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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


Giorgio Piacentini and Laura Tenero

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


Sedat Oktem and Refika Ersu

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

ERS Handbook: Paediatric Respiratory Medicine 3


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

4 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 5


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

6 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 7


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

8 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 9


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.

10 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 11


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.

12 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 13


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

14 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 15


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

16 ERS Handbook: Paediatric Respiratory Medicine


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,

ERS Handbook: Paediatric Respiratory Medicine 17


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.

18 ERS Handbook: Paediatric Respiratory Medicine


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,

ERS Handbook: Paediatric Respiratory Medicine 19


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

20 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 21


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.

22 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 23


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.

24 ERS Handbook: Paediatric Respiratory Medicine


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,

ERS Handbook: Paediatric Respiratory Medicine 25


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

26 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 27


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.

28 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 29


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).

30 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 31


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.

32 ERS Handbook: Paediatric Respiratory Medicine


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,

ERS Handbook: Paediatric Respiratory Medicine 33


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;

34 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 35


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

36 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 37


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)

38 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 39


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

40 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 41


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.

42 ERS Handbook: Paediatric Respiratory Medicine


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.
may be associated with (usually painful) Urgent and Emergent Care. Philadelphia,
periostosis in the context of hypertrophic Elsevier-Mosby, 2005; pp. 5865.
osteoarthropathy.

ERS Handbook: Paediatric Respiratory Medicine 43


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

44 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 45


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

46 ERS Handbook: Paediatric Respiratory Medicine


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).

ERS Handbook: Paediatric Respiratory Medicine 47


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.

48 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 49


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,

50 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 51


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,

52 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 53


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.

54 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 55


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

56 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 57


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.

58 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 59


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.

60 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 61


(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.

62 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 63


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.

64 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 65


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

66 ERS Handbook: Paediatric Respiratory Medicine


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,

ERS Handbook: Paediatric Respiratory Medicine 67


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.

68 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 69


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

70 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 71


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

72 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 73


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

74 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 75


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.

76 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 77


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

78 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 79


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

80 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 81


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.

82 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 83


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

84 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 85


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;

86 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 87


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

88 ERS Handbook: Paediatric Respiratory Medicine


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
relationship of EIB with markers of airway virus infections and aeroallergens in
inflammation, the slower response to acute bronchial asthma. Arch Dis Child;
treatment, and the relationship of 59: 310315.
methacholine BHR with basement N Carlsen KH, et al. The response to heavy
membrane thickness, it has been stated that swimming exercise in children with and
EIB reflects airway inflammation, whereas without bronchial asthma. In: Morehouse
direct bronchial responsiveness to CA, ed. Children and Exercise XIII.
methacholine reflects airway remodelling. Champaign, Human Kinetics Publishers,
1989; p. 351360.
Conclusion N Carlsen KH, et al. (1998). Cold air
inhalation and exercise-induced broncho-
Measurements of BHR are useful tools in constriction in relationship to metacho-
assessing the severity of childhood asthma. line bronchial responsiveness: different
However, the different methods of patterns in asthmatic children and chil-
assessment differ to a certain extent in their dren with other chronic lung diseases.
ability to differentiate asthma from other Respir Med; 92: 308315.
chronic lung diseases, and they are N Carlsen KH, et al. (2000). Exercise-
influenced by therapy to a different degree. induced bronchoconstriction depends
Measurements of BHR have given insight on exercise load. Respir Med; 94:
into the pathophysiological mechanisms of 750755.
asthma and they are frequently employed in

ERS Handbook: Paediatric Respiratory Medicine 89


N Carlsen KH (2012). Sports in extreme asthma and the effect of varying the
conditions: the impact of exercise in cold severity and duration of exercise.
temperatures on asthma and bronchial Pediatrics; 56: 893898.
hyper-responsiveness in athletes. Br J N Godfrey S, et al. (1991). Exercise but not
Sports Med; 46: 796769. metacholine differentiates asthma from
N Clough JB, et al. (1991). Effect of atopy on chronic lung disease in children. Thorax;
the natural history of symptoms, peak 46: 488492.
expiratory flow, and bronchial responsive- N Goleva E, et al. (2007). Airway remodel-
ness in 7- and 8-year-old children with ing and lack of bronchodilator response
cough and wheeze. Am Rev Respir Dis; in steroid-resistant asthma. J Allergy Clin
143: 755760. Immunol; 120: 10651072.
N Cockcroft DW, et al. (1977a). Bronchial N Hargreave FE, et al. (1981). Bronchial
reactivity to inhaled histamine: a method responsiveness to histamine or metacho-
and clinical survey. Clin Allergy; 7: 235243. line in asthma: measurement and clinical
N Cockcroft DW, et al. (1977b). Allergen- significance. J Allergy Clin Immunol; 68:
induced increase in non-allergic bronchial 347355.
reactivity. Clin Allergy; 7: 503513. N Heir T (1994). Longitudinal variations in
N Cockcroft DW (1983). Mechanism of bronchial responsiveness in cross-coun-
perennial allergic asthma. Lancet; 2: try skiers and control subjects. Scand J
253256. Med Sci Sports; 4: 134139.
N Cockcroft DW, et al. (1992). Sensitivity N Heir T, et al. (1995a). The influence of
and specificity of histamine PC20 deter- training intensity, airway infections and
mination in a random selection of young evironmental conditions on seasonal
college students. J Allergy Clin Immunol; variations in bronchial responsiveness in
89: 2330. cross-country skiers. Scand J Med Sci
N Crapo RO, et al. (2000). Guidelines for Sports; 5: 152159.
methacholine and exercise challenge test- N Heir T, et al. (1995b). Respiratory tract
ing 1999. This official statement of the infection and bronchial responsiveness in
American Thoracic Society was adopted elite athletes and sedentary control sub-
by the ATS Board of Directors, July 1999. jects. Scand J Med Sci Sports; 5: 949.
Am J Respir Crit Care Med; 161: 309329. N Henriksen JM, et al. (1983). Effects of
N Edmunds AT, et al. (1978). The refractory inhaled budesonide alone and in combi-
period after exercise-induced asthma: its nation with low-dose terbutaline in chil-
duration and relation to the severity of dren with exercise-induced asthma. Am
exercise. Am Rev Respir Dis; 117: 247254. Rev Respir Dis; 128: 993937.
N Empey DW, et al. (1976). Mechanisms of N Hopp RJ, et al. (1985). The effect of age
bronchial hyperreactivity in normal sub- on metacholine response. J Allergy Clin
jects after upper respiratory tract infec- Immunol; 76: 609613.
tion. Am Rev Respir Dis; 113: 131139. N Janssen NA, et al. (2003). The relation-
N Forastiere F, et al. (1994a). Bronchial ship between air pollution from heavy
responsiveness in children living in areas traffic and allergic sensitization, bronchial
with different air pollution levels. Arch hyperresponsiveness, and respiratory
Environ Health; 49: 111118. symptoms in Dutch schoolchildren.
N Forastiere F, et al. (1994b). Passive Environ Health Perspect; 111: 15121518.
smoking as a determinant of bronchial N Johnston SL, et al. (1995). Community
responsiveness in children. Am J Respir study of viral infections in exacerbations
Crit Care Med; 149: 365370. of asthma in 911 year old children. BMJ;
N Gehring U, et al. (2010). Traffic-related air 310: 12251229.
pollution and the development of asthma N Jones RS, et al. (1963). The place of
and allergies during the first 8 years of physical exercise and bronchodilator
life. Am J Respir Crit Care Med; 181: 596 drugs in the assessment of the asthmatic
603. child. Arch Dis Child; 38: 539545.
N Godfrey S, et al. (1975). The use of the N Landwehr LP, et al. (1996). Vocal cord
treadmill for assessing exercise-induced dysfunction mimicking exercise-induced

90 ERS Handbook: Paediatric Respiratory Medicine


bronchospasm in adolescents. Pediatrics; N Rosenthal RR (1984). Simplified eucap-
98: 971974. nic voluntary hyperventilation challenge.
N Ldrup Carlsen KC, et al. (1995). J Allergy Clin Immunol; 73: 676
Eosinophil cationic protein and tidal flow 679.
volume loops in children 02 years of N Salome CM, et al. (1987). Bronchial
age. Eur Respir J; 8: 11481154. responsiveness in two populations of
N Mele L, et al. (2010). Assessment and Australian schoolchildren. I. Relation to
validation of bronchodilation using the respiratory symptoms and diagnosed
interrupter technique in preschool chil- asthma. Clin Allergy; 17: 271281.
dren. Pediatr Pulmonol; 45: 633638. N Salter HH. On Asthma: Its Pathology and
N Miller MR, et al. (2005). General con- Treatment. 1st Edn. London, J. Churchill,
siderations for lung function testing. Eur 1860.
Respir J; 26: 153161. N Sharma S, et al. (2008). Clinical predic-
N Nakazawa H, et al. (1994). Viral respira- tors and outcomes of consistent bronch-
tory infection causes airway hyperrespon- odilator response in the childhood
siveness and decreases histamine N- asthma management program. J Allergy
methyltransferase activity in guinea pigs. Clin Immunol; 122: 921928.
Am J Respir Crit Care Med; 149: 11801185. N Sont JK, et al. (1999). Clinical control and
N Nieminen MM, et al. (1988). histopathologic outcome of asthma
Methacholine bronchial challenge using when using airway hyperresponsiveness
a dosimeter with controlled tidal breath- as an additional guide to long-term
ing. Thorax; 43: 896900. treatment. The AMPUL Study Group.
N Nordenhall C, et al. (2001). Diesel Am J Respir Crit Care Med; 159: 1043
exhaust enhances airway responsiveness 1051.
in asthmatic subjects. Eur Respir J; 17: N Soyseth V, et al. (1995). Relation of
909915. exposure to airway irritants in infancy to
N Pauwels R, et al. (1988). Bronchial prevalence of bronchial hyper-responsive-
hyperresponsiveness is not bronchial ness in schoolchildren. Lancet; 345: 217
hyperresponsiveness is not bronchial 220.
asthma. Clin Allergy; 18: 317321. N Stadelmann K, et al. (2011). Respiratory
N Pellegrino R, et al. (2005). Interpretative symptoms and bronchial responsiveness
strategies for lung function tests. Eur in competitive swimmers. Med Sci Sports
Respir J; 26: 948968. Exerc; 43: 375381.
N Peroni DG, et al. (1994). Effective allergen N Stearns DR, et al. (1981). Reanalysis of the
avoidance at high altitude reduces refractory period in exertional asthma. J
allergen- induced bronchial hyperrespon- Appl Physiol; 50: 503508.
siveness. Am J Respir Crit Care Med; 149: N Sterk PJ (1996). Bronchial hyperrespon-
14421446. siveness: definition and terminology.
N Refsum HE, et al. Exercise-associated Pediatr Allergy Immunol; 7: Suppl.,
ventilatory insufficiency in adolescent 79.
athletes. The asthmatic child in play and N Thio BJ, et al. (2001). Effects of single-
sports. London, Pitmann Books Limited, dose fluticasone on exercise-induced
1983. asthma in asthmatic children: a pilot
N Riiser A, et al. (2012a). Bronchial hyperre- study. Pediatr Pulmonol; 32: 115121.
sponsiveness decreases through child- N Tiffeneau R (1995). Lhyperexcitabilite
hood. Respir Med; 106: 215222. acetylcholinique du poumon; crite`re phy-
N Riiser A, et al. (2012b). Does bronchial siopharmacodynamique de la maladie
hyperresponsiveness in childhood predict asthmatique [Acetylcholine hyperexcit-
active asthma in adolescence? Am J ability of the lung; physicopharmacody-
Respir Crit Care Med; 186: 493500. namic criterion in asthma]. Presse Med;
N Roizin H, et al. (1996). Atopy, bronchial 63: 227230.
hyperresponsiveness, and peak flow N van Essen-Zandvliet EE, et al. (1993).
variability in children with mild occa- Minor acute effect of an inhaled corti-
sional wheezing. Thorax; 51: 272276. costeroid (budesonide) on bronchial

ERS Handbook: Paediatric Respiratory Medicine 91


hyperresponsiveness to methacholine in N Yan K, et al. (1983). Rapid method for
children with asthma. Eur Respir J; 6: 383 measurement of bronchial responsive-
386. ness. Thorax; 38: 760765.
N Waalkens HJ, et al. (1993). The effect of N Zach MS, et al. (1987). Cold air challenge
an inhaled corticosteroid (budesonide) of airway hyperreactivity in children:
on exercise- induced asthma in children. doseresponse interrelation with a reac-
Dutch CNSLD Study Group. Eur Respir J; tion plateau. J Allergy Clin Immunol; 80:
6: 652656. 917.

92 ERS Handbook: Paediatric Respiratory Medicine


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).

ERS Handbook: Paediatric Respiratory Medicine 93


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.

94 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 95


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).

96 ERS Handbook: Paediatric Respiratory Medicine


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,

ERS Handbook: Paediatric Respiratory Medicine 97


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.

98 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 99


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.

100 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 101


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

102 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 103


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.

104 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 105


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.

106 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 107


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.

108 ERS Handbook: Paediatric Respiratory Medicine


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,

ERS Handbook: Paediatric Respiratory Medicine 109


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.

110 ERS Handbook: Paediatric Respiratory Medicine


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,

ERS Handbook: Paediatric Respiratory Medicine 111


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.

112 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 113


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

114 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 115


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].

116 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 117


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

118 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 119


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

120 ERS Handbook: Paediatric Respiratory Medicine


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.
cystic fibrosis. Chest; 113: 5559. N Thamrin C, et al. (2007). Assessment of
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
N Lebecque P, et al. (1997). Respiratory resi- children with and without bronchopul-
stance by the forced oscillation technique monary dysplasia. J Pediatr; 150: 256261.

ERS Handbook: Paediatric Respiratory Medicine 121


Polysomnography

Sedat Oktem and Refika Ersu

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

122 ERS Handbook: Paediatric Respiratory Medicine


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)

ERS Handbook: Paediatric Respiratory Medicine 123



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

124 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 125


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.

126 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 127


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.

128 ERS Handbook: Paediatric Respiratory Medicine


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
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
657 657 658 658
10 20 30 40 50 60

Figure 5. Obstructive apnoea.

ERS Handbook: Paediatric Respiratory Medicine 129


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
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 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.

130 ERS Handbook: Paediatric Respiratory Medicine


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.
enuresis. N Iber C, et al. The AASM Manual for the
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
diagnosis and treatment of pediatric
muscular or neuromuscular disorders
OSA: a proposal of two pediatric sleep
(e.g. Duchenne muscular dystrophy or
centers. Sleep Med; 13: 217227.
cerebral palsy), or major craniofacial N Katz ES, et al. (2002). Night-to-night
abnormality (e.g. midface hypoplasia or variability of polysomnography in children
mandibular hypoplasia), or a with suspected obstructive sleep apnea. J
combination of pathogenetic Pediatr; 140: 589594.
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
more clusters of desaturation events. breathing. Pediatr Res; 53: 580588.
Alternatively, oxygen desaturation (o3%) N Marcus CL, et al. (1992). Normal polysom-
of haemoglobin index .3.5 episodes?h-1. nographic values for children and adoles-
cents. Am Rev Respir Dis; 146: 12351239.
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
infants and children with alveolar Childhood. Standards for Services for
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.

ERS Handbook: Paediatric Respiratory Medicine 131


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

132 ERS Handbook: Paediatric Respiratory Medicine


(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.

ERS Handbook: Paediatric Respiratory Medicine 133


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.

134 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 135


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,

136 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 137


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.

138 ERS Handbook: Paediatric Respiratory Medicine


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 broncho- scopy 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.

ERS Handbook: Paediatric Respiratory Medicine 139


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.

140 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 141


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

142 ERS Handbook: Paediatric Respiratory Medicine


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).

ERS Handbook: Paediatric Respiratory Medicine 143


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).

144 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 145


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

146 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 147


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

148 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 149


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).

150 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 151


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.

152 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 153


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;
traindicated, such as in vertebral instability. 106: 206209.
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.

154 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 155


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

156 ERS Handbook: Paediatric Respiratory Medicine


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,

ERS Handbook: Paediatric Respiratory Medicine 157


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.

158 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 159


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 broncho- scopy 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.

160 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 161


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

162 ERS Handbook: Paediatric Respiratory Medicine


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).

ERS Handbook: Paediatric Respiratory Medicine 163


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).

164 ERS Handbook: Paediatric Respiratory Medicine


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.

ERS Handbook: Paediatric Respiratory Medicine 165


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

166 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 167


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

168 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 169


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

170 ERS Handbook: Paediatric Respiratory Medicine


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

ERS Handbook: Paediatric Respiratory Medicine 171


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

172 ERS Handbook: Paediatric Respiratory Medicine


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 need