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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
ISBN 978-1-84984-038-5
Table of contents
Contributors xii
Preface xvii
Get more from this Handbook xviii
List of abbreviations xxix
Cough 44
Ahmad Kantar, Michael Shields, Fabio Cardinale and Anne B. Chang
Exercise intolerance 65
Kai-Hkon Carlsen
Exhaled nitric oxide, induced sputum and exhaled breath analysis 100
Johan C. de Jongste
Polysomnography 122
Sedat Oktem and Refika Ersu
Ultrasonography 183
Carolina Casini, Vincenzo Basile, Mariano Manzionna and
Roberto Copetti
Epidemiology 207
Steve Turner
Chapter 8 Tuberculosis
Pulmonary TB, latent TB, and in vivo and in vitro tests 270
Zorica Zivkovic and James Paton
Anaphylaxis 349
Antonella Muraro
Home oxygen therapy, invasive ventilation and NIV, and home 545
ventilatory support
Brigitte Fauroux, Adriana Ramirez and Sonia Khirani
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
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
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
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
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.
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
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
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
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
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.
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.
Paediatric
Lung Function
EUROPEAN
RESPIRATORY
EUROPEAN
RESPIRATORY
SOCIETY
EUROPEAN RESPIRATORY
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
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
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.
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
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.
Flow L.s-1
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.
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.
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
V9: ventilation; Q9: perfusion; ARDS: acute respiratory distress syndrome; PPHN: primary pulmonary
hypertension of the newborn; CNS: central nervous system; DIC: diffuse intravascular coagulation.
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.
(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
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
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,
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
Acute
dyspnoea
Rigid
bronchoscopy and
removal, no
2-agonists
Figure 2. Management of acute dyspnoea. PCO2: carbon dioxide tension; PO2: oxygen tension.
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
Extrathoracic airway
C7
T1
Intrathoracic airway
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.
Kai-Hakon Carlsen
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
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.
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
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.
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
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
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
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
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
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
Flow Ls-1
preferred, inhalation may be given by
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
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 %
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).
Reproduced from Dzierba et al. (2011), with permission from the publisher.
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
40
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.
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).
Figure 1. Preschool child performing spirometry. Figure 2. Preschool child performing Rint.
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,
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
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
Nasal PETCO2
Airflow
Chin EMG (2)
Microphone
ECG
SpO2
Video camera to
Respiratory record behaviour
effort
Technicians note
Leg EMG (2)
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.
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
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
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.
Jacques de Blic
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
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.
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
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).
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.
Thomas Nicolai
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
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.
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.
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.
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.
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
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).
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
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.
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
MRI of the chest is a new technique in the the diagnosis can be obtained by other
imaging of the lung. The lack of ionising means. CT is the gold standard in:
radiation makes MRI an attractive alternative
to CT in paediatric applications, in which N the evaluation of congenital anomalies,
repeated or serial scanning is required. N parenchymal pathologies,
N the case of chronic airway disease for a
Paediatric lung imaging morphological study,
N the assessment of the complications of
Diseases of the respiratory system are of inflammatory process,
great importance in paediatrics. Imaging of N the staging of tumoural masses.
the chest has led to improvements in the
diagnosis and treatment of numerous MRI is a radiation-free technique and offers
medical conditions in children. alternative solutions to routine diagnostic
challenges for the imaging of the lung. It is
The first, and most widely used, modality is especially relevant to young patients and
represented by radiographic imaging. It is pregnant patients, as well as subjects who
fast and inexpensive and provides a good need to undergo multiple investigations.
overview of anatomy and pathology. However, in the approach of lung diseases,
the feasibility of MRI investigation is limited
For most paediatric pulmonary pathologies by several technical problems. Despite this,
a plain film is the first, and only, step in the in recent years many efforts have been made
absence of complications and when the and there have been significant advances.
clinical course is regular. The best case is to
avoid additional imaging, especially CT, if MRI techniques For many years MRI
imaging was considered useful in the
evaluation of mediastinal abnormalities and
Key points not the lung parenchyma. However, the lack
of radiation exposure makes MRI of the lung
N MRI techniques allow for fast and particularly attractive for paediatric
reliable assessment of pulmonary radiology.
diseases in children. The subordinate role of MRI in the
N Thoracic MRI is a radiation-free evaluation of lung is caused by different
method and can be performed technical problems, especially:
frequently without contrast media
application. N artefacts related to cardiac and breathing
motion,
N The diagnostic value of MRI is shown N the low signal-to-noise ratio because of
in patients with infectious diseases, low proton density of the lung,
immunodeficiency, anatomic N the susceptibility of artefacts because of
abnormalities, acquired chronic airsoft tissue transition,
diseases and pulmonary tumours. N the low-spatial resolution in comparison
to CT.
c) d)
Figure 1. A CT scan from a 9-year-old boy with cough and dyspnoea of b) the coronal and d) the axial
plane showed bronchiectatic areas and bronchial wall thickening next to the heart (white arrows). a, c)
The same findings are visible on MRI sequences, confirming sensitivity of these protocols for bronchiectasis
is at least similar to CT.
a) b) c)
d) e)
Figure 2. A 12-year-old boy with dyspnoea following lung transplantation. a) The chest radiograph showed
an opacity in the right lung (#). b, d) T2-weighted fat saturation images clearly demonstrate a pneumonic
infiltrate (arrows), e) confirmed with a particularly high signal in diffusion weighted imaging (arrow),
associated with posterior hyperintensity in T2-weighted imaging (arrowheads) and c) hypointensity in T1-
weighted imaging (arrowhead) indicating pleural effusion.
Figure 3. A CT scan, performed after a chest radiograph, in a 10-year-old girl with a history of progressive
difficulty in breathing and chest pain. a) A dishomogeneous space-occupying lesion in the mediastinum
(arrow) associated with pleural effusion (short arrow) from the upper mediastinal area, in front of the
aorta and pulmonary artery, is visible. b, c) MRI confirmed the mediastinal mass causing a compressive
effect on pulmonary vessels and parenchyma with almost total collapse of the left lung (arrow) and pleural
effusion (short arrow). The signal intensity demonstrated the presence of water intensity cystic spaces with
fat-fluid levels (specific for teratoma).
and without ventilation/perfusion mismatch ratio (the difference in signal intensity between
(V9/Q9) and has shown high sensibility in the area of interest and the background) and
comparison to gold standard references such difficulties in performing the examination.
as scintigraphy. However, its clinical Further clinical studies in children are
application is limited by a low signal-to-noise necessary to prove its great potential.
a) b)
c) d)
Figure 4. An 11-year-old girl with a history of fever and cough. Acute phase dorsal consolidations on the left
are well represented as hyperintense focus in a) diffusion weighted imaging sequence b600 (arrow) and b)
turbo spin echo (arrow). After 3 weeks of therapy the focus appears less hyperintense in c) diffusion
weighted imaging sequence b600 (arrow) and d) turbo spin echo (arrow) showing a response to therapy
(image courtesy of G. Morana, Department of Radiology, Ca Foncello Hospital, Treviso, Italy; personal
communication).
d) e) f)
Figure 5. A fetus at 23 months +4 days of gestation. ae) Hyperinflation of the left lung (arrows)
associated with trans mediastinal hernia (arrowheads) and right medistinal shift (#). Many centimetric
lesions are present in the pulmonary parenchyma (black arrows). f) These lesions are hyperintense in T2-
and hypointense in T1-weighted fat saturation images, indicating cystic lesions suggestive of a Type II
CPAM (Stocker classification).
Paediatric lung MRI: indications and empyema or lung abscess. In these cases
features MRI allows the complications and the
extension of pleural empyema to be
Major clinical indications for MRI arise from evaluated; it can also be repeated to
three major fields: evaluate the development and to monitor
N lung infections, CF, asthma and the response to treatment (fig. 4).
pulmonary hypertension (fig. 1), Some authors emphasise the role of MRI in
N regular imaging in patients in whom the characterisation of pulmonary infiltrates,
radiation exposure should be avoided especially in patients suffering from
(fig. 2), neutropenic fever, although cost-efficiency
N mediastinal masses (fig. 3). has not been proven for this indication.
Lung infections The diagnostic value of MRI CF is the most common indication for MRI.
is shown in patients with infectious diseases. By using common proton-MRI sequences it
MRI detects pulmonary infiltrates, hilar is possible to visualise the structural
changes and pleural or pericardial effusions changes of CF lung disease such as:
as well as, or better than, chest radiography.
The predominant MRI findings are alveolar N bronchial wall thickening,
or interstitial parenchymal changes, pleural N mucus plugging,
thickening and fluid and lymph node N bronchiectasis,
enlargement. It is very important to N airfluid levels,
highlight the role of MRI in complicated N consolidation,
pneumonia when there is the suspicion of N segmental/lobar destruction.
Pleural line
Rib
A lines
A lines
Acoustic shadowing
Figure 1. Normal lung. a) Longitudinal scan showing the ribs and their acoustic shadowing, the pleural line
and A lines. b) Transverse scan showing the pleural line and A lines.
B lines
Coalescent B lines
Figure 4. a) Superior and b) inferior field of the lung in a newborn with RDS. In both areas, there is
evidence of coalescent B lines (white lung). The pleural line is poorly defined and coarse.
a) b)
Coalescent B lines
White lung
Spared area
c) d)
Subpleural
consolidations
Muitiple B lines
Figure 5. a) Evidence of a spared area in infant affected by BPD. b) Area of white lung in BPD.
c) Area of interstitial syndrome in BPD. d) Subpleural consolidations in BPD.
Air bronchograms
Lung hepatisation
Air bronchograms
Pleural effusion
Normal lung
Lung consolidation
Air bronchograms
Georg Berding
N V9/Q9 scintigraphy enables accurate Notable per cent fractions of V9 and Q9in the
diagnosis of congenital abnormalities left and right lung can be determined. In the
of the lungs, vessels and heart, as well case of right-to-left shunts, these can be
as in patients with bronchiectasis or measured semi-quantitatively based on
CF. kidney and brain uptake during the lung
N V9/Q9 scintigraphy is easy to perform, perfusion scan. These measurements can be
typically without sedation, and causes valuable in the assessment and treatment of
only low-radiation exposure. patients with cyanosis, e.g. due to the
tetralogy of Fallot or arteriovenous
N A more recent method, 18F-FDG PET/ malformations. Assessment of suspected
CT, contributes to the diagnosis of pulmonary embolism in children is, in
malignancies and inflammation. contrast to adults, a rare indication. Damage
to lung tissue due to infection can be
0 0
% %
100 100
0 0
Figure 1. V9/Q9 scintigraphy in a 6-year-old boy with decreased physical capacity and recurring pneumonia
of the right lung. Planar 99mTc-Technegas scintigraphy showed hypoplasia of the right lung (30% versus
70%; upper row). A subsequent 99mTc-MAA scan revealed a complete lack of perfusion (from vasa
publica) in the right lung (lower row). In angiographic CT the pulmonary veins could not be detected.
Angiography showed an outflow of the contrast medium from the right to the left pulmonary artery. V9/Q9
scintigraphy helped to identify noninvasively congenital abnormality of the pulmonary vessels.
assessed. Regional lung function (V9/Q9) in the literature so far suggests that 18F-
can be evaluated in children with FDG-PET can be useful for the detection of
bronchiectasis as well as CF. Beyond which active infective foci in children with chronic
delayed mucociliary clearance can been seen granulomatous disease and monitoring of
in both diseases; however, this is still an disease activity in children with CF.
experimental indication. Effects of foreign
Patient preparation
body aspiration (e.g. air trapping) can be
demonstrated using V9/Q9 scanning. In There is no specific preparation that is
paediatric oncology with respect to thoracic necessary for children before V9/Q9scanning.
masses, 18F-FDG-PET is used specifically in However, mucus secretions should be
children with lymphoma for staging, removed with mucolytics and chest
treatment response assessment and physiotherapy to facilitate ventilation
planning of radiation therapy. In scanning. Patients must avoid moving
inflammatory diseases, evidence provided during acquisition. In children who are old
Figure 1. A 7-year-old girl with LouisBarr syndrome, fever and cough. a) Initial chest radiograph and b)
subsequent CT scan revealed left lower lobe consolidation (black arrow, a). Consolidation was not resolved
after persistent appropriate treatment (antibiotics) and bronchoalveolar lavage was negative for common
bacteria, mycobacteria and fungi. An additional PCR test was negative for Cryptococcus aspergillus,
Candida and Pneumocystis carinii, whereas cytology was negative for malignancy. c) The child was
referred to our department for lung biopsy, which was performed under ultrasound guidance. The white
arrow indicates the needle inside the lesion. Histology proved lymphoproliferative syndrome. #: the spleen.
Post embo
Figure 3. A teenager with CF and massive haemoptysis. a) Angiography after selective right bronchial
artery catheterisation shows hyperaemia with dilated and tortuous vessels at the right upper lobe. b)
Superselective catheterisation with a microcatheter was performed and subsequent embolisation with
polyvinyl alcohol particles followed. c) Final post-embolisation (post embo) angiography revealed complete
vessel obstruction.
Drainage complications include septic The majority of pulmonary AVMs are simple,
shock, bacteraemia, bleeding, multiple and located on lower lobes of the
superinfection, bowel or pleural lungs. Complications of transcatheter
transgression, bronchopleural fistula and embolisation include pleurisy, transient
complications associated with sedation or angina, severe perioral pain or leg pain,
general anaesthesia. brachial plexus injury or deployment
complications.
Transcatheter embolisation
Due to the decreased incidence of TB and
Transcatheter embolisation is mainly
bronchiectasis, CF has become the major
indicated for treatment of pulmonary
cause of haemoptysis in childhood. Minor
arteriovenous malformations (AVM) or in
bleeding in the form of blood streaking is
cases of major haemoptysis. Embolic
more common whilst major haemoptysis
materials include coils, particles, gel foam
occurs in ,1% of children with CF. The term
and detachable balloons, as well as others
major haemoptysis implies the presence of
depending upon pathological substrate,
acute bleeding (.240 mL?day-1) or recurrent
vessel size/location and material availability.
bleeding of small volumes (.100 mL?day-1
Scarce data are found in the literature over several days or weeks).
concerning pulmonary AVM in children and Pathophysiology of haemoptysis in CF
no data are found for the same pathological includes erosion of enlarged thin-walled
entity in infants. There is a clear association tortuous neovasculature of the
between pulmonary AVM and hereditary bronchovascular net, which are located in
haemorrhagic telangiectasia. Transcatheter bronchiectatic areas secondary to chronic
embolotherapy seems to be an attractive infection. Cases of minor bleeding are
alternative for these patients. Since this usually self-limited. However, cases of major
technique is governed by a 15% reperfusion haemoptysis can be self-limited or require
rate of the AVM it should be reserved for treatment, either conservative (bed rest,
symptomatic children. However, pulmonary intravenous antibiotics, blood transfusion,
AVMs are often embolised when they are vitamin K administration, temporarily
o3 mm due to the risk of paradoxical postpone positive pressure chest physio-
embolisation and stroke. Symptoms include therapy) or transcatheter embolisation
exercise intolerance, cyanosis or clubbing, of bronchial arteries (fig. 3). It is noteworthy
neurological or haemorrhagic complications that both therapeutic arms are governed
(which mainly occur in cyanotic patients). by similar success and recurrence rates.
Hettie M. Janssens
Aerosol therapy has gained importance in croup (Rittichier, 2004), and atelectasis
the treatment of paediatric respiratory (Hendriks et al., 2005). Aerosol therapy is
disorders over the last few decades. It is now considerably more complex than oral
the mainstay of asthma management in therapy, as drugs must be delivered to an
children (GINA, 2012) and is increasingly organ that has mechanisms to exclude
important for the treatment of other foreign material.
respiratory disorders, such as CF
(Heijerman et al., 2009) and broncho- As a rule of thumb, one needs to consider
pulmonary dysplasia (Tin et al., 2008). the five Ds for prescribing optimal aerosol
Other indications are impaired mucociliary therapy:
clearance such as in primary ciliary
dyskinesia (PCD), neuromuscular diseases,
N disease,
tracheobronchomalacia and non-CF
N drug,
bronchiectasis (Boogaard et al., 2007),
N deposition,
N device,
N disability of the patient.
Key points
One needs to be informed about the
pathophysiology and the severity of the lung
N To match the correct aerosol delivery
disease, the pharmacological aspects of the
device to a patient, a clinician should
various drugs, and how the disease, drug,
be informed about the disease, drug,
device and patients characteristics will
deposition and device characteristics,
influence the deposition of the aerosol into
and the ability or disability of the
the lungs. This information and the
patient to perform an inhalation
technical qualities of the aerosol delivery
manoeuvre.
devices are needed to be able to match the
N A pMDI/VHC with an attached device to the patient. Last but not least, the
facemask is the first choice in asthma abilities and disabilities of the child and
maintenance treatment in young parents should be known in order to use the
children. device correctly. Available inhaled drugs
include steroids, bronchodilators,
N DPIs are convenient for older children,
mucolytics, inhaled antibiotics,
who can perform a fast, deep
prostaglandins, antiproteases, analgesia,
inhalation.
anticarcinoid therapy, proteins and
N New (smart) nebulisers are promising surfactant. Many more inhaled therapies are
but monitoring of safety and efficacy in development. For the treatment and
is important. choice of drugs of the different diseases,
please see the sections relating to those
N Correct inhalation technique and
diseases elsewhere in this Handbook.
adherence are mandatory for
successful aerosol therapy. This section will discuss some basic
principles of aerosol technology and the
Nebuliser
(+ mask,
Sufficient Insufficient
<4 years)
inspiratory flow# inspiratory flow#
>78 years <78 years
pMDI spacer
pMDI spacer + mask
Breath-actuated pMDI spacer (nebuliser + mask)
pMDI (nebuliser)
DPI
(nebuliser)
Figure 1. How to choose the right aerosol delivery device for a child. #: sufficient inspiratory flow depends
on the intended inhaler; it is usually .30 L?min-1 but for some inhalers (DPIs) is o60 L?min-1.
Steve Turner
65+ years
400
200
0
40
41
42
43
44
45
46
47
48
49
50
51
52
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2
3
4
5
6
7
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9
10
11
12
13
14
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26
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29
Time week
Figure 1. Laboratory reports of respiratory syncytial virus by week of specimen and age in 20092010.
Reproduced from Salisbury et al. (2013) with permission from the publisher.
Risk factors. Young age, male sex, exposure bronchiolitis suggest that RSV does not
to tobacco smoke and reduced lung function cause asthma.
prior to onset of symptoms are associated
Pneumonia
with increased risk for bronchiolitis. More
Definition. There are a number of definitions
serious features of bronchiolitis are
of pneumonia but no single gold standard
associated with prematurity (with or without
definition. Pneumonia is a clinical diagnosis
bronchopulmonary dysplasia),
which is defined by the WHO as the
haemodynamically significant heart disease
presence of cough, fever and tachypnoea.
and infection with RSV (compared with
Community-acquired pneumonia (CAP) is
other viruses). defined as the presence of signs and
Prognosis. Approximately 20% of infants symptoms of pneumonia in a previously
with bronchiolitis have respiratory healthy child due to an infection which has
symptoms for more than 1 month during been acquired outside hospital. Crackles
convalescence. An association with may be heard with a stethoscope in up to
two-thirds of cases. A chest radiograph is
increased risk for later asthma symptoms
not required for the diagnosis of
has been described but this relationship is
uncomplicated pneumonia. Among infants,
not straightforward. The association is seen
there is some overlap between bronchiolitis
more clearly in those who were hospitalised
and pneumonia in clinical presentation. A
for bronchiolitis rather than cared for in the
broader term acute lower respiratory tract
community. The association usually
infection includes pneumonia and for the
becomes weaker as the children become purpose of this chapter is considered
older. One explanation for these synonymous.
observations is that a common airway
abnormality or genetic predisposition may There are a number of classifications of
lead an individual to develop bronchiolitis pneumonia. Different infective agents may
in infancy and asthma in later childhood. be associated with different classifications
Observations that infants with RSV so there is clinical merit in distinguishing
bronchiolitis are less likely to develop between categories. Typical CAP is by far the
asthma compared to those with non-RSV most common presentation.
Figure 2. Incidence of childhood clinical pneumonia at the country level. Reproduced from the World
Health Organization (2008) with permission from the publisher.
Risk factors. Assuming that other alternative Incidence. There are approximately 200
diagnoses for chronic cough are excluded, million cases of pertussis each year and
the main risk factor is young age. There is no there are peaks (epidemics) every 4 years.
evidence of an immune deficiency but As in all respiratory infections, incidence is
absence of evidence is not the same as age-dependent; a survey of cases across
evidence of absence. Europe reported an overall incidence of 10
cases per 100 000 children but this was 100
Prognosis. This is uncertain but is probably cases per 100 000 among infants and one
very good for most cases. There is a case per 100 000 among older teenagers.
possibility that recurrent infection leads to
progressive airway damage (a vicious cycle Risk factors. The major risk factor for
hypothesis) and, in some cases, to pertussis is not being vaccinated (i.e. very
bronchiectasis. young infants and older children who have
not been vaccinated). Prior vaccination does
Pertussis not protect all individuals against pertussis
Definition. Pertussis (or whooping cough) is but is associated with less severe symptoms
characterised by paroxysms of coughing if these develop.
which can last for up to 4 months. There are
three stages to the infection: Prognosis. Pertussis remains a serious
condition on a world-wide scale and is
N the initial catarrhal phase lasts for 1 week associated with 200 000 deaths,
and is characterised by runny nose and predominantly in infants. Once paroxysms
nonspecific cough; fully resolve most children have made a
N the subsequent paroxysmal phase lasts complete recovery although some may
for 1 month and is characterised by develop bronchiectasis.
paroxysmal cough and often also an
inspiratory whoop and vomit at the end of Conclusion
paroxysms;
Acute lung infections are extremely common
N the convalescent phase lasts for up to
in children and chronic infections are also
3 months and is characterised by
common. The epidemiology of acute and
paroxysms of shorter and less frequent
chronic infections is a dynamic field where
duration.
incidence changes over time due to variation
The catarrhal and early paroxysmal phases in both pathogen and host.
are when the individual is highly infectious.
Inspiratory whoop and post-tussive Further reading
vomiting are not necessarily specific for
pertussis. In one community study of N Celentano LP, et al. (2005). Resurgence of
children aged less than 3 years, these pertussis in Europe. Pediatr Infect Dis J;
symptoms were present in 50% and 70%, 24: 761765.
N Chang AB, et al. (2008). Chronic wet
respectively, of cases of pertussis and 25%
cough: protracted bronchitis, chronic
and 40%, respectively, of cases with
suppurative lung disease and bronchiec-
chronic cough but not pertussis. In older tasis. Pediatr Pulmonol; 43: 519531.
children with pertussis who had been N Crocker JC, et al. (2012). Paediatric
vaccinated, less than 15% of cases had pneumonia or empyema and prior anti-
whoop or vomiting and generally, those biotic use in primary care: a case-control
children who have been vaccinated study. J Antimicrob Chemother; 67:
and have pertussis have a less severe 478487.
illness.
Specimens for bacteriological culture should Lower respiratory tract infections are the third
be collected as soon as possible after the most important cause of mortality globally
onset of disease and before the initiation of and are responsible for .4 million deaths
antimicrobial therapy. annually. The aetiology of pneumonia varies
based on patient age, vaccination status,
Upper respiratory tract infections Pharyngitis immunological status and the clinical
includes tonsillitis, tonsillopharyngitis and setting in which the causative agent was
nasopharyngitis. Streptococcus pyogenes acquired. Determining the aetiology of
causes 1530% of acute pharyngitis in pneumonia is difficult and the choice of
The upper respiratory tract (URT) lies cranial due to respiratory infections. URTIs make up
to the thoracic inlet and comprises the nose 95% of these infections. Preschool children
(in continuity with the sinuses and the have six to eight URTIs per year. The vast
lacrimal sac) and nasopharynx, the mouth majority of URTIs are self-limiting viral
and oropharynx (in continuity with the infections. Human rhinovirus is the most
middle ear via the Eustachian tube), and the common causative organism (,40% of
larynx and laryngopharynx. The respiratory infections), and respiratory syncytial virus,
role of the URT is three-fold. influenza, parainfluenza and adenovirus are
among the numerous (,200) viruses
N To warm inspired air before it reaches the associated with infections throughout the
lungs. URT (table 1).
N To trap and remove inhaled particles that
may irritate the respiratory epithelium This chapter will outline clinical features and
(dust, smoke or organic matter such as the management of common URTIs,
pollen). alongside important rarer infections, rare
N To perform innate and adaptive immune complications of common infections, and
responses against inhaled pathogens. important differential diagnoses.
The URT is also responsible for phonation Common cold or viral rhinitis
and for preparing food and fluids for
digestion. URT infections (URTIs) are the Common colds are self-limiting viral
most common human malady (Johnston, illnesses involving the nasal mucosa, and
2005). For example, in the UK, one quarter are experienced annually by the majority of
of the population visit their doctor every year individuals.
Clinical features Inflammation of the nasal
Key points epithelium (rhinitis) leads to a mucous or
muco-purulent discharge (coryza). There
may be associated sneezing, cough and/or
N The majority of upper respiratory tract
fever. A cold is a diagnosis of exclusion: if
infections are viral in aetiology and
there are symptoms associated with
self limiting.
adjacent structures (such as sore throat or
N Consider epiglottitis or bacterial mid-facial sinus pain) then the diagnosis will
tracheitis in a child with stridor who be ascribed to inflammation at that site
looks unwell. (tonsillitis/pharyngitis or rhinosinusitis) as a
matter of convention.
N Decisions regarding antibiotics for
otitis media and tonsillitis are difficult Management Treatment is support
and involve pros and cons for the (antipyretics) and reassurance, once
patients and for society; these should relevant negatives have been excluded. A
be openly discussed when making meta-analysis of the use of antibiotics for
treatment choices. the treatment of common colds has been
published by Arroll et al. (2005). It shows no
Table 2. Centor score and McIsaac adjustment for assessing the likelihood of streptococcal infection in tonsillitis/
pharyngitis
Centor score (1 point for each) Guidance
Fever Score 01: do not prescribe antibiotics
Absence of cough Score 2: treat if the rapid antigen test is positive
Tonsillar exudates Score 3: treat if the test is positive or treat empirically
Anterior cervical lymphadenopathy Score 4: treat empirically
Aged ,15 years (McIsaac adjustment)
Clinical features: The illness often begins with Clinical features: Children present with a
rhinitis as the upper airway is infected first. coryzal, feverish illness which mimics a self-
Distal progression irritates the larynx, limiting URTI. At this stage the coryzal
resulting in a cough. With subsequent vocal infant is highly infectious to non-immune
cord oedema the cough becomes harsh or close contacts. The classic, paroxysmal
barking and inspiratory stridor will cough follows this stage and lasts for weeks
develop. Airway obstruction is progressive or months; in China, whooping cough is
with limitation of airflow until the condition known as the hundred-day cough. The
begins to resolve or anti-inflammatory cough has a characteristic rise in pitch and
measures are instigated. The onset of may or may not be followed by a whoop or
stridor usually occurs over 612 hours. episodes of vomiting in younger infants.
Sudden onset of stridor should prompt There may also be episodes of cyanosis,
consideration of an inhaled foreign body or apnoea or bradycardia in infants. The cough
anaphylaxis. may occasionally result in petechiae,
subconjunctival haemorrhages, rib fractures
Treatment: Management should be aimed at and pneumothoraces.
maximising airflow through the larynx. Risk
factors for significant hypoxia include Treatment: Accurate diagnosis with
diffusion limitation (e.g. chronic lung pernasal swab or PCR of nasopharyngeal
disease of prematurity) or pre-existing aspirate is key; although cultures take up to
airway compromise (e.g. subglottal 1 week and decline in sensitivity the longer
stenosis). It is imperative to keep the child the illness continues. Children requiring
as relaxed as possible as anxiety (e.g. from hospitalisation should be isolated and
unwelcome or unwarranted interventions) subject to barrier nursing. A macrolide
may worsen airflow. Steroids reduce vocal antibiotic (conventionally 14 days of
cord oedema, facilitating respiration. They erythromycin) is first-line treatment,
can be nebulised or delivered orally. More although shorter courses of newer
severely affected children may gain macrolides may be considered (these may
temporary benefit from nebulised improve adherence). Supportive treatment
epinephrine, with doses repeated as including mechanical ventilation may
necessary due to the short half-life. be required.
Supplemental oxygen (which can be Epiglottitis
administered by a parent with the child on
their lap) may be required and analgesia Haemophilus influenzae type b (Hib) causes
should be offered to all children. Decreasing epiglottitis, a severe swelling of the
the viscosity of inhaled gases results in epiglottis that leads to airway obstruction.
improved large airway flow, and in severe Since the introduction of the conjugate Hib
cases a heliumoxygen mixture may be vaccine, the incidence of epiglottitis has
helpful. fallen considerably.
Pneumonia and lower respiratory tract inflammation primarily in the terminal and
infections respiratory bronchioles with exudate
spreading to surrounding peri-
Pneumonia is defined as an inflammatory bronchoalveolae often resulting in a number
disorder of the lung characterised by of discreet foci. A wide range of organisms
consolidation due to presence of exudate in including viruses, bacteria, atypical
the alveolar spaces. There is, inevitably, organisms and fungi are capable of
associated inflammation in the surrounding creating a pneumonic illness.
interstitial tissues. In classic lobar
pneumonia, watery exudates and pus filling The limited response repertoire of the lungs
the alveoli flow directly into adjacent zones, ensures that many of the clinical features of
which extend to create a confluent and pneumonia, such as fever, cough,
confined area of infection generally within respiratory distress and tachypnoea, are also
the affected lobe; spread of infection features of other clinical entities, such as
predominantly occurs via the lumen of the acute bronchiolitis, wheezy bronchitis and
airways (fig. 1). Invasive disease inevitably indeed viral exacerbations of asthma.
involves organisms penetrating into the Diagnosis remains largely clinical with most
interstitial tissues and, more importantly, community-acquired pneumonia (CAP)
adjacent capillaries leading to bacteraemia. guidelines recommending that chest
Bronchopneumonia is characterised by radiographs are only undertaken in those
with a more severe or atypical clinical
course. This inevitably leads to over
Key points diagnosis of pneumonia and this reality is
reflected in the use of the significantly less
N Around 2 million children ,5 years of specific term lower respiratory tract
age die from pneumonia each year. infection (LRTI) in certain guidelines,
which includes pneumonia and other clinical
N While Streptococcus pneumoniae is the entities.
classic organism it probably
accounts for less than half of the Importance of CAP
cases of pneumonia.
CAP usually refers to a pneumonia
N Many guidelines do not recommend developing in a generally well individual who
the use of chest radiographs to make has acquired the organism outside of a
a diagnosis on pragmatic grounds but healthcare setting.
this is associated with over and under
diagnosis. Worldwide, CAP remains the biggest killer of
children and, thus, is a major health issue. It
N Most children can be treated with oral has been estimated that approximately 2
antibiotics unless they have severe million deaths per year in children ,5 years
and/or atypical disease or cannot of age are attributable to pneumonia, a fifth
tolerate oral therapy. of all deaths in this age group. This is likely
to be an underestimate as most deaths
Hospital-acquired infections, also known as (Foglia et al., 2007). In the 2011 English Net
nosocomial infections, are infections that Point Study, HAP in neonates and children
are not present and that lack evidence of was the second most common cause of
incubation at the time of admission to nosocomial infection after clinical sepsis,
hospital. Pneumonia and other lower accounting for 15.9% of cases and occurring
respiratory tract infections (LRTIs) account most commonly in those aged ,2 years old.
for a large proportion of these potentially
serious complications of hospitalisation. HAP poses greatest risk to those
Such infections can be transmitted to the undergoing mechanical ventilation in which
case it is termed ventilator-associated
patient from another source or may be due
pneumonia (VAP). VAP is generally defined
to an organism already carried by the
as development of a pneumonia .48 h after
patient. Interventions, such as endotrachel
intubation. Many publications have
intubation or use of broad-spectrum
addressed the issue of VAP although it
antibiotics, may compromise host defences
should be remembered that most HAPs
increasing the patients predisposition to
occur outside the intensive care unit (ICU).
infection. Hospital-acquired pneumonia
Attempting to define HAP and VAP has been
(HAP) is generally defined as one that challenging for those designing
presents with signs and symptoms that epidemiological and intervention studies.
occur after, and not originating before, 48 h Variations in definition probably contribute
to differing reports of incidence, with a
recent UK paediatric ICU (PICU) review of
Key points ventilated patients reporting an incidence of
5.6%, accounting for 9.2 per 1000 ventilator
N Hospital-acquired LRTIs are days (Hunter, 2012), while US data indicates
associated with significant mortality, rates of 2.9 to 8.1 per 1000 ventilator days
morbidity and prolonged (Bingham et al., 2009). Differing rates are
hospitalisation. likely to reflect variation in the case mix of
different units.
N Risk factors include intensive care,
immunosuppression and admission HAP in neonatal ICUs (NICU) poses an even
of infants to paediatric wards greater challenge as it is difficult to
containing patients with LRTIs. distinguish between hospital-acquired and
N Organisms may be part of the vertically transmitted infections. This
patients normal flora or maybe uncertainty is compounded by usual NICU
transmitted from another patient or practices being early intervention in
healthcare provider. suspected sepsis, often prior to chest
radiograph changes, a feature usually
N Following recommended infection, integral to the definition of VAP, in addition
control policies significantly reduces to endotracheal secretions that can often
rates of nosocomial infection. yield positive growth in which colonisers and
pathogens are difficult to distinguish.
N Long-term sequelae vary from mild The most important pathogens causing
restrictive or obstructive defects to disease in immunocompromised children
end-stage respiratory failure. are listed here. It should be noted that this
list is certainly not exhaustive.
Aspergillus and Candida are highly These organisms rarely cause disease in
prevalent in our normal environment, in soil healthy individuals, but can do in the
and as part of the skin flora, respectively. immunocompromised.
Elif Dagli
In 1819, Laennec first described the finding nutrition, vaccination and use of early
of ectatic bronchi in pathological specimens. antibiotics. However, the ability to recognise
Since then, bronchiectasis has been a bronchiectasis improved with novel imaging
morphological term used to describe techniques has renewed the interest in this
dilatation of the airways, supported by clinical condition globally.
radiological and clinical evidence. Dilated
Pathophysiology
airways are often manifested with a
thickened wall, bacterial colonisation and Bronchiectasis is categorised into three
destruction of the surrounding tissue due to main phenotypes according to the shape of
excessive inflammation. the dilatation:
Epidemiology N tubular,
Non-CF bronchiectasis (NCFB) is still an
N varicose,
important cause of chronic suppurative lung
N cystic.
disease in low-income countries and among This classification describes the progression
disadvantaged populations of high-income of the disease without providing information
countries. A decline in prevalence has been about aetiology. The aetiology of NCFB is
noted since the 1950s in high-income variable, but the common
countries with improved sanitation, pathophysiological mechanism contains
infection, inflammation and tissue damage.
Chest drain alone Following the introduction Video-assisted thoracoscopic surgery (VATS)
of appropriate antibiotics, the decision to achieves debridement of fibrinous material,
proceed to drainage should take into breakdown of loculations and drainage of
consideration a number of factors including pus from the pleural cavity under direct
clinical and laboratory response to antibiotic vision. The more controversial area is the
therapy at 4872 h and evidence of role of VATS versus chest drainage with
enlarging effusion on repeated ultrasound. intrapleural fibrinolysis in the primary
management of empyema. In a systematic
Development of respiratory compromise is review of 67 studies published over a period
an indication for drainage. While chest drain of .20 years, primary operative therapy was
insertion alone can be effective in children associated with a lower LOS, time of
with empyema, the length of stay (LOS) in drainage, time of antibiotic therapy, re-
hospital is prolonged (20 versus 10.7 days) intervention rate and mortality rate
and there is a higher failure rate (23.6% compared with nonoperative treatment.
versus 9.4%) compared to chest drain with However, the majority of these studies did
intrapleural fibrinolytics. not include treatment with fibrinolytics in
addition to chest drainage.
Chest drain plus intrapleural fibrinolytic agent
The aim of instilling a fibrinolytic agent in Two prospective randomised trials have
the pleural cavity is to break down fibrin compared primary VATS to chest drain with
strands in order to improve drainage and re- intrapleural fibrinolysis, either urokinase or
establish pleural circulation. Numerous case tissue plasminogen activator, in children.
series and a few randomised controlled No difference between treatment groups
trials on the use of intrapleural fibrinolytic was found in the main outcomes, but VATS
therapy in childhood empyema have been cost significantly more. Current evidence
published to date. They have used different suggests that chest drain with fibrinolysis is
agents, dosage schedules and treatment the preferred primary therapy in empyema,
protocols, and there was a great diversity in and that VATS should be reserved for failure
the stage at which treatment was started. of medical management. In clinical practice,
Not surprisingly, outcomes varied greatly. the choice of one of these options is often
conditioned by local experience and
Urokinase is actually the preferred fibrinolytic
tradition.
agent for the treatment of empyema. The
most widely used dosage regimen is 40 000 Open thoracotomy enables removal of the
units of urokinase in 40 mL of normal saline, thickened pleural rind and irrigation of the
or 10 000 units in 10 mL of normal saline for pleural cavity. Potential drawbacks include a
children ,1 year of age, which is large scar and the risk of wound infection,
administered twice daily for 3 days. After persistent air leaks and bleeding. Mini-
instillation, the chest drain is clamped for 4 h thoracotomy involves a similar procedure
and the child is encouraged to mobilise. The through a small incision.
drain is then left on a suction pressure of -
20 cmH2O until the next dose. There is some A number of retrospective studies have
evidence to suggest a potential advantage for compared VATS to open thoracotomy for
smaller catheters in reducing the time of rescue treatment demonstrating less post-
drainage, time until the patient became operative pain, a better cosmetic result and,
afebrile, and LOS. in some cases, a shorter LOS.
Alveolar macrophage
15
organisms
Alveolus
3050%
No infection: Infection:
alveolar macrophage release of acid-fast bacilli
kills acid-fast bacilli into extracellular space;
recruitment of additional
mononuclear cells
Granuloma formation:
spread to lymph nodes, blood stream Exogenous
and other organs reinfection
90% 10%
Latent: Active:
strong cellular immunity, poor cellular immunity,
containment progressive disease
Reactivation
Senescence
Exogenous steroids
Malnutrition
Figure 1. Outcomes following exposure to Mycobacterium tuberculosis. The percentages in red are
typical of outcomes in older children and adults. Reproduced from Manabe et al. (2000) with permission
from the publisher.
Bone
Lung
CNS
Peripheral
lymph nodes
Intrathoracic
lymph nodes
Side-effects Hepatotoxicity is the major childhood. Screening for visual related side-
drug-related adverse event, with case effects is not required.
reports of hepatic failure even when
recommended doses of anti-tuberculous Other drugs Corticosteroids may be used for
therapies are used. However, extensive the management of some specific cardio-
experience has demonstrated that the first- respiratory complications of TB, e.g. airway
line drugs used in treating TB are well obstruction and atelectasis secondary to TB
tolerated in children with a low risk of side- mediastinal lymph gland enlargement, or
effects. Indeed, the drugs are better pericardial TB. Corticosteroids have been
tolerated in children than adults perhaps used in advanced pulmonary disease with
because of the lower peak serum levels clinical and radiological benefits. They are
achieved in children when using the same recommended for all children with TB
dose per kg as adults. meningitis. Prednisolone (12 mg?kg-1 daily
for 34 weeks and then tapered) has been
Hepatotoxicity may be detected more the most commonly used drug. Rifampicin
frequently in children who are malnourished, induces hepatic enzymes that catabolise
immunocompromised, e.g. with HIV corticosteroids and reduce effective
infection, or who present with extensive and bioavailability by ,50%.
serious TB disease. If signs of hepato-
toxicity develop (vomiting, jaundice, liver Corticosteroids are also used in the
tenderness and hepatomegaly) all drugs management of the immune reconstitution
should be stopped and levels of hepatic syndrome (also known as paradoxical
enzymes monitored. Reintroduction of anti- reaction). In this, a temporary deterioration
TB therapy should not be tried until liver occurs after the start of anti-tuberculous
function is normal and should then proceed treatment due to restitution of the capacity
on a step-wise basis with one drug to mount an inflammatory immune
reintroduced at a time. response. It may cause fever, increased
lymph node size and tuberculomas. It can
Ethambutol is now recommended for use in occur after the start of anti-TB treatment,
children of all ages including those aged e.g. commonly as the enlargement of the
,5 years. At the recommended doses and mediastinal lymph node on chest
durations, a review of the evidence radiographs, after improved nutrition or
suggested that ethambutol is safe with a following the initiation of antiretroviral
negligible risk of toxicity throughout therapy in children with HIV infection.
Rates of resistant TB are increasing. Drug Children with TB should be screened for
resistance originates in adults with TB who HIV. Similarly, children newly diagnosed for
have a high bacillary load and who receive HIV should be screened for TB by history
inadequate anti-tuberculous therapy or are and chest radiograph. Drug interactions
poorly compliant. Acquisition of resistance between HIV antiretroviral therapy and the
is rare in the pauci-bacillary disease that similar side-effect profiles of the drugs
occurs in children. involved in treating the two diseases make
managing the two treatments challenging.
Resistance to isoniazid and/or rifampicin is Rifampicin, in particular, reduces the
most important because these two drugs are concentrations of many HIV drugs. For
the mainstay of current first line treatment. children with significant
In MDR-TB, the organism is resistant to immunosuppression, treatment for HIV
both rifampicin and isoniazid with or should be delayed for 28 weeks once anti-
without resistance to other anti-TB drugs. tuberculous treatment is started. For those
Infection is usually the result of with mild or no immunosuppression,
transmission of a strain of MDR-TB from an treatment for HIV may be deferred until
adult index case. treatment of TB is completed.
Treatment is often complex and specialist Guidelines recommend that TB in HIV-
advice should be sought. There is infected children should be treated with a 6-
uncertainty about activity and safety of the month regimen as for uninfected children.
available second line drugs. Suitable The WHO recommends that rifampicin
formulations for children are often not should be used for the entire duration of
available. If an isolate from the child is not treatment. In children, intermittent
available, the best guide to treatment is the regimens (twice or thrice weekly) should not
susceptibility pattern of the adult source be used in areas with high HIV prevalence
case. In general, at least four drugs certain for the treatment of pulmonary TB or TB
to be effective (and to which the child is lymphadenitis.
nave), including an injectable and a
fluorquinolone, are given on a daily basis Immune recovery in children with HIV after
using DOT for an extended initial period of initiation of antiretroviral therapy, nutritional
6 months followed by at least three of the rehabilitation or sometimes just beginning
most active and best tolerated drugs for a anti-TB therapy may unmask subclinical
further period of 1218 months. disease or induce a paradoxical temporary
deterioration despite adequate therapy for
Current recommendations are to avoid TB, the so-called immune response
using primary chemoprophylaxis or inflammatory syndrome (IRIS). This can
treatment for latent TB in cases of close simulate worsening TB disease with fever
contact with a case of MDR-TB if the child is and increased size of lymph nodes or
clinically well, and to observe for 2 years. tuberculomas. Treatment for TB should not
Globally, an estimated 11% of the nearly 10 The risk of disease progression and
million new cases of active TB diagnosed extrapulmonary dissemination is highest in
annually occur in the paediatric population, the first 2 years of life, with risk of disease
but the true burden of TB in children progression estimated at 4050% in the
remains underestimated. absence of Bacille CalmetteGuerin (BCG)
vaccination or prophylactic therapy. The
Extrapulmonary TB is common in children majority of disease occurs within 2
and refers to the isolated occurrence of 12 months of initial infection with
active TB at body sites other than the lung. pulmonary TB accounting for 6080% of all
The exact mechanisms that determine the cases.
clinical outcomes following infection in
children are not completely understood, but Extrapulmonary TB usually originates from
include: lymphohaematogenous spread of TB bacilli
from a primary pulmonary focus,
N age, contiguous spread from infected lymph
N nutritional status, nodes or direct inoculation of bacilli.
N underlying immunity, Generally, superficial lymphadenopathy is
N vaccination status, the most common form followed by central
nervous system (CNS) disease, pleural,
N genetic susceptibility,
miliary/disseminated and skeletal TB. Less
N microbial virulence.
common forms include abdominal,
pericardial, renal and cutaneous TB.
Key points The role of age-related immune responses
in clinical manifestations of TB in children
N Young children are more likely to
It is well established that less mature or
develop extrapulmonary
impaired immune responses contribute to
manifestations of TB, associated with
the disseminated forms of TB seen in
age-related impairment of cellular
children and immunocompromised hosts.
immune responses.
N Extrapulmonary TB can have very A number of studies have reported an age-
severe consequences and thorough related functional impairment of both innate
investigations and prolonged therapy and adaptive immune responses in children.
are required. The current paradigm in TB immunology is
the crucial importance of Mycobacterium
N Conditions of immunosuppression, in tuberculosis-specific CD4+ T-cells and the key
particular HIV, are more likely to lead cytokines such as interferon gamma (IFN)-c
to extrapulmonary severe produced in the protection against M.
manifestations. This is proportionate tuberculosis. However, M. tuberculosis-
to the level of suppression of T-cell specific IFN-c responses alone are not an
function. absolute correlate of protection against the
development of TB.
the diagnosis. Acid-fast bacilli stains of bone ribs with forearm bones and clavicles often
specimen are often negative but culture may involved. Short bones of the hands and feet
be positive in up to 75% of cases. may be affected in younger children (TB
dactylitis). Systemic symptoms may be
TB arthritis is usually a monoarticular
observed.
disease affecting the large weight-bearing
joints; the hips or knees are involved in Diagnosis Radiography shows soft tissue
,30% of cases. swelling, osteoporosis, cystic bone changes
and sequestrum. An infiltrative pattern
Clinical features resemble those of spinal TB.
resembling Ewings sarcoma, fungal
The diagnosis is established through
radiography of the affected joint and reveals infection and chronic pyogenic osteomyelitis
joint effusion, periarticular osteopenia, may sometimes be seen. Cyst-like cavities
irregularity of the bone cortex, lytic lesions with expansion of the diaphysis, the so-
and periosteal new bone formation. called Spina ventosa, may be seen. BCG
Decreased joint space and widening of the osteomyelitis presents similarly and can
intercondylar notch in the knee are observed occur a few months to 5 years post-BCG
in advanced disease. Marked joint vaccination. Culture of the BCG strain
destruction and fibrous or bony ankylosis establishes this differential diagnosis.
are seen in end-stage disease. An ultrasound Abdominal TB is generally less common in
scan demonstrates joint effusion and aids children. It may complicate untreated
the aspiration for acid-fast bacilli and pulmonary TB in ,638% of cases.
culture. MRI demonstrates marrow changes, Abdominal TB due to M. bovis can result
joint effusions and cartilage and bone
when unpasteurised milk is ingested, but
erosions. Joint fluid aspiration or synovial
this is now rare.
biopsy is necessary for confirmation of
diagnosis. Clinical features Abdominal TB is more
Tuberculous osteomyelitis is a very rare form common in older children and adolescents,
of skeletal TB in children. Lesions are either and usually presents as enteritis or
solitary or multifocal. peritonitis. Patients suffer with chronic
abdominal symptoms over several months:
Clinical features are local pain, swelling and vague abdominal pain, abdominal mass,
tenderness of the skull vault, hands, feet and anorexia and vomiting in association with
Studies of the epidemiology of asthma have diagnosis, which cannot be made by a single
flourished in the last 30 years, reflecting the measurement or test. Physicians diagnose
fact that the disease is common in asthma on the basis of medical history,
developed and developing countries, the physical examination and assessment of
aetiology still largely unknown, and costs are reversibility of airway obstruction. In
high. This section explains how asthma is epidemiological studies, the most common
assessed in epidemiological surveys, approach uses questionnaires to ascertain
describes time trends and prevalence whether subjects have had symptoms of
differences by age and sex, explains the asthma or have ever received a diagnosis of
concept of asthma phenotypes, and asthma from a physician.
summarises the current knowledge on
The prevalence of asthma diagnosis and
natural history and long-term outcome.
symptoms is dependent on the awareness of
Assessment of asthma in epidemiologic the disease in the populations studied and
studies and time trends on diagnostic labels. The same child might
be diagnosed with asthma by one doctor
Paediatric asthma guidelines emphasise and with wheezy bronchitis by another.
that asthma remains a complex clinical Thus, the preferred approach to assessing
asthma prevalence in epidemiological
studies is based on symptoms, particularly
Key points current wheeze (wheeze during the past
12 months).
N Asthma and wheezing disorders are
heterogeneous conditions in terms of The International Study of Asthma and
risk factors, age of onset, clinical Allergies in Childhood (ISAAC) is a major
phenotype, severity, response to initiative involving nearly 2 million
treatment and long-term course. schoolchildren aged 67 and 1314 years
from .100 countries. It was designed to
N Despite a large body of research, the compare prevalence of asthma, rhinitis and
factors explaining time trends and eczema between countries (phase I, 1994
international disparities in asthma 1995) and their trends over time (phase III,
prevalence remain largely unknown. 510 years later) using standardised
N Both severity of asthma and lung questionnaires (Asher et al., 2006). Key
function show a track from early findings included the high prevalence of
childhood to adulthood. asthma symptoms and asthma diagnosis in
English-speaking countries and Latin
N It is important to study phenotype and America (.20% in most centres),
clinical course of wheezing illness intermediate prevalence in Western Europe,
early in life when it might still be and low prevalence (,5%) in Eastern
possible to modify the natural history Europe, with a clear northwestsoutheast
of the disease. gradient. The lowest prevalence is found in
Africa and Asia with the exception of affluent
Studies in migrants also point to the Wheezing disorders might comprise several
distinct phenotypes, possibly representing
importance of socio-cultural and
different disease entities (Silverman et al.,
environmental factors. These studies
1997). If this is true, early distinction of
generally found a steep increase in
phenotypes would allow more focused
prevalence among groups migrating from
research into aetiology and pathophysiology,
low- to high-prevalence areas, particularly
prescription of treatments and preventive
among those who were born in the host
measures targeted to the phenotypes, and
country or migrated during the first years of
improvement in the prediction of long-term
life. Unfortunately, numerous changes occur
outcome. Classical approaches for
simultaneously in migrants, so it is difficult
distinguishing asthma phenotypes have
to disentangle the role of environmental
relied on trigger factors or time course. A
factors (e.g. climate and allergens),
distinction by the main triggers led to the
behaviours (diet and smoking) and social definitions of:
factors that might affect their interaction
with the healthcare system; for example, the N episodic viral wheeze (wheeze occurring
likelihood of being diagnosed and treated episodically only during viral infections);
(Kuehni 2011). Asthma risk factors are N multiple-trigger wheeze (wheeze also
described in detail in the Genetic and occurring in response to other factors
environmental factors in bronchial asthma such as crying, laughter, exercise or
and wheezing disorders section in this allergens, and often associated with
Handbook. atopy).
LD: linkage dysequilibrium; OR: odds ratio; RR: relative risk; MAF: minor allele frequency; ROI: region of interest.
Figure 1. Genetic loci discovered in GWASs until the end of 2012 on asthma (*) and related traits: IgE
levels (**), eosinophil count (***), lung function (****) and atopic dermatitis (*****). Locus positions
are shown down to chromosome, region and bands. Arrows represent partly sub-bands. Short arms of
chromosomes (p) face upwards and long arms (q) face downwards. Data courtesy of D. Vercelli (Arizona
Respiratory Center, Tucson, AZ, USA; personal communication). Image courtesy of M. Rocchi (University
of Bari, Bari, Italy; personal communication).
variants, epigenetic modifications may be in and of FOXP3 for regulatory T-cells (Treg)).
a constant state of flux. It is difficult to Thus, epigenetic modification may possibly
decide when to measure and what cell types impact asthma with Th2-skewing, as it is
or tissue to analyse. Likewise, their relative known that such immune responses
contribution to gene expression and contribute to asthma development. Here,
especially their heritability across human studies have demonstrated the
generations is unknown. impact of air pollution as an environmental
factor on FOXP3 methylation and Treg cell
There is evidence from both animal and function in asthmatic children. Furthermore,
human studies for epigenetic regulation in epigenetic effects on more intermediate
asthma and wheezing disorders. Mouse outcomes such as atopy and allergic airway
studies demonstrated an influence of inflammation, lung function and on
maternal methyl-donor rich diet on BHR, childhood wheeze subtypes are also
airway inflammation and serum IgE levels in supported by data derived from human
offspring. Also exposure to environmental studies. Due to ethical constraints, human
microbes can act by epigenetic regulation as studies have examined epigenetic effects in
shown by a study in mice where prenatal cells outside the lung, mostly peripheral
administration of the farm-related bacterial blood cells, but also in possibly more
species Acinetobacter lwoffii F87A prevented relevant buccal and nasal cells or in cells
an asthmatic phenotype in the offspring. In from sputum. Such easily obtained material
immunology, epigenetic mechanisms are might be useful for markers of childhood
known to be involved in T-cell differentiation asthma as demonstrated by the fact that
(e.g. by modification of the IFNG promoter hypo-methylation in Alox12 even in
for T-helper (Th)-1 cells, as well as for Th2, peripheral blood cells was associated with
Figure 1. Chest radiograph of an infant with severe Indications for intensive care unit
acute bronchiolitis showing diffuse air trapping consultation and admission include failure
and peribronchial thickening. to maintain SpO2 .92% with oxygen
NO
Nasal suction
Assess respiratory status
Start oxygen if SpO2 consistently 9094%
Meets discharge
criteria?
NO
Continue observation
Figure 2. An algorithm for the management of bronchiolitis in the emergency department. PICU:
paediatric intensive care unit; PCP: primary care physician.
Wheezing and dyspnoea in preschool have at least one episode of wheeze before
children are among the most common their third birthday. There is much clinical
presenting symptoms in paediatric practice. heterogeneity in phenotypes of children with
Approximately one in three children will preschool wheeze, which appears to be
similar between populations. Due to this
heterogeneity, and despite its common
occurrence, relatively little evidence is
Key points available on the pathophysiology and
treatment of wheezing in preschool children.
N Despite the favourable natural history Therefore, considerable controversy exists in
in the majority of children with the literature about the classification and the
wheeze during preschool years, treatment of preschool wheezing disorders.
symptoms in this age range can be To end this controversy, the underlying
severe or frequent, justifying pathophysiology and aetiology of preschool
maintenance treatment. wheezing disorders need to be properly
N Limited information is available on understood.
the pathophysiology of recurrent
Epidemiology
wheeze in preschool children, which is
likely to be complex and Much of the knowledge on recurrent wheeze
multifactorial. As a result, one- and dyspnoea in preschool children comes
dimensional classification systems from a series of well-designed, large-scale
(e.g. episodic viral versus multiple- birth cohort studies. The most well-known of
trigger wheeze) are of limited value in these was conducted in Tucson, AZ, USA.
diagnosis and management. The main results of this landmark study, the
N ICS are recommended as first choice Tucson Childrens Respiratory Study, are as
maintenance therapy in children with follows:
frequent or severe symptoms
irrespective of phenotype.
N 826 infants were followed from birth;
Montelukast is an alternative
N during the first 3 years of life 30% of
children had had at least one episode of
maintenance treatment option,
wheeze and half of these children had
although it is less effective than ICS.
wheezed more than once;
N If symptoms persist despite N 60% of wheezy preschool children ceased
maintenance treatment ongoing to wheeze before the age of 6 years
exposure to relevant inhalant (transient wheeze associated with
allergens and tobacco smoke, poor maternal smoking and with wheeze
adherence or inhalation technique, occurring only during viral colds);
alternative diagnoses and relevant N 40% continued to wheeze after their sixth
comorbidity should be excluded birthday (persistent wheeze associated
before stepping up therapy. with eczema, maternal asthma and
elevated cord blood IgE).
Data from Brand et al. (2008), Pedersen et al. (2011), and Schultz et al. (2011).
With respect to inhaled steroid treatment, a conditions. The initial diagnostic approach
systematic review showed that ICS are to a preschool child with wheeze is aimed at
effective in reducing preschool wheeze, excluding serious underlying conditions,
irrespective of the reported symptom pattern which usually present in the form of
(EVW or MTW). A recent large trial in the USA atypical wheeze (table 2). A detailed
showed that daily nebulised low-dose history and thorough physical examination
budesonide was no more effective in reducing when the child is symptomatic are usually
the number and severity of wheezing sufficient to exclude atypical wheeze. If
episodes in preschool children than history and physical examination suggest
intermittent use only during symptomatic the possibility of atypical wheeze, specific
episodes. While episodic nebulised further diagnostic testing is indicated.
budesonide was no more effective than
episodic use of montelukast in preschool The majority of preschool children
children with viral-induced wheeze, daily use presenting with troublesome wheeze and
of nebulised budesonide was more effective dyspnoea will have typical wheeze, after
than daily montelukast in children aged 2 exclusion of the unlikely causes listed in
8 years with mild persistent wheezing. table 1. Because parents differ from
physicians in their understanding of the
Different ways to classify preschool wheeze term wheeze, confirmation of the
Based on the available evidence, several presence of wheeze by a physician is
classification systems of preschool wheeze recommended before initiating therapy. In
have been proposed (table 1). None of these children with confirmed typical wheeze, the
systems is universally accepted, which is not only potentially useful diagnostic test is a
surprising given the limited evidence on test of allergic sensitisation (either skin-
which they are based. There is no consensus prick test or measurement of specific IgE to
on the preferred terminology. a panel of allergens in blood) for
classification purposes (table 1).
Diagnostic approach to preschool children
with recurrent wheeze and dyspnoea Treatment of acute episodes
Additionally
Figure 1. Specific symptoms that should be asked in assessing asthma diagnosis. PE: physical education.
Informaton from Bacharier et al. (2008).
Airway inflammation The underlying airway cells (APCs) that facilitate presentation to
inflammation in asthma is generally the T-cells. IgE is synthesised in the
considered to be eosinophilic. However, the presence of interleukins (ILs) (e.g. IL-4 and
strength of the association between atopic IL-13) and other cytokines. The allergic
sensitisation and asthma varies, and most inflammation is characterised by a T-helper
sensitised subjects do not have asthma. cell (Th) type 2 cascade involving Th2
Allergen exposure may, in some, lead to a cytokines and other immune mediators. It is
break in natural tolerance, triggering allergic currently believed that directing nave T-cells
inflammation, and an allergen-specific to Th1 versus Th2 immunity involves
immune response involving T- and B- regulatory T-cells (Tregs), a process which is
lymphocytes. The innate immune system is, important in tolerance development and
in effect, the barrier between the organism suppression of allergic inflammation.
and external environment, being the
important first line of defence against In addition, dendritic cells in the airway
infections and intruders. The adaptive epithelium facilitate uptake of allergens
immune system, however, classically bound to FceRI. Such mechanisms are
involves (T-)cellular responses to antigens probably propagated through defects in
(or allergens), typically with production of barrier function that have recently been
specific IgE antibodies from B-cells, and shown in the airway epithelium of asthmatic
adapts to environmental challenges. subjects.
The allergic response is initiated when an Viral infections are important triggers of
allergen binds to the high-affinity receptor symptoms and exacerbations of asthma in
for IgE (FceRI) on the antigen-presenting childhood, whereas many children with
Symptoms Treatment
Figure 2. Stepwise management of asthma treatment in children aged 512 years. #: BDP or equivalent.
Reproduced and modified from BTS et al. (2012) with permission from the publisher.
visited the emergency room for asthma. The and irritants that worsen the disease,
optimum setting and content for such nonadherence to therapy, psychosocial
educational interventions and relative issues, or true severe asthma that is
effectiveness of the various components are resistant to therapy.
largely unknown.
Each age group has particular features that
In general, a written personal action plan is contribute to the severity of asthma, as
recommended for all children with asthma outlined in table 4.
and, in particular, for children with poorly
controlled asthma. Furthermore, parental In contrast to adults, children with severe
education in asthma is recommended to asthma may not yet have developed
improve assessment of the childs disease remodelling, although increases in smooth
as well as adherence to treatment. muscle and evidence of reticular membrane
layer are frequently found. Furthermore, the
Problematic, difficult or severe asthma inflammation in childhood severe asthma
may appear to be eosinophilic without the
Severe asthma is relatively rare, occurring in classical Th2 inflammation, in contrast to
approximately 45% of children with asthma the more commonly neutrophilic
and 0.5% of the general child population. inflammation in adults.
However, there is no uniform or generally
accepted definition of severe childhood Managing children with severe asthma
asthma, and several criteria are used, such requires a systematic approach to assess
as the need for or use of high-dose diagnosis, airway inflammation and
corticosteroids, severe and/or frequent therapeutic responses to corticosteroids.
exacerbations, chronic asthma symptoms, This should enable further differentiation of
or reduced lung function. Thus, severe or those children who have a true severe,
difficult asthma may be related to wrong therapy-resistant asthma, from those with
diagnosis, exposure to environmental the wrong diagnosis, those with asthma with
factors such as allergens, tobacco smoking significant comorbidities that need to be
Vitamin D Recent research has shown that Nevertheless, positive effects of macrolides
vitamin D has an important role in the have not yet been fully demonstrated in
modulation of the immune system clinical trials in asthma and recent studies
response, especially through the inhibition have presented conflicting conclusions on
of Th1 response and T-cell proliferation. the use of macrolides in routine clinical
practice in patients with uncontrolled
An epidemiological study suggested that asthma. Further studies investigating the
low concentration of vitamin D in children effects of macrolides in asthma
with asthma is associated with more severe management are, therefore, required.
symptoms, frequent exacerbations,
reduction in lung function and an increase Theophylline Theophylline may act through
in medication use. Vitamin D has been different molecular mechanisms to inhibit
postulated to play an important role in the phosphodiesterase and adenosine receptor
modulation of inflammatory response and antagonism at therapeutic concentrations.
maintenance of airway homeostasis as well Some studies show that low doses of oral
as to have a role in the improvement of the theophylline increase histone deacetylase-2
anti-inflammatory action of glucocorticoids (HDAC2) expression in alveolar
in patients with refractory asthma. macrophages in patients with COPD and it
also downregulates inflammatory gene
Though some observational studies show expression via effects on histone acetylases
lower plasma levels of vitamin D in (HATs) and histone deacetylases (HDACs).
asthmatic patients as well as inverse In asthma, HAT levels are increased while
associations between vitamin D and total HDACs are reduced; this is inverted by
IL-5-specific
antibody Eosinophil
TH0 cell
APC
IL-12 IFN-
Figure 1. Schematic diagram showing the interplay between local, as well as systemic, immune cells and
biomarkers of the innate and adaptive immune system in allergic inflammation. TCR: T-cell receptor;
rhIL: recombinant human IL; IFN: interferon; rhIFN: recombinant IFN. Reproduced from Holgate
(2008), with permission from the publisher.
as the cells move from the bone marrow to cycle in asthma development suggests that
the mucosal lining. repeated airborne irritant stimuli (such as
allergens or viruses) evoke cycles of
Such mechanisms are probably propagated inflammation leading to intermittent
through defects in barrier function, and have inflammation and initially resulting in
recently been demonstrated in the airway episodic symptoms. However, with repeated
epithelium of asthmatic subjects and the insults the inflammatory resolution becomes
skin of subjects with atopic eczema, as well less complete leading to tissue repair and
as in other allergic diseases. A link has been regeneration, which may trigger prolonged
reported through a common genetic variant
periods of pathological changes. These
of filaggrin.
periods may progress to deterioration in
Viral infections are important triggers of respiratory function and perhaps to
symptoms and exacerbations of asthma in remodelling. A commonly asked question,
childhood, whereas many children with viral the answer to which is not clear at present, is
wheeze will not go on to develop asthma. what is the role and potential interaction
Recent studies suggest that respiratory between allergic sensitisation and viral
viruses, possibly (sub-types of) human infections in eliciting disease development,
rhinovirus in particular, may play a role in in contrast to both viruses and allergens
triggering the immune system. The being potential triggers of disease
mechanisms are not known, but a series of exacerbations? However, it was recently
interactions between antiviral and atopic deduced that allergic sensitisation appears to
inflammatory pathways mediated by local precede viral infections in children who have
activation of myeloid cell populations are both conditions. Another aspect of the
probable in the airways, as well as in the bone damaged epithelium in asthma is the
marrow. A recently hypothesised immune reduced ability to handle viruses in an
Neutrophil
Figure 2. Different T-cell subtypes are involved in the pathogenesis of asthma. Cytokines and contact
signals, together with dendritic cells and the thymic epithelium, drive the inflammatory process into
various cell lines (blue circle), maintaining inflammatory responses involved in asthma and airway
hyperreactivity. GM-CSF: granulocyte-macrophage colony-stimulating factor; TNF: tumour necrosis
factor; IFN: interferon; NKT: natural killer T-cell; Th: T-helper; iTreg: inducible regulatory T-cell.
Reproduced and modified from Holgate (2012), with permission from the publisher.
optimal way. It appears that the reduced parasympathetic mechanisms involving heat
ability of airway epithelial cells to produce and fluid exchange over the epithelium. BHR
interferon-c may lead to cytotoxic cell death is a modest, but significant, risk factor for
and subsequent dissemination of viruses, later onset of asthma and tends to decrease
rather than apoptosis, possibly explaining the throughout childhood.
prolonged symptomatic viral infection
The role of lung function reductions in the
observed in asthmatics.
development of asthma, in contrast to lung
function decline with chronic asthma, is not
Bronchial hyperresponsiveness (BHR) is a
entirely clear. There is no doubt that asthma
common, but not necessary, feature of
is associated with reduced lung function as
childhood asthma. BHR typically presents as
well as a more rapid decline in lung function
a general tendency to develop symptoms via
compared to healthy individuals. In a few
exposure to various physiological or
birth cohorts, reduced lung function has
environmental stimuli, with exercise being a
been found to precede asthma in some, but
classical childhood asthma symptom trigger.
not all, children with asthma.
The underlying mechanisms for BHR
development are not clear, but may involve Airway remodelling is a common feature in
barrier dysfunction, as well as possibly neural adult asthma but this is not as clear in
In the International Study of Asthma and The observed increase in allergic diseases is
Allergy phases IIII, asthma prevalence particularly worrying since it not only affects
varied up to 15-fold in the .50 included the subjects with the diseases, but is likely
countries and almost 200 000 67-year-old to increase the burden of allergic disease in
children and 300 000 1314-year-old the offspring of the current younger
children. In 20012003, the prevalence of generation.
current asthma symptoms in 67-year-olds
ranged from 5.0% (Nigeria) to 37.6% (Costa
Further reading
Rica) with respective figures in 1314-year-
olds ranging from of 5.1% (Georgia) to N Annamalay AA, et al. (2012). Prevalence
31.2% (Isle of Man). The corresponding of and risk factors for human rhinovirus
figures for allergic rhinitis were 2.2% (Iran) infection in healthy aboriginal and non-
to 24.2% (Taiwan) for 67-year-olds and aboriginal Western Australian children.
4.5% (Baltic countries) to 45.1% (Paraguay) Pediatr Infect Dis J; 31: 673679.
in 1314-year-olds, and for atopic eczema N Ballardini N, et al. (2012). Development
were 2.0% (Iran) to 22.3% (Sweden) and and comorbidity of eczema, asthma and
1.8% (Georgia) to 21.8% (Morocco), rhinitis to age 12: data from the BAMSE
birth cohort. Allergy; 67: 537544.
respectively. Overall, since the mid-1990s,
N Bousquet J, et al. (2012). Severe chronic
an increase in allergic disease prevalence
allergic (and related) diseases: a uniform
has been found more often than a decrease,
approach a MeDALL/GA2LEN/ARIA
most often in the younger age group and position paper. Int Arch Allergy Immunol;
particularly for atopic eczema. In Europe, 158: 216231.
pooled data from 11 birth cohorts (.14 000 N Carlsen KH (2012). Sports in extreme
children) demonstrated a mean prevalence conditions: the impact of exercise in cold
of current asthma in children aged 6 temperatures on asthma and bronchial
10 years of 8.1%; approximately half of the hyper-responsiveness in athletes. Br J
children had concomitant allergic Sports Med; 46: 796799.
sensitisation, 7.7% had current allergic N Haland G, et al. (2006). Reduced lung
rhinitis and 29.5% had allergic sensitisation, function at birth and the risk of asthma at
demonstrating large variations between 10 years of age. N Engl J Med; 355: 16821689.
countries and cohorts. N Holgate, et al. (2008). Treatment strate-
gies for allergy and asthma. Nat Rev
The prevalence of food allergy is more difficult Immunol; 8: 218230.
to assess due to the relatively large difference
Gunilla Hedlin
Many children who start to wheeze during is also a clear relationship between exposure
airway infections in early life will improve and allergic symptoms, yet this may not
with age when infections become less always be the case. Exposure to dander
frequent and the airways grow. There is, present on clothes, hair or on surfaces at
however, a large group of children who start home and school or in other public places
with viral wheeze and continue to develop constitutes an invisible source of allergen.
persistent asthma. In many of these Under these and other circumstances it can
children, IgE-mediated allergy will play an be difficult to evaluate the impact of allergy
important role as a trigger of symptoms. In on a childs symptoms. These examples
some, allergy testing will confirm an IgE- highlight the importance of performing a
mediated sensitisation sometimes careful, thorough, diagnosis of allergy before
preceding the clinically relevant allergy. In the decision is made to take action on
others, asthma symptoms at allergen allergen avoidance and/or initiate
exposure will appear before sensitisation immunotherapy. The allergens responsible
can be confirmed. Thus, although allergy is a for causing asthma symptoms have to be
common cause of symptoms of asthma and confirmed.
often of asthma exacerbations, it is not Prevalence of allergic sensitisation
always clear what role a specific allergen
plays in the severity of the disease. This is Allergic sensitisation can start at any age
particularly obvious when the relationship and is a common phenomenon. In the US
between exposure and symptoms is not National Health and Nutrition Survey 54%
clear. In pollen allergy, the relationship of 10 500 participants had one or more
between exposure and symptoms is easy to positive SPT to one or more of 10 allergens.
assess using pollen count reports. There is The sensitisation rate had more than
usually no need to confirm a relationship doubled between the tests performed during
between sensitisation, exposure and 19761980 and 19881994. Similar trends
symptoms by any other means than taking a have been seen in European longitudinal
history and performing a skin prick test and/or cross-sectional population-based
(SPT) and/or an analysis of allergen-specific studies. In a Swedish study of the
IgE in serum. In animal dander allergy there sensitisation rate in schoolchildren the
prevalence of one or more positive SPT
increased from 2130% between 1996 and
Key points 2006.
Diagnosis of allergy
N Allergy is a common trigger of
asthma. History The first and foremost step in the
N Allergy can start at any age. evaluation of children with asthma is a
careful detailed history. Important questions
N Allergy testing should be performed in include family history of allergic disease,
all children with asthma. known triggers of symptoms, frequency and
severity of symptoms, other signs of atopic
disease like rhinitis without relation to colds, has developed tolerance. A SPT can be
atopic dermatitis and adverse reactions to performed at any age but skin reactions tend
food. In some children allergic rhinitis may to be smaller in young children (table 2).
precede asthma and act as a predictor of an
increased risk of asthma. Early development IgE in serum can be analysed for:
of eczema and/or food allergies can also be N single allergens,
signs of risk of later allergic asthma in N allergenic molecules (components) of
children. single allergens,
Allergy sensitisation testing: practice and N a mix of allergens (mix of rodents,
interpretation The most common mode of moulds and dust mites),
allergy testing is in vivo testing by the SPT; N for screening purposes by a multi-
usually the test of choice. The alternative is allergen test, including the common SPT
in vitro testing, which is analysis of allergen- panel of allergens (table 3).
specific IgE antibodies in serum. Both tests The in vitro IgE measurement and the SPT
have advantages and disadvantages result usually agree, but not always. If the
(table 1). SPT does not agree with the history IgE in
SPTs should be performed with well- serum should be measured before rolling
standardised extracts. Usually a panel of out a suspected allergy. Analysis of serum
aeroallergens are used. The test is applied IgE can be performed at any age or any time;
by drops of allergen extract on the volar side current pharmacotherapy does not
of the forearm. The drops are then interfere with the test result. Negative test
punctured by a needle-like device (fig. 1). results in young children should be
After 1520 min any wheal and skin flare interpreted with caution. Low specific-IgE
reactions are recorded and the longest levels (0.10.35 kUa?L-1) can indicate
diameter of each wheal is measured. A sensitisation. There are a number of
wheal diameter o3 mm is considered a companies that provide assays for the in vitro
significant skin reaction. A false-negative IgE antibody tests. Most commonly, a solid
test result can be seen when the patient has phase matrix with allergen extract is used.
ongoing antihistamine therapy, ongoing
dermatitis and/or when a topical
corticosteroid has recently been applied on
the skin. A false-negative result can also be
seen at an early stage of sensitisation or if
sensitisation is weak. A false-positive SPT
can be seen if the child suffers from
dermographism or when sensitisation does
not reflect clinical allergy; in the latter case
the history is more important than the test
result, although a positive test can precede
the clinical allergy. In food allergy that
subsides, such as egg and milk allergy, the
skin sensitivity can remain after the child Figure 1. Performance of a SPT.
After adding the patients serum an anti-IgE whose symptoms are mainly caused by
antibody is added and the amount of bound other factors in spite of confirmed allergen
allergen-specific IgE in the patients serum sensitisations.
is analysed. The result is usually expressed
Food challenges, open or double-blind, are
in arbitrary mass units (kUa?L-1).
sometimes warranted to confirm an allergy
Allergen challenge tests While in vitro tests or but also to support development of
SPTs are good enough for confirming pollen tolerance, which is common in children
and animal dander allergy, it may be with, for instance, milk and egg allergy.
necessary to perform allergen provocation
Total IgE measurements in serum are mainly
tests in the eyes and/or the nose to confirm
needed when treatment with anti-IgE
a dust mite or mould allergy. Bronchial (omalizumab) is considered, an injection
allergen challenge is rarely indicated. It can therapy with monoclonal anti-IgE
be dangerous in children with asthma, antibodies. Dosing is based on the patients
inducing a severe asthmatic reaction, and age, weight and level of total IgE.
should be avoided.
Molecular diagnosis in allergy is usually
Nasal and conjunctival allergen challenges performed by measuring IgE antibodies
can be important if there is doubt about the towards individual allergenic components.
impact of the specific allergy on the severity An alternative is microarray-based testing
of symptoms. This may be the case when against multiple recombinant or purified
allergen immunotherapy is considered. natural allergen components. This has
The rationale is to avoid treating a child made it possible to analyse IgE antibodies
to numerous allergen components of many
common allergens simultaneously in small
Table 3. Common panels of allergens included in SPT samples of serum (20 uL). The allergen
and/or IgE antibody screening components can be classified by protein
Tree pollen (relevant for geographical area) families. This detailed analysis improves
Grass pollen (relevant for geographical area) the possibility to identify antibodies to
proteins that cross-react between different
Weed pollen (relevant for geographical area)
allergens from a sensitisation that is
Animal dander species specific. Currently, the only
Cat commercially available component
resolved microarray diagnostic method is
Dog
the Immuno Solid phase Allergen Chip
Horse microarray (Phadia, Uppsala, Sweden).
Dust mite
Allergy diagnostics is an important part of
Mould the evaluation and management of children
Alternaria with preschool wheeze and asthma.
Cladosporium Together with a careful history it is one of
the first steps in identifying possible triggers
Antonella Muraro
The severity score should be based on the organ system most affected. Bold indicates a mandatory indication for the use of adrenaline. GI: gastrointestinal. #: defined as systolic
Light headedness and
a feeling of impending
Change in activity level
Confusion, loss of
consciousness
circulation. Patients experiencing acute
Neurological
plus anxiety
doom
comfort, which usually involves lying
recumbent or semi-recumbent. This
accomplishes two therapeutic goals:
blood pressure ,70 mmHg at 1 month to 1 year of age, ,70 mmHg+[26age] at 110 years of age and ,90 mmHg at 1117 years of age.
N
As above
difficulty swallowing,
saturation ,92%,
respiratory arrest
barky cough,
abdominal pain
bowel control
administration. Adrenaline in a
angioedema
anaphylaxis as they do not act quickly. The Prescription of self-injectable adrenaline The
efficacy of corticosteroids in reducing the decision about whether to prescribe a self-
risk of late-phase reactions has not been injectable adrenaline device involves
proven. High-flow oxygen should be given to analysis of the risks of experiencing
any patient with respiratory symptoms or anaphylaxis, the benefits of a self-injectable
evidence of shock. Volume support with adrenaline device, the risks associated with
crystalloid solution or colloid expander is it and its cost on health services and
mandatory in the case of hypotension. individual families. Absolute and relative
indications about prescribing adrenaline are
Long-term management Identification of
shown in table 3.
triggers In order to identify the allergen,
patients with a history suggestive of an Immunomodulation Venom immunotherapy
anaphylactic reaction need urgent referral to is 95100% and ,80% successful in wasp
an allergy clinic for a diagnostic assessment, and bee sting allergies, respectively.
based on clinical history and in vivo and in Desensitisation protocols have also been
vitro examinations (skin prick test, established for some medications, such as a
intradermal test, prick-by-prick with raw few antibiotics and nonsteroidal anti-
food, IgE for suspected allergens and inflammatory drugs, although they are only
recombinant allergens, and oral challenges recommended in exceptional cases.
for food or drugs).
Food-induced anaphylaxis could
Risk reduction Strategies to avoid the theoretically be modulated by allergen
precipitants should be customised taking desensitisation through immunotherapy,
into consideration factors such as age, similarly to hymenoptera sting anaphylaxis.
occupation, activities, hobbies, living However, food allergen immunotherapy
conditions and access to medical care. As remains experimental and although several
most episodes of anaphylaxis occur in the trials of oral tolerance induction are
community, children and their caregivers underway, this procedure is not yet
must know how to prevent further reactions recommended in routine clinical practice.
and how to promptly recognise and
appropriately manage any anaphylactic
reactions that occur outside the hospital. Further reading
Allergists, emergency physicians and general N Boyle RJ, et al. (2012). Venom-
paediatricians/practitioners, as well as immunotherapy for preventing allergic
teachers and caregivers, need to develop a reactions to insect stings. Cochrane
coordinated approach, including actions for Database Syst Rev; 10: CD008838.
primary and secondary prevention and N Castells M (2006). Desensitization
emergency response, in order to prevent for drug allergy. Curr Opin Allergy Clin
fatalities and improve quality of life of Immunol; 6: 476481.
patients and families.
The allergic pathologies are frequent and paediatric population and is often
bothersome diseases. In the past 30 years, associated with other allergic diseases.
epidemiological studies have shown that the According to various epidemiological
prevalence of allergic rhinitis continues to studies this disease affects more than 10%
increase worldwide although it is often of children ,14 years of age and 2030% of
underestimated, underdiagnosed and adolescents and young adults.
undertreated. Allergic rhinitis is the most
Definition
frequent allergic, chronic disease in the
Allergic rhinitis is defined as a symptomatic
disorder of the nose characterised by:
Figure 1. The nasal allergic response. Reproduced from Van Cauwenberger et al. (2003) with permission
from the publisher.
Intermittent Persistent
Symptoms Symptoms
< 4 days / week > 4 days / week
or < 4 week or > 4 week
Moderate
Mild severe
Moderate persistent
persistent
severe
Mild intermittent
intermittent
Intranasal steroid
Oral or local nonsedative H1-blocker
Immunotherapy
Figure 3. Management of allergic rhinitis: ARIA guidelines. Reproduced from Bousquet et al. (2001).
Direct proteolytic
allergen activity Allergic and
Therapeutic
(Der p, others) immunological
options
inflammation
Irritant/allergen
Irritants, allergens, avoidance
infective agent
Environmental entry Emollients
Atopic
factors Anti-inflammatories
Humidity, Dermatitis
aggressive (TCs, TCIs, others)
substances
Control of infections
Control of pruritus
Figure 1. AD is a multifactorial disease that arises from multiple genetic and environmental interactions.
Genetic factors include complex epidermal barrier and immunological defects. Mutations of filaggrin (FLG)
and other structural genes induce damage to epithelial barrier functions. In this way, cutis may become more
permeable to irritants, allergens and infective agents. If an allergic predisposition also exists (T-helper (Th)2
polarisation), potential allergens that come into contact with the skin can provoke an allergic inflammation.
Irritants can further worsen epithelial barrier functions. Moreover, AD cutis is defective in controlling
infections, and Staphylococcus aureus, in particular, may in turn worsen AD. It is now hypothesised that if
the damaged skin of a potential allergic subject comes into contact with a food allergen this can result in food
allergy. Avoiding irritants/allergens, restoring epithelial barrier functions, fighting inflammation and
controlling infections and pruritus are the mainstays of AD therapy. Der p: Dermatophagoides
pteronyssinus allergen; TCs: topical corticosteroids; TCIs: topical calcineurin inhibitors.
lateral neck and the dorsa of the feet and more extensive, severe forms, with
hands. This distribution can vary from patient widespread erythrodermic rash.
to patient and can differ according to age.
The distribution of lesions and the typology
Moreover, it should be remembered that all and severity of AD may vary according to the
these divisions are artificial and that in any patients age and disease activity. During
individual case, acute relapsing of subacute infancy, AD generally presents more acute
or chronic lesions may occur. Both the lesions mainly affecting the face, scalp, and
extent and severity may vary. Thus, AD extensor surfaces of the extremities.
presents a broad clinical spectrum ranging Bacterial secondary infection
from minor and less severe forms (dry (impetiginisation) is frequent. In older
depigmented skin, hand eczema) to major, children and in those with persisting AD,
Food allergy is an adverse health effect foods cause the majority of allergic
arising from a specific immune response reactions: peanuts, tree nuts, eggs, milk,
that occurs reproducibly on exposure to a fish, crustacean shellfish, wheat and soy
given food (Boyce et al., 2010). This (Boyce et al., 2010).
definition of food allergy includes IgE-
Symptoms of food allergy (table 2) can occur
mediated and non-IgE-mediated immune
within minutes to hours of ingesting the
responses, or a combination of both, and is
trigger food and can vary in severity from
in agreement with recent international
mild to life threatening. Co-factors of
guidelines (Urisu et al., 2011; Fiocchi et al.,
severe allergic reactions include co-
2010a; Sackeyfio et al., 2011) and statements ingestion of other foods, exercise and
(Burks et al., 2012). Table 1 shows specific comorbid conditions. Food-induced
food-induced allergic conditions on the anaphylaxis is the most serious, potentially
basis of pathophysiology, with particular lethal allergic reaction. Fatalities are
emphasis on respiratory manifestations. primarily reported from allergic reactions to
peanuts and tree nuts.
Food allergens can cause reactions when
ingested, touched or inhaled. Cross- The natural history of food allergy resolution
reactivity can occur when a food allergen has is variable and some patients reach
structural or sequence similarity with a tolerance (i.e. they develop a specific
different food allergen or aeroallergen. More nonreactivity to the food). The time courses
than 170 foods have been reported to cause appear to be influenced by several factors.
IgE-mediated reactions but a minority of
N Age of development: food allergy that
starts in adulthood often persists.
Key points N Type of food: allergy to milk, eggs, soy or
wheat is more likely to be outgrown than
N Food allergy is on the rise especially in allergy to fish, shellfish, tree nuts or
children. peanuts.
N Level of IgE: patient with high specific IgE
N Its symptoms may include respiratory level by ImmunoCAP assay (Quest
complaints. Diagnostics, Madison, NJ, USA) are at
N The presence of asthma is a negative risk of persistence (Fiocchi et al., 2008).
prognostic factor for anaphylactic N Size of skin-prick test (SPT) wheal: but in
reactions. some cases, SPT responses remain
positive long after tolerance has
N Severe asthma may be associated with developed.
food allergy. N IgE patterns: the epitope-binding profile
N Currently, the treatment for food of IgE might help to predict the clinical
allergy treatment is avoidance, but course of food allergy (Wang et al., 2010).
OIT is a promising new approach. Prevalence determined on the basis of
patient self-report is higher than that
determined by clinical testing and medical Prevalence rates of admissions for food
history. In general, food allergy affects more anaphylaxis in Australia increased by 350%
than 12% but ,10% of the population (Keil between 1994 to 2005, and rates of increase
et al., 2010). It seems that prevalence is were greater for children ,4 years of age and
rising: a large population-based study of for peanut and tree nut anaphylaxis, with
challenge-proven food allergy in 12-month- more modest increases noted for older age
old infants in Australia reported prevalences groups and other allergies such as cows
of 3% for peanut allergy, 8.9% for egg allergy milk or egg.
and 0.8% for sesame allergy (Osborne et al.,
2011). The prevalence of food allergy Food allergy symptoms include:
appears to have increased in recent years.
Self-reported survey data in the USA N food refusal in young children,
suggested there has been an 18% increase in N skin symptoms (urticaria, angio-oedema,
food or digestive allergies from 1997 to erythema, itching and eczema),
2007, and Chinese paediatricians reported N gastrointestinal tract symptoms
an increased rate of challenge-confirmed (oropharyngeal tingling and burning, oral
food allergy from 3.5% in 1999 to 7.7% in allergy syndrome, vomiting, and
2009 (p50.017) (Chen et al., 2011). abdominal pain),
Reproduced and modified from Boyce et al. (2010) with permission from the publisher.
Strict avoidance of allergens is not curative N Boyce JA, et al. (2010). Guidelines for the
and the patients remain at risk of accidental diagnosis and management of food
exposure. For this reason, several new allergy in the United States: report of
the NIAID-sponsored expert panel. J
therapeutic approaches are being tested in
Allergy Clin Immunol; 126: S1S58.
clinical trials, but none is ready for clinical
N Branum AM, et al. (2009). Food allergy
care (Nowak-Wegrzyn et al., 2011). Systemic, among children in the United States.
subcutaneous immunotherapy has been Pediatrics; 124: 15491555.
investigated in the past but gave severe N Brozek JL, et al. (2012). Oral immunother-
adverse effects. Newer forms of therapy (e.g. apy for IgE-mediated cows milk allergy: a
immunotherapy) have sought to provide systematic review and meta-analysis. Clin
systemic treatment with reduced risk and Exp Allergy; 42: 363374.
side-effects. For a variety of food allergens, N Burks AW, et al. (2012). ICON: Food allergy.
oral immunotherapy (OIT) is able to reduce J Allergy Clin Immunol; 129: 906920.
clinical reactivity in some patients. Its ability
Andrew Bush
Unlike in adults and for reasons which are N Ensure that atypical forms of CF have
not clear, allergic bronchopulmonary been excluded. Even if the sweat test is
aspergillosis (ABPA) in children is virtually unequivocally normal, genetic testing and
always seen in the context of CF. ABPA measurement of transepithelial potential
complicating paediatric asthma has only differences should be considered.
been the subject of isolated case reports. N Consider alternative differential
Other, even more rarely, reported diagnoses, such as mucus plugging and
associations in children include hyper IgE atelectasis, gastro-oesophageal reflux
syndrome, chronic granulomatous disease, disease, eosinophilic or other
bronchocentric granulomatosis, previous TB noninfective pneumonias, and collagen
and treatment of sarcoidosis with infliximab. vascular disease.
In adults, it has been described in N Consider the possibility of the rare
association with COPD. Unsurprisingly, late associations mentioned above.
diagnosis after a prolonged clinical course is
common in this rare setting. If ABPA is Aspergillus fumigatus is ubiquitous in the
suspected in the context of another environment. Two features make it
paediatric respiratory illness, three steps are particularly prone to infect the human lower
essential. airway.
damage, but proteolytic and other enzymes patients will have a positive sputum culture
may lead to non-allergic, direct pulmonary for A. fumigatus.
toxicity. ABPA is the result of a skewed
CD4+, Th2 T-cell response to A. fumigatus Confirming the diagnosis of ABPA
leading to interleukin (IL)-4 and IL-5 Making the diagnosis of ABPA in the context
production and, hence, elevation of serum of CF may be difficult; there is no single
IgE and airway eosinophilia. A. fumigatus diagnostic test. The classical case is easy to
may directly lead to the production of pro-
diagnose. However, many of the symptoms
inflammatory cytokines from bronchial
and signs of ABPA are common to the
epithelial cells. The importance of genetics
underlying CF. Furthermore, markers of
has been suggested by the occurrence of
sensitisation to A. fumigatus and positive
familial cases. Important factors include
sputum cultures are frequently seen in
HLA-DR and HLA-DQ (the latter protective),
otherwise uncomplicated CF; and true cases
and polymorphisms in the genes for IL-4RA,
of ABPA may be culture negative for A.
IL-10, surfactant protein A and Toll-like
fumigatus. We found that the single most
receptor 9. Recently, elevated levels of the
useful test is an abrupt, at least four-fold rise
co-stimulatory molecule OX40 ligand
in total IgE to .500 IU?mL-1; IgE may
(OX40L) have been shown to be important
sometimes, but not always, fall with
in driving the Th2 response to A. fumigatus
treatment so serial IgE measurements
in peripheral CD4+ T-lymphocytes. Of
should be used with caution in monitoring
possible therapeutic interest, OX40L levels
response. A high level of IgG precipitating
fell with in vitro addition of vitamin D.
antibodies to A. fumigatus may also be
However, A. fumigatus downregulates the
suggestive (.90 mg?mL-1; ImmunoCap;
vitamin D receptor, which may affect the
Thermo-Fisher Scientific, Uppsala, Sweden);
response to vitamin D therapy.
multiple positive precipitins are more
Presentation suggestive of mycetoma. Major and minor
criteria for ABPA have been proposed, but
ABPA should be at least suspected in CF atypical cases may not meet classical criteria
children with increased respiratory yet still require treatment, which should not
symptoms, particularly if there is wheeze, be delayed if the index of suspicion is high
chest tightness or pleuritic chest pain and but classical criteria are not met. In
an audible pleural rub. Exceptionally, pleural doubtful cases, many would initially give a
effusion and pneumomediastinum have trial of intravenous antibiotics and then treat
been described in ABPA. There may be a for ABPA if there was no response.
sharp decline in spirometry, and the chest
radiograph typically shows one or more new The tables of major and minor criteria are
soft fluffy shadows (fig. 1), with a gloved useful guides to the diagnosis of ABPA, but
finger appearance of mucus impaction in are no more than guides, and atypical cases
the airways, which are very unusual in a CF will continue to be diagnosed on an
pulmonary exacerbation. Less than half the individual clinical basis. The United States
Figure 1. Chest radiograph from a CF patient recently diagnosed with ABPA. a) A combination of
widespread indistinct nodular opacities, ring shadows (bronchiectatic airways) in the right mid zone, and
consolidation in the left lower lobe can be seen. b) Several months later, most of the shadowing has
resolved but there is a new elliptical opacity (a plugged bronchiectatic airway) just above the left hilum.
Corticosteroids: Conventionally, the mainstay Figure 2. HRCT through the upper lobes showing
of treatment is oral prednisolone, which may bilateral bronchiectasis; the varicose pattern of
need to be given in high dose for a bronchiectasis in the anterior segment of the right
prolonged period of time. A typical regimen upper lobe is typical of APBA.
Sabina Gallati
CF has been recognised as a distinct of the two parental CF mutations and a 25%
inheritable clinical entity for more than chance that the child will inherit two intact
70 years. It is the most common life- genes. Phenotypically healthy siblings of CF
threatening autosomalrecessive disorder patients have a 66% risk of a positive carrier
among Caucasians with an incidence of state.
approximately one in 2500 and a carrier
The CFTR gene and protein
frequency of 4%. Heterozygotes carry one
normal and one mutant CF gene and are The gene causing CF, identified in 1989, is
therefore healthy, but they have a 50% risk located on chromosome 7q31.2 spanning
of passing the defective gene on to their ,200 kb of genomic DNA and containing
offspring. If two partners are carriers they 27 exons. It is transcribed into 6.13 kb
face a 25% risk of having a child with CF, a messenger ribonucleic acids (mRNAs)
50% chance that the child will carry only one encoding a transmembrane protein of 1480
amino acids known as the cystic fibrosis
transmembrane conductance regulator
Key points (CFTR). The CFTR protein is a member of
the ATP-binding cassette (ABC) transporter
N CF is the most common life- superfamily whose proteins transport
threatening autosomal-recessive various molecules across extra- and
disorder in Caucasian populations intracellular membranes. The predicted
with an incidence of 1/2500 and a structure of CFTR includes:
carrier frequency of 1/25.
N CF is caused by mutations in the
N a symmetrical, multi-domain structure
consisting of two membrane-spanning
CFTR gene on chromosome 7. domains (MSD1 and MSD2) with six
N The CF phenotype is very hydrophobic transmembrane helices
heterogeneous and depends on both forming the channel through the
nature and localisation of the membrane;
underlying CFTR mutations, as well as N two nucleotide binding domains (NBD1
genetic background and and NBD2) gating the channel through
environmental influences. ATP-binding and hydrolysis;
N CFTR analysis is indicated for
N a central, highly charged regulatory
domain with multiple consensus sites for
diagnostic purposes in individuals phosphorylation by protein kinase (PK)A
with clinical suspicion of CF or CFTR- and PKC.
related disorders, fetuses with
echogenic bowel or whose parents are The regulatory domain is unique for CFTR as
proven CF carriers, and for carrier it is not present in the other members of the
testing in persons with a positive ABC superfamily. CFTR is mainly located at
family history or in partners of proven the apical membrane of polarised epithelial
CF carriers. tissues. Its main function is that of a cyclic
AMP-regulated chloride channel, which is
MSD1 MSD2
X
ATP NBD1 NBD2 ATP
X
C
RD
Class III
ATP ATP
Class V
Nucleus
Golgi E
apparatus F
Gene defect
Class VI
A
B X
X Class I
ER
Class II
Figure 1. Class I (A): nonsense, frame-shift and splice site mutations resulting in no functional CFTR
protein. Class II (B): mutations (e.g. F508del) that lead to abnormal processing and trafficking of proteins.
Class III (C): mutations in this group (e.g. G551D) affect the regulation of CFTR and channel gating
activity. Class IV (D): mutations (e.g. R117H, R334W, R347P and R347H) within the MSDs reducing CFTR
channel conductance. Class V (E): mutations associated with reduced biosynthesis of fully active CFTR due
to alternative splicing (e.g. T5). Class VI (F): nonsense and frame-shift mutations causing truncation of the
C-terminus of CFTR and leading to highly unstable proteins. ER: endoplasmic reticulum; RD: regulatory
domain.
Normal CF Error
Figure 3. Newborn screening programmes in Europe 2012. Data from Southern (2013).
Lung disease accounts for most of the episodes of acute worsening of respiratory
morbidity and mortality in CF. CF lung symptoms, often referred to as pulmonary
disease begins early in life. It is exacerbations. Tissue damage ultimately
characterised by impaired mucociliary results in lung failure and death in most
clearance and mucus obstruction, as well as people with CF.
chronic pulmonary infection and
Pathophysiology
inflammation, leading to tissue destruction.
Early CF lung disease is characterised by The most commonly accepted
small airways obstruction and the pathophysiological explanation for airway
development of bronchiectasis. There is a disease in CF is the low volume
progressive decline of lung function with hypothesis. This hypothesis postulates that
cystic fibrosis transmembrane conductance
regulator (CFTR) dysfunction leads to a loss
Key points of inhibition of airway epithelial sodium
channels which, in turn, leads to excess
N CF lung disease begins early in life. It sodium and water reabsorption. This results
is characterised by impaired in dehydration of airway surface liquid.
mucociliary clearance and mucus Reduced volume of the airway surface liquid
obstruction, and chronic pulmonary causes failure of mucociliary clearance,
infection and inflammation. which leads to mucus obstruction of the
N There is a progressive decline of lung small airways. The lungs are not able to
function with episodes of acute effectively clear inhaled bacteria, viruses,
worsening of respiratory symptoms, fungi and airborne pollutants. The thickened
referred to as pulmonary mucus on the epithelium forms plaques
exacerbations. with hypoxic areas that can harbour bacteria
and other pathogens.
N Pulmonary effects of CF typically have
the largest impact on morbidity and The lungs of children with CF appear normal
mortality, and account for over 80% at birth but quickly become infected by
of fatalities due to the disease. organisms that are not adequately cleared.
Infants with CF develop persistent
N Current management of CF lung
endobronchial infections early in life due to
disease is predominantly
symptomatic. The cornerstones of CF Staphylococcus aureus, nontypable
respiratory care are airway clearance Haemophilus influenzae and Gram-negative
and treatment of pulmonary bacilli. By the end of the second decade of
infections. life, Pseudomonas aeruginosa is the
predominant pathogen. Chronic bacterial
N Lung transplantation is the final endobronchial infection is associated with
therapeutic option for patients with an intense neutrophilic inflammatory
end-stage lung disease. response that damages the airway, impairs
local host-defence mechanisms and
1
2 2 2
3
Figure 2. Chest radiograph of a 15-year-old female CF patient with advanced lung disease a)
posteroanterior view and b) lateral view. The radiograph shows pronounced pulmonary hyperinflation with
sternal bowing, bronchial wall thickening and bilateral bronchiectasis, infiltrates mainly in the right upper
lobe (1) and in the lower lobes on both sides (2) as well as atelectasis of the left lower lobe (3). Note the
central venous access (Port-a-Cath system; Smiths Medical, St Paul, MN, USA). Image courtesy of E.
Stranzinger (Division of Radiology, University Childrens Hospital of Bern, Bern, Switzerland).
Figure 3. CT scan of a 15-year-old female CF patient (same patient as in fig. 2) a) coronal plane view and
b) sagittal plane view of the left lung. Bilateral mucus plugging and bronchiectasis, as well as atelectasis of
the left lower lobe (#) is clearly visible. Image courtesy of E. Stranzinger (Division of Radiology, University
Childrens Hospital of Bern, Bern, Switzerland).
RBP: retinol binding protein; 25(OH)D: 25-hydroxyvitamin D. Reproduced and modified from Maqbool et al.
(2008).
Figure 1. Potential options of CFTR directed therapies. Reproduced from Welsh (2001) with permission
from the publisher.
While these gating mutations are relatively known therapeutics. The lead compound is
rare, this has proven the concept that CFTR currently called VX-809 and has recently
directed pharmacotherapy can have shown some promising results in early
significant beneficial effects in patients that phase clinical studies. In CF patients
exceed the efficacy of any other treatment homozygous for the F508del mutation, oral
previously studied in this disease. application of the compound VX-809 was
well tolerated and there was a dose-
CFTR correctors Class II mutations, such as
dependent effect on sweat chloride levels at
the most common mutation, F508del, result
higher doses, suggesting an effect of this
in misfolded CFTR protein which, when
drug on F508del activity. However, no
expressed at the apical membrane, has
change in lung function was observed.
some chloride conducting ability, but with a
much shorter half-life than wild-type CFTR. It is important to appreciate that CFTR
Most of this misfolded protein will be corrector therapy alone may not be sufficient
recognised as abnormal by the intracellular to induce a clinically meaningful response
quality control machinery and degraded and for this reason VX-809 is currently being
prior to leaving the endoplasmic reticulum. studied in combination with a CFTR
Thus, a potential treatment strategy is potentiator to enhance activity (described
rescue of CFTR (rescue from endoplasmic below).
degradation). Compounds that result in
CFTR rescue are called correctors referring Combining potentiator and corrector While
to their effect on correcting the intracellular VX-809 is designed to move CFTR to the cell
trafficking defect. A number of drugs have surface, ivacaftor is intended to improve the
been identified to potentially improve proteins function once it has reached the
mutated CFTR processing using high- cell surface. A recently completed phase II
throughput assays to screen libraries of clinical trial studying multiple dose
The CF patient with end-stage or rapidly in the 20032004 cohort. In the paediatric
deteriorating lung disease will usually have series all but one of the children had severe
been followed up in a specialist centre for obstructive lung disease, and most were
many years, with intensive therapeutic being actively managed at the time of death;
attempts to improve lung function. Part of most deaths were in the paediatric intensive
the management should be a detailed re- care unit (PICU). A key message from these
evaluation of all aspects of care to ensure two studies and other data is that
that nothing has been missed. spirometry is a poor predictor of prognosis,
although frequently used clinically as such.
The nature of the problem
The combined Royal Brompton Hospital/ Lessons from problematic severe asthma:
Great Ormond Street Hospital (both are the basics right?
London, UK) experience of death and
transplantation in CF in the decade 2000 More than half of all children referred to the
2009 was of 1022 children cared for, there Royal Brompton Hospital quaternary referral
were 11 deaths (median age 14.2 years) and severe asthma service for consideration of
eight transplantations (median age beyond guidelines therapy in fact do not
13 years), with a female predominance for have severe asthma at all, but merely need
both. Of note, spirometry 5 years before to get the basics right for good asthma
death was not predictive. This is in control to be restored. No comparable study
agreement with an adult study which has been performed in CF, but it seems
showed that median survival for patients likely that similar issues are present in what
with an FEV1 ,30% predicted had increased we term challenging CF (table 1). The
from 1.2 years in the 1991 cohort to 5.3 years definition is somewhat arbitrary; it should be
noted that children may become challenging
very quickly (e.g. failure to improve after two
Key points or more courses of intravenous antibiotics
in quick succession) or gradually, with a
N Every effort should be made to series of small, almost subclinical,
optimise standard therapy in patients deteriorations.
with apparently end-stage CF lung
disease. Experience from asthma has identified four
key areas often needing attention as:
N Prediction of prognosis in end-stage
CF lung disease is difficult, and more N medication adherence and
prolonged survival than previously administration;
expected can be anticipated. N adverse environmental circumstances,
N Timely referral for lung transplant particularly environmental tobacco
assessment is essential to maximise smoke;
chances of benefit. N allergen exposure;
N psychosocial factors.
In the context of asthma, a nurse-led home before deploying some of the experimental
visit is often enlightening, and perhaps this therapies described below.
should be used more in CF. Adherence is
notoriously difficult to judge in the clinic; Is the diagnosis really CF?
doctors obtain prescription records This may seem an odd question, but it is
(acknowledging that collecting a important for two reasons. First, if the
prescription does not mean that the diagnosis is wrong it is important to
medication has been administered, but determine whether there is a disease-
failure to collect prescriptions does
specific treatment for what is actually the
guarantee non-adherence) and the nurses
problem, for example bone marrow
assess the availability and accessibility of
transplantation for certain
medications in the home, and whether they
immunodeficiencies. Secondly, innovative
are in date. Obviously inhaler and nebuliser
therapies are increasingly being discovered
techniques are also checked. More objective
that are CF gene mutation or mutation class
data about nebuliser usage can be
specific. It would be ludicrous to try to apply
downloaded from the microchips in some
these therapies to a patient who did not
modern nebulisers. Active and passive
have CF! So, it is essential to make every
tobacco smoke exposure is checked by
effort to establish the genotype of the
measuring urinary or salivary cotinine.
patient with whole gene sequencing if this
Allergic sensitisation and allergen exposure
has not already been done, to check
is less important in CF than in really severe
eligibility for these potential treatments. The
asthma, but should at least be considered in
Clinical and Functional Translation of CFTR
the atopic CF patient. Finally, psychosocial
website (www.cftr2.org) provides current
factors are explored. Most referrals in the
knowledge of the probable disease causing
asthma context are made after discussions
status of rare mutations and should be
in the home, where families are much more
consulted in cases of doubt.
ready to discuss personal matters. It is
suggested that adaptations of this sort of Management of end stage lung disease:
approach may be beneficial in challenging pulmonary aspects
CF. This should include ensuring that all
standard therapies have been trialled, or Our experience is that there are two main
discarded as having not been beneficial, types of end-stage lung disease: the more
including nebulised antibiotics, rhDNAse, common is characterised by severe
hypertonic saline and azithromycin, certainly bronchiectasis, chronic infection and
be excluded. Bile acids can frequently be who are becoming difficult to manage. Early
found in CF sputum and are associated with referral before a patient becomes critically
increased inflammatory markers, suggesting unwell facilitates a number of processes:
that we are underdiagnosing this
complication. There is no gold standard N careful assessment by a multidisciplinary
test, but at the very least 24-h oesophageal transplant team,
pH monitoring should be performed. An N suggestions for further clinical
isotope milk scan is less invasive, but optimisation,
probably a less accurate way of determining N information gathering for the patient,
if reflux is present. The role of impedance family and medical team and education
monitoring is not clear pre-transplant but about the complications,
should be completed post-transplant. N intense follow-up required after
Gastro-oesophageal reflux, including non- transplant.
acid reflux, may be an important factor in
the development of post-transplant Timely referral allows the patient time to
bronchiolitis obliterans syndrome (BOS). reflect on the risks and benefits of both
transplant and the alternative of non-
Bone mineral density Severe osteopenia is a transplant, and also allows the transplant
relative contraindication to transplantation, physician to monitor an individuals clinical
so DEXA scanning and appropriate trajectory over a period of time (table 2).
treatment (calcium supplements, vitamin D
and bisphosphonates) should be instituted When to list for transplant? Deciding when to
early if bone mineral density is decreased. list a patient for transplant is one of the
most difficult decisions. A transplant
Lung transplant Lung transplant is an physicians aim is to list a patient early
accepted therapeutic option for patients enough that they can survive the possible
with end-stage CF lung disease who are wait for an organ but not so early that a
failing maximal medical therapy. Paediatric transplant does not offer a survival benefit.
recipients from the International Society for Most centres aim to list for transplant when
Heart and Lung Transplantation (ISHLT) the predicted chance of surviving 2 years is
international registry had a 5-year survival of ,50%, although this is an increasingly
54% for the era 20022010. difficult time-point to identify.
As previously noted there is no one specific Various survival models have been
clinical or physiological measurement that proposed for CF, all of which are imprecise
portends poor prognosis signifying referral and not particularly useful for an individual.
for transplant assessment. Most paediatric In practice many clinical, physiological,
centres welcome early referral of patients functional and quality of life factors are
This chapter cannot cover the complete malformations discovered incidentally. Early
spectrum of congenital airway and accurate diagnosis as well as
malformations but rather gives an overview appropriate management is particularly
of important anomalies (table 1). important in children with severe central
airway stenoses. Flexible airway endoscopy
Most children with airway malformations are is the most important diagnostic procedure.
already symptomatic in the neonatal period In many instances, essential diagnostic
or in infancy; only rarely are airway techniques are MRI and CT, frequently
including angiography (especially
preoperatively and in children with
Key points associated cardiovascular anomalies).
N Many children with airway Depending on the type and severity of the
malformations are already malformation, conservative or surgical
symptomatic in the neonatal period management options may be chosen. With
or in infancy. airway growth, in particular mild to
moderate stenoses in the first years of life
N Airway anomalies are important frequently become less prominent. Thus,
differential diagnoses in children with conservative symptomatic treatment and
many respiratory abnormalities. support is often the preferred approach.
N Airway abnormalities may be part of With adequate management, in most
complex syndromes, and in many patients the long-term prognosis is
cases are associated with other favourable.
congenital anomalies.
Nasopharyngeal airway
N Early, accurate diagnosis and
Choanal stenosis and atresia This
appropriate management is
particularly important in severe malformation represents one of the most
central airway stenosis. common congenital upper airway anomalies
(1 in 8000 births). Most cases are due to
N With airway growth, mild-to-moderate bony occlusion of the airway; some children
stenoses in the first years of life show membranous obstruction. About two-
frequently become less prominent. thirds of patients with choanal atresia have
N Depending on the type and extent of associated congenital anomalies (e.g.
the malformation, conservative or CHARGE association). Unilateral lesions are
surgical management options have to twice as common as bilateral ones.
be chosen on an individual basis.
Bilateral choanal atresia causes immediate
N With adequate management, in most respiratory distress at birth; unilateral
patients the long-term prognosis is lesions are often not detected until later in
favourable. childhood. Some children present with
feeding difficulties and persistent
According to Holinger et al. (1997), five types The diagnosis is suspected based on history
of laryngomalacia can be distinguished (two and physical examination, and confirmed by
or more may occur simultaneously) (table 3). flexible airway endoscopy. Laryngoscopy
Laryngomalacia is frequently associated with demonstrates supraglottic collapse during
other airway lesions and with gastro- inspiration (fig.1). Topical anaesthesia can
oesophageal reflux. potentially exaggerate the findings; thus, the
larynx should be examined before applying
The natural history is characterised by onset topical anaesthesia.
of inspiratory stridor usually within the first
46 weeks of life; cry and cough are normal. In most cases, apart from parental
Stridor varies considerably with posture and reassurance and support, no specific
airflow, is loudest with increased ventilation therapeutic measures are needed. In severe
(e.g. crying, agitation, feeding) and worsens cases (failure to thrive and/or obstructive
during respiratory tract infections. Some apnoeas) surgical treatment (various forms
of supraglottoplasty, rarely tracheostomy) is
patients will have increasing symptoms
needed. In isolated forms prognosis is
during the first few months of life; thereafter,
excellent, with associated malformations
stridor tends to resolve with time. In the very
prognosis usually depends on the latter.
rare severe cases with significant airway
obstruction, serious complications such as Laryngeal cyst Supraglottic cysts, commonly
failure to thrive, pulmonary hypertension located at the aryepiglottic folds or at the
and cor pulmonale may develop. epiglottis, are usually congenital. In contrast,
a) b) c)
Figure 1. Laryngomalacia (infantile larynx). a) Patent airway during expiration; b) prolapse of arytenoids
and aryepiglottic folds into the glottis during mid-inspiration; c) prolapse of arytenoids and aryepiglottic
folds and folding of epiglottis along its long axis (floppy epiglottis) at end-inspiration, resulting in
complete obstruction of the larynx. Reproduced from Eber (2010) with permission from the publisher.
Congenital thoracic malformations (CTMs) (table 1); however, we will only cover
are a heterogeneous group of rare congenital cystic adenomatoid
congenital developmental anomalies and malformations (CCAMs) and relative
disorders of the lung parenchyma and bronchopulmonary sequestrations (BPS).
airways with an incidence of approximately Close multidisciplinary cooperation between
3.5 per 10 000 live births. The use of routine fetal medicine experts, neonatologists,
antenatal ultrasound scans, post-natal CT paediatric surgeons, geneticists,
and MRI imaging, and advances in neonatal paediatricians and/or paediatric
surgery and intensive care have widened our pulmonologists is crucial to the overall
knowledge of the pathophysiology of CTMs management and outcome of children with
but at the same time have also introduced CTMs.
complexities, especially to the management
of asymptomatic lesions. Many excellent Embryology
recent studies and textbooks of paediatric
respiratory medicine cover all CTMs in detail The lungs develop as an out pouching from
the developing foregut at 3 weeks of
gestation. The respiratory diverticulum
Key points begins to grow caudally and divides at
4 weeks and further subdivides in a
N The routine introduction of antenatal dichotomous fashion. Further lung growth
ultrasound scanning has not only occurs in tightly regulated stages of lung
increased our knowledge of CTMs but development, namely the embryonic,
has resulted in improved antenatal pseudoglandular, cannalicular, saccular and
counselling and management of these alveolar phases. By the end of the sixth
conditions. month of gestation, 17 generations of
N Antenatal resolution of CCAMs is subdivisions have formed. Lung growth and
reported in up to 20% cases but in development continues post-natally until at
most cases there is evidence of their least 2 years of age or beyond. The exact
persistence on post-natal CT images. aetiology for most CTMs remains unknown
but for CCAMs the embryological insults are
N Management of asymptomatic speculated to occur during the
CCAMs is controversial with some pseudoglandular stages of lung
physicians opting for regular follow-up development for Types I to III CCAMs and
and imaging to gauge progress whilst during the late saccular phase of lung
others opt for surgical removal. development for Type IV lesions. It is
N Long-term follow-up studies to assess postulated that transcription and growth
the natural history, including factors, such as homeobox protein Hox-B5
respiratory and neurodevelopmental (HOXb5), thyroid transcription factor 1
outcomes, especially after fetal (TTF) and platelet-derived growth factor
intervention, are required. (PDGF-BB), may play a role in the
pathogenesis of CCAMs.
c) d)
Figure 1. a) Antenatal ultrasound and b) MRI scan of an extensive right sided CCAM, which was
symptomatic at birth, with respiratory distress and mediastinal shift as confirmed by c) a chest radiograph
and d) a CT scan. It was surgically removed successfully at 3 days of age.
There have been many classifications for ciliated cuboidal or columnar epithelial
CCAMs but the two by Stocker (2002) and cells.
Langston (2003) are most commonly used N Type 3 are solid lesions without cystic
with significant overlap between the two. components with an excess of acinar
The Langston classification includes lesions structures.
other than CCAMs, including bronchial
atresia and pulmonary hyperplasia. The Other types have subsequently been added
Stocker classification, which focuses on to this classification including Type 0, which
CCAMs, is based on histology and the size is best viewed as describing congenital
of the lesions as follows. acinar dysplasia, and Type 4, which overlaps
with type 1 pleuropulmonary blastoma. Type
N Type 1 where individual cysts are .2 cm 1 is the commonest lesion forming ,50
in diameter and are lined by 70% of all CCAMs and has the best
pseudostratified epithelium. prognosis. Type 2 CCAMs are often
N Type 2 where individual cysts are ,2 cm associated with other malformations, which
in diameter with the cysts resembling should be looked for at antenatal ultrasound
dilated bronchioles; they are lined by screening.
Currently the best available indicator of Post-natally, most CCAMs will have been
prognosis for CCAM is the CCAM volume identified antenatally and infants with large
ratio (CVR). This is the ratio of the lesion lesions may need supportive therapy for
volume compared to the head stabilisation prior to surgical intervention.
circumference. CVR values .1.6 are Planning to deliver in appropriate centres
associated with increased risk of between with the required expertise is a must for
15% and 75% for developing fetal hydrops, these babies. The majority of CCAMs,
i.e. poor prognosis. Due to the increased risk however, are asymptomatic but some may
of developing a complicated course, the CVR present with acute (fig. 1c and d) or chronic
is often used to guide antenatal fetal respiratory distress, recurrent pulmonary
surgical intervention but has limited infections, bronchiectasis, lung abscesses,
sensitivity and specificity. Antenatal haemoptysis, pneumothorax, air embolism,
interventions include steroid administration, haemothorax, pyopneumothorax, steroid-
thoracentesis, thoracoamniotic shunt, laser resistant asthma or high output cardiac
ablation, fetal surgery or injection of a failure (if there is a large systemic arterial
Oliviero Sacco, Serena Panigada, Nicoletta Solari, Elena Ribera, Chiara Gardella,
Silvia Rosina, Michele Ghezzi and Francesca Rizzo
c) d) e)
Figure 1. a) Right-sided dominant double aortic arch (arrow); MDCT axial view. b) Same patient, MDCT
three-dimensional imaging; posterior view. ce) Endoscopic images of double aortic arch compression of
trachea, increasing severity. e) The tracheal rings are complete or circumferential.
The origin of the left subclavian artery from arch and has an oblique course toward the
the descending aorta is frequently dilated, other side, across the superior
forming the so-called Kommerell mediastinum, passing behind the
diverticulum (fig. 2a and c). In patients with oesophagus on its way to the upper
a right aortic arch, the airway compression extremity. An aberrant right subclavian
can be due to different mechanisms: artery as single malformation is rarely
vascular ring due to a left ligamentum symptomatic, although in older children and
arteriosum (fig. 2b), enlargement of the in adults, mild dysphagia may be present
Kommerell diverticulum and/or a midline/ due to compression of the oesophagus.
left descending aorta. However, an aberrant left subclavian artery,
crossing behind the oesophagus as the last
Aberrant subclavian artery, the most common branch of a right aortic arch, forms a
among the aortic arch anomalies, occurs in complete vascular ring together with a left-
nearly 1% of the population and in 25% of sided ligamentum arteriosum, as previously
Down syndrome patients. Originally described, and commonly causes symptoms
described by Bayford in the 18th century as due to compression of both the trachea and
dysphagia lusus naturae (dysphagia freak oesophagus (Kellemberg, 2010).
of nature), this anomaly most commonly
involves the right subclavian artery or, rarely, Pulmonary sling The embryonic origin of
the left subclavian artery when there is a pulmonary artery sling occurs when the
right-sided aortic arch, as previously developing left lung captures its arterial
described. The aberrant subclavian artery supply from the right sixth arch through
originates as the last vessel of the aortic capillaries caudal, rather than cephalad, to
b)
Figure 2. a) Right aortic arch, Kommerel diverticulum (arrow); MDCT axial view. b) Right aortic arch, a
rare MDCT imaging of ligamentum arteriosum; axial view. c) Kommerel diverticulum and aberrant left
subclavian artery (arrow), MDCT three-dimensional imaging; posterior view.
the developing tracheobronchial tree. As 50% of pulmonary artery sling cases, most
consequence, the anomalous left pulmonary commonly atrial septal defect, patent ductus
artery arises from an elongated right arteriosus, ventricular septal defect and left
pulmonary artery, turns dorsally encircling superior vena cava.
the right main bronchus, and passes to the
left between the trachea and oesophagus Aberrant innominate artery causes tracheal
before entering the hilum of the left lung compression of various degrees. Why an
(fig. 4a). innominate artery, which arises from the
aortic arch to the left and crosses in front of
The airway may also be compromised by the trachea to the right side, should
associated complete cartilage rings, the so compress the trachea in some cases and not
called ring-sling complex present in 4050% others is not well understood. In innominate
of cases, where the membranous portion of artery compression patients, the artery
the trachea is absent and the tracheal appears to originate somewhat more
cartilages are circumferential or O- posteriorly and leftward on the aortic arch
shaped. Associated tracheobronchial than usual. This condition is more
abnormalities may occur, including frequently symptomatic when associated
tracheomalacia, hypoplasia and stenosis of with tracheomalacia and/or oesophageal
long tracheal segments (fig. 4b and c) (Elliot atresia (fig. 5). Severe compression of the
et al., 2003). Both the right main bronchus trachea results in chronic or recurrent brassy
and the trachea are affected and cough, stridor, tachypnoea and recurrent
compression by the sling can result in respiratory infection (Gardella et al., 2010).
hyperinflation or atelectasis of the right The most severe presentations in infancy
lung. Congenital heart defects are found in include life-threatening events.
Figure 4. Pulmonary sling. a) MDCT axial view: the anomalous left pulmonary artery (arrow) arises from
an elongated right pulmonary artery, turns dorsally encircling the right main bronchus, and passes to the
left between the trachea and oesophagus before entering the hilum of the left lung. b) MDCT coronal view
of the associated long-segment tracheal stenosis: two-thirds of the trachea are stenotic and show complete
cartilage rings (line). c) MDCT three-dimensional imaging of the trachea and bronchi: the origin of the
right main bronchus is stenotic due to compression by the anomalous left pulmonary artery.
suggest a double aortic arch, while posterior noninvasive angiography have widely
indentation with an oblique course angled replaced other diagnostic techniques, such
toward the left shoulder suggests an as the now obsolete catheter angiography.
aberrant subclavian artery. Anterior pulsatile The direct multiplanar imaging capability of
indentation of the oesophagus is virtually MRI allows accurate evaluation of vascular
pathognomonic for pulmonary artery sling. malformation and its relationships with
adjacent organs and, possibly, associated
Echocardiography and angiography intracardiac defects in a single sitting,
Echocardiography has the advantage of a without ionising radiation and iodinated
comprehensive assessment of intracardiac contrast material. However, most MRI
anatomy and function. However, it is limited studies for vascular compression are quite
by acoustic windows, a lack of depiction of prolonged (.30 min), the need for absolute
airway/oesophageal involvement and high immobility during image acquisition
interobserver variability. Conventional requires general anaesthesia with controlled
angiography is invasive and is limited by ventilation, and sedation risks are increased
high radiation dose and the need for in children with compromised airways.
iodinated contrast material. Contrast-enhanced MDCT overcomes this
Although the diagnosis of a vascular ring disadvantage by allowing accurate imaging
can be established or suspected with chest in very short scanning times and mild
radiography and oesophagography, the sedation is sufficient in younger,
exact configuration of the vascular uncooperative children. The disadvantages
abnormality cannot be fully defined with of MDCT include ionising radiation and the
conventional radiology alone. The exact need for iodinated contrast material;
anatomy of an aortic arch malformation and however, recent adjustment of specific
its relationship to adjacent structures can be techniques minimises the radiation dose. If
accurately defined only by cross-sectional assessment of the airways is important,
imaging techniques, as MRI and CT MDCT is currently more reliable than MRI
(Hellinger et al., 2011). for the definition of the airway by
multiplanar and three-dimensional image
MRI and MDCT Contrast-enhanced helical reconstruction (figs 1b, 2c and 4c), including
MRI or MDCT imaging allow excellent virtual bronchoscopy, without appreciable
delineation of the aortic arch, its branches respiratory artefacts. For both MRI and
and their spatial arrangement. The MDCT, the major diagnostic limit is that an
multiplanar and three-dimensional imaging obliterated vascular segment (e.g. the
capabilities of magnetic resonance and CT ligamentum arteriosum or an atretic aortic
Figure 5. Tracheal compression by aberrant innominate artery in two patients, a) 15 and b) 20 months of
age. a) Endoscopic image of tracheal lumen compressed on the front right side. Good vision of the tracheal
rings is achieved and tracheal compression is visible without tracheomalacia. b) Patient with repaired
oesophageal atresia and less well-delineated tracheal rings. The association of vascular compression and
tracheomalacia caused a severe clinical picture with brassy cough, stridor and life-threatening events.
arch) can be visualised only rarely (fig. 2b). Bronchoscopy and bronchography Despite the
The final decision to image with MRI versus accuracy of both MRI and MDCT in
MDCT should take into consideration evaluating the nature of the vascular
availability of equipment and ease of compression of the airways, current MRI
scheduling, as well as the patients ability to and MDCT techniques do not reliably
cooperate. In practice, the increase in speed distinguish between dynamic or static
and quality of multiplanar reconstruction narrowing of the airways.
provided by MDCT technology means that
CT is used more and more often than MRI in Such distinction can have important clinical
most centres. consequences, as many children with
a) b)
Figure 6. Vascular ring due to right aortic arch, aberrant left subclavian artery and left ligamentum
arteriosum; same patient as in figure 3. Intraoperative view: a) ligamentum arteriosum (arrow) resection;
b) the two ends of the ligamentum (arrows) spontaneously move .1 cm away soon after resection.
Bronchopulmonary dysplasia (BPD) is a The disease was first described in 1967 but
chronic lung disease that affects premature the pathophysiology has changed
babies, usually following mechanical significantly since that time. Earlier
ventilation. Over the past 20 years, changes descriptions of fibroproliferation, smooth
in antenatal steroid use, surfactant therapy muscle hyperplasia and decreased
and changes in ventilator strategy have led alveolarisation have changed in the post-
to major improvements in the outcomes of surfactant era. BPD (commonly referred to
very premature infants. However, at the as new BPD) shows less regional
same time, the incidence of BPD has variability, large alveoli and characteristic
changed very little. This has meant that a vascular changes. The features
greater number of affected infants are differentiating old from new BPD are shown
surviving into childhood and beyond. These in table 1.
infants have an increased need for The National Institutes of Health (NIH)
healthcare, with frequent readmissions to diagnostic criteria for bronchopulmonary
hospital in the first 2 years and persistent dysplasia are shown in table 2. All infants
abnormalities of lung function into need to have been in room oxygen for at
adolescence and adulthood. least 4 weeks. For infants born at less than
32 weeks gestation, assessment is made at
36 weeks post-menstrual age or discharge
Key points (whichever comes first), whereas for those
infants born after 32 weeks, assessment is
N BPD remains a significant cause of made at 56 days of age or discharge.
long-term respiratory illness despite Diagnostic criteria remain an important
major advances in the care of the issue, as studies evaluating outcomes have
preterm newborns. historically used varying definitions of BPD,
making comparison difficult. For example,
N The primary pathological process is different units may administer additional
inflammation, driven through the NF- oxygen at varying levels of saturation.
kB pathway, and triggered by a variety
of genetic and environmental factors. The incidence of BPD varies with gestational
age, and particularly birth weight. Infants
N Management is directed at with a birth weight between 500 and 750 g
minimising lung insults, by limiting have a 42% chance of developing BPD
oxygen toxicity and ventilator-induced whereas in infants weighing between 1250
lung trauma. and 1500 g the chance of incidence drops to
N Drugs that may influence 4%.
development of BPD include caffeine
Aetiology and pathogenesis
and vitamin A, although new anti-
inflammatory drugs are in The primary basis of respiratory disease in
development. the preterm infant is a lack of surfactant
leading to the development of respiratory
some suggestion that the combination of Again, however, there is little evidence that
antenatal steroids and chorioamnionitis this approach will have a significant impact
may even be protective for BPD. on the incidence of BPD.
Other factors The role of nutrition in the Post-natally, there are several strategies
pathogenesis of BPD remains unclear. Poor that can help to minimise risk. In the
nutrition is associated with an increased resuscitation room there has been
incidence of BPD but equally there is no considerable interest in minimising lung
evidence that improving nutrition in these trauma and hyperoxia. Recent studies have
infants will reduce the risk of subsequent suggested that normal oxygen saturations
BPD. Tight control of fluid balance in high- in the neonate may well be lower than
risk infants may be beneficial. It is known previously thought and that initial
that infants with a patent ductus arteriosus resuscitation with air, adding in oxygen only
(PDA) have a greater risk of developing when needed, may reduce morbidity. A
subsequent BPD. At the same time, large study (SUPPORT) of 1300 babies
aggressive treatment of a PDA with fluid evaluating CPAP against surfactant, and
restriction, indomethacin or surgery has also high and low oxygen saturation,
been shown to reduce BPD, although the
showed no difference in outcomes
effect may be relatively minor.
(including death, BPD and
Prevention and management neurodevelopment); however, BOOST II
(designed to specifically consider
The ideal approach to the care of preterm oxygenation targets) was terminated early
infants would be to prevent BPD occurring. due to an increase in mortality in the lower
This either requires a reduction in premature oxygenated group. The use of noninvasive
delivery, or a method to prevent or attenuate ventilation (CPAP or noninvasive positive-
BPD in those babies who are born early. pressure ventilation (NIPPV)) has been
However this is difficult in the context of a shown to be safe in neonates and studies
disease that is so multifactorial. suggest that this, used in conjunction with
Prenatally, females who go into premature early surfactant and extubation, is as safe as
labour are routinely treated with oral conventional ventilation. However, this
steroids. It has been shown that this will approach does not result in any significant
increase lung maturity and surfactant reduction in BPD. Ventilation strategies
production and reduce the likelihood of have centred on low-volume ventilation
RDS. Disappointingly, this approach with permissive hypercapnia to minimise
appears to have little impact on the traumatic injury to the lung, and a recent
prevalence of BPD. Similarly, an aggressive Cochrane review has shown reduced deaths
approach to both antenatal and post-natal and chronic lung disease in patients treated
infection would appear to be worthwhile in with volume-targeted ventilation. The use of
view of concerns about their effect on high-frequency oscillation has not shown
inflammation and the development of BPD. any significant impact on BPD.
Kajsa Bohlin
The aim of this chapter is to review the with BPD show characteristic radiographic
neurodevelopmental outcome of preterm changes (fig. 1).
infants with bronchopulmonary dysplasia
The clinico-pathological problem of BPD
(BPD). We discuss the influence of neonatal
Despite the many advances, very preterm
intensive care on the development of
infants (defined as ,32 weeks of gestation)
chronic lung disease and neurological
still suffer from BPD, leading to long-term
development in preterm infants.
respiratory morbidity and oxygen
Mechanical ventilation (MV) and its adverse dependency. Sadly, this morbidity is also
effects on the lungs found in survivors of preterm birth who have
never been given MV. Our understanding of
Advances in respiratory support of the preterm the underlying pathophysiology of BPD has
neonate The widespread use of antenatal changed. It is thought that affected infants
corticosteroids and the introduction of with BPD now primarily suffer from a
exogenous surfactant replacement therapy, maturational arrest of alveolar
together with gentler MV, have led to better differentiation (fig. 2).
outcomes for preterm infants. Alongside
these improvements came a change in Classification, incidence and disease burden of
characteristics of NICU patients. Whilst BPD According to the National Institutes of
most NICU patients in the 1960s were more Health consensus definition, BPD is graded as
than 32 weeks of gestation and weighed mild, moderate or severe on the basis of
.1500 g at birth, treatment is now offered oxygen requirements at 28 days and 36 weeks
to many infants ,25 weeks of gestation and of corrected age. Despite many improvements
with a birth weight ,500 g. Lungs of infants in care, BPD still affects approximately 20
40% of very preterm infants. Infants with BPD
are known to have a higher disease burden
than their non-BPD preterm peers. Even after
Key points
initial discharge, they require more adjunct
therapy and have more hospital readmissions
N BPD is a distinct disease entity of in the first 2 years of life.
survivors of preterm birth.
Impact of premature birth and intensive
N The prevalence of BPD among
care treatment on neurodevelopmental
survivors of very preterm birth is
outcome
2040%.
N BPD is associated with a risk for Effects of preterm birth and NICU admission
significant neurodevelopmental delay. on health The disruptive environment of
NICUs per se results in poorer growth and
N Compared with non-BPD peers, impaired neurosensory development.
infants with BPD may exhibit poorer According to a recent meta-analysis, the
academic achievements and impaired incidence of developmental delay or learning
emotional and physical development. difficulties in very preterm infants is 60%,
cerebral palsy is 27%, impaired vision or
Anita K. Simonds
SMA: spinal muscular atrophy; DMD: Duchenne muscular dystrophy. Reproduced from Hull et al. (2012) with
permission from the publisher.
that both chest radiography and lung are at risk of developing end-stage renal
function testing do not reliably reflect the disease.
degree of respiratory morbidity. Studies
suggest that sleep studies may be more Spondylocostal and spondylothoracic dysostosis
sensitive to detect respiratory limitation. (JarchoLevin syndrome/LavyMoseley
syndrome): The JarchoLevin syndrome
Asphyxiating thoracic dystrophy is a rare encompasses individuals with a very short
osteochondrodysplasia with autosomal spine and malformed vertebral bodies, and a
recessive inheritance and variable dysplastic rip cage with fused, dysplastic or
expression that occurs in all ethnicities with absent ribs. Various gene mutations have
an estimated incidence of 1 in 130 000. A been found and underlie the phenotypic
narrow, bell-shaped and very stiff thorax with variations. Spondylocostal dysostosis
an almost normal-sized vertebral column is (JarchoLevin syndrome sensu stricto) may
the hallmark of the syndrome. Chest width is be distinguished from spondylothoracic
reduced in both the sagittal and the coronal dysostosis (LavyMoseley syndrome).
plane with shortened ribs typically bowed Severe pulmonary restriction leads to
inwards at the tips, resulting in a cloverleaf chronic respiratory failure, recurrent
appearance of the thoracic cage in the pneumonias, and right heart failure.
transverse plane. Other skeletal features of
Spondylocostal dysostosis occurs both as
the pelvis and extremities are common and
autosomal recessive and autosomal
associated with short stature, and vertebral
dominant trait, and is mainly characterised
malformations of the neck need special
by:
attention for their potential to damage the
cervical medulla. One-third of affected N an abnormal segmentation of at least 10
individuals have renal disease including consecutive vertebral bodies,
cysts, tubular atrophy and renal failure. N a costal malalignment, fused ribs and
Other frequently encountered organ costal bifurcations, or occasionally absent
manifestations involve the liver, the ribs,
pancreas, and the eyes. There is apparently N a mild scoliosis with variable potential for
no correlation between the severity of progression, depending on the
thoracic dystrophy and the extent of asymmetry of the costal malformations
parenchymal involvement. (TIS type II or type IIIa).
More than 120 cases have been described in Multiple associated malformations are
the literature. Mortality is as high as 50%, known. Without early thoracic expansion,
with up to 80% dying within the first 2 years progression of scoliosis occurs in 75% of
due to respiratory failure and cor pulmonale. cases. Mean survival has improved
Most survivors need some sort of ventilatory significantly, but long term prognosis is as
support. Thorax-expansion surgery increases yet unknown.
the transverse cross-sectional area, but its
effect on lung growth remains uncertain. Spondylothoracic dysostosis is an
Jeune patients surviving into adolescence autosomal recessive syndrome seen mostly
The two-process model of sleep and overview of basic sleep physiology and
wakefulness predicts the day-to-day pathophysiology, and describes the
synchronisation of an organism with its characteristics of rapid eye movement
environment by the interaction of a circadian (REM) and non-REM (NREM) sleep. Sleep
(process C) and a homeostatic process and circadian-generating systems are also
(process S). This section provides an discussed.
The switch for sleep is considered to be NREM sleep The thalamus, dorsal raphe,
the ventrolateral pre-optic nucleus (VLPO) nucleus tractus solitarius, anterior
of the anterior hypothalamus. This area hypothalamus and adjacent forebrain areas
becomes active during sleep and uses the are important in producing NREM sleep.
inhibitory neurotransmitters GABA and Neurotransmitters such as serotonin and
galanin to initiate sleep by inhibiting the GABA, which may be important in sleep
arousal regions of the brain. The VLPO mechanisms, are located in these brain
innervates and can inhibit the wake- regions and play an important role in sleep.
promoting regions of the brain including the Serotonin (5-hydroxytryptamine), found in
tuberomammillary nucleus, lateral raphe neurons of the brainstem, may be
hypothalamus, locus coeruleus, dorsal involved in sleep onset. Insomnia occurs
raphe, laterodorsal tegmental nucleus and when serotonergic cells of the dorsal raphe
pedunculopontine tegmental nucleus. The are lesioned. In addition, there is evidence
hypocretin (orexin) neurons in the lateral that substances in the biosynthetic pathway
hypothalamus help stabilise this switch. of serotonin (such as tryptophan and
REM sleep occurs with activation of vitamin B6) may facilitate sleep (Jones,
cholinergic neurons in the laterodorsal and 1989). However, in spite of all the evidence
pedunculopontine tegmental nuclei. This supporting the role of serotonin in sleep
cholinergic activation occurs when onset, there are studies that suggest that the
withdrawal of the aminergic arousal systems role of serotonin in sleep is not clear.
(noradrenergic neurons in the locus
coeruleus and serotonergic neurons in the The inhibitory neurotransmitter GABA is
dorsal raphe nuclei) produces disinhibition. released in its highest concentrations during
This causes the release of acetylcholine, NREM sleep. GABAergic neurons are
which triggers the increased neural activity located throughout the brain, including the
that is a feature of REM sleep. Suppression basal forebrain, hypothalamus, thalamus,
of motor activity, the other marker of REM brainstem and cortex. Hypnotics, such as
sleep, is generated by glutamate-mediated benzodiazepines and barbiturates, tend to
activation of descending medullary reticular work by potentiating GABA-mediated
formation relay neurons. The activity of inhibitory processes. They may shut off
these neurons is inhibitory to spinal motor neurons in the reticular activating system
neurons via the release of glycine, and to a and inhibit transmission and activity of
lesser extent, GABA. neurons that project to the cortex and
thalamus.
Neurochemistry of sleep Sleep results from
the complex interaction of multiple Overall, hypnotics increase total sleep time,
neurotransmitter systems, as well as the decrease sleep latency, decrease the number
influence of other physiological or of awakenings, decrease the amount of time
psychological states. spent in NREM sleep stage 3 and, in some
cases, REM sleep.
Wakefulness Waking and consciousness
depend on the activity of neurons in the REM sleep Acetylcholine is located within
ascending reticular activating system of the neurons in the pontine tegmentum and is
brainstem. These neurons project into the involved in REM sleep generation. REM-
thalamus, hypothalamus and basal on cells are cholinergic cells in the lateral
forebrain, and eventually send projections to pontine and medial medullary reticular areas
the cortex. There are particular that innervate the thalamus, hippocampus
neurotransmitters, such as the and hypothalamus. These cells discharge at
~.O1M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~.O2M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~.F3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~.F4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chin EMG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Stage W W W W W W W W W W W W W W W W W W W W W W W W W W W W W W
3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
0 5 10 15 20 25 30
Time s
Figure 1. 30-s epoch of wakefulness. During eyes-open wake, the EEG is characterised by high-frequency,
low-voltage activity. Electro-oculography (EOG) shows REM and the chin EMG activity is relatively high.
During eyes-closed wake, the EEG is characterised by prominent a-wave activity. The amplitude of the
channels is 70 mV. W: wake.
between 45% and 55% of the total sleep with durations of 0.51.5 s. The K-complex is
episode. An individual in stage 2 sleep a high-amplitude, biphasic wave of o0.5 s
requires more intense stimuli than in stage 1 duration. A K-complex consists of an initial
to awaken. The EEG during stage 2 sleep sharp, negative voltage (by convention, an
shows relatively low-voltage, mixed- upward deflection) followed by a positive
frequency activity characterised by the deflection (down) slow wave. Spindles are
presence of sleep spindles and K-complexes. frequently superimposed on K-complexes
Sleep spindles are oscillations of 1214 Hz (fig. 3).
Left EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Right EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~C3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~C4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~O1M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~O2M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~.F3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~.F4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chin EMG
107 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
0 5 10 15 20 25 30
Time s
Figure 2. 30-s epoch of stage 1 sleep. EEG is characterised by low-voltage, mixed-frequency activity. Slow
rolling eye movements often are present. Vertex waves are common in stage 1 sleep (arrow). The
amplitude of the channels is 70 mM. EOG: electro-oculogram.
0 5 10 15 20 25 30
Time s
Figure 3. 30-s epoch of stage 2 sleep. Stage 2 sleep is characterised by the presence of one or more K-
complexes (arrow) or sleep spindles (arrowheads). The amplitude of the channels is 70 mM. EOG: electro-
oculogram.
During stage 3 sleep (SWS), the EEG is arousal threshold, especially in children
synchronised. Stage 3 lasts approximately (fig. 4).
2040 min in the first cycle and makes up
about 1432% of sleep. This stage is REM sleep is defined by the presence of
characterised by increased amounts of high- desynchronised (low-voltage, mixed-
voltage, slow-wave activity on the EEG. frequency) brain wave activity, muscle
d-wave (slow wave) activity is defined as atonia and bursts of REMs. Sawtooth
waves slower than 2 Hz (.0.5 s duration) wave forms, h-wave activity (37 Hz) and
with a peak-to-peak amplitude .75 mV. slow a-wave activity also characterise REM
During SWS, we see the highest auditory sleep. During the initial cycle, the REM
Left EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Right EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~C3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~C4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~O1M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~O2M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~F3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~F4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chin EMG
208 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
0 5 10 15 20 25 30
Time s
Figure 4. 30-s epoch of stage 3 sleep. Stage 3 NREM sleep is called slow-wave, d-wave or deep sleep. Stage
3 is scored when slow-wave activity (frequency ,2 Hz and amplitude .75 mV peak to peak) is present for
.20% of the epoch. The amplitude of the channels is 70 mM. EOG: electro-oculogram.
Left EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Right EOG
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~C3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~C4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~O1M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~O2M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~F3M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
~F4M1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Chin EMG
623 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
0 5 10 15 20 25 30
Time s
Figure 5. 30-s epoch of REM sleep. REM sleep is characterised by a low-voltage, mixed-frequency EEG, the
presence of episodic REMs, and a relatively low-amplitude chin EMG. Sawtooth waves also may occur
in the EEG. The amplitude of the channels is 70 mM. EOG: electro-oculogram.
As the function of sleep has not been fully A sleep disorder is loosely defined as any
determined, the absolute number of hours condition or process that alters the patients
necessary to fulfil its function is still previously established sleepwake cycle.
unknown. Some individuals claim full Sleep disorders are divided into two general
effectiveness with only 35 h of sleep per classes: dyssomnias and parasomnias.
night, while others claim to need o8 h of
Dyssomnias are conditions that manifest
sleep per night to perform effectively. Sleep
themselves as either hypersomnia
deprivation is a relative concept. Small
(abnormal sleep cycles causing the urge to
amounts of sleep loss (e.g. 1 h per night over
sleep at times when the circadian cycle
many nights) have subtle cognitive costs,
would suggest that wakefulness was
which appear to go unrecognised by the
appropriate) or insomnia (the inability to
individual experiencing the sleep loss. More
sleep). The dyssomnias can be further
severe restriction of sleep for a week leads to
subdivided into three classes that are
profound cognitive deficits similar to those
dependent on the source of the sleep
seen in some stroke patients. Glucose
interference.
positron emission tomography (PET)
studies in individuals deprived of sleep have N Intrinsic (arising within the body):
shown that after 24 h of sustained primary insomnia, OSA, restless leg
wakefulness, the metabolic activity of the disorder and unspecified limb
brain decreases significantly. In humans, movements.
sleep deprivation also results in a decrease N Extrinsic (arising outside the body):
in core body temperature, a decrease in environmental conditions not conducive
immune system function as measured by to uninterrupted sleep, such as noise or
white blood cell count and activity, and a ambient temperature.
decrease in the release of growth hormone. N Alteration or interference with the
Sleep deprivation has also been implicated circadian rhythm: jet lag or variations in
as a cause of increased heart rate variability occupational schedules (shift work).
(Banks et al., 2007).
Parasomnias include sleep terror (sudden
Short-term sleep deprivation has been awakening and unreasonable fear),
implicated in contributing to obesity as well bedwetting, somnambulism (sleep walking)
as glucose dysregulation contributing to and somniloquy (talking in ones sleep)
poor control of type II diabetes. (American Academy of Sleep Medicine,
2005).
Children differ from adults in their response
to acute restriction in sleep. When sleep has This AASM classifies sleep disorders into
been restricted by o4 h, there is a decrease eight major categories:
in all stages of sleep (except SWS), a
reduction in sleep onset latency, stage 3 1. insomnia,
latency and REM latency. Multiple sleep 2. sleep-related breathing disorders,
latency tests show a significant increase in 3. hypersomnias of central origin,
daytime sleepiness, which persists into the 4. circadian rhythm sleep disorders,
despite their impact on public health, widely low-grade inflammatory condition. The
ignored. A narrow upper airway with induction of systemic inflammatory
maxillary constriction and/or some degree of responses is most likely related to the
mandibular retrusion is a common generation of systemic oxidative stress
paediatric phenotype of OSAS. In such secondary to the recurrent hypoxic
cases, children are typically described as and arousal episodes that characterise
having a narrow, long face, they may have OSAS.
retrognathic mandibles and increased
posterior facial height associated (or not) Failure to thrive was extremely frequent and
with severe tonsillar hypertrophy. Whether attributed to increased metabolic
this skeletal conformation is genetically expenditure caused by the elevated work of
determined or influenced by the early onset breathing during sleep, reduced nutrient
of habitual snoring has yet to be assessed. intake due to tonsillar hypertrophy and,
Another common abnormality in patients most likely, to disrupted growth hormone
with OSAS is a high arched (ogival) palate, insulin growth factor pathways in the
which results in posterior tongue presence of recurrent hypoxaemia and
displacement forcing the lateral palatine disturbed sleep patterns. In more recent
processes to expand over the abnormally years, however, obesity has emerged as a
placed tongue. frequent finding and it is likely to amplify the
morbidities of OSAS and obesity alone. The
Comorbidities Paediatric OSAS is associated
concomitant presence of OSAS in obese
with a multitude of end-organ morbidities,
children further amplifies the risk for lipid
such as daytime sleepiness, neurocognitive
disturbances and reveals the presence of an
impairment, behavioural problems, failure
interaction between adiposity and insulin
to thrive, hypertension, cardiac dysfunction
resistance. Adipokines, including leptin, are
and systemic inflammation.
cytokines released from adipose tissue that
In recent years, research from many are important in the regulation of appetite,
paediatric sleep centres has accumulated metabolic homeostasis, sleep and
substantial evidence suggesting that respiratory control. A recent study reported
paediatric OSAS constitutes a systemic on the elevation of circulating leptin levels in
ECQ
ECQ
Effort
Effort
Nasal Nasal
cannula cannula
Chest Chest
Abdomen Abdomen
SaO2 SaO2
Figure 1. Examples of a) obstructive apnoea, b) central apnoea, c) mixed apnoea and d) hypopnea sleep
epochs of 120 s. ROC: right electro-oculogram; LOC: left electro-oculogram.
NO
Diagnostic evaluation? Refer to paediatrician
YES
NO
High risk or <2 years Overnight pulse oximetry
YES NO
Positive?
YES#
Attended video PSG Adenotonsillectomy or
or unattended PSG craniofacial surgery or
orthodontic treatment, CPAP
Refer to paediatrician, follow-up NO Positive?
YES
YES# Signs and symptoms
Drug therapy, plus orthodontic NO
Surgical intervention? after therapy?
therapy and/or diet, or CPAP
NO
NO YES YES
Symptoms? Adenotonsillectomy or Signs and symptoms
craniofacial surgery after 6 months?
YES
Adjusting therapy and or CPAP YES NO
Clinical evaluation and or
Signs and symptoms? overnight pulse oximetry
YES
Signs and symptoms?
NO YES
NO Positive?
Clinical evaluation and/or
Clinical evaluation PSG after 6 months NO
and/or PSG after 6 months
YES YES NO
Positive? Positive? Refer to paediatrician
NO
Refer to paediatrician, follow-up
Figure 2. Algorithmic approach to the diagnosis and treatment of paediatric OSAS. ORL:
otoringolarhingologic examination; PSG: polysomnography. #: refer to the orthodontist for ORL, assess
for obesity, and perform cardiologic (ECG, blood pressure holter) and neuropsychological assessment.
algorithm for the diagnosis and treatment of N Bhattacharjee R, et al. (2010). Adeno-
paediatric OSAS using a multi-step tonsillectomy outcomes in treatment
approach. As multi-therapies might act of obstructive sleep apnea in children:
synergistically, a greater degree of a multicenter retrospective study.
collaboration between sleep medicine, ENT Am J Respir Crit Care Med; 182:
specialists and orthodontists is warranted to 676683.
N Gozal D, et al. (2008a). Metabolic
establish the contribution of each therapy to
alteration and systemic inflammation
the outcome of paediatric OSAS. in obstructive sleep apnea among non-
obese and obese prepubertal children.
Further reading Am J Respir Crit Care Med; 177: 1142
1149.
N Amin RS, et al. (2008). Activity-adjusted 24- N Gozal D (2008b). Obstructive sleep
hour ambulatory blood pressure and cardiac apnea in children: implications for the
remodelling in children with sleep disor- developing central nervous system.
dered breathing. Hypertension; 51: 8491. Semin Pediatr Neurol; 15: 100106.
Sleep alters the function and control of the cessation of breathing for at least two
respiratory system. These changes may result breaths. Central sleep apnoea can be
in clinically significant abnormalities in upper idiopathic but it can also occur secondary to
airway function and pulmonary gas exchange another medical condition. Central apnoeas
among healthy children as well as those with are common in the neonatal period,
an underlying disease. Sleep disordered particularly among pre-term newborns, and
breathing (SDB) is a common cause of this is viewed as a physiological immaturity of
morbidity in childhood that can result in breathing control and ceases spontaneously
severe complications if left untreated. Central around term post-conceptional age. Central
sleep apnoea, hypoventilation syndromes and hypoventilation is caused by an inability of the
OSA are sleep-related breathing disorders, central nervous system to maintain
and this section will focus on the first two ventilation sufficient to overcome the
conditions. Central sleep apnoea is respiratory load. Alveolar hypoventilation
characterised by a decreased or absent syndromes are often caused by an abnormal
respiratory drive that results in reduction or central integration of chemoreceptor signals
and can be primary, as in congenital central
hypoventilation syndrome (CCHS), or
Key points secondary to diseases of the central nervous
system or neuromuscular disorders. Early
N Central sleep apnoea and diagnosis and comprehensive treatment will
hypoventilation syndromes are causes minimise the number of sequelae and
of morbidity in childhood that may improve individual outcomes.
result in severe complications if left
Clinical features
untreated.
N Complications of sleep apnoea Sleep apnoea should be considered in
include pulmonary hypertension, cor children of all ages who present with
pulmonale, systemic hypertension, nonspecific symptoms of daytime
cardiac arrhythmias, hypoxic cerebral dysfunction. More specific signs and
injury and seizures. symptoms of SDB include nocturnal or
early-morning headache, poor sleep quality
N PSG is the gold standard test for SDB with nocturnal awakenings, failure to thrive,
and is required to diagnose sleep- and daytime breathing disturbances.
related disorders. Children with daytime sleepiness due to
N Treatments include supplementary SDB often act out behaviourally (e.g.
oxygen, caffeine (apnoea of hyperactivity, impulsivity and increased
prematurity), diaphragm pacing, aggression) rather than complaining
CPAP, BiPAP and mechanical verbally. Younger children are less likely than
ventilation via tracheostomy. older children to show signs of tiredness
(e.g. yawning and rubbing eyes).
requisite to the diagnosis of CCHS. The Patients with PWS, particularly if they are
PHOX2B gene promotes neuronal obese or have symptoms suggestive of SDB,
differentiation and development of the require a PSG to exclude or characterise
autonomic nervous system. Knowledge of abnormal breathing. An early diagnosis of
the specific PHOX2B mutation aids in SDB and appropriate treatment may delay or
anticipating CCHS phenotype severity prevent the development of cor pulmonale.
(Weese-Mayer et al., 2010). CCHS is
Secondary hypoventilation syndromes
associated with an increased risk of
Alveolar hypoventilation syndromes can be
Hirschsprungs disease and tumours of
secondary to an underlying disease and
neural crest origin. A fairly recent study
therefore cause an abnormal central
from the French CCHS registry estimates
integration of chemoreceptor signals.
an incidence of one per 200 000 live births
Examples include diseases affecting the
(Trang et al., 2005). PHOX2B mutation-
central nervous system (trauma, tumours
confirmed CCHS confers a risk of adverse
and cerebrovascular incidents),
neurocognitive outcome, though the range
neuromuscular disorders, chest wall
of observed functioning raises questions
deformities and obesity. This is a
about factors that may contribute to
heterogeneous group of diseases and
neurocognitive variability. The
incurs variable degrees of damage to the
recommended management options in
respiratory control centres.
optimising CCHS patient care and
neurocognitive outcome are summarised Neuromuscular disorders SDB is now well
in an official American Thoracic Society recognised in children with neuromuscular
clinical policy statement (Weese-Mayer disorders and may lead to significant
et al., 2010). morbidity and increased mortality.
Obese children present different lung defined as: mass (kg)/[height (m)]2. In
anatomy and function and have more adults, a BMI .30 kg?m-2 defines obesity,
respiratory symptoms than their normal- but as the normal BMI changes throughout
weight peers. Paediatric obesity is now childhood and is age- and sex-specific, a
considered a major public health problem centile chart has to be used in children. In
and data from many observational studies UK centile charts, overweight is taken as a
show an increase of this disease in recent BMI .91st centile and obesity a BMI .98th
decades, in all age-groups: about 7% of the centile. Other methods of assessment
world population is obese. In Europe the include Ideal Body Weight (IBW), waist
prevalence of childhood obesity ranges from circumference, waist/hip ratios, skinfold
1020% in the north to 2040% in the cities thickness, abdominal fat from CT/MRI
of the Mediterranean basin. In the USA, the scans, bioelectrical impedance and dual
prevalence of overweight children has tripled energy X-ray absorptiometry (DEXA).
in the past 20 years. Globally, an estimated
Lung function in obesity
43 million preschool children (under age
5 years) were overweight or obese in 2010, a There are limited data on obese children,
60% increase since 1990. but studies on adults show that obesity has
a profound effect on the anatomy and
The commonest and simplest method of physiology of breathing (table 1).
measuring and determining obesity is BMI,
The upper airways may be directly narrowed
by fatty infiltration of muscles and
Key points subcutaneous fat deposits.
Andreas Schibler
a) 100 b) 100
95 95
90 90
SaO2 %
SaO2 %
85 85
10 kPa 15%
80 20 kPa 80 25%
30 kPa 35%
75 75
0 20 40 60 0 20 40 60
FIO2 FIO2
Figure 1. The effect of a) low V9/Q9 and b) shunt on the ODC. Note that reduced (but not absent) ventilation
will tend to move the curve to the right, and can be overcome with additional inspired oxygen. However, in
pure shunt the maximal saturation that can be reached is reduced. FIO2: inspiratory oxygen fraction.
Respiratory Capillary
control
Respiratory
muscle capacity Alveolus
Respiratory
load
Neuromuscular
diseases
Lung and airway
diseases
PaCO2 PaO2
Figure 1. The two different types of respiratory failure: ventilatory imbalance (left) and abnormalities of the
alveolarcapillary membrane (right).
also during daily activities), the cost and The most common diseases that may need
local facilities. An oxygen concentrator is a NIV are neuromuscular disorders,
cheap and safe source but does not allow hypercapnic lung diseases, such as
ambulation. When LTOT is required during advanced CF or COPD, and central
the daytime, and especially during daily hypoventilation if the patient has a minimal
activities, gaseous or liquid oxygen is respiratory autonomy while awake. The
preferred. The efficacy of LTOT should be criteria to start NIV are not validated in
checked by overnight gas recording to check children but most experts recommend NIV
the SpO2 but also the carbon dioxide level, in when nocturnal PtcCO2 exceeds 50 mmHg
order to detect hypercapnia, especially in despite optimal medical treatment. The aim
patients with lung diseases such as CF, and of NIV is to maintain the maximal PtcCO2
the possibility of NIV should be discussed. below 50 mmHg, by providing a sufficient
tidal volume and V9E.
Noninvasive ventilation
Numerous ventilators are available for home
The aim of NIV is to correct alveolar ventilation but few have been specifically
hypoventilation, i.e. chronic hypercapnia. designed for children. However,
Even if the deleterious consequences of manufacturers have improved the
chronic hypoxaemia are not well documented performances of the most recent devices
in children, our knowledge is even more with some ventilators being as performant
limited with regard to the consequences of as intensive care ventilators. The ventilatory
long-term hypercapnia. Besides systemic modes have improved significantly over
hypertension, very few side-effects have been recent years. Initially, two modes were
objectively reported in children. Again, in available, a volume-target and a pressure-
clinical practice, the target values are derived target mode, with the former being
from the values observed in healthy children. preferentially prescribed for patients with a
As such, most authors and experts restrictive lung disease, such as patients
recommend that the maximal (nocturnal) with a neuromuscular disease, and the latter
PtcCO2 should not exceed 50 mmHg. being preferentially prescribed for patients
B
A
Radial spoke
ODA
Nexin link
IDA
b) c)
Figure 1. Cross section of the cilia. a) Schematic diagram of a cilium revealing 9+2 arrangement of nine
peripheral microtubule doublets surrounding a central microtubule pair. b, c) Transmission electron
microscopy of normal cilia (b) and absent IDA and ODA (c). Reproduced from Becker-Heck (2012).
In addition, virtually all subjects have evidence Ear symptoms (recurrent otitis media and
of chronic upper airway symptoms such as glue ear) are a frequent complication that
chronic rhinitis (nasal discharge, episodic can require multiple interventions, including
facial pain and anosmia). This may be repeated courses of antibiotics.
confirmed by either physical examination and/
or sinus imaging. Continuous rhinorrhoea can PCD should be suspected in cases of situs
be present from the first day of life. inversus totalis or heterotaxy; ,25% of
PCD with MR
heterotaxy subclass is unknown. In PCD
PCD with RP
Phenotype
PCD+KS
PCD+KS
PCD+KS
PCD+KS
PCD+KS
PCD+KS
PCD+KS
PCD+KS
patients, 4050% present with situs inversus
PCD
PCD
KS
c.801_803delGAA
IVS1 + 3insT
Not known
c.10815delT
Not known
Not known
Not known
Not known
Not known
Not known
Not known
Not known
Not known
Exon 5
,25
20
20
20
82
23
14
12
18
6
5
3
Variable
Normal
ODA
ODA
ODA
ODA
features of PCD.
3q26.33
16q24.1
17q25.3
14q21.3
17q25.1
Xp21.1
7p14.1
Locus
Xp22
6q22
6p21
CCDC40
RSPH4A
CCDC39
LRRC50
RSPH9
DNAI2
DNAI1
RPGR
OFD1
Gene
KTU
PCD.
N Polycystic kidney or liver disease.
Proximal
0
5000
0
5000
Impedance
Intermediate
0
5000
0
5000
Distal
0
5000
0
8
pH
0
Time
Figure 2. Example of acid reflux episodes reaching the proximal oesophagus. Impedance measurements from
the proximal, intermediate and distal oesophagus, and pH are shown. The episode is categorised as acid
because of the presence of a pH drop to ,4 during the impedance-detected episode (arrow and shaded area).
variation in its sensitivity (57100%) and before and after lung transplantation
specificity (5789%) (Colombo et al., 2012). (Blondeau et al., 2008). Though a promising
An increase in LLMs has been described in investigative measure, the detection of
pulmonary conditions other than aspiration, pepsin in BAL fluid as a marker of gastric
such as CF, infections, use of intravenous aspiration has a number of concerns. Firstly,
lipid infusion and pulmonary fat embolism early cross-sectional studies only provide a
in sickle cell disease, suggesting that any snapshot in time of its presence, and there
pulmonary insult severe enough to cause are no data on how pepsin concentrations
tissue destruction may result in an increase change over time following aspiration or
in LLMs by releasing lipids from cell with frequency of aspiration events.
membranes (Knauer-Fischer et al., 1999). Secondly, alterations in content and
However, despite these significant concentrations may be dependent on BAL
limitations, an elevated LLMI may provide technique. However, based on current data,
supporting evidence of aspiration in a the specificity of the pepsin makes this
selected group of children. biomarker highly appealing.
5000
Proximal
0
5000
0
5000
Impedance
Intermediate
0
5000
0
5000
Distal
0
5000
0
8
pH 0
Time
Figure 3. Example of nonacid reflux episode reaching the proximal oesophagus. Impedance measurements from
the proximal, intermediate and distal oesophagus, and pH are shown. The episode is categorised as nonacid on
the absence of a pH drop to ,4 during the impedance-detected episode (arrow and shaded area).
Iolo Doull
Foreign body aspiration (FBA) is a serious airflow, so even small foreign bodies can be
and potentially fatal condition in infants and dangerous. Compared to adults the larynx is
children. Choking may occur due to an in a relatively high position in infants with
obstruction in the oral cavity, and insertion the epiglottis close to the root of the tongue,
injuries may occur when foreign objects are increasing the risk of aspiration. Infants
present in either the nose or nasopharynx. have gag, cough and glottic closure reflexes
Ingestion injuries occur due to foreign to protect against aspiration, but they may
bodies in the oesophagus or stomach. not always be fully developed from birth, and
Depending on the age of the child and the swallowing, in particular, may be delayed.
size of the foreign body, airway obstruction Children with developmental delay are at
and aspiration can occur anywhere in the increased risk of aspiration.
respiratory tract. Large airway obstruction
preventing adequate ventilation can be fatal, Incisors are necessary to bite through food,
while more distal obstruction can lead to and molars are necessary to masticate the
emphysema, atelectasis and subsequent food in preparation for swallowing.
chronic changes including bronchiectasis. However, incisors erupt approximately
6 months before molars and so food may
Aetiology and predisposing factors not be appropriately pulped, remaining as a
small smooth or rounded mass, the ideal
Children ,3 years of age are at greatest risk. shape to obstruct an airway if aspirated.
Infants have smaller airways than adults. Infants and children are less able to cough
Flow through an airway is inversely out foreign bodies aspirated into the airway;
proportional to the radius to the fourth peak cough flows at 4 years of age are
power, thus small changes in airway radius approximately a quarter of that of adults.
lead to proportionately greater changes in Once lodged in an airway, mucus and local
inflammation will quickly result in complete
airway obstruction, thus diminishing the
Key points possibility of forced clearance. Finally
infants are easily distracted and often
N Children ,3 years of age are at inattentive, are more likely to talk and run
greatest risk of FBA. around while chewing, and more likely to put
N FBA must be suspected for any a small non-organic foreign body in their
witnessed choking episodes. mouth while playing.
Figure 1. HRCT scan of a 2-year-old girl with There have been many different approaches
surfactant protein C deficiency (I73T mutation in to the classification of paediatric DPLD;
SFTPC gene). The scan shows diffuse ground-glass several of them are now being reconsidered.
attenuations with parenchymal cysts and It is believed that some forms are more
interlobular septal thickening. prevalent in very young children. However,
Eosinophilic lung diseases constitute a The diversity of DPLD conditions and the
diverse group of disorders of various lack of randomised clinical trials in groups
origins. The diagnosis is suggested by of well-phenotyped paediatric patients
increased peripheral eosinophilia and explain the difficulty to propose treatment
confirmed by the presence of eosinophils in strategies. Longitudinal care of these
BAL and/or lung tissue. Eosinophilic lung children needs to be organised in
diseases of known cause in children mainly specialised centres. In this section, general
include allergic bronchopulmonary management with the most usual
aspergillosis, parasitic infections and drug pharmacological therapies is indicated.
reactions. Eosinophilic lung diseases of
General measures are essential and mainly
unknown cause comprise Loeffler syndrome
include administration of oxygen for chronic
(characterised by migrating pulmonary
hypoxaemia and maintenance of nutrition
opacities), acute eosinophilic pneumonia
with an adequate energy intake.
and chronic eosinophilic pneumonia.
Immunisation with the influenza vaccine on
Among the diffuse developmental disorders is an annual basis is recommended along with
alveolar capillary dysplasia, a rare disorder other routine immunisations against major
presenting with persistent pulmonary hyper- respiratory pathogens. In addition, aggressive
tension of the newborn. A definitive diagnosis treatment of intercurrent infections and strict
can only be made by histological examination, avoidance of tobacco smoke and other air
documenting poor capillary apposition and pollutants are strongly recommended.
density, allied with medial arterial hypertrophy
and misalignment of pulmonary vessels. Pharmacological therapy includes anti-
Interestingly, capillary proliferation in the inflammatory and immunosuppressive
alveolar wall has been reported in hereditary molecules. Steroids are the preferred choice,
haemorrhagic telangiectasia. administered orally and/or intravenously.
Oral prednisolone is most commonly
DPLD specific to infancy includes administered at a dose of 12 mg?kg-1?day-1.
neuroendocrine cell hyperplasia, pulmonary Children with significant disease are best
interstitial glycogenosis and chronic treated with pulsed methylprednisolone, at
pneumonitis in infancy. Neuroendocrine cell least initially. This is usually given at a dose
severity are given in table 3; these are largely of pulmonary hypertension with a normal
adult based and there is a need for a specific chest radiograph are interstitial lung disease
paediatric classification. and sleep disordered breathing, usually
OSA. Hence, every case of apparently
Epidemiology
idiopathic pulmonary hypertension should
Pulmonary hypertension may present at any have these conditions excluded. The
age. Paediatric pulmonary hypertension is management of secondary pulmonary
ceasing to be an orphan disease; there are hypertension is largely of the underlying
increasing numbers of national and respiratory conditions, and this will not be
international specifically paediatric discussed further. If secondary pulmonary
registries, which have increased our hypertension is thought to be
information base. The incidence and point disproportionate to the severity of lung
prevalence of isolated pulmonary disease, then consideration should be given
hypertension are less than one and five to the use of therapies used in primary
cases per million children, respectively. The pulmonary hypertension (PPH) (see later),
number of cases of pulmonary hypertension probably best as part of a randomised
secondary to congenital heart disease is of a controlled trial. Any child thought to have
similar order of magnitude. The prevalence primary pulmonary vascular disease should
of pulmonary hypertension in have Eisenmengers syndrome and other
bronchopulmonary dysplasia is probably cardiological conditions excluded by a
underestimated due to ascertainment bias. careful cardiological evaluation. The
management of this latter group is usually
Pulmonary hypertension secondary to
medical in specialist paediatric cardiological
respiratory disease is usually dominated by
centres and discussions of these conditions
obvious features of the underlying cause, for
are beyond the scope of this chapter.
example, very severe bronchiectasis in CF.
The underlying mechanism is intermittent or Normal pulmonary vascular development
continuous alveolar hypoxia leading to
pulmonary vasoconstriction and ultimately The pulmonary arteries develop
vascular remodelling. Systemic arterial embryologically from the sixth bronchial
hypoxaemia in the absence of alveolar arches. The pre-acinar vessels follow the
hypoxia (for example, due to multiple airway development and are largely
pulmonary arteriovenous malformations) complete by the end of the first 16 weeks of
does not lead to pulmonary hypertension. pregnancy, the end of the pseudoglandular
Two important occult respiratory causes phase. Blood vessels form by
PAH: pulmonary arterial hypertension; APAH: associated PAH; CTEPH: chronic thromboembolic PH.
Reproduced from Simonneau et al. (2009) with permission from the publisher.
There are three groups of compounds that Novel innovative therapies may include the
may be used to treat pulmonary use of Rho kinase inhibitors, vasoactive
hypertension. These are prostacyclin and its intestinal peptide (VIP), oestrogen
derivatives, phosphodiesterase-5 inhibitors derivatives, modulation of the serotonin
(e.g. sildenafil), and the endothelin receptor pathway, L-arginine and therapies (including
antagonists. Their use has led to enhanced gene therapy) that may modulate apoptosis
survival. to attenuate vascular remodelling.
For an otherwise well child who has had a Given that heritable coagulopathies may
pulmonary thromboembolism and is present with thromboembolic disease,
clinically stable, anticoagulation with consideration should be given to screening
heparin and warfarin is indicated. If there is the child and first-degree relatives for at
an underlying coagulopathy, the advice of a least for protein C, protein S and
paediatric haematologist should be sought. antithrombin III deficiency, given the risk of
If the child is critically unstable, then thromboembolic events in these conditions.
consideration should be given to
Invasive pulmonary capillary
thrombolysis and even embolectomy, in
haemangiomatosis This rare condition is
consultation with a paediatric cardiologist
characterised by proliferating sheets of thin-
and cardiothoracic surgeon.
walled vessels, which infiltrate the
pulmonary circulation leading to vascular
Table 6. Four clinical questions if pulmonary embolic occlusion. The condition behaves like a low-
disease is suspected grade vascular neoplasm. Rarely, there is
extrathoracic spread of the abnormal
Has there been embolic occlusion of part of
vasculature. Presenting features include
the pulmonary arterial tree?
dyspnoea, thrombocytopenia and
Is the child cardiovascularly stable or is haemoptysis, and symptoms of pulmonary
urgent intervention required? hypertension. There may be digital clubbing
What is the material embolised? and pleural and pericardial effusions.
What has predisposed to the embolic event? Familial and congenital cases have been
described. HRCT differentiates the
Robert Dinwiddie
Pulmonary haemorrhage can occur at any ,1%. The underlying causes are shown in
age in childhood, from birth through to table 1.
adolescence. The presentation can be acute
or chronic, clinically obvious or covert and The underlying mechanism is thought to be
subtle over a period of time. Presenting due to capillary leakage into the interstitium.
features can vary from the acute and life- Haemorrhagic fluid can also leak directly
threatening to chronic ill health secondary to into the alveolar spaces and then into the
iron deficiency anaemia. The aetiology is small and large airways. Neonatal
best divided into two age groups: neonatal pulmonary haemorrhage has also been
and childhood. associated with the administration of
exogenous surfactant. Other predisposing
Neonatal factors include birth asphyxia, excessive
fluid administration, hypoglycaemia,
Neonatal pulmonary haemorrhage most coagulation defects, intercurrent infection,
commonly occurs in preterm infants hypothermia and cardiac failure.
secondary to severe pulmonary oedema in
association with respiratory distress Frothy haemorrhagic fluid appears through
syndrome and patency of the arterial duct the nose and mouth or via the endotracheal
(patent ductus arteriosus). The incidence is tube. In its most acute form it is associated
with the sudden onset of shock and can be
life-threatening. Chest radiographs show
Key points diffuse interstitial shadowing throughout
both lung fields. Treatment includes the use
of high levels of positive end-expiratory
N Pulmonary haemorrhage can occur at
pressure (PEEP), replacement of blood loss
any age.
but with overall fluid restriction and
N Presentation varies from the acute correction of coagulation deficiencies. If
and life-threatening to hidden, with there is an associated patent ductus
no obvious haemoptysis. arteriosus then this should be closed as
N Many cases are idiopathic but a soon as possible.
number of clear underlying causes Infancy and childhood
can be recognised by selective
investigations. Pulmonary haemorrhage in infancy and
childhood can occur due to a variety of
N Known complications include chronic
causes. They are best divided into those
iron deficiency anaemia and
which result in diffuse or focal areas of
pulmonary fibrosis.
bleeding. These are shown in table 2.
N Systemic corticosteroids are the most Consideration should also be given to the
effective treatment in the majority of possibility that bleeding from the nose or
cases. mouth can be due to other causes, such as
epistaxis or haematemesis.
Chest radiograph Chest radiograph Chest radiograph Chest radiograph Review upper airway
Chest CT Chest CT Chest CT Chest CT Chest radiograph
Bronchoscopy Bronchoscopy Bronchoscopy Bronchoscopy Chest CT
BAL BAL BAL BAL CF screen
Haematology Autoantibodies ECG Virology Non-CF bronchiectasis screen
Immunology screen Echo Bacteriology Ciliary biopsy
Renal function TB screen Factitious
Induced
Figure 1. Algorithm for the diagnosis of pulmonary haemorrhage. BAL: bronchoalveolar lavage; Echo:
echocardiography.
Tobias Ankermann
The term sickle cell disease (SCD) is used to the rheological properties of the erythrocyte
refer to a haemoglobinopathy that results leads to dysfunction in the microcirculation
from a genetic variant giving rise to sickle with vaso-occlusive crises. Vascular
haemoglobin (HbS). This includes the occlusions can occur in almost all organs
homozygote SCD (HbSS, previously named (e.g. skin, lung, liver, spleen, bone, kidney
sickle cell anaemia) and compound and brain). The clinical consequences of this
heterozygote haemoglobinopathies (HbS-b- are acute and chronic pain, hyposplenism
thalassaemias, HbSC disease, etc.). In (or functional asplenia in older children
Europe, ,1300 children will be born with following splenic infraction and splenic
SCD per year. 6070% of these children sequestration) with secondary
suffer from HbSS. immunodeficiency, osteonecrosis,
nephropathy and cerebral infarction. The
HbS-haemoglobinopathies cause a chronic most common causative organisms of
haemolytic anaemia and a disease of the infectious complications following
blood vessels. HbS is caused by a mutation secondary immunodeficiency are
in the b-globin locus on chromosome 11; Streptococcus pneumoniae, Salmonella,
HbSS leads to polymerisation and a loss of Haemophilus influenzae type b, Neisseria
solubility of the haemoglobin during meningitidis and Mycoplasma. In acute chest
deoxygenation. The subsequent change in syndrome (ACS) of infectious origin, the
most commonly identified agents are
atypical bacteria and viruses.
Key points The chronic disease of the vessels results in
priapism, cerebrovascular disease,
N SCD includes HbS- hypercoagulability and inflammation of
haemoglobinopathies, which lead to endothelial structures.
haemoglobin polymerisation with
subsequent vaso-occlusion, a chronic In the lungs and airways, SCD leads to acute
haemolytic anaemia and endothelial manifestations (acute pulmonary vascular
damage in blood vessels, with occlusions, ACS and acute lower respiratory
consequent chronic organ failure. tract infections (LRTIs)), and a chronic lung
N In the lungs and airways, SCD induces disease with lung fibrosis and secondary
acute pulmonary vascular occlusions, pulmonary hypertension with cor
ACS, LRTIs, and chronic lung disease pulmonale. Children with SCD frequently
with lung fibrosis and pulmonary exhibit bronchial hyperresponsiveness and
hypertension. bronchial asthma. The comorbidity of SCD
and asthma is associated with a two-fold
N Important pulmonary comorbidities increased mortality and a reduced life span
of children with SCD are bronchial of patients with asthma and SCD compared
hyperresponsiveness, atopy and to patients with SCD without asthma. The
asthma. role of OSAS is not yet clearly defined.
Pulmonary complications are the most
No
No
Figure 2. Practical approach if criteria for ACS are met in children with SCD. Reproduced and modified
from Miller (2011) with permission from the publisher.
the endothelium and the metabolism of pulmonologist should examine children with
nitric oxide. ACS and asthma are important SCD when they are well on an individual
risk factors for this process. Lung function basis (every 4 months in small children; up
tests in preschool children mostly to 612 months in older children with HbSS
demonstrate an obstructive pattern. A and HbS-b0-thalassemia). Integral parts of
restrictive pattern occurs beginning in the the consultation are:
second decade. In the third decade, there
can be a progressive decline in TLC and N history,
diffusion capacity. CT may show interstitial N recording of room-air oxygen saturation,
lung disease. N lung function testing (according to age,
including diffusion capacity in older
Atopy, asthma and bronchial children),
hyperresponsiveness are important N allergy tests (skin-prick test or specific
comorbidities in children with SCD. The IgE), and
prevalence of asthma in children with SCD is N checking for signs and symptoms of OSA.
between 20% and 48%. Children with SCD
and asthma and/or specific sensitisation If, in asthma, a decline in lung function or a
suffer more frequent and earlier episodes of specific sensitisation is detected, lung
ACS. A possible explanation is the function should be tested every 6 months.
ventilation/perfusion mismatch in asthma
with local tissue hypoxia in the lung Children with abnormal overnight oxygen
following sickling and vaso-occlusion, and saturation (,95%) and/or abnormal lung
the higher incidence of LRTIs in children function test should be screened for OSA,
with atopy and asthma. The paediatric interstitial lung disease and pulmonary
Oxygen
Antibiotics (third-generation cephalosporin (or ampicillin + -lactamase inhibitor)
+ macrolide)
Inhalation with 2-sympathomimetics
Balanced i.v. hydration
Analgesia
Physiotherapy (PEP, incentive spirometry)
Figure 3. Procedure and therapy if criteria for ACS are met in children with SCD. CRP: C-reactive protein;
LDH: lactate dehydrogenase; BUN: blood urea nitrogen; PEP: positive expiratory pressure. Reproduced
and modified from Miller (2011) with permission from the publisher.
hypertension. At present, there is no specific disease and early mortality. With optimal
therapy for chronic lung disease in SCD. care, children with SCD are able to reach the
Asthma in SCD is associated with ACS, sixth decade of life. Without structured care,
faster decline in lung function and mortality, many children will not reach adulthood.
and should therefore be managed based on
established asthma guidelines. In Further reading
childhood, pulmonary hypertension is less
common. Therefore, evidence-based N Colombatti R, et al. (2011). Pulmonary
recommendations for the treatment of hypertension in sickle cell disease chil-
pulmonary hypertension in children with dren under 10 years of age. Br J Haematol;
SCD are lacking. The application of 150: 601609.
sildenafil, bosentan and prostacyclins has N Gladwin MT, et al. (2008). Pulmonary
been reported. complications of sickle cell disease. N
Engl J Med; 359: 22542265.
Course of lung disease in SCD N Kavanagh PL, et al. (2011). Management
of children with sickle cell disease: a
Children with SCD demonstrate a decline in comprehensive review of the literature.
lung function with increasing age, Pediatrics; 128: e1552e1574.
accompanied by decreasing exercise N Knight J, et al. (1999). The lung in sickle
tolerance. The incidence of ACS and cell disease. Pediatr Pulmonol; 28: 205
comorbidity with asthma are important risk 216.
factors for the development of chronic lung
Amalia Schiavetti
Figure 2 Hodgkin lymphoma in 7-year-old boy. a) Anteroposterior and b) lateral chest radiographs
demonstrate a large anterior mediastinal mass lesion.
and the tracheal cross-sectional area seem to infancy and young childhood, the
be the most reliable. General anaesthesia histological subtypes are restricted to
should not be administered to children if the benign teratoma and yolk sac tumour. In
PEFR and tracheal cross-sectional area are adolescence, histological subtypes most
both ,50% predicted. If both are .50% commonly include yolk sac tumour,
pred, general anaesthesia can be seminoma, teratoma and immature
administered safely. teratoma. Seminomas lack serological
markers, whereas non-seminomatous
Treatment After diagnoses and staging
tumours are often associated with increased
evaluation by imaging, chemotherapy is the
serum b-human chorionic gonadotropin or
main component of treatment for childhood
alpha-fetoprotein levels. Adolescents may be
non-Hodgkin lymphoma, while the majority
relatively asymptomatic, whereas infants
of patients with Hodgkin lymphoma are
may have severe respiratory symptoms.
currently managed with combined modality,
Surgical excision is the therapy of choice in
incorporating radiotherapy and
benign tumours such as teratomas.
chemotherapy.
Malignant germ cell tumours are
Germ cell tumours/teratomas chemosensitive tumours.
Andrew Bush
The lung can be affected by systemic disease N An extrapulmonary disease may itself be
in a number of ways, which are not a single-organ disease but the
necessarily mutually exclusive. consequence of that disease (causing
dysfunction of that organ) affects the
N The underlying condition has both lung either through relatively specific
systemic and pulmonary specific (e.g. hepatopulmonary syndrome) or
manifestations, for example ciliopathy, in nonspecific mechanisms (e.g.
which ciliary disease can cause pulmonary oedema secondary to renal
combinations of upper and lower or cardiac failure), or by causing
respiratory disease, complex congenital dysfunction in an another
heart disease, retinitis pigmentosa, and organ.
renal, hepatic and pancreatic cystic N Lung disease or its treatment may affect
disease. Only those diseases not covered another organ and dysfunction of that
elsewhere in this Handbook will be organ may create a positive feedback
discussed in this section. loop, worsening lung disease. An obvious
example is OSA leading to congestive
cardiac failure and secondary pulmonary
Key points
oedema.
N Although individual rare diseases are,
N The treatment of a systemic disorder may
affect the lungs (e.g. chemotherapy with
by definition, rare, taken together,
bleomycin leading to pulmonary fibrosis).
they are sufficiently common that they
need to be considered in paediatric
N Finally, apparent associations that are in
fact artefacts of receiving medical
respiratory differential diagnosis.
attention for another condition must not
N Respiratory paediatricians need to be be confused with real connections
aware that multisystem diseases may between diseases.
present with respiratory signs and
symptoms. This section will give a brief overview of the
lung manifestations of liver, kidney and
N Respiratory paediatricians also need
heart disease; haemoglobinopathy,
to be ready to advise specialists in
excluding sickle cell disease, which is
other fields, especially cardiology,
discussed elsewhere; connective tissue
nephrology and hepatology, about
disorders (both acquired inflammatory (e.g.
respiratory complications of their
systemic lupus erythematosus (SLE)) and
disease specialities.
inherited (e.g. EhlersDanlos syndrome)),
N Ciliary dysfunction, far from being a metabolic diseases and miscellaneous
purely respiratory issue, affects disorders (e.g. familial dysautonomia and
multiple organs. The basic science lymphangiomatosis). Pulmonary
and clinical aspects of ciliopathy are a manifestations of congenital and acquired
huge growth area. immunodeficiencies are discussed
elsewhere.
Contraindications vary between transplant centres and the referring physician should always check with their
own centre. #: multiorgan transplantation (e.g. lungliver, heartlung or lungkidney) may be considered in
this situation.
inflammation, to B4, for severe airway N Many centres use specific therapies like
inflammation). ribavirin for proven cases of lower
respiratory tract infection (LRTI) with
N The clinical relevance of A1 rejection is respiratory syncytial virus (RSV) and
unclear, although frequent A1 episodes paramyxoviruses (e.g. parainfluenza and
have been linked to a greater risk of human metapneumovirus).
chronic graft rejection in adults (Benden N The role of viral infections in acute and
et al., 2010; Hopkins et al., 2004). At chronic refection remains more
present, A1 is not usually treated. controversial (Vu et al., 2011; Liu et al.,
N More severe episodes (A2A4) are 2009), and is particularly relevant in
managed with a 3-day course of high- children given the increased frequency,
dose methylprednisolone (typically particularly in the infantpreschool age
10 mg?kg-1?day-1), though some centres range. Day-care is discouraged,
will occasionally treat A2 rejection with compliance with active immunisation is
oral corticosteroids. critical and prophylactic palivizumab may
N Steroid-resistant rejection is exceptionally be considered in infants.
rare, although true cases may require
second-line therapy such as polyclonal The histological diagnosis of chronic
anti-lymphocyte antibodies (anti- rejection (or bronchiolitis obliterans) is
thymocyte globulin). challenging due to the patchy distribution of
N The clinical relevance of airway disease; therefore, a clinical diagnosis based
inflammation and optimal method of on the pattern of lung function seen following
treatment remains unclear. transplantation has been developed, termed
N Patients with positive bacterial or fungal bronchiolitis obliterans syndrome (BOS)
cultures should be treated. (table 5) (Estenne et al., 2002).
Baseline lung function is defined as the average of the two highest values achieved after transplantation,
recorded o3 weeks apart. FEF2575%: forced expiratory flow at 2575% of FVC. Reproduced and modified from
Estenne et al. (2002) with permission from the publisher.
N BOS is defined by an irreversible fall in spirometry and CT data suggest the lungs
lung function when other causes have continue to grow with age (Cohen et al.,
been excluded, such as infection. 1999).
N Important potential contributing factors
Complications A variety of noninfectious
include gastro-oesophageal reflux disease
complications may be encountered
(GORD) or airway infection (e.g. RSV or
subsequent to lung transplantation
Pseudomonas), and should be treated
(table 6).
aggressively to reverse this dysfunction.
N GORD is common in transplant Early surgical complications, beyond the
recipients (Benden et al., 2005), and immediate post-transplantation period,
emerging data in adults appear to include:
support early surveillance and
fundoplication, although equivalent N bronchial anastomosis stenosis,
paediatric data are lacking. managed with balloon dilatation with or
N Low-dose macrolide therapy appears to without laser treatment (repeated as
be beneficial in those with neutrophilic necessary);
inflammation. N damage to the phrenic nerve affecting
N In general, advanced BOS is poorly diaphragmatic function;
responsive to therapy and interventions N damage to the vagus nerve causing
aim to stabilise and prevent ongoing lung delayed gastric emptying.
function decline. Other BOS therapeutic
options include leukotriene receptor Common later complications include the
antagonists, augmentation of following.
immunosuppression, total body
lymphoid irradiation or photopheresis.
N Hypertension, ,70% at 5 years; typically
managed with calcium channel blockers
N Retransplantation is offered in some
such as amlodipine.
centres but the risks are often increased
due to previous thoracotomy, making
N BOS, ,50% at 5 years.
explantation more challenging, and the N Diabetes mellitus, approximately one-
increased prevalence of other third at 5 years; corticosteroids and CNIs
complications such as renal dysfunction. are major risk factors.
N CNI-induced nephropathy, approximately
Graft monitoring by spirometry is one-third at 5 years; due to the prevalence
challenging in the preschool age range due of renal dysfunction in survivors,
to the cooperation and coordination exposure to other agents associated with
required. Modification of reported indices potential renal toxicity are minimised or
may be required (e.g. FEV0.75 rather than avoided (e.g. nonsteroidal anti-
FEV1). The use of age-appropriate reference inflammatory drugs (NSAIDs),
equations is essential, and longitudinal amphotericin and aminoglycosides).
N Increased malignancy risk due to ongoing around the world. Long-term outcomes are
immunosuppression, with PTLD steadily improving for paediatric patients but
(typically EBV-driven B-cell expansion) have yet to reach those achieved by other
and skin cancers being the most relevant solid-organ transplants. There are many
to the paediatric population; advice about similarities in management between adult and
sunlight exposure is important. paediatric subjects but several differences
N CF children continue to be at risk of unique to the paediatric age range exist.
nonrespiratory complications of their Future work to improve the availability and
underlying disease (e.g. DIOS, allocation of suitable organs will hopefully see
malabsorption and bone disease). this therapeutic option offered to a greater
Long-term outcomes proportion of children who are eligible.
Andreas Jung
Reproduced from Jung et al. (2012) with permission from the publisher.
exercise safely and to significantly improve therefore, exceed the general requirements
their cardiovascular fitness and quality of life of pulmonary rehabilitation programmes.
has been demonstrated. From this Physiotherapists, sports therapists,
perspective it seems logical to subject psychologists, dieticians, diabetologists,
asthmatic patients to exercise training to gastroenterologists, pulmonologists and
increase fitness and strength. Indeed, many other healthcare specialists need to work
rehabilitation centres focus on exercise closely together in a multidisciplinary
interventions with remarkable success on setting. If this aspect is properly addressed,
quality of life and exercise capacity, leading rehabilitation programmes are likely to
to the assumption that exercise training significantly ameliorate the short- and long-
should be part of all asthma rehabilitation term quality of life of affected individuals
programmes. and improve symptom score, pulmonary
function, grade of inflammation and weight.
Cystic fibrosis During the past decades the Exercise and endurance training results in
fear of cross-infection, especially for significant improvements in exercise
Pseudomonas aeruginosa, has determined the tolerance, aerobic fitness, peak work
evolution of rehabilitation programmes for capacity, strength, coordination and
CF patients. To date, rigorous hygiene ventilation parameters. Moreover, clinical
standards addressing disinfection and experience demonstrates a remarkable
segregation (spatial and temporal) are a improvement in treatment adherence after
widely accepted prerequisite to qualify rehabilitation as a result of educational
centres for inpatient CF rehabilitation activities, possibly leading to longer periods
programmes. Still, in the view of potential of mild symptoms and prolonging the time
cross-infections, close contact between the between intravenous antibiotic cycles, thus
CF centres and the rehabilitation clinics is demonstrating the importance of such
advisable to foster mutual trust, minimise programmes in CF care.
risk for the patient and optimise intervention
outcome. To achieve this goal, structured Pre- and post-lung transplantation Published
interventions need to take into account all data on protocols and outcome of
aspects of CF multi-organ disease and, rehabilitation programmes for patients with
Beatrice Oberwaldner
Aircraft cabins are pressurised to 1500 and 6 months of age little is known about
2400 m, resulting in an oxygen tension oxygen saturation levels during flight.
(PO2) of 15 kPa (112 mmHg), which is
The normal physiological compensation to
equivalent to an ambient oxygen level of 15
this hypoxia is an increase in V9E, mostly by
17%. At sea level the alveolar oxygen tension
increasing tidal volume, and a moderate
(PAO2) is ,98 mmHg while at the maximum
tachycardia. A patient with pulmonary disease
cruising altitude the PAO2 drops to
may not be able to increase V9E enough to
55 mmHg, which corresponds to an oxygen
compensate for the fall in PAO2 and their PAO2
saturation of 90%. In healthy passengers
may end up on the steep part of the oxygen
.6 months of age, SpO2 declines to 8994%
dissociation curve resulting in low oxygen
during flight without changes in clinical saturation. Physiological factors such as lower
status, whereas 35% of healthy ex-preterm respiratory system compliance, more
infants flying near term exhibit significant horizontal rib placement, higher airways
desaturation (SpO2 ,85%). Figure 1 shows resistance and fewer alveoli in infants and
the SpO2 for a term and pre-term infant young children mean they are more at risk
during air travel. In infants between birth than adults of developing hypoxaemia in
aircraft. In addition, infants are at risk of even
greater hypoxaemia due to fetal haemoglobin,
increased pulmonary vascular reactivity and
Key points biphasic hypoxic ventilation response.
N Infants and children with chronic lung The aim of this chapter is to highlight the key
disease are at risk of developing points for paediatricians and neonatologists
hypoxia and respiratory symptoms considering the safety of air travel in
during air travel. newborns and young infants. Readers
seeking more detailed information relating to
N The hypoxia challenge test is the the broader changes that occur during air
currently recommended tool for the travel and the most appropriate approach in
identification of at-risk indviduals. older children are directed to the recent
N The hypoxia challenge test does not guidelines from the British Thoracic Society
predict the incidence of in-flight (BTS) on identifying which patients with lung
hypoxia in infants born preterm and disease are at risk during air travel.
travelling by air at near term.
Methods of pre-flight testing for infants and
N The accuracy of the hypoxia challenge children
test in infants and young children has
not been assessed. The hypoxia challenge test was first reported
by Gong et al., (1984) and subsequently
N Further research into the prediction of validated in a variety of adult populations
in-flight hypoxia is required in infants with chronic respiratory disease. The
and young children. primary aim of the hypoxia challenge test is
to identify patients prior to flight who are at
90
SpO2 %
80
70
Ascent commenced Descent commenced
60
23:30 00:00 00:30 01:00 01:30 02:00 02:30
b) 100
90
SpO2 %
80
70
Ascent commenced Oxygen commenced Descent commenced
60
00:30 01:00 01:30 02:00 02:30 03:00 03:30
Flight time
Figure 1. Recording of in-flight SpO2 in a) a 7 month-old term born infant and b) a 9.6 month-old preterm
infant (corrected post-natal age 27 weeks). The red dotted line indicates a SpO2 of 85%. The term infant
maintained their SpO2 above 90% for the majority of the flight. The SpO2 of the preterm infant decreased
to 8590% once cruising altitude was reached and remained stable for approximately half of the flight
before decreasing to ,85%. Supplemental oxygen was commenced at this time for the remainder of the
flight. Reproduced from Withers (2011) with permission from the publisher.
Finally, it is important to underline that Most patients with congenital lung diseases
asthmatic children can be active and (e.g. pulmonary hypoplasia) and other
participate in any sports they choose when conditions such as bronchopulmonary
their asthma is well controlled. dysplasia are relatively sedentary. It is
important to motivate these children to
Exercise-induced anaphylaxis Exercise- increase their fitness level through
induced anaphylaxis (EIAn) is a rare but participation in regular physical activity. In
potentially life-threatening clinical syndrome these subjects it is necessary to perform an
characterised by anaphylaxis concomitant evaluation including an accurate clinical and
with exercise. EIAn may occur independently functional assessment before starting a
of food allergen ingestion or may require the sport to minimise any potential risk.
combined ingestion of sensitising food
before exercise to trigger symptoms. Clinical Clinical exercise testing
features and management do not differ
significantly from other types of anaphylaxis. Cardiopulmonary exercise testing provides a
Therapy includes epinephrine, global assessment of the integrative exercise
antihistamines, and systemic responses involving the pulmonary,
corticosteroids. cardiovascular, and skeletal muscle
systems. The primary cardiovascular
Cystic fibrosis is the most common parameters routinely measured during
hereditary disease in white populations. It is exercise testing are the electrocardiogram,
caused by mutations in the CF heart rate, blood pressure, cardiac output,
transmembrane conductance regulator stroke volume and systemic vascular
(CFTR) gene. resistance. All these parameters are
678
cystic fibrosis 430 allergic crease 35
disease entities 666667 allergic disorders/diseases 339344
evidence 668 asthma and 31
gasliquid pumping 666 diagnostic tests 345348
mechanisms 666 in vitro 346347
neuromuscular disorders 667 in vivo 346347
patients 666667 epidemiology 343
plastic bronchitis 580 history 345346
positioning 666 immunotherapy 383389
primary ciliary dyskinesia 557 molecular diagnosis 347
techniques 666 pathophysiology 339343
airway compression phenotypes 340
cardiovascular causes 335t, 336 physical examination 35
dynamic 7475 prevalence 343
right aortic arch 454 prevention measures 383389
airway endoscopy see bronchoscopy viral infections and 339, 341
airway epithelium see also individual disorders/diseases
cancers 631632 allergic inflammation 27, 340, 341f
pathogen recognition 2022 allergic-like reactions, contrast media 169
as physical barrier 19 allergic march 339
airway hyperresponsiveness, BPD 475 allergic response
airway malacia 267 asthma 318
airway malformations 435444, 436t nasal 354355, 355f
airway obstruction allergic rhinitis 354362
equal pressure point 74f, 75 asthma 360
flexible bronchoscopy indications 135t classification 354, 355356, 356f
foreign body aspiration 566 clinical testing 357358
inspection 53 comorbidities 356, 360361
non-CF bronchiectasis 256 complications 360361
airway remodelling, asthma 316, 319, 342343 physical changes 360
A lines, ultrasound 183, 184f definition 354
alkalaemia 94, 94t diagnosis 354, 356357
alkalosis 94 epidemiology 354
allergen avoidance 383386, 388 food allergy 373
atopic dermatitis 367 health-related consequences 361
allergen challenge tests 347, 386 IgE-mediated allergy 354
allergen exposure 31 intermittent 356, 356f
asthma 302, 318 management 47, 358360, 358f
bronchial hyperresponsiveness 87 asthma severity reduction 359
fetal cells 26 medications 358359
see also individual allergens mechanisms 354355, 355f
allergen-specific immunotherapy see immunotherapy perennial 355356, 357
allergic bronchopulmonary aspergillosis (ABPA) persistent 356, 356f
376382, 405, 610, 612 plant-derived foods, adverse reactions 361
complications 380f, 381 pollen allergy 356
definition 376 prevalence 343
diagnosis 378379, 378t, 379t, 405, 612 seasonal 356
genetics 378 signs 35
management 380381 social problems 357
pathophysiology 377378 symptoms 356, 357
presentation 378, 379f therapeutic strategies 354
prevalence 377 Allergic Rhinitis and its Impact on Asthma (ARIA),
prevention 380 allergic rhinitis classification 356
prognosis 381 allergic salute (nasal salute) 35, 357
screening 380 allergic sensitisation 31, 340
stages 381, 381t prevalence 343, 345
treatment 376, 380, 405 viral infection and 319
complications 381 allergic sensitisation testing 346347
future developments 381 advantages 346t
679
allergic bronchopulmonary aspergillosis 379 idiopathic 349
preschool wheezing 312, 312t IgE-mediated reactions 349
allergy see allergic disorders/diseases immunomodulation 352
alligator shape forceps 148, 149 incidence 349
allokinesis 366 laboratory tests 350
1-antitrypsin deficiency 637t management 350352
-waves, sleep 508, 509f patient positioning 351
alteplase 479 risk reduction 352
alternative therapies, atopic dermatitis 368369 prevalence 343
alveolararterial oxygen tension difference (PA-aO2) reaction time course 350
9596 severity grading 351, 351t
alveolar capillary dysplasia 593 triggers 349, 352
alveolar capillary dysplasia spectrum 604 angiography, vascular malformations 457
alveolarcapillary membrane animal dander allergy 345, 358
diffuse alveolar haemorrhage syndromes 593 anion gap 9697, 97f
lung failure 545 antibiotics
rupture 534 acute chest syndrome 626
alveolar gaswater phases 78 acute otitis media 229
alveolar haemorrhage, BAL 142143, 143f allergic bronchopulmonary aspergillosis 380
alveolar hypoventilation 526 atopic dermatitis 368
Prader-Willi syndrome 524 bronchiolitis 307
alveolar hypoventilation syndromes 521, 523 common cold 227228
secondary 524 community-acquired pneumonia 233, 239, 240
alveolar macrophages 20f, 23 resistance 239
bronchoalveolar lavage 141, 142t cough, acute 47
haemosiderin detection 143, 143f cough, moist/wet 48
pulmonary haemorrhage 620 cystic fibrosis 425426, 430
tuberculosis 285 early disease stages 407408
alveolar pressure (Palv) 73, 74 end-stage lung disease 429430
alveolar volume (VA) restriction assessment 17 intravenous 408409, 429430
alveoli, post-natal development 9, 604 pulmonary exacerbations 409
alveolitis 142, 143f, 143t dyspnoea 56
ambrisentan 606 foreign body aspiration 568
American Academy of Sleep Medicine (AASM) hospital-acquired pneumonia 244, 245t, 246
electroencephalogram recommendations 123125 lung abscess 264265
sleep disorder categories 512513 lung transplantation 650
sleep stages 508 necrotising pneumonia 263
sleep study scoring criteria 517 neuromuscular disorders 496
American College of Chest Physicians (ACCP) non-CF bronchiectasis 255
pneumothorax size guidelines 487 otitis media 227
amiloride 424, 429 otitis media with effusion 229
amino acid toxicity, BPD 468 parapneumonic effusion 260
aminoglycosides 423 plastic bronchitis 579
amniotic fluid, reduced volumes 10 pleural effusion 478, 480
amoxicillin 230, 239 pleural infection 260
amoxicillin-clavulanate 260, 269 pneumomediastinum 490
amphotericin primary ciliary dyskinesia 557
allergic bronchopulmonary aspergillosis 381 protracted bacterial bronchitis 269
cystic fibrosis 430 rhinosinusitis, acute 228
lung transplantation 650 tonsillitis 227, 230
anaesthesia see also individual drugs
foreign body removal 568 antibodies 24
rigid bronchoscopy 159 anticholinergics 323, 579
see also sedation anticoagulation 606, 608
anaphylaxis 349353 antidepressants 508
clinical manifestation 349350 antidiabetic drugs 418
desensitisation protocols 352 antifungals
diagnosis 349350, 350t allergic bronchopulmonary aspergillosis 380381
food allergy 371, 371t cystic fibrosis 430
680
lung transplantation 650 ascites 638
opportunistic fungal infections 250 Askins tumour 635
antigen avoidance, hypersensitivity pneumonitis 616 Aspergillus 218
antigen C 216 hospital-acquired pneumonia 244
antigen detection hypersensitivity reactions 218
bacterial pneumonia 216 opportunistic infections 249250
viruses 215 Aspergillus fumigatus 376, 377t, 430
antigen presentation 26 asphyxiating thoracic dystrophy (Jeune syndrome) 10,
antigen-presenting cells (APCs) 24, 27, 340 500
antihistamines aspiration syndrome 559565
allergic rhinitis 358359 asplenia 554
anaphylaxis 351352 assisted coughing 666
atopic dermatitis 368 asthma 316327
food allergy 374 airway resistance, preschool children 111
anti-IgE see omalizumab allergic 31, 383388
anti-IL-5, asthma 331 allergic rhinitis treatment 359
anti-inflammatories Aspergillus fumigatus lung disease 377t
bronchopulmonary dysplasia 464 atopic dermatitis 367
cystic fibrosis 430 biomass smoke 30
primary ciliary dyskinesia 557 bronchial hyperresponsiveness 88
anti-interleukin antibodies, asthma 331 bronchodilator reversibility 8485
antimicrobial peptides (AMPs) 21, 2223 bronchopulmonary dysplasia versus 476
cystic fibrosis 23 characteristics 316
exuberant inflammation 23 classification 295
antimicrobials clinical control level 320, 321t
hospital-acquired pneumonia 245t definitions 316, 317, 529
resistance 244 diagnosis 34, 293, 317
Pneumocystis jirovecii opportunistic infections 251 dietary interventions 320
antineutrophil cytoplasmic antibody (ANCA) 613 differential diagnosis 334338, 335t
anti-protease therapy, cystic fibrosis 425 early lung function loss 295
antipyretics 227 educational programmes 657
1-antitrypsin deficiency 637t environmental factors/triggers 294, 302303, 662,
antiviral prophylaxis, lung transplantation 650 663t
aortic arch 452 epidemiology 293297, 334
anomalies, prenatal diagnosis 456 socio-cultural factors 294
Apert syndrome 436 epigenome 299302
apical parietal pleurectomy 489 exacerbations 322323, 323t
apnoea 50, 522, 525 exercise intolerance 66t
apnoeahypopnoea index (AHI) 128t, 517, 525 exercise/physical activity 65, 658659, 674675
apnoea index 128t exhaled breath condensate 104
apnoea of prematurity 522, 526 exhaled nitric oxide fraction 101, 102103
appendiceal mucocoele 415416 food allergy 373
appendicitis, acute 415 forced oscillation technique 119120
applied respiratory physiology 1118 future risk to patient 320, 321t
arousal, from sleep 506 geneenvironment interaction 303
arousal index 127 genetics 298304, 301f
arterial blood gas (ABG) analysis 9798 association assessment methods 298299, 300t
acute respiratory failure 540 heritability 298
dyspnoea 54 history 345346
interpretation 94t infantile 108
pitfalls 98 innate-adaptive immune systems interaction 26
reference values 98t lifestyle factors 302
uses 93 long-term prognosis 295296
arterial oxygen saturation (SaO2) 95 prediction scores 296
acute hypoxic respiratory failure 539 management 319323
exercise testing 676 nonpharmacological 319320
arteriovenous malformations (AVM) 196 medical history 317, 318f
aryepiglottic folds 1 migrant studies 294
arytenoid cartilage 1 monitoring 323325
681
inflammation markers 324 as multifactorial disease 363, 364f
morbidity 316 phases 363
multiple-breath washout 115 prevalence 343
natural history 295296 skin pH changes 366
obesity and 529530 therapeutic options 367369
pathogenesis 317319, 340342, 342f atopic march 363, 367
airway inflammation 318319 atopy 87, 311
bronchial obstruction 317 atropine 156157
lung function reductions 319, 342 attention deficit, BDP 471
phenotypes 294295, 317, 329 atypical wheeze 312, 313t
plastic bronchitis 578579 auscultation 3637
prevalence 293294, 316, 343 chronic hypersensitivity pneumonitis 614
problematic/difficult 325326 community-acquired pneumonia 237
protective environments 303 dyspnoea 5354
as public health problem 316 haemothorax 482
rehabilitation programmes 658659 post-lung transplant bronchiolitis obliterans 572
self-management 324325 speech 39
severe 316, 325326, 325t autoimmune disorders 572
management 325326 azithromycin
sex differences 294 asthma 330
sickle cell disease and 625, 627, 628 bronchiolitis obliterans 575
sputum induction 103 bronchopulmonary dysplasia 464
steroid-resistant 640 cystic fibrosis 408, 425
symptoms 317, 318f non-CF bronchiectasis 256
therapy-resistant 325326 azoles 250
time trends 293294 aztreonam 408, 425426, 429
treatment
adherence 320, 322t, 428
aims/goals 316, 320
critical issues 328329
B
Bacille CalmetteGurin (BCG) vaccination 281282
exacerbations 322323 back slaps 568
inhalation therapy 328 bacteraemic pneumococcal pneumonia 223
new/emerging strategies 322, 328333, 329331 bacterial bronchitis with wet cough see protracted
pharmacotherapy 328329 bacterial bronchitis (PBB)
stepwise approach 320322, 322f, 328 bacterial infections
viral infections 341 chronic 207
wheeze 59 chronic bronchitis 211
asthma camps 658 community-acquired pneumonia 234235, 235t
asthma concert 54 empyema 211
Asthma Control Questionnaire (ACQ) 324 hospital-acquired pneumonia 244
Asthma Control Test (ACT) 324 lung abscess 264
ataluren (PTC124) 423, 431 microbiology 215217
atelectasis necrotising pneumonia 263
bronchiolitis 306 see also individual infections/pathogens
ultrasound 186f, 187 bacterial tracheitis 232
athletes bactericidal drugs, tuberculosis 278
competitive 673 BAL see bronchoalveolar lavage (BAL)
exercise intolerance 67 barium oesophagography
atopic dermatitis (AD) 363369 aberrant subclavian artery 457
allergen-induced inflammation 365 double aortic arch 456457
allergic disease link 366367 vascular malformations 456457
asthma risk 367 vascular ring 456, 456f
clinical manifestations 363365 barotrauma 10, 675
diagnosis 363365 barrel-shaped chest 53
epidermal barrier dysfunction 365366 base excess/deficit 96
food allergy 367 base excess of the blood sample (standard base
immunological dysregulation 366367 excess) 96
itch-scratch cycle 366 base excess of the extracellular fluid (actual base
monitoring 363365 excess) 96
682
basiliximab 650 bone mineral density, cystic fibrosis 432
basophils 20 bone (skeletal) tuberculosis 289290
BCG-osis 285 BOOST II study 463
BCG osteomyelitis 290 Bordetella parapertussis 212
beclomethasone dipropionate 320, 359 Bordetella pertussis 212, 231
bedding, house dust mites 384, 385 bosentan 606
behavioural therapy, habit coughing 48 bradypnoea 50
benzodiazepine 157 brain-lung-thyroid syndrome (TTF1 deficiency syn-
benzyl penicillin 239 drome) 592, 598
Bernoulli effect, stridor 5960 brainstem respiratory network 522
Bernoullis principle 59 Brasfield scoring system 163
2-agonists, asthma exacerbations 323 breast milk, BPD 467
-lactam antibiotics, tonsillitis 230 breath-actuated pressurised metered-dose inhalers
Bewitched sign (rabbit nose) 35 200, 202203
Bhalla scoring system 255 breathing, noisy see noisy breathing
BHR see bronchial hyperresponsiveness (BHR) breathing control 89
bicarbonate 95, 96 breathing movements, fetal 5, 7
biomass smoke 3031, 30f breathing patterns, abnormal 50
biopsy breath sounds 37
mediastinal tumours 633 bridging bronchus 443
see also individual techniques British Thoracic Society (BTS)
biopsy forceps 147148, 148f, 149 pneumonia guidelines 236237, 238
Biot breathing 50 pneumothorax guidelines 487, 488
blebectomy, pneumothorax 489 stepwise asthma management guidelines 321
B lines, ultrasound 183, 184f bronchi 2, 2f
bronchiolitis 186f, 187 abnormal 136
bronchopulmonary dysplasia 186 blood supply 2
respiratory distress syndrome 185, 186 gastric content aspiration 560
blood bronchial anastomosis stenosis 653
acute reactants bronchial artery embolisation 623
parapneumonic effusion 259 bronchial asthma see asthma
pleural infection 259 bronchial atresia 443
carbon dioxide measurement 95 bronchial biopsy 146, 147149, 148f
pH 94 complications 148149
blood cultures indications 147
bacterial pneumonia 216 bronchial brushing 146147, 147f
community-acquired pneumonia 238 bronchial challenges 83, 87
parapneumonic effusion 259 bronchial hyperresponsiveness (BHR) 83, 85
blood gas analysis 9399 age-related variations 88
acute respiratory failure 539, 540 air pollution 87
blood sample type 9798 allergic rhinitis 360361
dyspnoea 54 asthma 88, 319, 342
issues 9798 classification 85
systemic hypothermia 98 development mechanisms 319
bloodgas barrier 5 diagnostic significance 88
blood pressure, OSAS 516 environmental conditions, effects of 87
blood transfusion, acute chest syndrome 626 forced oscillation technique 120
B-lymphocytes 24, 249t, 340 measurement 85, 88
BMPR2 (bone morphogenetic protein receptor II) gene respiratory symptoms and 88
mutations 605 respiratory system admittance 120
body mass index (BMI) therapeutic effects 8889
asthma 302 bronchial obstruction, asthma 317
obesity 528 bronchial provocation test (BPT) 8392, 85
bone marrow, eosinophilic lung diseases 611 asthma treatment monitoring 89
bone marrow transplant, bronchiolitis obliterans doseresponse curve 85, 85f
571572 bronchial responsiveness
nonimmunological factors 573 measurement methods 83, 8586
prognosis 576 objective 85
risk factors 572573 subjective 85
683
bronchial smooth muscle tone 83 vasculitis 572
bronchial sound 37 bronchiolitis obliterans organising pneumonia (BOOP)
pneumonia 54 571, 642
bronchial stenosis 444 bronchiolitis obliterans syndrome (BOS) 653
bronchial tree malformations 436t, 440444 breath washouts 116
bronchiectasis 253 gastro-oesophageal reflux in 431432, 560, 653
allergic bronchopulmonary aspergillosis 380, 381 grading 653t
classification 253 post-lung transplantation 652653
cystic fibrosis 403, 429 therapy 653
diagnosis 45, 170 bronchitis
exercise intolerance 67, 68f chronic 209t, 211212
GORD 560 cough 47
imaging 178f, 181 crackles 54
non-CF see non-CF bronchiectasis (NCFB) bronchoalveolar lavage (BAL) 140145, 218219, 406
primary ciliary dyskinesia 551, 552 aliquots calculation 140
bronchioarterial ratio 170 bacterial pneumonia 216
bronchioles 2 bronchiolitis obliterans 574
bronchiolitis 305309 bronchoscopic 140
acute respiratory distress syndrome 535 complications 138, 144
aetiology/risk factors 305 contraindications 144
asthma risk 208 cystic fibrosis 140, 429
definition 207, 305 differential cell counts 142t
diagnosis 306 diffuse alveolar haemorrhage syndromes 593
epidemic 305 diffuse parenchymal lung disease, chronic 141, 143
epidemiology 207208, 305 diffuse parenchymal lung diseases 590
follow-up 309 dyspnoea 55
hospital admission criteria 306 eosinophilic lung diseases 611
incidence 207 fluid preparation 141
infective agents 207, 209t fungal infections 218219
management algorithm 308f galactomannan in fluid 219
natural history 306 hypersensitivity pneumonitis 615
pathophysiology 305306 indications 141144
pharmacological therapy 307 cellular components 142144
prevention 309 microbiology 141142
prognosis 208, 309 mycobacterial infections 217218
prophylaxis 309 nonbronchoscopic 140
risk factors 208 noncellular components 141
supportive therapies 305, 307, 308f opportunistic fungal infections 250
symptoms 305, 306 Pneumocystis jirovecii 251
ultrasound 187 protracted bacterial bronchitis 268
wheeze 59 pulmonary alveolar proteinosis 599
bronchiolitis obliterans 570576 slide preparation 141
autoimmune disorders 572 specimen processing 141
causes 570 technique 140
clinical entities 571572 therapeutic 144
diagnosis 570, 573574 total fluid cell count 141, 142t
epidemiology 570571 tuberculosis 251
gastro-oesophageal reflux 573 bronchocentric granulomatosis 612
graft versus host disease 572 bronchoconstriction, exercise-induced 67
histology 571 bronchodilator(s)
lung transplant survivors see lung transplantation bronchiolitis 305, 307
morbidity 576 bronchiolitis obliterans 575
mortality 576 cystic fibrosis 407
pathology 571 forced oscillation technique 120
post-infectious 570572, 575576 neuromuscular disorders 496
prognosis 575576 preschool wheezing 312313
risk factors 572573 primary ciliary dyskinesia 557
surgical resection 575 wheeze 59
treatment 570, 575 bronchodilator reversibility 8392
684
ERS/ATS Task Force recommendations 84 bronchoscopy
preschool children assessment 84 chronic stridor 61
responsiveness 8385, 84f cystic fibrosis 406, 429
steroid-resistance asthma 84 dyspnoea 55
bronchofibrevideoscope 132 fasting periods 156
bronchogenic cysts 446 flexible see flexible bronchoscopy
bronchography foreign body aspiration 568
non-CF bronchiectasis 255 general anaesthesia 157, 158t
vascular malformations 458459, 458f laryngeal clefts 439, 439f
bronchomalacia 136, 267, 443 local anaesthesia 158
broncho-pleural fistulae 240 lung transplant recipients 651
bronchopneumonia 233 lung tumours 630
bronchopulmonary dysplasia (BPD) 337, 461476 lymphangiomas 584, 584f
aetiology 461463 moderate sedation 157158, 158t
airflow limitations 474 post-procedural care 159
airflow obstruction 475476 premedication 156
asthma versus 476 pre-operative assessment 156
birth weight in 461 pre-operative procedures 156157
catch-up growth 468 protracted bacterial bronchitis 268
characteristics 466 recovery 159
classification 469 rigid see rigid bronchoscopy
clinico-pathological problem 469, 470f rigid telescope use 153154, 154f
definition 337, 472 sedation 156160
diagnostic criteria 461, 463t tracheomalacia 458f
disease burden 469 tuberculosis 218, 276, 276f
energy expenditure 467 vascular malformations 458459, 458f
energy intake 467468 bronchovesicular sound see bronchial sound
forced oscillation technique 120 bronchovideoscope 132
genetics 462 bronchus see bronchi
growth failure 466469 bronchus intermedius 2
incidence 461, 469 budesonide 312, 320
infant plethysmography 109 Burkholderia cepacia 405
infection in 462463
inflammation 462
interrupter technique 111
long-term respiratory outcomes 472476
C
caffeine 307, 464
asthma-like symptoms 475476 calcification 639
COPD phenotype 471, 475 calcineurin inhibitors (CNIs) 649, 651, 652t, 653
imaging anomalies 474 calcium channel antagonists 606
severity lessening 473 Candida 244, 249250
lung function studies 474475 candidate-gene studies, asthma 298299, 300t, 303
management 463464 Cantrell pentalogy 498
morbidity 469, 473 capillary blood 39, 97, 98t
neurodevelopmental assessment 469471 carbachol 508
neurodevelopmental outcomes 469471 carbon dioxide 95
new 461, 462t, 466, 472473 carbon dioxide diffusion capacity (DLCO), obesity 529
nutritional management 466469 carbon monoxide diffusion, dyspnoea 55
post-discharge 468 carcinoid tumour 631
old 462t, 472 cardiac catheterisation 474
pathogenesis 461463 cardiac disease, lung manifestations 640642, 641t
physical activity 675 cardiac dysfunction 640642
prevention 463464 cardiac failure, crackles 38
pulmonary arterial hypertension 473474 cardiac surgery complications 640642
respiratory syncytial virus 221222 cardiovascular disease, OSAS 516
respiratory tract infections 473 -carotene, CF 412
ultrasound 186 cartilage 5
bronchopulmonary malformations (BPMs) 180f, 181 cast bronchitis see plastic bronchitis
bronchopulmonary sequestration (BPS) 450 cat allergens (dander) 356, 385, 662
bronchoscopes, flexible see flexible bronchoscopes cathelicidin (LL-37) 23, 366
685
cathelicidins, atopic dermatitis 366 chest deformities 35
cavitation chest drains
eosinophilic lung diseases 610 chylothorax 481
HPV infection 585586 empyema 261
CCAM volume ratio (CVR) 448 necrotising pneumonia 263
CCR7 24 pleural effusion 479
CD4+ T-cells 24 pleural infection 261
HIV/TB coinfection 286 chest examination 33, 3539
tuberculosis 285 chest excursion 36
CD14 variants 31 chest expansion examination 36
cefotaxime 478 chest pain 5052, 52t, 250
cefuroxime 478 chest radiography 161165, 176
celecoxib 586 acute respiratory failure 541
cell culture see culture allergic bronchopulmonary aspergillosis 378, 379f
cell cycle inhibitors 650 anteriorposterior view 161
centile charts, obesity 528 ARDS 533, 534f
Centor score 230, 230t bronchiolitis 306, 306f
central apnoea 128t, 129f, 517, 518f, 525526 bronchiolitis obliterans 573574
infants 526 bronchopulmonary dysplasia 470f, 474
neonatal period 521 chylothorax 480, 482f
central cyanosis 39 clinical examples 163165, 163f, 164f
central hypoventilation 521 community-acquired pneumonia 233, 237238
central microtubular agenesis 556 cystic fibrosis 163164, 164f, 403405, 405f, 406
central nervous system diffuse parenchymal lung diseases 589590
sleep regulation 506 digital 162
tuberculosis 287288, 287f dose reference values 162163
central sleep apnoea 521527 dyspnoea 54
cephalosporin 239, 260 foreign body aspiration 567
cerebrospinal fluid (CSF), CNS tuberculosis 287 gloved finger appearance 379f
CF see cystic fibrosis (CF) haemothorax 483
CFTR correctors 422 hospital-acquired pneumonia 246
CFTR potentiators and 422423 image quality criteria 162t
CFTR gene/protein 390391 indications 162t
analysis indications 390, 393t isolated tracheo-oesophageal fistula 441
CF-related liver disease 416 lateral projection 161162
F508del mutation 391, 395, 422 lung abscess 264, 264f
function 390391 miliary tuberculosis 288, 288f
G551D mutation 421 necrotising pneumonia 262
low volume hypothesis 402 non-CF bronchiectasis 254255
mutations 391392 opportunistic fungal infections 250
classes 391392, 392f, 395, 421, 422 paediatric intensive care unit 161, 163, 163f
pathophysiology 392393 parapneumonic effusion 258259
pharmacotherapy 421423, 422f pericardial tuberculosis 289
combination treatments 423 pleural effusion 163f, 477, 480
intracellular trafficking 423 pleural infection 258259
structure 390 Pneumocystis jirovecii infection 251
treatment strategies 393 pneumomediastinum 490
CFTR potentiators 421422 pneumonia 163, 163f
CFTR correctors and 422423 pneumothorax 487, 487f
CFTR replacement therapy 423 posterioranterior projection 161
CharcotMarieTooth disease 495t preterm babies 54
charge-coupled devices (CCD), flexible bronchoscopes primary pulmonary hypertension 605
132 pulmonary alveolar proteinosis 599
chemical pleurodesis 482 pulmonary haemorrhage 620
chemokines 21 pulmonary sling 456
chemotherapy role 161
lung tumours 631 shielding 163
tuberculosis 281 spinal tuberculosis 289
chest-clapping 666 technical parameters 162t
686
technique 161163 movements 552
tracheomalacia 441 cilia dyskinesia see primary ciliary dyskinesia (PCD)
tracheo-oesophageal fistula 440 ciliary beat frequency analysis, primary ciliary dyskinesia
tuberculosis 275276, 275f, 276f 555556
abdominal 291 ciliary beat pattern analysis, primary ciliary dyskinesia
immunocompromised child 251 555556
vascular malformations 456 ciliary transposition 556
chest tubes, pleural effusion 479 ciliated cells 551, 555, 556
chest wall 4 ciliopathy 636, 637t, 639t, 641t
congenital defects 497498 circadian cycle 503504
disorders 497502 circadian drive for sleep 504
tumours 635 circadian drive for wakefulness 504
CheyneStokes breathing 50 circadian rhythms 503, 504
Childhood Asthma Control Test (C-ACT) 34, 324 clarithromycin 330
Childhood Asthma Management Program (CAMP) clindamycin 260, 478
study 84, 530 Clinical and Functional Translation of Cystic Fibrosis
Childrens Interstitial Lung Disease (chILD-syndrome) website 428
597 close contact, TB 274
chILD-syndrome (Childrens Interstitial Lung Disease) closed lung regions 534
597 cloxaciline 478
Chlamydia pneumoniae 235236 clubbing 43, 53
chloral hydrate 107 co-amoxiclav 48, 239, 478, 480
chloride 96 coarse (crepitant) crackles 38
depletion 97 Cobb angle 499
chloride channel modulators, CF 424 cockroach allergens 31, 32, 383, 385
chloride responsive alkalosis 97 coeliac disease 416, 642
chloride unresponsive alkalosis 97 colistin 408, 429430
choanal atresia 435436 collectins 21
choanal stenosis 435436 Collins syndrome 436
choking 566, 567 common cold (viral rhinitis) 227228
cholecalciferol (vitamin D3) supplementation, CF 412 common cold virus (rhinovirus) 87, 214, 341
chorioamnionitis 462463 community-acquired pneumonia (CAP) 209, 233241
chronic bronchitis 209t, 211212 acute-phase reactants 238
chronic eosinophilic pneumonia 612 aetiology 234236
chronic lung disease clinical assessment 236237
fitness-to-fly testing 672 comorbidities 237
physical training, benefits 68 complications 239240
chronic lung disease of prematurity see bronchopulmo- definition 208, 233
nary dysplasia (BPD) diagnosis 233, 236237
chronic pulmonary aspiration (CPA) 559 extrapulmonary symptoms 237
gastro-oesophageal reflux 560, 561 importance of 233234
chronic respiratory disorders incidence 234
exercise intolerance 66t, 6768, 68f investigations 237238
physical activity participation 65 microbiology 238
chronic respiratory failure 542544 mortality rate 233234
assessment 543544 prevention 239
causes 543, 543t sampling difficulties 234
cystic fibrosis 406, 543 severity 237
long-term ventilation 542, 544 symptoms 237
neuromuscular disorders 543544 treatment 238239
types 545546, 547f complement 249t
chronic right-sided heart failure (cor pulmonale) 406 complementary therapies, atopic dermatitis 368369
chronic suppurative otitis media 229 complex syndromal thoracovertebral malformations
ChurgStrauss syndrome 610, 613 499501
chylothorax 3, 477, 480482, 481t, 482f compliance 78
ciclesonide 320 volume dependent 78, 79f
cidofovir 250, 585 compliance of respiratory system (CRS) 7880, 79f
cilia 5, 551552, 553f compression, airway clearance therapy 666
beat frequency 552 computed tomography (CT) 166175, 176
687
appendiceal mucocoele 416 computed tomography (CT) angiography 168
bronchiectasis 178f computerised acoustic analysis technology 58
bronchopulmonary dysplasia 474 conductance 81, 81f
children under 4 169170 conductivity measurement, cystic fibrosis 398
congenital cystic adenomatoid malformation 448 congenital abnormalities 335t, 336
contrast media 168169, 172f congenital central hypoventilation syndrome (CCHS)
cystic fibrosis 173, 403 523524, 524f, 526
dual-source scanners 167 congenital cystic adenomatoid malformation (CCAM)
dynamic versus static imaging 171 337, 446449
dyspnoea 54 antenatal resolution 445, 448
empyema 259, 259f bronchopulmonary sequestration versus 450
expiration scans 170171, 171f classification 447448
fan-beam geometry 166 diagnosis 447f, 448
haemothorax 483, 483f antenatal 446, 447f
high-resolution see high-resolution computed embryology 445
tomography (HRCT) hybrid lesions 446
image analysis 173174 incidence 446
image-guided percutaneous biopsy 194 macrocytic 448
image noise 168 microcytic 448
image processing 171173 natural history 449
inspiration scans 170171, 171f pathogenesis 445
intussusception 416 presentation 447f, 448
level of detail required 168 pressure effects 448
lung abscess 264 prognosis indicators 448
lung tumours 630 as space occupying lesions 446, 448
mediastinal mass 179f surgery 449
miliary tuberculosis 288 treatment 448449
movement artefacts 167 antenatal 448
multidetector see multidetector computed asymptomatic lesions 445, 449
tomography (MDCT) wait and see approach 449
necrotising pneumonia 262, 263f tumours and 449
opportunistic fungal infections 250 types 447
pitch value 167168 congenital heart disease 136, 554, 578
pleural effusion 478 congenital high airway obstruction syndrome (CHAOS)
pleural infection 259 437
pneumomediastinum 490 congenital (infantile) lobar emphysema 337
pneumothorax 487 congenital malformations 9
pulmonary embolic disease 607 congenital muscular dystrophy 494t
pulmonary haemorrhage 623f congenital myasthenic syndromes 495t
pulmonary metastases 632, 633f congenital myopathy 494t
radiation 168 congenital pulmonary airway malformation (CPAM) see
reconstruction kernel 172, 172f congenital cystic adenomatoid malformation (CCAM)
reconstruction protocols 172 congenital thoracic malformations (CTMs) 445451
resolution 167168 antenatal diagnosis 446t
scoring systems 173 differential diagnosis 446, 446t
sequential scans 166, 167, 167f embryology 445
spiral/volumetric 166, 167f incidence 445
technology 166167 congenital tuberculosis 273274
tracheal stenosis 442 conjugated pneumococcal vaccines 234235, 239
tracheomalacia 441442 conjunctival allergen challenges 347
trapped air areas 170171, 174 connective tissue disorders (CTD) 591, 643644
tuberculosis 275276 conscious sedation 157158
CNS 288 bronchoscopy 157158, 158t
pericardial 289 consolidation 179f, 181, 611
spinal 289 constrictive bronchiolitis see bronchiolitis obliterans
ultrafast scanners, children under 4 169170 continuous positive airway pressure (CPAP) 548549
volume control 169170 acute respiratory failure 542
spirometer-controlled breathing manoeuvres 170 apnoea 546
volumetric scans 167, 167f automatic modes 548
688
bronchiolitis 307 chronic 4546, 45t, 48
bronchopulmonary dysplasia 463 clinical syndromes 45
devices 548 community-acquired pneumonia 237
follow-up polysomnography 123 defining features 44
hypopnoea 546 environmental tobacco smoke 4647
lung injury 536 foreign body aspiration 567
OSAS 62, 518, 548 history taking 34
starting criteria 548 importance of 44
tracheomalacia 442 management 4748
vented interface 548 neuromuscular disorders 492
contrast enema, appendiceal mucocoele 416 pertussis 231
contrast media reflex pathway 44
adverse reactions 168169, 169t respiratory infections 335
CT 168169, 172f study validity 47
MRI 177 time-period effect 47
controlled laminar airflow treatment 385 tuberculosis 274, 275t
conventional radiography 161165 variants 44
core body temperature (CBT) 504 cough-assist devices
cor pulmonale (chronic right-sided heart failure) 406 cystic fibrosis 430
cortical arousal, sleep 506 plastic bronchitis 580
corticosteroids cough augmentation, neuromuscular disorders
acute chest syndrome 626 493495
acute respiratory distress syndrome 536 cough inexsufflator device 493495
allergic bronchopulmonary aspergillosis 380 cough sound 45
allergic rhinitis 359 cough-variant asthma 34
anaphylaxis 351352 cows milk allergy 621
asthma 321322 cows milk allergy (Heiner syndrome) 343, 371t
exacerbations 323 COX-2 inhibitors 586
atopic dermatitis 368 CPAP see continuous positive airway pressure (CPAP)
bronchiolitis obliterans 575 crackles 38
bronchopulmonary dysplasia 464, 470 bronchitis 54
croup 231 classification 38
cystic fibrosis 408, 430 community-acquired pneumonia 237
diffuse parenchymal lung diseases 593 dyspnoea 54
dyspnoea 56 physical examination 38
extrapulmonary tuberculosis 291 pneumonia 54
food allergy 374 craniofacial anomalies 436
foreign body aspiration 568 OSAS 514515
haemangiomas 583 crepitant (coarse) crackles 38
hypersensitivity pneumonitis 616 crepitations see crackles
as immunosuppression 650 CrispinNorman score 163
inhaled see inhaled corticosteroids (ICS) Crohns disease 416
OSAS 518 croup 53, 231
Pneumocystis jirovecii opportunistic infection 251 causative agents 231
preschool wheezing 313 clinical features 231
pulmonary haemorrhage 623 haemangioma versus 582
response assessment 17 management 56, 231
rhinosinusitis, acute 228 stridor 60, 231
safety 359 Crouzon syndrome 436
tuberculosis 279 CT see computed tomography (CT)
see also individual drugs culture
Corynebacterium diphtheriae 230 bacterial pneumonia 216
coryza 227 fungal infections 218219
co-trimoxazole 251 mycobacterial infections 218
cough 4449 pleural tuberculosis 289
acute 45t, 47 tuberculosis 218
after exercise 34 viruses 215
air pollution 46 cyanosis 3943, 53, 189
causes 4546, 45t, 46t, 47 differential diagnosis 4042t
689
hypoxaemia evaluation 39 pathophysiology 392393
cyclosporine 431 phenotypic features 398t
cysteinyl leukotrienes (cysLTs) 355 physical activity 675
cystic fibrosis (CF) 390434 preschool children 111
adherence 428 prognosis 427434
antibiotic allergy 430 psychosocial factors 428
antimicrobial peptides inactivation 23 pulmonary exacerbations 402, 405, 409, 424
bronchoalveolar lavage 140 pulmonary haemorrhage 623
cardiac manifestations 641t rehabilitation programmes 659
carriers 390, 394t respiratory complications 405
screening 399 respiratory infections 402
challenging 427, 428t screening 397401
chronic respiratory failure 543 family members 399
compassionate ground therapy 431 severe asthma, lessons from 427428
diagnosis 397398, 428 sinus disease 418
emerging pathogens 405 treatment modalities 404t, 407409
end-stage lung disease management early disease stages 407408
extrapulmonary aspects 431434 intermediate disease stages 408409
pulmonary aspects 428431 late disease stages 409
resistant/unusual microorganisms 429 new/innovative therapies 407, 421426, 431
epidemiology 394t, 395396 viral infection 403
epigenetics 395 cystic fibrosis (CF)CT scoring system 173
exhaled nitric oxide fraction measurement 17 Cystic Fibrosis Genetic Analysis Consortium 391
extrahepatic biliary complications 413 cystic fibrosis-related diabetes (CFRD) 411, 417418
extrapulmonary manifestations 410420 cystic fibrosis-related liver disease (CFLD) 416417
forced oscillation technique 120 cystic fibrosis team 406
founder effect genetic drift 391 cystic fibrosis transmembrane conductance regulator
gastrointestinal complications 403, 412416 (CFTR) see CFTR gene/protein
histology 412 cytokines 21, 23, 340
gastro-oesophageal reflux disease 560 cytomegalovirus (CMV) infection
gene therapy 423 immunocompromised children 250251
genetics 390396 lung transplantation 650
modifying factors 395 pneumonitis 250251
genetic testing 393, 393t cytotoxic CD8 T-cells 24
genotypic and phenotypic heterogeneity 393395
imaging 163164, 164f, 173, 180181, 190
incidence 390, 394t
inheritance 390
D
daclizumab 650
kidney manifestations 639t damage-associated molecular patterns (DAMPs) 21
liver manifestations 637t daytime sleepiness 512, 521
long-term oxygen therapy 546 decortication 480
lung disease 402409 deep sleep see slow-wave sleep (SWS)
characteristics 402 defence mechanisms 1928
clinical manifestations 398t, 403406, 404t development 2627
dry and distal 429, 430 defensins 23, 366
early stages 403 -wave (slow wave) activity 510
follow-up 406 -wave sleep see slow-wave sleep (SWS)
management 402, 406407 dendritic cells 1920, 27
pathophysiology 402403, 403f allergen uptake 318, 340341
stages 404t allergic response 340341, 342f
therapeutic goals 407 tuberculosis 285
treatment 404t denufosol (Lancovutide) 424
lung function 403 dermatitis, atopic see atopic dermatitis (AD)
management 427434 dermatomyositis 643
molecular microbiology studies 429 dexamethasone 464
newborn screening 398399, 400f diaphragm 4
nurse-led home visit 428 acute respiratory failure 540
nutrition 410, 660 dysfunction, obesity 529
pancreatic exocrine complications 413 inspiratory movements 51
690
weak/incompetent 1617 dynamic lung volumes 7076, 72t, 73f, 74f
diaphragmatic breathing 497 measurement 7576
diesel exhaust particles 30 obesity 529
diet see nutrition dysphagia, hoarseness 63
dietary fat intake, cystic fibrosis 411 dysphonia (hoarseness) 57, 6263
differential cyanosis 39 dyspnoea 5056
diffuse alveolar haemorrhage syndromes 593 assessment 5256, 53f
diffuse developmental disorders 593 causes 50, 51t
diffuse parenchymal lung diseases (DPLD) 587595 non-respiratory 51t, 56
bronchoalveolar lavage 141, 143 physiological triggers 52
classification 590593 definition 5051
clinical approach 589 differential diagnosis 5256
diagnosis 589590, 592t exercise intolerance 67
specific 590593 history taking 52
syndromes 589590 imaging 5455
examination 589 inspection 5253
exposure-related disease 591592 lung function measurement 55
history 589 management 55f, 56
infancy-specific 593 pathophysiology 5152
long-term oxygen therapy 546 preschool children 312
lung histology 590 dyssomnias 512
lung-restricted 592593
outcome 593594
pathophysiology 588589
prevalence 587588
E
early-onset primary pulmonary hypertension 604
restrictive pattern 17 early onset scoliosis (EOS) 498499, 501
subpleural air cysts 590, 590f early transient wheeze 295
symptoms 589 echocardiography
systemic disease-associated 591592 hepatopulmonary syndrome 638
therapy 587 pericardial tuberculosis 289
treatment strategies 593594 primary pulmonary hypertension 605
future developments 594 pulmonary arterial hypertension 473474
pharmacological therapy 593594 vascular malformations 457
diffusion problems 538 effective specific airway resistance (sReff) 111
digestion, cystic fibrosis 412 effector T-cells 24
digestive tract cancer, cystic fibrosis 416 EhlersDanlos syndrome 643
diphtheria 230231 Eisenmengers syndrome 642
directly observed therapy (DOT) programmes 278, 280 elastance (E) 78
disseminated BCG disease 282 electrocardiography (ECG)
disseminated tuberculosis 272 pericardial tuberculosis 289
distal intestinal obstruction syndrome (DIOS) 415, 650 primary pulmonary hypertension 605
diuretics 468 electroencephalography (EEG)
dog dander 662 polysomnography 123125, 127
doping, sports 674 REM sleep 510511, 511f
double aortic arch 136, 453, 454f, 456457, 459 sleep disordered breathing 525
double-blind, placebo-controlled food challenge stage 1 sleep 508
(DBPCFC) 373 stage 2 sleep 509, 510f
double lung point, ultrasound 184, 184f stage 3 sleep 510, 510f
Down syndrome 436, 531, 641t electrolytes, BPD 468
dry-powder inhalers (DPIs) 198, 203204 electromyogram (EMG) 125, 126
inspiratory flow 199200 infant sleep 511
recommended inhalation manoeuvre 204 electron microscopy, primary ciliary dyskinesia 556
dual-energy X-ray absorptiometry (DEXA) 419 electrooculogram 125
Duchenne muscular dystrophy 492, 493, 494t, 496 emollients 368
chronic respiratory failure 543544 emphysema 174
orthopaedic treatment 501 empty vena cava/empty ventricle syndrome 351
ductus arteriosus 5 empyema 210
Dunedin birth cohort 295 clinical presentation 210, 258
dynamic airway compression 7475 community-acquired pneumonia 239240, 240f
691
diagnosis 217 acute infections 207211
epidemiology 210211 chronic infections 211212
haemothorax complication 483 epigenetic effect, asthma 299
imaging 259, 259f epigenetics
incidence 211, 211f, 258 asthma 299302
infective agents 209t, 210211 cystic fibrosis 395
management 260, 261 epiglottitis 53, 215, 231232
prognosis 211, 262 epinephrine see adrenaline
risk factors 211 episodic viral wheeze (EVW) 294, 295, 311312
surgery 261 epithelial lung cancers 631632
empyema thoracis see empyema equal pressure point 7475, 74f
endobronchial biopsy see bronchial biopsy ergocalciferol (vitamin D2) supplementation, CF 412
endoscopy room equipment 157 erythromycin 47, 231
flexible bronchoscopy 133 etanercept 330, 594
endothelin-1 606 ethambutol
endothelin receptors 606 adverse effects 252
endotracheal intubation, flexible bronchoscopy 158 toxicity 279
endotracheal tubes, hospital-acquired pneumonia risk tuberculosis 278, 279t, 280t
243 extrapulmonary 290t
end-tidal carbon dioxide (PetCO2) 125 immunocompromised child 251252
endurance athletes 86 eucapnic voluntary hyperpnoea (EVH) 86
endurance training 667 European Society of Paediatric Gastroenterology, Hepa-
enteral feeding 411, 467 tology and Nutrition (ESPGHAN), BPD guidelines
environmental determinants, respiratory health/disease energy intake 467
2932 lipid intake 468
environmental exposures protein intake 468
adverse effects 2931 EVLP (Ex vivo Lung Perfusion) programmes 433
genetic factors and 3132 Ewings sarcoma 635
genetic susceptibility 29 excessive daytime sleepiness (EDS) 516, 524
hypersensitivity pneumonitis 614 exercise-induced anaphylaxis 66t, 67, 675
pregnancy 26 exercise-induced arrhythmias 674
primary ciliary dyskinesia 557 exercise-induced asthma (EIA) 65, 66t, 674675
protective effects 29, 31 cardiac dysfunction 640
environmental history 35 diagnosis 675
environmental tobacco smoke (ETS) 2930 differential diagnosis 8687
asthma 302, 303, 319, 663 mechanisms 674
bronchial hyperresponsiveness 87 obesity 530
cough 4647 exercise-induced bronchoconstriction (EIB) 65, 66t,
exposure reduction 663664, 663t 86, 87, 89
genetic factors and 3132 exercise-induced vocal cord dysfunction (EIVCD)
post-natal exposure 29 6667, 66t, 87
in pregnancy 29 exercise intolerance 6569, 66t
protracted bacterial bronchitis risk factor 267 dysfunctional breathing 66t, 6768
enzyme linked immunospot assay, TB 275 exercise/physical activity
eosinophilic alveolitis 143f, 143t airway clearance therapy 666
eosinophilic lung diseases 593, 610613 asthma 658659, 674675
classification 610 benefits 68
diagnosis 610611 bronchial responsiveness 8788
drug-induced 613 bronchopulmonary dysplasia 475, 675
histopathology 611 chronic pulmonary diseases 674675
known cause 612613 congenital lung diseases 675
laboratory testing 610611 cystic fibrosis 408, 675
of unknown cause 611 definition 673
eosinophilic oesophagitis 371t plastic bronchitis 580
eosinophils 20 prescription 676
allergic rhinitis 355 primary ciliary dyskinesia 557
asthma 324 risks of 674
bronchoalveolar lavage 141, 142t weight control 660661
epidemiology 207213 exercise testing 8687, 675676
692
cardiopulmonary 676
cardiovascular 675676
exercise-induced asthma 675
F
face masks
sensitivity 86 flexible bronchoscopy 158, 159f
exercise tolerance, adolescent idiopathic scoliosis 499 noninvasive ventilation 548
exhalation 60f facial examination 35
stridor 60 facioscapulohumeral muscular dystrophy 494t
exhaled breath analysis 104 faecal elastase-1 test 411
exhaled breath condensate (EBC) 104, 105 failure to thrive, 515
exhaled nitric oxide fraction (FeNO) 100103, 105 false vocal cords 1
advantages/limitations 102 familial dysautonomia (RileyDay syndrome) 523,
allergic rhinitis 361 644645
asthma 101, 102103, 324 familial pulmonary hypertension 605
bronchopulmonary dysplasia 476 family history 35
clinical applications 101103 farmers lung 614, 616
clinical studies 102 farming lifestyle 31, 302303
equipment 17, 100, 101f fat-soluble vitamins 413t
factor affecting 101 cystic fibrosis 410, 412
increased 100, 101 feeding problems 496
infants 101 bronchopulmonary dysplasia 467
inflammation assessment 17 Fel d 1 allergen 662, 663t
low values 101 female athlete triad 674
methodology 101 fenestrated cup forceps 147148, 148f
normal values, age-dependent increase 101, 102f FeNO analysers 100, 101f
preschool children 101 fetal breathing movements 5, 7
procedure 17 absence 910
spirometry versus 102 fetal cells, allergen exposure 26
exocrine pancreatic insufficiency (EPI) 410, 411, 413 fetal haemoglobin 39
exon skipping 395 fetal lung fluid 5
expansion thoracoplasty 501 fetal MRI 181
expiration 7273 fetal ultrasound, vascular malformations 456
newborns 80 18F-FDG-PET 190
693
prevention measures 132, 138 food-dependent exercise-induced anaphylaxis (FDEIA)
dyspnoea 55 67, 371t
equipment 132133 food-induced anaphylaxis 370
extrinsic obstructions 136 food-induced asthma 371t, 373
foreign body removal 568 food-induced rhinitis 371t, 373
general anaesthesia 159 forced expiration 72, 73
indications 132, 134, 135t flowvolume loops 74f, 75
inflammation 136 volumetime relationship 73f
information provided 134136 forced expiratory flow at 25-75% of FVC (FEF2575%)
lower airways 135136 bronchiolitis obliterans 573
upper airway 134135 bronchopulmonary dysplasia survivors 475
intrinsic obstructions 136 forced expiratory flow at x% of FVC (FEFx) 72t
isolated tracheo-oesophageal fistula 441 forced expiratory volume in 1 s (FEV1) 72t, 73f
moderate sedation 159 asthma monitoring 324
neonatal ICUs 137 bronchodilator reversibility 83
paediatric ICUs 136137, 137t bronchopulmonary dysplasia 474
procedure 134, 134f chronic respiratory failure 543
protracted bacterial bronchitis 268 lung transplantation 648
rigid bronchoscopy versus 152 obesity 529
secretions 136 obstructive respiratory disease 14
sedation 156 forced expiratory volume in 1 s /forced vital capacity
stridor 61, 132, 134 (FEV1/FVC) ratio
tolerance 137138 bronchopulmonary dysplasia survivors 475
tracheal stenosis 442 obstructive respiratory disease 14
floor coverings 384385 forced expiratory volume in x second(s) (FEVx) 72t
flowvolume loop 1112, 13f forced oscillation technique (FOT) 85, 118121
forced expiration 74f, 75 asthma 119120
obstructive respiratory disease 1415 bronchial hyperresponsiveness 120
restrictive diseases 16, 16f bronchodilator response 120
flucoxaciline 478 bronchopulmonary dysplasia 120
fluid dynamic flutter theory 38 clinical utility 119120, 119f
fluid restriction, BPD 463, 464, 467 cystic fibrosis 120
flumazenil 157 frequency dependence 119
fluoroscopy 164f, 165 future directions 120121
foreign body aspiration 164f, 165 oscillation frequency 118
hyperinflation, regional 164f repeatability 118119
indications 161, 162t respiratory mechanics 120
transbronchial lung biopsy 149, 149f theoretical background 118, 119f
fluticasone 320, 359, 368 wheeze 119120
foam mattresses 384t, 385 in young children 118119
Fontan procedure complications 642 forced vital capacity (FVC) 72t
food allergens acute respiratory failure 541
anaphylaxis 349 obesity 529
avoidance 373, 383 obstructive respiratory disease 14
cross-reactivity 370 foreign body aspiration 566569
immunotherapy 352 aetiology 566
food allergy 370375 complications 568569
anti-IgE monoclonal antibodies 374 cough 47
atopic dermatitis 367 epidemiology 566567
diagnosis 372373 fluoroscopy 164f, 165
emergency action plan 373374 history 567
prevalence 343, 370371 investigations 190, 567568
quality-of-life disruption 374 misdiagnosis 567
resolution natural history 370 mortality rates 568569
respiratory disease and 373 partial airway obstruction 567
symptoms 370, 371372, 372t predisposing factors 566
tolerance 370 presentation 567
treatment 373374 removal 152, 153f, 568
food challenges 347, 373 stridor 60
694
treatment 568 gastrostomy, cystic fibrosis 411, 431
wheeze 54, 59, 335t, 336 Gaucher disease 637t, 644
foscarnet 250 gel phase 552
fosfomycin 429 geneenvironment interaction 29, 32
fossil fuels 30 asthma 303
friction, resistance due to 80 wheezing disorders 303
friction rub (pleural friction sound) 39 geneenvironment-wide interaction studies (GEWIS),
functional residual capacity (FRC) 70, 71f, 71t asthma 303
age-related changes 7879 general anaesthesia
calculation, from helium dilution 1314 bronchoscopy 157, 158t
compliance 78 flexible bronchoscopy 159
diffuse parenchymal lung diseases 590 inhalational agents 157
inert-gas washout 114115 interventional radiology 193
newborns 7980 genetic diseases, dyspnoea 335t, 336
obesity 529 genome-wide association study (GWAS)
sleep 546 asthma 299, 300t, 301f
functional residual capacity by plethysmography environmental exposures 3031
(FRCpleth) 12, 108 gentamicin 423
functional residual capacity-multiple-breath washouts geometric standard deviation (GSD)
(FRC-MBW) 75 aerosol particles 199
functional shunts 79 dry-powder inhalers 204
fundoplication 564 germ cell tumours 634
fungal infections gibbus 289
hospital-acquired pneumonia 244 Global Initiative for Asthma (GINA) guidelines 320, 321,
lung abscess 264 321t, 324
microbiology 218219 glomerulonephritis 230, 639t
nucleic acid detection 219 glottic haemangiomas 582
opportunistic 249250 glue ear (otitis media with effusion) 229, 360
glutathione, inhaled 425
G
GABRIEL Consortium 299
glycated haemoglobin (HbA1c) 418
glycopeptide 260
GM-CSF-receptor- mutations 598, 599
galactomannan assay 219 Gohn focus 272
galanin 507 Goldenhar syndrome 436
gallstones 413 Golde score 620
-aminobutyric acid (GABA) 506, 507 Goodpastures syndrome 621, 623, 639t
T-cells 20 graft versus host disease 572, 575
ganciclovir 250 Gram staining, bacterial pneumonia 216
gas exchange measurement, polysomnography 525 granulations 136
gas exchanging cells 5, 7 granulocyte-macrophage colony-stimulating factor
Gastrografin (sodium meglumine diatrizoate) 414, 415 (GM-CSF) 596597, 598
gastrointestinal disease 642 granulocytes 20
gastrojejunal feeding 564 granulomas 611
gastrojejunostomy 564 granulomatosis with polyangiitis (Wegners) 639t,
gastro-oesophageal reflux (GOR) 643644
bronchiolitis obliterans 573 granulomatous diseases 591
chronic pulmonary aspiration 559 grommets 229
cystic fibrosis 414, 431432 group B -haemolytic streptococci (GBS) 216
diagnosis 414 grunting 58t, 62
hoarseness 63 GSDMB-ORMDL3 locus 299
management 414 guaifenesin 408
respiratory manifestations 559565 GuillainBarr syndrome 16
gastro-oesophageal reflux disease (GORD) 335t, 336,
559
chronic pulmonary aspiration 560
cystic fibrosis 560
H
H1-antihistamines, allergic rhinitis 358, 359
prevalence 560 H2 receptor antagonists 243
respiratory manifestations 560 habit (psychogenic) coughing 48
transplant recipients 653 haemangiomas 582583
695
haematopoietic malignancies 611 bronchopulmonary dysplasia 474
haematopoietic stem-cell transplantation (HSCT) chronic hypersensitivity pneumonitis 615
bronchiolitis obliterans 571 crazy paving pattern 599
graft versus host disease 575 cystic fibrosis 429
haemodialysis 639640 diffuse parenchymal lung diseases 590, 590f
haemodynamic collapse, haemothorax 483 non-CF bronchiectasis 254255
haemoglobin, cyanosis 39 Pneumocystis jirovecii infection 251
haemoglobinopathies 642643 primary ciliary dyskinesia 557558
Haemophilus influenzae 209, 209t protracted bacterial bronchitis 268
chronic bronchitis 211 pulmonary alveolar proteinosis 599
cystic fibrosis 408 subacute hypersensitivity pneumonitis 615
protracted bacterial bronchitis 266 surfactant protein-C deficiency 597, 598f
sinusitis 215 tuberculosis 275276
Haemophilus influenzae type B (Hib) high-sensitivity C-reactive protein (hsCRP), OSAS 516
community-acquired pneumonia 235, 235t hila (hilum) 12
epiglottitis 231 hilar lymphadenopathy, TB 275, 276f
invasive diseases 237 histamine 88, 350, 354355
haemoptysis histamine receptors 366
cystic fibrosis 196, 196f, 405 histone acetylases (HATs) 330331
idiopathic pulmonary haemorrhage 621 histone deacetylases (HDACs) 330331
pulmonary haemorrhage 620 history 3343
haemothorax 477, 482483, 483f environmental 35
HagenPoiseuille equation 80 family 35
Haller index 498 medical see medical history
hamartomas 632 social 35
Hammans syndrome (spontaneous pneumomediasti- HIV
num) 489490 post-TB exposure prophylaxis 281
hay fever 35 testing, tuberculosis patients 277
head and neck palpation 36 tuberculosis coinfection 280281, 285286
head box use 541 HIV-associated anergy 286
Heads paradoxical reflex 89 hoarseness (dysphonia) 57, 6263
heart-lung transplant 647 Hodgkin lymphoma 632, 633, 634, 634f
heel prick test, cystic fibrosis 398 home oxygen therapy 545550
height graphs 3435 home ventilatory support 545550
Heimlich manoeuvre 568 respiratory physiotherapy 667668
Heiner syndrome (cows milk allergy) 343, 371t, 621 honey medications 47
heliox 307 Hoover sign 36
helium dilution 1314 hospital-acquired (nosocomial) infections 242
helminth infestation 286 hospital-acquired pneumonia (HAP) 209, 242247
hemithoraces, asymmetry 36 aetiology 244245
HenochSchnlein purpura 639t definition 242
heparin 579, 608 diagnosis 246
hepatopulmonary syndrome (HPS) 637, 638 post-surgical patients 243244
hepatorenal syndrome 638 prevention 245
heptavalent polysaccharideprotein conjugate vaccine risk factors 242, 243244
(PCV7) 223, 224 sampling techniques 246
hereditary haemorrhagic telangiectasia 593, 605 surveillance 246
HeringBreuer reflex 8 treatment 245t, 246
heritable coagulopathies 608 house dust mite (HDM) allergen 358
heterotaxy (situs ambiguus) 553554 allergic rhinitis 356, 357
HiB vaccine 239 asthma 302
high-affinity receptor for IgE (FCRI) 340 atopic dermatitis 367
high-arched (ogival) palate, OSAS 515 avoidance 384385, 662, 663t
high-efficiency particulate air (HEPA) 385, 663664 multifacet intervention 385
high flow oxygen, acute respiratory failure 542 no documented effect 384, 384t
high-frequency oscillatory ventilation (HFOV) 536 recommendations 384, 384t
high-resolution computed tomography (HRCT) particle size 383
allergic bronchopulmonary aspergillosis 380 reduction 320
bronchiolitis obliterans 574, 574f HRCT see high-resolution computed tomography
696
(HRCT) acute respiratory failure 540
H-type fistula (isolated tracheo-oesophageal fistula) dialysis-induced 640
440441 hypoventilation syndromes 521527
human bocavirus 214 hypovolaemic shock 483
human coronaviruses 214 hypoxaemia
human metapneumovirus (MPV) 214 bronchiolitis 306
human neutrophil peptides (HNP-1) 23 differential diagnosis 4042t
human papilloma viruses 584586 flexible bronchoscopy induced 138
vaccination 586 hepatopulmonary syndrome 638
humoral immune system 24 hypersensitivity pneumonitis 616
Hunter syndrome 644 hypoxia
Hurler syndrome 644 acute respiratory failure 540
hyaline membrane disease see respiratory distress in-flight 670, 671
syndrome (RDS) hypoxia challenge test, fitness-to-fly 670672
hydrocortisone 464 hysteresis 78
hydrogen cyanide 104
hydrogen peroxide 104
hydroxychloroquine 594
5-hydroxytryptamine (serotonin), sleep 507
I
iatrogenic (traumatic) pneumothorax 485, 486t, 488
hygiene hypothesis 31 ibuprofen 408
hyperbilirubinaemia, neonatal 417 idiopathic hypereosinophilic syndrome 612
hyperinflation idiopathic pulmonary haemorrhage (IPH) 620,
fluoroscopy 164f, 165 621624
tuberculosis 275 iloprost 606
hyperkinesis 366 image-guided percutaneous biopsy 194, 195f, 196f
hyperoxia 546547 image-guided percutaneous drainage 193, 194196,
bronchopulmonary dysplasia 462 195f
hyperpnoea 50 fibrinolytic therapy and 195
hypersensitivity pneumonitis 591, 610, 613616 image-guided percutaneous thermoablation 194
acute 614, 615 immune hypersensitivity reactions, TB 272
chronic 614, 615 immune programming 26
acute exacerbation 614 immune reconstitution syndrome (paradoxical
clinical features 614 reaction) 279
diagnosis 614616 immune regulation 25
environmental exposures 614 coexisting, non-harmful 26
histology 615 immune response inflammatory syndrome (IRIS)
incidence 613614 280281
lung function 615616 immunisation 221226
lymphocytosis 615 healthcare workers 245
occupational exposures 614 primary ciliary dyskinesia 557
predictors 615 immunoassays, virus detection 215
prevalence 613614 immunochromatographic membrane test 260
subacute 614, 615 immunodeficiency
treatment 616 Aspergillus fumigatus lung disease 377t
hypersomnia 512 lung involvement 248252
hypertonic saline non-CF bronchiectasis 253, 254f
bronchiolitis 307 opportunistic infections 248252
cystic fibrosis 407, 423424, 430 protracted bacterial bronchitis risk factor 267
sputum induction 103 tuberculosis 284292
hyperventilation 50, 95 immunofluorescent microscopy 556
hypnogram 126, 126f immunoglobulin A (IgA) 25
hypnotics 507 immunoglobulin E (IgE)
hypocarbia 54 allergic bronchopulmonary aspergillosis 378, 380,
hyponychial angle 43 612
hypopnoea 50, 128t, 130t, 517, 518f, 525 allergic inflammation 340
hypopnoea index 128t asthma 318
hypothalamicpituitaryadrenal (HPA) axis, corticoster- immunoglobulin G (IgG) 25
oids and 359 immunoglobulin M (IgM) 24, 25
hypoventilation 50 immunological memory 25
697
immunological testing, protracted bacterial bronchitis foreign body aspiration 566
268 pulmonary function tests 107, 108109
immunology 1928 see also newborns
immunomodulation, anaphylaxis 352 infantile larynx see laryngomalacia
immunoreactive trypsinogen (IRT) 398399 infantile (congenital) lobar hyperinflation 337
Immuno Solid phase Allergen Chip microarray 347 infant plethysmography 108109
immunosuppression Infant Study of Inhaled Saline in Cystic Fibrosis (ISIS)
lung transplantation 647, 649650 108, 109
drug interactions 652t infected emboli 607
malignancy risk 654 infection see respiratory infection(s)
side-effects 651, 651t infection control measures, hospital-acquired pneu-
opportunistic infections 639 monia 245
pulmonary haemorrhage 623 inflammation
surfactant protein-C deficiency 597 allergic 27, 340, 341f
tuberculosis 286 assessment 1718
immunotherapy asthma 318319
allergic asthma 386388 flexible bronchoscopy 136
anti-IgE therapy and 383, 387388 noninvasive tests 100106
indications 386t, 387 OSAS 515
allergic disorders 383389 inflammatory bowel disease 642
allergic rhinitis 359360 inflammatory myofibroblastic tumour (inflammatory
dust mite allergy 360 pseudotumour) 631
efficacy 386, 386t inflammatory pseudotumour (inflammatory myofibrob-
perennial allergens 386 lastic tumour) 631
pollen allergy 360 infliximab 575
seasonal and perennial allergens 386387 influenza viruses 214, 578
systemic side-effects 387, 387t, 388 inhalation 60f
impulse oscillation system (IOS) 118 stridor 5960
inactivity 674 inhalational agents
incipient respiratory failure 544 conscious sedation 157158
increased work of breathing 36 general anaesthesia 157
indoor air pollution 3031 inhaled corticosteroids (ICS)
asthma 302 allergic bronchopulmonary aspergillosis 381
prevention 662664, 663t asthma 320321, 328
induced sputum see sputum induction bronchial hyperresponsiveness 8889
inducible NOS (iNOS) 100 bronchiolitis obliterans 575
industrial pollution 267 bronchopulmonary dysplasia 464
inert-gas washout (IGW) 113 chronic cough 48
anatomical background 113 cystic fibrosis 408
clinical applications 114116 episodic viral wheeze 312
clinical utility 115116 exercise-induced bronchoconstriction 89
cystic fibrosis 113 exhaled nitric oxide fraction reduction 102103
evolution 113114 multiple-trigger wheeze 311, 312
future directions 116 non-CF bronchiectasis 255
normative data 114115 preschool wheezing 310, 312, 313
open questions 116 as maintenance treatment 313314
physiological background 113 primary ciliary dyskinesia 557
infant(s) protracted bacterial bronchitis 269
airway collapse 8182 innate immune system 1923
anaphylaxis 349350 adaptive immune system, interaction with 19, 26
asthma severity 325t allergic response 340
atopic dermatitis 364 antimicrobial factors 20f, 2223
cystic fibrosis cell types 1920, 20f
energy requirement 410 phagocytic defence enhancement 23
infant plethysmography 109 inner-city asthma 31
raised volume rapid thoracic compression 108 inner dynein arm (IDA) 552, 553f
respiratory infections 402 innominate artery, anomalous 136
signs/symptoms 398t insomnia 507, 512
exhaled nitric oxide fraction 101 inspiration 72
698
respiratory mechanics 77 extrapulmonary 290t
inspiratory capacity (IC) 71f, 71t HIV coinfection 281
inspiratory reserve volume (IRV) 71f, 71t immunocompromised child 251252
insulin deficiency, cystic fibrosis 431 as preventive therapy 281
insulin treatment, CF-related diabetes 418 recently infected children 281
interarytenoid cartilage 1 resistance 280
intercostal chest catheter (ICC) insertion 8-isoprostane 104
pneumothorax 488489 isotope imaging methods 189192
triangle of safety 488, 489f imaging equipment/acquisition 191
intercostal muscles 4 indications 189190
interferon regulatory factors (IRFs) 21 patient preparation 190191
interferon- release assays (IGRAs) 214 itching (pruritus), atopic dermatitis 363, 366
tuberculosis 217, 274275 itraconazole 380, 650
interictal epileptiform discharges (IEDs) 516 ivacaftor
interleukin(s), allergic response 340 approval 421
interleukin-5 (IL-5), asthma 328, 331 cystic fibrosis 407, 421, 426, 431
interleukin 31 heterodimeric receptor (IL-31R) 366 VX-809 and 423
intermittent hypoxia 522
International Plastic Bronchitis Registry 579, 580
International Study of Asthma and Allergies in Child-
hood (ISAAC) 293294
J
JarchoLevin syndrome (spondylocostal dysostosis)
International Study of Asthma and Allergy phase I-III 500501
343 jet nebulisers 201202
interrupter resistance (Rint), preschool children 110, 111 Jeune syndrome (asphyxiating thoracic dystrophy) 10,
interrupter technique 8485 500
preschool children 110111, 110f joint flexures, atopic dermatitis 363364
interstitial lung disease (ILD) see diffuse parenchymal joint tuberculosis 272, 273
lung diseases (DPLD)
interval training 676
interventional endoscopy 151155
anaesthesia 159
K
Kalydeco see ivacaftor
interventional radiology 193197 Kartageners syndrome (situs inversus totalis) 553554
consent 193 Kawasaki disease 643
post-procedural follow-up 193 K-complex, stage 2 sleep 509, 510f
pre-procedural planning 193 KCO restriction assessment 17
sedation 193 ketamine 157, 158t
intestinal current measurement, cystic fibrosis 398 kidney disease, lung manifestations 638640, 639t
intraalveolar pressure (PA) 77 Kommerell diverticulum 454, 455f, 459
intrapleural pressure (Ppleur) 77 Kussmaul breathing 50
intubation
acute respiratory failure 542
hospital-acquired pneumonia risk 243
intussusception 416
L
-lactam antibiotics, tonsillitis 230
invasive bacterial diseases (IPDs) 223 lactoferrin 23
invasive pulmonary aspergillosis 218, 219 laminar flow 80
invasive pulmonary capillary haemangiomatosis Lancovutide (denufosol) 424
608609 Langerhans cell histiocytosis 143, 487, 487f, 630635
iodides 408 Langerhans cells 143, 367
ion channel function modulators 424 language skills delay, BPD 471
ipratropium bromide 84 large airway obstruction, flowvolume loop 15, 15f
IQ, bronchopulmonary dysplasia 471 laryngeal atresia 436437
iron overload 642 laryngeal cleft 439440, 439f
irritant avoidance, atopic dermatitis 367 classification 439, 439t
ischaemiareperfusion injury 572 laryngeal cysts 438439
isolated congenital scoliosis 498499 laryngeal haemangiomas 582
isolated tracheo-oesophageal fistula (H-type fistula) laryngeal infections 231
440441 laryngeal masks 158, 159f
isomerism 136 laryngeal obstruction, foreign body aspiration 567
isoniazid, tuberculosis 278, 279t, 280t laryngeal polyp 15f
699
laryngeal webs 437 flexible bronchoscopy 135136
laryngocele 439 obstruction 136
laryngomalacia 335t, 336, 437438 resistance 8182
complications 438 lower respiratory tract infections
diagnosis 438, 438f bacterial, microbiology testing 215217
flexible bronchoscopy 134 biomass smoke 31
stridor 6061, 336, 438 hospital-acquired 243, 246
types 438, 438t pneumonia and 233
laryngoscopy 63, 438, 438f low volume hypothesis 402
laryngotracheobronchitis see croup lumbar hump 499
laryngo-tracheo-oesophageal cleft see laryngeal cleft lumbar puncture, CNS tuberculosis 287
laryngotracheoscopy 582, 583f, 585, 585f lung(s) 1
larynx 1, 2f anatomical subdivisions 3t
airway malformations 436440 at birth 604
resistance 81 development 46, 445
laser surgery 152, 583, 585 factors affecting 910, 9t
latent class analysis, asthma 295 genetic factors 9
latent tuberculosis infection (LTBI) 217, 281, 282 intrauterine 46, 78
late-onset wheeze 295 post-natal 9
LavyMoseley syndrome (spondylothoracic dysostosis) signaling pathways 6
500501 elastic properties 77
law of Laplace 78 gastric content microaspiration prevention 560
learning problems, OSAS 516 immune defences 248, 249t
left main bronchus 2, 136 innate immunity 19, 20f
left ventricle, OSAS 516 initial mechanical barrier 19
leptin 515516, 530 lymphatic drainage 3
leukaemia 632 mechanical barriers 248
leukotriene (LT)B4 antagonist 430 renal medication side-effects 639
leukotriene modifiers 320 topographic anomalies 443
leukotriene receptor antagonists (LTRA) 320321, 355 ultrasonic anatomy 183, 184f
lidocaine 158 lung abscess 240, 263265
limb girdle muscular dystrophies 496 lung agenesis/aplasia 136
limb movements, polysomnography 126, 127 lung allocation score (LAS) 649
lingual tonsil enlargement, obesity 530 lung biopsy
linkage studies, asthma 298, 300t bronchiolitis obliterans 573
lipid intake, BPD 467468 ChurgStrauss syndrome 613
lipid-laden macrophage index (LLMI) 144, 561562 diffuse parenchymal lung diseases 590
lipid-laden macrophages (LLMs) 561, 561f dyspnoea 55
lipoid pneumonia, chronic 143144, 144f eosinophilic lung diseases 611
liposomal amphotericin B 430 pulmonary haemorrhage 620621
liver disease, lung manifestations 637638, 637t surfactant dysfunction mutations 597
liver dysfunction 637638 lung bud 4
liver enzymes 417 lung clearance index (LCI) 14, 75
liver transplantation 638 bronchiolitis obliterans 573
living-related lobar lung transplantation 649 calculation 113, 114
LL-37 (cathelicidin) 23, 366 cystic fibrosis 115
lobar atelectasis, cystic fibrosis 405 normative data 114
lobar pneumonia 233, 234f variability 114115
lobectomy 557 lung compliance (CL) 78, 79f
local anaesthesia 158, 193 age, influence of 7880
Lffler syndrome (simple pulmonary eosinophilia) obesity 528
593, 611 lung contusions 482
long-acting 2-agonists (LABA) 320321 lung failure 545
long face syndrome 360 lung fibrosis 589
long-term oxygen therapy (LTOT) 546547 lung function tests see pulmonary function tests (PFTs)
long-term ventilation 542 lung growth 910, 9t
low birth-weight babies 9 lung injury 533537
lower respiratory tract 14 causes 535, 536t
abnormal distribution 136 insult during development 535
700
secondary 534 lymph node tuberculosis 287
two-hit model 534535 lymphocytes
lung sounds 37 bronchoalveolar lavage 141, 142t
dyspnoea 54 phenotyping, hypereosinophilia 611
lung transplantation 647655 see also individual types
acute cellular rejection 572 lymphocytic alveolitis 143t
anti-infective prophylaxis 650 lymphoma 190, 632, 633634, 634f
bridging measures 649 lymph vessel development 5
bronchiolitis obliterans 571, 572 lysinuric protein intolerance 600
nonimmunological factors 573 lysozyme 23
prognosis 576
risk factors 572
complications 653654, 654t
contraindications 649t
M
macrolides
cystic fibrosis 402, 409, 427434, 432434, 647 asthma 330
contraindications 432, 433434 bronchiolitis obliterans syndrome 653
list for transplant timing 432433 diffuse parenchymal lung diseases 594
patient care whilst waiting 434 pertussis 231
post-operative care 650 plastic bronchitis 579
referral 432, 432t macrophages 19
diffuse parenchymal lung diseases 594 alveolar see alveolar macrophages
donor allocation 648649 magnesium sulphate 323
donor organ lack 433 magnetic resonance imaging (MRI) 176182
early post-transplant period 649 advantages 176, 181
graft rejection 651653 anatomic abnormalities 181
grading 651652 balanced steady-state free precession sequence 177
indications 647, 648t bronchiectasis 181
induction therapy 650 CNS tuberculosis 288
listing criteria 648 congenital thoracic malformations 446
long-term outcomes 654 consolidation 179f, 181
marginal donors 648 contrast media 177
non-CF bronchiectasis 256 cystic fibrosis 180181
ongoing management 650654 diffusion-weighted imaging 177
post-transplant management 647 drawbacks 177
primary ciliary dyskinesia 557 dyspnoea 54
quality of life 648 features 180181
referral 648 haemangiomas 582
management following 649650 indications 180181
rehabilitation programmes 659660 lung infections 178f, 180
retransplantation 653 lung tumours 630
selection for 647648 lymphangiomas 584, 584f
steroid-resistant rejection 652 mediastinal mass 179f
survival rates 654 miliary tuberculosis 288
tuberculosis 286 neoplasm 181
lung tumours 630632 non-CF bronchiectasis 255
benign 632 patient compliance 177
malignant 631632 pneumonia 178f, 180, 181f
metastatic 632 pulmonary infiltrates 180
primary 630631 regular imaging 178f, 180
surgery 631 respiratory phase control 177
systemic disease, secondary involvement 632 single-shot fast spin echo sequence 177
see also individual tumours spinal tuberculosis 289
lung volume spoiled gradient echo (3D gradient-echo) sequence
increases through childhood 9 177
measurements 1214 technical problems 176
lymphangiomas 582, 583584, 584f techniques 176177
lymphangiomatosis 645 tracheal stenosis 442
lymphatic abnormalities, plastic bronchitis 578 tracheomalacia 441442
lymph node biopsy 287 tuberculous arthritis 290
701
vascular malformations 457458 metabolic acidosis 94t, 96
magnetic resonance imaging (MRI) perfusion 177 anion gap 9697
magnetic resonance imaging (MRI) ventilation 177179 metabolic alkalosis 94t, 96, 97
major basic protein (MBP) 355 compensatory response 94t, 97
malnutrition 286, 431 metabolic disorders 96
mannitol 86, 424, 430 compensation for 93, 94t
Mantoux test 274 diffuse parenchymal lung diseases in 591
Marfans syndrome 643 metabolic equivalent (METs) 676
mass median aerodynamic diameter (MMAD) 199, 204 metabolomics 104
mast cells 20, 354 methacholine 8586, 85f, 88, 89, 573
maternal-fetal tolerance, paternal allo-antigens 2627 methicillin-resistant Staphylococcus aureus (MRSA) 244
maternal malnutrition 9 methylprednisolone 380, 430, 575, 593594
maternal smoking 10 methylxanthine compounds 526
mattress encasings 384, 384t microarray testing, allergy 347
maximal expiratory flow at x% of FVC (MEFx) 72t microbiology 214220
maximal midexpiratory flow (MMEF) 72t microliths 143
maximum intensity projection (MIP), CT 172, 172f microorganism recognition 21
McLeods syndrome 573574 microscopy
Mclsaac score 230, 230t bacterial infections 215, 216
MDCT see multidetector computed tomography fungal infections 218219
(MDCT) midazolam 157, 158t, 191
mechanical ventilation middle ear otitis 360
adverse effects on lungs 469 miliary tuberculosis 272, 273, 282, 288, 288f
alveoli, effects on 534 milk protein intolerance 416
closed lung regions 534 minimum intensity projection (MinIP) 172173, 173f
evaluation, polysomnography 123 mini-thoracotomy 261262, 480
meconium ileus 414 mitochondrial myopathy 495t
meconium plug syndrome 414 mitogen-activated protein kinase (MAPK) 21
median sternotomy 484 mixed acidbase disorders 93
mediastinal lymphadenopathy, TB 275, 275f mixed apnoea 128t, 517, 518f, 526
mediastinal lymph nodes 4, 272 moderate sedation, flexible bronchoscopy 159
mediastinal mass 179f moist cough 48
mediastinal tumours 633634 Moli 1901 (lancovutide) 424
anterior mediastinum 633 mometasone 320
germ cell 634 monkey trap phenomenon 568
posterior mediastinum 633, 634 monoclonal antibody therapy 322, 650
mediastinitis 483484 monophonic wheeze 59
mediastinum 1, 34 montelukast
lymphatic drainage 3 bronchiolitis obliterans 575
medical history 3335 episodic viral wheeze 311
age of onset, symptoms 3435 preschool wheezing 310, 312, 314
chief complaint 3435 Moraxella catarrhalis 209, 209t, 211, 215, 266
past 3435 Morquios syndrome 644
symptoms seasonality 34 mosaic attenuation pattern, CT 170
medication history 34 mould avoidance 386, 663, 663t
melatonin 503, 504 mouse exposure 386
Melbourne Asthma Study 295 MRI see magnetic resonance imaging (MRI)
membranous glomerulonephritis 607, 639t mucoepidermoid carcinoma 631
memory B-cells 25 mucopolysaccharidoses 637t, 641t, 644
Memory Encoding theory, sleep 504 mucosa examination 136
memory performance, BPD 471 mucosal immune system 25
memory T-cells 25 mucus hydrators, cystic fibrosis 423424
menarche, early, asthma 302 mucus plugging, plastic bronchitis versus 577
Mendelian susceptibility to mycobacterial diseases mucus plug removal 144
(MSMD) 285 multichannel intraluminal impedance and pH (MII-pH)
meniscus sign 259, 259f, 477 monitoring 563
meperidine 157, 158t multichannel intraluminal impedance (MII) monitoring
mesenchymal hamartomas, chest wall 635 563
mesh nebulisers 202 multidetector computed tomography (MDCT)
702
double aortic arch 454f nasopharyngeal airway malformations 435436, 436t
pulmonary sling 457f nasopharyngeal prongs 158
right aortic arch 455f National Institutes of Health (NIH) BPD diagnostic
scanners 167 criteria 462, 463t
vascular malformations 454f, 455f, 457458, 457f natural killer cells 20
multidrug-resistant tuberculosis (MDR-TB) 252, 280, nebulisers 200202
291 advantages/disadvantages 201
multilobular cirrhosis (MLC) 416 drugs used 200
multiple-breath washout (MBW) 113117 recommended fill volume 201
bronchiolitis obliterans syndrome 116 types 201202
bronchopulmonary dysplasia 116 necrotising pneumonia 262263
clinical utility 115116 needle aspiration, pneumothorax 488489
cystic fibrosis 115 neonatal hyperbilirubinaemia 417
functional residual capacity 75 neonatal intensive care units (NICU)
future directions/open questions 116 early life challenges 466
outcome parameter 113 energy consumption 466
parameters 114 health, effects on 469470
static lung volumes 75 hospital-acquired pneumonia 242, 243
technique 114, 115f neurodevelopment outcomes 469470
multiple-trigger wheeze (MTW) 294, 295, 311312 neonates
multi-slice spiral computed tomography 166167 cystic fibrosis signs/symptoms 398t
muscle fatigue 540 grunting 62
muscle sounds 37 see also newborns
mycobacterial infections 217218, 245 neuroendocrine cell hyperplasia of infancy 593
Mycobacterium abscessus 429 neurological disease 641t
Mycobacterium tuberculosis neuromuscular disorders 492496
gastric aspirates 217 acute respiratory complications 495496
hospital-acquired pneumonia 245 bulbar involvement 493
immune responses to 284285 chronic respiratory failure 543544
interferon- responses 284 long-term assisted ventilation 493
PCR 218 orthopaedic treatment 501
pleural infection 260 other systems/complications 496
mycophenolate mofetil 651t palliative care 496
Mycoplasma pneumoniae 209, 209t, 235236, 235t, 263 pathophysiology assessment 492493
Mycoplasma tuberculosis 270272, 273 prevalence 492
myeloid differentiation primary response gene 88 respiratory complications 494495t
(MyD88)-in/dependent pathways 21 sleep disordered breathing 524525
myocardial tuberculosis 289 surgical interventions, intercurrent 495496
myotonic dystrophy 495t neutropenic sepsis 244
neutrophilic alveolitis 143t
N
nanoduct sweat analysing system 397, 399f
neutrophils 20, 249t
bronchoalveolar lavage 141, 142t
protracted bacterial bronchitis 267
napkin ring cartilages 442 recruitment 23
nasal airway, choanal stenosis/atresia 436 newborns
nasal allergen challenges 347, 358 chest radiography 161
nasal cannulas 541, 548 expiration 80
nasal crease 357 FRC upregulation 7980
nasal mask 548 sleep 511512
nasal mucosa examination 35 tuberculosis 274
nasal-oral airflow measurement 125 see also infant(s)
nasal passages examination 35 next-generation sequencing, asthma 300t
nasal polyps 35 NiemannPick disease 600, 637t, 644
nasal potential difference, cystic fibrosis 398 nitric oxide
nasal prongs 548 acute respiratory distress syndrome 536
nasal salute (allergic salute) 35, 357 bronchopulmonary dysplasia 464
nasogastric feeding 307, 411, 564 conscious sedation 157158
nasogastric tubes, hospital-acquired pneumonia risk nitric oxide scrubber 101
243 nitric oxide synthases (NOS) 100
703
nitrogen analyser 13 REM sleep versus 505t
nitrogen multiple-breath washout 113114, 115f, 116 slow-wave activity 506
BPD 116 stages 503, 508
nitrogen washout 13, 14, 113114 nuclear factor (NF)-B 21, 462
NIV see noninvasive ventilation (NIV) nucleotide-binding oligomerisation domain (NOD)
NKX2-1 gene mutation 597 proteins 21
nocturnal hypoventilation 546 nutrition 660661
noisy breathing 5764 asthma 302
causes 57, 58t bronchiolitis obliterans 575
non-CF bronchiectasis (NCFB) 253257 bronchopulmonary dysplasia 463, 464
aetiology 253254 cystic fibrosis 410411, 431
diagnosis 254 neuromuscular disorders 493
epidemiology 253 plastic bronchitis 580
idiopathic cases 253 nutritional deficiencies, TB 286
imaging 254255 nystatin 650
immunodeficiency 253, 254f
inpatient treatment 256
microbiology 254
pathophysiology 253
o
obesity 528532
prevalence 253 assessment methods 528
prognosis 256 asthma 302, 319320, 529530
pulmonary function 255 chronic inflammation 530
sleep disturbances 256 definition 528
surgery 256 exercise intolerance 66t, 68
symptoms 254 lung function in 528529, 529t
treatment 255 OSAS 515, 530531
non-Hodgkin lymphoma 632, 633, 634f prevalence 528
noninvasive positive-pressure ventilation (NIPPV), prevention 660661
BPD 463 obesity-associated syndromes 531
noninvasive pressure support, acute respiratory failure obesity hypoventilation syndrome (Pickwickian syn-
541542 drome) 531
delivery methods 541542 Objective-SCORAD (O-SCORAD) 365
mechanisms 541 obstructive alveolar hypoventilation 517
noninvasive ventilation (NIV) 545550 obstructive apnoea 128t, 129f, 514, 518f, 526, 530531
aims 547 scoring criteria 517
bronchopulmonary dysplasia 463 obstructive apnoeahypopnoea index 128, 128t
chronic alveolar hypoventilation 548 obstructive apnoea index 128t
cystic fibrosis 430431 obstructive disorders 11, 12f
Duchenne muscular dystrophy 493 assessment 1415
at home 547548 expiratory flowvolume loop 14
indications 547 obstructive sleep apnoea syndrome (OSAS) see OSAS
interface 548 octreotide 481482
lung injury 536 oesophageal atresia 440
modes 547, 548 oesophageal pH measurement
neuromuscular disorders 493, 496 gastro-oesophageal reflux disease 563
spinal muscular atrophy 493 polysomnography 126
starting criteria 547 oesophageal pressure monitoring 125
target values 547 oesophageal reflux 496
ventilators 547 oesophageal studies 562f, 563, 563f
non-rapid eye movement (NREM) sleep see NREM omalizumab
sleep allergic asthma 383, 388
nontuberculous mycobacteria 429 allergic bronchopulmonary aspergillosis 381
Noonans syndrome 641t asthma 322, 328, 329330, 331
nosocomial (hospital-acquired) infections 242 costs 329330
NREM-REM cycles 508 oncomycosis 250
NREM sleep Ondines curse (congenital central hypoventilation
central nervous system regulation 507 syndrome) 523524, 524f, 526
infants 511 open-lung biopsy 250, 607
neurochemistry 507 opportunistic infections 248252
704
Optiflow system 542 cystic fibrosis 409, 430431
oral appliances, OSAS 518 in-flight 672
oral glucose tolerance test (OGTT) 418 pneumothorax 488
oral immunotherapy (OIT), food allergy 374 primary pulmonary hypertension 606
oral nutritional supplements, cystic fibrosis 411 pulmonary arterial hypertension 474
orphan drug therapies, cystic fibrosis 393 respiratory failure 545545
orthodontic abnormalities, OSAS 514515 oxyhaemoglobin dissociation curve 95f
orthodontic treatment, OSAS 518
OSAS 61, 514520
associated conditions 514, 515t
cardiovascular complications 516
P
PaCO2 94t, 95
clinical examination 62 paediatric intensive care unit (PICU)
comorbidities 515516 asthma exacerbations 323
definition 514 bronchiolitis 306307
diagnosis 61, 514517, 519f chest radiography 161, 163, 163f
history 6162 hospital-acquired pneumonia 243
as inflammatory condition 515 post-cardiac surgery 640
learning problems 516 ventilator-associated pneumonia 242, 243
mild 128 paediatric lung imaging 176179
moderate 128 palatal plates 436
obesity 530531 palivizumab
pathogenesis 514515 bronchiolitis 309
as polygenic disease 514 national guidelines 222
polysomnography 122123, 517 respiratory syncytial virus 221222, 309
predisposing conditions 531 palliative care, neuromuscular disorders 496
prevalence 514 pancreatic enzyme replacement therapy (PERT)
risk factors 62 cystic fibrosis 411412
severe 128 fibrosing colonopathy and 411, 415
signs/symptoms 6162, 514515, 515t pancreatic exocrine complications, cystic fibrosis 413
treatment 517518, 519f pancreatitis, acute 642
indications 128131 PaO2 95
upper airway collapsibility 514 PaO2/inspiratory oxygen fraction (FiO2) 95
osteopenia 432 PaO2/PAO2 ratio 96
osteoporosis, CF-associated 418419 papillomas 584586
osteosarcoma 632 papillomatosis 63, 582, 585f
otitis media with effusion (glue ear) 229, 360 paradoxical breathing 5152
outdoor air pollution paradoxical reaction (immune reconstitution syn-
asthma 302 drome) 279
prevention 662664, 663t parainfluenza viruses 214
outer dynein arm (IDA) 552, 553f parapneumonic effusion (PPE) 258, 260
ovalbumin allergy 367 acute reactants 259
OX40 ligand (OX40L) 378 imaging 258259, 259f
oxidative stress, OSAS 516 parapneumonic pleural effusion 477, 478
oximetry see pulse oximetry parasites 612613
oxygenation adequacy assessment 9596 parasomnias 511, 512
oxygen concentrator 547 parenteral nutrition 467, 481
oxygen desaturation, flexible bronchoscopy-induced paroxysmal activity, OSAS 516
138 partial pressure of inspired oxygen (PiO2), acute
oxygen dissociation curve (ODC) 538539, 539f respiratory failure 541
oxygen-enhanced MRI 177 particulate matter (PM) 30, 267
oxygen saturation exposure reduction 663t, 664
exercise testing 676 patent ductus arteriosus (PDA) 463
polysomnography 125, 127 pathogen-associated molecular patterns (PAMPs) 21
oxygen supplementation/therapy patient education 657
acute respiratory failure 541 pattern recognition molecules (PRR) 21
asthma exacerbations 323 PCO2 54
bronchiolitis 307 PCR
bronchopulmonary dysplasia 473 Aspergillus 219
community-acquired pneumonia 238239 bacterial pneumonia 216
705
community-acquired pneumonia 238 treatment planning 665
fungal infection 219 physostigmine 508
pleural infection 259 Pickwickian syndrome (obesity hypoventilation syn-
pneumonia 209 drome) 531
tuberculosis 218 PierreRobin sequence 436
virus detection 215 pig bronchus (tracheal bronchus) 136, 443
PCV10 vaccine 223, 224 pilocarpine iontophoresis 397
PCV13 vaccine 223, 224 pimecrolimus 368
peak expiratory flow 72t pineal body 504
peanut allergy 367 placebo effect, cough 47
pectus carinatum 498 plasma cell granuloma 631
pectus excavatum 498 plastic bronchitis 577581, 642
pentamidine 251 diagnosis 577578, 578f
pepsin 144, 561, 562 disease associations 578579, 579t
percussion 36 mucus plugging versus 577
dyspnoea 5354 therapy 579580, 580t
peribronchial thickening 255 plethysmography see whole body plethysmography
pericardial tuberculosis 289 pleurae, lymphatic drainage 3
pericardiocentesis 289 pleural drain, pleural effusion 478479
periodic breathing 128t, 526 pleural effusion 259f, 477480
periodic leg movement index 127 aetiology 477
peripheral cyanosis (acrocyanosis) 39 chylothorax 480, 482f
peripheral eosinophilia 611 clinical picture 477
peritoneal dialysis 640 community-acquired pneumonia 239
peritonsillar abscess 229230 diagnosis 477478
persistent fetal circulation 604 follow-up 480
persistent wheeze 295 imaging 163f, 477478, 478f
pertussis (whooping cough) 212, 231 intrauterine 10
pertussis vaccination 212 long-term outcome 480
pest avoidance 385386 management 478480
pet allergens necrotising pneumonia 262
avoidance 320, 385, 385t, 662 peritoneal dialysis 640
particle size 383 physical examination 477
Pfeiffer syndrome 436 pleural tuberculosis 288
pH 9495 pneumonia 477
asthma 104 renal disease 638639
phalangeal depth ratio inversion 43 surgery 479480
pharyngitis 215, 229231 yellow nail syndrome 645
phosphodiesterase-5 inhibitors 606 pleural fluid analysis
phototherapy 369 chylothorax 480
PHOX2B gene 523524 pleural infection 260
phthalates 30 pleural tuberculosis 289
physical activity see exercise/physical activity pleural friction sound (friction rub) 39
physical examination 3343 pleural infection 258262
physical fitness 673 diagnosis 258
exercise intolerance 66t, 68 imaging 258259
physiotherapy 665669 laboratory findings 259260
aims 665 management 260
cystic fibrosis 407, 430, 650 microbiology 260
evidence 668 prognosis 262
group events 668 stages 258262
neuromuscular disorders 493495 surgery 261
organisational aspects 668669 treatment 260262
primary ciliary dyskinesia 557 pleural line, ultrasound 186
principles 665 pleural space, adhesion forces 7778
protracted bacterial bronchitis 269 pleural tuberculosis 288289
rehabilitation 667 pleural tumours 635
technology-dependent child management 667668 pleuritic chest pain 250
training 668669 pleurodesis 482
706
pleuroperitoneal shunt 482 polyethylene glycol (PEG) lavage 415
pleuropulmonary blastoma (PPB) 631 polymorphisms, cystic fibrosis 395
pneumatoceles 240, 240f, 262, 478 polymorphonuclear leukocytes (PMLs) 23
pneumococcal pneumonia 223224 polyphonic wheeze 59
23-valent pneumococcal polysaccharide vaccine polysomnography (PSG) 122131
(PPV23) 223 arousal summary 127
pneumococcal vaccination 210, 223224 body position measurement 126
Pneumocystis carinii see Pneumocystis jirovecii carbon dioxide
Pneumocystis carinii pneumonia (PCP) 251 interpretation 127
Pneumocystis jirovecii measurement 125126
hospital-acquired pneumonia 244245 components 123, 124f, 124t
opportunistic infections 251 congenital central hypoventilation syndrome 523
pneumomediastinum 489490, 489f, 490t cystic fibrosis 431
pneumonia first night effect 123
acute respiratory distress syndrome 535 gas exchange 127
aetiology 215216 interpretation 126128
atypical 209 heart rate/rhythm 127
biomass smoke 31 sleep architecture components 126127
bronchial sounds 54 manual scoring 123
bronchoalveolar lavage 141142 normal values 128131, 130t
classifications 208209 OSAS 62, 122123, 517
community-acquired see community-acquired obesity and 531
pneumonia (CAP) pre-operative 122
crackles 38, 54 respiratory effort measurement 125
definition 208209, 233 respiratory events 127128, 128t, 525526
epidemiology 208210 respiratory indications 122123
gastro-oesophageal reflux disease 560 setting 123
hospital-associated see hospital-acquired sleep disordered breathing 525526
pneumonia (HAP) sleep stage analysis 126, 126f
imaging 163, 163f, 178f, 180, 181f, 186f, 187188, 187f study timing 126
incidence 209210, 210f technique 123
infective agents 209, 209t, 215216 treatment indications 128131
nonspecific laboratory evaluations 216217 treatment response assessment 122123
overdiagnosis 233 polysplenia 554
pleural effusion 477 Pompe disease 495t
prognosis 210 portal hypertension (PHT) 416, 417
radiological 209 posaconazole 381, 430
risk factors 210 positional cloning, asthma 298, 300t
tachypnoea 52 positive airway pressure, foreign body removal 568
typical 209 positive end-expiratory pressure (PEEP)
pneumothorax 485489 acute respiratory distress syndrome 535536
bronchial biopsy complication 148149 lung recruitment 534535
classification 485 tracheomalacia 442
cystic fibrosis 406, 486, 487f positive expiratory pressure (PEP) 666
epidemiology 485 positive pressure devices 431
imaging 187, 487488, 487f positive pressure in pleural space (Ppl) 73, 74
large 487 positive pressure ventilation
observation 488 biotrauma 534
pathogenesis 485486 bronchopulmonary dysplasia 462
physical examination 486487 cardiovascular system, effects on 542
recurrence 489 positron emission tomography (PET), sleep deprivation
size calculation 487488 512
suction 489 post-bronchoalveolar lavage fever 132, 138, 144
surgical management 489 post-cardiac surgical whiteout 640642
symptoms 486487 post-infectious cough 47, 48
therapy 488489 post-nasal drip syndrome 47
Poland syndrome (sequence) 497498 post-transplant lymphoproliferative disease (PTLD)
pollen allergy 345, 356, 383 650
pollenfood syndromes 361 potassium depletion 97
707
Potters syndrome 639t inflight SpO2 670, 671f
Potts disease 289 neurodevelopment outcome 469470
Prader-Willi syndrome 524, 531 bronchopulmonary dysplasia 470471
preacinar region 2 respiratory distress syndrome 54
prebiotics 374 respiratory support advances 469
pre-Botzinger complex 522 surfactant deficient 7
prednisolone/prednisone primary ciliary dyskinesia (PCD) 551558
allergic bronchopulmonary aspergillosis 380 as associated diagnosis 554555
allergic rhinitis 359 bronchial brushing 147
asthma exacerbations 323 bronchiectasis 551, 552
ChurgStrauss syndrome 613 carrier status 552
cystic fibrosis 430 clinical aspects 552555, 555t
diffuse parenchymal lung diseases 593 diagnosis 551, 554, 555556
extrapulmonary tuberculosis 291 ear symptoms 553
farmers lung 616 environmental exposures 557
graft versus host disease 575 exhaled nitric oxide fraction measurement 17
pulmonary haemorrhage 623 genetics 552, 556
side-effects 651t genetic testing 556
tuberculosis 279 infertility 554
pregnancy inheritance 552, 554t
cystic fibrosis 411 lower airway disease 552
environmental pollution exposure 26 outpatient follow-up 557558
history taking 35 prevalence 551
innate-adaptive immune systems interaction 26 respiratory treatment 556557
smoking during 10, 29 screening tests 555
tuberculosis 273 surgery 557
premature stop codons (PTCs) 423 ultrastructural defects 551
premature stop codons (PTCs) suppressors 423 upper airway symptoms 553
premedication, bronchoscopy 156 primary graft dysfunction/failure 572, 650
preschool children primary progressive tuberculosis 272
asthma severity 325t primary pulmonary hypertension (PPH) 605607, 605t
pulmonary function tests see pulmonary function novel therapies 606607
tests (PFTs) primary pulmonary vascular disease 604609
preschool wheeze/wheezing 310315 primary spontaneous pneumothorax (PSP) 485
acute episode treatment 312313 primitive aortic arch 452
birth cohort studies 310 probiotics 368, 374
classification 311, 312, 312t process C, sleep 504506
diagnostic approach 312 process S interactions 505506
epidemiology 310311 process S, sleep 506
maintenance treatment 313314, 314t process C interactions 505506
nonpharmacological 313 prone positioning, ARDS 536
outcome prediction 311 propofol 157, 158t, 159
pathophysiology 310 propranolol 583, 583f
persistence to school age 311 prostacyclin 606
phenotype distinction limitations 311312 prostaglandins 355
treatment failure 314, 314t protective ventilation 534535
typical wheeze 312 acute respiratory distress syndrome 534536
Preservation Theory of sleep 504 protein hydrolysate formulas 410
pressure-controlled ventilation (PCV) technique 169 protein intake, BPD 467468
pressure in the airway lumen (Pintrabronch) 74 proton pump inhibitors (PPIs) 563564
pressurised metered-dose inhalers (pMDIs) 200, protracted bacterial bronchitis (PBB) 34, 266269
202203 aetiology 266
breathing manoeuvre 202203 diagnosis 268
pressurised metered-dose inhalers/valved holding differential diagnosis 266
chamber (pMDI/VHC) 198, 200, 202203 epidemiology 266
preterm babies/infants management 269
health, effects on 469470 pathogenesis 267
imaging 54 prognosis 269
infant plethysmography 109 relapse 269
708
risk factors 266267 pulmonary haemorrhage 619624
symptoms 267268 aetiology 619, 620t, 621t
vaccination, impact of 266 childhood 619, 621t
provocative concentration causing a 20% fall in FEV1 clinical presentation 620
(PC20) 8586, 85f cystic fibrosis 623
provocative dose causing a 20% fall in FEV1 (PD20) diagnostic workup 620, 622, 622f
8586 differential diagnosis 621t
pruritus (itching), atopic dermatitis 363, 366 diffuse 621623
Pseudomonas aeruginosa focal 623
cystic fibrosis 408, 425 histopathology 620621
non-CF bronchiectasis 254 imaging 620
primary ciliary dyskinesia 557 infancy 619, 621t
pseudorandom noise 118 management 623
psychogenic (habit) coughing 48 neonatal 619, 620t
PTC 124 (ataluren) 423, 431 physical examination 620
puberty, allergic disorders 339 prognosis 623624
pulmonary alveolar microlithiasis 143 pulmonary hypertension 601, 602, 638
pulmonary alveolar proteinosis (PAP) 7, 142, 592, classification 601602, 602t, 603t
596600 due to pulmonary vascular disease 604
bat wing pattern 599 epidemiology 602
causes 598, 599t functional classes 603t
clinical course 599600 surfactant dysfunction mutations 597
clinical manifestations 598599 pulmonary hypoplasia 910
diagnosis 598599 pulmonary infiltrates 180, 610
differential diagnosis 600 pulmonary interstitial glycogenosis 593
pathomechanism 596597 pulmonary lymphatics 3
physical examination 599 pulmonary oedema, renal disease 638
therapeutic strategies 599600 pulmonary rehabilitation 656
pulmonary arterial hypertension (PAH) 473474 pulmonary sequestration 336
pulmonary arterial pressure (PAP), pulmonary hyper- pulmonary sling 136, 454455, 457f
tension 601 associated tracheobronchial anomalies 455, 457f
pulmonary artery 3 chest radiography 456
development 5, 602 congenital heart defects and 455
pulmonary aspiration embryology 454455
bronchoalveolar lavage 144 surgery 459
gastro-oesophageal reflux-related pulmonary tethering 81, 81f
biomarkers 561562 pulmonary trunk development 45
diagnosis 144 pulmonary valves, absent 136
radiology 562563 pulmonary vascular disorders 601609
treatment 563564 pulmonary vascular resistance (PVR), pulmonary
pulmonary embolic disease 607608, 608t hypertension 601
cardiac disease and 642 pulmonary vasculature 3
pulmonary function tests (PFTs) 107112 development 78, 602604
acute respiratory failure 541 abnormal 604
allergic bronchopulmonary aspergillosis 379380 pulmonary vasculitis 591592
bronchiolitis obliterans 573 pulmonary veins 3
chronic respiratory failure 544 development 5
difficulties in 75 pulmonary veno-occlusive disease 607
diffuse parenchymal lung diseases 590 pulse oximetry 93
dyspnoea 55 bronchiolitis obliterans 574
hypersensitivity pneumonitis 616 community-acquired pneumonia 237
infants 108109 cyanosis 39
preschool children 107, 109111 dyspnoea 54
protracted bacterial bronchitis 268 exercise testing 676
pulmonary alveolar proteinosis 599 neuromuscular disorders 493
pulmonary haemorrhage 620 polysomnography 127
sedation 107 respiratory distress 54
sickle cell disease 627 restriction assessment 17
tracheal stenosis 442 sleep disordered breathing 62
709
pyrazinamide 251252, 278, 279t, 280t, 290t tonic characteristics 511
renal dysfunction 638640
Q
questionnaires, asthma 324
residual volume (RV) 71f, 71t
bronchiolitis obliterans 573
bronchopulmonary dysplasia survivors 475
quiet sleep, newborns 511 diffuse parenchymal lung diseases 590
measurement 70
R
rabbit nose (Bewitched sign) 35
restrictive disorders 16
skeletal abnormalities 16
residual volume/total lung capacity (RV/TLC) ratio
radiation exposure 183 adolescent idiopathic scoliosis 499
radiofrequency ablation 194 bronchiolitis obliterans 573
radionuclide imaging, BPD 474 bronchopulmonary dysplasia survivors 475
radiopharmaceuticals 191 diffuse parenchymal lung diseases 590
radiotherapy 631 early airway closure 15
raised volume rapid thoracic compression (RVRTC) resistance 8082
108 lower airways 8182
rales see crackles lung volume relationship 81, 81f
rapid antigen tests 238 upper airways 81
rapid eye movement (REM) sleep see REM sleep volume dependent 81, 81f
rapid maxillary expansion, OSAS 518 resistance of the airway (RAW) 80
rattle 57, 58t, 62 resistance of the whole respiratory system (RRS) 8081
reactive oxygen species, OSAS 516 respirable particles 199
recombinant human DNase (rhDNase) 430, 557 respiratory acidosis 94t, 95, 539
rectal prolapse 416 respiratory alkalosis 54, 94t
recurrent laryngeal nerves 1 respiratory depression, flexible bronchoscopy-induced
recurrent respiratory papillomatosis (RRP) 584586 138
recurrent wheeze respiratory disease
bronchopulmonary dysplasia 473 cardiovascular presentation 640
infant plethysmography 109 environmental determinants 2932
raised volume rapid thoracic compression 108 respiratory disorders 9596
regulatory T-cells (Tregs) 22, 24, 340 compensation for 93, 94t
rehabilitation programmes 656661 metabolic compensation 95
components 659t respiratory distress 5056
disease-specific 657661 causes 50, 51t
educational programmes 657 history taking 52
elements of 657 management 56
evidence-based support 658 objective signs 50
inpatient versus outpatient 656 pulse oximetry 54
multidisciplinary team approach 657 respiratory distress syndrome (RDS)
participation criteria 657, 658t preterm babies 54
physiotherapy 667 surfactant abnormalities 7, 461462, 597
targets 656657, 657t ultrasound 184186, 185f
remifentanil 157, 158t see also acute respiratory distress syndrome (ARDS)
REM-off cells 508 respiratory diverticulum 4
REM-on cells 507508 respiratory failure
REM sleep 126, 127, 508 acute see acute respiratory failure (ARF)
apnoea of prematurity 522 chronic see chronic respiratory failure
behaviour disorders 511 respiratory health, environmental determinants 2932
central nervous system regulation 507 respiratory infection(s) 335336, 335t
cholinergic activation 507 acute
EEG 510511, 511f epidemiology 207211
infants 511 global burden 207
latency 127 bronchoalveolar lavage 141
motor activity suppression 507 bronchopulmonary dysplasia 473
neurochemistry 507508 chronic, epidemiology 211212
NREM sleep versus 505t, 511 diffuse parenchymal lung diseases 592
phasic characteristics 511 early life
snoring 61 allergic inflammation and 27
710
effects of 10 rib hump 499
innate-adaptive immune systems interaction 26 rib hump resection 501
flexible bronchoscopy indications 135t ribs 4
neuromuscular disorders 495496 Rich foci 287
wheezing 335336 rifampicin
see also individual diseases extrapulmonary tuberculosis 290t
respiratory mechanics 7782 interactions 279, 280
determining factors 77 resistance 277, 280
forced oscillation technique 120 tuberculosis 278, 279t, 280t
impedance 77 HIV coinfection 280
non-elastic forces 77 immunocompromised child 251252
respiratory muscles recently infected children 281
obesity 528529 right aortic arch 136, 453454
weakness, neuromuscular disorders 492 associated cardiac malformations 453
respiratory physiotherapy see physiotherapy clinical presentation 453454, 455f, 456f
respiratory rate imaging 455f
normal, age-related changes 50 treatment 458f, 459
physical examination 36 right bronchomediastinal lymphatic trunk 3
respiratory related arousals (RERA) 128t right heart catheterisation 604, 605606
respiratory sounds 37 right main bronchus 2
chronic bronchitis 211 right-to-left shunts 189
future development 6364 rigid bronchoscopy 151155
respiratory syncytial virus (RSV) 214, 221223 anaesthesia 159
bronchiolitis 207 contraindications 154
epidemiology 221 difficulties 154
hospital-acquired 244 dyspnoea 55
hospital-acquired pneumonia 244 flexible bronchoscopy versus 152
immunisation 221223 foreign body aspiration 59, 60, 152, 153f, 568
passive 221222 future developments 154
pertussis-like illness 212 historical aspects 151
risk factors 221 indications 152
seasonality 207, 208f instruments used 152, 153f
respiratory system isolated tracheo-oesophageal fistula 441
air flow 7273 laryngeal clefts 439
anatomy 110 monophonic wheeze 59
development 110 sedation 156, 159
elastic properties 7780 stridor 60
physiological changes during sleep 505t technical considerations 151152
time constant () 81 tubes 151, 152t
respiratory system impedance (Zrs) 118, 119f rigid laryngotracheoscopy, stridor 61
respiratory system reactance (Xrs) 118, 119 rigid spine muscular dystrophy 494t
respiratory system resistance (Rrs) 118, 119 rigid telescopes 151, 152t, 153154, 154f
Restorative Theory of sleep 504 RileyDay syndrome (familial dysautonomia) 523,
restrictive diseases/disorders 11, 12f 644645
assessment 1617 ring-sling complex 455
flowvolume loop 16, 16f running test 86
tachypnoea 5253
retropharyngeal abscess 230
Rett syndrome 522
reversibility see bronchodilator reversibility
S
salbutamol
Reynolds number (Re) 80 asthma 56
rheumatic fever 230 asthma exacerbations 323
rhinosinusitis 228 bronchiolitis 307
cystic fibrosis 418 bronchodilator reversibility 8384, 84f
rhinovirus(es) (common cold virus) 87, 214, 341 cystic fibrosis 407
rhonchus (rhonchi) 38 obstructive bronchitis 56
rhythm electrocardiogram, polysomnography 125 preschool wheezing 313
ribavirin 652 saliva, chronic aspiration 559
rib cage, postnatal development 9 sarcoidosis 591, 637t, 641t
711
sawtooth wave forms, REM sleep 510, 511f sickle haemoglobin (HbS) 39, 625
Schamroth sign 43 siderophages 620
scintigraphy, GOR-related aspiration 562563 sildenafil 584, 606
scleroderma 639t, 641t, 643 simple pulmonary eosinophilia (Lffler syndrome)
sclerosing substances 482 593, 611
scoliosis single-breath washout (SBW) 17, 113117
lung function 501 asthma 115
neuromuscular disorders 492493 bronchiolitis obliterans 573
orthopaedic techniques 497 bronchiolitis obliterans syndrome 116
orthopaedic treatment 501 clinical utility 115116
respiratory compromise 497 cystic fibrosis 115
SCORAD index 365 expirogram 114, 114f
scuba diving 675 future directions/open questions 116
secondary hypoventilation syndromes 524 parameters 114f
secondary spontaneous pneumothorax (SSP) 485, 486, technique 114, 114f
486t, 489 single-photon emission computed tomography
second-hand smoke see environmental tobacco smoke (SPECT) 191
(ETS) sinus disease, cystic fibrosis 418
secretory immunoglobulin A (sIgA) 2425 sinusitis 215, 335
secretory immunoglobulin M (sIgM) 2425 sirolimus 584
secretory immunoglobulins 2425 situs ambiguus (heterotaxy) 553554
sedation situs inversus 136
bronchoscopy 156160 situs inversus totalis (Kartageners syndrome) 553554
interventional radiology 193 skeletal tuberculosis 272, 273, 289290
isotope imaging methods 191 skin prick tests (SPTs) 346, 346t, 347t
rigid bronchoscopy 159 allergic rhinitis 357
see also anaesthesia food allergy 373
segmental bronchi 2 interpretation 347t
self-injectable adrenaline, anaphylaxis 352, 352t procedure 346, 346f
self-management education, preschool wheezing 313 sleep 503513
seminomas 634 age-related changes 511512
serology architecture 508512
bacterial pneumonia 216 biological function theories 504
upper respiratory tract infections 215 central nervous system regulation 506
virus detection 215 duration 511
serotonin (5-hydroxytryptamine), sleep 507 neurochemistry 507508
serum allergen-specific IgE analysis newborns 511512
allergen panels 347t physiology 503506, 505t
allergic disorders 346347, 346t REM see REM sleep
allergic rhinitis 357 respiratory failure during 546
allergy 347 slow-wave see slow-wave sleep (SWS)
food allergy 373 stages 508512
sevoflurane 159 switch 507
SFTPB gene mutation 597 Sleep Clinical Record, OSAS 517
SFTPC gene mutation 597 sleep deprivation 512
short-acting 2-agonists (SABA) 320 sleep disordered breathing (SDB) 61
shunt 538539 clinical features 521525
SIADH (syndrome of inappropriate secretion of anti- evaluation 62
diuretic hormone) 306 neuromuscular disorders 492, 493, 524525
sickle cell disease (SCD) 625629, 642 polysomnography 525526
acute chest syndrome (ACS) 625, 626 sequelae 522
diagnosis 626, 626f, 627f treatments 526
plastic bronchitis 578 sleep disorders 512513
therapy 628f sleep efficiency 127
asthma comorbidity 625, 627, 628 sleep hypoventilation syndrome 125, 126
care 626 sleep latency 127
chronic lung disease 626628 sleep-onset REM 511512
comorbidities 627 sleep pressure 506
lung disease course 628 sleep-related hypoxaemia 522
712
manoeuvres 109
sleep spindles 509, 510f
reference values 110
sleep studies
procedure 1112
chronic respiratory failure 544
restrictive diseases 16
neuromuscular disorders 492, 493
static lung volumes 71f, 75
OSAS 517
vocal cord dysfunction 61
sleep terror 512
SpO2
sleepwake regulation 503506
acute respiratory failure 540
sleep walking (somnambulism) 511, 512
inflight 670, 671f
sliding sign, ultrasound 183
spondylocostal dysostosis (JarchoLevin syndrome)
slow-wave activity 506, 510
500501
slow-wave sleep (SWS) 126, 127, 506, 508, 510, 510f, 511
spondylothoracic dysostosis (LavyMoseley syndrome)
process S 506
500501
small airway obstruction assessment 1415
spontaneous pneumomediastinum (Hammans syn-
smart nebulisers 198, 201, 202
drome) 489490
smoke inhalation injury 535
sports injuries 674
smoking, pregnancy 10, 29
sports medicine 673677
snoring 57, 6162, 129f, 516
pre-competition assessment 673
causes 58t
sports programmes, benefits 673674
history 6162
sputum, inflammation assessment 1718
severity 61
sputum cultures
site of origin 58t
community-acquired pneumonia 238
snorts (snuffles) 58t, 62
non-CF bronchiectasis 254
snuffles (snorts) 58t, 62
pleural infection 259260
social history 35
protracted bacterial bronchitis 268
sodium 96
sputum examination
sodium channel blockers 424
fungal infections 218219
sodium meglumine diatrizoate (Gastrografin) 414, 415
mycobacterial infections 217218
sodium supplementation, cystic fibrosis 411
sputum induction 100, 103104
soft-mist inhalers 204
asthma 103
sol phase 552
clinical applications 103, 105
somatostatin 481482
cystic fibrosis 429
somatostatin analogues 481482
methodology 103
somnambulism (sleep walking) 511, 512
tuberculosis 276277
somniloquy 512
squawk 3839
sound recording, polysomnography 126
stage 1 sleep 126, 508, 509f
spared areas, ultrasound 185f, 186
stage 2 sleep 126, 508509, 510f
specific airway resistance (sRaw) 111
stage 3 sleep see slow-wave sleep (SWS)
speech, auscultation 39
stage 4 sleep 508
spinal muscular atrophy 493, 494t
standard base excess (base excess of the blood sam-
spinal tuberculosis 289290
ple) 96
Spina ventosa 290
Staphylococcus aureus 209t
spine-based growing rods, early onset scoliosis 501
atopic dermatitis 366
spirometers 11, 12f
community-acquired pneumonia 235, 235t
spirometry 1112, 12f
cystic fibrosis 408
allergic bronchopulmonary aspergillosis 380
necrotising pneumonia 263
asthma monitoring 324
pneumonia 209, 216
bronchopulmonary dysplasia survivors 475
protracted bacterial bronchitis 266
cystic fibrosis 427, 543
sinusitis 215
dyspnoea 55
tracheitis 215
equipment 1112
static lung volumes 7076, 71f
exhaled nitric oxide fraction versus 102
measurable 70, 71t
lung graft monitoring 653
measurement 7576
neuromuscular disorders 16, 492
obesity 529
non-CF bronchiectasis 255
steatosis 417
obesity 529
stents 442
obstruction assessment 14
sterilising drugs, tuberculosis 278
preschool children 107, 109110, 110f
sternal clefts 498
acceptability criteria 109
sternal defects, congenital 497498
AYS/ERS recommendations 109110
steroid phobia 368
713
steroids see corticosteroids superior caval vein thrombosis 642
stethoscope 3637 supplemental oxygen see oxygen supplementation/
Stickler syndrome 436 therapy
storage disorders 644 SUPPORT study 463
streptococcal infections, tonsillitis 229 suprachiasmatic nucleus (SCN) 503, 504
probability scoring systems 230, 230t supraglottic cysts 438
Streptococcus pneumoniae 209t surfactant 67, 6t, 78
acute otitis media 215 at birth 7
chronic bronchitis 211 dysfunction 7, 596600
community-acquired pneumonia 233, 234235, 235t functions 6, 7
empyema 211 secretion 67
invasive bacterial diseases 223, 237 surface tension reduction 78
pneumonia 209, 216, 223 surfactant deficiency syndromes 596
protracted bacterial bronchitis 266 surfactant disorders 592
sinusitis 215 surfactant protein (SP)-A 6, 7
Streptococcus pyogenes 215, 235t surfactant protein (SP)-B 6, 588, 592, 597
stress incontinence, cystic fibrosis 430 surfactant protein (SP)-C 6, 588, 597
stridor 38, 57, 5961 surfactant protein (SP)-D 6, 7
acute 60 surfactant replacement, ARDS 536
assessment 6061 surfactant system, genetic defects 588
causes 58t, 59, 6061 surgery
chronic 6061 bronchiolitis obliterans 575
croup 60, 231 bronchopulmonary sequestration 450
definition 59 chylothorax 482
exercise-induced vocal cord dysfunction 67 congenital cystic adenomatoid malformation 449
exhalation 60, 60f distal intestinal obstruction syndrome 415
expiratory 53 double aortic arch 459
flexible bronchoscopy 132, 134 empyema 261
foreign body aspiration 60 isolated tracheo-oesophageal fistula 441
generation 59 laryngeal clefts 439440
haemangiomas 582 lung abscess 265
history 60 lung tumours 631
inhalation 5960 meconium ileus 414
inspiratory 53, 56 mediastinitis 484
investigations 61 necrotising pneumonia 263
laryngomalacia 336, 438 non-CF bronchiectasis 256
physical examination 60 papillomas 585
site of origin 58t PierreRobin sequence 436
vocal cord dysfunction 61 pleural effusion 479480
subcortical arousal, sleep 506 pleural infection 261
subcrepitant (fine) crackles 38 primary ciliary dyskinesia 557
subcutaneous emphysema 489490 pulmonary sling 459
subcutaneous immunotherapy (SCIT) 383, 386388 subglottic stenosis 437
allergic asthma 383 tracheal stenosis 443
cat allergen extracts 386387 tracheomalacia 442
dosing schedules 387 surgical jejunostomy 564
side-effects 387, 387t suspension laryngoscopy 153, 154f
subglottic cysts 439 suxamethonium 159
subglottic haemangiomas 582583, 583f swallowing dysfunction 559
subglottic stenosis 15, 53, 135, 437, 437t swallowing function assessment 493
sublingual immunotherapy (SLIT) 383, 387388 sweat test
subpleural blebs, pneumothorax 485 cystic fibrosis 397, 399f, 421
subpleural bulla, pneumothorax 485 false-negative results 400t
subpleural consolidations 187 false-positive results 400t
subunit vaccines, tuberculosis 282 macroduct collection system 397, 399f
sudden death event 674 non-CF bronchiectasis 255
sudden fatal asthma 674 protracted bacterial bronchitis 268
sulfur hexafluoride 113 SwyerJames syndrome 573574
sulfur mustard inhalation 578 syncope 604
714
syndrome of inappropriate secretion of antidiuretic thorax 1
hormone (SIADH) 306 compliance 7880, 79f
systemic disorders, lung involvement 636646 elastic properties 77
systemic hypothermia 98 hyperinflation 3536
systemic inflammatory response syndrome (SIRS) 533 thrombocytes 20
systemic lupus erythematosus (SLE) 639t, 641t, thromboembolism 607
643644 thymocytes 3
thymus 34
T
tachypnoea 50
thymus-activated-regulated chemokine (TARC) 379
thyroid transcription factor-1 deficiency -syndrome
(brain-lung-thyroid syndrome) 592, 598
community-acquired pneumonia 237 tidal volume (VT) 71f, 71t
inspection 5253 Tiffeneau index (FEV1/FVC) 72t
restrictive lung disease 5253 time-period effect, cough 47
tacrolimus 368, 649, 651t time taken to achieve peak tidal expiratory flow
tactile fremitus 36 (tPTEF)/expiratory time (tE) ratio 8485
tadalafil 606 TIRAP (TIR domain-containing adaptor protein) 21
talc emboli 607 TIR domain-containing adaptor protein (TIRAP) 21
T-cell mediated immune response 24 TIR domain-containing inducing interferon- (TRIF) 21
T-cells 20, 20f, 24 tissue plasminogen activator (tPA) 579
allergic bronchopulmonary aspergillosis 378 TLCO
antigen contact 24 bronchiolitis obliterans 573
Technegas 191 diffuse parenchymal lung diseases 590
technetium-99m (99mTc) 189 restriction assessment 17
telomerase 588 TLR2 22
tension pneumothorax 487, 487f TLR4 22
teratomas 633, 634 T-lymphocytes 3, 249t
terbutaline 323 tobramycin
terminal bronchiole 2 cystic fibrosis 408, 425, 429
development 5 dry-powder inhalers 204
Th2 high phenotype, asthma 329 Toll-like receptors (TLRs) 21
Th2 low phenotype, asthma 329 signalling cascade 2122, 22f
Th9 cells 24 tonsillectomy 230
Th17 cells 24 tonsillitis 229231
Th22 cells 24 topical calcineurin inhibitors (TCIs) 368
T-helper (Th)-1 lymphocytes 3, 24, 285 total beam collimation 167
T-helper (Th)-2 lymphocytes 34, 24 total lung capacity (TLC) 70, 71f, 71t
allergic response 340 diffuse parenchymal lung diseases 590
allergic rhinitis 355 increases through life 9
asthma 301, 318 obesity 529
theophylline 321, 330331 restrictive diseases 16
therapeutic hypothermia 98 total lung lavage 144
thoracentesis 260261 total respiratory system compliance, obesity 528529
thoracic cage, reduced development 10 total sleep time (TST) 126
thoracic duct 3 total specific airway resistance (sRaw,tot) 111
thoracic duct ligation 482, 578, 579 tracer gases 13
thoracic gas volume 111 trachea 2, 2f
thoracic insufficiency syndrome (TIS) 499500, 500t, malformations 436t, 440444
501 venous drainage 2
thoracic malformation, congenital see congenital tracheal agenesis 440
thoracic malformations (CTMs) tracheal atresia 440
thoracic wall compliance 78 tracheal bronchus (pig bronchus) 136, 443
thoracoamniotic shunting 448 tracheal collapse 441
thoracoscopic drainage 265 tracheal infarction 642
thoracotomy tracheal obstruction 567
haemothorax 483 tracheal sounds 37
pleural infection 261262 tracheal stenosis 442443, 442f
thoracovertebral deformities 498501 tracheitis 215
thoracovertebral malformations 497, 501 tracheobronchial tree 5f, 134f
715
topographic anomalies 443 control 281282
tracheomalacia 136, 441442 diagnosis 217218, 274, 277
aberrant innominate artery 459 disease sites 272274, 273f
congenital versus acquired 441 examination 274
dynamic airway compression 441 extrapulmonary see extrapulmonary tuberculosis
flexible airway endoscopy 441 genetic susceptibility 285
protracted bacterial bronchitis risk factor 267 history 274
signs/symptoms 441 HIV coinfection 280281, 285286
surgery 442 HIV testing 277
tracheo-oesophageal fistula 136, 440 imaging/radiography 275276
tracheo-oesophageal fistula-cough 440 immune response 272, 284285
tracheoscopes 152 immunocompromised host 251252, 284292
tracheoscopy, aberrant innominate artery 458f, 459 infection likelihood influencing factors 270
tracheostomy liver manifestations 637t
hospital-acquired pneumonia risk 243 microbiological confirmation 276277
neuromuscular disorders 495, 495t molecular testing 277
respiratory physiotherapy 667668 natural history 270274, 271f
tracheostomy-associated pneumonia 209 passive case finding 274
tracheotomy 549 prevention 281282
TRAM (TRIF-related adaptor molecular) 21 primary progressive 272
transairway pressure (Pta) 73 pulmonary 272273
transbronchial lung biopsy (TBLB) 146, 149150 signs 274
lung transplant recipients 651 symptoms 274, 275t
technique 149, 149f treatment 277279
transcatheter embolisation 193, 196197 adherence 278
transcutaneous carbon dioxide (PtcCO2) 125, 126 combination regimens 278
transfusion-related acute lung injury (TRALI) 535 hepatotoxicity induction 279
transient tachypnoea of the newborn (TTN) 184 HIV-infected children 278
transpulmonary pressure (Ptranspulm) 77 recently infected children 281
transthoracic biopsy, bronchiolitis obliterans 573 recommended doses 278, 280t
traumatic (iatrogenic) pneumothorax 485, 486t, 488 regimens 278, 279t
Treacher syndrome 436 side-effects 279
triamcinolone 322 underestimation 270
triangle of safety 488, 489f vaccines, new development 282
TRIF (TIR domain-containing inducing interferon-) 21 tuberculous arthritis 290
TRIF-related adaptor molecular (TRAM) 21 tuberculous dactylitis 289, 290
tri--gliadin 67 tuberculous lymphadenitis 277, 287
true vocal cords (fold) 1 tuberculous meningitis 273, 282, 287, 287f
tryptase 350 tuberculous osteomyelitis 290
TTF-1 gene mutations 592 tuberose sclerosis 639t
tuberculin skin test (TST) 217, 274, 275 tube thoracostomy 479, 483
HIV/TB coinfection 286 tubular myelin 7
miliary tuberculosis 288 tubulin 551
tuberculomas 287, 288 tumour ablation 193, 194
tuberculosis (TB) 270283 tumour emboli 607
abdominal 290291 tumour localisation 193, 194
acquired susceptibility 285286 tumour necrosis factor (TNF) 330
active case finding 274 tumour necrosis factor (TNF) blockers 330
active disease management 277 tumours 630635
adaptive immunity tests 274275 turbulent flow 80
adult-type 272, 273 22q11.2 deletion syndrome 436
age-related progression risk 272, 273t two-process model of sleep and wakefulness 503, 504
bone tuberculosis 272, 273, 289290 Type I alveolar lining cells 5, 7
burden of disease 270 Type II alveolar lining cells 5, 6, 7
cardiac manifestations 641t
chemoprophylaxis 281
clinical manifestations 284285
congenital 273274
U
UK CF Trust registry report 377
contact history 273t, 274 ulcerative colitis 642
716
ultrasonic nebulisers 202 valved holding chamber (VHC) 203
ultrasound 183188 Vapotherm system 542
anatomy 183, 184f vapour rub 47
appendiceal mucocoele 415416 vardenafil 606
artefacts 183, 184f variceal bleeding 416
bronchiolitis 186f, 187 vascular compression, flexible bronchoscopy 136
bronchopulmonary dysplasia 185f, 186 vascular endothelial growth factor (VEGF)-A 462
CF-related liver disease 417 vascular malformations 452460
congenital cystic adenomatoid malformation 447f, classification 452455
448 clinical presentation 452455
congenital thoracic malformations 446, 446f diagnosis 453, 456459
cystic fibrosis 412 incidence 452, 453
dyspnoea 54 outcomes 459
fetal MRI versus 181 symptoms 452
haemangiomas 582 treatment 459
haemothorax 483 vascular ring 136, 452, 453, 456, 456f, 459, 640
image-guided percutaneous biopsy 194, 195f vascular sling 452, 459, 640
image-guided percutaneous drainage 194195 vasculitis
intussusception 416 bronchiolitis obliterans 572
lung abscess 264 pulmonary 591592
miliary tuberculosis 288 systemic, pulmonary involvement 643644, 644t
parapneumonic effusion 259 VATER syndrome 641t
pleural effusion 477478, 478f venom immunotherapy 352
pleural infection 259 venous blood, blood gas analysis 9798, 98t
pneumonia 186f, 187188, 187f ventilation
pneumothorax 187 acute respiratory failure 542
pulmonary atelectasis 186f, 187 adequacy assessment measures 95
respiratory distress syndrome 184186, 185f cystic fibrosis 433
TB arthritis 290 lung transplantation 649, 650
technique 183 ventilation distribution 534
transient tachypnoea of the newborn 184 ventilation/perfusion (V/Q) inequality, acute respira-
tuberculosis 276 tory failure 538
undernutrition, BPD 467 ventilation/perfusion (V/Q) scintigraphy
united airway concept 360 bronchiolitis obliterans 574
upper airway collapsibility, OSAS 514, 530531 imaging equipment/acquisition 191
upper airway resistance syndrome 514520 indications 189190, 190f
upper airways patient preparation 190191
chronic obstruction 548 pulmonary embolic disease 607
flexible bronchoscopy 134135 ventilator-associated interstitial emphysema 486
obesity 528 ventilator-associated pneumonia (VAP) 209, 242, 245t,
physical examination 35 640
resistance 81 ventilator-induced lung injury (VILI) 533534
upper respiratory tract (URT) 227 ventilatory/pump failure 545
upper respiratory tract infections (URTIs) 227232 ventral diverticulum 4
bacterial, microbiology testing 215 ventrolateral pre-optic nucleus (VLPO) 507
prevalence 227 vertebral fusion 501
viral 227, 228t vertex waves, sleep 508, 509f
uraemic lung 638 vertical expandable prosthetic titanium rib (VEPTR) 501
Ureaplasma infection 462 vesicular breath sound 37
urine specimens, bacterial pneumonia 216 vestibular folds 1
urinothorax 639 vibrating-mesh nebulisers 202
urokinase 261, 479 vibration, airway clearance 666
ursodeoxycholic acid (UDCA) 417 Victorian Infant Collaborative Study Group 470471
video-assisted thoracoscopic surgery (VATS)
V
VACTERL association 440, 641t
empyema 261
haemothorax 483
necrotising pneumonia 263
VACTER syndrome 641t pleural effusion 479480
vacuum cleaners 384t, 385 pneumothorax 489
717
video recording, polysomnography 126, 525
viral infection
acute respiratory distress syndrome 535
W
wakefulness 506, 507
allergic disorders 339, 341 Waldeyers ring of lymphoid tissue 229
allergic sensitisation and 319 warfarin 608
asthma trigger 318319, 341 wave-speed limitation 75
bronchial hyperresponsiveness 87 weight gain 660
bronchiolitis 207, 305 weight graphs 3435
chronic bronchitis 211 weight loss 660
community-acquired pneumonia 236 asthma 319320
diffuse parenchymal lung diseases 592 sleep apnoea 531
early life, asthma development 302 wet cough 34, 48
graft rejection 652 in bacterial bronchitis see protracted bacterial bron-
history taking 34 chitis (PBB)
hospital-acquired pneumonia 244 wheat proteins 67
microbiology 214215 wheeze/wheezing 3738, 5859
pneumonia 209 after exercise 34
protracted bacterial bronchitis risk factor 266267 assessment 59
upper respiratory tract 227, 228t asthma 59
viral rhinitis (common cold) 227228 bacterial bronchitis 267268
virus(es) bronchiolitis 59
as copathogens 214 causes 58t
detection 215 clinical conditions presenting with 335, 335t
visceral lymph nodes 3 definition 57, 58, 334
vital capacity (VC) 70, 71t forced oscillation technique 119120
diffuse parenchymal lung diseases 590 foreign body aspiration 54, 59, 567
muscle disease 1617 history taking 34
muscular dystrophy 16 inspiratory 38
neuromuscular disorders 492 intensity-obstruction degree relationship 38
obesity 529 intrathoracic airway obstruction 5354
obstructive disorders 15 monophonic 59
pectus excavatum 498 physical examination 38
single-breath washout 114, 114f polyphonic 59
spirogram 71f preschool children see preschool wheeze/wheezing
vitamin(s), BPD 468 prevalence 294
vitamin A 412, 413t, 464, 468 production 59
vitamin D 330, 412, 413t recurrent 334
deficiency, TB 286 site of origin 57, 58, 58t
vitamin D2 (ergocalciferol) supplementation 412 wheezing disorders
vitamin D3 (cholecalciferol) supplementation 412 environmental factors 302303
vitamin E 412, 413t epidemiology 293297
vitamin K 413t geneenvironment interaction 303
deficiency, cystic fibrosis 412 genetic factors 298304
VO2max 676 whispered pectoriloquy 39
vocal abuse 63 white cell count, empyema 217
vocal apparatus 1 white lung, ultrasound 184, 185, 185f, 186
vocal cord(s) 1, 80 whole body plethysmography 1213, 14
vocal cord dysfunction (VCD) 61, 135, 335t, 336 airway resistance, preschool children 111
vocal cord paralysis 63, 135 obstructive disorders 15
vocal nodules 63 static lung volumes 75
voice, physical examination 36 whole-exon sequencing, asthma 299
volatile organic compounds (VOCs) 664 whole-genome sequencing, asthma 299, 300t
volume resuscitation, haemothorax 483 whole lung lavage, pulmonary alveolar proteinosis
vomiting 34 599600
voriconazole 381, 430, 650 whooping cough (pertussis) 212, 231
VX-770 see ivacaftor Williams syndrome 641t
VX-809 422, 423 Wilms tumour 632, 633f, 639t
718
World Health Organization (WHO) Xpert MTB/RIF 277
pneumonia diagnosis recommendations 236, 238 X-ray, chest see chest radiography
pulmonary hypertension classification 603t
tuberculosis treatment recommendations 278
wound healing, age-related changes 589 Y
yellow nail syndrome (YNS) 645
X
xenon-133 (133Xe) 191 Z
xolair see omalizumab zeitgebers 504
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