals deprived of sleep have N Intrinsic (arising within the body):
shown that after 24 h of sustained primary insomnia, OSA, restless leg
wakefulness, the metabolic activity of the disorder and unspecified limb
brain decreases significantly. In humans, movements.
sleep deprivation also results in a decrease N Extrinsic (arising outside the body):
in core body temperature, a decrease in environmental conditions not conducive
immune system function as measured by to uninterrupted sleep, such as noise or
white blood cell count and activity, and a ambient temperature.
decrease in the release of growth hormone. N Alteration or interference with the
Sleep deprivation has also been implicated circadian rhythm: jet lag or variations in
as a cause of increased heart rate variability occupational schedules (shift work).
(Banks et al., 2007).
Parasomnias include sleep terror (sudden
Short-term sleep deprivation has been awakening and unreasonable fear),
implicated in contributing to obesity as well bedwetting, somnambulism (sleep walking)
as glucose dysregulation contributing to and somniloquy (talking in ones sleep)
poor control of type II diabetes. (American Academy of Sleep Medicine,
2005).
Children differ from adults in their response
to acute restriction in sleep. When sleep has This AASM classifies sleep disorders into
been restricted by o4 h, there is a decrease eight major categories:
in all stages of sleep (except SWS), a
reduction in sleep onset latency, stage 3 1. insomnia,
latency and REM latency. Multiple sleep 2. sleep-related breathing disorders,
latency tests show a significant increase in 3. hypersomnias of central origin,
daytime sleepiness, which persists into the 4. circadian rhythm sleep disorders,

5. parasomnias, N Achermann P, et al. Sleep homeostasis
6. sleep-related movement disorders, and models of sleep regulation. In: Kryger
7. isolated symptoms and normal MH, et al., eds. Principles and Practice of
variants, Sleep Medicine. 5th Edn. Philadelphia,
8. other sleep disorders. Elsevier Saunders, 2011; pp. 431-444.
N Carskadon M, et al. Normal human sleep:
Conclusion an overview. In: Kryger MH, et al., eds.
Principles and Practice of Sleep Medicine.
Humans spend about one-third of their lives 4th Edn. Philadelphia, Elsevier Saunders,
asleep, yet most individuals know little 2005; pp. 1323.
about sleep. Although its function remains N Dijk DJ, et al. (1995). Contribution of the
to be fully elucidated, sleep is a universal circadian pacemaker and the sleep
need of all higher life forms including homeostat to sleep propensity, sleep
humans, absence of which has serious structure, electroencephalographic slow
physiological consequences. Sleep is divided waves, and sleep spindle activity in
into two periods: NREM sleep and REM humans. J Neurosci; 15: 35263538.
sleep. NREM sleep is conventionally divided N Dijk DJ, et al. (2002). Integration of
into three or four stages, each with its own human sleep-wake regulation and circa-
distinguishing characteristics. Sleep begins dian rhythmicity. J Appl Physiol; 92: 852
in NREM and progresses through deeper 862.
NREM stages (stages 13) before the first N Douglas NJ. Respiratory physiology: con-
episode of REM sleep occurs approximately trol of ventilation. In: Kryger MH, et al.,
80100 min later. Thereafter, NREM sleep eds. Principles and Practice of Sleep
and REM sleep cycle with a period of Medicine. 4th Edn. Philadelphia, Elsevier
,90 min. NREM and REM sleep alternate Saunders, 2005; pp. 224229.
N Iber C, et al. The AASM Manual for the
cyclically. The function of alternations
Scoring of Sleep and Associated Events:
between these two types of sleep states is
Rules, Terminology and Technical
not yet understood but irregular cycling and/ Specifications. Westchester, American
or absent sleep stages are associated with Academy of Sleep Medicine, 2007.
sleep disorders. N Jones BE. Basic mechanisms of sleep-
wake states. In: Kryger MH, et al., eds.
Further reading Principles and Practice of Sleep Medicine.
4th Edn. Philadelphia, Saunders, 2005;
N American Academy of Sleep Medicine. pp. 136153.
International Classification of Sleep N National Heart, Lung and Blood Institute.
Disorders: Diagnostic and Coding Sleep, Sleep Disorders, and Biological
Manual. 2nd Edn. Westchester, American Rhythms: NIH Curriculum Supplement
Academy of Sleep Medicine, 2005. Series, Grades 912. Colorado Springs,
N Anders TF, et al. Normal sleep in Biological Sciences Curriculum Study,
neonates and children. In: Ferber RKM, 2003.
ed. Principles and Practice of Sleep N Vitaterna M, et al. Molecular genetic
Medicine in the Child. Philadelphia, basis for mammalian circadian rhythms.
Saunders, 1995; pp. 718. In: Kryger MH, et al., eds. Principles and
N Banks S, et al. (2007). Behavioral and Practice of Sleep Medicine. 4th Edn.
physiological consequences of sleep Philadelphia, Elsevier Saunders, 2005;
restriction. J Clin Sleep Med; 3: 519528. pp. 363374.

OSAS and upper airway
resistance syndrome
Maria Pia Villa and Silvia Miano
OSAS in children is defined as a disorder of

breathing during sleep characterised by Key points
prolonged partial upper airway obstruction
and/or intermittent complete obstruction N OSAS in children is a complex, multi-
(obstructive apnoea), which disrupts normal organ syndrome consisting of
ventilation during sleep and normal sleep habitual snoring, witnessed apnoea,
patterns. Prevalence ranges from 1.2% to sleep fragmentations and diurnal
5.7%. Although no specific genes have been consequences.
identified for OSAS to date, it has become N The most frequent cause is adeno-
apparent that OSAS is probably a polygenic tonsillar hypertrophy and treatment
disease. Specific genes impacting on factors involves adeno-tonsillectomy;
such as oral mucosa thickness and facial however, many children do not
structure may play a deterministic role in resolve and need further therapy, such
OSAS. as orthodontic therapy.
Diagnosis
Signs and symptoms Paediatric OSAS is Other rare conditions include foreign body
accompanied by habitual snoring aspiration, vascular haemangioma or other
(o3 nights?week-1) and major nocturnal and tumours.
diurnal symptoms and signs (table 1). Other
conditions that may be associated with OSA One of the mechanisms implicated in the
are: pathogenesis of OSAS is increased
collapsibility of the upper airway during
N allergic rhinitis, sleep, because the activity of the upper
N asthma, airway dilator muscles is not enough to
N Down syndrome, compensate for an anatomically small upper
N nasoseptal obstruction, airway. Children with OSAS often have
N cleft palate repair and velopharyngeal significantly large adenoids and tonsils,
flap, causing the upper airway to collapse.
N craniofacial syndromes (Treacher However, enlarged adeno-tonsillar tissues
Collins, midfacial hypoplasia, Crouzon may not always lead to OSAS. A complex
syndrome, Apert syndrome, Pierre Robin interaction between the anatomical
sequence, etc.), component and other elements, such as
N achondroplasia, upper airway tone, respiratory drive, etc., has
N mucopolysaccharidoses, been postulated. Several anatomical and
N macroglossia, functional mechanisms may lead to OSAS in
N sickle-cell disease, children and in adults, one being a smaller
N myelomeningocele, upper airway, which predisposes subjects to
N cerebral palsy, airway collapse during sleep in all age
N prematurity, groups. Orthodontic and craniofacial
N neuromuscular disorders. abnormalities associated with OSAS are,

Table 1. Major signs, symptoms and other conditions accompanying paediatric OSAS
Symptoms Signs Other conditions
Laboured breathing during sleep Underweight or overweight AfricanAmerican
Gasps/observed episodes of Tonsillar hypertrophy Allergic rhinitis
apnoea
Sleep enuresis Adenoidal facies Asthma
Sleeping in a seated position or Micrognathia Prematurity
with the neck hyperextended
Cyanosis Retrognathia Neurological conditions
(cerebral palsy or
neuromuscular diseases)
Headaches on awakening High-arched palate Craniofacial syndromes
Daytime sleepiness Failure to thrive Down syndrome
Attention deficit/hyperactivity Hypertension Rare diseases such as
disorder and or learning achondroplasia or
problems mucopolysaccharidoses
Data from Marcus et al. (2012) and Bhattacharjee et al. (2009).
despite their impact on public health, widely low-grade inflammatory condition. The
ignored. A narrow upper airway with induction of systemic inflammatory
maxillary constriction and/or some degree of responses is most likely related to the
mandibular retrusion is a common generation of systemic oxidative stress
paediatric phenotype of OSAS. In such secondary to the recurrent hypoxic
cases, children are typically described as and arousal episodes that characterise
having a narrow, long face, they may have OSAS.
retrognathic mandibles and increased
posterior facial height associated (or not) Failure to thrive was extremely frequent and
with severe tonsillar hypertrophy. Whether attributed to increased metabolic
this skeletal conformation is genetically expenditure caused by the elevated work of
determined or influenced by the early onset breathing during sleep, reduced nutrient
of habitual snoring has yet to be assessed. intake due to tonsillar hypertrophy and,
Another common abnormality in patients most likely, to disrupted growth hormone
with OSAS is a high arched (ogival) palate, insulin growth factor pathways in the
which results in posterior tongue presence of recurrent hypoxaemia and
displacement forcing the lateral palatine disturbed sleep patterns. In more recent
processes to expand over the abnormally years, however, obesity has emerged as a
placed tongue. frequent finding and it is likely to amplify the
morbidities of OSAS and obesity alone. The
Comorbidities Paediatric OSAS is associated
concomitant presence of OSAS in obese
with a multitude of end-organ morbidities,
children further amplifies the risk for lipid
such as daytime sleepiness, neurocognitive
disturbances and reveals the presence of an
impairment, behavioural problems, failure
interaction between adiposity and insulin
to thrive, hypertension, cardiac dysfunction
resistance. Adipokines, including leptin, are
and systemic inflammation.
cytokines released from adipose tissue that
In recent years, research from many are important in the regulation of appetite,
paediatric sleep centres has accumulated metabolic homeostasis, sleep and
substantial evidence suggesting that respiratory control. A recent study reported
paediatric OSAS constitutes a systemic on the elevation of circulating leptin levels in

children with OSAS, independent of the that have evaluated autonomic dysfunction
degree of obesity. reported an increase in diastolic blood
pressure, both during wakefulness and
The exact prevalence of excessive daytime sleep, as well as an increase in sympathetic
sleepiness (EDS) in paediatric OSAS is activity demonstrated by peripheral arterial
unclear and, when objective measurements tonometry and catecholamine concentration
on sleep propensity are used (i.e. multiple measurements in plasma and urine. An
sleep latency test), the prevalence of EDS in increase in basal sympathetic activity during
paediatric OSAS ranged from 13% to 20%. wakefulness has been demonstrated in
Furthermore, the presence of obesity patients with OSAS. In children with OSAS,
appeared to increase the likelihood of EDS. an increase in the baseline systolic and
It is estimated that 30% of all children with diastolic blood pressure and heart rate has
frequent and loud snoring will manifest been observed, whereas the autonomic
significant hyperactivity and inattention cardiovascular tests revealed a greater
(attention deficit-hyperactivity disorder variability of blood pressures during the
(ADHD)), and learning problems. Moreover, supine-to-orthostatic posture change, as
children with OSAS have a lower global well as less heart rate variability during deep
intelligence compared to controls, with breathing. Cardiovascular diseases reported
positive correlations between sleep in patients with moderate-to-severe OSAS
fragmentations and global intelligence and also include pulmonary hypertension with
ADHD scores, while a positive correlation cor pulmonale, left ventricular (LV)
was found between ADHD scores and oxygen hypertrophy or dysfunction, cardiac
saturation during the night. This study arrhythmias, atherosclerosis and coronary
indicated that arousal is a protective artery disease. A common
mechanism to preserve cognitive function by pathophysiological aspect of these
counteracting the respiratory events, at the alterations is the presence of a condition of
expense of sleep maintenance. A study oxidative stress and increased reactive
previously reported a high prevalence of oxygen species generation, which directly or
paroxysmal activity in a population of indirectly promotes the development and
children with OSAS (14.3% of the sample progression of LV dysfunction or
investigated). Interictal epileptiform hypertrophy and vascular remodelling.
discharges (IEDs) mostly occurred over the Oxidative stress and asymptomatic
centro-temporal regions, suggesting some (subclinical) proinflammatory state, as
similarities with IEDs of benign epilepsy with demonstrated by the higher serum levels of
central temporal spikes. Since the occurrence high-sensitivity C-reactive protein (hsCRP),
of IEDs during sleep may disrupt cognitive have been observed in adults and children
abilities and impair learning and memory in with OSAS and have been interpreted as
children, the findings may represent a new pathogenetic factors that promote cardiac
possibility to explain the neurocognitive remodelling and LV structural and
dysfunction in children with OSAS. functional adaptations in these patients. The
presence of both left and right ventricular
Of particular interest are the cardiovascular hypertrophies, as well as diastolic
complications that may develop in children abnormalities, detected by means of
with OSAS, since they may have not only an conventional Doppler examination of LV
immediately significant impact on filling patterns, in children with severe
cardiovascular health during childhood, but OSAS, hypertension or obesity have been
may also affect cardiovascular outcomes demonstrated. A two-dimensional colour
during adult life. Studies in children with Doppler cardiac examination with LV mass
OSAS have reported increased blood assessment and systolic and diastolic
pressure, changes in cardiac structure and function evaluation revealed that LV
function, increased fasting insulin and lipid diastolic dysfunction was significantly more
levels, and endothelial dysfunction as signs frequent in patients with severe OSAS,
of cardiovascular damage. The few studies associated with higher hsCRP levels.

Sleep polysomnography analysis The airflow signal amplitude compared with the
American Academy of Pediatrics pre-event baseline amplitude for at least
recommends that if a child or adolescent 90% of the duration of the event; the event
snores on a regular basis and has any of the had to last at least two missed breaths and
major symptoms then clinicians should be associated with an arousal, awakening or
obtain a polysomnograph (PSG). Although a .3% desaturation (fig. 1). The AHI is
history and physical examination are useful defined as the average number of apnoeas,
to screen patients and determine which hypopneas and respiratory event-related
patients need further investigation for arousals per hour of sleep. The diagnosis is
OSAS, the sensitivity and specificity of the defined by an obstructive AHI .1 event?h-1.
history and physical examination are poor.
As part of the OSAS spectrum of severity,
Recently, a simple Sleep Clinical Record
upper airway resistance syndrome and
based on physical examination, subjective
another PSG feature of obstructive alveolar
symptoms and clinical history has been
hypoventilation constitute mild forms of
validated. In children with a score less than
OSAS, characterised by an increased
6.5 PSG is not performed.
number of arousals that can be attributed to
However, the gold standard test remains increased respiratory effort (upper airway
overnight, attended, in-laboratory PSG resistance syndrome) and increased end-
(sleep study). This is a noninvasive test tidal carbon dioxide levels during sleep.
involving the measurement of a number of If PSG is not available, then clinicians may
physiological functions overnight, typically perform alternative diagnostic tests, such as
including electroencephalography (EEG), nocturnal video recording, nocturnal
pulse oximetry, oronasal airflow, abdominal oximetry, daytime nap PSG or ambulatory
and chest wall movements, partial pressure PSG, although they have weaker positive-
of carbon dioxide, oxygen saturation and and negative-predictive values than PSG. If
video recording. Specific paediatric an alternative test fails to demonstrate
measuring and scoring criteria should be OSAS in a patient with signs and symptoms,
used. Central, obstructive and mixed apnoea a full PSG should be performed with
events were counted according to the extended EEG montage in order to exclude
criteria established by the American the presence of IEDs.
Academy of Sleep Medicine (AASM).
Obstructive apnoea was scored when there Treatment
was a .90% drop in the signal amplitude of Adeno-tonsillectomy is recommended when
airflow for .90% of the entire event, a child with OSAS has a clinical examination
compared with the pre-event baseline consistent with adeno-tonsillar hypertrophy
amplitude with continued chest wall and and does not have a contraindication to
abdominal movement for a duration of at surgery. Clinical judgment is required to
least two breaths. Central apnoea was determine the benefits of adeno-
defined as the absence of airflow, with the tonsillectomy compared with other
cessation of respiratory effort, lasting .20 s treatments in obese children with varying
or at least two missed breaths (or the degrees of adeno-tonsillar hypertrophy.
duration of two baseline breaths), Other treatment options, such as anti-
associated with an arousal, an awakening or inflammatory medications, weight loss or
a .3% desaturation. Central apnoea tracheostomy, are less effective. Risk factors
occurring after gross body movements or for post-operative complications of adeno-
after sighs was not considered a tonsillectomy are:
pathological finding. Mixed apnoea was
defined as apnoea that usually began as N children ,3 years of age,
central and ends in obstruction, according N severe OSAS on PSG,
to changes in the chest, abdominal and flow N cardiac complications,
traces. An event could be scored as N failure to thrive,
hypopnoea if there was a .50% drop in N obesity,

a) C4-A1
b) C4-A1
C3-A2 C3-A2
D2-A1 D2-A1
D1-A2 D1-A2
LOC LOC
ROC ROC
Chin Chin
ECQ
ECQ
Nasal
cannula Effort
Chest Nasal
cannula
Abdomen Chest
Abdomen
SaO2
SaO2
Pulse
d)
c) C4-A1
C4-A1
C3-A2
C3-A2
D2-A1
D2-A1
D1-A2
D1-A2
LOC
LOC
ROC
ROC
Chin Chin
ECQ
ECQ
Effort
Effort
Nasal Nasal
cannula cannula
Chest Chest
Abdomen Abdomen
SaO2 SaO2
Figure 1. Examples of a) obstructive apnoea, b) central apnoea, c) mixed apnoea and d) hypopnea sleep
epochs of 120 s. ROC: right electro-oculogram; LOC: left electro-oculogram.
N craniofacial anomalies, or supplementary treatment in children

N neuromuscular disorders, presenting with OSAS. Although the use of
N current respiratory infection. oral appliances has received relatively little
attention in the literature, interest in this
It is also recommended that all patients with
approach is growing rapidly. Oral appliances
an oxygen saturation ,80% and an AHI
may improve upper airway patency during
o24 events?h-1 should be observed as
sleep by enlarging the upper airway and/or by
inpatients.
decreasing upper airway collapsibility, thereby
Clinicians should refer patients for CPAP improving upper airway muscle tone. The
management if symptoms and signs or treatment options available for growing
objective evidence of OSAS persists after children are rapid maxillary expansion,
adeno-tonsillectomy or if adeno- mandibular retropositioning and a modified
tonsillectomy is not performed. There is no monobloc. Rapid maxillary expansion, which is
clear advantage of using bilevel pressure a dentofacial orthopaedic treatment procedure
over CPAP. Clinicians should recommend routinely used in young patients .4 years with
weight loss in addition to other therapy if a constricted maxillary arches, is considered to
child/adolescent with OSAS is overweight or be an effective treatment for OSAS.
obese. Clinicians may prescribe topical
intranasal corticosteroids for children with Conclusion
mild OSAS in whom adeno-tonsillectomy is
There is a great need for further research
contraindicated or for children with mild
into the prevalence of OSAS, consequences
post-operative OSAS (AHI ,5 events?h-1).
of OSAS and the best treatments. In
Orthodontic treatment by means of oral particular, randomised controlled trials of
devices is considered to represent a potential treatment are needed. Figure 2 shows an

Sleep-disordered breathing:
multidisciplinary approach
Paediatrician, ORL, orthodontist,

sleep record
NO
Diagnostic evaluation? Refer to paediatrician
YES
NO
High risk or <2 years Overnight pulse oximetry
YES NO
Positive?
YES#
Attended video PSG Adenotonsillectomy or
or unattended PSG craniofacial surgery or
orthodontic treatment, CPAP
Refer to paediatrician, follow-up NO Positive?
YES
YES# Signs and symptoms
Drug therapy, plus orthodontic NO
Surgical intervention? after therapy?
therapy and/or diet, or CPAP
NO
NO YES YES
Symptoms? Adenotonsillectomy or Signs and symptoms
craniofacial surgery after 6 months?
YES
Adjusting therapy and or CPAP YES NO
Clinical evaluation and or
Signs and symptoms? overnight pulse oximetry
YES
Signs and symptoms?
NO YES
NO Positive?
Clinical evaluation and/or
Clinical evaluation PSG after 6 months NO
and/or PSG after 6 months
YES YES NO
Positive? Positive? Refer to paediatrician
NO
Refer to paediatrician, follow-up
Figure 2. Algorithmic approach to the diagnosis and treatment of paediatric OSAS. ORL:
otoringolarhingologic examination; PSG: polysomnography. #: refer to the orthodontist for ORL, assess
for obesity, and perform cardiologic (ECG, blood pressure holter) and neuropsychological assessment.
algorithm for the diagnosis and treatment of N Bhattacharjee R, et al. (2010). Adeno-
paediatric OSAS using a multi-step tonsillectomy outcomes in treatment
approach. As multi-therapies might act of obstructive sleep apnea in children:
synergistically, a greater degree of a multicenter retrospective study.
collaboration between sleep medicine, ENT Am J Respir Crit Care Med; 182:
specialists and orthodontists is warranted to 676683.
N Gozal D, et al. (2008a). Metabolic
establish the contribution of each therapy to
alteration and systemic inflammation
the outcome of paediatric OSAS. in obstructive sleep apnea among non-
obese and obese prepubertal children.
Further reading Am J Respir Crit Care Med; 177: 1142
1149.
N Amin RS, et al. (2008). Activity-adjusted 24- N Gozal D (2008b). Obstructive sleep
hour ambulatory blood pressure and cardiac apnea in children: implications for the
remodelling in children with sleep disor- developing central nervous system.
dered breathing. Hypertension; 51: 8491. Semin Pediatr Neurol; 15: 100106.

N Iber C, et al., eds. The AASM manual N Tresaco B, et al. (2005). Homeostatic
for the scoring of sleep and associated model assessment (HOMA) index cut-off
events: rules, terminology, and tech- values to identify the metabolic syndrome
nical specifications. Westchester, in children. J Physiol Biochem; 61: 381388.
American Academy of Sleep Medicine, N Villa MP, et al. (2012a). Early cardiac
2007. abnormalities and increased C-reactive
N Marcus CL, et al. (2012). American protein levels in a cohort of children with
Academy of Pediatrics. Diagnosis and sleep disordered breathing. Sleep Breath;
management of childhood obstructive 16: 101110.
sleep apnea syndrome. Pediatrics; 130: N Villa MP, et al. (2012b). Mandibular advance-
714755. ment devices are an alternative and valid
N Miano S, et al. (2011). Neurocognitive treatment for pediatric obstructive sleep
assessment and sleep analysis in children apnea syndrome. Sleep Breath; 16: 971976.
with sleep-disordered breathing. Clin N Villa MP, et al. Mandibular Advancement
Neurophysiol; 122: 311319. Devices in Sleep Disordered Breathing in
N Montesano M, et al. (2010). Autonomic Children A Comprehensive Clinical Guide
cardiovascular tests in children with to Evaluation and Treatment. Heidelberg,
obstructive sleep apnea syndrome. Humana Press, 2012c; pp. 542551.
Sleep; 33: 13491355. N Villa MP, et al. (2013). Sleep clinical
N Tauman R, et al. (2004). Peripheral ar- record: an aid to rapid and accurate
terial tonometry events and electroence- diagnosis of paediatric sleep disordered
phalographic arousals in children. Sleep; breathing. Eur Respir J 41: 13351361.
27: 502506. N Waters KA, et al. (2007). Structural
N Tauman R, et al. (2007). Adipokines in equation modeling of sleep apnea,
children with sleep disordered breathing. inflammation, and metabolic dysfunction
Sleep; 30: 433449. in children. J Sleep Res; 16: 388395.

Central sleep apnoea and
hypoventilation syndromes
Malin Rohdin and Hugo Lagercrantz
Sleep alters the function and control of the cessation of breathing for at least two
respiratory system. These changes may result breaths. Central sleep apnoea can be
in clinically significant abnormalities in upper idiopathic but it can also occur secondary to
airway function and pulmonary gas exchange another medical condition. Central apnoeas
among healthy children as well as those with are common in the neonatal period,
an underlying disease. Sleep disordered particularly among pre-term newborns, and
breathing (SDB) is a common cause of this is viewed as a physiological immaturity of
morbidity in childhood that can result in breathing control and ceases spontaneously
severe complications if left untreated. Central around term post-conceptional age. Central
sleep apnoea, hypoventilation syndromes and hypoventilation is caused by an inability of the
OSA are sleep-related breathing disorders, central nervous system to maintain
and this section will focus on the first two ventilation sufficient to overcome the
conditions. Central sleep apnoea is respiratory load. Alveolar hypoventilation
characterised by a decreased or absent syndromes are often caused by an abnormal
respiratory drive that results in reduction or central integration of chemoreceptor signals
and can be primary, as in congenital central
hypoventilation syndrome (CCHS), or
Key points secondary to diseases of the central nervous
system or neuromuscular disorders. Early
N Central sleep apnoea and diagnosis and comprehensive treatment will
hypoventilation syndromes are causes minimise the number of sequelae and
of morbidity in childhood that may improve individual outcomes.
result in severe complications if left
Clinical features
untreated.
N Complications of sleep apnoea Sleep apnoea should be considered in
include pulmonary hypertension, cor children of all ages who present with
pulmonale, systemic hypertension, nonspecific symptoms of daytime
cardiac arrhythmias, hypoxic cerebral dysfunction. More specific signs and
injury and seizures. symptoms of SDB include nocturnal or
early-morning headache, poor sleep quality
N PSG is the gold standard test for SDB with nocturnal awakenings, failure to thrive,
and is required to diagnose sleep- and daytime breathing disturbances.
related disorders. Children with daytime sleepiness due to
N Treatments include supplementary SDB often act out behaviourally (e.g.
oxygen, caffeine (apnoea of hyperactivity, impulsivity and increased
prematurity), diaphragm pacing, aggression) rather than complaining
CPAP, BiPAP and mechanical verbally. Younger children are less likely than
ventilation via tracheostomy. older children to show signs of tiredness
(e.g. yawning and rubbing eyes).

Sequelae of SDB The reason why some syringobulbia, Chiari malformation, high
children become hypoxic and others arouse cervical spinal cord injuries, encephalitis,
from sleep in response to respiratory multiple system atrophy, and autonomic
compromise is unclear. Intermittent hypoxia disorders such as Rett syndrome and
is an important mediator of neurocognitive familial dysautonomia. Respiratory
deficit in children. Animal models dysfunction constitutes an early and
simulating isolated intermittent hypoxia relatively major manifestation of several
have shown neuronal cell loss in brain areas neurological disorders, and may be due to
critical for executive function and memory, an abnormal breathing pattern generation
namely the pre-frontal cortex and due to involvement of the cardiorespiratory
hippocampus. network or more frequently to respiratory
muscle weakness.
Sleep-related hypoxaemia in children is
associated with neurobehavioral, cognitive Apnoea of prematurity is a common problem
and cardiovascular morbidities. Other affecting pre-term infants and probably
sequelae in infants and young children secondary to a physiological immaturity of
include pulmonary hypertension, failure to respiratory control. The incidence of apnoea
thrive, cor pulmonale, systemic is inversely correlated with gestational age
hypertension, cardiac arrhythmias, hypoxic and birth weight. During rapid eye
cerebral injury and seizures. Perturbation in movement (REM) sleep, these infants have
neonatal respiratory control and chronic more paradoxical breathing with a less
intermittent hypoxia in premature infants stable baseline oxygen saturation. Therefore,
may contribute to later SDB. apnoeas occur more frequently in REM sleep
than in quiet sleep. Apnoea of prematurity
Severe apnoea that lasts .20 s is usually
may be exacerbated by diseases such
associated with bradycardia or desaturation,
as infections, intracranial haemorrhage,
which may lead to disturbances of cerebral
hypoxicischaemic encephalopathy,
haemodynamics and possibly affect
seizures, patent ductus arteriosus, and
neurodevelopmental outcome. However, it is
difficult to demonstrate a link between apnoea glucose or electrolyte imbalance. Resolution
and poor neurodevelopmental outcome due of apnoea and establishment of a normal
to a number of comorbidities and respiratory pattern is a major developmental
confounding factors affecting neurological milestone for many pre-term infants.
development. In addition, reports of severity Rett syndrome is a severe
may be unreliable, and impedance monitoring neurodevelopmental disorder that almost
techniques may fail to identify mixed and exclusively affects females. After Down
obstructive events. Therefore, evaluating the syndrome, Rett syndrome is the most
consequences of apnoea and hypoventilation common specific cause of severe cognitive
on long-term neurological development impairment in females, affecting one in
remains a challenge. 10 000. Rett syndrome causes severe
Central sleep apnoea The word apnoea autonomic dysregulation, probably due to
comes from the Greek word meaning brainstem dysfunction. The patients have
without wind. The brainstem respiratory severely disturbed breathing and heart rate
network contains neurons critical for both when awake and when asleep (Rohdin
respiratory rhythmogenesis (pre-Botzinger et al., 2007). The cardiorespiratory morbidity
complex). This network receives inputs from is characterised by hypoventilation, central
peripheral and central chemoreceptors, and apnoea, episodic hyperventilation,
from forebrain structures. Manifestations tachycardia, bradycardia and poor peripheral
associated with disorders of this network circulation. A mouse model of Rett
include sleep apnoea and dysrhythmic syndrome revealed breathing disturbances
breathing. Common disorders associated that probably originate from a deficiency in
with impaired cardiorespiratory control noradrenergic and serotonergic modulation
include brainstem stroke or compression, of the medullary respiratory network.

Familial dysautonomia is a ventilation during wakefulness, to complete
neurodevelopmental disorder that affects apnoea during sleep and severe
autonomic and sensory functions. Familial hypoventilation during wakefulness. CCHS
dysautonomia is caused by mutations in the is, however, far more complex than a simple
IKBKAP gene on chromosome 9 and orphan disorder of respiratory control.
transmitted as an autosomal recessive Patients with CCHS also have disturbances
disorder. Patients with familial of autonomic nervous system regulation.
dysautonomia have SDB with both central Characteristically, patients have diminutive
and obstructive apnoea. Many individuals tidal volumes and monotonous respiratory
with familial dysautonomia initially increase rates both while awake and asleep, although
ventilation during shorter periods of hypoxia more profound alveolar hypoventilation
but have a decreased ventilatory drive primarily occurs during sleep. Furthermore,
during prolonged hypoxia. It follows that CCHS patients display a reduced influence
familial dysautonomia patients must be of breathing on cardiac rate variation as well
cautious in settings where the partial as a range of disturbances in both
pressure of oxygen is decreased, such as at sympathetic and parasympathetic nervous
high altitudes or during aeroplane travel. system control. Despite reduced ventilatory
responses to hypercapnia and hypoxaemia,
Alveolar hypoventilation syndromes are often
peripheral chemoreceptor responses are
caused by an abnormal central integration
partially preserved, particularly among
of chemoreceptor signals and could be
primary, as in CCHS and PraderWilli children who are able to sustain near-
syndrome (PWS), or secondary to diseases adequate ventilatory output during
of the spinal cord or brainstem. The wakefulness. There is stage-related
respiratory deficit is typically more severe cardiorespiratory and autonomic regulation
during sleep than wakefulness and is that can be learned from the care of infants
characterised by alveolar hypoventilation, with CCHS (fig. 1). Polysomnography (PSG)
resulting in hypoxaemia and hypercarbia. often shows different ventilatory responses
depending on sleep stage, with more severe
The goddess Ondine and her curse According hypoventilation during non-REM sleep than
to a Medieval folk tale, the water nymph during REM sleep in CCHS patients. Huang
Ondine would became mortal only when she et al. (2008) speculated that this
fell in love with a human. She sacrifices her phenomenon may be due to increased
immortality by marrying a knight, Sir excitatory inputs to the respiratory system
Lawrence, and bearing his child. Sir during REM sleep. CCHS appears to be the
Lawrence promises Ondine that his every only respiratory disorder in which breathing
waking breath will be a testimony of his love, is better during REM than during non-REM
but he is soon unfaithful to her. Witnessing sleep (Huang et al., 2008).
Sir Lawrences adultery, the king of the
nymphs curses the knight. The kings curse In most cases, CCHS is diagnosed in the
makes the mortal responsible for newborn infant, although an increasing
remembering to perform all bodily number of patients are diagnosed after the
functions. When Sir Lawrence falls asleep, neonatal period and even up to adulthood
he forgets to breathe and dies. (late-onset CCHS). An increased clinical
awareness of CCHS may prevent potential
Ondines curse is a term used to denote life-threatening decompensation or
CCHS, a rare neurological condition neurocognitive impairment. Clinical
causing lifelong failure of respiratory suspiciousness towards unexplained
regulation. CCHS is characterised by sleep- alveolar hypoventilation is likely to identify
related, life-threatening hypoventilation a higher incidence of milder cases of
requiring lifetime mechanically assisted CCHS.
ventilation during sleep. The severity of
ventilatory dysregulation ranges from A mutation in the disease-defining gene
hypoventilation during sleep and adequate PHOX2B (paired-like homeobox) is a

mmHg kPa PraderWilli syndrome is a complex disorder
12 with hypothalamic dysfunction where the
clinical features vary with age. Early
80
Quiet sleep symptoms include hypotonia, feeding
10
difficulties and failure to thrive, and later
Active sleep symptoms are hypogonadism, hyperphagia
60 8
End-tidal PCO2
obesity, and behavioural and cognitive

problems. PWS is a genetic disorder where a
Awake state
6 majority (7075%) of the affected
40 individuals have a deletion in the paternally
4 derived chromosome 15q11q13. Individuals
with PWS are at risk for a variety of
20 abnormalities of breathing during sleep,
2
including alveolar hypoventilation, central
apnoeas and OSA. The incidence and
2 7 9 severity of alveolar hypoventilation are
8
related to the degree of obesity. Individuals
Time months
with PWS may have a restrictive lung
disease due to muscle weakness or
Figure 1. End-tidal carbon dioxide tension (PCO2) in scoliosis. They also have impaired
a toddler (3-year-old girl) with CCHS. End-tidal
ventilatory control during sleep with
PCO2 was highest during quiet sleep and lowest
abnormal ventilatory responses to
during wakefulness, while it was moderately
hypercapnia and hyperoxia, and reduced
elevated during active (REM) sleep. It illustrates
how the suprapontine respiratory drive can sustain arousal responses to hypoxia. Excessive
ventilation during wakefulness and, to some extent, daytime sleepiness is a common feature and
during REM sleep, but not during quiet sleep. is suggested to be a primary feature of PWS
rather than a consequence of insufficient
sleep quantity or quality.
requisite to the diagnosis of CCHS. The Patients with PWS, particularly if they are
PHOX2B gene promotes neuronal obese or have symptoms suggestive of SDB,
differentiation and development of the require a PSG to exclude or characterise
autonomic nervous system. Knowledge of abnormal breathing. An early diagnosis of
the specific PHOX2B mutation aids in SDB and appropriate treatment may delay or
anticipating CCHS phenotype severity prevent the development of cor pulmonale.
(Weese-Mayer et al., 2010). CCHS is
Secondary hypoventilation syndromes
associated with an increased risk of
Alveolar hypoventilation syndromes can be
Hirschsprungs disease and tumours of
secondary to an underlying disease and
neural crest origin. A fairly recent study
therefore cause an abnormal central
from the French CCHS registry estimates
integration of chemoreceptor signals.
an incidence of one per 200 000 live births
Examples include diseases affecting the
(Trang et al., 2005). PHOX2B mutation-
central nervous system (trauma, tumours
confirmed CCHS confers a risk of adverse
and cerebrovascular incidents),
neurocognitive outcome, though the range
neuromuscular disorders, chest wall
of observed functioning raises questions
deformities and obesity. This is a
about factors that may contribute to
heterogeneous group of diseases and
neurocognitive variability. The
incurs variable degrees of damage to the
recommended management options in
respiratory control centres.
optimising CCHS patient care and
neurocognitive outcome are summarised Neuromuscular disorders SDB is now well
in an official American Thoracic Society recognised in children with neuromuscular
clinical policy statement (Weese-Mayer disorders and may lead to significant
et al., 2010). morbidity and increased mortality.

Predisposing factors include reduced PSG in children. Overnight PSG studies are
ventilatory responses, reduced activity of preferred because negative nap studies
respiratory muscles during sleep and poor have been shown not to exclude the
lung mechanics due to the underlying possibility of SDB. Studies should be
neuromuscular disorder. Children with performed without sedation in order to
different neuromuscular disorders are at most accurately mimic the childs normal
risk of developing both central and sleep. PSG requires an overnight stay at a
obstructive apnoea and hypoventilation sleep laboratory and the attachment of
during sleep. These neuromuscular multiple sensors to the patient. Qualitative
disorders include Duchenne muscular respiratory effort is detected using thoracic
dystrophy, myotonic dystrophy, spinal and abdominal belts, which is essential in
muscular atrophy, cerebral palsy, distinguishing between central and
poliomyelitis, myasthenia gravis, peripheral obstructive respiratory events. Sleep stages
neuropathies, metabolic myopathies and can be assessed by behavioural criteria
congenital muscle diseases (Arens et al., using video recording or determined using
2010). Symptoms of SDB in children with electroencephalography (EEG), chin
neuromuscular diseases may be subtle. electromyography (EMG) and electro-
The physician should be especially vigilant oculography (EOG). Gas exchange is
for any of the following complaints: assessed by monitoring SpO2 and end-tidal
snoring, increasing numbers of nocturnal or transcutaneous carbon dioxide. Airflow
awakenings, daytime sleepiness, or can be assessed with a thermistor, nasal
morning headache that may be caused by pressure or capnography. ECG is essential
cerebral vasodilation due to to evaluate cardiorespiratory regulation, as
hypoventilation and carbon dioxide respiratory events may be associated with
retention. Additional symptoms, such as different heart rate regulation. Audio and
fatigue, exertional dyspnoea, orthopnoea, digital video recordings are useful in
swallowing difficulties, weakened cough, documenting snoring, body position and
weight loss and frequent respiratory movements.
infections, could suggest progression of
the underlying respiratory muscle disorder Respiratory events during PSG Apnoea is
and worsening of nocturnal ventilation and often defined as a cessation or decrease in
SDB. Abnormal respiration during sleep in airflow by o90% compared to the baseline
these disorders is often not predicted by flow observed before the event when the
awake pulmonary function testing, arterial event meets duration and respiratory effort
blood gases or the degree of muscle criteria for an obstructive, mixed or central
involvement. apnoea (Berry et al., 2012). Partial airway
obstruction is characterised by shallower or
Polysomnography slower breathing, and has been described by
the term hypopnoea. Hypopneas are
PSG is the gold-standard test for SDB in defined as a o30% reduction in airflow, for
infants and children. It is a noninvasive the duration of two or more breaths in
method to diagnose sleep-related association with either o3% oxygen
hypoventilation due to central mechanisms desaturation or an arousal. The apnoea
or upper airway obstruction, or mixed hypopnoea index (AHI), expressed as the
apnoeas. This in-laboratory, multichannel number of apnoeas and hypopneas per hour
method obtains information about sleep of sleep, is an important measure for
architecture, respiratory effort, movements quantifying disease severity. Apnoeas and
during sleep, respiratory events and gas hypopnoeas can be further classified as
exchange, facilitating the evaluation of being central, obstructive or mixed in
children with suspected SDB. Children should nature.
preferably be studied in a sleep laboratory
equipped for, and staffed with personnel A central apnoea is when the event meets
comfortable with and experienced in, criteria for an apnoea, there is an absence of

inspiratory effort throughout the event and unfortunately, only symptomatic treatments
at least one of the following conditions is exist, including positive pressure ventilation
met: via tracheostomy, BiPAP, negative pressure
ventilation or diaphragm pacing. It is of
N the event is o20 s in duration, utmost importance to select the best mode
N the event is associated with an arousal or of artificial ventilatory support for each
o3% oxygen desaturation, individual patient. CCHS does not seem to
N in infants (,1 year of age) only, the event improve with age, except in rare anecdotal
is associated with a decrease in heart rate cases.
to ,50 beats per minute for o5 s or ,60
beats per minute for 15 seconds (Berry
et al., 2012). Further reading
The respiratory pause in central apnoea is N American Thoracic Society (1996).
not associated with a physical attempt to Standards and indication for cardiopul-
breathe: the PSG shows no breathing monary sleep studies in children. Am J
movements from the thoracic cage or Respir Crit Care Med; 153: 866878.
abdomen. Obstructive apnoea is a cessation N Arens R, et al. (2010). Sleep, sleep
of airflow at both the nose and mouth disordered breathing, and nocturnal
associated with out-of-phase movements of hypoventilation in children with neuro-
muscular diseases. Paediatr Respir Rev; 11:
the rib cage and abdomen. A mixed apnoea
2430.
has no inspiratory effort in the initial portion
N Beck SE, et al. (2009). Pediatric polysom-
of the event, followed by resumption of
nography. Sleep Med Clin; 4: 393406.
inspiratory effort before the end of the event. N Berry RB, et al. (2012). Rules for scoring
Periodic breathing is defined as more than respiratory events in sleep: update of the
three episodes of central apnoea lasting 2007 AASM Manual for the Scoring of
.3 s separated by f20 s of normal Sleep and Associated Events. Deliberations
breathing. Alveolar hypoventilation is when of the Sleep Apnea Definitions Task Force
PaCO2 (or a surrogate measure) is of the American Academy of Sleep
.50 mmHg for .25% of total sleep time. Medicine. J Clin Sleep Med; 8: 597619.
Surrogates of PaCO2 are end-tidal or N Bixler EO, et al. (2009). Sleep disordered
transcutaneous carbon dioxide tension. breathing in children in a general popula-
tion sample: prevalence and risk factors.
Treatments for SDB Sleep; 32: 731736.
N Bourke R, et al. (2011). Cognitive and
Clinical management of apnoea of
academic functions are impaired in
prematurity includes continuous positive or
children with all severities of sleep-
nasal intermittent positive pressure
disordered breathing. Sleep Med; 12:
ventilation to prevent pharyngeal collapse 489496.
and alveolar atelectasis. Methylxanthine N Huang J, et al. (2008). Effect of sleep
compounds such as caffeine, theophylline stage on breathing in children with
and aminophylline stimulate the central central hypoventilation. J Appl Physiol;
nervous system and respiratory muscle 105: 4453.
function, and probably reduce apnoea by N Iber C, et al. The AASM manual for the
multiple physiological and pharmacological scoring of sleep and associated events:
mechanisms. rules, terminology, and technical specifi-
cations. 1st Edn. Westchester, American
Other treatments for SDB include Academy of Sleep Medicine, 2007.
supplementary oxygen, CPAP, bi-level N Lal C, et al. (2012). Neurocognitive
positive pressure ventilation (BiPAP) and impairment in obstructive sleep apnea.
mechanical ventilation via tracheostomy. In Chest; 141: 16011610.
hypoventilation syndromes, the primary N Lesser DJ, et al. (2009). Congenital
goals are often to secure the airway, and hypoventilation syndromes. Semin Respir
ensure optimal ventilation and oxygenation Crit Care Med; 30: 339347.
with artificial ventilation. For CCHS,

N Patwari PP, et al. (2010). Congenital N Trang H, et al. (2005). The French
central hypoventilation syndrome and Congenital Central Hypoventilation
the PHOX2B gene: a model of respiratory Syndrome Registry. General data, pheno-
and autonomic dysregulation. Respir type, and genotype. Chest; 127: 7279.
Physiol Neurobiol; 173: 322335. N Weese-Mayer DE, et al. (2010). An official
N Rohdin M, et al. (2007). Disturbances in ATS clinical policy statement: congenital
cardio-respiratory function during day central hypoventilation syndrome genetic
and night in Rett syndrome. Pediatr basis, diagnosis, and management. Am J
Neurol; 37: 338344. Respir Crit Care Med; 181: 626644.

Impact of obesity on
respiratory function
Andrea Bon, Martina Tubaro and Mario Canciani
Obese children present different lung defined as: mass (kg)/[height (m)]2. In
anatomy and function and have more adults, a BMI .30 kg?m-2 defines obesity,
respiratory symptoms than their normal- but as the normal BMI changes throughout
weight peers. Paediatric obesity is now childhood and is age- and sex-specific, a
considered a major public health problem centile chart has to be used in children. In
and data from many observational studies UK centile charts, overweight is taken as a
show an increase of this disease in recent BMI .91st centile and obesity a BMI .98th
decades, in all age-groups: about 7% of the centile. Other methods of assessment
world population is obese. In Europe the include Ideal Body Weight (IBW), waist
prevalence of childhood obesity ranges from circumference, waist/hip ratios, skinfold
1020% in the north to 2040% in the cities thickness, abdominal fat from CT/MRI
of the Mediterranean basin. In the USA, the scans, bioelectrical impedance and dual
prevalence of overweight children has tripled energy X-ray absorptiometry (DEXA).
in the past 20 years. Globally, an estimated
Lung function in obesity
43 million preschool children (under age
5 years) were overweight or obese in 2010, a There are limited data on obese children,
60% increase since 1990. but studies on adults show that obesity has
a profound effect on the anatomy and
The commonest and simplest method of physiology of breathing (table 1).
measuring and determining obesity is BMI,
The upper airways may be directly narrowed
by fatty infiltration of muscles and
Key points subcutaneous fat deposits.
N Obesity is defined as BMI .98th An important respiratory abnormality in

centile according to age- and sex- obesity is a decrease in total respiratory
specific centile charts. system compliance. The primary reason is a
decrease in chest wall compliance
N Obesity is associated with a change in associated with the accumulation of fat.
static and dynamic lung volumes. Lung compliance is decreased as well and
N Obese children experience more may relate to the increased pulmonary blood
respiratory symptoms compared to volume seen in obese individuals. Total
their normal-weight peers. respiratory compliance is reduced markedly,
mainly in supine position. This reduction
N There is a parallel increase in asthma increases the work of breathing, along with
and obesity prevalence, but a true an increase in nonelastic work and
relationship is controversial. inefficiency of respiratory muscles. The
N Obese children should be screened at nonelastic work comes from the raised
routine visits for the presence of upper and lower airway resistance, the latter
snoring, apnoea, sleep disordered resulting from a reduction in lung volumes
breathing and daytime drowsiness. due to obesity. Moreover, studies suggest
that the pressures generated by the

Table 1. Main changes in lung physiology in obesity decreased lung volumes with increasing
obesity.
Q Total respiratory compliance
Q chest wall compliance Finally, gas exchange, assessed by the
Q lung compliance carbon monoxide diffusion capacity (DLCO),
q Work of breathing is increased in obesity. This may be
q nonelastic work explained by increased pulmonary blood
Q muscle efficiency volume and flow. This rise has been
Change in static lung volumes observed without evidence of pulmonary
Q ERV congestion or heart disease.
Q FRC
Asthma and obesity
Change in dynamic lung volumes
Q FEV1 The relationship between asthma and
Q FVC obesity in children is controversial. The
q Gas exchange increasing prevalence of asthma in children
in recent decades, demonstrated by several
Q: decrease; q: increase. epidemiological studies, goes hand in hand
with the rise in obesity, making these
diseases among the top priorities in
childhood health both in Western countries
respiratory muscles in obese patients are and in the developing world. The definition
lower than those of nonobese patients at all of asthma is crucial if we are to find any
lung volumes. This may result from definite correlation with obesity. Asthma is
diaphragm dysfunction due to increased characterised by increased airway
abdominal and visceral adipose tissue responsiveness with chronic inflammation,
deposition, or from overstretching of resulting in reversible airway obstruction.
diaphragm fibres leading to length-tension The criteria for asthma diagnosis and
disadvantage. asthma definition vary between studies and
frequently rely on self-reported symptoms
In obese individuals, there are changes in
(or on physician diagnosis based solely on
static and dynamic lung volumes. Among
self-reported symptoms). Review of the
the static lung volumes, expiratory reserve
evidence suggests that a higher BMI in
volume (ERV) and functional residual
children is associated with a higher
capacity (FRC) are decreased, and this is
prevalence of symptoms commonly
more evident in the supine position due to
attributed to asthma, such as wheeze, but
the increased gravitational effects of the
not a higher prevalence of objective
abdomen. TLC and vital capacity (VC) may
asthma. Obese children are less fit and
be reduced, while residual volume (RV) is may have more symptoms of
usually maintained. These changes breathlessness on exertion than their peers.
influence ventilation:perfusion ratio mainly An increased perception of symptoms in
at the bases, where airway closure and the obese may further complicate
alveolar collapse are responsible for this issue.
underventilation. Dynamic lung volumes
are affected only in morbidly obese However the parallel increases in prevalence
subjects. An increase in body mass suggest a link between the two conditions,
correlates with reduced FEV1 and FVC. even if the pathophysiological basis of this
Generally, in mild obesity, spirometry is relationship remains unclear. Correlation
normal. Patients with mild-to-moderate mechanisms seem to be possible: sedentary
obesity present a restrictive pattern whereas lifestyle, dietary factors, systemic
with severe and morbid obesity spirometry inflammation, reduced chest wall
is more likely to show true airflow compliance, insulin resistance, the presence
obstruction. One mechanism may be of comorbidities and common genetic
related to small airway collapse due to predispositions.

Cross-sectional studies show a weak link children with mild or moderate asthma have
between asthma and obesity. However, a a significant risk of becoming overweight.
number of longitudinal studies in children
and adolescents show a positive Paediatricians should be cautious about
association, in particular supporting the diagnosing asthma in an obese child on the
correlation between overweight and future basis of self-reported symptoms alone, and
risk of developing asthma. In addition, should seek objective evidence from peak-
obesity may be associated with asthma flow recordings, exercise tests or laboratory
severity and/or poor asthma control. Studies measurement of airway reactivity.
in adult asthma patients show that obese Obstructive sleep apnoea syndrome
patients are more symptomatic, require
more medications and make more OSAS is a disorder of breathing during sleep
emergency department visits than their characterised by prolonged partial upper
nonobese counterparts. However, such airway obstruction and/or intermittent
reports in the paediatric population are complete obstruction (obstructive apnoea)
controversial. that disrupts normal ventilation during sleep
and normal sleep patterns. Obese children
Asthma and obesity are both characterised have a 4.5-fold increased risk for OSAS
by chronic inflammation. Asthma is, by compared with the general population. In the
definition, a chronic inflammatory disease. pathophysiology of OSAS in obese children,
Obese patients show a low degree of anatomical and functional factors play a role.
systemic inflammation involving a number In the first group, adenoid and tonsillar
of mediators, known as adipokines. The hypertrophy is found in 45% of obese children
adipokines include tumor necrosis factor-a, with OSAS. However, after
interleukin-6, eotaxin, vascular endothelial adenotonsillectomy OSAS persists in nearly
growth factor and chemotactic proteins for half of obese paediatric patients, compared to
monocytes. These factors have been 1020% residual OSAS in nonobese children.
associated with asthma and may play a role Other anatomical factors, such as fat pads,
in the common state of inflammation. soft palate, lateral pharyngeal wall, and
Leptin, one of the main hormones involved tongue may restrict upper airway size. A
in the regulation of inflammation in obesity, recent study suggests that the development
is potentially relevant in asthma as well. of OSAS in obese children is linked to marked
High levels of leptin are associated with an visceral adiposity, increased parapharyngeal
increased prevalence of asthma during life, fat pads and upper airway lymphoid
especially nonatopic asthma. Leptin serum hypertrophy, even if the size of these tissues
levels in asthmatic patients are high do not correlate with the BMI. Obese children
independently of BMI, possibly because have an increased incidence of both the
leptin contributes to the typical presence and marked enlargement of the
inflammatory cascade of asthma. lingual tonsils. This enlargement can be
responsible for persistent OSAS after
Obesity is often associated with sedentary adenotonsillectomy and require specific
lifestyle leading to dyspnoea and treatment. In obese children, as previously
breathlessness during exercise, which could stated, there is a change in chest wall
be interpreted easily as asthma or wheezing. mechanics, reducing compliance and FRC,
These symptoms lead to a further reduction leading to hypoventilation, atelectasis, and
in physical activity and increase in body ventilation:perfusion mismatch. Functional
weight in a vicious circle. Poorly controlled factors leading to airway collapsibility may be
exercise-induced asthma as well may neuromotor tone, tissue properties and
contribute to reduction in physical activity increased resistance. Studies on obese adults
and to weight gain, showing an overlap with OSAS have demonstrated higher critical
among obese and asthmatic phenotypes. closing pressure of the pharynx, a direct sign
The Childhood Asthma Management of increased airway collapsibility. It is possible
Program (CAMP) Study has shown that that obese children have altered ventilatory

responses, although the role of the ventilatory the respiratory system with muscular
drive in OSAS in children is unclear. exhaustion leading to chronic hypoxia and
hypercapnia, with blunting of chemo-
Although true cardiovascular diseases are receptor responsiveness in susceptible
not detected in young children with OSAS, individuals. The chronic fatigue, daytime
predisposing conditions such as the sleepiness and headaches of these patients
dysregulation of blood pressure, cardiac are associated with hypercapnia and
function, autonomic function and hypoxaemia; with time these patients
endothelial function are independently develop polycythaemia, pulmonary
associated with it. Studies suggest OSAS as hypertension and later right ventricular
a possible independent cause of metabolic failure. The most appropriate treatment
syndrome, augmenting insulin resistance, includes weight loss and nocturnal NIV.
dyslipidaemia, hypertension and
inflammation through increased Breathing disorders in obesity-associated
sympathetic tone, intermittent hypoxaemia, syndromes
sleep fragmentation and insufficient sleep.
PraderWilli syndrome Commonly
Obese children should be screened at associated characteristics of this syndrome
routine visits for the presence of snoring, include neonatal hypotonia, obesity due to
apnoea, disordered breathing during sleep excessive intake and inactivity, mental
and daytime drowsiness. Polysomnography retardation, short stature, scoliosis,
is considered the gold standard for the hypogonadotropic hypogonadism,
diagnosis of OSAS. Other methods, such strabismus, and small hands and feet.
nocturnal pulse oximetry or daytime nap Typically these children may present a
polysomnography are specific but need variety of abnormalities of breathing,
confirmation if negative. Weight loss is including OSAS and sleep-related alveolar
associated with a significant reduction in hypoventilation. Although the abnormal
sleep apnoea and is the most effective long- response to hypercapnia is probably related
term treatment, but the least likely to take to obesity, there is an altered ventilatory
place. However, the majority of patients response to hypoxaemia and chemoreceptor
continue to experience sleep disordered responsiveness both in obese and nonobese
breathing. In obese children with OSAS and patients with PraderWilli syndrome. They
adenotonsillar hypertrophy, adenotonsill- may not arouse normally following
ectomy is an important option, with effective prolonged airway obstruction, leading to
resolution of symptoms in about 50%. CPAP increased risk of morbidity, including
is considered in patients without sudden death. Severely obese patients with
adenotonsillar hypertrophy or ineffective respiratory impairment receiving human
adenotonsillectomy. Other treatments growth hormone are potentially at risk of
include oral appliances, uvulopalato- sudden death especially in the first 12
pharyngoplasty and positional therapy, with 18 months of therapy.
variable results.
The treatment of OSA in PraderWilli
Obesity hypoventilation syndrome patients includes weight loss, which is
particularly difficult for these patients,
Obesity hypoventilation syndrome (OHS), adenotonsillectomy, and NIV, which could
also known as Pickwickian syndrome, is be challenging with the behavioural
defined as a combination of obesity and problems associated with this syndrome.
awake arterial hypercapnia (arterial carbon
dioxide tension .45 mmHg) in the absence Down syndrome Many features that
of other causes of hypoventilation. This characterise this syndrome, such as
disorder is associated with gross obesity, micrognathia, hypotonia, macroglossia,
with only few case reports in children. The midfacial hypoplasia, along with obesity,
pathophysiology is thought to be the increase the risk of airway obstruction. The
exasperation of the mechanical loading of first-line treatment is adenotonsillectomy.

Further reading N De Onis M, et al. (2010). Global pre-
valence and trends of overweight and
N American Academy of Pediatrics (2012). obesity among preschool children. Am J
Diagnosis and management of childhood Clin Nutr; 92: 12571264.
obstructive sleep apnea syndrome. N Deane S, et al. (2006). Obesity and the
Pediatrics; 130: 576584. pulmonologist. Arch Dis Child; 91: 188191.
N Arens R, et al. (2011). Upper airway N Koenig SM. (2001). Pulmonary complica-
structure and body fat composition in tions of obesity. Am J Med Sci; 321:
obese children with obstructive sleep 249279.
apnea syndrome. Am J Respir Crit Care N Parameswaran K, et al. (2006). Altered
Med; 183: 782787. respiratory physiology in obesity. Can
N Black MH, et al. (2012). Higher preva- Respir J; 13: 203210.
lence of obesity among children with N Raanan A, et al. (2010). Childhood
asthma. Obesity; 20: 10411047. obesity and obstructive sleep apnea
N Costa DJ, et al. (2009). Adenoton- syndrome. J Appl Physiol; 108: 436444.
sillectomy for obstructive sleep apnea N Redline S, et al. (2007). Association
in obese children: a meta-analysis. between metabolic syndrome and sleep-
Otolaryngol Head Neck Surg; 140: disordered breathing in adolescents. Am J
455460. Respir Crit Care Med; 176: 401408.

Lung injury
Andreas Schibler
A multitude of endogenous and exogenous ventilation/perfusion mismatch exists (a

factors can cause acute lung injury in infants false low PaO2/FIO2 ratio). Lung injury can be
and children. The clinical picture is seen as part of a systemic inflammatory
characterised by an increased work of process (sepsis, pancreatitis and post-blood
breathing and impaired gas exchange. transfusion), or directly related to local
Depending on the severity of the lung injury injury caused by infection, aspiration or toxic
mechanical respiratory support is needed. gas inhalation. The histopathological
An adult-based definition for acute lung characteristics are a widespread destruction
injury (ALI) or acute respiratory distress of the capillary endothelium, extravasation
syndrome (ARDS) has been developed for of protein-rich fluid and interstitial oedema
the purpose of clinical trials. The definition followed by damage to the alveolar
of ALI or ARDS has changed little over the membrane, and fluid leaks into the alveolar
past 20 years and is mainly defined by a space.
bilateral pulmonary infiltrate on chest
radiography (fig. 1), a pulmonary capillary ARDS is characterised by two distinct
wedge pressure of ,18 mmHg (for stages. The acute phase is defined by
paediatric purpose excluding heart failure disruption of the alveolarcapillary
due to congenital heart disease or membrane with leakage of protein-rich fluid
cardiomyopathy) and a PaO2/inspiratory in interstitial and alveolar space combined
oxygen fraction (FIO2) ratio ,200 or ,300 by release of cytokines and inflammatory
for ARDS and ALI, respectively. A recent cells. This leads to a secondary leakage of
review of the ARDS and ALI criteria defines inflammatory proteins into the circulation
severe ARDS as a PaO2/FIO2 ratio ,100 and (systemic inflammatory response syndrome
moderate ARDS as a PaO2/FIO2 ratio 100 (SIRS)). The second reparative stage shows
200. ALI is defined as a PaO2/FIO2 ratio 200 fibroproliferative changes with organisation
300. This definition doesnt consider the of lung tissue. Although any lung injury is a
considerable large range of possible causes diffuse process, it is also a heterogeneous
for lung injury and fails to accurately disease and not all lung units are affected
characterise the severity if significant equally. This causes two different
pathophysiological outcomes. First,
ventilation-induced lung injury (VILI) is
Key points more likely to affect the open and less
injured lung unit than the closed and hardly
N ALI can be caused by endogenous or aerated diseased lung. Secondly, the
exogenous factors. ventilation/perfusion mismatch increases
intrapulmonary shunting, which decreases
N VILI causes additional harm in the
oxygen delivery. Hence the corner stone of
presence of lung injury.
optimal mechanical support is to open the
N Protective ventilation strategies have previously closed lung units and have them
reduced the mortality of ARDS. participating in the gas exchange. In
achieving this, airway pressures are more

man-made disease. Avoiding high airway
pressures and potentially even avoiding
invasive mechanical ventilation may
improve outcome of patients with ARDS.
Human and experimental studies in healthy
lungs have shown that the mechanical
stress inflicted on the tissue and skeleton of
the lung during positive pressure
ventilation can be seen within 20 min of
ventilation. For a better understanding of
the differences between healthy and sick
lungs knowledge of ventilation distribution
is important. In healthy lungs the alveolar
structure hardly changes its geometry
during tidal breathing and volume changes
occur mainly in the peripheral airways and
alveolar ducts. The alveolar structure is
maintained by the elastic stretch and recoil
forces of the lung parenchyma and the
Figure 1. Chest radiograph from a 5-year-old girl presence of surfactant within the alveoli.
with sepsis-induced ARDS. Note, the bilateral Hence the lung parenchyma does not
chest infiltrate affecting the majority of the lung experience significant mechanical stress
fields. during regular tidal breathing. This delicate
balance and geometry is destroyed in lung
disease and alveoli may additionally be
evenly distributed throughout the lung and
filled with secretion containing loose
less damage is seen to the healthier parts of
alveolar or epithelial cells, neutrophils,
the lung. Intrapulmonary shunts are
macrophages, lymphocytes and airway
decreased and oxygen uptake improved.
secretion. This then leads to collapse or
The two-hit model atelectasis, especially of the dependent lung
regions. Gas exchange is consequently
For a comprehensive understanding of the impaired and these so-called closed lung
characteristics of lung injury the concept of regions experience significant shunting of
the two-hit model needs to be discussed. pulmonary blood flow, which adds to low
The initial primary hit consists of the systemic oxygen saturation. Mechanical
underlying pathological process such as ventilation directs positive pressure into
hyaline membrane disease, bacterial or viral these affected lung regions and causes
infection, or aspiration of meconium or cyclic opening and closing of the alveoli.
water in drowning. In case mechanical Alveoli do not tolerate these extreme stress
ventilatory support is required for adequate forces and the previously mentioned
gas exchange a secondary hit may occur, rupture of the alveolarcapillary membrane
previously described as VILI. This occurs. In the past, rather large tidal
secondary hit causes an augmentation of volumes were delivered during mechanical
the already pre-existing inflammatory ventilation (1015 mL?kg-1), which were
response of the lung, which is commonly detrimental to the lung and led to
defined as biotrauma caused by positive significant secondary lung injury. The newer
pressure ventilation. Most of the recent approach of mechanical ventilation these
research efforts aimed to reduce and days is to reopen and stabilise the
minimise this secondary insult have collapsed lung regions and expose the lung
improved ventilation strategies with to small tidal volumes (protective
significantly better outcomes and reduced ventilation). This is mainly achieved by
morbidity and mortality. Many experts in using recruitment manoeuvres of the lung
the field even argue that ARDS is a partially and the use of high positive end-expiratory

pressures (PEEP). Studies using CT-guided N an increase in airway calibre and length,
lung recruitment have shown significantly N development of the immune system,
improved respiratory mechanics and gas including the plasticity of T-helper cell
exchange, but this has not yet translated response,
into reduced mortality. The concept of N exposure to a range of pathogens and
protective ventilation with high PEEP and viruses, in particular for the first time.
low tidal volumes as a general strategy has
improved outcome overall (mainly studied The interaction of the disease process with
in adult patients with ARDS). In clinical normal lung development may have long
practice, however, we lack good monitoring lasting impact on lung function. It is
tools indicating optimal lung recruitment therefore not surprising that the impact of
and mechanical support. In general, tidal positive pressure ventilation in addition to
volumes of 6 mL?kg-1 and generous PEEP the interactions mentioned above further
have been accepted also in paediatric augments the potential for more severe lung
ventilation. The personal experience of injury. Another important factor is that
during invasive ventilation, secondary lung
many ventilation experts is that the severity,
infections (ventilator-associated pneumonia
morbidity and mortality of children with
(VAP)) and aspiration of saliva and acidic
ARDS have been reduced. Mortality of
fluids from gastro-oesophageal reflux occur.
ARDS has been reported for infants and
children to as high as 40% Respiratory causes are responsible for
and, for ALI, 20%. The availability of ,25% of all admissions to paediatric
extracorporeal membrane oxygenation intensive care units. Bronchiolitis and
(ECMO) in combination with the use of pneumonia are the most common among
protective ventilation has further improved respiratory causes but with a relative low
outcome. Newer adult figures show an mortality (1.9%). All common respiratory
ARDS mortality of 25% and it is suspected viruses, such as RSV, HMV and influenza,
that the current paediatric figure is well can cause ARDS similar to any bacterial
below 25%. Most of the patients die infection. Other exogenous causes are fresh
because of the associated multiorgan water aspiration during drowning, inhalation
failure and not lung failure. Pulmonary of toxic fumes in a house fire or aspiration of
oedema can present clinically and on gastric content in the unconscious or
radiography is very similarly to ARDS. seizing patient (table 1). In cases of smoke
Hence, in all patients echocardiography of inhalation injury, carbon monoxide and
the heart needs to be performed. cyanide poisoning complicate the care of the
patient. Transfusion-related acute lung
Cause and pathophysiology of ALI needs to injury (TRALI) is a potentially fatal side-
be discussed based on the following three effect of blood transfusion. It is now
factors: stage of lung development at which considered to be the most frequent cause of
the insult occurred, and endogenous or transfusion-related morbidity and mortality
exogenous cause for the injury. and is under-reported and underdiagnosed.
TRALI is thought to develop via transfusion
Insult during lung development of either an anti-leukocyte antibody or a
biological response modifier. Transfusion of
There are fundamental differences in the
blood products in a patient with an already
remodelling process during and after lung
existing ALI may aggravate the lung disease.
injury between adults and children despite
Conservative blood transfusion
similarities in the structural changes of the
management in ARDS is suggested.
disease process. In adults, the lung injury
occurs in a fully developed lung whereas, in A few ARDS/ALI-specific treatment options
contrast, in infants and young children will be briefly discussed. Most evidence is
,3 years of age airway and lung tissue adult-based as there are only a few
development still occurs. The changes in the paediatric ARDS trials. The general concept
developing lung include: of a high PEEP (10-15 cmH2O) and low tidal

Table 1. Causes of lung injury ARDS if they are treated with NIV at an early
stage. Further to the appropriate
Exogenous antimicrobial therapy, surfactant
Sepsis replacement has been successfully used in
Pneumonia paediatric ARDS. The key to success is to
use surfactant in the early stage to keep the
Aspiration and drowning
lung open for adequate ventilation. Inhaled
Meconium aspiration syndrome nitric oxide to treat hypoxaemia and reverse
Inhalation of noxious fumes the associated pulmonary hypertension has
Endogenous
been widely used but the sobering fact is
that nitric oxide has not had any impact on
TRALI outcome. Currently, nitric oxide should only
Pancreatitis be offered in desperate cases before transfer
Burns to ECMO and if the patient doesnt respond
then nitric oxide should be ceased. The use
Poisoning
of steroids is also controversial. It is
suggested that the use of steroids in a low
dose and mainly during the early stage of
volume ventilation (6 mL?kg-1) strategy is ARDS may be beneficial. Steroids may have
mostly accepted in paediatric intensive care, a short-term benefit in improving gas
despite the lack of paediatric-specific data. exchange and lung function, and even
With the use of low tidal volumes clinicians ventilator-free days in adults but long-term
accept higher PaCO2 levels as long as the pH outcome i.e. discharge to home, was not
is .7.2 (permissive hypercapnia). Lung necessarily improved in all studies. Prone
recruitment using either a sustained positioning is one of the simple means to
inflation manoeuvre (i.e. maintaining an improve gas exchange in children with ARDS
inspiratory pressure as high as 40 cmH2O and adult studies have shown improved
for 2040 s) or a staircase PEEP trial have outcomes and reduced mortality. The
shown improved gas exchange and lung concept of changing the body position
compliance in most human and between supine and prone is to redistribute
experimental studies, but only a few studies pulmonary fluids, reopening of the collapsed
have reported better outcomes. Not all lung regions in the previously dependent
patients with ARDS have recruitable lungs. lung regions and improving chest wall
Patients with a pulmonary cause of ARDS mechanics. Because of the ease of
are less likely to benefit from lung repositioning an infant or child compared to
recruitment in the early stage of the disease. adults, prone positioning is widely used in
High-frequency oscillatory ventilation paediatric intensive care settings. ECMO is
(HFOV) is commonly used in severe used as a rescue treatment if conventional
paediatric ARDS. There are only a few, and treatment or HFOV fails. The international
small, controlled trials demonstrating a ECMO database reports an ,50% ECMO
benefit of HFOV in children. A recent adult success rate for patients who otherwise
trial using HFOV in ARDS has shown a would have died on conventional ventilation.
higher morbidity and mortality in the HFOV
arm. Like many diseases, early detection and
treatment is key to a good outcome. Hence, Further reading
there is a similar shift in the paradigm to N Amato MB, et al. (1998). Effect of a
support any acute lung failure. With the use protective-ventilation strategy on mortal-
of NIV and CPAP in the very early stage of ity in the acute respiratory distress
lung injury we may see a significant syndrome. N Engl J Med; 338: 347354.
reduction in the severity of many patients N Arnold JH (2000). High-frequency venti-
with ARDS. Some adult and paediatric trials lation in the pediatric intensive care unit.
are already reporting a significant reduction Pediatr Crit Care Med; 2: 9399.
in mortality and morbidity in patients with

N Gattinoni L (2006). Lung recruitment in N Steinberg KP (2006). Efficacy and safety
patients with the acute respiratory dis- of corticosteroids for persistent acute
tress syndrome. N Engl J Med; 354: 1775 respiratory distress syndrome. N Engl J
1786. Med; 354: 16711684.
N Peek GJ, et al. (2009). Efficacy and N UK collaborative randomised trial of
economic assessment of conventional neonatal extracorporeal membrane oxy-
ventilatory support versus extracorporeal genation. (1996). UK collaborative ECMO
membrane oxygenation for severe adult trail group 1996. Lancet; 348: 7582.
respiratory failure (cesar): a multicentre N Ware LB (2000). The acute respiratory
randomised controlled trial. Lancet; 374: distress syndrome. N Engl J Med; 342:
13511363. 13341349.

Acute and chronic respiratory
failure
Robert I. Ross-Russell and Colin Wallis
Acute respiratory failure in the Blood gas assessment and oximetry

section.
Acute respiratory failure occurs when the
lungs are unable to adequately deliver Acute respiratory failure (ARF) can occur as
oxygen to the arterial blood or clear carbon a result of several different causes including
dioxide from the blood. Although there are hypoxaemia, hypoventilation, diffusion
no formal definitions, a PaO2 ,50 mmHg or impairment or shunt. Diffusion problems
a PaCO2 .60 mmHg is generally considered can be observed due to direct impairment of
an appropriate threshold. Measurement of the movement of gas between alveoli and
arterial blood gas is critical to the blood (such as is seen in interstitial lung
determination of respiratory failure. disease), or due to changes in the balance of
Interpretation and analysis of blood gas ventilation/perfusion (V9/Q9) in different
results have been covered in this Handbook parts of the lung. Of these, V9/Q9 inequality
is the most common and important in the
majority of clinical conditions.
Key points Definition and physiology Acute hypoxic (Type
I) respiratory failure is a common
N There are a wide range of causes of presentation in children with severe
both acute and chronic respiratory respiratory disease. It is important, as
failure in children. reduced oxygen delivery to the rest of the
N Blood gas analysis remains the central body can lead to tissue hypoxia, which can,
investigation when assessing in turn, cause organ dysfunction or injury.
respiratory failure. Severe hypoxia is therefore a potentially
critical situation and can lead to
N Methods of support, and particularly neurological, renal, cardiac and other organ
noninvasive techniques, have allowed failure. However, such findings are
a much greater ability to avoid uncommon, and mild or moderate hypoxia
prolonged intensive care. is well tolerated in the short term. Most
N Improvements in technology, hypoxic respiratory failure in children will
intensive care and the provision of occur as a result of acute parenchymal
home care for children in chronic disease caused by infection.
respiratory failure have led to
increasing numbers of these children In most cases the hypoxia is related to
being cared for in the community. abnormalities in V9/Q9 matching and in
particular to areas of low V9/Q9. If an area of
N Early recognition of chronic the lung has a blood flow but no ventilation
respiratory failure should lead to (V9/Q950) this allows deoxygenated blood
interventions that will correct gas to pass directly through to the systemic
exchange as far as possible before circulation, and is termed a shunt. In normal
secondary complications develop. circumstances we have an effective (virtual)
shunt of 34%, but if this increases, SaO2 is

unable to reach 100% and the plateau of the Type I failure can give rise to significant
oxygen dissociation curve (ODC) is organ dysfunction and injury, but this is not
depressed. Conversely, if there is reduced usually an immediate effect (unless the
(but measurable) ventilation to a well failure is coupled with systemic shock).
perfused area (low V9/Q9), the alveolar gas Blood gas results will therefore tend to show
tends to contain increased levels of carbon an isolated hypoxia but without much
dioxide and PaO2 is reduced, as predicted by change in pH. The development of a
the alveolar gas equation. This will also tend significant acidosis (often seen as a
to reduce the saturation of arterial blood, metabolic acidosis) implies that organ
but (unlike shunt) can be overcome by perfusion has been compromised, and may
increasing oxygen concentration. The effect indicate the severity of the problem.
on the ODC is therefore to move the curve
Acute hypercarbic (Type II) respiratory failure
to the right (fig. 1). Areas that are well
is less common in paediatric practice. It can
ventilated but poorly perfused will generate
be seen in children with underlying
well-oxygenated blood, but the reduced flow neuromuscular disease or major skeletal
limits their contribution to the overall blood abnormality such as severe scoliosis. Acute
gases. presentation in such cases would be rare but
In many diseases, such as acute asthma, can follow intercurrent infection (acute on
chronic lung disease and bronchiolitis, there chronic). Unusual causes include Guillain
Barre syndrome, acute upper airway
are significant changes to V9/Q9 throughout
obstruction (e.g. foreign body) or over
the lung, due to areas of hyperinflation and
sedation, which may be witnessed following
atelectasis. This causes some shunting as
administration of anticonvulsants.
well as significant areas of low V9/Q9
matching and it is this that causes SaO2 to Unlike Type I failure, carbon dioxide
fall. This becomes more evident when we retention will produce a rapid fall in pH
consider that children with lung aplasia, or (respiratory acidosis). Measurement of
following lobar resection, will have entirely carbon dioxide and pH is more difficult than
normal blood gases despite the loss of lung saturation, and although there are some
volume. noninvasive techniques (such as end-tidal or
a) 100 b) 100
95 95
90 90
SaO2 %
SaO2 %
85 85
10 kPa 15%
80 20 kPa 80 25%
30 kPa 35%
75 75
0 20 40 60 0 20 40 60
FIO2 FIO2
Figure 1. The effect of a) low V9/Q9 and b) shunt on the ODC. Note that reduced (but not absent) ventilation
will tend to move the curve to the right, and can be overcome with additional inspired oxygen. However, in
pure shunt the maximal saturation that can be reached is reduced. FIO2: inspiratory oxygen fraction.

transcutaneous monitoring), Type II failure with falling consciousness, and urine output
can be easily missed or overlooked. may decrease.
Consideration of this possibility in patients
Hypoventilation can be much more difficult
at risk is therefore critical and measurement
to assess clinically and measurement of
of a blood gas (capillary of arterial) is
arterial saturations may miss significant
important. This will show a low pH and
problems, particularly if additional oxygen is
raised carbon dioxide, but even pure
being administered. In more chronic
respiratory acidosis may involve some
conditions, headaches and other
lowering of the bicarbonate (and hence the
neurological changes can be seen. If
base excess) due to the intimate
acidosis is significant (,7.25), cellular
relationship between carbon dioxide and enzyme systems start to be affected. In
bicarbonate levels. particular contraction of myocardial cells
It is also important to understand the role of starts to decrease, causing reduced cardiac
muscle fatigue in the presentation of output with implications for organ
children with ARF. The diaphragm, just like perfusion.
other skeletal muscle within the body, is Investigation of ARF Faced with a child with
unable to indefinitely sustain a workload respiratory problems in whom ARF is
that is .40% of its maximal capacity. When possible, the immediate concerns should be
this occurs, the metabolic demands of the to address the ABC of resuscitation:
muscle result in cellular energy failure and
an inability to maintain contraction. This N oxygen should be administered;
energy failure is usually quite sudden, N support summoned and;
particularly in children, and so children with N the patients airway and breathing
significantly increased work of breathing can evaluated in a systematic manner.
deteriorate and decompensate very rapidly. However, once the immediate issues have
been addressed a more measured
Another clinical situation where respiratory
assessment can be made. A clear history
failure can present rapidly is in acute lung
must be obtained, including the duration of
injury (sometimes referred to as acute
symptoms, previous medical problems,
respiratory distress syndrome (ARDS)). In
family history, etc. A thorough clinical
this situation, which may follow sepsis
examination aims to determine the cause of
aspiration or trauma amongst other things,
the failure and the acute consequences.
interstitial fluid and alveolar oedema
develop rapidly causing significant The mainstay of investigation in ARF is the
difficulties in oxygenation. It is unusual for measurement of arterial blood gases.
this to present de novo and usually occurs in Clinical assessment or SpO2 alone are unable
a child who is already unwell from one of the to provide a complete picture of the
underlying causes, such as a severe respiratory and metabolic components
pneumonia. However, it is a devastating involved. As an example, a patient with
disease with a high mortality. High diabetic ketoacidosis may present with
ventilatory pressures are often required that, tachypnoea, increased work of breathing but
in turn, further damage the lung and often normal oxygenation. Immediate physical
lead to interstitial fibrosis and lung scarring. examination may show dehydration, but
may not demonstrate any indication of
Clinical effects of respiratory failure: Increasing metabolic acidosis and it may initially
hypoxaemia stimulates increased respiratory appear as though the patient is suffering
drive and together with the underlying cause from a respiratory problem. However, blood
of the hypoxia will present clinically as an gas analysis would rapidly show that the pH
increase in respiratory effort and distress. was low but so was the carbon dioxide, and
Symptoms from other organ involvement that the respiratory effort was a response to
become more apparent with increasing a metabolic problem and not the underlying
hypoxia. Neurological status can be affected cause of distress.

A chest radiograph may be very helpful in dioxide levels can be missed if blood gases
the acute setting. In patients with extensive are not obtained.
shadowing, consideration of an ultrasound
should be made as pulmonary effusions can Delivery of additional oxygen can be via a
otherwise be missed, and management mask, nasal cannula or a head box. Masks
would be altered if a large effusion were are easily tolerated but can entrain air at
present. The exception to this may be a child higher inspiratory airflows, and so a
with bronchiolitis, where the diagnosis is reservoir bag is needed to deliver high
clinical and chest radiographs are not concentrations. Delivery of oxygen via nasal
recommended routinely. Radiographs are of cannula or head box has been shown to be
limited value in assessing a child with equally effective, and the choice of method
hypoventilation. is mostly down to tolerability and personal
preference.
Lung function testing may be useful to
Maintaining a high level of inspired oxygen
document recovery from an acute event or
is important, but other factors may also
track a slow deterioration. Measurements of
affect delivery of oxygen to the tissues.
flow and volume (peak expiratory flow rate,
Cardiac output, haemoglobin concentration
FEV1 and FVC) are valuable in asthma, and
and local blood flow need to be considered.
can help to determine the degree of
obstruction. They can also be useful in Noninvasive pressure support: Applying a flow
patients with acutely progressing Guillain of gas to the upper airway, often with an
Barre syndrome, as FVC has been used as a increased positive airway pressure, has been
marker of disease severity, and as an used to support ventilation for many years.
indication for intubation. Pressure can be delivered via a mask to the
nose or face or with nasal prongs in the
Management of ARF The prerequisites of
small child. There are several mechanisms
respiratory support are to improve the
by which this may help.
oxygenation and the clearance of carbon
dioxide. This can be managed through N Increased pressure in the airway may be
improving oxygen delivery (increasing transmitted to the lung. In a lung with
inspired oxygen concentration, using reduced compliance this may move the
positive pressure ventilation, relieving pressurevolume curve to a more
obstruction), or by reducing demand compliant phase, allowing better air entry
(reducing work of breathing and reducing for the same effort, and reducing work of
metabolic demand). breathing.
Oxygen administration: The simplest way to
N Pressure in the upper airways may help
reduce resistance to airflow. This may be
improve arterial oxygen levels is to increase
especially useful in patients with
the partial pressure of inspired oxygen
neuromuscular disease who can develop
(PiO2). The rate of gas diffusion across the
obstruction due to weak pharyngeal
alveolar basement membrane is directly
muscles, or in patients with obstructive
related to the concentration gradient, and so
sleep apnoea.
a higher inspired PiO2 will lead to greater
absorption. The effect that increasing PiO2
N High flow nasal oxygen (see below) may
also reduce dead space. Normally, air
will have on blood gases will depend, to
within the oropharynx constitutes part of
some extent, on the underlying disease. If
the anatomical dead space but high flow
there is significant shunt, then the effect will
gas will remove this component of the
be small, but for patients with
dead space, which can reduce the work of
hypoventilation or with V9/Q9 inequality,
breathing.
oxygen administration should be effective at
improving the abnormality. This is Noninvasive support may be delivered either
important, as oxygen administration can through a tight fitting mask (nasal mask or
readily correct arterial saturation values in a full facial mask), or through nasal catheters.
hypoventilating patient, and high carbon Proper sizing and fitting of the mask is

essential. Support may be CPAP, with a Another critical factor when instituting
single pressure (designed to reduce work of ventilation in patients is the effect that
breathing, but not directly contributing to positive pressure ventilation will have on the
ventilation), or biphasic positive airway cardiovascular system. Cardiac output is
pressure (BiPAP), where bilevel support integrally tied to venous return. Positive
enables direct ventilation. pressure ventilation (especially in
noncompliant lungs) will lead to a
High flow oxygen, such as the Optiflow restriction on venous return to the heart,
(Fisher and Paykel, Auckland, New Zealand) and this can act to reduce cardiac output
and Vapotherm (Stevensville, MD, USA) and organ perfusion. High airway pressure
systems, are a recent innovation. Heated will also affect lung perfusion and affect V9/
and humidified gas is passed through nasal Q9 ratios. Hypoxia and hypercarbia in the
cannulae at high flow rates (,5 L?min-1 in pulmonary circulation further contribute to
neonates and up to 70 L?min-1 in adults). vasoconstriction. Recognising these factors
Although the exact mechanism is uncertain, and adjusting cardiorespiratory parameters
it is a technique that is simple to use and accordingly usually requires the skills of an
there is increasing evidence of its anaesthetist or intensivist.
effectiveness in neonatal, paediatric and
adult practice. Reduction of dead space and Chronic respiratory failure
airway resistance, or an increase in airway There is no satisfactory definition of chronic
pressure, has been postulated as a potential respiratory failure in children. In practice
benefit. one encounters chronic respiratory failure in
Intubation and ventilation remains the two different scenarios:
definitive method of supporting respiratory
failure. The securing of a clear airway is
N the child with an underlying chronic
condition who, as part of the natural
obtained by passing an endotracheal tube
history of the disorder, is developing a
through the vocal cords and into the central
slow failure of ventilation or oxygenation;
trachea. A detailed discussion of the
management of ventilated patients is
N the child who has been on ventilatory
support for an acute respiratory insult
beyond the scope of this Handbook, but
and then fails to wean and will require
basic physiological principles apply. The
long-term ventilation or supplemental
settings used need to allow adequate oxygen
oxygen. For the purposes of audit and
delivery and carbon dioxide removal. Oxygen census the following definition of long-
delivery requires adequate pressures to term ventilation is often accepted: Any
deliver gas to the alveoli, and for the partial child who, when medically stable,
pressure of inspired oxygen (PIO2) to be continues to need a mechanical aid for
sufficient that oxygen will diffuse across to breathing which may be acknowledged
the blood. Carbon dioxide removal depends after a failure to wean or a very slow
on adequate alveolar ventilation, but wean, 3 months after the institution of
diffusion is rarely a problem (carbon dioxide ventilation. Some of these children will
diffuses 20 times more readily than oxygen), have had an underlying incipient
and so tidal volume and rate become the respiratory failure and represent as
critical factors. In simplistic terms, oxygen acute-on-chronic respiratory failure.
delivery is often increased by adjusting the
airway pressures, whereas carbon dioxide For children with an evolving underlying
removal is effected by adjusting the rate. disorder, unlike ARF, characterised by life-
Inevitably things are more complex than threatening derangements in arterial blood
this, and proper lung expansion is critical to gases and acid-base status, the
both, but the differing factors involved in manifestations of chronic respiratory failure
determining gas exchange for each gas need are less apparent or dramatic. Acute
to be understood when interpreting and respiratory failure develops over minutes to
reacting to blood gas results. hours with a commensurate drop in pH.

Chronic respiratory failure develops over a Table 1. Examples of causes of chronic respiratory failure
much longer period, allowing time for renal in children
compensation and an increase in
bicarbonate concentration with a normal or Loss of central respiratory drive to breathe
near normal pH. Congenital central hypoventilation
syndrome
Causes of chronic respiratory failure There are
Acquired central hypoventilation
many causes of chronic respiratory failure in
syndrome
children. Any aetiological classification
results in artificial lumping especially Post-infectious encephalopathy
where dual pathology exists. However, for Non-accidental injury
epidemiological studies and audit it is
High spinal injury
useful to consider three main categories:
Birth injury
N a loss of central respiratory drive to Vascular malformations
breathe;
Post-neurosurgery
N ineffective thoracic musculoskeletal
function; Ineffective thoracic musculoskeletal
N disorders of the respiratory tract. function
Spinal muscular atrophy
Examples from each of these broad
Congenital myopathy
categories are listed in table 1.
Duchenne muscular dystrophy
Assessment for chronic respiratory failure For
Kyphoscoliosis
children with an underlying condition who
are at risk of developing chronic respiratory Neurometabolic conditions
failure, assessments should be designed to Skeletal dysplasia
determine the earliest signs of failure so that
Mucopolysaccharidosis
appropriate intervention can be introduced
before secondary complications develop. As Thoracic dystrophy
with acute failure there will be those who will Phrenic nerve damage
predominantly have hypoxic Type I failure Disorders of the respiratory tract
(e.g. a child with severe CF) and those with
hypercapnic Type II failure (e.g. a boy with Conditions of the upper airways
Duchenne muscular dystrophy). Craniofacial disorders
Achondroplasia
For children with CF, spirometry will give an
indication that chronic respiratory failure Tracheo-bronchomalacia
may be developing. When the FEV1 falls Acquired: prematurity, post-surgery to
below 3040% predicted, oxygen saturation the trachea
will often begin to decrease with exercise or
Congenital: following repair of tracheo-
physiotherapy and additional oxygen may be oesophageal fistula or vascular ring
required. This may progress to overnight
decline in oxygen saturation with an Disorders of pulmonary parenchyma
eventual rise in carbon dioxide, triggering Pulmonary hypoplasia
discussion about the use of overnight NIV. Chronic lung disease of prematurity
Failure to notice chronic failure can lead to
Progressive lung diseases such as CF
increasing lethargy, failure to clear
or interstitial lung diseases
secretions, increased propensity to chest
infections and even cor pulmonale and signs Recurrent aspiration
of carbon dioxide retention.
For children with Duchenne muscular notice early signs of respiratory failure so
dystrophy, and other slowly progressive that additional respiratory support can be
neuromuscular disorders, it is important to introduced in a timely fashion; not too soon

before it is required, but not too late so that in the pattern of work for many respiratory
complications have developed. paediatricians. Contributing factors to this
change in practice include:
Regular assessments will include a history of
decreasing cough efficacy, fatigue, weight N the development of portable ventilators
loss, poor appetite and morning headaches. that can be used in the home setting;
Lung function can provide important clues N the use of paediatric noninvasive
as to the likelihood of impending respiratory interfaces to deliver ventilation, either in
failure; an FVC ,40%, FEV1 ,40%, a poor the form of CPAP or BiPAP;
peak cough flow and a specialised test of N increasing acceptance on the use of a
respiratory muscle strength, such as the tracheostomy in the home setting;
maximal inspiratory and expiratory efforts. N improvements in intensive care allowing
for the survival of children with
It is now known that a sleep study is life-threatening illness but ending in
essential in the early assessment for chronic incomplete recovery and a chronic
respiratory failure in progressive ventilatory need;
neuromuscular weakness. Measurement of N a growing experience (especially in
overnight oxygen and carbon dioxide can children with neuromuscular conditions)
allow categorisation of incipient respiratory that long-term ventilatory support
failure into three levels: improves quality of life and even alters
N level I: intermittent rapid eye movement the natural history of some conditions;
(REM) sleep, hypercapnia and N enthusiastic internet-based organisations
hypoxaemia; and support groups advocating the value
N level II: nocturnal hypoventilation in REM and gain of moving children from the
and non-REM sleep; hospital to home setting.
N level III: hypoventilation during all sleep
and wakefulness. Further reading
The documentation of these changes during N Fauroux B, et al. (2008). NIV and chronic
sleep provides early evidence of a need for respiratory failure in children. Eur Respir
additional respiratory support. If missed, the Monogr; 41: 272284.
neuromuscular patient may lose carbon N Hull J, et al. (2012). British Thoracic
dioxide sensitivity in their respiratory drive Society guideline for the respiratory man-
and run carbon dioxide levels at a chronically agement of children with neuromuscular
high level. The patient now has little weakness. Thorax; 67: Suppl. 1, i140.
respiratory reserve and relies entirely on a N Simonds AK. Non-invasive Respiratory
hypoxic drive to breathe, making them very Support. A Practical Handbook. 2nd
Edn. London, Arnold, 2001.
vulnerable to acute on chronic deterioration.
N Wallis C, et al. (2011). Children on long-
Conclusion term ventilatory support: 10 years of
progress. Arch Dis Child; 96: 9981002.
The number of children using long-term N West J. Respiratory Physiology The
ventilatory support for chronic respiratory Essentials. 8th Edn. Lippincott, Williams
failure has increased significantly over the & Wilkins, 2011.
past decade and constitutes a major change

Home oxygen therapy,
invasive ventilation and NIV,
and home ventilatory support
Brigitte Fauroux, Adriana Ramirez and Sonia Khirani
The ability to sustain spontaneous oxygen. The second type of respiratory

ventilation can be viewed as a balance failure, ventilatory/pump failure, is the
between neurological mechanisms result of an imbalance of the respiratory
controlling ventilation together with system. In normal individuals, central
respiratory muscle strength on the one respiratory drive and ventilatory muscle
hand, and the respiratory load, determined power exceed the respiratory load, thus
by lung, thoracic and airway mechanics, on explaining the ability to maintain adequate
the other hand. spontaneous ventilation during different
physiological conditions such as
Chronic respiratory failure is constituted by wakefulness, sleep and exercise. However,
two different types of respiratory failure, significant dysfunction of any of these three
which have a distinct pathophysiological components of the respiratory system may
background and therapeutic implication impair the ability to generate spontaneously
(fig. 1). The first type of respiratory failure, efficacious breaths. Indeed, if the
lung failure, is characterised by an respiratory load is too high and/or
abnormality of the alveolarcapillary ventilatory muscle power or central
membrane, as observed in interstitial lung respiratory drive is too low or inefficient,
diseases. In this type of failure, the different ventilation may become insufficient. This
components of the ventilatory balance are type of respiratory failure is characterised by
globally normal, with the main abnormality alveolar hypoventilation with hypercapnia
being the transfer of the gases from the and hypoxaemia.
alveoli through the alveolar capillary
membrane, resulting primarily in The treatment of respiratory failure is
hypoxaemia due to the greater diffusion determined by the type of respiratory failure.
capacity of carbon dioxide compared to In the case of an abnormality of the
alveolarcapillary membrane, the treatment
is oxygen. Oxygen therapy, by increasing the
Key points oxygen concentration within the alveolar
space, will increase the alveolarcapillary
N The main objective of oxygen therapy gradient and, as a consequence, the arterial
and mechanical ventilation is to oxygen concentration. While in the case of
restore a normal nocturnal and an imbalance of the ventilatory balance, the
daytime gas exchange and a normal aim of the treatment is to correct the
sleep quality. disequilibrium, by either unloading the
respiratory muscles in the case of an
N LTOT is the treatment of choice of
increase in respiratory load (as observed in
chronic hypoxaemia.
CF), or by replacing them in the case of
N Mechanical ventilation is the respiratory muscle weakness (as observed in
treatment of choice of chronic neuromuscular diseases). In the rare cases
hypercapnia. of a failure of central drive (as in Ondines
curse) the aim of the treatment is to replace

the brain. Ventilatory assistance, Oxygen therapy
preferentially by a noninvasive route such as
NIV, represents the treatment of choice for The aim of LTOT is to prevent or correct the
this type of respiratory failure, by deleterious consequences of chronic
maintaining sufficient minimal ventilation. hypoxaemia, such as pulmonary
hypertension and heart failure. But in
Besides these two types of respiratory failure, children, in the absence of validated markers
children may present with structural or of end-organ morbidity, the minimal level
anatomical upper airway obstruction, (and duration) of hypoxaemia that may be
exposing them to recurrent episodes of upper safely tolerated is not known. Moreover, it is
airway closure, which are responsible for probable that the consequences of chronic
apnoeas or hypopnoeas, especially during hypoxaemia vary according to age, with
sleep. These children do not present with younger children being more susceptible,
overt respiratory failure as the bypass of the and to the type of underlying disease.
obstruction restores normal breathing. In
these patients, CPAP delivered by a In clinical practice, recommendations for
noninvasive interface, such as a nasal mask, LTOT derive from the normal SpO2 values
is the technique of choice, with a observed in healthy children. As such,
tracheostomy being reserved for CPAP failure. nocturnal SpO2 should not fall below 90%
without any desaturation (rapid drops in
During sleep, the breathing process is less SpO2 of o3%). Thus, the oxygen flow should
efficient. Indeed central drive, be adapted to reach this target, without any
chemoreceptor and mechanoreceptor excessive correction in order to avoid the
sensitivity are less performant during sleep potential side-effects of hyperoxia. The
than during wakefulness with a relationship harmful consequences of hyperoxia have
to the depth of sleep, with stages 3 and 4 been well documented in the premature
sleep being the least responsive. Sleep is child, with retinopathy being one of the most
also associated with changes in respiratory important side-effects. The deleterious
mechanics with an increase in ventilation consequences of hyperoxia have not been
(functional residual capacity). Although the documented in the older child and in other
activity of the diaphragm is preserved, those diseases, but an SpO2 target between 94%
of the intercostal and the upper airway and 96% is safe and largely sufficient.
muscles decrease significantly. All these
The most common paediatric diseases that
abnormalities explain a physiological degree
may need LTOT are bronchopulmonary
of nocturnal hypoventilation causing a 23%
dysplasia (BPD), interstitial lung disease and
fall in SpO2 and an increase in PaCO2 of up to CF. BPD is probably the disease in which the
3 mmHg (0.4 kPa) in healthy adults. In consequences and benefits of LTOT have
children with moderate abnormal gas been studied the most extensively. As such, it
exchange during wakefulness, these has been shown that oxygen therapy
physiological modifications may precipitate decreases central sleep apnoeas and
respiratory failure during sleep, underlining improves sleep quality in infants with BPD. A
the importance of systematic sleep studies sleep SpO2 level .9192% is also associated
in all children who present with, or who are with a better weight gain compared to lower
suspected of, respiratory failure. This SpO2 levels. In CF, nocturnal desaturation,
worsening of breathing abnormalities during but not the minimal nocturnal SpO2, has been
sleep is of major importance for the shown to be associated with pulmonary
diagnosis and treatment of all types of hypertension. No information on the
respiratory failure. Indeed, the criteria to deleterious consequences of chronic
start long-term oxygen therapy (LTOT) and hypoxaemia is available for children with
NIV will be based on overnight parameters interstitial lung disease.
such as SpO2 and transcutaneous oxygen
and carbon dioxide pressure (PtcO2 and The choice of the oxygen source depends on
PtcCO2, respectively). the daily duration of LTOT (sleep only or

Abnormalities of the Abnormalities of the
respiratory mechanics alveolarcapillary barrier
Respiratory Capillary
control
Respiratory
muscle capacity Alveolus
Respiratory
load
Neuromuscular
diseases
Lung and airway
diseases
PaCO2 PaO2
Figure 1. The two different types of respiratory failure: ventilatory imbalance (left) and abnormalities of the
alveolarcapillary membrane (right).
also during daily activities), the cost and The most common diseases that may need
local facilities. An oxygen concentrator is a NIV are neuromuscular disorders,
cheap and safe source but does not allow hypercapnic lung diseases, such as
ambulation. When LTOT is required during advanced CF or COPD, and central
the daytime, and especially during daily hypoventilation if the patient has a minimal
activities, gaseous or liquid oxygen is respiratory autonomy while awake. The
preferred. The efficacy of LTOT should be criteria to start NIV are not validated in
checked by overnight gas recording to check children but most experts recommend NIV
the SpO2 but also the carbon dioxide level, in when nocturnal PtcCO2 exceeds 50 mmHg
order to detect hypercapnia, especially in despite optimal medical treatment. The aim
patients with lung diseases such as CF, and of NIV is to maintain the maximal PtcCO2
the possibility of NIV should be discussed. below 50 mmHg, by providing a sufficient
tidal volume and V9E.
Noninvasive ventilation
Numerous ventilators are available for home
The aim of NIV is to correct alveolar ventilation but few have been specifically
hypoventilation, i.e. chronic hypercapnia. designed for children. However,
Even if the deleterious consequences of manufacturers have improved the
chronic hypoxaemia are not well documented performances of the most recent devices
in children, our knowledge is even more with some ventilators being as performant
limited with regard to the consequences of as intensive care ventilators. The ventilatory
long-term hypercapnia. Besides systemic modes have improved significantly over
hypertension, very few side-effects have been recent years. Initially, two modes were
objectively reported in children. Again, in available, a volume-target and a pressure-
clinical practice, the target values are derived target mode, with the former being
from the values observed in healthy children. preferentially prescribed for patients with a
As such, most authors and experts restrictive lung disease, such as patients
recommend that the maximal (nocturnal) with a neuromuscular disease, and the latter
PtcCO2 should not exceed 50 mmHg. being preferentially prescribed for patients

with a lung disease such as CF or COPD. obstruction. These diseases may be
But presently, new dual control modes, congenital and/or acquired, and may require
combining a volume- and a pressure- CPAP in order to prevent airway closure and,
targeted mode are being increasingly used, thus, the consequent apnoeas and
even if they have not been validated hypopneas. Indeed, by maintaining a normal
specifically for the paediatric population. In airway patency during the entire breathing
practice, in the case of chronic alveolar cycle, CPAP may improve alveolar
hypoventilation, the main objective is to ventilation. CPAP may also prevent the
maintain a sufficient minimal tidal volume decrease of functional residual capacity by
to correct chronic hypercapnia. This may be delivering a continuous distending pressure.
achieved by setting a sufficient tidal volume, Common diseases that may cause severe
inspiratory pressure and inspiratory time, upper airway obstruction are craniofacial
without forgetting a back-up rate for patients malformations, such as Crouzon and Apert
at risk for sleep apnoeas or those who are disease, Franceschetti syndrome, Pierre
not able to trigger the ventilator, such as Robin syndrome, achondroplasia, and other
patients with neuromuscular disease. As a congenital bone diseases, as well as
consequence, the adjustment of the metabolic disorders such as
ventilator will thus be based on the mucopolysaccharidoses, and Down
combined recording of SpO2 and PtcCO2. syndrome. The maintenance of airway
patency throughout the entire breathing
The NIV interface is as important as the cycle restores normal ventilation with
ventilator. Indeed, the patient will not be correction of the OSA. The criteria to start
able to tolerate the NIV if there is CPAP have not been validated in children. In
discomfort, pain or leaks due to a non- the absence of reliable markers of end-organ
adapted interface. A large number of
morbidity of OSA, the indication is based on
industrial interfaces are available for long-
the association of clinical and
term NIV in children, even if the range is
polysomnographic parameters.
smaller for children compared to adults.
Adenotonsillectomy is the treatment of first
The choice will be guided by the age of the
choice followed, eventually, by an anti-
patient, the underlying disease and the
inflammatory treatment in the case of
ventilatory mode (allowing an interface with
moderate residual OSA. If the OSA persists
or without a manufacturer leak) and, most
and is associated with abnormal gas
importantly, the facial physiognomy of the
exchange, CPAP should be initiated. If the
child. The majority of children are ventilated
residual OSA is less severe, without
with a nasal mask. A facial mask is reserved
significant abnormalities in gas exchange, a
for those who have mouth leaks during
1-month trial, followed by an objective and
sleep. Nasal prongs or cannula are relatively
subjective sleep evaluation, may be
new interfaces available for older children
proposed.
that have minimal contact with the patients
face. Of note, because of the cutaneous and Numerous simple CPAP devices are
facial side-effects, such as facial flattening available but most do not have an internal
or maxilla retrusion, which may be observed battery and alarms adapted for young
with all types of interfaces in young children. Numerous new automatic CPAP
children, a systematic and close follow-up modes are available for adult patients. These
by a paediatric maxillofacial team is new modes are based on the analysis of the
mandatory. flow pattern of the patient with the aim to
Continuous positive airway pressure automatically adapt the level of CPAP to a
change in airflow. However, it is not known
Obstructive diseases of the upper airways if these devices are able to detect the
are not rare in children. Apart from nasal changes in airflow in young children and, in
obstruction and tonsils and adenoids a recent clinical study, the use of such a
hypertrophy, children may present with mode was not associated with an increase in
numerous causes of chronic upper airway CPAP efficacy or compliance.

The CPAP mode requires a vented interface exchange and a normal sleep quality, by
with a manufacturer leak, allowing carbon means of the least invasive treatment, in
dioxide clearance through the constant leak. order to preserve the best quality of life for
The choice of vented interfaces is much the child and their family.
broader than for nonvented interfaces. The
side-effects of CPAP interfaces are similar to
that of NIV interfaces, justifying the same Further reading
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Primary ciliary dyskinesia
Deborah Snijders, Serena Calgaro, Massimo Pifferi, Giovanni Rossi and

Angelo Barbato
Primary ciliary dyskinesia (PCD) is from a European Respiratory Society Task

predominantly inherited as an autosomal Force on PCD in children, a prevalence of
recessive disorder leading to recurrent and diagnosed cases in 514-year-olds was found
chronic upper and lower respiratory tract to be between one in 10 000 and one in
infection and, in 4050% of cases, mirror 20 000.
image organ arrangement and other forms
of heterotaxy. Ciliary dysfunction is also In clinical samples of patients with diffuse
implicated in a wider spectrum of diseases, bronchiectasis, PCD is naturally more
such as polycystic liver and kidney disease, common. It might account for up to 13% of
biliary atresia, and central nervous system all patients with bronchiectasis, being
abnormalities including retinopathy and relatively more common in North African
hydrocephalus. patients than European patients. The
average age at diagnosis, in a paediatric
The prevalence of PCD is very difficult to case series by Coren et al. (2002), was
estimate accurately. In a European survey 4.4 years (6 years for those without situs
inversus). More recent data showed a
median age at diagnosis of 5.3 years, lower
Key points in those with situs inversus (3.5 versus
5.8 years).
N The gold standard for the diagnosis of Cilia structure
PCD is a combination of ciliary beat
pattern and frequency analysis and Normal cilia structure The epithelial lining of
electron microscopy in patients with the large airways and contiguous structures,
upper or lower airway disease. including the paranasal sinuses, middle ears
N Specific ultrastructural defects and Eustachian tubes, consists of ciliated
responsible for PCD result in specific pseudostratified columnar epithelium.
abnormalities in beat frequency and Ciliated cells are also found in the
pattern; however, a small number of ependymal lining of the brain and fallopian
milder phenotypes may appear with tubes. In addition, the spermatozoal flagella
subtle or no apparent structural (tail of spermatozoa) has a core structure
defects or ciliary dysfunction. that is identical to cilia.
N When diagnosis by ultrastructural Each matured ciliated cell has up to 200

analysis or beating patterns analysis is cilia. Each cilium has an array of longitudinal
not conclusive, but the suspicion of microtubules arranged as nine doublets
PCD is high, further testing should be formed in an outer circle around a central
performed in order to find the right pair. The main structural protein of these
diagnosis, such as nasal nitric oxide, doublets is tubulin. The microtubules are
immunofluorescent microscopy and anchored by a basal body in the apical
genetic analysis. cytoplasm of the cell. Radial spokes connect
the outer microtubular doublets with a

central sheath of proteins around the central stasis of the respiratory tract secretions,
tubules. which will be responsible for the clinical
manifestations of the disease.
Cross-section of the cilia (fig. 1) reveals
inner and outer dynein arms (IDA and ODA, Genetics of PCD
respectively), which are attached to a
Inheritance PCD (MIM#242650) is a
subunit A of each microtubule doublet. The
genetically heterogeneous disorder, which is
microtubules are interconnected by nexin
links, radial spokes and dynein arms. Cilia predominantly inherited as an autosomal
beating originates from the sliding of recessive trait. To date, the majority of the
microtubule doublets, which is generated by genes identified for autosomal recessive
the ATPase activity of the dynein arms. PCD variants (DNAI1, DNAI2, DNAH5,
DNAH11 and TXNDC3) encode ODA
The dynein arms are periodically distributed components while KTU and LRRC50 are
along the axoneme; ODAs with a 24-nm required for cytoplasmic pre-assembly of
periodicity and IDAs with a 96-nm axonemal dyneins (table 1). In addition,
periodicity. The dynein arms are mutations in the two genes RSPH9 and
multiprotein complexes that project from RSPH4A have been reported in PCD patients
the microtubule A of every outer doublet. with abnormalities of the central
The outer arms face towards the boundary microtubular pair. Molecular defects
of the axoneme and the inner arms face the affecting dynein regulatory complexes (DRC)
central sheath. and IDAs are characterised by the absence
of GAS11 (a DRC component) and the IDA
Ciliary movement involves two phases: component DNALI1 from the ciliary
axoneme (CCDC38 and CCDC40). In a
N an effective stroke phase that sweeps
minority of cases, other inheritance patterns
forward,
have been recognised.
N a recovery phase during which the cilia
bend backward and extend into the Genetic analyses may help to assess the
starting position for the stroke phase. carrier status of family members and
provide tools for informed reproductive
The mucous lining present on the
choices, although this is only currently
respiratory epithelium has an inner serous
possible for a minority of families. They may
layer called the sol phase, in which the cilia
also become more important diagnostically
recover from their active beat, and an outer,
as ,35% of PCD patients carry either
more viscous layer, the gel phase. The tips
DNAH5 or DNAI1 mutations (hot spots and
of the cilia are in contact with the gel layer
founder mutations are worthy of analysis in
during the stroke phase in order to propel
patients with ODA).
the secretions forward. During the recovery
phase the cilia lose contact with the mucus Clinical aspects of PCD
layer, reinforcing the forward thrust of the
mucus. Children with PCD often have a clinical
history of lower airway disease, manifested
Normal ciliary beat frequency is 1000 by a chronic wet sounding cough and
1500 beats?min-1. The frequency is slower in occasionally wheeze or shortness of breath.
the peripheral airways (e.g. bronchioles)
compared to the larger airways (e.g. Moreover, .75% of full-term neonates with
trachea). The ciliary motility is maintained in PCD have neonatal respiratory distress
the same plane along the length of the requiring supplemental oxygen for days to
airways and results in mucociliary transport weeks.
rates up to 2030 mm?min-1.
Complications of chronic lower airway
Whenever there is an alteration in ciliary infections, such as bronchiectasis, can be a
structure or function, there will be an sign of detoriation of lung function and are
alteration in mucociliary clearance, with more frequent in adults.

Ciliary membrane Peripheral microtubule doublet
a)
B
A
Radial spoke
ODA
Nexin link
IDA
Central microtubule pair

Central sheath
b) c)
Figure 1. Cross section of the cilia. a) Schematic diagram of a cilium revealing 9+2 arrangement of nine
peripheral microtubule doublets surrounding a central microtubule pair. b, c) Transmission electron
microscopy of normal cilia (b) and absent IDA and ODA (c). Reproduced from Becker-Heck (2012).
In addition, virtually all subjects have evidence Ear symptoms (recurrent otitis media and
of chronic upper airway symptoms such as glue ear) are a frequent complication that
chronic rhinitis (nasal discharge, episodic can require multiple interventions, including
facial pain and anosmia). This may be repeated courses of antibiotics.
confirmed by either physical examination and/
or sinus imaging. Continuous rhinorrhoea can PCD should be suspected in cases of situs
be present from the first day of life. inversus totalis or heterotaxy; ,25% of

individuals with situs inversus totalis have
PCD. Prevalence of PCD within the
PCD with MR
heterotaxy subclass is unknown. In PCD
PCD with RP
Phenotype
PCD+KS
PCD+KS
PCD+KS
PCD+KS
PCD+KS
PCD+KS
PCD+KS
PCD+KS
patients, 4050% present with situs inversus
PCD
PCD
KS
totalis (Kartageners syndrome) and 6%

have heterotaxy (situs ambiguus).
Adult males with PCD may be infertile due

to impaired sperm motility because the
flagella of the sperm and cilia often, but not
always, have the same ultrastructural and
Founder mutations
c.801_803delGAA
IVS1 + 3insT
functional defects. Some females with PCD
Not known
c.10815delT
Not known
Not known
Not known
Not known
Not known
Not known
Not known
Not known
Not known
have normal fertility, but others have

impaired fertility and an increased risk for
ectopic pregnancy because of impaired
ciliary function in the oviduct.
The clinical aspects of PCD are shown

according to the different age groups in
Exons 34, 50, 63, 76 and 77
table 2. A positive family history of PCD is

Exons 13, 16 and 17
an indication to undergo diagnostics, as this

Not known
Not known
Not known
Not known
Not known
Not known
Not known
Not known
Not known
Not known
accounted for 10% of cases in one series.

Hot spot
Exon 5
Also siblings of probands should have PCD

excluded.
Diagnosis of PCD is frequently delayed, in

part, because it presents with symptoms
(rhinitis, secretory otitis media, cough and
recurrent bronchitis) that are common in
healthy children.
Exons
79+1
,25
20
20
20
82
23
14
12
18
6
5
3
PCD as an associated diagnosis Beside the

classical signs and symptoms, we
recommend that PCD should be at least
considered when the following diagnoses
are made, in particular if there is a family
KS: Kartagener syndrome; RP: retinitis pigmentosa; MR: mental retardation.
Defective structure
history of more than one of these

IDA, central pair
IDA, central pair
Central pair
Central pair
Not known
conditions, or if the patient has other

ODA+IDA
ODA+IDA
Variable
Normal
ODA
ODA
ODA
ODA
features of PCD.
N Complex congenital heart disease,

especially with disorders of laterality,
such as atrial isomerism, transposition of
Table 1. Description of the genes involved in PCD
the great vessels, double outlet right

ventricle, anomalous venous return,
7p15.3-21
9p21-p13
3q26.33
16q24.1
17q25.3
14q21.3
17q25.1
Xp21.1
7p14.1
Locus
Xp22
6q22
6p21
interrupted inferior vena cava and

5p15
bilateral superior vena cava.

N Asplenia (predominant bilateral right-
sidedness (right isomerism)), or
polysplenia (predominant bilateral left-
sidedness (left isomerism)). This is
TXNDC3
DNAH11
CCDC40
RSPH4A
CCDC39
present in at least 6% of individuals with

DNAH5
LRRC50
RSPH9
DNAI2
DNAI1
RPGR
OFD1
Gene
KTU
PCD.
N Polycystic kidney or liver disease.

Table 2. Clinical presentation of symptoms
Antenatal period Situs inversus totalis or heterotaxy on antenatal ultrasound
scanning
Mild fetal cerebral ventriculomegaly
Newborn period Neonatal respiratory distress in full-term neonates
Continuous rhinorrhoea from the first day of life
Mirror image organ arrangement and other forms of heterotaxy
Hydrocephalus may occur in some individuals with PCD and may
reflect dysfunctional ependymal cilia
Childhood Chronic productive or wet sounding cough, associated or not
with recurrent atelectasis or pneumonia
Atypical asthma
Idiopathic bronchiectasis
Daily rhinitis, without remission
Severe chronic sinusitis in older children
Otitis media with effusion/hearing loss
Adolescence and adulthood Same as for childhood
Bronchiectasis, more evident in adulthood
Chronic mucopurulent sputum production
Digital clubbing
Pulmonary function tests with progressive obstructive or mixed
pattern
Nasal polyposis and halitosis
Infertility
N Hydrocephalus. Samples of ciliated cells can be obtained by

N Biliary atresia. nasal brushing or bronchoscopic samples.
N Severe oesophageal disease With the only notion that patients should be
(oesophageal atresia or severe reflux). free from an acute upper respiratory tract
N Retinal degeneration, including retinitis infection for 46 weeks to help minimise
pigmentosa. poorly ciliated samples or secondary
N Oral-facial-digital syndrome type 1. dyskinesia, avoiding complication of the
analysis.
Diagnostic testing
Ciliary beat pattern and frequency analysis
The diagnosis of PCD should be based on Analysis of ciliary beat pattern using a slow
the presence of a typical clinical phenotype motion replay videotape recorder and a
and appropriate diagnostic testing. PCD is a digital high speed video camera is
rare disease and diagnostic analysis and recommended as part of the diagnostic
interpretation is difficult. There is no one testing for PCD. Ciliated samples at 37uC are
gold standard test, a combination of ciliary observed using a 6100 objective. A digital
function and ultrastructural analysis is high speed video camera mounted on a
recommended. Screening tests may precede conventional microscope allows over 500
ciliary analysis, such as nasal nitric oxide frames per second to be recorded. These are
measurement, saccharin test and played back in slow motion allowing ciliary
radioaerosol mucociliary clearance tests beat pattern to be assessed. A permanent

recording can be made for audit purposes that do not have significant secondary
and beat frequency can also be measured by damage can be difficult. This may lead to
directly observing the beating cilia in slow erroneous reports of new cases of PCD.
motion. In PCD, all of the cilia are seen to be Various methods to improve analysis of
dyskinetic on slow motion replay. Analysis images from electron microscopy have been
also allows measurement of ciliary beat suggested. Some patients with PCD may not
frequency. Specific beat patterns have been have an obvious ultrastructural defect;
shown to be related to particular however, normal ciliary ultrastructure
ultrastructural defects. This analysis is should always prompt a full diagnostic
particularly useful in identifying patients review.
who have ciliary dyskinesia due to an
ultrastructural defect where beat frequency Other techniques to assist diagnosis are
is normal: for example, in those with a ciliated cell culture to improve diagnostic
central microtubular defect such as ciliary certainty of PCD and to confirm less
transposition or central microtubular common phenotypes, such as ciliary
agenesis. A major advantage is that videos disorientation, ciliary aplasia, central
may be stored as a permanent record, microtubular agenesis and IDA defects.
allowing reassessment if the clinical picture
changes. In addition, the analysis of dynein protein
localisation by immunofluorescent
Until recently, prior to advances in high- microscopy may help in the clinical
speed video analysis, ciliary beat frequency diagnosis of PCD. Not only can it diagnose
without assessment of beat pattern was ODA but it can also diagnose IDA
common. When the beat frequency is low, abnormalities in the various genetic
suspicion of PCD is high. It had been mutations. In addition, the
recommended that if the ciliary beat immunofluorescent microscopy method is
frequency was above a certain threshold not altered by secondary ciliary
further tests, such as electron microscopy, abnormalities.
were not indicated. However, in the
Genetic analysis for some cases of PCD is
experience of some ciliary diagnostic
possible, but it is not recommend as part of
centres, using ciliary beat frequency
initial diagnostic testing. After a clinical
readings to reject the diagnosis of PCD will
diagnosis has been ascertained genetic
result in 1015% of patients with the disease
testing may be directed according to the
being missed, since these have beat pattern
specific PCD variant (i.e. DNAH5 and DNAI1
abnormalities despite normal beat
testing in PCD patients with ODA defects or
frequency.
DNAH11 testing in a special functional defect).
Electron microscopy is important in the
diagnosis of PCD, and is always performed Respiratory treatment
when there is any suspicion of the diagnosis. As with all chronic respiratory diseases, the
However, specialist knowledge is required to aim of therapy for PCD is to prevent
interpret the various ultrastructural defects bronchiectasis and to restore or maintain
responsible for PCD and it is acknowledged normal lung function for as long as possible,
that ultrastructural analysis has limitations. based on early detection and vigorous
In particular, IDA defects are difficult to treatment of complications. There are no
determine because they are less electron randomised trials of PCD treatment and
dense and less frequent along the ciliary consequently all treatment
axoneme. In addition, it has been shown recommendations are based on very low
that the dynein motor protein composition level evidence, or extrapolated from CF
varies along the ciliary length meaning that guidelines.
ultrastructural defects depending on the site
of the ciliary cross-section can be missed by Management of PCD involves aggressive
electron microscopy. Obtaining samples treatment of upper and lower airways

infections and airway clearance by b2-agonist in PCD. Exercise is encouraged at
combinations of physiotherapy and physical all ages to promote general health and
exercise. wellbeing.
Antibiotics Airway infection with Surgical procedures Complications of
Haemophilus influenzae, Staphylococcus bronchiectasis and chronic lung disease
aureus and Streptococcus pneumoniae become more prominent with age. The role
frequently occur, but Pseudomonas aeruginosa of lobectomy in advanced bronchiectasis is
and non-tuberculous mycobacteria have also similar to that in other aetiologies, and can
been reported, usually in adults. The use of rarely be recommended. Although
antibiotic prophylaxis should be considered stabilisation or improvement of lung disease
when repeated courses of antibiotics are is expected with institution of modern
necessary. At the first sign of worsening treatment, there are reports of PCD patients
respiratory symptoms or deterioration in lung going on to lung transplantation, both living
function, high-dose oral antibiotics should be related and cadaveric. This underlines that
administered, even better if the evidence is PCD is a serious condition, from which
based on sputum or cough swab culture. adults die, and that paediatricians are
mandated to treat children aggressively to
If P. aeruginosa is isolated, an eradication retard later lung deterioration.
regime similar to CF should be used,
although evidence of efficacy has yet to be Environmental exposures Preventive
obtained in PCD patients. counselling should include:
Other inhaled medications Regular N the avoidance of active and passive
bronchodilators do not seem to be very smoking;
effective. The role of nebulised recombinant N minimisation of exposure to respiratory
human DNase (Pulmozyme; Genentech Inc., pathogens;
San Francisco, CA, USA) in PCD patients N minimisation of exposure to indoor and
remains unproven. However, anecdotally environmental pollutants.
some patients show an improvement in
respiratory symptoms. As for the use of Cough suppressant medications must be
nebulised normal or hypertonic saline, it may avoided.
theoretically be effective in increasing mucus
clearance. N-acetylcysteine has been shown Immunisations PCD patients should receive
not to be useful. all childhood immunisations, as well as
pneumococcal and influenza immunisation.
Anti-inflammatory strategies There are no
data on which to recommend or avoid Outpatient follow-up
inhaled corticosteroids; although the
PCD patients should be managed in
neutrophillic profile of sputum is similar to
CF. Corticosteroids are probably best specialised centres, in which they have regular
avoided unless they can be shown to be of access to respiratory paediatricians,
definite benefit in an individual patient. audiology, ENT specialists and respiratory
physiotherapists. Some patients need access
Airway clearance techniques Airway clearance to clinical psychology and social work services.
is widely used in PCD patients. Since cough
clearance is intact, techniques promoting In addition to general paediatric care, each
cough seem helpful. Physiotherapy varies patient should have regular visits to a
with age, the changing clinical state and tertiary centre to check growth, lung
local expertise and resources. function (including pulse oximetry) and
hearing function. Regular sputum or cough
The effect of physical exercise on airway swab cultures should be performed. Chest
clearance in PCD may help sputum radiographs are probably relatively
clearance. Exercise has been shown to be a insensitive. HRCT of the lungs is used to
better bronchodilator than the use of a define the extent of bronchiectasis, and can

be repeated to monitor the progression of N Bush A, et al. (2007). Primary ciliary
the disease when necessary. dyskinesia: current state of the art. Arch
Dis Child; 92: 11361140.
N Ferkol T, et al. (2006). Current issues in
Further reading the basic mechanisms, pathophysiology,
diagnosis and management of primary
N Afzelius BA (1976) A human syndrome ciliary dyskinesia. Eur Respir Monogr; 37:
caused by immotile cilia. Science; 193: 291313.
317319. N Engesaeth VG, et al. (1993). New associa-
N Armengot M, et al. (2010). Cilia motility tions of primary ciliary dyskinesia syn-
and structure in primary and secondary drome. Pediatr Pulmonol; 16: 912.
ciliary dyskinesia. Am J Rhinol Allergy; 24: N Kuehni CE, et al. (2010). Factors influen-
175180. cing age at diagnosis of primary ciliary
N Barbato A, et al. (2009). Primary ciliary dyskinesia in European children. Eur
dyskinesia: a consensus statement on Respir J; 36: 12481258.
diagnostic and treatment approaches in N Midulla F, et al. (2003). Flexible endo-
children. Eur Respir J; 34: 12641276. scopy of paediatric airways. Eur Respir J;
N Becker-Heck A, et al. Dynein dysfunction 22: 698708.
as a cause of primary ciliary dyskinesia N Noone PG, et al. (2004). Primary ciliary
and other ciliopathies. In: King SM, ed. dyskinesia: diagnostic and phenotypic
Dyneins: Structure, Biology and Disease. features. Am J Respir Crit Care Med; 169:
London, Academic Press, 2012: pp. 602 459467.
628. N OCallaghan C, et al. (2007). Diagnosing
N Brueckner M (2007). Heterotaxia, con- primary ciliary dyskinesia. Thorax; 62:
genital heart disease, and primary ciliary 656657.
dyskinesia. Circulation; 115: 27932795. N Strippoli MP, et al. (2012). Management
N Bush A, et al. (1998). Primary ciliary of primary ciliary dyskinesia in European
dyskinesia: diagnosis and standards of children: recommendations and clinical
care. Eur Respir J; 12: 982988. practice. Eur Respir J; 39: 14821491.

Gastro-oesophageal reflux-
associated lung disease and
aspiration syndrome
Osvaldo Borrelli, Efstratios Saliakellis, Fernanda Cristofori and Keith J. Lindley
Chronic pulmonary aspiration (CPA) common in pre-term infants, it remains a

syndrome is defined as the entry of food major health risk throughout infancy and
materials, gastric contents and/or saliva into childhood.
the subglottic airways in a manner sufficient
to induce chronic or recurrent respiratory Different physiological mechanisms have
symptoms (Boesch et al., 2006). These been suggested to be involved in the
symptoms include: pathogenesis of CPA, including swallowing
dysfunction, salivary aspiration and gastro-
N cough, oesophageal reflux (GOR). Swallowing
N asthma and wheezing, dysfunction during feeding commonly
N recurrent pneumonia, occurs in neurologically impaired children as
N choking, failure to thrive, the different phases of the swallowing
N apnoea of prematurity, process require complex coordination
N acute life-threatening events, between voluntary and involuntary actions,
N bronchiectasis/pulmonary fibrosis, and although it should be also considered in
N delayed resolution of chronic neonatal neurologically normal infants with recurrent
lung disease. pneumonia, wheezing, chronic cough and
stridor. Chronic aspiration of saliva is the
CPA constitutes one of the most serious least commonly recognised form of
threats to the normal development of the aspiration and is usually diagnosed after the
respiratory tract and, although more development of significant lung injury. It
generally occurs in children with
neurological impairment as a consequence
Key points of their swallowing dysfunction and
abnormal laryngeal sensation rather than
N CPA constitutes one of the most abnormal production of saliva. Finally, GOR
serious challenges to the normal has been implicated in the pathogenesis of
development of the respiratory tract, CPA, although their relationship is still
and it represents a major health risk matter of debate.
throughout infancy and childhood.
GOR is a physiological phenomenon
N Several studies have reported an occurring in healthy infants and children
association between GOR and CPA. several times daily. In contrast, gastro-
N Both acid and nonacid reflux are oesophageal reflux disease (GORD) is
implicated in the pathophysiology of defined as a condition in which the reflux of
parenchymal lung disease. gastric contents causes troublesome
symptoms and/or complication, and
N The diagnosis of GOR-related represents one of the most common causes
aspiration remains challenging of foregut symptoms in children (Sherman
because of the absence of sensitive et al., 2009). Although several studies in
and specific tests. children have emphasised the role of GOR
in the pathogenesis of upper and lower

airway respiratory disorders, the likelihood Although a significant body of literature in
of interactions between GOR and the children has emphasised the role of GOR in
respiratory system remains an area of the pathogenesis of lower airway respiratory
controversy in paediatric GORD (Tolia et al., disorders, it should be stressed that the
2009). It is now generally agreed that certain range of methodologies used hampers the
underlying disorders predispose children to interpretation of the results. Examples
higher risk of severe GORD, and thus to include the lack of standardised definitions
higher risk of GOR-induced respiratory for respiratory symptoms and/or diseases,
manifestations. These include neurological and the lack of temporal relationships
disorders, such as cerebral palsy, metabolic between the onset of respiratory symptoms
or genetic diseases (e.g. Pierre Robin and/or signs and GORD symptoms and/or
syndrome), congenital abnormalities, (e.g. signs. Moreover, it is difficult to evaluate
oesophageal atresia with tracheo- whether GORD children are at increased risk
oesophageal fistula), chronic lung disease of respiratory disorders in studies that do
(e.g. CF), and anatomical abnormalities not assess the prevalence of same disorders
characterised by a direct connection in a representative control group. Similarly,
between the oesophagus and airway. For the estimation of the prevalence of GORD in
instance, while type III tracheo-oesophageal children with respiratory disorders using
fistulas are often apparent at birth, H-type investigational tools cannot be extrapolated
fistulas may be more difficult to detect. to the general population, as the children are
investigated by a paediatric
The relationship between GORD and CPA gastroenterologist after the failure of
has been the subject of a number of conventional therapy. Finally, although it is
epidemiological and clinical studies. In now generally agreed that the presence of
children with severe neurodisability, severe abnormal GOR extending into the proximal
lower respiratory infections are associated oesophagus and cricopharyngeal region is a
with severe GOR only with coexistence of risk factor for aspiration, its finding does not
swallowing dysfunction (Morton et al., inevitably imply aspiration.
1999). GOR seems to be involved in the Pathophysiology of GOR-induced CPA
pathogenesis of recurrent pneumonia in
,6% of cases (Owayed et al., 2000). Proximal reflux episodes followed by direct
However, the prevalence of pneumonia irritation of the airway epithelium are the
and bronchiectasis among children with pathophysiological mechanism of GOR-
GORD without neurological disability or related CPA. Through elaborate reflex
congenital oesophageal anomalies is also mechanisms, a close functional relationship
increased between three and six times over exists between the oesophagus and the
that among controls (El-Serag et al., 2001; airway, which ensures the safety of the
Piccione et al., 2012). Finally, several airway against aspiration of material during
studies have reported an association an episode of GOR. For instance,
between GORD and CF. The prevalence of microaspiration of gastric contents into the
GORD in children with CF ranges between lung can be prevented by protective
25% and 100%, which is six to eight times mechanisms such as oesophageal clearance
the rate of GORD in the non-CF and reflex closure of the upper oesophageal
population. One-fifth of newly diagnosed sphincter and/or vocal cords. However, even
infants and 2555% of CF children older if aspiration occurs, gastric aspirate may be
than 1 year show pathological reflux when rapidly cleared from the lung. In
investigated (Mousa et al., 2012). GOR experimental animals, acute instillation of
may contribute to poor CF control at the gastric contents into the main bronchi leads
end stage of disease, and may cause to a wide array of histopathological changes
bronchiolitis obliterans syndrome (BOS) both in areas directly in contact with acid as
after lung transplantation (DOvidio et al., well as in distant areas, including alveolar
2006). haemorrhage and pulmonary oedema

(Sherrington, 2006). These changes seem
not to be related to direct tissue damage
induced by acid, but to the inflammatory
cascade triggered by release of preformed
cytokines from damaged cells, such as
leukotriene B4 and thromboxane A2. These
in turn stimulate the synthesis of other
cytokines, including interleukin (IL)-1,
tumour necrosis factor (TNF)-a and IL-8,
followed by neutrophil recruitment.
Repetitive chronic aspiration induces loss of
parenchymal architecture, collagen
deposition with fibrosis, bronchiectasis and Figure 1. Fluid from BAL stained with Oil Red O.
obliterative bronchiolitis. The lipid is seen within the cytoplasm of alveolar
macrophages. Image courtesy of F. Midulla
Several experimental and clinical data have (Paediatric Emergency Department, Policlinico
suggested the role of acid microaspiration in Umberto I, Sapenzia University of Rome, R0me,
the pathophysiology of bronchial Italy; personal communication).
inflammation and bronchoconstriction.
However, recent studies also emphasise the Biomarkers Ideally, a biomarker for
role of nonacid reflux in the pathophysiology aspiration should be a noninvasive measure
of some parenchymal lung diseases in both of a quantifiable marker within the lung,
adult and children. Bile acids and pepsin specific for reflux aspiration and reliably
from patients on antisecretory therapy detectable over a sustained period after
stimulate the production of transforming aspiration.
growth factor (TGF)-b via a p38 mitogen-
activated protein (MAP) kinase-dependent Lipid-laden macrophages (LLMs) in the
pathway, connective tissue growth factor bronchoalveolar lavage (BAL) have been
and IL-8 secreted by bronchial epithelial reported as useful markers of GOR-related
cells, suggesting their ability to provoke a pulmonary aspiration. The amount of lipid
significant bronchial reaction (Mertens et per single macrophage is determined after
al., 2010). Moreover, it has been recently Oil Red O staining of BAL using a
shown that nonphysiological levels of pepsin semiquantitative method, which assigns to
and acid are able to induce inflammation each cell a score ranging from 0 to 4
and death of airway epithelial cells with an according to the amount of lipid in the
effect inversely related to the acid cytoplasm (fig. 1). The number of cells
concentration. graded 0, 1, 2, 3 and 4 is calculated for each
patient, and the final LLM index (LLMI) is
Diagnosis
determined by evaluating 100 cells, with the
Before considering GOR as cause of CPA, highest possible score being 400 (Corwin et
the clinician needs to rule out the presence al., 1985). A LLMI of 165 is considered to be
of swallowing dysfunction and, consistent with aspiration (Furuya et al.,
consequently, a direct aspiration of fluid/ 2007). A rapid increase in LLMs occurs after
food with swallowing. The following steps intratracheal milk instillation, lasting for
are to determine whether pathological GOR o2 days after a single instillation and longer
is occurring, with gastric contents entering with recurrent instillation. LLMI seems to
the lungs, and to assess the likelihood of an correlate with total number of nonacid reflux
association between GOR and respiratory episodes and the number of nonacid reflux
symptoms and/or signs. Unfortunately, at episodes reaching the proximal oesophagus
the present time, there is no sensitive, (Borrelli et al., 2010). However, these
specific test for GOR-related aspiration, and findings are highly debated. The role of LLMI
the diagnosis is made combining clinical, as a standard test for aspiration is widely
laboratory and radiological tests. disputed, as studies have shown significant

5000
Proximal
0
5000
0
5000
Impedance
Intermediate
0
5000
0
5000
Distal
0
5000
0
8
pH
0
Time
Figure 2. Example of acid reflux episodes reaching the proximal oesophagus. Impedance measurements from
the proximal, intermediate and distal oesophagus, and pH are shown. The episode is categorised as acid
because of the presence of a pH drop to ,4 during the impedance-detected episode (arrow and shaded area).
variation in its sensitivity (57100%) and before and after lung transplantation
specificity (5789%) (Colombo et al., 2012). (Blondeau et al., 2008). Though a promising
An increase in LLMs has been described in investigative measure, the detection of
pulmonary conditions other than aspiration, pepsin in BAL fluid as a marker of gastric
such as CF, infections, use of intravenous aspiration has a number of concerns. Firstly,
lipid infusion and pulmonary fat embolism early cross-sectional studies only provide a
in sickle cell disease, suggesting that any snapshot in time of its presence, and there
pulmonary insult severe enough to cause are no data on how pepsin concentrations
tissue destruction may result in an increase change over time following aspiration or
in LLMs by releasing lipids from cell with frequency of aspiration events.
membranes (Knauer-Fischer et al., 1999). Secondly, alterations in content and
However, despite these significant concentrations may be dependent on BAL
limitations, an elevated LLMI may provide technique. However, based on current data,
supporting evidence of aspiration in a the specificity of the pepsin makes this
selected group of children. biomarker highly appealing.
Pepsin is a proteolytic enzyme of gastric Radiology An upper gastrointestinal contrast

origin and should not be detectable in the study is not a reliable test for discriminating
lower respiratory tract. Therefore, its between physiological and pathological
detection in the BAL fluid should be a highly GOR. However, it is useful to confirm or rule
sensitive and specific marker for GOR- out anatomical abnormalities of the upper
related aspiration. The presence of pepsin in gastrointestinal tract that may predispose to
the BAL is detected in a high percentage of GOR-related aspiration. Scintigraphy has
children with GORD and chronic respiratory been widely used for the evaluation of GOR
symptoms (83%) and its level correlates in children. However, its low sensitivity and
with proximal acid GOR (Starosta et al., specificity compared with 24-h oesophageal
2007). Pepsin has been used as a marker of pH monitoring makes this test unsuitable
aspiration in both preterm infants and for the routine diagnosis and management
children ventilated in the intensive care of GOR in infants and children. Evidence of
setting. Finally, increased BAL pepsin has pulmonary aspiration during the test is
been found in adults and children with CF, usually assessed through images obtained

up to 24 h after administration of the there is a degree of subjectivity in the
radionuclide. However, a negative test does interpretation of the results, but
not exclude the possibility of infrequent improvements in automated software
aspiration. Furthermore, even in the analysis will help to overcome this pitfall.
presence of aspiration, the technique is not Secondly, a positive test in a child with
able to discriminate between aspiration due symptoms and signs of aspiration does not
to swallowing dysfunction and GOR-related inevitably imply a causeeffect relationship,
aspiration. and negative test does not exclude the
possibility of GOR-related aspiration. Finally,
Oesophageal studies Although oesophageal the results of MII-pH monitoring are still
pH monitoring has been regarded for many difficult to interpret given the absence of
years as the most sensitive and specific normal paediatric reference values.
diagnostic tool for diagnosing GORD, its
Treatment
sensitivity and specificity are not well
established. In fact, pH monitoring has Medical and conservative therapies are the
significant limitations because of its inability initial choice for children with GORD and
to detect nonacidic retrograde bolus features of aspiration, including thickened
movement in the oesophagus, and in feeds, prokinetics and acid secretion
particular in infants who are frequently fed inhibitors. Proton pump inhibitors (PPIs)
milk and/or milk-based formulas. have been widely used to decrease acid
Multichannel intraluminal impedance (MII) reflux and the perceived risks of PPIs are
monitoring is a new clinically available tool low. Although the efficacy of PPIs has been
able to detect anterograde or retrograde shown for the treatment of patients with
bolus movement into the oesophagus in a oesophageal symptoms and signs, no data
pH-independent fashion. MII and pH (MII- are available for GORD-related respiratory
pH) monitoring combined can characterise symptoms. This is especially true in children
the reflux episodes as acid or nonacid (figs 2 with chronic pulmonary aspiration due to
and 3) and determine the composition GORD who do not seem to benefit from
(liquid, gas or mixed) and height reached by medical therapy in terms of improving lower
the refluxate. However, there are some respiratory tract injury. Moreover, it is
limitations of MII-pH monitoring. First, important to point out that although PPIs
5000
Proximal
0
5000
0
5000
Impedance
Intermediate
0
5000
0
5000
Distal
0
5000
0
8
pH 0
Time
Figure 3. Example of nonacid reflux episode reaching the proximal oesophagus. Impedance measurements from
the proximal, intermediate and distal oesophagus, and pH are shown. The episode is categorised as nonacid on
the absence of a pH drop to ,4 during the impedance-detected episode (arrow and shaded area).

change the gastric pH, they do not prevent Further reading
episodes of reflux-related microaspiration.
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Naso- or gastrojejunal feeding provides an phageal reflux and gastric aspiration in
approach to prevent reflux-related lung transplant patients with or without
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N Boesch RP, et al. (2006). Advances in the
severe neurological impairment; sometimes,
diagnosis and management of chronic
it needs to be combined with
pulmonary aspiration in children. Eur
fundoplication. Respir J; 28: 847861.
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antireflux procedure of choice in children with
pected pulmonary aspiration. Dig Liv Dis;
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treatment. It represents one of the three most common event and a clinical challenge.
commonly performed major operations in Pediatr Pulmonol; 47: 317320.
childhood. Resolution or improvement of N Corwin RW, et al. (1985). The lipid-laden
respiratory symptoms after fundoplication alveolar macrophage as a marker of
occurs in 4892% of patients. It has been aspiration in parenchymal lung disease.
demonstrated that fundoplication could Am Rev Respir Dis; 132: 576581.
reverse bronchiolitis obliterans syndrome in N DOvidio F, et al. (2006). The effect of
some lung transplant recipients with reflux and bile acid aspiration on the lung
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undergo Nissen fundoplication needs to be diagnosing aspiration in infants and
accurate and alternative surgical strategies, children. Pediatr Pulmonol; 42: 452457.
such as jejunostomy feeding, need to be N Knauer-Fischer S, et al. (1999). Lipid-
considered. The insertion of a laden macrophages in bronchoalveolar
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allowing gastric venting as well as aspiration. Pediatr Pulmonol; 27: 419422.
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patients on acid suppressive therapy can
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still provoke a significant inflammatory
type of jejunal feeding, aspiration of gastric
reaction by human bronchial epithelial
juice may still occur, they show a similar rate cells. J Clin Gastroenterol; 44: e230e235.
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compared with fundoplication (Srivastava et infections due to direct and reflux aspira-
al., 2009). Finally, in children with severe, tion in children with severe neurodisa-
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Foreign body aspiration
Iolo Doull
Foreign body aspiration (FBA) is a serious airflow, so even small foreign bodies can be
and potentially fatal condition in infants and dangerous. Compared to adults the larynx is
children. Choking may occur due to an in a relatively high position in infants with
obstruction in the oral cavity, and insertion the epiglottis close to the root of the tongue,
injuries may occur when foreign objects are increasing the risk of aspiration. Infants
present in either the nose or nasopharynx. have gag, cough and glottic closure reflexes
Ingestion injuries occur due to foreign to protect against aspiration, but they may
bodies in the oesophagus or stomach. not always be fully developed from birth, and
Depending on the age of the child and the swallowing, in particular, may be delayed.
size of the foreign body, airway obstruction Children with developmental delay are at
and aspiration can occur anywhere in the increased risk of aspiration.
respiratory tract. Large airway obstruction
preventing adequate ventilation can be fatal, Incisors are necessary to bite through food,
while more distal obstruction can lead to and molars are necessary to masticate the
emphysema, atelectasis and subsequent food in preparation for swallowing.
chronic changes including bronchiectasis. However, incisors erupt approximately
6 months before molars and so food may
Aetiology and predisposing factors not be appropriately pulped, remaining as a
small smooth or rounded mass, the ideal
Children ,3 years of age are at greatest risk. shape to obstruct an airway if aspirated.
Infants have smaller airways than adults. Infants and children are less able to cough
Flow through an airway is inversely out foreign bodies aspirated into the airway;
proportional to the radius to the fourth peak cough flows at 4 years of age are
power, thus small changes in airway radius approximately a quarter of that of adults.
lead to proportionately greater changes in Once lodged in an airway, mucus and local
inflammation will quickly result in complete
airway obstruction, thus diminishing the
Key points possibility of forced clearance. Finally
infants are easily distracted and often
N Children ,3 years of age are at inattentive, are more likely to talk and run
greatest risk of FBA. around while chewing, and more likely to put
N FBA must be suspected for any a small non-organic foreign body in their
witnessed choking episodes. mouth while playing.
N FBA cannot be excluded on either Epidemiology

normal physical examination or chest
radiograph. The exact incidence of fatal and non-fatal
FBA and choking-related injuries in children
N Removal of the foreign body is the is unclear; the available data are probably an
primary objective and mainstay of under-representation, and international
treatment. comparisons are difficult. Analysis of the US
National Electronic Injury Surveillance

System in 2001 identified 17 537 children Respiratory distress and/or cyanosis suggest
aged f14 years treated in emergency obstruction to a large airway and warrants
departments for choking related episodes emergency treatment. Laryngeal obstruction
(rate 29.9 per 100 000 population). Rates may cause a hoarse voice or aphonia,
were highest for infants (140.4 per 100 000) drooling, stridor and/or wheezing and
decreasing with each successive age cohort respiratory distress. Tracheal obstruction
to a rate of 4.6 per 100 000 for those aged may present with biphasic or monophonic
1014 years. Many choking-related episodes wheeze and bilaterally decreased breath
were mild and included minor pharyngeal sounds and respiratory distress. More distal
irritation without FBA, but ,10% required obstruction may result in unilateral
hospitalisation and for every 110 children monophonic wheeze and unilateral
treated there was one death. The decreased breath sounds. Cough and
commonest food substance was sweets/ wheeze are the most sensitive signs, while
chewing gum (19%) while the commonest stridor and cyanosis are the most specific.
non-food item was coins (12.7%). In Italy
there are about 400 children admitted per Late presentations may be misdiagnosed as
year who require removal of a foreign body. pneumonia, asthma or laryngitis presenting
with decreased chest movement, decreased
A review of 13 266 cases (91 reports) of FBA breath sounds, wheezing and possibly
from high-income countries and 24 731 crackles and pyrexia.
cases (83 reports) from low-/medium-
income countries (total 37 997) Investigations
demonstrated similar demographics in both
populations. 60% of subjects were male and A chest radiograph is mandatory for all
40% were female, and the majority were cases of suspected FBA to localise potential
aged f3 years (high-income countries 75%, foreign bodies and assess chest asymmetry,
low-/middle-income countries 60%). The but also to exclude other causes for
diagnosis of inhaled foreign bodies was respiratory distress. Flat objects such as
delayed by more than 24 h in approximately coins tend to align in the sagittal plane in
60% of the cases. the trachea whereas objects in the
oesophagus tend to align in the coronal
In a review of 30 reports comprising 12 979 plane. Lateral chest radiographs can
children with suspected FBA; of whom sometimes be helpful.
11 145 had aspirated an object (14% false
negative rate), over 80% of foreign bodies Chest radiograph abnormalities may include
were organic materials, with nuts and seeds asymmetry, such as air trapping and
being the most common. Approximately emphysema, infiltrates and possibly
90% were lodged in the bronchial tree, with mediastinal shift. For older children who are
the remainder in the larynx or trachea. able to co-operate, a combination of
Foreign bodies were more likely to lodge on inspiratory and expiratory films should be
the right side (52%) than the left (33%), obtained. Partial airway obstruction may
while a small number of objects fragmented cause a valve-like effect resulting in air
and lodged in different parts of the airways. trapping and mediastinal shift being more
prominent on expiratory films. The majority
Presentation of foreign bodies are organic materials and
A history of a witnessed choking event is are not usually radio opaque. Only 10% of
very suggestive of FBA, a child aged foreign bodies will be visible on a chest
,3 years is rarely able to give a clear history, radiograph. Pneumothorax and
and an adult is present in over half of such pneumomediastinum are infrequent
cases. findings. Chest radiographs may be normal
in approximately 17% of children
The clinical findings will depend on the level subsequently shown to have FBA. Later
at which obstruction has occurred, although radiographic features include segmental
most patients will have a paroxysmal cough. collapse, consolidation or atelectasis.

CT and generation of virtual bronchoscopy rare circumstance where the foreign body is
can be useful in assessment of FBA in stable too large to pass through the subglottic
children, offering greater sensitivity than space (the so-called monkey trap
plain radiographs. phenomenon) a temporary tracheostomy
may be required.
Treatment
Although the vast majority of foreign bodies
Immediate treatment of FBA by parents or are removed with rigid bronchoscope, there
carers may dislodge the foreign body. In is increasing evidence for the use of flexible
infants, back slaps in a head down position bronchoscopy. In a study of .1000 children,
with or without chest thrusts are the foreign bodies were successfully removed by
treatment of choice. Abdominal thrusts flexible bronchoscopy in .90%. Flexible
including the Heimlich manoeuvre appear bronchoscopy may be superior to rigid
more appropriate for older children. bronchoscopy in the removal of foreign
Foreign body aspiration must be suspected bodies from distal airways and, particularly,
for any witnessed choking episodes. the upper lobe bronchi.
Although a history of inhalation can be There is lack of consensus on the best
elicited from the parent in many cases, FBA anaesthetic regime with some authors
cannot be excluded on either normal advocating paralysis, while others advocate
physical examination or chest radiograph. spontaneous ventilation. Positive airway
Removal of the foreign body is the primary pressure during the procedure and
objective and mainstay of treatment. Rigid particularly afterwards is useful for re-
bronchoscopy is the classical investigation inflation of atelectatic lung areas. It is
and treatment of choice, although a important that after removal of a foreign
common strategy is to use rigid body the rest of the airways are checked to
bronchoscopy for children with convincing ensure there are no smaller objects. If there
evidence of FBA, while children with a less is significant bleeding during the procedure,
clear-cut history or findings undergo flexible dilute (100 mg?L-1) adrenaline can be
bronchoscopy. The majority of cases of FBA administered topically. Pre-operative
in Europe are treated in ENT departments. A antibiotics are usually administered and
number of negative bronchoscopies are continued for a 5-day course. Corticosteroids
required, with the reported incidence varying may be beneficial following removal of a
between 9% and 16.5%. foreign body to decrease airway oedema.
Rigid bronchoscopy requires general For patients presenting with respiratory

anaesthesia but allows control of the airway distress or cyanosis, emergency
at the same time, as instruments can be bronchoscopy is essential. However for
advanced to remove the foreign body in a patients who are clinically stable without
safe way, while also facilitating removal of respiratory compromise, it is reasonable to
mucous plugging and installation of saline take the child to theatre in a planned
or mucolytics to areas of lung collapse. manner during normal working hours, even
Removal is completed most often either if this incurs a delay. It is unlikely that a
with an alligator jaw or cup forceps. Balloon delay of ,24 h in removal of the foreign
tipped catheters can be used, particularly for body will have any significant long-term
round foreign bodies, to dislodge foreign effects on the lung. A review of over 3000
bodies that may be lodged with surrounding FBAs suggested that sequelae were more
granulation tissue. For organic material in common where a foreign body had been
particular, considerable care is required to present for .1 week: 27.2% versus 6.7% for
prevent disintegration of the foreign body those ,1 week.
resulting in multiple smaller foreign bodies. Complications
Once manoeuvred to the larynx it should be
removed via the lower triangle of the glottis In a meta-analysis of 26 studies where major
to avoid trauma to the vocal cords. In the complications were specified, deaths

occurred in 43 (0.42%) out of 10 236 cases. N Fidkowski CW, et al. (2010). The anes-
Death rates in individual studies varied thetic considerations of tracheobronchial
between 0.21% and 0.94% with foreign bodies in children: a literature
approximately a third presenting with review of 12,979 cases. Anesth Analg; 111:
hypoxic arrest and a third arresting during 10161025.
the procedure. Major non-fatal N Foltran F, et al. (2011). Foreign bodies
complications occurred in 0.96% and inhalation as a research field: what can
included severe laryngospasm or we learn from a bibliometric perspective
over 30 years of literature? Int J Pediatr
bronchospasm requiring tracheostomy or
Otorhinolaryngol; 75: 721722.
intubation, pneumothorax or N Foltran F, et al. (2013). Inhaled foreign
pneumomediastinum. Approximately a third bodies in children: a global perspective
required thoracotomy to remove the foreign on their epidemiological, clinical, and
body. preventive aspects. Pediatr Pulmonol; 48:
344351.
Prevention
N Gang W, et al. (2012). Diagnosis and
Public health strategies can reduce the risk treatment of tracheobronchial foreign
bodies in 1024 children. J Pediatr Surg;
of FBA in children. There are European and
47: 20042010.
US recommendations about the types of
N Gregori D, et al. (2010). Ingested foreign
food that are inappropriate for younger bodies causing complications and requir-
children, and choking hazard warnings on ing hospitalization in European children:
small toys that pose particular risks of FBA. results from the ESFBI study. Pediatr Int;
Parents can receive education and basic 52: 2632.
instructions on what to do in an emergency N Mani N, et al. (2009). Removal of inhaled
situation. foreign bodies middle of the night or
the next morning? Int J Pediatr
Otorhinolaryngol; 73: 10851089.
N Mantor PC, et al. (1989). An appropriate
Further reading
negative bronchoscopy rate in suspected
N Adaletli I, et al. (2007). Utilization of low- foreign body aspiration. Am J Surg; 158:
dose multidetector CT and virtual 622624.
bronchoscopy in children with suspected N Martinot A, et al. (1997). Indications for
foreign body aspiration. Pediatr Radiol; 37: flexible versus rigid bronchoscopy in
3340. children with suspected foreign-body
N Altkorn R, et al. (2008). Fatal and non- aspiration. Am J Respir Crit Care Med;
fatal food injuries among children (aged 155: 16761679.
014 years). Int J Pediatr Otorhinolaryngol; N Pinzoni F, et al. (2007). Inhaled foreign
72: 10411046. bodies in pediatric patients: review of
N CDC (2002). Non fatal choking-related personal experience. Int J Pediatr
episodes amongst children United Otorhinolaryngol; 71: 18971903.
States, 2001. Morb Mort Week Rep; 51: N Righini CA, et al. (2007). What is the
945948. diagnostic value of flexible bronchoscopy
N Cohen S, et al. (2009). Suspected foreign in the initial investigation of children with
body inhalation in children: what are the suspected foreign body aspiration? Int J
indications for bronchoscopy? J Pediatr; Pediatr Otorhinolaryngol; 71: 13831390.
155: 276280. N Sersar SI, et al. (2006). Inhaled foreign
N Committee on Injury, Violence and bodies: presentation, management and
Poison Prevention (2010).Prevention of value of history and plain chest radio-
choking among children. Pediatrics; 125: graphy in delayed presentation.
601607. Otolaryngol Head Neck Surg; 134: 9299.

Bronchiolitis obliterans
Francesca Santamaria, Silvia Montella and Salvatore Cazzato
Bronchiolitis obliterans, or constrictive

bronchiolitis, is a rare chronic obstructive
Key points lung disease, which follows a severe insult
to the respiratory tract and results in
N Bronchiolitis obliterans is a rare narrowing and/or complete obliteration of
paediatric chronic obstructive lung the small airways. Although the term
disease, which follows a severe insult describes a pathology confined to small
to the respiratory tract and results in airways, inflammation and fibrosis may
narrowing and/or complete extend to the alveoli and interstitium.
obliteration of the small airways.
In children, bronchiolitis obliterans is a long-
N The most common cause is severe term sequela of severe infections occurring
lower airway infection, followed by most commonly after acute pneumonia or
bone marrow or lung transplantation, bronchiolitis. Other causes include
drug toxicity, noxious inhalation transplantation of bone marrow or lung,
injury, vasculitis and autoimmune drug toxicity, noxious inhalation injury,
disorders. vasculitis and autoimmune disorders.
N Open lung biopsy for histological The onset of bronchiolitis obliterans is
confirmation of the diagnosis is rarely frequently insidious and symptoms may be
necessary. In the appropriate setting, misinterpreted, thus resulting in delayed
after the exclusion of other chronic diagnosis. Mortality remains high and most
obstructive lung disease, HRCT patients die of respiratory failure
provides adequate evidence for a complicated by additional infections.
correct diagnosis.
Epidemiology
N Lung function is characterised by a
moderate-to-severe fixed airflow Although childhood post-infectious
obstruction unresponsive to bronchiolitis obliterans is rare, its
bronchodilators that may slowly prevalence seems greater than previously
progress to fatal deterioration even a thought, particularly in South America,
few months after diagnosis. Mortality Europe, USA, India, East Asia, New Zealand
rates range from 3.2% to 16.7%, and Australia. Although the prevalence of
depending on bronchiolitis obliterans post-infectious bronchiolitis obliterans is
severity. unknown, its epidemiology is directly related
N The treatment of bronchiolitis to severe viral respiratory infections in young
obliterans is often unsuccessful children, mainly adenovirus. Race has also
because patients are referred to been suggested as a predisposing factor for
specialised centres when irreversible post-infectious bronchiolitis obliterans.
fibrotic changes and airway However, while an Argentinean group found
obliteration have already occurred. that their post-infectious bronchiolitis
obliterans patients had an increased
frequency of an allele highly expressed in an

Amerindian population, 70% of the post- N Influenza virus,
infectious bronchiolitis obliterans children N Parainfluenza virus,
followed up by a Brazilian centre were N Measles virus,
Caucasian. This suggests that a different N Varicella virus,
distribution may be found among centres N Mycoplasma pneumoniae,
according to the local racial composition. N Chlamydophilia pneumoniae,
In long-term lung transplant survivors,
N Staphylococcus aureus,
bronchiolitis obliterans represents the
N Streptococcus pneumoniae,
leading cause of morbidity and mortality,
N Bordetella pertussis.
and occurs in 6070% of patients surviving Although respiratory syncytial virus (RSV) is
at 5 years, whereas in allogeneic frequently associated with bronchiolitis,
haematopoietic stem-cell transplantation evidence for a causative role of it in
(HSCT) incidence ranges from 0% to 48%. determining post-infectious bronchiolitis
Pathology obliterans is lacking. Increased serum
interleukin (IL)-6, IL-8 and tumour necrosis
Bronchiolitis obliterans is primarily a lesion factor (TNF)-a in children with adenovirus
of the membranous and respiratory infection suggest that the host
bronchioles with fibrosing inflammatory immunological response may play an
process surrounding the lumen, which important role in the development of post-
results in progressive airways narrowing, infectious bronchiolitis obliterans.
distortion and obliteration. Histological
features have a wide spectrum from chronic The acute infection leading to post-
inflammation to bronchiolar scarring infectious bronchiolitis obliterans usually
without extensive changes in alveolar ducts requires hospital admission for oxygen
therapy and sometimes requires mechanical
or walls, and show a patchy distribution.
ventilation. Despite appropriate initial
The term bronchiolitis obliterans organising treatment, hypoxaemia, cough,
pneumonia (BOOP) identifies an airspace breathlessness, wheezing, tachypnoea,
filling process with granulation tissue plugs exercise intolerance and crackles on
extending to small airways, and is auscultation are common clinical findings.
distinguished from bronchiolitis obliterans Oxygen may be required for months or years
on the basis of clinical, functional and after the acute infection. Failure to thrive,
radiographic features, including response to clubbing, chest deformity and pulmonary
corticosteroids and prognosis. It was long arterial hypertension are reported in severe
considered a small airways disease, but cases.
current classification lists BOOP among Bronchiolitis obliterans following bone marrow
interstitial pneumonias. transplant Bronchiolitis obliterans is the
Clinical entities most common late, non-infectious
pulmonary complication of allogeneic
Post-infectious bronchiolitis obliterans Post- HSCT. Generally, bronchiolitis obliterans
infectious bronchiolitis obliterans should does not develop after autologous HSCT.
always be suspected in previously healthy Although there are reports of bronchiolitis
children who develop chronic respiratory obliterans as early as 30 days following
symptoms lasting for longer than 48 weeks HSCT, 80% of cases present 612 months
after an episode of acute, usually severe, post-transplantation.
infection at preschool age.
The presentation is usually insidious, and
Several pathogens are associated with main symptoms include dry cough (60
paediatric post-infectious bronchiolitis 100% of cases) and dyspnoea (5070% of
obliterans, and adenovirus (serotypes 3, 7, 11 patients). Wheezing and sinusitis are also
and 21) is most frequently implicated. Other frequent, while fever is rare unless there is a
microorganisms include: concomitant infection. Approximately 20%

of patients are asymptomatic, and diagnosis disease process or the medication used as
may be suspected based on lung function. treatment.
In the advanced stages, patients are
Risk factors
physically limited because of severe airway
obstruction and may require home oxygen. Pathogen load, immunological response,
Some patients may develop bronchiectasis and genetic and environmental factors may
with recurrent respiratory infections and be associated with bronchiolitis obliterans.
colonisation by Pseudomonas spp., S. aureus However, it is still unknown why some
and, occasionally, Aspergillus spp. Usual children, but not all, develop bronchiolitis
examination features are decreased breath obliterans.
sounds, wheezing, inspiratory squeaks and
signs of hyperinflation, while basal crackles Possible risk factors for post-infectious
are rare. However, thoracic examination may bronchiolitis obliterans are prolonged
be normal in early stages. Almost all hospitalisation, multifocal pneumonia, need
patients also have symptoms and signs of for mechanical ventilation and hypercapnia.
It remains unclear whether the need for
chronic graft versus host disease (GVHD),
mechanical ventilation is an indicator of
especially skin changes and sicca syndrome,
disease severity or is responsible for the
with dryness in the eyes and mouth.
direct induction of airway injury. Moreover,
Bronchiolitis obliterans following lung bilateral pulmonary involvement is
transplantation Lung transplantation associated with more severe post-infectious
recipients often have a variable period of bronchiolitis obliterans.
good graft function, followed by insidious
Recurrent acute cellular rejection (ACR)
onset of symptoms. Clinical presentation of
episodes following lung transplantation, as
bronchiolitis obliterans may vary from
well as high-grade ACR, are primary risk
asymptomatic disease to nonspecific factors for bronchiolitis obliterans. However,
symptoms as dyspnoea, cough and exercise a single episode of minimal ACR without
intolerance, while wheezing and chest pain recurrence or progression to rejection is also
are less common. Chest auscultation a significant independent predictor of
includes expiratory wheezing and occasional bronchiolitis obliterans. As a result, early
crackles, as well as distant breath sounds and aggressive treatment of ACR represents
with only mild expiratory prolongation. an important preventive strategy. Indeed,
Digital clubbing rarely occurs. recognition and treatment of ACR are often
delayed, as patients may be stable.
Compared to deceased donor transplant,
Moreover, ischaemiareperfusion injury
the incidence of bronchiolitis obliterans is
after transplantation or primary graft
lower in living donor lobar transplant
dysfunction are associated with bronchiolitis
recipients, probably due to less frequent and
obliterans, and the risk depends on the
less severe rejection episodes. Moreover,
severity of graft dysfunction. Ischaemia and
children aged ,3 years undergoing lung reperfusion, or other insults, may damage
transplantation show lower risk of the respiratory epithelium with resulting
bronchiolitis obliterans, probably because of exposure of hidden epitopes of collagen type
decreased incidence of acute rejection. V, which may result in bronchiolitis
Bronchiolitis obliterans following autoimmune obliterans secondary to autoimmune injury.
disorders or vasculitis The majority of Furthermore, leukocyte antigen mismatches
described cases with collagen-vascular following lung transplantation might
diseases and associated bronchiolitis promote bronchiolitis obliterans, but this is
obliterans (i.e. rheumatoid arthritis, controversial.
scleroderma, systemic lupus erythematosus, The presence of chronic GVHD is the most
Crohns disease and StevensJohnson important, but not the 9 unique, risk factor
syndrome) are adults. It remains unclear for bronchiolitis obliterans in HSCT. Other
whether this association is due to the frequent risk factors include:

N airflow obstruction (FEV1/FVC ratio ,0.7) Pulmonary function tests (PFTs) provide
prior to HSCT; information about disease severity and
N recipients age .20 years; progression over time. Infant PFTs, when
N viral infections (e.g. influenza, available, indicate severe obstruction,
parainfluenza and RSV) within 100 days diminished lung distensibility and increased
following HSCT; airway resistance since a few months after
N busulfan-based conditioning regimen; the disease onset. Older children exhibit
N mismatched or unrelated donor; severe and irreversible airflow obstruction
N hypogammaglobulinaemia (especially and the greater the air-trapping, the greater
IgG and IgA); the compromise during exercise. The
N methotrexate prophylaxis against GVHD; decrease in forced expiratory flow at 2575%
N older age of the donor; of FVC (FEF25-75) is the typical functional
N HSCT for chronic myelogenous marker of the disease, often associated with
leukaemia; reduced FEV1 and FVC. Increased residual
N blood-derived stem cells; volume (RV) and RV/TLC ratio indicate
hyperdistension. A positive methacholine
N interval from diagnosis of leukaemia to
challenge test following transplant is a risk
transplantation .14 months;
to developing bronchiolitis obliterans at an
N female donor to male recipient;
accelerated rate. Single-breath nitrogen
N prior interstitial pneumonitis;
washout may reveal heterogeneous
N low pre-transplant serum surfactant
ventilation and alteration in expiratory flow
protein D levels;
rates 612 months before conventional
N nucleotide-binding oligomerisation
PFTs. The lung clearance index (LCI) is
domain 2/caspase recruitment domain 15
increasingly used to detect the earliest
variants.
bronchiolitis obliterans abnormalities. The
In lung or bone marrow graft recipients, first evidence of its effectiveness in detecting
nonimmunological factors leading to post-bone marrow transplant bronchiolitis
bronchiolitis obliterans include EpsteinBarr obliterans in adults and children was
virus reactivation and infection of the lung reported by Khalid et al. (2007). In that
allograft by cytomegalovirus, adenovirus, study, paediatric patients demonstrated an
influenza and parainfluenza viruses, RSV, increased LCI from an early stage of
fungi and bacteria. The lung transplantation bronchiolitis obliterans compared to healthy
type may also be a risk factor, with single controls. This finding has been recently
transplant recipients being at higher risk confirmed in Australian adults who
than bilateral. Gastro-oesophageal reflux underwent repeated LCI measurements after
may contribute to allograft rejection, and HSCT (Lahzami et al., 2011). Finally, in
bile acids and pepsin in bronchoalveolar children with post-infectious bronchiolitis
lavage fluid (BALF) from lung transplant obliterans the impairment of TLCO related to
recipients indicate aspiration. poorly ventilated lung units with marked
small airways obstruction may be helpful in
Diagnosis the differential diagnosis with severe
asthma, which often shows normal or even
Although diagnosis is based on clinical, increased TLCO due to hypervascularity.
functional and radiographic criteria, lung
biopsy remains the gold standard to Chest radiographs are often unspecific or
diagnose bronchiolitis obliterans. Since even normal, but may reveal bilateral
parenchymal involvement is patchy, peribronchial thickening and/or
transbronchial biopsy has a small yield. hyperinflation with or without opacities,
Transthoracic biopsy from two sites is sometimes with associated pneumothorax
recommended. One of the major challenges or pneumomediastinum. Rarely there is
for paediatricians is the search less predominant unilateral hyperlucency
invasive diagnostic methods for (SwyerJames or McLeods syndrome), with
bronchiolitis obliterans. the affected lung being smaller on

inspiration and the mediastinum shifted on inspiratory scan. Indeed, the extent of air-
expiration towards the controlateral lung trapping may correlate with bronchiolitis
because of air-trapping. obliterans severity. The severity of HRCT
within the first 2 years after the acute
HRCT is extremely helpful for diagnosis, and event seems to predict the subsequent
structural changes include: lung function evolution. Furthermore, the
N mosaic perfusion, characteristic mosaic perfusion on HRCT,
N air-trapping, due to areas of attenuated density
N bronchial wall thickening, alternating with areas of increased
N bronchiectasis, attenuation with a patchy distribution,
N thickening of septal lines, may be useful in discriminating between
N narrowing of the pulmonary vessels due patients with bronchiolitis obliterans and
to reflex vasoconstriction secondary to those with severe asthma and irreversible
tissue hypoxia, obstruction. For all the above mentioned
N tree-in-bud pattern (fig. 1). reasons and given the relative risk of lung
biopsy, it has been emphasised that in the
Expiratory scans are helpful in identifying appropriate setting, once other congenital
air-trapping that may be missed on an or acquired disorders have been excluded
(e.g. CF, primary ciliary dyskinesia,
immunodeficiency, bronchopulmonary
a) dysplasia, congenital heart disease, severe
asthma, inhaled foreign body, extrinsic
bronchial compression and a1-antitrypsin
deficiency), HRCT provides clear evidence
for a correct diagnosis without the need
for biopsy. Thus, lung biopsy is
recommended if HRCT is inconclusive or
not available, or when severe progression
and gradual deterioration occur despite
treatment.
b) Ventilation-perfusion scintigraphy with the

typical matched ventilation/perfusion defect
in one or more pulmonary segments
provides a valuable assessment of
extension, distribution and severity of lung
involvement that correlates with the number
of exacerbations.
BALF neutrophilia in the absence of an

identifiable pathogen might be a
reproducible marker of bronchiolitis
Figure 1. a) HRCT scan of a 4-year-old boy with obliterans as it increases with the severity of
bronchiolitis obliterans following Mycoplasma bronchiolitis obliterans stage.
pneumoniae infection. Bilateral areas of
increased and decreased parenchymal attenuation
Finally, in severe bronchiolitis obliterans
(mosaic perfusion), bronchiectasis and air- oximetry may reveal overnight
trapping can be seen. b) Bronchiolitis obliterans in hypoxaemia that should prompt
a 13-year-old boy 2 years after bone marrow a thorough cardiovascular assessment,
transplantation for acute lymphoblastic including electrocardiogram,
leukaemia. The HRCT scan shows a bilateral echocardiogram and cardiac
mosaic perfusion pattern, air-trapping and catheterisation, if necessary, to detect
bronchial dilatation. pulmonary arterial hypertension.

Treatment bronchiolitis obliterans, but should be
discontinued in the absence of benefits.
Patients should be treated by a
multidisciplinary team with: In lung transplant and bone marrow
transplant recipients, azithromycin may
N a paediatric pulmonologist,
improve bronchiolitis obliterans symptoms,
N a paediatric cardiologist,
lung function and exercise tolerance, probably
N a physical therapist,
because it exerts anti-inflammatory and
N a nutritionist,
immunomodulatory activity through
N a psychologist,
neutrophil chemotaxis inhibition and
N a social worker.
proinflammatory cytokine reduction.
Bronchiolitis obliterans treatment for Empirical monthly intravenous Ig
children has not been clearly defined, and administration was used in few cases. There
pharmacological approaches are often are also some anecdotal reports of symptom
based on the clinical experience of different improvement after chloroquine and
healthcare workers. hydroxychloroquine in bronchiolitis obliterans,
and after TNF-a monoclonal antibodies
The treatment of bronchiolitis obliterans is (infliximab) in bronchiolitis obliterans
often unsuccessful because patients are complicating bone marrow transplantation.
referred to specialised centres when airway Finally, in bronchiolitis obliterans following
changes are irreversible. It is mainly lung transplantation the addition of
supportive, including prolonged oxygen montelukast to immunosuppressive drugs
supplementation, particularly during the was reported to decrease lung function
first period of the disease, antibiotics, decline over 6 months.
annual influenza vaccination and chest
physiotherapy for cases complicated by In localised bronchiectasis or atelectasis
bronchiectasis. Adequate nutritional unresponsive to pharmacological therapy,
support is fundamental as up to 20% of surgical resection is indicated. Severe cases
children with bronchiolitis obliterans may with oxygen dependency, important physical
have some degree of malnutrition. Gastro- limitation and extremely impaired lung
oesophageal reflux must be adequately function should be referred for lung
treated. transplantation.
Although frequently used in the clinical Prognosis
practice, corticosteroids in post-infectious
bronchiolitis obliterans are controversial The long-term prognosis of bronchiolitis
because no trials have confirmed their obliterans is variable and depends on
efficacy. There are only clinical reports of several factors, including the underlying
beneficial effects of pulse causes and the speed of development. In
methylprednisolone (2530 mg?day-1 for most cases, post-infectious bronchiolitis
3 days) in children with post-infectious obliterans is chronic and nonprogressive, in
bronchiolitis obliterans. Conversely, in contrast with bronchiolitis obliterans
GVHD occurring after HSCT high-dose occurring after StevensJohnson syndrome
systemic prednisone (11.5 mg?kg-1?day-1 for or bone marrow transplantation. Most
26 weeks) or methylprednisolone patients with post-infectious bronchiolitis
(10 mg?kg-1?day-1 for 3 days on monthly obliterans improve slowly and progressively,
basis for 16 cycles) should be prescribed, but this may be due to airways growth rather
and immunosuppressive therapy should be than to resolution of inflammation.
reinstituted or augmented. In paediatric Nevertheless, most patients continue to
lung transplant recipients, the development have mild symptoms especially during
of bronchiolitis obliterans should lead to exercise. Neutrophils, CD8+ T-cell
augmentation of immunosuppression. lymphocytes, activated T-cells (CD3+HLA-
Inhaled corticosteroids and/or DR+) and IL-8, a potent chemoattractant and
bronchodilators may be considered in activator for neutrophils, are increased in

the BALF several years after the initial insult, N Camargos P, et al. Bronchiolite obliterante
suggesting that lung inflammation persists. post-infectieuse. In: de Blic J, ed.
Pneumologie Pediatrique. Paris, Medecine-
In most bone marrow transplant recipients, Sciences Flammarion, 2009; pp. 7276.
bronchiolitis obliterans progressively leads N Cazzato S, et al. (2008). Airway inflam-
to irreversible airflow obstruction over mation and lung function decline in
months to years because of frequent childhood post-infectious bronchiolitis
exacerbations. The mortality is 9% at obliterans. Pediatr Pulmonol; 43: 381
3 years, 12% at 5 years and 18% at 10 years. 390.
Patients with advanced bronchiolitis N Champs NS, et al. (2011). Post-infectious
obliterans usually die from pneumonia. bronchiolitis obliterans in children. J
Factors associated with mortality include Pediatr (Rio J); 87: 187198.
rapid FEV1 deterioration (.10% per year), N Fischer GB, et al. (2010). Post infectious
progressive chronic GVHD, underlying bronchiolitis obliterans in children.
disease relapse, respiratory viral infections, Paediatr Respir Rev; 11: 233239.
airflow obstruction within 150 days following N Khalid Y, et al. (2007). Obliterative
transplantation, and no response to the bronchiolitis after stem cell transplanta-
tion: inert gas washout makes early
primary treatment.
diagnosis of this serious complication
Chronic bacterial airway colonisation in lung possible. Lakartidningen; 104: 33733376.
transplant recipients with bronchiolitis N Kurland G, et al. (2005). Bronchiolitis
obliterans is commonly associated with obliterans in children. Pediatr Pulmonol;
poor outcome. Moreover, bronchiolitis 39: 193208.
N Lahzami S, et al. (2011). Small airways
obliterans, or its complications, are the
function declines after allogeneic haema-
single most common cause of death in lung
topoietic stem cell transplantation. Eur
transplant recipients, accounting for 40% of Respir J; 38: 11801188.
deaths .1 year later. N Mallory GB, et al. (2004). Paediatric lung
Morbidity due to frequent obstructive transplantation. Eur Respir J; 24: 839845.
N Moonnumakal SP, et al. (2008).
exacerbations and infections requiring
Bronchiolitis obliterans in children. Curr
hospitalisations is high in bronchiolitis
Opin Pediatr; 20: 272278.
obliterans. Mortality rates range from 3.2% N Pandya CM, et al. (2010). Bronchiolitis
to 16.7%. Fatal course may occur secondary obliterans following hematopoietic stem
to progressive respiratory failure. cell transplantation: a clinical update. Clin
Transplant; 24: 291306.
Further reading N Robertson AGN, et al. (2009). Targeting
allograft injury and inflammation in the
N Boehler A, et al. (2000). Obliterative management of post-lung transplant
bronchiolitis after lung transplantation. bronchiolitis obliterans syndrome. Am J
Curr Opin Pulm Med; 6: 133139. Transplant; 9: 12721278.
N Bosa VL, et al. (2008). Assessment of N Teper AM, et al. (2004). Association
nutritional status in children and adoles- between HLA and the incidence of
cents with post-infectious bronchiolitis bronchiolitis obliterans in Argentina. Am
obliterans. J Pediatr; 84: 323330. J Respir Crit Care Med; 169: A382.
N Bowdish ME, et al. (2004). Surrogate N Williams KM, et al. (2009). Bronchiolitis
markers and risk factors for chronic lung obliterans after allogeneic hematopoietic
allograft dysfunction. Am J Transplant; 4: stem cell transplantation. JAMA; 302:
11711178. 306314.

Plastic bronchitis
Bruce K. Rubin and William B. Moskowitz
Plastic bronchitis is an uncommon disease

characterised by the presence of cohesive Key points
branching casts filling the airways. This
disease has been recognised for thousands N Plastic bronchitis in children is usually
of years and was first described by Galen associated with congenital heart
who believed that patients were disease post-surgery with Fontan
expectorating pulmonary veins; venae physiology.
arteriosae expectoranti. Plastic bronchitis has N Cast formation appears to be related
had many names through the years although to poor cardiac output, lymphatic
the terms plastic bronchitis, fibrinous abnormalities, inflammation, and
bronchitis and cast bronchitis are most tissue factor activation.
commonly used.
N There is no proven therapeutic value
Diagnosis in using hypertonic saline,
salbutamol, corticosteroids,
Plastic bronchitis is part of the secretory acetylcysteine, dornase alfa,
hyperresponsiveness disease spectrum. antibiotics or expectorants.
The diagnosis of plastic bronchitis is
confirmed by identifying the cohesive, N There is some evidence to support the
branching airways casts that are use of low-dose azithromycin and
expectorated by the patient or removed aerosol heparin to prevent casts, and
bronchoscopically (fig. 1). Bronchoscopic tPA can help mobilise casts in situ but
removal is most common in young children can be very irritating to the airway.
with severe, life-threatening respiratory Airway clearance therapy, such as high
distress due to both the cast and the frequency chest wall compression, is
underlying cardiac disease. These casts strongly recommended.
contain an abundance of mucin but unlike N Thoracic duct ligation and cardiac
normal mucin polymers that are linearly transplantation appear to reduce or
joined, there is significant cross-linking eliminate cast formation in some
between adjacent mucin strands. The casts patients.
contain variable amounts of fibrin with
many patients having only small amounts
of fibrin in expectorated casts.
bronchitis casts further distinguishing them
In patients with bronchiectasis and CF there from mucus plugging. Plastic bronchitis
are large amounts of polymeric DNA and F- also appears to be different from the mucus
actin as the principal polymer gel substance. plugging associated with fungal
These mucus (sputum) plugs have low inflammation of the airway, as noted in
cohesivity and rarely, if ever, develop into allergic bronchopulmonary aspergillosis. It
solid cohesive complex branching casts is not clear if plastic bronchitis can be part
diagnostic of plastic bronchitis. There is also of the asthma spectrum in patients with
no polymeric DNA or F-actin in plastic severe asthma and secretory

exacerbations of plastic bronchitis varies
markedly among patients with congenital
heart disease; sometimes first appearing
years after surgery. Some patients may have
subclinical disease with the expectoration of
small casts or resolution of casts between
exacerbations. It is not clear which patients
with single ventricle physiology are most
likely to develop plastic bronchitis, although
there are associations with protein losing
enteropathy, poor cardiac function, central
venous pressure elevation, arrhythmias and
low cardiac output. The cardiac and
Figure 1. Typical expectorated branching cast from pulmonary interaction leading to plastic
a child with plastic bronchitis and congenital heart bronchitis is not known, but may be
disease. associated with abnormalities in tissue
factor.
hyperresponsiveness. These patients
Plastic bronchitis has been associated with
probably should not be classified as having
lymphatic abnormalities both in patients
plastic bronchitis.
with congenital heart disease and in patients
We have examined plastic bronchitis casts with primary abnormalities of lymphatic
from more than 50 adults and children with flow. Case reports suggest that thoracic duct
a variety of associated conditions and all ligation can attenuate, or even cure, plastic
show the presence of inflammatory cells. bronchitis in some patients. A plastic
Although plastic bronchitis was once bronchitis-like condition can be triggered by
classified as Type 1 or Type 2 (cellular and the inhalation of toxic gases such as sulfur
acellular) the consistent appearance of mustard. In experimental animals that have
inflammatory cells, predominantly inhaled sulfur mustard there is extensive
lymphocytes with a minor component of plugging of the airway with fibrin rich casts
macrophages, makes this classification of that appear similar to those seen in humans
limited therapeutic or prognostic value. with plastic bronchitis.
Inflammatory cells are more commonly
Plastic bronchitis is also associated with
seen in association with asthma and allergy
sickle cell disease acute chest syndrome. It
and other non-cardiac associated
is not known if development of casts in
conditions.
sickle cell disease leads to areas of
Plastic bronchitis is probably under hypoxaemic sickling within the lung
diagnosed. The diagnosis is often made at producing the symptoms of acute chest
autopsy after death from respiratory failure. syndrome, or if the acute chest syndrome
Patients with milder forms of plastic itself predisposes to cast formation. Plastic
bronchitis probably undergo spontaneous bronchitis is not associated with pulmonary
recovery. Thus, identified patients probably bacterial infection and, in general,
represent the most severe cases with antibiotics are not recommended as part of
dramatic branching casts, airway therapy. However, plastic bronchitis has
obstruction and extensive atelectasis. been shown to be associated with influenza
A infection in children and similar cast
Disease associations formation has been described in birds who
have been experimentally infected with avian
Plastic bronchitis in young children is influenza.
primarily associated with congenital heart
disease, particularly in children with single It is controversial as to whether severe asthma
ventricle Fontan physiology (table 1). The and airway plugging should be considered a
occurrence, severity and the frequency of plastic bronchitis-like disease. Fatal asthma

Table 1. Conditions associated with plastic bronchitis or hypertonic saline, or mucolytics, such as
N-acetylcysteine. These medications
Proven should only be used with caution as some
Congenital heart disease with Fontan can induce mucus secretion or increase
physiology airway inflammation.
Sickle cell disease acute chest syndrome
There have been several case reports that
Pulmonary lymphatic abnormalities the inhalation of tissue plasminogen
Influenza A pulmonary infection activator (tPA) can improve plastic
Toxic inhalation
bronchitis, most probably through fibrin
depolymerisation. tPA is extremely
Possible expensive and can be irritating to the
Other congenital cyanotic cardiac disease airway with haemoptysis or dyspnoea
Non-pulmonary lymphatic abnormalities being reported after inhalation. In patients
with severe plastic bronchitis a trial of
Hypersecretory and near-fatal asthma aerosol tPA should be considered at a dose
(eosinophilic casts)
of 0.71.0 mg?kg-1 every 4 h. Inhaled
Allergic bronchopulmonary aspergillosis heparin has also been effective in patients
Unlikely with plastic bronchitis. Heparin has no
effect on preformed fibrin but has been
CF
shown to reduce mucin secretion and
COPD prevent tissue factor activation of the fibrin
Bronchiectasis pathway. Heparin also has anti-
Bacterial pneumonia inflammatory properties and is far less
irritating to the airway and dramatically
less expensive than some of the other
agents. A trial of aerosolised heparin at a
secretions are extremely cohesive and when dose of 5000 units every 4 h should be
extracted from the airway appear to have a considered.
formation of branching casts; and in that
respect they more closely resemble plastic Isolated reports suggest that inhaled
bronchitis than mucus plugging. anticholinergics may reduce cast
formation. Although there has been
Therapy concern that inhaled anticholinergics may
Because plastic bronchitis is an thicken secretions, this has not been the
case when these have been used to treat
uncommonly reported condition, most
asthma, CF or COPD. There is no role for
reports of effective therapy are isolated
the use of antibiotics to treat bacterial
case reports or small case series.
infection in plastic bronchitis. However,
Furthermore, most patients reported in
low-dose macrolides can decrease mucin
these case studies have received a number
production by inhibiting extracellular
of different medications making it difficult
regulated kinase (ERK)1/2. There are case
to ascertain which of these therapies, if
reports suggesting that low-dose
any, are effective (table 2). Evaluation of
macrolides, similar to their use in CF or
data from the International Plastic
diffuse panbronchiolitis, can attenuate the
Bronchitis Registry suggests no benefit severity of plastic bronchitis.
from the use of asthma medications, such
as short-acting b-agonists or inhaled In patients with documented lymphatic
corticosteroids. There is no therapeutic abnormalities, thoracic duct ligation may be
benefit from using inhaled dornase alfa of benefit. There is limited evidence that
(Pulmozyme; Roche, San Francisco, CA, improving cardiac physiology by fenestrated
USA) as plastic bronchitis casts do not Fontan has a beneficial effect on the severity
contain polymeric DNA. There is no benefit or resolution of plastic bronchitis.
in using expectorants, such as guaifenesin Improving cardiac output, when possible,

Table 2. Recommendations for therapy The future
Good evidence Through the US National Institutes of
Airway clearance including physical Health, Office of Rare Diseases we have
therapy and devices such as high- established an International Plastic
frequency chest compression vest Bronchitis Registry to collect data on
Aerosol heparin patients worldwide (www.clinicaltrials.gov
identifier NCT01663948). This will help us
Aerosol tPA to generate hypotheses that can be tested
Cardiac transplantation clinically and will, potentially, allow us to
Anecdotal or case report evidence use genome or inflammasome screening to
interrogate potential causes for this
Hyperosmolar saline
devastating disease. Through the Office of
Low-dose oral macrolides (clarithromycin Rare Diseases we have also set up a
or azithromycin) tissue repository of expectorated bronchial
Oral or inhaled corticosteroids (only for casts and, with an approved protocol,
eosinophilic casts) we will make these available to
Thoracic duct ligation investigators interested in studying
Modifications of Fontan (fenestration or
this devastating disease. Information
take down) can be accessed through www.clinicaltrials.
gov.
No evidence
b-agonist aerosol
Further reading
Dornase alfa (Pulmozyme)
Mucolytics such as N-acetylcysteine N Akhter J, et al. (2004). Flexible fiberscope
directed removal of mucus plugs in a child
Expectorants such as guaifenesin with plastic bronchitis. J Bronchol; 11: 112114.
Non-macrolide antibiotics N Deng J, et al. (2010). Plastic bronchitis in
three children associated with 2009
influenza A(H1N1) virus infection..
Chest; 138: 14861488.
can reduce the severity of plastic bronchitis. N Eason DE, et al. (2013). Aerosolized
There are reports that cardiac heparin in the treatment of Fontan
transplantation in children and young adults related plastic bronchitis. Cardiol Young
with heart failure can cure plastic bronchitis 23: 13.
when medical management is ineffective. N Goldberg DJ, et al. (2010). Rare problems
associated with the Fontan circulation.
Airway clearance appears to be among the Cardiol Young; 20: 113119.
safest and most effective therapy. Once N Heath L, et al. (2011). Prospective, long-
plastic bronchitis has been diagnosed, itudinal study of plastic bronchitis cast
starting the routine with daily use of a pathology and responsiveness to tissue
high-frequency chest compression vest, for plasminogen activator. Paediatr Cardiol;
those with an effective cough, or the 32: 11821189.
N Kanoh S, et al. (2010). Macrolides as
CoughAssist device (Philips Respironics,
immunomodulatory medications.
France), for those with impaired cough, can Mechanisms of action and clinical
prevent cast re-accumulation. We also applications. Clin Microbiol Rev; 23:
recommend exercise, if possible, and good 590615.
nutrition, which can consist of protein N Laubisch JE, et al. (2011). Treatment of
repletion in children with protein losing plastic bronchitis by orthotopic heart
enteropathy or, sometimes, weight loss, transplantation. Pediatr Cardiol; 32: 1193
especially in obese adults with plastic 1195.
bronchitis (table 2).

N Madsen P, et al. (2005). Plastic bronchi- azithromycin. Pediatr Pulmonol; 35: 135
tis: new insights and a classification 143.
scheme. Paediatric Respir Rev; 6: 292300. N Shah SS, et al. (2006). Plastic bronchi-
N Moser C, et al. (2001). Plastic bronchitis tis: is thoracic duct ligation a real
and the role of bronchoscopy in the acute surgical option? Ann Thorac Surg; 81:
chest syndrome of sickle cell disease. 22812283.
Chest; 120: 608613. N Wilson J, et al. (2005). Fenestration of the
N Schultz KD, et al. (2003). Treatment Fontan circuit as treatment for plastic
of cast bronchitis with low-dose oral bronchitis. Pediatr Cardiol; 26: 717719.

Haemangiomas,
lymphangiomas and
papillomatosis
Thomas Nicolai
Haemangiomas 412 weeks of life, depending on the size of

the haemangioma and its rate of growth.
Airway haemangiomas are benign capillary Quite often an acute viral airway infection
tumours. Generally, benign capillary
will acutely increase the pre-existing airway
tumours occur in 12% of newborns, usually
obstruction caused by a haemangioma. The
involving the skin. However, haemangiomas
most common differential diagnosis is
may also occur in the airways and ,25% of
croup or laryngomalacia. In contrast to
these cases also have haemangiomas of the
croup the symptoms caused by a laryngeal
skin.
or tracheal haemangioma exacerbated by a
The most common benign capillary tumours viral infection will not disappear fully after
in the paediatric airway are subglottic and the acute phase of the respiratory infection
glottic haemangiomas, which may be and may actually progress to overt
present at birth and usually grow for the next respiratory insufficiency. Often, an
46 months. Haemangiomas of the lower expiratory component of the stridor
airways have been described but are rare. becomes apparent with critical obstruction,
Laryngeal haemangiomas can also be part of and the voice or cry is changed in quality
larger haemangiomas that may extend into and loudness.
the intrathoracic cavity.
Diagnosis The diagnosis is suspected by a
Clinical signs Sometimes, the haemangioma typical history and an inspiratory and,
may be present at birth leading to neonatal sometimes, also expiratory noise. A very
inspiratory stridor. However, this early useful instrument for diagnosis is
presentation is rare. In a typical case, ultrasound, which can define the typical
inspiratory stridor develops over the first subglottic tumour structures. In addition, an
MRI scan can show the typical blood filled
glottic or subglottic rounded object.
Key points However, care must be taken as children
may need sedation for MRI scans, and when
N Haemangiomas are benign and these children are intubated for this purpose
respond to propranolol. the haemangioma will be compressed by the
N Lymphangiomas may need to be endotracheal tube and may then be missed.
resected if they obstruct the airway; Also, the intubation itself can be quite
the clinical course is less predictable. dangerous with damage to the subglottic
area or even bleeding. Therefore,
N Papillomatosis of the larynx may
laryngotracheoscopy (usually performed
require repeated surgical resection
with a flexible endoscope) is often the
and often responds to cidofivir.
easiest way to diagnosis when ultrasound
N Newer therapies are currently being has failed to rule out haemangioma.
explored for lymphangiomas and Subglottic haemangiomas have a quite
papillomas. typical appearance and may form a rounded
unilateral or bilateral structure in the

Various methods of surgically removing the
a) haemangioma have been described. Careful
endoscopic laser resection has been
reported to be quite successful in avoiding
tracheotomy in almost all cases, and will, in
my view, remain a good option in
nonresponders to propranolol. Before these
therapeutic options became available many
children had to remain tracheotomised for
23 years until the size of the malformation
had become small enough to allow
decannulation.
However, recently it was found, by a

serendipitous discovery, that propranolol
will shrink haemangiomas and arrest further
growth (fig. 1). Therefore, today, therapy
consists of the administration of
b) propranolol, sometimes accompanied by
initial short-term steroid therapy. With this
strategy it is usually possible to avoid
tracheotomy, as only about 14% of infants
with airway haemangioma are
nonresponders. The optimal duration of
propranolol therapy has not been
established, and it is recommended to treat
until the involution phase of the
haemangioma is reached (usually at 6
8 months of age but some authors advocate
12 months). Catch-up growth of airway
haemangioma in infants after cessation of
propranolol has been reported in about 7%
of children and may need extended therapy.
Refractoriness of the regrowth to
Figure 1. a) Subglottic haemangioma almost propranolol has been described. The long-
totally obstructing the airway. b) Subglottic time prognosis of this tumour is excellent.
haemangioma that is reduced in size after 1 week of
treatment with propranolol (2 mg?kg-1?day-1). Lymphangiomas
Lymphangiomas are not neoplastic growing

subglottic area (fig. 1). The surface is lesions, but malformations of the lymphoid
smooth and often has a reddish colour. In tissues. It is assumed that these
very rare cases a biopsy may be needed and malformations originate from primitive
histology and staining for glucose lymphatic sacks formed of mesenchymal or
transporter 1 (GLUT1) will establish the epithelial embryonic tissue. Dysplastic
diagnosis. lymph capillaries do not allow normal
drainage of interstitial fluid and lead to
Therapy Mortality without treatment has tissue swelling and cystic transformation of
been reported to be ,50%. Therapy used to the affected structures. This malformation is
rely on long-term systemic steroids with all usually not confined to specific organs and
their known side-effects. Intra-lesional local may involve larger regions of the body. This
application of steroids was also tried, with explains the changeable course of the size
only limited success; almost two-thirds of with, for example, sudden increases of
the children were eventually tracheotomised. pharyngeal masses in size during viral

infections or with bleeding into the
lymphangioma. It also explains why
therapeutic options are sometimes limited:
total resection of the affected tissue is not
always possible and remaining (often
clinically unapparent) malformed regions
may later expand in size when drainage of
the lymphatic fluid is obstructed. Other
manifestations of lymphatic malformations
may concern the whole lung and or
mediastinum and lead to chylothorax and
respiratory failure.
Lymphangioma
Clinical signs Lymphangiomas can involve
the pharynx and larynx and lead to severe
airway compromise (fig. 2). Sometimes the Figure 3. MRI scan of a lymphangioma of the
lymphangioma may be present at birth, larynx.
being visible as a cranial, pharyngeal or neck N interferon-a2b,
mass, and/or leading to neonatal inspiratory N laser resection.
stridor. Clinical manifestations may also
occur later in life, e.g. with swelling due to an However, the optimal selection of therapy
acute viral infection or when bleeding into requires considerable experience. The
the lymphangioma leads to an abrupt natural history of lymphangiomas is less
increase in lesion size. benign than that of haemangioma, as
Diagnosis Airway endoscopy shows an involution is not seen regularly.
obstructing mass that may have a typical Future developments Recently, the use of
multicystic appearance, and allow for sildenafil has been described in case reports
biopsy. MRI scans will delineate the and seems to open up a promising new
extension of the lymphangioma into therapeutic approach, but controlled studies
adjacent tissues (fig. 3). are only currently under way. Another
Therapy Therapeutic options include: promising therapeutic agent in complicated
refractory lymphangioma seems to be
N surgical resection, sirolimus.
N infiltration with sclerosing agents, Papillomas
Recurrent respiratory papillomatosis (RRP)

of the larynx of children is the most common
tumour of the paediatric larynx, and
involvement of the lower airways does occur.
Its incidence has been estimated to be two
to four cases per 100 000. The papilloma
viruses most frequently seen in the aetiology
are human papilloma virus (HPV) type 6
and 11; however, there are more than 100
types of HPV. The infection is caused by
transmission during birth from the mothers
genital lesions to the childs airways.
Caesarean section can reduce but not totally
eliminate the infection risk. However, only
very few children born to mothers with
Figure 2. Lymphangioma of the larynx infiltrating genital HPV infections later develop airway
the right dorsal aspect. papillomatosis; therefore, individual risk

factors have to play a role in disease normal larynx. However, surgery sometimes
manifestation. Subtle complex leads to highly dangerous laryngeal scarring
abnormalities of the immune response to at the level of the vocal fold, in particular if
HPV in these patients have been found. the resection of the papillomas has been
either too aggressive, including more than
Clinical signs The usual time-point of clinical one vocal cord during one session, or
manifestation is 34 years of age. Clinical resection was close to the anterior
signs include: commissure of the vocal folds. The use of
N progressive dyspnoea, laser surgery may lead to heating structures
N hoarseness, below the level of the papillomas, such as
N stridor. the vocal fold, and thereby cause damage
with scar formation. These scars can lead to
Papillomas can grow quite large and complete airway obstruction and
obstruct the laryngeal opening completely. tracheostomy. Children with airway
papillomatosis and tracheostomy are at risk
Diagnosis Laryngotracheoscopy will show of generalisation of the papillomatosis to
the typical cauliflower-like appearance of the lower airways (trachea and bronchi)
growth, usually above the vocal folds, a where an eradication of the papillomas is
biopsy will allow the identification of the usually impossible.
virus type (fig. 4).
A therapeutic modality used widely is the
Clinically an aggressive form can be virustatic cidofovir. This antiviral has shown
observed with HPV type 6, while the milder clinical effectiveness in treating adults with
course seems to be associated with HPV AIDS and systemic HPV infection, and is
type 11. Manifestation before the age of also widely used to infiltrate papillomas
3 years and more than four surgical locally. At present there are no good
procedures to remove airway-obstructing randomised studies, but well-documented
papillomas are associated with a more case series in children and adults with
aggressive clinical form, which may not aggressive papillomatosis show that ,60
resolve spontaneously. 80% of patients will respond, with the
Therapy Therapy may include resection of therapy either leading to less frequent
the papillomas either surgically or with a interventions for papilloma resection or
microdebrider or laser. However, utmost even disappearance of the lesions.
care must be taken not to cause secondary
From experiments in cell cultures and
airways stenosis. It must be kept in mind
marker expression studies some concern
that papillomatosis itself does not lead to
has been voiced that cidofovir may increase
scarring and once overcome will leave a
the risk for laryngeal cancer. However, such
cancer has never been clearly attributed to
cidofovir use, and papillomatosis itself can
lead to airway cancer when it is present for
many years. A recent paper assessing its
safety in a large number of patients found
no increased laryngeal malignancies.
Therefore, in cases with aggressive diseases,
cidofovir may be useful and sometimes the
only option available. However, parents have
to be informed about their choices and the
conceivable side-effects of the drug and the
infection itself.
In rare cases, a generalised HPV infection

Figure 4. Papillomatosis of the larynx with of the lung follows tracheobronchial
obscured vocal folds. dissemination, resulting in cavitation.

This is more frequent in adult patients and it N Lucs AV, et al. (2012). Constitutive over-
may be difficult to differentiate this from expression of the oncogene Rac1 in the
carcinoma formation. airway of recurrent respiratory papilloma-
tosis patients is a targetable host-sus-
Future developments Recent research has ceptibility factor. Mol Med; 18: 244249.
elucidated that in many people HPV is N Meeuwis J, et al. (1990). Subglottic
present in the airway mucosa without overt haemangioma in infants: treatment with
papillomatosis and that the oncogene Rac1 intralesional corticosteroid injection and
is overexpressed in the epithelium of these intubation. Int J Pediatr Otorhinolaryngol;
individuals. The downstream product of 19: 145150.
Rac1, COX-2, can be blocked with a COX-2 N Nicolai T, et al. (2005). Subglottic hae-
inhibitor, which leads to diminished HPV mangioma: a comparison of CO(2) laser,
transcription in cell culture. One study has Neodym-Yag laser, and tracheostomy.
Pediatr Pulmonol; 39: 233237.
treated three patients with the COX-2
N Pransky SM, et al. (1999). Intralesional
inhibitor celecoxib and achieved disease
cidofovir for recurrent respiratory papillo-
remission in all. A prospective study has matosis in children. Arch Otolaryngol
been initiated. Other agents tried for Head Neck Surg; 125: 11431148.
papillomatosis, but for which no clear N Richter GT, et al. (2012). Haemangioma
benefit has as yet been demonstrated and vascular malformations:et al current
convincingly include avastin, artemisinin theory and management. Int J Pediatr;
and propranolol, while interferon seems 645678.
effective but has had unacceptable side- N Rozman Z, et al. (2011). Lymphangioma:
effects in some children. is intralesional bleomycin sclerotherapy
effective? Biomed Imaging Interv J; 7: e18.
Vaccination programmes against HPV will N Sherrington CA, et al. (1997). Subglottic
hopefully reduce the frequency of this haemangioma. Arch Dis Child; 76: 458
worrisome disease. In established disease 459.
the currently available vaccinations cannot N Sie KC, et al. (1994). Subglottic haeman-
be expected to be effective, but a therapeutic gioma: ten years experience with the
DNA vaccine is currently being developed. carbon dioxide laser. Ann Otol Rhinol
Laryngol; 103: 167172.
N Snoeck R, et al. (1998). Treatment of
severe laryngeal papillomatosis with
intralesional injections of cidofovir. J
Further reading Med Virol; 54: 219225.
N Swetman GL, et al. (2012). Sildenafil for
N Bonagura VR, et al. (2010). Recurrent severe lymphatic malformations. N Engl J
respiratory papillomatosis: a complex Med; 366: 384386.
defect in immune responsiveness to N Tjon Pian Gi RE, et al. (2013). Safety of
human papillomavirus-6 and -11. APMIS; intralesional cidofovir in patients with
118: 455470. recurrent respiratory papillomatosis: an
N Grasso DL, et al. (2008). international retrospective study on 635
Lymphangiomas of the head and neck RRP patients. Eur Arch Otorhinolaryngol;
in children. Acta Otorhinolaryngol Ital; 28: 270: 16791687.
1720. N Vlastarakos PV, et al. (2012). Propranolol is
N Hammill AM, et al. (2011). Sirolimus for an effective treatment for airway haeman-
the treatment of complicated vascular giomas: a critical analysis and meta-
anomalies in children. Pediatr Blood analysis of published interventional stu-
Cancer; 57: 10181024. dies. Acta Otorhinolaryngol Ital; 32: 213221.
N Laranne J, et al. (2002). OK-432 N Wierzbicka M, et al. (2011). Effectiveness
(Picibanil) therapy for lymphangiomas in of cidofovir intralesional treatment in
children. Eur Arch Otorhinolaryngol; 259: recurrent respiratory papillomatosis. Eur
274278. Arch Otorhinolaryngol; 268: 13051311.

Interstitial lung diseases
Annick Clement, Guillaume Thouvenin, Harriet Corvol and Nadia Nathan
Interstitial lung disease (ILD) in infants and

Key points children represents a heterogeneous group
of respiratory disorders that are mostly
N ILD in children represents a chronic and impair the respiratory function
heterogeneous group of respiratory of the lung. In pathology, the term ILD
disorders that are mostly chronic and describes structural alterations of the lung
impair the respiratory function of the interstitium. However, in clinical practice, it
lung. refers to processes that affect the lung
N The term ILD has been replaced by parenchyma, which include the alveolar
the term DPLD, thus covering all structure (i.e. the alveolar epithelium, the
pathological entities affecting lung interstitium and the pulmonary capillary
homeostasis and remodelling endothelium), as well as the terminal
following injury. bronchioles. Based on these anatomic and
functional considerations, a new term
N The mechanisms underlying disease diffuse parenchymal lung diseases (DPLD)
development are dependent on the has recently been introduced to more
type of DPLD; the common basis is accurately describe these diseases.
the interaction between injurious Therefore, the term DPLD will be used in
environmental triggers and genetic this chapter instead of ILD.
predisposition.
DPLD covers a large number of disorders
N The presenting clinical manifestations characterised by inflammation and/or
are often subtle and nonspecific, remodelling of the lung parenchyma. They
therefore, a two-step diagnosis include rare diseases with established
approach is required: 1) diagnosis of diagnosis criteria (such as genetic disorders
DPLD syndrome; 2) diagnosis of of the surfactant system), as well as
specific DPLD. pathological conditions with uncertain
N Treatment protocols remain difficult diagnosis and/or unknown causes. This
to produce but the overall strategies explains the fact that the estimated
include general measures and incidences of the various forms of DPLD are
pharmacological therapy, difficult to establish, especially in children.
mainly anti-inflammatory and Indeed, in the paediatric population, disease
immunosuppressive expressions are dynamically influenced by
molecules. the ongoing process of lung growth and
maturation. Several reports in the literature
N A favourable response to anti- have provided information on a national
inflammatory therapy can be expected survey of paediatric DPLD. An estimated
in almost two-thirds of cases, prevalence of 3.6 per million cases was
although significant sequelae are reported in immunocompetent children in
often observed. the UK and Ireland. In Germany, a rate of
1.32 new cases per 1 million children per

year has been observed. These numbers are member 3 (ABCA3) and the thyroid
certainly underestimated due to the lack of transcription factor (TTF)-1. More than 30
standardised definitions, the absence of SFTPB mutations have been identified
organised reporting systems and the variety among patients with a congenital deficiency
of pathological conditions. In addition, in SP-B. For SFTPC, at least 35 mutations
clinical presentation is nonspecific, have been reported, localised primarily in the
contributing to a poor recognition of the COOH- terminal Brichos domain.
disorders that may be confused with other Alterations in this domain can lead to
diseases. Nevertheless, it seems that DPLD diseases via mechanisms related to
is more frequently observed in the younger abnormal protein processing and cell
age and in males. In addition, nearly 10% of toxicity. Recently, several studies have
cases appear to be familial. described genetic variations of ABCA3 in
DPLD, with the information that ABCA3 plays
Pathophysiology
an important role in the transport of
DPLD can be caused by a number of factors surfactant lipids into lamellar bodies.
with distinct prognosis and natural history. Another molecular contributor of surfactant
Agents responsible for initiation of the homeostasis is TTF-1, a regulator of
pathological process can be introduced transcription for SP-B and SP-C. Other
through the airways and the circulation, or genetic factors/predispositions currently
can occur as a result of sensitisation. being discussed include genes associated
Consequently, the mechanisms underlying with lung development and embryonic
disease progression will be influenced by the pathways, and those involved in the
causative event, as well as by the host and telomerase system. Telomerases are
the environment. These mechanisms are important regulators of the re-population of
developed through interactions of multiple the damaged epithelium, partly through
pathways. activation and proliferation of tissue-
resident stem cells and their differentiation
Based on results from experimental models leading to replacement of the injured cells.
and patient lung tissue analysis, it is Telomere shortening has been linked to
proposed that injury of the respiratory decreased activity of telomerase and a
epithelium is the key determinant of the reduced capacity for stem cell renewal.
disorders. Repeated multi-focal epithelial Several studies have also indicated that
micro-injury and/or delayed surface telomerase is mainly expressed during lung
regeneration lead to epithelial cell apoptosis development with a peak expression before
and altered epithelialmesenchymal birth followed by a decrease to nearly
interactions, with consequently disturbed undetectable levels in mature alveolar
epithelium homeostasis, dysregulated epithelium. Interestingly, exposure of
inflammatory response and lung normal quiescent alveolar cells to injury
remodelling.
induces induction of telomerase expression
The mechanisms underlying disease and activity. The contribution of telomerase
development are dependent on the type of mutation and/or dysfunction in the
DPLD, with the common basis being the progression of paediatric DPLD remains to
interaction between injurious environmental be explored.
triggers (which include oxidants and toxic
agents, immune complexes, viruses and DPLD seems to be observed less frequently
gastro-oesophageal reflux) and genetic in children than in adults. In addition, the
predisposition. overall outcome and prognosis of the
disease are thought to be less severe in
Genetic defects of the surfactant system are paediatric patients. These differences may
increasingly described in paediatric DPLD. be explained by the types of initial injury
They include variations in genes encoding (which might not be similar due to changes
the surfactant protein (SP)-B (SFTPB), SP-C in the host environment), as well as
(SFTPC), ATP-binding cassette, sub-family A, modifications of the process of wound

healing after injury with age. Recent Diagnosis of DPLD syndrome
experimental studies have shown that a
single episode of lung injury by either The diagnosis of DPLD is established on
bleomycin or virus can induce pulmonary presenting history and clinical, radiological
fibrosis only in aged wild-type mice and not and functional findings. Major criteria
in young animals, supporting the view that include dyspnoea, diffuse infiltrates on chest
age-related physiological changes contribute radiographs and abnormal pulmonary
to distinct disease expressions. Several function tests (PFTs) with restrictive
factors may participate in the altered ventilatory defect and/or impaired gas
response to wound with ageing. One of exchange with hypoxaemia.
these is the progressive modification in cell The presenting clinical manifestations are
renewal capacity due to increased epithelial often subtle and nonspecific. The onset of
cell apoptosis and accumulation of symptoms is, in most cases, insidious and
senescent stem cells. Apoptosis is necessary many children may have had symptoms for
for the removal of inflammatory cells months before the diagnosis of DPLD is
following injury, but this process requires a confirmed. Common symptoms at
complex balance between the various presentation include:
parenchyma cell types. In several models of
lung fibrosis, an abnormal pattern of N tachypnoea/dyspnoea (observed in 80%
enhanced apoptosis of alveolar epithelial of patients),
cells in combination with a decreased N cough (present in almost 75% of the
capacity of fibroblast to apoptosis has been patients),
documented, leading to insufficient surface N exercise limitation,
re-population and fibrotic tissue N frequent respiratory infections.
development. Studies of the molecular
mechanisms have recently led to targeting Failure to thrive (37%), tiring during feeding
of the endoplasmic reticulum and the and weight loss are also common
transforming growth factor (TGF)-b symptoms, mainly in young patients.
pathways. Dysregulation of these pathways Unexplained fever is also reported in infants.
is increasingly observed in ageing tissues
with abnormal scar formation. Among the The past medical history should be deeply
other contributors to altered healing with reviewed for precipitating factors such as
ageing are the increased burden of oxidative feeding history, infections or exposure to
stress and epigenetic changes. Several environmental agents and drugs. In
recent studies tend to suggest that ageing is addition, family history needs to be
associated with a general relaxation of investigated for relatives or siblings with
epigenetic control, including progressive similar lung conditions.
changes in DNA methylation and histone The frequent clinical findings are inspiratory
modifications, with consequently impaired crackles, tachypnoea and retraction. In a
renewal capacity of the stem/progenitor cells child with a normal birth history, these are
of the lung parenchyma. strongly suggestive of DPLD. Other findings
Clinical approach and diagnosis observed in older patients include finger
clubbing and cyanosis during exercise or at
The number of separate disorders under the rest. Depending on the types of DPLD,
DPLD umbrella implicates selected associated nonrespiratory symptoms may
investigation strategies. However, despite be observed, such as cutaneous rashes,
the differences in causes and outcomes, the joint manifestations, uveitis and recurrent
clinical presentation of the majority of DPLD fever in situations of collagenvascular
is globally similar. Therefore, a two-step disorders.
diagnosis approach is required:
Chest imaging is an essential contributor for
N Step 1: diagnosis of DPLD syndrome, the diagnosis. Plain radiographs are usually
N Step 2: diagnosis of specific DPLD. performed at first presentation. In almost all

cases, abnormalities are documented but defined by a reduced resting SaO2 or a
the information provided is often limited reduced resting PaO2, is often present.
and the key chest imaging tool for diagnosis Hypercapnia occurs only late in the disease
is HRCT. The most common HRCT feature course. During exercise the previously
of paediatric DPLD is widespread ground- described dysfunctions become even more
glass attenuation, with some observations pronounced, and gas exchange during
of intralobular lines and irregular exercise might be a more consistent and
interlobular septal thickening. Large sensitive indicator of early disease.
subpleural air cysts in the upper lobes
adjacent to areas of ground-glass opacities Bronchoalveolar lavage (BAL) and lung
are also reported in young patients (fig. 1). tissue analysis are not commonly proposed
These cysts are interpreted as paraseptal or in the first-step diagnostic approach.
irregular emphysema. HRCT is useful not Besides infections, BAL can be of diagnostic
only for diagnosis, but also for selection of value in specific situations, which include
lung area to be biopsied. pulmonary alveolar haemorrhage,
Langerhans cell histiocytosis, lipid disorders
PFT represents a useful investigation for with lung involvement, or alveolar
both the diagnosis and the management of proteinosis. In other pathological situations,
DPLD in children and adolescents. In BAL can usefully serve to direct further
preschool children, the techniques currently investigations, by providing specimens for
available are limited. Common pulmonary cytological examination, microbial cultures
function abnormalities reflect a restrictive and molecular analysis.
ventilatory defect with reduced lung
compliance and decreased lung volumes. Histological evaluation of lung tissue
Vital capacity (VC) is variably diminished usually represents the final step in a series
and the decrease in TLC in general is of diagnostic approaches. Different methods
relatively less than in VC. Functional residual of biopsy are reported, based on expertise of
capacity (FRC) is also reduced but relatively the surgical teams and the balance between
less than VC and TLC, and residual volume procedure invasiveness and the potential for
(RV) is generally preserved; thus, the ratios obtaining adequate and sufficient tissue
of FRC/TLC and RV/TLC are often increased. material for diagnosis. The techniques of
Airway involvement is observed in only a choice are open lung biopsy and video-
minority of patients. TLCO is often markedly assisted thoracoscopy biopsy. The other
reduced and may be abnormal before any methods, such as transbronchial lung
radiological findings. However, TLCO biopsy, are less frequently proposed. The
corrected for lung volume may also be lung histological patterns observed in
normal in many children. Hypoxaemia, various forms of DPLD have been reviewed
in several reports. The most common
abnormalities include thickening of alveolar
interstitial walls, accumulation of
inflammatory cells, fibrotic components,
epithelial cell hyperplasia, and alveolar
spaces filled with inflammatory cells, hyaline
membranes containing surfactant proteins
or cellular debris.
Specific diagnosis of DPLD and
classification
Figure 1. HRCT scan of a 2-year-old girl with There have been many different approaches
surfactant protein C deficiency (I73T mutation in to the classification of paediatric DPLD;
SFTPC gene). The scan shows diffuse ground-glass several of them are now being reconsidered.
attenuations with parenchymal cysts and It is believed that some forms are more
interlobular septal thickening. prevalent in very young children. However,

increasing reports in older patients and tests focus on the search for serum-
adults have documented genetic causes precipitating IgG antibodies against the
previously documented in infants, such as offending antigen. Other exposure-related
mutations in the genes encoding proteins of diseases are those caused by radiation and
the surfactant system. In addition, along drugs including anti-inflammatory agents
with the continuous improvement of (e.g. aspirin and etanercept),
investigation procedures, diseases immunosuppressive and chemotherapeutic
associated with lung parenchyma structural agents (e.g. azathioprine, methotrexate and
abnormalities have been reported in cyclophosphamide), and illicit drugs in
patients beyond infancy. Another important teenagers.
issue relates to the inclusion of some forms
of bronchopulmonary dysplasia (BPD) in the Systemic disease-associated DPLD comprises
list of causes. The debate, with the expertise a complex group of disorders requiring
of clinicians and pathologists, is still specific investigations oriented by the
ongoing. Indeed, BPD may favour repeated clinical expression. They mainly include:
insults of the lung parenchyma with delayed N granulomatous diseases,
surface regeneration early in life. Also, the N metabolic disorders,
question of the role of chronic aspiration
syndromes as a causal or precipiting factor
N connective tissues disorders (CTD),
is increasingly being addressed and will
N pulmonary vasculitis,
require further prospective studies.
N Langerhans cell histiocytosis.
In situations of granulomatous diseases, the

From a clinical point of view, a step-by-step
discussed diagnoses are mainly sarcoidosis,
aetiological search is critical, starting with a
infections and disorders of neutrophil
clinical evaluation requiring careful attention
function. Sarcoidosis is relatively
to exposure and environment, systemic
uncommon among children. Its diagnosis is
manifestations and family disorders. This
based on a combination of suggestive
clinical approach will lead to determining
clinical features, with histologically
the specific investigations, which will be
documented noncaseating granuloma, in
performed according to the following
the absence of other known causes of
grouping:
granuloma formation. Its incidence seems
N exposure-related DPLD; to be influenced by age, race and geographic
N systemic disease-associated DPLD; localisation. Most of the cases in children
N lung-restricted DPLD; occur in pre-adolescents and adolescents,
N DPLD specific to infancy (table 1). with more observations documented in
Black children than Caucasian children.
Exposure-related disease refers to diseases DPLD in metabolic disorders are reported in
caused by a sufficient level of exposure lysosomal diseases such as Gauchers
(dose) to components with target organ disease, NiemannPick diseases and
contact, and subsequent biologic changes HermanskyPudlak syndrome. CTD refers to
and clinical expression. Many agents have any disease that has the connective tissues
been associated with pulmonary of the body as a primary target of pathology
complications of various types, including and whose development implicates genetic,
DPLD. In children, this diagnosis is certainly constitutional and environmental elements.
underestimated, as paediatricians do not The main disorders to be considered during
usually have the expertise necessary to childhood are rheumatoid arthritis, systemic
obtain an environmental history. The sclerosis and systemic lupus erythematosus.
diagnoses most commonly reported include Pulmonary vasculitis is observed in
hypersensitivity pneumonitis, a cell- vasculitic syndromes that preferentially
mediated immune reaction to inhaled affect small vessels (arterioles, venules, and
antigens in susceptible persons, e.g. bird capillaries): anti-neutrophil cytoplasmic
fanciers diseases, humidifier lung diseases antibody-associated vasculitis
and chemical lung diseases. Laboratory (granulomatosis with polyangiitis

Table 1. DPLD diagnosis in children disorders and lymphatic system dysfunction.
As mentioned previously, some forms of
Exposure-related DPLD chronic neonatal lung diseases associated
Hypersensitivity pneumonitis with BPD and pulmonary hypertension may
Radiation exposure also be discussed.
Drugs The role of infections, mainly viral, in DPLD
Systemic disease-associated DPLD is sustained by a number of human and
Granulomatous diseases experimental studies documenting targeted
injury of the alveolar epithelium. The list of
Metabolic disorders
viruses comprises adenovirus, members of
Connective tissue disorders the herpes virus family (EpsteinBarrr virus
Pulmonary vasculitis and cytomegalovirus) and respiratory
Langerhans cell histiocytosis
syncytial virus. Among the other pathogens,
Chlamydophila pneumoniae and Mycoplasma
DPLD-associated with other organ pneumoniae are currently drawing increasing
diseases consideration.
Lung-restricted DPLD
Surfactant disorders include genetic
Infections
surfactant protein disorders and pulmonary
Surfactant disorders alveolar proteinosis. Mutations in SFTPC are
Pulmonary alveolar proteinosis currently the main reported genetic
Diffuse alveolar haemorrhage disorders with the most prevalent mutation
being I73T (c.218 T.C). The phenotype
Eosinophilic lung diseases
associated with SFTPC mutations is
Diffuse developmental disorders extremely heterogeneous, from neonatal
Lymphatic system disorders fatal respiratory failure to DPLD children and
DPLD specific to infancy adults. The deficiency in SP-B is a rare
autosomal recessive condition known to be
Neuroendocrine cell hyperplasia mainly responsible for lethal neonatal
Pulmonary interstitial glycogenosis respiratory distress. Recessive mutations in
Chronic pneumonitis in infancy the ABCA3 gene were first attributed to fatal
respiratory failure in term neonates but are
increasingly being recognised as a cause of
(Wegeners granulomatosis), ChurgStrauss DPLD in older children and young adults.
syndrome and microscopic polyangitis); Mutations in the TTF-1 gene are associated
anti-glomerular basement membrane with brain-lung-thyroid syndrome which
disease; HenochSchonlein purpura and combines congenital hypothyridism,
cryoglobulinemia vasculitis. neurological symptoms (hypotonia and
chorea) and lung diseases.
In addition to Langerhans cell histiocytosis,
other causes of systemic disease-associated Pulmonary alveolar proteinosis is a rare lung
DPLD include inflammatory bowel diseases disorder characterised by alveolar filling with
(Crohns disease), liver and neurocutaneous floccular material derived from surfactant
disorders, and amyloidosis. phospholipids and protein components.
Pulmonary alveolar proteinosis is described
Lung-restricted DPLD include disorders as primary or secondary to lung infections,
primarily affecting the components of the haematological malignancies and inhalation
distal parenchyma. The main diagnosis is of mineral dusts. Abnormalities in
infections, surfactant disorders, pulmonary granulocyte/macrophage colony-stimulating
alveolar proteinosis, diffuse alveolar factor are increasingly reported in
haemorrhage and eosinophilic lung pulmonary alveolar proteinosis
diseases, as well as diffuse developmental pathogenesis.

Diffuse alveolar haemorrhage syndromes hyperplasia of infancy is a non-lethal disease
are caused by the disruption of alveolar characterised by tachypnoea without
capillary basement membrane as a respiratory failure. On lung biopsy, the
consequence of injury to the alveolar septal histological abnormality is hyperplasia of
capillaries, and less commonly to the neuroendocrine cells within bronchioles
arterioles and veinules. The hallmarks are documented by bombesin
intra-alveolar accumulation of red blood immunohistochemistry. In some cases, the
cells, fibrin and haemosiderin-laden follow-up reveals the persistence of
macrophages. In approximately one-third of tachypnoea and oxygen requirement for
patients, diffuse alveolar haemorrhage does several months. Usually, there is a good
not manifest haemoptysis, and BAL can be prognosis. Pulmonary interstitial
extremely helpful by documenting the glycogenosis is also a non-lethal disease
presence of siderophages or red blood cells reported in neonates with respiratory
within the alveoli. Diffuse alveolar distress syndrome that develops shortly
haemorrhage can be observed in the after birth. The histological hallmark is the
absence of systemic diseases or in the accumulation of monoparticulate glycogen
context of other diseases, which include in the interstitial cells on lung biopsy. It is
pulmonary hypertension, congenital heart thought to represent a maturation defect of
diseases, pulmonary veno-occlusive disease, interstitial cells that causes them to
arteriovenous malformations, hereditary accumulate glycogen within their cytoplasm.
haemorrhagic telangiectasia, coagulation
disorders and coeliac disease. Treatment strategies and outcome
Eosinophilic lung diseases constitute a The diversity of DPLD conditions and the
diverse group of disorders of various lack of randomised clinical trials in groups
origins. The diagnosis is suggested by of well-phenotyped paediatric patients
increased peripheral eosinophilia and explain the difficulty to propose treatment
confirmed by the presence of eosinophils in strategies. Longitudinal care of these
BAL and/or lung tissue. Eosinophilic lung children needs to be organised in
diseases of known cause in children mainly specialised centres. In this section, general
include allergic bronchopulmonary management with the most usual
aspergillosis, parasitic infections and drug pharmacological therapies is indicated.
reactions. Eosinophilic lung diseases of
General measures are essential and mainly
unknown cause comprise Loeffler syndrome
include administration of oxygen for chronic
(characterised by migrating pulmonary
hypoxaemia and maintenance of nutrition
opacities), acute eosinophilic pneumonia
with an adequate energy intake.
and chronic eosinophilic pneumonia.
Immunisation with the influenza vaccine on
Among the diffuse developmental disorders is an annual basis is recommended along with
alveolar capillary dysplasia, a rare disorder other routine immunisations against major
presenting with persistent pulmonary hyper- respiratory pathogens. In addition, aggressive
tension of the newborn. A definitive diagnosis treatment of intercurrent infections and strict
can only be made by histological examination, avoidance of tobacco smoke and other air
documenting poor capillary apposition and pollutants are strongly recommended.
density, allied with medial arterial hypertrophy
and misalignment of pulmonary vessels. Pharmacological therapy includes anti-
Interestingly, capillary proliferation in the inflammatory and immunosuppressive
alveolar wall has been reported in hereditary molecules. Steroids are the preferred choice,
haemorrhagic telangiectasia. administered orally and/or intravenously.
Oral prednisolone is most commonly
DPLD specific to infancy includes administered at a dose of 12 mg?kg-1?day-1.
neuroendocrine cell hyperplasia, pulmonary Children with significant disease are best
interstitial glycogenosis and chronic treated with pulsed methylprednisolone, at
pneumonitis in infancy. Neuroendocrine cell least initially. This is usually given at a dose

of 1030 mg?kg-1?day-1 for 3 consecutive Lung transplantation is a viable option in
days at monthly intervals. When the disease children of all ages, even in young infants,
is under control, the dosage of and lung or heartlung transplantation may
methylprednisolone can be reduced or the be offered as an ultimate therapy for end-
time between cycles can be spaced out. An stage DPLD. The outcome and survival do
alternative to steroids is hydroxychloroquine not seem to be different from those reported
with a recommended dose of 6 in other pulmonary conditions. Among other
10 mg?kg-1?day-1. Individual case reports specific treatments is whole lung lavage in
have described a response to situations of pulmonary alveolar proteinosis.
hydroxychloroquine, even in the presence of
steroid resistance. Some groups have The prognosis of children with DPLD is
proposed to base the decision as to which extremely variable. It is highly dependent on
agent to use on the lung biopsy findings, the cause, the expertise and environment of
with a preference for steroids in the case of the patient care system, and the individual
large amounts of desquamation and response to treatment. It is also very difficult
inflammation, but for hydroxychloroquine if to predict: some children with relatively
increased amounts of collagen representing severe fibrosis on lung biopsy make good
pre-fibrotic change are found. However, as progress, whereas others with mild
documented in the European Respiratory desquamation have a poor outcome.
Society Task Force on paediatric ILD, the Overall, a favourable response to anti-
preferred choice between steroids or inflammatory therapy can be expected in
hydroxychloroquine in children is highly almost two-thirds of cases, although
dependent on the expertise of the centre in significant sequelae, such as limited exercise
charge of the patient, and does not seem to tolerance or the need for long-term oxygen
be oriented by the histopathological pattern. therapy, are often observed. Reported
In the case of severe disease, steroids and mortality rates are approximately 15%.
hydroxychloroquine may be associated. In
situations of inefficiency of steroids and Conclusion
hydroxychloroquine, other
immunosuppressive or cytotoxic agents, DPLD in children comprises a large
such as azathioprine, cyclophosphamide, spectrum of disorders, resulting from
cyclosporine, or methotrexate, may be used. interactions between injurious
environmental triggers and genetic
Other therapeutic options include predisposition. Although much effort has
macrolides. Indeed, these antibiotics have been made in the clinical approach, there is
been shown to display a number of anti- still a lack in disease characterisation,
inflammatory and immunomodulatory identification of specific phenotypes linked
actions. Of interest is the ability of to documented molecular mechanisms, and
macrolides to accumulate in parenchymal proposals of novel therapeutic interventions.
cells including epithelial cells and The current development of international
phagocytes. New therapeutic strategies collaborations, including European and
currently proposed in adult patients target North American teams, with the aim of
fibrogenic cytokines. Antagonists to TGF-b sharing cohorts of well-phenotyped
include pirfenidone and decorin. The use of paediatric patients is a major opportunity to
molecules directed against tumour necrosis efficiently progress in DPLD understanding
factor (TNF)-a, such as the soluble TNF-a and management.
receptor agent etanercept, is also under
investigation. In the future, it is probable
Further reading
that an expanding number of molecules
aimed at favouring alveolar surface N Clement A (2004). Task force on chronic
regeneration and repair through activation interstitial lung disease in immunocom-
and proliferation of tissue-resident petent children. Eur Respir J; 24: 686697.
(progenitor) cells will be discovered.

N Clement A, et al. (2008). Interstitial lung N Kapetanaki MG, et al. (2013). Influence of
diseases in infants and children. Eur age on wound healing and fibrosis. J
Respir J; 31: 658666. Pathol; 229: 310322.
N Clement A, et al. (2010). Interstitial lung N Langston C, et al. (2009). Diffuse lung
diseases in children. Orphanet J Rare Dis; disease in infancy: a proposed classifi-
5: 22. cation applied to 259 diagnostic biop-
N Costabel U (2011). Emerging potential sies. Pediatr Dev Pathol; 12: 421
treatments: new hope for idiopathic 437.
pulmonary fibrosis patients? Eur Respir N Nathan N, et al. (2011). Interstitial lung
Rev; 20: 201207. disease: physiopathology in the context of
N Dinwiddie R, et al. (2002). Idiopathic lung growth. Paediatr Respir Rev; 12: 216
interstitial pneumonitis in children: a 222.
national survey in the United Kingdom N Nathan N, et al. (2012). A national
and Ireland. Pediatr Pulmonol; 34: 2329. internet-linked based database for
N Driscoll B, et al. (2000). Telomerase in pediatric interstitial lung diseases: the
alveolar epithelial development and French network. Orphanet J Rare Dis; 7:
repair. Am J Physiol Lung Cell Mol 40.
Physiol; 279: L1191L1198. N Popler J, et al. (2012). New coding in the
N Epaud R, et al. (2012). Genetic disorders International Classification of Diseases,
of surfactant. Arch Pediatr; 19: 212219. Ninth Revision, for childrens interstitial
N Flamein F, et al. (2012). Molecular and lung disease. Chest; 142: 774780.
cellular characteristics of ABCA3 muta- N Thouvenin G, et al. (2010).
tions associated with diffuse parenchy- Characteristics of disorders associated
mal lung diseases in children. Hum Mol with genetic mutations of surfactant
Genet; 21: 765775. protein C. Arch Dis Child; 95: 449454.
N Griese M, et al. (2009). Incidence and N Tuder RM, et al. (2011). Stress responses
classification of pediatric diffuse parench- affecting homeostasis of the alveolar
ymal lung diseases in Germany. Orphanet capillary unit. Proc Am Thorac Soc; 8:
J Rare Dis; 4: 26. 485491.
N Guillot L, et al. (2009). New surfactant N van Moorsel CH, et al. (2010). Surfactant
protein C gene mutations associated with protein C mutations are the basis of a
diffuse lung disease. J Med Genet; 46: significant portion of adult familial pul-
490494. monary fibrosis in a Dutch cohort. Am J
N Guillot L, et al. (2010). NKX2-1 mutations Respir Crit Care Med; 182: 14191425.
leading to surfactant protein promoter N Wuyts WA, et al. (2010). Azithromycin
dysregulation cause interstitial lung dis- reduces pulmonary fibrosis in a bleomy-
ease in Brain-Lung-Thyroid Syndrome. cin mouse model. Exp Lung Res; 36:
Hum Mutat; 31: E1146E1162. 602614.

Surfactant dysfunction and
alveolar proteinosis
Armin Irnstetter, Carolin Kroner, Ralf Zarbock and Matthias Griese
Pulmonary surfactant is a complex mixture Detailed molecular knowledge of these

of the surfactant proteins (SP)-A, B, C and D components led to the discovery of primary
and lipids, and a is key component of disorders of the surfactant system.
alveolar integrity and function. These Deficiencies of SP-B and SP-C, the lipid
proteins are essential for lowering surface transporter ABCA3 located in type II
tension (mainly SP-B/C) and play a major pneumocytes, and the transcription factor
role in innate immunity (mainly SP-A/D). TTF1, which regulates expression of SP-B
and SP-C, lead to clinical entities that are
summarised here as surfactant dysfunction
Key points mutations. On histopathological
examination characteristic features include
N Two major groups of disorders are interstitial widening, hyperplasia of type II
associated with the surfactant system: alveolar epithelial cells and proteinaceous
surfactant dysfunction mutations and material in the distal airspaces. Of interest,
PAP. association with a deficiency of surfactant or
its components, such as SP-B-deficiency and
N Surfactant dysfunction mutations
other surfactant deficiency syndromes, may
include diseases caused by mutations
show a pulmonary alveolar proteinosis
in the genes coding for SP-B, SP-C, the
(PAP)-like pattern on histology. This
lipid transporter ABCA3 and the
accumulation of surfactant is the result of an
transcription factor TTF1.
impaired surfactant metabolism leading to
N Although these entities may show a local surfactant accumulation; the extent of
PAP-like pattern on histology, the alveolar filling is much less than in PAP. In
extent of alveolar filling is much less the past this has contributed to some
than in PAP and this term should be confusion and we suggest not using the
avoided when naming the surfactant term congenital alveolar proteinosis to
dysfunction mutations. describe newborns with surfactant
N Hereditary deficiency of the a-chain of dysfunction.
the receptor for GM-CSF is
In contrast to a deficiency of surfactant and
responsible for increased
its components, other clinical entities lead
accumulation of surfactant in the
to a surplus of surfactant, because its
alveolar space and resulting PAP.
removal from the alveolar space is deficient.
N Surfactant dysfunction mutations may Such accumulation of surfactant material in
present at birth as respiratory distress the alveolar space is called PAP. The primary
syndrome or later in infancy as pathomechanism responsible for PAP in
chronic dyspnoea and hypoxia (chILD children is hereditary deficiency of the a-
syndrome), whereas mutations in the chain of the receptor for granulocyte-
a-chain of the receptor for GM-CSF macrophage colony-stimulating factor (GM-
present only as chILD syndrome. CSF). GM-CSF is responsible for the
metabolism and degradation of surfactant

by alveolar macrophages. Disruption of its evaluated by an experienced
receptor leads to PAP. Several other histopathologist.
diseases are known to cause PAP. These, as
well as secondary surfactant deficiency Clinical course and therapeutic strategies SP-B
syndromes, have to be included in the deficiency: Two decades ago Nogee et al.
differential diagnosis of patients with (1994), first described a mutation in SP-B
disturbance of the surfactant system. causing a severe neonatal respiratory
distress syndrome in term infants ultimately
Surfactant dysfunction mutations leading to death. SP-B deficiency is a very
rare disease affecting approximately one
Deficiencies of SP-B and SP-C, the lipid
child in every 1 000 000 live births. The
transporter ABCA3 located in type II
mode of inheritance is autosomal recessive,
pneumocytes, and the transcription factor
the most common mutation is the insertion
TTF1 are caused by mutations in the SFTPB-,
of two amino acids (121ins2). All mutations
SFTBC-, ABCA3- and NKX2-1 genes. The
lead to an absolute or partial loss of SP-B.
resulting diffuse parenchymal lung diseases
clinically present with two major The diagnosis is confirmed by sequencing of
phenotypes, although other modes of SP-B (SFTPB). Currently, there are no
presentation (e.g. as an asthma syndrome) therapeutic options, except lung
have also been observed. transplantation. Experimental therapy with
Clinical presentation At birth children with inhaled RNA was shown to be successful in
dysfunction mutations typically manifest animals. Palliative therapy is indicated for
with idiopathic respiratory distress children with classic mutation.
syndrome or idiopathic pulmonary
hypertension without being preterm or SP-C deficiency: Inheritance of this disease,
having other explanations for their clinical which occurs more frequently than SP-B
manifestations (i.e. infections, congenital deficiency, is autosomal dominant. The
heart defects, blood vessel abnormalities or clinical syndromes described above will
other anatomic abnormalities). The lead to sequencing of the candidate gene.
pulmonary symptoms are often so severe In early stages of the disease the
that the children require mechanical radiological findings are similar to those in
ventilation. Depending on the underlying PAP with the typical alveolar filling pattern
mutation the clinical course is variable, and ground-glass opacities (fig. 1). Further
ranging from rapid disease progression and in the disease course increased interstitial
death to mild forms. Transient response to markings are seen with distinct triangular
medication, such as systemic steroids or shaped subpleural or interlobar septa,
administration of surfactant, may be which develop into multiple subpleural,
observed. interstitial bullae. If biopsy is performed, an
experienced paediatric pathologist should
The other clinical manifestation, the so- evaluate the specimen in order to ensure
called chILD-syndrome (Childrens the correct diagnosis. Therapeutic options
Interstitial Lung Disease), is characterised may include anti-inflammatory therapy
by an insidious start of dyspnoea, dry (corticosteroids) or treatment with
coughing, fine crackles and failure to thrive.
hydroxychloroquine or azithromycin.
Such clinical symptoms together with a
Additional treatment with
familial history of fatal or chronic lung
immunosuppressants has anecdotally been
diseases or presence of consanguinity must
described for these and other entities. To
lead to specific genetic testing for the
date, no controlled trials have been
conditions that are potentially disease
performed; all treatments should be tried
causing.
and assessed in the framework of a registry
If the diagnosis cannot be established, open for ILD (www.childeu.net) in order to
or thoracoscopic lung biopsy should be systematically record these rare
performed. The lung biopsy should be experiences.

ranging from neonatal respiratory distress
syndrome to typical manifestations of chILD
syndrome. Furthermore, recurrent
bronchopulmonary infections are seen in
childhood. About 40% of the cases present
with respiratory symptoms alone. To date
there is still relatively little experience
concerning the treatment of the disease.
Thus, empiric therapy should be evaluated
and registered prospectively in order to
establish and compare different therapeutic
options.
Figure 1. HRCT scan of an infant with SP-C
deficiency and presentation of chILD syndrome at Pulmonary alveolar proteinosis
6 months of age. Note the crazy paving pattern in
both lower lobes. PAP represents a group of rare diseases that
are characterised by an accumulation of
ABCA3-transporter deficiency: ABCA3 is a lipid periodic acidSchiff (PAS) reaction-positive
transfer protein which is essential for the granular eosinophilic material in the alveolar
biogenesis of lamellar bodies of type 2- space. As mentioned previously, PAP is a
pneumocytes. More than 100 different histological diagnosis. In paediatrics, the
classic form of PAP is due to GM-CSF-
mutations with autosomal recessive
receptor-a deficiency. The other forms must
inheritance mode have been described. As
be differentiated and include a large number
heterozygous frequency in the population is
of causes leading to this group of diseases
relatively high, ABCA3-transporter deficiency
(table 1). An imbalance between the
represents one of the most frequent genetic
synthesis and secretion of surfactant from
changes detected in interstitial lung
type II pneumocytes, its intra-alveolar
diseases in children and adolescents. The
metabolism and surfactant recycling, and
clinical course and prognosis are highly
elimination, mainly by macrophages, leads
variable depending on the mutations
to the accumulation of surfactant material in
present, may begin at birth or later, and are
the alveolar space. GM-CSF is a key
difficult to foresee. Effective therapeutic regulatory cytokine for the catabolism of
interventions should be determined surfactant by alveolar macrophages.
empirically, evaluated systematically and Although other primary forms of PAP in
registered prospectively. In addition to paediatrics have been described, the
diverse systemic steroid therapy regimes, underlying mutations have yet to be
hydroxychloroquine or azithromycin are characterised.
used.
Clinical manifestations and diagnosis The
Brain-thyroid-lung syndrome: this disease, alveolar accumulation of surfactant leads to
also called thyroid transcription factor-1 impaired gas exchange, detected early
deficiency-syndrome or NKX2-1, is caused by during exercise. Carbon dioxide transfer is
haplo-insufficiency of the transcription usually not affected. Therefore, the clinical
factor TTF1. This factor modulates the course typically starts insidiously at various
expression of SP-B, SP-C and ABCA3 in the ages ranging from infancy to young
lung and other proteins in the thyroid and adulthood. The diagnosis is frequently made
basal ganglia. The clinical trials of in the context of an acute respiratory
congenital hypothyroidism, neurological infection that does not resolve appropriately
syndromes (muscular hypotonia, which or has a very severe course. Primary
develops to benign hereditary chorea after presenting symptoms include exercise-
infancy) and symptoms of chronic induced non-productive cough, at times
respiratory insufficiency represent the full developing into coughing with expectoration
disease spectrum of pulmonary symptoms of whitish surfactant material. Other

Table 1. Conditions associated with PAP due to a reduction in the number and function of alveolar macrophages
Autoimmune PAP due to GM-CSF autoantibodies that block macrophages (overall most frequent
form .90%, especially in adults)
Hereditary GM-CSF receptor a/b chain mutations
Inhalation exposure to aluminium, cement, silica, titanium, indium, tin, organic dust, sawdust,
fertiliser/agricultural dust, bakery flour, fumes, gasoline, chlorine and petroleum
Infections including Cytomegalovirus, Mycobacterium tuberculosis, Nocardia, Pneumocystis jirovecii,
HIV
Haematological disorders including myelodysplastic syndrome, acute lymphatic leukaemia,
acute myeloid leukaemia, chronic myeloid leukaemia, hairy cell leukaemia, Hodgkins and non-
Hodgkins lymphoma, multiple myeloma, essential thrombocythemia, polycythemia vera,
amyloidosis and Fanconis anaemia
Other malignancies including adenocarcinoma, glioblastoma and melanoma
Immunological diseases including monoclonal gammopathy, selective IgA deficiency and severe
combined immunodeficiency
Metabolic diseases such as NiemannPick disease type C2 and type B, and lysinuric protein
intolerance
Others including membranous nephropathy, dermatomyositis and lung transplantation
Data from Bonella et al. (2012).
symptoms include exercise intolerance, as siblings of affected children) or suffer

weight loss or failure to thrive. The physical from dyspnoea and oxygen
examination may reveal dyspnoea with supplementation, initially during exercise
intercostal retractions, digital clubbing and and later at rest. Chest CT scans showed
sometimes fine crackles and reduced abnormalities in all cases and lavage
breathing sounds. Chest radiographs samples suggest PAP due to whitish
typically show bilateral alveolar filling recovered fluid in some cases. GM-CSF
pattern, which are often more prominent in auto-antibodies are usually not detectable;
the perihilar regions, the so-called bat wing serum levels of GM-CSF are elevated.
pattern. HRCT initially shows a diffuse
distribution of interstitial markings and, Whole lung lavage represents the most
subsequently, the so-called crazy paving important therapeutic option which has
pattern. The most common abnormalities in clearly shown to be effective. In older
pulmonary function tests are significant children, a double lumen endotracheal tube
restrictive patterns and a reduction in the is used to ventilate one lung while lavaging
diffusion capacity. Bronchoalveolar lavage the other. In young children, where this
(BAL) fluids show typically extracellular PAS- procedure is not feasible, other strategies
positive material and frequently oval bodies. are applied, such as using an inflatable
Diagnosis is made genetically or by open catheter. Lavaging of both lungs is
lung biopsy, because in infants and children performed sequentially using total volumes
the typical BAL fluid features are sometimes of 50200 mL?kg-1 body weight of normal
not as prominent. GM-CSF auto-antibodies saline.
are rarely elevated in children, but should be
assessed to exclude this condition. The time required for lavaging one lung is
,46 h. If the child is in a good clinical
Clinical course and therapeutic strategies GM- condition, lavaging the other lung is
CSF-receptor-a mutations: The age of possible in the same session. It is important
diagnosis ranges from 2 to 11 years. Patients to take care to ensure a balanced recovery
may have no clinical symptoms (diagnosed and avoid electrolyte displacements.

Injection or inhalation of recombinant GM- Many other conditions associated with
CSF is ineffective and therefore not alveolar proteinosis must be differentiated;
recommended. In several cases the patients almost all are due to a reduced number or
have to undergo whole lung lavage at regular function of alveolar macrophages (table 1).
intervals for long periods in order to enable
physiologic gas exchange and development. Further reading
Such a therapy should be performed in
specialised centres to offer a good long-term N Bonella F, et al. (2012). Wash out kinetics
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often manifests with respiratory distress dysfunction. Paediatr Respir Rev; 12: 223
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age of death from respiratory insufficiency is N Griese M, et al. (2010). Respiratory
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lipid material which, in contrast to normal caused by pulmonary alveolar proteino-
surfactant, also contains high sis. Clin Genet; 77: 119130.
concentrations of ceramids, N Griese M, et al. (2011). Long-term follow-
up and treatment of congenital alveolar
glucosylceramids and SP-A, is at the centre
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Lysinuric protein intolerance: This is an the X chromosome pseudoautosomal
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ary alveolar proteinosis caused by muta-
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However, recurrence of PAP after lung 12921304.
transplantation has been reported.

Pulmonary vascular disorders
Andrea McKee and Andrew Bush
The cardinal manifestation of pulmonary present. There are no data to define

vascular disorders is pulmonary pulmonary hypertension on exercise.
hypertension. The international definition of
pulmonary hypertension is a pulmonary Classification of pulmonary hypertension in
children
arterial pressure (PAP) .25 mmHg. For pre-
capillary pulmonary hypertension, There are significant differences in the
pulmonary capillary wedge pressure must be pathophysiology of pulmonary hypertension
,15 mmHg and cardiac output normal or in children and adults. Abnormalities of
reduced. Post-capillary pulmonary growth and development are more likely in
hypertension (usually due to left heart paediatric cases; so, for example, infants
disease) wedge pressure is .5 mmHg and with pulmonary hypertension may have
cardiac output normal or reduced. If the failed to reduce the antenatally
transpulmonary pressure gradient is physiologically high pulmonary vascular
.12 mmHg with an elevated wedge resistance (PVR) during the post-natal
pressure, then a reactive component is period. Abnormalities of vasculogenesis and
angiogenesis have increasingly been
implicated in paediatric pulmonary
hypertension. A recent proposed
Key points classification of pulmonary hypertension in
children is given in table 1; this differs from
N The symptoms of pulmonary the World Health Organization (WHO)
hypertension are nonspecific and the classification (table 2), which has been
possibility of the condition should criticised as less applicable to children (e.g.
always be remembered. Syncope on pulmonary hypertension secondary to
exercise should never be ignored. bronchopulmonary dysplasia and congenital
diaphragmatic hernia do not fit neatly into
N If pulmonary hypertension is the WHO classification). Pulmonary
secondary to lung disease, this is hypertension does not, of itself, mean the
usually obvious from the chest child has pulmonary vascular disease; a high
radiograph. pulmonary venous pressure and a high
N In a child with pulmonary pulmonary blood flow can both elevate PAP
hypertension and a normal chest without there necessarily being any
radiograph, remember OSA and pulmonary vascular disease. Although the
occult interstitial lung disease are WHO definition does not include
possible causes. measurement of PVR (pulmonary blood
flow/transpulmonary vascular pressure
N Children with pulmonary hypertension gradient; normal range ,3 Wood units), in
should be referred to specialist paediatric practice, it is wise to include a
centres for consideration of emerging PVR .3 Wood units as part of the definition,
therapies. particularly in children with left-to-right
shunts and anaemia. Functional classes of

Table 1. A practical approach to pulmonary hypertension in children: 10 basic categories of paediatric pulmonary
hypertensive disease
Pre-natal or developmental pulmonary hypertensive vascular disease
Perinatal pulmonary vascular maladaptation
Paediatric cardiovascular disease
Bronchopulmonary dysplasia
Isolated paediatric pulmonary hypertensive vascular disease (isolated paediatric pulmonary
arterial hypertension)
Multifactorial pulmonary vascular disease in congenital malformation syndromes
Paediatric lung disease
Paediatric thromboembolic disease
Paediatric hypobaric hypoxic exposure
Pulmonary vascular disease associated with other system disorders
severity are given in table 3; these are largely of pulmonary hypertension with a normal
adult based and there is a need for a specific chest radiograph are interstitial lung disease
paediatric classification. and sleep disordered breathing, usually
OSA. Hence, every case of apparently
Epidemiology
idiopathic pulmonary hypertension should
Pulmonary hypertension may present at any have these conditions excluded. The
age. Paediatric pulmonary hypertension is management of secondary pulmonary
ceasing to be an orphan disease; there are hypertension is largely of the underlying
increasing numbers of national and respiratory conditions, and this will not be
international specifically paediatric discussed further. If secondary pulmonary
registries, which have increased our hypertension is thought to be
information base. The incidence and point disproportionate to the severity of lung
prevalence of isolated pulmonary disease, then consideration should be given
hypertension are less than one and five to the use of therapies used in primary
cases per million children, respectively. The pulmonary hypertension (PPH) (see later),
number of cases of pulmonary hypertension probably best as part of a randomised
secondary to congenital heart disease is of a controlled trial. Any child thought to have
similar order of magnitude. The prevalence primary pulmonary vascular disease should
of pulmonary hypertension in have Eisenmengers syndrome and other
bronchopulmonary dysplasia is probably cardiological conditions excluded by a
underestimated due to ascertainment bias. careful cardiological evaluation. The
management of this latter group is usually
Pulmonary hypertension secondary to
medical in specialist paediatric cardiological
respiratory disease is usually dominated by
centres and discussions of these conditions
obvious features of the underlying cause, for
are beyond the scope of this chapter.
example, very severe bronchiectasis in CF.
The underlying mechanism is intermittent or Normal pulmonary vascular development
continuous alveolar hypoxia leading to
pulmonary vasoconstriction and ultimately The pulmonary arteries develop
vascular remodelling. Systemic arterial embryologically from the sixth bronchial
hypoxaemia in the absence of alveolar arches. The pre-acinar vessels follow the
hypoxia (for example, due to multiple airway development and are largely
pulmonary arteriovenous malformations) complete by the end of the first 16 weeks of
does not lead to pulmonary hypertension. pregnancy, the end of the pseudoglandular
Two important occult respiratory causes phase. Blood vessels form by

Table 2. Updated clinical classification of pulmonary hypertension (PH)
PAH
Idiopathic PAH
Heritable: BMPR2, ALK1, endoglin (with or without hereditary haemorrhagic telangiectasia),
unknown
Drug and toxin induced
APAH: connective tissue diseases, HIV infection, portal hypertension, congenital heart
disease, schistosomiasis, chronic haemolytic anaemia, persistent PH of the newborn
PVOD and/or pulmonary capillary haemangiomatosis
PH due to left heart disease
Systolic dysfunction
Diastolic dysfunction
Valvular disease
PH due to lung diseases and/or hypoxia
COPD
Interstitial lung disease
Other pulmonary diseases with mixed restrictive and obstructive pattern
Sleep disordered breathing
Alveolar hypoventilation disorders
Chronic exposure to high altitude
Developmental abnormalities
CTEPH
PH with unclear and/or multifactorial mechanisms
Haematological disorders: myeloproliferative disorders, splenectomy.
Systemic disorders, sarcoidosis, pulmonary Langerhans cell histiocytosis,
lymphangioleiomyomatosis, neurofibromatosis, vasculitis
Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure on dialysis
PAH: pulmonary arterial hypertension; APAH: associated PAH; CTEPH: chronic thromboembolic PH.
Reproduced from Simonneau et al. (2009) with permission from the publisher.
Table 3. Functional classes of pulmonary hypertension

Functional class Status
I No limitation of physical activity
Ordinary activity does not cause dyspnoea, fatigue, chest pain or near
syncope
II Slight limitation of physical activity
Comfortable at rest; ordinary physical activity causes undue dyspnoea,
fatigue, chest pain or near syncope
III Marked limitation of physical activity
Comfortable at rest; less than ordinary physical activity causes undue
dyspnoea, fatigue, chest pain or near syncope
IV Symptomatic on any physical activity
Signs of right heart failure
May have dyspnoea and fatigue at rest; discomfort increased by physical
activity
This classification may be more appropriate to adults; for example, adults are more prone to right heart failure
earlier in the disease.

vasculogenesis (de novo formation of underlying cause is found. It is thought to be
vessels in the mesenchyme) with the airways related to failure of regression of the
acting as a template for vascular antenatal physiologically hypertensive
development. Acinar vessels develop in pulmonary circulation. Although
parallel with the terminal bronchioles and anecdotally, some cases respond to medical
alveoli. Alveolar development is largely a management, generally the prognosis is
post-natal phenomenon and capillaries form poor.
by angiogenesis (sprouting from existing
Alveolar capillary dysplasia spectrum is an
vessels). Uniquely, the lung has no function
overlapping group of diseases, comprising
as it develops in the intrauterine
acinar dysplasia, alveolar capillary dysplasia,
environment. It is a fluid-filled, fluid-
and alveolar capillary dysplasia with
excreting organ with a very low blood flow
misalignment of the pulmonary veins,
and no role in gas exchange. At birth, the
considered by some to be part of the
most profound adaptations must take place
spectrum of paediatric interstitial lung
if the baby is to survive. The lung absorbs
disease. Mutations in the FOXF1 (forkhead
fluid and becomes dry; the alveoli expand,
box F1) and STRA6 (stimulated by retinoic
PVR falls and the pulmonary blood flow rises
acid 6) genes should be sought.
from ,5% to equal that of the systemic Presentation is usually in a term baby with
circulation. The arterial duct and the oval relentlessly progressive respiratory distress.
foramen become functionally, and later These conditions should be distinguished
structurally, closed. In the subsequent weeks, from disease due to mutations in SFTPB
there is thinning of the alveolar capillary (surfactant protein B), SFTPC (surfactant
membrane and profound increases in the protein C), ABCA3 (ATP-binding cassette
number of alveoli, produced by secondary sub-family A member 3) and TTF1 (thyroid
septation and modulated through elastin and transcription factor 1), which may present in
the retinoic acid pathways. Post-natally, a similar way (see the section on Interstitial
alveolar development was thought to be lung diseases). Diagnosis is on lung biopsy
largely complete by 2 years of life, but recent or at autopsy. There is no treatment and
work in rhesus monkeys and also using prognosis is poor.
hyperpolarised helium to measure alveolar
size in humans has shown that alveolar size Presentation of pulmonary hypertension
is largely stable during the phase of somatic due to pulmonary vascular disease
growth, implying neoalveolarisation, and by
The symptoms of pulmonary hypertension
implication pulmonary capillary growth,
are nonspecific and the condition can be
continues to puberty.
missed initially. Breathlessness may be
Abnormal pulmonary vascular development attributed to airway disease and early
cyanosis may be difficult to detect. Syncope,
Most of these conditions present to the particularly on exercise, is an ominous
neonatologist and are only briefly discussed symptom that should never be ignored.
here. Once suspected, ECG, or better
echocardiography, confirms the diagnosis. If
Persistent fetal circulation is the most
there is tricuspid or pulmonary
dramatic example of failure of normal
regurgitation, PAP can be estimated
developmental homeostasis. Shortly after reasonably accurately from the Bernoulli
birth, the baby becomes deeply cyanosed equation. The gold standard is right heart
and very difficult to oxygenate. This is a catheterisation, which also allows cardiac
neonatal intensive care unit emergency and output and pulmonary capillary wedge
will not be discussed further here. pressure to be measured.
Early-onset primary pulmonary Primary pulmonary vascular disease
hypertension comprises babies presenting at
a few weeks of age with very severe The three main causes encountered in
pulmonary hypertension for which no paediatrics are PPH, pulmonary

veno-occlusive disease (PVOD) and pulmonary of vasoconstrictor and pro-proliferative
embolism (thrombotic and nonthrombotic). agents, such as endothelin-1 and
Each will be considered in turn. thromboxane A2, but multiple other
mediators are probably involved.
Primary pulmonary hypertension is a
diagnosis of exclusion, requiring the The most common genetic mutation is in
documentation of pulmonary hypertension the BMPR2 (bone morphogenetic protein
and an elevated PVR, and the exclusion of receptor II) gene, found in ,70% of familial
any secondary cause of the condition PPH. BMPR2 is part of the transforming
(table 4). Pulmonary hypertension and other growth factor (TGF)-b superfamily and,
vascular disease secondary to liver disease among other properties, contributes to the
are described in more detail in the section modulation of vascular proliferation.
on Systemic disorders with lung Mutations in other receptors for these
involvement. polypeptides are associated with familial
pulmonary hypertension, including activin
The pathophysiology of PPH is unclear. receptor-like kinase 1 (encoded by the ALK1
Important components are vasoconstriction gene) and endoglin, both of which are also
(which may be related to potassium channel associated with hereditary haemorrhagic
dysfunction), obstructive remodelling of the telangiectasia.
pulmonary circulation, thrombosis and
inflammation. Histopathology reveals Symptoms are nonspecific but fainting
combinations of arterial medial hypertrophy, during exercise should always be taken
concentric laminar fibroelastosis, plexiform seriously. Infants typically present with right
lesions, necrotising vasculitis and fibrosis. heart failure and cyanosis. There may be
There may be increased neuroendocrine cell suggestive physical signs such as a loud
numbers and positive endothelial staining pulmonary component of the second heart
for endothelin-1 immunoreactivity. Children sound, the murmurs of pulmonary or
tend to have more medial hypertrophy, less tricuspid insufficiency, a parasternal heave
intimal fibrosis and fewer plexiform lesions or, in advanced cases, the signs of right
than adults. The clinical correlate may be heart failure. Blood tests should be directed
greater pulmonary vascular reactivity and a to eliminating any underlying cause of the
propensity to sudden death from pulmonary pulmonary hypertension, as well as
hypertensive crises, especially in infants. excluding thyroid disease, which is not
Endothelial dysfunction manifests as uncommon in PHT. Elevated N-terminal
reduced production of vasodilator and pro-brain natriuretic peptide and brain
antiproliferative mediators, such as nitric natriuretic peptide have been reported in
oxide and prostacyclin, and overproduction children with pulmonary hypertension, and
are likely to be increasingly used in the
future as biomarkers. Chest radiography
Table 4. Differential diagnosis of apparent PPH
may lead to suspicion of the diagnosis if
HIV infection there is peripheral oligaemia and enlarged
Substance abuse: smoking crack cocaine, central pulmonary arteries. The ECG may
amphetamine ingestion show signs of right ventricular hypertrophy
Liver disease leading to pulmonary and strain, and right atrial dilatation and
hypertension right axis deviation, but these signs should
not be relied upon. Echocardiography is
Connective tissue disease, especially
mandatory to exclude occult cardiac disease
scleroderma
and to estimate PAP, most easily using the
Pulmonary vasculitis Bernoulli equation, if pulmonary or tricuspid
Metabolic: Gaucher disease, NiemannPick insufficiency is present. The 6-min walk test
disease may give useful functional information. The
Sarcoidosis decision to proceed to the definitive
diagnostic investigation, right heart

catheterisation and measurement of bronchoconstriction when nebulised.
vascular reactivity, is taken in conjunction Subcutaneous and inhaled treprostinil are
with a paediatric cardiologist; the procedure other options.
is not without risk, especially in children
with suprasystemic PAP. Overall, children The first ever randomised controlled trial in
appear to have a better preserved cardiac children with pulmonary hypertension
output than adults and go into right showed that sildenafil reduced PVR and
ventricular failure later in the course of the improved survival. Sildenafil is thus the only
disease. soundly evidence-based treatment for
paediatric patients. There is emerging, but
Any underlying condition, such as HIV or currently less strong, evidence that
connective tissue disease, should be treated vardenafil may be a better agent. Tadalafil
as usual. Oxygen should be given to prevent may also offer further advantages but the
hypoxaemia, even this is of controversial evidence base is more flimsy.
benefit. A single, nonrandomised study of
pulmonary hypertension in children with Endothelin-1 is a potent vasoconstrictor and
congenital heart disease suggested oxygen mitogen for fibroblasts and smooth muscle
had a beneficial effect on survival. Calcium cells. There are two isoforms of the
channel antagonists are prescribed only for endothelin receptor found in pulmonary
those children with marked vascular vascular smooth muscle cells, ETA and ETB.
reactivity; the exact definition of this is ETB receptors are also found in the
unclear. Anticoagulation should be endothelium and are involved in endothelin
considered in selected children, usually clearance and release of nitric oxide leading
those with right heart dysfunction, to vasodilatation. However, despite these
indwelling lines or a hypercoaguable state, physiological differences, dual-receptor and
but is used much less often with the advent selective ETA receptor antagonists are
of advanced therapies (see later). There are equally effective. Bosentan, a dual-receptor
no paediatric studies suggesting benefit antagonist, is not licensed in children but
from anticoagulation. Blade atrial observational studies suggest it may be
septostomy may help symptomatically by beneficial. However, 1015% of children
decompressing the right-sided circulation discontinue therapy because of side-effects,
but may be associated with significant including abnormal liver function tests.
mortality. Patients with end-stage disease There may be additional benefit with the
should be considered for heartlung addition of ambrisentan, a specific ETB
transplantation. antagonist.
There are three groups of compounds that Novel innovative therapies may include the
may be used to treat pulmonary use of Rho kinase inhibitors, vasoactive
hypertension. These are prostacyclin and its intestinal peptide (VIP), oestrogen
derivatives, phosphodiesterase-5 inhibitors derivatives, modulation of the serotonin
(e.g. sildenafil), and the endothelin receptor pathway, L-arginine and therapies (including
antagonists. Their use has led to enhanced gene therapy) that may modulate apoptosis
survival. to attenuate vascular remodelling.
Continuous intravenous infusion of In general, these new options are expensive

prostacyclin has been associated with and potentially toxic medications that are
improved survival in children as well as best utilised in centres accredited for the
adults but the logistic challenge of this care of pulmonary hypertension. There is a
treatment is considerable. The benefit may scarcity of randomised controlled trials in
be not only by vasodilation but also children and treatment algorithms are
restoration of endothelial function. Inhaled unfortunately extrapolated from adult
iloprost has also been used but the need for studies; this is dangerous, because the
six to eight nebulisations a day has limited pathophysiology of pulmonary hypertension
its value in children; it may also cause may not be the same. It is likely in the future

that combinations of these medications will underdiagnosed in children because it is
be prescribed. They are also increasingly frequently not considered. Presentation may
used in pulmonary vascular disease be with acute collapse due to a massive
complicating congenital heart disease. embolism or the more subtle onset of
breathlessness due to repeated small
Prognosis is usually poor in children, emboli. There are four important questions
although the suggestion that it is worse than if pulmonary embolic disease is suspected
in adults has not been confirmed. However, (table 6).
children are often sicker at presentation. 5-
year survival is of the order of 75%. Factors The factors predisposing to
carrying a poor prognosis include WHO thromboembolism are intravascular foreign
functional class III/IV, poor nutrition and body (e.g. a portacath), a sluggish
older age at presentation, and lower mixed circulation, coagulopathy and immobility.
venous oxygen saturation and higher PVR. More than one factor may be operative.
Typical causes of a sluggish circulation
Pulmonary veno-occlusive disease include the post-Fontan situation and left
Presentation is indistinguishable from PPH. atrial dilatation secondary to
Physical examination may reveal digital cardiomyopathy. Numerous congenital and
clubbing (unusual in other forms of PAH acquired prothrombotic disorders have been
than cyanotic congenital heart disease) and implicated in pulmonary embolism or in situ
crackles. Chest radiograph and HRCT will thrombosis. Membranous
show signs of pulmonary venous glomerulonephritis is a notorious source of
congestion. The diagnostic gold standard is pulmonary thromboemboli from the renal
open-lung biopsy but noninvasive testing veins.
may obviate the need for this. If lung tissue
is obtained, the pulmonary veins and There are numerous causes of
venules contain organised and recanalised nonthrombotic emboli. Tumour emboli
thrombi with intimal fibrous pads and originating from Wilms, hepatoblastoma or
medial hypertrophy. The veins may show testicular teratoma are among the
medial hypertrophy and arterialisation. commonest. In tropical regions,
There may be similar changes in pulmonary schistosomal ova are an important cause of
capillaries and the pre-capillary circulation, pulmonary hypertension. Talc emboli from
including fibrinoid necrosis in the latter. If injecting crushed up tablets as a form of
cardiac catheterisation is undertaken, wedge substance abuse is another cause. The
pressure is often normal because the large presentation of infected emboli, another
pulmonary veins are not affected and complication of intravenous drug abuse, is
pulmonary vasodilator trials may precipitate usually dominated by a septic picture.
pulmonary oedema. There is no medical
therapy and referral to the local transplant Since these conditions are so rare in
centre is indicated at diagnosis. childhood, there is usually insufficient
experience to rely on noninvasive diagnosis,
The majority of cases are idiopathic; rare for example with D-dimer. Suspicion may be
familial cases are described, and cases aroused by a ventilation/perfusion scan, which
secondary to chemotherapy, bone marrow typically shows normal ventilation but marked
transplantation and congenital heart disease perfusion defects. Contrast-enhanced CT
have been described. Differential diagnosis scanning will demonstrate filling defects in the
includes congenital absence or stenosis of proximal pulmonary arteries. If distal disease
the pulmonary veins and pulmonary venous not visible on CT scanning is suspected and,
obstruction due to mediastinal pathology in particular, if nonthromboembolic disease is
such as fibrosing mediastinitis. a diagnostic consideration, then a lung biopsy
may be indicated.
Pulmonary embolic disease Causes of
pulmonary embolic disease are summarised Management is of the underlying cause, for
in table 5. This is undoubtedly example, removal of the indwelling line.

Table 5. Causes of pulmonary embolic disease
Thromboembolic disease Nonthrombotic embolic disease
Indwelling venous catheters (.25% cases) Tumour emboli
Low flow states Right atrial myxoma
Cardiac failure Liver, renal or testicular tumours
Fontan circulation Tropical
Dilated cardiomyopathy Schistosomiasis
Coagulopathy Fat embolism
Factor V Leiden Trauma
Protein C deficiency (congenital or Burns
acquired) Cardiopulmonary bypass
Protein S deficiency (congenital or Acute pancreatitis (always consider an
acquired) underlying diagnosis of CF if no other
Antithrombin III obvious cause)
Dysfibrinogenaemias Adolescent issues
Miscellaneous, including oral Pregnancy complications (amniotic fluid
contraception embolism)
Immobility Intravenous drug abuse (talc emboli from
Blunt thoracic trauma injecting crushed up tablets)
Axillary vein thrombosis
May be associated with acquired
lymphangiectasia and chylothorax
Renal vein thrombosis
Membranous nephropathy, may also
have a coagulopathy
More than one cause may be operative in a given child; for example, a boy with Duchenne muscular dystrophy
has immobility and cardiomyopathy as predisposing factors.
For an otherwise well child who has had a Given that heritable coagulopathies may
pulmonary thromboembolism and is present with thromboembolic disease,
clinically stable, anticoagulation with consideration should be given to screening
heparin and warfarin is indicated. If there is the child and first-degree relatives for at
an underlying coagulopathy, the advice of a least for protein C, protein S and
paediatric haematologist should be sought. antithrombin III deficiency, given the risk of
If the child is critically unstable, then thromboembolic events in these conditions.
consideration should be given to
Invasive pulmonary capillary
thrombolysis and even embolectomy, in
haemangiomatosis This rare condition is
consultation with a paediatric cardiologist
characterised by proliferating sheets of thin-
and cardiothoracic surgeon.
walled vessels, which infiltrate the
pulmonary circulation leading to vascular
Table 6. Four clinical questions if pulmonary embolic occlusion. The condition behaves like a low-
disease is suspected grade vascular neoplasm. Rarely, there is
extrathoracic spread of the abnormal
Has there been embolic occlusion of part of
vasculature. Presenting features include
the pulmonary arterial tree?
dyspnoea, thrombocytopenia and
Is the child cardiovascularly stable or is haemoptysis, and symptoms of pulmonary
urgent intervention required? hypertension. There may be digital clubbing
What is the material embolised? and pleural and pericardial effusions.
What has predisposed to the embolic event? Familial and congenital cases have been
described. HRCT differentiates the

condition from other causes of pulmonary N Cerro MJ, et al. (2011). A consensus
hypertension. The distinction is important approach to the classification of pediatric
because vasodilator trials may cause pulmonary hypertensive vascular disease:
pulmonary oedema in this condition. report from the PVRI Pediatric Taskforce.
Typically, there is diffuse bilateral Pulm Circ; 1: 286298.
thickening of the interlobular septa and N Galie` N, et al. (2009). Guidelines for the
small centrilobular opacities, which are diagnosis and treatment of pulmonary
poorly defined. There may also be diffuse hypertension: the Task Force for the
ground-glass opacities. Definitive diagnosis Diagnosis and Treatment of Pulmonary
is by lung or other tissue biopsy. Hypertension of the European Society of
Occasional children have an associated Cardiology (ESC) and the European
Respiratory Society (ERS), endorsed by
connective tissue disease or other
the International Society of Heart and
comorbidity. Localised forms may be
Lung Transplantation (ISHLT). Eur Heart
treated surgically, disseminated disease J; 30: 24932537.
with interferon-a2a or heartlung or N Gatzoulis MA, et al. (2009). Pulmonary
bilateral-lung transplant. However, most arterial hypertension in paediatric and
affected children die quickly. adult patients with congenital heart dis-
ease. Eur Respir Rev; 18: 154161.
Further reading N Holzhauser S, et al. (2012). Inherited
thrombophilia in children with venous
N Abman SH, et al. (2011). Recent progress thromboembolism and the familial risk of
in understanding pediatric pulmonary thromboembolism: an observational
hypertension. Curr Op Pediatr; 23: 298 study. Blood; 120: 15101515.
304. N Ivy D (2012). Advances in pediatric
N Adatia I, et al. (2010). The role of calcium pulmonary arterial hypertension. Curr
channel blockers, steroids, anticoagula- Opinion Cardiol; 27: 7081.
tion, antiplatelet drugs, and endothelin N Janda S, et al. (2010). HIV and pulmonary
receptor antagonists. Pediatr Crit Care arterial hypertension: a systematic review.
Med; 11: Suppl., S46S52. HIV Med; 11: 620634.
N Barst RJ, et al. (2011). Pulmonary arterial N Kirkpatrick EC. Echocardiography in pedia-
hypertension: a comparison between tric pulmonary hypertension. Paediatr
children and adults. Eur Respir J; 37: Respir Rev 2013 [In press DOI: 10.1016/
665677. j.prrv.2012.12.008].
N Barst RJ, et al. (2012). A randomized N Roofthooft MTR, et al. (2010). Management
double-blind placebo-controlled dose-ran- of pulmonary arterial hypertension in chil-
ging study of oral sildenafil citrate in the dren. Paediatr Respir Rev; 11: 240245.
treatment of children with pulmonary N Simonneau G, et al. (2009). Updated
arterial hypertension. Circulation; 125: clinical classification of pulmonary hyperten-
324334. sion. J Am Coll Cardiol; 54: Suppl., S43S54.

Eosinophilic lung diseases
and hypersensitivity
pneumonitis
Carlo Capristo, Giuseppina Campana, Francesca Galdo, Emilia Alterio and
Laura Perrone
Eosinophilic lung diseases disease, such as ChurgStrauss syndrome

and hypereosinophilic syndrome.
Eosinophilic lung diseases are a diverse
group of disorders characterised by Based on aetiology, eosinophilic lung
pulmonary opacities associated with tissue diseases are generally classified as those of
or peripheral eosinophilia. The diagnosis of unknown cause (idiopathic
eosinophilic lung disease can be made if any hypereosinophilic syndrome) and those of
of the following findings is present: known cause (ABPA, bronchocentric
granulomatosis, parasitic infection and drug
N pulmonary opacities with peripheral reactions), as well as eosinophilic vasculitis.
eosinophilia,
N tissue eosinophilia confirmed at lung Diagnosis The diagnostic methods consist
biopsy, and of a detailed medical history and physical
N increased eosinophils in bronchoalveolar examination. The duration and severity of
lavage (BAL) fluid. symptoms are also of critical importance.
Testing for potential helminth infections,
Eosinophilic lung diseases are generally including stool examination and serology,
classified in terms of presentation (clinical should be guided by the exposure history. If
or radiological) and aetiology. Clinical and no inciting drug or infection is identified, a
radiological presentations can include thorough investigation for allergic/atopic or
simple pulmonary eosinophilia, chronic autoimmune disorders, blood cell disorders
eosinophilic pneumonia, acute eosinophilic and other neoplastic conditions should be
pneumonia, allergic bronchopulmonary initiated. A history of asthma may raise
aspergillosis (ABPA) and pulmonary suspicion of ChurgStrauss syndrome,
eosinophilia associated with a systemic ABPA, or bronchocentric granulomatosis.
Pulmonary infiltrates, characterised by foci

Key points of air-space consolidation and focal ground-
glass opacities, can be seen in pulmonary
N Eosinophilic lung diseases are a eosinophilia of all causes. Cavitation can
diverse group of disorders occur in certain cases of ABPA and Churg
characterised by pulmonary opacities Strauss syndrome, as well as in certain
associated with tissue or peripheral parasitic infections.
eosinophilia.
Important initial parameters that can be
N Hypersensitivity pneumonitis, or obtained from routine laboratory testing
extrinsic allergic alveolitis, is a diffuse include:
granulomatous ILD caused by
inhalation of various antigenic organic N a complete blood count with differential
particles or low molecular weight counts (confirmed by microscopy),
chemicals. N routine chemistries (including tests of
hepatic and renal function),

N levels of inflammatory markers and diagnosis of pulmonary eosinophilia. Biopsy
autoantibodies, and is performed to rule out the hypotheses of
N serum IgE, infection and neoplasia, as well as to make a
N vitamin B12 and differential diagnosis with other interstitial
N tryptase levels. diseases and cryptogenic organising
pneumonia, or to confirm ChurgStrauss
Bone marrow investigations should also
syndrome. Histopathological findings that
include a core biopsy with histology and
are common to virtually all causes include
immunohistochemistry, including CD34,
intra-alveolar exudation of histiocytes and
CD117, tryptase and CD25. In addition,
eosinophils, also present in the interstitium,
cytogenetics, FISH (fluorescent in situ
and eosinophilic microabscesses,
hybridisation) and molecular analyses
macrophages containing CharcotLeyden
should be performed. Bone marrow
investigation is warranted in all patients in crystals and findings of bronchiolitis
whom hypereosinophilia remains obliterans or organising pneumonia. Small
unexplained or if a haematopoietic focal areas of interstitial fibrosis, as well as
neoplasm is suspected. Haematopoietic intra-alveolar necrosis and even a certain
malignancies typically accompanied by degree of vasculitis, can occur, although
eosinophilia are myeloproliferative without granulomas. Granulomas, as well as
neoplasms (MPNs), certain variants of being present in ABPA, are indicative of
acute myeloid leukaemia (AML), a smaller parasitic infections and ChurgStrauss
subset of patients with myelodysplastic syndrome.
syndromes (MDS), some MDS/MPN Eosinophilic lung diseases of unknown cause
overlap disorders, several (mostly T-cell Simple pulmonary eosinophilia, or Loffler
derived) lymphoproliferative disorders and syndrome, was originally reported as a
(advanced) systemic mastocytosis.
benign acute eosinophilic pneumonia of
Finally, lymphocyte (T-cell) phenotyping (by unknown cause characterised by increased
flow cytometry) should be performed in peripheral blood eosinophils, minimal or no
patients with hypereosinophilia to identify pulmonary symptoms, and spontaneous
aberrant populations, most commonly CD3- resolution. In some patients, these clinical
CD4+ T-cells, which have been associated characteristics may prove to be secondary to
with eosinophilopoietic cytokine production. the presence of parasites, ABPA or drugs.
Pathological specimens show oedema and
Peripheral eosinophilia occurs in virtually all accumulation of eosinophils in the alveolar
cases, either in the initial presentation or septa and interstitium.
during the course of the disease.
Eosinophilia is not always severe in blood The radiographic manifestations consist of
samples, with eosinophil counts of 500 transient and migratory areas of
1000 cells?mm-3, or it can even be absent consolidation. These consolidations are
from the initial clinical presentation, thereby non-segmental, may be single or multiple,
making diagnosis difficult. usually have ill-defined margins, and often
Increased eosinophil counts in the air have a predominantly peripheral
spaces, common to various causes of distribution. The prognosis is excellent. The
pulmonary eosinophilia, result in severe use of corticosteroids is rarely necessary,
eosinophilia in the BAL fluid and are the and spontaneous resolution occurs within
principal method of confirming the 30 days.
diagnosis of acute and chronic eosinophilic
Acute eosinophilic pneumonia presents
pneumonia. In such cases, eosinophils
frequently in young smokers as acute
account for .25% of the cells in the BAL
hypoxaemic respiratory failure. These
fluid.
patients present without peripheral
Lung biopsy (transbronchial or by thora- eosinophilia but usually have .25%
cotomy) is not a prerequisite for the eosinophils in bronchoalveolar fluid.

Acute eosinophilic pneumonia may be There are two variants of idiopathic
secondary to a number of causes, such as hypereosinophilic syndrome:
vaccinations (BCG (bacille Calmette myeloproliferative and lymphocytic. The
Guerin) vaccination and minocycline) and myeloproliferative variant is a
drugs (fludarabine, progesterone and haematological disorder that belongs to the
sertraline), infections (Aspergillus and leukaemia group, and is accompanied by
Coccidioides) or environmental factors dysplasia, hepatosplenomegaly and
(smoking, tear gas, gasoline and demolition increased vitamin B12 level. The lymphocytic
dust). It is important to rule out fungi variant results from a proliferation of T-
infection. helper (Th) type 2 cells with overexpression
of the cytokines interleukin (IL)-3,
The principal histological finding in acute granulocytemacrophage colony-stimulating
eosinophilic pneumonia is diffuse alveolar factor (GM-CSF) and, especially, IL-5. In the
damage associated with interstitial lymphocytic variant, as in allergic disorders
eosinophilia. The predominant radiographic (IgE levels are usually increased), the three
findings are bilateral reticular densities (with sites most commonly involved are the
or without areas of patchy consolidation) respiratory tract, gastrointestinal tract and
and pleural effusion. skin. Treatment includes corticosteroids,
and other agents, such as anti-IL-5, have
Chronic eosinophilic pneumonia is an been considered.
idiopathic condition characterised by
chronic and progressive clinical features Eosinophilic lung diseases of known cause
and specific pathological findings. The ABPA is a hypersensitivity reaction to
clinical manifestation is usually insidious Aspergillus antigens. ABPA is typically seen in
and the patient experiences symptoms for patients with long-standing asthma or CF. It
an average of 7.7 months before the is usually suspected on clinical grounds, and
diagnosis is made. Most patients are the diagnosis is confirmed by radiology and
middle aged and ,50% have asthma. serological testing. Diagnostic criteria
Females are more frequently affected than include the presence of:
males. Pulmonary function tests can be
normal in mild cases but usually show N asthma,
restrictive defects. N peripheral blood eosinophilia,
N an immediate positive skin test for
Idiopathic hypereosinophilic syndrome is a rare Aspergillus antigens,
disorder characterised by marked, N increased serum IgE levels, and
prolonged idiopathic eosinophilia and N pulmonary opacity on chest radiographs.
variable organ dysfunction related either to
infiltration by eosinophils or secondarily The IgE level is probably the most useful
eosinophil-associated tissue damage. laboratory test for ABPA, as it correlates well
with disease activity. Lung biopsies are
The diagnosis is based on three criteria rarely performed for diagnosis.
established by Chusid et al. (1975):
Bronchocentric granulomatosis is a rare
disorder characterised by a necrotising
N persistent eosinophilia (eosinophil count
granulomatous inflammation of bronchial
.1500 cells?mm-3) for o6 months or
and bronchiolar epithelium with chronic
death within 6 months due to the signs
inflammatory changes in the surrounding
and symptoms related to eosinophilia;
lung parenchyma. Approximately one-third
N eosinophilia-related involvement of at
of affected patients have tissue eosinophilia
least one organ; and
and tend to have asthma, peripheral
N absence of a known causes of
eosinophilia and positive sputum cultures
eosinophilia, such as drugs, parasites,
for Aspergillus organisms.
malignancy, vasculitis, chronic
eosinophilic pneumonia and Churg Many parasites can cause pulmonary
Strauss syndrome. opacities with blood or tissue eosinophilia.

Because the prevalence of individual syndrome, confirmation of at least four
parasitic infections varies from one being necessary: asthma; eosinophilia
geographic region to another, familiarity (eosinophil count .1500 cells?mm-3);
with the common parasites in ones paranasal sinus involvement; transient
geographic area of practice is critical to pulmonary infiltrates; mononeuropathy or
arriving at a correct diagnosis. polyneuropathy; and biopsy findings of
vasculitis. Therefore, the histopathological
A wide variety of drugs and toxic substances criterion of small vessel biopsy findings of
are important causes of pulmonary extravascular eosinophils can be dispensed
eosinophilic infiltrates. Patients with drug- with if the other clinical criteria are present.
induced eosinophilic lung disease can
present with a variety of pathologic With these new criteria, a diagnosis of
conditions ranging from a mild, simple ChurgStrauss syndrome has come to be
pulmonary eosinophilia-like syndrome to a more common. Skin, muscle and sural nerve
fulminant, acute pulmonary eosinophilia-like biopsy can reveal perivascular eosinophilic
syndrome. Pulmonary involvement by inflammation and confirm the diagnosis.
cutaneous adverse drug reactions is rare Lung biopsy is considered the gold
and is considered to be a severity factor. standard, although transbronchial biopsy is
Many patients with drug-induced typically insufficient. Chief among biopsy
eosinophilic lung disease will improve by findings is small vessel vasculitis associated
simply discontinuing the medication; in with positivity for antineutrophil cytoplasmic
severe or persistent cases, however, short antibody (ANCA), perinuclear ANCA test
courses of corticosteroids appear to hasten results being positive in 5070% of cases.
recovery. The diagnosis is usually made on The combination of ChurgStrauss
the basis of clinical history and blood syndrome and positive ANCA test results
eosinophilia rather than imaging findings. represents a more significant form of
vasculitis and has therapeutic implications.
ChurgStrauss syndrome was first described A study evaluating the radiological test
in 1951 by Churg and Strauss on the basis of results of nine patients revealed bilateral foci
the histologic criteria necrotising vasculitis, of non-segmental consolidation in most of
tissue infiltration by eosinophils and the cases.
extravascular granulomas.
Currently, the mean survival among Churg
This syndrome is characterised by three Strauss syndrome patients is 9 years. Doses
phases. of prednisone (4060 mg?day-1) for several
weeks are usually necessary in order to
N Allergic phase: presence of asthma or
control vasculitis and should be followed by
rhinitis.
a maintenance regimen for 1 year.
N Eosinophilic phase: presence of severe
persistent peripheral eosinophilia Hypersensitivity pneumonitis
(eosinophil count .1500 cells?mm-3) for
.6 months. Hypersensitivity pneumonitis, or extrinsic
N Vasculitic phase: presence of systemic allergic alveolitis, is a diffuse granulomatous
manifestations and small vessel interstitial lung disease (ILD) caused by
vasculitis, represented by the inhalation of various antigenic organic
involvement of two or more particles or low molecular weight chemicals.
extrapulmonary organs. Because the resulting inflammatory
response involves not only the alveoli but
However, the three phases can be the terminal bronchioli and the interstitium,
dissociated and asthma is present in 100% the term hypersensitivity pneumonitis
of cases. may be more correct than extrinsic allergic
alveolitis.
In 1990, the American College of
Rheumatology established the following The prevalence and incidence of
criteria for the diagnosis of ChurgStrauss hypersensitivity pneumonitis vary

considerably depending upon disease chronic, resulting in fibrosis. It is
definitions, methods used to establish the characterised by an insidious onset of
diagnosis, intensity of exposure, dyspnoea, fatigue and cough. Because the
environmental conditions and host/genetic respiratory symptoms are usually mild or
risk factors that remain poorly understood. absent in subacute hypersensitivity
The disease may also arise in children. pneumonitis, infectious pneumonia or
Clinical behaviour in children is similar to noninfectious ILD is the important
adult cases. differential diagnosis.
Occupational and environmental exposures A Chronic hypersensitivity pneumonitis may
number of occupations have been result from continuous, low-level exposure
associated with the risk of hypersensitivity to inhaled antigens. Bird antigen exposure
pneumonitis, including farmers, mushroom is the most common in this form of
and tobacco workers, woodworkers, maple disease. The onset of chronic
bark strippers, stucco workers, malt hypersensitivity pneumonitis is insidious,
workers, millers, machinists, foundry with slowly increasing dyspnoea, dry
workers, office workers, etc., or hobbyists cough, fatigue and weight loss. Digital
such as bird fanciers. clubbing may be present in 2050% of
patients and predicts clinical deterioration.
Clinical features The spectrum of clinical
Chronic hypersensitivity pneumonitis often
features varies and has been conventionally
develops progressive fibrosis with cor
classified into acute, subacute and chronic
pulmonale and mimics idiopathic
forms. The interval between sensitisation by
pulmonary fibrosis (IPF) or fibrotic
antigen inhalation and the symptomatic
nonspecific interstitial pneumonia (NSIP)
onset of HP is unknown. It seems to be
in the advanced stage. This form of
variable and may range from several months
disease, therefore, often leads the
to several years after the antigen exposure.
physician to mistake the disease for other
Acute hypersensitivity pneumonitis is chronic ILDs. The auscultatory findings
characterised by an influenza-like syndrome include bibasilar crackles and,
(fever, chills, malaise, myalgia and characteristically, inspiratory squeaks
headache) and respiratory symptoms (dry resulting from the coexisting bronchiolitis.
cough, dyspnoea, tachypnoea and chest
Acute exacerbation of chronic hypersensitivity
tightness). However, respiratory symptoms pneumonitis is an emerging concept
in acute hypersensitivity pneumonitis are showing an accelerated respiratory
sometimes absent. The disease onset is deterioration with the presence of new
abrupt and usually occurs 412 h after bilateral ground-glass opacities on HRCT.
antigen exposure. In general, acute The pathogenesis of acute exacerbations in
hypersensitivity pneumonitis is non- chronic hypersensitivity pneumonitis is
progressive and spontaneously improves unknown.
within a few days after antigen avoidance.
The disease often recurs after re-exposure to Diagnosis Several diagnostic criteria for
antigen. Clinical examination shows hypersensitivity pneumonitis have been
bibasilar crackles and occasional cyanosis, recommended. However, none of these
whereas finger clubbing is rare. Patients with criteria has been validated. The diagnosis of
recurrent acute farmers lung may hypersensitivity pneumonitis relies on a high
sometimes develop an obstructive lung level of clinical suspicion, the recognition of
disease with centrilobular emphysema antecedent antigen exposure, and a
instead of fibrosis. constellation of clinical, radiological,
laboratory and pathological findings.
Subacute hypersensitivity pneumonitis may be
associated with repeated low-level exposure A large prospective multicentre cohort study
to inhaled antigens. After recurrent acute (116 patients with hypersensitivity
episodes, this form may also become pneumonitis and 284 control subjects with

other ILD) showed that the diagnosis of lymphocytic interstitial pneumonitis; minor
hypersensitivity pneumonitis could be made degrees of organising pneumonia, when
with six significant predictors: present, also can contribute to this
appearance. The poorly defined centrilobular
N exposure to a known offending antigen; nodules may be caused by cellular
N positive precipitating antibodies; bronchiolitis, the predominantly
N recurrent episodes of symptoms; peribronchiolar distribution of interstitial
N inspiratory crackles; pneumonitis or focal areas of organising
N symptoms 48 h after exposure; and pneumonia. The lobular areas of decreased
N weight loss. attenuation and air trapping are presumably
caused by small-airway obstruction by
If all six predictors are present, the
cellular bronchiolitis or by constrictive
probability of having hypersensitivity
bronchiolitis.
pneumonitis is 98%. If none of the six
predictors is present, the probability is 0%. Chronic hypersensitivity pneumonitis is
characterised by the presence of reticulation
Careful history taking is mandatory.
and traction bronchiectasis and
Clinicians should have specific expertise
bronchiolectasis on HRCT, due to fibrosis
concerning the antigens relevant to
superimposed on findings of acute or
hypersensitivity pneumonitis. Important
subacute hypersensitivity pneumonitis. The
factors are hay feeding, bird keeping, feather
reticulation in chronic hypersensitivity
duvets and pillows in the home, air
pneumonitis can be patchy or random or
conditioning or ventilators in the buildings,
have a predominantly subpleural and
and formation of mould on room walls or in
peribronchovascular distribution but
cellars.
typically tends to spare the lung bases. In a
Important diagnostic tools include BAL, small percentage of cases, chronic
HRCT, provocation tests and lung biopsies. hypersensitivity pneumonitis results in
subpleural honeycombing.
The most sensitive diagnostic test is BAL. In
our experience and based on a literature Acute hypersensitivity pneumonitis is
review, a normal BAL widely excludes the characterised histologically by the presence
diagnosis of hypersensitivity pneumonitis. of neutrophilic infiltration of the respiratory
The characteristic finding is a lymphocytosis bronchioles and alveoli. A pattern of diffuse
in the subacute and chronic forms. In alveolar damage and temporally uniform,
asymptomatic sensitised individuals nonspecific, chronic interstitial
(subclinical alveolitis), BAL lymphocytosis is pneumonitis may also be seen. Subacute
also apparent. BAL lymphocytosis .30% is hypersensitivity pneumonitis is
recommended as a discriminative factor of characterised histologically by the presence
chronic hypersensitivity pneumonitis from of cellular bronchiolitis, noncaseating
IPF, showing usual interstitial pneumonia granulomas and bronchiolocentric
(UIP) pattern on HRCT. interstitial pneumonitis with a
predominance of lymphocytes. Areas of
The radiological manifestations of acute organising pneumonia (bronchiolitis
hypersensitivity pneumonitis are those of obliterans with organising pneumonia) may
acute pulmonary oedema. The characteristic be identified. These findings, however, are
HRCT manifestations of subacute not present in all cases. Furthermore, in
hypersensitivity pneumonitis consist of some patients, the predominant histologic
patchy or diffuse bilateral ground-glass pattern is NSIP or UIP.
opacities, poorly defined small centrilobular
nodules, and lobular areas of decreased Although lung function may be normal in
attenuation and vascularity on inspiratory acute hypersensitivity pneumonitis,
images and of air trapping on expiratory abnormal lung function is common in most
images. The ground-glass opacities patients with chronic hypersensitivity
primarily reflect the presence of diffuse pneumonitis. The most frequent functional

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Pulmonary haemorrhage
Robert Dinwiddie
Pulmonary haemorrhage can occur at any ,1%. The underlying causes are shown in
age in childhood, from birth through to table 1.
adolescence. The presentation can be acute
or chronic, clinically obvious or covert and The underlying mechanism is thought to be
subtle over a period of time. Presenting due to capillary leakage into the interstitium.
features can vary from the acute and life- Haemorrhagic fluid can also leak directly
threatening to chronic ill health secondary to into the alveolar spaces and then into the
iron deficiency anaemia. The aetiology is small and large airways. Neonatal
best divided into two age groups: neonatal pulmonary haemorrhage has also been
and childhood. associated with the administration of
exogenous surfactant. Other predisposing
Neonatal factors include birth asphyxia, excessive
fluid administration, hypoglycaemia,
Neonatal pulmonary haemorrhage most coagulation defects, intercurrent infection,
commonly occurs in preterm infants hypothermia and cardiac failure.
secondary to severe pulmonary oedema in
association with respiratory distress Frothy haemorrhagic fluid appears through
syndrome and patency of the arterial duct the nose and mouth or via the endotracheal
(patent ductus arteriosus). The incidence is tube. In its most acute form it is associated
with the sudden onset of shock and can be
life-threatening. Chest radiographs show
Key points diffuse interstitial shadowing throughout
both lung fields. Treatment includes the use
of high levels of positive end-expiratory
N Pulmonary haemorrhage can occur at
pressure (PEEP), replacement of blood loss
any age.
but with overall fluid restriction and
N Presentation varies from the acute correction of coagulation deficiencies. If
and life-threatening to hidden, with there is an associated patent ductus
no obvious haemoptysis. arteriosus then this should be closed as
N Many cases are idiopathic but a soon as possible.
number of clear underlying causes Infancy and childhood
can be recognised by selective
investigations. Pulmonary haemorrhage in infancy and
childhood can occur due to a variety of
N Known complications include chronic
causes. They are best divided into those
iron deficiency anaemia and
which result in diffuse or focal areas of
pulmonary fibrosis.
bleeding. These are shown in table 2.
N Systemic corticosteroids are the most Consideration should also be given to the
effective treatment in the majority of possibility that bleeding from the nose or
cases. mouth can be due to other causes, such as
epistaxis or haematemesis.

Table 1. Causes of pulmonary haemorrhage in the diagnostic tests is shown in table 3 and an
neonatal period algorithm for diagnosis is shown in figure 1.
Respiratory distress syndrome Lung function tests may demonstrate
Patent arterial duct (patent ductus evidence of airflow obstruction, reduced
arteriosus) lung volumes and functional residual
capacity and associated hypoxaemia with
Fluid overload
reduced oxygen saturation levels in air. The
Cardiac failure, left-to-right shunt diffusion of carbon monoxide is also
Birth asphyxia reduced over the longer term if progressive
Administration of surfactant lung damage occurs. This parameter is
difficult to measure in young children.
Coagulation disorders
Neonatal sepsis Radiological changes include bilateral
patchy interstitial infiltrates throughout one
or both lungs. In the longer term the chest
Clinical presentation radiograph may develop more chronic
changes including reticulo-nodular
The most obvious clinical presentation of shadowing due to pulmonary fibrosis.
diffuse or focal pulmonary haemorrhage is
with clinically apparent bleeding manifesting Depending on the severity, a CT scan of the
itself as haemoptysis. However, only a chest will show patchy interstitial infiltrates
proportion of children present in this way in one or both lung fields. More generalised
and many present with less specific areas of consolidation may also be evident
symptoms such as cough, breathlessness, (fig. 2). In those with prolonged disease,
wheezing and exercise limitation. In some changes of pulmonary fibrosis can develop.
cases, in which the underlying condition has Any associated bronchiectasis will also be
been present over a longer period of time, a seen.
faltering growth pattern is seen. A few
Histopathology
patients with focal intrapulmonary
haemorrhage, such as in CF, complain of a When acute pulmonary haemorrhage occurs
localised bubbling sensation within the red blood cells are seen in large numbers in
chest. At the other extreme, major acute the alveoli and interstitial spaces. Within
cases may present with massive 4872 h many alveolar macrophages are
haemoptysis, profound anaemia and shock, seen which have phagocytosed red blood
which can be life-threatening. cells and are in the process of digesting
them. These cells are called siderophages
Physical examination may reveal pallor,
and stain positive with Prussian blue. A
tachycardia, fever, tachypnoea and
specific parameter used for reporting
dyspnoea, with indrawing of the chest
alveolar haemorrhage in bronchoalveolar
muscles and cyanosis. Localised chest signs
lavage specimens is the Golde score. This
include focal or generalised areas of
gives a ranking score of 04 depending on
decreased air entry and crackles or wheeze.
the density of haemosiderin in the cells. 100
Finger clubbing is also seen but is
cells are counted and the Golde score is
uncommon.
reported. In normal individuals this is ,20.
Diagnostic work-up A score of 2070 is found in those with
significant alveolar haemorrhage. Other
As shown in table 2 the differential pathology groups have used a cut-off of
diagnosis is extensive. A carefully .20% of siderophages present among the
considered diagnostic work-up exploring total number of alveolar macrophages as
known causes is warranted in every case, diagnostic for haemorrhage.
bearing in mind that a significant proportion
are idiopathic and no specific underlying Lung biopsy is rarely indicated but if
condition will be found. A suggested list of undertaken may show abnormalities of the

Table 2. Causes of pulmonary haemorrhage in infants alveolar capillary endothelial basement
and children membrane and, in cases of repeated
bleeding episodes, early pulmonary fibrosis.
Diffuse
Haemosiderosis Diffuse pulmonary haemorrhage
IPH Idiopathic pulmonary haemosiderosis (IPH) is
Goodpasture syndrome a rare condition in children with a variable
and, at times, severe prognosis. It can
Cows milk protein allergy, Heiner
syndrome appear at any age throughout childhood but
its onset is more common in the early years.
Systemic vasculitis
It varies in severity and presents when there
Granulomatosis with polyangiitis is active bleeding into the lung tissue itself.
(Wegeners) This can take the form of haemoptysis, from
HenochSchonlein purpura small amounts to massive acute life-
ChurgStrauss syndrome threatening episodes, or the gradual onset
of severe anaemia without any clinically
Microscopic angiitis
obvious haemoptysis. Patients can become
Collagen vascular breathless and occasionally wheezy or may
Systemic lupus erythematosis be asymptomatic. If haemoptysis does occur
Cardiac it is manifested by cough and small or large
amounts of blood which may continue over
Left-to-right shunt
several days or weeks. The full blood count
Left-sided obstruction shows an acute reticulocyte response and
Cardiac failure evidence of iron deficiency anaemia.
Coeliac disease Diagnosis is made by the finding of
haemosiderin laden macrophages in
Alveolar injury
bronchoalveolar lavage fluid, gastric
Bleeding diatheses aspirates or on lung biopsy in the absence of
Focal any other known aetiology for pulmonary
Viral or bacterial lung haemorrhage.
infection
Other associations with pulmonary
TB haemorrhage include acute
Atypical mycobacterial glomerulonephritis and Goodpastures
infection syndrome. These patients also present with
Bronchiectasis haematuria and proteinuria. Antibodies to
glomerular and alveolar basement
CF
membranes can be detected in the blood.
Non-CF bronchiectasis Renal biopsy, which is rarely indicated,
Primary ciliary dyskinesia demonstrates specific antibodies to basement
Immunodeficiency
membrane and disruption of the underlying
vascular endothelial membrane. Similar
Foreign body changes have been demonstrated in the lung.
Vascular Chest radiography findings are similar to IPH
Haemangiomas with patchy interstitial infiltrates seen
bilaterally, increasing in severity during
Arterio-venous malformations
episodes of active bleeding. Over the longer
Neoplasms term, if this is recurrent, pulmonary fibrosis
Tracheostomy occurs and the changes, which are initially
Fabricated or induced illness ground-glass in appearance, become more
reticular and nodular.

Table 3. Possible diagnostic tests for cases of pulmonary haemorrhage
Full blood count ECG
Coagulation studies Echocardiogram
Erythrocyte sedimentation rate Pulmonary function tests
C-reactive protein Chest radiograph
Serum iron and ferritin CT scan of the chest
Renal function tests Sputum culture and sensitivity
Immune deficiency screen including HIV/AIDS Mantoux test
Total IgE Viral antibodies
Cows milk protein antibodies CF mutation analysis
Anti-neutrophil cytoplasmic antibodies Ciliary biopsy and electron microscopy
Antinuclear antibodies Bronchoalveolar lavage
Anti-glomerular basement membrane Lung biopsy (rarely necessary)
antibodies
IgA anti-tissue transglutaminase antibodies
Pulmonary haemorrhage is also associated to cor pulmonale. Chest radiographs show

with allergy to cows milk protein, i.e. Heiner patchy bilateral infiltrates. Blood counts
syndrome. Apart from acute episodes of show a marked eosinophilia and elevated
pulmonary haemorrhage it most commonly levels of IgE. Antibodies to cows milk
presents in children under the age of three protein are diagnostic. A cows milk-free diet
with clinical signs of cows milk protein results in the disappearance of symptoms.
intolerance including vomiting, diarrhoea, Pulmonary haemorrhage occurs in cardiac
gastrointestinal bleeding, rhinorrhoea and failure, particularly where there is a left-sided
faltering growth. Some patients develop obstructive lesion or a large left-to-right
significant lymphoid hyperplasia of the shunt. Such conditions are usually evident
upper airway, specifically, adenotonsillar clinically before a bleeding episode occurs.
hypertrophy, which in severe cases can lead Diffuse pulmonary haemorrhage is also a
Algorithm for the diagnosis

of pulmonary haemorrhage
Idiopathic Immune mediated Cardiac Infection Focal
Chest radiograph Chest radiograph Chest radiograph Chest radiograph Review upper airway
Chest CT Chest CT Chest CT Chest CT Chest radiograph
Bronchoscopy Bronchoscopy Bronchoscopy Bronchoscopy Chest CT
BAL BAL BAL BAL CF screen
Haematology Autoantibodies ECG Virology Non-CF bronchiectasis screen
Immunology screen Echo Bacteriology Ciliary biopsy
Renal function TB screen Factitious
Induced
Figure 1. Algorithm for the diagnosis of pulmonary haemorrhage. BAL: bronchoalveolar lavage; Echo:
echocardiography.

conditions heavily blood-stained sputum is
more common than the major bleeding
episodes which can occur in IPH and CF.
Localised lesions such as haemangiomas
and arteriovenous malformations can also
be the cause of acute bleeding episodes.
Bleeding can occur as a complication of an
underlying clotting disorder. Pulmonary
haemorrhage can be real or imagined as
part of the spectrum of factitious or induced
illness in childhood.
Management
Figure 2. CT scan of 5-year-old boy with diffuse
bilateral alveolar haemorrhage. Major bleeding episodes can occur without
warning and may be fatal. Chronic covert
known complication of systemic lupus haemorrhage also occurs over a period of
erythematosis, HenochSchonlein purpura, several weeks and may present only with
granulomatosis with polyangiitis chronic but sometimes severe anaemia.
(Wegeners), microscopic polyangiitis, Management of the acute situation requires
coeliac disease and diffuse alveolar injury oxygen therapy and other respiratory
from exposure to external toxic agents. support including bronchodilators, blood
transfusion and ventilation in severe cases.
Focal pulmonary haemorrhage CF is the Corticosteroids such as pulsed
most common cause of massive pulmonary methylprednisolone 1030 mg?kg-1?day-1 for
haemorrhage in older children. Many 3 days are given at monthly intervals. In less
episodes are precipitated by an acute severe cases oral prednisolone is given at
exacerbation of long-term infection. 2 mg?kg?-1?day-1 for a minimum of 57 days
Bleeding can be exacerbated in individual following which the dose is titrated to the
cases by the use of over aggressive chest lowest level that controls symptoms. In a
physiotherapy techniques, high- number of cases oral steroids may only be
concentration mucolytic agents and, necessary for short periods while in others a
occasionally, as a complication of rhDNase continuing dosage on a daily basis or
therapy. preferably on alternate days is required to
control symptoms. Other
Management includes reduction of physical
immunosuppressive agents such as
activity, adaptation of chest clearance
hydroxychloroquine, azathioprine and
techniques to less physically stressful
cyclophosphamide have been used. If there
methods and appropriate intensification of
is evidence of cows milk allergy then a milk
antibiotic therapy. Should this be
free diet is indicated. Inhaled corticosteroids
unsuccessful then bronchial artery
have also been used in an attempt to reduce
embolisation is indicated. This is not underlying inflammation. Plasmapheresis
without risk as embolisation of an adjacent has been used in Goodpastures syndrome.
anterior spinal artery with paraplegic
consequences is a known complication. This Prognosis
procedure is, however, successful in the
majority of cases. Limited lung resection is The natural history of most causes of
the final option if other procedures fail to pulmonary haemorrhage is to wax and wane
control the bleeding. over a period of time. Because of the rarity of
these conditions there are no formal clinical
Pulmonary haemorrhage can occur as a trials of any the above treatments. The
complication of non-CF bronchiectasis, with overall prognosis is therefore variable, in
or without immunodeficiency, TB and severe cases of IPH, mortality rates as high
primary ciliary dyskinesia. In these as 50% over a 5-year period have been

reported in the past. Results with recent N Brunner J, et al. (2009). Successful
more intensive treatment regimens have treatment of severe juvenile microscopic
reduced this to around 14%. Those who polyangiitis with rituximab. Clin
have major haemorrhagic episodes are most Rhematol; 28: 997999.
at risk. Other patients may show only small N Esposito S, et al. (2010). Wegeners
episodes of a milder degree and in these granulomatosis presenting with life threa-
tening lung haemorrhage in a 7-year-old
cases there is a tendency to improve with
child. Rheumatol Int; 30: 16651668.
age, especially during adolescence and early
N Godfrey S (2004). Pulmonary hemor-
adult life. rhage/hemoptysis in children. Pediatr
Pulmonol; 37: 476484.
Further reading N McCoy KS. Hemosiderosis. In: Pediatric
Respiratory Medicine. 1st Edn. Taussig
N Boat TF. Pulmonary hemorrhage and LM, et al., eds. St Louis, Mosby, 1999;
hemoptysis. In: Chernick V, et al., eds. pp. 835841.
Kendigs Disorders of the Respiratory N Roberton NRC. Pulmonary oedema/pul-
Tract in Children. 7th Edn. Philadel- monary haemorrhage. In: Greenough A, et
phia, Saunders Elsevier, 2006; pp. al., eds. Neonatal Respiratory Disorders. 1st
676685. Edn. London, Arnold, 1996; pp. 375385.

Sickle cell disease
Tobias Ankermann
The term sickle cell disease (SCD) is used to the rheological properties of the erythrocyte
refer to a haemoglobinopathy that results leads to dysfunction in the microcirculation
from a genetic variant giving rise to sickle with vaso-occlusive crises. Vascular
haemoglobin (HbS). This includes the occlusions can occur in almost all organs
homozygote SCD (HbSS, previously named (e.g. skin, lung, liver, spleen, bone, kidney
sickle cell anaemia) and compound and brain). The clinical consequences of this
heterozygote haemoglobinopathies (HbS-b- are acute and chronic pain, hyposplenism
thalassaemias, HbSC disease, etc.). In (or functional asplenia in older children
Europe, ,1300 children will be born with following splenic infraction and splenic
SCD per year. 6070% of these children sequestration) with secondary
suffer from HbSS. immunodeficiency, osteonecrosis,
nephropathy and cerebral infarction. The
HbS-haemoglobinopathies cause a chronic most common causative organisms of
haemolytic anaemia and a disease of the infectious complications following
blood vessels. HbS is caused by a mutation secondary immunodeficiency are
in the b-globin locus on chromosome 11; Streptococcus pneumoniae, Salmonella,
HbSS leads to polymerisation and a loss of Haemophilus influenzae type b, Neisseria
solubility of the haemoglobin during meningitidis and Mycoplasma. In acute chest
deoxygenation. The subsequent change in syndrome (ACS) of infectious origin, the
most commonly identified agents are
atypical bacteria and viruses.
Key points The chronic disease of the vessels results in
priapism, cerebrovascular disease,
N SCD includes HbS- hypercoagulability and inflammation of
haemoglobinopathies, which lead to endothelial structures.
haemoglobin polymerisation with
subsequent vaso-occlusion, a chronic In the lungs and airways, SCD leads to acute
haemolytic anaemia and endothelial manifestations (acute pulmonary vascular
damage in blood vessels, with occlusions, ACS and acute lower respiratory
consequent chronic organ failure. tract infections (LRTIs)), and a chronic lung
N In the lungs and airways, SCD induces disease with lung fibrosis and secondary
acute pulmonary vascular occlusions, pulmonary hypertension with cor
ACS, LRTIs, and chronic lung disease pulmonale. Children with SCD frequently
with lung fibrosis and pulmonary exhibit bronchial hyperresponsiveness and
hypertension. bronchial asthma. The comorbidity of SCD
and asthma is associated with a two-fold
N Important pulmonary comorbidities increased mortality and a reduced life span
of children with SCD are bronchial of patients with asthma and SCD compared
hyperresponsiveness, atopy and to patients with SCD without asthma. The
asthma. role of OSAS is not yet clearly defined.
Pulmonary complications are the most

frequent reason for death in children with haemoglobin concentration decreases
SCD. (,2 g?dL-1 of individual baseline) or the
PaO2 decreases ,70 mmHg below the
Keystones of care are: normal range during oxygen therapy, then
N protection against infections (e.g. blood transfusion is indicated. One small
vaccination against pneumococci, trial (DeNOVO) suggested that patients
H. influenzae B, Neisseria, influenza A, and with ACS and early transfusion had an
antibiotics (prophylactic penicillin in improved outcome, when compared with
small children continued until the historical data. In very severe cases or when
immunisation series is complete, with transfusion fails to reduce the HbSS to
pneumococcal polysaccharide vaccine ,30%, an exchange transfusion should be
with HbSS and HbS-b0-thalassaemia), considered. Extracorporeal membrane
N early intervention to prevent disease oxygenation (ECMO) and nitric oxide are
progression if pain or fever occurs, therapy options in very severe cases but are
N optimal asthma therapy, and not standard therapies.
N together with haematologists,
The application of glucocorticoids is
hydroxyurea, folic acid and occasionally a
controversial. In mild ACS, positive effects
transfusion regimen.
have been described, but there are reports
In acute vaso-occlusive crisis and ACS, that administration of glucocorticoids in
oxygen, hydration, analgesia, antibiotics and ACS leads to relapse after sudden
incentive spirometry are required. termination, reactive vaso-occlusive disease
and longer hospitalisation. In children with
Acute chest syndrome ACS on artificial ventilation, it may be
ACS is an acute lung injury and is caused by necessary to perform bronchoscopy and to
infection, fat embolism, vaso-occlusion or a apply DNase to remove mucus and/or
combination of these factors. It is defined as bronchial casts. Figure 3 delineates the
respiratory signs and/or symptoms (cough, therapy of ACS.
tachypnoea, chest pain, retractions, rales, Chronic lung disease in SCD
crackles, wheezing and hypoxaemia) and/or
new infiltrates on the chest radiography and Fibrotic remodelling of the lung occurs due
fever (.38.5uC) (fig. 1). One-third of children to changes in the structure and function of
with ACS complain about abdominal pain
and pain in their extremities. Figure 2 shows
a practical approach to the diagnosis of A new pulmonary infiltrate detected by chest
ACS. The discrimination of ACS from radiograph involving at least one complete
pneumonia or other LRTIs is often difficult lung segment that is not consistent with the
but not essential for treatment. Children appearance of atelectasis
with suspected or manifest ACS should be and
admitted to hospital for close observation of one or more of the following signs
their clinical and respiratory status. The or symptoms:
treatment should be initiated early and is cough
based on the administration of oxygen to signs of increased work of breathing
counter the polymerisation of HbS. (retractions, tachypnoea)
Furthermore, antibiotic treatment (third- chest pain
generation cephalosporin or amoxicillin/b- wheezing
lactamase inhibitor plus a macrolide; if rales
methicillin resistant Staphylococcus aureus body temperature >38.5C
hypoxaemia relative to baseline
(MRSA) is suspected, consider
measurement
vancomycin), inhalation of b2-
sympathomimetics, intravenous hydration,
analgesia and incentive spirometry are Figure 1. Clinical criteria for diagnosis of ACS in
keystones of the therapy of ACS. If the children with SCD.

Fever
and/or
Cough
and/or
Respiratory distress (tachypnoea, chest retractions)
and/or
SaO2 95%
and/or
Chest pain
Rales? Yes Acute chest syndrome

Reduced breath sound?
Start therapy
Percussion dullness?
No
Chest radiography Yes Acute chest syndrome

Infiltrates? Start therapy
No
Monitoring clinical course and SaO2

If pain present: optimise analgesia
Other cause?
Figure 2. Practical approach if criteria for ACS are met in children with SCD. Reproduced and modified
from Miller (2011) with permission from the publisher.
the endothelium and the metabolism of pulmonologist should examine children with
nitric oxide. ACS and asthma are important SCD when they are well on an individual
risk factors for this process. Lung function basis (every 4 months in small children; up
tests in preschool children mostly to 612 months in older children with HbSS
demonstrate an obstructive pattern. A and HbS-b0-thalassemia). Integral parts of
restrictive pattern occurs beginning in the the consultation are:
second decade. In the third decade, there
can be a progressive decline in TLC and N history,
diffusion capacity. CT may show interstitial N recording of room-air oxygen saturation,
lung disease. N lung function testing (according to age,
including diffusion capacity in older
Atopy, asthma and bronchial children),
hyperresponsiveness are important N allergy tests (skin-prick test or specific
comorbidities in children with SCD. The IgE), and
prevalence of asthma in children with SCD is N checking for signs and symptoms of OSA.
between 20% and 48%. Children with SCD
and asthma and/or specific sensitisation If, in asthma, a decline in lung function or a
suffer more frequent and earlier episodes of specific sensitisation is detected, lung
ACS. A possible explanation is the function should be tested every 6 months.
ventilation/perfusion mismatch in asthma
with local tissue hypoxia in the lung Children with abnormal overnight oxygen
following sickling and vaso-occlusion, and saturation (,95%) and/or abnormal lung
the higher incidence of LRTIs in children function test should be screened for OSA,
with atopy and asthma. The paediatric interstitial lung disease and pulmonary

Markers of inflammation (CRP, sedimentation rate)
Blood gas analysis
Complete blood count, reticulocytes
Markers of haemolysis (haptoglobin, LDH, bilirubin direct + total), electrolytes, creatinine, BUN,
Blood culture, sputum culture, urine culture
Pulse oximetry, ECG and respiratory rate, repeated clinical examination
Oxygen
Antibiotics (third-generation cephalosporin (or ampicillin + -lactamase inhibitor)
+ macrolide)
Inhalation with 2-sympathomimetics
Balanced i.v. hydration
Analgesia
Physiotherapy (PEP, incentive spirometry)
Hb 2 gdL-1 < baseline Yes

PaO2 <70 mmHg Transfusion
Deterioration over 612 h
Mechanical ventilation, exchange transfusion (ECMO)
Figure 3. Procedure and therapy if criteria for ACS are met in children with SCD. CRP: C-reactive protein;
LDH: lactate dehydrogenase; BUN: blood urea nitrogen; PEP: positive expiratory pressure. Reproduced
and modified from Miller (2011) with permission from the publisher.
hypertension. At present, there is no specific disease and early mortality. With optimal
therapy for chronic lung disease in SCD. care, children with SCD are able to reach the
Asthma in SCD is associated with ACS, sixth decade of life. Without structured care,
faster decline in lung function and mortality, many children will not reach adulthood.
and should therefore be managed based on
established asthma guidelines. In Further reading
childhood, pulmonary hypertension is less
common. Therefore, evidence-based N Colombatti R, et al. (2011). Pulmonary
recommendations for the treatment of hypertension in sickle cell disease chil-
pulmonary hypertension in children with dren under 10 years of age. Br J Haematol;
SCD are lacking. The application of 150: 601609.
sildenafil, bosentan and prostacyclins has N Gladwin MT, et al. (2008). Pulmonary
been reported. complications of sickle cell disease. N
Engl J Med; 359: 22542265.
Course of lung disease in SCD N Kavanagh PL, et al. (2011). Management
of children with sickle cell disease: a
Children with SCD demonstrate a decline in comprehensive review of the literature.
lung function with increasing age, Pediatrics; 128: e1552e1574.
accompanied by decreasing exercise N Knight J, et al. (1999). The lung in sickle
tolerance. The incidence of ACS and cell disease. Pediatr Pulmonol; 28: 205
comorbidity with asthma are important risk 216.
factors for the development of chronic lung

N Miller ST (2011) How I treat acute chest N Rees DC, et al. (2010). Sickle-cell disease.
syndrome in children with sickle cell Lancet; 376: 20182031.
disease. Blood; 117: 52975305. N Shilo NR, et al. (2011). Asthma and
N Miller AC, et al. (2012). Pulmonary chronic sickle cell lung disease: a
complications of sickle cell disease. Am dynamic relationship. Paediatr Respir
J Respir Crit Care Med; 185: 11541165. Rev; 12: 7882.

Lung and mediastinal
tumours
Amalia Schiavetti
Benign or malignant paediatric chest

tumours can originate from the lung Key points
parenchyma, mediastinum, pleura or chest
wall. N Primary pulmonary neoplasms are
rare in childhood; metastatic disease
Primary lung tumours or inflammatory/congenital diseases
Primary pulmonary neoplasms are rare in are more frequently recognised.
children, whilst metastatic disease or N The most common primary lung
inflammatory/congenital diseases are more malignancies in children are
frequently recognised. The ratio of primary pleuropulmonary blastoma and
to metastatic to inflammatory/congenital carcinoid tumour; bronchogenic
tumours is reported to be 1:5:60. In a carcinomas are exceptionally rare.
published large series of childhood lung
tumours, 16.7% were primary and 83.3% N Symptoms of primary lung tumours in
reflected metastatic disease or secondary childhood are nonspecific (cough,
involvement by a haematolymphoid or haemoptysis, chest pain or shortness
histiocytic process. of breath); persistent symptoms or
persistent radiographic findings
Clinical picture Primary pulmonary tumours despite therapy require a CT scan and/
in children present with nonspecific or a MRI of the chest.
symptoms. Some lesions are found
incidentally on radiological studies
N Tumours arising in the anterior
mediastinum are most commonly due
requested for unrelated medical diseases.
to lymphoma followed by germ cell
Common presenting symptoms include
tumours; large masses present life-
cough, chest pain, haemoptysis or shortness
threatening airway compromise,
of breath and they may mimic common
especially during anaesthesia.
entities. Due to the paucity of primary
pulmonary malignancies in paediatric and
adolescent patients, delays in diagnosis are
provides better visualisation of soft tissue
common. At least half of these lesions can
lesions, vascular anatomy and masses of the
present with advanced stage disease. Most
mediastinum. The presence of a suspicious
patients are initially diagnosed as having
mass lesion can require bronchoscopy for
pneumonia that contributes to a delay in
central lesions and thoracoscopic or image-
diagnosis.
guided biopsy for peripheral lesions.
Diagnosis Initial workup consists of baseline Bronchoscopic evaluation should consist of
laboratory and chest radiography. Persistent gross inspection. Tracheal and
symptoms or persistent radiographic endobronchial tumours are most likely to be
findings despite therapy require a CT scan carcinoid tumours or mucoepidermoid
and/or MRI of the chest, as well as carcinomas; both are malignant processes.
evaluation by a pulmonologist. CT is most Tissue biopsy of endobronchial lesions can
useful for parenchyma lesions, whereas MRI be performed, although this procedure is

opposed by some authors because of the survival is 63% (type I 80%; type II 73%; type
risk of fatal haemorrhage. If attempted, III 48%). Although PPB has not been
endobronchial biopsy should be performed identified as part of a specific syndrome, it is
in a setting where thoracic surgery is a strikingly familial cancer with genetic
immediately available. A history of a implications for others in the immediate and
congenital cystic malformation of the lung extended families. In fact, in ,25% of cases,
has been reported to increase the risk of PPB is associated with other extrapulmonary
lung malignancy. It is thought that these lesions in the same patient or family
malformations may undergo malignant members.
degeneration with time.
Carcinoid tumour is considered a low-grade
Prognosis and treatment The frequency of the neuroendocrine carcinoma due to its
various histology types and the outcome for potential for locally aggressive growth and
children with pulmonary malignancies is low potential for metastasis. These lesions
different to adults. In adults, ,80% of the are typically obstructive endobronchial
lung tumours are adenocarcinoma, small masses in older children and adolescents
cell carcinoma or squamous cell carcinoma and have been reported to account for 50
and the 5-year overall survival for all patients 80% of primary malignant lung tumours in
is very poor. In children, pleuropulmonary children. These lesions tend to be
blastoma, inflammatory myofibroblastic endobronchial and this probably explains
tumour and carcinoid tumour are frequently the presentation with haemoptysis. Patients
recognised. The prognosis is dependent on with carcinoid tumours seem to have the
the histology and stage. All patients with best prognosis. No adjuvant therapies are
localised disease are treated with surgical recommended for paediatric pulmonary
resection. Some patients with advanced carcinoid tumours. The outcome is related
disease can be treated with chemotherapy, to the extent of disease at presentation and
radiotherapy and selective surgery either to the tumour resection.
independently or in combination.
Mucoepidermoid carcinoma is typically an
Malignant tumours exophytic polypoid mass that causes
Primary lung tumours are mostly malignant. bronchial obstruction (80% of cases).
Treatment is primarily surgical, with
Pleuropulmonary blastoma (PPB) is a rare chemotherapy and radiotherapy reserved for
malignant embryonal mesenchymal those tumours with incomplete resection.
neoplasm of the lung and pleura described The prognosis in children appears to be
in 1988 as a unique entity distinct from more favourable than in adults.
pulmonary blastoma. This tumour occurs
almost exclusively in children ,6 years of Inflammatory myofibroblastic tumour (IMT)
age. Three subtypes of PPB have been has traditionally been considered benign
described; defined grossly: and is known by many names including
plasma cell granuloma and inflammatory
N type I is cystic and lacks solid pseudotumour. More recently, the World
component, Health Organization recognised IMT as a
N type III is solid without a cystic low-grade mesenchymal malignancy. These
component, nodular lesions are rarely endobronchial,
N type II consists of a mixture of solid and and more frequently intraparenchymal.
cystic components. Surgical resection is the treatment of choice,
although chemotherapy and radiation have
PPB has a propensity to metastasis to the been proposed as adjuvant therapy.
brain. The differential diagnosis for type I
PPB includes more common benign cystic Among the rare epithelial lung cancers most
lung malformations. Treatment is based on paediatric cases are adenocarcinomas. The
aggressive surgery followed by multimodal actual incidence in children is difficult to
chemo-radiotherapy. The overall 2-year determine and is limited to individual case

reports and small case series. These excised for diagnosis and staging purposes,
tumours may occur in children at any age, others are removed as a part of oncological
but they are more usually found during management to achieve long-term survival
adolescence. The adenocarcinomas in these and cure. Conversely, surgical management
patients are histologically similar to of metastatic disease is not used for
conventional pulmonary adenocarcinomas chemosensitive and radiosensitive
of adults and should be managed according malignancies. Wilms tumour and
to reasonable adult guidelines with surgical osteosarcoma are the two most common
resection of operable tumours. Radiation solid tumours leading to surgical excision of
therapy and chemotherapy may be of some isolated metastatic lung nodules.
benefit to patients with unresectable
tumours. Delay in diagnosis and metastasis Secondary involvement of the lung in
at presentation has led to generally poor systemic diseases
survival in the few cases of bronchogenic Langerhans cell histiocytosis presents in
carcinoma in children. multiple organs including lungs. The lung is
Benign tumours considered a high-risk organ, but is less
frequently involved in children than in
Among benign lung tumours, hamartomas adults. Chest radiographs may show a
may present as large parenchymal masses nonspecific interstitial infiltrate. A chest CT
with respiratory distress. Chest CT is needed to visualise the cystic/nodular
classically shows fat and popcorn pattern of the Langerhans cell histiocytosis,
calcifications, which suggest the diagnosis. which leads to the destruction of lung
tissue. Medical treatment following
Metastatic lung tumours Histiocyte Society clinical trials is
recommended.
Metastases to the lung are more common
than primary lung malignancies in children, Leukaemia and lymphoma Leukaemic
and they may be excised for diagnosis, infiltration of the lung may cause a pattern
staging or therapeutic purposes. Most that is radiographically similar to primary
malignant lung lesions are metastases from infections. Lung involvement by leukaemia
distant organs or direct invasions from usually manifests as patchy interstitial,
adjacent structures. Metastatic tumours septal or pleural infiltrates in contrast to
account for ,80% of all lung tumours in non-Hodgkin and Hodgkin lymphoma,
children and .95% of malignant tumours of which tend to form larger, well-
the lung in this population. Wilms tumour, circumscribed nodules. An associated
lymphoma, hepatoblastoma, mediastinal mass or hilar adenopathy are
rhabdomyosarcoma, Ewing sarcoma, variable features. Leukaemia and
osteosarcoma and gonadal tumours can lymphoma are closely related and patients
produce metastases in the lungs, both with leukaemia may present with an
isolated and multiple (fig. 1). Although a anterior mediastinal mass and pleural
wide variety of childhood tumours produce effusions. The distinction between the two
lung metastases, Wilms tumour and is arbitrarily based on the degree of bone
osteosarcoma are the most frequent. marrow involvement such that patients
Metastases to the lung can be seen on chest with o25% marrow blasts are designated
radiography, but CT frequently identifies as having leukaemia. The differential
small pulmonary nodules that are occult on diagnosis for lymphoma involving the lung
conventional chest radiography. It is difficult in children primarily includes Hodgkin
to distinguish benign from malignant lymphoma and non-Hodgkin lymphoma.
pulmonary nodules in children based on CT Associated pulmonary nodules and pleural
imaging features. Pulmonary metastases effusions occur in only ,5% of patients
often appear as round, sharply marginated with Hodgkin lymphoma, whereas
nodules, but they may be also ill-defined. effusions occur in 5075% of those with
While some metastatic lung nodules are non-Hodgkin lymphoma.

metastatic tumours and primary tumours
a)
such as lymphomas, germ cell tumours,
carcinoid and thymoma.
Lymphoma Lymphoma accounts for ,13%
of all childhood cancers and is the most
common cause of a mediastinal mass in
children. 60% of all lymphomas in this age
group are non-Hodgkin lymphomas while
Hodgkin lymphoma makes up the
remainder (fig. 2).
Diagnosis The growth rate in non-Hodgkin
lymphoma is often more rapid than in
Hodgkin lymphoma. Non-Hodgkin
b)
lymphomas have a rapidly growing tumour
mass that can cause life-threatening
complications. In particular, children with
anterior mediastinal masses are at high risk
of life-threatening airway compromise
during anaesthesia. Large mediastinal
masses can cause compression of
surrounding mediastinal structures and
patients may have symptoms of airway
obstruction or cardiovascular compromise.
The additive effects of an anaesthetic with
paralysis and positioning during biopsy can
lead to acute airway obstruction and death.
The least invasive procedure should be used
Figure 1. Metastatic Wilms tumour in a 9-year-old to establish the diagnosis. Lymph nodes in
girl. a) A chest axial CT scan showing bilateral, areas outside the mediastinum provide
large, hilar nodes and multiple round lung lesions access for tissue diagnosis; in the other
with right pleural thickening. b) A chest axial CT cases, a diagnostic and management
scan performed after chemotherapy showing a challenge arises for paediatric surgeons.
dramatic decrease in parenchyma lesions and hilar Some patients at greatest risk require pre-
nodes. There is no pleural involvement. treatment of the mass before tissue
diagnosis. Anterior mediastinal masses in
Mediastinal tumours children should be approached in a step-
wise fashion with multi-disciplinary
Tumours in the mediastinum are best involvement, starting with the least invasive
characterised by the compartment in which
techniques and progressing cautiously.
they arise. Malignant tumours arising in the
Biopsy may be obtained by trans-thoracic
anterior mediastinum are most commonly
puncture under CT or ultrasound guidance
due to lymphoma followed by germ cell
and it can be considered a viable, safe and
tumours. Tumours of the posterior
accurate method of reaching a diagnosis in
mediastinum are usually of neurogenic
the paediatric population. If these children
origin with neuroblastoma being most
require general anaesthesia for diagnosis, the
common.
surgeon should have a well-defined and pre-
Benign tumours are typically teratomas operatively established contingency plan. Of
localised in the anterior mediastinum. About the many clinical, functional and radiological
half of mediastinal tumours in childhood criteria used to identify the children at
occur in the anterior mediastinum .The greatest risk for anaesthetic complications,
majority of these are malignant, including the peak expiratory flow rate (PEFR)

a) b)
Figure 2 Hodgkin lymphoma in 7-year-old boy. a) Anteroposterior and b) lateral chest radiographs
demonstrate a large anterior mediastinal mass lesion.
and the tracheal cross-sectional area seem to infancy and young childhood, the
be the most reliable. General anaesthesia histological subtypes are restricted to
should not be administered to children if the benign teratoma and yolk sac tumour. In
PEFR and tracheal cross-sectional area are adolescence, histological subtypes most
both ,50% predicted. If both are .50% commonly include yolk sac tumour,
pred, general anaesthesia can be seminoma, teratoma and immature
administered safely. teratoma. Seminomas lack serological
markers, whereas non-seminomatous
Treatment After diagnoses and staging
tumours are often associated with increased
evaluation by imaging, chemotherapy is the
serum b-human chorionic gonadotropin or
main component of treatment for childhood
alpha-fetoprotein levels. Adolescents may be
non-Hodgkin lymphoma, while the majority
relatively asymptomatic, whereas infants
of patients with Hodgkin lymphoma are
may have severe respiratory symptoms.
currently managed with combined modality,
Surgical excision is the therapy of choice in
incorporating radiotherapy and
benign tumours such as teratomas.
chemotherapy.
Malignant germ cell tumours are
Germ cell tumours/teratomas chemosensitive tumours.
About 20% of mediastinal germ cell Posterior mediastinum Approximately 90%

tumours are malignant and include of posterior mediastinal masses in children
seminomas and non-seminomatous are of neurogenic origin. These include
tumours, such as teratocarcinoma, yolk sac ganglion cell tumours and nerve tumours.
tumour, embryonal carcinoma, Most are ganglion cell tumours that arise
choriocarcinoma and mixed types, the from sympathetic chain ganglia and form a
others are teratomas. Malignant germ cell spectrum of disease ranging from the most
tumours are generally a complex tumour, aggressive, neuroblastoma, to the less
often containing coexisting benign aggressive, ganglioneuroblastoma and
components. There are two age peaks for benign ganglioneuroma. About 30% of
mediastinal germ cell tumours at about these contain calcifications on radiological
2 years of age and at adolescence. During imaging.

Tumours of the pleura partially calcified soft-tissue mass arising
from one or more ribs, with associated
Mesothelioma of the pleura is primarily a destruction and distortion of the bone.
tumour of the adult, .90% of Although these features suggest an
mesothelioma are diagnosed after the fifth aggressive process, mesenchymal
decade of life; the prognosis is dismal. hamartomas are benign lesions, with no
Pleural involvement by malignant tumours reports of recurrence or metastasis
in children is typically from metastatic following complete surgical resection.
diseases, invasive chest wall neoplasms,
lymphoma or pleuropulmonary blastoma.
Further reading
Chest wall tumours
N Dishop MK, et al. (2008). Primary and
The most common malignant primary metastatic lung tumors in the pediatric
tumours of the chest wall arise from bone or population: a review and 25-year experi-
soft tissue. They are mostly commonly of the ence at a large Childrens Hospital. Arch
Ewing types (Askin or primitive Pathol Lab Med; 132: 10791103.
neuroectodermal tumour) or N Garey CL, et al. (2011). Management of
rhabdomyosarcoma; others include anterior mediastinal masses in children.
fibrosarcoma or osteosarcoma. Non- Eur J Pediatr Surg; 21: 310313.
malignant chest wall tumours are N Jaggers J, et al. (2004). Mediastinal
masses in children. Semin Thorac
neurofibroma, haemangiomas and
Cardiovasc Surg; 16: 201208.
osteochondromas. Imaging findings that
N Lal DR, et al. (2005). Primary epithelial
suggest a malignant chest wall mass include lung malignancies in the pediatric popu-
rib destruction, pleural extension and large lation. Pediatr Blood Cancer; 45: 683686.
size. The prognosis is dependent on the N McCarville MB (2010). Malignant pul-
total resection, as well as on the histology monary and mediastinal tumors in chil-
and stage. Small-cell malignant tumours, dren: differential diagnoses. Cancer
such as Ewings sarcoma and Askins Imaging; 10: 3541.
tumour, should be treated with an N Petroze R, et al. (2012). Pediatric chest II:
aggressive multimodality approach benign tumors and cysts. Surg Clin North
combining chemotherapy, radiation therapy Am; 92: 645658.
and surgery. N Priest JR, et al. (1996). Pleuropulmonary
blastoma: a marker for familial disease. J
Mesenchymal hamartomas of the chest wall Pediatr; 128: 220224.
are unusual rib lesions most commonly N Yu DC, et al. (2010). Primary lung tumors
affecting infants. The typical radiographic in children and adolescents: a 90-year
manifestation of a chest wall mesenchymal experience. J Pediatr Surg; 45: 10901095.
hamartoma is that of a large, extrapleural,

Systemic disorders with lung
involvement
Andrew Bush
The lung can be affected by systemic disease N An extrapulmonary disease may itself be
in a number of ways, which are not a single-organ disease but the
necessarily mutually exclusive. consequence of that disease (causing
dysfunction of that organ) affects the
N The underlying condition has both lung either through relatively specific
systemic and pulmonary specific (e.g. hepatopulmonary syndrome) or
manifestations, for example ciliopathy, in nonspecific mechanisms (e.g.
which ciliary disease can cause pulmonary oedema secondary to renal
combinations of upper and lower or cardiac failure), or by causing
respiratory disease, complex congenital dysfunction in an another
heart disease, retinitis pigmentosa, and organ.
renal, hepatic and pancreatic cystic N Lung disease or its treatment may affect
disease. Only those diseases not covered another organ and dysfunction of that
elsewhere in this Handbook will be organ may create a positive feedback
discussed in this section. loop, worsening lung disease. An obvious
example is OSA leading to congestive
cardiac failure and secondary pulmonary
Key points
oedema.
N Although individual rare diseases are,
N The treatment of a systemic disorder may
affect the lungs (e.g. chemotherapy with
by definition, rare, taken together,
bleomycin leading to pulmonary fibrosis).
they are sufficiently common that they
need to be considered in paediatric
N Finally, apparent associations that are in
fact artefacts of receiving medical
respiratory differential diagnosis.
attention for another condition must not
N Respiratory paediatricians need to be be confused with real connections
aware that multisystem diseases may between diseases.
present with respiratory signs and
symptoms. This section will give a brief overview of the
lung manifestations of liver, kidney and
N Respiratory paediatricians also need
heart disease; haemoglobinopathy,
to be ready to advise specialists in
excluding sickle cell disease, which is
other fields, especially cardiology,
discussed elsewhere; connective tissue
nephrology and hepatology, about
disorders (both acquired inflammatory (e.g.
respiratory complications of their
systemic lupus erythematosus (SLE)) and
disease specialities.
inherited (e.g. EhlersDanlos syndrome)),
N Ciliary dysfunction, far from being a metabolic diseases and miscellaneous
purely respiratory issue, affects disorders (e.g. familial dysautonomia and
multiple organs. The basic science lymphangiomatosis). Pulmonary
and clinical aspects of ciliopathy are a manifestations of congenital and acquired
huge growth area. immunodeficiencies are discussed
elsewhere.

Table 1. Diseases affecting the liver and lung
Disease Liver manifestations Lung manifestations
CF Fatty liver Chronic infection and
Biliary cirrhosis inflammation
Portal hypertension Pneumothorax
Gall stones Haemoptysis
aspergillosis
a1-antitrypsin deficiency Cirrhosis Bronchiectasis and
emphysema
Ciliopathy Biliary atresia Recurrent infections
Cystic liver disease Bronchiectasis
Chest wall deformity (Jeunes
and other syndromes)
TB Granulomas Granulomas
Fibrosis
Bronchiectasis
Lymphadenopathy
Pleural effusion
Sarcoidosis Hepatosplenomegaly Granulomas
Lymphadenopathy
Pulmonary fibrosis
Gaucher disease Hepatosplenomegaly Pulmonary infiltration with
Gaucher cells
Mucopolysaccharidoses Hepatosplenomegaly Upper airway obstruction
Skeletal malformations leading
to extrapulmonary restrictive
lung disease
NiemannPick disease Hepatosplenomegaly Pulmonary infiltrates
Extensive bronchial casts
Lung manifestations of liver disease ventilation/perfusion mismatch and,

possibly, the creation of a functional
Diseases affecting the liver and the lungs The diffusion barrier; it must be distinguished
more important of these are summarised in from hypoxia as a nonspecific complication
table 1. of liver disease due to ascites, pulmonary
Effects of liver dysfunction on the lung The oedema or pleural effusion. Pulmonary
definition of hepatopulmonary syndrome angiogenesis may also be a feature.
(HPS) in children is the presence of: Prevalence is reported as up to 35% in
cirrhotic children but the syndrome may be
N liver disease; seen even with relatively mild disease. There
N hypoxaemia (alveolararterial oxygen will be signs of liver disease, especially
tension gradient .15 mmHg or PaO2 spider naevi, and platypnoea (worsening
,80 mmHg while breathing room air); hypoxaemia ongoing from the supine to the
N evidence of intrapulmonary shunting; and erect position). Digital clubbing is common.
N no other cause of hypoxaemia. Spirometry and lung volumes are usually
normal, with reduced diffusion capacity; in
HPS is manifest by profound hypoxaemia severe disease, restrictive physiology may be
due to intrapulmonary right-to-left shunting, seen. Cases have been described in

association with noncirrhotic portal Hepatocellular failure may lead to ascites
hypertension and otherwise uncomplicated and, in theory, large volumes of intra-
viral hepatitis. The pathophysiology is not abdominal fluid may splint the diaphragm
known but the physiological abnormality is causing respiratory impairment. In fact, old
usually due to dilatation of pulmonary studies looking at lung function before and
capillaries; occasionally, the syndrome after tapping even huge volumes of ascites
arises as a result of the development of (a practice now known to be dangerous)
anastomoses between pulmonary and showed remarkably little change in lung
systemic veins, in the portal or function. However, if there are
paraoesophageal regions. This syndrome discontinuities in the diaphragm, pleural
should be remembered in children with effusions may result. Hepatorenal syndrome
diseases affecting liver and lung (e.g. CF) if is a serious consequence of advanced
there is hypoxaemia disproportionate to the ascites, due to systemic and splanchnic
apparent severity of the lung disease. The vasodilatation, and renal vasoconstriction,
abnormal shunting may be detected by leading to multiorgan (including lung)
contrast echocardiography (peripheral failure. There are two types of HPS. Type 1
injection of saline containing microbubbles, presents as acute renal failure, type 2 as
which rapidly appear in the left atrium); a reduced glomerular filtration rate and
perfusion scan, which will show refractory ascites. Pulmonary oedema may
accumulation of technetium that has be exacerbated by hypoalbuminaemia and
bypassed the lungs in the brain and kidneys, cirrhotic cardiomyopathy, the latter of which
and can be used to quantify shunt; and is characterised by diastolic dysfunction.
contrast HRCT. Technetium scanning may Treatment of these serious complications
be the most sensitive test. Contrast should be in a specialist liver unit. Another
echocardiography may be positive even in indirect mechanism of lung disease is
nonhypoxaemic liver disease, suggesting pulmonary compression by a hugely
that subclinical HPS is common. Treatment involved liver and spleen; partial and total
is of the underlying liver disease, if this is excision of a huge spleen has been reported
susceptible to medical management, which in CF with at least transient benefit. Finally,
may resolve HPS. Nonspecific measures there may be dilation of bronchial veins in
include supplemental oxygen but the child is children with portal hypertension, similar to
likely eventually to undergo liver oesophageal varices. If there is haemoptysis
transplantation due to rapidly progressive as well as haematemesis complicating
hypoxaemia. Hypoxaemia related to portal hypertension, bronchial embolisation
pulmonary angiogenesis (see earlier) may may be considered as well as variceal
not respond to liver transplantation. The banding.
rare cases with large shunts may benefit
Lung manifestations of kidney disease
from coil embolisation. Medical
management is anecdotal; for example, case Diseases affecting the kidney and the lungs
series of the use of methylene blue and The more important of these are
antibiotics. Untreated the prognosis is poor summarised in table 2.
(23% 5-year survival versus 69% in patients
matched for severity of liver disease but Effects of renal dysfunction on the lung
without HPS). Pulmonary oedema and pleural effusion are
the most common pulmonary
Pulmonary hypertension is covered in more manifestations of renal disease. Uraemic
detail in the section on Pulmonary vascular lung, manifested by pulmonary oedema, is
diseases; it is far less common than HPS and, multifactorial in origin and is not a simple
rarely, features of both may co-exist. transudate. Aetiological factors in a given
Presentation is as with primary pulmonary individual may include fluid overload,
hypertension. The reasons why some patients hypoproteinaemia, myocardial dysfunction
develop HPS while others develop severe and increased pulmonary capillary
pulmonary hypertension are not known. permeability. Pleural effusion is also

Table 2. Diseases affecting the kidney and lung
Disease Kidney manifestations Lung manifestations
CF Acute and chronic renal failure Chronic infection and
Renal stones inflammation
Renal amyloid Pneumothorax
Haemoptysis
aspergillosis
Ciliopathy Cystic kidney disease Recurrent infections
Nephronophthisis Bronchiectasis
Renal dysplasia Chest wall deformity (Jeunes
Wilms tumour Renal mass Pulmonary metastases
Pulmonary embolism
Tuberose sclerosis Angiolipoma Lymphangioleiomyomatosis
Renal cystic disease
Renal carcinoma
Goodpastures syndrome Glomerulonephritis Pulmonary haemorrhage
Renal failure
Granulomatosis with Glomerulonephritis Pulmonary haemorrhage
polyangiitis (Wegeners) Renal failure (Upper airway disease)
SLE Glomerulonephritis Interstitial lung disease
Renal failure Pleuritis and pleural effusion
Acute pneumonitis
Pulmonary haemorrhage and
increased risk of infection
HenochSchonlein purpura Glomerulonephritis Pulmonary haemorrhage
Renal failure
Scleroderma Renal failure Pulmonary fibrosis
Aspiration
Pulmonary vasculopathy and
pulmonary hypertension
Glomerulonephritis Nephrotic syndrome Pulmonary embolism
(especially membranous)
Potters syndrome Renal agenesis Pulmonary hypoplasia
multifactorial, including fluid overload and index of suspicion should be maintained

uraemic pleuritis. because presentation may be atypical.
Other indirect effects include opportunistic Side-effects of medications used to treat
infection secondary to immune suppression, renal disease may affect the lung, including
urinothorax secondary to obstructive iatrogenic immunosuppression, the
uropathy, respiratory muscle dysfunction, consequences of plasmapheresis, and
and dystrophic calcification secondary to medications used to treat hypertension,
chronic acidosis and abnormal calcium and including angiotensin-converting enzyme
phosphate homeostasis. Calcification is (ACE) inhibitors causing chronic cough.
frequently an asymptomatic finding.
Immunosuppression leads to a higher than Haemodialysis complications include the
expected prevalence of TB, for which a high potential for silicone emboli and activation

of the complement cascade and other Primary respiratory disease may have a
immunological issues of dialysis cardiovascular presentation; for example,
membranes causing hypoxaemia. apparent dilated cardiomyopathy may be a
Hypoventilation secondary to carbon dioxide presentation of OSA, and primary pulmonary
loss across the dialysis membrane may hypertension with a normal chest radiograph
contribute to hypoxaemia. Peritoneal may be the presentation of OSA, interstitial
dialysis may cause pleural effusions if there lung disease and pulmonary embolism.
are diaphragmatic defects. The volumes of
fluid used for peritoneal dialysis have little The child in a paediatric intensive care unit
acute effect on lung function. (PICU) after cardiac surgery presents
particular challenges to the paediatric
Lung manifestations of cardiac disease pulmonologist. Respiratory failure and acute
respiratory distress syndrome (ARDS) are
Respiratory paediatricians inevitably interact well-described complications of
with paediatric cardiologists and, often, the cardiopulmonary bypass, and activation of
debate is whether respiratory issues are complement and other immunological
primary or secondary to heart disease. In my cascades by the membrane oxygenator is
experience, the clinical scenario the child thought to be responsible. Ventilator-
has a respiratory problem and its not the acquired pneumonia is an important
heart is usually resolved when it is complication of especially prolonged
discovered that it is the heart. ventilation and must be distinguished from
Diseases affecting the heart and the lungs The other causes of new infiltrates, such as
more important of these are summarised in atelectasis and pulmonary oedema. Another
table 3. common referral is the ventilated child who
weans to minimal support but then fails
Effects of cardiac dysfunction on the lung extubation. Significant pulmonary
Respiratory diseases may be the first parenchymal disease is excluded by a low
presentation of an underlying cardiovascular oxygen requirement. The differential
abnormality. Steroid-resistant asthma may diagnosis lies between upper airway
be the presentation of a vascular ring or obstruction (usually subglottic stenosis or
pulmonary artery sling; the latter may also vocal cord paralysis secondary to recurrent
be associated with complete cartilage rings, laryngeal nerve damage) and respiratory
complicating assessment. Diagnosis of muscle disease (usually due to phrenic
vascular compression is with contrast- nerve damage, occasionally an intensive
enhanced CT or MRI. Exercise-induced care unit myopathy). If upper airway
asthma in young adults who have had obstruction is suspected, bronchoscopy
ligation of the arterial duct as part of the should be performed with the child being
management of lung disease of prematurity extubated for the purpose, under a formal
may, in fact, be a late complication of general anaesthetic. Another common
recurrent laryngeal nerve damage. The referral is a unilateral, post-cardiac surgical
breathless child may have pulmonary whiteout. Fluid (pleural effusion, chylothorax
oedema secondary to a hitherto or haemothorax) is excluded with thoracic
unsuspected congenital cardiac lesion ultrasound. The differential diagnosis then
(pulmonary venous hypertension or high lies between extrinsic compression of the
pulmonary blood flow due to left-to-right airway by an enlarged cardiac chamber,
shunting), or a congenital or acquired surgically placed shunt or great vessel,
cardiomyopathy. Enlarged cardiac chambers airway malacia (which is relatively common
secondary to these conditions may cause in cardiac patients), and airway plugging by
airway compression and localised mucus or a blood clot. A particularly difficult
atelectasis or pneumonia. Recurrent issue to deal with is the airway compression
multifocal consolidation may be the by the hugely enlarged pulmonary arteries
presentation of increased pulmonary blood seen in absent pulmonary valve syndrome,
flow due to left-to-right shunts. usually associated with tetralogy of Fallot.

Table 3. Diseases affecting the heart and lung
Disease Cardiac manifestations Lung manifestations
Down syndrome Congenital heart disease Gastro-oesophageal reflux
Incoordinate swallowing
OSA
VATER, VACTER, and Congenital heart disease, Tracheo-oesophageal fistula
VACTERL syndromes especially ventricular and atrial Vertebral abnormalities
septal defects leading to scoliosis
Tetralogy of Fallot
Williams and Noonans Aortic and pulmonary stenosis Pulmonary lymphangiectasia
syndromes Cardiomyopathy Chest wall deformity
Ciliopathy Complex congenital heart Recurrent infections
disease, especially with Bronchiectasis
heterotaxic syndromes Chest wall deformity (Jeunes
TB Pericardial effusion Ghon focus
Constrictive pericarditis Pleural effusion
Lung cavities and fibrosis
Sarcoidosis Cardiomyopathy Lung granulomas
Arrhythmia Pulmonary fibrosis
Neurological disease Cardiomyopathy Inspiratory and expiratory
muscle dysfunction
Incoordinate swallowing
Upper airway obstruction
CF Impaired function and Chronic infection and
tamponade due to air leaks inflammation
Pneumothorax
Haemoptysis
aspergillosis
Mucopolysaccharidoses Cardiomyopathy Upper airway obstruction
Restrictive lung disease
Chest wall deformity
Recurrent respiratory
infections
SLE Myocarditis Interstitial lung disease
Pericarditis Pleuritis and pleural effusion
Endocarditis Acute pneumonitis
Pulmonary haemorrhage
Increased risk of infection
Scleroderma Cardiomyopathy Pulmonary fibrosis
Aspiration
Pulmonary vasculopathy
Pulmonary hypertension
VATER: vertebral anomalies, anal atresia, tracheo-oesophageal fistula, renal and/or radial anomalies; VACTER:
vertebral anomalies, anal atresia, cardiovascular anomalies, tracheo-oesophageal fistula, renal and/or radial
anomalies; VACTERL: vertebral anomalies, anal atresia, cardiovascular anomalies, tracheo-oesophageal
fistula, renal and/or radial anomalies, and limb defects.

Very rarely, a pneumonia involving all lobes gastro-oesophageal reflux disease and CF,
of the lung is the cause of a complete which are discussed in detail elsewhere.
whiteout; in such cases, the child is
obviously septic. Inflammatory bowel disease Pulmonary
manifestations are rare. In ulcerative colitis,
Other post-surgical respiratory the commonest parenchymal problem is
complications include tracheal infarction bronchiolitis obliterans organising
secondary to unifocalisation procedures, pneumonia (BOOP). Other manifestations
and superior caval vein thrombosis leading include pulmonary fibrosis and pulmonary
to secondary pulmonary lymphangiectasia interstitial pneumonia. Pulmonary nodules
and chylothorax. An intriguing late and pleural disease are rare. Airway disease,
complication of the Fontan procedure is including bronchiectasis and chronic airway
hypoxaemia due to microscopic pulmonary sepsis, are reported and pulmonary
arteriovenous malformation, analogous to complications can occur after
HPS (see earlier). Exclusion of hepatic blood panproctocolectomy for ulcerative colitis.
flow from the affected areas of the lung may Laryngeal and tracheal granulomatous
be the cause and revision surgery may lesions have been rarely reported. Other
relieve hypoxaemia. issues are a thrombotic tendency leading to
pulmonary embolism and the iatrogenic
Among the most feared and difficult-to-treat complications of corticosteroids and other
late pulmonary complications of cardiac immunosuppressants used for treatment.
disease is type 2 plastic bronchitis, usually
seen in association with low-flow circuits Acute pancreatitis ARDS and respiratory
such as after the Fontan procedure. The failure are well-described complications of
child expectorates branching, mucoid this condition.
bronchial casts, which may be so large as to
be life-threatening. Treatments include Coeliac disease There are case reports of co-
nebulised fibrinolytics, macrolides and existence of coeliac disease and idiopathic
lymphatic duct ligation. In extreme, pulmonary haemosiderosis (Lane-Hamilton
treatment-refractory cases, heart syndrome). There may also be an increased
transplantation may be indicated. susceptibility to TB in coeliac disease
patients, possibly related to
Medical cardiac treatments may also affect immunodeficiency secondary to
the lungs; for example, ACE inhibitors cause malabsorption.
chronic cough. Finally, chemotherapy and
mediastinal radiotherapy for malignant Lung manifestations of
disease may have cardiac and respiratory haemoglobinopathies
repercussions. Sickle cell disease (SCD) is the best studied
Pulmonary embolism is dealt with in more haemoglobinopathy, which has a number of
detail in the section on Pulmonary vascular acute and chronic complications. These are
disorders. Predisposing factors in the discussed in the section on Sickle cell
context of cardiac disease include the disease and, therefore, are not detailed here.
placement of intravascular catheters, low Other haemoglobinopathies The chronic
cardiac output, left atrial dilatation, main pulmonary consequences are related
arrhythmia, right-sided endocarditis to iatrogenic iron overload, which may affect
secondary to valve disease and immobility. the liver, kidneys and endocrine systems,
Eisenmengers syndrome is associated both with renal and hepatic consequences having
with coagulopathy and a bleeding diathesis. indirect effects on the lungs. Direct
Lung manifestations of gastrointestinal pulmonary effects are less studied, although
disease pulmonary iron deposition has been
documented. Other findings include
The most common causes of lung and restrictive lung disease suggestive of either
gastrointestinal disease are or both of pulmonary fibrosis and interstitial

pulmonary oedema, abnormal lung pulmonary effects may arise from renal and
mechanics and haemosiderin-laden cardiac disease and coagulopathy, including
macrophages in bronchoalveolar lavage pulmonary embolism. Pulmonary
(BAL) fluid. Pulmonary hypertension may hypertension may be asymptomatic until
also occur. late on and has an ominous prognosis. Lung
function testing usually shows a restrictive
Lung manifestations of inherited pattern. Airway disease is rare in SLE.
connective tissue disorders
Dermatomyositis Respiratory problems are
EhlersDanlos syndrome is a heterogeneous usually secondary to muscle dysfunction.
group of conditions, characterised by skin Oropharyngeal muscle problems may lead
hyperextensibility and tissue fragility, and to incoordinate swallowing and recurrent
joint hypermobility. It is inherited as an aspiration. Inspiratory and expiratory muscle
autosomal dominant mutation. Pulmonary weakness may lead to respiratory failure
manifestations are seen in types IV and VI, initially during sleep, and a weak cough and
and include emphysema, bullae and recurrent infections respectively. Direct lung
pneumothorax, tracheobronchomegaly and involvement is rare in children but may
haemoptysis. include vasculitis and pulmonary alveolar
Marfans syndrome is autosomal dominant proteinosis.
with an incidence of one in 5000. It is Scleroderma Lung involvement is present in
caused by mutations in the FBN1 gene, the majority (90%) of children afflicted by
which encodes fibrillin, an important this very rare disease and is the leading
structural molecule, which also is pivotal in cause of death. Manifestations include
the control of transforming growth factor pulmonary fibrosis, aspiration secondary to
(TGF)-b signalling. Systemic features of oesophageal problems and pulmonary
Marfans syndrome include aortic root vasculopathy leading to pulmonary
dilatation and aneurysm, mitral valve hypertension.
prolapse, joint hypermotility, and a high-
arched palate. The respiratory Granulomatosis with polyangiitis (Wegeners)
manifestations, which are usually a minor and other pulmonary vasculitides A
feature of the condition, include scoliosis, classification of systemic vasculitides
pectus excavatum and carinatum, and affecting the lung is given in table 4.
pneumothorax. Bronchiectasis, Pulmonary involvement in vasculitides is
tracheobronchomegaly and histological common in granulomatosis with
changes of distal acinar emphysema have polyangiitis and Kawasaki disease, and less
been reported. common in ChurgStrauss syndrome,
polyarteritis nodosa, HenochSchonlein
Lung manifestations of acquired purpura and Takayasus arteritis. Vasculitis
inflammatory connective tissue disorders may be complicate connective tissue
These are rare in childhood and, in most disorders such as dermatomyositis (see
cases, do not affect the lungs. Space earlier) and Behcets disease.
precludes describing many rarer entities. Manifestations depend on the size of the
vessels involved: medium-to-large artery
Systemic lupus erythematosus Pulmonary involvement leads to pulmonary infarction
manifestations may be the presenting and necrosis, sometimes with granulomas;
feature in children and eventually occur in small-vessel arteritis causes pulmonary
2040%. These include pleuritis and pleural haemorrhage. There may be clues as to the
effusion (the commonest manifestation), underlying aetiology from systemic features,
interstitial lung disease, acute lupus such as upper airway and renal disease in
pneumonitis that may progress rapidly to granulomatosis with polyangiitis, and the
respiratory failure, pulmonary haemorrhage, typical oropharyngeal appearances and
and increased risk of infection, including lymphadenopathy in Kawasaki disease. A
Pneumocystis jirovecii pneumonia. Indirect positive cytoplasmic anti-neutrophil

cytoplasmic antibody (c-ANCA) test is as a result of mutations in lysosomal
reasonably specific for granulomatosis with enzyme genes. Respiratory issues include
polyangiitis; perinuclear anti-neutrophil upper airway obstruction leading to sleep
cytoplasmic antibody (p-ANCA) elevation is disordered breathing (especially in Hurler
also seen in other vasculitides. Pulmonary syndrome) and restrictive lung disease. This
vasculitis enters the differential diagnosis of is multifactorial, is especially seen in Hunter
pulmonary haemosiderosis and should be and Hurler syndromes, and includes
excluded by lung biopsy if necessary deposition of GAGs in the lung and
because this may affect treatment decisions, skeletal deformity, indirectly via
for example the use of pulsed hepatosplenomegaly. The child may have
cyclophosphamide. recurrent respiratory infections. Indirect
pulmonary effects may also arise from the
Lung manifestations of storage disorders effects of cardiomyopathy. Finally, instability
Gaucher disease is an autosomal recessive of the odontoid process, which may cause
condition characterised by accumulation of fatal cord compression, should be
glucosylceramide in macrophages. Type 1 remembered, especially in type IV
commonly presents in childhood. Clinical (Morquios syndrome).
lung disease is unusual, being seen in NiemannPick disease There are at least six
,10% of cases (usually those presenting forms, all of which may show pulmonary
early with severe systemic disease), but infiltrates, but especially type B (the visceral
subclinical respiratory issues may be form). The first presentation may be with
present in 70%. These include both airway interstitial lung disease. Other direct
obstruction and restrictive lung disease. pulmonary manifestations include recurrent
Respiratory problems may be due to infection and haemoptysis. There may be
infiltration of the interstitium and alveolar extensive bronchial casts. There is a
spaces by Gaucher cells, or indirectly as a restrictive pattern of lung disease, and
consequence of lung compression by progressive respiratory failure. Liver and
massive hepatosplenomegaly, or the neurological involvement may also impact
consequences of liver disease, including lung disease.
HPS (see earlier). Types 2 and 3 are
dominated by neurological disease, which Lung manifestations of miscellaneous
may also lead to secondary lung disorders
complications. Treatment is with enzyme
therapy (which, however, will not reverse Familial dysautonomia (RileyDay syndrome),
neurological disease) or bone marrow an autosomal recessive disorder, is mainly
transplantation. found in Ashkenazi Jews, and is
characterised by progressive autonomic
Mucopolysaccharidoses At least nine forms dysfunction and crises. The most common
are known, characterised by abnormal tissue respiratory manifestations include
deposition of glycosaminoglycans (GAGs) aspiration leading to recurrent pneumonia
Table 4. Systemic vasculitides that may affect the lung

Predominant large vessel vasculitis: Takayasus arteritis
Predominant medium vessel vasculitis: Kawasaki disease, childhood polyarteritis nodosa,
cutaneous polyarteritis
Predominantly small vessel arteritis
Granulomatous: granulomatosis with polyangiitis (Wegeners), ChurgStrauss syndrome
Nongranulomatous: HenochSchonlein purpura, microscopic polyangiitis, Goodpastures
syndrome
Others: Behcets disease, associated with connective tissue disease

and bronchiectasis, and nocturnal N Caboot JB, et al. (2008). Pulmonary
hypoventilation. Respiratory disease is the complications of sickle cell disease in
major cause of morbidity. children. Curr Op Pediatr; 20: 279
287.
Lymphangiomatosis is rare and N Cerda J, et al. (2007). Flexible fiberoptic
characterised by abnormal proliferation of bronchoscopy in children with heart
lymphatics affecting the lung, mediastinum, diseases: a twelve years experience.
liver, soft tissue, bones and spleen. 80% of Pediatr Pulmonol; 42: 319324.
cases have lung involvement, manifested by N Christopoulos AI, et al. (2009). Risk
chylous effusions, interlobular septal factors for tuberculosis in dialysis
thickening and thickened pleura. Bony patients: a prospective multi-center clin-
infiltration and rib fractures can worsen ical trial. BMC Nephrol; 7: 36.
N Cooper DS, et al. (2008). Pulmonary
respiratory status. Typically, fractures fail to
complications associated with the treat-
heal. Prognosis is poor, and death usual ment of patients with congenital cardiac
from extensive pulmonary and systemic disease: consensus definitions from
disease. Successful treatment with the multi-societal database committee
interferon-a2b has been reported. for pediatric and congenital heart dis-
ease. Cardiol Young; 18: Suppl. 2, 215
Yellow nail syndrome (YNS) This condition 221.
is characterised by nail dystrophy, and N Dinwiddie R, et al. (2005). Systemic
combinations of (nonpitting) lymphoedema diseases and the lung. Paediatr Respir
and bronchiectasis, sometimes with chronic Rev; 6: 181189.
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protein pleural effusion. Lung cysts have complications of liver disease. Am J Respir
been described in YNS. The underlying Crit Care Med; 187: 133143.
cause is thought to be structural or N Gold-von Simson G, et al. (2006).
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Presentation is mainly, but not exclusively, recent advances. Curr Probl Pediatr
in adult life. The diagnosis is clinical. Adolesc Health Care; 36: 218237.
N Grace JA, et al. (2013). Hepatopulomary
Autosomal dominant cases have been
syndrome: update on recent advances in
reported, although most are sporadic. There
pathophysiology, investigation and treat-
is no specific treatment for YNS, although ment. J Gastroenterol Hepatol; 28: 213
anecdotally, some improvement with 219.
vitamin E therapy has been reported. N Gulhan B, et al. (2012). Different features
Management of bronchiectasis is as for the of lung involvement in NiemannPick
idiopathic condition. Recurrent troublesome disease and Gaucher disease. Respir Med;
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for improvement over time, although overall cations of congenital heart disease.
survival is decreased. Although a number of Paediatr Respir Rev; 13: 1015.
rare associations with YNS have been N Lee T, et al. (2001). Systemic lupus
erythematosus and antiphospholipid syn-
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malignancy, connective tissue disease and
Opin Rheumatol; 13: 415421.
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spurious in many cases. tions of gastrointestinal disease. Paediatr
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tis: new insights and a classification
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N Miller AC, et al. (2012). Pulmonary N Sari S, et al. (2012). Hepatopulmonary
complications of sickle cell disease. Am syndrome in children with cirrhotic and
J Respir Crit Care Med; 185: 11541165. non-cirrhotic portal hypertension: a
N Milliner DS, et al. (1990). Soft tissue single-center experience. Dig Des Sci; 57:
calcification in pediatric patients with end- 175181.
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N OSullivan PP (2012). Pulmonary compli- systemic or localised forms. Pediatr Clin
cations of systemic vasculitides. Paediatr North Am; 59: 381405.
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N Rabinovitch CE (2012). Pulmonary com- tions of renal disease. Paediatr Respir Rev;
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N Rodriguez-Roisin R, et al. (2004). renal syndrome in childhood: a report of
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(PHD). Eur Respir J; 24: 861880. literature. Pediatr Pulmonol; 29: 382388.

Lung transplantation and
management of post-lung
transplant patients
Paul Robinson and Paul Aurora
N Lung transplantation is now a well-

established treatment for children with Key points
end-stage lung disease, with .120
paediatric lung transplantations now N Short- and long-term outcomes have
performed worldwide each year, across improved but still lag behind other
4050 centres (Benden et al., 2012). solid-organ transplant groups.
N The majority of centres (.80%) perform Chronic graft rejection remains a
fewer than five transplantations a year, significant barrier to further
improvements in survival.
with only two or three centres performing
.10 procedures each year . N Donor organ shortage remains a
N Infant lung transplantation has been critical issue. Given this limited
established at centres in North America resource, optimal timing of
but this remains a small proportion of transplantation is both essential and
total paediatric transplantations (only challenging, especially in conditions
eight performed in 2010). where survival can be difficult to
N Procedures performed have changed: predict.
bilateral single sequential lung N A lifelong regimen of triple
transplantation now is preferred to immunosuppression is used,
heartlung transplantation, with the consisting of a CNI, a cell cycle
latter reserved mainly for cases with inhibitor (or antimetabolite) and a
significant left heart dysfunction (e.g. corticosteroid. Important drug
idiopathic pulmonary arterial interactions exist with CNIs which the
hypertension (IPAH) and congenital physician must be aware of.
heart disease).
N Single-lung transplantation is rarely N Post-transplantation management
performed in the paediatric age range, focuses on ongoing rehabilitation,
mainly reflecting its contraindication in careful surveillance, and treatment of
suppurative lung disease, such as CF. acute and chronic complications,
including infection and graft rejection.
Indications for lung transplantation
The most common indication for lung

transplantation in the paediatric age range
Selection for lung transplantation
is CF, although the indications are age
dependent (table 1). CF is the most Current international guidelines for referral
common indication from school age, and selection of lung transplant recipients
whereas in younger children, other (Orens et al., 2006) are based upon limited
pathologies such as IPAH, congenital heart paediatric data and the decision to list a
disease, idiopathic pulmonary fibrosis and child for lung transplant is often based on a
surfactant protein dysfunction are the multidisciplinary team consensus within the
indications. individual centre. Potential survival and

Table 1. Common indications for lung transplantation N No specific contraindications (table 2).
by age group Relative contraindications are assessed
on a case-by-case basis.
Indication Cases %
N An acceptable psychological profile.
Infancy (age ,1 year) N Fully informed commitment by the child
Surfactant protein B deficiency 18 and family. This includes good social
support to aid rehabilitation following
Congenital heart disease 15
transplantation surgery and a
IPAH 13 commitment to the procedure involved,
Preschool (age 15 years) the required lifestyle adjustments and
IPAH 23 strict adherence to the medication
regimen.
Idiopathic pulmonary fibrosis 18
Bronchiolitis obliterans 8 Life expectancy criteria also account for the
Early school age (611 years) probable waiting period for a suitable organ
to become available and may vary
CF 54 depending on the centre. Existing survival
IPAH 10 prediction models for CF are only
Bronchiolitis obliterans 7 estimations and have limitations: changing
CF survival rates over time, lack of
Adolescence (1217 years)
paediatric-specific validation and lack of
CF 72 validation in children being assessed for
IPAH 7 transplantation. The referral criterion of
Bronchiolitis obliterans 4 FEV1 ,30% predicted is widely quoted but
important exceptions, where referral should
Data from Benden et al. (2012). be considered at higher FEV1 due to an
increased risk of accelerated future decline,
exist:
quality of life (QoL) benefits are offset
against an individuals risk of perioperative N females;
mortality and both short- and long-term N very young patients;
complications of transplantation. Early N subjects declining quickly;
referral is preferable, as late referral N subjects with a history of massive
potentially affects not only the ability of the haemoptysis, pneumothorax or
family to make a carefully considered increasing acute exacerbation frequency.
decision about whether they want a
transplant, but also because poor clinical Donor allocation
status may adversely affect suitability for
listing. Lung transplantation is indicated in N Standard donor criteria exist but have
children where lung function parameters been criticised for being too restrictive.
and QoL are declining despite maximal Only 2030% of lungs offered for
medical therapy (Aurora, 2004). Broad use in organ transplantation are
criteria for listing are as follows. usable.
N Marginal donors are considered but
N Predicted life expectancy, without only used with informed consent from the
transplantation, of f2 years. recipient and family.
N Poor QoL, which is likely to be improved N Organs procured from brain-dead
by transplantation. Assessment of QoL is donors, the use of non-heart beating
taken ideally from the childs perspective, donors (used in other solid-organ
and details their ability to complete daily transplant groups successfully) and ex
routine activities, participate in school vivo lung perfusion attempt to address
and social activities, and the time spent this imbalance, with encouraging results
in hospital. (Cypel et al., 2012).

Table 2. Specific contraindications to lung transplantation in children
Absolute Relative
Active malignancy Pan-resistant bacterial infection
Active TB Nontuberculous mycobacterial infection
Major psychiatric illness Other organ failure
Hepatic, renal and left ventricular failure# HIV infection
Irreversible and significant respiratory muscle Nonadherence to treatment
dysfunction Invasive ventilation
Long-term high-dose steroid therapy
Hepatitis B or C
Burkholderia cenocepacia (genomovar III)
Severe scoliosis or thoracic rib cage deformity
Severe tracheomegaly and/or tracheomalacia
Severe transpleural systemic to bronchial artery
collateral arteries
Contraindications vary between transplant centres and the referring physician should always check with their
own centre. #: multiorgan transplantation (e.g. lungliver, heartlung or lungkidney) may be considered in
this situation.
N Living-related lobar lung transplantation oxygenation, is controversial and not

has decreased in recent years, in part due universally adopted. Despite demonstrated
to the potential 300% mortality risk. feasibility in paediatric patients (Schmidt
N The lung allocation score (LAS) allocates et al., 2012), post-transplantation
organs to recipients based on calculated outcomes remain inferior. The projected
survival benefit but is not appropriate for timeframe of bridging until suitable donor
use in children due to a lack of paediatric organ availability is an unknown
data. Paediatric allocation is based upon factor.
donorrecipient blood group
compatibility, size matching and the The early post-transplant period is
current clinical conditions of individual characterised by establishment of effective
waiting list patients at that centre. immunosuppression (started immediately
prior to surgery), minimisation of infection
Management following referral risk, rehabilitation, and protection of both
Changes in clinical status during the pre- the newly implanted donor organ and other
transplant period may affect suitability, important organ systems.
necessitating regular review. Optimisation
A lifelong regimen of triple
of current management during the pre-
immunosuppression is used, consisting of
transplantation period is an essential
the following.
component of managing future
transplantation risk. This includes: N A calcineurin inhibitor (CNI), most
commonly Tacrolimus. CNIs act by
N maintaining good nutrition and bone
binding to calcineurin in the cytoplasm
density;
N optimising anti-infective and anti- and interfere with the transcription of
inflammatory therapies; important cytokine genes, thereby
N screening for and treatment of associated inhibiting T-cell stimulation. Tacrolimus
respiratory failure with NIV. is favoured over cyclosporin in paediatric
centres due to its more favourable side-
The use of more invasive bridging effect profile, aiding compliance (less
measures to transplantation, such as hirsuitism and gingivism, but a greater
ventilation and extracorporeal membrane incidence of diabetes).

N A cell cycle inhibitor (or antimetabolite), CMV-negative recipient) or medium risk
most commonly mycophenolate mofetil. (donor and recipient both CMV positive);
Cell cycle inhibitors inhibit the and valaciclovir in those at increased
proliferation of T- and B-cells by risk of herpes simplex virus (HSV)
interrupting DNA, RNA and purine re-activation.
synthesis. N Prophylaxis against Pneumocystis jirovecii:
N Corticosteroids: initially high-dose co-trimoxazole.
methylprednisolone, subsequently
weaned to oral prednisolone. Ventilation is weaned as rapidly as can be
tolerated, with extubation often occurring
Many centres further augment this with within the first 24 hours. Inotropic support
induction therapy at the time of may be brief, particularly if transplantation
transplantation, namely a monoclonal occurs on cardiopulmonary bypass. A
antibody such as basiliximab or daclizumab, relative hypovolaemia strategy protects the
which bind irreversibly to T-cell interleukin lung from ischaemiareperfusion injury and
(IL)-2 receptors. Increasing levels of pulmonary oedema.
immunosuppression must be balanced
against increased risk of severe infection or Primary graft failure:
later malignancy (e.g. EpsteinBarr virus
(EBV)-driven post-transplant
N occurs in ,10% and resembles the
clinical appearance of acute respiratory
lymphoproliferative disease (PTLD)).
distress syndrome (ARDS);
Anti-infective prophylaxis starts with N is a risk with marginal donors and longer
attempts to minimise bacterial load prior to graft ischaemia times (.6 h);
transplantation, and extends through N is managed supportively.
stringent surgical aseptic techniques and, in
some cases, thoracic cavity washout with In CF subjects, regular aperients (e.g.
weak antibiotic solutions prior to organ lactulose, N-acetylcysteine and magrocol)
implantation. Other aspects after lung and early introduction of enteral feeds are
transplantation include the following. used to prevent distal ileal obstruction
syndrome (DIOS), which may occur in 10%.
N Intravenous antibiotics based on the Physical mobilisation following chest drain
sensitivities of organisms present before removal aids respiratory secretion clearance
transplantation, especially in CF, are in conjunction with regular chest
given until the patient is mobilising and physiotherapy. The typical in-patient stay in
able to clear secretions. Nebulised uncomplicated cases is 64 weeks.
antibiotics are often continued for a
Ongoing management
prolonged period if the recipient lungs
are chronically infected with Pseudomonas Management focuses on ongoing
aeruginosa before transplantation, as it is rehabilitation, and surveillance for and
assumed that the sinuses will remain treatment of acute complications, including
chronically infected. infection and graft rejection, and education
N Antifungal prophylaxis in children with CF regarding transplant-orientated medication
and others in whom pre-transplantation and follow-up regimens.
fungal colonisation is suspected: oral
nystatin during the first 612 months; and N Careful surveillance and monitoring of
either oral itraconazole or voriconazole, both immunosuppression (using
or nebulised amphotericin for tacrolimus trough levels) and graft
o6 months. function (using daily home spirometry)
N Antiviral prophylaxis in patients at aims to maintain adequate
increased risk: prophylactic valganciclovir immunosuppression and protect the
in those at high risk for cytomegalovirus graft from both immune and nonimmune
(CMV) disease reactivation (transplant insults to prevent rejection (both cellular
from a CMV-positive donor to a and antibody-mediated).

N Bronchoscopy and transbronchial biopsy N Adopting a strict routine of drug timing,
is performed in almost all transplant administration and compliance is a key
recipients, across centres, at defined element to better outcomes.
surveillance points during the first year
following transplantation and additionally Graft rejection The clinical picture of early
as clinically indicated, based on acute rejection is nonspecific and may be
respiratory symptom monitoring and difficult to distinguish from infection. As a
daily home spirometry readings, with result, periods of coughing, malaise, low-
grade pyrexia or a minor drop in lung
drops of .10% triggering urgent clinical
function should be thoroughly evaluated (De
review.
Vito Dabbs et al., 2004).
N CNIs operate within a narrow therapeutic
window, which gradually shifts to lower N Chest radiography may be normal and
targeted trough levels during the first year does not distinguish the two pathologies.
before plateauing at a suitable level N Urgent flexible bronchoscopy,
dictated by the relative balance of bronchoalveolar lavage and
episodes of rejection, infection and CNI transbronchial biopsy are indicated.
side-effects.
N Minimising the risk of infection and other The presence and severity of rejection in
unwanted side-effects of biopsy specimens is classified on the
immunosuppressive therapy (in presence of perivascular and interstitial
particular renal dysfunction). mononuclear cell infiltrates in alveolar tissue
N Specific drug-related side-effects and (from grade A0, for no acute rejection, to
medication interactions must be grade A4, for severe rejection), with an
monitored for and considered (tables 3 additional classification for associated
and 4). airway inflammation (from B0, for no airway
Table 3. Common side-effects of maintenance immunosuppression

Drug Side-effect
Tacrolimus Nephrotoxicity
Tremor
Paraesthesia/hypersensitivity
Hypertension
Hypercholesterolaemia
Neurotoxicity
Diabetes mellitus
Alopecia
MMF Bone marrow suppression
Nausea, dyspepsia, diarrhoea, constipation
Hyperglycaemia
Hypercholesterolaemia
Prednisolone Cushings syndrome
Dyspepsia
Peptic ulceration
Osteoporosis
Proximal myopathy
Increased appetite
Neuropsychiatric effects
Glaucoma, papilloedema, cataracts
Skin atrophy, striae, bruising, acne
MMF: mycophenolate mofetil.

Table 4. Agents interacting with CNIs
CYP3A inhibitors (increase CNI levels) CYP3A inducers
(decrease CNI levels)
Antibiotics Antibiotics
Erythromycin Rifampicin
Clarithromycin Clindamycin
Chloramphenicol Ethambutol
Ciprofloxacin (rare) Antifungals
Antifungals Caspofungin
Itraconazole Antiepileptics
Fluconazole Phenytoin
Voriconazole Phenobarbitone
Imidazoles (e.g. ketoconazole) Carbamazepine
Triazoles (e.g. posaconazole) Others
Cardiovascular drugs Cigarette smoking
Amiodarone St Johns wort
Calcium channel blockers (e.g. verapamil, diltiazem, felodipine)
Nifedipine (rare)
Gastrointestinal
Cimetidine
Omeprazole (rare)
Other
Grapefruit juice
Antiretrovirals (e.g. atazanavir, nelfinavir and ritonavir)
Danazol
This is not intended to be an exhaustive list. CYP: cytochrome P450.
inflammation, to B4, for severe airway N Many centres use specific therapies like
inflammation). ribavirin for proven cases of lower
respiratory tract infection (LRTI) with
N The clinical relevance of A1 rejection is respiratory syncytial virus (RSV) and
unclear, although frequent A1 episodes paramyxoviruses (e.g. parainfluenza and
have been linked to a greater risk of human metapneumovirus).
chronic graft rejection in adults (Benden N The role of viral infections in acute and
et al., 2010; Hopkins et al., 2004). At chronic refection remains more
present, A1 is not usually treated. controversial (Vu et al., 2011; Liu et al.,
N More severe episodes (A2A4) are 2009), and is particularly relevant in
managed with a 3-day course of high- children given the increased frequency,
dose methylprednisolone (typically particularly in the infantpreschool age
10 mg?kg-1?day-1), though some centres range. Day-care is discouraged,
will occasionally treat A2 rejection with compliance with active immunisation is
oral corticosteroids. critical and prophylactic palivizumab may
N Steroid-resistant rejection is exceptionally be considered in infants.
rare, although true cases may require
second-line therapy such as polyclonal The histological diagnosis of chronic
anti-lymphocyte antibodies (anti- rejection (or bronchiolitis obliterans) is
thymocyte globulin). challenging due to the patchy distribution of
N The clinical relevance of airway disease; therefore, a clinical diagnosis based
inflammation and optimal method of on the pattern of lung function seen following
treatment remains unclear. transplantation has been developed, termed
N Patients with positive bacterial or fungal bronchiolitis obliterans syndrome (BOS)
cultures should be treated. (table 5) (Estenne et al., 2002).

Table 5. Grading of BOS
Grade Definition
BOS 0 FEV1 .90% of baseline and FEF2575% .75% of baseline
BOS 0-p FEV1 8190% of baseline and/or FEF2575% f75% of baseline
BOS 1 FEV1 6680% of baseline
BOS 2 FEV1 5165% of baseline
BOS 3 FEV1 f50% of baseline
Baseline lung function is defined as the average of the two highest values achieved after transplantation,
recorded o3 weeks apart. FEF2575%: forced expiratory flow at 2575% of FVC. Reproduced and modified from
Estenne et al. (2002) with permission from the publisher.
N BOS is defined by an irreversible fall in spirometry and CT data suggest the lungs
lung function when other causes have continue to grow with age (Cohen et al.,
been excluded, such as infection. 1999).
N Important potential contributing factors
Complications A variety of noninfectious
include gastro-oesophageal reflux disease
complications may be encountered
(GORD) or airway infection (e.g. RSV or
subsequent to lung transplantation
Pseudomonas), and should be treated
(table 6).
aggressively to reverse this dysfunction.
N GORD is common in transplant Early surgical complications, beyond the
recipients (Benden et al., 2005), and immediate post-transplantation period,
emerging data in adults appear to include:
support early surveillance and
fundoplication, although equivalent N bronchial anastomosis stenosis,
paediatric data are lacking. managed with balloon dilatation with or
N Low-dose macrolide therapy appears to without laser treatment (repeated as
be beneficial in those with neutrophilic necessary);
inflammation. N damage to the phrenic nerve affecting
N In general, advanced BOS is poorly diaphragmatic function;
responsive to therapy and interventions N damage to the vagus nerve causing
aim to stabilise and prevent ongoing lung delayed gastric emptying.
function decline. Other BOS therapeutic
options include leukotriene receptor Common later complications include the
antagonists, augmentation of following.
immunosuppression, total body
lymphoid irradiation or photopheresis.
N Hypertension, ,70% at 5 years; typically
managed with calcium channel blockers
N Retransplantation is offered in some
such as amlodipine.
centres but the risks are often increased
due to previous thoracotomy, making
N BOS, ,50% at 5 years.
explantation more challenging, and the N Diabetes mellitus, approximately one-
increased prevalence of other third at 5 years; corticosteroids and CNIs
complications such as renal dysfunction. are major risk factors.
N CNI-induced nephropathy, approximately
Graft monitoring by spirometry is one-third at 5 years; due to the prevalence
challenging in the preschool age range due of renal dysfunction in survivors,
to the cooperation and coordination exposure to other agents associated with
required. Modification of reported indices potential renal toxicity are minimised or
may be required (e.g. FEV0.75 rather than avoided (e.g. nonsteroidal anti-
FEV1). The use of age-appropriate reference inflammatory drugs (NSAIDs),
equations is essential, and longitudinal amphotericin and aminoglycosides).

Table 6. Common noninfectious complications after lung transplantation
Time Complication
Early Anastomotic dehiscence or stenosis
Pulmonary vein or artery stenosis
Nerve damage (phrenic or vagal nerve injury, loss of cough reflex,
swallowing difficulty)
Intermediate and late Malignancy (e.g. lymphoproliferative disease)
Nephrotoxicity
Hypertension
Hyperlipidaemia
Osteopenia and osteoporosis
Avascular necrosis of the femoral head
Growth failure
Diabetes mellitus
Hyperuricaemia/gout
Viral papillomatosis
Cytopaenias (anaemia, leukopaenia, thrombocytopaenia)
Thromboembolism
GORD
N Increased malignancy risk due to ongoing around the world. Long-term outcomes are
immunosuppression, with PTLD steadily improving for paediatric patients but
(typically EBV-driven B-cell expansion) have yet to reach those achieved by other
and skin cancers being the most relevant solid-organ transplants. There are many
to the paediatric population; advice about similarities in management between adult and
sunlight exposure is important. paediatric subjects but several differences
N CF children continue to be at risk of unique to the paediatric age range exist.
nonrespiratory complications of their Future work to improve the availability and
underlying disease (e.g. DIOS, allocation of suitable organs will hopefully see
malabsorption and bone disease). this therapeutic option offered to a greater
Long-term outcomes proportion of children who are eligible.
Median survival after lung transplantation is

Further reading
now ,5 years, and is identical in children and
adults. Better survival of recipients aged 1 N Aurora P (2004). When should children
11 years is seen compared with those aged 12 be referred for lung or heartlung trans-
17 years (Benden et al., 2012). The onset of plantation? Pediatr Pulmonol Suppl; 26:
puberty and adolescence brings with it several 116118.
challenges, including risk-taking behaviour N Benden C, et al. (2005). High prevalence of
and noncompliance, with adverse effects on gastroesophageal reflux in children after
post-transplantation outcomes. While there is lung transplantation. Pediatr Pulmonol; 40:
little evidence of how best to manage this, 6871.
most centres encourage adolescents to take N Benden C, et al. (2010). Minimal acute
increasing responsibility for their own care, rejection in pediatric lung transplantation
does it matter? Pediatr Transplant; 14:
maintain adherence to therapy, and develop
534539.
long-term goals and ambitions.
N Benden C, et al. (2012). The registry of the
Conclusion international society for heart and lung
transplantation: fifteenth pediatric lung
Lung transplantation is now an established, and heart-lung transplantation report-2012.
accepted treatment option for children with J Heart Lung Transplant; 31: 10871095.
end-stage lung disease at many centres

N Cohen AH, et al. (1999). Growth of lungs N Kirk R, et al. (2011). Fourteenth Pediatric
after transplantation in infants and in Heart Transplantation Report 2011. J
children younger than 3 years of age. Am J Heart Lung Transplant; 30: 10951103.
Respir Crit Care Med; 159: 17471751. N Liu M, et al. (2009). Respiratory viral infec-
N Cypel M, et al. (2012). Experience with the tions within one year after pediatric lung
first 50 ex vivo lung perfusions in clinical transplant. Transpl Infect Dis; 11: 304312.
transplantation. J Thorac Cardiovas Surg; N Orens JB, et al. (2006). International guide-
144: 12001207. lines for the selection of lung transplant
N De Vito Dabbs A, et al. (2004). Are candidates: 2006 update a consensus
symptom reports useful for differentiat- report from the Pulmonary Scientific
ing between acute rejection and pulmon- Council of the International Society for
ary infection after lung transplantation? Heart and Lung Transplantation. J Heart
Heart Lung; 33: 372380. Lung Transplant; 25: 745755.
N Estenne M, et al. (2002). Bronchiolitis N Schmidt F, et al. (2012). Concept of
obliterans syndrome 2001: an update of awake venovenous extracorporeal mem-
the diagnostic criteria. J Heart Lung brane oxygenation in pediatric patients
Transplant; 21: 297310. awaiting lung transplantation. Pediatr
N Hopkins PM, et al. (2004). Association of Transplant; 17: 224230.
minimal rejection in lung transplant N Vu DL, et al. (2011). Respiratory viruses in
recipients with obliterative bronchiolitis. lung transplant recipients: a critical
Am J Respir Crit Care Med; 170: 1022 review and pooled analysis of clinical
1026. studies. Am J Transplant; 11: 10711078.

Rehabilitation programmes
and nutritional management
Andreas Jung
Targets of rehabilitation programmes in

Key points childhood and adolescence
Rehabilitation programmes in children Pulmonary rehabilitation is defined as an
and adolescents with chronic respiratory evidence-based multidisciplinary and
disorders: comprehensive intervention for patients
with chronic respiratory diseases who are
N aim at preventing worsening of the symptomatic and often have decreased daily
disease, improving self-management life activities. Integrated into the
and restoring quality of life in order to individualised treatment of the patient,
enable full participation in daily life, pulmonary rehabilitation is designed to
including school, and social and reduce symptoms, optimise functional
physical activities, status, increase participation, and reduce
N consist of standardised health care costs through stabilising or
multidisciplinary interventions, reversing systemic manifestations of the
disease (Nici et al., 2006). Rehabilitation
N include diagnostic procedures, programmes in children and adolescents
specific medical care and nursing, target preventive measures, which aim to
nutritional and psychological stop the disease worsening, improve self-
counselling and educational management and restore quality of life. It is
interventions, anticipated that the child, or the adolescent,
N address a broad spectrum of chronic will be able to fully participate in daily life,
respiratory conditions and can such as school, social activities and sports,
contribute efficiently to a general in the same ways as their healthy peers.
improvement in morbidity and Today, rehabilitation programmes have been
mortality, in the context of a complex developed in many countries in inpatient
disease management. and outpatient settings. Inpatient
programmes are often more standardised
N Advanced lung disease results in than outpatient programmes, as the latter
increased energy expenditure, an are often tailored to meet local needs. In
augmented level of inflammation and addition, inpatient programmes provide the
diminished appetite, contributing to a possibility of individual, daily monitoring of
loss of body weight and requiring patients over several weeks in specific
specific nutritional management, institutions in order to optimise therapeutic
including counselling, installation of a interventions and complete diagnostic
daily nutrition plan, high-protein procedures that are beyond the possibilities
calorie supplementation and of an outpatient setting. Independent of the
substitution of vitamins and rehabilitation setting, objectives of current
micronutrients. rehabilitation programmes include a
number of specific considerations, as shown

in table 1. Rehabilitation centres and A multidisciplinary team closely follows each
sponsors of healthcare systems have patient or family during the whole
defined criteria for the eligibility of an interventional period. This approach
individual intending to participate in a facilitates an individual treatment in the
rehabilitation programme (table 2). If the context of an often group-based
criteria of the rehabilitation institution, the rehabilitation programme. As patients can
patient and their family are met, the most be monitored intensively over a longer
important preconditions for successful period of time, individual symptoms and
pulmonary rehabilitation are given. risk factors, as well as psychological aspects,
can be evaluated continuously and, as a
Elements of paediatric rehabilitation result, specific diagnostic procedures can be
programmes for respiratory diseases applied. In the same way, treatment
modifications can be carried out and the
Pulmonary rehabilitation programmes
subsequent course of the disease can be
consist of standardised, multidisciplinary
observed over time.
interventions performed by a range of highly
qualified health professionals. Depending Patient education: a core element of
on the disease spectrum and the severity rehabilitation programmes
addressed by rehabilitation centres,
potentially essential components include a Educational programmes are important
wide range of actions, such as diagnostic components of contemporary rehabilitation
procedures, specific medical care, programmes, featuring theoretical
educational interventions and a instructions accompanied by practical
multidisciplinary team approach (table 3). exercises. Knowledge is disseminated to
Standardised care may also include promote disease understanding, and
consultation of specific medical recognition of individual risk-factors and
professionals in case of multi-organ or coping strategies. Practical training is
psychiatric symptoms and diseases. In provided to improve medication application
inpatient programmes, children and skills and techniques. Written action plans
adolescents often participate in educational foster the adherence to the individual
preschool or school activities for the treatment strategy. As a result, compliance,
duration of the hospitalisation period. Some self-management and outcome of the
rehabilitation centres offer a family-oriented disease are often significantly increased.
intervention and treat parents and other Educational programmes for children and
family members together with their children. adolescents have been developed for various
diseases in many countries. In the
Table 1. Goals of pulmonary rehabilitation programmes respiratory field, the most wide-spread and
in children and adolescents best standardised protocols exist for
asthma. Asthma education programmes
Maintenance and restoration of social and have often been developed independently of
professional activities
pulmonary rehabilitation programmes and
Improvement of health condition are often performed in an outpatient setting.
Preventive measures of disease worsening Inpatient rehabilitation programmes have
or progression integrated sections or whole protocols of
Amendment of disease perception and
national or regional asthma education
management programmes, resulting in standardised en
bloc interventions.
Improvement of compliance
Restoration of quality of life Disease-specific rehabilitation programmes
Change of lifestyle A vast spectrum of chronic respiratory
conditions are addressed by paediatric
Reproduced from Jung et al. (2012) with
rehabilitation programmes, including
permission from the publisher.
asthma, CF, bronchopulmonary dysplasia,

Table 2. General criteria for children and adolescents to participate in rehabilitation programmes
Ability for rehabilitation is fulfilled: willingness to actively participate in the programme, capacity
to fulfil rehabilitation aims and ability to integrate into groups
Improvement of prognosis can be achieved: improvement of health and restoration of
professional and/or social activity
Measures of outpatient care are exhausted but not sufficient to adequately ameliorate health or
suspend health impairment
Secondary health damage is imminent or has already occurred
Psychosomatic or psychosocial problems are difficult to address in an outpatient setting
(demarcation from the social environment)
Interventions to promote coping and to adhere to treatment are necessary
Reproduced from Jung et al. (2012) with permission from the publisher.
primary ciliary dyskinesia, neuromuscular N increase a childs locus of control,

disorders, interstitial lung diseases, N improve self-efficacy and attitude to
cardiovascular diseases and pre- and post- disease,
lung transplantation. A recent joint N improve asthma-related behaviour and
statement of the American Thoracic Society pulmonary function measures,
and the European Respiratory Society on N improve metered-dose inhaler technique.
pulmonary rehabilitation highlights the huge
progress that has been made in evidence- Furthermore, asthma camps decrease
based support for pulmonary rehabilitation anxiety, symptoms, exacerbations, school
in the management of patients with chronic absences, emergency department visits and
respiratory disease, focusing on adults with hospitalisations. Although asthma camps
COPD. Similarly, there is a growing body of also exist in Europe, standardised inpatient
evidence that rehabilitation programmes for asthma rehabilitation programmes in
chronic respiratory diseases in the paediatric specialised hospitals are predominant.
population are efficient in terms of health Nevertheless, the literature on protocols and
improvement. Most published studies outcome of the intervention is relatively
investigated protocols and outcome in limited. Studies found significant
patients with asthma and CF, as these improvements in pulmonary function and
disorders constitute the majority of bronchial inflammation, as well as a
indications for pulmonary rehabilitation in decrease in days absent from school and in
the first two decades of life. In future, visits to a physician, supporting the
structured interventions before and after importance of multidisciplinary
lung transplantation will become more and rehabilitation programmes for disease
more important in light of a growing management and compliance modification.
number of patients on the transplantation Long-term effects following an inpatient
waiting list, as well as a rapidly increasing intervention in terms of better lung function
number of transplanted individuals. parameters, less asthma-related school
absence, and improved asthma
Asthma In the USA, asthma camps often management and quality of life compared to
focus on health education and interaction an outpatient reference group have been
with peers. Despite the fact that asthma documented.
camps cannot replace specific rehabilitation
programmes, there is evidence that these Several studies have implicated lifestyle
interventions can: changes, specifically decreased physical
activity, as a contributor to the increase in
N improve the parents and childs asthma prevalence and severity. Moreover,
knowledge of asthma, the capacity for asthmatic subjects to

Table 3. Essential components of a comprehensive paediatric pulmonary rehabilitation programme
Respiratory diagnostics including body plethysmography
Comprehensive allergy testing including provocation tests
Routine laboratory including blood gas analysis
(Chest) radiograph
Disease-specific nursing
Separation of patients according to microbiological profile
Monitoring of vital parameters and possibility of oxygen application
Physiotherapy
Physical exercise training and sports therapy
Occupational therapy
Nutritional intervention and advice by a dietician
Psychological counselling and family support
Standardised specific education in disease understanding and management
Advice in matters of financial, educational and occupational aspects
Reproduced from Jung et al. (2012) with permission from the publisher.
exercise safely and to significantly improve therefore, exceed the general requirements
their cardiovascular fitness and quality of life of pulmonary rehabilitation programmes.
has been demonstrated. From this Physiotherapists, sports therapists,
perspective it seems logical to subject psychologists, dieticians, diabetologists,
asthmatic patients to exercise training to gastroenterologists, pulmonologists and
increase fitness and strength. Indeed, many other healthcare specialists need to work
rehabilitation centres focus on exercise closely together in a multidisciplinary
interventions with remarkable success on setting. If this aspect is properly addressed,
quality of life and exercise capacity, leading rehabilitation programmes are likely to
to the assumption that exercise training significantly ameliorate the short- and long-
should be part of all asthma rehabilitation term quality of life of affected individuals
programmes. and improve symptom score, pulmonary
function, grade of inflammation and weight.
Cystic fibrosis During the past decades the Exercise and endurance training results in
fear of cross-infection, especially for significant improvements in exercise
Pseudomonas aeruginosa, has determined the tolerance, aerobic fitness, peak work
evolution of rehabilitation programmes for capacity, strength, coordination and
CF patients. To date, rigorous hygiene ventilation parameters. Moreover, clinical
standards addressing disinfection and experience demonstrates a remarkable
segregation (spatial and temporal) are a improvement in treatment adherence after
widely accepted prerequisite to qualify rehabilitation as a result of educational
centres for inpatient CF rehabilitation activities, possibly leading to longer periods
programmes. Still, in the view of potential of mild symptoms and prolonging the time
cross-infections, close contact between the between intravenous antibiotic cycles, thus
CF centres and the rehabilitation clinics is demonstrating the importance of such
advisable to foster mutual trust, minimise programmes in CF care.
risk for the patient and optimise intervention
outcome. To achieve this goal, structured Pre- and post-lung transplantation Published
interventions need to take into account all data on protocols and outcome of
aspects of CF multi-organ disease and, rehabilitation programmes for patients with

chronic lung diseases pre- and post-lung literature in this field focuses on the
transplantation are largely lacking. However, pancreatic insufficient type of CF. However,
with the increasing number of paediatric advanced lung disease in many other
and adult transplanted patients, specific conditions can lead to an enhanced calorie
rehabilitation programmes will have to be need and, subsequently, to a decreased
established. The majority of the transplanted BMI. This process is often a result of
paediatric population consists of patients increased energy expenditure due to
with CF, followed by pulmonary fibrosis. respiratory work, as well as of a general
Rehabilitation programmes for severely augmented level of inflammation and/or
affected individuals clearly exceed the regular use of systemic corticosteroids.
general requirements for pulmonary Diminished appetite and a consequently
rehabilitation. Next to medical experience decreased energy intake might contribute to
and know-how, specific psychological and a loss of body weight. If weight gain cannot
educational conditions have to be provided be achieved by regular nutrition,
by the rehabilitation centre. Access to acute coordinated actions need to be
interventions and intensive care units implemented to improve the patients
should be available, as well as an emergency condition. These potentially include
laboratory and advanced respiratory intensive counselling by a dietician,
diagnostics, such as bronchoscopy. installation of a daily nutrition plan,
prescription of high-protein calorie
Major objectives for programmes pre- supplementation or substitution of vitamins
transplantation are the stabilisation of and micronutrients. In case of progressive
general and pulmonary health in weight loss or failure to regain weight over a
conjunction with psychological priming with longer period of time, insertion of a
respect to the intervention. The effect of
percutaneous, gastrointestinal tube and
rehabilitation for adults awaiting lung
subsequent additional feeding might
transplantation has been demonstrated by a
become indispensable. The specific
significant increase in physical efficiency and
nutritional management of CF patients with
endurance.
pancreatic insufficiency leading to
Rehabilitation programmes following lung malnutrition, which includes regular
transplantation have to consider various counselling by a nutritionist, oral
complex aspects, from education in substitution of pancreatic enzymes and fat-
adherence to treatment to early recognition soluble vitamins, and high-protein calorie
of organ rejection and, at the same time, supplementation, is discussed elsewhere in
promoting physical fitness to prepare the this Handbook.
individual for re-entry into the social
When respiratory disease leads to general
community, including school or workplace.
inactivity, uncontrolled weight gain and
Next to inpatient interventions, protocols for
obesity can result. Prevention of becoming
outpatient rehabilitation programmes have
overweight is, therefore, an important
been established, with reported success in
element of the management of chronic
terms of patient satisfaction. Nevertheless,
respiratory disorders such as asthma. As
both inpatient and outpatient interventions
well as encouraging patients to exercise
need to be scientifically evaluated and better
regularly and supporting their sportive
standardised in future to meet the
complexity of the requirements of paediatric ambitions, it is crucial to provide individuals
transplant rehabilitation programmes and to and their families with specific education on
improve their outcome. the prevention of and behaviour in
emergency situations. This includes
Nutritional management In many chronic knowledge about individual risk factors,
respiratory disorders, nutritional awareness of the available rescue
interventions are mandatory to improve medication and an action plan, which the
respiratory function and ameliorate disease patient needs to follow in the case of severe
symptoms and outcome, although available respiratory symptoms. The goal is to foster

trust of the patient and the families in their N Coffman JM, et al. (2008). Effects of
self-management skills and in the asthma education on childrens use of
implemented treatment strategies in order acute care services: a meta-analysis.
to overcome the fear of respiratory Pediatrics; 121: 575586.
symptoms in situations of increased N Jung A, et al. (2012). Inpatient paediatric
physical activity. At the same time, rehabilitation in chronic respiratory dis-
nutritional education should be orders. Paediatr Respir Rev; 13: 123129.
implemented to support the efforts of N Moeller A, et al. (2010). Effects of a short-
term rehabilitation program on airway
physical activity, especially when excess
inflammation in children with cystic
weight is already an issue and weight
fibrosis. Pediatr Pulmonol; 45: 541551.
reduction is desired. This might include N Nesvold JH, et al. (2006). Assessing the
shopping and cooking guidance, education value of childrens asthma camps. J
in nutritional components and meal plans, Asthma; 43: 273277.
and even in offering temporary household N Nici L, et al. (2006). American Thoracic
support, where available. Society/European Respiratory Society
Statement on Pulmonary Rehabilitation.
In situations where increased physical Am J Respir Crit Care Med; 173: 13901413.
activity is not or is hardly possible, such as N Poustie VJ, et al. (2000). Oral protein
neuromuscular disorders, optimisation of calorie supplementation for children with
the nutritional management by the families chronic disease. Cochrane Database Syst
is of general importance, especially because Rev; 3: CD001914.
many parents tend to allow their sick or N Scaparrotta A, et al. (2012). Growth
disabled children any desired foods that are failure in children with cystic fibrosis. J
high in carbohydrates as comfort. Empathic Pediatr Endocrinol Metab; 25: 393405.
nutritional guidance, e.g. by a dietician, can N Schmitz TG, et al. (2006). The effect of
inpatient rehabilitation programmes on
often strengthen awareness of the families
quality of life in patients with cystic
of a more reasonable food composition, and
fibrosis: a multi-center study. Health
must include regular and thorough diet Qual Life Outcomes; 4: 8.
education and advice. N Smith JR, et al. (2005). A systematic
review to examine the impact of psychoe-
Further reading ducational interventions on health out-
comes and costs in adults and children
N Abrams SA (2001). Chronic pulmonary with difficult asthma. Health Technol
insufficiency in children and its effects on Assess 9: iiiiv, 1167.
growth and development. J Nutr; 131: N Spindler T (2010). Was kann und muss
938S941S. eine Rehabilitation bei Kindern und
N Basaran S, et al. (2006). Effects of Jugendlichen mit schweren Atemwegserk-
physical exercise on quality of life, exer- rankungen leisten? Kinder-und Jugendarzt;
cise capacity and pulmonary function in 41: 2832.
children with asthma. Rehabil Med; 38: N Stachow R, et al. (2006). Medication
130135. behaviour of children and adolescents
N Bauer CP, et al. (2002). Long-term effect with asthma before and after inpatient
of indoor rehabilitation on children and rehabilitation a multicenter study.
young people with moderate and severe Rehabilitation; 45: 1826.
asthma. Pneumologie; 56: 478485. N Van Doorn N (2010). Exercise programs
N Burton JH, et al. (2009). Rehabilitation for children with cystic fibrosis: a sys-
and transition after lung transplantation tematic review of randomized controlled
in children. Transplant Proc; 41: 296299. trials. Disabil Rehabil; 32: 4149.

Prevention of indoor and
outdoor pollution
Giuliana Ferrante, Velia Malizia, Roberta Antona and Stefania La Grutta
Asthma is a multifactorial disease affected by

biological, environmental and social factors. Key points
Consequently, reducing asthma morbidity
requires management that addresses the N Environmental triggers, such as in-
several contributing factors and not only the and outdoor allergens and irritants,
clinical aspects. It is well known that can elicit and exacerbate acute attacks
environmental triggers, such as in- and in asthmatic children.
outdoor allergens and irritants, can elicit and N Children are particularly susceptible to
exacerbate acute attacks in asthmatic air pollution because of their higher
children. Many studies have demonstrated ventilation rate, with an increased risk
the effectiveness of environmental trigger of medication use and hospitalisation.
reduction in lowering the burden of the
disease at the individual level (table 1). N Interventions must be addressed to
multiple triggers through multiple
Today, children spend most of the day in intervention components.
indoor environments. The most common
indoor allergens and irritants are dust mites,
N Simple measures (mattress covers,
HEPA filters, air filtration, home repairs,
pets, mould and environmental tobacco
and limiting levels of exertion in
smoke (ETS) (Crocker et al., 2011).
outdoor activities when pollutant
Dust mites concentrations are elevated) may
protect childrens respiratory health,
House dust mite (HDM) is considered one of reducing asthma symptom-days, school
the most common indoor allergens and the days missed and healthcare utilisation.
main trigger for allergic asthma. Dust mites are
prevalent in rural and in tropical areas
compared to urban centres and areas with a of the studies (sample size, multiple
temperate climate. Temperatures ranging sensitisation and exposures) (Rao et al., 2011).
between 15uC and 30uC and relative humidity of Pets
6080% represent the ideal parameters for
their development and survival. The home Cat and dog dander are well-known asthma
represents an optimal environment for dust triggers in sensitised individuals. In
mites as it is a source of food with good particular, Fel d 1, the major cat allergen, is
microclimate conditions (Brunetto et al., widespread in homes as well as in public
2009). Easy measures are suggested to reduce places (schools). There is conflicting
the risk of mite exposure (allergen- evidence whether pet elimination prevents
impermeable pillow and mattress covers; childhood asthma development. The current
washing bedding in hot water; removing standard of care, including pet removal in
carpet, upholstered furniture and stuffed toys; patients with a proven allergy, is reported to
and reducing humidity levels to ,60%), but reduce the need for medication, even if the
evidence of a reduction in asthma morbidity is efficacy of this recommendation is still
controversial, mainly due to the inhomogeneity unclear (Rao et al., 2011).

Table 1. Essential measures to reduce the exposure to main in- and outdoor allergens and pollutants
Allergen/pollutant Measures to reduce exposure Comments
HDM Allergen-impermeable pillow and Evidence is controversial
mattress covers
Washing bedding in hot water
Removing carpet, upholstered furniture
and stuffed toys
Reducing humidity levels to ,60%
Fel d 1 Pet removal in patients with a proven Cat owners may diffuse cat
allergy allergen through their clothes,
making it ubiquitous
Mould Removing mould from surfaces Reduction in emergency
Discarding mould-contaminated department visits and
materials hospitalisation after home
Addressing the source of moisture renovations
responsible for mould growth
ETS Counselling to encourage parents to quit Ineffectiveness of most of the
smoking intervention studies in lowering
Use of HEPA air cleaners ETS exposure in children
Outdoor Limiting level of exertion in outdoor Decreasing levels of PM10 were
pollutants (PM, activities when pollutants concentrations associated with reduced
NOx, VOCs, are elevated prevalence of respiratory
ozone) Breathing through the nose, at rest or at symptoms in children
low level of exertion
Exercising early in the morning, when air
pollution levels are lower
Indoor pollutants HEPA filters Interventions to address multiple
(PM, NOx, VOCs) Air filtration/ventilation triggers through multiple
Home repair interventions are suggested
Mould smoking cessation and use of high-

efficiency particulate air (HEPA) air cleaners
Early exposure to mould or damp is strongly to lower airborne particles in the air
related to asthma in children and (Crocker et al., 2011). The education of
adolescents. Mould remediation includes children with asthma, including avoidance
removing mould from surfaces, discarding of asthma triggers, showed an association
mould-contaminated materials and between ETS exposure reduction and fewer
addressing the source of moisture episodes of poorer asthma control,
responsible for mould growth (Crocker et al., respiratory-related emergency department
2011). A study reported an important visits and hospitalisations (Gerald, 2009).
reduction in emergency department visits A recent Cochrane review showed the
and hospitalisation after home renovations ineffectiveness of most of the intervention
such as leak repair, removal of water- studies in lowering ETS exposure in
damaged materials and improvements of children (Priest et al., 2008). Finally, ETS
damp basements (Rao et al., 2011). should be an integral part of the standard
ETS and exposure to air pollutants environmental assessment, education
and evaluation components in home-
Interventions to reduce ETS exposure focus based environmental interventions (Crocker
on counselling to encourage parental et al., 2011).

Children are more susceptible to air Further reading
pollution because of their higher relative
N Brunetto B, et al. (2009). Differences in
ventilation, with an increased risk of
the presence of allergens among several
medication use and hospitalisation
types of indoor environments. Ann Ist
(Laumbach, 2010). Exposure to outdoor air Super Sanita`; 4: 409414.
pollution has been associated with N Clark NM (2012). Community-based
respiratory outcomes in children. Asthmatic approaches to controlling childhood
people are considered to be especially asthma. Ann Rev Public Health; 33: 193208.
vulnerable because outdoor pollutants, such N Crocker DD, et al. (2011). Effectiveness of
as particulate matter, nitrogen oxides (NOx), home-based, multi-trigger, multicompo-
volatile organic compounds (VOCs) and nent interventions with an environmental
ozone, can trigger exacerbations. Recently, it focus for reducing asthma morbidity. A
has been demonstrated that decreasing community guide systematic review. Am J
levels of particulate matter ,10 mm in Prev Med; 41: S5S32.
diameter (PM10) were associated with N Gerald LB, et al. (2009). Changes in
reduced prevalence of respiratory symptoms environmental tobacco smoke exposure
and asthma morbidity among urban
in children. Simple recommendations to
school children. Chest; 135: 911991.
reduce exposure and prevent health effects N Gilliland FD (2009). Outdoor air pollu-
might be to: avoid heavy traffic areas, if tion, genetic susceptibility, and asthma
possible; spend less time outdoors and limit management: opportunities for interven-
level of exertion in outdoor activities when tion to reduce the burden of asthma.
pollutants concentrations are elevated; Pediatrics; 123: S168S173.
breathe through the nose at rest or at low N Priest N, et al. (2008). Family and carer
levels of exertion to reduce the amount of smoking control programmes for redu-
pollutants reaching the lung; and exercise cing childrens exposure to environmen-
early in the morning, when air pollution tal tobacco smoke. Cochrane Database
levels are lower (Laumbach, 2010). Syst Rev; 4: CD001746.
N Laumbach RJ (2010). Outdoor air pollu-
Interventions aimed at limiting exposure to tants and patients health. Am Fam
indoor pollutants may be more easily Physician; 81: 175180.
applicable, less costly and more effective in N Rao D, et al. (2011). Impact of environ-
reducing respiratory health outcomes. mental controls on childhood asthma.
Recent studies suggest that interventions Curr Allergy Asthma Rep; 11: 414420.
N Rosen LJ, et al. (2012). Parental smoking
that address a single trigger may not be as
cessation to protect young children: a
effective as those that address multiple
systematic review and meta-analysis.
triggers through multiple intervention Pediatrics; 129: 141152.
components (Crocker et al., 2011). Since N Sauni R, et al. (2011). Remediating build-
single preventive measures are seldom ings damaged by dampness and mould
effective, comprehensive strategies for preventing or reducing respiratory tract
combining the most appropriate measures symptoms, infections and asthma.
are recommended. In fact, a large number Cochrane Database Syst Rev; 9: CD007897.
of environmental variables can affect the N Sublett JL (2011). Effectiveness of air filters
patterns of exposure as well as and air cleaners in allergic respiratory
sensitisation, development of symptoms diseases: a review of the recent literature.
and exacerbations. Even if attempting to Curr Allergy Asthma Rep; 11: 395402.
control every possible kind of exposure may N Sundell J, et al. (2011). Ventilation rates
be difficult, simple measures (mattress and health: multidisciplinary review of the
scientific literature. Indoor Air; 21: 191204.
covers, HEPA filters, air filtration and home
N USEnvironmentalProtectionAgency.Asthma
repairs) may protect childrens respiratory home environmental checklist. www.epa.gov/
health, reducing asthma symptom-days, asthma/pdfs/home_environment_checklist.
school days missed and healthcare pdf
utilisation.

Respiratory physiotherapy
Beatrice Oberwaldner
Paediatric respiratory physiotherapy has

some origins in the attempt to clear Key points
tenacious secretions from the airways of
children with CF by simple mechanical N Paediatric respiratory physiotherapy
means. From this starting point, it has has developed into a wide field,
developed into a broad spectrum of encompassing airway clearance,
techniques and a wide field of therapeutic rehabilitation, aerosol treatment,
approaches to various disease entities and tracheostomy management and long-
patients. It should, therefore, be understood term home ventilation programmes.
as a rapidly developing area of knowledge- N Paediatric respiratory physiotherapy is
and skill-based competencies with a special therapeutic approach to
considerable potential for further growth. respiratory disorders in newborns,
Most of these competencies have been infants, children and adolescents. As
developed at the bedside by trial and error, such it needs a profound
but more recently there has been interest in understanding of the structure and
establishing a scientific basis for paediatric the function of the growing respiratory
respiratory physiotherapy and to understand tract and the necessary competencies
how these mechanical interventions work. required for working with paediatric
Aims and general principles patients.
Aims vary with the patients treated and

N An individualised approach to the
treatment of a specific patient is
pathophysiology encountered. However,
preferable to any kind of rigid
there are a few general principles that
therapeutic routine.
constitute the basis of every therapeutic
approach. A detailed knowledge of the N Airway clearance employs basic
structure and function of the immature and mechanisms like expiratory airflow,
growing respiratory tract of the premature, forced expiration and gasliquid
newborn, infant, toddler, schoolchild and pumping. It might, therefore, be
adolescent are fundamental. Based on a considered as a therapeutic
careful analysis of prevailing application of respiratory physiology.
pathophysiology, as derived from history,
clinical investigation, imaging, lung function
testing and other relevant investigations, a predominant principle when planning
therapeutic goal and a treatment plan treatment. In situations where cooperation
should be defined for any individual patient. of the patient is required, an age-dependent
An individualised approach to the patient is psychological approach is a prerequisite.
preferable to any kind of routine that uses Furthermore, involving parents and
standardised techniques for the caregivers in the therapeutic management is
management of certain disease entities. essential for young patients, but also helps
Depending on the vulnerability of the to provide a supportive environment for
patient, avoiding unwanted side-effects is a older ones.

Airway clearance therapy autogenic drainage, PEP therapy, oscillating
PEP, hi-PEP and various combinations of
Aims Airway clearance therapy (ACT) aims at these. They are of special interest for
preventing, treating or alleviating the patients with bronchiectasis-effected airway
mechanical (atelectasis, local hyperinflation, wall instability, where a subtle balance
ventilation/perfusion imbalance and between sustained expiratory airflow and
increased work of breathing) and biochemical moderate airway compression is found on
(increased proteolytic stress on the airway one side and the avoidance of compression-
walls, local proliferation of infectious agents effected airway closure on the other.
and mechanisms) consequences of
intrabronchial retention of secretions. Mechanisms The physiology of cough, which
Sometimes ACT also has diagnostic aims, mobilises and transports secretions, serves
such as the need for bacteriological analysis as a model for all these techniques.
of mucus from the lower airways. Expiratory airflow transports material
towards the airway opening; its effectiveness
Techniques One can distinguish between
depends on airflow velocity, bronchial
therapist-applied and self-applied
calibre and viscoelasticity of secretions. The
techniques.
physiology of a forced expiration combines
Therapist-applied techniques: Chest-clapping, expiratory airflow with the upstream
vibration and compression, all in migration of bronchial choke-points, thereby
combination with assisted coughing, are catching material in a stenosis through
traditional therapeutic approaches that are which it is blown downstream. In the airway
still valid for uncooperative patients such as periphery, where airflow is almost negligible,
newborns and infants, as well as the gasliquid pumping takes over for
unconscious. Suction techniques for mobilising secretions. This incompletely
patients with and without an artificial airway understood mechanism is based on
remove secretions that have been mobilised breathing-effected lung volume changes,
and transported by the former interventions. mixing secretions and air. All these key
Lung volume management (manual mechanisms, in combination with posture-
hyperinflation/bagging and CPAP) is a effected redistribution of ventilation, are
complementary approach for patients modified and combined in different ways in
unable to inspire sufficiently to bring air the various techniques mentioned above.
behind the obstructing secretions.
Positioning effects redistribution of Physical exercise and sports often contain
ventilation; by locally changing lung some of these key mechanisms; in
distension and ventilator excursions, it may particular, exercise-induced hyperventilation
serve as a means to target gasliquid may effect significant gasliquid pumping.
pumping and opening airways. For patients Consequently, physical activity must be seen
who require ACT in the long term, parents as a complementary means for ACT and
and other caregivers are trained in these thus should constitute an important
techniques by the therapist. element in the long-term management of
patients with bronchiectasis.
Some techniques, originally developed for
self-application, can also be used by Patients and disease entities Patients with
therapists, such as assisted autogenic bronchiectasis (CF, primary ciliary
drainage and positive expiratory pressure dyskinesia and localised bronchiectasis)
(PEP) techniques, for infants and severely ill require ACT in the long term. In any kind of
and weak patients. atelectasis that is caused by airway
occlusion (after removal of a foreign body or
Self-applied techniques: These are taught to mucoid impaction), therapeutic ACT is
cooperating patients who require ACT indicated. Due to an immature respiratory
regularly over several months and years. tract with a very special physiology, the term
Several techniques have been developed, newborn, and especially the preterm
e.g. the active cycle of breathing techniques, newborn, is particularly prone to airway

obstruction by mucus impaction and other capacity, and a gain in muscle strength and
respiratory complications. This highly motor skills, as well as more effective ACT
vulnerable patient group requires are important components. Clearly the
specialised therapeutic approaches in order medical management of these patients
to achieve the desired therapeutic effects must be optimised in order to provide a
with a minimum of risk. Paediatric patients solid basis for any rehabilitation effort.
undergoing thoracic surgery are also prone
to airway occlusion and therefore often need Rehabilitation is an option for all paediatric
ACT post-operatively. The special group of patients with chronic respiratory disorders,
children with neuromuscular disorders malformations or severe respiratory
suffer from an unstable chest in complications and side-effects from other
combination with small breathing disorders and/or treatments.
excursions and a weak cough and, therefore,
Aerosol therapy
require long-term support from paediatric
respiratory physiotherapy. Aims Aerosol therapy is a targeted approach
to the inner surface of the respiratory tract
Rehabilitation
and thereby offers itself as a means to
Aims Rehabilitation aims at preventing and deliver medication topically. In contrast to
alleviating disease-inflicted disabilities that this simple and convincing principle, the
interfere with the age-specific activities of technical details of aerosol therapy are
childhood and adolescence. Paediatric complex and complicated. Paediatric
respiratory physiotherapists, by their respiratory physiotherapists, by their
expertise in working with children of all ages, competence in working with the breathing
may design, organise and conduct patterns of their patients, may serve as
rehabilitation programmes. teachers and trainers, thereby providing the
necessary quality assurance. The aim is to
Techniques, mechanisms and patients
provide optimised aerosol therapy to the
Endurance training has been proven to be a
individual patient.
valuable component of rehabilitation for
patients with chronic respiratory disorders. Techniques, mechanisms and patients
Strength training may prevent disease- Depending on the disorder, disease
inflicted abnormalities of posture, thoracic situation, prevailing pathophysiology, age
mobility, breathing excursions and body and psychosocial profile of the child,
image. Breathing exercises and respiratory nebulisers and metered-dose inhalers with
muscle training may be desirable additions or without spacers, as well as powder
in special cases. inhalers may be the ideal choice. Interfaces
(masks and mouthpieces) are dependent on
It is of note that the effective application of
age and cooperation. The required breathing
these principles in paediatric patients
manoeuvres have to be demonstrated,
requires an age-specific approach, which
taught and optimised. Patients with an
considers the special characteristics of
artificial airway require specific approaches.
children such as shorter attention span and
enjoyment of games/playing, as well as a The paediatric asthma spectrum is a wide
general tendency towards increased mobility. field for aerosol therapy, but, beyond that, all
Programmes designed for adults may work in other respiratory disorders may also require
adolescents but are rarely suitable for younger aerosol medication either intermittently or
children. In these, fun group activities and in the long term.
competitions are more important than strict
adherence to formal training plans. Management of the technology-dependent
child
The effective mechanisms for the
rehabilitation of paediatric patients with Aims The long-term management of children
chronic respiratory disorders are complex. with a tracheostomy and those on home
Improved aerobic fitness and exercise ventilation calls for a highly specialised,

multidisciplinary approach and the paediatric respiratory physiotherapist, while always
respiratory physiotherapist may be an considering infection control issues and
important member of this team. Aims range guidelines. Last but not least, by their
from maintenance of upper airway patency to familiarity with chronically diseased patients,
the mechanical substitution of inefficient therapists may grow into the role of a trusted
breathing movements, and in all those cases confidant of the patient and their family in
successful management is characterised by various psychosocial situations.
achieving these aims while avoiding
tracheostomy- and ventilation-related Evidence
complications, as well as respiratory There is a certain discrepancy between a
inefficiency. paucity of studies and the wide clinical
Techniques, mechanisms and patients The application of paediatric respiratory
respiratory physiotherapist may have a physiotherapy. Some studies document
crucial role in selecting the appropriate beneficial effects of ACT techniques in chronic
tracheal cannula, choosing the optimal respiratory disorders. Such studies, however,
home ventilator and interface, training are difficult to conduct since outcomes are
patients and parents and monitoring the multifactorial and patients, as well as disease
entire long-term management. situations, vary considerably. Studies
comparing different ACTs are, at least in part,
The patient spectrum is wide, ranging from contradictory. Such comparisons are based
children with severe upper airway stenosis and on the potential misconception that one ACT
infants with bronchopulmonary dysplasia, to is superior to another; maybe, however, there
children with central hypoventilation is no best technique that is equally effective
syndrome and those with severe and in all patients. An individualised approach
progressive neuromuscular disease. employing key components of several
Furthermore, home ventilation is a means to techniques, skilfully tailored to the prevailing
bridge the time-span to lung transplantation disease situation, may be superior to any rigid
for patients with end-stage lung disease. All application of therapeutic protocols. Another
these disease situations require a highly interesting analytic approach is the attempt to
individualised approach where, again, careful more profoundly understand the basic
analysis of the prevailing pathophysiology is a physiologic mechanisms behind various
prerequisite for successful management. ACTs. This means asking the question how
paediatric respiratory physiotherapy works.
Other aspects Today, leading experts consider airway
Occasionally there are other disease clearance in paediatric respiratory
situations and problems where the expertise physiotherapy as a therapeutic application of
of the paediatric respiratory physiotherapist respiratory physiology.
may be of significant benefit for patient and Organisational aspects
disease management. For patients
undergoing any kind of surgery, the therapist The role of the paediatric respiratory
may provide valuable help in pre-surgical physiotherapist in the caregiving team varies
respiratory optimisation, early extubation and widely across Europe and worldwide
post-operative respiratory care and return to depending on local traditions, formal
baseline function. In paediatric intensive care training, specialisation and professional
the therapist may assist in the weaning expertise, as well as the legal and
process from mechanical ventilation. administrative background and framework.
Therapists can help in adapting the home Authorities responsible for hospital structure
environment for long-term ventilation and and function must provide appropriate
they may also offer home visits in special professional positions of respiratory
cases. Group events, like training classes and physiotherapists in caregiving teams, thus
rehabilitation camps, may be planned, ensuring maximum effectiveness within a
organised and conducted by the paediatric multidisciplinary care. General training in

physiotherapy, however, rarely suffices to N McIlwaine M (2007). Chest physical
provide enough competencies to manage therapy; breathing techniques and exer-
patients with chronic, complex and severe cise in children with CF. Paediatr Respir
respiratory disorders. Lack of sufficient Rev; 8: 816.
expertise carries the risk of side-effects and N Oberwaldner B (2000). Physiotherapy for
complications. It follows that specialised airway clearance in paediatrics. Eur Respir
training is required and should be available J; 15: 196204.
across Europe and internationally. At present N Oberwaldner B, et al. (2006).
this is not the case and different countries Tracheostomy care in the home.
have different concepts and traditions (or Paediatr Respir Rev; 7: 185190.
lack thereof) in their paediatric respiratory N Pryor JA, et al. (2010). Beyond postural
drainage and percussion: airway clear-
physiotherapy training. Scientific medical
ance in people with cystic fibrosis. J Cyst
societies like the European Respiratory
Fibros; 9: 187192.
Society are called upon to provide trans- N Zach MS, et al. Chest physiotherapy. In:
European harmonisation and Taussig LM, et al., eds. Pediatric
standardisation of training and standards. Respiratory Medicine. St. Louis, Mosby
Inc., 1999; pp. 299311.
Further reading N Zach MS, et al. Paediatric mucus clear-
ance by chest physiotherapy principles
N Lannefors L, et al. (2004). Physiotherapy and practice. In: Rubin BK, et al., eds.
in infants and young children with cystic Therapy for Mucus-Clearance Disorders.
fibrosis: current practice and future devel- Vol.191. New York, Marcel Dekker, Inc.,
opments. J R Soc Med; 97: Suppl. 44, 824. 2004; pp. 471502.

Fitness-to-fly testing
Mary J. Sharp and Graham L. Hall
Aircraft cabins are pressurised to 1500 and 6 months of age little is known about
2400 m, resulting in an oxygen tension oxygen saturation levels during flight.
(PO2) of 15 kPa (112 mmHg), which is
The normal physiological compensation to
equivalent to an ambient oxygen level of 15
this hypoxia is an increase in V9E, mostly by
17%. At sea level the alveolar oxygen tension
increasing tidal volume, and a moderate
(PAO2) is ,98 mmHg while at the maximum
tachycardia. A patient with pulmonary disease
cruising altitude the PAO2 drops to
may not be able to increase V9E enough to
55 mmHg, which corresponds to an oxygen
compensate for the fall in PAO2 and their PAO2
saturation of 90%. In healthy passengers
may end up on the steep part of the oxygen
.6 months of age, SpO2 declines to 8994%
dissociation curve resulting in low oxygen
during flight without changes in clinical saturation. Physiological factors such as lower
status, whereas 35% of healthy ex-preterm respiratory system compliance, more
infants flying near term exhibit significant horizontal rib placement, higher airways
desaturation (SpO2 ,85%). Figure 1 shows resistance and fewer alveoli in infants and
the SpO2 for a term and pre-term infant young children mean they are more at risk
during air travel. In infants between birth than adults of developing hypoxaemia in
aircraft. In addition, infants are at risk of even
greater hypoxaemia due to fetal haemoglobin,
increased pulmonary vascular reactivity and
Key points biphasic hypoxic ventilation response.
N Infants and children with chronic lung The aim of this chapter is to highlight the key
disease are at risk of developing points for paediatricians and neonatologists
hypoxia and respiratory symptoms considering the safety of air travel in
during air travel. newborns and young infants. Readers
seeking more detailed information relating to
N The hypoxia challenge test is the the broader changes that occur during air
currently recommended tool for the travel and the most appropriate approach in
identification of at-risk indviduals. older children are directed to the recent
N The hypoxia challenge test does not guidelines from the British Thoracic Society
predict the incidence of in-flight (BTS) on identifying which patients with lung
hypoxia in infants born preterm and disease are at risk during air travel.
travelling by air at near term.
Methods of pre-flight testing for infants and
N The accuracy of the hypoxia challenge children
test in infants and young children has
not been assessed. The hypoxia challenge test was first reported
by Gong et al., (1984) and subsequently
N Further research into the prediction of validated in a variety of adult populations
in-flight hypoxia is required in infants with chronic respiratory disease. The
and young children. primary aim of the hypoxia challenge test is
to identify patients prior to flight who are at

a) 100
90
SpO2 %
80
70
Ascent commenced Descent commenced
60
23:30 00:00 00:30 01:00 01:30 02:00 02:30
b) 100
90
SpO2 %
80
70
Ascent commenced Oxygen commenced Descent commenced
60
00:30 01:00 01:30 02:00 02:30 03:00 03:30
Flight time
Figure 1. Recording of in-flight SpO2 in a) a 7 month-old term born infant and b) a 9.6 month-old preterm
infant (corrected post-natal age 27 weeks). The red dotted line indicates a SpO2 of 85%. The term infant
maintained their SpO2 above 90% for the majority of the flight. The SpO2 of the preterm infant decreased
to 8590% once cruising altitude was reached and remained stable for approximately half of the flight
before decreasing to ,85%. Supplemental oxygen was commenced at this time for the remainder of the
flight. Reproduced from Withers (2011) with permission from the publisher.
risk of significant in-flight respiratory to predict in-flight hypoxia in children aged

symptoms. During the hypoxia challenge 1116 years with CF; however, in a larger
test the infant or young child sits on a carers study of children with CF the hypoxia
lap in a body plethysmograph and 100% challenge test predicted in-flight hypoxia in
nitrogen is introduced to reduce the only two out of 10 cases. One study has
inspiratory oxygen fraction (FIO2) to 1415%. reported that the hypoxia challenge test is not
Alternatively, the infant can have a face mask accurate in ex-preterm infants flying near
placed over their nose and mouth through term. These studies imply there may be a
which high flow 14% oxygen is administered. developmental trajectory for the hypoxia
The typical duration of the test is 20 min. challenge test. In addition, there have been
Oxygen saturations are monitored no studies between the body box and face
throughout but, unlike in adults, arterial gas mask technique to compare whether they
samples are not routinely collected and ECGs give similar results. The cut-off for normal
are not monitored. Nasal cannulas are worn and abnormal hypoxia challenge test results
so that if SpO2 decreases supplemental is also unclear. The BTS guidelines
oxygen can be commenced and titrated to an recommend that infants ,1 year of age with
appropriate level. a hypoxia challenge test result of ,85%
Whilst the hypoxia challenge test is a valuable should fly with supplemental oxygen but in
tool there are a number of unanswered children .1 year of age the cut-off is 90%.
questions, including how reliable is the test There are no studies supporting the choice of
in infants and children? A preliminary study 85% or 90% in children .1 year of age. One
reported the hypoxia challenge test was able study compared hypoxia challenge test cut-off

levels of 85% and 90% and found that the to be restricted to those individuals with
90% cut-off in children ,2 years of age did severe airway obstruction. In infants the
not discriminate between healthy children primary risk group is those born preterm or
and those with a history of neonatal chronic with chronic lung disease requiring
lung disease whereas the 85% cut-off did. supplemental oxygen. While the hypoxia
However, this study did not report whether challenge test is the currently recommended
the hypoxia challenge test results predicted tool for the identification of at-risk
in-flight oxygen saturation levels. indviduals it does not predict the incidence
of in-flight hypoxia in infants born preterm
The European Lung Foundation (www. and travelling by air near term and its
european-lung-foundation.org) has accuracy in older infants and young children
developed a database that provides has not been established.
information facilitating the organisation of
air travel and supplemental oxygen for
respiratory patients and healthcare Further reading
providers. The most relevant guidelines are
N Audley AM, et al. (2010). The European
from the BTS and these are briefly Lung Foundation database on airlines
summarised below. Readers are directed to policies for patients who require oxygen
the guidelines for detailed information. supplementation during air travel. Prim
Care Respir J; 19: 284.
N Healthy term infants should delay air N Buchdahl RM, et al. (2001). Predicting
travel for 7 days after the expected term hypoxaemia during flights in children
date. with cystic fibrosis. Thorax; 56: 877879.
N Preterm infants that have not yet reached N Dine CJ, et al. (2008). Hypoxia altitude
their expected date of delivery should fly simulation test. Chest; 133: 10021005.
with supplemental oxygen available, N Gong H Jr, et al. (1984). Hypoxia-altitude
should respiratory symptoms develop. simulation test. Evaluation of patients
N Infants and children receiving with chronic airway obstruction. Am Rev
supplemental oxygen at the time of air Respir Dis; 130: 980986.
travel should have their oxygen flow N Hall GL, et al. (2007). Assessing fitness
doubled. to fly in young infants and children.
N Young infants (,1 year of age) with a Thorax; 62: 278279.
neonatal lung disease should be referred N Lee AP, et al. (2002). Commercial airline
to a paediatric respiratory physician and a travel decreases oxygen saturation in
hypoxia challenge test performed. children. Pediatr Emerg Care; 18: 7880.
N Martin AC, et al. (2008). Definition of
Supplemental oxygen should be available
cutoff values for the hypoxia test used for
if the hypoxia challenge test results in a
preflight testing in young children with
SpO2 ,85% or if SpO2 is 8590% and
neonatal chronic lung disease. Chest; 133:
there is physician doubt. 914919.
N Infants and children with recent long- N Oades PJ, et al. (1994). Prediction of
term oxygen therapy (in the past hypoxaemia at high altitude in children
6 months) should have a hypoxia with cystic fibrosis. BMJ; 308: 1518.
challenge test. N Resnick SM, et al. (2008). The hypoxia
N Children with chronic lung disease (such challenge test does not accurately predict
as CF) with a FEV1 ,50% predicted hypoxia in flight in ex-preterm neonates.
should have a hypoxia challenge test and Chest; 133: 11611166.
in-flight oxygen should be used if the N Shrikrishna D, et al. (2011). Managing
hypoxia challenge test result is ,90%. passengers with stable respiratory disease
planning air travel: British Thoracic Society
In summary, infants and children with recommendations. Thorax; 66: 831833.
chronic lung disease are at risk of the N Withers A, et al. (2011). Air travel and the
development of respiratory symptoms and risks of hypoxia in children. Paediatr
signs, including hypoxia when undertaking Respir Rev; 12: 271276.
air travel. In older children the risk appears

Sports medicine
Giancarlo Tancredi, Giovanna De Castro and Anna Maria Zicari
Definition When considering sports activity, it is

possible to differentiate between
Sports medicine concerns scientific and competitive and non-competitive or
medical aspects of physical activity, physical leisure-time sports. According to a scientific
fitness, and sports performance. The World statement of the American Heart
Health Organization defines physical activity Association (2005), a competitive athlete is
as any bodily movement produced by defined as one who participates in an
skeletal muscles that requires energy organised team or individual sport that
expenditure and physical fitness as the ability requires systematic training and regular
to perform muscular work satisfactorily. competition against others and that places a
high premium on athletic excellence and
achievement.
Key points Pre-competition medical assessment and
screening is an important part of preventive
N A physically active lifestyle including measures to detect compromising health
sports and supervised conditioning conditions in competitive athletes. The
programmes provides physiological physical examination should include, but
improvements in muscle function, not be limited to, cardiovascular,
cardiopulmonary efficiency, immune pulmonary, and musculoskeletal
system function, obesity prevention assessment.
and self-esteem.
Since 1982, Italian law has mandated that
N Cardiopulmonary exercise testing
every participant engaged in competitive
provides a global assessment of the
sports must undergo a clinical evaluation to
integrative exercise responses
obtain eligibility. Furthermore, a medical
involving the pulmonary,
history, physical examination, and any
cardiovascular, and skeletal muscle
required additional assessments are
systems.
recommended for all subjects who practice
N V9O2max reflects the maximal ability of physical activity.
the body to take in, transport and
utilise oxygen and it is the best single Benefits of sports programmes
measure of aerobic fitness. Participation in sports programmes
N Exercise prescriptions to improve provides an opportunity for children to
cardiopulmonary fitness in patients increase their physical activity and develop
with chronic health diseases are based physical and social skills.
on the initial level of fitness and
In particular, the American Academy of
include the modalities of physical
Pediatrics recommends that organised
activity as well as the frequency,
sports programmes for pre-adolescents
intensity and duration of the training.
should complement, not replace, the regular
physical activity that is a part of free play,

child-organised games, recreational sports, include musculoskeletal injuries, which can
and physical education programmes at occur from excessive amounts of activity or
school. sudden beginning of an activity for which
the body is not conditioned. These include
Inactivity is a risk factor for many chronic muscle tears, acute damage to joints and
diseases such as hypertension, diabetes, ligaments, fractures, and overuse injuries.
obesity, depression, cancer and cardiovascular However, many injuries associated with
disease. Conversely, a physically active lifestyle physical activity may be prevented by
helps to maintain body weight, and leads to gradually increasing the level of activity and
favourable health habits, such as not smoking avoiding excessive amounts of activity.
and a healthy diet.
Doping in sports is a big social problem.
The numerous benefits of regular physical Adolescents employ a wide variety of drugs
activity include physiological improvements hoping to improve their athletic
in skeletal muscle function, performance and to look better. Studies
cardiopulmonary efficiency, immune system report that 312% of male adolescents admit
function, obesity prevention, self-esteem they have used an anabolic-androgenic
and psychological and social conditions. In steroid.
particular, physical activity may induce
beneficial immune system changes with a Female athlete triad is a syndrome
reduction in pro-inflammatory cytokines of characterised by the presence of disordered
allergic inflammation. eating, amenorrhoea, and osteopenia or
osteoporosis. The prevalence of this
Risks of physical activity syndrome is unknown but it will probably
continue to grow because of the increased
The most significant, but extremely rare, risk
number of girls participating in sports such
associated with exercise in youth is a sudden
as cross-country running, gymnastics, and
death event. Among children and
figure skating.
adolescents, cardiovascular causes of death
include hypertrophic cardiomyopathy, Adolescents engaged in contact sports after
myocarditis, anomalous coronary artery having infectious mononucleosis are at
anatomy, Marfan syndrome and commotio potential risk of splenic rupture secondary to
cordis. Exercise-induced arrhythmias with abdominal trauma. It is safe to allow these
or without pre-existing anomalies of cardiac athletes to return to contact sports after a
electrical excitation and repolarisation may period ranging from 36 months.
also lead to death.
Physical activity in children with chronic
Becker et al. (2004) reported that sudden pulmonary diseases
fatal asthma can occur in competitive and
recreational athletes during sporting Asthma The prevalence of bronchial asthma
activities. These subjects were usually white in children is about 10%, and 4090% of
male subjects in the age range of 10 these patients have exercise induced asthma
20 years, and many of them had mild (EIA), a manifestation that is frequently
asthma. The possible causes of this type of undiagnosed. EIA is defined as a condition
fatal asthma attack include sudden severe in which physical activity triggers acute
asphyxia as well as a reduced airway narrowing in people with heightened
chemosensitivity to hypoxia and blunted airway reactivity. The exact mechanisms of
perception of dyspnoea by the patient. In how exercise may trigger an asthmatic
this study, only three subjects were reported attack in susceptible people are still a matter
to be using long-term control medications. of research. It is likely that cytokine release
It is essential to ensure that an athlete with and parasympathetic nerve reflexes
asthma is receiving proper care and therapy. triggered by water and heat loss from the
respiratory epithelium associated with the
Sports injuries are other common problems exercise-induced increase in ventilation play
associated with physical activity; they a key role.

The diagnosis of EIA is suggested by the There is good evidence suggesting that
symptoms of cough, wheezing, chest children with mild-to-moderate CF can
tightness or dyspnoea during or shortly after benefit in terms of pulmonary function from
exercise, and demonstrated by a decrease of either an aerobic or resistance training
1215% in forced expiratory volume in 1 s programme. Moreover, team sports are
(FEV1). EIA is usually studied with important for the social integration of any
ergometers such as the treadmill and cycle child with a chronic disease.
ergometer, or free running. These tests are
complex, expensive or require a large space. Specific sports such as scuba diving and
The current authors have found that the step sports at high altitude should be
test is a quick, economical, reproducible and discouraged for children with CF with
portable alternative procedure for identifying significant air trapping. In both types of
EIA in out-patients and epidemiological activity, unfavourable situations can happen
studies. in which oxygen becomes limited and severe
desaturation can occur over longer time-
Moreover, it is necessary to underline that periods.
exercise testing is less sensitive but more
specific than pharmacological challenges Pulmonary barotrauma is relevant in scuba
(histamine, methacholine) in detecting EIA. diving. The lung injury is caused by
overdistention of alveoli and rupture of
In a systematic review of 16 studies and 516 alveolar walls as a consequence of
subjects, Crosbie (2012) evaluated the effect expanding gases during ascent.
of physical training in children with asthma.
This review confirms that there is an Other problems that may occur include
increase in aerobic capacity as measured by pneumothorax with weight training, rupture
V9O2max (mL?kg-1?min-1) in asthmatic of spleen and oesophageal varices in
children with physical training, with a patients with portal hypertension
response similar to healthy controls. performing contact sports, and dehydration
However, physical training does not improve and electrolyte losses during prolonged
pulmonary function in asthmatic children. exercise in the heat.
Finally, it is important to underline that Most patients with congenital lung diseases
asthmatic children can be active and (e.g. pulmonary hypoplasia) and other
participate in any sports they choose when conditions such as bronchopulmonary
their asthma is well controlled. dysplasia are relatively sedentary. It is
important to motivate these children to
Exercise-induced anaphylaxis Exercise- increase their fitness level through
induced anaphylaxis (EIAn) is a rare but participation in regular physical activity. In
potentially life-threatening clinical syndrome these subjects it is necessary to perform an
characterised by anaphylaxis concomitant evaluation including an accurate clinical and
with exercise. EIAn may occur independently functional assessment before starting a
of food allergen ingestion or may require the sport to minimise any potential risk.
combined ingestion of sensitising food
before exercise to trigger symptoms. Clinical Clinical exercise testing
features and management do not differ
significantly from other types of anaphylaxis. Cardiopulmonary exercise testing provides a
Therapy includes epinephrine, global assessment of the integrative exercise
antihistamines, and systemic responses involving the pulmonary,
corticosteroids. cardiovascular, and skeletal muscle
systems. The primary cardiovascular
Cystic fibrosis is the most common parameters routinely measured during
hereditary disease in white populations. It is exercise testing are the electrocardiogram,
caused by mutations in the CF heart rate, blood pressure, cardiac output,
transmembrane conductance regulator stroke volume and systemic vascular
(CFTR) gene. resistance. All these parameters are

measurable using standard noninvasive (approximately 3.5 mL O2?kg-1?min-1), and
techniques. Cardiopulmonary exercise serves as a unit to estimate the amount of
testing is essential because pulmonary and oxygen used by the body during physical
cardiac function assessed at rest cannot activity. Activity that burns 36 METs is
reliably predict exercise performance or considered moderate-intensity physical
functional capacity, and overall health status activity.
will correlate more closely with exercise
tolerance than with measurements taken at It is established that well-directed aerobic
rest. Exercise testing has been proven to be training programmes result in a significant
useful for differentiating between improvement in V9O2max. Classically,
cardiovascular and pulmonary causes of V9O2max will increase by about 1520%,
exercise intolerance and identifying although there may be a large inter-subject
disorders of pulmonary gas exchange, variation owing to genetic factors.
certain muscle diseases and psychological
disorders. We have measured V9O2max during a
cardiopulmonary exercise test in children
V9O2max reflects the maximal ability of the with different pathologies, girls with Turner
body to take in, transport and utilise oxygen. syndrome and children after a renal
It is widely recognized as the gold standard transplant. In these patients V9O2max
indicator of aerobic fitness and may be provides valuable information on health
determined using standardised testing on a status and effects of exercise training
treadmill or a cycle ergometer. programs.
V9O2max is correctly defined by the Fick Prescription of physical activity
equation:
Exercise prescription has received a growing
V9O2max 5 Q 6 (CaO2 CvO2) interest in general clinical practice and
specifically in the care of people with chronic
when these values are obtained during an
health conditions. The objective of each
exertion at a maximal effort, and where Q is
prescription would be to recommend a
the cardiac output, CaO2 is the arterial
particular quantity of physical activity to an
oxygen content and CvO2 is the venous
individual in a way that results in specific
oxygen content. V9O2 can be measured
therapeutic goals such as health benefits or
noninvasively and directly by the product of
ventilation and the difference of oxygen improved cardiorespiratory fitness.
concentration of inhaled and exhaled air that The principles that rule exercise prescription
has been utilised by the working muscles. are based on exercise mode, frequency,
V9O2max can be influenced by age, sex, intensity and duration. The recommended
exercise habits, body size, heredity, and mode of aerobic exercise in chronic
cardiovascular clinical status.
respiratory disease is walking or any type of
Measurement of oxygen saturation on aerobic exercise that uses large muscles; the
exercise, using a pulse oximeter, at rest and optimal frequency is 35 days per week; and
on exertion, is a noninvasive method the intensity of exercise is at 5085% of
allowing the monitoring of arterial oxygen maximum oxygen uptake or at limits as
saturation (SaO2). The assessment of SaO2 is tolerated by the patient. Duration of exercise
an important indication in patients with should be 2060 min of continuous aerobic
chronic lung disease since neither the activity.
presence nor the severity of desaturation
during exercise can be predicted readily In patients with significant cardiac or
from resting SaO2. pulmonary disease, interval training can be a
valid alternative. Interval training is a type of
METs or metabolic equivalent is a physical training that consists of high
physiological measure expressing the intensity work alternated with periods of rest
amount of oxygen consumed at rest or low activity.

Further reading N Janssen I, et al. (2010). Systematic
review of the health benefits of physical
N American College of Sports Medicine. activity and fitness in school-aged
ACSMs Guidelines for Exercise Testing children and youth. Int J Behav Nutr
and Prescription. 9th Edn. Philadelphia, Phys Act; 7: 40.
Lippincott Williams & Wilkins, 2013. N Longmuir PE, et al. (2013). Promotion of
N American Academy of Pediatrics, physical activity for children and adults
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Index
A
ABCA3 gene/protein 6, 588, 592, 597, 598
obesity in 530, 531
adeno-tonsillectomy
OSAS 62, 517518, 531
abdominal pain 237, 410 polysomnography 122
abdominal tuberculosis 290291 post-operative complications 517518
aberrant innominate artery 455, 458f, 459 adenovirus(es) 10, 214, 570, 571
aberrant subclavian artery 454, 457, 459 adipokines 530
absent pulmonary valve syndrome 640 adolescent(s)
acaricides 385 asthma severity 325t
acetylcholine, REM sleep 507 bronchopulmonary dysplasia survivors 473
N-acetylcysteine 424425 cystic fibrosis signs/symptoms 398t
acidaemia 94, 94t physical activity risks 674
acidbase disorders/disturbances 93, 94t primary ciliary dyskinesia 555t
mixed 93 tuberculosis 273
acidosis 94, 539 adolescent idiopathic scoliosis (AIS) 498499, 501
acinar region 2 adrenaline
acinus 5, 8f anaphylaxis 349, 351, 352, 352t
acrocyanosis (peripheral cyanosis) 39 bronchiolitis 307
action plans croup 56, 231
asthma 324325 food allergy 374
food allergy 373374 inspiratory stridor 56
active sleep, newborns 511 adults
actual base excess (base excess of the extracellular bronchopulmonary dysplasia survivors 473
fluid) 96 cystic fibrosis, nutritional status 411
acute cellular rejection (ACR) 572 adult-type tuberculosis 272, 273
acute eosinophilic pneumonia 611612 adventitious sounds 3739
acute glomerulonephritis 621 continuous (musical) see wheeze/wheezing
acute hypercarbic (type II) respiratory failure 539540 discontinuous (nonmusical) see crackles
acute hypoxic (type I) respiratory failure 538539, 539f aegophony 39
acute lung injury (ALI) 472, 533, 535536, 540 aerosol 199
acute-on-chronic respiratory failure 542 aerosol therapy 198206, 667
acute otitis media (AOM) 215, 228229 adherence 204205
acute pancreatitis 642 aims 667
acute respiratory distress syndrome (ARDS) 533, 540, delivery devices 199204
640 choice of 199200, 200f
causes 535, 536t five Ds for prescribing 198
imaging 533, 534f indications 198
lung recruitment 536 inhalation instructions 204205
outcomes 534, 535 mechanisms 667
pathophysiological outcomes 533534 particle deposition 199
phases 533 patients 667
treatment 535536 techniques 667
acute respiratory failure (ARF) 538542 technology 199
causes 538 air filtration 385
clinical effects 540 air inflammation modulation, CF 424425
cystic fibrosis 406 air pollution
definitions 538540 anthropogenic 30
history taking 540541 bronchial hyperresponsiveness 87
investigations 540541 cough 46
management 541542 lung function growth 30
physiology 538540 see also individual types/pollutants
adaptive immune system 19, 2327 air trapping
allergic response 340, 342f bronchiolitis 306, 306f
induction 24 bronchiolitis obliterans 574
innate immune system, interaction with 19, 26 tuberculosis 275
adaptor molecules 2122 airway abnormalities 336
adenocarcinomas 631632 airway clearance therapy (ACT) 665, 666667
adenosine, sleep 504 aims 666
adeno-tonsillar hypertrophy, OSAS 514, 517 bronchiectasis 667
678
cystic fibrosis 430 allergic crease 35
disease entities 666667 allergic disorders/diseases 339344
evidence 668 asthma and 31
gasliquid pumping 666 diagnostic tests 345348
mechanisms 666 in vitro 346347
neuromuscular disorders 667 in vivo 346347
patients 666667 epidemiology 343
plastic bronchitis 580 history 345346
positioning 666 immunotherapy 383389
primary ciliary dyskinesia 557 molecular diagnosis 347
techniques 666 pathophysiology 339343
airway compression phenotypes 340
cardiovascular causes 335t, 336 physical examination 35
dynamic 7475 prevalence 343
right aortic arch 454 prevention measures 383389
airway endoscopy see bronchoscopy viral infections and 339, 341
airway epithelium see also individual disorders/diseases
cancers 631632 allergic inflammation 27, 340, 341f
pathogen recognition 2022 allergic-like reactions, contrast media 169
as physical barrier 19 allergic march 339
airway hyperresponsiveness, BPD 475 allergic response
airway malacia 267 asthma 318
airway malformations 435444, 436t nasal 354355, 355f
airway obstruction allergic rhinitis 354362
equal pressure point 74f, 75 asthma 360
flexible bronchoscopy indications 135t classification 354, 355356, 356f
foreign body aspiration 566 clinical testing 357358
inspection 53 comorbidities 356, 360361
non-CF bronchiectasis 256 complications 360361
airway remodelling, asthma 316, 319, 342343 physical changes 360
A lines, ultrasound 183, 184f definition 354
alkalaemia 94, 94t diagnosis 354, 356357
alkalosis 94 epidemiology 354
allergen avoidance 383386, 388 food allergy 373
atopic dermatitis 367 health-related consequences 361
allergen challenge tests 347, 386 IgE-mediated allergy 354
allergen exposure 31 intermittent 356, 356f
asthma 302, 318 management 47, 358360, 358f
bronchial hyperresponsiveness 87 asthma severity reduction 359
fetal cells 26 medications 358359
see also individual allergens mechanisms 354355, 355f
allergen-specific immunotherapy see immunotherapy perennial 355356, 357
allergic bronchopulmonary aspergillosis (ABPA) persistent 356, 356f
376382, 405, 610, 612 plant-derived foods, adverse reactions 361
complications 380f, 381 pollen allergy 356
definition 376 prevalence 343
diagnosis 378379, 378t, 379t, 405, 612 seasonal 356
genetics 378 signs 35
management 380381 social problems 357
pathophysiology 377378 symptoms 356, 357
presentation 378, 379f therapeutic strategies 354
prevalence 377 Allergic Rhinitis and its Impact on Asthma (ARIA),
prevention 380 allergic rhinitis classification 356
prognosis 381 allergic salute (nasal salute) 35, 357
screening 380 allergic sensitisation 31, 340
stages 381, 381t prevalence 343, 345
treatment 376, 380, 405 viral infection and 319
complications 381 allergic sensitisation testing 346347
future developments 381 advantages 346t
679
allergic bronchopulmonary aspergillosis 379 idiopathic 349
preschool wheezing 312, 312t IgE-mediated reactions 349
allergy see allergic disorders/diseases immunomodulation 352
alligator shape forceps 148, 149 incidence 349
allokinesis 366 laboratory tests 350
1-antitrypsin deficiency 637t management 350352
-waves, sleep 508, 509f patient positioning 351
alteplase 479 risk reduction 352
alternative therapies, atopic dermatitis 368369 prevalence 343
alveolararterial oxygen tension difference (PA-aO2) reaction time course 350
9596 severity grading 351, 351t
alveolar capillary dysplasia 593 triggers 349, 352
alveolar capillary dysplasia spectrum 604 angiography, vascular malformations 457
alveolarcapillary membrane animal dander allergy 345, 358
diffuse alveolar haemorrhage syndromes 593 anion gap 9697, 97f
lung failure 545 antibiotics
rupture 534 acute chest syndrome 626
alveolar gaswater phases 78 acute otitis media 229
alveolar haemorrhage, BAL 142143, 143f allergic bronchopulmonary aspergillosis 380
alveolar hypoventilation 526 atopic dermatitis 368
Prader-Willi syndrome 524 bronchiolitis 307
alveolar hypoventilation syndromes 521, 523 common cold 227228
secondary 524 community-acquired pneumonia 233, 239, 240
alveolar macrophages 20f, 23 resistance 239
bronchoalveolar lavage 141, 142t cough, acute 47
haemosiderin detection 143, 143f cough, moist/wet 48
pulmonary haemorrhage 620 cystic fibrosis 425426, 430
tuberculosis 285 early disease stages 407408
alveolar pressure (Palv) 73, 74 end-stage lung disease 429430
alveolar volume (VA) restriction assessment 17 intravenous 408409, 429430
alveoli, post-natal development 9, 604 pulmonary exacerbations 409
alveolitis 142, 143f, 143t dyspnoea 56
ambrisentan 606 foreign body aspiration 568
American Academy of Sleep Medicine (AASM) hospital-acquired pneumonia 244, 245t, 246
electroencephalogram recommendations 123125 lung abscess 264265
sleep disorder categories 512513 lung transplantation 650
sleep stages 508 necrotising pneumonia 263
sleep study scoring criteria 517 neuromuscular disorders 496
American College of Chest Physicians (ACCP) non-CF bronchiectasis 255
pneumothorax size guidelines 487 otitis media 227
amiloride 424, 429 otitis media with effusion 229
amino acid toxicity, BPD 468 parapneumonic effusion 260
aminoglycosides 423 plastic bronchitis 579
amniotic fluid, reduced volumes 10 pleural effusion 478, 480
amoxicillin 230, 239 pleural infection 260
amoxicillin-clavulanate 260, 269 pneumomediastinum 490
amphotericin primary ciliary dyskinesia 557
allergic bronchopulmonary aspergillosis 381 protracted bacterial bronchitis 269
cystic fibrosis 430 rhinosinusitis, acute 228
lung transplantation 650 tonsillitis 227, 230
anaesthesia see also individual drugs
foreign body removal 568 antibodies 24
rigid bronchoscopy 159 anticholinergics 323, 579
see also sedation anticoagulation 606, 608
anaphylaxis 349353 antidepressants 508
clinical manifestation 349350 antidiabetic drugs 418
desensitisation protocols 352 antifungals
diagnosis 349350, 350t allergic bronchopulmonary aspergillosis 380381
food allergy 371, 371t cystic fibrosis 430
680
lung transplantation 650 ascites 638
opportunistic fungal infections 250 Askins tumour 635
antigen avoidance, hypersensitivity pneumonitis 616 Aspergillus 218
antigen C 216 hospital-acquired pneumonia 244
antigen detection hypersensitivity reactions 218
bacterial pneumonia 216 opportunistic infections 249250
viruses 215 Aspergillus fumigatus 376, 377t, 430
antigen presentation 26 asphyxiating thoracic dystrophy (Jeune syndrome) 10,
antigen-presenting cells (APCs) 24, 27, 340 500
antihistamines aspiration syndrome 559565
allergic rhinitis 358359 asplenia 554
anaphylaxis 351352 assisted coughing 666
atopic dermatitis 368 asthma 316327
food allergy 374 airway resistance, preschool children 111
anti-IgE see omalizumab allergic 31, 383388
anti-IL-5, asthma 331 allergic rhinitis treatment 359
anti-inflammatories Aspergillus fumigatus lung disease 377t
bronchopulmonary dysplasia 464 atopic dermatitis 367
cystic fibrosis 430 biomass smoke 30
primary ciliary dyskinesia 557 bronchial hyperresponsiveness 88
anti-interleukin antibodies, asthma 331 bronchodilator reversibility 8485
antimicrobial peptides (AMPs) 21, 2223 bronchopulmonary dysplasia versus 476
cystic fibrosis 23 characteristics 316
exuberant inflammation 23 classification 295
antimicrobials clinical control level 320, 321t
hospital-acquired pneumonia 245t definitions 316, 317, 529
resistance 244 diagnosis 34, 293, 317
Pneumocystis jirovecii opportunistic infections 251 dietary interventions 320
antineutrophil cytoplasmic antibody (ANCA) 613 differential diagnosis 334338, 335t
anti-protease therapy, cystic fibrosis 425 early lung function loss 295
antipyretics 227 educational programmes 657
1-antitrypsin deficiency 637t environmental factors/triggers 294, 302303, 662,
antiviral prophylaxis, lung transplantation 650 663t
aortic arch 452 epidemiology 293297, 334
anomalies, prenatal diagnosis 456 socio-cultural factors 294
Apert syndrome 436 epigenome 299302
apical parietal pleurectomy 489 exacerbations 322323, 323t
apnoea 50, 522, 525 exercise intolerance 66t
apnoeahypopnoea index (AHI) 128t, 517, 525 exercise/physical activity 65, 658659, 674675
apnoea index 128t exhaled breath condensate 104
apnoea of prematurity 522, 526 exhaled nitric oxide fraction 101, 102103
appendiceal mucocoele 415416 food allergy 373
appendicitis, acute 415 forced oscillation technique 119120
applied respiratory physiology 1118 future risk to patient 320, 321t
arousal, from sleep 506 geneenvironment interaction 303
arousal index 127 genetics 298304, 301f
arterial blood gas (ABG) analysis 9798 association assessment methods 298299, 300t
acute respiratory failure 540 heritability 298
dyspnoea 54 history 345346
interpretation 94t infantile 108
pitfalls 98 innate-adaptive immune systems interaction 26
reference values 98t lifestyle factors 302
uses 93 long-term prognosis 295296
arterial oxygen saturation (SaO2) 95 prediction scores 296
acute hypoxic respiratory failure 539 management 319323
exercise testing 676 nonpharmacological 319320
arteriovenous malformations (AVM) 196 medical history 317, 318f
aryepiglottic folds 1 migrant studies 294
arytenoid cartilage 1 monitoring 323325
681
inflammation markers 324 as multifactorial disease 363, 364f
morbidity 316 phases 363
multiple-breath washout 115 prevalence 343
natural history 295296 skin pH changes 366
obesity and 529530 therapeutic options 367369
pathogenesis 317319, 340342, 342f atopic march 363, 367
airway inflammation 318319 atopy 87, 311
bronchial obstruction 317 atropine 156157
lung function reductions 319, 342 attention deficit, BDP 471
phenotypes 294295, 317, 329 atypical wheeze 312, 313t
plastic bronchitis 578579 auscultation 3637
prevalence 293294, 316, 343 chronic hypersensitivity pneumonitis 614
problematic/difficult 325326 community-acquired pneumonia 237
protective environments 303 dyspnoea 5354
as public health problem 316 haemothorax 482
rehabilitation programmes 658659 post-lung transplant bronchiolitis obliterans 572
self-management 324325 speech 39
severe 316, 325326, 325t autoimmune disorders 572
management 325326 azithromycin
sex differences 294 asthma 330
sickle cell disease and 625, 627, 628 bronchiolitis obliterans 575
sputum induction 103 bronchopulmonary dysplasia 464
steroid-resistant 640 cystic fibrosis 408, 425
symptoms 317, 318f non-CF bronchiectasis 256
therapy-resistant 325326 azoles 250
time trends 293294 aztreonam 408, 425426, 429
treatment
adherence 320, 322t, 428
aims/goals 316, 320
critical issues 328329
B
Bacille CalmetteGurin (BCG) vaccination 281282
exacerbations 322323 back slaps 568
inhalation therapy 328 bacteraemic pneumococcal pneumonia 223
new/emerging strategies 322, 328333, 329331 bacterial bronchitis with wet cough see protracted
pharmacotherapy 328329 bacterial bronchitis (PBB)
stepwise approach 320322, 322f, 328 bacterial infections
viral infections 341 chronic 207
wheeze 59 chronic bronchitis 211
asthma camps 658 community-acquired pneumonia 234235, 235t
asthma concert 54 empyema 211
Asthma Control Questionnaire (ACQ) 324 hospital-acquired pneumonia 244
Asthma Control Test (ACT) 324 lung abscess 264
ataluren (PTC124) 423, 431 microbiology 215217
atelectasis necrotising pneumonia 263
bronchiolitis 306 see also individual infections/pathogens
ultrasound 186f, 187 bacterial tracheitis 232
athletes bactericidal drugs, tuberculosis 278
competitive 673 BAL see bronchoalveolar lavage (BAL)
exercise intolerance 67 barium oesophagography
atopic dermatitis (AD) 363369 aberrant subclavian artery 457
allergen-induced inflammation 365 double aortic arch 456457
allergic disease link 366367 vascular malformations 456457
asthma risk 367 vascular ring 456, 456f
clinical manifestations 363365 barotrauma 10, 675
diagnosis 363365 barrel-shaped chest 53
epidermal barrier dysfunction 365366 base excess/deficit 96
food allergy 367 base excess of the blood sample (standard base
immunological dysregulation 366367 excess) 96
itch-scratch cycle 366 base excess of the extracellular fluid (actual base
monitoring 363365 excess) 96
682
basiliximab 650 bone mineral density, cystic fibrosis 432
basophils 20 bone (skeletal) tuberculosis 289290
BCG-osis 285 BOOST II study 463
BCG osteomyelitis 290 Bordetella parapertussis 212
beclomethasone dipropionate 320, 359 Bordetella pertussis 212, 231
bedding, house dust mites 384, 385 bosentan 606
behavioural therapy, habit coughing 48 bradypnoea 50
benzodiazepine 157 brain-lung-thyroid syndrome (TTF1 deficiency syn-
benzyl penicillin 239 drome) 592, 598
Bernoulli effect, stridor 5960 brainstem respiratory network 522
Bernoullis principle 59 Brasfield scoring system 163
2-agonists, asthma exacerbations 323 breast milk, BPD 467
-lactam antibiotics, tonsillitis 230 breath-actuated pressurised metered-dose inhalers
Bewitched sign (rabbit nose) 35 200, 202203
Bhalla scoring system 255 breathing, noisy see noisy breathing
BHR see bronchial hyperresponsiveness (BHR) breathing control 89
bicarbonate 95, 96 breathing movements, fetal 5, 7
biomass smoke 3031, 30f breathing patterns, abnormal 50
biopsy breath sounds 37
mediastinal tumours 633 bridging bronchus 443
see also individual techniques British Thoracic Society (BTS)
biopsy forceps 147148, 148f, 149 pneumonia guidelines 236237, 238
Biot breathing 50 pneumothorax guidelines 487, 488
blebectomy, pneumothorax 489 stepwise asthma management guidelines 321
B lines, ultrasound 183, 184f bronchi 2, 2f
bronchiolitis 186f, 187 abnormal 136
bronchopulmonary dysplasia 186 blood supply 2
respiratory distress syndrome 185, 186 gastric content aspiration 560
blood bronchial anastomosis stenosis 653
acute reactants bronchial artery embolisation 623
parapneumonic effusion 259 bronchial asthma see asthma
pleural infection 259 bronchial atresia 443
carbon dioxide measurement 95 bronchial biopsy 146, 147149, 148f
pH 94 complications 148149
blood cultures indications 147
bacterial pneumonia 216 bronchial brushing 146147, 147f
community-acquired pneumonia 238 bronchial challenges 83, 87
parapneumonic effusion 259 bronchial hyperresponsiveness (BHR) 83, 85
blood gas analysis 9399 age-related variations 88
acute respiratory failure 539, 540 air pollution 87
blood sample type 9798 allergic rhinitis 360361
dyspnoea 54 asthma 88, 319, 342
issues 9798 classification 85
systemic hypothermia 98 development mechanisms 319
bloodgas barrier 5 diagnostic significance 88
blood pressure, OSAS 516 environmental conditions, effects of 87
blood transfusion, acute chest syndrome 626 forced oscillation technique 120
B-lymphocytes 24, 249t, 340 measurement 85, 88
BMPR2 (bone morphogenetic protein receptor II) gene respiratory symptoms and 88
mutations 605 respiratory system admittance 120
body mass index (BMI) therapeutic effects 8889
asthma 302 bronchial obstruction, asthma 317
obesity 528 bronchial provocation test (BPT) 8392, 85
bone marrow, eosinophilic lung diseases 611 asthma treatment monitoring 89
bone marrow transplant, bronchiolitis obliterans doseresponse curve 85, 85f
571572 bronchial responsiveness
nonimmunological factors 573 measurement methods 83, 8586
prognosis 576 objective 85
risk factors 572573 subjective 85
683
bronchial smooth muscle tone 83 vasculitis 572
bronchial sound 37 bronchiolitis obliterans organising pneumonia (BOOP)
pneumonia 54 571, 642
bronchial stenosis 444 bronchiolitis obliterans syndrome (BOS) 653
bronchial tree malformations 436t, 440444 breath washouts 116
bronchiectasis 253 gastro-oesophageal reflux in 431432, 560, 653
allergic bronchopulmonary aspergillosis 380, 381 grading 653t
classification 253 post-lung transplantation 652653
cystic fibrosis 403, 429 therapy 653
diagnosis 45, 170 bronchitis
exercise intolerance 67, 68f chronic 209t, 211212
GORD 560 cough 47
imaging 178f, 181 crackles 54
non-CF see non-CF bronchiectasis (NCFB) bronchoalveolar lavage (BAL) 140145, 218219, 406
primary ciliary dyskinesia 551, 552 aliquots calculation 140
bronchioarterial ratio 170 bacterial pneumonia 216
bronchioles 2 bronchiolitis obliterans 574
bronchiolitis 305309 bronchoscopic 140
acute respiratory distress syndrome 535 complications 138, 144
aetiology/risk factors 305 contraindications 144
asthma risk 208 cystic fibrosis 140, 429
definition 207, 305 differential cell counts 142t
diagnosis 306 diffuse alveolar haemorrhage syndromes 593
epidemic 305 diffuse parenchymal lung disease, chronic 141, 143
epidemiology 207208, 305 diffuse parenchymal lung diseases 590
follow-up 309 dyspnoea 55
hospital admission criteria 306 eosinophilic lung diseases 611
incidence 207 fluid preparation 141
infective agents 207, 209t fungal infections 218219
management algorithm 308f galactomannan in fluid 219
natural history 306 hypersensitivity pneumonitis 615
pathophysiology 305306 indications 141144
pharmacological therapy 307 cellular components 142144
prevention 309 microbiology 141142
prognosis 208, 309 mycobacterial infections 217218
prophylaxis 309 nonbronchoscopic 140
risk factors 208 noncellular components 141
supportive therapies 305, 307, 308f opportunistic fungal infections 250
symptoms 305, 306 Pneumocystis jirovecii 251
ultrasound 187 protracted bacterial bronchitis 268
wheeze 59 pulmonary alveolar proteinosis 599
bronchiolitis obliterans 570576 slide preparation 141
autoimmune disorders 572 specimen processing 141
causes 570 technique 140
clinical entities 571572 therapeutic 144
diagnosis 570, 573574 total fluid cell count 141, 142t
epidemiology 570571 tuberculosis 251
gastro-oesophageal reflux 573 bronchocentric granulomatosis 612
graft versus host disease 572 bronchoconstriction, exercise-induced 67
histology 571 bronchodilator(s)
lung transplant survivors see lung transplantation bronchiolitis 305, 307
morbidity 576 bronchiolitis obliterans 575
mortality 576 cystic fibrosis 407
pathology 571 forced oscillation technique 120
post-infectious 570572, 575576 neuromuscular disorders 496
prognosis 575576 preschool wheezing 312313
risk factors 572573 primary ciliary dyskinesia 557
surgical resection 575 wheeze 59
treatment 570, 575 bronchodilator reversibility 8392
684
ERS/ATS Task Force recommendations 84 bronchoscopy
preschool children assessment 84 chronic stridor 61
responsiveness 8385, 84f cystic fibrosis 406, 429
steroid-resistance asthma 84 dyspnoea 55
bronchofibrevideoscope 132 fasting periods 156
bronchogenic cysts 446 flexible see flexible bronchoscopy
bronchography foreign body aspiration 568
non-CF bronchiectasis 255 general anaesthesia 157, 158t
vascular malformations 458459, 458f laryngeal clefts 439, 439f
bronchomalacia 136, 267, 443 local anaesthesia 158
broncho-pleural fistulae 240 lung transplant recipients 651
bronchopneumonia 233 lung tumours 630
bronchopulmonary dysplasia (BPD) 337, 461476 lymphangiomas 584, 584f
aetiology 461463 moderate sedation 157158, 158t
airflow limitations 474 post-procedural care 159
airflow obstruction 475476 premedication 156
asthma versus 476 pre-operative assessment 156
birth weight in 461 pre-operative procedures 156157
catch-up growth 468 protracted bacterial bronchitis 268
characteristics 466 recovery 159
classification 469 rigid see rigid bronchoscopy
clinico-pathological problem 469, 470f rigid telescope use 153154, 154f
definition 337, 472 sedation 156160
diagnostic criteria 461, 463t tracheomalacia 458f
disease burden 469 tuberculosis 218, 276, 276f
energy expenditure 467 vascular malformations 458459, 458f
energy intake 467468 bronchovesicular sound see bronchial sound
forced oscillation technique 120 bronchovideoscope 132
genetics 462 bronchus see bronchi
growth failure 466469 bronchus intermedius 2
incidence 461, 469 budesonide 312, 320
infant plethysmography 109 Burkholderia cepacia 405
infection in 462463
inflammation 462
interrupter technique 111
long-term respiratory outcomes 472476
C
caffeine 307, 464
asthma-like symptoms 475476 calcification 639
COPD phenotype 471, 475 calcineurin inhibitors (CNIs) 649, 651, 652t, 653
imaging anomalies 474 calcium channel antagonists 606
severity lessening 473 Candida 244, 249250
lung function studies 474475 candidate-gene studies, asthma 298299, 300t, 303
management 463464 Cantrell pentalogy 498
morbidity 469, 473 capillary blood 39, 97, 98t
neurodevelopmental assessment 469471 carbachol 508
neurodevelopmental outcomes 469471 carbon dioxide 95
new 461, 462t, 466, 472473 carbon dioxide diffusion capacity (DLCO), obesity 529
nutritional management 466469 carbon monoxide diffusion, dyspnoea 55
post-discharge 468 carcinoid tumour 631
old 462t, 472 cardiac catheterisation 474
pathogenesis 461463 cardiac disease, lung manifestations 640642, 641t
physical activity 675 cardiac dysfunction 640642
prevention 463464 cardiac failure, crackles 38
pulmonary arterial hypertension 473474 cardiac surgery complications 640642
respiratory syncytial virus 221222 cardiovascular disease, OSAS 516
respiratory tract infections 473 -carotene, CF 412
ultrasound 186 cartilage 5
bronchopulmonary malformations (BPMs) 180f, 181 cast bronchitis see plastic bronchitis
bronchopulmonary sequestration (BPS) 450 cat allergens (dander) 356, 385, 662
bronchoscopes, flexible see flexible bronchoscopes cathelicidin (LL-37) 23, 366
685
cathelicidins, atopic dermatitis 366 chest deformities 35
cavitation chest drains
eosinophilic lung diseases 610 chylothorax 481
HPV infection 585586 empyema 261
CCAM volume ratio (CVR) 448 necrotising pneumonia 263
CCR7 24 pleural effusion 479
CD4+ T-cells 24 pleural infection 261
HIV/TB coinfection 286 chest examination 33, 3539
tuberculosis 285 chest excursion 36
CD14 variants 31 chest expansion examination 36
cefotaxime 478 chest pain 5052, 52t, 250
cefuroxime 478 chest radiography 161165, 176
celecoxib 586 acute respiratory failure 541
cell culture see culture allergic bronchopulmonary aspergillosis 378, 379f
cell cycle inhibitors 650 anteriorposterior view 161
centile charts, obesity 528 ARDS 533, 534f
Centor score 230, 230t bronchiolitis 306, 306f
central apnoea 128t, 129f, 517, 518f, 525526 bronchiolitis obliterans 573574
infants 526 bronchopulmonary dysplasia 470f, 474
neonatal period 521 chylothorax 480, 482f
central cyanosis 39 clinical examples 163165, 163f, 164f
central hypoventilation 521 community-acquired pneumonia 233, 237238
central microtubular agenesis 556 cystic fibrosis 163164, 164f, 403405, 405f, 406
central nervous system diffuse parenchymal lung diseases 589590
sleep regulation 506 digital 162
tuberculosis 287288, 287f dose reference values 162163
central sleep apnoea 521527 dyspnoea 54
cephalosporin 239, 260 foreign body aspiration 567
cerebrospinal fluid (CSF), CNS tuberculosis 287 gloved finger appearance 379f
CF see cystic fibrosis (CF) haemothorax 483
CFTR correctors 422 hospital-acquired pneumonia 246
CFTR potentiators and 422423 image quality criteria 162t
CFTR gene/protein 390391 indications 162t
analysis indications 390, 393t isolated tracheo-oesophageal fistula 441
CF-related liver disease 416 lateral projection 161162
F508del mutation 391, 395, 422 lung abscess 264, 264f
function 390391 miliary tuberculosis 288, 288f
G551D mutation 421 necrotising pneumonia 262
low volume hypothesis 402 non-CF bronchiectasis 254255
mutations 391392 opportunistic fungal infections 250
classes 391392, 392f, 395, 421, 422 paediatric intensive care unit 161, 163, 163f
pathophysiology 392393 parapneumonic effusion 258259
pharmacotherapy 421423, 422f pericardial tuberculosis 289
combination treatments 423 pleural effusion 163f, 477, 480
intracellular trafficking 423 pleural infection 258259
structure 390 Pneumocystis jirovecii infection 251
treatment strategies 393 pneumomediastinum 490
CFTR potentiators 421422 pneumonia 163, 163f
CFTR correctors and 422423 pneumothorax 487, 487f
CFTR replacement therapy 423 posterioranterior projection 161
CharcotMarieTooth disease 495t preterm babies 54
charge-coupled devices (CCD), flexible bronchoscopes primary pulmonary hypertension 605
132 pulmonary alveolar proteinosis 599
chemical pleurodesis 482 pulmonary haemorrhage 620
chemokines 21 pulmonary sling 456
chemotherapy role 161
lung tumours 631 shielding 163
tuberculosis 281 spinal tuberculosis 289
chest-clapping 666 technical parameters 162t
686
technique 161163 movements 552
tracheomalacia 441 cilia dyskinesia see primary ciliary dyskinesia (PCD)
tracheo-oesophageal fistula 440 ciliary beat frequency analysis, primary ciliary dyskinesia
tuberculosis 275276, 275f, 276f 555556
abdominal 291 ciliary beat pattern analysis, primary ciliary dyskinesia
immunocompromised child 251 555556
vascular malformations 456 ciliary transposition 556
chest tubes, pleural effusion 479 ciliated cells 551, 555, 556
chest wall 4 ciliopathy 636, 637t, 639t, 641t
congenital defects 497498 circadian cycle 503504
disorders 497502 circadian drive for sleep 504
tumours 635 circadian drive for wakefulness 504
CheyneStokes breathing 50 circadian rhythms 503, 504
Childhood Asthma Control Test (C-ACT) 34, 324 clarithromycin 330
Childhood Asthma Management Program (CAMP) clindamycin 260, 478
study 84, 530 Clinical and Functional Translation of Cystic Fibrosis
Childrens Interstitial Lung Disease (chILD-syndrome) website 428
597 close contact, TB 274
chILD-syndrome (Childrens Interstitial Lung Disease) closed lung regions 534
597 cloxaciline 478
Chlamydia pneumoniae 235236 clubbing 43, 53
chloral hydrate 107 co-amoxiclav 48, 239, 478, 480
chloride 96 coarse (crepitant) crackles 38
depletion 97 Cobb angle 499
chloride channel modulators, CF 424 cockroach allergens 31, 32, 383, 385
chloride responsive alkalosis 97 coeliac disease 416, 642
chloride unresponsive alkalosis 97 colistin 408, 429430
choanal atresia 435436 collectins 21
choanal stenosis 435436 Collins syndrome 436
choking 566, 567 common cold (viral rhinitis) 227228
cholecalciferol (vitamin D3) supplementation, CF 412 common cold virus (rhinovirus) 87, 214, 341
chorioamnionitis 462463 community-acquired pneumonia (CAP) 209, 233241
chronic bronchitis 209t, 211212 acute-phase reactants 238
chronic eosinophilic pneumonia 612 aetiology 234236
chronic lung disease clinical assessment 236237
fitness-to-fly testing 672 comorbidities 237
physical training, benefits 68 complications 239240
chronic lung disease of prematurity see bronchopulmo- definition 208, 233
nary dysplasia (BPD) diagnosis 233, 236237
chronic pulmonary aspiration (CPA) 559 extrapulmonary symptoms 237
gastro-oesophageal reflux 560, 561 importance of 233234
chronic respiratory disorders incidence 234
exercise intolerance 66t, 6768, 68f investigations 237238
physical activity participation 65 microbiology 238
chronic respiratory failure 542544 mortality rate 233234
assessment 543544 prevention 239
causes 543, 543t sampling difficulties 234
cystic fibrosis 406, 543 severity 237
long-term ventilation 542, 544 symptoms 237
neuromuscular disorders 543544 treatment 238239
types 545546, 547f complement 249t
chronic right-sided heart failure (cor pulmonale) 406 complementary therapies, atopic dermatitis 368369
chronic suppurative otitis media 229 complex syndromal thoracovertebral malformations
ChurgStrauss syndrome 610, 613 499501
chylothorax 3, 477, 480482, 481t, 482f compliance 78
ciclesonide 320 volume dependent 78, 79f
cidofovir 250, 585 compliance of respiratory system (CRS) 7880, 79f
cilia 5, 551552, 553f compression, airway clearance therapy 666
beat frequency 552 computed tomography (CT) 166175, 176
687
appendiceal mucocoele 416 computed tomography (CT) angiography 168
bronchiectasis 178f computerised acoustic analysis technology 58
bronchopulmonary dysplasia 474 conductance 81, 81f
children under 4 169170 conductivity measurement, cystic fibrosis 398
congenital cystic adenomatoid malformation 448 congenital abnormalities 335t, 336
contrast media 168169, 172f congenital central hypoventilation syndrome (CCHS)
cystic fibrosis 173, 403 523524, 524f, 526
dual-source scanners 167 congenital cystic adenomatoid malformation (CCAM)
dynamic versus static imaging 171 337, 446449
dyspnoea 54 antenatal resolution 445, 448
empyema 259, 259f bronchopulmonary sequestration versus 450
expiration scans 170171, 171f classification 447448
fan-beam geometry 166 diagnosis 447f, 448
haemothorax 483, 483f antenatal 446, 447f
high-resolution see high-resolution computed embryology 445
tomography (HRCT) hybrid lesions 446
image analysis 173174 incidence 446
image-guided percutaneous biopsy 194 macrocytic 448
image noise 168 microcytic 448
image processing 171173 natural history 449
inspiration scans 170171, 171f pathogenesis 445
intussusception 416 presentation 447f, 448
level of detail required 168 pressure effects 448
lung abscess 264 prognosis indicators 448
lung tumours 630 as space occupying lesions 446, 448
mediastinal mass 179f surgery 449
miliary tuberculosis 288 treatment 448449
movement artefacts 167 antenatal 448
multidetector see multidetector computed asymptomatic lesions 445, 449
tomography (MDCT) wait and see approach 449
necrotising pneumonia 262, 263f tumours and 449
opportunistic fungal infections 250 types 447
pitch value 167168 congenital heart disease 136, 554, 578
pleural effusion 478 congenital high airway obstruction syndrome (CHAOS)
pleural infection 259 437
pneumomediastinum 490 congenital (infantile) lobar emphysema 337
pneumothorax 487 congenital malformations 9
pulmonary embolic disease 607 congenital muscular dystrophy 494t
pulmonary haemorrhage 623f congenital myasthenic syndromes 495t
pulmonary metastases 632, 633f congenital myopathy 494t
radiation 168 congenital pulmonary airway malformation (CPAM) see
reconstruction kernel 172, 172f congenital cystic adenomatoid malformation (CCAM)
reconstruction protocols 172 congenital thoracic malformations (CTMs) 445451
resolution 167168 antenatal diagnosis 446t
scoring systems 173 differential diagnosis 446, 446t
sequential scans 166, 167, 167f embryology 445
spiral/volumetric 166, 167f incidence 445
technology 166167 congenital tuberculosis 273274
tracheal stenosis 442 conjugated pneumococcal vaccines 234235, 239
tracheomalacia 441442 conjunctival allergen challenges 347
trapped air areas 170171, 174 connective tissue disorders (CTD) 591, 643644
tuberculosis 275276 conscious sedation 157158
CNS 288 bronchoscopy 157158, 158t
pericardial 289 consolidation 179f, 181, 611
spinal 289 constrictive bronchiolitis see bronchiolitis obliterans
ultrafast scanners, children under 4 169170 continuous positive airway pressure (CPAP) 548549
volume control 169170 acute respiratory failure 542
spirometer-controlled breathing manoeuvres 170 apnoea 546
volumetric scans 167, 167f automatic modes 548
688
bronchiolitis 307 chronic 4546, 45t, 48
bronchopulmonary dysplasia 463 clinical syndromes 45
devices 548 community-acquired pneumonia 237
follow-up polysomnography 123 defining features 44
hypopnoea 546 environmental tobacco smoke 4647
lung injury 536 foreign body aspiration 567
OSAS 62, 518, 548 history taking 34
starting criteria 548 importance of 44
tracheomalacia 442 management 4748
vented interface 548 neuromuscular disorders 492
contrast enema, appendiceal mucocoele 416 pertussis 231
contrast media reflex pathway 44
adverse reactions 168169, 169t respiratory infections 335
CT 168169, 172f study validity 47
MRI 177 time-period effect 47
controlled laminar airflow treatment 385 tuberculosis 274, 275t
conventional radiography 161165 variants 44
core body temperature (CBT) 504 cough-assist devices
cor pulmonale (chronic right-sided heart failure) 406 cystic fibrosis 430
cortical arousal, sleep 506 plastic bronchitis 580
corticosteroids cough augmentation, neuromuscular disorders
acute chest syndrome 626 493495
acute respiratory distress syndrome 536 cough inexsufflator device 493495
allergic bronchopulmonary aspergillosis 380 cough sound 45
allergic rhinitis 359 cough-variant asthma 34
anaphylaxis 351352 cows milk allergy 621
asthma 321322 cows milk allergy (Heiner syndrome) 343, 371t
exacerbations 323 COX-2 inhibitors 586
atopic dermatitis 368 CPAP see continuous positive airway pressure (CPAP)
bronchiolitis obliterans 575 crackles 38
bronchopulmonary dysplasia 464, 470 bronchitis 54
croup 231 classification 38
cystic fibrosis 408, 430 community-acquired pneumonia 237
diffuse parenchymal lung diseases 593 dyspnoea 54
dyspnoea 56 physical examination 38
extrapulmonary tuberculosis 291 pneumonia 54
food allergy 374 craniofacial anomalies 436
foreign body aspiration 568 OSAS 514515
haemangiomas 583 crepitant (coarse) crackles 38
hypersensitivity pneumonitis 616 crepitations see crackles
as immunosuppression 650 CrispinNorman score 163
inhaled see inhaled corticosteroids (ICS) Crohns disease 416
OSAS 518 croup 53, 231
Pneumocystis jirovecii opportunistic infection 251 causative agents 231
preschool wheezing 313 clinical features 231
pulmonary haemorrhage 623 haemangioma versus 582
response assessment 17 management 56, 231
rhinosinusitis, acute 228 stridor 60, 231
safety 359 Crouzon syndrome 436
tuberculosis 279 CT see computed tomography (CT)
see also individual drugs culture
Corynebacterium diphtheriae 230 bacterial pneumonia 216
coryza 227 fungal infections 218219
co-trimoxazole 251 mycobacterial infections 218
cough 4449 pleural tuberculosis 289
acute 45t, 47 tuberculosis 218
after exercise 34 viruses 215
air pollution 46 cyanosis 3943, 53, 189
causes 4546, 45t, 46t, 47 differential diagnosis 4042t
689
hypoxaemia evaluation 39 pathophysiology 392393
cyclosporine 431 phenotypic features 398t
cysteinyl leukotrienes (cysLTs) 355 physical activity 675
cystic fibrosis (CF) 390434 preschool children 111
adherence 428 prognosis 427434
antibiotic allergy 430 psychosocial factors 428
antimicrobial peptides inactivation 23 pulmonary exacerbations 402, 405, 409, 424
bronchoalveolar lavage 140 pulmonary haemorrhage 623
cardiac manifestations 641t rehabilitation programmes 659
carriers 390, 394t respiratory complications 405
screening 399 respiratory infections 402
challenging 427, 428t screening 397401
chronic respiratory failure 543 family members 399
compassionate ground therapy 431 severe asthma, lessons from 427428
diagnosis 397398, 428 sinus disease 418
emerging pathogens 405 treatment modalities 404t, 407409
end-stage lung disease management early disease stages 407408
extrapulmonary aspects 431434 intermediate disease stages 408409
pulmonary aspects 428431 late disease stages 409
resistant/unusual microorganisms 429 new/innovative therapies 407, 421426, 431
epidemiology 394t, 395396 viral infection 403
epigenetics 395 cystic fibrosis (CF)CT scoring system 173
exhaled nitric oxide fraction measurement 17 Cystic Fibrosis Genetic Analysis Consortium 391
extrahepatic biliary complications 413 cystic fibrosis-related diabetes (CFRD) 411, 417418
extrapulmonary manifestations 410420 cystic fibrosis-related liver disease (CFLD) 416417
forced oscillation technique 120 cystic fibrosis team 406
founder effect genetic drift 391 cystic fibrosis transmembrane conductance regulator
gastrointestinal complications 403, 412416 (CFTR) see CFTR gene/protein
histology 412 cytokines 21, 23, 340
gastro-oesophageal reflux disease 560 cytomegalovirus (CMV) infection
gene therapy 423 immunocompromised children 250251
genetics 390396 lung transplantation 650
modifying factors 395 pneumonitis 250251
genetic testing 393, 393t cytotoxic CD8 T-cells 24
genotypic and phenotypic heterogeneity 393395
imaging 163164, 164f, 173, 180181, 190
incidence 390, 394t
inheritance 390
D
daclizumab 650
kidney manifestations 639t damage-associated molecular patterns (DAMPs) 21
liver manifestations 637t daytime sleepiness 512, 521
long-term oxygen therapy 546 decortication 480
lung disease 402409 deep sleep see slow-wave sleep (SWS)
characteristics 402 defence mechanisms 1928
clinical manifestations 398t, 403406, 404t development 2627
dry and distal 429, 430 defensins 23, 366
early stages 403 -wave (slow wave) activity 510
follow-up 406 -wave sleep see slow-wave sleep (SWS)
management 402, 406407 dendritic cells 1920, 27
pathophysiology 402403, 403f allergen uptake 318, 340341
stages 404t allergic response 340341, 342f
therapeutic goals 407 tuberculosis 285
treatment 404t denufosol (Lancovutide) 424
lung function 403 dermatitis, atopic see atopic dermatitis (AD)
management 427434 dermatomyositis 643
molecular microbiology studies 429 dexamethasone 464
newborn screening 398399, 400f diaphragm 4
nurse-led home visit 428 acute respiratory failure 540
nutrition 410, 660 dysfunction, obesity 529
pancreatic exocrine complications 413 inspiratory movements 51
690
weak/incompetent 1617 dynamic lung volumes 7076, 72t, 73f, 74f
diaphragmatic breathing 497 measurement 7576
diesel exhaust particles 30 obesity 529
diet see nutrition dysphagia, hoarseness 63
dietary fat intake, cystic fibrosis 411 dysphonia (hoarseness) 57, 6263
differential cyanosis 39 dyspnoea 5056
diffuse alveolar haemorrhage syndromes 593 assessment 5256, 53f
diffuse developmental disorders 593 causes 50, 51t
diffuse parenchymal lung diseases (DPLD) 587595 non-respiratory 51t, 56
bronchoalveolar lavage 141, 143 physiological triggers 52
classification 590593 definition 5051
clinical approach 589 differential diagnosis 5256
diagnosis 589590, 592t exercise intolerance 67
specific 590593 history taking 52
syndromes 589590 imaging 5455
examination 589 inspection 5253
exposure-related disease 591592 lung function measurement 55
history 589 management 55f, 56
infancy-specific 593 pathophysiology 5152
long-term oxygen therapy 546 preschool children 312
lung histology 590 dyssomnias 512
lung-restricted 592593
outcome 593594
pathophysiology 588589
prevalence 587588
E
early-onset primary pulmonary hypertension 604
restrictive pattern 17 early onset scoliosis (EOS) 498499, 501
subpleural air cysts 590, 590f early transient wheeze 295
symptoms 589 echocardiography
systemic disease-associated 591592 hepatopulmonary syndrome 638
therapy 587 pericardial tuberculosis 289
treatment strategies 593594 primary pulmonary hypertension 605
future developments 594 pulmonary arterial hypertension 473474
pharmacological therapy 593594 vascular malformations 457
diffusion problems 538 effective specific airway resistance (sReff) 111
digestion, cystic fibrosis 412 effector T-cells 24
digestive tract cancer, cystic fibrosis 416 EhlersDanlos syndrome 643
diphtheria 230231 Eisenmengers syndrome 642
directly observed therapy (DOT) programmes 278, 280 elastance (E) 78
disseminated BCG disease 282 electrocardiography (ECG)
disseminated tuberculosis 272 pericardial tuberculosis 289
distal intestinal obstruction syndrome (DIOS) 415, 650 primary pulmonary hypertension 605
diuretics 468 electroencephalography (EEG)
dog dander 662 polysomnography 123125, 127
doping, sports 674 REM sleep 510511, 511f
double aortic arch 136, 453, 454f, 456457, 459 sleep disordered breathing 525
double-blind, placebo-controlled food challenge stage 1 sleep 508
(DBPCFC) 373 stage 2 sleep 509, 510f
double lung point, ultrasound 184, 184f stage 3 sleep 510, 510f
Down syndrome 436, 531, 641t electrolytes, BPD 468
dry-powder inhalers (DPIs) 198, 203204 electromyogram (EMG) 125, 126
inspiratory flow 199200 infant sleep 511
recommended inhalation manoeuvre 204 electron microscopy, primary ciliary dyskinesia 556
dual-energy X-ray absorptiometry (DEXA) 419 electrooculogram 125
Duchenne muscular dystrophy 492, 493, 494t, 496 emollients 368
chronic respiratory failure 543544 emphysema 174
orthopaedic treatment 501 empty vena cava/empty ventricle syndrome 351
ductus arteriosus 5 empyema 210
Dunedin birth cohort 295 clinical presentation 210, 258
dynamic airway compression 7475 community-acquired pneumonia 239240, 240f
691
diagnosis 217 acute infections 207211
epidemiology 210211 chronic infections 211212
haemothorax complication 483 epigenetic effect, asthma 299
imaging 259, 259f epigenetics
incidence 211, 211f, 258 asthma 299302
infective agents 209t, 210211 cystic fibrosis 395
management 260, 261 epiglottitis 53, 215, 231232
prognosis 211, 262 epinephrine see adrenaline
risk factors 211 episodic viral wheeze (EVW) 294, 295, 311312
surgery 261 epithelial lung cancers 631632
empyema thoracis see empyema equal pressure point 7475, 74f
endobronchial biopsy see bronchial biopsy ergocalciferol (vitamin D2) supplementation, CF 412
endoscopy room equipment 157 erythromycin 47, 231
flexible bronchoscopy 133 etanercept 330, 594
endothelin-1 606 ethambutol
endothelin receptors 606 adverse effects 252
endotracheal intubation, flexible bronchoscopy 158 toxicity 279
endotracheal tubes, hospital-acquired pneumonia risk tuberculosis 278, 279t, 280t
243 extrapulmonary 290t
end-tidal carbon dioxide (PetCO2) 125 immunocompromised child 251252
endurance athletes 86 eucapnic voluntary hyperpnoea (EVH) 86
endurance training 667 European Society of Paediatric Gastroenterology, Hepa-
enteral feeding 411, 467 tology and Nutrition (ESPGHAN), BPD guidelines
environmental determinants, respiratory health/disease energy intake 467
2932 lipid intake 468
environmental exposures protein intake 468
adverse effects 2931 EVLP (Ex vivo Lung Perfusion) programmes 433
genetic factors and 3132 Ewings sarcoma 635
genetic susceptibility 29 excessive daytime sleepiness (EDS) 516, 524
hypersensitivity pneumonitis 614 exercise-induced anaphylaxis 66t, 67, 675
pregnancy 26 exercise-induced arrhythmias 674
primary ciliary dyskinesia 557 exercise-induced asthma (EIA) 65, 66t, 674675
protective effects 29, 31 cardiac dysfunction 640
environmental history 35 diagnosis 675
environmental tobacco smoke (ETS) 2930 differential diagnosis 8687
asthma 302, 303, 319, 663 mechanisms 674
bronchial hyperresponsiveness 87 obesity 530
cough 4647 exercise-induced bronchoconstriction (EIB) 65, 66t,
exposure reduction 663664, 663t 86, 87, 89
genetic factors and 3132 exercise-induced vocal cord dysfunction (EIVCD)
post-natal exposure 29 6667, 66t, 87
in pregnancy 29 exercise intolerance 6569, 66t
protracted bacterial bronchitis risk factor 267 dysfunctional breathing 66t, 6768
enzyme linked immunospot assay, TB 275 exercise/physical activity
eosinophilic alveolitis 143f, 143t airway clearance therapy 666
eosinophilic lung diseases 593, 610613 asthma 658659, 674675
classification 610 benefits 68
diagnosis 610611 bronchial responsiveness 8788
drug-induced 613 bronchopulmonary dysplasia 475, 675
histopathology 611 chronic pulmonary diseases 674675
known cause 612613 congenital lung diseases 675
laboratory testing 610611 cystic fibrosis 408, 675
of unknown cause 611 definition 673
eosinophilic oesophagitis 371t plastic bronchitis 580
eosinophils 20 prescription 676
allergic rhinitis 355 primary ciliary dyskinesia 557
asthma 324 risks of 674
bronchoalveolar lavage 141, 142t weight control 660661
epidemiology 207213 exercise testing 8687, 675676
692
cardiopulmonary 676
cardiovascular 675676
exercise-induced asthma 675
F
face masks
sensitivity 86 flexible bronchoscopy 158, 159f
exercise tolerance, adolescent idiopathic scoliosis 499 noninvasive ventilation 548
exhalation 60f facial examination 35
stridor 60 facioscapulohumeral muscular dystrophy 494t
exhaled breath analysis 104 faecal elastase-1 test 411
exhaled breath condensate (EBC) 104, 105 failure to thrive, 515
exhaled nitric oxide fraction (FeNO) 100103, 105 false vocal cords 1
advantages/limitations 102 familial dysautonomia (RileyDay syndrome) 523,
allergic rhinitis 361 644645
asthma 101, 102103, 324 familial pulmonary hypertension 605
bronchopulmonary dysplasia 476 family history 35
clinical applications 101103 farmers lung 614, 616
clinical studies 102 farming lifestyle 31, 302303
equipment 17, 100, 101f fat-soluble vitamins 413t
factor affecting 101 cystic fibrosis 410, 412
increased 100, 101 feeding problems 496
infants 101 bronchopulmonary dysplasia 467
inflammation assessment 17 Fel d 1 allergen 662, 663t
low values 101 female athlete triad 674
methodology 101 fenestrated cup forceps 147148, 148f
normal values, age-dependent increase 101, 102f FeNO analysers 100, 101f
preschool children 101 fetal breathing movements 5, 7
procedure 17 absence 910
spirometry versus 102 fetal cells, allergen exposure 26
exocrine pancreatic insufficiency (EPI) 410, 411, 413 fetal haemoglobin 39
exon skipping 395 fetal lung fluid 5
expansion thoracoplasty 501 fetal MRI 181
expiration 7273 fetal ultrasound, vascular malformations 456
newborns 80 18F-FDG-PET 190
expiration reflex 44 18F-FDG-PET/CT scan 191

expiratory braking 7980 fibreoptic bronchoscope 132
expiratory flow (V) 72t, 73, 75 fibrinolytic therapy
expiratory muscle weakness 492 empyema 261
expiratory reserve volume (ERV) 71f, 71t, 529 image-guided percutaneous drainage and 195
extracorporeal membrane oxygenation (ECMO) necrotising pneumonia, risk of 263
acute respiratory distress syndrome 535, 536 pleural effusion 479
cystic fibrosis 433 pleural infection 261
lung transplantation 433, 649 fibrinous bronchitis see plastic bronchitis
extrapulmonary tuberculosis 273, 284292 fibrosing colonopathy 411, 415
clinical manifestations 287291 fibrothorax 483
definition 284 filaggrin (FLG) gene 365
forms 284 fine (subcrepitant) crackles 38
pathogenesis 284 fine-needle aspiration, tuberculous lymphadenitis
sample collection 277 277, 287
signs 274 fitness-to-fly testing 670672
treatment 291 flexible bronchoscopes 132133, 133t
extrathoracic airways 51 bronchoalveolar lavage 140
extrathoracic variable obstruction 15, 15f choice of 133
extrinsic allergic alveolitis see hypersensitivity pneu- cleaning/disinfection 133
monitis external diameter 132133
ex utero intrapartum treatment (EXIT) procedure storage 133
congenital cystic adenomatoid malformation 448 working channel 133
tracheal atresia/agenesis 440 flexible bronchoscopy 132139
Ex vivo Lung Perfusion (EVLP) programmes 433 adequate ventilation-ensuring techniques 158, 159f
airway malformations 435
complications 137138
693
prevention measures 132, 138 food-dependent exercise-induced anaphylaxis (FDEIA)
dyspnoea 55 67, 371t
equipment 132133 food-induced anaphylaxis 370
extrinsic obstructions 136 food-induced asthma 371t, 373
foreign body removal 568 food-induced rhinitis 371t, 373
general anaesthesia 159 forced expiration 72, 73
indications 132, 134, 135t flowvolume loops 74f, 75
inflammation 136 volumetime relationship 73f
information provided 134136 forced expiratory flow at 25-75% of FVC (FEF2575%)
lower airways 135136 bronchiolitis obliterans 573
upper airway 134135 bronchopulmonary dysplasia survivors 475
intrinsic obstructions 136 forced expiratory flow at x% of FVC (FEFx) 72t
isolated tracheo-oesophageal fistula 441 forced expiratory volume in 1 s (FEV1) 72t, 73f
moderate sedation 159 asthma monitoring 324
neonatal ICUs 137 bronchodilator reversibility 83
paediatric ICUs 136137, 137t bronchopulmonary dysplasia 474
procedure 134, 134f chronic respiratory failure 543
protracted bacterial bronchitis 268 lung transplantation 648
rigid bronchoscopy versus 152 obesity 529
secretions 136 obstructive respiratory disease 14
sedation 156 forced expiratory volume in 1 s /forced vital capacity
stridor 61, 132, 134 (FEV1/FVC) ratio
tolerance 137138 bronchopulmonary dysplasia survivors 475
tracheal stenosis 442 obstructive respiratory disease 14
floor coverings 384385 forced expiratory volume in x second(s) (FEVx) 72t
flowvolume loop 1112, 13f forced oscillation technique (FOT) 85, 118121
forced expiration 74f, 75 asthma 119120
obstructive respiratory disease 1415 bronchial hyperresponsiveness 120
restrictive diseases 16, 16f bronchodilator response 120
flucoxaciline 478 bronchopulmonary dysplasia 120
fluid dynamic flutter theory 38 clinical utility 119120, 119f
fluid restriction, BPD 463, 464, 467 cystic fibrosis 120
flumazenil 157 frequency dependence 119
fluoroscopy 164f, 165 future directions 120121
foreign body aspiration 164f, 165 oscillation frequency 118
hyperinflation, regional 164f repeatability 118119
indications 161, 162t respiratory mechanics 120
transbronchial lung biopsy 149, 149f theoretical background 118, 119f
fluticasone 320, 359, 368 wheeze 119120
foam mattresses 384t, 385 in young children 118119
Fontan procedure complications 642 forced vital capacity (FVC) 72t
food allergens acute respiratory failure 541
anaphylaxis 349 obesity 529
avoidance 373, 383 obstructive respiratory disease 14
cross-reactivity 370 foreign body aspiration 566569
immunotherapy 352 aetiology 566
food allergy 370375 complications 568569
anti-IgE monoclonal antibodies 374 cough 47
atopic dermatitis 367 epidemiology 566567
diagnosis 372373 fluoroscopy 164f, 165
emergency action plan 373374 history 567
prevalence 343, 370371 investigations 190, 567568
quality-of-life disruption 374 misdiagnosis 567
resolution natural history 370 mortality rates 568569
respiratory disease and 373 partial airway obstruction 567
symptoms 370, 371372, 372t predisposing factors 566
tolerance 370 presentation 567
treatment 373374 removal 152, 153f, 568
food challenges 347, 373 stridor 60
694
treatment 568 gastrostomy, cystic fibrosis 411, 431
wheeze 54, 59, 335t, 336 Gaucher disease 637t, 644
foscarnet 250 gel phase 552
fosfomycin 429 geneenvironment interaction 29, 32
fossil fuels 30 asthma 303
friction, resistance due to 80 wheezing disorders 303
friction rub (pleural friction sound) 39 geneenvironment-wide interaction studies (GEWIS),
functional residual capacity (FRC) 70, 71f, 71t asthma 303
age-related changes 7879 general anaesthesia
calculation, from helium dilution 1314 bronchoscopy 157, 158t
compliance 78 flexible bronchoscopy 159
diffuse parenchymal lung diseases 590 inhalational agents 157
inert-gas washout 114115 interventional radiology 193
newborns 7980 genetic diseases, dyspnoea 335t, 336
obesity 529 genome-wide association study (GWAS)
sleep 546 asthma 299, 300t, 301f
functional residual capacity by plethysmography environmental exposures 3031
(FRCpleth) 12, 108 gentamicin 423
functional residual capacity-multiple-breath washouts geometric standard deviation (GSD)
(FRC-MBW) 75 aerosol particles 199
functional shunts 79 dry-powder inhalers 204
fundoplication 564 germ cell tumours 634
fungal infections gibbus 289
hospital-acquired pneumonia 244 Global Initiative for Asthma (GINA) guidelines 320, 321,
lung abscess 264 321t, 324
microbiology 218219 glomerulonephritis 230, 639t
nucleic acid detection 219 glottic haemangiomas 582
opportunistic 249250 glue ear (otitis media with effusion) 229, 360
glutathione, inhaled 425
G
GABRIEL Consortium 299
glycated haemoglobin (HbA1c) 418
glycopeptide 260
GM-CSF-receptor- mutations 598, 599
galactomannan assay 219 Gohn focus 272
galanin 507 Goldenhar syndrome 436
gallstones 413 Golde score 620
-aminobutyric acid (GABA) 506, 507 Goodpastures syndrome 621, 623, 639t
T-cells 20 graft versus host disease 572, 575
ganciclovir 250 Gram staining, bacterial pneumonia 216
gas exchange measurement, polysomnography 525 granulations 136
gas exchanging cells 5, 7 granulocyte-macrophage colony-stimulating factor
Gastrografin (sodium meglumine diatrizoate) 414, 415 (GM-CSF) 596597, 598
gastrointestinal disease 642 granulocytes 20
gastrojejunal feeding 564 granulomas 611
gastrojejunostomy 564 granulomatosis with polyangiitis (Wegners) 639t,
gastro-oesophageal reflux (GOR) 643644
bronchiolitis obliterans 573 granulomatous diseases 591
chronic pulmonary aspiration 559 grommets 229
cystic fibrosis 414, 431432 group B -haemolytic streptococci (GBS) 216
diagnosis 414 grunting 58t, 62
hoarseness 63 GSDMB-ORMDL3 locus 299
management 414 guaifenesin 408
respiratory manifestations 559565 GuillainBarr syndrome 16
gastro-oesophageal reflux disease (GORD) 335t, 336,
559
chronic pulmonary aspiration 560
cystic fibrosis 560
H
H1-antihistamines, allergic rhinitis 358, 359
prevalence 560 H2 receptor antagonists 243
respiratory manifestations 560 habit (psychogenic) coughing 48
transplant recipients 653 haemangiomas 582583
695
haematopoietic malignancies 611 bronchopulmonary dysplasia 474
haematopoietic stem-cell transplantation (HSCT) chronic hypersensitivity pneumonitis 615
bronchiolitis obliterans 571 crazy paving pattern 599
graft versus host disease 575 cystic fibrosis 429
haemodialysis 639640 diffuse parenchymal lung diseases 590, 590f
haemodynamic collapse, haemothorax 483 non-CF bronchiectasis 254255
haemoglobin, cyanosis 39 Pneumocystis jirovecii infection 251
haemoglobinopathies 642643 primary ciliary dyskinesia 557558
Haemophilus influenzae 209, 209t protracted bacterial bronchitis 268
chronic bronchitis 211 pulmonary alveolar proteinosis 599
cystic fibrosis 408 subacute hypersensitivity pneumonitis 615
protracted bacterial bronchitis 266 surfactant protein-C deficiency 597, 598f
sinusitis 215 tuberculosis 275276
Haemophilus influenzae type B (Hib) high-sensitivity C-reactive protein (hsCRP), OSAS 516
community-acquired pneumonia 235, 235t hila (hilum) 12
epiglottitis 231 hilar lymphadenopathy, TB 275, 276f
invasive diseases 237 histamine 88, 350, 354355
haemoptysis histamine receptors 366
cystic fibrosis 196, 196f, 405 histone acetylases (HATs) 330331
idiopathic pulmonary haemorrhage 621 histone deacetylases (HDACs) 330331
pulmonary haemorrhage 620 history 3343
haemothorax 477, 482483, 483f environmental 35
HagenPoiseuille equation 80 family 35
Haller index 498 medical see medical history
hamartomas 632 social 35
Hammans syndrome (spontaneous pneumomediasti- HIV
num) 489490 post-TB exposure prophylaxis 281
hay fever 35 testing, tuberculosis patients 277
head and neck palpation 36 tuberculosis coinfection 280281, 285286
head box use 541 HIV-associated anergy 286
Heads paradoxical reflex 89 hoarseness (dysphonia) 57, 6263
heart-lung transplant 647 Hodgkin lymphoma 632, 633, 634, 634f
heel prick test, cystic fibrosis 398 home oxygen therapy 545550
height graphs 3435 home ventilatory support 545550
Heimlich manoeuvre 568 respiratory physiotherapy 667668
Heiner syndrome (cows milk allergy) 343, 371t, 621 honey medications 47
heliox 307 Hoover sign 36
helium dilution 1314 hospital-acquired (nosocomial) infections 242
helminth infestation 286 hospital-acquired pneumonia (HAP) 209, 242247
hemithoraces, asymmetry 36 aetiology 244245
HenochSchnlein purpura 639t definition 242
heparin 579, 608 diagnosis 246
hepatopulmonary syndrome (HPS) 637, 638 post-surgical patients 243244
hepatorenal syndrome 638 prevention 245
heptavalent polysaccharideprotein conjugate vaccine risk factors 242, 243244
(PCV7) 223, 224 sampling techniques 246
hereditary haemorrhagic telangiectasia 593, 605 surveillance 246
HeringBreuer reflex 8 treatment 245t, 246
heritable coagulopathies 608 house dust mite (HDM) allergen 358
heterotaxy (situs ambiguus) 553554 allergic rhinitis 356, 357
HiB vaccine 239 asthma 302
high-affinity receptor for IgE (FCRI) 340 atopic dermatitis 367
high-arched (ogival) palate, OSAS 515 avoidance 384385, 662, 663t
high-efficiency particulate air (HEPA) 385, 663664 multifacet intervention 385
high flow oxygen, acute respiratory failure 542 no documented effect 384, 384t
high-frequency oscillatory ventilation (HFOV) 536 recommendations 384, 384t
high-resolution computed tomography (HRCT) particle size 383
allergic bronchopulmonary aspergillosis 380 reduction 320
bronchiolitis obliterans 574, 574f HRCT see high-resolution computed tomography
696
(HRCT) acute respiratory failure 540
H-type fistula (isolated tracheo-oesophageal fistula) dialysis-induced 640
440441 hypoventilation syndromes 521527
human bocavirus 214 hypovolaemic shock 483
human coronaviruses 214 hypoxaemia
human metapneumovirus (MPV) 214 bronchiolitis 306
human neutrophil peptides (HNP-1) 23 differential diagnosis 4042t
human papilloma viruses 584586 flexible bronchoscopy induced 138
vaccination 586 hepatopulmonary syndrome 638
humoral immune system 24 hypersensitivity pneumonitis 616
Hunter syndrome 644 hypoxia
Hurler syndrome 644 acute respiratory failure 540
hyaline membrane disease see respiratory distress in-flight 670, 671
syndrome (RDS) hypoxia challenge test, fitness-to-fly 670672
hydrocortisone 464 hysteresis 78
hydrogen cyanide 104
hydrogen peroxide 104
hydroxychloroquine 594
5-hydroxytryptamine (serotonin), sleep 507
I
iatrogenic (traumatic) pneumothorax 485, 486t, 488
hygiene hypothesis 31 ibuprofen 408
hyperbilirubinaemia, neonatal 417 idiopathic hypereosinophilic syndrome 612
hyperinflation idiopathic pulmonary haemorrhage (IPH) 620,
fluoroscopy 164f, 165 621624
tuberculosis 275 iloprost 606
hyperkinesis 366 image-guided percutaneous biopsy 194, 195f, 196f
hyperoxia 546547 image-guided percutaneous drainage 193, 194196,
bronchopulmonary dysplasia 462 195f
hyperpnoea 50 fibrinolytic therapy and 195
hypersensitivity pneumonitis 591, 610, 613616 image-guided percutaneous thermoablation 194
acute 614, 615 immune hypersensitivity reactions, TB 272
chronic 614, 615 immune programming 26
acute exacerbation 614 immune reconstitution syndrome (paradoxical
clinical features 614 reaction) 279
diagnosis 614616 immune regulation 25
environmental exposures 614 coexisting, non-harmful 26
histology 615 immune response inflammatory syndrome (IRIS)
incidence 613614 280281
lung function 615616 immunisation 221226
lymphocytosis 615 healthcare workers 245
occupational exposures 614 primary ciliary dyskinesia 557
predictors 615 immunoassays, virus detection 215
prevalence 613614 immunochromatographic membrane test 260
subacute 614, 615 immunodeficiency
treatment 616 Aspergillus fumigatus lung disease 377t
hypersomnia 512 lung involvement 248252
hypertonic saline non-CF bronchiectasis 253, 254f
bronchiolitis 307 opportunistic infections 248252
cystic fibrosis 407, 423424, 430 protracted bacterial bronchitis risk factor 267
sputum induction 103 tuberculosis 284292
hyperventilation 50, 95 immunofluorescent microscopy 556
hypnogram 126, 126f immunoglobulin A (IgA) 25
hypnotics 507 immunoglobulin E (IgE)
hypocarbia 54 allergic bronchopulmonary aspergillosis 378, 380,
hyponychial angle 43 612
hypopnoea 50, 128t, 130t, 517, 518f, 525 allergic inflammation 340
hypopnoea index 128t asthma 318
hypothalamicpituitaryadrenal (HPA) axis, corticoster- immunoglobulin G (IgG) 25
oids and 359 immunoglobulin M (IgM) 24, 25
hypoventilation 50 immunological memory 25
697
immunological testing, protracted bacterial bronchitis foreign body aspiration 566
268 pulmonary function tests 107, 108109
immunology 1928 see also newborns
immunomodulation, anaphylaxis 352 infantile larynx see laryngomalacia
immunoreactive trypsinogen (IRT) 398399 infantile (congenital) lobar hyperinflation 337
Immuno Solid phase Allergen Chip microarray 347 infant plethysmography 108109
immunosuppression Infant Study of Inhaled Saline in Cystic Fibrosis (ISIS)
lung transplantation 647, 649650 108, 109
drug interactions 652t infected emboli 607
malignancy risk 654 infection see respiratory infection(s)
side-effects 651, 651t infection control measures, hospital-acquired pneu-
opportunistic infections 639 monia 245
pulmonary haemorrhage 623 inflammation
surfactant protein-C deficiency 597 allergic 27, 340, 341f
tuberculosis 286 assessment 1718
immunotherapy asthma 318319
allergic asthma 386388 flexible bronchoscopy 136
anti-IgE therapy and 383, 387388 noninvasive tests 100106
indications 386t, 387 OSAS 515
allergic disorders 383389 inflammatory bowel disease 642
allergic rhinitis 359360 inflammatory myofibroblastic tumour (inflammatory
dust mite allergy 360 pseudotumour) 631
efficacy 386, 386t inflammatory pseudotumour (inflammatory myofibrob-
perennial allergens 386 lastic tumour) 631
pollen allergy 360 infliximab 575
seasonal and perennial allergens 386387 influenza viruses 214, 578
systemic side-effects 387, 387t, 388 inhalation 60f
impulse oscillation system (IOS) 118 stridor 5960
inactivity 674 inhalational agents
incipient respiratory failure 544 conscious sedation 157158
increased work of breathing 36 general anaesthesia 157
indoor air pollution 3031 inhaled corticosteroids (ICS)
asthma 302 allergic bronchopulmonary aspergillosis 381
prevention 662664, 663t asthma 320321, 328
induced sputum see sputum induction bronchial hyperresponsiveness 8889
inducible NOS (iNOS) 100 bronchiolitis obliterans 575
industrial pollution 267 bronchopulmonary dysplasia 464
inert-gas washout (IGW) 113 chronic cough 48
anatomical background 113 cystic fibrosis 408
clinical applications 114116 episodic viral wheeze 312
clinical utility 115116 exercise-induced bronchoconstriction 89
cystic fibrosis 113 exhaled nitric oxide fraction reduction 102103
evolution 113114 multiple-trigger wheeze 311, 312
future directions 116 non-CF bronchiectasis 255
normative data 114115 preschool wheezing 310, 312, 313
open questions 116 as maintenance treatment 313314
physiological background 113 primary ciliary dyskinesia 557
infant(s) protracted bacterial bronchitis 269
airway collapse 8182 innate immune system 1923
anaphylaxis 349350 adaptive immune system, interaction with 19, 26
asthma severity 325t allergic response 340
atopic dermatitis 364 antimicrobial factors 20f, 2223
cystic fibrosis cell types 1920, 20f
energy requirement 410 phagocytic defence enhancement 23
infant plethysmography 109 inner-city asthma 31
raised volume rapid thoracic compression 108 inner dynein arm (IDA) 552, 553f
respiratory infections 402 innominate artery, anomalous 136
signs/symptoms 398t insomnia 507, 512
exhaled nitric oxide fraction 101 inspiration 72
698
respiratory mechanics 77 extrapulmonary 290t
inspiratory capacity (IC) 71f, 71t HIV coinfection 281
inspiratory reserve volume (IRV) 71f, 71t immunocompromised child 251252
insulin deficiency, cystic fibrosis 431 as preventive therapy 281
insulin treatment, CF-related diabetes 418 recently infected children 281
interarytenoid cartilage 1 resistance 280
intercostal chest catheter (ICC) insertion 8-isoprostane 104
pneumothorax 488489 isotope imaging methods 189192
triangle of safety 488, 489f imaging equipment/acquisition 191
intercostal muscles 4 indications 189190
interferon regulatory factors (IRFs) 21 patient preparation 190191
interferon- release assays (IGRAs) 214 itching (pruritus), atopic dermatitis 363, 366
tuberculosis 217, 274275 itraconazole 380, 650
interictal epileptiform discharges (IEDs) 516 ivacaftor
interleukin(s), allergic response 340 approval 421
interleukin-5 (IL-5), asthma 328, 331 cystic fibrosis 407, 421, 426, 431
interleukin 31 heterodimeric receptor (IL-31R) 366 VX-809 and 423
intermittent hypoxia 522
International Plastic Bronchitis Registry 579, 580
International Study of Asthma and Allergies in Child-
hood (ISAAC) 293294
J
JarchoLevin syndrome (spondylocostal dysostosis)
International Study of Asthma and Allergy phase I-III 500501
343 jet nebulisers 201202
interrupter resistance (Rint), preschool children 110, 111 Jeune syndrome (asphyxiating thoracic dystrophy) 10,
interrupter technique 8485 500
preschool children 110111, 110f joint flexures, atopic dermatitis 363364
interstitial lung disease (ILD) see diffuse parenchymal joint tuberculosis 272, 273
lung diseases (DPLD)
interval training 676
interventional endoscopy 151155
anaesthesia 159
K
Kalydeco see ivacaftor
interventional radiology 193197 Kartageners syndrome (situs inversus totalis) 553554
consent 193 Kawasaki disease 643
post-procedural follow-up 193 K-complex, stage 2 sleep 509, 510f
pre-procedural planning 193 KCO restriction assessment 17
sedation 193 ketamine 157, 158t
intestinal current measurement, cystic fibrosis 398 kidney disease, lung manifestations 638640, 639t
intraalveolar pressure (PA) 77 Kommerell diverticulum 454, 455f, 459
intrapleural pressure (Ppleur) 77 Kussmaul breathing 50
intubation
acute respiratory failure 542
hospital-acquired pneumonia risk 243
intussusception 416
L
-lactam antibiotics, tonsillitis 230
invasive bacterial diseases (IPDs) 223 lactoferrin 23
invasive pulmonary aspergillosis 218, 219 laminar flow 80
invasive pulmonary capillary haemangiomatosis Lancovutide (denufosol) 424
608609 Langerhans cell histiocytosis 143, 487, 487f, 630635
iodides 408 Langerhans cells 143, 367
ion channel function modulators 424 language skills delay, BPD 471
ipratropium bromide 84 large airway obstruction, flowvolume loop 15, 15f
IQ, bronchopulmonary dysplasia 471 laryngeal atresia 436437
iron overload 642 laryngeal cleft 439440, 439f
irritant avoidance, atopic dermatitis 367 classification 439, 439t
ischaemiareperfusion injury 572 laryngeal cysts 438439
isolated congenital scoliosis 498499 laryngeal haemangiomas 582
isolated tracheo-oesophageal fistula (H-type fistula) laryngeal infections 231
440441 laryngeal masks 158, 159f
isomerism 136 laryngeal obstruction, foreign body aspiration 567
isoniazid, tuberculosis 278, 279t, 280t laryngeal polyp 15f
699
laryngeal webs 437 flexible bronchoscopy 135136
laryngocele 439 obstruction 136
laryngomalacia 335t, 336, 437438 resistance 8182
complications 438 lower respiratory tract infections
diagnosis 438, 438f bacterial, microbiology testing 215217
flexible bronchoscopy 134 biomass smoke 31
stridor 6061, 336, 438 hospital-acquired 243, 246
types 438, 438t pneumonia and 233
laryngoscopy 63, 438, 438f low volume hypothesis 402
laryngotracheobronchitis see croup lumbar hump 499
laryngo-tracheo-oesophageal cleft see laryngeal cleft lumbar puncture, CNS tuberculosis 287
laryngotracheoscopy 582, 583f, 585, 585f lung(s) 1
larynx 1, 2f anatomical subdivisions 3t
airway malformations 436440 at birth 604
resistance 81 development 46, 445
laser surgery 152, 583, 585 factors affecting 910, 9t
latent class analysis, asthma 295 genetic factors 9
latent tuberculosis infection (LTBI) 217, 281, 282 intrauterine 46, 78
late-onset wheeze 295 post-natal 9
LavyMoseley syndrome (spondylothoracic dysostosis) signaling pathways 6
500501 elastic properties 77
law of Laplace 78 gastric content microaspiration prevention 560
learning problems, OSAS 516 immune defences 248, 249t
left main bronchus 2, 136 innate immunity 19, 20f
left ventricle, OSAS 516 initial mechanical barrier 19
leptin 515516, 530 lymphatic drainage 3
leukaemia 632 mechanical barriers 248
leukotriene (LT)B4 antagonist 430 renal medication side-effects 639
leukotriene modifiers 320 topographic anomalies 443
leukotriene receptor antagonists (LTRA) 320321, 355 ultrasonic anatomy 183, 184f
lidocaine 158 lung abscess 240, 263265
limb girdle muscular dystrophies 496 lung agenesis/aplasia 136
limb movements, polysomnography 126, 127 lung allocation score (LAS) 649
lingual tonsil enlargement, obesity 530 lung biopsy
linkage studies, asthma 298, 300t bronchiolitis obliterans 573
lipid intake, BPD 467468 ChurgStrauss syndrome 613
lipid-laden macrophage index (LLMI) 144, 561562 diffuse parenchymal lung diseases 590
lipid-laden macrophages (LLMs) 561, 561f dyspnoea 55
lipoid pneumonia, chronic 143144, 144f eosinophilic lung diseases 611
liposomal amphotericin B 430 pulmonary haemorrhage 620621
liver disease, lung manifestations 637638, 637t surfactant dysfunction mutations 597
liver dysfunction 637638 lung bud 4
liver enzymes 417 lung clearance index (LCI) 14, 75
liver transplantation 638 bronchiolitis obliterans 573
living-related lobar lung transplantation 649 calculation 113, 114
LL-37 (cathelicidin) 23, 366 cystic fibrosis 115
lobar atelectasis, cystic fibrosis 405 normative data 114
lobar pneumonia 233, 234f variability 114115
lobectomy 557 lung compliance (CL) 78, 79f
local anaesthesia 158, 193 age, influence of 7880
Lffler syndrome (simple pulmonary eosinophilia) obesity 528
593, 611 lung contusions 482
long-acting 2-agonists (LABA) 320321 lung failure 545
long face syndrome 360 lung fibrosis 589
long-term oxygen therapy (LTOT) 546547 lung function tests see pulmonary function tests (PFTs)
long-term ventilation 542 lung growth 910, 9t
low birth-weight babies 9 lung injury 533537
lower respiratory tract 14 causes 535, 536t
abnormal distribution 136 insult during development 535
700
secondary 534 lymph node tuberculosis 287
two-hit model 534535 lymphocytes
lung sounds 37 bronchoalveolar lavage 141, 142t
dyspnoea 54 phenotyping, hypereosinophilia 611
lung transplantation 647655 see also individual types
acute cellular rejection 572 lymphocytic alveolitis 143t
anti-infective prophylaxis 650 lymphoma 190, 632, 633634, 634f
bridging measures 649 lymph vessel development 5
bronchiolitis obliterans 571, 572 lysinuric protein intolerance 600
nonimmunological factors 573 lysozyme 23
prognosis 576
risk factors 572
complications 653654, 654t
contraindications 649t
M
macrolides
cystic fibrosis 402, 409, 427434, 432434, 647 asthma 330
contraindications 432, 433434 bronchiolitis obliterans syndrome 653
list for transplant timing 432433 diffuse parenchymal lung diseases 594
patient care whilst waiting 434 pertussis 231
post-operative care 650 plastic bronchitis 579
referral 432, 432t macrophages 19
diffuse parenchymal lung diseases 594 alveolar see alveolar macrophages
donor allocation 648649 magnesium sulphate 323
donor organ lack 433 magnetic resonance imaging (MRI) 176182
early post-transplant period 649 advantages 176, 181
graft rejection 651653 anatomic abnormalities 181
grading 651652 balanced steady-state free precession sequence 177
indications 647, 648t bronchiectasis 181
induction therapy 650 CNS tuberculosis 288
listing criteria 648 congenital thoracic malformations 446
long-term outcomes 654 consolidation 179f, 181
marginal donors 648 contrast media 177
non-CF bronchiectasis 256 cystic fibrosis 180181
ongoing management 650654 diffusion-weighted imaging 177
post-transplant management 647 drawbacks 177
primary ciliary dyskinesia 557 dyspnoea 54
quality of life 648 features 180181
referral 648 haemangiomas 582
management following 649650 indications 180181
rehabilitation programmes 659660 lung infections 178f, 180
retransplantation 653 lung tumours 630
selection for 647648 lymphangiomas 584, 584f
steroid-resistant rejection 652 mediastinal mass 179f
survival rates 654 miliary tuberculosis 288
tuberculosis 286 neoplasm 181
lung tumours 630632 non-CF bronchiectasis 255
benign 632 patient compliance 177
malignant 631632 pneumonia 178f, 180, 181f
metastatic 632 pulmonary infiltrates 180
primary 630631 regular imaging 178f, 180
surgery 631 respiratory phase control 177
systemic disease, secondary involvement 632 single-shot fast spin echo sequence 177
see also individual tumours spinal tuberculosis 289
lung volume spoiled gradient echo (3D gradient-echo) sequence
increases through childhood 9 177
measurements 1214 technical problems 176
lymphangiomas 582, 583584, 584f techniques 176177
lymphangiomatosis 645 tracheal stenosis 442
lymphatic abnormalities, plastic bronchitis 578 tracheomalacia 441442
lymph node biopsy 287 tuberculous arthritis 290
701
vascular malformations 457458 metabolic acidosis 94t, 96
magnetic resonance imaging (MRI) perfusion 177 anion gap 9697
magnetic resonance imaging (MRI) ventilation 177179 metabolic alkalosis 94t, 96, 97
major basic protein (MBP) 355 compensatory response 94t, 97
malnutrition 286, 431 metabolic disorders 96
mannitol 86, 424, 430 compensation for 93, 94t
Mantoux test 274 diffuse parenchymal lung diseases in 591
Marfans syndrome 643 metabolic equivalent (METs) 676
mass median aerodynamic diameter (MMAD) 199, 204 metabolomics 104
mast cells 20, 354 methacholine 8586, 85f, 88, 89, 573
maternal-fetal tolerance, paternal allo-antigens 2627 methicillin-resistant Staphylococcus aureus (MRSA) 244
maternal malnutrition 9 methylprednisolone 380, 430, 575, 593594
maternal smoking 10 methylxanthine compounds 526
mattress encasings 384, 384t microarray testing, allergy 347
maximal expiratory flow at x% of FVC (MEFx) 72t microbiology 214220
maximal midexpiratory flow (MMEF) 72t microliths 143
maximum intensity projection (MIP), CT 172, 172f microorganism recognition 21
McLeods syndrome 573574 microscopy
Mclsaac score 230, 230t bacterial infections 215, 216
MDCT see multidetector computed tomography fungal infections 218219
(MDCT) midazolam 157, 158t, 191
mechanical ventilation middle ear otitis 360
adverse effects on lungs 469 miliary tuberculosis 272, 273, 282, 288, 288f
alveoli, effects on 534 milk protein intolerance 416
closed lung regions 534 minimum intensity projection (MinIP) 172173, 173f
evaluation, polysomnography 123 mini-thoracotomy 261262, 480
meconium ileus 414 mitochondrial myopathy 495t
meconium plug syndrome 414 mitogen-activated protein kinase (MAPK) 21
median sternotomy 484 mixed acidbase disorders 93
mediastinal lymphadenopathy, TB 275, 275f mixed apnoea 128t, 517, 518f, 526
mediastinal lymph nodes 4, 272 moderate sedation, flexible bronchoscopy 159
mediastinal mass 179f moist cough 48
mediastinal tumours 633634 Moli 1901 (lancovutide) 424
anterior mediastinum 633 mometasone 320
germ cell 634 monkey trap phenomenon 568
posterior mediastinum 633, 634 monoclonal antibody therapy 322, 650
mediastinitis 483484 monophonic wheeze 59
mediastinum 1, 34 montelukast
lymphatic drainage 3 bronchiolitis obliterans 575
medical history 3335 episodic viral wheeze 311
age of onset, symptoms 3435 preschool wheezing 310, 312, 314
chief complaint 3435 Moraxella catarrhalis 209, 209t, 211, 215, 266
past 3435 Morquios syndrome 644
symptoms seasonality 34 mosaic attenuation pattern, CT 170
medication history 34 mould avoidance 386, 663, 663t
melatonin 503, 504 mouse exposure 386
Melbourne Asthma Study 295 MRI see magnetic resonance imaging (MRI)
membranous glomerulonephritis 607, 639t mucoepidermoid carcinoma 631
memory B-cells 25 mucopolysaccharidoses 637t, 641t, 644
Memory Encoding theory, sleep 504 mucosa examination 136
memory performance, BPD 471 mucosal immune system 25
memory T-cells 25 mucus hydrators, cystic fibrosis 423424
menarche, early, asthma 302 mucus plugging, plastic bronchitis versus 577
Mendelian susceptibility to mycobacterial diseases mucus plug removal 144
(MSMD) 285 multichannel intraluminal impedance and pH (MII-pH)
meniscus sign 259, 259f, 477 monitoring 563
meperidine 157, 158t multichannel intraluminal impedance (MII) monitoring
mesenchymal hamartomas, chest wall 635 563
mesh nebulisers 202 multidetector computed tomography (MDCT)
702
double aortic arch 454f nasopharyngeal airway malformations 435436, 436t
pulmonary sling 457f nasopharyngeal prongs 158
right aortic arch 455f National Institutes of Health (NIH) BPD diagnostic
scanners 167 criteria 462, 463t
vascular malformations 454f, 455f, 457458, 457f natural killer cells 20
multidrug-resistant tuberculosis (MDR-TB) 252, 280, nebulisers 200202
291 advantages/disadvantages 201
multilobular cirrhosis (MLC) 416 drugs used 200
multiple-breath washout (MBW) 113117 recommended fill volume 201
bronchiolitis obliterans syndrome 116 types 201202
bronchopulmonary dysplasia 116 necrotising pneumonia 262263
clinical utility 115116 needle aspiration, pneumothorax 488489
cystic fibrosis 115 neonatal hyperbilirubinaemia 417
functional residual capacity 75 neonatal intensive care units (NICU)
future directions/open questions 116 early life challenges 466
outcome parameter 113 energy consumption 466
parameters 114 health, effects on 469470
static lung volumes 75 hospital-acquired pneumonia 242, 243
technique 114, 115f neurodevelopment outcomes 469470
multiple-trigger wheeze (MTW) 294, 295, 311312 neonates
multi-slice spiral computed tomography 166167 cystic fibrosis signs/symptoms 398t
muscle fatigue 540 grunting 62
muscle sounds 37 see also newborns
mycobacterial infections 217218, 245 neuroendocrine cell hyperplasia of infancy 593
Mycobacterium abscessus 429 neurological disease 641t
Mycobacterium tuberculosis neuromuscular disorders 492496
gastric aspirates 217 acute respiratory complications 495496
hospital-acquired pneumonia 245 bulbar involvement 493
immune responses to 284285 chronic respiratory failure 543544
interferon- responses 284 long-term assisted ventilation 493
PCR 218 orthopaedic treatment 501
pleural infection 260 other systems/complications 496
mycophenolate mofetil 651t palliative care 496
Mycoplasma pneumoniae 209, 209t, 235236, 235t, 263 pathophysiology assessment 492493
Mycoplasma tuberculosis 270272, 273 prevalence 492
myeloid differentiation primary response gene 88 respiratory complications 494495t
(MyD88)-in/dependent pathways 21 sleep disordered breathing 524525
myocardial tuberculosis 289 surgical interventions, intercurrent 495496
myotonic dystrophy 495t neutropenic sepsis 244
neutrophilic alveolitis 143t
N
nanoduct sweat analysing system 397, 399f
neutrophils 20, 249t
bronchoalveolar lavage 141, 142t
protracted bacterial bronchitis 267
napkin ring cartilages 442 recruitment 23
nasal airway, choanal stenosis/atresia 436 newborns
nasal allergen challenges 347, 358 chest radiography 161
nasal cannulas 541, 548 expiration 80
nasal crease 357 FRC upregulation 7980
nasal mask 548 sleep 511512
nasal mucosa examination 35 tuberculosis 274
nasal-oral airflow measurement 125 see also infant(s)
nasal passages examination 35 next-generation sequencing, asthma 300t
nasal polyps 35 NiemannPick disease 600, 637t, 644
nasal potential difference, cystic fibrosis 398 nitric oxide
nasal prongs 548 acute respiratory distress syndrome 536
nasal salute (allergic salute) 35, 357 bronchopulmonary dysplasia 464
nasogastric feeding 307, 411, 564 conscious sedation 157158
nasogastric tubes, hospital-acquired pneumonia risk nitric oxide scrubber 101
243 nitric oxide synthases (NOS) 100
703
nitrogen analyser 13 REM sleep versus 505t
nitrogen multiple-breath washout 113114, 115f, 116 slow-wave activity 506
BPD 116 stages 503, 508
nitrogen washout 13, 14, 113114 nuclear factor (NF)-B 21, 462
NIV see noninvasive ventilation (NIV) nucleotide-binding oligomerisation domain (NOD)
NKX2-1 gene mutation 597 proteins 21
nocturnal hypoventilation 546 nutrition 660661
noisy breathing 5764 asthma 302
causes 57, 58t bronchiolitis obliterans 575
non-CF bronchiectasis (NCFB) 253257 bronchopulmonary dysplasia 463, 464
aetiology 253254 cystic fibrosis 410411, 431
diagnosis 254 neuromuscular disorders 493
epidemiology 253 plastic bronchitis 580
idiopathic cases 253 nutritional deficiencies, TB 286
imaging 254255 nystatin 650
immunodeficiency 253, 254f
inpatient treatment 256
microbiology 254
pathophysiology 253
o
obesity 528532
prevalence 253 assessment methods 528
prognosis 256 asthma 302, 319320, 529530
pulmonary function 255 chronic inflammation 530
sleep disturbances 256 definition 528
surgery 256 exercise intolerance 66t, 68
symptoms 254 lung function in 528529, 529t
treatment 255 OSAS 515, 530531
non-Hodgkin lymphoma 632, 633, 634f prevalence 528
noninvasive positive-pressure ventilation (NIPPV), prevention 660661
BPD 463 obesity-associated syndromes 531
noninvasive pressure support, acute respiratory failure obesity hypoventilation syndrome (Pickwickian syn-
541542 drome) 531
delivery methods 541542 Objective-SCORAD (O-SCORAD) 365
mechanisms 541 obstructive alveolar hypoventilation 517
noninvasive ventilation (NIV) 545550 obstructive apnoea 128t, 129f, 514, 518f, 526, 530531
aims 547 scoring criteria 517
bronchopulmonary dysplasia 463 obstructive apnoeahypopnoea index 128, 128t
chronic alveolar hypoventilation 548 obstructive apnoea index 128t
cystic fibrosis 430431 obstructive disorders 11, 12f
Duchenne muscular dystrophy 493 assessment 1415
at home 547548 expiratory flowvolume loop 14
indications 547 obstructive sleep apnoea syndrome (OSAS) see OSAS
interface 548 octreotide 481482
lung injury 536 oesophageal atresia 440
modes 547, 548 oesophageal pH measurement
neuromuscular disorders 493, 496 gastro-oesophageal reflux disease 563
spinal muscular atrophy 493 polysomnography 126
starting criteria 547 oesophageal pressure monitoring 125
target values 547 oesophageal reflux 496
ventilators 547 oesophageal studies 562f, 563, 563f
non-rapid eye movement (NREM) sleep see NREM omalizumab
sleep allergic asthma 383, 388
nontuberculous mycobacteria 429 allergic bronchopulmonary aspergillosis 381
Noonans syndrome 641t asthma 322, 328, 329330, 331
nosocomial (hospital-acquired) infections 242 costs 329330
NREM-REM cycles 508 oncomycosis 250
NREM sleep Ondines curse (congenital central hypoventilation
central nervous system regulation 507 syndrome) 523524, 524f, 526
infants 511 open-lung biopsy 250, 607
neurochemistry 507 opportunistic infections 248252
704
Optiflow system 542 cystic fibrosis 409, 430431
oral appliances, OSAS 518 in-flight 672
oral glucose tolerance test (OGTT) 418 pneumothorax 488
oral immunotherapy (OIT), food allergy 374 primary pulmonary hypertension 606
oral nutritional supplements, cystic fibrosis 411 pulmonary arterial hypertension 474
orphan drug therapies, cystic fibrosis 393 respiratory failure 545545
orthodontic abnormalities, OSAS 514515 oxyhaemoglobin dissociation curve 95f
orthodontic treatment, OSAS 518
OSAS 61, 514520
associated conditions 514, 515t
cardiovascular complications 516
P
PaCO2 94t, 95
clinical examination 62 paediatric intensive care unit (PICU)
comorbidities 515516 asthma exacerbations 323
definition 514 bronchiolitis 306307
diagnosis 61, 514517, 519f chest radiography 161, 163, 163f
history 6162 hospital-acquired pneumonia 243
as inflammatory condition 515 post-cardiac surgery 640
learning problems 516 ventilator-associated pneumonia 242, 243
mild 128 paediatric lung imaging 176179
moderate 128 palatal plates 436
obesity 530531 palivizumab
pathogenesis 514515 bronchiolitis 309
as polygenic disease 514 national guidelines 222
polysomnography 122123, 517 respiratory syncytial virus 221222, 309
predisposing conditions 531 palliative care, neuromuscular disorders 496
prevalence 514 pancreatic enzyme replacement therapy (PERT)
risk factors 62 cystic fibrosis 411412
severe 128 fibrosing colonopathy and 411, 415
signs/symptoms 6162, 514515, 515t pancreatic exocrine complications, cystic fibrosis 413
treatment 517518, 519f pancreatitis, acute 642
indications 128131 PaO2 95
upper airway collapsibility 514 PaO2/inspiratory oxygen fraction (FiO2) 95
osteopenia 432 PaO2/PAO2 ratio 96
osteoporosis, CF-associated 418419 papillomas 584586
osteosarcoma 632 papillomatosis 63, 582, 585f
otitis media with effusion (glue ear) 229, 360 paradoxical breathing 5152
outdoor air pollution paradoxical reaction (immune reconstitution syn-
asthma 302 drome) 279
prevention 662664, 663t parainfluenza viruses 214
outer dynein arm (IDA) 552, 553f parapneumonic effusion (PPE) 258, 260
ovalbumin allergy 367 acute reactants 259
OX40 ligand (OX40L) 378 imaging 258259, 259f
oxidative stress, OSAS 516 parapneumonic pleural effusion 477, 478
oximetry see pulse oximetry parasites 612613
oxygenation adequacy assessment 9596 parasomnias 511, 512
oxygen concentrator 547 parenteral nutrition 467, 481
oxygen desaturation, flexible bronchoscopy-induced paroxysmal activity, OSAS 516
138 partial pressure of inspired oxygen (PiO2), acute
oxygen dissociation curve (ODC) 538539, 539f respiratory failure 541
oxygen-enhanced MRI 177 particulate matter (PM) 30, 267
oxygen saturation exposure reduction 663t, 664
exercise testing 676 patent ductus arteriosus (PDA) 463
polysomnography 125, 127 pathogen-associated molecular patterns (PAMPs) 21
oxygen supplementation/therapy patient education 657
acute respiratory failure 541 pattern recognition molecules (PRR) 21
asthma exacerbations 323 PCO2 54
bronchiolitis 307 PCR
bronchopulmonary dysplasia 473 Aspergillus 219
community-acquired pneumonia 238239 bacterial pneumonia 216
705
community-acquired pneumonia 238 treatment planning 665
fungal infection 219 physostigmine 508
pleural infection 259 Pickwickian syndrome (obesity hypoventilation syn-
pneumonia 209 drome) 531
tuberculosis 218 PierreRobin sequence 436
virus detection 215 pig bronchus (tracheal bronchus) 136, 443
PCV10 vaccine 223, 224 pilocarpine iontophoresis 397
PCV13 vaccine 223, 224 pimecrolimus 368
peak expiratory flow 72t pineal body 504
peanut allergy 367 placebo effect, cough 47
pectus carinatum 498 plasma cell granuloma 631
pectus excavatum 498 plastic bronchitis 577581, 642
pentamidine 251 diagnosis 577578, 578f
pepsin 144, 561, 562 disease associations 578579, 579t
percussion 36 mucus plugging versus 577
dyspnoea 5354 therapy 579580, 580t
peribronchial thickening 255 plethysmography see whole body plethysmography
pericardial tuberculosis 289 pleurae, lymphatic drainage 3
pericardiocentesis 289 pleural drain, pleural effusion 478479
periodic breathing 128t, 526 pleural effusion 259f, 477480
periodic leg movement index 127 aetiology 477
peripheral cyanosis (acrocyanosis) 39 chylothorax 480, 482f
peripheral eosinophilia 611 clinical picture 477
peritoneal dialysis 640 community-acquired pneumonia 239
peritonsillar abscess 229230 diagnosis 477478
persistent fetal circulation 604 follow-up 480
persistent wheeze 295 imaging 163f, 477478, 478f
pertussis (whooping cough) 212, 231 intrauterine 10
pertussis vaccination 212 long-term outcome 480
pest avoidance 385386 management 478480
pet allergens necrotising pneumonia 262
avoidance 320, 385, 385t, 662 peritoneal dialysis 640
particle size 383 physical examination 477
Pfeiffer syndrome 436 pleural tuberculosis 288
pH 9495 pneumonia 477
asthma 104 renal disease 638639
phalangeal depth ratio inversion 43 surgery 479480
pharyngitis 215, 229231 yellow nail syndrome 645
phosphodiesterase-5 inhibitors 606 pleural fluid analysis
phototherapy 369 chylothorax 480
PHOX2B gene 523524 pleural infection 260
phthalates 30 pleural tuberculosis 289
physical activity see exercise/physical activity pleural friction sound (friction rub) 39
physical examination 3343 pleural infection 258262
physical fitness 673 diagnosis 258
exercise intolerance 66t, 68 imaging 258259
physiotherapy 665669 laboratory findings 259260
aims 665 management 260
cystic fibrosis 407, 430, 650 microbiology 260
evidence 668 prognosis 262
group events 668 stages 258262
neuromuscular disorders 493495 surgery 261
organisational aspects 668669 treatment 260262
primary ciliary dyskinesia 557 pleural line, ultrasound 186
principles 665 pleural space, adhesion forces 7778
protracted bacterial bronchitis 269 pleural tuberculosis 288289
rehabilitation 667 pleural tumours 635
technology-dependent child management 667668 pleuritic chest pain 250
training 668669 pleurodesis 482
706
pleuroperitoneal shunt 482 polyethylene glycol (PEG) lavage 415
pleuropulmonary blastoma (PPB) 631 polymorphisms, cystic fibrosis 395
pneumatoceles 240, 240f, 262, 478 polymorphonuclear leukocytes (PMLs) 23
pneumococcal pneumonia 223224 polyphonic wheeze 59
23-valent pneumococcal polysaccharide vaccine polysomnography (PSG) 122131
(PPV23) 223 arousal summary 127
pneumococcal vaccination 210, 223224 body position measurement 126
Pneumocystis carinii see Pneumocystis jirovecii carbon dioxide
Pneumocystis carinii pneumonia (PCP) 251 interpretation 127
Pneumocystis jirovecii measurement 125126
hospital-acquired pneumonia 244245 components 123, 124f, 124t
opportunistic infections 251 congenital central hypoventilation syndrome 523
pneumomediastinum 489490, 489f, 490t cystic fibrosis 431
pneumonia first night effect 123
acute respiratory distress syndrome 535 gas exchange 127
aetiology 215216 interpretation 126128
atypical 209 heart rate/rhythm 127
biomass smoke 31 sleep architecture components 126127
bronchial sounds 54 manual scoring 123
bronchoalveolar lavage 141142 normal values 128131, 130t
classifications 208209 OSAS 62, 122123, 517
community-acquired see community-acquired obesity and 531
pneumonia (CAP) pre-operative 122
crackles 38, 54 respiratory effort measurement 125
definition 208209, 233 respiratory events 127128, 128t, 525526
epidemiology 208210 respiratory indications 122123
gastro-oesophageal reflux disease 560 setting 123
hospital-associated see hospital-acquired sleep disordered breathing 525526
pneumonia (HAP) sleep stage analysis 126, 126f
imaging 163, 163f, 178f, 180, 181f, 186f, 187188, 187f study timing 126
incidence 209210, 210f technique 123
infective agents 209, 209t, 215216 treatment indications 128131
nonspecific laboratory evaluations 216217 treatment response assessment 122123
overdiagnosis 233 polysplenia 554
pleural effusion 477 Pompe disease 495t
prognosis 210 portal hypertension (PHT) 416, 417
radiological 209 posaconazole 381, 430
risk factors 210 positional cloning, asthma 298, 300t
tachypnoea 52 positive airway pressure, foreign body removal 568
typical 209 positive end-expiratory pressure (PEEP)
pneumothorax 485489 acute respiratory distress syndrome 535536
bronchial biopsy complication 148149 lung recruitment 534535
classification 485 tracheomalacia 442
cystic fibrosis 406, 486, 487f positive expiratory pressure (PEP) 666
epidemiology 485 positive pressure devices 431
imaging 187, 487488, 487f positive pressure in pleural space (Ppl) 73, 74
large 487 positive pressure ventilation
observation 488 biotrauma 534
pathogenesis 485486 bronchopulmonary dysplasia 462
physical examination 486487 cardiovascular system, effects on 542
recurrence 489 positron emission tomography (PET), sleep deprivation
size calculation 487488 512
suction 489 post-bronchoalveolar lavage fever 132, 138, 144
surgical management 489 post-cardiac surgical whiteout 640642
symptoms 486487 post-infectious cough 47, 48
therapy 488489 post-nasal drip syndrome 47
Poland syndrome (sequence) 497498 post-transplant lymphoproliferative disease (PTLD)
pollen allergy 345, 356, 383 650
pollenfood syndromes 361 potassium depletion 97
707
Potters syndrome 639t inflight SpO2 670, 671f
Potts disease 289 neurodevelopment outcome 469470
Prader-Willi syndrome 524, 531 bronchopulmonary dysplasia 470471
preacinar region 2 respiratory distress syndrome 54
prebiotics 374 respiratory support advances 469
pre-Botzinger complex 522 surfactant deficient 7
prednisolone/prednisone primary ciliary dyskinesia (PCD) 551558
allergic bronchopulmonary aspergillosis 380 as associated diagnosis 554555
allergic rhinitis 359 bronchial brushing 147
asthma exacerbations 323 bronchiectasis 551, 552
ChurgStrauss syndrome 613 carrier status 552
cystic fibrosis 430 clinical aspects 552555, 555t
diffuse parenchymal lung diseases 593 diagnosis 551, 554, 555556
extrapulmonary tuberculosis 291 ear symptoms 553
farmers lung 616 environmental exposures 557
graft versus host disease 575 exhaled nitric oxide fraction measurement 17
pulmonary haemorrhage 623 genetics 552, 556
side-effects 651t genetic testing 556
tuberculosis 279 infertility 554
pregnancy inheritance 552, 554t
cystic fibrosis 411 lower airway disease 552
environmental pollution exposure 26 outpatient follow-up 557558
history taking 35 prevalence 551
innate-adaptive immune systems interaction 26 respiratory treatment 556557
smoking during 10, 29 screening tests 555
tuberculosis 273 surgery 557
premature stop codons (PTCs) 423 ultrastructural defects 551
premature stop codons (PTCs) suppressors 423 upper airway symptoms 553
premedication, bronchoscopy 156 primary graft dysfunction/failure 572, 650
preschool children primary progressive tuberculosis 272
asthma severity 325t primary pulmonary hypertension (PPH) 605607, 605t
pulmonary function tests see pulmonary function novel therapies 606607
tests (PFTs) primary pulmonary vascular disease 604609
preschool wheeze/wheezing 310315 primary spontaneous pneumothorax (PSP) 485
acute episode treatment 312313 primitive aortic arch 452
birth cohort studies 310 probiotics 368, 374
classification 311, 312, 312t process C, sleep 504506
diagnostic approach 312 process S interactions 505506
epidemiology 310311 process S, sleep 506
maintenance treatment 313314, 314t process C interactions 505506
nonpharmacological 313 prone positioning, ARDS 536
outcome prediction 311 propofol 157, 158t, 159
pathophysiology 310 propranolol 583, 583f
persistence to school age 311 prostacyclin 606
phenotype distinction limitations 311312 prostaglandins 355
treatment failure 314, 314t protective ventilation 534535
typical wheeze 312 acute respiratory distress syndrome 534536
Preservation Theory of sleep 504 protein hydrolysate formulas 410
pressure-controlled ventilation (PCV) technique 169 protein intake, BPD 467468
pressure in the airway lumen (Pintrabronch) 74 proton pump inhibitors (PPIs) 563564
pressurised metered-dose inhalers (pMDIs) 200, protracted bacterial bronchitis (PBB) 34, 266269
202203 aetiology 266
breathing manoeuvre 202203 diagnosis 268
pressurised metered-dose inhalers/valved holding differential diagnosis 266
chamber (pMDI/VHC) 198, 200, 202203 epidemiology 266
preterm babies/infants management 269
health, effects on 469470 pathogenesis 267
imaging 54 prognosis 269
infant plethysmography 109 relapse 269
708
risk factors 266267 pulmonary haemorrhage 619624
symptoms 267268 aetiology 619, 620t, 621t
vaccination, impact of 266 childhood 619, 621t
provocative concentration causing a 20% fall in FEV1 clinical presentation 620
(PC20) 8586, 85f cystic fibrosis 623
provocative dose causing a 20% fall in FEV1 (PD20) diagnostic workup 620, 622, 622f
8586 differential diagnosis 621t
pruritus (itching), atopic dermatitis 363, 366 diffuse 621623
Pseudomonas aeruginosa focal 623
cystic fibrosis 408, 425 histopathology 620621
non-CF bronchiectasis 254 imaging 620
primary ciliary dyskinesia 557 infancy 619, 621t
pseudorandom noise 118 management 623
psychogenic (habit) coughing 48 neonatal 619, 620t
PTC 124 (ataluren) 423, 431 physical examination 620
puberty, allergic disorders 339 prognosis 623624
pulmonary alveolar microlithiasis 143 pulmonary hypertension 601, 602, 638
pulmonary alveolar proteinosis (PAP) 7, 142, 592, classification 601602, 602t, 603t
596600 due to pulmonary vascular disease 604
bat wing pattern 599 epidemiology 602
causes 598, 599t functional classes 603t
clinical course 599600 surfactant dysfunction mutations 597
clinical manifestations 598599 pulmonary hypoplasia 910
diagnosis 598599 pulmonary infiltrates 180, 610
differential diagnosis 600 pulmonary interstitial glycogenosis 593
pathomechanism 596597 pulmonary lymphatics 3
physical examination 599 pulmonary oedema, renal disease 638
therapeutic strategies 599600 pulmonary rehabilitation 656
pulmonary arterial hypertension (PAH) 473474 pulmonary sequestration 336
pulmonary arterial pressure (PAP), pulmonary hyper- pulmonary sling 136, 454455, 457f
tension 601 associated tracheobronchial anomalies 455, 457f
pulmonary artery 3 chest radiography 456
development 5, 602 congenital heart defects and 455
pulmonary aspiration embryology 454455
bronchoalveolar lavage 144 surgery 459
gastro-oesophageal reflux-related pulmonary tethering 81, 81f
biomarkers 561562 pulmonary trunk development 45
diagnosis 144 pulmonary valves, absent 136
radiology 562563 pulmonary vascular disorders 601609
treatment 563564 pulmonary vascular resistance (PVR), pulmonary
pulmonary embolic disease 607608, 608t hypertension 601
cardiac disease and 642 pulmonary vasculature 3
pulmonary function tests (PFTs) 107112 development 78, 602604
acute respiratory failure 541 abnormal 604
allergic bronchopulmonary aspergillosis 379380 pulmonary vasculitis 591592
bronchiolitis obliterans 573 pulmonary veins 3
chronic respiratory failure 544 development 5
difficulties in 75 pulmonary veno-occlusive disease 607
diffuse parenchymal lung diseases 590 pulse oximetry 93
dyspnoea 55 bronchiolitis obliterans 574
hypersensitivity pneumonitis 616 community-acquired pneumonia 237
infants 108109 cyanosis 39
preschool children 107, 109111 dyspnoea 54
protracted bacterial bronchitis 268 exercise testing 676
pulmonary alveolar proteinosis 599 neuromuscular disorders 493
pulmonary haemorrhage 620 polysomnography 127
sedation 107 respiratory distress 54
sickle cell disease 627 restriction assessment 17
tracheal stenosis 442 sleep disordered breathing 62
709
pyrazinamide 251252, 278, 279t, 280t, 290t tonic characteristics 511
renal dysfunction 638640
Q
questionnaires, asthma 324
residual volume (RV) 71f, 71t
bronchiolitis obliterans 573
bronchopulmonary dysplasia survivors 475
quiet sleep, newborns 511 diffuse parenchymal lung diseases 590
measurement 70
R
rabbit nose (Bewitched sign) 35
restrictive disorders 16
skeletal abnormalities 16
residual volume/total lung capacity (RV/TLC) ratio
radiation exposure 183 adolescent idiopathic scoliosis 499
radiofrequency ablation 194 bronchiolitis obliterans 573
radionuclide imaging, BPD 474 bronchopulmonary dysplasia survivors 475
radiopharmaceuticals 191 diffuse parenchymal lung diseases 590
radiotherapy 631 early airway closure 15
raised volume rapid thoracic compression (RVRTC) resistance 8082
108 lower airways 8182
rales see crackles lung volume relationship 81, 81f
rapid antigen tests 238 upper airways 81
rapid eye movement (REM) sleep see REM sleep volume dependent 81, 81f
rapid maxillary expansion, OSAS 518 resistance of the airway (RAW) 80
rattle 57, 58t, 62 resistance of the whole respiratory system (RRS) 8081
reactive oxygen species, OSAS 516 respirable particles 199
recombinant human DNase (rhDNase) 430, 557 respiratory acidosis 94t, 95, 539
rectal prolapse 416 respiratory alkalosis 54, 94t
recurrent laryngeal nerves 1 respiratory depression, flexible bronchoscopy-induced
recurrent respiratory papillomatosis (RRP) 584586 138
recurrent wheeze respiratory disease
bronchopulmonary dysplasia 473 cardiovascular presentation 640
infant plethysmography 109 environmental determinants 2932
raised volume rapid thoracic compression 108 respiratory disorders 9596
regulatory T-cells (Tregs) 22, 24, 340 compensation for 93, 94t
rehabilitation programmes 656661 metabolic compensation 95
components 659t respiratory distress 5056
disease-specific 657661 causes 50, 51t
educational programmes 657 history taking 52
elements of 657 management 56
evidence-based support 658 objective signs 50
inpatient versus outpatient 656 pulse oximetry 54
multidisciplinary team approach 657 respiratory distress syndrome (RDS)
participation criteria 657, 658t preterm babies 54
physiotherapy 667 surfactant abnormalities 7, 461462, 597
targets 656657, 657t ultrasound 184186, 185f
remifentanil 157, 158t see also acute respiratory distress syndrome (ARDS)
REM-off cells 508 respiratory diverticulum 4
REM-on cells 507508 respiratory failure
REM sleep 126, 127, 508 acute see acute respiratory failure (ARF)
apnoea of prematurity 522 chronic see chronic respiratory failure
behaviour disorders 511 respiratory health, environmental determinants 2932
central nervous system regulation 507 respiratory infection(s) 335336, 335t
cholinergic activation 507 acute
EEG 510511, 511f epidemiology 207211
infants 511 global burden 207
latency 127 bronchoalveolar lavage 141
motor activity suppression 507 bronchopulmonary dysplasia 473
neurochemistry 507508 chronic, epidemiology 211212
NREM sleep versus 505t, 511 diffuse parenchymal lung diseases 592
phasic characteristics 511 early life
snoring 61 allergic inflammation and 27
710
effects of 10 rib hump 499
innate-adaptive immune systems interaction 26 rib hump resection 501
flexible bronchoscopy indications 135t ribs 4
neuromuscular disorders 495496 Rich foci 287
wheezing 335336 rifampicin
see also individual diseases extrapulmonary tuberculosis 290t
respiratory mechanics 7782 interactions 279, 280
determining factors 77 resistance 277, 280
forced oscillation technique 120 tuberculosis 278, 279t, 280t
impedance 77 HIV coinfection 280
non-elastic forces 77 immunocompromised child 251252
respiratory muscles recently infected children 281
obesity 528529 right aortic arch 136, 453454
weakness, neuromuscular disorders 492 associated cardiac malformations 453
respiratory physiotherapy see physiotherapy clinical presentation 453454, 455f, 456f
respiratory rate imaging 455f
normal, age-related changes 50 treatment 458f, 459
physical examination 36 right bronchomediastinal lymphatic trunk 3
respiratory related arousals (RERA) 128t right heart catheterisation 604, 605606
respiratory sounds 37 right main bronchus 2
chronic bronchitis 211 right-to-left shunts 189
future development 6364 rigid bronchoscopy 151155
respiratory syncytial virus (RSV) 214, 221223 anaesthesia 159
bronchiolitis 207 contraindications 154
epidemiology 221 difficulties 154
hospital-acquired 244 dyspnoea 55
hospital-acquired pneumonia 244 flexible bronchoscopy versus 152
immunisation 221223 foreign body aspiration 59, 60, 152, 153f, 568
passive 221222 future developments 154
pertussis-like illness 212 historical aspects 151
risk factors 221 indications 152
seasonality 207, 208f instruments used 152, 153f
respiratory system isolated tracheo-oesophageal fistula 441
air flow 7273 laryngeal clefts 439
anatomy 110 monophonic wheeze 59
development 110 sedation 156, 159
elastic properties 7780 stridor 60
physiological changes during sleep 505t technical considerations 151152
time constant () 81 tubes 151, 152t
respiratory system impedance (Zrs) 118, 119f rigid laryngotracheoscopy, stridor 61
respiratory system reactance (Xrs) 118, 119 rigid spine muscular dystrophy 494t
respiratory system resistance (Rrs) 118, 119 rigid telescopes 151, 152t, 153154, 154f
Restorative Theory of sleep 504 RileyDay syndrome (familial dysautonomia) 523,
restrictive diseases/disorders 11, 12f 644645
assessment 1617 ring-sling complex 455
flowvolume loop 16, 16f running test 86
tachypnoea 5253
retropharyngeal abscess 230
Rett syndrome 522
reversibility see bronchodilator reversibility
S
salbutamol
Reynolds number (Re) 80 asthma 56
rheumatic fever 230 asthma exacerbations 323
rhinosinusitis 228 bronchiolitis 307
cystic fibrosis 418 bronchodilator reversibility 8384, 84f
rhinovirus(es) (common cold virus) 87, 214, 341 cystic fibrosis 407
rhonchus (rhonchi) 38 obstructive bronchitis 56
rhythm electrocardiogram, polysomnography 125 preschool wheezing 313
ribavirin 652 saliva, chronic aspiration 559
rib cage, postnatal development 9 sarcoidosis 591, 637t, 641t
711
sawtooth wave forms, REM sleep 510, 511f sickle haemoglobin (HbS) 39, 625
Schamroth sign 43 siderophages 620
scintigraphy, GOR-related aspiration 562563 sildenafil 584, 606
scleroderma 639t, 641t, 643 simple pulmonary eosinophilia (Lffler syndrome)
sclerosing substances 482 593, 611
scoliosis single-breath washout (SBW) 17, 113117
lung function 501 asthma 115
neuromuscular disorders 492493 bronchiolitis obliterans 573
orthopaedic techniques 497 bronchiolitis obliterans syndrome 116
orthopaedic treatment 501 clinical utility 115116
respiratory compromise 497 cystic fibrosis 115
SCORAD index 365 expirogram 114, 114f
scuba diving 675 future directions/open questions 116
secondary hypoventilation syndromes 524 parameters 114f
secondary spontaneous pneumothorax (SSP) 485, 486, technique 114, 114f
486t, 489 single-photon emission computed tomography
second-hand smoke see environmental tobacco smoke (SPECT) 191
(ETS) sinus disease, cystic fibrosis 418
secretory immunoglobulin A (sIgA) 2425 sinusitis 215, 335
secretory immunoglobulin M (sIgM) 2425 sirolimus 584
secretory immunoglobulins 2425 situs ambiguus (heterotaxy) 553554
sedation situs inversus 136
bronchoscopy 156160 situs inversus totalis (Kartageners syndrome) 553554
interventional radiology 193 skeletal tuberculosis 272, 273, 289290
isotope imaging methods 191 skin prick tests (SPTs) 346, 346t, 347t
rigid bronchoscopy 159 allergic rhinitis 357
see also anaesthesia food allergy 373
segmental bronchi 2 interpretation 347t
self-injectable adrenaline, anaphylaxis 352, 352t procedure 346, 346f
self-management education, preschool wheezing 313 sleep 503513
seminomas 634 age-related changes 511512
serology architecture 508512
bacterial pneumonia 216 biological function theories 504
upper respiratory tract infections 215 central nervous system regulation 506
virus detection 215 duration 511
serotonin (5-hydroxytryptamine), sleep 507 neurochemistry 507508
serum allergen-specific IgE analysis newborns 511512
allergen panels 347t physiology 503506, 505t
allergic disorders 346347, 346t REM see REM sleep
allergic rhinitis 357 respiratory failure during 546
allergy 347 slow-wave see slow-wave sleep (SWS)
food allergy 373 stages 508512
sevoflurane 159 switch 507
SFTPB gene mutation 597 Sleep Clinical Record, OSAS 517
SFTPC gene mutation 597 sleep deprivation 512
short-acting 2-agonists (SABA) 320 sleep disordered breathing (SDB) 61
shunt 538539 clinical features 521525
SIADH (syndrome of inappropriate secretion of anti- evaluation 62
diuretic hormone) 306 neuromuscular disorders 492, 493, 524525
sickle cell disease (SCD) 625629, 642 polysomnography 525526
acute chest syndrome (ACS) 625, 626 sequelae 522
diagnosis 626, 626f, 627f treatments 526
plastic bronchitis 578 sleep disorders 512513
therapy 628f sleep efficiency 127
asthma comorbidity 625, 627, 628 sleep hypoventilation syndrome 125, 126
care 626 sleep latency 127
chronic lung disease 626628 sleep-onset REM 511512
comorbidities 627 sleep pressure 506
lung disease course 628 sleep-related hypoxaemia 522
712
manoeuvres 109
sleep spindles 509, 510f
reference values 110
sleep studies
procedure 1112
chronic respiratory failure 544
restrictive diseases 16
neuromuscular disorders 492, 493
static lung volumes 71f, 75
OSAS 517
vocal cord dysfunction 61
sleep terror 512
SpO2
sleepwake regulation 503506
acute respiratory failure 540
sleep walking (somnambulism) 511, 512
inflight 670, 671f
sliding sign, ultrasound 183
spondylocostal dysostosis (JarchoLevin syndrome)
slow-wave activity 506, 510
500501
slow-wave sleep (SWS) 126, 127, 506, 508, 510, 510f, 511
spondylothoracic dysostosis (LavyMoseley syndrome)
process S 506
500501
small airway obstruction assessment 1415
spontaneous pneumomediastinum (Hammans syn-
smart nebulisers 198, 201, 202
drome) 489490
smoke inhalation injury 535
sports injuries 674
smoking, pregnancy 10, 29
sports medicine 673677
snoring 57, 6162, 129f, 516
pre-competition assessment 673
causes 58t
sports programmes, benefits 673674
history 6162
sputum, inflammation assessment 1718
severity 61
sputum cultures
site of origin 58t
community-acquired pneumonia 238
snorts (snuffles) 58t, 62
non-CF bronchiectasis 254
snuffles (snorts) 58t, 62
pleural infection 259260
social history 35
sodium 96
sputum examination
sodium channel blockers 424
fungal infections 218219
sodium meglumine diatrizoate (Gastrografin) 414, 415
mycobacterial infections 217218
sodium supplementation, cystic fibrosis 411
sputum induction 100, 103104
soft-mist inhalers 204
asthma 103
sol phase 552
clinical applications 103, 105
somatostatin 481482
cystic fibrosis 429
somatostatin analogues 481482
methodology 103
somnambulism (sleep walking) 511, 512
tuberculosis 276277
somniloquy 512
squawk 3839
sound recording, polysomnography 126
stage 1 sleep 126, 508, 509f
spared areas, ultrasound 185f, 186
stage 2 sleep 126, 508509, 510f
specific airway resistance (sRaw) 111
stage 3 sleep see slow-wave sleep (SWS)
speech, auscultation 39
stage 4 sleep 508
spinal muscular atrophy 493, 494t
standard base excess (base excess of the blood sam-
spinal tuberculosis 289290
ple) 96
Spina ventosa 290
Staphylococcus aureus 209t
spine-based growing rods, early onset scoliosis 501
atopic dermatitis 366
spirometers 11, 12f
community-acquired pneumonia 235, 235t
spirometry 1112, 12f
cystic fibrosis 408
allergic bronchopulmonary aspergillosis 380
necrotising pneumonia 263
asthma monitoring 324
pneumonia 209, 216
bronchopulmonary dysplasia survivors 475
cystic fibrosis 427, 543
sinusitis 215
dyspnoea 55
tracheitis 215
equipment 1112
static lung volumes 7076, 71f
exhaled nitric oxide fraction versus 102
measurable 70, 71t
lung graft monitoring 653
measurement 7576
neuromuscular disorders 16, 492
obesity 529
non-CF bronchiectasis 255
steatosis 417
obesity 529
stents 442
obstruction assessment 14
sterilising drugs, tuberculosis 278
preschool children 107, 109110, 110f
sternal clefts 498
acceptability criteria 109
sternal defects, congenital 497498
AYS/ERS recommendations 109110
steroid phobia 368
713
steroids see corticosteroids superior caval vein thrombosis 642
stethoscope 3637 supplemental oxygen see oxygen supplementation/
Stickler syndrome 436 therapy
storage disorders 644 SUPPORT study 463
streptococcal infections, tonsillitis 229 suprachiasmatic nucleus (SCN) 503, 504
probability scoring systems 230, 230t supraglottic cysts 438
Streptococcus pneumoniae 209t surfactant 67, 6t, 78
acute otitis media 215 at birth 7
chronic bronchitis 211 dysfunction 7, 596600
community-acquired pneumonia 233, 234235, 235t functions 6, 7
empyema 211 secretion 67
invasive bacterial diseases 223, 237 surface tension reduction 78
pneumonia 209, 216, 223 surfactant deficiency syndromes 596
protracted bacterial bronchitis 266 surfactant disorders 592
sinusitis 215 surfactant protein (SP)-A 6, 7
Streptococcus pyogenes 215, 235t surfactant protein (SP)-B 6, 588, 592, 597
stress incontinence, cystic fibrosis 430 surfactant protein (SP)-C 6, 588, 597
stridor 38, 57, 5961 surfactant protein (SP)-D 6, 7
acute 60 surfactant replacement, ARDS 536
assessment 6061 surfactant system, genetic defects 588
causes 58t, 59, 6061 surgery
chronic 6061 bronchiolitis obliterans 575
croup 60, 231 bronchopulmonary sequestration 450
definition 59 chylothorax 482
exercise-induced vocal cord dysfunction 67 congenital cystic adenomatoid malformation 449
exhalation 60, 60f distal intestinal obstruction syndrome 415
expiratory 53 double aortic arch 459
flexible bronchoscopy 132, 134 empyema 261
foreign body aspiration 60 isolated tracheo-oesophageal fistula 441
generation 59 laryngeal clefts 439440
haemangiomas 582 lung abscess 265
history 60 lung tumours 631
inhalation 5960 meconium ileus 414
inspiratory 53, 56 mediastinitis 484
investigations 61 necrotising pneumonia 263
laryngomalacia 336, 438 non-CF bronchiectasis 256
physical examination 60 papillomas 585
site of origin 58t PierreRobin sequence 436
vocal cord dysfunction 61 pleural effusion 479480
subcortical arousal, sleep 506 pleural infection 261
subcrepitant (fine) crackles 38 primary ciliary dyskinesia 557
subcutaneous emphysema 489490 pulmonary sling 459
subcutaneous immunotherapy (SCIT) 383, 386388 subglottic stenosis 437
allergic asthma 383 tracheal stenosis 443
cat allergen extracts 386387 tracheomalacia 442
dosing schedules 387 surgical jejunostomy 564
side-effects 387, 387t suspension laryngoscopy 153, 154f
subglottic cysts 439 suxamethonium 159
subglottic haemangiomas 582583, 583f swallowing dysfunction 559
subglottic stenosis 15, 53, 135, 437, 437t swallowing function assessment 493
sublingual immunotherapy (SLIT) 383, 387388 sweat test
subpleural blebs, pneumothorax 485 cystic fibrosis 397, 399f, 421
subpleural bulla, pneumothorax 485 false-negative results 400t
subpleural consolidations 187 false-positive results 400t
subunit vaccines, tuberculosis 282 macroduct collection system 397, 399f
sudden death event 674 non-CF bronchiectasis 255
sudden fatal asthma 674 protracted bacterial bronchitis 268
sulfur hexafluoride 113 SwyerJames syndrome 573574
sulfur mustard inhalation 578 syncope 604
714
syndrome of inappropriate secretion of antidiuretic thorax 1
hormone (SIADH) 306 compliance 7880, 79f
systemic disorders, lung involvement 636646 elastic properties 77
systemic hypothermia 98 hyperinflation 3536
systemic inflammatory response syndrome (SIRS) 533 thrombocytes 20
systemic lupus erythematosus (SLE) 639t, 641t, thromboembolism 607
643644 thymocytes 3
thymus 34
T
tachypnoea 50
thymus-activated-regulated chemokine (TARC) 379
thyroid transcription factor-1 deficiency -syndrome
(brain-lung-thyroid syndrome) 592, 598
community-acquired pneumonia 237 tidal volume (VT) 71f, 71t
inspection 5253 Tiffeneau index (FEV1/FVC) 72t
restrictive lung disease 5253 time-period effect, cough 47
tacrolimus 368, 649, 651t time taken to achieve peak tidal expiratory flow
tactile fremitus 36 (tPTEF)/expiratory time (tE) ratio 8485
tadalafil 606 TIRAP (TIR domain-containing adaptor protein) 21
talc emboli 607 TIR domain-containing adaptor protein (TIRAP) 21
T-cell mediated immune response 24 TIR domain-containing inducing interferon- (TRIF) 21
T-cells 20, 20f, 24 tissue plasminogen activator (tPA) 579
allergic bronchopulmonary aspergillosis 378 TLCO
antigen contact 24 bronchiolitis obliterans 573
Technegas 191 diffuse parenchymal lung diseases 590
technetium-99m (99mTc) 189 restriction assessment 17
telomerase 588 TLR2 22
tension pneumothorax 487, 487f TLR4 22
teratomas 633, 634 T-lymphocytes 3, 249t
terbutaline 323 tobramycin
terminal bronchiole 2 cystic fibrosis 408, 425, 429
development 5 dry-powder inhalers 204
Th2 high phenotype, asthma 329 Toll-like receptors (TLRs) 21
Th2 low phenotype, asthma 329 signalling cascade 2122, 22f
Th9 cells 24 tonsillectomy 230
Th17 cells 24 tonsillitis 229231
Th22 cells 24 topical calcineurin inhibitors (TCIs) 368
T-helper (Th)-1 lymphocytes 3, 24, 285 total beam collimation 167
T-helper (Th)-2 lymphocytes 34, 24 total lung capacity (TLC) 70, 71f, 71t
allergic response 340 diffuse parenchymal lung diseases 590
allergic rhinitis 355 increases through life 9
asthma 301, 318 obesity 529
theophylline 321, 330331 restrictive diseases 16
therapeutic hypothermia 98 total lung lavage 144
thoracentesis 260261 total respiratory system compliance, obesity 528529
thoracic cage, reduced development 10 total sleep time (TST) 126
thoracic duct 3 total specific airway resistance (sRaw,tot) 111
thoracic duct ligation 482, 578, 579 tracer gases 13
thoracic gas volume 111 trachea 2, 2f
thoracic insufficiency syndrome (TIS) 499500, 500t, malformations 436t, 440444
501 venous drainage 2
thoracic malformation, congenital see congenital tracheal agenesis 440
thoracic malformations (CTMs) tracheal atresia 440
thoracic wall compliance 78 tracheal bronchus (pig bronchus) 136, 443
thoracoamniotic shunting 448 tracheal collapse 441
thoracoscopic drainage 265 tracheal infarction 642
thoracotomy tracheal obstruction 567
haemothorax 483 tracheal sounds 37
pleural infection 261262 tracheal stenosis 442443, 442f
thoracovertebral deformities 498501 tracheitis 215
thoracovertebral malformations 497, 501 tracheobronchial tree 5f, 134f
715
topographic anomalies 443 control 281282
tracheomalacia 136, 441442 diagnosis 217218, 274, 277
aberrant innominate artery 459 disease sites 272274, 273f
congenital versus acquired 441 examination 274
dynamic airway compression 441 extrapulmonary see extrapulmonary tuberculosis
flexible airway endoscopy 441 genetic susceptibility 285
protracted bacterial bronchitis risk factor 267 history 274
signs/symptoms 441 HIV coinfection 280281, 285286
surgery 442 HIV testing 277
tracheo-oesophageal fistula 136, 440 imaging/radiography 275276
tracheo-oesophageal fistula-cough 440 immune response 272, 284285
tracheoscopes 152 immunocompromised host 251252, 284292
tracheoscopy, aberrant innominate artery 458f, 459 infection likelihood influencing factors 270
tracheostomy liver manifestations 637t
hospital-acquired pneumonia risk 243 microbiological confirmation 276277
neuromuscular disorders 495, 495t molecular testing 277
respiratory physiotherapy 667668 natural history 270274, 271f
tracheostomy-associated pneumonia 209 passive case finding 274
tracheotomy 549 prevention 281282
TRAM (TRIF-related adaptor molecular) 21 primary progressive 272
transairway pressure (Pta) 73 pulmonary 272273
transbronchial lung biopsy (TBLB) 146, 149150 signs 274
lung transplant recipients 651 symptoms 274, 275t
technique 149, 149f treatment 277279
transcatheter embolisation 193, 196197 adherence 278
transcutaneous carbon dioxide (PtcCO2) 125, 126 combination regimens 278
transfusion-related acute lung injury (TRALI) 535 hepatotoxicity induction 279
transient tachypnoea of the newborn (TTN) 184 HIV-infected children 278
transpulmonary pressure (Ptranspulm) 77 recently infected children 281
transthoracic biopsy, bronchiolitis obliterans 573 recommended doses 278, 280t
traumatic (iatrogenic) pneumothorax 485, 486t, 488 regimens 278, 279t
Treacher syndrome 436 side-effects 279
triamcinolone 322 underestimation 270
triangle of safety 488, 489f vaccines, new development 282
TRIF (TIR domain-containing inducing interferon-) 21 tuberculous arthritis 290
TRIF-related adaptor molecular (TRAM) 21 tuberculous dactylitis 289, 290
tri--gliadin 67 tuberculous lymphadenitis 277, 287
true vocal cords (fold) 1 tuberculous meningitis 273, 282, 287, 287f
tryptase 350 tuberculous osteomyelitis 290
TTF-1 gene mutations 592 tuberose sclerosis 639t
tuberculin skin test (TST) 217, 274, 275 tube thoracostomy 479, 483
HIV/TB coinfection 286 tubular myelin 7
miliary tuberculosis 288 tubulin 551
tuberculomas 287, 288 tumour ablation 193, 194
tuberculosis (TB) 270283 tumour emboli 607
abdominal 290291 tumour localisation 193, 194
acquired susceptibility 285286 tumour necrosis factor (TNF) 330
active case finding 274 tumour necrosis factor (TNF) blockers 330
active disease management 277 tumours 630635
adaptive immunity tests 274275 turbulent flow 80
adult-type 272, 273 22q11.2 deletion syndrome 436
age-related progression risk 272, 273t two-process model of sleep and wakefulness 503, 504
bone tuberculosis 272, 273, 289290 Type I alveolar lining cells 5, 7
burden of disease 270 Type II alveolar lining cells 5, 6, 7
cardiac manifestations 641t
chemoprophylaxis 281
clinical manifestations 284285
congenital 273274
U
UK CF Trust registry report 377
contact history 273t, 274 ulcerative colitis 642
716
ultrasonic nebulisers 202 valved holding chamber (VHC) 203
ultrasound 183188 Vapotherm system 542
anatomy 183, 184f vapour rub 47
appendiceal mucocoele 415416 vardenafil 606
artefacts 183, 184f variceal bleeding 416
bronchiolitis 186f, 187 vascular compression, flexible bronchoscopy 136
bronchopulmonary dysplasia 185f, 186 vascular endothelial growth factor (VEGF)-A 462
CF-related liver disease 417 vascular malformations 452460
congenital cystic adenomatoid malformation 447f, classification 452455
448 clinical presentation 452455
congenital thoracic malformations 446, 446f diagnosis 453, 456459
cystic fibrosis 412 incidence 452, 453
dyspnoea 54 outcomes 459
fetal MRI versus 181 symptoms 452
haemangiomas 582 treatment 459
haemothorax 483 vascular ring 136, 452, 453, 456, 456f, 459, 640
image-guided percutaneous biopsy 194, 195f vascular sling 452, 459, 640
image-guided percutaneous drainage 194195 vasculitis
intussusception 416 bronchiolitis obliterans 572
lung abscess 264 pulmonary 591592
miliary tuberculosis 288 systemic, pulmonary involvement 643644, 644t
parapneumonic effusion 259 VATER syndrome 641t
pleural effusion 477478, 478f venom immunotherapy 352
pleural infection 259 venous blood, blood gas analysis 9798, 98t
pneumonia 186f, 187188, 187f ventilation
pneumothorax 187 acute respiratory failure 542
pulmonary atelectasis 186f, 187 adequacy assessment measures 95
respiratory distress syndrome 184186, 185f cystic fibrosis 433
TB arthritis 290 lung transplantation 649, 650
technique 183 ventilation distribution 534
transient tachypnoea of the newborn 184 ventilation/perfusion (V/Q) inequality, acute respira-
tuberculosis 276 tory failure 538
undernutrition, BPD 467 ventilation/perfusion (V/Q) scintigraphy
united airway concept 360 bronchiolitis obliterans 574
upper airway collapsibility, OSAS 514, 530531 imaging equipment/acquisition 191
upper airway resistance syndrome 514520 indications 189190, 190f
upper airways patient preparation 190191
chronic obstruction 548 pulmonary embolic disease 607
flexible bronchoscopy 134135 ventilator-associated interstitial emphysema 486
obesity 528 ventilator-associated pneumonia (VAP) 209, 242, 245t,
physical examination 35 640
resistance 81 ventilator-induced lung injury (VILI) 533534
upper respiratory tract (URT) 227 ventilatory/pump failure 545
upper respiratory tract infections (URTIs) 227232 ventral diverticulum 4
bacterial, microbiology testing 215 ventrolateral pre-optic nucleus (VLPO) 507
prevalence 227 vertebral fusion 501
viral 227, 228t vertex waves, sleep 508, 509f
uraemic lung 638 vertical expandable prosthetic titanium rib (VEPTR) 501
Ureaplasma infection 462 vesicular breath sound 37
urine specimens, bacterial pneumonia 216 vestibular folds 1
urinothorax 639 vibrating-mesh nebulisers 202
urokinase 261, 479 vibration, airway clearance 666
ursodeoxycholic acid (UDCA) 417 Victorian Infant Collaborative Study Group 470471
video-assisted thoracoscopic surgery (VATS)
V
VACTERL association 440, 641t
empyema 261
haemothorax 483
necrotising pneumonia 263
VACTER syndrome 641t pleural effusion 479480
vacuum cleaners 384t, 385 pneumothorax 489
717
video recording, polysomnography 126, 525
viral infection
acute respiratory distress syndrome 535
W
wakefulness 506, 507
allergic disorders 339, 341 Waldeyers ring of lymphoid tissue 229
allergic sensitisation and 319 warfarin 608
asthma trigger 318319, 341 wave-speed limitation 75
bronchial hyperresponsiveness 87 weight gain 660
bronchiolitis 207, 305 weight graphs 3435
chronic bronchitis 211 weight loss 660
community-acquired pneumonia 236 asthma 319320
diffuse parenchymal lung diseases 592 sleep apnoea 531
early life, asthma development 302 wet cough 34, 48
graft rejection 652 in bacterial bronchitis see protracted bacterial bron-
history taking 34 chitis (PBB)
hospital-acquired pneumonia 244 wheat proteins 67
microbiology 214215 wheeze/wheezing 3738, 5859
pneumonia 209 after exercise 34
protracted bacterial bronchitis risk factor 266267 assessment 59
upper respiratory tract 227, 228t asthma 59
viral rhinitis (common cold) 227228 bacterial bronchitis 267268
virus(es) bronchiolitis 59
as copathogens 214 causes 58t
detection 215 clinical conditions presenting with 335, 335t
visceral lymph nodes 3 definition 57, 58, 334
vital capacity (VC) 70, 71t forced oscillation technique 119120
diffuse parenchymal lung diseases 590 foreign body aspiration 54, 59, 567
muscle disease 1617 history taking 34
muscular dystrophy 16 inspiratory 38
neuromuscular disorders 492 intensity-obstruction degree relationship 38
obesity 529 intrathoracic airway obstruction 5354
obstructive disorders 15 monophonic 59
pectus excavatum 498 physical examination 38
single-breath washout 114, 114f polyphonic 59
spirogram 71f preschool children see preschool wheeze/wheezing
vitamin(s), BPD 468 prevalence 294
vitamin A 412, 413t, 464, 468 production 59
vitamin D 330, 412, 413t recurrent 334
deficiency, TB 286 site of origin 57, 58, 58t
vitamin D2 (ergocalciferol) supplementation 412 wheezing disorders
vitamin D3 (cholecalciferol) supplementation 412 environmental factors 302303
vitamin E 412, 413t epidemiology 293297
vitamin K 413t geneenvironment interaction 303
deficiency, cystic fibrosis 412 genetic factors 298304
VO2max 676 whispered pectoriloquy 39
vocal abuse 63 white cell count, empyema 217
vocal apparatus 1 white lung, ultrasound 184, 185, 185f, 186
vocal cord(s) 1, 80 whole body plethysmography 1213, 14
vocal cord dysfunction (VCD) 61, 135, 335t, 336 airway resistance, preschool children 111
vocal cord paralysis 63, 135 obstructive disorders 15
vocal nodules 63 static lung volumes 75
voice, physical examination 36 whole-exon sequencing, asthma 299
volatile organic compounds (VOCs) 664 whole-genome sequencing, asthma 299, 300t
volume resuscitation, haemothorax 483 whole lung lavage, pulmonary alveolar proteinosis
vomiting 34 599600
voriconazole 381, 430, 650 whooping cough (pertussis) 212, 231
VX-770 see ivacaftor Williams syndrome 641t
VX-809 422, 423 Wilms tumour 632, 633f, 639t
718
World Health Organization (WHO) Xpert MTB/RIF 277
pneumonia diagnosis recommendations 236, 238 X-ray, chest see chest radiography
pulmonary hypertension classification 603t
tuberculosis treatment recommendations 278
wound healing, age-related changes 589 Y
yellow nail syndrome (YNS) 645
X
xenon-133 (133Xe) 191 Z
xolair see omalizumab zeitgebers 504
UPLOADED BY [STORMRG]
719
handbook
handbook Paediatric Respiratory Medicine

The 18 chapters of the ERS Handbook of Paediatric
Respiratory Medicine cover the whole spectrum
of paediatric respiratory medicine, from anatomy
and development to disease, rehabilitation and Paediatric
treatment. The Editors have brought together
leading clinicians to produce a thorough and easy-
to-read reference tool. The Handbook is structured
to accompany the paediatric HERMES syllabus,
Respiratory
making it an essential resource for anyone
interested in this field and an ideal educational
training guide.
Medicine
Ernst Eber is a Professor of Paediatrics and Head
of the Respiratory and Allergic Disease Division in
Editors
the Department of Paediatrics and Adolescence Ernst Eber
Medicine at the Medical University of Graz, and is
also Head of the ERS Paediatric Assembly. Fabio Midulla
Fabio Midulla is an Assistant Professor and
Director of the Paediatric Emergency Department,
Policlinico Umberto I. Sapienza University of
Rome, and is Secretary of the ERS Paediatric
Assembly.

ERS Handbook of Paediatric Respiratory Medicine - E. Eber, F Midulla

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ERS Handbook of Paediatric Respiratory Medicine - E. Eber, F Midulla

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handbook Paediatric Respiratory Medicine

2013 European Respiratory Society

Design by Claire Turner, ERS

All material is copyright to the European Respiratory Society.

CONTACT, PERMISSIONS AND SALES REQUESTS:

Chapter 1 Structure and function of the respiratory system

Anatomy and development of the respiratory system 1

Applied respiratory physiology 11

Immunology and defence mechanisms 19

Environmental determinants of childhood respiratory health 29

Chapter 2 Respiratory signs and symptoms

History and physical examination 33

Tachypnoea, dyspnoea, respiratory distress and chest pain 50

Snoring, hoarseness, stridor and wheezing 57

Chapter 3 Pulmonary function testing and other diagnostic tests

Static and dynamic lung volumes 70

Reversibility, bronchial provocation testing and exercise testing 83

Blood gas assessment and oximetry 93

Pulmonary function testing in infants and preschool children 107

Single- and multiple-breath washout techniques 113

Forced oscillation techniques 118

Chapter 4 Airway endoscopy

Flexible bronchoscopy 132

Bronchoalveolar lavage 140

Bronchial brushing and bronchial and transbronchial biopsies 146

Rigid and interventional endoscopy 151

General anaesthesia, conscious sedation and local anaesthesia 156

Conventional radiography 161

Computed tomography 166

Magnetic resonance imaging 176

Isotope imaging methods 189

Interventional radiology 193

Chapter 6 Inhalation therapy

Aerosol therapy 198

Chapter 7 Acute and chronic lung infections

Microbiology testing and interpretation 214

Immunisation against respiratory pathogens 221

Upper respiratory tract infections 227

Community-acquired pneumonia 233

Lung involvement in immunodeficiency disorders 248

Non-CF bronchiectasis 253

Pleural infection, necrotising pneumonia and lung abscess 258

Bacterial bronchitis with chronic wet lung 266

Extrapulmonary TB and TB in the immunocompromised host 284

Chapter 9 Bronchial asthma and wheezing disorders

Epidemiology and phenotypes of bronchial asthma and 293

Genetic and environmental factors in bronchial asthma and 298

Acute viral bronchiolitis 305

Preschool wheezing 310

Bronchial asthma 316

Differential diagnosis of bronchial asthma 334

Chapter 10 Allergic disorders

Pathophysiology and epidemiology of allergic disorders 339

In vivo and in vitro diagnostic tests in allergic disorders 345

Allergic rhinitis 354

Atopic dermatitis 363

Food allergy 370

Allergic bronchopulmonary aspergillosis 376

Specific immunotherapy, prevention measures and alternative treatment 383

Chapter 11 Cystic fibrosis

Genetics, pathophysiology and epidemiology of CF 390

Screening and diagnosis of CF 397

CF lung disease 402