ERS Handbook For SEPAR First Edition

ERS
HANDBOOK
RESPIRATORY
MEDICINE
FIRST EDITION
Editors
Paolo Palange
Anita Simonds
PUBLISHED BY
EUROPEAN RESPIRATORY SOCIETY
CHIEF EDITORS
Paolo Palange (Rome, Italy)
Anita Simonds (London, UK)
SCHOOL COMMITTEE
Mario Cazzola Gilbert Massard
Johannes H. Wildhaber Leif Bjermer
Enrico Clini Paolo Pelosi
Thomas Geiser Wilfried De Backer
Guy Joos Bo E.J. Lundback
Ernst Eber Annette Boehler
Geraldine Burge Gernot Rohde
Johan Vansteenkiste Konrad Bloch
MANAGING EDITORS
Matt Broadhead, Tania Sverin
SUPPORT STAFF
Sharon Mitchell, Veronica Pock, Claire Turner,
Victoria Morton, Matt Heald, Pippa Powell
FIRST EDITION 2010

2010 European Respiratory Society
Design by Ian Turpin

Typeset in China by Charlesworth Group
Printed in the UK by Latimer Trend & Co. Ltd
Indexed by Merrall-Ross International Ltd
All material is copyright to the European Respiratory Society.

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

European Respiratory Society, 442 Glossop Road, Sheffield, S10 2PX, UK
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ISBN 978-1-904097-99-0
PREFACE The mind is not a vessel to be
filled but a fire to be kindled.
Plutarch
Why an ERS Handbook of Respiratory Medicine? Education is one

of the pillars of the European Respiratory Society (ERS) and the
fundamental aim of the ERS School is to provide excellence in
education in the field of respiratory medicine. Five years ago, the
School started a very ambitious project, to Harmonise Education
in Respiratory Medicine for European Specialists (HERMES).
A preliminary survey among 29 European countries showed
considerable variation in post-graduate training. Based on these
findings, the School developed a range of consensus documents: a
core syllabus describing the competencies required, a curriculum of
recommendations indicating how competencies should be taught
and learned, an accreditation methodology for training centres, and
a voluntary European examination to assess whether specialists
have acquired the knowledge-based component of competence.
Moreover, during the past few years, a vast array of educational
material, such as lectures, articles published in two of the societys
publications Breathe and the European Respiratory Monograph
web lectures and courses, have been produced and made available
on the School website (the ERS School maintains the biggest online
resource in respiratory medicine, which functions both as an e-library
and as an interactive education).
The School committee has now decided that the time is right
to deliver the first edition of the ERS Handbook of Respiratory
Medicine. We hope it will inform our trainees and provide an
easily accessible, comprehensive update for medical, nursing and
paramedical colleagues at all levels across the specialty.
The ERS Handbook consists of concise state-of-the art summaries
which will be updated regularly in electronic and hard copy versions.
Hard copy users will have access to electronic updates and further
CME questions. Our contributors are all clinical experts in the field.
We are particularly indebted to the ERS School Committee,
Managing Editor Matt Broadhead who curated the contents of
the handbook, Tania Sverin who oversaw the project, and all the
contributors.
Paolo Palange, Anita Simonds

CHIEF EDITORS
CONTENTS
1. STRUCTURE AND FUNCTION
OF THE RESPIRATORY SYSTEM
GENETICS 2
G. Zissel
MOLECULAR BIOLOGY OF THE LUNG 7
M. Knigshoff and O. Eickelberg
ANATOMY OF THE RESPIRATORY SYSTEM 11
P.L. Shah
RESPIRATORY PHYSIOLOGY 15
S.A. Ward
IMMUNOLOGY AND DEFENCE MECHANISMS 26
B. Balbi, C. Vicari and A. Di Stefano
2. SIGNS AND SYMPTOMS

COUGH AND SPUTUM 34
A.H. Morice
DYSPNOEA 41
G. Scano and P. Laveneziana
CHEST PAIN 49
M. Hind
PHYSICAL EXAMINATION IN 51
RESPIRATORY MEDICINE
MR. Partridge
3. PULMONARY FUNCTION TESTING

STATIC AND DYNAMIC LUNG VOLUMES 58
R. Pellegrino and A. Antonelli
RESPIRATORY MECHANICS 63
D. Navajas and R. Farr
GAS TRANSFER (TL,CO) 68
J.M.B. Hughes
CONTROL OF VENTILATION 72
B.J. Whipp
ARTERIAL BLOOD GAS ASSESSMENT 77
P. Palange, A. Ferrazza and J. Roca
EXERCISE TESTING 83
P. Palange
BRONCHIAL PROVOCATION TESTING 88
K-H. Carlsen
SPUTUM AND EXHALED BREATH ANALYSIS 92
O. Toungoussova, S. Dragonieri, A. Zanini, and A. Spanevello
4. OTHER DIAGNOSTIC TESTS

BRONCHOSCOPY 98
P.L. Shah
BRONCHOALVEOLAR LAVAGE 103
P.L. Haslam
FINE-NEEDLE BIOPSY 110
S. Gasparini
MEDICAL THORACOSCOPY/PLEUROSCOPY 112
R. Loddenkemper
THORACENTESIS 115
E. Canalis and M.C. Gilavert
INTERVENTIONAL PULMONOLOGY 118
M. Noppen
5. LUNG IMAGING
CHEST X-RAY AND FLUOROSCOPY 126
W. De Wever
LUNG CT AND MRI 130
J.A. Verschakelen
NUCLEAR MEDICINE OF THE LUNG 135
A. Palla
TRANSTHORACIC ULTRASOUND 138
F. Von Groote-Bidlingmaier, C.F.N. Koegelenberg and C.T. Bolliger
CONTENTS
6. LUNG INJURY AND RESPIRATORY FAILURE
LUNG INJURY 146
B. Schnhofer
RESPIRATORY FAILURE 148
N. Ambrosino and F. Guarracino
OXYGEN THERAPY AND VENTILATORY SUPPORT 151
A.K. Simonds
INTENSIVE CARE AND HIGH-DEPENDENCY UNIT 154
S. Nava and P. Navalesi
ASSESSMENT FOR ANAESTHESIA/SURGERY 156
M.M. Schuurmans, C.T. Bolliger and A. Boehler
7. RESPIRATORY INFECTIONS
MICROBIOLOGY TESTING AND INTERPRETATION 162
M. Ieven
UPPER RESPIRATORY TRACT INFECTIONS 168
G. Rohde
INFECTIVE EXACERBATIONS OF COPD 172
M. Miravitlles
PNEUMONIA 176
M. Woodhead
HOSPITAL-ACQUIRED PNEUMONIA 180
F. Blasi
PNEUMONIA IN THE IMMUNOCOMPROMISED HOST 183
S. Ewig
PLEURAL INFECTION AND LUNG ABSCESS 186
C. Hooper and N. Maskell
INFLUENZA, PANDEMICS AND SARS 191

W.S. Lim
8. TUBERCULOSIS
PULMONARY TUBERCULOSIS 200
G. Sotgiu, C. Lange and G.B. Migliori
EXTRAPULMONARY TUBERCULOSIS 209
A. Bossink
TUBERCULOSIS IN THE 212
IMMUNOCOMPROMISED HOST
M. Sester
LATENT TUBERCULOSIS 215
J-P. Zellweger
NONTUBERCULOUS MYCOBACTERIAL DISEASES 218
C. Piersimoni
9. AIRWAY DISEASES
CHRONIC RHINITIS 224
A. Bourdain and P. Chanez
ASTHMA 227
B. Begh and L.M. Fabbri
VOCAL CORD DYSFUNCTION 236
A.H. Mansur
BRONCHITIS 240
G. Rohde
GASTRO-OESOPHAGEAL REFLUX 242
L. Dupont
COPD AND EMPHYSEMA 246
E.G. Tzortzaki, K.D. Samara and N.M. Siafakas
BRONCHIECTASIS 252
N. Ten Hacken
CYSTIC FIBROSIS 256
A. Bush, J. Davies
CONTENTS
10.OCCUPATIONAL AND ENVIRONMENTAL
LUNG DISEASES
WORK-RELATED AND OCCUPATIONAL ASTHMA 268
E. Zervas and M. Gaga
RESPIRATORY DISEASES CAUSED BY ACUTE 273
INHALATION OF GASES, VAPOURS AND DUSTS
B. Nemery
HYPERSENSITIVITY PNEUMONITIS 278
T. Sigsgaard and A. Rask-Andersen
PNEUMOCONIOSIS 282
R.D. Stevenson
INDOOR AND OUTDOOR POLLUTION 285
G. Viegi, M. Simoni, S. Maio, S. Cerrai, G. Sarno and S. Baldacci
SMOKING-RELATED DISEASES 291
Y. Martinet and N. Wirth
TREATMENT OF TOBACCO DEPENDENCE 295
L. Clancy and Z. Kabir
HIGH-ALTITUDE DISEASE 298
Y. Nussbaumer-Ochsner and K.E. Bloch
DIVING-RELATED DISEASES 302
E. Thorsen
RADIATION-INDUCED DISEASE 304
R.P. Coppes and P. Van Luijk
11. INTERSTITIAL LUNG DISEASE

SARCOIDOSIS 308
U. Costabel
IDIOPATHIC INTERSTITIAL PNEUMONIAS 311
D. Olivieri, S. Chiesa and P. Tzani
EOSINOPHILIC DISEASES 319
A. Menzies-Gow
DRUG-INDUCED RESPIRATORY DISEASE 322
Ph. Camus
12. PULMONARY VASCULAR DISEASES
PULMONARY EMBOLISM 332
M. Pistolesi
PULMONARY VASCULITIS 336

A.U. Wells
PULMONARY HYPERTENSION 340
M. Humbert and G. Simonneau
13. PLEURAL, MEDIASTINAL AND

CHEST WALL DISEASES
PLEURAL EFFUSION 348
R. Loddenkemper
PNEUMOTHORAX AND PNEUMOMEDIASTINUM 352
P. Schneider
MEDIASTINITIS 358
P-E. Falcoz, N. Santelmo and G. Massard
NEUROMUSCULAR DISORDERS 361
A. Vianello
CHEST WALL DISORDERS 366
14. THORACIC TUMOURS

LUNG CANCER 372
J. Vansteenkiste and S. Derijcke
CHEMOTHERAPY AND OTHER ANTI-TUMOUR 377
THERAPY FOR THORACIC MALIGNANCIES
A. Tufman and R.M. Huber
PRINCIPLES OF SURGICAL TREATMENT FOR 382
EARLY-STAGE NONSMALL CELL LUNG CANCER
G. Massard, N. Santelmo and P-E. Falcoz
CONTENTS
METASTATIC TUMOURS 388
E. Quoix
PLEURAL AND CHEST WALL TUMOURS 392
A. Scherpereel
MEDIASTINAL TUMOURS 399
P.E. Van Schil, P. Lauwers, J.M. Hendriks
15.SLEEP-RELATED DISORDERS
OBSTRUCTIVE SLEEP APNOEA/ 404
HYPOPNOEA SYNDROME
W. De Backer
CENTRAL SLEEP APNOEA 410
K.E. Bloch and T. Brack
HYPOVENTILATION SYNDROMES 414
J-F. Muir
16.IMMUNODEFICIENCY DISORDERS AND

ORPHAN LUNG DISEASE
PULMONARY DISEASES IN PRIMARY 420
IMMUNODEFICIENCY SYNDROMES
I. Quinti, C. Milito, L. Bonanni and F. La Marra
HIV-RELATED DISEASE 423
M.C.I. Lipman and R.F. Miller
GRAFT VERSUS HOST DISEASE 430
AMYLOIDOSIS 433
H.J. Lachmann
PULMONARY ALVEOLAR PROTEINOSIS 435
M. Luisetti
ADULT PULMONARY LANGERHANS 438
CELL HISTIOCYTOSIS
J-F. Cordier and V. Cottin
LYMPHANGIOLEIOMYOMATOSIS 441
17. PULMONARY REHABILITATION
RESPIRATORY PHYSIOTHERAPY 446
J. Bott
PULMONARY REHABILITATION 451

T. Troosters, H. Van Remoortel, D. Langer and C. Burtin
SELF-ASSESSMENT 458
INDEX 462
ers_chapter pages.indd 2 10/08/2010 11:55:37
CHAPTER 1:
STRuCTuRE And funCTion
of THE RESPiRAToRy SySTEm
gEnETiCS 2
G. Zissel
molECulAR biology of THE lung 7

M. Knigshoff and O. Eickelberg
AnATomy of THE RESPiRAToRy SySTEm 11

P.L. Shah
RESPiRAToRy PHySiology 15
S.A. Ward
immunology And dEfEnCE mECHAniSmS 26

B. Balbi, C. Vicari and A Di Stefano

GENETICS
G. Zissel
Dept of Pneumology, Medical University Hospital Freiburg, Freiburg,
Germany
E-mail: gernot.zissel@uniklinik-freiburg.de
Genetics addresses the composition, function an altered or missing protein. Because we are
and transmission of inherited entities (genes). all equipped with a double set of
Generally, the term gene is understood as a chromosomes, in the vast majority of cases, a
unit coding for a single RNA that gives rise to dysfunctional gene is corrected by its
a single and specific protein. However, due to counterpart gene with normal function. A
alternative splicing, one gene may code for deficiency occurs only when the respective
different proteins and in addition there are gene is dysfunctional on both chromosomes,
also genes coding for catalytic RNA (tRNA, or the gene product is either missing or does
rRNA) or regulatory (micro)RNAs (miRNA). not exert its task.
The genotype is the specific composition of
genes of an individual; it influences the Diseases caused by the alteration of a single
phenotype of an individual. However, in gene that pulmonologists are most frequently
contrast to the genotype, which is simply faced with are cystic fibrosis (CF) and a1-
inherited, a phenotype is shaped by proteinase inhibitor (PI) deficiency (formerly
epigenetic phenomena, environment, climate, a1-antitrypsin (AT) deficiency; see below). In
nutrition and other external factors. other diseases, such a clear-cut relationship
between a gene and a disease is not evident,
It is, in some respect, worthwhile to stress that although facts such as geographical
genes code for proteins, and not for distribution or familial clusters indicate a
diseases. Every genetic disease is based on genetic background to the disease. This is the
case in asthma, sarcoidosis, pulmonary fibrosis
and primary pulmonary hypertension. Table 1
Key points
shows mutated genes involved in respiratory
disorders.
N A few respiratory diseases, such as CF
and a1-PI deficiency, are single-gene There are also a number of gene variations
conditions. that are regarded as neutral variation of the
human gene pool. These variations are not
N A large range of respiratory diseases, harmful per se but, together with distinct
including asthma, sarcoidosis and external stimuli, they foster the development
primary pulmonary hypertension, have of certain diseases. Glutamine at position 69
a genetic background. in the human leukocyte antigen (HLA)-DPB1
N Non-harmful gene variants can gene is not considered as an illness; however,
nonetheless confer susceptibility to when in contact with beryllium dust, carriers
conditions such as chronic beryllium of Glu69+ HLA-DPB1 are at an increased risk
of developing chronic beryllium disease
disease.
(CBD). Up to 97% of CBD patients are
N The role of epigenetic regulatory Glu69+ HLA-DPB1 positive. Another example
mechanisms in respiratory disease is is the lack of functional receptors for
likely to be very significant. interferon-c or interleukin-12. In this case,
individuals grow up normally and reach
2 ERS Handbook: Respiratory Medicine

Table 1. Mutated genes involved in respiratory disorders
Disease Gene Mutation(s)
Cystic fibrosis Cystic fibrosis transmembrane .1,500
conductance regulator (CFTR)
Emphysema Serpin peptidase inhibitor, clade A SNP at position 342 G?A
(a1-antiproteinase, antitrypsin) (glycine to lysine) .90% of
cases
Chronic beryllium disease HLA-DPB1 Glutamine at position 69
Sarcoidosis Butyrophilin-like 2 SNP G?A causing alternative
splicing and premature stop
codon
Sarcoidosis Annexin A11 SNP C?T, arginine to cysteine
Cancer c-myc Promoter translocation
HLA: human leukocyte antigen; SNP: single nucleotide polymorphism.
adolescence; however, after BCG vaccination acetylation, methylation and various other
or when they encounter environmental mechanisms. Generally, acetylation of
mycobacteria (e.g. Mycobacterium fortuitum, histones opens the nucleosome structure and
Mycobacterium chelonae), these patients the gene becomes accessible for transcription.
develop severe and sometimes fatal diseases. In contrast, histone methylation leads to the
accumulation of other proteins leading to a
Epigenetics and regulatory genes compacted nucleosome, which inhibits gene
In additon to these classical forms of genetics, transcription.
coded in the sequence of the four bases A/T miRNAs are short, highly conserved,
and C/G, additional mechanisms of genetic noncoding RNAs binding to 59-untranslated
regulation epigenetics and regulatory genes regions (59-UTR) of messenger RNAs.
have been discovered in recent years. Incomplete binding leads to silencing, and
complete binding to degradation of the RNA.
The term epigenetics describes a wide field of
In fact, miRNAs are powerful regulators.
DNA and histone modifications that
Activation of transcription factors such as
contribute to the regulation of gene
nuclear factor-kB leads to transcription of a
transcription. One of these modifications is
variety of immune mediator genes.
the methylation of the nucleobase cytosine.
Simultaneous activation of miRNAs
Cytosine is methylated only in CG islands;
suppresses certain mediators giving rise to a
single cytosines are not methylated. Cytosine
specific pattern of mediator activation. This
methylation inhibits binding of RNA
area of research is at an early stage, and novel
polymerases to the gene, which is
aspects of gene regulation might be expected.
subsequently not translated. Cytosine
methylation is important in promoter silencing Genetics in CF
and inactivation of the X chromosome.
As mentioned above, CF is caused by the
Histone modifications are an additional form dysfunction of the cystic fibrosis
of epigenetic regulation. Histones are protein transmembrane conductance regulator (CFTR)
spheres that bind DNA; there are four gene, which codes for a chloride channel.
different histones, and two of each histone However, although in all CF patients the CFTR
together with the bound DNA make up a is dysfunctional, there are .1,500 different
nucleosome, the core of a chromosome. mutations known to affect CFTR and lead to a
Histones can be modified, mainly by dysfunctional chloride channel. CF is inherited
Genetics 3
in an autosomally recessive fashion: the population being heterozygotic. However, the
disease becomes manifest only when the frequency declines to ,1% in southern
CFTR genes on both chromosomes are Europe. The lowest frequency is found in
mutated, although not necessarily by the African-Americans (0.4%).
same mutation. The most common defect is
the deletion of a phenylalanine at position Genetics in interstitial lung diseases
508 (DF508), which is responsible for up to There is some indication that interstitial lung
70% of all CF cases. Interestingly, there is a diseases such as sarcoidosis, CBD, or
marked difference in the frequency of this idiopathic pulmonary fibrosis (IPF) are based
disease in different populations. With a on a specific genetic background. In
frequency of 1:2,000, CF is most common in sarcoidosis and IPF, familial clusters are seen.
Caucasians (being highest in Scotland and In Europe, sarcoidosis frequency increases
the Faroe Islands). Populations of African from South to North. This might also be a
descent have a risk of 1:15,000; populations matter of climate, as the same distribution is
of Asian descent have the lowest risk seen in Japan. However, the Ainu, a minority
(1:30,000). CFTR mutations can be grouped distinct from the Japanese population in
into classes based on their functional northern Japan, exhibit a markedly lower
consequences on the CFTR within the cell:
frequency. The Swedish population encounters
CFTR is either not synthesised, inadequately
the highest prevalence in Europe (5564 per
processed, not regulated, shows abnormal
100,000); in contrast, the Finnish population
conductance, discloses partially defective
live at the same latitude but the prevalence is
production, or shows accelerated degradation.
just half that of the Swedish (28 per
Genetics in PIs 100,000). These differences point to a strong
genetic background in the pathogenesis of
The PI a1-AT belongs to a family of serine PIs sarcoidosis.
(serpins) and blocks serine proteases such as
neutrophil elastase, cathepsin G and The contribution of an inherited pre-
proteinase 3, all released by neutrophils. disposition to the aetiology of sarcoidosis is
Because more than one proteinase is blocked indicated by an increased risk of sarcoidosis in
by this inhibitor, it is more precisely named a1- close relatives of patients. The percentage of
PI. The lack of a1-PI leads to an incomplete or patients with a positive family history ranges
absent containment of proteinases resulting from 2.7% in Spain to 17% in African-
in severe organ damage (emphysema), mostly Americans. Analysis of familial sarcoidosis
in the lung. In the USA, a1-PI deficiency suggests that multiple small or moderate
causes 7.6% of lung transplantations. genetic effects cause a predisposition for
sarcoidosis.
There are several known mutations in the a1-
PI gene, such as base substitutions, in-frame Genes of interest have been HLA class II
deletions, frame shift mutations and exon antigens. Although some of these linkages are
deletions. .90% of the cases are caused by largely dependent on the population
single amino acid exchange at position 342 investigated, several associations do seem to
(glycine to lysine), which is called Z mutation. be preserved, e.g. HLA-DRB1*03 associates
The Z mutation results in a structural with spontaneous resolution and mild disease,
alteration, which inhibits post-translational as demonstrated in Swedish, Polish, Croatian
modifications and secretion. Patients bearing and Czech populations.
the Z allele disclose ,15% of the normal a1-
PI level in serum, which, additionally, seems to Using genome-wide association scans, two
be nonfunctional. additional candidate genes were identified,
the butyrophilin-like 2 gene (BTNL2) and
The gene frequency of the Z allele is rather Annexin A11 (ANXA11) gene. The BTNL2
common in Europe, with up to 4% of the disease-associated splice site (rs 276530)

introduces a premature stop resulting in SP-C in the alveolar lumen. This phenomenon
truncated nonfunctional protein. Because provides an explanation for the dominant
BTNL2 is necessary for the down-regulation of autosomal heredity of this mutation.
T-cell activation, the dysfunctional gene The second mutation causes a change from
product contributes to the exaggerated T-cell thymidine to adenine in exon 5 that results in
activation in sarcoidosis. the substitution of glutamine (position +188)
Annexin A11 exerts complex and essential by leucine. This variant of SP-C cannot be
functions in several biological pathways, processed and accumulates as pro-SP-C in the
including apoptosis and proliferation. cell. The pathological pattern of fibrosis is in
both forms consistent with nonspecific
There is a large body of studies analysing the interstitial pneumonitis in younger patients and
association of cytokine genes with sarcoidosis. usual interstitial pneumonia in the elderly.
With exception of the association of Lofgrens
syndrome and a variant of the tumour CBD is largely linked with Glu69+ HLA-DPB1,
necrosis factor (TNF)-a gene related to higher as 97% of CBD patients bear this HLA
cytokine production (TNFA2), these studies variant. However, the frequency of Glu69+
did not reveal conclusive results. HLA-DPB1 is also increased in beryllium-
sensitised healthy individuals. Interestingly,
Angiotensin-converting enzyme (ACE) is often Glu69+ HLA-DPB1 homozygosity was higher
used in the diagnosis and clinical monitoring in CBD patients compared with beryllium-
of sarcoidosis. However, serum levels of ACE sensitised individuals. Therefore, Glu69+ HLA-
(sACE) are highly variable, which impairs the DPB1 is a risk marker of beryllium
clinical use of ACE. The variability of sACE is sensitisation and homozygote Glu69+ HLA-
based on a deletion/insertion in intron 16 of DPB1 increases the risk for the progression
the ACE gene. The homozygote deletion from beryllium sensitisation to CBD; however,
variant is associated with higher sACE, there is a large variation in the time course for
whereas homozygote insertion is associated this conversion. This, together with the fact
with lower levels. Heterozygotes exhibit that Glu69+ HLA-DPB1 heterozygotes also
intermediate values. Therefore, in populations develop CBD, implies that additional genes
of Caucasian origin, the knowledge of the may add to the predisposition to CBD.
zygosity of the deletion/insertion variants
Genetics in asthma
allows the application of genotype-corrected
reference values of sACE, which leads to an There is a plethora of work related to the
improvement of the clinical application of this genetics of asthma. The idea of a genetic
marker. However, this is not applicable in basis for asthma is supported by the fact that
populations of African origin: the ACE gene in there are familial clusters of asthma and
these populations is much more polymorphic differences of asthma frequency in different
and sACE levels are not linked with the populations (with the highest being .20% of
deletion/insertion polymorphism. the population of the South Atlantic island
Tristan da Cunha). However, no single gene is
Familial pulmonary fibrosis is linked with two
responsible for the development or the clinical
mutations in the surfactant protein C (SP-C)
course of asthma; instead, several genes are
gene. The first mutation causes a change from
regarded as risk genes for developing asthma.
guanine to adenine at the starting point of
The gene products of these genes are involved
exon 4, resulting in a splice deletion of exon 4
in T-cell activation, cytokine release and
and subsequently a final protein lacking 37
balance, epithelial function and repair or
amino acids. This shortened protein is
smooth muscle contractility.
misfolded and accumulates in a perinuclear
pattern in the cells. The misfolded SP-C As methods in association studies improve
protein aggregates with the normal SP-C, rapidly, new candidate genes will be added to
which subsequently leads to a lack of mature this list in future.
Genetics 5
Nevertheless, although there are predisposing Conclusion
genes in asthma, the influence of lifestyle on
Genetic aspects have to be considered in all
the development of asthma is also evident.
areas of pulmonary medicine. As physicians
There is a clear increase in asthma incidences
are faced with phenotypes, the underlying
in developing countries. Therefore, asthma
degree of genetic influence is not always
might be an elucidating example for the
obvious. The knowledge of the genotype
complex genotype/phenotype relationship.
causing a respective phenotype might be a
Genetics in cancer promising tool to predict outcome or
therapeutic options, and would enable
Mutations and epigenetic modifications are individual genotype/phenotype-based
passed to the offspring as far as the germ cells therapies.
are concerned. However, there are also
mutations outside the germline so-called References
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MOLECULAR BIOLOGY OF
THE LUNG
nigshoff and O. Eickelberg
M. Ko
Comprehensive Pneumology Center, Ludwig-Maximilians-University and
Helmholtz Zentrum Mu nchen
E-mail: oliver.eickelberg@helmholtz-muenchen.de
Understanding of lung disease on the cellular signal through the ECM via adhesive
and molecular level is crucial to develop new molecules, surface receptors or growth factors.
approaches for the diagnosis, treatment and
prevention of lung disease. Although our The lung fibroblast is the main producer of
knowledge on the molecular level is steadily pulmonary ECM, which consists of collagens,
increasing, we still have a limited understanding elastins and proteoglycans. The interstitium of
of the molecular events underlying the diseases, the lung parenchyma contains mostly
which is reflected by the fact that very few collagen type I and III, which are mainly
therapies target specific defects. responsible for tensile strength.
The field of molecular biology focuses on the The pulmonary ECM is subjected to a
interactions between various systems of a cell continuous turnover of .10% of the total
and between cells, and particularly includes: ECM per day. Thus, a dynamic equilibrium
between synthesis and degradation of the
N gene structure, expression, replication, and pulmonary ECM maintains the physiological
recombination balance. This balance is tightly controlled by
N structure, function, chemistry, and in vivo three regulatory mechanisms: 1) de novo
modification and processing of proteins synthesis and deposition of ECM components
and nucleic acids such as collagens, mainly by interstitial
fibroblasts; 2) proteolytic degradation of
N cellular and developmental biology existing ECM by matrix metalloproteinases
N genetics, structure and growth cycles of (MMPs), a family of zinc enzymes; and 3)
viruses, bacteria, and bacteriophages. inhibition of MMP activity by specific
endogenous antiproteases, the tissue
This article focuses on selective (signal) inhibitors of metalloproteinases (TIMPs).
molecules and structures, all of which are
altered in various lung diseases and are
important topics in the field of molecular
biological research. Key points
The extracellular matrix Major features of lung diseases are:
Components of the extracellular matrix (ECM) N altered deposition of extracellular

surround and support the cell and cellcell matrix
interaction. In the lung, the ECM around the N impaired surfactant metabolism
conducting airways, alveolar cells and the
vascular system has a major impact on lung N distorted endogenous defence
architecture and function, in particular gas mechanisms
exchange. All lung cell types interact and
Molecular biology of the lung 7

Excessive or inappropriate expression of macrophage- and neutrophil-mediated release
MMPs is related to the pathogenesis of tissue of cytokines, such as interleukins 1 and 8,
destructive processes in many of lung tumor necrosis factor (TNF)-a, or granulocyte
diseases, such as MMP-12 in emphysema, or macrophage colony-stimulating factor (GM-CSF).
MMP-7 in lung fibrosis.
Pulmonary alveolar proteinosis is caused by
The surfactant system disruption of GM-CSF signalling. Loss of GM-
CSF signalling in macrophages results in an
The maintenance of normal lung function impaired ability to catabolise surfactant
throughout the life of an organism is ensured proteins. Abnormal surfactant accumulation
largely by alveolar epithelial cells, which form leads to respiratory insufficiency.
a tight functional barrier essential for gas
exchange. The alveolar epithelium is Mucociliary clearance represents the primary
composed of alveolar type I (ATI) and type II physiological defense mechanism. The ciliated
(ATII) cells. ATII and ATI cells produce and airway cells clear the mucus, which is
secrete components of the extracellular matrix produced by secretory cells, by forcing the
and growth factors thereof, which facilitates mucus toward the larynx for elemination. An
restoration of the interstitium and, impaired mucociliary clearance is the main
subsequently, functional alveolar structure. feature of cystic fibrosis.
ATII cells are cuboidal secretory cells mainly
Transforming growth factor-b
responsible for surfactant secretion.
Pulmonary surfactant is a complex mixture of The transforming growth factor (TGF)-b
phospholipids and proteins, with surfactant superfamily is critically involved in embryonic
proteins (SP)-A, -B and -C constituting 10% of development, organogenesis and tissue
surfactant. Its main role is to reduce surface homeostasis. TGF-b superfamily members act
tension in the alveoli following the onset of as multifunctional regulators of cell growth
breathing, thereby leading to lung expansion. and differentiation. The TGF-b superfamily
Mechanical stretching of the lung forces the comprises more than 40 members, including
secretion of lamellar bodies, the intracellular TGF-bs themselves. Three TGF-b isoforms have
storage granules of surfactant, which form been characterised so far: TGF-b1, TGF-b2 and
tubular myelin. The surfactant film stabilises TGF-b3. TGF-b1 is the most important isoform
the alveolarair interface with a low surface in the cardiopulmonary system, as it is
tension and prevents lung collapse. Following ubiquitously expressed and secreted by
secretion, both surfactant proteins and lipids several cell types, such as endothelial,
are recycled by the respiratory epithelium. epithelial and smooth muscle cells, as well as
fibroblasts and most cells of the immune
Surfactant abnormalities have been described system. TGF-b is secreted in covalent
in many infant and adult lung diseases, such association with the latent TGF-b binding
as respiratory distress syndrome, bronchiolitis, protein (LTBP), thus providing a reservoir in
chronic obstructive pulmonary disease (COPD) the ECM. For active signalling, TGF-b needs to
or interstitial lung disease. dissociate from the complex by a mechanism
Defence and clearance mechanisms that involves proteases, such as plasmin or
matrix metalloproteinases, as well as
From the above-mentioned proteins, interaction with integrins. Active TGF-b
surfactant proteins SP-A and SP-D are ligands bind to the type II TGF-b receptor,
primarily involved in the innate host defence which binds to the type I TGF-b receptors.
of the lung. In addition, antimicrobial Subsequent transphosphorylation of the type I
peptides (AMPs), such as defensins, receptor results in recruitment of specific
cathelicidins or lactoferrin, are present in the intracellular signals mediators, called Smad
airways to prevent infection. Moreover, proteins. Smad2 and Smad3 have been shown
cellular defence mechanisms include to be phosphorylated by the type I receptor,

followed by complex formation with Smad4 Increased TGF-b signalling is the key
and, finally, nuclear translocation and pathophysiological mechanism that leads to
regulation of gene transcription (fig. 1). The fibrotic lung disease, which is characterised by
receptor-regulated Smad2 or Smad3, in an increase in activated (myo)fibroblasts and
combination with the co-Smad Smad4, excessive deposition of ECM.
positively regulate TGF-b-induced effects,
while the inhibitory Smads (Smad6 and There is emerging interest in the role of TGF-b
Smad7) negatively regulate TGF-b signalling. in the pathogenesis of COPD, particularly
Active
TGF-
T RI T RII
P
SMAD2/3 P
SMAD6/7
SMAD2/3 P
SMAD4
P
SMAD2/3
SMAD4
DNA
Transcriptional regulation
Figure 1. Transforming growth factor-b signalling.
Molecular biology of the lung 9

since genetic studies have demonstrated an chemotherapeutic agents, or cytokines and
association of gene polymorphisms of the growth factors, activate NF-kB, and increased
TGF-b superfamily with COPD. In addition, NF-kB signalling has been associated with
increased expression of TGF-b1 in COPD has COPD or asthma.
been reported, suggesting an impact of TGF-b
signalling in the development and progression References
of COPD. N Bartram U, Speer CP. The role of transforming
growth factor beta in lung development and
Nuclear factor-kB disease. Chest 2004; 125: 754765.
Nuclear factor (NF)-kB is a ubiquitous N Edwards MR, et al. Targeting the NF-kB pathway
transcription factor present in all cell types. In in asthma and chronic obstructive pulmonary
disease. Pharmacol Ther 2009; 121: 113.
its resting stage, this factor resides in the
cytoplasm as a heterotrimer consisting of p50,
N Herzog EL, et al. Knowns and unknowns of the
alveolus. Proc Am Thorac Soc 2008; 5: 778
p65 and the inhibitory protein IkBa. Upon 782.
activation, the IkBa protein undergoes N Konigshoff M, et al. TGF-beta signaling in COPD:
phosphorylation, ubiquitination and deciphering genetic and cellular susceptibilities
degradation. p50 and p65 are then released for future therapeutic regimen. Swiss Med Wkly
to be translocated to the nucleus, where they 2009; 139: 554563.
bind specific DNA sequences present in the N Marraro GA. Surfactant in child and adult
promoters of various genes and initiate pathology: is it time to review our acquisitions?
transcription. IkBa kinase or IKK is Pediatr Crit Care Med 2008; 9: 537538.
responsible for the initial phosporylation. N Oikonomidi S, et al. Matrix metalloproteinases in
respiratory diseases: from pathogenesis to
Several kinases have been shown to activate potential clinical implications. Curr Med Chem
IKK, such as AKT, mitogen-activated protein/ 2009; 16: 12141228.
extracellular signal-regulated kinase kinase N Suki B, Bates JH. Extracellular matrix mechanics
kinase 1 (MEKK1), and protein kinase C. In in lung parenchymal diseases. Respir Physiol
the nucleus, NF-kB induces a range of gene Neurobiol 2008; 163: 3343.
expression, in particular of mediators of N Sun SC, Ley SC. New insights into NF-kB
inflammation, cell proliferation, metastasis regulation and function. Trends Immunol 2008;
and angiogenesis. 29: 469478.
N Suzuki T, et al. Role of innate immune cells and
Many noxious substances related to lung their products in lung immunopathology. Int J
disease, such as cigarette smoke, radiation, Biochem Cell Biol 2008; 40: 13481361.

ANATOMY OF THE
RESPIRATORY SYSTEM
P.L. Shah
Royal Brompton Hospital, London, UK
E-mail: pallav.shah@ic.ac.uk
The thoracic structures include the vital and diaphragmatic pleura. The costo-
organs for respiration and circulation. This mediastinal recess is between the costal and
anatomical section will focus on the pleura, mediastinal pleura and is found behind the
lungs, mediastinum and the diaphragm. The sternum and costal cartilages.
anatomy of the heart is not discussed.
The pleura is supplied by its regional blood
Pleura vessels. Hence, the cervical pleura is supplied
by branches of the subclavian artery, the
The lungs are covered by a fine membrane costo-vertebral pleura by the intercostal
known as the pleura. The parietal pleura is the arteries, and the diaphragmatic pleura from
outer layer and the visceral pleura is adherent the vascular plexus from the surface of the
to the lungs. The two are in continuity with diaphragm. The venous drainage occurs into
each other and there is a very fine space the corresponding veins, which then drain into
between the two, the pleural cavity. The the vena cava. The lymphatic drainage is into
parietal pleura is described according to the the corresponding lymph nodes, e.g. the
surface that it is adjacent to: costo-vertebral, intercostal lymphatics drain into the posterior
diaphragmatic, cervical and mediastinal. lymph nodes and then into the thoracic duct.
There are also pleural recesses where the two The visceral pleura is supplied by the
different pleural surfaces are situated next to bronchial vessels and the lymphatics drain
each other without any intervening lung in into the intercostal and peri-bronchial
normal respiration. The costo-diaphragmatic lymphatics. The parietal pleura is supplied by
recesses are a thin area between the costal the regional nerves and contains the pain
fibres. The costal and peripheral aspects of
the diaphragmatic pleura are supplied by the
Key points corresponding intercostal nerves, whereas the
diaphragmatic and mediastinal pleura are
N The anatomy of the thorax can be supplied by the phrenic nerves.
divided broadly into the pleura, lungs,
mediastinum, diaphragm and heart. Lungs
N The lungs can be further sub-divided The apex of the lung extends into the thoracic
into lobes, segments, trachea and inlet and on the anterior aspect lies above the
bronchi and hila. first costal cartilage. On the posterior aspect,
the apex of the lung is level with the neck of
N The mediastinal space contains the first rib. At its highest position it is
structures including the thymus gland, ,2.5 cm above the clavicle. The base of the
thoracic lymph nodes, thoracic duct, lung is a concave structure and lies over the
vagus nerve and autonomic nerve diaphragm. The main surface of the lung is
plexus. the costal surface, which is smooth and
shaped according to the chest wall. The
Anatomy of the respiratory system 11

medial surface of the lung is shaped posteriorly ,25 mm long and divides into the right
according to the vertebral column and medially upper lobe at the level of the fifth thoracic
by the heart. The lungs are also indented by vertebra. It then continues as the bronchus
the numerous vascular structures, such as the intermedius, which is ,20 mm in length. The
aorta, that are in contact with them. right main bronchus is wider, shorter and
more vertical than the left main bronchus and
The right lung consists of upper, middle and hence foreign bodies tend to lodge more
lower lobes. The left lung is composed of an frequently into the right main bronchus. The
upper and lower lobe. In the right lung there bronchus intermedius then branches into the
are two fissures. The oblique fissure separates middle and lower lobes. The right middle lobe
the lower lobe from the upper and the middle is formed on the anterior aspect of the
lobe. The smaller horizontal fissure separates bronchus intermedius. The right lower lobe
the upper and middle lobes. In the left lung, bronchus gives off a branch to the superior
the oblique fissure separates the upper lobe segment and continues to descend postero-
from the lower lobe. laterally giving off branches to the medial,
Bronchopulmonary segments anterior, lateral and posterior segments of the
lower lobe.
The main bronchi divide into lobar bronchi
that in turn divide into segmental bronchi. The left main bronchus is longer, measuring
Each divides into a structurally and ,40 mm in length, and enters the hilum of
functionally independent unit of tissue. The the left lung at approximately the level of the
right lung consists of 10 bronchopulmonary sixth thoracic vertebra. It divides into the left
segments, three in the upper lobe, two in the upper lobe and left lower lobe bronchus; the
middle lobe and five in the lower lobe. left upper lobe bronchus in turn gives off the
superior division and supplies the apical
The left lung comprises nine segments, five in posterior and anterior branches of the left
the upper lobe, including two within the
lingula, and four in the lower lobes. There is
no true medial segment in the left lower lobe
as this area is occupied by the heart.
Each bronchus continues to subdivide into
smaller narrower airways until they finally
form terminal bronchioles and then
respiratory bronchioles, which are devoid of
cartilage. These in turn lead to several alveolar
ducts, which in turn end in several alveoli. The
collective structure is termed an acinus. The
secondary pulmonary lobule is the smallest
part of the peripheral lung bounded by
connective tissue and usually consists of six
bronchi forming a hexagonal pattern with a
central artery, lymphatic and peripheral veins.
Trachea and bronchi
The trachea (fig. 1) is 100 mm long and

made up of anterolateral cartilage rings with
a fibro-muscular posterior wall. The trachea
divides at the level of the fourth vertebral
body (level with the aortic arch) into the right
and left bronchi. The right main bronchus is Figure 1. The trachea and bronchi. P.L. Shah.

upper lobe and the inferior division, which bronchi. The artery then enters the lung via
supplies the superior segment of the lingula the hilum. On the right side the upper lobe
and inferior segment of the lingula. The left branch of the pulmonary arteries is anterior
lower lobe descends postero-laterally and first and lateral to the right upper lobe whereas
gives off a posteriorly located branch to the the inferior branch of the pulmonary artery
apical segment of the lower lobe and then passes laterally and posterior to the lower lobe
gives branches to antero-medial, lateral and bronchus. On the left side, both upper and
posterior basal bronchi. lower lobe pulmonary artery branches are
lateral and posterior to the corresponding
The trachea is supplied superiorly by branches airways. The descending branch of the left
of the inferior thyroid arteries and more pulmonary artery passes behind the left upper
inferiorly by branches of the bronchial lobe and travels laterally and inferior to the
arteries. The venous drainage tends to be left lower lobe bronchi.
towards the inferior thyroid venous plexus and
the lymphatic drainage to the pre-tracheal There are two pulmonary veins on each side
and para-tracheal lymph nodes. The bronchi (superior and inferior pulmonary veins) that
and the airways are supplied by the bronchial pass anterior and inferior to the pulmonary
arteries, which originate from the systemic artery and bronchi. The lymphatic vessels
circulation and arise either directly from the drain into the hilar and subsequently into the
descending thoracic aorta or indirectly via the tracheo-bronchial lymph nodes.
intercostal arteries. The venous drainage of
the airways is more complicated and consists Mediastinum
of deep bronchial veins that communicate The mediastinum is the space between the
with pulmonary veins that drain back into the two lungs. The superior extent of the
left atrium. There are also superficial mediastinum is the thoracic inlet and the
bronchial veins that drain into the azygos or inferior extent the diaphragm. The anterior
the intercostal veins. The innervation of the border is the sternum and the posterior border
endobronchial tree is via the anterior and is the vertebral column. It is divided into the
posterior pulmonary plexus, which include superior, anterior, middle and posterior
branches from the vagus, recurrent laryngeal mediastinum. The mediastinum contains
and sympathetic nerves. numerous structures, such as the thymus
Hila gland, thoracic lymph nodes, thoracic duct,
vagus nerve and the autonomic nerve plexus.
The pulmonary hila join the medial aspect of
the lung to the heart and the trachea. In each The thymus gland lies in the superior and
hilum there are a number of structures either anterior mediastinum. The lower border is
entering or leaving the structure. They include down to the fourth costal cartilage. Its blood
the main bronchi, pulmonary artery, superior supply is derived from a branch of the internal
pulmonary vein, inferior pulmonary vein, thoracic artery and the inferior thyroid artery.
bronchial artery, bronchial vein, pulmonary The thymic veins drain into the left brachial
autonomic neural plexus, lymphatics and cephalic vein and internal thoracic veins. The
loose connective tissue. lymphatic drainage is into the trachea-
bronchial lymph nodes.
Pulmonary vasculature and lymphatic
drainage The mediastinum lymph nodes have special
significance in the staging of lung cancer.
The pulmonary artery carries deoxygenated They are found in the pre-tracheal,
blood to the alveoli and the oxygenated blood paratracheal, subcarinal and para-
then returns via the pulmonary veins to the oesophageal positions. They are classified
left atrium. The pulmonary arteries lie anterior according to the International Association for
to the carina and the corresponding main the Study of Lung Cancer (IASLC) lymph node
Anatomy of the respiratory system 13

map into lymph node stations, e.g. station 4 is an important role in the mechanism of
the right paratracheal lymph node. The breathing and coughing. It is a convex upper
thoracic duct starts at the lower level of the surface and is circumferentially attached to
12th thoracic vertebra and enters the the lower aspect of the thorax with muscle
mediastinum through the aortic opening of fibres that converge to a central tendon. The
the diaphragm. It runs in the posterior aspect diaphragm has three openings within it
of the mediastinum just right of the mid line through which pass the inferior vena cava (at
between the aorta and the azygos vein. In the the level of eighth thoracic vertebra, T8), the
superior mediastinum, it ascends onto the left oesophagus (T10) and the aorta (T12). Its
side adjacent to the oesophagus. It finally blood supply is from the lower five intercostal
terminates into one of the subclavian veins or arteries, the subcostal artery and phrenic
the internal jugular vein. arteries. The venous drainage is from the
The vagus nerve on the right side is found phrenic nerves, which drain into the inferior
lateral to the trachea and posterior medial to vena cava. The diaphragm is supplied by the
the right brachial cephalic vein and super phrenic nerve, which primarily originates from
vena cava. It then passes behind the right C4, C5 and C6 cervical nerve root (the course
main bronchus and continues to the posterior of which is described above).
aspect of the right atrium. Here it divides into Development
braches, which form the pulmonary
autonomic plexus. The left vagus nerve is The development of the respiratory system
found between the left common carotid and occurs at ,26 days of gestation with
subclavian artery and behind the left proliferation of a diverticulum that originates
brachiocephalic vein. It crosses the aortic arch from the foregut. The larynogotracheal tube
and passes behind the left hilum. Here it and main bronchi are formed first. Over the
divides and forms the pulmonary plexus. The next 10 weeks, the lower conducting airways
autonomic nervous plexus in the mediastinum develop and finally the acinar structures
is formed from the vagus nerve, thoracic develop. The alveoli and interstitial tissue is
sympathetic chain and the autonomic plexus then formed. Alveolar development occurs
(cardiac, oesophageal and pulmonary plexus). from 28 weeks gestation and continues
The right phrenic nerve descends lateral to the during early childhood.
super vena cava anterior to the pulmonary References
hilar and then along the pericardium (over the
right atrium) before reaching the diaphragm. N Shah PL. Pleura, lungs, trachea and bronchi. In:
The left phrenic nerve runs antero-medial to Standring S., ed. Grays Anatomy. 40th Edn.
the vagus nerve above the aortic arch and Churchill Livingstone, London, 2008; pp. 989
then anterior to the left hilum. It then runs 1006.
along the pericardium (covering the left N Shah PL. Diaphragm and phrenic nerve. In:
Standring S., ed. Grays Anatomy. 40th Edn.
ventricle) before supplying the diaphragm.
Churchill Livingstone, London, 2008; pp. 1007
Diaphragm 1012.
N Shah PL, Spratt J. Mediastinum. In: Standring S.,
This is a musculo-fibrous sheet that separates ed. Grays Anatomy. 40th Edn. Churchill
the thorax and abdomen. The diaphragm has Livingstone, London, 2008; pp. 939957.

RESPIRATORY PHYSIOLOGY
S.A. Ward
Human Bio-Energetics Research Centre, Crickhowell, UK
E-mail: saward@dsl.pipex.com
The appropriateness of the ventilatory (V9E) respiratory-muscle work, perfusion and O2

response to a challenge such as hypoxia or consumption.
altered metabolic rate depends not on the
Ventilatory requirements
level of V9E achieved but whether the
pulmonary gas-exchange and acidbase Alveolar, and hence arterial, CO2 and O2
requirements are achieved: i.e. regulating tension (PA,CO2, PA,O2, Pa,CO2 and Pa,O2,
arterial CO2 tension (Pa,CO2), pH (pHa) and O2 respectively) can only be regulated if alveolar
tension (Pa,O2) within the relatively narrow ventilation (V9A) increases in an appropriate
range that provides optimal functioning. This proportion to V9CO2 and V9O2, respectively.
regulation involves a cascade of mechanisms: With respect to CO2 exchange (Ficks principle):
airflow and volume generation, pulmonary O2
V9A 5 863?V9CO2/PA,CO2 (1)
uptake (V9O2) and CO2 output (V9CO2), and
V9E control with its associated respiratory where 863 is the constant that corrects for the
perceptions. Each of these mechanisms can be different conditions of reporting gas volumes
adversely affected in pulmonary disease, with (i.e. standard temperature and pressure, dry,
impaired respiratory-mechanical and gas- body temperature and pressure, saturated)
exchange function increasing the V9E and the transformation of fractional
demands of a particular task and, in turn, the concentration to partial pressure.
costs of meeting these demands in terms of Similarly, for O2:
V9A 5 863?V9O2/[PI*,O2PA,O2] (2)
Key points
where PI,O2 is the inspired PO2, and * is a
N The mechanical work of breathing relatively small correction factor (5 FA,N2/
comprises elastic (or volume - related) FI,N2, where FA,N2 and FI,N2 are the alveolar
and resistive (flow related) components. and inspired nitrogen fractions, respectively)
that takes account of inspired ventilation
N With expiratory efforts that cause normally being slightly greater than expired
intrapleural pressure to become ventilation. This is a consequence of the
positive, the presence of an equal bodys metabolic processes releasing less CO2
pressure point results in expiratory relative to the O2 used for a normal western
flow limitation. diet, for which the respiratory quotient (RQ 5
N Arterial hypoxaemia can result from metabolic CO2 production/metabolic O2
alveolar hypoventilation, diffusion consumption) is normally <0.85.
limitation, ventilation - perfusion As V9A is common to equations 1 and 2, then:
maldistribution and/or right-to-left
[863?V9CO2]/PA,CO2 r V9A R [863?V9O2]/
shunt. Only the latter three mechanisms
[PI*,O2-PA,O2] (3)
also lead to a widened alveolar-to-
arterial PO2 difference (i.e. inefficient Thus, if V9CO2 and V9O2 are equal (i.e.
pulmonary O2 exchange). respiratory exchange ratio (RER) 5 1), both
PA,CO2 and PA,O2 can be regulated. However,
Respiratory physiology 15
both cannot be regulated if V9CO2 and V9O2 Respiratory mechanics
differ, as is the case when: 1) RQ changes as a
result of dietary- or activity-related alterations A particular V9E requirement can, in theory, be
in the metabolic substrate utilisation profile or accomplished with an infinite combination of
2) there are transient variations in body gas VT and breathing frequency (fR). The VT-fR
stores (particularly the CO2 stores) that occur combination, in turn, will influence the
as metabolic rate changes. Under such inspiratory-muscle pressure (PMUS) needed to
conditions V9A changes in closer proportion to effect inspiration:
V9CO2 than to V9O2, with PA,CO2 consequently PMUS 5 E?V + R?v9 + I?v99 (7)
being the more closely regulated variable and
PA,O2 consequently being allowed to change. where V, v9 and v99 are volume, air (and
However, as these PO2 changes are normally pulmonary tissue) flow and acceleration,
within the range in which the O2 dissociation respectively, and E, R and I are the pulmonary
curve is relatively flat, arterial O2 content elastance, resistance and inertance,
(Ca,O2) will not be affected to any great respectively. Normally, the inertance-related
extent. The regulatory outcome becomes more term does not make a significant contribution,
complex if, for example, significant arterial i.e. although the acceleration of the air can be
hypoxaemia develops when V9A increases out large, its mass is small, and while the mass of
of proportion to V9CO2 (hyperventilation) in the thorax is relatively large, its acceleration is
order to constrain the fall in PA,O2 or with small (c.f. conditions such as obesity where
metabolic acidbase disturbances that evoke the mass of the thorax can be abnormally
respiratory compensatory responses to increased). Thus, PMUS typically has a static, or
ameliorate the pHa change. volume-related, component (i.e. with no
associated air flow) and a resistive, or flow-
However, it is the total V9E rather than V9A
related, component.
that is controlled to effect these regulatory
functions. Account can be taken of the The static component of PMUS equals the
influence of the physiological dead space increment in transpulmonary pressure (PTP)
volume (VD) by substituting V9E?(1-VD/VT), required to effect the required degree of lung
where VT is the tidal volume, for V9A in distension under static conditions, i.e.
equation 1 (where VD/VT is the physiological
dead space fraction of the breath), and PA,CO2 PTP 5 PALV-PIP 5 V/C (8)
being assumed equal to PA,CO2, i.e. where PALV and PIP are the alveolar and
V9E 5 [863?V9CO2]/[Pa,CO2?(1-VD/VT)] (4) intrapleural pressures, respectively; and C is
lung compliance. C is determined by the
Thus, the V9E requirement is determined by elastic properties of the lung parenchyma and
Pa,CO2, V9CO2 and VD/VT. Furthermore, the also by the surface-active forces operating at
influence of metabolic acidbase disturbances the alveolar airliquid interface; the latter
can be accommodated by substituting for being offset by the influence of surfactant.
Pa,CO2 from equation 4 into the Henderson
Hasselbalch equation, i.e. The static VPTP relationship (fig. 1, line 2)
shows C to be largely independent of V over
pHa 5 pK9 + log([HCO3-]a/a?Pa,CO2) (5) the tidal range; however, C decreases
where a is the CO2 solubility coefficient which progressively as total lung capacity (TLC) is
relates Pa,CO2 to CO2 content. This yields: approached. A decreased compliance (e.g.
restrictive lung disease) requires a greater
pHa 5 pK9 + than normal increase in PTP to effect a given
[log([HCO3-]a/25.6)]?[V9E/V9CO2]?[1- VD/VT] (6) lung inflation (fig. 1, line 1), while a reduced
Y Y Y compliance (e.g. emphysema) requires a
smaller PTP increment (fig. 1, line 3). Also, as
set-point control efficiency forced residual capacity (FRC) and the

which imposes a greater demand on pressure
generation because of the v92 term. Turbulent
flow develops when the Reynolds number
(Re) exceeds a value of ,2,000. As Re 5
(3)
v?2r?r/g, where v is the linear velocity and r
is gas density, it is readily apparent that
turbulent flow predominates when v is high,
(2) or at branch points, or across constricted

V
regions. Hence, reducing r, e.g. by breathing

high concentrations of helium instead of
nitrogen (heliox), makes turbulence less
(1)
likely.

The thoracic expansion that occurs during
inspiration causes PALV to become negative
PTP (i.e. below PATM) and flow to occur, until the
end of inspiration when PALV again equals
Figure 1. Lung compliance curve between forced PATM (fig. 2a). Thus, the pressure
residual capacity ($) and total lung capacity (6) for requirements for inspiratory flow and volume
increased (1) and decreased (3) lung recoil relative to generation are reflected in PIP: under static
normal (2). The slope at any point represents
conditions, volume changes are simply related
compliance, i.e. change in lung volume (V) induced
by change in transpulmonary pressure (PTP).
to changes in PIP through the static lung
compliance relationship (as PALV is zero) while,
during a normal inspiration, the additional
associated PIP are determined by the muscular force needed to overcome R causes
magnitude of the opposing chest wall and a greater negativity of PIP at any given lung
lung recoil forces, FRC is smaller and PIP more volume. The difference between the PIP
subatmospheric under conditions of increased change needed to provide v9 and that
recoil (fig. 1, line 1) than when recoil is required to distend the lung statically is
reduced (fig. 1, line 3). represented by the blue area in figure 2a, and
is consequently greatest when v9 is greatest.
The resistive or flow-related component of The respiratory-muscle work (W) performed in
PMUS is the increment in driving pressure producing the inspiration can thus be
required to effect air flow, i.e. the difference calculated as: DV?DPIP (fig. 2b), i.e. the sum
between PALV and pressure at the airway of the elastic work required to overcome the
opening (atmospheric pressure, PATM): static lung recoil forces (red area) and the
PALV-PATM 5 v9?R 5 k1?v9 + k2?v92 (9) resistive work (blue area). When breathing is
stimulated (e.g. in exercise), the greater PALV
The major site of this resistance lies in the required to generate the increased v9
segmental bronchi and larger-sized small amplifies the dynamic component of the VP
bronchi; because of their very large number, relationship (fig. 2a, right) and therefore
the bronchioles, which individually constitute increases W. A similar effect is seen in patients
sites of high resistance because of their very with an abnormally increased R, in whom a
small radius, collectively contribute relatively greater PALV is required to achieve a particular
little to the overall resistance (only ,1020% v9. Expressing W relative to time yields the
of the airway resistance being related to power output (W9) of the inspiratory muscles
airways ,2 mm in diameter). The term k1?v9 which, when related to their O2 consumption
reflects the laminar component of airflow, (Q9O2), allows considerations of overall
with k158gl/r4 where l is airway length, r is respiratory muscle efficiency. It is only at very
airway radius and g is gas viscosity. The term high levels of V9E (e.g. at peak exercise in
k2?v92 reflects the turbulent component, highly fit endurance athletes) or when
a) b)
1.5
VT L
1.0
0.5
-5
PIP cmH2O
-10
V
-15
2
1
PIP
0
V' Ls-1
1
2
I E I E
Figure 2. a) Tidal volume (VT), intrapleural pressure (PIP) and flow (v9) changes for normal resting and
exercising breaths. The dashed line on the PIP curve represents pressure needed to produce lung inflation
statically. The shaded area is the extra PIP required to generate flow. b) Dynamic inspiratory volume (V)PIP
curve. The stippled area represents static inspiratory work of breathing; the shaded area is the dynamic
component. I: inspiration; E: expiration.
respiratory impedance is abnormally high (as Furthermore, the equality for PREC deriving
in pulmonary disease) that W, W9 and Q9O2 from equations 8 and 9 yields:
are anything other than insignificant in
V/C 5 R?v9
magnitude; this can lead to respiratory muscle
fatigue. which can be rearranged as:
When V9E is low, expiration can be achieved v9/V 5 1/R?C (12)

entirely through the recoil pressure (PREC) The term R?C is the mechanical time
generated in the elastic structures of the lungs constant (t) of the respiratory system, and
during the previous inspiration, i.e. providing has the unit of time, i.e.
the necessary driving pressure by increasing (cmH2O?L-1?s)?(L?cmH2O-1) 5 s. Thus, if R or C
PALV (fig. 2a, left): (or, of course, both) are large, then v9 will be
low for a given lung volume. Complete passive
PTP 5 PREC 5 PALV-PIP 5 R?v9 (10) emptying (i.e. down to FRC) for a spontaneous
Flow at any point in expiration is thus expiration requires expiratory duration to be
determined by the interplay between static sufficiently long (i.e. effectively four time
lung recoil, PIP and resistance: constants for an exponential process).
Considering a normal t of ,0.4 s (R and C
v9 5 PREC + PIP/R (11) being ,2 cmH2O?L-1?s and 0.2 L?cm H2O-1,

respectively), this minimum period is ,1.6 s right), and thus v9 at a particular lung volume
and translates to a total breath duration (ttot) is lower than normal. In contrast, for restrictive
of ,3 s, assuming an inspiratory duty cycle lung disease, while maximal v9 at TLC is low
(tI/ttot, where tI is inspiratory duration) of owing to poor dispensability (fig. 1, line 1), v9
,0.4. Thus, if fR exceeds ,20 min-1, complete at a particular lung volume can be even
emptying requires expiratory flow to be slightly higher than normal owing to an
augmented by expiratory muscle action; increased PREC. Furthermore, when there is
without this, end-expiratory lung volume will regional nonuniformity of t, as in COPD, for
be greater than FRC. Such dynamic example, this can contribute to the typically
hyperinflation is a hallmark of the exercising scooped maximal expiratory v9 profile
chronic obstructive pulmonary disease (COPD) (fig. 3, right).
patient (fig. 3, right), where disease-related
increases in R and/or C can lower this limiting The effects of PIP on expiratory v9 are not
fR quite considerably. quite as straightforward, however, as those of
R and PREC (equation 12). PIP is an index of
That the maximal volitionally generated the effort transmitted from the respiratory
expiratory v9 is greater at high lung volumes muscles to the lungs via the chest wall.
than when lung volume is low (fig. 3) is, of During expiration, PIP can become positive as
course, implicit in equation 11. That is, R and a function of the applied expiratory effort, i.e.
PREC are each volume-dependent: at high the chest wall volume decreases faster than
volumes, R is relatively low reflecting a the lungs intrinsic recoil. This results in a
modest degree of airway distension (whose compressive force being applied to the
effect is amplified through the r4 term) while intrapleural space. As PALV 5 PIP + PREC
PREC is relatively high. Indeed, for a given t, v9 (equation 10), PALV will be more positive than
decreases as a linear function of V (equation PIP by an amount equal to PREC. Airway
12), accounting for the descending limb of pressure (PAW) declines from the alveolar
the maximal expiratory flowvolume curve value down to zero at the mouth as a result of
normally being so linear (fig. 3, left). frictional losses along the airways. At the
point at which PAW 5 PIP (i.e. the transmural
In COPD, however, the lower maximal v9 at pressure across the airway is zero) (fig. 4), an
TLC, despite the higher absolute lung volume equal pressure point (EPP) results.
(fig. 1, line 3), is indicative of an increased R
and, for emphysema, decreased PREC (fig. 3, In normal subjects, the EPP occurs in the large
airways (lower trachea or mainstem bronchi),
a) 10 b) which, despite the tendency to become
8 compressed, are prevented from collapsing by
6 their cartilaginous support. Thus, the EPP
4 becomes the limiting point for expiratory flow
Flow Ls-1
2 generation, dictating the maximum expiratory

0 flow (v9max):
2 1 2 3 4 5 1 2 3 4 5
4 v9max 5 PREC/Rus (13)
6 where Rus is the resistance of the upstream
8 Volume L Volume L
segment of the airways (between the
alveolus and the EPP) (fig. 4). This explains
Figure 3. Inspiratory (downwards) and expiratory
why progressively greater expiratory efforts,
(upwards) flowvolume curves at rest, maximal
exercise and with maximal volitional effort for a) a although leading to a progressively more
normal subject and b) a patient with chronic positive PIP, do not lead to a progressively
obstructive pulmonary disease. Reproduced from greater v9; greater expiratory effort simply
KLAS (1989), with permission from the compresses the airways more, raising
publisher. downstream resistance in proportion to the
Rus few mmHg or so when R?1 and is zero when
R51, yielding:
PIP = 20
PAi,O2 5 PI,O2-Pa,CO2/R (14)
Impairments of pulmonary gas exchange
PALV typically result in arterial hypoxaemia and, in
= 30 20 0 some instances, arterial hypercapnia. Six
mechanisms can be identified as independent
causes of arterial hypoxaemia: three of these
PREC = 10 affect PA,O2 (ambient hypoxia as occurs on
ascent to altitude, reduced RQ and alveolar
EPP hypoventilation) and three affect PAa,O2
(diffusion limitation, increased right-to-left
Figure 4. Airflow limitation in expiration. An equal shunt and ventilationperfusion (Q9)
pressure point (EPP) results when airway pressure maldistribution (V9A/Q9)).
declines to a value equal to the recoil pressure
(PREC); Rus is the resistance of the upstream
segment of the airways. PIP: intrapleural pressure; Reduced RQ Recalling that V9E normally
PALV: alveolar pressure. operates to regulate Pa,CO2, by responding in a
proportional fashion to V9CO2, when the RQ of
the dietary substrate is reduced (i.e. by
increased effort. v9 therefore becomes ingestion of a high-fat diet), the associated
maximised at a constant value (at that lung reduction in metabolic CO2 production will
volume), independent of effort. require less ventilation to maintain a stable
Pa,CO2 (equation 3). This leads to
With loss of lung recoil and/or increases in hypoventilation relative to O2, i.e. V9E is
small airways resistance, however, the EPP normal relative to V9CO2 but low relative to
migrates upstream. If it encroaches into the V9O2. Thus, PA,O2 and Pa,O2 will fall.
small unsupported airways, airways collapse
occurs with, consequently, profound effects
Alveolar hypoventilation Alveolar
on v9max (equation 13).
hypoventilation can occur in diseases or with
Pulmonary gas exchange drugs that affect the medullary respiratory-
integrating centres or respiratory
The effectiveness of pulmonary O2 exchange neuromuscular function and therefore reduce
is conventionally judged by the magnitude of the level of respiratory motor output. It may
the alveolararterial O2 tension difference also be seen in severe COPD, consequent to
(PAa,O2) where PAi,O2 is considered the PA,O2 the abnormally increased small-airways
of the ideal lung, which hypothetically resistance and high resistive work of
exchanges gases ideally. PAi,O2 thus breathing. Arterial hypoxaemia and
circumvents the difficulty of providing a single hypercapnia result (equations 2 and 1,
representative value for PA,O2 when there are respectively), with the fall of Pa,O2 being
regional variations in gas-exchange efficiency, related to the rise of Pa,CO2 by R (equation
and can be derived as follows (i.e. by re- 14). Thus, when R51, the increase in PA,CO2
arranging and amalgamating equations 1 and and the fall in PA,O2, which result from a
2: V9CO2/V9O2 5 RER 5 {V9A?[(PI,O2?FA,N2/ reduction in V9A , are numerically equal, as
FI,N2)-PAi,O2]}/(V9A?PA,CO2): notionally are the corresponding changes in
PAi,O2 5 PI,O2-Pa,CO2/R + [Pa,CO2?FI,O2?(1-R)/R] Pa,CO2 and Pa,O2. However, as R is normally
,0.8 at rest, for each 10 mmHg decrease in
It is common practice to neglect the term in Pa,O2 that results from a fall of V9A , Pa,CO2 will
the square brackets, as it only contributes a increase by ,8 mmHg. It should be noted

that the hypoxaemia can be offset by alveolar gas and pulmonary capillary blood.
administration of supplementary O2. The rate of diffusive uptake of O2 into blood is
given by:
Diffusion impairment Ficks law indicates V9O2 5 A/1?d?(PA,O2-Pc ,O2)
that impairments in the pulmonary diffusive
flux of O2 (or CO2) can result from 1) a where A is the alveolar surface area in contact
reduction in the driving pressure (for O2, with perfused pulmonary capillaries; l is the
DPO2); 2) a reduction in the available surface diffusion pathlength which extends from the
area for diffusion (A); and/or 3) an increased alveolar surface fluid lining to the erythrocyte
path length for diffusion (l): interior to include the alveolar epithelium,
interstitial space, capillary endothelial cells,
plasma, the erythrocyte cell membrane and,
V9O2 5 A/l?d?DPO2 (15)
for a reactive gas species such as O2, its
where d is the diffusion coefficient for O2 chemical combination with haemoglobin
which is inversely proportional to gas (Hb); and Pc ,O2 is the mean pulmonary
molecular_ weight (MW) in the gas phase capillary PO2. It is conventional to combine A,
(d51/!MW ), while directly proportional also l and d into a single term, the pulmonary
to_gas solubility (s) in the blood phase (d 5 s/ diffusing capacity of the lung for O2 (DL,O2) or
!MW ). Hence, as O2 is lighter than CO2, it transfer factor:
diffuses 18% more rapidly in the gas phase V9O2 5 DL,O2?(PA,O2-Pc ,O2) (16)
for the same partial pressure gradient. In the
blood phase, however, CO2 is 20 times more DL,O2 can be usefully subdivided into its
diffusible than O2, owing to its greater functional components, i.e. the membrane
solubility. component (DM,O2) and that due to chemical
combination:
During inspiration, O2 is transported down the
tracheobronchial tree by convective or bulk 1/ DL,O2 5 1/ DM,O2 + 1/h?Vc (17)
flow. At the level of the alveolar ducts, owing where h is the reaction rate coefficient for
to the large overall cross-sectional area of the chemical combination of O2 with
airways and the resulting reduction in the haemaoglobin (Hb), and Vc is the pulmonary
linear velocity of the inspired gas, movement capillary blood volume. Because of technical
to the alveolarcapillary membrane relies on limitations associated with estimating Pc ,O2, it
diffusion. Diffusion through the alveolar gas is conventional to determine diffusing
space does not normally limit gas transfer into capacity of the lung and membrane in terms
pulmonary capillary blood. Thus, as the of carbon monoxide (DL,CO, DM,CO) as the
average alveolar diameter is normally only high affinity of Hb for CO ensures that the
,100 mm, diffusion equilibrium (i.e. pulmonary capillary CO tension (PCO) is
DPO250) throughout the alveolus is attained effectively zero (see Chapter 3, Gas transfer).
rapidly: this is normally 80% complete within
, 0.002 s, which is several orders of The initial driving pressure across the
magnitude less than the time for which the alveolarcapillary membrane (i.e. at the
pulmonary capillary blood is exposed to the entrance to the capillary bed) is given by the
alveolar gas-exchange surface (i.e. the difference between PA,O2 (normally
pulmonarycapillary transit time (tTR), which ,100 mmHg) and the mixed venous PO2
is ,0.8 s at rest). In conditions such as (Pv,O2, normally ,40 mmHg at rest, although
emphysema, air-sac enlargement increases the latter decreases as in exercise). The rate at
intra-alveolar diffusion distances, predisposing which O2 is taken up into the blood decreases
to less efficient O2 and CO2 exchange. from this point as blood traverses the
capillary, reflecting the increasing Pc,O2 (and
More commonly, however, diffusion limitation consequent decrease in PA,O2), which in turn
reflects exchange impairments between reduces the instantaneous DPO2. Diffusion
equilibrium is normally reached within 0.25 pulmonary embolism, where there are fewer
0.3 s (i.e. well before the blood reaches the participating capillaries), the reduction in tTR
end of the capillary), such that pulmonary can lead to a widening of the PAa,O2 and
end-capillary PO2 (Pc9,O2)5PA,O2. This large arterial hypoxaemia. Supplemental O2 can,
safety margin becomes compromised, through its effects on PA,O2 and therefore
however, when tTR is shortened to a degree driving pressure, speed the increase of Pc,O2
that there is insufficient time for the and thus ameliorate the degree of gas-
attainment of diffusion equilibrium, i.e. exchange impairment.
Pc9,O2,PA,O2. As tTR5Vc/Q9 (where Q9 is
pulmonary blood flow), an increase in Q9 (e.g. Even though severe degrees of arterial
high-intensity exercise) predisposes to lack of hypoxaemia can result from diffusion
diffusion equilibrium resulting in arterial impairment, CO2 retention is rarely a problem.
hypoxaemia. However, the decrease in tTR This is because any increase in Pa,CO2 that
with increases in Q9 is less than expected might occur tends to be corrected by
because Qc actually increases with Q9, ventilatory control mechanisms, which are
consequent to distension of already-perfused considered to be exquisitely sensitive to CO2
capillaries and recruitment of previously (i.e. central and carotid body chemoreflexes);
unperfused capillaries; this serves to protect in contrast, hypoxic ventilatory stimulation
against diffusion disequilibrium. only becomes appreciable when Pa,O2 falls
below , 60 mmHg (see Chapter 3, Control of
A lowered PA,O2, as occurs with ascent to high ventilation). Hence, moderate diffusion
altitude, or when a subject breathes an impairment is accompanied by a decreased
hypoxic inspirate or with hypoventilation, will Pa,O2, a widened PAa,O2 and a relatively
slow the Pc,O2 rise time. This is because the normal Pa,CO2; more severe impairment which
initial driving pressure (PA,O2Pv,O2) is smaller, leads to hypoxic ventilatory stimulation will
as the operating slope of the O2 dissociation evidence more marked arterial hypoxaemia,
curve (b) is steeper, with the arterio-venous O2 greater widening of PAa,O2 and a low Pa,CO2.
content difference expressing a smaller
arterio-venous PO2 difference. Right-to-left shunt A right-to-left shunt
(Q9s) occurs when venous blood by-passes the
A useful expression relating to the interplay of pulmonary capillary circulation, thus
factors which dictate whether or not diffusion providing a degree of venous admixture with
equilibrium will actually be attained (i.e. blood from the exchanging alveolar units. It
whether Pc9,O25PA,O2) is: normally reflects venous drainage from the
larger airways (which enters the pulmonary
(PA,O2Pc ,O2) 5 (PA,O2Pv,O2)?e-DL,O2/Q9?b (18) veins) and from coronary venous blood (which
The term DL,O2/Q9?b has been termed the enters the left ventricles via the thebesian
equilibrium coefficient by PIIPER and SCHEID veins). This represents only a small percentage
(1980) and the diffusiveperfusive of the cardiac output (Q9) and therefore
conductance ratio by WEST and WAGNER amounts to a reduction in PA,O2 of only a few
(1998). Thus, diffusion equilibrium is less mmHg below Pc9,O2. However, Q9s/Q9 can be
likely to be attained if DL,O2 is low, and Q9 markedly increased in patients with
and b are high. For example, an increased congenital heart disease (e.g. atrial or
path length (e.g. alveolar proteinosis, ventricular septal defects; pulmonary arterio-
pulmonary oedema) and/or a reduced surface venous fistulae), leading to significant arterial
area for exchange (e.g. pulmonary embolism, hypoxaemia and widening of the PAa,O2.
restrictive lung disease) slow the diffusive flux
of O2 because of their effects on DL,O2 With The Q9s/Q9 relationship derives from the
very high levels of Q9 (e.g. highly fit recognition that the rate of O2 delivery into
endurance athletes exercising at or close to the systemic arterial circulation can be viewed
maximum) or very high linear velocities (e.g. as being made up of a homogeneous ideal

pulmonary capillary component and a pure (,6 mmHg at rest; c.f. ,60 mmHg for O2)
shunt component. Reverting again to the Fick and also (see above) the mechanisms of
principle, but now for the blood side, and ventilatory control can normally restore an
using the simple equality Q95Q9c+Q9s: increased Pa,CO2 back to normal. Again,
however, should Pa,O2 fall sufficiently to cause
Q9?Ca,O25Q9c?Cc9,O2+Q9s?Cv,O2
hypoxic stimulation of the carotid
which rearranges to yield: chemoreceptors, then Pa,CO2 will fall (see
Chapter 3, Control of ventilation); but,
Q9s/Q95(Cc9,O2-Ca,O2)/(Cc9,O2-Cv,O2) (19) without this, Pa,CO2 will rise. Thus, a moderate
where Cv,O2 and Cc9,O2 are mixed-venous and right-to-left shunt leads to a reduced Pa, O2, a
pulmonary end-capillary O2 content, widened PAa,O2, but a relatively normal
respectively. Ca,O2 and Cv,O2 can be measured Pa,CO2. Severe right-to-left shunts cause a
directly from blood samples, while Cc9,O2 is markedly reduced Pa,O2 and a markedly
derived through the standard O2 dissociation widened PAa,O2, with the possibility of a
curve, assuming Pc9,O25PAi,O2 (equation 14). lowered Pa,CO2.
It should be noted that this equation also
V9A/Q9 maldistribution Although overall
assumes that all the shunted blood is of
V9A may be approximately equal to overall Q9
mixed-venous composition, which may not
in the lung, there may nonetheless be regions
necessarily be the case for bronchial venous
with high, normal and low V9A/Q9 ratios. This
blood. This estimate of Q9s/Q9 thus provides
has important implications for regional
an overestimate of the true shunt, as it
alveolar gas and pulmonary end-capillary
incorporates a fraction of the perfusion
blood composition, and therefore for overall
draining from units having poorly functional
arterial blood-gas status. That is, gas and
capillaries (with low V9A/Q9 values), i.e.
creating a shunt-like effect. blood from low V9A/Q9 regions will reflect
hypoventilation (i.e. low PO2, high PCO2) and,
A right-to-left shunt must therefore result in in the extreme, alveolar shunt (V9A/Q950)
arterial hypoxaemia, i.e. even a small (see above); gas and blood from normal V9A/
contribution from nonarterialised blood will Q9 regions will have a normal PO2 and PCO2;
depress the resulting Ca,O2, owing to the and gas and blood from high V9A/Q9 regions
influence of the nonlinear O2 dissociation will reflect hyperventilation (i.e. high PO2, low
curve. The severity of the hypoxaemia will PCO2) with alveolar dead space in the extreme
depend both on Q9s/Q9 and Cv,O2, being more (V9A/Q95).
marked when the former is larger and the
latter is lower. A hallmark feature of a pure An analogous formulation to that for
right-to-left shunt is that the response of Pa,O2 estimation of Q9s/Q9 can be applied to the
to administration of 100% O2 is appreciably estimation of VD/VT (recalling that VD reflects
less than expected. This is because the shunt
the sum of the anatomical and alveolar dead
flow cannot see the elevated PA,O2 in the
spaces). That is, the assumption is made that
exchanging alveoli, and also that further
the volume of CO2 cleared in exhalation
increases in PA,O2 will have little effect on the
originates solely from a homogeneous
Cc9,O2 because the blood is already essentially
exchanging alveolar compartment (Bohr
fully saturated; it is only the dissolved
technique):
component of the O2 content that can be
increased, and this will be relatively small VT?F E,CO25VA?FA,CO2
because of the low solubility of O2 in plasma.
where F E,CO2 is the mixed expired CO2
A right-to-left shunt also has the potential to fraction and VA is the volume of exchanging
cause CO2 retention, but this is rarely alveoli. Rearranging and substitution yields:
observed owing to the normally small venous-
to-arterial CO2 tension (PCO2) difference VD/VT 5 (Pa,CO2-PE,CO2)/Pa,CO2(20)
high V'A/Q'
low

V'A/Q'
low
V'A/Q'
CO2 content
O2 content
normal

points
high
V'A/Q'

Pa,O2 Pa,CO2
Figure 5. Influence of altered ventilation-to-perfusion ratios on mean arterial oxygen (Pa,O2) and carbon
dioxide (Pa,CO2) tensions. The nonlinear O2 dissociation curve results in hypoxaemia (Q) compared with
normal (6); this effect is not evident for CO2, because the CO2 dissociation curve is linear. V9A/Q9: alveolar
ventilationperfusion ratio. Reproduced from WHIPP (2002) with permission from the publisher.
(The shift from PA,CO2 to Pa,CO2 is attributable In the presence of V9A/Q9 maldistribution, the
to Enghoff.) overall (or mean) PA,O2 and PA,CO2 will result
from an averaging of the respective gas
Even in the normal lung, there is evidence of concentrations from each individual gas
mild V9A/Q9 maldistribution. Owing to the "stream", in proportion to the local V9A.
influence of gravity, Q9 is distributed Likewise, the overall (or mean) Pa,O2 and
preferentially to the dependent regions of the Pa,CO2 will result from a flow-weighted
lung (i.e. towards the base in the upright averaging of the respective gas contents from
posture). A similar, gravitationally induced each individual blood "stream". However, it is
effect is also seen for V9A , though it is less important to recognise in this regard that
striking. Thus, the alveoli in the dependent account has also to be taken of the shape of
regions of the lung adopt a smaller volume, the O2 and CO2 dissociation curves in order to
with a greater hydrostatic pressure in the derive these Pa,O2 and Pa,CO2 values (fig. 5).
alveolar interstitium. They are therefore
constrained to operate over the steeper, lower Owing to the sigmoid shape of the O2
portion of the lung compliance curve, in dissociation curve, low V9A/Q9 regions lead
contrast to the larger apical units. Thus, the both to low PO2 and low O2 content in
smaller basal units undergo a greater volume pulmonary end-capillary blood; in contrast,
increase for a given increase of PTP during while high V9A/Q9 regions lead to a high
inspiration, and are therefore better ventilated Pc9,O2, Cc9,O2 is only slightly increased above
than are the apical units. Taking these effects normal value because the O2 dissociation
together, the apical units have a relatively curve is relatively flat in this range (fig. 5).
high V9A/Q9 while the basal units have a low Mixing blood from low V9A/Q9 regions with
V9A/Q9. Naturally, the degree of V9A/Q9 blood from high V9A/Q9 regions will therefore
maldistribution is considerably more marked result in an average Pa,O2 that is "weighted"
in many pulmonary disease states (e.g. COPD, towards low V9A/Q9 blood values (fig. 5). The
diffuse interstitial fibrosis, pulmonary vascular Pa,O2 will also depend on the volumes of
occlusive disease), and its topographical blood from each "region" contributing to the
location is not predictable. mixed arterial blood. Thus, the high V9A/Q9

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Physiology. The Respiratory System, Mechanics
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N DAngelo E. Dynamics. In: Milic-Emili J, ed. American Physiological Society, 1986;
Respiratory Mechanics. Eur Respir Mon 1999; pp. 131144.
12: 5467. N Weibel ER. Pathway for Oxygen. Cambridge,
N Farhi LE. Ventilationperfusion relationships. In: MA, Harvard University Press. 1984.
Farhi LE, Tenney SM, eds. Handbook of N West JB. Ventilation/Blood Flow and Gas
Physiology. The Respiratory System, Mechanics Exchange. Oxford, Blackwell, 1990.
of Breathing, vol. IV. Bethesda, MD, American N West JB, Wagner PD. Pulmonary gas exchange.
Physiological Society, 1986; pp. 199215. Am J Respir Crit Care Med 1998; 157: S82S87.
N Hughes JMB. Diffusive gas exchange. In: Whipp N Whipp BJ. The physiology and pathophysiology
BJ, Wasserman K, eds. Pulmonary Physiology of gas exchange. In: Bittar EE, ed. Pulmonary
and Pathophysiology of Exercise. New York, Biology in Health and Disease. New York,
Dekker, 1991; pp. 143171. Springer-Verlag, 2002; pp. 189217.
IMMUNOLOGY AND DEFENCE
MECHANISMS
B. Balbi, C. Vicari and A. Di Stefano
Fondazione Salvatore Maugeri, I.R.C.C.S., Veruno, Italy
E-mail: bbalbi@fsm.it
Each day, 10,00015,000 L of air is inhaled

by the respiratory system. This air contains Key points
micro-organisms and pollutant gases and
particles. It is conceivable therefore that N An integrated system of innate, intrinsic
adequate and efficient immunological and and adaptive acquired defences
defence mechanisms exist inside the protects the lungs from injury by
respiratory system to avoid damage to its inhaled pathogens or substances.
structure, and to limit the number, extent and
severity of upper and lower respiratory tract N The components of the system range
(URT and LRT) infections. from mechanical barriers and reflexes
to antimicrobial molecules, professional
The first line of defence against pathogens is phagocytes and acquired immune
represented by the epithelial barrier of the reactions.
airways. Additional protection comes from
polypeptide mediators of the innate, non- N Impairments of the system underly a
antibody-mediated host defence and by range of respiratory disorders.
professional phagocytes. Once the innate host
defence system is activated, also by the
cytokine and chemokine pathways, acquired toward the oro-pharynx to be swallowed. LRT
antibody-mediated immune responses and airways represent a system with a physical
subsequent tissue repair and remodelling barrier that is difficult to overcome.
following infection are orchestrated by Dichotomous branching and angulation of
immunocompetent cells and mediators. airways favour the impact of inhaled particles
on to the bronchial mucosa surface. At points
Anatomical barriers of impact, bronchial-associated lymphoid
The density of microbes is greater in the URT tissue (BALT) is able to interact with inhaled
than in the LRT. In fact, it is usually airborne microbes and particles, and to start
considered that only a small number of clearance processes via phagocytes and
bacteria are present in the LRT of healthy immune reactions by immunocompetent cells.
individuals. This process of exclusion of Reflex mechanisms
bacteria is also due to mechanical barriers
and reflex mechanisms. The nose itself can be A number of reflex mechanisms may help the
considered a first-line barrier. Its vibrissae, defence of the respiratory tract. They are
present on the vestibular region of the nasal made possible by the presence of irritant and
cavity, are able to filter the largest particles stretching receptors on the mucosa of the
contained in inhaled air. Nasal mucosa is a airways of the URT and of the larger LRT.
type of respiratory mucosa able to trap other Sneezing is a complex reflex initiated by the
smaller particles by means of its mucus layer. irritant receptors in the nose, usually triggered
Nasal cilia are able to transport the mucus by inhaled particles, followed by itching,

mucus secretion and ultimately leading to a although these innate antimicrobial
forceful and sudden expiration through the molecules have many differences depending
nose, preceded by a deep and fast inspiration, on the site and cell types producing them,
able to eliminate the potentially harmful secretory stimuli, and direct and indirect
inhaled particles. In the tracheobronchial tree, activities (table 1), they provide an
the cough reflex plays a similar role in evolutionarily highly conserved and powerful
eliminating foreign inhaled particles (see the screen against infections in the naive host.
article on Cough and sputum). Dyspnoea can They also trigger more specific and targeted
also be considered, at least under certain immune reactions taking place in the airways
circumstances, to be a defence mechanism, as and alveolar structures. In addition, the same
it can result from both hypersecretion of molecules have a role as immune-modulators,
mucus and/or bronchospasm. By reducing the and as antioxidants and antiproteases. Not
airway calibre, both are able to impair the surprisingly, attempts have been made to use
ability of inhaled harmful particles to reach some of these natural antibiotics for
the LRT. therapeutic purposes.
Mucociliary clearance and fluid Professional phagocytes
homeostasis
Microbial pathogens activate pattern
The constant mechanical clearance of mucus recognition cell receptors (e.g. toll-like
from the airways is considered a primary receptors, scavenger receptors, etc.) on
airway defence mechanism. The airway phagocytes, namely macrophages and
epithelial surface is able to act through ciliary neutrophils, and also epithelial cells, mast
function and mucus secretion with proper cells, eosinophils and natural killer cells. This
salt/water components in order to maintain is followed by the release of several mediators
the mucociliary clearance with a mucus and factors with effector functions and
escalator from the lower airways to the top. inflammatory cascades, such as the
With a mucus layer at the top containing complementary acute phase reactant proteins,
different types of mucins and a largely oxidative and nitrosative stress molecules,
aqueous layer at the bottom, the airway prostaglandins, interferons, cytokines and
secretions are, under normal conditions, able chemokines. Macrophages are the resident
to entrap the vast majority of inhaled foreign respiratory phagocytes. Although they are
particles and microbes on the mucus layer and present throughout the airways and
to transport the mucus up to the larger interstitium, their major roles are played in the
airways to be swallowed or eliminated by alveolar spaces, as alveolar macrophages
coughing. More recent studies have (AMs). In normal people, the vast majority of
emphasised the role of a chemical shield cells recovered through bronchoalveolar
from inhaled bacteria. This view underlines lavage (BAL) are AMs. These cells initiate and
the importance of the production and orchestrate the immune reactions against
secretion into the airway lumen by the airway pathogens and chemicals inhaled by the host
epithelia of two components: salt-sensitive (e.g. mineral particles). In a hypothetical
defensins (see below) and low-salt liquid able model of infection by a bacterial species, a
to activate defensins. pathogen that has reached the alveolar space,
Innate defence molecules eluding URT and LRT first-line defences,
represents a risk for the host as its replication
The epithelial lining fluid in the airways and and associated alveolar inflammation may
in the lung contains myriad molecules, damage respiratory structures. This invader
peptides and proteins exerting innate microorganism will ultimately be enmeshed
antimicrobial activities, not only against with the epithelial lining fluid and thus be
bacteria and viruses but also, in some cases, coated with opsonins. The latter can be either
against fungi and parasites. As a whole, nonimmune (see previous paragraph) or
Immunology and defence mechanisms 27

Table 1. Key antimicrobial factors in epithelial lining fluid and their activities
Factors, Cell origin Antimicrobial Main
structures activities immuno-modulatory
activities
Defensins, peptides Phagocytic cells, lymphocytes, BC, BS, Mitogenic,
airway epithelial cells AV, AF, CT, degranulate MC
AP
Cathelicidins, Neutrophils, monocytes, MC, BC, BS, Downregulation of
pro-peptides lymphocytes, airway epithelial AV, AF TNF-a, CT
cells
SLPI, protein Macrophages, neutrophils, BC, BS, Antiprotease
airway epithelial cells AV
SPA, SPD Alveolar type II cells, Clara BC, BS, Opsonin, modulate
lipoproteins cells AV, AF leukocyte functions,
structural barrier
Lactoferrin, Neutrophils, airway epithelial BC, BS, Antioxidant, binds LPS
glycol-protein cells AV, AF, inhibits
biofilm formation
Lysozyme, enzyme Neutrophils, airway epithelial BC, BS Unknown
cells
Lactoperoxidase, Airway epithelial cells BC, AV, Antioxidant?
enzyme AF
BC: bactericidal; BS: bacteriostatic; AV: anti-viral; AF: anti-fungal; AP: anti-parasitic; CT: chemotaxis; MC: mast cells;
TNF: tumour necrosis factor; LPS: lipopolysaccharide.
immune, i.e. specific immunoglobulins (Ig) and alveolar surface. BALT is also considered
originated by previous immunisation of the to be part of a lymphoid network common to
host against the pathogen. Opsonins facilitate other types of mucosa. In this model, an
AM phagocytosis and subsequent bacterial immunisation can occur at a distant site (e.g.
clearance by the intracellular killing systems gastrointestinal mucosa) and, by the
of AMs. The size of the bacterial inoculum, recirculation of lymphocytes, protection can
their virulence and resistance and possibly also be provided to the respiratory system.
deficits in the local immune mechanisms of Acquired immune reactions also start in the
the host may alternatively cause the failure, at lung, with the interaction between antigens
least in a first round, of host defences. This and antigen-presenting cells (APC). In the
will cause recruitment of additional lung, at least two types of APC exist:
phagocytes, as neutrophils, at sites of macrophages and dendritic cells. Dendritic
infection and sustain an immune and cells are present in the bronchi, representing
inflammatory reaction. roughly 1% of epithelial cells, in the alveolar
Acquired immune reactions with Ig, septa and in the interstitium. Together with a
cytokine and chemokine production phagocytic function, they share with AMs the
ability to process microbial proteins into small
Lymphoid tissue is present in the respiratory peptide fragments that are then transported
tract in different forms: tonsils and adenoids on the cell surface together with major
in the URT, lymph nodes in the mediastinum histocompatibility complex molecules. The
and hila, submucosal aggregates in branching complex between the major histocompatibility
points of the airways (BALT) and complex and antigenic epitopes is then
immunocompetent cells free on the airways presented to T-lymphocytes. Antigen

Table 2. Integrated host defence system in the respiratory tract
Intrinsic and innate host Adaptive and acquired
defences immune defences
Anatomical barriers and defence S-IgA and other immune opsonins
reflexes and antigen recognition and
presentation
Mucociliary clearance and fluid Pathogens and particles Cellular immunity and T- and B-
homeostasis lymphocytes
Innate defence molecules and Cytokine/chemokine production
nonimmune opsonins and networking
Professional phagocytes Chemotactic influx of
inflammatory, immunoeffector
cells
S-IgA: secretory-IgA.
presentation is made through the T-cell roughly 5% of the total protein content in BAL
receptor on the T-lymphocyte surface. fluid from normal individuals. IgM is present
only in trace amounts, due to its large size.
The antigen presentation initiates the
production of immuno-enhancing cytokines Conclusions
and chemokines. Apart from the interleukins
The complex, integrated host defence system
(ILs) and other mediators associated with the
described and depicted in table 2 represents
T-helper type I or II immune reactions, IL-17 is
a superb model of how the human body is
a pro-inflammatory cytokine mainly produced
able to efficiently interact with the external
by T-lymphocytes with an important role in
environment in order to preserve its structure
induction of the neutrophil-mediated
and function.
protective immune response against bacteria
or fungal pathogens. IL-17 seems to be an Conversely, impairment and/or dysfunction of
example of the crossroads between different each of the different and variously acting
host defence mechanisms, as it regulates cell- components of this system represents the
mediated immunity and induction of pathogenetic basis for the development of
antimicrobial peptides, such as defensins. many respiratory disorders. As an example,
primary ciliary dyskinesia results in recurrent
The process of specific immune reaction
airway infections; cystic fibrosis is associated
described above also promotes adaptive B-
with dysfunction of mucociliary clearance and
lymphocyte proliferation and specific Ig
fluid homeostasis; while in chronic
production. The relative proportions of
colonisation and/or infection of the airways
different Igs in the URT and LRT differ, and and in inflammatory airway disorders, many
also differ compared with the blood. In the different mechanisms undergo changes,
URT, IgA represents the vast majority of Igs, enhancement or impairment.
the latter as a whole being roughly 10% of
the total proteins in airway secretions. Airway To summarise, the respiratory system is
IgA is predominantly polymeric. Secretory IgA exposed to a variety of microbiological,
comprises two IgA monomers held together physical and chemical insults through inhaled
by a joining chain and by another air. Innate intrinsic and adaptive acquired
glycoprotein, the secretory component host and immune defences cooperate in
produced by serous and epithelial cells. In lowering the risk of being damaged for the
contrast with the airways, IgG is predominant respiratory structures in an integrated host
in the lung, as detected by BAL, representing defence system. In diseased states, one or
Immunology and defence mechanisms 29

more of these complex mechanisms can be N Oppenheim JJ, et al. Roles of antimicrobial
impaired and/or dysfunctional. peptides such as defensins in innate and
adaptive immunity. Ann Rheum Dis 2003; 26:
References ii17ii21.
N Pignatti P, et al. Tracheostomy and related host-
N Bals R, Hiemstra PS. Innate immunity in the pathogen interaction are associated with airway
lung: how epithelial cells fight against inflammation as characterised by tracheal
respiratory pathogens. Eur Respir J 2004; 23: aspirate analysis. Respir Med 2009; 103:
327333. 201208.
N Di Stefano A, et al. T helper type 17-related N Reynolds HY. Integrated host defense against
cytokine expression is increased in the bronchial infections. In: Crystal RG, et al., eds. The Lung:
mucosa of stable chronic obstructive pulmonary Scientific Foundation. Philadelphia, Lippincott-
disease patients. Clin Exp Immunol 2009; 157: Raven Publishers, 1997; pp. 23532365.
316324. N Rogan MP, et al. Antimicrobial proteins and
N Knowles MR, Boucher RC. Mucus clearance as a polypoptides in pulmonary innate defence.
primary innate defense mechanism for Respir Res 2006; 7: 2940.
mammalian airways. J Clin Invest 2002; 109: N Whitsett JA. Intrinsic and innate defenses in the
571577. lung: intersection of pathways regulating lung
N Martin TR, Frevert CW. Innate immunity in the morphogenesis, host defense, and repair. J Clin
lungs. Proc Am Thorac Soc 2005; 2: 403411. Invest 2002; 109: 565569.
N Matsuzaki G, Umemura M. Interleukin-17 as an N Yang D, et al. Participation of mammalian
effector molecule of innate and acquired defensins and cathelicidins in antimicrobial
immunity against infections. Microbiol Immunol immunity: receptors and activities of human
2007; 51: 11391147. defensins and cathelicidin (LL-37). J Leuk Biol
N McCormack FX, Whitsett JA. The pulmonary 2001; 69: 691697.
collectins, SP-A and SP-D, orchestrate innate N Zanetti M. The role of cathelicidins in the innate
immunity in the lung. J Clin Invest 2002; 109: host defenses of mammals. Curr Issues Mol Biol
707712. 2005; 7: 179196.

ers_book blank.indd 1 10/08/2010 10:59:00
CHAPTER 2:
SignS And SymPTomS
CougH And SPuTum 34

A.H. Morice
dySPnoEA 41
CHEST PAin 49
M. Hind
PHySiCAl ExAminATion in 51
RESPiRAToRy mEdiCinE
M.R. Partridge

COUGH AND SPUTUM
A.H. Morice
Hull York Medical School, University of Hull, Hull, UK
E-mail: a.h.morice@hull.ac.uk
Cough is a vital protective mechanism measures, such as hand washing and

defending the airways from inhalation and avoidance of contact, there is no specific
aspiration. Patients with a defective cough treatment for upper respiratory tract infection-
reflex, such as those with stroke or Parkinsons induced cough. The demonstrable effect of
disease, have an increase in mortality and the many cough remedies is likely to be due to
morbidity caused by the increased propensity a physicochemical (demulcent) effect rather
for aspiration. However, in lung disease, than through a specific pharmacological
cough is often not helpful. Thus, in the action of any particular agent.
commonest form of cough, that due to upper
respiratory tract infection, coughing serves no Chronic cough
useful purpose from the sufferers point of Chronic cough is one of the commonest
view, but is useful for the virus aiding its presentations to the respiratory physician. A
transmission to the next victim. In chronic survey in Yorkshire, UK, indicated that 12% of
cough, the frequency and severity of coughing the normal population complain of a chronic
bouts may cause serious disruption to the cough and 7% of these thought it interfered
patients life. Quality-of-life instruments have with activities of daily living. Many reports
indicated that patients with chronic cough from specialist cough clinics point to a
may have a similar decrement to that seen particular syndrome in patients with chronic
with conditions such as cancer and chronic cough. The average patient is middle-aged
obstructive pulmonary disease. Cough may and female. The cough appears to have no
have significant comorbidity. 50% of the pattern to it but a careful history will often
females attending cough clinics are reveal many features in common with other
incontinent and cough syncope is thought to patients presentation. It has been traditional
be responsible for a number of driving to divide this group of patients who have
fatalities. chronic cough without radiographic
Acute cough abnormalities and no obvious other lung
disease into a triad of diagnoses, namely
Acute cough due to one of the myriad upper asthmatic cough, post-nasal drip syndrome
respiratory tract viruses places an enormous
demand on the healthcare community. It is
the commonest new presentation to primary Key points
care, accounting for 50% of consultations. In
temperate regions there is a marked seasonal N Cough is characterised by irritant
variation with autumn and winter epidemics. receptor hypersensitivity.
Viral transmission requires person-to-person N Nonacid reflux into the airways
contact, either through airborne droplet frequently precipitates cough.
infection or the manual passage of secretions.
Superimposed on this seasonal pattern are N Clinical history followed by therapeutic
peaks caused by socialisation, e.g. return to trials is the management strategy of
school for the autumn term and Christmas choice.
family gatherings. Apart from general health

Table 1. Early reports from cough clinics illustrating the variety of cough diagnosis dependent on criteria used
First author, year Mean Patients n Diagnosis (% of total)
age (female n)
Asthma GOR Rhinitis
yrs
syndrome
I RWIN 1981 50.3 49 (27) 25 10 29
P OE 1982 - 109 (68) 36 0 8
P OE 1989 44.8 139 (84) 35 5 26
I RWIN 1990 51 102 (59) 24 21 41
H OFFSTEIN 1994 47 228 (139) 25 24 26
O C ONNELL 1994 49 87 (63) 6 10 13
S MYRNIOS 1995 58 71 (32) 24 15 40
M ELLO 1996 53.1 88 (64) 14 40 38
M ARCHESANI 1998 51 92 (72) 14 5 56
M CG ARVEY 1998 47.5 43 (29) 23 19 21
PALOMBINI 1999 57 78 (51) 59 41 58
B RIGHTLING 1999 - 91 (-) 31 8 24
The typical patient is a middle-aged female. These diagnoses are now thought to represent phenotypes of the cough
hypersensitivity syndrome. GOR: gastro-oesophageal reflux. Studies can be found in MORICE et al. (2004).
and reflux cough (table 1). These subdivisions Table 2. Areas of enquiry in chronic cough
have recently been called into question. For Hoarseness or a problem with your voice
example, asthmatic cough is unlike classic Clearing your throat
atopic asthma in that it is of late onset
The feeling of something dripping down the
without obvious precipitants and often back of your nose or throat
without evidence of bronchoconstriction. In
the form known as eosinophilic bronchitis Retching or vomiting when you cough
there is even an absence of bronchial Cough on first lying down or bending over
hyperreactivity. Similar caveats apply to the Chest tightness or wheeze when coughing
post-nasal drip syndrome and reflux cough,
Heartburn, indigestion, stomach acid coming up
which does not conform to the criteria for
or do you take medications for this?
heartburn-related gastro-oesophageal reflux
disease. Because of the commonality of the A tickle in your throat, or a lump in your throat
clinical history (see table 2), it has been Cough with eating (during or soon after meals)
suggested that there is a single unifying Cough with certain foods
diagnosis in chronic cough of the cough
Cough when you get out of bed in the morning
hypersensitivity syndrome with the other
diagnoses representing different phenotypes Cough brought on by singing or speaking (for
of the condition. The risk factors for chronic example, on the telephone)
cough suggest that nonacid reflux may be an Coughing more when awake rather than asleep
important precipitant (see table 3). A strange taste in your mouth
Virtually all patients presenting with a chronic Responses may either lead to further questioning or
cough complain of increased sensitivity to a be scored 05 and used as a diagnostic tool to
wide range of environmental stimuli. This demonstrate the presence of cough hypersensitivity
hypersensitivity can be objectively syndrome. A questionnaire version in various languages
is available at www.issc.info
demonstrated in the laboratory using cough
Cough and sputum 35

challenge. Thus patients cough with ethanol potential (TRP) receptor, TRPA1 is highly
inhalation, whereas normal subjects do not. reactive to a wide range of environmental
There is a wide variation in cough reflex irritants and causes cough in man. Up-
sensitivity in normal subjects, with females regulation of this receptor provides a
being more sensitive than males. Sensitivity is mechanism the hypersensitivity in patients to
accentuated in cough patients. Inhalation of agonist such as acreolin, the pro-tussive
capsaicin, the pungent extract of peppers, is ingredient in smoke.
typically used to demonstrate cough reflex
Management of chronic cough
responsiveness (fig. 1). Capsaicin works by
stimulating one of a family of nociceptors of All patients presenting with chronic cough
the transient receptor potential group (fig. 2). should have a chest radiograph. The clinical
The capsaicin sensitive hot receptor (TRPV1) history should indicate the most likely
is up-regulated in patients with cough. This is treatment options. The European Respiratory
due to pro-inflammatory mediators increasing Society guidelines recommend therapeutic
expression of TRPV1, either on the neurones or trials based on clinical judgement. Thus, in
in other airway tissues. Rather than directly patients with episodes of wheezing and
causing a cough, angiotensin-converting evidence of eosinophilic inflammation a trial
enzyme inhibitors alter cough sensitivity by a of asthmatic medication may well be
TRPV1-dependent mechanism explaining the beneficial (fig. 3). Where available, exhaled
continued irritation long after drug nitric oxide fraction may be a useful screening
withdrawal. Another transient receptor tool. Bronchoconstriction may not be a major
Table 3. Risk factors for chronic cough

Variable With cough Unadjusted 95% CI p-value
n (%) OR
Sex
Male 78/1704 (4.6) 1.0 1.031.86 0.028
Female 135/2179 (6.2) 1.38
Heartburn
No 148/2990 (4.9) 1.0 1.102.06 0.009
Yes 65/889 (7.3) 1.51
Regurgitation
No 158/3314 (4.8) 1.0 1.492.92 ,0.0001
Yes 54/568 (9.5) 2.10
IBS
No 111/2914 (3.8) 1.0 2.274.09 ,0.0001
Yes 98/909 (10.8) 3.05
BMI category
Normal 74/1547 (4.8) 1.0
Overweight 72/1448 (5.0) 1.04 0.741.47 0.86
Obese 60/776 (7.7) 1.67 1.152.41 0.006
Nonacid reflux symptoms in the form of regurgitation are more closely associated with cough than acid reflux. OR:
odds ratio; CI: confidence interval; IBS: irritable bowel syndrome.

30 Sputum

25
In subjects with chronic cough, production of
Coughsmin-1
20 moderate amounts of sputum does not alter

15 the diagnostic profile. The separation from
individuals with excessive sputum production
10
is arbitrary, but is generally regarded as a cup
5
of sputum per day. Above this limit a

0
diagnosis of bronchiectasis becomes
0.5 1 3 10 20 increasingly likely. The presence of sputum
Capsaicin dose M
purulence indicates a greater likelihood, but
does not seem to predict the degree of
Figure 1. Capsaicin cough challenge in normal
subjects. The effect of capropril increasing cough anatomical damage to the airway. Indeed the
reflex sensitivity. &: placebo; : captopril. N diagnosis of bronchiectasis, relying as it does
on the dilation and destruction of the airways,
will not include many patients with functional
component of this phenotype of the cough abnormalities of the bronchi.
hypersensitivity syndrome and consequently
long-acting b-agonists may be less effective In conditions characterised by sputum hyper-
than anti-eosinophilic medication such as secretion, there is usually a change in the
leukotriene antagonists. Reflux disease may composition of the mucus. Several
be very problematical since much airway mechanisms are responsible for this change.
reflux is nonacidic and therefore not Thus in cystic fibrosis the increase in sodium
amenable to blockade by proton pump reabsorption leads to a reduction in the sol
inhibitors. Pro-motility agents such as phase of airway surface liquid. Airway
metoclopramide and domperidone may be inflammation, particularly caused by release
used. Other motility agents such as of enzymes such as myeloperoxidase (which
erythromycin and magnesium have also been produces the characteristic green colour) and
advocated. Finally, operative treatment via neutral endopeptidase and from polymorphs
Nissan fundoplication can be effective in causes alteration of MUC gene expression
intractable coughing. An alternative strategy through proteinase activated receptors. The
is to use cough suppression in the form of death of inflammatory cells and bacteria lead
anti-tussive agents such as low-dose morphine. to a soup of DNA which cross-links with
This has been demonstrated to ameliorate filamentous actin-producing gelatinous plugs
cough in a third of patients with otherwise which increases ventilation/perfusion ratio
intractable symptoms. mismatch with resulting systemic hypoxia.
HOT COLD
55C 43C 33C 30C 25C 17C
TRPV2 TRPV1 TRPV3 TRPV4 TRPM8 TRPA1
VRL1 VR1 VRL3 VR-OAZ CMR1 Coexpressed

capsaicin OTRPC4 cold/menthol with VR1
protons osmotic acreolin
cinnamaldehyde
etc.
Figure 2. The thermosensitive transient receptor potential (TRP) channels important in cough reflex sensitivity.
Cough and sputum 37

14 frank blood is a common sign of pulmonary

12 embolism or infarction.
10
Obviously recurrent haemoptysis initially
Coughs n
8
presents with acute haemoptysis. Typically,
6
bronchiectasis leads to recurrent, sometimes
4
massive and occasionally fatal haemoptysis.

2 The bronchial blood supply arises from the

0 aorta and, in contrast to the pulmonary

1 3 10 30 100 300 1000
Citric acid nM circulation, is at systemic pressure. In
bronchiectasis there is hypertrophy of the
Figure 3. Cough challenge with citric acid in bronchial arteries as a consequence of
eosinophilic bronchitis and the response to inhaled recurrent infection. When the patient presents
steroids. &: number of coughs off budesonide; with life-threatening haemoptysis,
: number of coughs on budesonide. percutaneous bronchial artery embolisation is
the treatment of choice. Vasculitis is a
common and frequently missed cause of
The treatment of mucus hyper-secretion may recurrent haemoptysis and diffuse alveolar
be challenging. In the presence of purulent haemorrhage. Whilst the systemic connective
sputum, every effort should be made to tissue diseases, such as systemic lupus
identify the causative organism. Eradication erythematosus, may produce small vessel
with appropriate high-dose antibiotic therapy haemoptysis, the commonest cause is
may lead to sustained remission. More microcytic polyangiitis. The perinuclear anti-
frequently there is rapid relapse indication the neutrophil cytoplasmic antibody (pANCA) is
need for maintenance antibiotics either orally positive in ,70% of cases. Finally,
or via the nebulised route. The advantage of haemoptysis may be the result of alveolar
this latter strategy is that side-effects may be haemorrhage. Disease of the vascular or
minimised by using agents with high local alveolar wall, such as Goodpastures syndrome
potency but poor oral bioavailability such as or alveolar haemosiderosis, may present with
colomycin or tobramycin. Antioxidant recurrent haemoptysis. Clearly, disorders of
mucolytics are widely prescribed but coagulation, such as warfarin therapy or
evidence of efficacy is limited. The largest thrombocytopenia, will predispose to
study of N-acetylcysteine over 3 yrs showed haemoptysis.
no effect on decline in lung function or
exacerbation rate. References
Haemoptysis N Birrell MA, et al. TRPA1 agonists evoke coughing
in guinea-pig and human volunteers. Am J
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de novo haemoptysis without pre-existing lung outcomes in chronic obstructive pulmonary
disease. Any mucosal lesion may cause disease (Bronchitis Randomized on NAC Cost-
haemoptysis of small amounts of blood mixed Utility Study, BRONCUS): a randomised placebo-
with sputum. Since a common presentation of controlled trial. Lancet 2005; 365: 15521560.
this is lung cancer, chest radiography is N Ford AC, et al. Cough in the community: a cross
sectional survey and the relationship to
obligatory in patients when presenting with
gastrointestinal symptoms. Thorax 2006; 61:
haemoptysis. Aspergiloma and tuberculosis 975979.
may similarly cause a blood-stained bronchitis. N Millqvist E, et al. Inhaled ethanol potentiates the
More peripheral lung pathology, such as lobar cough response to capsaicin in patients with
pneumonia, gives rise to sputum that is airway sensory hyperreactivity. Pulm Pharmacol
frequently described as rusty. Haemoptysis of Ther 2008; 21: 794797.

N Mitchell JE, et al. Expression and characterization N Morice AH, et al. The diagnosis and
of the intracellular vanilloid receptor (TRPV1) in management of chronic cough. Eur Respir J
bronchi from patients with chronic cough. Exp 2004; 24: 481492.
Lung Res 2005; 31: 295306. N Palombini BC, et al. A pathogenic triad in
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312315. Care 2007; 52: 11341146.
Cough and sputum 39

ers_book_red_blank.indd 1 10/08/2010 12:45:55

DYSPNOEA
Dept of Pulmonary Rehabilitation, Fondazione Don C. Gnocchi, and Dept of
Internal Medicine, Section of Immunology and Respiratory Medicine,
University of Florence, Florence, Italy
E-mail: pier_lav@yahoo.it
Dyspnoea is the major reason for referral to

Key points pharmacological treatment and respiratory
rehabilitation programmes in patients with
N Dyspnoea is a subjective experience of chronic obstructive pulmonary disease
breathing discomfort that consists of (COPD). Dyspnoea is a subjective experience
qualitatively distinct sensations that of breathing difficulty that consists of
vary in intensity. qualitatively distinct sensations that vary in
intensity. This definition underlines the
N Its aetiology can be elucidated to some importance of the different qualities (cluster
degree by taking a medical history and descriptors) covered by the term dyspnoea,
physical examination. the involvement of integration of multiple
sources of neural information about breathing
N The mechanisms of dyspnoea are and the physiological consequences.
complex and multifactorial there is no
unique central or peripheral source of Aetiology
this symptom.
Dyspnoea has many pulmonary, cardiac and
N The sense of heightened inspiratory other causes, which vary by acuity of onset
effort is an integral component of (tables 1 and 2).
exertional dyspnoea and is pervasive
across health and disease. Different causes of dyspnoea are associated
with derangements of a number of functions
N The neuroventilatory dissociation (NVD) and apparatus:
theory of dyspnoea states that the
symptom arises when there is a N Alveoli
disparity between the central reflexic N Ventilatory pump
drive (efferent discharge) and the
simultaneous afferent feedback from a N Upper and lower airways
multitude of peripheral sensory N Pulmonary vasculature
receptors throughout the respiratory
system. The feedback system provides N Cardiac pump
information about the extent and N Red blood cells
appropriateness of the mechanical
response to central drive. N Peripheral circulation
N Despite the diversity of causes, the N Skeletal muscles

similarity of described experiences of It is important to remember that the most
dyspnoea suggests common underlying common cause of dyspnoea in patients with
mechanisms. chronic pulmonary or cardiac disorders is an
exacerbation of their underlying disease.
Dyspnoea 41
Table 1. Some common causes of acute (within minutes) and subacute (within hours or days) dyspnoea
Suggestive findings
Acute cause
Pulmonary causes
Pneumothorax Abrupt onset of sharp chest pain, tachypnoea, diminished breath sounds,
and hyperresonance to percussion. May follow injury or occur
spontaneously (especially in tall, thin patients and in those with COPD).
Pulmonary embolism Abrupt onset of sharp chest pain, tachypnoea and tachycardia. Often risk
factors for pulmonary embolism (e.g. cancer, immobilisation, deep
venous thrombosis, pregnancy, use of oral contraceptives or other
oestrogen-containing drugs, recent surgery or hospitalisation, family
history).
Asthma, bronchospasm, or Wheezing and poor air exchange that arise spontaneously or after
reactive airway disease exposure to specific stimuli (e.g. allergen, upper respiratory infection,
cold, exercise). Possibly pulsus paradoxus. Often a pre-existing history of
reactive airway disease.
Foreign body inhalation Sudden onset of cough or stridor in a patient (typically an infant or
young child) without upper respiratory infection or constitutional
symptoms.
Cardiac causes
Acute myocardial Substernal chest pressure with or without radiation to the arm or jaw,
ischaemia or infarction particularly in patients with risk factors for CAD.
Heart failure Crackles, S3 gallop and signs of central or peripheral volume overload
(e.g. elevated neck veins, peripheral oedema). Orthopnea or appearing
12 h after falling asleep (paroxysmal nocturnal dyspnoea).
Other causes
Diaphragmatic paralysis Sudden onset after trauma affecting the phrenic nerve. Frequent
orthopnoea.
Anxiety disorder- Situational dyspnoea often accompanied by psychomotor agitation and
hyperventilation paresthesias in the fingers or around the mouth. Normal examination
findings and pulse oximetry measurements.
Subacute cause
Pulmonary causes
Pneumonia Fever, productive cough, dyspnoea, sometimes pleuritic chest pain. Focal
lung findings, including crackles, decreased breath sounds and
egophony.
COPD exacerbation Cough, productive or nonproductive. Poor air movement. Accessory
muscle use or pursed lip breathing.
Cardiac causes
Angina or CAD Substernal chest pressure with or without radiation to the arm or jaw,
often provoked by physical exertion, particularly in patients with risk
factors for CAD.
Pericardial effusion or Muffled heart sounds or enlarged cardiac silhouette in patients with risk
tamponade factors for pericardial effusion (e.g. cancer, pericarditis, systemic lupus
erythematosus). Possibly pulsus paradoxus.
COPD: chronic obstructive pulmonary disease; CAD: coronary artery disease; S3: 3rd heart sound.

Table 2. Some common causes of chronic (hours to years) dyspnoea
Suggestive findings
Pulmonary causes
Obstructive lung disease Extensive smoking history, barrel chest and poor air entry and exit.
Restrictive lung disease Progressive dyspnoea in patients with known occupational exposure or
neurological condition.
Interstitial lung disease Fine crackles on auscultation.
Pleural effusion Pleuritic chest pain and lung field that is dull to percussion with
diminished breath sounds. Sometimes history of cancer, heart failure,
rheumatoid arthritis, systemic lupus erythematosus, or acute pneumonia.
Cardiac causes
Heart failure Crackles, S3 gallop and signs of central or peripheral volume overload
(e.g. elevated neck veins, peripheral oedema). Orthopnea or paroxysmal
nocturnal dyspnoea.
Stable angina or CAD Substernal chest pressure with or without radiation to the arm or jaw,
often provoked by physical exertion, particularly in patients with risk
factors for CAD.
Other causes
Anaemia Dyspnoea on exertion progressing to dyspnoea at rest. Normal lung
examination and pulse oximetry measurement. Sometimes systolic heart
murmur due to increased flow.
Physical deconditioning Dyspnoea only on exertion in patients with sedentary lifestyle.
CAD: coronary artery disease; S3: 3rd heart sound.
Medical history anchored such that zero represents no

breathlessness at all and 10 is the most
It is important to ask patients how long they severe breathlessness that one had ever
have had dyspnoea and in what situations it experienced or could imagine experiencing.
occurs. Therefore, clinical history should cover By pointing to the Borg scale, subjects rate
the duration, temporal onset (e.g. abrupt, the magnitude of their perceived breathing
insidious), and provoking or exacerbating discomfort during exercise. Most patients with
factors (e.g. allergen exposure, cold, exertion, dyspnoea, not just those with heart failure,
supine position). Severity of dyspnoea can be
feel worse when they lie down (orthopnea).
determined by assessing the activity level
required to produce dyspnoea (i.e. dyspnoea
at rest is more severe than dyspnoea only with The physician should seek symptoms of
climbing stairs). For this purpose, the Medical possible causes, including chest pain
Research Council dyspnoea scale can be used (pulmonary embolism, myocardial ischaemia,
(table 3), along with other scales such as the pneumonia); dependent oedema, orthopnea
Baseline Dyspnoea Index (BDI). For patients and paroxysmal nocturnal dyspnoea (heart
with baseline dyspnoea, the physician should failure); fever, chills, cough and sputum
note how much dyspnoea has changed from production (pneumonia); black, tarry stools or
the patients usual state. Dyspnoea can also heavy menses (occult bleeding possibly
be evaluated during a physical task, such as causing anaemia); and weight loss or night
cardiopulmonary exercise testing. For this sweats (cancer or chronic lung infection). Past
purpose, the 10-point Borg scale can be used medical history should cover disorders known
(table 3). In the Borg scale, the end-points are to cause dyspnoea, including asthma, COPD
Dyspnoea 43
Table 3. The Medical Research Council (MRC) dyspnoea scale and the Borg scale
MRC Grade Description
1 Not troubled by breathlessness except with strenuous exercise
2 Troubled by shortness of breath when hurrying on the level or walking up a slight hill
Walks slower than people of the same age on the level because of breathlessness or has
3
to stop for breath when walking at own pace on the level
4 Stops for breath after walking ,90 m or after a few minutes on the level
5 Too breathless to leave the house or breathlessness when dressing or undressing
Borg scale Severity
0 No breathlessness at all
0.5 Very very slight (just noticeable)
1 Very slight
2 Slight breathlessness
3 Moderate
4 Somewhat severe
5 Severe breathlessness
6
7 Very severe breathlessness
8
9 Very very severe (almost maximum)
10 Maximum
and heart disease, as well as risk factors for Physical examination focuses on the
the different aetiologies: cardiovascular and pulmonary systems. A full
lung examination is done, particularly
N smoking history for cancer, COPD and including adequacy of air entry and exit,
heart disease. symmetry of breath sounds, and presence of
N family history, hypertension and high crackles, rhonchi, stridor and wheezes.
cholesterol levels for coronary artery Wheezing suggests asthma or COPD. Stridor
disease. suggests extrathoracic airway obstruction (e.g.
foreign body, epiglottitis, vocal cord
N recent immobilisation or surgery, recent dysfunction). In-drawing of the lower ribcage
long-distance travel, cancer or risk factors towards the end of inspiration (Stock or
for or signs of occult cancer, prior or family Hoovers sign) suggests (but does not prove)
history of clotting, pregnancy, oral the presence of chronic lung hyperinflation
contraceptive use, calf pain, leg swelling from COPD. Paradoxical inspiratory inward
and known deep venous thrombosis for motion of the abdomen is seen in bilateral
pulmonary embolism. diaphragm paralysis (easier to see when the
patients are lying down and/or when they
Occupational exposures (e.g. gases, smoke sniff). The presence of contraction of the
and asbestos) should also be investigated. accessory muscles when the patient is at rest
Physical examination could make the physician think of a more
generalised muscle or nerve problem which
The history and physical examination often has affected the diaphragm and the
suggest a cause and guide further testing. intercostals and parasternal muscles.

Inspiratory squeaks usually mean extrinsic lung diseases share some common underlying
allergic alveolitis, although sometimes they mechanisms?
are heard in bronchiectasis. Crackles suggest
left heart failure, interstitial lung disease or, if Dyspnoea is perceived as a sense of
accompanied by signs of consolidation (e.g. effort During voluntary increase in
egophony, dullness to percussion), ventilation, the motor cortex increases the
pneumonia. The cervical, supraclavicular and outgoing motor signal to respiratory muscles
inguinal areas should be inspected and and conveys a copy (central corollary
palpated for lymphadenopathy. Neck veins discharge) through cortical interneurones to
should be inspected for distension (suggestive the sensory/association cortex, which is
of heart failure, pulmonary embolism or informed of the voluntary effort to increase
pulmonary hypertension), and the legs and ventilation. It is also likely that the sense of
presacral area should be palpated for pitting the respiratory effort arises from the
oedema (suggesting heart failure). Heart simultaneous activation of the sensory cortex
sounds should be auscultated with notation of and muscle contraction: a variety of muscle
any extra heart sounds, muffled heart sounds, receptors provides feedback to the central
or murmur. It should be remembered, nervous system about force and tension, and
however, that signs and symptoms of life- information from these receptors may
threatening conditions, such as myocardial conceivably underlie the sense of effort. For
ischaemia and pulmonary embolism, can be clinical purposes the perceived magnitude of
nonspecific. Furthermore, the severity of respiratory effort is expressed by the ratio of
symptoms is not always proportional to the the tidal oesophageal pressure (Poes) to the
severity of the cause (e.g. pulmonary maximal pressure generation capacity of the
embolism in a fit, healthy person may cause respiratory muscles (PI,max). In healthy
only mild dyspnoea). Thus, a high degree of subjects, volitional respiratory effort is
suspicion for these common conditions is matched with lung/chest wall displacement
prudent. It is often appropriate to rule out (i.e. change in tidal volume percentage vital
these conditions before attributing dyspnoea capacity) via concurrent afferent
to a less serious aetiology. A clinical proprioceptive information, transmitted via
prediction rule can help estimate the risk for vagal, glossopharyngeal, spinal and phrenic
pulmonary embolism. Note that a normal nerves, that monitors displacement and is
oxygen saturation does not exclude processed and integrated in the sensory
pulmonary embolism. Hyperventilation cortex. The result is a harmonious
syndrome is a diagnosis of exclusion. Because neuromechanical coupling (NMC) with
hypoxia may cause tachypnoea and agitation, avoidance of respiratory discomfort or distress.
it is unwise to assume every rapidly breathing,
anxious young person merely has Dyspnoea is perceived as a sense of air
hyperventilation syndrome. hunger Under some clinical and
experimental circumstances the relationship
Physiology between dyspnoea and effort is less apparent.
If normal subjects suppress their ventilation to
To gain more insight into our understanding a level below that dictated by chemical drive
of dyspnoea, a case can be made for (CO2), dyspnoea increases without
answering the following questions: 1) what is corresponding increases in indices of
the role of mechanical factors and ventilatory respiratory effort. Likewise, in experimental
constraints in dyspnoea?; 2) what are the and clinical conditions where peripheral
neurophysiological underpinnings of the most stretch receptors are inhibited, the sensory
selected cluster descriptors that define the cortex is not informed of the ventilatory
qualitative dimension of dyspnoea in response. In these circumstances, dyspnoea is
patients?; 3) do obstructive and restrictive perceived as a sensation of air hunger whose
Dyspnoea 45
intensity depends on a mismatching between respiratory drive. The data support the central
the level of chemical stimulated drive and importance of mechanical restriction in
ongoing inhibition from pulmonary causing dyspnoea in COPD patients.
mechanosensors signalling the current level of
ventilation. In turn, dyspnoea arises and may Neuromuscular disorders
qualitatively change when peripheral afferent (NMD) Patients with NMD exhibit
feedback is altered and inspiratory motor heightened neuromotor output, which is
output either increases or stabilises. sensed as increased respiratory muscle effort
and, as such, is likely to be the principal
mechanism of dyspnoea in NMD.
Pathophysiology
Nonetheless, a significant positive
relationship between increased dyspnoea per
COPD Two clusters of dyspnoea are unit increase in ventilation and dynamic
commonly selected by patients with COPD elastance affects the coupling between
during physical activity. respiratory effort and displacement (fig. 2).
The cluster respiratory effort is commonly Interstitial lung disease (ILD) One of the
selected by patients with COPD. Acute characteristic features of ILD is a reduction in
mechanical loading and functional respiratory lung compliance and lung volumes. The
muscle weakness decrease PI,max , and further mechanical response of the respiratory system
increase Poes percentage PI,max. Furthermore, is similarly restricted in patients with ILD as in
because of the limbic system activation, the those with COPD: tidal volume expansion is
corollary discharge may be sensed as constrained from above (reflecting the
abnormal, thus evoking a sensation of distress. reduced total lung capacity and inspiratory
The other cluster is unsatisfied inspiration. reserve volume), which results in greater
Structural abnormalities (chronic bronchitis reliance on an increase in breathing frequency
and emphysema) via their physiological to increase ventilation. Differences in dynamic
negative consequences, i.e. expiratory flow ventilatory mechanics, including possible
limitation and dynamic hyperinflation, result expiratory flow limitation in some patients,
in dyspnoea. A patients physical activity is account for distinct qualitative perception in
indeed characterised by a mismatch between ILD patients, namely inspiratory difficulty and
increase in neural output to the respiratory
muscles and lung/chest wall displacement. We 60
50
Inspiratory effort
call this mismatch neuroventilatory

Poes % PI,max
dissociation (NVD). In a clinical setting, the 40 Elastic and

Dyspnoea
slope that defines NVD (i.e. effort versus 30 resistive load

displacement) is steeper and shifted upward 20
compared with healthy subjects. The steeper 10

the slope, the greater the intensity of 0
dyspnoea (fig. 1). In particular, patients 0 5 10 15 20 25 30
experience intolerable dyspnoea during Tidal volume % VC
exercise because tidal volume expansion is
constrained from below (by the effects of Figure 1. Neuroventilatory dissociation. The slope
dynamic lung hyperinflation) as there is no that defines the mismatch between increase in
neural output (inspiratory effort, i.e. Poes %PI,max)
space to breathe. This so-called dyspnoea
and lung/chest wall displacement (tidal volume,
threshold seems to be at the level at which %VC) is steeper and shifted upwards in patients
the inspiratory reserve volume approaches with COPD ( ) compared with healthy subjects
0.5 L. In turn, unsatisfied inspiration reflects a (). Poes: tidal oesophageal pressure; PI,max:
discrepancy between high ventilatory drive maximal pressure generation capacity of the
and ventilation less than that dictated by the respiratory muscles.

80
The available data suggest that increased

ventilatory demand, abnormal dynamic
60 ventilatory mechanics and respiratory muscle
Pes,sw % Pes,sn
Dyspnoea

dysfunction are instrumental in causing
40

exertional dyspnoea in patients with severe

cardiac impairment.
20

0 Obesity An increase in respiratory neural
0 5 10 15 20 25 30 35 drive is deemed to be the reason for the
VT % VC,pv similar increase in dyspnoea in obese and
lean subjects. However, different underlying
Figure 2. A mismatch between inspiratory effort mechanisms may affect dyspnoea in obese
(Poes,sw % Poes,sn) and lung/chest wall displacement
subjects. Exercise performance is impaired
(VT %VC ,pv) in patients with NMD () as
compared with average data from controls ( ). compared with healthy normal-weight
The steeper the slopes the greater the perception of subjects when corrected for the increased lean
dyspnoea. Poes,sw: swing in oesophageal pressure; body mass, but normal when expressed as a
Poes,sn: oesophageal pressure during a sniff percentage of predicted for ideal body weight
manoeuvre; VT: tidal volume; VC,pv: predicted values in subjects who hyperinflate the lungs to the
of vital capacity. same extent as those obese subjects who
deflate the lungs, with both volume
rapid shallow breathing. Because of increase subgroups reaching similar dyspnoea scores.
in both dynamic elastance and efferent In hyperinflators, dynamic hyperinflation
respiratory drive, inspiratory difficulty may along with a decrease in inspiratory reserve
have its psychophysical basis in the conscious volume increases respiratory muscle loading,
awareness of a dissociation between respiratory drive and perception of respiratory
respiratory effort and the mechanical discomfort. In contrast, deflators exhibit a
response, i.e. inability to expand tidal volume negative relationship between resting end-
appropriately in the face of an increased drive expiratory lung volume (EELV) and perceptual
to breathe. In turn, the possibility has also respiratory response during exercise: the lower
been put forward that intensity of exertional the EELV the greater the Borg score. A low
dyspnoea in ILD is more closely linked to resting EELV has three important
mechanical constraints on volume expansion consequences linked together during exercise:
than to indexes of inspiratory effort per se. 1) decrease in expiratory reserve volume, 2)
dynamic airway compression, and 3) changes
Chronic heart failure (CHF) The key in transmural airway pressure resulting in
message that has emerged from therapeutic airway dynamic compression. Thus, an
intervention studies in patients with CHF is alteration in the central drive to the
that exertional dyspnoea alleviation is respiratory muscles in response to afferent
consistently associated with reduced excessive activity from upper airway mechanoreceptors
ventilatory demand (secondary to reduced may also contribute to the unpleasant
central neural drive), improved respiratory respiratory sensation in obese subjects.
mechanics and muscle function and,
consequently, enhanced neuromechanical Diabetes A study on respiratory muscle
coupling of the respiratory system during effort and load has helped elucidate the
exercise. Pressure support is reported to pathophysiology of dyspnoea during hypoxic
reduce the tidal inspiratory pleural pressure stimulation of ventilation in type I diabetes
time slope without affecting submaximal mellitus. The study shows that because of an
dyspnoea ratings but allows patients to increase in dynamic elastance, the greater
exercise for additional minutes without perception of dyspnoea is associated with
experiencing any significant rise in dyspnoea. changes in inspiratory effort, which is out of
Dyspnoea 47
proportion with changes in tidal volume in N Laveneziana P, et al. Effect of biventricular
patients with no smoking history. pacing on ventilatory and perceptual responses
to exercise in patients with stable chronic heart
failure. J Appl Physiol 2009; 106: 15741583.
Conclusions N ODonnell DE, et al. Pathophysiology of dyspnea
in chronic obstructive pulmonary disease. Proc
We are still a long way from understanding Am Thorac Soc 2007; 4: 145168.
the symptom of dyspnoea. Although N ODonnell DE, et al. Qualitative aspects of
mechanical factors are important contributors exertional breathlessness in chronic airflow
to dyspnoea, the precise mechanisms of limitation: pathophysiologic mechanisms. Am J
dyspnoea remain obscure. One approach to Respir Crit Care Med 1997; 155: 109115.
the study of this symptom is to identify the N ODonnell DE, et al. Qualitative aspects of
major qualitative dimensions of the symptom exertional dyspnoea in patients with interstitial
in an attempt to uncover different underlying lung disease. J Appl Physiol 1998; 84: 2000
2009.
neurophysiological mechanisms. The
remarkable similarity in choices of qualitative
N ODonnell DE, et al. Sensorymechanical
relationships during high intensity, constant-
descriptors (work/effort, inspiratory difficulty/ work-rate exercise in COPD. J Appl Physiol 2006;
unsatisfied inspiration, air hunger, rapid 101: 10251035.
breathing) for exertional dyspnoea in patients N ODonnell DE, et al. Ventilatory assistance
with restrictive and obstructive syndromes improves exercise endurance in stable
raises the intriguing possibility that they share congestive heart failure. Am J Resp Crit Care
some common underlying mechanisms. Med 1999; 160: 18041811.
N Ofir D, et al. Ventilatory and perceptual
References responses to cycle exercise in obese females. J
Appl Physiol 2007; 102: 22172226.
N DeLorey DS, et al. Mild to moderate obesity: N Romagnoli I, et al. Role of hyperinflation vs
implications for respiratory mechanics at rest deflation on dyspnea in severely to extremely
and during exercise in young men. Int J Obes obese subjects. Acta Physiol 2008; 193: 393
(Lond) 2005; 29: 10391047. 402.
N Killian KJ, Campbell EJM. Dyspnoea. In: Roussos N Scano G, et al. Dyspnoea, peripheral airway
C, ed. The Thorax, part B. New York, Dekker, involvement and respiratory muscle effort in
1995; pp. 17091747. patients with type I diabetes mellitus under good
N Lanini B, et al. Perception of dyspnea in patients metabolic control. Clin Sci 1999; 96: 499506.
with neuromuscular disease. Chest 2001; 120: N Scano G, et al. Understanding dyspnoea by its
402408. language. Eur Respir J 2005; 25: 380385.

CHEST PAIN
M. Hind
NIHR Advanced Lung Diseases Unit, Royal Brompton and Harefield NHS
Foundation Trust, London, UK
E-mail: M.Hind@rbht.nhs.uk
Chest pain is a frequent symptom of illness

and a common reason for seeking medical Key points
attention. Rapid assessment is crucial so that
life-threatening disease, such as cardiac chest N Chest pain can be a feature of a wide
pain, aortic dissection and oesophogeal range of pathology
rupture, can be identified and managed N An accurate history is essential to direct
appropriately. A basic history often points to appropriate investigation of patients
the cause and is used in triage of patients presenting with chest pain
attending emergency rooms. Questions are
typically asked about the character, location,
radiation, severity, exacerbating and relieving
airways and mediastinum, but visceral lung
factors of the pain, and its relationship to
pain is unusual.
movements such as breathing or coughing.
Objective assessment using a questionnaire, Pleural pain is often described as sharp,
such as the McGill Pain score can be useful. stabbing and made worse by movement such
Occasionally, it is difficult to tease out as deep respiration. The pain is often
differences between cardiac, gastrointestinal unilateral, reflecting the site of the disease. A
and respiratory causes of pain. pleural rub may be heard. Pleuritic pain with
sudden onset prompts a diagnosis of
The pathophysiology of chest pain is complex pulmonary emboli, infarction or
and not completely understood but involves pneumothorax, whereas pleuritic pain
peripheral noiciceptors, either small Ad building over a few hours may suggest
myelinated or unmyelinated C afferent fibres infection such as pneumonia or pleurisy.
that project via sympathetic and para- Onset over days suggests empyema,
sympathetic nerves into the dorsal horn of the malignancy or tuberculosis.
spinal cord. These neurones synapse with
spinothalamic fibres which ascend, cross the Tracheobronchitis can present with a midline
spinal cord and terminate in the contralateral burning pain made worse with respiration.
ventero-posterior thalamic nucleus. Thalamo- Massive mediastinal lymphadenopathy can
cortical neurons project via the posterior limb cause an indistinct, heavy central chest pain.
of the internal capsule to the somatosensory Similarly, chest pain associated with
cortex. The diaphragm has dual noiciceptive pulmonary hypertension can be difficult to
sensory innervation from both the phrenic distinguish from cardiac chest pain.
Nondescript, heavy chest pain is quite
nerve and the lower six intercostal nerves,
common in exacerbations of bronchiectasis.
therefore diaphragmatic irritation can present
with pain referred to the shoulder or upper Chest wall pain is usually well localised,
abdomen. The trachea and large airways have reproduced with movement and associated
afferent fibres that project along the vagus with tenderness. Costo-condritis and Tietzes
nerve. Respiratory chest pain can therefore syndrome are inflammatory disorders of
originate from the chest wall, pleura, large thoracic joints that present with chest wall
Chest pain 49
pain and tenderness. Bornholm disease tomography scanning has made identification
(epidemic pleurodynia or devils grip), often of pulmonary emboli, aortic dissection and
associated with Coxsackie B virus, can present oesophogeal rupture straightforward, and can
with epidemics of chest wall pain of sudden identify abnormalities often missed on plain
onset. radiographs. Nuclear medicine scans have a
role in both diagnosis and management of
Neuralgic pain can be sharp and knife-like or
pulmonary emboli. Bone scintigraphy is useful
dull and heavy, and there may be associated
in evaluation of bony pain. Magnetic
sensory symptoms. Pain in a dermatomal
resonance examination is of particular use in
distribution requires examination of overlying
visualising nerve roots. Direct endoscopic
skin for the characteristic vesicular rash of
herpes zoster. visualisation of either the upper
gastointestinal tract
ECG is essential for immediate assessment of (oesophagogastroduodenoscopy) or major
cardiac chest pain. Further investigation may airways (bronchoscopy) allows epithelial
include exercise ECG, stress echocardiography inspection and offers the opportunity for
or myocardial perfusion scan. Angiography direct microbiological, cytological and
offers the opportunity for therapeutic histological sampling.
angioplasty and stent insertion.
Chest radiographs are useful to identify Reference
consolidation, pneumothorax, pleural N Melzack R, The McGill Pain Questionnaire: major
effusion, and bony abnormalities such as properties and scoring methods. Pain 1975; 1:
vertebral fractures. Contrast computed 277299.

PHYSICAL EXAMINATION IN
RESPIRATORY MEDICINE
M.R. Partridge
Imperial College, London, UK
E-mail: m.partridge@imperial.ac.uk
Physical findings in the context of the complaining of shortness of breath we

history consider the following points.
The purpose of clinical assessment is to make Is this patient breathless because of:
an accurate diagnosis. Making an accurate
diagnosis in cases of respiratory disease can
N Heart disease?
be challenging not only because of the N Lung disease?
diversity of respiratory ill-health, but also
because symptoms of respiratory disease are
N Pulmonary vascular disease?
shared with disorders of other body systems. N A systemic disorder (anaemia, obesity or
hyperthyroidism), or
Breathlessness (a sensation of difficult,
laboured or uncomfortable breathing) may N Respiratory muscle weakness
have a physiological or psychological It is vital that we go through this checklist
explanation but it is extremely important that both with new presentations of the symptom
every time we are faced with a patient of breathlessness and also in those with
established disease, and we need to bear this
list in mind when examining the patient. The
Key points patient with chronic obstructive pulmonary
disease might this time be breathless, not
N It is essential to bear in mind that because of an exacerbation, but because they
breathlessness can have a variety of have gone into atrial fibrillation; or the
causes. patient with known heart failure may this time
be breathless because of a complicating
N Physical examination should follow pneumonia.
the taking of the medical history and
Asking specifically about the onset of the
differential diagnoses, and is an
symptom of breathlessness can be helpful in
opportunity to confirm normality or
the differential diagnostic process and this is
discover abnormality.
summarised in table 1.
N Physical examination comprises
Cough
inspection, palpation, auscultation
and percussion. A practical approach to the assessment of
cough and breathlessness is summarised in
N The respiratory physician must not fig. 1.
forget that other systems may also be
Physical examination
the cause of the symptoms and that
comorbidity is common. In the vast majority of cases, the taking of the
medical history should lead to the
Physical examination in respiratory medicine 51

Table 1. Breathlessness: differential diagnosis according to onset
Within minutes Think: pulmonary embolus, pneumothorax, myocardial infarction,
cardiac rhythm disturbance, dissecting aneurysm, acute asthma
Over hours or days Think: pneumonia, pleural effusion, LVF (LV dysfunction or valve
dysfunction or septal rupture post-MI), asthma, blood loss, lobar collapse,
respiratory muscle weakness (GuillainBarre syndrome)
Over weeks Think: infiltration (malignancy, sarcoidosis, fibrosing alveolitis, extrinsic
allergic alveolitis, eosinophilic pneumonia), respiratory muscle weakness
(motor neurone disease), main airway obstruction, anaemia, valvular
dysfunction (SBE)
Over months Think: same as for weeks plus obesity, muscular dystrophy, asbestos-
related conditions.
Over years Think: COPD, chest wall deformity, heart valve dysfunction, obesity.
LVF: left ventricular failure; MI: myocardial infarction; SBE: subacute bacterial endocarditis; COPD: chronic obstructive
pulmonary disease.
construction of a list of differential diagnoses. Palpation

The examination is then an opportunity either
to confirm normality or to discover This involves the following:
abnormalities consistent with one or other of N Assessment of chest expansion, where we
ones differential diagnoses. Key features, as may be able to elicit reduced expansion
with all clinical examination, depend upon symmetrically suggestive of hyperinflation,
inspection, palpation, auscultation and
or reduced movement on one side sug-
percussion.
gesting localised pathology on that side.
Inspection N Determining the position of the trachea by
inserting the index and middle fingers in
On inspection the key points to observe are:
the supra sternal notch.
N General appearance (breathlessness? N Examining the cervical and supra clavicular
cachetic?) lymph nodes for enlargement.
N Respiratory rate N Assessing vocal fremitus by asking the
N Appearances of the hand (finger clubbing? patient to loudly and deeply repeat the
tremor? tobacco staining? flapping tremor words 99 whilst you compare both sides
suggestive of CO2 retention?) of the chest. Voice sounds are better
transmitted through consolidated lung
N Does the chest wall move symmetrically? than normal lung and poorly transmitted
N Are there any chest wall deformities through pleural effusions.
(scoliosis, pectus excavatum) or scars? Percussion
N Any abnormal vessels suggestive of super- Percussion is often poorly undertaken and the
ior vena cava obstruction (fig. 2)? key features are to make the movement of
N Nasal stuffiness or obstruction should be your finger as a stroke from the wrist and
noted. strike firmly at right angles upon the finger of
the other hand which lies along the
N A note should be made of the neck/collar intercostal space, and to do so in a
size and also of obvious jaw abnormalities symmetrical manner systematically comparing
and oropharyngeal abnormalities. both sides of the chest at a point equidistant

Cough
Breathlessness?
Check the patient is not taking an ACE Pulmonary
Heart disease? embolus/ Asystemic Diaphragm Psychogenic
inhibitor. If yes stop, if not determine length
of history of cough Lung infarction? disorder? weakness? dyspnoea?
Irregular pulse?
Clinical signs of left ventricular disease?
Cough has <12 Is a major risk factor present? Anaemia - check Is the breathlessness Note that
Cough has lasted hypertrophy or failure? Recent immobility
weeks if no >12 weeks haemoglobin worse on lying flat or this is
Personal or family history Recent lower limb usually a
sinister features of ischaemic heart disease? Obesity - check BMI in water? Does the
(and not a smoker Send for trauma/surgery Overactive thyroid - vital capacity fall on diagnosis
ECG abnormal? Clinical DVT of exclusion
or ex-smoker) may chest check T4 lying compared with
be post-viral radiograph Previous or FH of VTE sitting or standing?
Chest radiograph shows cardiac Pregnancy or puerperium
enlargement? Major medical illness Treat or refer If in doubt
Chest Chest
radiograph Refer to a refer to a
radiograph Refer urgently for investigation respiratory physician respiratory
abnormal: is normal Treat or refer to cardiologist
physician
Physical examination in respiratory medicine

refer to
respiratory Infection Small lung disease? Pulmonary Airways
physician embolus/infarction? disease?
Is there a fever, Is this an airway disorder? Is there a cough, wheeze,
Abnormal a cough productive Is this a small lung disorder, and if breathless or obstructive spirometry or reduced peak
spirometry or of purulent sputum so is it due to an abnormality? flow? If so is it a localised or a generalised obstruction?
personal or family or focal signs on
history Nasal examination of Within the lung: Sarcoidosis,
of other Symptoms of Asbestosis, Extrinsic allergic Localised obstruction? Generalised obstruction?
gastro- stuffiness or the chest? Stridor
atopic disease; alveolitits, Fibrosing alveolitis Polyphonic wheezing
oesophageal catarrh or Monophonic wheeze Bilateral wheezing
consider asthma other
or COPD reflux or or Unilateral wheezing
overweight suggestion of
consider trial post-
Advise nasal drip Outside the lung: Pleural effusions, Localised obstruction: Generalised obstruction:
smoking of proton Scoliosis, Respiratory muscle
pump inhibitor disease Laryngeal carcinoma? Asthma?
cessation or trial consider weakness, Obesity Retrosternal thyroid? Chronic obstrutive
of anti-asthma in highish
dosage for trial of Relapsing polychondritis? pulmonary disease?
therapy as intranasal Abronchial or tracheal tumour? Bronchiectasis?
appropriate 2/12
steroids Post-tracheostomy stenosis? Cystic fibtosis?
Inhaled foreign body? Obliterative bronchiolitis?
Bronchopulmonary dysplasia?
Treat and/or refer for a
chest radiograph and or a
respiratory opinion
Refer to a respiratory Refer to an ENT or Treat or refer to a
No response - refer to a respiratory specialist physician respiratory physician respiratory physician
Figure 1. Diagnosis and management of respiratory disease. ACE: angiotensin-converting enzyme; DVT: deep vein thrombosis; FH: family history; VTE: venous thromboembolism;
BMI: body mass index; COPD: chronic obstructive pulmonary disease; ENT: earnosethroat.
53
phonic and bilateral, as in asthma or COPD,
or monophonic and localised, as may be
found in cases of lung cancer or bronchial
stenosis or inhaled foreign bodies.
N Crackles may be fine and occur in cases of
interstitial lung disease or acutely in cases
of pulmonary oedema, or coarse, as often
heard in patients with bronchiectasis.
N Pleural rubs sound like a squeaky noise, are
usually localised and clearly vary in
intensity with respiration. Care in inter-
Figure 2. Dilated vessels over the anterior chest wall preting a noise as a pleural rub is necessary
are often the most obvious pointer to superior vena in very thin patients where the diaphragm
cava obstruction, with the other features being a of the stethoscope may move over the ribs.
raised jugular venous pressure, which is
nonpulsatile. N Vocal resonance is found under the same
circumstances as vocal fremitus, and when
from the midline. The percussion note may be found in conjunction with bronchial
hyper-resonant symmetrically in patients with breathing is highly suggestive of consoli-
underlying hyperinflated lungs or dation. Some physicians find detection of
asymmetrically in a large pneumothorax, or whispering pectoriloquoy (WP) a more
may be dull in cases of consolidation or definite sign; to elicit WP, one asks the
pleural effusion. patient to whisper 99 and, when it is
present, for example, in cases of consoli-
Auscultation
dation, the whispered sound is heard
Listening to the breath sounds involves the clearly over the chest wall when trans-
following: mitted through consolidated lung whereas
a normally air-filled lung would muffle the
N Checking for the presence of bronchial
whispered sound and make it indistinct.
breathing, which is the presence of breath
sounds that are similar to those heard over Finally, one should remember that disorders of
the large central airways in a more other systems may coexist and, whilst
peripheral location. Bronchial breathing is examining the chest, one should especially
classically heard over a consolidated lung look for evidence of heart and pulmonary
(and in association with dullness to vascular disease, noting signs of peripheral
percussion), but is also sometimes heard oedema and elevation of the jugular venous
over the upper aspect of a pleural effusion pressure.
and sometimes over a collapsed lung.
References
N Determining whether there are or are not
N Gibson GJ, et al. Respiratory Medicine. Saunders
any abnormal added sounds, which may be Elsevier Science Ltd, 2002.
musical sounds (wheezing) or crackles. In N Partridge MR. Understanding Respiratory
cases of wheezing, it is important to Medicine: a Problem-Orientated Approach.
determine whether the wheezing is poly- Manson Publishing Ltd, 2006.

CHAPTER 3:
PulmonARy funCTion TESTing
STATiC And dynAmiC lung volumES 58

RESPiRAToRy mECHAniCS 63
D. Navajas and R. Farr
gAS TRAnSfER (Tl,Co) 68

J.M.B. Hughes
ConTRol of vEnTilATion 72
B.J. Whipp
ARTERiAl blood gAS ASSESSmEnT 77

P. Palange, A. Ferrazza and J. Roca
ExERCiSE TESTing 83
P. Palange
bRonCHiAl PRovoCATion TESTing 88

K-H. Carlsen
SPuTum And ExHAlEd bREATH AnAlySiS 92

O. Toungoussova, S. Dragonieri, A. Zanini and A. Spanevello

STATIC AND DYNAMIC LUNG
VOLUMES
Allergologia e Fisiopatologia Respiratoria, ASO S. Croce e Carle, Cuneo, Italy
E-mail: pellegrino.r@ospedale.cuneo.it
Ventilation is constrained by the mechanical chest wall stiffness are balanced by the
properties of the airways, lung and chest wall. progressive loss of lung elastic recoil.
The latter two set up the volume at which the
movement of gas is accomplished at rest and In contrast, TLC tends to increase in
with daily activities, such as exercise, emphysema and sometimes in chronic
phonation, laughing, changes in body posture bronchitis and severe asthma. Though the
and others. However, with the occurrence of decrease in lung elastic recoil is presumably
cardiopulmonary diseases, lung volumes may the most important mechanism of the
also be modified as a result of dynamic increase in TLC under these conditions, an
mechanisms within the airways and changes increased force of the inspiratory muscles and
in breathing pattern in addition to static chest wall remodelling may also play a role.
changes in lung and chest wall properties. Surprisingly, for the same level of airflow
obstruction, TLC tends to increase during
Determinants of lung volumes in health spontaneous long-lasting but not acutely
and disease induced bronchospasm. This is presumably
because of the different time course necessary
Tidal volume (VT) is the volume of gas inspired
to produce airflow obstruction and
during each breath (fig. 1) necessary to
hyperinflation. That this may be so is shown
preserve gas exchange. In healthy subjects,
by a study documenting that when a resistive
inspiration is switched off by neural reflexes,
valve was implanted in the dog trachea, it
whereas expiration is terminated near the
took time for TLC to increase. Thus it is
relaxation volume (Vr) as a result of static or
dynamic mechanisms (see section dedicated
to functional residual capacity). Except during
Key points
exercise, when a lack of increase in VT with
ventilation is a functional marker of Measurement of lung volumes in clinical
ventilatory limitation, and perhaps in patients practice has been proven to be important
undergoing assisted ventilation, VT has little to assist in the following.
clinical usefulness in clinical practice.
N Diagnosis of pulmonary defects.
Total lung capacity (TLC) is the volume of gas N Evaluation of candidates for lung
contained in the lungs after a deep breath. It
volume resection surgery.
is determined by the maximum force exerted
by the inspiratory muscles to balance lung N prognosis of COPD and interstitial lung
and chest wall elastic recoils (figs 1 and 2). diseases.
In healthy conditions, TLC tends to remain N Evaluation of the bronchomotor
fairly stable with ageing, presumably because response to constrictor and dilator
the natural decrease of the force of the agents as well as to physical exercise.
inspiratory muscles and/or the increase in

100 TLC
IRV
Pe,m
Lung
TLC % pred
IC
ax
EVC TLC
Volume
Chest wall FRC

Vt
Pi,max
ERV FRC
RV
RV 0
100 -100
Time Ppl cmH2O
Figure 1. Lung volume plotted versus time. VT: tidal Figure 2. Quasi-static pressurevolume curves of the
volume; EVC: slow expiratory vital capacity; IRV and chest wall and the lung (dashed lines) related to
ERV: inspiratory and expiratory volume reserves, pleural pressure (Ppl) generated during maximum
respectively; IC: inspiratory capacity; RV: residual inspiratory and expiratory static efforts (Pi,max and
volume; FRC: functional residual capacity; TLC: total Pe,max , respectively; continuous lines). Volume is
lung capacity. expressed as % of total lung capacity (TLC). TLC is
the volume at which Pi,max equals the inward elastic
possible that breathing at high lung volumes recoils of both lung and chest wall. Residual volume
for long periods of time as a result of severe (RV) is the volume at which Pe,max overcomes the
outward elastic recoil of the chest wall. Functional
chronic airflow obstruction may also
residual capacity (FRC) is the volume at which
contribute to the increase in TLC. inward lung recoil equals outward chest wall recoil
TLC decreases in all conditions characterised (arrows with opposite direction). % pred: % predicted.
by an increase in lung elastic recoil (e.g.
pulmonary fibrosis, cardiac failure), chest wall In obstructive pulmonary diseases, RV is
stiffness (e.g. neuromuscular diseases, obesity, higher than predicted because of premature
ascitis and pregnancy) or thoracic space airway closure, loss of lung elastic recoil, and
competition (e.g. pleural effusions, stiffness of chest wall. Additional mechanisms
pneumothorax). may dynamically contribute to elevate RV in
obstructive lung diseases. For instance, in
Measuring TLC is of great importance in patients with acutely induced or chronic
clinical practice as it allows identification of airflow obstruction, RV achieved after a forced
the restrictive pulmonary defects. In addition, expiration is always higher than after a slow
TLC is also useful in the evaluation of an expiration. This is mainly because of two
emphysematous patient as a candidate for mechanisms. First, during forced expiration in
lung volume resection surgery or for follow-up airflow obstruction, expiratory flow limitation
of interstitial lung diseases. (EFL) occurs soon after initiation of the
Residual volume (RV) is the volume of gas manoeuvre, especially within the airways that
that remains in the lungs after a complete are already narrowed. In contrast, during a
expiration. In young healthy individuals, RV is slow expiration, pleural pressure will exceed
mostly determined by the balance between the critical pressure necessary to generate
the force of the expiratory muscles and the maximal flow, and thus EFL late on expiration
outward recoil of the chest wall (figs 1 and and at a lower lung volume. Secondly, some
2). In the elderly, it increases as a result of airways could close near TLC early on
airway closure. expiration as a result of the disease, thus
preventing the subtending alveolar units from
In restrictive diseases, RV decreases in emptying and contributing to increased RV.
proportion to the increase in lung elastic or
chest wall recoils and/or loss of lung Also, the effects of volume history of the
parenchyma. manoeuvre preceding the expiration may
Static and dynamic lung volumes 59

affect RV. For instance, in healthy subjects or parenchyma and airways. Both tissues may
mild-to-moderate asthmatics exposed to a lose energy or pressure and deform with
bronchoconstrictor agent, a manoeuvre stretching, a phenomenon named hysteresis.
initiated from TLC will generate greater flow Since lung elastic recoil and transmural
and lower RV than a manoeuvre initiated from pressure are the forces that determine airway
end-tidal inspiration. The opposite occurs in size, any change relative to one of these will
chronic airflow obstruction. This suggests that necessarily entail a change in flow and RV. As
RV is also modulated through the changes in shown in figure 3, if airway hysteresis exceeds
airway calibre caused by large lung inflations. parenchymal hysteresis, airway volume will be
How the deep inspiration manoeuvre affects greater during deflation than inflation and RV
lung and airways mechanics is still a matter of will be achieved at a lower lung volume. This
debate. When a deep breath is taken, the generally occurs when constriction is mostly
inflating stimulus is transmitted to the lung as limited to the airways and little affects lung
well as the airways through the elastic parenchyma, such as with induced airway
network of lung parenchyma. According to narrowing. In contrast, when lung
FROEB and MEAD (1968), the effects of volume parenchyma hysteresis is larger than airway
history on airway size depend on the hysteresis, airway volume will be reduced on
mechanical characteristics of lung expiration compared with inspiration and RV
Airways Lung
a) parenchyma b)
Flow
Volume
Flow
exp exp
insp
insp
Flow
Pressure Volume
Constrictor Dilator
force force
Figure 3. Effects of deep breath on maximum expiratory flow and residual volume according to the relative
hysteresis theory of FROEB and MEAD (1968). a) Pressurevolume loops of lung parenchyma and airways on
inspiration and expiration. The area inside the loop is called hysteresis. b) Partial and maximal flowvolume loops
(dotted and continuous lines, respectively). Upper panels of a) and b): both hystereses are similar, so that the
constrictor and dilator forces after the deep breath remain equal compared to before inflation. As a result, forced
flow and residual volume during the maximum forced expiratory manoeuvre are the same of the partial
manoeuvre. Central panels of a) and b): airway hysteresis prevails over lung hysteresis, so that the constrictor force
is reduced after the large inflation. Consequently, for a given lung volume, maximum flow will exceed partial flow
and residual volume will decrease more after a maximal compared to partial manoeuvre. Lower panels of a) and
b): lung parenchyma hysteresis prevails over airway hysteresis, so that the dilator force will decrease after the deep
breath. Under these conditions, forced expiratory flow and residual volume after a maximal manoeuvre will
decrease and increase, respectively, compared to a partial manoeuvre. exp: expiration; insp: inspiration.

achieved at a higher volume. This is what as a result of either an increase in airflow
presumably occurs in chronic airflow resistance or a decrease in lung compliance,
obstruction or severe ASM shortening. Finally, will lead to an expiratory time relatively too
when airway and lung parenchyma hystereses short to allow the respiratory system to empty
change by similar extent, airway size will be fully. Presumably, the occurrence of EFL during
similar before and after a deep breath and so tidal expiration may also contribute to an
will RV. The effects of volume history may be increase in FRC to a lung volume where EFL is
easily assessed in vivo by comparing forced minimal. Under these circumstances, the
expiratory manoeuvres initiated from total dynamic compression of the airways
lung capacity and a volume below it (fig. 3b), downstream from the flow limiting segment
or by changes in airflow resistance soon after may evoke neural reflexes that prematurely
taking a deep breath. activate the inspiratory muscles to avoid
breathing for too long a time under EFL
Vital capacity (VC) is the difference between conditions. On the one hand the increase in
TLC and RV. Because RV is dependent on FRC in airflow obstruction is beneficial as it
volume and flow histories in addition to airway, allows breathing at a volume where the
parenchyma, and/or chest wall components of airways are larger, thus decreasing the
the diseases as discussed above, VC will resistive work of breathing. On the other hand,
depend on the type of respiratory manoeuvre however, breathing at high lung volume is
from which it is taken and the underlying associated with an increase in the elastic work
disease. In general, the largest VC is that of breathing and causes dyspnoea.
obtained during a full inflation from RV
(achieved after a slow expiration from end-tidal A decrease in FRC occurs in restrictive
inspiration) to TLC (inspiratory vital capacity), respiratory diseases due to an increase in lung
followed by the slow expiratory vital capacity elastic recoil (e.g. in pulmonary fibrosis,
from TLC to RV (EVC), and the VC measured atelectasis, lung resection, alveolar liquid
during a forced expiratory manoeuvre (forced filling, cardiac diseases) or in chest wall
vital capacity). A decrease of VC does not allow elastance (e.g. in chest wall and pleural
differentiation between restriction and diseases, respiratory muscle paralysis, obesity).
obstruction, as it may be due to a decrease in
TLC or an increase in RV, or both. Inspiratory capacity (IC) is the volume
difference between TLC and FRC. In
In clinical practice, VC is of central importance pulmonary diseases, it tends to decrease as a
for the diagnosis of obstructive pulmonary result of an increase in FRC (obstructive
defects. conditions) or a decrease in TLC (restrictive
diseases), or both. In clinical practice, changes
Functional residual capacity (FRC) is the in IC with acute interventions on airway
volume of gas remaining in the lungs at the calibre, such as bronchoprovocation or
end of a tidal expiration in a seated or upright reversibility tests, or during exercise, reflect
position (fig. 1). Its mechanical determinants mirror-like changes in FRC, assuming that TLC
are the inward elastic recoil of the lung remains unmodified.
balancing the outward recoil of the chest wall
(fig. 2). In supine position, the abdominal IC has no role in the diagnosis of ventilatory
content is displaced towards the chest cavity, defects.
thus reducing FRC. Also during speech,
singing, laughing or exercise FRC tends to Expiratory and inspiratory reserve volumes are
decrease to favour these activities. the volumes available to VT to expand when
necessary (fig. 1). Though of little interest at
In obstructive pulmonary diseases, FRC tends rest, they play a critical role during exercise.
to increase for a series of reasons. For For instance, in healthy subjects the increase
instance, an increase in breathing frequency in VT with exercise is achieved at the expenses
or in time constant of the respiratory system of a decrease in end-expiratory lung volume
Static and dynamic lung volumes 61

(EELV) and an increase in end-inspiratory lung prognostic implications in both obstructive
volume (EILV). In contrast, in airflow and restrictive diseases, and plays an integral
obstruction, the increase in VT is limited by the role in the functional evaluation for lung
premature and sustained increase in EELV that volume reduction surgery in emphysema.
may eventually contribute to cause dyspnoea.
References
Measurements of lung volumes in
clinical practice: technical aspects
N Agostoni E, Hyatt RE. Static behaviour of the
respiratory system. In: Macklem PT, Mead J, eds.
VC, VT, IC, EILV and EELV can be measured by Handbook of Physiology. The Respiratory
System. Mechanics of breathing. Section 3, Vol.
simple spirometry. In contrast, TLC, RV and
III, part 1. Bethesda, American Physiological
FRC need to be measured with special Society, 1986; pp. 113130.
techniques described below. N Brusasco V, et al. Vital capacities during acute
Gas dilution techniques (nitrogen washout and chronic bronchoconstriction. Dependence of
flow and volume histories. Eur Respir J 1997; 10:
and helium dilution) are based on the
13161320.
principle of the conservation of mass, that is N Casanova C, et al. Inspiratory-to-total lung
the amount of gas resident in the lungs at the capacity ratio predicts mortality in patients with
beginning of the test can be calculated as the chronic obstructive pulmonary disease. Am J
product of concentration and volume of Respir Crit Care Med 2005; 171: 591597.
eliminated nitrogen or diluted helium. Both N Criner GJ, Sternberg AL, for the National
methods yield measurements of lung volumes Emphysema Treatment Trial Research Group, A
that communicate with open airways only. In clinicians guide to the use of lung volume
severely obstructed patients, an underestimation reduction surgery. Proc Am Thorac Soc 2008; 5:
461467.
of the true lung volume may be a result of some
regions with long time constants.
N Froeb HF, Mead J. Relative hysteresis of the dead
space and lung in vivo. J Appl Physiol 1968; 25:
Body plethysmography allows rapid and 244248.
reproducible measurements of absolute lung N King TE, Jr, et al. Predicting survival in
idiopathic pulmonary fibrosis. Scoring system
volumes. The test is based on Boyles law, in
and survival model. Am J Respir Crit Care Med
that lung volume can be calculated from the 2001; 164: 11711181.
relationship between changes in mouth N Olive JT, Hyatt RE. Maximal expiratory flow and
pressure (assumed equal to alveolar pressure) total respiratory resistance during induced
and box pressure (constant-volume bronchoconstriction in asthmatic subjects. Am
plethysmography) or volume (constant- Rev Respir Dis 1972; 106: 366376.
pressure plethysmography) during gentle N Pellegrino R, et al. Expiratory flow limitation and
panting manoeuvres against a closed shutter. regulation of end-expiratory lung volume during
As opposed to gas dilution techniques, exercise. J Appl Physiol 1979; 74: 25522558.
plethysmography measures the whole N Pellegrino R, et al. Interpretative strategies for lung
function tests. Official statement of the American
intrathoracic gas, thus including Thoracic Society and the European Respiratory
nonventilated and/or poorly ventilated lung Society. Eur Respir J 2005; 26: 948968.
regions. This method may overestimate lung N Pellegrino R, et al. Lung mechanics during
volumes in cases of severe airflow obstruction induced bronchoconstriction. J Appl Physiol
if the panting frequency .1 Hz. 1996; 81: 964975.
N Pride NB, Macklem PT. Lung mechanics in
Conclusions disease. In: Macklem PT, Mead J, eds. Handbook
of Physiology. The Respiratory System.
Measuring lung volumes is now an integrative
Mechanics of breathing. Section 3, Vol. III, part
part of lung function assessment. In addition 2. Bethesda, American Physiological Society,
to assist in the diagnosis of the ventilatory 1986; pp. 659692.
defects, it helps explain the presence of N Vinegar A, et al. Dynamic mechanisms determine
respiratory symptoms and hypoxia in functional residual capacity in mice, Mus
cardiopulmonary diseases, has clinical musculus. J Appl Physiol 1979; 46: 867871.

RESPIRATORY MECHANICS
D. Navajas1,2,3 and R. Farre1,2,4
1
Unitat de Biofisica i Bioenginyeria, Facultat de Medicina,
Universitat de Barcelona
2
CIBER Enfermedades Respiratorias
3
Institut de Bioenginyeria de Catalunya
4
Institut de Investigacions Biome`diques August Pi Sunyer, Barcelona, Spain
E-mail: rfarre@ub.edu
Pulmonary ventilation is determined by the exhibiting outward and inward elastic recoil
resistive and elastic properties of the lungs pressure (PCW) below and above its resting
and chest wall and by the driving pressure of volume, respectively.
the respiratory muscles. Both the lungs and
chest wall are elastic structures. The lungs At end-expiratory volume during quiet
have a very small resting volume. Above this breathing (functional residual capacity (FRC))
volume the lungs are distended, exerting an in a healthy subject the respiratory muscles
inward elastic recoil pressure (PL) that rises are relaxed and the lungs and chest wall
reach the combined resting state (fig. 1). In
markedly with lung volume (VL). The chest
this situation, the inward PL is
wall has a much higher resting volume,
counterbalanced by the outward PCW and the
alveolar pressure (Palv) equals atmospheric
Key points pressure. Inspiration is produced by activation
of inspiratory muscles. The outward muscular
N Alveolar pressure is lower and higher pressure (Pmus) expands the chest wall,
than pressure at the airway opening thereby lowering pleural pressure (Ppl). This
during inspiration and expiration, drop in Ppl expands the lung and decreases
respectively. Palv to subatmospheric values. The mouth
alveolar pressure gradient drives inspiratory
N The lungs exert inward elastic recoil flow. During quiet breathing in a normal
that increases with lung volume. subject, expiration is achieved by relaxing
inspiratory muscles. The net inward elastic
N Body plethysmography allows the
recoil of the total respiratory system
measurement of both airway resistance
(PRS 5 PL + PCW) tends to return the system to
and lung volume. the overall equilibrium volume, increasing Palv
N The forced oscillation technique allows to above mouth pressure (Pmo) and driving
the measurement of respiratory expiratory flow. The activation of the
resistance during spontaneous expiratory muscles results in a faster
breathing with minimum patient expiration.
collaboration. Airway resistance
N Respiratory mechanics can be
The airflow generated by the pressure
monitored in sedated mechanically
gradient between the mouth and the alveoli is
ventilated patients performing
determined by airway resistance (Raw),
post-inspiratory and post-expiratory defined as
pauses.
Raw 5 (Pmo Palv)/V9
Respiratory mechanics 63
V'
transducer. As the alveolar airspace is not
directly accessible, Palv can be estimated by
means of a whole-body plethysmograph
(fig. 2). This technique involves the subject
sitting inside a closed cabin breathing the gas
from the box. The mouth can be occluded
with a shutter coupled to the mouthpiece.
First, the shutter is opened and the ratio
between V9 and the pressure within the box
(Pbox) is measured during breathing (V9/Pbox).
During inspiration the air moves from the box
to the lung. The inspired gas takes on a higher
Palv VL
volume in the lungs than in the box due to
the decrease in pressure (Palv,Pbox), the
PL increase in temperature (37uC) and the
addition of water vapour. The calibration ratio
PCW Pmus
of the plethysmograph (k 5 Palv/Pbox) is
experimentally determined by closing the
shutter at FRC and recording Pmo and Pbox
Figure 1. Mechanial behaviour of the respiratory
during gentle respiratory efforts against the
system. V9: gas flow; Palv: alveolar pressure; VL: lung
volume; PL: lung elastic recoil pressure; PCW: chest occlusion. Under zero airflow conditions,
wall elastic recoil pressure; Pmus: outward muscular Palv < Pmo and
pressure.
k 5 Palv/Pbox
where V9 is the gas flow.
In healthy adults, Raw measured at FRC is
about 2 hPa?s?L-1. Intrathoracic airway calibre
increases as lungs expand, resulting in a Shutter
hyperbolic dependence of Raw on lung V'
volume. Therefore, an approximately linear Pmo

relationship is obtained by computing airway
conductance (Gaw 5 1/Raw). Since large lungs
have wider airways, the specific airway
resistance computed as
Pbox
sRaw 5 Raw?FRC
provides a resistance measurement
normalised for differences in lung size.
Palv VL
Similarly, specific conductance is defined as
sGaw 5 Gaw/FRC.
Body plethysmography
Measurement of Raw requires the recording of
airflow and driving pressure. Airflow can be
recorded with a pneumotachograph Figure 2. Measurement of airway resistance by body
connected to the mouth. Mouth pressure is plethysmography. V9: gas flow; Pmo: mouth pressure;
simply atmospheric pressure or, alternatively, Palv: alveolar pressure; VL: lung volume; Pbox:
it can be readily measured with a pressure pressure within the box.

Therefore, exhibit resistive load because of internal
frictional resistance to motion. Resistance of
Raw 5 Palv/V9 5 k?Pbox/V9
the total respiratory system (Rrs) is the sum of
Body plethysmography measurements of Raw airway and tissue resistance. The tissue
are usually computed at low respiratory flows component of Rrs is generally small in
(,0.5 L) recorded during shallow panting to comparison with Raw.
minimise the effects of temperature changes
Rrs can be measured during quiet breathing
during inspiration and expiration.
by the forced oscillation technique (FOT). This
Alternatively, measurements can be made
technique is based on applying a small
during quiet breathing after computer
amplitude (1 hPa) pressure oscillation to
correction for changes in the physical
the patients mouth or nose with a
conditions of the gas.
loudspeaker or a small pump. Rrs is computed
Whole-body plethysmography is the procedure as the ratio of forced pressure oscillation and
most commonly used to measure Raw. An in-phase flow. The ratio between forced
added advantage of this technique is that it pressure and the out-of-phase flow defines the
provides a FRC measurement for the reactance (Xrs) that provides a combined
computation of sRaw. However, the device is measurement of the inertial and elastic
bulky and expensive and is not suited to properties of the respiratory system. Forced
measurement in supine patients. oscillation is applied at frequencies (.4 Hz)
higher than the breathing rate to facilitate the
Interrupter technique separation of forced oscillation from tidal
Airway resistance can also be measured breathing. The use of multifrequency
outside the box with a pneumotacograph oscillation (usually 432 Hz) provides a
shutter system. The subject breathes at rest measurement of the frequency dependence of
through the pneumotacograph. When airflow respiratory mechanics.
reaches a given threshold the mouth is briefly Current FOT devices are portable and easy to
(,0.1 s) occluded with the shutter. During use. The technique does not require any
flow interruption the pressure is equilibrated special collaboration from the patient and
within the different lung compartments. measurements can be performed in supine.
Therefore, Raw can be computed as the ratio Changes in Rrs during the breathing cycle can
between the flow just before occlusion and be precisely monitored. Moreover, FOT can be
the mouth pressure recorded during flow coupled to mechanical ventilators. Therefore,
interruption. Raw is usually computed as the FOT is especially useful for epidemiological
mean of flow interruptions performed in studies, measurements in infants and
several breathings. monitoring respiratory mechanics in patients
The interrupter technique can be during sleep and mechanical ventilation.
implemented in handy devices and requires Lung compliance
only minimal patient cooperation. However,
due to progressive equilibration between The elastic behaviour of the lung is described
mouth and alveolar pressure the computed by the PLVL relationship. Lung deformability
value of Raw depends on the time lag is measured as lung compliance (CL), defined
between the start of occlusion and Pmo as the change in volume divided by the
measurement. Slow pressure equilibration in change in pressure.
patients with airflow obstruction results in an
underestimation of Raw. CL5 DVL/DPL
Forced oscillation technique The change in volume can readily be

measured with a spirometer connected to the
In addition to the airflow resistance of the mouth. The measurement of DPL requires the
airways, lung and chest wall tissues also simultaneous recording of Ppl and Palv. Pleural
pressure is usually estimated from the In patients ventilated with a constant flow
oesophageal pressure (Psoe) recorded with a waveform, Rrs and Ers can also be measured
small balloon attached to the tip of a catheter by performing a post-inspiratory pause. Flow
introduced through the nose into the lower interruption results in a sharp drop in pressure
oesophagus. Alveolar pressure is estimated in from the peak value at end inspiration (Pmax)
the mouth during brief flow interruptions. In to P1, followed by a slow decay to a plateau
practice, the subject performs a full inspiration (P2). The sudden decrease in Pao is associated
followed by a very slow expiration to FRC. A with the resistive load of the airways.
shutter attached to the spirometer performs Therefore, Raw is estimated as
successive brief (,1 s) occlusions during
expiration. The PLVL relationship is Raw 5 (Pmax P1)/V9
curvilinear, with CL decreasing markedly with A higher value of resistance due to the
volume. CL is habitually computed in the contribution of tissue viscoelasticity and gas
range of tidal volume at rest (between FRC redistribution within the lungs is computed from
and FRC+0.5 L). In the normal adult, CL is the pressure drop to the plateau (Pmax P2).
about 0.2 L?hPa-1. The elastic behaviour of the
lung can also be characterised by lung The additional performance of a post-
elastance (EL), defined as the reciprocal of CL expiratory pause allows Ers to be computed as
(EL 5 1/CL). the ratio of pressure and volume changes at
the end of the post-inspiratory and post-
Chest wall compliance is computed as expiratory pauses.
CCW 5 DVL/DPCW Respiratory muscle strength
In healthy subjects, the value of CCW is Since direct measurements of muscular
comparable to that of CL. Since the elastic pressure are not clinically available,
pressure of the respiratory system is Prs 5 PL + respiratory muscle performance is commonly
PCW, the compliance of the respiratory system assessed by measuring maximal pressures
(Crs) is related to the compliance of the lungs generated at the mouth during maximal
and chest wall components as inspiratory and expiratory efforts against an
1/Crs 5 1/CL + 1/CCW occluded airway (or occluded except for a
small leak). Maximum expiratory pressure
Crs or CCW can only be measured during (PE,max) is measured at total lung capacity
complete respiratory muscle relaxation, which (TLC). Maximum inspiratory pressure
is extremely difficult to achieve in conscious measurements (PI,max) are taken at either FRC
patients. or residual volume (RV). Alternatively,
inspiratory muscle strength can be assessed
Measurement of respiratory mechanics during sniffing with one nostril occluded with a
in mechanical ventilation plug. Maximum pressure (sniff Pdi) is recorded
Respiratory mechanics can be measured in into the occluded nostril during a rapid forceful
sedated mechanically ventilated patients by inspiratory sniff performed at FRC.
recording airflow and pressure at the airway The clinical testing of maximal respiratory
opening (Pao). The driving pressure required to pressures is quick and simple but
overcome the elastic and resistive loads (Ers measurement is dependent on effort. The test
and Rrs, respectively) of the respiratory system is useful for excluding significant respiratory
is muscle weakness.
Pao 5 Rrs?V9 + Ers?V References
where V is volume. Rrs and Ers can be N ATS/ERS Statement on Respiratory Muscle
computed by least squares fitting of this Testing. Am J Respir Crit Care Med 2002; 166:
equation to Pao, V9 and V recordings. 518624.

N Beydon N, et al. An official American Thoracic Philadelphia, Lippincott Williams & Wilkins,
Society/European Respiratory Society statement: 2008; pp. 7586.
pulmonary function testing in preschool N Lucangelo U, et al. Lung mechanics at the
children. Am J Respir Crit Care Med 2007; 175: bedside: make it simple. Curr Opin Crit Care
13041345. 2007; 13: 6472.
N Farre R, et al. Noninvasive monitoring of N Oostveen E, et al. The forced oscillation
respiratory mechanics during sleep. Eur Respir J technique in clinical practice: methodology,
2004; 24: 10521060. recommendations and future developments. ERS
N Gibson GJ. Clinical tests of respiratory function. task force. Eur Respir J 2003; 22: 10261041.
3rd Edn. London, Hodder Arnold, 2009; pp. 3 N Pride NB. Airflow resistance. In: Hughes JMB,
52. Pride NB, eds. Lung function tests: Physiological
N Hyatt RE, et al. Interpretation of pulmonary principles and clinical applications. London, W.B.
function tests. A practical guide. 3rd Edn. Saunders, 1999; pp. 2744.
GAS TRANSFER (TL,CO)
J.M.B. Hughes
National Heart and Lung Institute, Imperial College, London, UK
E-mail: mike.hughes@imperial.ac.uk
Apart from spirometry, the transfer factor of carbon monoxide tension (PCO) difference. CO
the lung for carbon monoxide (TL,CO) is the is chosen for alveolarcapillary exchange
most frequently performed pulmonary because, after diffusing into capillary blood,
function test. It focuses on the integrity of the CO binds to haemoglobin (Hb) as carboxy-Hb,
alveolar (gas exchanging) part of the lung. but at an extremely low partial pressure (PCO).
The TL,CO can detect abnormalities limited to Plasma PCO is so low that it is not usually
the pulmonary microcirculation, the only measured, but it may reach significant levels in
routine test which can do so. It helps to think current smokers. CO uptake is independent of
of the TL,CO as a measure of the anatomy of blood flow, but it is dependent on the number
the alveolar region, whereas blood gas of Hbbinding sites, i.e. on capillary volume.
measurements (arterial oxygen (Pa,O2) and Transfer is the better term, because chemical
carbon dioxide (Pa,CO2) tension) measure a reaction as well as diffusion is involved.
physiological efficiency, which involves
airways and larger blood vessels, as well as Technique
alveolar structures. For example, the TL,CO is Nearly all clinical laboratories use the single
normal in asthma (alveoli are uninvolved), but breath (sb) technique of OGILVIE et al. The
the Pa,O2 may be considerably reduced. TL,CO is measured during a 10-s breath-hold at
Definition maximal inspiration (volume 5 total lung
capacity (TLC)).
The transfer factor (called the diffusing
capacity of the lung for carbon monoxide Breath-holding at TLC optimises the distribution
(DL,CO) in the USA) measures the surface area of the inhaled marker gases (He and CO), and
available for gas exchange. It is closely related makes TL,CO independent of ventilation. The
to the oxygen diffusing capacity (DL,O2). TL,CO breathing manoeuvre is shown in fig. 1. The
is the quantity of inhaled CO absorbed, per subject is asked to: 1) exhale slowly to residual
unit time and per unit CO partial pressure. volume; 2) make a signal; 3) inspire rapidly to
The pressure gradient is the alveolarplasma full inflation; and 4) breath-hold. The breath-
hold is assisted by automatic closure of the
inspiratory and expiratory valves for a pre-set
Key points time (911 s), after which exhalation occurs
rapidly (there is no need for a forced expiration)
N TL,CO measures alveolar function. and an alveolar sample taken, from which water
vapour and CO2 are absorbed before He and
N TL,CO is the product of KCO and VA. CO concentrations are analysed.
N KCO (or TL/VA) is the more specific index
Calculation of the TL,CO
of alveolar integrity.
N KCO is low in emphysema and fibrosis. The key point is that the TL,CO is the product
of two measurements, the alveolar volume
N KCO is high in extrapulmonary (VA) and the rate of alveolar uptake of CO,
restriction. given by the transfer coefficient of the lung
for CO (KCO). During the breath-hold at

Single breath
0.3% CO
14% He
18% O2
FA,CO
FA,He
Spirometer
CO2+H2O He+CO
absorption analysis
Dead space
wash-out
Volume inspired
on
Fast
Inspirati
Sample
Volume
Expiration
Effective breath-holding time

RV
Time s
0 10
Figure 1. Transfer factor of the lung for carbon monoxide (TL,CO) set-up and breathing protocol. The breath-
hold time is set automatically, and is calculated from 0.336 inspired time to 1 L expiratory time. FA,CO:
alveolar carbon monoxide fraction; FA,He: alveolar helium fraction; RV: residual volume.
maximal inspiration, VA should equal TLC KCO by VA (in mmol: 1 mmol 5 22.4 mL
minus anatomical dead space (9798% TLC). standard temperature, pressure and dry).
In practice, VA in normal subjects 5 94% TLC
KCO 6 VA 5 TL,CO (mmol?min-1?kPa-1)
with a lower confidence limit (-1.64 SD) of
83%. The 10-s breath-hold is insufficient time TL,CO/VA 5 KCO (mmol?min-1?kPa-1?L-1)
for complete gas mixing; in airflow
obstruction, the measured VA may be much but the units are equivalent to (min-1?kPa-1).
less than 80% of the actual TLC (measured If VA remains constant, TL,CO and KCO will
by multi-breath gas dilution or change equally (as % predicted). There are
plethysmography). formulae to correct TL,CO for anaemia, so the
Hb level should always be known. Oxygen
The kCO is the rate of alveolar uptake of CO breathing with an increase in PA,O2 reduces
during the breath-hold (the slope in fig. 2). It TL,CO and KCO by competitive antagonism
is a rate constant with units of s-1 or min-1. between O2 and CO; it is the basis of the
When normalised to barometric pressure RoughtonForster equation which partitions
(minus water vapour pressure) (Pb*), kCO/Pb* 1/TL,CO (transfer resistance) into 1/DM
5 KCO (min-1?kPa-1). The final step in the (alveolarcapillary membrane resistance) and
calculation of TL,CO is the multiplication of 1/hVc (transfer resistance of red cells).
Gas transfer (TL,CO) 69

He(i) Inspired concentrations
Exhalation
100
CO(i) sample
He(i)
VA = VI
He(t)
Gas concentration % inspired (log)
50
He(t)
Helium (He)

CO(o)
Calculated from CO
CO(i)(He(t) /He(i))
Expired
concentrations
20

Slope=KCO CO(t)
VI
10
Inhalation
0 5 10
Breath-hold times
Figure 2. Transfer factor of the lung for carbon monoxide (TL,CO): CO and He analysis. CO and He
concentrations versus breath-hold time to illustrate the origin and calculation of the two components (slope of
the transfer coefficient of the lung for CO (KCO) and alveolar volume (VA)) from which TL,CO is derived. CO(i)
and CO(t) are CO concentrations inspired (i) and after exhalation (with dead space discard) at time t after
breath-hold (the same for He(i) and He(t)). CO(0) is the calculated alveolar concentration at breath-hold start
before alveolar uptake has begun. VI: inspired volume.
When VA is reduced, TL,CO and KCO may N anaemia

change in opposite directions (table 1) if the
cause is a) reduced alveolar expansion, e.g. Causes of a high KCO:
extrapulmonary restriction, or b) a reduction
in aerated alveolar units, e.g. pneumonectomy
N extrapulmonary restriction
or consolidation or atelectasis. Other causes of N loss of aerated units
a reduced VA are c) diffuse alveolar damage
(emphysema or fibrosis) (TL,CO and KCO both
N increased pulmonary blood flow
reduced) and d) airflow obstruction (VA low N acute alveolar haemorrhage
due to poor gas mixing). In d), TL,CO and KCO
are variable, being low in emphysema and N polycythaemia
normal or high in asthma. Implications of KCO x VA 5 TL,CO
Causes of a low KCO (and TL,CO): 1. Transfer factor of the lung (TL)/VA does not
correct TL,CO for a low VA because a) TL/VA
N diffuse alveolar damage (fibrosis, emphy-
may rise when VA falls, and b) TL/VA 5 KCO 5
sema)
the rate constant for alveolar uptake of CO.
N pulmonary vascular diseases
2. The same TL,CO (say 60% predicted) can
N chronic heart failure arise from different combinations of KCO and

Table 1. Physiological influences on the transfer factor of the lung for carbon monoxide (TL,CO) and the transfer coefficient
of the lung for CO (KCO)
TL,CO KCO
Anaemia Q Q
Cardiac output increase q q
PA,O2 increase Q Q
VA Q (reduced alveolar expansion) Q qq
VA Q (reduction in no. of aerated units) Q q
PA,O2: alveolar oxygen tension; VA: alveolar volume.
VA , such as a) high KCO and low VA estimation of pulmonary diffusing capacity by

(extrapulmonary restriction), b) low KCO and the single breath method. Q J Exp Physiol 1961;
normal VA (pulmonary vasculopathy), or c) 46: 131143.
low-ish KCO and low-ish VA (fibrosis). N Ogilvie CM, et al. A standardized breath
holding technique for the clinical
References measurement of the diffusing capacity of the
lung for carbon monoxide. J Clin Invest 1957;
N Hughes JMB, Pride NB. In defence of the carbon 36: 117.
monoxide transfer coefficient KCO (TL/VA). Eur N Roberts CM, et al. Multi-breath and helium
Respir J 2001; 17: 168174. single breath dilution lung volumes as a test
N Jones RS, Meade F. A theoretical and of airway obstruction. Eur Respir J 1990; 3:
experimental analysis of anomalies in the 515520.
Gas transfer (TL,CO) 71

CONTROL OF VENTILATION
B.J. Whipp
Human Bio-Energetics Research Centre, Crickhowell, UK
E-mail: bjwhipp@dsl.pipex.com
The ventilatory control system is highly

Key points complex, involving the transmission of
primary humoral stimuli from their sites of
N The slope of the V9EPET,CO2 generation to the sensing elements; the
relationship (DV9E/DPET,CO2) is driven integration of chemoreceptor afferent activity
by central chemoreceptor CO2 within brainstem "respiratory centres"; the
responsiveness and, if Pa,O2 is not generation of respiratory motor-discharge
excessive, also that of peripheral patterns; neuromuscular transmission at the
chemoreceptors. respiratory muscles; and, finally, the
generation of appropriate pulmonary pressure
N The hyperoxic rebreathing method gradients to generate the required airflow and
appreciably reduces the time demands ventilation. Consequently, while the
of the steady-state, constant-concentration inhalation of hypercapnic or hypoxic gas
inspirate approach for measuring mixtures, either singly or in combination, is
DV9E/DPET,CO2, although DV9E/DPET,CO2 widely utilised to assess the normalcy of
obtained by this method reflects only ventilatory "chemoreflex" sensitivity,
the activity of the central chemoreflex. interpretation of the response should be made
N The isocapnic V9EPET,CO2 response is in the context of the entire "inputoutput"
relationship. Subjects with increased airways
curvilinear, and reflects solely the
resistance or impaired respiratory muscle
activity of the carotid chemoreceptors.
function, for example, may have an
It can be determined by steady-state,
abnormally low overall ventilatory CO2 or
constant-concentration inspirates or by hypoxic response despite normal
rebreathing. chemoreceptor responsiveness.
N Expressing the V9E response as a
Ventilatory response to inhaled CO2
function of Sa,O2 yields a linear profile
of hypoxic responsiveness; the actual The relationship between minute ventilation
V9E stimulus, however, is Pa,O2 not Sa,O2. (V9E) and arterial (a) or alveolar (A; typically
end-tidal (ET)) carbon dioxide tension (PCO2),
N The Dejours hypoxia-withdrawal test
with the subject sequentially inhaling a series
is a further means of estimating
of progressively greater hypercapnic inspirates
hypoxic V9E responsiveness. Abruptly (e.g. 36%), each for sufficiently long to
administering 100% O2 from a prior establish a steady state, is used to estimate
hypoxic background will acutely overall ventilatory CO2 responsiveness. The
suppress carotid body hypoxic resulting V9EPET,CO2 relationship is typically
responsiveness and cause V9E to fall linear in healthy, normoxic individuals, with a
transiently and rapidly; the maximum slope (DV9E/DPET,CO2) averaging ,2
decrease in V9E as a fraction of the 3 L?min-1?mmHg-1. This slope reflects the CO2
total hypoxic V9E provides the hypoxic responsiveness of both the central
index. "chemoreceptors", located predominantly on
the ventral medullary surfaces, and also, if

arterial oxygen tension (Pa,O2) is not excessive, a Pa,O2 of ,200 mmHg, the carotid body
the peripheral chemoreceptors component is effectively inactivated and
(predominantly, if not exclusively, the carotid hence the sufficiently hyperoxic CO2 response
bodies in humans). At Pa,O2 levels of entirely reflects that of the central
,90 mmHg, the central component accounts component. Interpreting the result depends
for 7075% of the response with the on the relationships between the typically
peripheral component accounting for the measured PET,CO2 (or, less typically, the Pa,CO2)
remainder. However, as the peripheral and the PCO2 (and local [H+]) at each set of
component of CO2 responsiveness increases chemoreceptors; these relationships depend
with reductions of Pa,O2 below normal, DV9E/ on factors such as the local-tissue perfusion,
DPET,CO2 increases with greater (but constant) CO2 production, CO2 capacitance, H+
degrees of hypoxaemia and decreases with buffering capacity and metabolic rate. The
greater (but constant) degrees of hyperoxia. equilibrium process is rapid at the carotid
This results in a fan of hypoxia-dependent body chemoreceptors, but is considerably
CO2 response slopes reflecting altered delayed at the sites of central
response sensitivity (also termed chemoreception.
potentiation), with little-or-no change in the
extrapolated zero V9E intercept on the PCO2 It has been has proposed that three or more
axis (fig. 1). By contrast, sustained metabolic levels of inspired (I) PCO2 should be used for
acidaemia or alkalaemia results in a parallel the slope characterisation. Each level is
shift in the CO2 response relationship (i.e. no maintained for ,8 min, with the average V9E
change in CO2 sensitivity) with a reduced or and PET,CO2 over the final 3 min providing the
increased zero V9E intercept, respectively. steady-state value. Consequently, the
demands of the test are time consuming,
The increasing V9E/PET,CO2 slope with greater although transiently "overshooting" PI,CO2
levels of simultaneous hypoxia reflects a beyond the required level can reduce the time
progressively greater carotid body response required to attain the new V9E steady-state
component; it is crucial, therefore, to maintain level.
Pa,O2 constant (iso-oxia) during the test. Above
This concern is obviated, to a considerable
Steady state test extent, by the rebreathing method of READ
PO2 mmHg and LEIGH, which takes a small fraction of the
~60 ~90 200 time to perform while providing effectively the
40 same DV9E/DPET,CO2 values as for the steady-
Ventilation Lmin-1
state method. The subject re-breathes from a

67 L bag initially containing ,7% CO2
25 balance O2. The high initial PI,CO2 is designed
to raise the Pa,CO2 rapidly to, or close to, the
mixed-venous level such that the subsequent
"Read" rebreathing
10 test
rebreathing provides an effectively linear
increase in Pa,CO2; the high inspired oxygen
tension (PI,O2) maintains Pa,O2 above levels for
which variations in carotid chemosensitivity
30 40 50 60
PET,CO2 mmHg would influence the response slope. The
rebreathing relationship is shifted to the right
of the steady-state relationship, as a result of
Figure 1. Steady-state ventilatory responses to
inhaled carbon dioxide tension (PCO2) at constant both the transit delay between the lungs and
oxygen tension (PO2; solid lines). The dotted line the sites of chemoreception and the kinetics
depicts the response to progressively increasing of the V9E response. Consequently, as the test
PCO2 (hyperoxic rebreathing test). PET,CO2: end-tidal is designed to provide a constant rate of
carbon dioxide tension. change of PCO2 at the chemoreceptor sites,
Control of ventilation 73
the rate of change of V9E is compared with the The pattern of the ventilatory response to a
rate of change of PET,CO2 (DV9E/DPET,CO2). This step decrease of PI,O2 is not monotonic, even
is currently the more common means of with PET,CO2 being maintained constant by
assessing CO2 responsiveness. It is important controlling the inspired level (i.e. isocapnic
to recognise, however, that the CO2 hypoxia): there is an initial increase to a peak,
responsiveness obtained by this hyperoxic usually well within 5 min, followed by a slow
method reflects only the activity of the central reduction (termed hypoxic ventilatory
chemoreflex. decline) to a final steady-state value (fig. 2a).
The initial increase is considered to be the
One must be careful, however, not to assume carotid body component and the subsequent
that hypoxia does not influence central decline is thought to result from the hypoxia-
chemoreceptor responsiveness; it does mediated increase in cerebral blood flow. This
indirectly by increasing cerebral blood flow. reduces the degree of central chemoreceptor
This tends to wash out CO2 from the region, stimulation as a result of cerebral CO2 wash-
narrowing the difference between the local out, although an involvement of altered
tissue PCO2 and Pa,CO2. neurotransmission has also been proposed. If
the hypoxic step is limited to the initial, or
Beginning at a value below the spontaneous primary, response phase, then the resulting
control condition, CO2 responsiveness is not V9EPa,O2 relationship over a range of
characterised by the extrapolated dashed lines increasingly hypoxic inspirates is curvilinear,
in fig. 1. Rather, there is a region of virtual with the V9E rate of change approaching
insensitivity to increasing PCO2, if previously infinity at a Pa,O2 of ,30 mmHg. Naturally, at
lowered by, for example, acute higher isocapnic PCO2 levels the curvature
hyperventilation or sufficient hypoxia. The constant of the response is increased as a
transition from the insensitive to the result of greater hypoxichypercapnic
sensitive region is considered to reflect a interaction at the carotid bodies. It is
ventilatory recruitment threshold. The recommended that the subject be switched to
difference between this threshold and the air or even a mildly hyperoxic mixture
lower PET,CO2 at which apnoea ensues is between successive hypoxic steady states to
thought to be important in conditions such as avoid possible depression of brainstem
sleep apnoea. Also, as this threshold is lower respiratory neurones. If, instead of isocapnia
in hypoxia than in hyperoxia, it can be used to being maintained in this test, Pa,CO2 is
further understand the interaction between allowed to decrease spontaneously as
peripheral and central chemoreceptor ventilation increases (poikilocapnia), then
mediation. As a practical expedient, the both the peak initial response and the final
difference in PET,CO2 between these conditions level achieved after the hypoxic ventilatory
at resting ventilation can be used as an index decline are reduced.
of the threshold change (DUFFIN has
suggested PET,O2 values of 150 and 50 mmHg A rebreathing test, notionally similar to the
for this assessment). ReadLeigh test of CO2 sensitivity, yields
considerably greater data density in a
Estimation of ventilatory response to significantly shorter period, although the
hypoxia requirement for isocapnia throughout the test
does demand a degree of sophistication in
The ventilatory response to hypoxia, if defined obviating, by means of a CO2-absorbing
under isocapnic conditions, is considered system, the otherwise progressive
solely to reflect the activity of the carotid hypercapnia. The resulting curvilinear
chemoreceptors. Both constant-concentration response to the progressive isocapnic hypoxia
inspirates and rebreathing techniques have is shown in fig. 2b for two subjects differing
been successfully utilised for the markedly in hypoxic sensitivity. There is little,
characterisation. from a physiological standpoint, to choose

a) d) 65
V'E Lmin-1
Hypoxic ventilatory decline
Primary
Ventilation
hypoxic 0
response Air O2 Air
50
PET,CO2 mmHg
Control Isocapnic hypoxic step
25 1 min
-5 0 5 10 15 20
Time min
b) 140
c) 140

120
120

Ventilation Lmin-1
Ventilation Lmin-1

100

100

80

80

60

60

40

40

20

20
0 0
0 30 40 50 60 70 80 90 100 110 0 65 70 75 80 85 90 95 100
PO2 mmHg SO2 %
Figure 2. Ventilatory time-course to prolonged isocapnic step-decrease in end-tidal oxgen tension (PET,O2; a).
Ventilatory response to progressive isocapnic hypoxia (in two subjects) as a function of PET,O2 (b) and oxygen
saturation (SO2; c; figure reproduced from REBUCK and SLUTSKY (1981), with permission from the publisher).
Ventilatory time-course to an hyperoxic step-increase in an exercising hypoxic subject with alveolar proteinosis
(d; figure reproduced from WASSERMAN et al. (1989), with permission from the publisher). PET,CO2: end-tidal
carbon dioxide tension; V9E: minute ventilation; PO2: oxygen tension.
between an exponential and a hyperbolic isocapnic levels, G is increased as a result of

characterisation of the response. The conflicting the potentiating effect of CO2 on carotid
issues regarding the most appropriate index for sensitivity, which sums with the further central
hypoxic response characterisation appear to be CO2H+ stimulation.
obviated (on empirical grounds) by the
demonstration that the curvilinear V9EPa,O2 In addition to the ease of measuring Sa,O2
relationship can be transformed into a linear noninvasively by pulse oximetry, and averting
relationship by substituting arterial O2 any assumption regarding the difference
saturation (Sa,O2) for Pa,O2 (fig. 2c): between PET,O2 and Pa,O2, the linearity of the
V9E response makes this rebreathing method a
V9E 5 G?Sa,O2 + V9E(0) very practical means of assessing hypoxic
ventilatory responsiveness. It is important to
where V9E(0) is the control V9E and the slope recognise, however, that the ventilatory
parameter G is the hypoxic responsiveness stimulus is Pa,O2; Sa,O2 is merely a practical
quantifier. G has been shown to average expedient, with uncertainties regarding the
,1.51.0 (averageSD) L?min-1?% decrease influence of conditions altering the
of Sa,O2-1 in normal subjects. At higher haemoglobin affinity for O2.
Control of ventilation 75
The current degree of a subjects hypoxic Conclusions
ventilatory drive may be estimated by the
While these approaches provide indices of
hypoxia-withdrawal test of DEJOURS. If a
acute ventilatory responsiveness, laboratory-
particular level of Pa,O2 is established by
based tests of more chronic bloodgas and
inhalation of a hypoxic gas mixture, or noting
acidbase regulatory challenges are less well
the spontaneous Pa,O2 if the subject is already
standardised.
hypoxaemic (as in fig. 2d for an exercising
subject with alveolar proteinosis), then the References
abrupt administration of 100% O2 will
acutely suppress carotid body hypoxic
N Cunningham DJC, et al. Integration of
respiratory responses to changes in alveolar
responsiveness and cause V9E to fall partial pressures of CO2 and O2 and in arterial
transiently and rapidly. The maximum pH. In: Widdicombe JG, Cherniack N, eds.
decrease in V9E as a fraction of the total Handbook of Physiology, Respiration, Vol II,
hypoxic V9E provides the hypoxic index. In Control of Breathing, Part 2. Washington DC,
addition to the assumption (probably justified American Physiological Society, 1986; pp. 475
in humans) that the consequently high level 528.
of PO2 actually "silences" the carotid bodies, N Dejours P. Chemoreflexes in breathing. Physiol
Rev 1962; 42: 335358.
the validity of the Dejours test depends upon N Dempsey JA, et al. The ventilatory
the V9E-decrement reaching its nadir prior to responsiveness to CO2 below eupnoea as a
the subsequently increased Pa,CO2 (caused by determinant of ventilatory stability in sleep. J
the reduced V9E) influencing central sites of Physiol 2004; 560: 111.
CO2 responsiveness. As the nadir of the N Edelman NH, et al. Effects of CNS hypoxia on
response commonly occurs ,2025 s after breathing. In: Crystal RG, et al. The Lung:
the hypoxichyperoxic transition, there is Scientific Foundations. 2nd Edn. New York,
some uncertainty regarding this latter point. Raven Press, 1997; pp. 17571765.
Although this test is quite easy to perform and
N Duffin J. Measuring the ventilatory response to
hypoxia. J Physiol 2007; 584: 285293.
provides a useful qualitative estimate of N Read DJC, Leigh J. Bloodbrain tissue PCO2
hypoxic responsiveness, it remains to be relationships and ventilation during rebreathing.
precisely standardised and quantified. J Appl Physiol 1967; 23: 5370.
N Rebuck AS, Slutsky AS. Measurement of
The peripheral-chemosensory potentiation of ventilatory responses to hypercapnia and
the CO2 response by hypoxia may also be hypoxia. In: Hornbein T, ed. The Regulation of
used to provide an index of hypoxic Breathing. New York, Dekker, 1981;
ventilatory responsiveness, as follows: 1) from pp. 745772.
the linear difference between the hyperoxic N Severinghaus JW. Proposed standard
and the hypoxic CO2 response, and 2) the determination of ventilatory responses to
hypoxia and hypercapnia in man. Chest 1976;
increase in V9E between the hyperoxic
70: Suppl. 1, 129131.
(peripheral chemoreceptors silenced) and N Wasserman K, et al. Respiratory control during
the hypoxic (40 mmHg Pa,O2) CO2 response exercise. In: Widdicombe JG, ed. International
relationship, measured at a standard target Review of Physiology, Respiratory Physiology III.
level of 40 mmHg Pa,CO2 (DV40). Baltimore, Univ Park Press, 1981; pp. 149211.

ARTERIAL BLOOD GAS
ASSESSMENT
P. Palange1, A.H. Ferrazza1 and J. Roca2
1
Dept of Clinical Medicine, Sapienza University of Rome, Rome, Italy
2
Hospital Clinic IDIBAPS, CIBERES, University of Barcelona, Barcelona,
Spain
E-mail: paolo.palange@uniroma1.it
The fundamental function of the lung is to ABG analysis is needed to assess the severity
contribute to the homeostasis of the system and causes of pulmonary gas exchange
by ensuring that pulmonary uptake of oxygen impairment and acidbase (AB)
(VO2) and clearance of carbon dioxide (VCO2) disequilibrium. ABG analysis is one of the
match with whole-body bioenergetic most useful diagnostic tests, not only in the
requirements. We must look at pulmonary critical care setting, but also in general clinical
function as the first step of the oxygen practice, to assess patients with respiratory
transport chain from the atmosphere to diseases and those with other disorders with
mitochondria. potential impact on pulmonary gas exchange
and AB disturbances (diabetes, heart failure,
Arterial blood gas (ABG) analysis provides renal failure). Moreover, ABG analysis is
direct measurements of partial pressures of mandatory to establish the diagnosis of
oxygen (Pa,O2) and carbon dioxide (Pa,CO2) respiratory failure.
and pH in arterial blood. In clinical practice,
Modern equipment to perform ABG
assessment uses electrodes to measure Pa,O2,
Pa,CO2 and pH. Other variables, such as
Key points
bicarbonates (actual HCO3- and standard
HCO3-), base excess (BE) and oxyhaemoglobin
N ABG is mandatory for the diagnosis of saturation (Sa,O2) are computed using well-
respiratory failure and of AB disorders. defined equations.
N Pulmonary gas exchange status is best
A simple and practical two-step approach for
evaluated by the integrated reading of
ABG interpretation in the clinical setting is
Pa,O2 and Pa,CO2. illustrated in figure 1. The first step aims at
N AB status is best evaluated by the the analysis of pulmonary gas exchange
integrated reading of Pa,CO2 and pH, status based primarily on Pa,O2 and Pa,CO2,
with concomitant measurement of while the second step addresses the
serum electrolytes. assessment of AB status using Pa,CO2, pH
and, eventually, HCO3- (or BE).
N Mixed AB disorders are very common
in clinical practice. Step 1: Evaluation of lung gas exchange
N The correct interpolation of ABG Healthy subjects at sea level breathing room
represents a fundamental step for the air (inspired oxygen fraction (FI,O2) 0.21) show
diagnosis and treatment of AB Pa,O2 values close to 9095 mmHg. Pa,O2
disorders. values ,80 mmHg are considered arterial
hypoxaemia and Pa,O2 ,60 mmHg indicates
Arterial blood gas assessment 77

Step 1 When Pa,CO2 values are close to 40 mmHg,
Pa,O2 is an excellent indicator of the efficacy
of the lung as an oxygen exchanger, but
Pa,O2 Pa,CO2 pH patients with abnormal Pa,CO2 values
(hypercapnia or hypocapnia) may benefit
from the integrated reading of Pa,O2 and
Step 2
Pa,CO2 values indicated in table 1. Such an
Figure 1. Two-step approach for arterial blood gas integrated view can be numerically obtained
interpretation. Pa,O2: arterial oxygen tension; Pa,CO2: by computing the alveolararterial oxygen
arterial carbon dioxide tension. gradient (PAa,O2) using the following
simplified formula:
hypoxaemic respiratory failure. Because of the
PA-a,O2 5 [ (PB PH2O) x FI,O2 Pa,CO2/R ] Pa,O2
characteristics of the oxyhaemoglobin
dissociation curve, a Pa,O2 of 60 mmHg where PB is barometric pressure, PH2O is
corresponds to a Sa,O2 of ,90% and is airway water vapour partial pressure and R is
located at the upper end of the steepest respiratory quotient (the ratio VCO2 and VO2,
portion of the curve. Pa,O2 values ,60 mmHg ,0.8 at rest).
will have a substantial impact, reducing
arterial O2 content and compromising tissue At sea-level, the normal expected PA-a,O2 value
oxygenation. The accepted reference interval is ,15 mmHg in young subjects and
for Pa,CO2 is 3545 mmHg. By convention, ,20 mmHg in the elderly. Table 1 shows the
hypercapnic respiratory failure is established contribution of PA-a,O2 in the identification of
at Pa,CO2 .50 mmHg. the mechanisms of alteration of ABG.
To further understand the cause of arterial
Abnormal levels of respiratory gases in arterial
hypoxaemia, the effect of supplemental
blood are generally due to impaired
oxygen breathing on Pa,O2 should be
pulmonary gas exchange. Intrapulmonary
examined, keeping in mind that in the normal
factors that may cause arterial hypoxaemia
lung PA-a,O2 widens when breathing additional
are listed in table 1. Pulmonary ventilation
oxygen. While hypoxaemia due to pulmonary
perfusion (V/Q) inequality is the most
V/Q inequalities and diffusion defects is
frequent determinant of hypoxaemia and
usually corrected by increasing inspired
hypercapnia in the clinical scenario. However,
oxygen concentrations, this does not correct
the identification of pulmonary shunt
respiratory failure due to shunt.
(perfusion of unventilated pulmonary units, V/
Q50) as the main cause of hypoxaemia in a A simple, but less accurate, way to compute
patient with severe pneumonia has relevant PA-a,O2 is to use the rule of 130. It is
therapeutic implications. It is of note, assumed that in a healthy subject, at sea-level
however, that alterations of extrapulmonary (FI,O2 0.21), the sum of Pa,O2 and Pa,CO2 should
factors such as cardiac output, FI,O2, VO2 and be ,130 mmHg. Consequently, the
minute ventilation are also determinants of difference between 130 and the sum of Pa,O2
Pa,O2 and Pa,CO2. + Pa,CO2 is a surrogate of (PA-a,O2). The
Table 1. Arterialalveolar oxygen gradient (PA-a,O2) in the evaluation of the causes of arterial hypoxaemia.
Cause Pa,O2 Pa,CO2 PA-a,O2
Hypoventilation Q q
V/Q mismatch Q Qq q
O2 diffusion limitation Q Q q
Shunt QQ Qq qq

Table 2. Respiratory failure
Hypoxaemic respiratory failure
Pa,O2 ,60 mmHg, Pa,CO2 normal or low, at sea-level (FI,O2 0.21)
Hypoxaemia due to pulmonary V/Q mismatching (Pa,O2 rises with FI,O2)
Chronic respiratory diseases (only pulmonary fibrosis shows oxygen diffusion limitation with V/Q mismatch)
Hypoxaemia due to intrapulmonary shunt (lung units with V/Q 5 0) (Pa,O2/FI,O2 f200 mmHg)
Hypercapnic respiratory failure
Pa,CO2 .50 mmHg and Pa,O2 low, at sea-level (FI,O2 0.21)
Normal lung (PA-a,O2 gradient preserved)
Reduced alveolar ventilation due to extrapulmonary factors
Advanced chronic respiratory disease or severe exacerbation
Hypoxaemia due to pulmonary V/Q mismatch
following examples illustrate the use of the within the reference interval. On the other
rule. A patient with Pa,O2 70 mmHg and hand, a patient with hypoxaemic respiratory
Pa,CO2 60 mmHg (130 ( Pa,O2 70 + Pa,CO2 failure and hypocapnia (130 (Pa,O2 50 +
60) 5 10 mmHg) is hypoventilating a lung Pa,CO2 20) 5 60 mmHg) shows worse
that is functionally normal, with a PA-a,O2 pulmonary oxygen exchange (higher PA-a,O2)
100 7.0
6 9 12 15 18 21
90
24
80 27
7.1
70 Case 1 30
Case 2
Me
tab
33
sis
o 7.2
[H+] nanoEq per L
60 d
oli
aci 36
ca
ry
ato
cid
espir 39
cidosis
osi
50 er a 7.3
pH
42
ut iratory
s
Ac ic resp 45
Chron 48
40 N 54 7.4
.
resp sis
onic
60
Chr alosis alo
30 l k y alk Metabolic 66 7.5
a r
ato alkalosis 75
pir 7.6
e res
20 u t 7.7
Ac
7.8
10 8.0
[H q p
m
CO er
E
-]
3 L
8.5
0
0 10 20 30 40 50 60 70 80 90 100 Torr
0 1 2 3 4 5.33 6 7 8 9 10 11 12 13 kPa
Pa,CO2
Figure 2. Arterial carbon dioxide tension (Pa,CO2)pH nomogram for the diagnosis of acidbase disorders.
Pa,CO2pH values that fall into acute or chronic, respiratory and nonrespiratory (or metabolic) bands should
be considered as simple disorders (Case 1: Pa,CO2 70 mmHg, pH 7.19, acute respiratory acidosis). Pa,CO2pH
values that fall between respiratory and metabolic bands should be considered as mixed disorders (Case
2: Pa,CO2 40 mmHg, pH 7.20, acute respiratory and metabolic acidosis). N: normal.

Table 3. Examples of simple acidbase disorders
pH Pa,CO2 [HCO3-]
Respiratory acidosis Q q
Respiratory alkalosis q Q
Metabolic acidosis Q Q Q
Metabolic alkalosis q q q
-
Pa,CO2: arterial carbon dioxide tension; [HCO3 ]: bicarbonate concentration.
than a patient with respiratory failure and is 0.07 for acidosis and 0.08 for alkalosis, while
hypercapnia (130 (Pa,O2 50 + Pa,CO2 50) 5 in simple chronic respiratory disorders it is 0.03
30 mmHg). The computation PA-a,O2 (and the for both acidosis and alkalosis.
use of the rule of 130) is not useful clinically
The metabolic component refers to the impact
when FI,O2 increases. Calculating the Pa,O2/FI,O2
of nonvolatile molecules generating acidosis
ratio is recommended to assess the efficacy of
or alkalosis. The variable most often used to
the lung as an oxygen exchanger in critical care
assess the metabolic component is
when comparing ABG measurements taken at
bicarbonate [HCO3-], computed through the
different FI,O2 levels. Lung injury is defined as
HendersonHasselbalch equation:
Pa,O2/FI,O2 ,300 while acute respiratory
distress syndrome (ARDS) is associated with a pH 5 6.1 + log ( [HCO3-] / (0.03 6 Pa,CO2))
Pa,O2/FI,O2 ratio ,200 (table 2).
In the past, the role of simple rules
Step 2: Diagnosis of AB disorders associating changes in Pa,CO2 with changes in
pH (and HCO3-) was emphasised as useful for
Arterial pH is highly regulated to be the diagnosis of simple and mixed AB
maintained between 7.387.42. In the clinical disorders. A graphical illustration of this
assessment of AB equilibrium, two main approach is shown in figure 2.
determinants of arterial pH must be taken into
Table 3 displays some examples of simple AB
account, namely: the respiratory component
disorders.
(Pa,CO2) and the metabolic component.
Hypercapnia (high Pa,CO2) generates The first two rows in table 3 indicate simple,
respiratory acidosis (low pH) whereas uncompensated, AB disorders. The first row
hypocapnia (low Pa,CO2) is associated to may correspond to a chronic obstructive
respiratory alkalosis (high pH). In simple acute pulmonary disease patient with an episode of
respiratory disorders, for each 10 mmHg severe exacerbation showing acute
variation in Pa,CO2, the expected change in pH hypercapnia leading to respiratory acidosis.
Table 4. Respiratory disorders

Respiratory acidosis
Central nervous system depression, neuromuscolar disorders
Chest wall abnormalities
Lung diseases
Respiratory alkalosis
Anxiety, central nervous system disorders
Hormones/drugs (catecholamine, progesterone, hyperthyroidism, salicylate)
Fever
Hypoxia
Liver diseases

Table 5. Metabolic disorders The second example fits with any situation
leading to hyperventilation and low Pa,CO2
Metabolic acidosis
Normochloraemic acidosis (or high anion gap
that generates respiratory alkalosis (e.g.
acidosis) interstitial oedema in heart failure). The third
Ketoacidosis row indicates an example of acidosis due to a
Lactic acidosis metabolic disturbance (e.g. exercise-related
Renal failure increase in blood lactate, ketoacidosis, renal
Toxins failure). Finally, the fourth example of AB
Hyperchloraemic acidosis (or normal anion disequilibrium corresponds to a metabolic
gap acidosis) alkalosis that may be seen in patients with
Extra-renal loss of Na+
Renal tubular acidosis
liquid depletion and low intracellular and
serum potassium concentrations (e.g.
Metabolic alkalosis excessive diuretic therapy).
Chloride-responsive type
Gastric fluid loss Common causes of AB disorders are
Volume contraction illustrated in tables 4 and 5. It is of note that
Chloride-resistant type although they may begin as simple disorders
Mineral corticoid disorders (respiratory or metabolic), they often evolve to
Milk-alkali and Bartter syndromes
become mixed AB abnormalities.
Hypoalbumin
V '/Q' mismatch
Shunt VA
Diffusion
Acidosis Alkalosis
PA-a,O2
O2 challenge Respiratory
Step 1 Pa,O2 Pa,CO2 pH Step 2
Metabolic
Acidosis Alkalosis
Electrolytes Step 3
AG- Cl- Cl- AG-
AGu Cl- u Albumin

Lactate
Cl- administration
Ketoacids
Creatinine Renal or Hypoalbuminamia
Extra-renal Cl- responsive
Cl- resistant
Figure 3. Comprehensive approach to interpreting arterial blood gases. V/Q: ventilation/perfusion; VA: alveolar
ventilation; PA-a,O2: alveolararterial oxygen gradient; Pa,O2: arterial oxygen tension; Pa,CO2: arterial carbon
dioxide tension; AG: anion gap; Cl-: chloride; U: urinary.

Conclusion degrees of acute hypercapnia on acidbase
equilibrium. N Engl J Med 1965; 272: 612.
In clinical practice, the correct interpretation N Hughes JMB. Pulmonary gas exchange. In:
of ABG provides unique information on the Hughes JMB, Pride NB, eds. Lung Function Tests:
characteristics and severity of lung gas Physical Principles and Clinical Applications.
exchange impairment and on AB London, WB Saunders, 1999; pp. 7592.
abnormalities. It represents a fundamental N Kassirer JP, Bleich HL. Rapid estimation of
plasma carbon dioxide tension from pH and
step towards an appropriate diagnosis of the total carbon dioxide content. N Engl J Med
patient and the adoption of the treatment 1965; 272: 10671068.
strategy. Figure 3 summarises the N Kellum JA. Clinical review: reunification of acid-
interpretative integrative approach to be base physiology. Crit Care 2005; 9: 500506.
used in the evaluation of ABG. As a first step N Kellum JA. Disorders of acidbase balance. Crit
(Step 1), the combined reading of Pa,O2 and Care Med 2007; 35: 26302636.
Pa,CO2 values, on room air and during N Narins RG, Emmett M. Simple and mixed acid
supplemental oxygen breathing, should be base disorders: a practical approach. Medicine
1980; 59: 161187.
used to identify the causes and the severity of
arterial hypoxaemia (blue squares and blue
N Roca J, Wagner PD. Principles and information
content of the multiple inert gas elimination
circles). As a second step (Step 2), the technique. Thorax 1994; 49: 815824.
combined reading of Pa,CO2 and pH is needed N Riley RL, Cournand A. "Ideal" alveolar air and
for the correct diagnosis of AB disorders (red the analysis of ventilationperfusion
squares). Furthermore, the study of serum relationships in the lungs. J Appl Physiol 1949;
electrolytes, and in particular serum chloride, 1: 825847.
may be of great help in the identification of N Riley RL, Cournand A. Analysis of factors
the causes of metabolic disorders (red affecting partial pressures of oxygen and carbon
dioxide in gas and blood of lungs: theory. J Appl
squares; further step, Step 3).
Physiol 1951; 4: 77101.
References N Severinghaus JW, Bradley AF. Electrodes of blood
PO2 and PCO2 determination. J Appl Physiol
N Astrup P. A simple electrometric technique for 1958; 13: 515520.
the determination of carbon dioxide tension in N Stewart PA. Modern quantitative acidbase
blood and plasma, total content of carbon chemistry. Can J Physiol Pharmacol 1983; 61:
dioxide in plasma and bicarbonate content in 14441461.
separated plasma at fixed carbon dioxide N Wagner PD, The biology of oxygen. Eur Respir J
tension. Scand J Clin Lab Invest 1956; 8: 33. 2008; 31: 887890.
N Brackett NC Jr, et al. Carbon dioxide titration N West JB. Causes of carbon dioxide retention in lung
curve of normal man. Effect of increasing disease. N Engl J Med 1971; 284: 12321236.

EXERCISE TESTING
P. Palange
Dept of Clinical Medicine, Sapienza University of Rome, Rome, Italy
E-mail: paolo.palange@uniroma1.it
The ability to exercise largely depends on the N impaired cardiovascular response to

integrated physiological responses of the exercise,
respiratory, cardiovascular and skeletal muscle
systems. In healthy individuals exercise N reduced oxygen delivery, and
tolerance is influenced by age, sex and level N peripheral muscle weakness/dysfunction.
of fitness. In patients with lung diseases,
exercise tolerance is typically reduced and Exercise protocols
limited by symptoms, such as dyspnoea and
leg fatigue. The symptom-limited maximal incremental
exercise protocol is recommended as a first
Cardiopulmonary exercise testing (CPET), i.e. step in the evaluation of exercise tolerance.
the study of ventilatory and pulmonary gas Minute ventilation (V9E), cardiac frequency
exchange variables during symptom-limited (fC), oxygen uptake (V9O2), CO2 output (V9CO2)
incremental exercise, is considered the gold and the end-tidal O2 and CO2 are the primary
standard for evaluating the degree and the variables measured, typically on a breath-by-
causes of exercise intolerance in disease breath basis using computerised systems.
states. Moreover, CPET has been extensively Additional required measurements include:
utilised in patients with chronic obstructive ECG, blood pressure, dyspnoea and leg
lung disease (COPD), cystic fibrosis (CF), discomfort, exercise-related arterial O2
interstitial lung diseases (ILD) and pulmonary desaturation and dynamic hyperinflation.
vascular disorders (PVD). In COPD and CF, Careful selection of patients minimises the
exercise tolerance is mainly limited by likelihood of serious complications during
pulmonary mechanic abnormalities (e.g. maximal incremental exercise testing.
reduction in ventilatory capacity, dynamic Myocardial infarction (within 35 days),
hyperinflation); in ILD exercise tolerance is unstable angina, severe arrhythmias,
limited by ventilatory constraints and pulmonary embolism, dissecting aneurism,
pulmonary gas exchange abnormalities (e.g.
arterial oxygen desaturation); in PVD, both
circulatory (e.g. reduced adaptation in cardiac Key points
output) and pulmonary gas exchange CPET is considered the gold standard for:
abnormalities contribute to exercise intolerance.
N an objective measure of exercise
Some causes of exercise intolerance in capacity
lung diseases:
N identifying the mechanisms limiting
N ventilatory limitation to exercise, exercise tolerance
N dynamic hyperinflation, N establishing indices of the patients
prognosis
N increased work of breathing,
N pulmonary gas exchange abnormalities,
N evaluating the effects of therapeutic
interventions
N excessive perception of symptoms,
Exercise testing 83
and severe aortic stenosis represent absolute Exercise variables and indexes
contraindication to CPET. Resting lung
function measurement and ECG are usually Peak oxygen uptake (V9O2,peak) The
obtained before CPET. Cycle and treadmill classical criterion for defining exercise
exercise have been utilised interchangeably, intolerance and classifying degrees of
although the former is largely utilised as the impairment is the V9O2,peak. With good subject
work rate for incremental and endurance tests effort on an incremental test, V9O2,peak reflects
is easier to quantify. As the exercise period a subjects maximal aerobic capacity
should last 1012 min, the work rate ("maximum" V9O2). This index is taken to
increment should be selected carefully. In reflect the attainment of a limitation in the O2
patients with lung diseases the usual rate of conductance pathway from the lungs to the
workload increase is 10 Watt?min-1, although mitochondria. Values ,80% predicted are
slower or faster rates are possible in the very considered abnormal while values ,40% of
sick and in fitter patients, respectively. The the predicted indicate severe impairment.
maximal incremental exercise test is also
utilised to determine the appropriate work Lactate threshold (hL) The hL is the
rate to be used in an endurance protocol. highest V9O2 at which arterial lactate is not
systematically increased, and is estimated
Constant work rate (CWR) tests, on either a using an incremental test. It is considered an
cycle ergometer or a treadmill, are utilised for important functional demarcator of exercise
the measurement of exercise endurance intensity. Sub-hL work rates can normally be
tolerance and ventilatory and pulmonary gas sustained for prolonged periods. hL is
exchange kinetics. CWR exercise results in dependent on age, sex, body mass and fitness.
steady-state responses when work rate is of Noninvasive estimation of hL requires the
moderate intensity (i.e. below the lactate demonstration of an augmented V9CO2 in
threshold, hL); conversely, high intensity CWR excess of that produced by aerobic metabolism,
exercise (i.e. above the hL) results in steady and its associated ventilatory sequelae.
states either being delayed or not attained at all.
Walking tests, such as the 6-min walking test O2 pulse The O2 pulse is the product of the
(6-MWT) have been increasingly utilised for stroke volume and difference between the
the assessment of exercise tolerance in arterio-mixed venous O2 content (Ca,O2Cv,O2).
chronic lung diseases. The object of this test is Given the Fick equation (V9O2 5 cardiac
to walk as far as possible for 6 min. The test output 6 (Ca,O2Cv,O2), the O2 pulse can be
should be performed indoors along a 30-m calculated as follows:
flat, straight corridor; encouragement
significantly increases the distance walked. O2 pulse 5 V9O2/fC
Measurements of arterial O2 saturation by In patients with ILD, the O2 pulse at peak
pulse oximetry (Sp,O2), fC and exertional exercise is lower and its rate of increase with
symptoms are recommended during the 6-MWT. increasing work rate is usually reduced
because of the reductions in stroke volume
Indications to CPET and Ca,O2. In PVD, the O2 pulse is
characteristically low at peak exercise and
In patients with lung diseases, exercise testing
may not increase during incremental exercise,
is mainly utilised for functional and prognostic
reflecting the abnormal CO adaptation.
purposes. Other indications include detection
of exercise-induced bronchoconstriction, Heart rate reserve (HRR) The peak
selection of candidates for surgery including cardiac frequency (fC,peak) achieved on a
lung transplant, and evaluation of the effects symptom-limited exercise test decreases with
of therapeutic intervention including age. The most commonly used equation to
pulmonary rehabilitation. predicted peak cardiac frequency (fC,peak pred)

is 220-age. HRR is defined as the difference
between fC,peak pred and fC,peak. In healthy
individuals, HHR is virtually zero; a high HRR
is usually observed in patients with COPD, CF
and ILD.
*
} BR
V 'E
V9E/V9CO2 slope and ventilatory
equivalent for CO2 It is conventional to } BR Normal
*
express the ventilatory response to exercise COPD
relative to V9CO2. It can be measured as the
slope of the V9EV9CO2 relationship (DV9E/
DV9CO2) over its linear region, i.e. typically
extending from unloaded pedalling to the Rest Exercise
respiratory compensation point. In normal
individuals, DV9E/DV9CO2 values of ,2325 Figure 1. Ventilatory limitation to exercise.
have been reported. Ventilatory limitation to exercise is typically
observed in patients with chronic obstructive
pulmonary disease (COPD; red lines) compared with
The adequacy of the ventilatory response to normal subjects (black lines). In COPD, but also in
exercise is also expressed by the ratio CF and ILD, breathing reserve (BR) is reduced at
V9E/V9CO2 that represents the litres of peak exercise. See text for further comments.
ventilation necessary to clear 1 L of CO2. Up
to the respiratory compensation point, decreases with increasing work rate by as
V9E/V9CO2 declines curvilinearly as the work much as 0.51.0 L below functional residual
rate increases. It is common practice to record capacity. Changes in EELV during exercise can
the value at hL (V9E/V9CO2@hL) or the be estimated by asking the subject to perform
minimum value (V9E/V9CO2,min). These have an inspiratory capacity manoeuvre at a
each been proposed to provide noninvasive selected point in the exercise test. In COPD,
indices of ventilatory inefficiency. In normal particularly in the advanced phases of the
individuals, V9E/V9CO2@hL values of 2528 have disease, EELV increases during exercise (i.e.
been reported. Several factors may increase dynamic hyperinflation) in spite of expiratory
DV9E/DV9CO2 and V9E/V9CO2@hL, e.g. muscle activity.
hypoxaemia, acidosis, increased levels of wasted
ventilation and pulmonary hypertension. Arterial O2 desaturation During exercise,
Breathing reserve (BR) BR provides an Sp,O2 is normally maintained in the region of
index of the proximity of the ventilation at the ,9798%. However, arterial oxygen
limit of tolerance (V9E,max) to the maximal desaturation can be observed in patients with
achievable ventilation (MVV, estimated from moderate-to-severe ILD and in patients with
the subjects resting forced expiratory volume primary pulmonary hypertension.
in 1 s 6 40). BR can be defined as V9E,max as
a percentage of MVV (i.e. 1-V9E,max /MVV). In Tolerable limit of exercise (Tlim) and
COPD, CF and ILD, BR is usually reduced or isotime measurements Tlim is expressed
absent at peak CPET exercise (fig. 1). Analysis as a function of time measured during CWR
of the flowvolume loops is also emerging as protocols. In clinical practice, high-intensity
an important tool to assess the degree of (,7080% Watt max) CWR protocols are
airflow and ventilatory limitation during utilised for the evaluation of interventions. In
exercise in patients with COPD. addition to Tlim, measurement of pertinent
physiological variables (e.g. V9E, inspiratory
Dynamic hyperinflation In normal capacity, dyspnoea) at standardised time
subjects, end-expiratory lung volume (EELV) (isotime) are obtained.
Exercise testing 85
Table 1. Cardiopulmonary exercise testing prognostic indices
COPD ILD CF PVD
Q V9O2,peak + + + +
q V9E / V9CO2 +
Arterial O2 desaturation ++ + +
COPD: chronic obstructive pulmonary disease; ILD: interstitial lung disease; CF: cystic fibrosis; PVD: pulmonary vascular
disorders; Q: decreased; V9O2,peak: peak oxygen uptake; q: increased; V9E: minute ventilation; V9CO2: CO2 output.
CPET response patterns usually remains below 2030 Torr. In most

patients with ILD and PVD, pulmonary gas
Ventilatory response The ventilatory exchange efficiency is impaired, as indicated
response to exercise in patients with lung by an abnormally large PAa,O2 (.30 Torr) at
disorders is abnormal. Conventionally, the peak exercise accompanied by arterial O2
ratio of V9E at peak exercise to the estimated desaturation. These changes reflect regional
MVV represents the assessment of the ventilationperfusion ratio (V9A/Q9) dispersion
ventilatory limitation or of the prevailing and alterations in pulmonary capillary transit
ventilatory constraints. Ventilatory limitation time resulting from the recruited pulmonary
is commonly judged to occur when V9E/MVV capillary volume becoming inadequate for the
exceeds 85%. In lung diseases, the increase in high levels of pulmonary blood flow.
V9E/MVV may reflect the reduction in MVV but
also the increase in V9E. The ventilatory Cardiovascular response CPET has proved
response during exercise is influenced by very useful in the detection and quantification
metabolic rate (V9CO2), the arterial carbon of cardiovascular abnormalities during
dioxide tension (Pa,CO2) and the physiological exercise. The characteristic findings are a
dead space fraction of the tidal volume (VD/VT). reduced V9O2,peak, reduced hL, steeper fCV9O2
The relationship existing among these variables relationship (with a reduced HRR at peak
is described by the following equation: exercise), and a shallower profile (or even
V9E 5 863 6 V9CO2/Pa,CO2 6 (1-VD/VT) flattening) of the O2 pulse increase with
increasing V9O2. An abnormal cardiovascular
(where 863 is a constant, Pa,CO2 is the arterial response to exercise is observed in PVD and in
carbon dioxide partial pressure in Torr and VD/ particular in patients with idiopathic
VT is the dead space (VD) expressed as a pulmonary arterial hypertension.
fraction of the tidal volume (VT)). In lung
diseases, for a given V9CO2 and Pa,CO2, V9E is Exercise testing in prognostic
usually increased because of a higher VD/VT. evaluation Exercise tolerance is well
DV9E/DV9CO2 or V9E/V9CO2@hL are often recognised as a valuable predictor of mortality
utilised in the functional assessment of in healthy subjects. This also appears to be
patients with lung diseases (e.g. COPD, ILD, the case in chronic pulmonary diseases.
PVD). V9E/V9CO2 is usually increased, Exercise testing has become an essential
particularly in patients with PVD. component in the prognostic evaluation of
Pulmonary gas exchange The efficiency of patients with lung diseases.
pulmonary gas exchange can be assessed by
studying the magnitude of alveolararterial Several studies have confirmed that V9O2,peak
O2 partial pressure difference (PAa,O2), at rest is superior to other indexes in the risk
and during exercise. Normally, arterial O2 stratification of patients with end-stage lung
partial pressure (Pa,O2) does not decrease diseases; many centres, however, utilise field
during exercise, and PAa,O2 at peak exercise tests for prognostic purposes.

Evaluating the effects of therapeutic standardization and interpretation strategies.
interventions Eur Respir J 1997; 10: 26622689.
N Johnson B, et al. ATS/ACCP Statement on
High-intensity endurance CWR protocols, Cardiopulmonary Exercise Testing. IV.
performed on a cycle ergometer or on a Conceptual and physiologic basis of
treadmill, to the Tlim have been successfully cardiopulmonary exercise testing measurements.
Am J Respir Crit Care Med 2003; 167: 228238.
utilised in COPD patients for the evaluation of
the effects of therapeutic interventions (e.g.
N ERS Task Force, Palange P, et al., Recommendations
on the use of exercise testing in clinical practice.
bronchodilators, oxygen, heliox, rehabilitation). Eur Respir J 2007; 27: 529541.
N Ward SA, Palange P, eds. Clinical Exercise
References Testing. Eur Respir Mon 2007, vol. 40.
N ATS statement: guidelines for the six-minute
N Wasserman K, et al. Principles of Exercise Testing walking test. Am J Respir Crit Care Med 2002;
and Interpretation, 4th Edn. Philadelphia, 166: 111117.
Lippincott, Williams & Wilkins 2005. N ODonnell DE, et al. Dynamic hyperinflation and
N ERS Task Force on Standardization of Clinical exercise intolerance in chronic obstructive
Exercise Testing. Clinical exercise testing with pulmonary disease. Am J Respir Crit Care Med
reference to lung diseases: indications, 2001; 164: 770777.
Exercise testing 87
BRONCHIAL PROVOCATION
TESTING
K-H. Carlsen
Oslo University Hospital, Rikshospitalet, Voksentoppen, Dept of
Paediatrics, University of Oslo, Norwegian School of Sport Science, Oslo,
Norway
E-mail: k.h.carlsen@medisin.uio.no
En dernier lieu entre en jeu lhyperexcitabilite mannitol and eucapnic voluntary

de lappareil bronchovasomoteur. Ce processus hyperventilation tests. The indirect tests
essentiel est le substratum pathologique de commonly act by causing mediator or
lasthma. Pas lintervention dun mechanisme transmitter release and their effect on
a` seul, le degre de lexcitabilite inflammatory cells and nerves.
bronchomotorice regit la quantite de
mediateurs necessaire (quantum critique) Previously, BPT was done qualitatively by
pour leffet ventilatoire asthmogene assurer. inhaling the test substance at a 10-fold
increase in concentration; however, during the
Tiffenau R. Reseche quantitatives sur les last 25 yrs a quantitative assessment by
mediateurs bronchoconstrictifs produits par doubling the concentration/dose of the test
inhalation continue dallerge`nes. Pathol Biol substance has been done.
1959; 21: 22932310.
Bronchial provocation testing (BPT) may be Key points
done with several different aims in mind, as
part of research and in the clinical setting, N BPT with metacholine/histamine is a
and with several different chemical sensitive measure of asthma, but not so
substances. It may be done to test specific specific when compared with other
bronchial responsiveness (BR) to an allergen chronic lung diseases.
using the allergen bronchial provocation test,
or to test nonspecific BR using a bronchial N BPT with indirect measures (exercise,
provocation test to histamine (a mediator adenosine monophosphate, hypertonic
substance) or metacholine (a transmitter saline, mannitol, eucapnic voluntary
substance), as well as several other different hyperpnoea) are specific, but not
substances (table 1). sensitive.
Methods of BPT N Indirect measures of BR (exercise, etc.)

respond rapidly (over 14 weeks) to
Testing BR has been divided into direct and inhaled steroids.
indirect methods. Metacholine BPT and
histamine BPT represent direct methods, using N Direct measures of BR (metacholine,
a transmitter substance (metacholine) or a histamine) respond slowly (over 3
mediator (histamine) as test agents. Indirect months or more).
methods include exercise testing (which may N Direct measures of BR (metacholine,
also be regarded as a bronchial provocation histamine) are presently the most exact
test, but which otherwise is regarded to fall monitoring tool for asthma.
outside the present topic), inhaled AMP,

Table 1. Different types of bronchial responsiveness, assessed by different types of bronchial provocation tests
Bronchial responsiveness Test method Bronchial provocation test substance
Specific Allergen bronchial provocation test
Nonspecific Direct Metacholine
Direct Histamine
Indirect Exercise test
Indirect Inhaled AMP
Indirect Inhaled mannitol
Indirect Eucapnic voluntary hyperventilation
AMP: adenosine monophosphate.
Taking bronchial provocation with (DeVilbiss Healthcare, Somerset, PA, USA)

metacholine as an example, fig. 1 shows the may be used.
reduction in forced expiratory volume in 1 s
Determination of PC20 or PD20 are used both
(FEV1) caused by inhaling doubling doses of
for BPT with metacholine and histamine as
metacholine, with interpolation on the x-axis well as with AMP, and may be used for
to determine the concentration of allergen BPT. A BPT with mannitol was
metacholine to cause a 20% decrease in FEV1 recently developed and launched
(PC20). Later, a simplification of the test was commercially by inhaling cumulative doses of
introduced by inhaling single doubling doses mannitol through a powder inhaler. Here a
of metacholine, determining PD20 (the dose 15% reduction in FEV1 (PD15) is used as the
of the test agent causing a reduction in FEV1 cut-off point.
of 20%). As it is easier and quicker to
determine PD20 as compared with PC20, PD20 Eucapnic voluntary hyperventilation (EVH)
may be recommended for clinical routine use. may also be seen as a bronchial provocation
test. In this test, the subject inhales dry air
The test is performed under standardised with 5% CO2 for 6 min at a preferred
conditions, with specified nebulisation rates ventilation rate of 85% of maximum
for the tidal breathing method (PC20), voluntary ventilation (MVV), often calculated
inhaling the test agent for 2 min, then
measuring FEV1, and then inhaling the 110
doubling concentration. The test is stopped
when FEV1 is reduced by o20%, and the 100

FEV1 % pred
PC20/PD20 determined by interpolating on

the semi-logarithmic doseresponse curve 90

(fig. 1).
80
When determining BR by measuring PD20, the

cumulative inhaled dose is determined. This is 70
done by inhaling doubling doses of the test
substance. The delivering device most often 60
NaCl 0.03 0.06 0.125 0.25
used at present as is an inspiration-triggered
Metacholine mgmL-1
nebuliser, such as the Spira nebuliser (Spira
Respiratory Care Centre, Hameenlinna, Figure 1. Determination of the concentration of
Finland) or the Aerosol Provocation System metacholine to cause a 20% decrease in forced
(APS) (Jaeger, Wurzburg, Germany). expiratory volume in 1 s (FEV1; PC20) by
Alternatively a hand-held DeVilbiss nebuliser interpolation on the logarithmic x-axis.
Bronchial provocation testing 89

as FEV1630, but tolerating a ventilation rate 1 week, whereas metacholine BR needed
down to 65% of MVV (FEV1622). A several months of inhaled steroids treatment
reduction in FEV1 o10% is taken as a positive to show an effect.
test. EVH test has been shown to be
particularly sensitive for asthmatic athletes, in Results of BPT may be used to monitor the
particular endurance athletes. effect of treatment in asthma. It has been
shown that metacholine BPT is superior to
Clinical relevance of BPT clinical assessment and lung function
measurements in the follow-up of asthma
Previously, allergen BPT was often used
patients. By monitoring the effect of
qualitatively to diagnose asthma, and to
treatment of asthma with inhaled steroids by
demonstrate the reaction of the airways to the
follow-up using metacholine BPT as compared
allergen. This has changed during recent years
with follow-up based upon clinical symptoms
through fear of worsening the asthma after
and lung function measurements, it was
such a bronchial provocation test. A long-
shown that follow-up by metacholine BPT
lasting worsening of nonspecific bronchial
improved asthma control and had a positive
hyperresponsiveness was demonstrated after
effect upon airways remodelling, as assessed
performing an allergen bronchial provocation
by bronchial biopsies.
test, thus the allergen bronchial provocation
test is now mostly a tool in research projects, Thus, BPT with various substances and
and is not used in clinical practice. performed in a standaridsed measure is
Conversely, the different measures of probably, at the present time, the best tool for
nonspecific bronchial hyperreactivity are often the continuing follow-up of asthma patients.
used, both in a research context, but also in a References
clinical setting. With the diagnosis of asthma
in mind, the direct measures of bronchial N Brannan JD, et al. The safety and efficacy of
hyperreactivity are seen as most sensitive for inhaled dry powder mannitol as a bronchial
provocation test for airway hyperresponsiveness:
bronchial asthma, whereas indirect measures
a phase 3 comparison study with hypertonic
are considered to be more specific and less (4.5%) saline. Respir Res 2005; 6: 144.
sensitive. In asthma patients from an N Carlsen KH, et al. Cold air inhalation and
outpatient clinic compared with healthy exercise-induced bronchoconstriction in
subjects, histamine BR was found to be more relationship to metacholine bronchial
sensitive but less specific in discriminating responsiveness: different patterns in asthmatic
asthmatics from healthy subjects. Compared children and children with other chronic lung
with exercise testing, metacholine bronchial diseases. Respir Med 1998; 92: 308315.
provocation tests were more sensitive, but N Cockcroft DW, et al. Allergen-induced increase in
were markedly less specific for discriminating non-allergic bronchial reactivity. Clin Allergy
between asthma and other chronic lung 1977; 7: 503513.
diseases; when adding cold air inhalation to N Cockcroft DW, et al. Bronchial reactivity to
inhaled histamine: a method and clinical survey.
exercise, a sensitivity comparable with
Clin Allergy 1977; 7: 235243.
metacholine was reached, while maintaining
the sensitivity. In a general population of
N Dickinson JW, et al. Screening elite winter
athletes for exercise induced asthma: a
university students, a PC20 .8 mg?mL-1 ruled comparison of three challenge methods. Br J
out current asthma, whereas a value Sports Med 2006; 40: 179182.
,1 mg?mL-1 was diagnostic of current N Essen-Zandvliet EE, et al. Effects of 22 months of
asthma symptoms. treatment with inhaled corticosteroids and/or
beta-2-agonists on lung function, airway
Other differences are also found between responsiveness, and symptoms in children with
direct and indirect BR. Indirect BR is rapidly asthma. The Dutch Chronic Non-specific Lung
influenced by treatment with inhaled steroids, Disease Study Group. Am Rev Respir Dis 1992;
with the first effects already appearing after 146: 547554.

N Henriksen JM, Dahl R. Effects of inhaled bronchial asthma. Clin Allergy 1988; 18:
budesonide alone and in combination with low- 317321.
dose terbutaline in children with exercise- N Sont JK, et al. Clinical control and histopathologic
induced asthma. Am Rev Respir Dis 1983; 128: outcome of asthma when using airway
993997. hyperresponsiveness as an additional guide to
N Nieminen MM, et al. Methacholine bronchial long-term treatment. The AMPUL Study Group. Am
challenge using a dosimeter with controlled J Respir Crit Care Med 1999; 159: 10431051.
tidal breathing. Thorax 1988; 43: 896900. N Yan K, et al. Rapid method for measurement of
N Pauwels R, et al. Bronchial hyperresponsiveness bronchial responsiveness. Thorax 1983; 38:
is not bronchial hyperresponsiveness is not 760765.
Bronchial provocation testing 91

SPUTUM AND EXHALED
BREATH ANALYSIS
O. Toungoussova1, S. Dragonieri1, A. Zanini2 and A. Spanevello1,3
1
Fondazione Salvatore Maugeri, IRCCS, Cassano delle Murge and
2
Tradate
3
Department of Clinical Medicine, University of Insubria, Varese, Italy
E-mail: antonio.spanevello@fsm.it
Recently, noninvasive techniques such as

induced sputum and exhaled breath analysis Key points
have been successfully established to reveal
an inflammatory status and to find oxidative N Sputum and exhaled breath analysis
stress indicators in the airways involved in the are useful noninvasive tools to appraise
pathogenesis of lung diseases. These airway inflammation, particularly in a
techniques allow longitudinal sampling of longitudinal sense.
various lung biomarkers of inflammation in N Healthy sputum is rich in macrophages
the same individual, providing a possibility to and neutrophils but poor in eosinophils,
monitor the lung damage process and
lymphocytes and epithelial cells.
evaluate treatment strategies in patients with
respiratory diseases, including children. N Many inflammatory mediators can be
measured in the fluid phase of sputum.
Induced sputum
N Although further validation of many
Induced sputum is one of the most referenced assays is needed, exhaled breath
methods used to determine airway analysis can reveal markers of both
inflammation in asthma, chronic obstructive asthma and COPD.
pulmonary disease (COPD) and chronic cough
both in research and in clinical practice. The
induced sputum technique is a relatively
noninvasive method allowing sampling of low After collection, sputum sample is processed
airway secretions from patients who are not according to a standardised method and
able to produce sputum spontaneously. centrifugation is required to separate sputum
Procedure Sputum induction consists of cells from the fluid phase.
inhalation of nebulised saline solution Safety issues Sputum induction is a simple,
(isotonic or hypertonic) over different time safe and well-tolerated procedure even in
periods and subsequent expectoration of patients with severe lung diseases and
secretions into a Petri dish. exacerbations. It is recommended to use
experienced personnel and to apply standard
The subject is asked to inhale 200 mg of operating procedures taking into
salbutamol before induction, and forced consideration the degree of airway
expiratory volume in 1 s (FEV1) is monitored obstruction, to use a modified protocol for
before and after each inhalation to either subjects with severe airway obstruction, and
prevent or detect possible to assess lung function and symptoms during
bronchoconstriction. the procedure. Sputum induction is considered

to be safe if the fall in FEV1 is within 5% of 40% of subjects with COPD have a high
baseline after waiting 15 min. Excessive eosinophil count, which appears to predict a
airway constriction may occur in asthmatics response to corticosteroid therapy.
and patients with COPD if they show a fall in
FEV1 of . 20%. This adverse effect can affect In up to 40% of subjects with chronic cough,
11% of asthmatics and patients with COPD. a sputum eosinophil count .3% is shown.
These subjects with cough and sputum
eosinophilia have an objective response to
Cell counts in different diseases A
corticosteroid treatment. Conversely, patients
sputum sample from a healthy subject is rich
without sputum eosinophils do not respond.
in macrophages and neutrophils and poor in
eosinophils, lymphocytes and epithelial cells. Many inflammatory mediators can be
These reference parameters can be used for measured in the fluid phase of sputum. These
comparison with cell counts obtained from mediators belong to the class of granulocyte
patients with airway inflammation pathology. proteins, leakage markers, cytokines and
chemokines, eicosanoids and proteases.
Asthma is characterised by sputum Table 1 summarises cellular and fluid phase
eosinophilia, which predicts a favourable markers of airway inflammation in different
response to corticosteroids. However, nonpulmonary diseases.
eosinopilic asthma accounts for 2555% of
Reproducibility and validity The method
steroid-naive asthmatics and it is associated
of induced sputum induction is reproducible,
with a poor response to corticosteroids.
sensitive and valid. The reproducibility is
In COPD, neutrophils are usually increased documented within sample, between samples
and they are associated with reduced FEV1, and between examiners for all types of cells. A
suggesting that neutrophilic airway standardised methodology of sputum
inflammation is functionally relevant. Up to induction and processing was issued in 2002
Table 1 Biomarkers in induced sputum

Parameters Asthma COPD Cystic Sarcoidosis
fibrosis
Cellular phase
TCC q
Eosinophils q
Neutrophils q q
CD8+ q q
Fluid phase ECP, MPO, albumin, IL-8, IL-6, TNF-a, IL-10, IL-8, NE
fibrinogen, nonkinase leptin, MPO, HNL, NE,
plasminogen activator, ECP, EPO, LTB-4, GRO-a,
plasmonogen activator MCP-1, GM-CSF, MMP-1,
inhibitor, neurokinin A, -8, -9, -12, hyaluronan
IL-8, IL-13, Cys-LTs,
8-isoprostane, MMP-9/
TIMP ratio
q: increased level; COPD: chronic obstructive pulmonary disease; TCC: total cell count; ECP: eosinophil cationic
protein; MPO: myeloperoxidase; IL: interleukin; Cys-LTs: cysteinyl leukotrienes; MMP-9: matrix metalloproteinasis-9; TIMP:
tissue inhibitor of metalloproteinases; TNF: tumour necrosis factor; HNL: human neutrophil lipocalin; NE: neutrophil
elastase; EPO: eosinophil peoxidase; LTB-4: leukotriene B-4; GRO-a: growth related oncogen-a; MCP-1: monocyte
chemotactic protein-1; GM-CSF: granulocyte-macrophage colony-stimulating factor; MMP: metalloproteinases.
Sputum and exhaled breath analysis 93

by the European Respiratory Society Task and water-soluble volatiles that are exhaled
Force in order to provide guidance for the and absorbed into the condensing breath are
reproducibility of the results obtained. the main components of EBC.
Sample collection and analysis The
Examination of samples obtained from method of exhaled breath analysis is
patients with different respiratory diseases completely noninvasive, and it is suitable for
demonstrated significant differences in cell longitudinal studies and for monitoring the
counts, confirming the validity of the response to pharmacological therapy.
technique. Reference values and the
distribution of cell counts in induced sputum
were established on a large number of Sample collection is noninvasive, simple and
samples from healthy subjects. easy to perform in patients of any age. Home-
made and commercially manufactured
Exhaled breath condensers are available.
Measuring biomarkers in breath is important Breath analysis consists of direct (on line) and
in monitoring airways inflammation and indirect (off line) reading methods. Breath
oxidative stress. Exhaled breath analysis can analysis is immediately available in the on-line
be defined as analysis of exhaled gases and/ method. The use of indirect methods generally
or exhaled breath condensate (EBC). involves collecting and trapping the breath
sample and subsequently transferring it to an
Variable-sized particles or droplets that are analytical instrument for analysis.
aerosolised from the airway lining fluid,
distilled water that condenses from gas phase Various kinds of breath samples include mixed
out of the nearly water-saturated exhalate, expired air and end expired air. End-exhaled-
Table 2 Biomarkers in exhaled breath condensate

Biomarker Clinical significance in Clinical significance in
asthma COPD
F2-isoprostanes Increased reflecting the severity Increased reflecting the severity
of the disease and the degree of of the disease and the degree
inflammation of inflammation
Leukotrienes Elevated in both adults and
children
Prostanoids Elevated in steroid-naive and
steroid-treated patients and
correlate with the degree of
airway inflammation
pH Decreased and normalises with
glucocorticoid therapy
Hydrogen peroxide Increased in both adults and Increased in patients with
children exacerbations
Nitrite/nitrate, nitrosothiol, Increased and correlate with Increased in early stages of
nitrotyrosine eosinophilic inflammation, exacerbations
reduced by corticosteroid therapy
FeNO Increased and falls after Increased during exacerbations
treatment with corticosteroids and falls after inhaled steroids
in stable COPD
COPD: chronic obstructive pulmonary disease; FeNO: exhaled nitric oxide fraction.

air represents the alveolar air concentration have been presented in ATS/ERS
and mixed-exhaled-air represents the gas recommendations.
mixture coming from the dead space of the
bronchial tree and the alveolar gas-exchange Conclusions
space. Noninvasive methods such as induced sputum
The analysis of sample and measurement of and exhaled breath analysis have been
different biomarkers are usually performed by successfully introduced in clinical practice and
immunoassays mass spectrometry, high- research to study airway inflammation
performance liquid chromatography, nuclear involved in the pathogenesis of respiratory
magnetic resonance spectra, luminometry, diseases.
spectophotometry and pH-meter.
References
Biomarkers Several biomolecules can be N ATS/ERS recommendations for FENO procedure.
detected in exhaled air of healthy subjects Am J Respir Crit Care Med 2005; 171: 912930.
and patients with different inflammatory lung N Barnes PJ, et al. Pulmonary biomarkers in
diseases (table 2). chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 2006; 174: 614.
Validity Immunoassays for many biomarkers N Brightling CE. Clinical applications of induced
still need to be validated by reference sputum. Chest 2006; 129; 13441348.
analytical techniques. Concentrations of N Corradi M, Mutti A. Exhaled breath analysis:
from occupational to respiratory medicine. Acta
markers are often close to the detection limit
Biomed 2005; 76: 2029.
of the assays making analytical data less
reliable. Dilution of airway lining fluid may
N European Respiratory Society Task Force,
Standardised methodology of sputum induction
influence the results of biomarker analysis in and processing. Eur Respir J 2002; 20: Suppl. 37,
EBC. A confident dilution marker for EBC has 1s55s.
not been standardised yet. However, dilution N Hunt J. Exhaled breath condensate: an overview.
markers can be avoided by: 1) testing for Immunol Allergy Clin North Am 2007; 27:
multiple biomarkers and calculating ratios 587596.
among them; and 2) identification of a N Montuschi P. Analysis of exhaled breath
substance that serves as an onoff indicator of condensate in respiratory medicine:
an abnormality. methodological aspects and potential clinical
applications. Ther Adv Respir Dis 2007; 1: 523.
N Pizzichini E, et al. Indices of airway inflammation
Standardisation and validation of exhaled in induced sputum: reproducibility and validity
breath analysis is important, and special of cell and fluid-phase measurements. Am J
attention should be given to technical issues Respir Crit Care Med 1996; 154: 308317.
of flow dependence, time dependence, N Spanevello A, et al. Induced sputum cellularity.
influence of respiratory patterns, origin of Reference values and distribution in normal
markers in EBC, and possible nasal, saliva and volunteers. Am J Respir Crit Care Med 2000; 62:
sputum contamination. 11721174.
N Spanevello A, et al. Induced sputum to assess
The latest achievements in standardisation airway inflammation: a study of reproducibility.
and validation of exhaled breath analysis Clin Exp Allergy 1997; 27: 11381144.
Sputum and exhaled breath analysis 95

CHAPTER 4:
oTHER diAgnoSTiC TESTS
bRonCHoSCoPy 98
P.L. Shah
bRonCHoAlvEolAR lAvAgE 103

P.L. Haslam
finE-nEEdlE bioPSy 110

S. Gasparini
mEdiCAl THoRACoSCoPy/PlEuRoSCoPy 112

R. Loddenkemper
THoRACEnTESiS 115
E. Canalis and M.C. Gilavert
inTERvEnTionAl Pulmonology 118

M. Noppen

BRONCHOSCOPY
P.L. Shah
E-mail: pallav.shah@ic.ac.uk
Bronchoscopy is an essential tool for the Investigation of symptoms

pulmonologist that allows inspection and
sampling of the airways. The procedure is N Haemoptysis
usually performed with or without conscious N Persistent cough
sedation.
N Recurrent infection
Equipment
Investigation of suspected neoplasia
The flexible bronchoscope has evolved from a
fibreoptic instrument to videobronchoscopes, N Unexplained paralysis of vocal cords or
which are now almost universally used in hemi-diaphragm
most centres (fig. 1). The videobronchoscope
consists of a video chip at the distal end, an N Stridor
instrument channel and optical fibres that N Localised monophonic wheeze
illuminate the airways. The images obtained
are then transmitted to a monitor. The distal N Suspicious sputum cytology
end of the bronchoscope can be angled N Unexplained pleural effusions
through to 180o. This, in combination with
manual rotation movements, allows the N Mediastinal tissue diagnosis and staging
bronchoscope to be manipulated in the N Assess suitability for surgery
airways.
N Staging of lung cancer
Indications
Assessment of persistent or recurrent infection
Bronchoscopy provides diagnostic information
in patients with suspected lung cancer, diffuse N Identification of organisms
lung disease and in patients with persistent
infection or local pulmonary infiltrates. N Evaluate airways if recurrent or persistent
infection
Assessment of diffuse lung disease

Key points
Therapeutic bronchoscopy was traditionally
N Bronchoscopy provides diagnostic performed for malignant disease. However,
information in suspected lung cancer there are now a number of therapeutic
and diffuse lung disease and in procedures for emphysema and asthma:
patients with persistent infection or
local pulmonary infiltrates.
N Clearance of airway secretions
N Bronchoscopy also has therapeutic uses

N Removal of foreign body
in tumour treatment, as well as asthma N Palliation of endobronchial airway
and emphysema. obstruction by tumour ablation or insertion
of stents

administered via a single nasal cannula.
Bronchoscopy can be performed with or
without light sedation (fig. 2).
In the nasal approach, the bronchoscope is
lubricated with 2% lidocaine gel and passed
through the nares under direct vision. It is
then inserted into the nasopharynx until the
epiglottis is visualised.
Figure 1. The flexible videobronchoscope.
In the oral approach, the patient is asked to
bite gently onto a mouth-guard; the
N Bronchoscopic lung volume reduction for bronchoscope is then inserted through this
emphysema mouth-guard into the posterior pharynx, to
N Bronchial thermoplasty for asthma the level of the epiglottis.
Patient preparation The movement of the vocal cords is assessed,

and they are then anaesthetised using 2-mL
Patients should be given a full explanation of aliquots of 2% lidocaine. When the coughing
the procedure accompanied by written has subsided, the bronchoscope is advanced
information. Below is a simple pre-procedure through the widest part of the glottis, taking
check list: care not to touch the vocal cords. The
subglottic area of the trachea is very sensitive,
N Patient information verbal and written and patients initially feel as though they are
N Informed consent choking. Further 2-mL aliquots of 2%
lidocaine are administered in the trachea,
N Full blood count and clotting before carina, and right and left main bronchi. The
transbronchial lung biopsy airways are carefully inspected down to the
N Electrocardiogram (ECG) if history of subsegmental level for the presence of
cardiac disease endobronchial lesions and mucosal
abnormalities (fig. 3). Narrowing of the
N Ensure patients do not eat or drink for at bronchial tree as a result of external
least 46 h before the procedure compression from large lymph nodes or
N Ensure patients have someone to take masses is also noted.
them home following the procedure if they Bronchoscopic sampling
receive sedation
Bronchoscopy also provides an opportunity to
N Patients are advised not to drive or operate obtain a variety of samples which may aid
machinery for at least 24 h after any diagnosis.
sedation
Patients are monitored by continuous
oximetry throughout the procedure. Those
with pre-existing cardiac disease or hypoxia
that is not fully corrected by oxygen therapy
should undergo continuous ECG monitoring.
Procedure
The oro-pharynx is anaesthetised with 4%
xylocaine and the nasal passage with 2%
lidocaine gel. Venous access should always be
secured before the procedure, and oxygen Figure 2. Performance of the bronchoscopy.
Bronchoscopy 99
evaluation of diffuse lung diseases. It is
particularly useful when a broncho-centric
component is visible on computed tomography
(CT) scans. The closed biopsy forceps are
advanced into a specific bronchial segment and
advanced until met with resistance. The forceps
are then withdrawn a short distance and the
jaws opened. The patient is asked to take a
deep breath and the open forceps are advanced
further. When there is further resistance, the
patient is asked to breathe out and a biopsy
sample is taken during expiration. Samples are
obtained from the periphery of the lung.
Transbronchial fine-needle aspiration

(TBNA) mediastinal and hilar lymph nodes
Figure 3. Image obtained through the can be sampled by TBNA. The site of
videobronchoscope.
aspiration is planned on the basis of a cross-
sectional CT. The needle is inserted at the
Bronchial washings The specimens are
obtained by injection of 20 mL of normal desired point perpendicular to the airway
saline into the affected segment of the lung, wall. The needle is moved back and forth after
followed by aspiration. penetration of the airway wall and suction
applied with a 20-mL syringe. Samples
Bronchial brushings A fine cytology brush collected can then be used to prepare slides or
may be used to scrape cells from the surface placed in cytolite or saline solution for
of any visible lesion or from segments when cytological analysis. This is useful in the
the lesion is not visible at bronchoscopy. The staging and diagnosis of suspected lung
bronchial brush specimen may be smeared cancer. This should be performed prior to any
onto a slide and fixed before cytological other aspects of bronchoscopy so as not to
analysis, or shaken into saline for cytospin carry over cells from endobronchial lesions
preparations. into TBNA specimens and hence falsely
upstage the patient. Needle aspiration of
Bronchial biopsy Any endobronchial submucosal lesions may also improve
abnormalities should be biopsied. At least diagnostic yield. Overall TBNA is a low risk
four samples should be obtained and placed procedure with a good yield.
in 10% formol saline solution. The diagnostic
yield for polypoid lesions should be high Complications
(.90%), but is less for submucosal lesions.
The adverse effects of flexible bronchoscopy
Bronchoalveolar lavage (BAL) This is may be due to the sedation, the local
used in the assessment of diffuse lung anaesthesia or the procedure. The overall
disease. The bronchoscope is wedged into the incidence of complications is about 2%.
segment of interest and 5060-mL aliquots of Mortality from the procedure is less than 0.02%.
warm saline are injected into the segment. Sedative drugs may depress respiration and
The fluid is then slowly aspirated using low- have cardiovascular effects (e.g. hypotension).
pressure suction or direct hand suction. A total Lidocaine may very rarely cause bradycardia,
of 150250 mL is instilled and aspirated. seizures, bronchospasm or laryngeal spasm.
Transbronchial lung biopsy Used to The procedure may cause bronchospasm,
obtain parenchymal lung tissue for the laryngospasm, hypoxaemia or cardiac

arrhythmias, particularly in patients with pre- The probe is manipulated in the airways with
existing cardiac disease or hypoxia not or without radiological guidance. Once the
corrected by oxygen supplementation. abnormal area is identified the sheath is
Infection can be introduced by the maintained in position, the radial ultrasound
bronchoscope. Therefore, it is essential to probe is removed and washings, brushings
clean and disinfect all instruments before use. and biopsies obtained via the guide sheath.
Haemorrhage and pneumothorax may follow
transbronchial lung biopsy. The risk is 57%, Therapeutic procedures
and this is increased with paroxysmal The therapeutic role of bronchoscopy is
coughing. Hypoxia and precipitation of rapidly increasing. It is well established in the
respiratory failure are the main complications treatment of endobronchial tumour
of bronchoalveolar lavage particularly as the obstruction. A variety of techniques such as
procedure is often performed in patients with cryotherapy, electrocautery or laser can be
diffuse lung disease. utilised by flexible bronchoscopy to rapidly
Advanced diagnostic procedures debulk tumours, which are obstructing the
main airways. Several clinical series have
The airway is illuminated by blue light during demonstrated that these techniques are very
fluorescence bronchoscopy. Normal tissue is effective in palliating symptoms and improving
visible as fluorescent green, whereas the quality of life for patients with
abnormal areas appear brown and red in endobronchial tumour occlusion. They also
colour. This absence of autofluorescence reduce the risk of post-obstructive pneumonia.
occurs in dysplasia, carcinoma in situ and Where the airway wall structure has been
invasive carcinoma, and may enable the extensively damaged or there is extrinsic
earlier detection of endobronchial tumours. It compression from the tumour, endobronchial
is currently used as a research tool but may stents can be used to support the airways.
also be useful in routine practice. Narrow Metal self-expanding stents can be inserted via
band imaging emphasises the blood vessels a flexible bronchoscopy and are available in
and increased capillary loops in the mucosa, both uncovered and covered formats.
which is associated with dysplasia and
carcinoma in situ. Magnification of images Brachytherapy is localised radiotherapy
and presentation at high definition further administered to an area of tumour infiltration.
enhances the ability of the operator to detect A blind-ending catheter is inserted through
subtle abnormalities. the instrument channel of the bronchoscope
into the desired airway. The bronchoscope is
Endobronchial ultrasound guided then removed whilst maintaining the catheter
transbronchial fine needle aspiration (EBUS in the appropriate position. The catheter can
TBNA) is performed with an integrated linear then subsequently be loaded with a remote
array ultrasound bronchoscope. It provides device which is used to insert radiotherapy
excellent ultrasound images of the beads and hence deliver local radiotherapy.
mediastinum and tissue adjacent to the This technique can also be used to treat
airways and allows ultrasound-guided endobronchial obstruction. However, there is a
sampling of mediastinal lymph nodes or peri- risk of acute localised oedema following the
bronchial tumour masses. The sensitivity of procedure and treatment carries a significant
this technique is high. Its use is rapidly risk of severe haemorrhage.
expanding and is establishing an important
role in the diagnosis and staging of lung More recently a number of innovations have
cancer. A radial or mini probe system can be been developed for the bronchoscopic
used for localising peripheral pulmonary treatment of patients with severe emphysema
masses. These probes are passed through the with significant hyperinflation. Endobronchial
instrument channel of a flexible bronchoscope valves, such as zephyr valves and intra-
into the desired segment with a guide sheath. bronchial valves, can be used for
Bronchoscopy 101
bronchoscopic volume reduction. Other to apply radiofrequency energy to the airways
developments include biological polymers, in order to destroy airway smooth muscle.
endobronchial coils and airway stents. A novel
treatment for patients with moderate to Weblinks
severe asthma is also delivered N www.bronchoscopy.org.
bronchoscopically. A special catheter is used N www.interventionalbronchoscopy.co.uk.

BRONCHOALVEOLAR LAVAGE
P.L. Haslam
National Heart and Lung Institute, Imperial College, and Royal Brompton
Hospital, London, UK
E-mail: p.haslam@ic.ac.uk
What it is and when to use it often increase diagnostic confidence.

However, BAL itself is rarely specifically
Bronchoalveolar lavage (BAL) involves using a diagnostic and must be interpreted together
fibreoptic bronchoscope to wash a with clinical, physiological, radiological and
subsegment of the lungs with sterile other multidisciplinary investigations.
physiological saline to sample components
from the peripheral air spaces in health and Prior to 2000, BAL was routinely included in
disease. These include immune and the diagnostic work-up of parenchymal lung
inflammatory cells, other pathological cells or diseases. Currently, for ILDs, specialists
features, cytokines, enzymes, lipids or other consider that high-resolution computerised
secreted products, inhaled environmental or tomography (HRCT) patterns are often
occupational agents, and infections. Since the sufficiently diagnostic to avoid the need for
1960s, BAL has been used extensively in BAL or lung biopsy. A recent American
research and to assist in the diagnosis of Thoracic Society/ERS consensus terminology
peripheral lung diseases, notably diffuse for the idiopathic interstitial pneumonias
(IIPs) has also changed the way specialists
interstitial lung diseases (ILDs), occupational
diagnose and manage this subgroup of ILDs.
lung diseases, rare lung diseases, thoracic
However, BAL is still indicated whenever the
malignancies and lower respiratory tract
preliminary clinical investigations plus HRCT
infections (table 1). Numerous publications,
fail to establish a confident diagnosis, or
including guidelines from the European
where additional information is needed to
Respiratory Society (ERS), confirm that BAL
confirm, strengthen or to exclude a diagnosis.
cytological or microbiological findings can
How to obtain a sample
This chapter will only describe the BAL
Key points
procedure recommended in Europe for routine
cytological investigation of adults with lung
N BAL is used to sample components from diseases where infection is not suspected. A
peripheral air spaces in health and modified procedure to minimise
disease. contamination with irrelevant microorganisms
N BAL is mainly used in the diagnosis of and target sites of maximal involvement is
interstitial lung diseases or lower used for the specialist diagnosis of lower
respiratory tract infections. respiratory tract infections.
N BAL must be interpreted in conjunction A standardised procedure must be followed in

with results from clinical, pathological order to minimise variability due to the
and radiological investigations. unknown dilution factor during lavage and
many other potential sources of variability.
N A standardised procedure must be There is still no globally agreed standard for
followed. the general conduct of BAL in adults for
cytological and other purposes, but the ERS
Bronchoalveolar lavage 103

104
Table 1. A guide to main types of bronchoalveolar lavage (BAL) inflammatory cells and other cytological features in lower respiratory diseases
Predominant BAL inflammatory cell types Other characteristic cytological features
increased compared with normal range#
Lower respiratory tract infections
Community-acquired pneumonia; nosocomial pneumonia Neutrophils very high in bacterial pneumonias Intracellular bacteria active pneumonia. Identify by special
stains, cultures etc.
Opportunistic infections in AIDS; organ transplant Neutrophils often moderately increased Pneumocystis carinii, Cytomegalovirus, fungal infections,
recipients; on chemotherapy others by special stains, cultures, etc.
Thoracic malignancies
Adenocarcinoma or bronchoalveolar cell carcinoma Not of diagnostic value Tumour cells readily detectable
Metastatic or lymphangitic spread from Not of diagnostic value Tumour cells readily detectable
non-pulmonary tumours
B-cell lymphomas; Hodgkins lymphoma Lymphocytes often strikingly increased Abnormal lymphocytes consistent with lymphoma;
Reed-Sternberg cells
Rare lung diseases
Alveolar lipoproteinosis Not of diagnostic value Globules of lipoprotein plus acellular debris. Original BAL
fluid milky
Pulmonary haemosiderosis Mainly macrophages containing particles similar to Majority of macrophages heavily laden with haemosiderin:
smoking but orange-brown Perl stain positive
Pulmonary Langerhans cell histiocytosis Mainly macrophages containing smoking-related .5% of the cells shown to be Langerhans cells by CD1a
particles staining or electron microscopy
Fibrosing mineral dust diseases
Asbestosis Moderate increases in neurophils eosinophils or Asbestos bodies indicating exposure
lymphocytes
Talc pneumoconiosis Insufficient information Talc bodies indicating exposure
Hard metal lung disease/giant cell interstitial Mild increases in neutrophils eosinophils or Refractile particles of hard metal in macrophages plus
pneumonia lymphocytes giant cells if also giant cell interstitial pneumonia
ERS Handbook: Respiratory Medicine

Table 1. Continued
Drug-induced lung diseases
Amiodarone-induced pneumonitis Lymphocytes increased Large phospholipid inclusions in macrophages
Acute alveolar haemorrhage Not of diagnostic value Numerous erythrocytes & bloody fluid
Bronchoalveolar lavage
Drug-induced eosinophilic pneumonia Eosinophils very high
Other pulmonary eosinophilias
Idiopathic eosinophilic pneumonia Eosinophils very high
Allergic diseases: asthma; ChurgStrauss syndrome; Mild to moderate increases in eosinophils plus
bronchopulmonary aspergillosis lymphocytes
Parasitic infections: schistosomiasis; stronguloides Eosinophils often high
Acute respiratory distress syndrome Neutrophils very high
Idiopathic interstitial pneumonias
Idiopathic pulmonary fibrosis Moderate increases in neutrophils eosinophils
Nonspecific interstitial pneumonitis Mild increases in lymphocytes plus neutrophils
eosinophils
Cryptogenic organising pneumonia Moderate increases in lymphocytes plus neutrophils
Lymphoid interstitial pneumonia Increases in lymphocytes
Respiratory bronchiolitis associated interstitial lung Mainly macrophages containing smoking-particles
disease plus a few neutrophils
Desquamative interstitial pneumonia Macrophages containing smoking particles plus
moderate increases in neutrophils eosinophils or
lymphocytes
Acute interstitial pneumonia Neutrophils very high
105
has long promoted BAL standardisation in a
series of European guidelines. The earliest on
CD4:CD8 ratios increased in nearly all. Lymphocytes

technical aspects and clinical applications
contain useful information but need some
updating. However, updated guidelines for a
standardised BAL procedure in adults were
CD4:CD8 ratios increased in about half

published in 1999. A protocol using this
CD4:CD8 ratios frequently decreased

European standard procedure is as follows.
proliferate to beryllium salts

1) Perform BAL under local anaesthesia using
fibreoptic bronchoscopy as part of pre-
treatment assessment. 2) Proceed initially as
for routine fibreoptic bronchoscopy: generally
semi-supine patient positioning; pre-
medication with a sedating compound; local
anaesthesia with lidocaine removing any
excess prior to lavage. 3) For lavage, gently
wedge the tip of the bronchoscope into an
Moderate increases in lymphocytes mild neutrophils
Moderate increases in neutrophils eosinophils or
appropriate subsegmental bronchus. The

Lymphocytes very high. Neutrophils and mast cells
Moderate increases in neutrophils lymphocytes
recommended standard site is right middle

lobe in diffuse lung diseases and healthy
Moderate to high increases in lymphocytes
controls, but the area of greatest radiographic

abnormality in localised lung diseases. 4)
also increased after recent exposure
Sequentially introduce then aspirate standard

: using differential percentage BAL cell counts (see text for full explanation); ": excluding infections.
aliquots (4 6 60 mL) of sterile physiological

saline pre-warmed to body temperature
through the application tube of the
bronchoscope. Do not exceed total
introduction volume of 240 mL. 5) Aspirate
each aliquot, keeping dwell time to the
lymphocytes
minimum, using very low suction pressure

(3.3313.3 kPa/25100 mmHg) to avoid
airway collapse. 6) Collect the recovered fluid
into a container to which cells are poorly
adherent, e.g. siliconised glass or a non-cell
adherent plastic designed for suspension
Hypersensitivity pneumonitis/ extrinsic allergic
tissue cultures. 7) Record the lavage site, total

BAL fluid introduction volume and number of
aliquots and the total recovery volume. 8)
Systemic connective tissue diseases
Immediately send the BAL sample to the

Granulomatous lung diseases"
laboratory to enable processing to commence

within 1 h because BAL cells deteriorate
Chronic beryllium disease
rapidly in saline. 9) Also send a patient

protocol with age, sex, provisional diagnosis
Sjorgrens syndrome
and other factors that influence BAL findings

Systemic sclerosis
including smoking history (current, ex- or

Table 1. Continued
nonsmoker), current medications and

Sarcoidosis
alveolitis
associated diseases. 10) If biopsies are

needed, perform these after BAL to avoid
contamination of BAL with blood or bronchial
#
tissue debris.

BAL is safe and side-effects are low and as for 1.56106 cells?mL to make cytocentrifuge
fibreoptic bronchoscopy alone, except for an slide preparations. Use 100-mL aliquots
increased risk of minor post-lavage pyrexia, (1.56105 cells) per slide (spin at 906g for
which can be minimised by keeping total BAL 4 min). Prepare at least six slides per patient.
introduction volumes to ,300 mL. After air drying, fix two slides in methanol
(not formalin which impairs staining of mast
Processing of samples for cytology
cells). Stain with MayGrunwaldGiemsa for
BAL cells deteriorate rapidly in saline and differential cell counting. Use other slides for
laboratory processing should commence special stains, e.g. GomoriGrocott silver stain
within a maximum of 1 h after BAL sample for fungi and Pneumocystis carinii, and Perl
collection. To delay deterioration, BAL cells stain for haemosiderin-laden macrophages.
should be transferred into serum-free
minimum essential medium containing Mucus contamination of BAL samples, if very
25 mM HEPES buffer (MEM-HEPES), which excessive, can cause serious technical
maintains pH7 in an open system. problems in processing. When there is such
heavy contamination from the upper airways,
Non-cell adherent containers and pipettes BAL results must be interpreted with caution.
must be used for all laboratory procedures. Mucus can be removed by filtering the lavage
The processing procedure is as follows. 1) through cotton gauze or nylon mesh, but this
Measure the total volume of the BAL sample. can cause loss of adherent cells, dust fibres
2) Record any abnormality in the gross and other components. An alternative to
appearance of the fluid, e.g. milky appearance avoid such loss is to remove mucus by treating
suggestive of alveolar lipoproteinosis, very the BAL cell pellet with the mucolytic
bloody suggestive of acute haemorrhagic dithiothreitol.
conditions. 3) Mix sample to ensure even
suspension then divide into measured aliquots Some workers consider that when BAL cells
for different departments if required (e.g. are in tissue culture medium, processing can
o20 mL for BAL cytology and flow be delayed for 24 h to enable long distance
cytometry, 10 mL for microbiology, 20 mL for transport to centralised processing centres.
electron microscopy). 4) For BAL cytology, the However, this is not advisable because
fluid aliquot should be mixed and a cell granulocytes are short lived and apoptotic
viability test conducted, e.g. trypan blue. Then changes start within 9 h. Therefore, it is
make a total count of nucleated cells (per mL) advisable to transfer BAL cells into tissue
using an improved Neubauer counting culture medium within 1 h and make
chamber and white cell counting stain, e.g. cytocentrifuge preparations within 14 h.
Kimura stain. If the original BAL sample is too Staining of air-dried preparations can be
dilute for an accurate cell count, the count delayed for o24 h if necessary. It is essential
should be performed after separating the cells that BAL is conducted by clinical and
by centrifugation and resuspending them in laboratory personnel who are highly trained in
higher concentration. 5) Centrifuge the BAL the procedure, applications and
sample at low speed (3006g at 4oC for interpretation.
10 min) to separate the cells and other
insoluble components from the supernatant Differential cell counting and other
fluid. Aspirate the supernatant and aliquot it cytological appearances
for storage at -70oC. Then wash the BAL cell
pellet in MEM-HEPES and resuspend in a The standard approach to counting BAL cells
small volume (12 mL) to achieve a more in cytocentrifuge preparations is to express
concentrated suspension. Perform a total cell the count of each type as a percentage of the
count/mL and calculate the number/mL and total BAL cells (differential percentage cell
total in the original BAL fluid. 6) Adjust the count). This proportionate approach is not
volume of the cell suspension to a standard affected by the unknown BAL dilution factor.

Differential cell counts are performed and Normal cell counts and the effect of
other cytological features identified by smoking
examining MayGrunwaldGiemsa stained
cytocentifuge slide preparations by light BAL cells from healthy nonsmokers are mainly
microscopy. First, low-power magnification macrophages and a few lymphocytes, but
(610 and 625 objectives) is used to search proportions of other cell types are very low.
the entire preparation and semi-quantitatively Smoking causes increases in BAL
grade (05) any mucus and erythrocytes, and macrophages up to four-fold higher (total and
identify any unusual cytological features, such per mL) in healthy smokers compared with
as inorganic dust particles or fibres, globules nonsmokers; smokers also have slight
of lipoprotein, giant cells, malignant cells or increases in neutrophils. Thus, smoking must
microorganisms. Secondly, higher-power be taken into account when defining normal
magnification (640 or 660 objectives) is ranges and interpreting any BAL studies.
used to count all the immune and Published normal ranges show considerable
inflammatory cells and any other type of variability when cell counts are expressed per
nucleated cells employing random-field mL or absolute total numbers. However,
counting methodology until a total of o400 results are very similar when expressed as
cells have been counted. The count for each differential percentage counts, consistent with
cell type is then expressed as a percentage of these not being influenced by dilution.
the total cells counted (differential percentage The following normal ranges can be employed
BAL cell count). For diagnostic purposes, all for differential BAL cell counts: macrophages
nucleated cells, not only inflammatory cells, o80% in nonsmokers and o90% in
must be included in the count to ensure that smokers; lymphocytes f20% in nonsmokers
important information is not omitted (e.g. and f10% in smokers; neutrophils f3% in
malignant cells, giant cells and epithelial nonsmokers and f4% in smokers;
cells). The presence of .5% of bronchial eosinophils f0.5% in nonsmokers and f3%
epithelial cells indicates excessive in smokers; mast cells f0.5% in nonsmokers
contamination from the upper airways, and and smokers; plasma cells 0%; and ciliated or
such samples are inadequate as a reliable squamous epithelial cells f5%. Smoking-
indicator of alveolar events. related inclusions are frequent in
Abnormal cell appearances must also be macrophages from smokers.
reported, including proportions of foamy
Main applications in the diagnostic
macrophages, multinucleate macrophages,
work-up of peripheral lung diseases
giant cells, macrophages containing smoking-
related particles, macrophages containing Although this chapter describes BAL
refractile or bi-refringent particles indicative of procedures, it would be incomplete not to
inorganic dusts, or macrophages heavily laden include a summary indicating how BAL is
with haemosiderin confirmed by Perl staining, used in routine clinical investigation to
indicating possible pulmonary increase confidence in the diagnosis of many
haemosiderosis. parenchymal lung diseases. A quick guide
showing the main types of increased BAL
When neutrophil counts are very high it is
inflammatory cells and other cytological
important to check for intracellular bacteria,
features in a wide range of lower respiratory
which can indicate active bacterial
diseases is given in table 1.
pneumonia.
Fungal spores or hyphae may also be seen, References
and their presence should be confirmed using N American Thoracic Society/European Respiratory
GomoriGrocott silver stain, which can also Society International Multidisciplinary
detect Pneumocystis carinii. Consensus Classification of Idiopathic Interstitial

Pneumonias. Am J Respir Crit Care Med 2002; N Haslam PL. Bronchoalveolar lavage. Semin
165: 277304. Respir Med 1984; 6: 5570.
N Bradley B, Branley HM, et al. Interstitial lung N Klech H, Hutter C, eds. Clinical guidelines and
disease guideline: the British Thoracic Society in indications for bronchoalveolar lavage (BAL):
collaboration with the Thoracic Society of report of the European Respiratory Society of
Australia and New Zealand and the Irish Pneumology Task Group on BAL. Eur Respir J
Thoracic Society. Thorax 2008; 63: Suppl. 5, 1990; 3: 937974.
v1v58. N Klech H, Hutter C, Costabel U, eds. Clinical
N Bronchoalveolar lavage constituents in healthy guidelines and indications for bronchoalveolar
individuals, idiopathic pulmonary fibrosis, and lavage (BAL): report of the European Society of
selected comparison groups. The BAL Pneumology Task Group on BAL. Eur Respir Rev
Cooperative Steering Group Committee. Am Rev 1992; 2: 8, 47127.
Respir Dis 1990; 141: Suppl. 5, S169S202. N Klech H, Pohl W, eds. Technical recommendations
N Costabel U. Ask the expert diffuse interstitial and guidelines for bronchoalveolar lavage (BAL):
lung disease. Breathe 2007; 4: 165172. report of the European Respiratory Society of
N Dhillon DP, Haslam PL, et al. Bronchoalveolar Pneumology Task Group on BAL.: Eur Respir J
lavage in patients with interstitial lung diseases: 1989; 2: 561585.
side effects and factors affecting fluid recovery. N Ohshimo S, Bonella F, et al. Significance of
Eur J Respir Dis 1986; 68: 342350. bronchoalveolar lavage for the diagnosis of
N Haslam PL, Baughman RP, eds, Guidelines for idiopathic pulmonary fibrosis. Am J Respir Crit
measurement of acellular components and Care Med 2009; 179: 10431047.
recommendations for standardization of N Reynolds HY, Newball HH. Analysis of proteins
bronchoalveolar lavage (BAL). Report of and respiratory cells obtained from human lungs
European Respiratory Society (ERS) Task Force. by bronchial lavage. J Lab Clin Med 1974; 84:
Eur Respir Rev 1999; 9: 66, 25157. 559573.
N Haslam PL, Baughman RP. Report of ERS Task N Woodhead M, Blasi F, et al. Guidelines for the
Force: guidelines for measurement of acellular management of adult lower respiratory tract
components and standardization of BAL. Eur infections: report of ERS Task Force in collaboration
Respir J 1999; 14: 245248. with ESCMID. Eur Respir J 2005; 26: 11381180.

FINE-NEEDLE BIOPSY
S. Gasparini
Pulmonary Diseases Unit, Dept of Internal Medicine, Immunoallergic and
Respiratory Diseases, Azienda Ospedaliero-Universitaria Ospedali Riuniti,
Ancona, Italy
E-mail: s.gasparini@fastnet.it
Percutaneous (or transthoracic) fine-needle consuming, it has several advantages: 1) it

biopsy (PFNB) is a technique that allows helps determine the safest needle trajectory
cytohistological diagnosis of thoracic lesions. avoiding vascular structures, fissures, bullae
While the first reports on the use of and necrotic areas of the tumour; 2) it allows
transthoracic needle biopsy date back to the an approach to lesions not visible on
end of the 19th century, the modern era of fluoroscopy; and 3) it avoid radiation exposure
PFNB did not begin until the mid-1960s when to the operators. However, there are no studies
NORDENSTROM (1965) introduced the use of that demonstrate a better sensitivity of CT
fine needles (diameter ,20 Gauge). compared with fluoroscopy. Ultrasound can
also be used as guidance system when the
Indications
lesion is in contact with the thoracic wall.
PFNB is indicated when a cytohistological
diagnosis is required of peripheral lung lesions Type of needle Commercially available
(nodules, mass or infiltrates) following a needles are either: 1) aspiration needles that
negative bronchoscopy. PFNB is also indicated yield material satisfactory for cytological
for expansive lesions of the chest wall or for evaluation (Chiba, Franseen, Westcott,
diagnosis of mediastinal masses, especially Nordenstrom); or 2) histology needles that
those located in the anterior mediastinum. yield a tissue core (Trucut, Menghini,
Silverman). Needle diameter should be
Contraindications
,20 Gauge and generally 2022 Gauge
Absolute contraindications are: contralateral needles are utilised. The use of an histology
pneumonectomy, bleeding disorders, needle is recommended when either a benign
uncooperative patient, uncontrollable cough,
and suspected arteriovenous malformation or
hydatid cyst. Relative contraindications that may Key points
increase the risk of complications are: respiratory
failure, severe chronic obstructive pulmonary N PFNB is indicated when a
diseases, pulmonary arterial hypertension and cytohistological diagnosis of peripheral
unstable ischaemic heart disease. lung lesion is required.
Technique N The most common guidance system for
PFNB is CT scan. Biplane fluoroscopy
Guidance systems Biplane fluoroscopy is and ultrasound can also be used.
the traditional guidance system for PFNB. Its N The sensitivity of PFNB for lung cancer
main advantage is the real-time visualisation of is 8595%.
the needle during the whole procedure. In
recent years, computed tomography (CT) has N The most frequently reported complication
become the most common means of guidance. is minor pneumothorax (25%).
Although performing a CT scan is more time-

lesion or a malignancy other than cancer (i.e. ,25%. Major pneumothorax, requiring chest
lymphoma) is suspected. tube drainage, occurs in 5% of cases.
Haemoptysis occurs in 510% of cases and is
Results generally mild and self-limited. Rare
complications include air embolism (0.07%),
The reported sensitivity of PFNB ranges from haemothorax, empyema, tumour implantation
6097%. In patients with lung cancer, a along the needle tract and
diagnosis by PFNB is generally established in haemopericardium.
8595% of cases. Lower sensitivities are
reported for benign lesions (414%). Sensitivity
References
may be affected by the size and location of the
lesion, number of needle passes, size of the N Gasparini S, et al. Integration of transbronchial
needle, availability of immediate cytological and percutaneous approach in the diagnosis of
assessment and experience of the operator. peripheral pulmonary nodules or masses. Chest
False-positive results are rare and the specificity 1995; 108: 131137.
of the technique is extremely high. However, it N Gould MK, et al. Evaluation of patients with
is important to emphasise that a nondiagnostic pulmonary nodules: when is it lung cancer.
Chest 2007; 132: Suppl. 3, 108s130s.
PFNB does not rule out the possibility
of malignancy.
N Nordenstrom B. A new technique for
transthoracic biopsy of lung cancer. Br J Radiol
Complications 1965; 38: 550553.
N Shaham D. Percutaneous transthoracic needle
The most frequently reported complication is biopsy. Radiol Clin North Am 2000; 38:
minor pneumothorax, with an incidence of 525534.
Fine-needle biopsy 111

MEDICAL THORACOSCOPY/
PLEUROSCOPY
R. Loddenkemper
Former Chief, Dept of Pneumology II, Lungenklinik Heckeshorn, HELIOS
Klinikum Emil von Behring, Berlin, Germany
E-mail: rloddenkemper@dzk-tuberkulose.de
Thoracoscopy was first used 100 yrs ago,

Key points primarily as a diagnostic procedure, but soon
also as a therapeutic technique for lysis of
N MT/P has the advantage compared with pleural adhesions by means of thoracocautery
VATS that it can be performed under (Jacobaeus operation) to facilitate
local anaesthesia or conscious sedation, pneumothorax treatment of tuberculosis. At
in an endoscopy suite using the end of the last century, the addition of the
nondisposable rigid (or semi-rigid) term medical was necessary in order to
instruments. Thus, it is considerably less distinguish this procedure from surgical
expensive. thoracoscopy, which is much more invasive,
using general anaesthesia, a double-lumen
N The leading indications for MT/P are endotracheal tube and multiple points of
pleural effusions, both for diagnosis entry. Surgical thoracoscopy is better
mainly in exudates of unknown described as video-assisted thoracic surgery
aetiology or for staging in diffuse (VATS), whereas medical thoracoscopy can be
malignant mesothelioma, lung cancer, performed under local anaesthetic or
and for talc poudrage, the best conscious sedation in an endoscopy suite
conservative method today for using nondisposable rigid or semi-rigid (semi-
pleurodesis. flexible) instruments. It is therefore
considerably less invasive and less expensive.
N MT/P can also be used efficiently in the
management of early empyema and Medical thoracoscopy/pleuroscopy (MT/P) are
pneumothorax. invasive techniques that would be used only
when other more simple methods fail. Today,
N In the above indications, MT/P can
it is considered to be one of the main areas of
replace most surgical interventions, interventional pulmonology. As with all
which are more invasive and more technical procedures, there is certainly a
expensive. learning curve before full competence is
N MT/P is a safe procedure, even easier to achieved. Therefore, appropriate training is
learn than flexible bronchoscopy, mandatory. Actually, the technique is very
provided sufficient experience with similar to chest-tube insertion by means of a
chest-tube placement has been gained. trocar, the difference being that, in addition,
the pleural cavity can be visualised (fig. 1)
N MT/P as part of the new field of and biopsies can be taken from all areas of
interventional pulmonology should be the pleural cavity including the chest wall,
included in the training programme of diaphragm, mediastinum and lung.
chest physicians.
There are two different techniques of
diagnostic and therapeutic thoracoscopy, as

a) The other technique uses two entries, one with
a 7-mm trocar for the rigid examination
telescope and the other with a 5-mm trocar
for accessory instruments, including the
biopsy forceps. For this technique, neuroleptic
or general anaesthesia is preferred.
For cauterisation of adhesions and blebs, or in
case of bleeding after biopsy,
electrocoagulation should be available. For
pleurodesis of effusions, 46 g of a sterile, dry,
asbestos-free talc is insufflated through a rigid
or flexible suction catheter with a pneumatic
atomiser. In pneumothorax patients, 23 g of
b) talc is sufficient. After thoracoscopy, a chest
tube is introduced through which immediate
suction is started carefully.
MT/P is a safe examination if the
contraindications are observed and if certain
2
standard criteria are fulfilled. An obliterated
pleural space is an absolute contraindication.
Relative contraindications include bleeding
disorders, hypoxaemia and an unstable
1
cardiovascular status, and persistent
uncontrollable cough. The most serious, but
fortunately least frequent, complication is
severe haemorrhage due to blood-vessel injury
during the procedure. However, this and also
Figure 1. a) Diagram of a computed tomography pulmonary perforations, can be avoided by
scan showing several malignant lesions of the
using safe points of entry and a cautious
parietal pleura for which biopsies can be taken
under visual control through the thoracoscope. b)
biopsy technique. Reported mortality rates
Tuberculous pleural effusion. After drainage of (,0.001) are very low. The most frequent
800-mL serous effusion, typical sago-like nodules on complication is nonspecific, transient fever.
the reddened inflamed posterior chest wall, firm
Pleural effusions are by far the leading
adhesions between right lower lobe (1) and chest
wall (2). Reproduced from LODDENKEMPER et al.
indication for MT/P, both for diagnosis, mainly
(2010), with permission from the publisher. in exudates of unknown aetiology, and for
staging in diffuse malignant mesothelioma or
lung cancer, and for treatment by talc
performed by the pneumologist. The one, very pleurodesis in malignant or other recurrent
similar to the technique first described by effusions, or in cases of empyema.
Jacobaeus for diagnostic purposes, uses a Spontaneous pneumothorax for staging and
single entry with a rigid 9-mm thoracoscope for local treatment is also an excellent
with a working channel for accessory indication. For those who are familiar with the
instruments and an optical biopsy forceps technique, other (mainly diagnostic)
under local anaesthesia. This single-entry indications are biopsies from the diaphragm,
technique has now been modified by the the lung, e.g. in interstitial lung diseases, the
introduction of an autoclavable semi-flexible mediastinum and the pericardium. In
pleuroscope (Olympus), which has the addition, MT/P offers a remarkable tool for
advantage that handling is very simple, research as a gold standard in the study of
similar to a flexible bronchovideoscope. pleural effusions.
Medical thoracoscopy/pleuroscopy 113

Needle Effusion Medical to determine operability. In diffuse malignant
biopsy (cytology) thoracoscopy mesothelioma, MT/P provides an earlier
diagnosis and a better histological
classification due to larger and consequently
44 62 95
more representative biopsies, as well as a
more precise staging.
74 96
In tuberculous pleural effusion, MT/P has a
high diagnostic sensitivity of almost 100%
97
(fig. 2). It provides much more often a
bacteriological confirmation of the diagnosis of
Figure 2. The different biopsy techniques used in
the diagnosis of malignant pleural effusions and
TB and thus the possibility to perform
their sensitivity expressed in percentages susceptibility tests. In parapneumonic pleural
(cytological and histological results combined). effusion (empyema), MT/P offers the possibility
Prospective intrapatient comparison (n5208). to remove fibrinopurulent membranes and
Reproduced from LODDENKEMPER (1998). break up loculations, thus creating one single
pleural cavity for successful local treatment.
Malignant pleural effusions represent the
leading diagnostic and therapeutic indication In other pleural effusions, when the origin
for MT/P. MT/P has a much higher diagnostic remains indeterminate, the main diagnostic
sensitivity and specificity in malignant pleural value of MT/P lies in its ability to exclude, with
effusions than closed needle biopsy and high probability, malignant or tuberculous
pleural fluid cytology (fig. 1). Biopsies can be disease. In pneumothorax patients, MT/P
taken under direct visual control not only of allows talc poudrage for pleurodesis, which is
the costal pleura, but also of the visceral and highly effective in recurrence prevention.
diaphragmatic pleura. An additional
advantage is that the diagnostic procedure References
can easily be combined with the therapeutic N Diacon AH, et al. Diagnostic tools in tuberculous
procedure of talc poudrage for pleurodesis. pleurisy: a direct comparative study. Eur Respir J
MT/P is helpful in the staging of lung cancer, 2003; 22: 589591.
diffuse malignant mesothelioma and N Loddenkemper R, et al. Medical Thoracoscopy/
metastatic cancers. In lung cancer patients, Pleuroscopy: Manual and Atlas. New York,
thoracoscopy can determine whether the Thieme, 2011.
tumour spread to the pleura is secondary to N Loddenkemper R. Thoracoscopy state of the
art. Eur Respir J 1998; 11: 213221.
venous or lymphatic obstruction or is
parapneumonic. As a result, it may be
N Loddenkemper R, et al. Treatment of parapneumonic
pleural effusion and empyema conservative view.
possible to avoid exploratory thoracotomy or Eur Respir Mon 2004; 29: 199207.
N Noppen M. Pleural biopsy and thorascopy. Eur
Needle Effusion Medical Respir Mon 2010; 48: 119132.
biopsy (culture) thoracoscopy N Rodriguez-Panadero F, et al. Thoracoscopy:
general overview and place in the diagnosis and
51 28 99 management of pleural effusion. Eur Respir J
2006; 28: 409422.
N Tassi GF, et al. Advanced techniques in medical
61 100 thoracoscopy. Eur Respir J 2006; 28: 10511059.
N Tschopp JM, et al. Management of spontaneous
Figure 3. The different biopsy techniques used in pneumothorax: state of the art. Eur Respir J
the diagnosis of tuberculous pleural effusions and 2006; 28: 637650.
their sensitivity expressed in percentages N Vansteenkiste J, et al. Medical thoracoscopic
(cytological and histological results combined). lung biopsy in interstitial lung disease: a
Prospective intrapatient comparison (n5100). prospective study of biopsy quality. Eur Respir J
Reproduced from LODDENKEMPER (1998). 1999; 14: 585590.

THORACENTESIS
E. Canalis1 and M.C. Gilavert2
1
Thoracic Surgery Service
2
Intensive Care Unit, Hospital Universitari Joan XXIII, IISPV, URV,
Tarragona, Spain
E-mail: emilio.canalis@urv.cat
Thoracentesis (pleural tap; fig. 1) is a down from where dullness on percussion

frequently performed procedure that is used starts. At least in pleural effusions of smaller
to remove and analyse pleural fluid. Its goals size, ultrasound guidance is strongly
may be diagnostic and/or therapeutic. recommended.
Diagnostic thoracentesis should be performed The thoracentesis set
on almost all patients with a pleural effusion
of unknown origin. Its main purpose is to The thoracentesis set is detailed in table 1.
differentiate between transudate and Procedure
exudate. The number of diagnoses established
by pleural fluid analysis varies with the 1. Under sterile conditions, the selected region
population being evaluated. Careful history of puncture is disinfected with povidone
and physical examination, radiological iodine or alcohol, and a sterile draping,
evaluation, and ancillary blood tests are preferably with a centre hole, is taped to the
crucial in establishing a pre-test diagnosis. patients back.
The main purpose of therapeutic thoracentesis 2. Local anaesthesia is injected stepwise, at
is to relieve dyspnoea and respiratory first with an intradermal injection producing a
insufficiency caused by pleural effusion. small wheal, then infiltrated subcutaneously
and into the intercostal muscle down to the
Patient position parietal pleura at the upper rim of the lower
A sitting position is preferred in conscious rib in order to avoid the intercostal nerve and
patients, as this will help the fluid to settle in vessels. During the injection, alternating
the posterior and basal regions of the lung aspiration is performed until the parietal
(usually the 7th to 8th intercostal spaces, pleura is penetrated and pleural fluid is
although clinical examination may reveal
different locations of the fluid).
Key points
Once a comfortable position for operating on
the patient is achieved, the site for the N Thoracentesis may be diagnostic or
puncture must be selected. This is decided therapeutic in patients with a pleural
according to the results of the physical effusion.
examination and the radiological findings,
which will indicate characteristics such as the N Ultrasound examination is valuable in
size and localisation of the main effusion and guiding the procedure.
whether it is free-organised, free-floating or N There are no absolute
encapsulated. Ultrasound examination is contraindications, and complications
valuable to assess fluid presence accurately. are rare, but the possibility should be
The puncture should be guided by ultrasound taken into account.
or attempted one intercostal space further
Thoracentesis 115
Figure 1. Thoracentesis needle through the intercostal space.
aspirated. Then 2060 mL of pleural fluid 5. Chest radiography should be carried out to
should be aspirated for fluid analysis. exclude the development of a pneumothorax,
unless the procedure has been performed
Diagnostic thoracentesis can occasionally be under ultrasound guidance without any
carried out without local anaesthesia if the problems.
adult patient is calm, the puncture is
anticipated to be easy, the subject is not
Contraindications
obese and the operator is experienced.
Diagnostic thoracentesis has no absolute
3. For therapeutic thoracentesis, a catheter
contraindications provided that it is done with
should be used, which is immediately
caution by experienced persons. The following
connected to a closed three-way stop-cock.
are relative contraindications.
This allows aspiration syringes to be changed
or facilitates connection to a suction device.
N Altered coagulation. A decision must be
4. As soon as the procedure is finished, the taken as to whether thoracentesis is really
needle or the catheter is removed and needed. If so, it may be necessary to
pressure is applied to the wound for a few reverse anticoagulation or to administer
minutes, followed by a sterile dressing. fresh frozen plasma or platelets.

Table 1. Thoracentesis set N Re-expansion pulmonary oedema. This can
be prevented by removing ,11.5 L of
Povidone iodine solution or alcohol
pleural fluid.
Sterile drapes, gloves and gauzes
Abbocath-type needle catheters Additional recommendations
Local anaesthesia
1. The region from the mid-clavicular line to
Syringes
the sternum should be avoided, as here the
Three-way stopcock vessels are located in the centre of the
Aspiration set (if therapeutic) intercostal space.
Adhesive strips
Instrumentation table 2. Sterile conditions are mandatory during the
whole procedure to prevent infection which
may lead to empyema.
N Mechanical ventilation with positive
pressure at the end of expiration. 3. For diagnostic purposes, 20 mL of pleural
Whenever possible, mechanical ventilation fluid is usually sufficient to assess the
is suspended briefly. If this is not possible, appearance of the fluid and for chemical,
thoracentesis must be carried out with cytological, and bacteriological analysis.
caution using ultrasound guidance. Recent work recommends ,60 mL for
cytology in case of suspected malignancy.
N Local skin infections such as cellulitis or
Herpes zoster. References
N Small effusions (this should be done under N Abouzgheib W, et al. A prospective study of the
volume of pleural fluid required for accurate
ultrasound control).
diagnosis of malignant pleural effusion. Chest
Complications 2009; 135: 9991001.
N Alcaide MJ, et al. Toracocentesis y drenaje
As with any invasive investigation, pleural. In: De Mendoza D, et al. Medicina
complications may occur, but these are rare. Intensiva Respiratoria. Tarragona, Silva ed.,
Patients have to be informed about possible 2008.
complications when asked to give their N Chest Trauma. In: Advanced Trauma Life Support
informed consent. The most important are: (ATLS) Course Manual. 7th Edn. Chicago,
American College of Surgeons, 2004; pp. 107121.
N Pneumothorax. This is usually only small if N Capizzi SA, Prakash UB. Chest roentgenography
caused by entrance of air into the pleural after outpatient thoracentesis. Mayo Clin Proc
1988; 73: 948950.
cavity through the needle or the aspiration
system. It can become larger if the lung is
N Dev SP, Nascimento B Jr. Videos in clinical
medicine. N Engl J Med 2007; 357: l5.
injured by the needle. N Duncan DR, et al. Reducing iatrogenic risk in
thoracentesis: establishing best practice via
N Hypotension. This may be induced by a
experiential training in a zero-risk environment.
vaso-vagal reaction when the parietal pleura Chest 2009; 135: 13151320.
is punctured. It can be avoided by careful N Feller-Kopman D, et al. Assessment of pleural
local anaesthesia and prevented by admin- pressure in the evaluation of pleural effusions.
istering atropine (not routinely necessary). Chest 2009; 135: 201209.
N Gaba DM, Dunn WF. Procedural risks in
N Bleeding. This can be prevented by thoracentesis: process, progress, and proficiency.
avoiding the lower rim of the upper rib and Chest 2009; 135: 11201123.
by excluding coagulopathies. N Sahn SA. Diagnostic value of pleural fluid
analysis. Clin Chest Med 1995; 16: 269278.
N Haemopneumothorax. This is rare when N Swiderek J, et al. Prospective study to determine
the above-described technique is observed the volume of pleural fluid required to diagnose
and the patient has no bleeding disorder. malignancy. Chest 2010; 137: 6873.
Thoracentesis 117
INTERVENTIONAL
PULMONOLOGY
M. Noppen
University Hospital UZ Brussel, Brussels, Belgium
E-mail: Marc.Noppen@uzbrussel.be
Interventional pulmonology encompasses focused on the technicality of the various

both diagnostic and therapeutic procedures; data pertaining to the functional
bronchoscopic, thoracoscopic and other assessment and evaluation are relatively
techniques that go beyond everyday simple scarce. Certainly in the pioneer era of
procedures performed by pulmonary interventional pulmonology, patients were
clinicians. In the context of pulmonary referred in a (very) late stage of disease, with
function testing and interventional severe dyspnoea and/or stridor or signs of
pulmonology, this chapter will be limited post-obstructive disease, requiring prompt
towards the effects on interventional intervention without additional testing. In
bronchoscopy of pulmonary function tests. stable and nonlife-threatened patients with or
without symptoms, however, additional
Interventional bronchoscopy here is limited to testing before proceeding an intervention may
all (rigid and flexible) bronchoscopic be helpful in patient selection, and post-
procedures designed to reopen obstructed procedure testing may focus the usefulness
central airways (including laser, and efficacy of an intervention. Thus, as more
electrocautery, cryotherapy, brachytherapy centres successfully perform various
and photodynamic therapy) or to establish interventional bronchoscopic techniques, the
airway patency (airway stenting). need is increasing for a critical evaluation and
selection of patients in order to understand the
The literature on interventional bronchoscopy
physiological effects of these interventions and
has, during the past few decades, mainly
gain an evidence-based, algorithmic integration
of these techniques in the overall care of these
Key points patients. Alternatively, abnormalities observed
during pulmonary function testing may prompt
N Symptoms of central airway stenosis the clinician to suspect an upper (or central)
airway stenosis (UAS).
occur late, after at least 50% (on
exercise) or 80% (at rest) of the In patients suffering from malignant airway
tracheal lumen is obstructed. stenosis, which is not candidate for, or
unresponsive to, classical oncological
N The diagnostic accuracy of spirometric
treatments, the main interest of interventional
indices and visual flowvolume loop
pulmonological treatment should lie in the
criteria in detecting central airway
improvement of quality of life and the
stenosis is relatively poor. avoidance of death by suffocation.
N Interventional bronchoscopic
Pulmonary function tests in UAS
techniques have been shown to
significantly improve objective Inspection of the maximal inspiratory and
pulmonary function and quality of life. expiratory flowvolume loop is currently the
most widely used method to detect/suspect

14
12
10
8
Exp
2
Flow Ls-1
2
4
6 Figure 2. Computed tomography image of the
patient in fig. 1.
8
In
10
12
14
0 1 2 3 4
Vol L
Figure 1. A typical flattened coffin flowvolume

loop curve in a patient with severe fixed tracheal
obstruction due to an inoperable intrathoracic
goitre. $: pre; m: post.
the presence of UAS (figs 13). However,

significant changes in spirometry appear
relatively late in the course of the stenosing
process. The airway cross-sectional area
indeed has to be reduced by o50% in order
to cause breathing impairment, a clinical Figure 3. Bronchoscopic image of the patient in
figs 1 and 2.
observation that recently has been
corroborated by a fluid dynamics study of
tracheal stenosis. There is also a very poor or
even absent correlation between the severity of
the UAS as determined by the flow loop Typical flowvolume appearances, however,
analysis and its spirometrically derived indices, may be helpful: a typical coffin or box
and breathing symptoms or radiological appearance of the flowvolume curve is
assessment of UAS. UAS becomes more suspicious for a fixed UAS due to severe
easily symptomatic during exercise (from a tracheal obstruction; an isolated plateau
tracheal diameter f8 mm), whereas at rest during expiration is suspicious for an
the diameter has to be f5 mm before intrathoracic airway stenosis; an isolated
symptoms occur. All of this may explain why plateau of the inspiratory loop suggests
the diagnostic accuracy of the various extrathoracic obstruction. Obstructive lesions
individual spirometric indices and visual flow at multiple airway sites and associated
volume loop criteria in detecting UAS is abnormalities such as severe chronic
relatively poor (receiver-operating-curve obstructive pulmonary disease may cause
analysis ,0.52). atypical flowvolume loop characteristics.
Interventional pulmonology 119

UAS may lead to typical flowvolume loop
abnormalities and spirometric derived indices,
but
N the diagnostic accuracy in detecting UAS

of these tests is (very) low;
N symptoms of UAS occur relatively late in
the UAS process; and
N symptoms of UAS occur earlier during
exercise.
The most commonly used quantitative criteria Figure 4. Computed tomography image of the same
to detect UAS include maximal expiratory patient after stenting.
flow at 50% of forced vital capacity (FVC;
MEF50%)/maximal inspiratory flow at 50% of stenting for inoperable malignant thyroid
FVC (MIF50%) (,0.30 for intrathoracic, and disease (FEV1 +540 mL, FVC +730 mL, peak
.1 for extrathoracic stenosis), forced expiratory flow +96 L?min-1) (figs 4 and 5).
expiratory volume in 1 s (FEV1)/maximum
expiratory flow (.10 mL?L-1?min-1), MIF50% ERNST et al. (2007) showed improvements in
(,100 L?min-1), and FEV1/FEV0.5 (.1.5). The some but not all patients stented for severe
visual criteria are the presence of a plateau, tracheomalacia, in respiratory symptoms,
biphasic shape, or oscillations in the quality of life, and in functional status
inspiratory or expiratory curves. assessed by exercise testing and FEV1. Overall,
these retrospective and prospective
Impact of interventional bronchoscopy observational case series, in selected patients,
on pulmonary function show significant but not homogeneous
In most patients, but not all, pulmonary improvements in a number of functional
function significantly improves after parameters. Data on physiological effects of
restoration of central airway patency. EISNER et repermeabilisation techniques without
al. (1999) demonstrated mean improvements additional stenting are even more scarce:
of 388 mL for FVC, 1,288 mL for peak objective improvements in pulmonary
expiratory flow, and 550 mL for FEV1 after function was seen in 58% of patients after
stenting in nine patients. GELB et al. (1992) cryotherapeutic debulking of central airways,
showed increases in FVC from 64% to 73%
predicted, and in FEV1 from 49% to 72%
predicted after stenting in 17 patients.
VERGNON et al. (1995) showed mean
improvements in FEV1 (440 mL), peak
expiratory flow (920 mL?s-1), maximum
expiratory flow 2575% (470 mL?s-1), and
forced inspiratory volume in 1 s (310 mL)
after stenting in a total of 24 patients.
Improvements were more outspoken in intra-
and extrathoracic tracheal stenosis as
compared with bronchial stenosis. NOPPEN et
al. (2004) showed improvements after
tracheal stenting for inoperable benign
thyroid disease (FEV1 +470 mL, FVC
+620 mL, peak expiratory flow +79 L?min-1)
and after tracheal laser debulking and/or Figure 5. The same patient, 1 yr after stent insertion.

and a trial of 19 patients with major airway general population, these abberations show a
obstruction due to lung cancer showed poor accuracy in predicting UAS. In extremely
significant improvements in a variety of symptomatic, almost suffocating patients,
parameters including FEV1, FVC and ratio of immediate intervention with
forced expiratory/forced inspiratory flow rate repermeabilisation/stenting is warranted. In
at 50% of vital capacity, after endobronchial nonlife-threatening cases, pre-intervention
radiotherapy. pulmonary function testing may yield useful
information on the type, site and extent of the
A breakthrough article by MIYAZAWA et al.
(2004) shed more light on the underlying stenosis, whereas post-procedure testing may
physiological phenomena occurring after be used to focus the response and can be
airway stenting, including the heterogeneity used as a basis for post-procedure follow-up.
of response. A total of 64 patients with In the case of a multi-site, extensive airway
extrinsic airway stenoses due to advanced stenosis, its relatively typical flowvolume
malignancy were studied; patients were loop pattern may be predictive of therapeutic
classified by location of the stenosis (tracheal, failure of single-site stenting and may predict
carinal, bronchial or multi-site). Pulmonary the necessity of additional stenting at
function tests and CT were performed before upstream choke points. Interventional
and after stenting. Prior to stent insertion, bronchoscopic procedures offer immediate
patients underwent endobronchial ultrasound (and often longstanding) palliation of
to evaluate the airway walls and ultrathin respiratory symptoms, improvements in
bronchoscopy to evaluate airway patency quality of life (and frequently length of life as
distal to the obstruction. Stents were placed at well), and objective improvements in
the visualised flow-limiting segments (choke pulmonary function in the majority of
points). Distinctive flowvolume loop patterns patients. When used judiciously, they have
were found for each of the four types of become an invaluable tool in the
stenosis. Most patients showed symptomatic armamentarium of modern pulmonology.
improvement after stenting, and most flow References
volume loops returned to normal. All 10
patients with multi-site, extensive stenosis, N Amjadi K, et al. Impact of interventional
however, showed persistent choke points, bronchoscopy on quality of life in malignant
associated with only minor improvements in airway obstruction. Respiration 2008; 76:
symptoms and spirometry. Repeat endoscopy 421442.
in these patients showed upstream N Brouns M, et al. Tracheal stenosis: a flow dynamics
study. J Appl Physiol 2007; 102: 11781184.
displacement of choke points (distally from
the inserted stents), and ultrasound showed
N Eisner MD, et al. Pulmonary function improves
after expandable metal stent placement for
destructed cartilage at these sites. Additional benign airway obstruction. Chest 1999; 115:
stenting at these sites then improved 10061011.
symptoms and pulmonary function to levels N Empay DW. Assessment of upper airways
comparable with the other groups. This obstruction. BMJ 1972 5825; 3: 503505.
additional physiological and imaging N Ernst A, et al. Airway stabilization with silicone
information excluded all therapeutic failures. stents for treating adult tracheobronchomalacia:
a prospective observational study. Chest 2007;
Conclusions 132: 609616.
When patients with UAS present with
N Ernst A, et al. Central airway obstruction. Am J
dyspnoea at exertion, and certainly with N Gelb AF, et al. Physiologic studies of
dyspnoea at rest, severe central airway tracheobronchial stents in airway obstruction.
stenosis is already present. In these patients, Am Rev Respir Dis 1992; 146: 10881090.
flowvolume loop analysis and spirometry will N Gittoes NJ, et al. Upper airways obstruction in
most probably show aberrations typical for 153 consecutive patients presenting with
UAS. However, as a screening tool in a thyroid enlargement. BMJ 1996; 312: 484.
Interventional pulmonology 121

N Goldman JM, et al. Physiological effect of the flow-volume loop: a comparison of
endobronchial radiotherapy in patients with quantitative and visual inspection criteria. Respir
major airway occlusion by carcinoma. Thorax Care 2009; 54: 474479.
1993; 48: 110114. N Noppen M, et al. Interventional bronchoscopy
N Lund ME, et al. Airway stenting: applications for treatment of tracheal obstruction secondary
and practice management considerations. Chest to benign or malignant thyroid disease. Chest
2007; 131: 579587. 2004; 125: 723730.
N Melissant CF, et al. Lung function, CT-scan and X- N Rotman HH, et al. Diagnosis of upper airway
ray in upper airway obstruction due to thyroid obstruction by pulmonary function testing.
goitre. Eur Respir J 1994; 7: 17821787. Chest 1975; 68: 796799.
N Miller RD, Hyatt RE. Evaluation of obstructing N Vincken W, et al. Flow oscillations on the flow-
lesions of the trachea and larynx by flowvolume loop: a nonspecific indicator of upper
volume loops. Am Rev Respir Dis 1973; 108: airway dysfunction. Bull Eur Physiopathol Respir
475481. 1985; 21: 559567.
N Miyazawa T, et al. Stenting at the flow-limiting N Vergnon JF, et al. Efficacy of tracheal and
segment in tracheobronchial stenosis due to bronchial stent placement on respiratory
lung cancer. Am J Respir Crit Care Med 2004; functional tests. Chest 1995; 107: 741746.
169: 10961102. N Walsh DA, et al. Bronchoscopic cryotherapy for
N Modrykamien AM, et al. Detection of upper advanced bronchial carcinoma. Thorax 1990;
airway obstruction with spirometry results and 45: 509513.

CHAPTER 5:
lung imAging
CHEST x-RAy And fluoRoSCoPy 126

W. De Wever
lung CT And mRi 130

J.A. Verschakelen
nuClEAR mEdiCinE of THE lung 135

A. Palla
TRAnSTHoRACiC ulTRASound 138

F. Von Groote-Bidlingmaier, C.F.N. Koegelenberg and C.T. Bolliger

CHEST X-RAY AND
FLUOROSCOPY
W. De Wever
University Hospitals Leuven, Leuven, Belgium
E-mail: walter.dewever@uz.kuleuven.be
Chest radiography is the most frequently used they are projected away from the lungs.
radiological chest imaging technique and also Patient respiration must be fully suspended,
one of the most challenging. The technical preferably at total lung capacity. Film
aspects of this imaging modality are studied exposure factors should be such that faint
extensively. New approaches to image visualisation of the thoracic spine and the
acquisition and display have been introduced intervertebral disks on the posteroanterior
in the past decade. As a general rule, (PA) radiograph is possible and that lung
establishing the presence of a lung disease markings behind the heart are clearly visible.
process on the radiograph should constitute Exposure should be as short as possible,
the first step in radiological diagnosis of chest consistent with the production of adequate
disease. contrast. A high-kilo voltage technique
appropriate to the film speed should be used.
Basic radiographic techniques
Projections
Diagnostic accuracy in chest disease is partly
related to the quality of the radiographic PA and lateral projection The most
images themselves. Several variables such as satisfactory routine radiographic views for
patient position, patient respiration and film evaluating the chest are the PA and lateral
exposure factors must be taken into account projections with the patient standing (fig. 1).
to ensure image quality (table 1). Positioning The combination of these two projections
of the patient must be such that the X-ray provides very good three-dimensional
beam is properly centred, the patients body information. In patients who are too ill to
not rotated and the scapulas rotated so that stand up, anteroposterior (AP) upright or
supine projections offer alternative but
considerably less satisfactory views. The AP
Key points projection is of inferior quality because of the
shorter focal-film distance, the greater
N Chest radiography is the first step in magnification of the heart, and often the
radiological diagnosis of chest diseases. restricted ability of these patients to suspend
N Although it is a common technique, respiration or achieve full inspiration. Based
achieving high image quality is on a review of the literature and
challenging and depends on getting recommendations of the American College of
Radiology and the American Thoracic Society,
several factors right.
recommendations on the use of chest
N The move from film to digital imaging radiographs are summarised in table 2.
offers exciting opportunities to improve
image consistency and data Lateral decubitus projection For the
management. lateral decubitus projection, the patient lies
on one side and the X-ray beam is oriented

Table 1. Key points to obtaining a good chest radiograph wall disease process (e.g. pleural plaque);
however, in most situations, computed
Radiographic appearance
tomography is preferred.
Frontal view (PA view)
Area from the lower cervical spine to below
the costophrenic angles Inspiratoryexpiratory radiography
Sterno-clavicular joints symmetrical about Comparison of radiographs exposed in full
the midline
inspiration and maximal expiration may
Shadows of the scapulae away from the supply useful information in two specific
lung field
situations. The first indication is the
Lateral view evaluation of air trapping, either focal or
Soft tissues of the axillae should be included general. With air trapping, diaphragmatic
Respiration excursion is reduced symmetrically and lung
End of normal inspiration density changes little between expiratory and
Positioning of the patient inspiratory radiographs. The second indication
Erect position is when a pneumothorax is suspected and
Very ill patients: horizontal or semi-erect when the visceral pleural line is not visible on
Postero-anterior (PA) position the standard inspiratory radiograph or the
findings are equivocal. In these situations, a
Film exposure factors film taken in full expiration may show the line
High kilo voltage more clearly.
Focus-film distance
Must be kept constant for any particular Bedside radiography
department
Chest radiography, performed at the bedside
150180 cm
with portable apparatus, is one of the most
frequently performed radiological
horizontally. This technique is particularly examinations; however, this technique is also
helpful for the identification of small pleural the examination with the most variation in
effusions. ,100 mL of fluid may be identified image quality. The amount of diagnostic
on well-exposed radiographs in this position. information provided by chest examinations
Radiography in the lateral decubitus position done with portable apparatus is high, and
is also useful to demonstrate a change in many abnormalities are detected. These
position of an airfluid level in a cavity or a examinations are useful 7694% of the time.
freely moving intracavitary loose body (e.g. However, poor image quality and day-to-day
fungus ball in aspergilloma). variations in film density interfere with the
detection of interval changes in patients with
Lordotic projection The lordotic projection pulmonary diseases. The need to improve the
can be made in AP or PA projection. For this image quality of this examination has long
projection, the patient stands erect and the X- been recognised, but it is a difficult problem
ray tube is angled 15u cephalad. The main to solve.
advantage of this modification is its
Digital chest radiography
reproducibility. The lordotic projection can be
used: 1) for improving visibility of the lung There have been many remarkable advances
apices, superior mediastinum and thoracic in conventional thoracic imaging over the past
inlet, and 2) for identifying the minor fissure decade. Perhaps the most remarkable is the
in suspected cases of atelectasis of the right rapid conversion from film-based to digital
middle lobe. radiographic systems. Digital radiography
(DR) is the common name for different
Oblique projection Oblique studies are technologies that are characterised by a direct
sometimes useful in locating a pleural or chest readout matrix that covers the whole exposure
Chest X-ray and fluoroscopy 127

a) b)
Figure 1. Posteo-anterior chest radiograph. Normal lungs are visible as black fields (air) (*) with superposition
of multiple white linear structures (vessels and walls of airways). The lunghili consist of bronchi (main stem
(1) and lobar bronchi) and vascular structures (pulmonary arteries (2) and pulmonary veins). A normal pleura
is not visible on a chest radiograph. In the mediastinum we can visualise the trachea (3) as a translucent tube
on the midline, the aortic arch (4), the pulmonary trunk (5), the left border or the heart formed by the left
ventricle (6) and the right border of the heart formed by right atrium (7). A normal heart has a normal cardio-
thoracic index: (a+b)/maximal diameter of the chest (c) must be less than 0.5. The bony components of the
chest visible on the frontal view are: the ribs (+), the manubrium sternum (8), the claviculae (9), the scapulae
(10) and the vertebral bodies on the midline. The diaphragm (11) is sharply delineated and also the costo-
phrenic angles (12) must be sharp and free. b) Lateral chest radiograph. The lateral chest film can be used to
localise better the findings on the frontal view. Numbers and symbols are as for a).
Table 2. Recommendations for the use of chest radiography

Indications
Signs and symptoms related to the respiratory and cardiovascular system
Follow-up of previously diagnosed thoracic disease for evaluation of improvement resolution, or
progression
Staging of intrathoracic and extrathoracic tumours
Pre-operative assessment of patients scheduled for intrathoracic surgery
Pre-operative evaluation of patients who have cardiac or respiratory symptoms or patients who have a
significant potential for thoracic pathology that may lead to increased peri-operative morbidity or
mortality
Monitoring of patients who have life support devices and patients who have undergone cardiac or
thoracic surgery or other interventional procedures
No indications
Routine screening of unselected populations
Routine pre-natal chest radiographs for the detection of unsuspected disease
Routine radiographs solely because of hospital admission
Mandated radiographs for employment
Repeated radiograph examinations after admission to a long-term facility

area. Conversion of X-ray intensity into were thought to be signs of effusion. Other
electrical signals can either be direct indications for fluoroscopy included the
(selenium-based systems) or indirect investigation of foreign bodies determined by
(scintillator/photodiode systems). Advantages air trapping and appropriate mediastinal shift
of DR systems are a high image quality and and the evaluation of diaphragmatic paralysis.
the potential for dose reduction. This technique This evaluation of diaphragmatic paralysis is
is now the preferred imaging modality for still an indication for fluoroscopy today.
bedside chest imaging because of its more
consistent image quality. DR is rapidly replacing References
film-based chest units for in-department PA and
lateral examinations. The final aim is to realise N American College of Radiology. ACR Standard
for the Performance of Pediatric and Adult Chest
a completely integrated digital radiology
Radiography. Reston, American College of
department throughout the hospital connected Radiology, 1997; p. 27.
to a large digital image archiving system. This N American Thoracic Society, Chest x-ray screening
concept, referred to as picture archiving and statements. Am Thoracic News 1984; 10: 14.
communication systems (PACS), represents the N MacMahon H, Doi K. Digital chest radiography.
logical culmination of the extensive research Clin Chest Med 1991; 12: 1932.
that is continuing in this area. N Rigler LG. Roentgen diagnosis of small pleural
effusions: a new roentgenographic position.
Chest fluoroscopy JAMA 1931; 96: 104108.
Chest fluoroscopy was a popular procedure a N Schaefer-Prokop C, et al. Digital radiography of
generation ago. Patients were examined the chest: detector techniques and performance
parameters. J Thorac Imaging 2003; 18: 124
fluoroscopically in various projections, and
137.
multiple spot radiographs were obtained with N Wandtke JC. Bedside chest radiography.
barium in the oesophagus. Examinations to Radiology 1994; 190: 110.
evaluate pericardial effusion also were N Zinn B, Monroe J. The lordotic position in
frequent. Overall diminution in cardiac fluoroscopy and roentgenography of the chest.
pulsation and greater pulsation of the Am J Roentgenol Radium Ther Nucl Med 1956;
posterior cardiac wall in the lateral projection 75: 682700.
Chest X-ray and fluoroscopy 129

LUNG CT AND MRI
J.A. Verschakelen
University Hospitals Leuven, Belgium
E-mail: johny.verschakelen@uz.kuleuven.ac.be
Computed tomography (CT) is the second

most important imaging modality of the chest Key points
and is, together with chest radiography, one
of the two basic imaging techniques for N CT is the second most important
visualising the lungs. Although there are imaging modality of the chest.
indications to perform a CT of the chest in N CT diagnosis of lung diseases is based
patients with normal chest radiography, this on the study of their appearance and
examination usually succeeds a chest X-ray on distribution patterns together with a
which a lesion is seen or suspected.
careful analysis of patient data.
Magnetic resonance imaging (MRI) of the N CT interpretation of diffuse and
chest is, except for visualisation of the heart interstitial lung diseases requires a
and great vessels, used less frequently in daily formal multidisciplinary approach.
clinical practice. In selected cases, this
imaging technique can sometimes add N MRI is second to CT when it comes to
information to what is seen on CT. Since its visualising pulmonary structure and
introduction CT has undergone several pathology.
technical changes and improvements. The first
scanners were incrementalCT scanners. In
order to complete one cross-sectional image, thickness and two-dimensional and three-
the patient needed to suspend respiration for dimensional reconstructions.
a few seconds. After that, the table was
moved and the next scan was performed. This Thin-section or high-resolution CT (HRCT) is a
was repeated about 25 times in order to special type of acquisition technique that uses
image the entire thorax. 0.51-mm slice thickness and high-frequency
reconstruction algorithms to produce high-
Spiral scanning (also known as helical or detail images. It is used when detailed
continuous-volume scanning) has radically information about the lung parenchyma is
altered CT scanning protocols (table 1). In this needed. These thin slices can be obtained
technique, there is continuous patient with the incremental acquisition technique
movement with simultaneous scanning by a in which 1-mm slices are produced with an
constantly rotating X-ray tube and detector image interval of 1020 mm. However, with
system. While the first spiral CT scanners had multislice spiral CT, it has become possible to
only one row of detectors, todays scanners produce a continuous set of thin slices of the
have multiple rows (multislice, multirow or entire chest. Although the quality of the
multidetector-row CT). This allows for individual images may be somewhat lower
simultaneous acquisition of multiple images when the multislice acquisition is used, the
in the scan plane with one rotation of the X- overall information obtained is usually larger.
ray tube around the patient. It also offers Indeed, instead of a small number of axial
flexible image reconstruction options such as slices with an image gap between, a
reconstructing images at various image continuous dataset is obtained that allows the

Table 1. Advantages of spiral computed tomography scanning
Sectional imaging without superposition of structures
Rapid acquisition within one breath-hold
Very good blood vessel opacification in vascular studies using limited amount of contrast
No respiratory misregistration between scans improving nodule detection
Fast and high-quality multiplanar and three-dimensional reconstructions
production of additional slices in different however, may be the increased radiation dose.
imaging planes. For this reason multislice is On the other hand, the lung parenchyma is
replacing the incremental technique in most very suitable for reduction of the radiation
institutions especially when it is the initial CT dose without important quality loss and first
examination in a patient with a suspected reports on the use of low-dose CT in
lung problem. An inportant drawback, demonstrating lung disease are indeed
promising.
a)
As mentioned earlier, CT of the chest is usually
performed when the chest radiography is
abnormal or suspicious for the presence of
pathology, although there are certainly
indications for doing this examination even
when the chest radiograph does not show any
(obvious) abnormalities. Table 2 lists the most
frequent indications for a CT of the chest.
Generally the diagnosis of lung disease on a
chest CT is based on three elements:
N Recognition of the appearance pattern of

the disease, i.e. classifying the abnormal-
ities in a category that is based on their
appearance.
b) N Determination of location and distribution
of the abnormalities in the lung: the
distribution pattern.
N Careful analysis of the patient data that
are available at the time the CT scan is
performed.
Although in some cases a diagnosis or a
narrow differential diagnosis list can be
proposed purely based on the study of the
appearance and the distribution pattern of
the disease on CT, the abnormalities seen in
Figure 1. Thin-slice computed tomography of the
the lung should be carefully correlated with
lung obtained with the multislice spiral acquisition observations made on other radiological
technique in a patient with sarcoidosis. The examinations and with all the clinical data
combination of axial (a) and coronal (b) views available at the time of the CT examination.
allows a better study of the appearance and In particular diffuse and interstitial lung
distribution pattern of the lung lesions. diseases are often very difficult to diagnose
Lung CT and MRI 131

Table 2. Indications for computed tomography of the chest
Abnormal chest radiography
Further evaluation of a chest wall, pleural, mediastinal or lung abnormality seen on a chest radiograph
Rule out or confirm a lesion seen on a chest radiograph
Lung cancer staging and follow-up
Assessment of thoracic vascular lesion
Normal chest radiography
Detection of diffuse lung disease
Detection of pulmonary metastases from a known extrathoracic tumour
Demonstration of pulmonary embolism
Investigation of a patient with haemoptysis
Investigation of patients with clinical evidence of a disease that might be related to the presence of
chest abnormalities (e.g. pulmonary infection in an immunocompromised patient with fever)
when the interpretation is based only on the gradient is set up along the magnetic field,
CT presentation. Ideally, cooperation should signal detection can be confined to a pre-
be established between the clinician selected body plane. Processing of the data
responsible for the patient, the radiologist then yields a sectional image of the plane of
and, when pathological information is present interest.
or probably required, the pathologist.
MRI has an established role in the imaging of
Continuous efforts are being made to improve the heart and the great thoracic vessels.
the image quality and the diagnostic Concerning the chest wall, the diaphragm, the
performance of CT imaging of the lung. A mediastinum and the lung, MRI was for many
further increase in the number of detector years considered a useful problem-solving
rows is feasible and may reduce acquisition technique for specific instances when used in
time and hence improve image quality. addition to CT. These instances include the
Automated and semi-automated software identification of tumour invasion in the chest
packages will help to interpret the CT images. wall and the mediastinal structures,
Dual-energy CT scanning may become helpful differentiation between solid and vascular
to study pulmonary perfusion in patients with hilar masses, assessment of diaphragmatic
pulmonary embolism. abnormalities and the study and follow-up of
mediastinal lymphoma during treatment. As
Magnetic resonance imaging
mentioned earlier, however, most centres now
Like CT, MRI produces multiplanar cross- use multidetector spiral CT for thoracic
sectional images, but it allows for a greater imaging, including the areas thought earlier
tissue characterisation because it has a better to be the domain of problem-solving MRI.
contrast resolution than CT. It also has the
Although it has become clear that MRI will
benefit of not using ionising radiation.
always be second to CT when it comes to
Tissue protons are exposed to a strong visualising pulmonary structure, disease and
external magnetic field and realign along the patterns with high spatial resolution, the
plane of the magnetic gradient. From this many research and development efforts that
position they are deflected momentarily by have been made in recent years have resulted
applying a so-called radio frequency (RF) in new and valuable applications that are very
pulse. As they return to their original promising and that may be implemented in
alignment, the protons emit a faint clinical practice. There has been much interest
electromagnetic signal which is detected by a in the role of MRI in the diagnosis of
receiving RF coil. When in addition a suitable pulmonary embolism as a radiation-free

a) in patients with asthma, chronic obstructive
pulmonary disease and cystic fibrosis.
Hyperpolarized xenon-129, fluorine and
oxygen-enhanced lung MRI are methods of
gas imaging that have opened up the field of
imaging pulmonary ventilation by MRI.
Diffusion-weighted (DW) MRI is another
interesting application. This technique
provides a measurement that reflects the
random Brownian motion of water protons in
tissue. This motion causes signal loss that can
b)
be measured with the use of diffusion-
sensitive sequences and that can be
quantified by calculating the apparent
diffusion coefficient. In the chest, it has been
used successfully to differentiate between
malignant and benign lesions.
Most of these techniques remain in the
experimental domain, but it can be expected
that some of them will reach daily clinical
c) practice.
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NUCLEAR MEDICINE OF THE
LUNG
A. Palla
Cardiothoracic and Vascular Dept, University of Pisa, Pisa, Italy
E-mail: a.palla@med.unipi.it
Nuclear medicine may contribute to the cumbersome, time-consuming and poorly

diagnosis of pulmonary embolism (PE) and available. Nowadays, VLS is only indicated in
inflammatory diseases, and the diagnosis and some individual patients with PE, since similar
staging of lung cancer. Among several results can be obtained by using chest
techniques available, pulmonary perfusion radiography. A few years ago, a new
and ventilation scintigraphy (PLS and VLS, classification of perfusion defects was
respectively), gallium-67 scintigraphy and published in order to optimise its diagnostic
positron emission tomography (PET) usefulness in conjunction with chest
scintigraphy are of interest in clinical practice. radiography; such a method has made it
possible to obtain a diagnostic accuracy
Diagnosis of PE
similar to that shown by angio-computed
Thanks to its noninvasiveness, safety and low tomography (CT). PLS also plays a leading role
cost, PLS still remains the cornerstone of the in the follow-up of patients with PE, as it helps
diagnosis and follow-up of PE. to monitor the efficacy of treatment in the
first days, it allows promptly detection of early
Perfusion lung scintigraphy has been proven and late recurrences and evolution towards
to be useful for: pulmonary hypertension, and it may
N diagnosis of PE
Key points
N detection of recurrences under treatment or
after its discontinuation N Nuclear medicine of the lung has a role
N differential diagnosis between in the diagnosis of pulmonary
thromboembolic and nonthromboembolic embolism and inflammatory diseases,
pulmonary hypertension and in the diagnosis and staging of
lung cancer.
Two main scintigraphic criteria must be
considered for the diagnosis: 1) identification
N Perfusion scintigraphy is key in the
of perfusion defects corresponding to one or diagnosis and follow-up of pulmonary
more pulmonary segments and 2) diversion of embolism as it is safe, cheap and
pulmonary blood flow from lower and noninvasive.
posterior lung regions. Perfusion defects N Gallium-67 scintigraphy is useful in
typically are multiple, wedge-shaped and identifying and localising intrathoracic
often bilateral. PLS has a sensitivity of 100% inflammation and infection.
in that it allows exclusion with certainty when
the diagnosis is negative. The specificity varies N FDG PET and PET/CT are used in
in different reported series, but on average diagnosis, treatment targeting and
does not reach acceptable values; to increase treatment in lung cancer.
the specificity, VLS has been introduced, but is
Nuclear medicine of the lung 135

differentiate between thromboembolic glucose analogue, whose tissue concentration
pulmonary hypertension and other types of is directly related to the glucose metabolism.
pulmonary hypertension. The uptake of FDG may be evaluated by a
semiquantitative measurement, the
Diagnosis of inflammatory diseases standardised uptake value (SUV), i.e. the
Gallium-67 citrate is the most widely ratio between the amount of tracer in a
employed positive tracer in order to identify specific area and the same amount potentially
and localise intrathoracic inflammations and present if the tracer had been evenly
infections. To acquire images, a scintillation distributed in the body.
gamma-camera with a low energy collimator is FDG PET is proven useful in:
required. Gallium scintigraphy may help in
evaluating the activity of granulomatous N diagnosing and staging lung cancer
disorders and the efficacy of steroid
treatment. In patients with sarcoidosis, it
N monitoring the efficacy of treatment
shows a high diagnostic sensitivity; in some N defining the biological target volume for
cases, the presence of highly specific signs, radiation treatment planning
such as panda or lambda signs, allows
avoidance of invasive diagnostic tests. An indication of increasing clinical relevance
Moreover, this tracer may differentiate of FDG PET and PET/CT is the differentiation
between sarcoidosis and non-Hodgkins of benign from malignant solitary pulmonary
lymphoma, and detect multiple nodules by replacing invasive modalities of
extrapulmonary sites of sarcoidosis. Also, investigation. A SUV of 2.5 has been reported
gallium scintigraphy is indicated in as a guideline for the cut-off between benign
investigating metabolic activity in pulmonary (SUV ,2.5) and malignant (SUV .2.5)
infections and the efficacy of proper therapy. lesions. A meta-analysis from 40 studies
In the diagnosis of pulmonary tuberculosis, showed a sensitivity of 97% but a lower
gallium scintigraphy may indicate the specificity (78%) due to FDG uptake within
necessity of a bronchoalveolar lavage and the inflammatory/granulomatous lesions.
site where it should be performed. This occurs However, a high rate of false-negative FDG
mostly in cases of suspected re-infection of results can occur when nodules are ,1 cm
areas of pleuroparenchymal fibrosis, in cases (sensitivity of 69% for nodules of 58 mm).
of suspicion where sputum is repeatedly Moreover, some histotypes, such as
negative, and in immunocompromised bronchoalveolar carcinomas and well-
patients. Finally, gallium scintigraphy may be differentiated neuroendocrine tumours,
of value in the evaluation of efficacy of usually present a low glucose metabolic
chemotherapy in lymphomatous diseases and activity and cannot be correctly depicted by
may help differentiate post-attinic fibrosis FDG imaging.
from residual tumour foci when a lung density FDG PET is also a standard modality for
persists after radiotherapy. staging nonsmall cell lung cancer. Several
Diagnosis of lung cancer studies have demonstrated that PET is more
accurate than CT in the staging of
PET is a nuclear medicine technique that mediastinum (N state). Due to its high
produces a three-dimensional imaging of negative predicted value, invasive staging
functional and biochemical processes within procedures (mediastinoscopy) can be omitted
the body. Recently, PET has been combined in patients with a negative FDG PET for
with CT (PET/CT) (fig. 1); such fusion mediastinal lymph node involvement. On the
generally improves diagnostic accuracy by contrary, a positive finding should not
upgrading specificity when compared with preclude mediastinoscopy. Moreover, the
PET alone. The most frequently used tracer is addition of FDG PET to the standard work-up
2-[18F]-fluoro-2-deoxy-D-glucose (FDG), a can prevent useless thoracotomies and

a) b) c)
Figure 1. Solitary pulmonary nodule as it appears on a) chest computed tomography (CT), c) 2-fluoro-2-deoxy-
D-glucose positron emission tomography (PET), and b) a combination of CT and PET.
change therapeutic approach in a significant PET/CT is useful in differentiating benign from

percentage of patients. PET is useful in malignant pulmonary nodules. Ann Thorac Surg
disclosing distant metastases (M state) with a 2006; 82: 10161020.
high sensitivity and specificity. However, PET N De Geus-Oei LF, et al. Predictive and prognostic
value of FDG-PET in nonsmall-cell lung cancer: a
cannot replace CT or magnetic resonance
systematic review. Cancer 2007; 110: 16541664.
imaging for detecting brain metastases. N Kita T, et al. Clinical significance of the serum IL-
Moreover, the measurement of FDG SUV 2R level and Ga-67 scan findings in making a
within the tumour correlates negatively with differential diagnosis between sarcoidosis and
patient prognosis; early changes of FDG SUV non-Hodgkins lymphoma. Ann Nucl Med 2007;
during radiotherapy and chemotherapy can 21: 499503.
predict therapy efficacy; and PET is more N Liu SF, et al. Monitoring treatment responses in
accurate than contrast-enhanced CT for patients with pulmonary TB using serial lung
detecting residual tumour after radiotherapy gallium-67 scintigraphy. Am J Roentgenol 2007;
188: 403408.
and chemotherapy.
N Miniati M, et al. Perfusion lung scintigraphy for the
A recent indication of PET/CT is the definition diagnosis of pulmonary embolism: a reappraisal
of the biological target volume for radiation and review of the prospective investigative study
treatment planning. This approach has the of pulmonary embolism diagnosis methods. Semin
Nucl Med 2008; 38: 450461.
goal of increasing the dose to the tumour and
focusing the treatment planning to the
N Sostman HD, et al. Sensitivity and specificity of
perfusion scintigraphy combined with chest
biological target, which reveals an elevated radiography for acute pulmonary embolism in
glucose metabolism. PIOPED II. J Nucl Med 2008; 49: 17411748.
Thanks to D. Volterrani, Nuclear Medicine, N Stein PD, et al. Multidetector computed
tomography for acute pulmonary embolism. N
University of Pisa, Pisa, Italy, for active Engl J Med 2006; 354: 23172327.
assistance. N Van Tinteren H, et al. Effectiveness of positron
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Nuclear medicine of the lung 137

TRANSTHORACIC
ULTRASOUND
F. von Groote-Bidlingmaier, C.F.N. Koegelenberg and C.T. Bolliger
Division of Pulmonology, University of Stellenbosch, South Africa
E-mail: florianv@sun.ac.za
Transthoracic ultrasonography can be Movement of the lung with the respiratory

performed with the most basic ultrasound cycle in relation to the chest wall on real-time
(US) equipment. It is used for the US is called the lung sliding sign. Its
investigation of chest wall abnormalities, presence is strong evidence against a
pleural thickening and pleural tumours, and pneumothorax.
the qualitative and quantitative description of
pleural effusions. Lung tumours, pulmonary US cannot visualise normal aerated lung
consolidations and other parenchymal tissue. The large change in acoustic
pulmonary processes abutting the pleura can impedance at the pleuralung interface,
also be visualised. Furthermore, US is ideal to however, causes horizontal artefacts that are
guide thoracentesis, drainage of effusions and seen as a series of echogenic parallel lines
other thoracic interventions. US is particularly equidistant from one another below the
useful in intensive care units where pleura. These bright but formless lines are
radiographic equipment is unavailable. known as reverberation artefacts (fig. 1).
Advantages of thoracic US include its Chest wall pathology

mobility, dynamic properties, lack of radiation
Soft-tissue masses, such as abscesses, lipomas
and low cost.
and a variety of other lesions, can be detected
The ultrasonographic appearance of the by US. These lesions are mostly benign, but
normal thorax and the most common variable echogenicity and nonspecific US
pathologies are reviewed in this chapter. findings make differentiation between various
aetiologies difficult. Supraclavicular and
General technical aspects and axillary lymph nodes are usually accessible,
appearance of the normal thorax and US may even help to distinguish benign
A low-frequency probe (e.g. 3.5 MHz) is from malignant lymph nodes. Hypoechoic
routinely used for screening purposes, while masses disrupting the normal structure of a
detailed assessment of an abnormal chest
wall or pleura can be performed with a high- Key points
frequency probe (e.g. 8 MHz).
Superficial muscles and fascia planes appear N Transthoracic US can be used to
as a series of echogenic layers during the investigate chest wall abnormalities,
initial surveillance of a normal chest. pleural thickening and pleural tumours,
Curvilinear structures on transverse scans, and to describe pleural effusions.
associated with posterior acoustic shadowing
represent the ribs.
N Advantages of the technique include its
mobility, dynamic properties, lack of
The visceral and parietal pleura normally radiation and low cost.
appear as one highly echogenic line.

a)
L
P
PE
R
Figure 1. The typical appearance of a normal chest

on ultrasound (US). A transverse view through the
intercostal space is shown. The chest wall is
visualised as multiple layers of echogenicity
representing muscles and fascia. The visceral and
b)
parietal pleura appear as an echogenic bright line
(two distinct lines sliding during respiration are
visible on real-time US). Reverberation artefacts
beneath the pleural lines imply an underlying air-
filled lung. P: pleura; L: lung; R: reverberation
artefact.
S
rib may represent bony metastases and can be

seen on US.
Pleural pathology
Transthoracic US is most commonly used to
investigate pleural effusions, and is more
sensitive than decubitus radiographs at
demonstrating minimal or loculated effusions. Figure 2. Example of an anechoic pleural effusion is
The US appearance of a pleural effusion shown in a). It presents as an echo-free space
depends on its nature and chronicity. Four between the visceral and parietal pleura.
Compressive atelectasis of the lung may be seen as
appearances based on the internal
a tongue-like structure in a large effusion. Note the
echogenicity are recognised: anechoic; difference to the effusion on b), which is classified
complex but nonseptated; complex and as complex septated. Multiple septa form many
septated; and homogenously echogenic. compartments in the same effusion. PE: pleural
Transudates are invariably anechoic, effusion; L: lung; S: septum.
unseptated and free flowing, whereas
complex, septated or echogenic effusions are
usually exudates. Malignant effusions are
Transthoracic ultrasound 139

Figure 3. A peripheral pulmonary lesion is shown schematically without (top) and with (bottom) pleural
contact. Only the lesion with pleural contact is visible on ultrasound. Reproduced from DIACON et al. (2005),
with permission from the publisher.
frequently anechoic. The atelectatic lung greater than the costophrenic angle but still
inside a large effusion may appear as a within the range of the area covered with a
tongue-like structure within the effusion. 3.5 MHz curvilinear probe; moderate, if the
Inflammatory effusions are often associated space is greater than a one-probe range but
with strands of echogenic material and within a two-probe range; and large, if the
septations that show more or less mobility space is bigger than a two-probe range.
with respiration and the cardiac cycle (fig. 2).
Both small effusions and pleural thickening
The volume of a pleural effusion can be may appear as hypoechoic on US, so
estimated using the following classification: differentiation might be difficult. An
minimal, if the echo-free space is confined to important sign in favour of an effusion is
the costophrenic angle; small, if the space is mobility on real-time US.

Non-infective causes of consolidations with
similar appearance on US include pulmonary
infarction, haemorrhage and bronchoalveolar
T P carcinoma.
A hypoechoic lesion with a well-defined or
irregular wall abutting the pleura might
represent a lung abscess. The centre of the
abscess is most often anechoic, but may
reveal septations and internal echoes.
L Conclusion
The value of US for chest physicians is firmly

established. Basic thoracic ultrasonography is
an elegant and inexpensive investigation that
Figure 4. A sonographic image showing a solid lung extends the physicians diagnostic and
lesion with posterior echo enhancement. Note that interventional potential at the bedside in
the tumour is abutting the pleura and is therefore peripheral lung, pleural, and chest wall
visible on ultrasound. P: pleura; L: lung; T: tumour.
disease.
Metastatic pleural tumours and malignant References
mesothelioma can be visualised as polypoid
pleural nodules or irregular sheet like pleural N Diacon AH, et al. Transthoracic ultrasound for
thickening. They are often associated with the pulmonologist. Curr Opin Pulm Med 2005;
11: 307312.
large pleural effusions. Benign pleural
tumours are rare.
N Evans AL, Gleeson FV. Radiology in pleural
disease: state of the art. Respirology 2004; 9:
QURESHI et al. found that pleural thickening 300312.
.1 cm, pleural nodularity and diaphragmatic N Gorg C, et al. Sonography of malignant pleural
effusion. Eur Radiol 1997; 7: 11951198.
thickening .7 mm were highly suggestive of
malignant disease. In their study, US correctly
N Herth FJ, et al. Diagnosis of pneumothorax by
means of transthoracic ultrasound: a prospective
identified 73% of malignant effusions. trial. Eur Respir J 2004; 24: S491.
The absence of normal lung sliding, the loss of N Hirsch JH, et al. Real-time sonography of pleural
comet-tail artefacts and exaggerated opacities. Am J Roentgenol 1981; 136: 297301.
horizontal reverberation artefacts are reliable N Kocijancic I, et al. Imaging of pleural fluid in
healthy individuals: Clin Radiol 2004; 59:
signs for the presence of a pneumothorax.
826829.
Pulmonary pathology N Koegelenberg CF, et al. Pleural Ultrasound. In:
Light RW, Lee YC, eds. Textbook of Pleural
A lung tumour abutting the pleura will be Disease, 2nd Edn. London, Hodder & Stoughton,
detectable by US (fig. 3). In most cases these 2008; pp. 27128.
tumours present as a hypoechoic mass with N Koh DM, et al. Transthoracic US of the chest:
posterior acoustic enhancement (fig. 4). clinical uses and applications. Radiographics
2002; 22: e1.
Visceral pleura or chest wall involvement is N Lichtenstein DA, Menu Y. A bedside ultrasound
important for staging of malignant lung sign ruling out pneumothorax in the critically ill.
tumours. Loss of movement of a visualised Chest 1995; 108: 13451348.
tumour with respiration suggests infiltration N Mathis G. Thoraxsonography part I: chest wall
beyond the parietal pleura. and pleura. Ultrasound Med Biol 1997; 23:
11311139.
US can detect pneumonic consolidations N Mayo PH, Doelken P. Pleural ultrasonography.
provided they have contact with the pleura. Clin Chest Med 2006; 27: 215217.
Transthoracic ultrasound 141

N Qureshi NR, et al. Thoracic ultrasound in the N Yang PC, et al. Value of sonography in determining
diagnosis of malignant pleural effusion. Thorax the nature of pleural effusion: analysis of 320
2009; 64: 139143. cases. Am J Roentgenol 1992; 159: 2933.
N Tsai TH, Yang PC. Ultrasound in the diagnosis N Yang PC. Ultrasound-guided transthoracic biopsy
and management of pleural disease. Curr Opin of peripheral lung, pleural, and chest wall
Pulm Med 2003; 9: 282290. lesions. J Thorac Imaging 1997; 12: 272284.

CHAPTER 6:
lung injuRy And
RESPiRAToRy fAiluRE
lung injuRy 146

B. Schnhofer
RESPiRAToRy fAiluRE 148

oxygEn THERAPy And vEnTilAToRy SuPPoRT 151

A.K. Simonds
inTEnSivE CARE And HigH-dEPEndEnCy uniT 154

S. Nava and P. Navalesi
ASSESSmEnT foR AnAESTHESiA/SuRgERy 156

M.M. Schuurmans, C.T. Bolliger and A. Boehler

LUNG INJURY
nhofer
B. Scho
Abteilung fur Pneumologie und Internistische Intensivmedizin,
Krankenhaus Oststadt-Heidehaus, Klinikum Region Hannover, Hanover,
Germany
E-mail: Bernd.Schoenhofer@t-online.de
Acute lung injury (ALI) and its most severe ventricular function if the invasive
manifestation, the acute respiratory distress measurement is unavailable.
syndrome (ARDS), are defined by
These criteria should be re-evaluated after
physiological (i.e. ratio of arterial oxyen
24 h, since their persistence is essential for
tension (Pa,O2) to inspiratory oxygen fraction the correct diagnosis of ALI/ARDS.
(FIO2) f300 mmHg for ALI and Furthermore, timing may be of influence on
f200 mmHg for ARDS, independent of the development of ALI/ARDS.
positive end-expiratory pressure) and bilateral
pulmonary infiltrates as radiological criteria. Lung oedema may evaluated by computed
tomography or other established methods.
Cardiac failure must be excluded based either
on pulmonary artery wedge pressure ALI/ARDS may be caused by various
(,18 mmHg) or on clinical evaluation of left aetiologies: direct lung injury, e.g. pneumonia,
aspiration, toxic inhalation, near drowning or
lung contusion; or indirect lung injury e.g.
Key points sepsis, burn, pancreatitis or massive blood
transfusion. The two aetiologies may coexist.
N ALI and its most severe manifestation The exact incidence of ALI/ARDS is not
ARDS are defined as Pa,O2/Fi,O2 known; its annual mortality rate has been
f300 mmHg and f200 mmHg, estimated to be .30,000 patients per year in
respectively, in addition to bilateral the USA. Despite recent advances in the
infiltrates as radiological criteria. understanding of the pathophysiology of
N Principles of protective ventilator ARDS, improvements in supportive care, and
multiple therapeutic efforts directed at
settings for patients with ALI/ARDS are
modifying the course of the condition,
low tidal volume (i.e. VT 5 6 mL?kg-1
mortality rates are persistently 3540%.
ideal body weight, plateau pressure
,30 cmH2O and peak pressure The pathophysiology of ALI/ARDS is related to
,35 cm H2O. altered pulmonary capillary permeability and
increased intrapulmonary shunt, which is
N Permissive hypercapnia may be helpful associated with impaired gas exchange. ARDS
to realise protective mechanical has been divided into three stages in which
ventilation. an initial inflammatory phase (exudative) is
N Protection of the lungs may also be followed by fibro-proliferation, which can lead
provided by the pump-driven to established interstitial and intra-alveolar
veno-venous extracorporeal membrane fibrosis, the final phase.
oxygenation (ECMO) or pumpless extra Mechanical ventilation itself can seriously
corporeal lung assist (ILA). damage lung parenchyma (ventilator-induced
lung injury). ALI/ARDS often has systematic

manifestations, triggering systemic inflammatory Protection of the lungs may also be provided
response syndrome (SIRS), or in extremis multiple by pump-driven veno-venous extracorporeal
organ dysfunction syndrome (MODS). membrane oxygenation, which improves both
oxygenation and carbon dioxide removal,
In general the spectrum of treatment ALI/ARDS
includes supportive care, ventilator support and either by leaving the lungs at rest (apnoeic
pharmacological treatment. The first principle oxygenation) or by using low-tidal-volume low-
of treatment is to identify potential underlying frequency ventilation. Recently, a pumpless
causes of ALI/ARDS. Furthermore, secondary extracorporeal lung assist was developed
lung injury has to be avoided, such as using arterio-venous bypass, in which a gas
aspiration, barotraumas, nosocomial infections exchange membrane is integrated
and oxygen toxicity. The main aims of (interventional lung assist (ILA)). ILA
supportive care are maintaining oxygen provides effective carbon dioxide elimination
delivery to end organs by avoiding anaemia and a moderate improvement in oxygenation.
and optimising cardiovascular function and Concerning pharmacological treatments of
body fluid balance; additionally catabolism
ALI/ARDS, inhaled nitric oxide has not been
and nutritional support have to be balanced.
found to be really effective and there is no
With regard to mechanical ventilation, the clear convincing data suggesting the
main goal is to improve oxygenation without widespread use of corticosteroids in both early
increasing the iatrogenic effects caused by and late phases of ALI/ARDS.
mechanical ventilation; there are different
methods available. Among the methods Finally, based on experimental models a series of
related to the ventilatory setting, those found molecular mechanisms offer innovative
really effective are to reduce tidal volume and opportunities for cell or gene therapy. These need
pressures and to apply positive end-expiratory to be elaborated in human studies, however.
pressure (PEEP) to reduce the amount of
nonaerated atelectatic lung. References
Principles of protective ventilator settings for N Dreyfuss D, Saumon G. Ventilator-induced lung

patients with ALI/ARDS are: injury. Lessons from experimental studies. Am J
N Tidal volume 6 mL?kg-1 ideal body weight. N Gattinoni L, Pesenti A. The concept of baby
lung. Intensive Care Med 2005; 31: 776784.
N Plateau pressure, ,30 cmH2O, peak pres-
N International consensus conference in intensive
sure ,35 cmH2O.
care medicine: ventilator-associated lung injury
N This strategy of protective mechanical in ARDS. Am J Respir Crit Care 1999; 160:
ventilation may be associated with per- 21182124.
missive hypercapnia. N Marini JJ, Gattinoni L. Ventilatory management of
acute respiratory distress syndrome - a consensus
The optimal setting of PEEP is not clear, of two. Crit Care Med, 2004; 32: 250255.
since several methods have been proposed N Matthay MA, Zimmerman GA. Acute lung injury
without any clear advantages over each other. and the acute respiratory distress syndrome: four
decades of inquiry into pathogenesis and
Higher PEEP (.15 cmH2O) might be
rational management. Am J Respir Cell Mol Biol
recommended in more severe ARDS patients. 2005; 33: 319327.
Prone position might be recommended in N The Acute Respiratory Distress Syndrome
more severe ARDS patients, according to the Network. Ventilation with lower tidal volumes as
expertise of the clinicians. Alternative compared with traditional tidal volumes for
methods of ventilation include include high- acute lung injury and the acute respiratory
frequency ventilation and airway pressure distress sydrome. N Engl J Med 2000; 342:
release ventilation. 13011308.
Lung injury 147

RESPIRATORY FAILURE
Cardio-Thoracic Dept, University Hospital, Pisa, Italy
E-mail: n.ambrosino@ao-pisa.toscana.it
The respiratory system consists of two parts. The to unapparent, due to mechanisms of
lung performs gas exchange, and the pump compensation of respiratory acidosis.
ventilates the lung. The pump consists of the
RF due to lung diseases (e.g. pneumonia,
chest wall, including the respiratory muscles,
acute lung injury, adult respiratory distress
the respiratory controllers in the central nervous
syndrome (ARDS), emphysema, interstitial
system (CNS) linked to respiratory muscles
lung disease) leads to hypoxaemia with
through spinal and peripheral nerves.
normocapnia or even hypocapnia (type I RF).
When respiratory failure (RF) ensues, the
Four pathophysiological mechanisms are
respiratory system fails in one or both of its
responsible for hypoxaemic RF:
gas exchange functions, i.e. oxygenation of
mixed venous blood and/or elimination of N ventilation/perfusion (V9/Q9) ratio inequalities
carbon dioxide (CO2) (fig. 1).
N shunt
The diagnosis of RF is not clinical but based
on arterial gas assessment: RF is defined by an N diffusion impairment
arterial oxygen tension (Pa,O2) ,60 mmHg N hypoventilation
and/or arterial CO2 tension (Pa,CO2)
.45 mmHg. These values are not rigid; they Hypoxaemia with hypoventilation is
must serve as a general guide in combination characterised by normal alveolararterial
with the history and clinical evaluation. RF oxygen difference, whereas disorders due to any
may be acute, chronic, or acute on chronic, of the other three mechanisms are characterised
with clinical presentation quite different by a widening of the alveolararterial gradient.
between the types. Abnormal desaturation of systemic venous
Acute respiratory failure (ARF) may be life- blood in the face of extensive lung disease is
threatening in clinical presentation, arterial an important mechanism of hypoxaemia.
blood gases and acidbase status; chronic Several non-chronic obstructive pulmonary
respiratory failure (CRF) is clinically indolent disease (COPD) diseases may lead to
hypoxaemic ARF, which is defined as a Pa,O2
Key points to oxygen inspiratory fraction (FI,O2) ratio
f300 (table 1).
N Respiratory failure is failure of one or Hypoxaemia is treated with an increase in
both of the respiratory systems gas FI,O2 (the lower the V9/Q9, the less the effect),
exchange functions. and by recruiting airspaces with assisted
N It is diagnosed by arterial blood gas ventilation. Airspace derecruitment occurs
assessment. when the transpulmonary pressure falls below
the airspace collapsing or closing pressure,
N The clinical presentations of acute, and when the transpulmonary pressure applied
chronic, and acute on chronic during inspiration fails to exceed airspace
respiratory failure can differ greatly. opening pressure. Accordingly, airspace
opening can be facilitated by increasing the

Respiratory failure Acute exacerbations of COPD (AECOPD) are
periods of acute worsening which greatly
affect the health status of patients with an
Lung failure Pump failure increase in hospital admission and mortality.
Estimates of in-patient mortality range
Gas exchange Ventilatory failure 430%, but patients admitted due to ARF
failure manifested manifested as experience a higher rate, in particular elderly
as hypoxaemia hypercapnia patients with comorbidities (up to 50%) and
those requiring intensive care unit admission
Figure 1. Types of respiratory failure. The respiratory (1126%).
system can be considered as consisting of two parts:
the lung and the pump. Reproduced from ROUSSOS Many causes may potentially be involved in
and KOUTSOUKOU (2003). determining ARF during AECOPD, such as
bronchial infections, bronchospasm, left
transpulmonary pressure applied at end ventricular failure, pneumonia, pneumothorax
expiration (continuous positive airway pressure and thromboembolism. Acute on chronic RF
(CPAP) or positive end-expiratory pressure due to AECOPD is characterised by the
(PEEP)) and at end inspiration (i.e. inspiratory worsening of hypoxaemia and a variable
positive airway pressure). degree of hypercapnia and respiratory
acidosis. The capacity of the patient to
Failure of the pump (e.g. neuromuscular
maintain acceptable indices of gas exchange
diseases, opiate overdose) results in alveolar
during an AECOPD or the development of
hypoventilation and hypercapnia with parallel ARF depends both on the severity of the
hypoxaemia (type II RF). precipitating cause and on the degree of
In some diseases (e.g. COPD, cardiogenic physiological dysfunction during the stable
pulmonary oedema), both conditions may state and the subsequent physiological
coexist, hypoxaemia usually appearing first. reserve. Worsening in V9/Q9 mismatching is
probably the leading mechanism in the
Hypercapnic RF may be the result of CNS occurrence of the hypoxaemia by the
depression, functional or mechanical defect of enlargement of physiological dead space and
the chest wall, imbalance of energy demands the rise of wasted ventilation. The increase in
and supplies of the respiratory muscles, and/ airway resistance and the need for a higher
or adaptation of central controllers in order to minute ventilation may result in expiratory
prevent respiratory muscle injury and avoid or flow limitation, dynamic hyperinflation and
postpone fatigue (table 2). Hypercapnic RF related intrinsic PEEP (PEEPi) with subsequent
may occur either acutely, insidiously, or increased inspiratory threshold load and
acutely upon a chronic CO2 retention. In all of dysfunction of the respiratory muscles, which
these conditions, the pathophysiological, may lead to their fatigue. A rapid shallow
common mechanism is reduced alveolar breathing pattern may ensue in attempting to
ventilation for a given CO2 production. maintain adequate alveolar ventilation (VA)
when these additional resistive, elastic and
Table 1. Most common causes of acute hypoxaemic inspiratory threshold loads are imposed on
respiratory failure weakened respiratory muscles. Nevertheless,
despite increased stimulation of the
Cardiogenic pulmonary oedema
respiratory centres, and large negative
Acute respiratory distress syndrome and acute intrathoracic pressure swings, CO2 retention
lung injury
and acidaemia may occur. Dyspnoea, right
Alveolar haemorrhage ventricular failure, and encephalopathy
Lobar pneumonia characterise severe AECOPD complicated by
Atelectasis ARF. Arterial pH reflects the acute worsening
of VA and, regardless of the chronic Pa,CO2
Respiratory failure 149

Table 2. Causes of acute hypercapnia Airway infection
Decreased central drive
Drugs ttot, ti and te Raw and EL,dyn
CNS diseases Expiratory flow
limitation
Altered neural and neuromuscular
transmission Hyperinflation Work of breathing
Spinal cord trauma
Myelitis O2 cost of breathing
PEEPi
Tetanus
Amyotrophic lateral sclerosis Effectiveness of
Poliomyelitis respiratory Respiratory muscle
GuillanBarre` muscles fatigue
Myasthenia gravis Control of breathing Mechanics
Organophosphate poisoning
Botulism Figure 2. Schematic representation of the sequence
Muscle abnormalities of responsible mechanisms that lead to acute-on-
Muscular dystrophies chronic respiratory failure in chronic obstructive
Disuse atrophy pulmonary disease patients. ttot: total respiratory
Prematurity cycle; tI: inspiratory time; te: expiratory time; Raw:
airway resistance; EL,dyn: dynamic elastance of the
Chest wall and pleural abnormalities
lung; PEEPi: intrinsic positive end-expiratory
Acute hyperinflation
pressure; Q: decrease; q: increase. Reproduced
Chest wall trauma
from ROUSSOS and KOUTSOUKOU (2003).
Lung and airway diseases
Acute asthma
Acute exacerbation of COPD
References
Cardiogenic and noncardiogenic pulmonary N Ambrosino N, et al. Advanced chronic
oedema obstructive pulmonary disease. Monaldi Arch
Pneumonia Chest Dis 1997; 52: 574578.
Upper airway obstruction N Ambrosino N, Vagheggini G. Noninvasive positive
Bronchiectasis pressure ventilation in the acute care setting:
Other causes where are we? Eur Respir J 2008; 31: 874886.
Sepsis N Calverley PMA. Respiratory failure in chronic
Circulatory shock obstructive pulmonary disease. Eur Respir J
2003; 22: Suppl. 47, 26s30s.
N Donaldson GC, Wedzicha JA. COPD exacerbations
1: epidemiology. Thorax 2006; 61: 164168.
level, it represents the best marker of the ARF N Koutsoukou A, Roussos C. Acute and chronic
severity. Figure 2 shows a schematic respiratory failure: pathophysiology and
representation of the sequence of responsible mechanics. In: Fein AM, Kamholz S, Ost D, eds.
mechanisms that lead to acute-on-chronic Respiratory Emergencies. London, Hodder
respiratory failure in COPD patients. Arnold, 2006; pp. 1730.
N Patil SP, et al. In-hospital mortality following
Besides medical treatment of the underlying acute exacerbations of chronic obstructive
disease, oxygen supplementation and pulmonary disease. Arch Intern Med 2003; 163:
eventually ventilator assistance is appropriate 11801186.
therapy for acute on chronic respiratory N Plant PK, Elliott MW. Chronic obstructive
pulmonary disease 9: management of ventilatory
failure. The goals of assisted ventilation
failure in COPD. Thorax 2003; 58: 537542.
(either invasive or noninvasive) during N Rossi A, et al. Intrinsic positive end-expiratory
AECOPD, is to unload the respiratory muscles pressure (PEEPi). Intensive Care Med 1995; 21:
and to reduce CO2 by increasing VA , thereby 522536.
stabilising arterial pH until the underlying N Roussos C, Koutsoukou A. Respiratory failure.
problem can be reversed. Eur Respir J 2003; 22: Suppl. 47, 3s14s.

OXYGEN THERAPY AND
VENTILATORY SUPPORT
A.K. Simonds
E-mail: A.Simonds@rbht.nhs.uk
Acute oxygen therapy delivered by a high concentration reservoir

mask at a flow rate of 15 L?min-1. In
Oxygen therapy is prescribed to correct hypercapnic patients, 28% and 24% Venturi
hypoxaemia, rather than to reduce masks can be used. All acute patients require
breathlessness, and so should always be regular or continuous assessment by oximetry
titrated to arterial saturation (Sa,O2) or blood to ensure hypoxaemia has been corrected and
gas measurements. In acutely ill patients, dose is still appropriate. Blood gas
high-concentration oxygen therapy should be measurements are indicated if there is
delivered to correct Sa,O2 to 9498%. In those deterioration in Sa,O2, features of CO2
with hypercapnic respiratory failure or at risk retention, such as drowsiness or flap, metabolic
of ventilatory decompensation (e.g. severe conditions or low cardiac output state.
chronic obstructive pulmonary disease
(COPD), neuromuscular disease, obesity Long-term oxygen therapy (LTOT)
hypoventilation syndrome, chest wall
disorder), a target Sa,O2 of 8892% should be Chronic hypoxaemia occurs either due to
the aim. If this cannot be achieved without ventilationperfusion mismatch, alveolar
progressive acidosis and hypercapnia, hypoventilation or diffusion problems in
ventilatory support should be added. In chronic lung disease, and in some conditions,
emergency situations, oxygen therapy can be e.g. COPD, all factors may be present. LTOT is
used to correct hypoxaemia diurnally and
nocturnally in the majority of patients. It has
Key points an additional use to palliate symptoms in
those with end-stage or terminal conditions. In
N Oxygen therapy is prescribed to correct COPD, LTOT increases survival, reduces
hypoxaemia and should thus be titrated polycythaemia and, in some patients, may
to arterial oxygen saturation. improve sleep quality and/or neuropsychiatric
N Long-term oxygen therapy can also symptoms. LTOT is prescribed for .15 h a
palliate symptoms in patients with end- day, e.g. via concentrator, to correct Sa,O2 to
o90% in those listed in table 1.
stage or terminal disease.
N NIV is the gold standard in treating Ambulatory O2 therapy is added to correct
acute hypercapnic COPD exacerbations, hypoxaemia on exercise. In sedentary patients
but is not useful in all acute respiratory using LTOT, ambulatory O2 is usually
situations. prescribed at the same flow rate as daytime
use. In active and mobile LTOT recipients and
N Long-term NIV home care can be more patients who desaturate on exertion but do
useful than oxygen therapy in chest not fulfil criteria for LTOT, optimum flow rates
wall and neuromuscular conditions. can be derived from a standard 6-min or
shuttle walk, again aiming to correct Sa,O2 to
Oxygen therapy and ventilatory support 151

Table 1. Criteria for long-term oxygen therapy minimal deadspace is also important to
success rates.
Chronic arterial oxygen tension (Pa,O2) f7.3 kPa
Pa,O2 7.38.0 kPa if additional pulmonary Home ventilatory support
hypertension, secondary polycythaemia, right
heart failure or nocturnal desaturation The evidence supporting long-term home NIV is
not as secure as acute NIV use in COPD
exacerbations but does have a longer track
.90%. There is no evidence to support the record in restrictive disorders. Long-term NIV is
use of short-burst O2 therapy. more effective than LTOT in patients with chest
Acute ventilatory support wall disease, and is the treatment of choice in
neuromuscular patients, e.g. those with
The term respiratory support embraces amyotrophic lateral sclerosis (ALS)/motor
invasive ventilation (via endotracheal tube or neurone disease with mild-to-moderate bulbar
tracheostomy), noninvasive positive pressure involvement and Duchenne muscular dystrophy,
ventilation (delivered through oronasal, nasal, where NIV use extends life expectancy. O2 use
oral or helmet interfaces), noninvasive in neuromuscular disease may exacerbate
negative pressure ventilation using an iron hypercapnia and should not be used without
lung or cuirass-type device and continuous close monitoring. Nocturnal NIV should be
positive airway pressure (CPAP). CPAP does initiated in patients with symptomatic nocturnal
not augment minute ventilation greatly, and hypoventilation, or daytime hypercapnia.
is therefore insufficient to control arterial
Home ventilation in COPD patients is more
carbon dioxide tension (Pa,CO2) in markedly
controversial. Several randomised studies of
hypercapnic patients.
LTOT versus LTOT plus NIV have been
On respiratory and high-dependency wards, performed but few had the power to examine
noninvasive positive pressure ventilation (NIV) survival and, in some, quality of life impact
is now gold standard therapy in managing seems variable. There is some evidence that
acute hypercapnic exacerbations of COPD as NIV in severe COPD may reduce ICU
it has been shown to reduce mortality by admissions and hospital admissions in COPD
about half and to decrease the need for patients with recurrent hospitalisations for
intubation and invasive ventilation, thereby hypercapnic exacerbations, although larger
reducing pressure on intensive care unit (ICU) studies are required.
beds. NIV can also facilitate weaning and
reduce the need for re-intubation. However, in Tracheostomy ventilation is required in
patients with acute lung injury, more than two patients with severe bulbar weakness,
system failures, and moderate or severe aspiration and in those in whom ventilatory
bulbar problems, NIV is unlikely to be failure cannot be controlled with NIV.
successful. In those with poor cough References
efficiency, e.g. due to neuromuscular disease,
NIV can be combined with cough-assist N British Thoracic Society, Guideline for emergency
oxygen use in adult patients. Thorax 2008; 63:
devices such as the cough inexsufflator.
Suppl. 6, vi1vi68.
There is no evidence that one type of N Domiciliary oxygen therapy services: Royal
noninvasive ventilator is superior, but bilevel College of Physicians Report. London, Royal
College of Physicians, 1999.
pressure support models are most commonly
used, often starting at initial settings of
N Elliott MW. Non-invasive ventilation in acute
exacerbations of chronic obstructive lung
inspiratory positive airway pressure disease. In: Simonds AK, ed. Non-Invasive
1012 cmH2O and expiratory positive airway Respiratory Support: A Practical Handbook.
pressure 4 cmH2O, increasing according to London, Hodder Arnold, 2007; pp. 3956.
comfort and arterial blood gas control. A N Medical Research Council Working Party Report.
close-fitting, comfortable mask/interface with Long term domiciliary oxygen therapy in chronic

hypoxic cor pulmonale complicating chronic Weblinks
bronchitis and emphysema. Lancet 1981; i:
681685. N Emergency O2: http://www.brit-thoracic.org.uk/
N Nocturnal Oxygen Therapy Trial Group. ClinicalInformation/EmergencyOxygen/tabid/
Continuous or nocturnal oxygen therapy in 219/Default.aspx.
hypoxaemic chronic obstructive lung disease, a N Non-invasive ventilation: http://www.rcplondon.
clinical trial. Ann Intern Med 1980; 93: 391398. ac.uk/pubs/brochure.aspx?e5258.
Oxygen therapy and ventilatory support 153

INTENSIVE CARE AND
HIGH-DEPENDENCY UNIT
S. Nava1 and P. Navalesi2
1
Respiratory Intensive Care Unit, Fondazione S. Maugeri, Istituto
Scientifico di Pavia, Pavia
2
Intensive Care Unit SCDU Anestesia, Terapia Intensiva e Rianimazione
Generale Eastern Piedmont University A. Avogadro University Hospital,
Maggiore della Carita `, Novara, Italy
E-mail: snava@fsm.it
The respiratory intensive care unit (RICU), and 3) requirement of intensive monitoring
sometimes referred to as the high dependency (preferably noninvasive).
unit, is intended for patients with respiratory
failure who do not require full ICU care but are The main expectations from a RICU are the
considered to need more care than can usually possibility to relieve congestion of ICU beds,
be offered in a general ward. to guarantee a high level of nursing
assistance, to adequately respond to potential
The main reasons for admission to RICU are: sudden changes in a patients clinical
1) acute respiratory failure requiring condition and, under certain conditions, to
noninvasive mechanical ventilation (NIV); 2) provide a multidisciplinary rehabilitative
weaning of patients considered ventilator- approach to patients of high complexity.
dependent, and eventually their discharge
home with a long-term ventilatory programme; The European Respiratory Society Task Force
on RICU has defined three levels of care: 1)
RICU, capable of applying both NIV and
Key points invasive ventilation, with a high nursepatient
ratio (.1:3) and an attending physician
N The main reasons for admission to 24 h?day-1, 7 days?week-1; 2) respiratory
RICU are use of acute NIV, weaning intermediate care unit, capable of applying
from mechanical ventilation and both NIV and invasive ventilation, with a
requirement of intensive monitoring. nursepatient ratio of 1:31:4 and the
availability of a physician 24 h?day-1,
N RICUs have three levels of care: 1)
7 days?week-1; and 3) respiratory monitoring
RICU, 2) respiratory intermediate care
unit with a nursepatient ratio ,1:4, a
unit, and 3) respiratory monitoring unit. physician on call within the hospital and the
N The approach to the patients admitted possibility of applying NIV.
to a RICU is usually multidisciplinary.
These facilities may be located inside or
N All the diagnostic (e.g., CT scans, NMR outside a so-called acute care hospital. It
imaging) and therapeutic (e.g. major should be borne in mind, however, that access
surgery) options should be readily to these different environments may differ
available. internationally or even regionally within the
same country.
N RICUs should provide a fair amount of
physical and pulmonary rehabilitation. Concerning the admission criteria, these are
pretty well established for those patients who

require acute application of NIV. As treatment in case of worsening. Furthermore, in
opposed to NIV application in the ward, the a subset of patients discharged from the ICU
closely monitored setting permits safe without the need for mechanical ventilation,
application of NIV also in tenuous patients. but still having a tracheotomic tube in place,
Noninvasive management of such patients, an associated increased mortality has been
including those with severe acute respiratory shown. An intermediate step in a protected
acidosis (i.e. pH ,7.30) secondary to environment after ICU discharge may be useful
exacerbation of chronic obstructive pulmonary in these patients, primarily to allow better
disease and those with hypoxaemia (i.e. management of artificial airways.
arterial oxygen tension to inspiratory oxygen
The approach to the patients admitted to a
fraction ratio ,200) requires a skilled,
RICU is usually multidisciplinary, in all cases
experienced staff and preparedness to
involving physicians, respiratory therapists
promptly intubate the patient who
and nurses, and, in some cases, also involving
deteriorates despite NIV. Delays in intubation
dieticians, psychologists, physical and speech
and application of invasive ventilation may
therapists, and social workers, as needed.
harm the patient. Theoretically, the worse the
derangement in arterial blood gases, the All the diagnostic (e.g. computed tomography
higher the level of care should be (i.e. RICU (CT) scans, nuclear magneic resonance (NMR)
versus respiratory monitoring unit). imaging) and therapeutic (e.g. major surgery)
There is still disagreement about the options should be readily available. Because
definition of a ventilator-dependent patient, in most of the units are located within an acute
whom the transfer from the ICU to RICU may care hospital, this is a problem in most cases.
be useful in an attempt to ameliorate the Furthermore, these units should be able to
chances of weaning. Various authors have allow a reasonable level of privacy, to favour
used times limits as short as 4872 h and as rest and permit, compared with ICUs, longer
long as 30 days. Realistically, ,20% of visiting hours for relatives and friends. Last
patients in an ICU require mechanical but not least, these units should provide a fair
ventilation for more than a week, and about amount of physical and pulmonary
half are successfully weaned over the following rehabilitation, which has been shown to help
few days. Therefore, a limit of 2 weeks has in freeing patients from mechanical
been chosen by most authors to define the ventilation and restoring them to an
threshold for ventilator-dependency. acceptable level of autonomy.
A definition, however, based only on time References

does not consider that for a particular patient N European Respiratory Task Force on epidemiology
to be regarded as ventilator-dependent (and, of respiratory intermediate care in Europe,
therefore, eligible for transfer to a RICU), the Respiratory intermediate care units: a European
precipitating cause of the respiratory failure survey. Eur Respir J 2002; 20: 13431350.
must have been reversed. N Ambrosino N, Vagheggini G. Noninvasive positive
pressure ventilation in the acute care setting:
Some patients affected by an acute respiratory where are we? Eur Respir J 2008; 31: 874886.
disorder may not fit the criteria of enrolment N Engoren M, et al. Hospital and long-term
for mechanical ventilation when admitted to outcome after tracheostomy for respiratory
the hospital. However, their fragility and, very failure. Chest 2004; 125: 220227.
often, the high number of comorbidities do not N Gosselink R, et al. Physiotherapy for adult
patients with critical illness: recommendations of
allow the clinicians to make any firm statement
the European Respiratory Society and European
about the immediate prognosis and risk of Society of Intensive Care Medicine Task Force on
progression towards overt respiratory failure. Physiotherapy for Critically Ill Patients. Intensive
These patients are likely to benefit from closer Care Med 2008; 34: 11881199.
monitoring in a specialised environment, to N Nava S, et al. Time of non-invasive ventilation.
avoid a delay in applying the appropriate Intensive Care Med 2006; 32: 361370.
Intensive care and high-dependency unit 155

ASSESSMENT FOR
ANAESTHESIA/SURGERY
M.M. Schuurmans1, C.T. Bolliger2 and A. Boehler1
1
University Hospital, Zurich, Switzerland
2
Tygerberg Academic Hospital, Cape Town, South Africa
E-mail: capybara@compuserve.com
Pre-operative assessment of pulmonary risk is

important in order to identify patients at risk Key points
for peri-operative morbidity and mortality, to
determine possible pre-operative interventions N A careful history and physical
that are beneficial for the outcome and to examination is necessary to assess the
identify patients where surgery may be risk of post-operative pulmonary
prohibitive. complications.
Pre-operative evaluation for lung resection N Pulmonary function testing is not

evaluates to which extent lung tissue can be routine except in the case of evaluation
resected without unacceptably increasing for lung resection.
post-operative morbidity and mortality. N A number of strategies are available to
A careful history and physical examination are reduce the risk of complications.
the most important tools for assessment of risk
for post-operative pulmonary complications.
compared with spinal or epidural
Symptoms suggesting occult underlying lung
anaesthesia); abnormal chest radiograph;
disease (exercise intolerance, unexplained
cigarette use within previous 8 weeks; and
dyspnoea and cough) and the following risk
current upper respiratory tract infection.
factors for increased post-operative pulmonary
complications need to be assessed.
It is noteworthy that pulmonary function tests
Surgery-specific risk factors include: are not part of routine pre-operative
upper abdominal procedures; aortic, thoracic, assessment unless patients are being
and head and neck surgery, including evaluated for lung resection (see Pulmonary
neurosurgery; surgery lasting .3 h; and resection) or have unexplained dyspnoea or
emergency procedures. exercise intolerance. Clinical evaluation
cannot determine whether airflow obstruction
Definite risk factors include: chronic has been optimally reduced in patients with
obstructive pulmonary disease (COPD); previously diagnosed COPD or asthma. Well-
congestive heart failure; diminished general controlled asthma (free of wheezing, peak
health status (American Society of flows .80% predicted, or personal best) has
Anesthesiologists (ASA) class .2 (table 1); been shown not to carry any added risk. Age
malnutrition (serum albumin ,35 mg?L-1); and and blood gases have no definitive role in the
use of pancuronium as a neuromuscular blocker. risk assessment when confounding issues such
as comorbidities have been considered.
Probable risk factors include: obstructive Patients with high risk (surgery-specific risk
sleep apnoea; general anaesthesia (when factor + one or more definite risk factors) will

Table 1. American Society of Anesthesiologists (ASA) classification of pre-operative risk
ASA class Systemic disturbance PPC % Mortality %
1 Healthy patient with no disease out- 1.2 ,0.03
side of the surgical process
2 Mild-to-moderate systemic disease 5.4 0.2
caused by the surgical condition or by
other pathological processes, medi-
cally well-controlled
3 Severe disease process that limits 11.4 1.2
activity but is not incapacitating
4 Severe incapacitating disease process 10.9 8
that is constant threat to life
5 Moribund patient not expected to NA 34
survive 24 h with or without an
operation
E Suffix to indicate emergency surgery Increased Increased
for any class
PPC: post-operative pulmonary complications; NA: not applicable.
benefit from strategies to reduce pulmonary Cardiac evaluation: history, physical

complications. examination and resting ECG are frequently
required for the initial estimate of the peri-
Pre-operative interventions: smoking operative cardiac risk. The definitive
cessation for 8 weeks; inhaled ipratropium or assessment of cardiac risk should respect
tiotropium for patients with clinically current guidelines for cardiologists.
significant COPD; inhaled b-agonists for
symptomatic COPD and asthma patients; pre-
operative systemic glucocorticoids for COPD Pulmonary resection
and asthma patients who are not optimised Pulmonary resection is a high-risk procedure
on inhalative treatment; delay elective surgery with a mortality of 23% for lobectomy and
if respiratory infection present; antibiotics for 46% for pneumonectomy in experienced
patients with purulent sputum or change in centres. The clinical evaluation should focus
sputum character; and inspiratory muscle on respiratory and cardiovascular pathology.
training. Air flow limitation should be optimised before
further evaluation and cardiac disease
Intraoperative interventions: choose identified and managed either medically or
alternative procedure lasting ,3 h when surgically. Initial pulmonary function
possible (video-assisted thoracoscopic and evaluation should include at least forced
laparoscopic procedures have ,1/10th the expiratory volume in 1 s (FEV1), forced vital
pulmonary complication rates of open capacity (FVC) and transfer capacity of the
procedures); minimise duration of anaesthesia; lung for carbon monoxide (TL,CO). Values
regional anaesthesia (nerve block) in very high- .80% pred for FEV1 and TL,CO are associated
risk patients; and avoid pancuronium. with an uncomplicated surgical course for
resection up to a pneumonectomy. All other
Post-operative interventions: deep- candidates should undergo a formal exercise
breathing exercises or incentive spirometry; test. Patients with a peak oxygen uptake
and epidural analgesia instead of parenteral (V9O2) .20 mL?kg-1?min-1 (or .75% pred)
opioids. tolerate pulmonary resection up to a
Assessment for anaesthesia/surgery 157

pneumonectomy, and values Cardiac
.15 mL?kg-1?min-1 are sufficient for assessment: FEV1 Both
lobectomy. Values ,10 mL?kg-1?min-1 are low risk or TL,CO >80%
treated patient
predictive of major post-operative Either one <80%
complications and disability. Further
evaluation according to a validated algorithm <35% or Exercise testing >75% or
<10 mLkg-1 Peak VO2 >20 mLkg-1
(fig. 1) necessitates the estimation of the min-1 min-1
relative contribution of the tissue earmarked 3575% or
for resection by means of the predicted post- 1020 mLkg-1min-1
operative (ppo) values for FEV1, TL,CO and V9O2
(split function). The ppo values of these Split function
ppo-FEV1 Both >30%
parameters are equal to their pre-operative ppo-TL,CO
values 6 (1 fractional contribution of the At least one <30%
tissue earmarked for resection). There are
<35% or
three acceptable ways of estimating the <10 mLkg-1 ppo-peakVO2
relative functional contribution or split lung min-1
>35% or
function: anatomical calculation; quantitative >10 mLkg-1min-1
computed tomography (CT) scanning; or split
perfusion scanning. Anatomical calculations Lobectomy or Resection up to
Resection
pneumonectomy calculated up to
are by far the simplest: the number of patent are usually not extent pneumonectomy
(or functional) segments that are due for recommended
resection is subtracted from the total number consider other
of segments (19) and this value is divided by options
19 to give a fraction. The FEV1-ppo is
estimated to be equal to the pre-operative Figure 1. Algorithm for assessment of
FEV1 6 ((19 patent segments removed)/ cardiopulmonary reserve before lung resection in
lung cancer patients. FEV1: forced expiratory volume
19). Anatomical calculations have been in 1 s; DL,CO: diffusing capacity of the lung for
shown to overestimate the functional loss so carbon monoxide; V9O2: oxygen uptake; ppo:
that patients who are deemed operable by predicted post-operative. Modified from BRUNELLI et
anatomical calculations will generally not al. (2009).
require radiological calculations.
Calculated ppo values on the basis of lung 20.6-m elevation and an uncomplicated
perfusion scans (with technetium 99m- surgical course.
labelled macroaggregates) have been shown Lung volume reduction surgery for end-stage
to correlate best with actual post-operative emphysema has partly redefined the limits of
values. Densitometric calculations on the lung resection. Many patients with pre-
basis of CT scans are marginally less accurate operative FEV1 and TL,CO between 2040%
than perfusion scans. The advantage of this pred have benefited from targeted removal of
method is the availability of the information the most emphysematous lung regions.
since most lung resection candidates
invariably have a pre-operative chest CT scan References
and modern software simplifies the three- N Bolliger CT, et al. Prediction of functional
dimensional reconstruction for the calculation reserves after lung resection: comparison
of the relative volume of lung to be resected. between quantitative computed tomography,
scintigraphy, and anatomy. Respiration 2002;
The recent revival of simple stair climbing as a 69: 482489.
low-cost alternative to assess exercise capacity N Brunelli A, et al. ERS/ESTS clinical guidelines on
and operative risk is still under investigation. fitness or radical therapy in lung cancer patients
One large study showed a significant (surgery and chemoradiotherapy). Eur Respir J
correlation between the ability to climb to a 2009; 34: 1741.

N Brunelli A, et al. Stair climbing test predicts Perioperative Cardiovascular Evaluation for
cardiopulmonary complications after lung Noncardiac Surgery). J Am Coll Cardiol 2002;
resection. Chest 2002; 121: 11061110. 39: 542.
N Eagle KA, et al. ACC/AHA guideline update for N Koegelenberg CFN, et al. Preoperative
perioperative cardiovascular evaluation for pulmonary evaluation. In: Albert RK, et al. eds.
noncardiac surgery executive summary: a Clinical Respiratory Medicine, 3rd Edn.
report of the American College of Amsterdam, Elsevier, 2008; pp. 275283.
Cardiology/American Heart Association Task N Schuurmans MM, et al. Functional evaluation
Force on Practice Guidelines (Committee to before lung resection. Clin Chest Med 2002; 23:
Update the 1996 Guidelines on 159172.
Assessment for anaesthesia/surgery 159

CHAPTER 7:
RESPiRAToRy infECTionS
miCRobiology TESTing And inTERPRETATion 162

M. Ieven
uPPER RESPiRAToRy TRACT infECTionS 168

G. Rohde
infECTivE ExACERbATionS of CoPd 172

M. Miravitlles
PnEumoniA 176
M. Woodhead
HoSPiTAl-ACQuiREd PnEumoniA 180

F. Blasi
PnEumoniA in THE immunoComPRomiSEd HoST 183

S. Ewig
PlEuRAl infECTion And lung AbSCESS 186

influEnZA, PAndEmiCS And SARS 191

W.S. Lim

MICROBIOLOGY TESTING
AND INTERPRETATION
M. Ieven
Laboratory for Microbiology, Vaccine and Infectious Disease Institute,
University of Antwerp, Wilrijk, Antwerp, Belgium
E-mail: Greet.Ieven@uza.be
In primary care, microbiological work-up in the more severely ill patients. Diagnostic
respiratory infections is primarily meant as an testing should not lead to delays in initiation
epidemiological investigation in order to of therapy, however. Even with extensive
guide future empiric antimicrobial policies. diagnostic testing, a specific aetiology is
Hardly any study has shown that initial usually identified in only half of all patients,
microbiological studies in primary care affect generally at least 12 days after the clinical
the outcome of respiratory infections. diagnosis is made. With the advent of recently
Nevertheless an aetiologic diagnosis, of both developed rapid techniques such as
bacteria and viruses and mixtures of these in immunochromatographic tests, urinary
community-acquired pneumonia (CAP) or antigen tests and particularly nucleic acid
lower respiratory tract infections (LRTI) may be amplification tests (NAATs) that produce
helpful in guiding treatment, particularly in results within 30 min or 45 h,
microbiological information is becoming
clinically useful (table 1).
Key points
Conventional culture techniques
For the aetiologic diagnosis of lower
respiratory tract infections (LRTIs): Blood culture For the diagnosis of
N Gram stain and culture of a good pneumonia, blood cultures have a very high
quality sputum can be valuable for the specificity but are positive in only about
microbiological diagnosis of LRTI 1020% of untreated cases. In some studies, a
caused by Streptococcus pneumoniae or direct correlation has been found between the
Haemophilus influenzae. severity (based on the Fine Severity Index) of
pneumonia and blood culture positivity rate.
N Urinary antigen detection is a very Two blood cultures should be obtained as early
helpful and rapid test for the diagnosis as possible in the disease and before any
of pneumococcal or Legionella antibiotic treatment is started. Blood cultures
infections. are more sensitive for the detection of
Streptococcus pneumoniae than for the
N Serology is rarely helpful in the
detection of Haemophilus influenzae. Despite
management of the individual patient
their low sensitivity, blood cultures in CAP are
with LRTI.
considered the gold standard because the
N Molecular tests for the detection of organisms are recovered from a normally sterile
respiratory viruses and atypical source. Results may be available after 2448 h.
pathogens in specific patient
populations are desirable. Sputum Gram stain and culture The most
frequently submitted specimen in cases of

Table 1. Diagnostic approach for the most common specific agents in lower respiratory tract infections
Pathogen Specimen Rapid tests Conventional Comments
tests
S. pneumoniae Blood Blood culture Positive in 1020% of cases when
collected within 4 days
Sputum Gram stain Culture Only purulent samples acceptable.
Obtained in 3540% of patients;
informative if .90% Gram-
positive, diplococci most relevant
if Gram stain informative
Pleural exu- Gram stain Culture Specific, only considered if less
dates invasive methods nondiagnostic
Urine Antigen test Sensitivity 5080% of bacteraemic
cases, lacks specificity in children,
more evaluation necessary
H. influenzae Blood Blood culture Less frequently positive than for S.
pneumoniae
Respiratory Gram stain Culture
specimens
Legionella spp. Urine Antigen test Sensitivity 6695%
Respiratory NAAT Culture Culture: on appropriate media,
specimens late results, less sensitive than
NAAT
Serum IgM and IgG Acute and convalescent specimens.
serology Retrospective diagnosis
C. pneumoniae Respiratory NAAT Culture Culture: on appropriate medium;
M. pneumoniae specimens low sensitivity compared to NAAT
Serum IgM and IgG Acute and convalescent specimens.
serology Lack of sensitivity, specificity, not
appropriate for individual patient
management. Retrospective results
Respiratory Respiratory Direct antigen Virus isolation Requirement for appropriate
viruses specimens tests, NAAT infrastructure. Isolation less
sensitive than NAAT
S. pneumoniae: Streptococcus pneumoniae; H. influenzae: Haemophilus influenzae; C. pneumoniae: Chlamydophila
pneumoniae; M. pneumoniae: Mycoplasma pneumoniae; BAL: bronchoalveolar lavage; PSB: protected specimen brush;
NAAT: nucleic acid amplification test; Ig: immunoglobulin
LRTI and more specifically in pneumonia is therefore be screened by microscopic

sputum. To be of value for microbial diagnosis examination for the relative number of
and early guidance to therapy, sputum polymorphonuclear cells and squamous
specimens must be representative of lower epithelial cells in a lower power (106) field.
respiratory secretions, and must be interpreted Invalid specimens (o10 squamous epithelial
according to strict criteria by an experienced cells and f25 polymorphonuclear cells/field)
observer. The most widely used method to should not be examined further. It may be
assess acceptability in this regard is based on difficult to obtain good-quality, purulent
cytological criteria. The specimen should sputum. Many LRTI or pneumonia patients,
Microbiology testing and interpretation 163

particularly older ones, do not produce the test could be reserved for high-risk
sputum. Satisfactory sputum specimens can patients for whom demonstrative results of a
be obtained in 3255% of patients. sputum Gram stain are unavailable.
Large studies on the diagnostic value of Gram The urinary antigen test may also be applied
staining in primary care patients are lacking, on pleural fluid with a high sensitivity and
but some hospital-based studies show that in specificity, and on serum samples with a
good-quality Gram-stained sputum, the sensitivity of 50% in bacteraemic patients
presence of a single or a preponderant and 40% in nonbacteraemic patients.
morphotype of bacteria (90%) may be Vaccination does not result in a positive
diagnostic. This is based on correspondence urinary antigen test. The immuno-
with the organisms recovered from blood chromatographic urinary antigen test for S.
cultures obtained in parallel, and which are pneumoniae is therefore useful for the
the gold standard. The sensitivity and aetiologic diagnosis of severe CAP, especially
specificity for the detection of S. pneumoniae for patients without demonstrative results of a
are ,3579% and 96%, respectively, and sputum Gram stain.
42% and 99% respectively for H. influenzae.
Sputum with a mixed flora in the Gram stain Urinary antigen detection is currently the
has no diagnostic value. The sputum Gram most helpful rapid test for the diagnosis of a
stain is therefore valuable in guiding the Legionella infection. Several test formats have
processing and interpretation of sputum been developed, the enzyme immunoassay
cultures. (EIA) format being more suited to test a larger
number of specimens and taking a few hours
The sensitivity and specificity of sputum to complete. The immunochromatographic
cultures are reduced by contamination with format is better suited for single specimens,
flora colonising the upper respiratory tract. and produces a result within minutes. These
The value of sputum cultures in establishing a tests are particularly useful since culture of
bacterial cause of LRTI depends on how the Legionella spp. is slow and takes 34 days.
specimens are collected and processed. The Legionella urinary antigen detection is
reported yield of sputum cultures has varied frequently the first positive laboratory test in
widely, from ,20% for outpatients to .90% this infection. The sensitivity of the tests varies
for hospitalised patients. The sputum Gram between 6570% in unconcentrated urine
stain is valuable in guiding the processing and increases significantly after concentration
and interpretation of sputum cultures. Sputum of the specimen. In Legionella infection, there
culture results are most convincing when the is also a relationship between the degree of
organism(s) isolated in culture are compatible positivity of the urinary antigen test and the
with the morphology of the organisms present severity of disease: for patients with mild
in the Gram stain. In the absence of an Legionnaires disease, test sensitivities range
informative Gram stain, the predictive value of from only 4050%, whereas for patients with
sputum culture is very low. severe Legionnaires disease who need
immediate special medical care, sensitivities
Rapid antigen tests
reach 88100%.
Urinary antigen tests The S. pneumoniae Antigen tests on pharyngeal
urinary antigen test in adult CAP has been specimens A variety of antigen tests have
shown to have a sensitivity of 65100% and a been evaluated on respiratory specimens. For
specificity of .90%; however, weak positive respiratory infections due to viruses, the
results should be interpreted with caution. optimal specimen is the nasopharyngeal
There is a relation between the degree of aspirate. During recent years, a considerable
S. pneumoniae urinary antigen test positivity number of previously unknown respiratory
and the pneumonia severity index. Therefore, viral agents have been discovered whose in

vitro culture is very slow or even unrealised: took place some time before the illness under
the human metapneumovirus, the novel observation started.
coronaviruses NL 63, HKU1 and human
The sensitivity and specificity of serologic tests
bocavirus. Antigens of the many common
are related to the antigen used. For
respiratory viruses, influenza virus, respiratory
M. pneumoniae and C. pneumoniae, a great
syncytial virus (RSV), adenovirus and
number of antigen preparations have been
parainfluenza viruses, can be detected by proposed: whole organisms, protein fractions,
direct immunofluorescence (DIF) or by glycoprotein fractions and recombinant
commercially available EIAs. The sensitivities antigens. Several studies illustrate a lack of
of these tests vary from 50.90% depending standardisation of antigens of
on the virus and the patient population M. pneumoniae.
studied. For the detection of influenza virus
infections, the sensitivity of immuno- For a number of respiratory agents, a variety
fluorescence can be increased by inoculation of tests are available commercially. Some
of the clinical sample on appropriate cells, assays lack both sensitivity and specificity,
followed by immunofluorescence after 48 h. emphasising the need for more validation and
Several common respiratory viruses can be quality control.
detected simultaneously by the use of pooled IgM antibodies against M. pneumoniae
monoclonal antibodies. The sensitivity of the require up to 1 week to reach diagnostic
DIF test is lower in adults and older people titres, and sometimes much longer.
than in children. Rapid methods for the Anti-M. pneumoniae IgM antibodies can be
detection of influenza virus are of particular detected in 725% (depending on the test
interest because of the availability of antiviral applied) of acute sera and IgG antibodies in
agents that must be given within 48 h after 4163% of convalescent sera depending on
onset of symptoms. the timing of the second sample illustrating
the low incidence of IgM antibodies in the
acute-phase serum specimens and importance
Serology of the delay between the two serum samples.
Legionella antibody tests also have a
Efforts have been made to diagnose infections sensitivity of only 6164% depending on the
caused by slowly growing or difficult to grow assay applied and also do not substantially
organisms by serology. This holds particularly improve the diagnosis of legionellosis. The
for Mycoplasma pneumoniae, Chlamydophila acute antibody test for Legionella in
pneumoniae, Legionella infections and Legionnaires disease is usually negative or
respiratory viruses. It should be remembered demonstrates very low titres. As for other
that the most reliable serologic evidence of an aetiologies, high titres of IgG and/or IgM,
ongoing infection is based on a fourfold above a certain threshold, present early
increase in titre of immunoglobulin (Ig)G (or during the disease, have been interpreted as
IgG+IgM) antibodies during the evolution of diagnostic but at least one study showed that
the disease episode based on two serum this titre had a very low positive predictive
samples collected at an interval of 1421 days value.
or longer, and/or the appearance of IgM
antibodies during the evolution of the For respiratory viral infections such as for
influenza and RSV, a significant or fourfold
disease. IgM tests are usually less sensitive
IgG antibody increase is detected by EIA in
and specific than fourfold changes in
,8090%% of patients at only 2030 days
antibody titres between paired specimens
after the onset of disease.
separated by several weeks. Solitary high IgG
titers have no diagnostic meaning for an The serologic measurement of specific
acute infection since the moment of the antibody responses can mostly not offer an
seroconversion is unknown and necessarily early diagnosis and therefore has limited

application for an aetiologic diagnosis and for yield in respiratory infections by 3050%:
the routine management of the individual combined with traditional bacteriological
patient with LRTI. Consequently, it is rather an techniques to diagnose S. pneumoniae
epidemiological than a diagnostic tool. infections, .50% and in some studies of
CAP up to 70% of aetiologic agents can be
Nucleic acid amplification tests
detected.
The newest approach in the diagnosis of
The wider application of multiplex reactions
respiratory tract infections is the detection of
during recent years has resulted in the
microbial nucleic acids by NAATs. Culture
detection of numerous simultaneous viral
procedures for viruses and fastidious bacteria,
infections with widely varying incidences:
M. pneumoniae, C. pneumoniae, Legionella
from 3% to even 23% or 35%, depending on
pneumophila, Bordetella pertussis, which
whether bacterial agents are also included.
normally do not colonise the human
The divergent incidences may result from the
respiratory tract, are too insensitive and too
variety of diagnostic panels applied.
slow to be therapeutically relevant and these
Combined viral and viralbacterial infections
pathogens therefore should be detected using
are diagnosed but no preferential
NAATs, whose sensitivity is almost always
combinations have been found. The clinical
superior to that of the traditional procedures.
significance of combined infections remains
A multitude of reports has appeared on the to be further clarified. Respiratory viruses have
epidemiology of LRTIs but most are restricted also been increasingly recognised as causes of
to a few viruses (influenza, sometimes severe LRTIs in immunocompromised hosts.
together with RSV, to rhino-, metapneumo- or Respiratory infections are more common in
coronaviruses) and/or to some population solid organ recipients, particularly in lung
groups, e.g. children, adults or the elderly. transplant recipients. Infections are especially
Great variations occur in function of time, dangerous prior to engraftment and during
place and the age-groups studied. Although 3 months after transplantation, in the setting
the role of some new viruses is becoming of graft versus host disease. The origin of the
more clear in specific patient populations, infections is community-acquired as well as
more studies are needed to identify the nosocomial.
clinical relevance of some others, such as the
bocavirus. All these studies were done with As more epidemiological information on the
the traditional NAATs that require at least 1 role of a panel of respiratory viral pathogens
2 days, producing a posteriori results that becomes available, it is clear that screening
were unavailable to the clinician in time to for these viruses in specific patient
have an impact on patient management. Real- populations such as transplant patients, very
time multiplex NAATs offer the solution. To young children or the elderly is desirable and
cover the wide spectrum of aetiologic preventive and therapeutic recommendations
respiratory agents, a number of uni- and/or may take this information into account.
multiplex reactions are performed
NAATs are, however, not required for every
simultaneously. Both in-house and
purpose. For cohorting RSV-infected paediatric
commercially available multiplex NAATs for
patients, the DIF tests can be as sensitive as
the simultaneousl detection of two, three or
an RT-PCR with results available within
up to 22 different respiratory pathogens,
including the atypical M. pneumoniae, 60 min (and at lower cost than with NAATs).
C. pneumoniae and L. pneumophila, and Very rapid chromatographic tests are also
respiratory viruses, with a mixture of primers available for RSV, which can be done in the
have been developed. laboratory outside virology laboratory
operating hours. These tests lack sensitivity,
The combined use of single target assays or of however, when applied to respiratory samples
multiplex assays has increased the diagnostic of adult patients.

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UPPER RESPIRATORY TRACT
INFECTIONS
G. Rohde
Dept of Respiratory Medicine, Maastrict University Medical Centre,
Netherlands
E-mail: gernot.rohde@mumc.nl
Upper respiratory tract infections (URTIs) are or exposure to second-hand smoke and travel
the most common infectious illness in the are additional risk factors.
general population. They are the leading
cause for people missing work or school.
Prevalence
Key points
URTIs usually occur during the cold months,
mainly due to overcrowding inside buildings. N URTIs are the most common infectious
The mean frequency is 24 episodes annually illness in the general population, and
for adults. In children it is higher. Antigenic are the leading cause of missed work
variation of 100s of respiratory viruses allows and school.
repeated circulation in the community.
N Most URTIs are viral in origin, and
Spectrum typical agents are rhinoviruses, corona-
The upper respiratory tract consists of the viruses, adenoviruses, coxsackieviruses,
nose, paranasal sinuses, pharynx, larynx, influenza- and parainfluenzaviruses,
trachea and bronchi. The most prevalent human metapneumovirus, and
illness is the common cold (rhino-sinusitis), respiratory syncytial virus.
followed by sinusitis, pharyngitis/tonsillitis, N URTIs rarely cause permanent sequelae
laryngitis and sometimes tracheobronchitis or death, but can progress to otitis media,
(table 1).
bronchitis, bronchiolitis, pneumonia,
Onset of symptoms usually begins after sepsis, meningitis, intracranial abscess,
13 days after exposure to a microbial and other infections.
pathogen. The duration of the symptoms is N Diagnosis is usually purely clinical;
typically 710 days but may persist longer. diagnostic investigations should only
Transmission and predisposition be performed in special circumstances,
such as influenza, group A
Transmission of pathogens happens by streptococcal pharyngitis, infectious
aerosol, droplet, or direct hand-to-hand mononucleosis and pneumonia.
contact. The pathogens invade the respiratory
epithelium of the corresponding area. N Infection will often be self-limiting, with
Sinusitis and acute bronchitis are often no specific treatment necessary; the
preceded by a common cold. There are only indications for antibiotic treatment
predisposing conditions as allergic are group A streptococcal pharyngitis,
rhinoconjunctivitis, nasal septum deviation, bacterial sinusitis and pertussis.
immundeficiency, or cocaine abuse. Smoking

Table 1. Signs and symptoms
Upper respiratory tract infection Symptoms Signs
Common cold Nasal congestion, Low-grade fever, nasal vocal tone,
mucopurulent nasal inflamed nasal mucosa
discharge, sneezing, sore
throat, halitosis
Sinusitis Unilateral facial pain, Swelling, redness, tenderness to
maxillary toothache, palpation or percussion overlying
headache, purulent nasal the affected sinuses, abnormal
discharge transillumination
Pharyngitis Sore throat, odynophagia, Pharyngeal erythema and exudate,
or dysphagia, fever, palatal petechiae (doughnut
absence of cough, lesions), tender anterior cervical
halitosis lympadenopathy, scalartiniform
rash, pharyngeal or palatal vesicles
and ulcers (herpangina), tonsillar
hypertrophy
Laryngitis Hoarseness, voicelessness, Low-grade fever, cervical
dry cough, odynophagia, lymphadenopathy, inspiratory
or dysphagia, halitosis stridor, tachypnoea
Tracheo-bronchitis Dry or productive cough, Low-grade fever, anterior cervical
dyspnoea lymphadenopathy, tachypnoea,
rhonchi
Pathogens media, bronchitis, bronchiolitis, pneumonia,

sepsis, meningitis, intracranial abscess, and
Most URTIs are viral in origin. More than 200 other infections. Specific complications can
different viruses are known to cause the occur with untreated group A streptococcal
common cold. Typical viral agents that cause pharyngitis resulting in acute rheumatic fever
URTIs are rhinoviruses, coronaviruses, (ARF), acute glomerulonephritis, peritonsillar
adenoviruses, coxsackieviruses, influenza- and abscess, and toxic shock syndrome. Sinusitis
parainfluenzaviruses, human metapneumovirus, can extend into surrounding deep tissue
respiratory syncytial virus and others. leading to orbital cellulitis, subperiosteal
Group A, but also group C and G Streptococci abscess, orbital abscess, frontal and maxillary
can cause pharyngitis (1020% of cases), as osteomyelitis, subdural abscess, meningitis,
well as other bacteria like Neisseria and brain abscess. Epiglottitis, a presentation
gonorrhoeae, Corynebacterium diphtheriae of laryngitis caused by H. influenzae type B,
and atypical bacteria (Chlamydia, poses a risk of death due to sudden airway
Mycoplasma). Streptococcus pneumoniae, obstruction and other complications,
Haemophilus influenzae and Moraxella including septic arthritis, meningitis,
catarrhalis can be the bacterial cause of empyema and mediastinitis.
rhinosinusitis or tracheobronchitis. Bordetella
Diagnosis
pertussis or Bordetella parapertussis are the
cause of whooping cough associated with In most cases, the diagnosis is purely clinical.
laryngotracheitis. History, inspection, palpation, percussion and
Complications auscultation (see table 1) are sufficient.
Additional diagnostic investigations should
URTIs rarely cause permanent sequelae or only be performed in special circumstances.
death. However they can progress to otitis These include suspicion of:
Upper respiratory tract infections 169

N Influenza (perform pharyngeal swab for Sufficient fluid intake should be advocated.
PCR). The effect of zinc and vitamin C is still
debated. Echinacea seems to be effective in
N Group A streptococcal pharyngitis (perform prevention and treatment of the common
pharyngeal swab for rapid antigen cold. Nonsteroidal anti-inflammatory drugs
detection test). relieve fever, headache and malaise. In
general, there is no role for antibiotic therapy
N Infectious mononucleosis (there are usually
in the management of common cold or any
additional symptoms such as
mild URTI. The only indications for antibiotic
hepatosplenomegaly and lymphocytosis;
treatment are group A streptococcal
perform mononucleosis spot test in blood). pharyngitis (oral penicillin or macrolide),
N Pneumonia (perform C-reactive protein and bacterial sinusitis (aminopenicilline +
chest radiography). b-lactamase inhibitor, cephalosporin 2nd/3rd
generation) and pertussis (erythromycin or
Differential diagnosis trimethoprim-sulfamethoxazole). Nasal
decongestants decrease symptoms in rhinitis
Influenza viruses can cause mild URTIs but
also systemic disease. The definition of and sinusitis, topical nasal steroids improve
sinusitis. Confirmed cases of influenza can be
influenza-like illness is fever .38.5uC) and
one of the following: cough, sore throat, considered for a therapy with neuraminidase
inhibitors according to Centers for Disease
headache and muscle ache.
Control and Prevention guidelines
Allergic rhinoconjunctivitis is characterised by (www.cdc.gov/flu). New treatment options for
oedema of the conjunctiva, itching and the most prevalent respiratory pathogens,
increased lacrimation additional to symptoms human rhinoviruses, are under development.
of rhinitis. Is shows seasonal variation related
Prevention
to allergen exposure.
Acute thyroiditis can present as sore throat, a Direct hand-to-hand contact is an important
common symptom in URTIs. Investigation of mechanism of pathogen transmission. Hence,
thyroid hormones, thyroid-specific frequent hand washing or disinfection in
autoantibodies, ultrasound and radioactive healthcare can limit spread of infection
iodine uptake can help with diagnosis. significantly. Influenza vaccination has been
shown to be very beneficial and has to be
Gastro-oesophageal reflux disease (GORD) advocated. In children, the routine
can clinically present as laryngopharyngitis administration of H. influenzae type B (Hib)
and/or tracheobronchitis. History and vaccination has practically eradicated Hib as
oesophagogastroduodenoscopy in more a cause of URTI. A herd effect could be
severe cases should be performed. demonstrated, as the introduction of the
pneumococcal vaccine in children with
Wegeners granulomatosis should be
significant reduction in invasive
considered in patients with sinusitis not
pneumococcal disease in adults.
responding to therapy. Classic antineutrophil
cytoplasmic antibodies and biopsy are key to References
diagnosis.
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Treatment streptococcal pharyngitis. Am Fam Physician
2009; 79: 383390.
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In most cases the infection will be self-limiting infection or inflammation? Medscape J Med
and no specific treatment is necessary. 2008; 10: 105.

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N Rohde G. Drug targets in rhinoviral infections.
Infect Disord Drug Targets 2009; 9: 126132. N http://emedicine.medscape.com/article/302460-
N Rohde G. Therapeutic targets in respiratory viral overview.
infections. Curr Med Chem 2007; 14: 27762782. N www.clevelandclinicmeded.com/medicalpubs/
N Shah SA, et al. Evaluation of echinacea for the diseasemanagement/infectious-disease/upper-
prevention and treatment of the common cold: a respiratory-tract-infection/.
meta-analysis. Lancet Infect Dis 2007; 7: 473480. N www.cdc.gov/flu.
Upper respiratory tract infections 171

INFECTIVE EXACERBATIONS
OF COPD
M. Miravitlles
Fundacio Clnic, Institut dInvestigacions Biome`diques August Pi i Sunyer
(IDIBAPS), Hospital Clnic, Barcelona, Spain
E-mail: marcm@separ.es
A recent American Thoracic Society (ATS)/ Identification of risk factors for failure of
European Respiratory Society (ERS) task force ambulatory treatment may allow the
has defined the exacerbation of chronic implementation of more aggressive broad-
obstructive pulmonary disease (COPD) as: an spectrum treatment and closer follow-up
increase in respiratory symptoms over baseline (table 1).
that usually requires medical intervention. In
fact, the chronic and progressive course of Aetiology of exacerbations
COPD is often aggravated by short periods of A variety of causes may deteriorate the
increasing symptoms, particularly increasing clinical stability of patients with COPD: cold
cough, dyspnoea and production of sputum, temperature, air pollution, lack of compliance
which can become purulent. Patients with with respiratory medication, worsening of
moderate-to-severe COPD present a mean of comorbidities, and pulmonary embolism,
between one and two of these episodes or among others. However, up to three-quarters
exacerbations per year, but this number is of exacerbations can be infectious in origin,
dependent on the degree of functional with bacteria being responsible for three
impairment at baseline. Patients with more quarters of these exacerbations. In addition,
advanced disease may suffer from an co-infection with respiratory viruses may be
increasing number of exacerbations. frequent in patients with severe COPD. The
Outcomes of exacerbations: most frequent microorganisms causing
risk factors for failure exacerbations are presented in table 2.
The failure rate of ambulatory treatment of

exacerbations of COPD ranges 1226%, and Key points
failure may lead to hospital admission. The
mortality of patients admitted to hospital with N Up to 75% of COPD exacerbations are
COPD exacerbation is ,1014% and the of infective aetiology.
mortality of those admitted to an intensive
care unit (ICU) may be as high as 24%. N Haemophilus influenzae is the most
Hospitalisation has an important impact on frequent pathogen causing exacerba-
COPD patients, and after the first admission tions.
to hospital the mean survival time has been N The relapse rate may be as high as
estimated to be 5.7 yrs. Frequent 20%.
exacerbations have been demonstrated to
have a negative impact on health-related N Risk factors and bacterial resistance to
quality of life in patients with COPD and antibiotics are the criteria used for the
survival is significantly related to the selection of antibiotics.
frequency and severity of exacerbations.

Table 1. Risk factors for failure after ambulatory treatment of exacerbations of COPD
Coexisting cardiopulmonary disease
Increasing number of visits to the GP for respiratory problems (.3?yr-1)
Increasing number of previous exacerbations (.3?yr-1)
Increasing baseline dyspnoea
Severity of FEV1 impairment (FEV1 ,35% predicted)
Use of home oxygen
Inadequate antibiotic therapy
GP: general practitioner; FEV1: forced expiratory volume in 1 s.
The role of bacteria in exacerbations has been increased production or purulence of sputum,
a matter of controversy since the respiratory have been widely used to identify
secretions of some patients with stable COPD exacerbations that require treatment with
carry significant concentrations of bacteria. antibiotics. However, new studies have
Therefore, the isolation of such microorganisms demonstrated that the presence of green
during exacerbations should not always be (purulent) sputum as opposed to white
interpreted as a definite demonstration of their (mucoid) is one of the best and easiest
pathogenic role. However, studies performed methods to predict the bacterial aetiology and
with specific invasive techniques have shown the need for antibiotic therapy.
that both the number of patients with
pathogenic bacteria in respiratory secretions Unfortunately, no signs or symptoms can help
and their concentrations in bronchial secretions the clinician to differentiate bacterial from
increase during exacerbations. The change in viral exacerbations. Both viral and bacterial
the colonising strain of bacteria is an important agents may co-infect a patient with COPD,
mechanism originating exacerbations. The host and mixed infection is associated with higher
does not have protective specific antibodies inflammation, more severe symptoms and
against the new strain of bacteria and the prolonged recovery time.
microorganism can thereby proliferate and The degree of airflow impairment in COPD
cause the exacerbation. patients indicates the presence of different
Diagnosis of infective exacerbations microorganisms during the course of
exacerbations. Individuals with severe
The combination of symptoms described by pulmonary function impairment, manifested
ANTHONISEN et al., i.e. increased dyspnoea and by FEV1 ,50% predicted, are at a six-fold
Table 2. Aetiology of exacerbations of COPD

Infectious exacerbations (,6080% of all exacerbations)
Frequent (7085% of infectious exacerbations) Infrequent (1530% of infectious
Haemophilus influenzae exacerbations)
Streptoccocus pneumoniae Pseudomonas aeruginosa
Moraxella catarrhalis Opportunistic Gram-negative
Viruses (influenza/parainfluenza, rhinoviruses, coronaviruses) Staphyloccocus aureus
Chlamydia pneumoniae
Mycoplasma pneumoniae
Noninfectious exacerbations (2040% of all exacerbations)

Heart failure
Pulmonary embolism
Nonpulmonary infections
Pneumothorax
Infective exacerbations of COPD 173

higher risk of developing acute exacerbations consider amoxycillin/clavulanate, the new
caused by Haemophilus influenzae or fluorquinolones (moxifloxacin, levofloxacin) or
Pseudomonas aeruginosa than patients cephalosporins (cefditoren, cefuroxime).
presenting FEV1 .50% pred. Those with FEV1 Table 3 describes the antibiotic alternatives
,30% pred have an even higher risk for P. according to the severity of COPD.
aeruginosa.
Nonantibiotic treatment of
However, the clinical presentation of exacerbations
exacerbation is not characteristic of any
particular microorganism and no Acute exacerbations of COPD present with
microbiological diagnostic test is available for increasing dyspnoea in most cases. Both
differential diagnosis in primary care. The use infectious and noninfectious exacerbations
of biomarkers such as procalcitonin to identify are the result of an ongoing inflammatory
bacterial exacerbations is promising, but more reaction in the bronchial mucosa making
studies are required. anti-inflammatory and bronchodilator therapy
mandatory.
Antibiotic treatment of exacerbations
A short course of oral corticosteroids has been
Antibiotics have been shown to be superior to demonstrated to accelerate recovery from
placebo in the treatment of exacerbations exacerbations and reduce the rate of relapse in
when all of the Anthonisen criteria are patients with moderate-to-severe COPD.
present; i.e. increased dyspnoea, increased Patients can be treated with 0.5 mg?kg-1?day-1
production and purulence of sputum. The of methylprednisolone or equivalent in a single
purulence of sputum has recently been morning dose for 714 days. Treatment for
demonstrated to be very sensitive and specific .14 days has not been demonstrated to be
for the diagnosis of bacterial exacerbation more beneficial and increases the likelihood of
and indicates the need for antibiotic therapy. adverse side-effects. Inhaled bronchodilators,
Therefore, most guidelines also recommend particularly short-acting inhaled b2-agonists,
antibiotic therapy in patients with two of the must be given at increased doses during
three aforementioned criteria if one of them is exacerbations. The short-acting bronchodilators
increased in purulence of sputum. may be prescribed with a chamber of
inhalation or by nebulisation. In acute phase,
The antibiotic of choice may vary from country repeated doses every 3060 min can be
to country based on the prevalence of administered with close monitoring of clinical
different bacteria and, more importantly, the signs and arterial gas exchange with a pulse
differences in susceptibility of the causative oximeter. If a prompt response to these drugs
bacteria to antibiotics. As an example, in does not occur, the addition of an
2000, the prevalence of macrolide-resistant anticholinergic is recommended.
Streptoccocus pneumoniae in the UK was
12.2%, but in France it was 58.1%, while the Oxygen therapy should be provided in cases of
production of b-lactamase by H. influenzae hypoxaemia. Adequate levels of oxygenation
was 13.9% in the UK and 33.1% in France. are arterial oxygen tension .8.0 kPa or
60 mmHg, or arterial oxygen saturation
Guidelines recommend the use of so-called .90%. These levels are easy to achieve in
first-line antibiotics, such as amoxicyllin or uncomplicated exacerbations. When oxygen is
tetracyclin, in low-risk patients in countries started, arterial blood gases should be checked
with a low prevalence of antibiotic resistance, 3060 min later to ensure satisfactory
such as the Netherlands, UK and other North oxygenation without CO2 retention or acidosis.
European countries. However, in countries
with a high percentage of resistant strains or The clinical and gasometric evolution of the
in patients with risk factors for treatment patients will guide the decision to step down
failure, the choice of an antibiotic must the treatment and discharge the patient from

Table 3. Risk classification and suggested antimicrobial therapy
FEV1 Most frequent Suggested treatment
% pred microorganisms
Mild-to-moderate .50 Haemophilus influenzae Amoxycillin, tetracycline
COPD without risk Moraxella catarrhalis In areas of high incidence of
factors Streptoccocus pneumoniae resistance: amoxycillin-clavulanate
Chlamydophilia pneumoniae Cefditoren, cefuroxime
Mycoplasma pneumoniae
Mild-to-moderate .50 H. influenzae Amoxycillinclavulanate
COPD with risk M. catarrhalis Moxifloxacin/levofloxacin
factors# PRSP Cefditoren, cefuroxime
Severe COPD 3050 H. influenzae Amoxycillinclavulanate
M. catarrhalis Moxifloxacin/levofloxacin
PRSP
Enteric Gram-negative
Very severe COPD ,30 H. influenzae Moxifloxacin/levofloxacin
PRSP Ciprofloxacin if Pseudomonas is
Enteric Gram-negative suspected
Pseudomonas aeruginosa Amoxicillin-clavulanate (if allergy to
quinolones)"
FEV1: forced expiratory volume in 1 s; PRSP: penicillin-resistant S. pneumoniae. #: risk factors are explained in table 1. ": in
the case of intravenous therapy, other antibiotics can be used, such as piperacillin-tazobactam, imipenem or cefepime.
the emergency department or hospital. Family obstructive pulmonary disease. N Engl J Med
and home support is crucial in the first days 1999; 340: 19411947.
after discharge. N Papi A, et al. Infections and airway
inflammation in chronic obstructive pulmonary
In mild and moderate ambulatory disease severe exacerbations. Am J Respir Crit
exacerbations, clinical evaluation is required Care Med 2006; 173: 11141121.
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cases, this evaluation can be performed by symptoms, and inflammatory markers in acute
exacerbations and stable chronic obstructive
telephone contact.
pulmonary disease. Am J Respir Crit Care Med
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N Balter MS, et al. Canadian guidelines for the exacerbations and mortality in patients with
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bronchitis. Can Respir J 2003; 10: Suppl. B, 2005; 60: 925931.
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Infective exacerbations of COPD 175

PNEUMONIA
M. Woodhead
Dept of Respiratory Medicine, Manchester Royal Infirmary, Manchester, UK
E-mail: mark.woodhead@cmft.nhs.uk
Background and definitions CAP is that which occurs in the absence of

immunocompromise or prior hospital
Pneumonia is a condition caused by microbial admission within the previous 7 days.
infection within the lung parenchyma. This
infection, together with the associated host Epidemiology
inflammatory response, impairs normal
CAP occurs in between one and 10 per 1,000
alveolar function (i.e. gas exchange), which,
of the adult population each year. It is more
together with the systemic effects of the
common in children aged ,5 yrs and
infection, causes the clinical features of
becomes progressively more common from
pneumonia. The gold standard for recognition
age 40 yrs onwards with a peak in the very
of pneumonia is the presence of new lung
elderly. It is more common in those with
shadowing on the chest radiograph in the
comorbidity, e.g. chronic obstructive
setting of a compatible clinical illness.
pulmonary disease (COPD), bronchiectasis,
Pneumonia is classified according to the chronic cardiac and renal disease. It occurs
origin of the infection as community-acquired throughout the year with a peak during the
(CAP) or hospital-acquired (nosocomial (NP)). winter months.
Additional pneumonia types are in the
NP can occur in anyone resident in hospital
immunocompromised and aspiration
for o7 days. It is especially common on the
pneumonia. In each group, the causative
intensive care unit after endotracheal
pathogens and hence the management are
intubation (ventilator-associated pneumonia
different.
(VAP)) with risk being proportional to
duration of intubation.
Two types of immune dysfunction predispose
to pneumonia: humoral immune dysfunction,
Key points
e.g. immunoglobulin deficiencies; and cell-
mediated immune function in e.g. cancer
N Pneumonia is very common and has a
chemotherapy, solid organ transplantation
significant mortality.
and bone marrow transplantation.
N Severity assessment, aided by a severity
Aspiration pneumonia occurs especially in
assessment score, is a key management
those with swallowing impairment and
step.
neurological impairment.
N A variety of different pathogens can
cause pneumonia. Most cases of CAP are managed in the
community with a variable, but significant,
N Antibiotic management is initially proportion requiring hospital admission. Of
empirical and based on guidelines and those admitted, 510% may die and of those
knowledge of local microbial patterns reaching the intensive care unit, 3050% may
and resistance rates. die. Mortality is generally higher in NP and
pneumonia in the immunocompromised.

Clinical features be abnormal. Measures of gas exchange such
as oxygen saturation and/or arterial blood
The duration of illness before presentation is gases also aid assessment of illness severity
usually short. Classically there is an abrupt and guide management.
onset with fever, shivers and pleuritic chest
pain. A slower onset over a few days may also In routine practice, tests to identify a
occur. Other common symptoms include microbial cause are positive in only about
cough, sputum production, which may be 15% of cases of CAP and hence seldom
purulent or blood-stained, breathlessness, influence management. They are probably not
muscle aches, headaches and anorexia. indicated unless the patient is severely ill. In
Nausea and diarrhoea are less common. In such cases blood culture, sputum Gram stain
elderly patients, symptoms of cerebral and culture, and urine for pneumococcal and
dysfunction, such as confusion, incontinence legionella antigen are indicated. Blood
or falls, may be the presenting feature. antibody levels or nose/throat secretion PCR-
based tests for microbe-specific nucleic acids
Abnormalities on clinical examination include can be used for the detection of viruses and
focal signs on chest examination, most less common bacteria such as Legionella,
commonly crackles, but occasionally the Mycoplasma and Coxiella.
classical features of lung consolidation
dullness to percussion, bronchial breathing In NP, and especially in VAP, lower respiratory
and enhanced vocal resonance. In addition, secretions should be sampled either by
raised temperature, raised heart and tracheal aspirate or from bronchoscopic
respiratory rates, low blood pressure and specimens. The latter may be of value also in
mental confusion may be found. the immunocompromised.
Clinical features are not helpful in predicting Differential diagnosis

the causative organism. This includes acute bronchitis, COPD
Investigations including radiology exacerbation, left ventricular failure,
pulmonary embolism, exacerbation of
Investigations are unnecessary outside pulmonary fibrosis and rare lung disorders,
hospital but in those admitted are performed e.g. pulmonary eosinophilia.
to aid precise diagnosis, assess illness severity
and identify the microbial cause. Microbial aetiology and resistance
The chest radiograph is essential to confirm Some 10 pathogens commonly cause CAP,
new lung shadowing in those admitted. with Streptococcus pneumoniae being the
Classically such shadowing conforms to a most common overall and the most important
lobar pattern and is associated with air cause of severe illness and death.
bronchograms. Shadowing may occupy less Mycoplasma pneumoniae is also a common
than a whole lobe and may also be patchy, cause of mild illness, especially in young
multilobar and bilateral. Additional features adults. Severe illness is most likely to be
may include pleural effusion and less associated with S. pneumoniae, legionella,
commonly cavitation and pneumothorax. The staphylococcal or Gram-negative bacterial
lower lobes are most commonly affected. infection. Legionella infection may occur in
outbreaks associated with a water aerosol
Of routine blood tests, peripheral blood white source such as showers or decorative
cell count may be raised, especially in fountains. Staphylococcal infection is
bacterial infection, but C-reactive protein and especially common following influenza virus
procalcitonin are probably more specific. infection. Influenza occurs in seasonal
Blood urea and creatinine are helpful in outbreaks during the winter months and
severity assessment and the assessment of occasional pandemics. It is the commonest
renal impairment, and liver function tests may viral cause of CAP.
Pneumonia 177
Table 1. CURB65 (or CRB65) score
Score 1 for each of:
C 5 mental confusion
U 5 blood urea .7 mmol?L-1
R 5 respiratory rate o30?min-1
B 5 systolic blood pressure ,90 mmHg or diastolic blood pressure f60 mmHg
65 5 age o65 yrs
Score: mild 01 (mortality 1.5%), moderate 2 (9%), severe 35 (22%)
Clinically significant resistance to penicillins and antimicrobial therapy. This should be done
in S. pneumoniae is rare, but clinically through clinical judgement guided by objective
significant macrolide resistance is more severity scores. There are many of these, but the
common, especially in Southern Europe (see best validated for CAP are the CURB65 (and its
www.earss.rivm.nl). This varies in frequency derivative CRB65) and the pneumonia severity
between countries. index (PSI). The latter is based on a score from
20 variables and is often not practical in
NP is most commonly caused by Gram- routine practice. The former is simpler and
negative enterobacteria or Staphylococcus based on the number of severity variables
aureus. Pseudomonas aeruginosa and present (table 1). The Clinical Pulmonary
multiresistant bacteria (e.g. methicillin- Infection Score (CPIS) may be useful in NP.
resistant S. aureus (MRSA)) are important
causes of VAP. Management
Humoral immune deficiency is associated Correction of gas exchange and fluid balance
with bacterial infection and cell-mediated abnormalities and the provision of appropriate
immune defects with viral and fungal antimicrobial therapy are the cornerstones of
infections such as Pneumocystis jirovecii. management. Outside hospital rest, oral fluids
and an oral antibiotic may all that is required.
Anaerobic bacteria may be important in In hospital, oxygen at a concentration to
aspiration pneumonia. maintain arterial oxygen saturation (.92%)
Severity assessment should be delivered. If this cannot be achieved
continuous positive airway pressure may be
Severity assessment is the key to deciding place helpful. If there is an unacceptable rise in
of care and should also guide diagnostic tests arterial carbon dioxide tension then assisted
Table 2. European Respiratory Society antibiotic guidelines for CAP

CAP severity Preferred Alternative
Nonsevere Aminopenicillin macrolide or co- Levofloxacin or moxifloxacin
amoxiclav macrolide or
penicillin G macrolide or third-
generation cephalosporin macrolide
Severe Third-generation cephalosporin + Third-generation cephalosporin +
macrolide (levofloxacin or moxifloxacin)
Severe + risk factors for Autopseudomonal cephalosporin + Piperacillin/tazobactam + (ciproflox-
Pseudomonas aeruginosa ciprofloxacin acin or levofloxacin) or carbapenem
+ (ciprofloxacin or levofloxacin)

ventilation should be considered. A place for disease and in the elderly, influenza and
noninvasive ventilation in pneumonia pneumococcal vaccination is indicated.
management has yet to be proven. Recent evidence suggests that conjugate
pneumococcal vaccination in children not
Initial antibiotic therapy must be empirical
only reduces invasive pneumococcal infection
and directed by illness severity according to
in this group, but also in adults.
national or international guidelines (table 2).
A single antibiotic for nonsevere CAP and References
dual therapy for severe CAP is usual.
Treatment for NP should be guided by N European Respiratory Society Task Force Report,
Guidelines for management of adult community-
knowledge of local microbial causes and that acquired lower respiratory tract infections.
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the type of immune suppression and likely press.
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7 days in the uncomplicated, but may need to community acquired pneumonia: a validation
be prolonged in severe illness. Failure to study. Thorax 2000; 55: 219223.
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for microbial cause, for example by bronchoscopic and nonbronchoscopic "blind"
bronchoscopy, as long as gas exchange bronchoalveolar lavage fluid. Am Rev Respir Dis
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N Torres A, et al. Defining, treating and preventing
Prevention hospital acquired pneumonia: European
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tobacco smoking. In those with comorbid Hodder Arnold, 2006.
Pneumonia 179
HOSPITAL-ACQUIRED
PNEUMONIA
F. Blasi
` degli Studi di Milano
Thoracopulmonary and Cardiocirculatory Dept, Universita
`
and IRCCS Fondazione Ca Granda Ospedale Maggiore Policlinico, Milan, Italy
E-mail: francesco.blasi@unimi.it
The currently proposed classification of Table 1. Definitions of hospital-acquired pneumonias

hospital-acquired pneumonias includes HAP Pneumonia that occurs o48 h after
hospital-acquired pneumonia (HAP), ventilator- admission, which was not incubating
associated pneumonia (VAP) and healthcare- at the time of admission
associated pneumonia (HCAP) (table 1). VAP Pneumonia that arises .4872 h
after endotracheal intubation
However, a recent statement issued by the
HCAP Pneumonia that occurs in any patient
European Respiratory Society/European
who was hospitalised in an acute
Society of Clinical Microbiology and Infectious care hospital for o2 days within
Diseases/European Society of Intensive Care 90 days of the infection; resided in a
Medicine calls for a redefinition of HCAP, nursing home or long-term care
particularly in terms of risk factors and facility; received intravenous
microbial aetiology. antibiotic therapy, chemotherapy, or
wound care within the 30 days prior
Epidemiology to the current infection; or attended
hospital or haemodialysis clinic
The incidence of HAP is ,0.52.0% among
all hospitalised patients and it is the second
most common nosocomial infection, yet the factors are age, type of hospital and type of
first in terms of mortality (ranging ward. Patients aged ,35 yrs are less prone to
30.70%). The incidence in different develop HAP than elderly patients; the
hospitals and different wards of the same incidence of HAP may vary between 515
hospital varies considerably. The main risk episodes per 1,000 discharges. In large
teaching hospitals, the incidence is higher
Key points than in district hospitals, possibly relating to
differences in patient complexity. HAP is quite
N Incidence of hospital-acquired pneumonias uncommon in paediatric and obstetric wards,
is ,0.52%, with risk factors including and clearly most common in surgical wards
age, type of hospital and type of ward. and intensive care units (ICUs), particularly in
ventilated patients in whom the incidence
N Mortality is high (3070%). may be .35 episodes per 1,000 patient-days.
N Diagnosis can be difficult, and requires Pathogenesis and risk factors
a combined clinical and bacteriological
approach. The understanding of the pathogenesis of HAPs
is a fundamental step for the comprehension of
N Antimicrobial therapy must be both prompt
risk factors involved. The main sources of HAP
and appropriate, and should be modified
pathogens include healthcare devices, the
as culture results become available.
environment, the transfer of microorganisms

Table 2. Main recommendations for the management of modifiable risk factors for HAP and VAP
Host related Adequate nutrition, enteral feeding via orogastric tubes
Reduction/discontinuation of immunosuppressive treatments
Prevent unplanned extubation (restraints, sedation)
Kinetic beds
Incentive spirometry, deep breathing and pain control
Device/treatment related Minimise use of sedatives and paralytics
Avoid gastric overdistention
Avoid intubation and reintubation
Expeditious removal of endotracheal and nasogastric tubes
Semirecumbent positioning
Drain condensate from ventilator circuits
Endotracheal tube cuff pressure (.20 cmH2O prevents leakage of
bacterial pathogens around the cuff into lower respiratory tract)
Continuous aspiration of subglottic secretions
Use of heat moisture exchangers (reduces ventilator circuit
colonisation but not VAP incidence)
Environment related Attention to infection-control procedures, i.e. staff education, hand
washing, patient isolation
Microbiological surveillance programme
between the patient and staff or other patients, baumannii, microorganisms belonging to the
and oropharyngeal and gastric colonisation, family Enterobacteriaceae (Klebsiella spp.,
with subsequent aspiration of their contents Enterobacter spp., Serratia spp., etc.) and, under
into the lungs in patients with impaired certain conditions, microorganisms such as
mechanical, cellular and humoral defences. Risk Haemophilus influenzae are involved in HAP
factors for the development of HAP can be aetiology. Among Gram-positive pathogens,
differentiated into modifiable and non- Staphylococcus aureus, Streptococcus spp. and
modifiable conditions (table 2) Streptococcus pneumoniae are the most
common agents, accounting for 3539% of all
Microbiology cases. Nonbacterial pathogens such as
Gram-negative pathogens are the main cause of Aspergillus spp. and viruses (cytomegalovirus)
HAP. Pseudomonas aeruginosa, Acinetobacter have been described.
In general, there are significant geographical
Table 3. Major points for HAP diagnosis differences in the rates of resistance between
Medical history and physical examination some European areas and even within
Chest radiograph (posteroanterior and lateral) countries, from one hospital to another.
Blood gas analysis
Taking into account the time course of
Blood cultures
pneumonia development, the expected
Thoracentesis if pleural effusion
pathogens in early-onset pneumonia (onset in
Endotracheal aspirate, bronchoalveolar lavage or f4 days of hospital admission) include S.
protected brush sample for culture before
aureus, S. pneumoniae and H. influenzae, as
antibiotic (negative results do not rule out viral
or Legionella infections) well as nondrug-resistant Gram-negative enteric
bacteria (GNEB), and in late-onset pneumonia
Extrapulmonary site of infection should be
investigated (onset .4 days of hospital admission) include
methicillin-resistant S. aureus, drug-resistant
Hospital-acquired pneumonia 181

Table 4. Antimicrobial treatment of nosocomial pneumonia
Recommended treatment options Recommended dosages
Early-onset pneu- Aminopenicillin plus b-lactamase-inhibitor Amoxi-clav 362.2 g;
monia without any or ampicillinsulbactam 363 g
additional risk Second/third generation cephalosporin
factors# or Cefuroxime 361.5 g;
Respiratory fluoroquinolone cefotaxime 362 g;
ceftriaxone 162 g
Levofloxacin 16750 mg; moxifloxacin

16400 mg
Late-onset or risk Anti-Pseudomonas b-lactams Piperacillin-tazo 364.5 g; ceftazidime
factors for or 362 g
multidrug-resistant Carbapenems
pathogens PLUS Imipenem 361g;
Fluoroquinolone meropenem 361 g
Addition of coverage for MRSA if sus-
pected Ciprofloxacin 36400 mg;
levofloxacin 16750 mg
Vancomicin 261 g;
linezolid 26600 mg
MRSA: methicillin-resistant Staphylococcus aureus. #: Ertapenem has been suggested; however, its use on a regular basis
would lead to a considerable risk of overtreatment.
GNEB, P. aeruginosa and A. baumannii among inappropriate antimicrobial treatment is

other potentially drug-resistant microorganisms. associated with an excess mortality from
pneumonia. Antibiotic selection for empirical
Diagnostic strategy therapy of HAP should be based primarily on
The clinical diagnosis of HAP is often difficult the risk of multidrug-resistant pathogen
to establish. The American Thoracic Society/ infection. Table 4 shows the proposed
Infectious Diseases Society of America empirical treatment approach.
guidelines suggest the use of a combined Once the results of respiratory tract and blood
clinical and bacteriological strategy. Table 3 cultures become available, therapy should be
summarises the major points and focused or narrowed, based on the identity of
recommendations of the guidelines. specific pathogens and their susceptibility to
In case of doubt or relevant disagreement specific antimicrobials. An 8-day antibiotic
between the clinical presentation and the course can be appropriate provided that the
radiological findings, it is recommended to patient has a good clinical response and
perform a computed tomographic scan. The difficult-to-treat pathogens are not involved as
presence of new chest radiographic infiltrates an aetiological agent.
plus one of the three clinical variables (fever References
.38uC, leukocytosis or leukopenia and
purulent secretions) is sufficient to start N American Thoracic Society, Infectious Diseases
antimicrobial treatment. Society of America, Guidelines for the management
of adults with hospital-acquired, ventilator-
Treatment associated, and healthcare-associated pneumonia.
Am J Respir Crit Care Med 2005; 171: 388416.
Prompt administration of appropriate N Torres A, et al. Defining, treating and preventing
antimicrobial treatment is crucial in order to hospital acquired pneumonia: European
achieve an optimal outcome, and perspective. Intensive Care Med 2009; 35: 929.

PNEUMONIA IN THE
S. Ewig
Thoraxzentrum Ruhrgebiet, Kliniken fu
r Pneumologie und Infektiologie,
Evangelisches Krankenhaus Herne und Augusta-Kranken-Anstalt Bochum,
Germany
E-mail: ewig@augusta-bochum.de
In contrast to community- and hospital- a systematic approach to the management of

acquired pneumonia, pneumonia in the these patients is required. This approach
immunocompromised host is not defined by should include a comprehensive diagnostic
the setting of pneumonia acquisition but by evaluation, indications for empirical initial
the immune status of the host. In this context, antimicrobial treatment, also in the absence
immune suppression is best defined as a of definite pathogen identification, and for
relevant risk for so-called opportunistic salvage management in case of treatment
pathogens such as fungi, viruses, failure.
mycobacteria and parasites.
The basic diagnostic evaluation should
The expected pathogen patterns differ include history, physical examination and
according to the type of immune suppression chest radiography as well as a basic
(table 1). Overall, there are five main types of microbiological work-up (sputum, blood
immunosuppression: cultures). A computed tomography (CT) scan
of the lung (multi-slice scan and high-
N iatrogenic (through steroidal and
resolution (HR)CT) is usually indicated in
nonsteroidal agents)
patients in whom a straightforward diagnosis
N neutropenia (usually through cannot be made. It can be particularly
antineoplastic chemotherapy) valuable in patients at risk of fungi
(Pneumocystis and Aspergillus). Bronchoscopy
N haematopoetic stem-cell transplantation is usually indicated in patients with bilateral
(HSCT) infiltrates, unusual clinical and radiographical
N solid organ transplantation
N HIV infection Key points
Each immunosuppressive condition confers
characteristic risk profiles for pulmonary N Different types of immunosuppression
infections according to the type of immune confer vulnerability to different
failure. Some conditions additionally show respiratory pathogens, which may be
time- or extent-dependent risk profiles. bacterial, viral, mycobacterial or fungal.
Pulmonary infections in the N The approach to treatment should

immunocompromised host usually consistute include comprehensive diagnostic
an emergency. Thus, immediate appropriate evaluation, indications for empirical
antimicrobial treatment is mandatory. Since antimicrobial treatment and a plan in
the spectrum of potential pathogens is far case of treatment failure.
more diverse than in immunocompetent hosts,
Pneumonia in the immunocompromised host 183

Table 1. Types of immunosuppression and typical infectious complications
Type of complication Main immune disorder Typical Infections
Iatrogenic (steroids) Macrophages, T-cells Bacteria, fungi (Aspergillus spp.),
Mycobacterium tuberculosis
Iatrogenic TNF-a M. tuberculosis
(anti-TNF-a)
Neutropenia, stem cell Neutrophils
transplantation Short duration (,10 days) Bacteria
Long duration (.10 days) Additionally:
fungi (Aspergillus spp.)
Solid organ transplantation Early (month 1): neutrophils Bacteria
Intermediate (months 2-6): Fungi, viruses, parasites
macrophages, T-cells
Late (months .6): depends on Variable
extent of immune suppression
HIV infection T-cells (CD-4)
CD4 .500?mL-1 No risk
-1
CD4 200500?mL Bacteria, M. tuberculosis
CD4 ,200?mL-1 Additionally:
Pneumocystis jirovecii
CD4 ,50?mL-1 Additionally: Aspergillus spp.,
atypical mycobacteria
TNF: tumour necrosis factor.
presentations and those with treatment radiograph typically discloses bilateral

failure. When performing bronchoscopy, interstitial infiltrates in a perihilar distribution
particular care has to be taken to comply with but may also be normal in the early course. In
the methodology of retrieving the latter case, HRCT may reveal ground glass
uncontaminated samples of the lower opacities in a patchy or geographical
respiratory tract, and a comprehensive distribution. Atypical cystic presentations may
evaluation of the samples retrieved. occur. Blood gas analysis shows wide
Bronchoalveolar lavage (BAL) is the most alveolararterial gradients. The typical
important sample, and stains and cultures laboratory finding is an elevated lactate
should be investigated for all relevant dehydrogenase. Specific diagnosis is required
pathogens. Occasionally, transbronchial and may be established by examination of
biopsies and/or transbronchial needle induced sputum or BAL. The treatment of
aspiration may be rewarding. choice (also for prophylaxis) is trimethoprim-
sulfamethazole. Second-line options include
In the following, typical pneumonias in the
pentamidine and clindamycin/primaquin.
immunosuppressed host are described in
Adjunctive steroids are indicated in patients
more detail.
with acute respiratory failure.
Pneumocystis jirovecii pneumonia (PJP)
PJP in non-HIV patients differs in that it
PJP in HIV-infected patients presents with at presents more frequently as an acute onset
least one of the following symptoms: fever, pneumonia and tends to be associated with
cough and dyspnoea on exertion. Chest higher mortality.

Cytomegalovirus pneumonia (CMVP) rarely be established. Therefore, probable and
possible diagnosis is based on a set of clinical,
CMVP is defined as pulmonary signs and
microbiological and radiographic criteria.
symptoms and the detection of CMV in
HRCT is the method of choice to detect AP
pulmonary samples. Nevertheless, patients
early in its course. Typical, albeit not specific
may shed CMV in the absence of CMVP. Co-
signs of AP include the halo sign, as well as
infections with other opportunistic pathogens
nodular and peripheral patchy densities near
are frequently encountered. After introduction
to vessels. The air crescent sign,
of CMV prophylaxis, the incidence in
representing cavitation, is a late marker of AP.
allogeneic HSCT is 1030%, with the highest
The galactomannan antigen test in serum and
risk in seropositive recipients, while it is rare in
BAL has a sensitivity of ,70% and a
autologous HSCT (, 10%). Also, the onset is
specificity of 90%. Bronchoscopy is usually
shifted to .100 days. Clinical presentation is
indicated. Early initiation of treatment is
unspecific. Radiologically, there is typically an
crucial. The treatment of choice for definite
interstitial pattern with tiny pulmonary
AP is voriconazole, or alternatively liposomal
nodules and patchy areas of consolidation.
amphotericin B. Second-line options include
HRCT is more sensitive. Diagnosis is made by
caspofungin and posaconazole. Mortality
demonstration of inclusion bodies within
reaches ,5060%.
epithelial cells of the lower respiratory tract
(sensitivity 90%, specificity 98%). Culture of References
BAL fluid lacks specificity. The value of CMV
pp65 antigen and PCR is controversial. The N Agusti C, Torres A.: Pulmonary Infection in the
Immunocompromised Patient. Strategies for
treatment of choice is ganciclovir and
Management. Oxford, Wiley-Blackwell, 2009.
valganciclovir, combined with CMV immune N Boersma WG, et al. Bronchoscopic diagnosis of
globulin. Second-line agents are foscarnet and pulmonary infiltrates in granulocytopenic
cidofivir. Antiviral prophylaxis and monitoring patients with hematologic malignancies: BAL
are the main preventive strategies. versus PSB and PBAL. Respir Med 2007; 101:
317325.
Tuberculosis (TB) N Chan KM, Allen SA. Infectious pulmonary
Patients with lowered CD-4 cell counts as well as complications in lung transplant recipients.
on chronic steroid and anti-tumour necrosis factor Semin Respir Infect 2002; 17: 291302.
(TNF)-a treatment are at increased risk of TB. Co- N DAvignon LC, et al. Pneumocystis pneumonia.
Semin Respir Crit Care Med 2008; 29: 132140.
infection with TB and HIV alters the natural
history of both diseases. TB in HIV-infected
N Davis JL, et al. Respiratory infection
complicating HIV infection. Curr Opin Infect Dis
patients presents like primary infection (patchy 2008; 21: 184190.
infiltrates, mediastinal lymph node enlargement, N Duncan MD, Wilkes DS. Transplant-related
pleural effusion and bacteraemia). Concurrent immunosuppression: a review of
treatment of TB and HIV is challenging due to immunosuppression and pulmonary infections.
the many complex interactions of anti-TB drugs Proc Am Thorac Soc 2005; 2: 449455.
and antiretroviral agents. Patients who are N Feller-Kopman D, Ernst A. The role of
candidates for chronic steroid or anti-TNF-a bronchoalveolar lavage in the
treatment should be evaluated for TB infection immunocompromised host. Semin Respir Infect
and, in case of positive skin testing or interferon-c 2003; 18: 8794.
release assay, receive prophylaxis.
N Rano A, et al. Pulmonary infiltrates in non-HIV
immunocompromised patients: a diagnostic
Aspergillus pneumonia (AP) approach using non-invasive and bronchoscopic
procedures. Thorax 2001; 56: 379387.
Definite diagnosis of AP in neutropenic N Rosen MJ. Pulmonary complications of HIV
patients requires tissue biopsy and can only infection. Respirology 2008; 13: 181190.
Pneumonia in the immunocompromised host 185

PLEURAL INFECTION AND
LUNG ABSCESS
North Bristol Lung Centre, University of Bristol, UK
E-mail: nick.maskell@bristol.ac.uk
Pleural infection Bacteriology
Pleural infection occurs when micro- Bacteria are ultimately cultured from either
organisms, most commonly bacteria, enter the pleural fluid or blood in 6070% of cases of
pleural space. It can be confirmed when pleural infection. The microbiology of
pleural fluid has a positive Gram stain or community-acquired pleural infection is
culture, is frankly purulent or, in the context of different from that of hospital-acquired pleural
sepsis, has an acidic pH. Pleural infection is a infection and CAP such that these should be
common and serious medical problem. It is considered three distinct diseases requiring
associated with a mortality rate of 1520%. different empirical antibiotic regimes.
In community-acquired pleural infection,
Epidemiology Streptococcus species (largely Streptococcus
N Greatest incidence in the elderly and milleri and Streptococcus pneumoniae)
children but can occur at any age. account for 50% of positive cultures with
Staphylococcus species, anaerobic and Gram-
N Twice as common in males. negative organisms making up the other half.
N 20% of adults with pleural infection have Anaerobic organisms commonly co-exist with
diabetes mellitus. aerobes, particularly the Streptococcus milleri
group. Atypical pneumonia organisms such as
N Other important risk factors include Legionella and Mycoplasma species are
aspiration, immunosuppression, poor extremely unusual causes of pleural infection.
dentition, pleural procedures, thoracic
surgery and penetrating chest trauma.
Key points
Pathophysiology
N Pleural infection is common and
Pleural infection most frequently follows serious, with a mortality rate of 1520%.
community-acquired pneumonia (CAP) with
bacterial migration from the lung parenchyma N Blood, in addition to pleural fluid,
into a parapneumonic effusion. It may also should always be cultured.
follow hospital-acquired and aspiration N Initial management is with broad spectrum
pneumonia with effusion, traumatic or antiobiotics and prompt chest drainage.
iatrogenic pleural penetration or be a
primary phenomenon. Primary pleural N Lung abscess has a 10% mortality rate.
infection is probably the consequence of N Invasive procedures are only required
bacteraemia, the origin of which has not been
when lung abcess does not respond to
fully elucidated. Microbiological data has
prolonged empirical antibiotics or
suggested the oropharynx as one possible
underlying neoplasm is suspected.
source.

Table 1. Clinical classification of pleural infection.
Simple parapneumonic Complicated parapneu- Empyema
effusion monic effusion
Pleural fluid appear- Straw-coloured, bloody or Straw-coloured, bloody or Frank pus
ance turbid turbid
Pleural fluid pH .7.2 Usually f7.2 Should not be measured
Pleural fluid Gram Negative May be positive May be positive
stain
Pleural fluid culture Negative May be positive May be positive
Thoracic ultrasound Usually anechoic but Can be anechoic, complex Homogenously
appearance septation can occur. No septated or complex echogenic. Usually
pleural thickening nonseptated evidence of pleural
thickening
Immediate Antibiotics for pneumonia. Intravenous antibiotics Intravenous antibiotics
management This does not represent and chest tube drainage and chest tube drainage
pleural infection
In nosocomial pleural infection, Radiology

Staphylococcus species (including MRSA) and N Chest radiography often demonstrates a
Gram-negative organisms are responsible for pleural effusion and consolidation. When
most positive cultures. pleural fluid has entered the organising
Investigations phase there may be a lentiform pleural
opacity (fig. 1).
N When a patient presents with sepsis and
N Ultrasound may demonstrate an anechoic,
clinical and chest radiographic signs of a
pleural effusion, a diagnostic pleural complex septated, complex nonseptated or
aspiration should always be performed to homogenously echogenic (reflecting pus in
establish the presence of pleural infection. empyema) appearance in pleural infection
and is important in guiding aspiration and
N Pleural fluid should always be sent for drain site.
culture and cytological examination. The
pH of nonpurulent pleural fluid should be N Contrast-enhanced computed tomography
measured using a heparinised arterial (CT) scans demonstrate brightly enhancing
blood gas syringe and blood gas machine, pleural thickening in the organising phase
and fluid should also be sent for protein of pleural infection. CT is only required
and lactate dehydrogenase. when initial drainage of fluid is incomplete
for the planning of further drains or
N In the correct clinical context, a pleural thoracic surgical intervention or if other
fluid pH of f7.2, positive pleural fluid pathology such as pulmonary abscess,
culture or Gram stain, purulent pleural neoplastic lesions or oesophageal rupture
fluid and loculation on thoracic ultrasound is suspected.
differentiate pleural infection from simple
parapneumonic effusion and indicate the Management
need for chest tube drainage. Immediate treatment The following steps
N Blood cultures should be sent (along with should be implemented.
standard baseline blood tests) as they may
achieve a microbiological diagnosis when
N Broad-spectrum intravenous antibiotics.
there is no growth from pleural fluid. N Chest tube drainage.
Pleural infection and lung abscess 187

o5 days i.v. antibiotics is followed by
24 weeks of oral treatment.
Chest tube drainage Small-bore (1214 f)
chest tubes are now generally preferred to
large-bore tubes as they can be placed via a
seldinger technique and are more comfortable
for patients. There is no evidence that large-
bore tubes acheive superior fluid drainage
(although this is still the subject of significant
debate). Regular saline flushes (20 mL
6-hourly) may help to maintain tube patency
and larger-volume 0.9% saline irrigation of
the pleural space has been adopted by some
European centres with reports of improved
primary treatment sucess rates (not yet
supported by published evidence).
The viscosity and degree of septation of

pleural fluid may impair tube drainage but
Figure 1. Chest radiograph of left empyema routine use of intrapleural fibrinolytics has not
demonstrating a D- shaped, lentiform pleural
been shown to be of benefit.
opacity.
Thoracic surgery The most compelling
N Nutritional supplementation (oral or indication for referral for surgical intervention
nasogastric). is failure of sepsis to improve despite
appropriate antibiotics and tube drainage.
N Thromboprophylaxis. This assessment is usually made after 5 days
N Vigilant monitoring for evidence of medical treatment. While surgical and
worsening sepsis indicating need for early anaesthetic complications are more common
thoracic surgery. in the elderly and frail, the vast majority of
deaths as a result of pleural infection are in
It is not possible to reliably identify, by patients aged .65 yrs, and this group in
presenting radiological, pleural fluid or particular should be considered at an early
clinical features, for which patients primary stage for limited surgical drainage procedures.
medical management will not achieve
resolution of sepsis, necessitating thoracic Available surgical approaches include:
surgery.
N video-assisted thoracoscopic surgery
Antibiotics Examples of suitable empirical (VATS).
antibiotic regimes with broad-spectrum
coverage and good penetration to the pleural
N open thoracotomy and decortication.
space include penicillin-clavulanic acid N rib resection and open drainage (often
combinations in community-acquired infection performed under local anaesthetic).
and carbopenems with vancomycin in
nosocomial infection. When cultures are
N mini-thoracotomy (usually VATS-assisted)
available, antibiotics should be modified Outcome
accordingly. As anaerobes can be difficult to
culture, their presence should be assumed and N Patients should be followed up for
cover continued (unless Streptococcus o3 months to allow the early detection
pneumoniae, which is not known to co-exist of recurrent sepsis or persistent
with anaerobes, is isolated). Conventionally, breathlessness.

N 2030% of patients ultimately require N On CT, abscesses have an irregular wall
surgical intervention. and an indistinct outer margin that makes
an acute angle with the chest wall. In
N Pleural infection in the elderly and
contrast, an empyema is lenticular, well
hospital-acquired disease have a
defined and causes compression of the
particularly poor outcome.
underlying lung with vascular crowding
N Mean mortality rates of 1520% have been (fig. 2).
reported in recent series.
Conditions with a similar radiological
Lung abscess presentation to lung abscess:
In contrast to pleural infection, the incidence N Neoplastic lesions

and mortality rate of lung abscess have steadily
declined since the advent of penicillin.
N Pulmonary vasculitis
Risk factors include:

N Pulmonary infarction
N Bullae and cysts
N more common in males (2:1).
N Rheumatoid nodules
N immunocompromised states.
N Pneumoconiosis
N aspiration of any cause.
Bacteriology and obtaining cultures
N pneumonia (particularly Staphylococcus
aureus and Klebsiella pneumoniae). The microbiology of lung abscesses has
changed over recent decades due to
N bronchial obstruction (e.g. endobronchial immunocompromise and immunosupression
neoplasm in 1020% cases). being at least as aetiologically important as
aspiration.
N haematogenous spread of infection.
Diagnosis N Polymicrobial in o50%.
Symptoms may be acute or insidious in onset

N Anaerobes (e.g. Fusobacterium, Prevotella
and commonly include cough, fever, chest sp., Peptostreptococcus sp.) present in
pain, night sweats, weight loss and purulent 3050%.
or bloodstained sputum. There may be no N Aerobic bacteria now appear to be cultured
specific examination findings or chest more commonly than anaerobes
ausculatation may mimic pneumonia. (particularly Klebsiella pneumoniae and
Anaemia is common in patients with a chronic Staphylococcus aureus).
lung abscess.
N Fungae, Nocardia, mycobacteria, Amoeba,
Radiology Actinomycosis and Echinococcus are more
unusual causes of a parenchymal abcess.
N Plain chest radiography classically
demonstrates a well circumscribed opacity Most patients are treated effectively with
within the lung field. Right-sided abscesses broad-spectrum antibiotics in the absence of a
are twice as common as left. Dependent microbiological diagnosis. Blood cultures
segments are most commonly affected should be sent and sputum cultured if
when the abscess follows aspiration. available.
N CT is often required to distinguish a N Bronchoscopy should be employed when

parenchymal abscess from empyema and there is particular suspicion of an
may assist in the detection of neoplastic underlying endobronchial neoplasm or
lesions. inhaled foreign body. Culture of bronchial
Pleural infection and lung abscess 189

b drainage and avoidance of surgery has been
reported in 84% of cases. It can be achieved
with CT, ultrasound or fluoroscopic guidance.
Complications, such as bronchopleural
fistulae, haemothorax and empyema, are
infrequent.
Percutaneous drainage should be considered

a
if signs of systemic sepsis persist after
2 weeks of broad-spectrum antibiotic therapy.
Figure 2. Computed tomography scan of a right Surgery Surgical excision can be avoided in
pleural empyema (a) and cavitating pulmonary .90% of patients. It should only be
abscess (b). considered at an early stage when there
evidence of localised obstructing malignancy
washings is of relatively low accuracy and or life-threatening complications such as
often fails to focus antibiotic selection intractible haemoptysis, bronchopleural fistula
beyond empirical choices. or empyema.
N Image-guided (CT, ultrasound or Perioperative mortality rates of up to 16%

fluoroscopic) percutaneous aspiration is have been reported following surgery for lung
associated with a 14% risk of pneumothorax abscess.
but obtains a microbiological diagnosis in Prognosis Lung abcesses are associated
8090% of cases and changes antibiotic with a 10% mortality rate.
choice in up to 47%. It is usually reserved for
cases that do not respond to empirical The elderly or immunocompromised and those
with large abscesses (.6 cm), underlying
broad-spectrum antibiotics.
malignancy, malnitrition or delay in diagnosis
Management and treatment have a particularly poor
outcome.
A prolonged course (46 weeks depending on
clinical and radiological response) of References
antibiotics is the foundation of treatment.
b-lactam/b-lactamase-inhibitor combinations
N Davies CWH, et al. The British Thoracic Society
Guidelines for the management of pleural
cover the majority of causative bacteria and infection. Thorax 2009; 58: Suppl. 2, ii18ii28.
are a good empirical choice. Local antibiotic N Davies CW, et al. Predictors of outcome and
policies differ. long-term survival in patients with pleural
infection. Am J Respir Crit Care Med 1999; 160:
Fever and infective symptoms usually settle 16821687.
within a week of appropriate antibiotics. N Maskell NA, et al. The bacteriology of pleural
Sustained resolution of sepsis is the most infection by genetic and standard methods and
important marker of successful conservative its mortality significance. Am J Respir Crit Care
management (radiological resolution can take Med 2006; 174: 817823.
.3 months). N Mwandumba HC, Beeching NJ. Pyogenic lung
infections: factors for predicting clinical
The elderly, immunocompromised and outcomeof lung abscess and thoracic empyema.
patients with very large abscesses (.6 cm) or Curr Opin Pulm Med 2000; 6: 234239.
bronchial obstruction are most likely to N Pena Grinan N, et al. Yield of percutaneous
require invasive intervention. needle lung aspiration in lung abscess. Chest
1990; 97: 6794.
Drainage When appropriate antibiotic N van Sonnenberg E, et al. Lung abscess: CT
therapy fails, image guided percutaneous guided drainage. Radiology 1984; 151: 337
drainage is preferred to surgery. Successful 341.

INFLUENZA, PANDEMICS
AND SARS
W.S. Lim
Respiratory Medicine, Nottingham University Hospitals NHS Trust,
Nottingham, UK
E-mail: WeiShen.Lim@nuh.nhs.uk
Seasonal and pandemic influenza release respectively. There are 16

haemagglutinin (H1 to H16) and 9
Virology Influenza viruses are RNA neuraminidase types (N1 to N9). Influenza
orthomyxoviruses with three main types, A, B viruses are described in a standardised
and C. Viral surface proteins include manner according to their type/location of
haemagglutinin (H) and neuraminidase (N) first isolate/laboratory strain number/year of
which are involved in viral attachment and isolate/H and N subtypes. For example:
influenza A/Hong Kong/1/68/H3N2 (the
cause of the 1968 Hong Kong pandemic).
Key points
The natural reservoir hosts of all influenza A
virus subtypes are water birds. The host
N Influenza is mostly a self-limiting viral specificity of the various influenza A virus
upper respiratory tract infection that is subtypes is partially determined by the
managed in the community. binding affinity of hemagglutinin to sialic
Pneumonia is the most frequent serious acid residues on the host cell.
complication of influenza.
A notable feature of influenza A viruses is
N The neuraminidase inhibitors, their propensity to undergo antigenic
oseltamivir and zanamivir, are effective variation. The appearance of a novel antigenic
in the prophylaxis and treatment of type demonstrating efficient human-to-human
influenza A infection. transmission is a prerequisite for a pandemic.
N The 2009 influenza A(H1N1) Only influenza A viruses have been associated
pandemic was of low severity compared with pandemics.
to the 1918 pandemic. Seasonal influenza Influenza is mostly a
N SARS coronavirus (SARS-CoV) is the self-limiting viral upper respiratory tract
causative agent of SARS. Wild infection that is managed in the community.
mammals, such as the palm civet cat, In temperate climates, outbreaks of infections
occur almost exclusively in winter. Attack rates
were most likely the pre-epidemic
are highest in young children and the elderly.
source of SARS-CoV. Bats are most likely
the natural reservoir for coronaviruses.
Influenza is highly transmissible. Human-to-
N The management of SARS is chiefly human transmission occurs through large
supportive. Basic infection control droplet spread and direct contact with
measures are the cornerstone of secretions (or fomites). There is also evidence
containment of any future outbreak. supporting aerosol transmission although the
extent and importance of this is debated.
Influenza, pandemics and SARS 191

The mean incubation period is 24 days with prophylactic agents reduce the chance of
a range up to 7 days. An abrupt onset of high symptomatic laboratory-confirmed influenza
fever (up to 41uC) is the main presenting (risk ratio 0.38, 95% CI 0.170.85 for
feature. The fever peaks within the first 24 h zanamivir 10 mg daily; risk ratio 0.39, 95%
of illness and usually lasts for 3 days. Cough CI 0.180.85 for oseltamivir 75 mg daily).
is the next commonest symptom (85%) which However, the effect of neuraminidase
may be associated with sputum production in inhibitors on the prophylaxis of influenza-like
up to 40% of cases. Malaise (80%), chills illness, which includes infections other than
(70%), headaches (65%) and myalgia (50%) influenza, is uncertain. Oseltamivir has also
may be prominent. Coryza and sore throat are been demonstrated to be 5884% efficacious
reported in about half of patients. In addition, as post-exposure prophylaxis.
children may present with vomiting, diarrhoea
and abdominal pain but these symptoms are Immunisation is the backbone of influenza
uncommon in adults. The mean duration of prevention. The relative protective efficacy in
symptoms is 4 days. children and young healthy adults is 70
.90%. Efficacy is lower (,40%) in the
Two main classes of drug are active against elderly.
influenza. The M2 ion channel inhibitors,
amantadine and rimantadine, are effective Oseltamivir resistance In 1977, influenza
against influenza A. However, their use is A(H1N1) re-emerged and co-circulated with
hindered by the rapid emergence of resistance influenza A(H3N2), with the latter remaining
to these drugs together with a high incidence the dominant seasonal human influenza virus
of side-effects. The neuraminidase inhibitors, (fig. 1). During the 2007/2008 influenza
oseltamivir and zanamivir, are effective against season, oseltamivir-resistant seasonal
influenza A and B. Fortunately, although influenza A(H1N1) viruses emerged suddenly
resistance to oseltamivir has been reported, this and spread globally. These viruses carried a
is not widespread in seasonal influenza histidine-to-tyrosine mutation at residue 275
A(H3N2). Oseltamivir is often preferred over of the neuraminidase protein (H275Y).
zanamivir because of ease of administration Laboratory and limited epidemiological data
(oral versus inhaled/intravenous). Other indicated that the viral fitness and virulence
neuraminidase inhibitors are also being of these oseltamivir-resistant influenza
developed, such as peramivir (intravenous). A A(H1N1) viruses were no different from
Cochrane meta-analysis of randomised oseltamivir-susceptible strains.
controlled trials of neuraminidase inhibitors in
the treatment of influenza reported that the In Europe, over the 2008/2009 influenza
efficacy of oral oseltamivir at 75 mg daily was season, influenza A(H3N2) continued to
61% (risk ratio 0.39, 95% CI 0.180.85) and predominate but almost all co-circulating
of inhaled zanamivir at 10 mg daily was 62% seasonal influenza A(H1N1) viruses were
(risk ratio 0.38, 95% CI 0.170.85). In clinical oseltamivir-resistant. In contrast, in the USA,
terms, this benefit translates to a shortening of oseltamivir-resistant influenza A(H1N1)
the illness by 0.51 day. The review found the viruses predominated in the 2008/2009
published evidence insufficient to answer the season, prompting the USA to issue guidelines
question whether neuraminidase inhibitors are recommending the use of zanamivir or a
effective in reducing the complications of lower combination of oseltamivir and rimantadine
respiratory tract infection, antibiotic use, or when seasonal influenza A(H1N1) virus
admissions to hospital. Oseltamivir use was infection was suspected.
associated with nausea (odds ratio 1.79, 95%
CI 1.102.93). H275Y mutations in 2009 pandemic
influenza A(H1N1) viruses have also been
Chemoprophylaxis and vaccination Both identified. Fortunately, such oseltamivir-
oseltamivir and zanamivir taken as resistant isolates have been infrequent and

2009 interstitial infiltrates similar to pulmonary
Pandemic congestion. Progression to respiratory failure is
H1N1 well recognised. Mortality rates of 640%
H1N1#
H3N2 have been reported. In severe cases,
H2N2 pathological findings are similar to those seen
H1N1 in acute respiratory distress syndrome.
1918 1957 1968 1977 2009 Patients with secondary bacterial pneumonia
complicating influenza typically experience an
amelioration of the initial symptoms of viral
Figure 1. Influenza pandemics and subtypes, 1918 infection. However, 410 days later, a
2009. #: re-emergence of H1N1, possibly from recurrence of fever together with
accidental laboratory release strain closely related
breathlessness and a productive cough
to 1950 strain. ": new reassortment of six gene
segments from triple reassortant North American
ensues. Clinical features at this point are
swine influenza virus lineages and two gene indistinguishable from community-acquired
segments from Eurasian swine influenza virus bacterial pneumonia. The three commonest
lineages. pathogens implicated are Streptococcus
pneumoniae, Staphylococcus aureus and
sporadic. They have been found mainly in Haemophilus influenzae.
immunosuppressed patients being treated In children, the commonest respiratory
with oseltamivir. complication, though not the most serious, is
Complications of influenza Although otitis media.
influenza is mostly a self-limiting illness even
In addition to the specific complications listed
without specific treatment, some patient
in table 1, patients with influenza may also
groups experience significant morbidity and
experience a worsening of a pre-existing
mortality. Persons at risk of complications
medical illness such as COPD or cardiac
from influenza include pregnant women, the
failure.
frail elderly, those who are immunosuppressed
and those with chronic medical conditions Management of the complications of
such as heart disease, chronic respiratory influenza should follow the same principles
disease (mostly asthma and chronic for each specific condition regardless of
obstructive pulmonary disease(COPD)), influenza. In the case of influenza A primary
cancer, diabetes, renal disease, rheumatologic viral pneumonia, higher doses of
disease, dementia and stroke. Rates of neuraminidase inhibitors (oseltamivir 150 mg
hospitalisation and death are increased in all b.i.d.) have been advocated based on
these patient groups. experience with human cases of viral
pneumonia resulting from avian influenza A
Pneumonia is the most frequent serious H5N1 infection. There are no randomised
complication of influenza. Two main clinical trials of therapy in primary viral pneumonia.
patterns are described: primary viral
pneumonia and secondary bacterial Pandemic influenza In the 20th century,
pneumonia. pandemics occurred in 1918 (H1N1), 1957
(H2N2) and 1968 (H3N2) (fig. 1). Each of
Patients with primary viral pneumonia these pandemics had a different impact and
typically become breathless within the first tempo. The 1918 pandemic was the most
few days of onset of fever. This may be deadly, claiming the lives of an estimated
associated with tachypnoea, cyanosis and 40100 million people globally. In contrast,
bilateral lung crackles on chest examination. the subsequent two pandemics were much
A leukocytosis is usual. The commonest chest less severe, accounting for an estimated
radiographic abnormality is of diffuse bilateral 12 million deaths each.

Table 1. Complications of influenza in adults and children.
Complication Incidence
Adults Children
Otitis media Common Very common
Secondary bacterial pneumonia Common Uncommon
Primary viral pneumonia Uncommon Uncommon
Myositis Uncommon Rare
Myocarditis Rare Rare
Encephalitis/encephalopathy Rare Rare
Reyes syndrome - Rare
Febrile convulsions - Common
In early April 2009, the first cases of the most H1N1 virus infection. In addition, pregnant
recent influenza pandemic were identified in women, especially in the third trimester and
Mexico. The 2009 pandemic influenza with HIV co-infection, were at higher risk of
A(H1N1) virus is a triple-reassortant virus severe infection. Some non-trial data suggested
containing genes from human, swine and that early treatment of 2009 influenza
avian influenza viruses. It caused an infection A(H1N1) virus infection with neuraminidase
that was clinically similar to seasonal inhibitors reduced the duration of
influenza. Gastrointestinal symptoms amongst hospitalisation and the risk of progression to
adults were commoner than in seasonal severe disease. Many critically ill patients
influenza. Mainly children and young adults received increased doses of antivirals for
were affected and most illnesses were self- extended durations during the pandemic (e.g.
limiting. In persons aged .60 yrs, it is likely oseltamivir 150 mg b.i.d. for 10 days in
that pre-existing cross-reactive antibodies due adults). This practice was not based on
to previous exposure to antigenically related evidence from randomised controlled trials.
influenza viruses provided protection against
infection. Severe acute respiratory syndrome
(SARS)
Compared to the 1918 pandemic,
hospitalisation and mortality rates were low.
Epidemiology The global outbreak of severe
In Canada, the risk of hospital admission
acute respiratory syndrome (SARS) in 2002/
amongst laboratory-confirmed cases was
2003 affected 8,096 individuals in 26
,4.5% and the case-fatality rate was 0.3%.
countries, 774 of whom died. The three most
In the UK, the overall estimated case-fatality
severely affected regions were mainland
rate was 26 per 100,000; lowest for children
China, Hong Kong and Taiwan with 5,327,
aged 514 yrs (11 per 100,000) and highest
1,755 and 674 cases, respectively.
for those aged o65 yrs (980 per 100,000).
Hospitalisation rates varied between
countries. Of those hospitalised, 931% The first human case was identified in the city
required intensive care support, of Foshan, Guangdong Province, China on
predominantly because of diffuse viral November 16, 2002 and the last known case
pneumonitis. Mortality of ICU admitted of the initial outbreak experienced the onset
patients was 1446%. of symptoms on June 16, 2003 in Taiwan.
Patients at risk of complications from seasonal A novel coronavirus, the SARS coronavirus
influenza were similarly at risk from 2009 (SARS-CoV), was identified as the causative

agent of SARS in April 2003. Close human individuals than average. In one SSE at the
animal contact associated with many of the Prince of Wales Hospital, Hong Kong, a single
early cases in China supported the concept of patient infected 143 people.
SARS as a zoonotic infection. The palm civet
cat Paguma larvata has been identified as the Clinical features The clinical presenting
likely main pre-epidemic animal source. Bats features of SARS infection are nonspecific.
are most probably the natural reservoir for Fever (93%), chills (61%), malaise (46%),
coronaviruses. Coronaviruses sharing 8792% cough (41%) and rigors (38%) were the
genome nucleotide identity with SARS-CoV predominant symptoms recorded in the Hong
have been found in horseshoe bats Kong-wide clinical database of SARS patients.
Rhinolophus sp. Accordingly, one hypothesis is High-volume, watery, nonbloody diarrhoea is
that coronaviruses were transmitted from present in a sizeable minority of patients
horseshoe bats to civet cats and then to (,20%) in the early stages of disease and
humans (fig. 2). increases in frequency (up to 70%) by the
second week of illness. It is usually self-
Infections later in the course of the outbreak limiting. Similarly, respiratory symptoms of
were due mainly to human-to-human cough, breathlessness and sputum production
transmission. Molecular evolutionary changes are less frequently (,50%) encountered in
of the SARS-CoV have been described that the first 4 days of illness, but increase to a
might explain the shift in mode of peak (70%) by day 910 of illness. Typically, a
transmission. Nosocomial transmission was dry cough is the first respiratory symptom. This
particularly high, with attack rates amongst is followed by breathlessness, which worsens
healthcare workers in some centres ranging at the start of the second week.
from 1060%. In contrast, community
transmission rates were much lower with
Radiological changes of airspace
typically ,10% of contacts infected.
consolidation are usually unilateral and
The mean incubation period of SARS is localised in the first week. The infiltrates are
estimated at 46 days with a maximum commoner in the lower lobes (70%) and the
incubation period of 10 days. Overall, SARS periphery (75%). Cavitation,
may be considered to be low to moderately lymphadenopathy and pleural effusions are
transmissible. A few remarkable super- not described in association with SARS
spreading events (SSEs) were associated with infection. The extent of radiological
SARS in which single individuals were abnormality correlates with severity of illness
responsible for infecting many more and prognosis.
Horseshoe bat coronavirus Palm civet cat coronavirus with Human SARS-CoV further
with 8792% genome 99.8% genome sequence identity to evolution during course of
sequence identify to human human SARS-CoV epidemic
SARS-CoV
? Single-step transmission
? Natural reservoir Pre-epidemic source Human epidemic
Figure 2. Possible origin of SARS, based on phylogenetic studies.

Laboratory test abnormalities include with the intention of limiting damage that
lymphopenia, neutropenia, thrombocytopenia might be caused by the host immune
and raised levels of lactate dehydrogenase response. In reported series, there were large
(LDH), alanine aminotransferase, creatinine variations in type, dose, route and duration of
kinase, and activated partial thromboplastin corticosteroids used. Unsurprisingly, different
time. conclusions about the efficacies of
corticosteroids were drawn.
Respiratory failure occurs in 2025% of
patients, mainly adults. Unusually, the Basic infection control measures are the
incidence of barotrauma (manifest as a cornerstone of containment of any future
pneumothorax or pneumomediastinum) was outbreak. As subclinical infection with SARS
observed to be higher in severely ill patients has not been described and the peak in viral
with SARS than might be expected despite the load occurs late (second week), effective
use of low-volume, low-pressure mechanical infection control measures can often be
ventilation strategies. The reason for this is instituted prior to widespread transmission.
unclear. Patients with SARS requiring critical
care support have a mortality of ,25%. Practice points regarding the clinical
diagnosis of influenza or SARS
Features associated with a poor prognosis
include advanced age, male sex, presence of The early symptoms in both influenza and
comorbid illness, high serum LDH and SARS are nonspecific, comprising primarily a
neutrophilia at presention, and an initial fever in association with respiratory symptoms
radiograph with more than one zone of such as cough and systemic symptoms such as
involvement. Overall, adults suffer a more malaise or chills. A clinical diagnosis of
severe disease than children. influenza or SARS is therefore crucially
Virology SARS-CoV is detectable by RT-PCR dependent on epidemiological features. In the
and by culture from respiratory tract, faecal case of influenza, an influenza-like illness (ILI)
and urine samples. Virus RNA is also in the setting of local or community
detectable in serum, plasma and circulation of influenza viruses (e.g. during an
cerebrospinal fluid thus indicating influenza season, or during a pandemic)
multisystem infection. Diagnostic yields are greatly increases the likelihood that the illness
better with nasopharyngeal aspirates and is due to influenza virus infection the
faeces compared to throat swabs. A positive predictive value of an ILI for
retrospective diagnosis of SARS is possible laboratory-confirmed influenza can range from
using serological tests. 2070%. Alternative pathogens to consider in
instances of an ILI include parainfluenza virus,
adenovirus, rhinovirus, Mycoplasma
Clinical management The management of
pneumoniae and even S. pneumoniae.
SARS is chiefly supportive. Chemical
Similarly, a clinical diagnosis of SARS requires
compounds that have reported activity
the establishment of an epidemiological link
against SARS-CoV include glycyrrhizin,
with another patient with SARS, or exposure
baicalin, reserpine, noclosamide, ribavarin,
to likely animal sources of SARS-CoV.
protease inhibitors (lopinavir, nelfinavir),
Virological testing is necessary to make a
interferon (IFN)-a and IFN-b. A comparative
definitive diagnosis in both influenza and
study using IFN alfacon-1 (n522), and
SARS.
another using a lopinavir/ritonavir
combination (n541), suggested clinical References
benefit. However, there are no randomised
controlled trials of treatment. N Cleri DJ, et al. Severe acute respiratory syndrome
(SARS). Infect Dis Clin North Am 2010; 24:
175202.
Corticosteroids were used during the SARS N Jefferson T, et al. Neuraminidase inhibitors for
outbreak as an immunomodulatory agent preventing and treating influenza in healthy

adults. Cochrane Database Syst Rev 2010; 2: N Palese P Influenza, old and new threats. Nat
CD001265. Med 2004; 10: S82S87.
N Lew TW, et al. Acute respiratory distress N Peiris JS, et al. The severe acute respiratory
syndrome in critically ill patients with severe syndrome. N Engl J Med 2003; 349: 24312441.
acute respiratory syndrome. JAMA 2003; 290: N Writing Committee of the WHO Consultation on
374380. Clinical Aspects of Pandemic (H1N1) 2009
N Miller E, et al. Incidence of 2009 pandemic Influenza, Clinical aspects of pandemic 2009
influenza A H1N1 infection in England: a cross- influenza A (H1N1) virus infection. N Engl J
sectional serological study. Lancet 2010; 375: Med 2010; 362: 17081719.
11001108. N Yip CW, et al. Phylogenetic perspectives on the
N Monto AS, Whitley RJ Seasonal, pandemic epidemiology and origins of SARS and SARS-like
influenza, a 2007 update on challenges and coronaviruses. Infect Genet Evol 2009; 9:
solutions. Clin Infect Dis 2008; 46: 10241031. 11851196.

CHAPTER 8:
TubERCuloSiS
PulmonARy TubERCuloSiS 200

G. Sotgiu, C. Lange and G.B. Migliori
ExTRAPulmonARy TubERCuloSiS 209

A. Bossink
TubERCuloSiS in THE 212

immunoComPRomiSEd HoST
M. Sester
lATEnT TubERCuloSiS 215

J-P. Zellweger
nonTubERCulouS myCobACTERiAl diSEASES 218

C. Piersimoni

PULMONARY TUBERCULOSIS
G. Sotgiu1, C. Lange2 and G.B. Migliori3
1
Hygiene and Preventive Medicine Institute, University of Sassari, Sassari
2
Division of Clinical Infectious Diseases, Medical Clinic, Research Center
Borstel, Borstel, Germany
3
WHO Collaborating Centre for TB and Lung Diseases, Fondazione S.
Maugeri, Care and Research Institute, Tradate, Italy
E-mail: giovannibattista.migliori@fsm.it
The World Health Organization (WHO) has typically associated with granuloma
declared tuberculosis (TB) a global emergency formation.
due to its burden in terms of cases and
deaths. Among the factors contributing to Aetiology
maintenance of the TB pandemic are: the
TB is an infectious disease caused by slightly
large number of patients co-infected with HIV;
bent, thin, aerobic, non-motile, non-spore-
bacterial multidrug resistance (MDR) to anti-
forming beaded rods belonging to the family
TB drugs (i.e. strains resistant to at least
Mycobacteriaceae and to the order
isoniazid and rifampicin); migration from high-
Actinomycetales. Of the pathogenic species
incidence countries; and the social
belonging to the Mycobacterium tuberculosis
determinants of the disease (poverty, drug
abuse and homelessness). complex, the most frequent and important
agent of human disease is M. tuberculosis.
TB can affect virtually every organ, most Mycobacteria are 24 mm long and 0.25 mm
importantly the lungs (pulmonary TB), and is wide. They are defined as acid-fast bacilli
(AFB) due to the cell wall structure, crucial to
their survival and characterised by a
Key points significant content of mycolic acid attached to
the underlying peptidoglycan-bound
N With 9.27 million new cases (0.5 being polysaccharide arabinogalactan. Another
multidrug-resistant tuberculosis) and important carbohydrate structural antigen
1.77 million deaths, tuberculosis is a of the cell wall is lipoarabinomannan,
first-class health priority. which facilitates the survival of
N Diagnosis of pulmonary tuberculosis is mycobacteria within macrophages. The
peptidoglycan network, located just
simple, being primarily based on
outside the cell membrane, confers cell
bacteriology (sputum smear microscopy
wall rigidity.
and culture).
N Treatment of pan-susceptible cases of This structure provides a barrier that is
pulmonary tuberculosis is effective and responsible for many of the medically
cheap. challenging characteristics of TB, including
resistance to antibacterial agents and to
N Management of pulmonary host defence mechanisms. It has been
tuberculosis in multidrug-resistant and clearly demonstrated that the quality and
HIV co-infected cases is particularly quantity of the cell wall components affect
complicated. mycobacterial virulence, pathogenicity and
growth rate.

Pathogenesis immunocompetent, the next defensive stage
is formation of granuloma around
Mycobacteria are spread through air droplets
mycobacteria, which limits bacterial
expelled when those with infectious
replication and spread to other pulmonary
pulmonary TB cough, sneeze or speak. Close
sites. This condition establishes latency of the
contacts (those with prolonged, frequent or
infection. Lesions in those with an adequate
intense contact with pulmonary TB sufferers)
immune system generally undergo fibrosis
are at highest risk of becoming infected.
and calcification, while in
Bacteria are carried on droplet nuclei in the
immunocompromised subjects, they progress
air and can enter the body through the
to primary progressive pulmonary TB.
airways. The majority of the bacilli are
trapped in the upper parts of the airways The majority of infected individuals who
where the mucus-secreting goblet cells are ultimately develop pulmonary TB do so within
located. The mucus catches antigens, and the the first year or two after infection; dormant
cilia on the surface of the cells constantly bacilli, however, may persist for years before
beat the mucus and its entrapped particles being reactivated to produce secondary
upward for removal. This system provides pulmonary TB, which is often infectious.
humans with an initial physical first-line Overall, it is estimated that lifetime risk of
defence that prevents infection in most developing TB is 10% in those who are
contacts of pulmonary TB patients. immunocompetent and f50% in HIV-
Bacteria in small droplets that can bypass the positive individuals. Age is an important
mucociliary system and reach the alveoli are determinant of the risk of disease after
quickly surrounded and engulfed by alveolar infection. Among infected subjects, the
macrophages, which are part of the innate incidence is highest in childhood up to the
immune system and are the most abundant age of 8 yrs, with a second peak during
phagocytic cells located in the alveolar adolescence and early adulthood. The risk
spaces; they are readily available without may increase in the elderly, possibly because
requiring previous exposure. Numerous of waning immunity and comorbidities (i.e.
bacterial and host mechanisms are involved in diabetes).
the uptake of the mycobacteria, such as
Epidemiology
mycobacterial lipoarabinomannans, ligands
for macrophages receptors or the WHO estimates that 9.27 million new cases
complement proteins C2a and C3b that bind of TB occurred in 2007 compared with
to the cell wall and enhance recognition of 9.24 million in 2006. Of them, an estimated
the mycobacteria by effector macrophages. 44% or 4.1 million were infectious (new
The subsequent phagocytosis starts a cascade pulmonary sputum smear-positive cases).
of events that results in successful control of India, China, Indonesia, Nigeria and South
the infection, followed by latent TB infection Africa have the highest numbers of incident
(LTBI) in the majority of cases; rarely, infection cases. Asia (South-East Asia and the Western
progresses to active disease, called primary Pacific region) accounts for 55% of global
progressive pulmonary TB (common among cases and Africa for 31%; the other three
children aged f4 yrs). The outcome is regions (the Americas, Europe and the Eastern
essentially determined by the balance that
Mediterranean region) account for small
occurs between host defences and the
fractions of global cases. Among the 15
invading mycobacteria.
countries with the highest estimated TB
During the initial phase (212 weeks) of incidence rates, 13 are in Africa, a
pulmonary TB, the bacteria continue to phenomenon linked to high rates of HIV co-
multiply slowly (a cell division every 2535 h) infection. In both the African and European
and T-lymphocytes are attracted by cytokines regions, prevalence rates increased
released by macrophages. In the substantially during the 1990s.
Pulmonary tuberculosis 201

There were an estimated 13.7 million In the majority of cases, the lesion heals
prevalent cases of TB in 2007, a slight spontaneously and may later be evident as a
decrease from 13.9 million in 2006. Of small calcified nodule (Ghon lesion). If the
these cases, an estimated 5% were HIV primary lesion enlarges, mainly seen in
positive. Of the 511,000 incident cases children and in individuals with impaired
of MDR-TB in 2007, 68% were sputum immunity, pleural effusion is a typical finding.
smear-positive. This effusion develops because the bacilli
infiltrate the pleural space from an adjacent
Overall, 1.77 million TB deaths occurred in subpleural focus. The effusion may remain
2007. An estimated 456,000 were of people small, resolving spontaneously, or it may
who were HIV-positive. Deaths from TB among become large enough to induce clinical
HIV-positive individuals accounted for 23% of symptoms such as fever, pain and dyspnoea.
the estimated 2 million HIV deaths that
occurred in 2007. Secondary pulmonary TB Secondary
pulmonary TB results from endogenous
The World Health Assembly outcome targets reactivation of LTBI and is frequently localised
(i.e. to achieve a case-detection rate of o70% to pulmonary segments, where the high
for new smear-positive cases and a treatment oxygen concentration favours mycobacterial
success rate of o85% for such cases) provide replication (upper lobes).
a quantitative indication of the effectiveness
of national TB programmes in finding,
Early signs and symptoms are often
diagnosing and successfully treating those
nonspecific and insidious, consisting mainly of
with TB.
fatigue (decreased muscle mass), general
The 2.6 million new smear-positive cases in malaise, weakness, weight loss (lack of
2007 represent 64% of the 4.1 million appetite and altered metabolism associated
estimated cases. This is a small increase from with systemic inflammatory response to
63% in 2006, following a slow increase from mycobacteria), and a low-grade fever
35 to 43% between 1995 and 2001, and a accompanied by chills and night sweats.
more rapid increase from 43 to 60% between Cough eventually develops in the majority of
2001 and 2005. Africa had the lowest case- patients; it could be initially non-productive,
detection rate (47%). Globally, the rate of but subsequently it may be accompanied by
treatment success was 85% in 2006; the the production of purulent sputum often
target for treatment success was reached streaked with blood. Haemoptysis may be due
because of the high treatment success rates to: the destruction of a vessel located in a
reported from South-East Asia and the pulmonary cavity; the rupture of a dilated
Western Pacific region (87 and 92%, vessel in a cavity (Rasmussens aneurysm); or
respectively). the formation of an aspergilloma in an old
cavity. In some patients, the presence of
Clinical features inflamed subpleural parenchyma may cause
pleuritic pain. Extensive disease may lead to
Before the recognition of HIV infection,
dyspnoea or orthopnoea. Although numerous
.7580% of all TB cases were limited to the
lungs. In recent decades, increases have been individuals with pulmonary TB have no
seen in extrapulmonary cases alone, and in physical characteristics, rales may be detected
over involved areas during inspiration,
pulmonary and extrapulmonary cases.
particularly after coughing. Haematologic
Primary pulmonary TB Pulmonary examinations might reveal mild or moderate
mycobacterial entry is often asymptomatic. anaemia, strictly related to the weakness, and
Associated paratracheal lymphadenopathy leukocytosis. Chronic cough (e.g. cough
may occur because the bacilli spread from the lasting for 23 weeks) has to be considered
lungs through the lymphatic system. the main clinical symptom.

Diagnosis order to better define the phenotype of the
isolated strain in culture-confirmed cases.
At .100 yrs old, sputum smear microscopy is
still the most widely used technique for the Molecular techniques, based on gene
diagnosis of pulmonary TB. Although highly amplification, offer increased sensitivity and
specific, the lower limit for detection of specificity for diagnosis. The major limitation,
microscopy is 0.516104 organisms?mL-1 mainly for low-income countries, is their
sputum and only about half of all culture- current high cost and the risk of
positive cases have sputum smear-positive contamination (false-positive results).
results. There is evidence that sensitivity may
be lower among HIV-infected subjects. AFB Chest radiology (fig. 1) and computed
microscopy is simple to perform but tomography (CT) are useful tools that
suboptimal results are described where complement bacteriological examinations in
adequate quality-assurance programmes are the diagnosis of pulmonary TB. Although over-
absent. WHO has proposed a case definition and under-reading have been described, these
for sputum smear-negative pulmonary TB tools can offer important information to the
based on three negative sputum smears, clinician. Chest radiography is commonly used
radiographic abnormalities consistent with to screen individuals harbouring a
active pulmonary TB, and no response to a significantly higher risk of pulmonary TB (e.g.
course of broad-spectrum antibiotics. prisoners, contacts of infectious cases, etc.)
Although smear-negative pulmonary TB cases than the general population. Among the tools
are not considered to be infectious, their high indirectly used to detect mycobacterial
number is causing increasing concern in high infection, the tuberculin skin test (TST)
HIV-prevalence, low-income settings. deserves to be mentioned; it must be noted,
however, that it has several limitations,
Sputum induction with hypertonic saline is a including poor specificity, difficult
useful technique for diagnosing pulmonary TB administration and the risk of anergy.
in individuals who are either sputum smear
negative or unable to produce sputum.
Repeated sputum induction increases the
yield of both smear and culture. It avoids
invasive procedures and provides a means of
diagnosis in resource-poor settings. It is worth
noting that sputum induction should be
carefully conducted in a well-ventilated
setting, as it is a cough-inducing procedure
with a high risk of transmission.
Mycobacterial culture is considered the gold
standard; however, false-positive results do
occur, primarily as a consequence of
laboratory contamination. Moreover, several
weeks are required for the performance of
culture-based methods, although the use of
liquid media has decreased pulmonary TB
diagnosis time. Presently, in Europe, a
definite case of TB is a culture-positive case,
while all other cases (including culture Figure 1. Pulmonary tuberculosis due to multidrug-
negative, sputum smear positive) are other resistant strains of Mycobacterium tuberculosis. A
than definite. Drug susceptibility testing for 21-yr-old female with isolated left upper lobe
first- and second-line drugs is also useful in infiltrate.

False-negative reactions are common in line anti-TB drugs, including isoniazid,
immunosuppressed patients and in those with rifampicin, pyrazinamide and ethambutol for
overwhelming pulmonary TB. Positive results 2 months, followed by isoniazid and
are obtained when patients have been rifampicin for 4 months (tables 1 and 2).
infected with M. tuberculosis but do not have Because of the higher probability of drug
active disease, and when subjects have been resistance, re-treatment cases (Category II)
sensitised by nontuberculous mycobacteria or require a fifth drug during the continuation
bacille Calmette-Gue`rin (BCG) vaccination. phase (streptomycin for 2 months). Both the
intensive and the continuation phases of
Finally, interferon (IFN)-c release assays treatment (3 and 5 months, respectively) are
(IGRAs) have recently been introduced into longer in Category II than in Categories I and
clinical practice. Their application in III (table 2).
specimens collected from the infected organ
or tissue is still under evaluation. These MDR-TB is caused by mycobacteria that are
techniques can increase the low specificity of resistant to at least isoniazid and rifampicin,
TST based on the immune response (release of the two most potent first-line anti-TB drugs.
IFN-c) to early-secreted antigenic target While MDR-TB has been documented for
protein (ESAT)-6 and culture filtrate protein many years, a new term, extensively drug-
(CFP)-10, which are antigens specific to resistant (XDR)-TB, appeared in the literature
M. tuberculosis and are not produced by for the first time in March 2006. It describes a
Mycobacterium bovis BCG. severe form of TB caused by strains of M.
tuberculosis that are resistant to at least
Treatment isoniazid and rifampicin (i.e. MDR-TB), as well
as any fluoroquinolone and at least one of
Due to their higher bacillary burden, three injectable drugs used in anti-TB
individuals with active TB and positive treatment: capreomycin, kanamycin and/or
sputum smear test results are the main source amikacin.
of TB transmission in the community. The
highest priority in TB control programmes is To achieve a regimen designed to treat the
the rapid identification of new cases of majority of patients with a minimum of four
sputum smear-positive pulmonary TB and effective drugs as is recommended, it may be
effective treatment. It has been estimated that necessary to use five, six or more drugs to
case-finding and effective treatment of smear- cover all the possible patterns of resistance
positive individuals could decrease the when drug susceptibility testing (DST) results
number of TB cases globally by one half for second-line agents are not available
within a decade. (table 3). An injectable agent and a
fluoroquinolone form the core of the preferred
The longer the interval between doses, the regimen.
easier and less expensive the task of providing
treatment to large numbers of patients, The most recent WHO guidelines propose
particularly in high-prevalence countries. different treatment strategies for individuals
Short-course regimens are divided into an suspected to harbour MDR-TB strains.
initial or bactericidal phase and a Depending on specific country conditions,
continuation or sterilising phase. Pan- treatment protocols may recommend a
susceptible TB is defined as TB susceptible to standardised treatment regimen for all MDR-
all first-line agents. TB cases (e.g. in countries where DST is not
widely available), or may alternatively
WHO recommends treatment of new cases of recommend individualised treatment based
pulmonary TB (both sputum smear-positive on individual DST results. If standardised
cases, belonging to Category I, and sputum combinations of second-line drugs are chosen,
smear-negative cases, belonging to Category representative national data on predominant
III) with a standardised regimen of four first- resistance patterns to specific treatment

Table 1. Anti-tuberculosis (TB) drugs, dosages and common adverse effects
Common adverse effects (not
Anti-TB drugs Recommended daily dosage
exclusive)
Group 1: first-line oral agents
Isoniazid 5 mg?kg-1 q.d. Elevated transaminases; hepatitis;
Should not exceed 300 mg per day peripheral neuropathy;
Always consider co-administering vitamin B6 GI intolerance; CNS toxicity
Rifampicin 10 mg?kg-1 q.d. Elevation of liver enzymes; hepatitis;
.50 kg: 600 mg; ,50 kg: 450 mg hypersensitivity; fever;
gastrointestinal disorders: anorexia,
nausea, vomiting, abdominal pain;
discoloration (orange or brown) of
urine, tears and other body fluids;
thrombopenia
Ethambutol 1525 mg?kg-1 q.d. Optic neuritis; hyperuricaemia;
Maximum 2.0 g per day peripheral neuropathy (rare)
Pyrazinamide 30 mg?kg-1 q.d. Arthralgia; hyperuricaemia; toxic
Maximum 2.0 g per day hepatitis; gastro-intestinal discomfort
Group 2: injectables
Streptomycin# 0.751 g q.d. Auditory and vestibular nerve
,50 kg: 0.75 g per day; .50 kg: 1 g per day damage (non-reversible); renal failure
Maximum cumulative dose 50 g (usually reversible); allergies;
nausea; skin rash, neuromuscular
blockade
Amikacin" 0.751 g q.d. Auditory and vestibular nerve
blockade
Capreomycin# 0.751 g q.d. Auditory and vestibular nerve
Maximum cumulative dose 50 g (usually reversible); Bartter-like
syndrome; allergies; neuromuscular
blockade
Kanamycin" 375500 mg b.i.d. Auditory and vestibular nerve
blockade
Group 3: fluoroquinolones
Levofloxacin+ 5001,000 mg q.d. Gastrointestinal discomfort, CNS
disorders, tendon rupture (rare);
hypersensitivity
Clostridium difficile colitis
Ciprofloxacin+ 500750 mg b.i.d. Gastrointestinal discomfort, CNS
disorders, tendon rupture (rare);
hypersensitivity

Table 1. Continued
Moxifloxacin+ 400 mg q.d. Gastrointestinal discomfort;
headache; dizziness,
hallucinations;
increased transaminases
QT prolongation:
Group 4: second-line oral agents
Rifabutin 150450 mg q.d. Anaemia; gastrointestinal discomfort;
Consider to monitor drug levels discoloration (orange or brown) of
urine and other body fluids; uveitis;
elevated liver enzymes
Ethionamid 0.751 g q.d. Severe gastrointestinal intolerance;
nausea; vomiting; hepatitis; CNS
disorders
Prothionamide 0.751 g q.d. Severe gastrointestinal intolerance;
nausea; vomiting; hepatitis; CNS
disorders
Cycloserine 250 mg t.i.d. CNS disorders; anxiety; confusion;
Maximum 1,000 mg per day dizziness; psychosis; seizures;
headache
Terizidone 250 mg t.i.d. CNS disorders; anxiety; confusion;
Maximum 1,000 mg per day dizziness; psychosis; seizures;
headache
Para-amino- 4 g t.i.d. Gastrointestinal intolerance; nausea;
salicylic acid diarrhoea; vomiting; hypersensitivity
Thiacetazone 50 mg t.i.d. Hypersensitivity; gastrointestinal
intolerance; vertigo; hepatitis
Group 5: oral reserve drugs with uncertain anti-TB activity
Linezolid 600 mg q.d. Thrombopenia, anaemia, neuropathy
(recommended for 600 mg b.i.d. dosage for
MRSA and VRE infections)
Clofazimine 100 mg q.d. Ichthyosis; gastrointestinal
discomfort; nausea; vomiting;
discoloration of the skin
Amoxicillin-- 875125 mg b.i.d. or 500250 mg t.i.d. Gastrointestinal discomfort;
clavunate diarrhoea; rash
Clarithromycin 500 mg b.i.d. Gastrointestinal discomfort
CNS: central nervous systemMRSA: methicillin-resistant Staphylococcus aureus; VRE: vancomycin-resistant Enterococcus.
#
: intravenous/intramuscular administration only; ": intravenous administration only; +: also available for intravenous injection.
categories are needed. An alternative Although an individual patients treatment

approach is to design a regimen on the basis duration should be guided by sputum smear
of the individual history of previous anti-TB and culture conversion, in general an
therapy, and eventually redesign it guided by injectable agent should be continued for at
individual DST. Relevant laboratory capacity is least the first 6 months of treatment. The
necessary if this option is chosen, as DST on entire treatment should be no less than
most second-line drugs must be performed. 18 months after culture conversion.

Table 2. World Health Organization (WHO)-recommended treatment categories and regimens
Patient treatment Patient diagnostic Treatment regimens#
category category Initial phase Continuation
phase
New pulmonary TB cases
Category I New smear-positive Preferred: 2 HRZE Preferred: 4 HR;
patients, new smear- Optional: 2 HRZE 4 HR3
negative patients with Optional: 2 HRZE3" Optional: 6 HE
extensive parenchymal Optional: 4 HR3
involvement, concomitant
HIV-related diseases
Category III New smear-negative Preferred: 2 HRZE Preferred: 4 HR, 4
pulmonary TB (other Optional: 2 HRZE HR3
than in Category I) Optional: 2 HRZE3 Optional: 6 HE
Optional: 4 HR3
Re-treatment pulmonary TB cases
Category II Relapses, treatment Preferred: 2 HRZES/1 HRZE Preferred: 5 HRE
after default+ Optional: 2 HRZES3/1 Optional: 5 HRE3
HRZE3
TB: tuberculosis; H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol; S: streptomycin. #: Numbers preceding regimens
indicate the length of treatment in months. Numbers following regimens indicate the frequency of administration per
week. Where no number is given after the regimen, administration is daily. ": The thrice weekly treatment was less effective
than daily treatment as measured by conversion rates at 2 months, with a suggestion of less favourable outcomes overall;
although the difference in outcome from the 8-month daily regimen was negligible. +: In settings with proven high
prevalence of drug-resistant or multidrug-resistant TB cases, national programmes can design standardised regimens or can
allow the use of individualised regimen, including second-line drugs to treat treatment failures of Category I.
Table 3. General principles for designing an empiric regimen to treat multidrug-resistant tuberculosis
Basic principles Comments
Use at least four drugs of Effectiveness is supported by a number of factors (the more of them that
known effectiveness or that are present, the more likely it is the drug will be effective):
are highly likely to be 1) susceptibility seen upon drug susceptibility testing
effective 2) no previous history of treatment failure with drug
3) no known close contacts with resistance to drug
4) drug resistance screening indicates resistance is rare in similar patients
5) no common use of drug in the area
If at least four drugs are not certain to be effective, use from five to seven
drugs, depending on the specific drugs and level of uncertainty
Do not use drugs for which 1) Rifamycins (rifampicin, rifabutin, rifapentin, rifalazil): have high level of
resistance crosses over cross-resistance
2) Fluoroquinolones: variable cross-resistance; in vitro data show some
higher-generation agents remain susceptible when lower-generation agents
are resistant (clinical significance of the phenomenon still unknown)
3) Aminoglycosides and polypeptides: not all cross-resist; in general, only
kanamycin and amikacin fully cross-resist
Eliminate drugs likely to be 1) Known severe allergy or difficult-to-manage intolerance
unsafe for the patient 2) High risk of severe adverse effects, including renal failure, deafness,
hepatitis, depression and/or psychosis
3) Unknown or questionable drug quality

Table 3. Continued
Include drugs from groups 1) Use any group 1 (oral first-line) drugs that are likely to be effective (see
15 in a hierarchical order, the first entry in the Comments column of this table)
based on potency 2) Use an effective injectable aminoglycoside or polypeptide (group 2)
3) Use a fluoroquinolone (group 3)
4) Use the remaining group 4 drugs to create a regimen consisting of at
least four effective drugs. For regimens with up to four effective drugs, add
second-line drugs that are likely to be effective, to give up to five to seven
drugs in total, with at least four of them highly likely to be effective. The
number of drugs will depend on the degree of uncertainty
5) Use group 5 drugs as needed so that at least four drugs are likely to be
effective
Be prepared to prevent, 1) Ensure laboratory services for haematology, biochemistry, serology and
monitor and manage audiometry are available
adverse effects for each of 2) Establish a clinical and laboratory baseline before starting the regimen
the drugs selected 3) Initiate treatment gradually for a difficult-to-tolerate drug, splitting daily
doses of Eto/Pto, Cs and PAS
4) Ensure ancillary drugs are available to manage adverse effects
5) Organise intake supervision for all doses
Eto: ethionamide; Pto: prothionamide; Cs: cycloserine; PAS: P-amino salicylic acid.
Treatment with second-line anti-TB Principles and Practice of Infectious Diseases.

chemotherapy in MDR- and XDR-TB is 6th Edn. Philadelphia, Churchill Livingstone,
frequently influenced by the occurrence of 2005; pp. 28522886.
adverse drug events. Unfortunately, reliable N Frieden TR, et al. Tuberculosis. Lancet 2003;
362: 887899.
indicators to individually guide the duration
of anti-TB drug treatment are not available.
N Hopewell PC, et al. International standards for
tuberculosis care. Lancet Infect Dis 2006; 6:
For all the reasons previously listed, treatment 710725.
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managed in highly specialised reference clinical features and diagnosis. Crit Care Nurse
centres, identified by national authorities. 2009; 29: 3443.
Scaling-up of culture and DST capacities, and
N Mack U, et al. LTBI: latent tuberculosis infection
or lasting immune responses to M. tuberculosis?
the expanded use of high-technology assays for A TBNET consensus statement. Eur Respir J
rapid determination of resistance are necessary 2009; 33: 956973.
if better control of MDR- and XDR-TB is to be N Raviglione MC, OBrien RJ. Tuberculosis. In: Fauci
achieved. The majority of resistant cases can be AS, et al., eds. Harrisons Principles of Internal
treated successfully if well-designed regimens Medicine. 17th Edn. New York, McGraw-Hill Medical
are used and surgical options are carefully Publishing Division Inc., 2008; pp. 10061020.
considered. Nevertheless, the development of N Sotgiu G, et al. Epidemiology and clinical
new (more effective and less toxic) drugs to management of XDR-TB: a systematic review by
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N World Health Organization. Global tuberculosis
control 2009. Epidemiology, Strategy, Financing.
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EXTRAPULMONARY
TUBERCULOSIS
A. Bossink
Diakonessenhuis, Utrecht, The Netherlands
E-mail: aikbossink@mac.com
The World Health Organization (WHO) definition because in countries with a

definition of extrapulmonary tuberculosis differentiated registry (PTB, EPTB, and
(EPTB) is: A patient with tuberculosis of EPTB+PTB), EPTB localisations comprise
organs other than the lungs, e.g. pleura, nearly 50% of all the cases.
lymph nodes, abdomen, genito-urinary tract,
skin, joints and bones, and meninges. In low-income countries, males appear to be
Diagnosis should be based on one culture- affected by tuberculosis (TB) more often than
positive specimen, or histological or strong females. However, this difference is not so
clinical evidence consistent with active clear in high-income countries; the mechanism
extrapulmonary disease, followed by a is not clearly understood. No evidence is
decision by a clinician to treat with a full available to suggest that EPTB affects one of
course of anti-tuberculosis chemotherapy. the sexes more frequently.
A patient diagnosed with both pulmonary Immunosuppression appears to be an

tuberculosis (PTB) and EPTB should be important cause for EPTB and is reflected by a
classified as a case of PTB. sharp incline in reported cases of EPTB with
the rise of the incidence of HIV infection.
The definition mentions neither the eyes nor In high-income countries, and countries with
the earnosethroat region. However, these a lower incidence of HIV infection,
tissues are also, but scarcely, possible biological agents like tumour necrosis factor-a
localisations. inhibitors are relatively important causes
General aspects of EPTB of EPTB.
Only a minority of cases (,30%) suffer from The result of tuberculous bacillaemia must
EPTB. However this could be biased by the be the insemination in various parts of the
body of foci most of which remain latent.
Therefore, EPTB can be the result of a primary
Key points infection in severely immunocompromised
hosts or can be the result of reactivation of
N EPTB localisations appear in up to 50% dormant bacilli in previously infected subjects.
of TB patients.
Sites of EPTB
N Obtaining culture confirmation is
essential in the treatment of both PTB The two most common localisations of EPTB
and EPTB. are the cervical lymph nodes and the
pulmonary pleura. Other sites are, in declining
N Treatment of EPTB does not differ from order, bones and joints, meninges and central
PTB in the majority of EPTB nervous system (CNS), abdominal lymph
localisations. nodes, peritoneum and gastrointestinal tract,
genito-urinary tract and pericardium.
Extrapulmonary tuberculosis 209

It should be noted that gastric aspirate in full course of at least four anti-TB drugs
children with PTB often contains (isoniazid, rifampicin, ethambutol and
mycobacteria. This is, however, not an pyrazinamide) in the first 2 months and than
indication of EPTB but should be considered another 47 months of isoniazid and rifampicin
as a local spread of mycobacteria by in culture confirmed cases with normal drug
swallowing sputum. susceptibility [D]. In countries with a high
prevalence of drug resistance for one or more of
In immunocompromised hosts, the
these drugs, a fifth or even sixth drug should be
presentation of EPTB is often different
compared with immunocompetent hosts. added awaiting culture and DST.
Dissemination of the disease is more common
Specific localisations
and clinicians should be aware of other
localisations. Dissemination is more likely Cervical lymph nodes Involvement of the
because ill-formed granuloma occur more lymph nodes or lymphadenitis is the most
frequently in immunocompromised hosts. common localisation of EPTB. Concomitant
The term miliary TB refers to a radiological pulmonary infection occurs in 510% of the
finding of the chest radiography and should cases and therefore generalised symptoms are
not be used in this context. unusual. During medical treatment the lymph
nodes can rapidly increase in size (paradox
Diagnosis reaction) and to prevent fistula, fine-needle
aspiration of its content may prove beneficial.
In countries with all possible diagnostic
In children, lymphadenitis is often caused by
resources on average 70% of all the TB cases
are culture confirmed. One can imagine that in nontuberculous mycobacteria and this
EPTB samples are more difficult to obtain requires a different treatment approach.
compared with PTB. Furthermore some of the Confirmation of the causative organism is
EPTB localisations contain only few therefore crucial.
mycobacteria. Culture or PCR confirmation will
thus be lower in these cases. Using the Dutch Other lymph nodes Other common sites of
TB registry PTB is culture confirmed in nearly lymph node involvement are axillary, inguinal
80% and EPTB in about 60% of the cases. and abdominal. Culture results
(Mycobacterium tuberculosis versus
Specific staining is in low-income countries nontuberculous mycobacteria) for these
often the only available diagnostic tool and localisations do not differ between children
because of the relative simplicity should and adults.
always be undertaken.
Some promising reports on interferon-c TB of the pleura In general, the pleurisy is
release assays in the diagnosis of EPTB one sided and the majority of cases have a
(pleural and meningitis TB) have been tendency toward spontaneous resolution.
published. However, these tests are no proof Therefore the diagnosis can be delayed for a
of active infection, they will not provide prolonged period until a new effusion
culture results or drug susceptibility reports appears. Large amounts of pleural fluid are
and can therefore only be supportive in the often observed with relatively low numbers of
search for mycobacteria. However, it remains mycobacteria. An accompanying
most important to obtain materials for culture hypersensitivity reaction is held responsible
and drug susceptibility tests (DST). for this phenomenon. Because of this low
bacterial burden, the confirmation of TB can
Treatment
often be difficult. TB empyema is a rare
In general, treatment for EPTB does not differ condition compared with pleurisy and often
from that for PTB. Depending on local or requires surgical drainage and decortication
national guidelines, the treatment consists of a combined with medical treatment.

TB of the meninges and CNS Meningitis is Bone and joint TB Any bone or joint can be
the most common presentation of affected, but the classical lesion is a fracture
involvement of the nervous system. The of the vertebrae resulting in a kyphotic
infection can cause hydrocephalus and change of the spine (Potts disease). In
through involvement of the cranial nerves general, the larger bones and joints are more
paralysis of the nervus abducens. Classically often affected compared with the smaller
the patient is not able to look outward with ones. Joint involvement presents as a mono-
one eye and this eye is rotated towards the arthritis. Diagnosis of both bone and joint
nose. Neurological deterioration is classified involvement is generally made by biopsy.
in three grades based on the performance on Aspiration of synovial fluid seldom yields the
the Glasgow Coma Scale. Apart from diagnosis. Medical treatment is the treatment
antibiotic treatment, it is recommended to of choice and should be prolonged to
add steroids (0.5 mg?kg-1) in stages II and III. 9 months. Surgery is reserved for complicated
Survival is positively influenced by this cases such as neurological involvement or
regimen, but neurological outcome is not instability of the spine.
better in the groups treated with steroids.
Others recommend steroids independent of References
the stage. Antibiotic treatment should be at
least 9 months. However, according to the N World Health Organization. Global tuberculosis
control epidemiology, strategy, financing.
British guidelines, treatment should be
Geneva, WHO, WHO/HTM/TB/2009.411.
continued for 1 yr. The WHO recommends to N Wilkinson MC. Pathogenesis of non-pulmonary
replace ethambutol by streptomycin in TB tuberculosis. Br Med J 1940; 2: 660661.
meningitis N Thwaites GE, et al. Dexamethasone for the
treatment of tuberculous meningitis in
TB of the pericardium This condition is adolescents and adults. N Engl J Med 2004;
sometimes difficult to diagnose because, just 351: 17411751.
like pleural effusion, the bacterial load is low. N Thwaites G, et al. British Infection Society
Pericardial effusion and, at a later stage, guidelines for the diagnosis and treatment of
tuberculosis of the central nervous system in
constrictive pericarditis can cause severe
adults and children. J Infect 2009; 59: 167187.
inflow limitation resulting in serious
haemodynamic problems. Steroids are Weblinks
recommended to reduce the effusion and to
prevent thickening of the pericardium
N www.who.int/tb/publications/global_report/en/.
adjuvant. No data is available on the amount
N ecdc.europa.eu/en/publications/Publications/
1003_SUR_tuberculosis_surveillance_in_
and duration of steroid treatment. It appears europe_2008.pd.
reasonable to prescribe 0.5 mg?kg-1 for the N www.kncvtbsurvey.nl/ziekte/index.php.
first 2 months and than decrease the dose N www.who.int/tb/publications/
gradually to zero over a period of 4 months. tb_treatmentguidelines/en/index.html.
Extrapulmonary tuberculosis 211

TUBERCULOSIS IN THE
M. Sester
Dept of Transplant and Infection Immunology, Institute of Virology,
University of the Saarland, Homburg, Germany
E-mail: martina.sester@uks.eu
The incidence of active tuberculosis (TB)

is increased in patients with impaired cellular Key points
immunity, such as HIV-infected patients,
solid-organ and stem cell transplant recipients, N TB has a higher incidence among
patients receiving tumour necrosis factor people with impaired cellular immunity.
(TNF)-a antagonists and patients with N Diagnosis is often delayed owing to
end-stage renal failure. This emphasises the early lack of symptoms or unusual
particular importance of the cellular arm of
presentation.
the adaptive immune response for efficient
control of Mycobacterium tuberculosis. N Screening for latent TB infection prior
Moreover, the presence of M. tuberculosis- to immunosuppresive treatments can
specific CD4 T-cell immunity is used as a be a useful preventive measure.
surrogate marker for a previous contact.
Consequently, a detailed knowledge of the
pathomechanisms leading to increased
incidence of TB in immunocompromised
percentage of false-negative diagnoses by
patients has also contributed to a better
immune-based tests. Similarly,
understanding of the principles of
immunosuppressive drug-treatment after
decreased test sensitivity in this vulnerable
transplantation is associated with a decrease
patient group.
in T-cell function and may lead to a
Pathomechanisms of impaired TB progressive decrease in M. tuberculosis
control specific T-cell immunity over time. This not
only facilitates reactivation but also
The general incidence of TB in contributes to a decreased sensitivity of
immunocompromised patients may vary immune-based testing. The uraemia-
depending on the geographical location and associated immunodeficiency syndrome
may range from ,1% to up to 15% in low- in patients with end-stage renal failure
and high-prevalence countries, respectively. has been characterised by a defect in
The relative risk to develop TB and its co-stimulatory signals to antigen-specific
underlying pathomechanisms may differ T-cells thereby contributing to an impaired
widely among the various groups due to efficiency of vaccinations and increased
differences in the cause and extent of risk of infectious complications including
immunodeficiency (table 1). The dramatic TB. Finally, an increased incidence of active
reduction in CD4 T-cell numbers in HIV- TB in patients receiving TNF-a antagonists
infected patients, in particular in those with is attributed to an impaired T-cell function and
AIDS, not only contributes to a severely failure to maintain the integrity of granuloma
impaired control of TB, but also to a high in latently infected patients.

Table 1. Pathomechanisms and relative risk for TB in of TB, the risk of progression from LTBI to
immunocompromised patients relative to persons without active disease may be minimised by the early
known risk factors (risk51) identification and treatment of latently
Risk factor Relative Pathomechanism
infected patients. Although risk assessment in
risk immunocompromised patients is often
hampered by a low sensitivity of commonly
HIV infection 100170 Low CD4 T-cell
used immune-based tests, current guidelines
(AIDS) counts
recommend a regular screening for evidence
HIV infection 50100 of LTBI and, if possible, treatment prior to
(no AIDS) conditions of immunodeficiency, i.e. screening
Transplanta- 2074 Decreased T-cell and treatment prior to transplantation or
tion function and TNF-a antagonist therapy. Until recently, LTBI
numbers screening was exclusively carried out by the
Chronic renal 1025 Co-stimulation use of tuberculin skin-testing, where the cut-
failure deficiency, chronic off of positivity is defined by the extent of
inflammation immunodeficiency. At present, however, novel
TNF-a 29 Disintegration of interferon-c release assays (IGRA) are more
antagonists granuloma widely applied that are of higher specificity as
compared with skin-testing. In addition,
accumulating evidence suggests that IGRA
Clinical presentation of active TB may be of higher sensitivity in
immunocompromised patients although
Active TB in immunocompromised patients
large studies, in particular in highly
can pose a number of challenges. Due to the
immunocompromised patients, are still lacking.
impaired immune response, patients may be
clinically oligosymptomatic in the beginning Conclusions
of active disease and its diagnosis is often
delayed due to atypical presentations and TB in immunocompromised patients is more
more frequent extrapulmonary dissemination. frequent as compared with the general
Active TB is further aggravated by a population, and morbidity and mortality is
significantly higher morbidity due to a more high. Risk assessment needs integrative
fatal course in the face of a weakened approaches that should consider clinical
immune system. In addition, treatment is findings, the extent of immunodeficiency and
frequently complicated due to complex drug the overall prevalence of TB.
interactions and altered pharmacokinetics. References
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manage in HIV-infected patients, as immune N Aaron L, et al. Tuberculosis in HIV-infected
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N Sester U, et al. Impaired detection of management. Clin Infect Dis 1998; 27:
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LATENT TUBERCULOSIS
J-P. Zellweger
Swiss Lung Association, Berne, Switzerland
E-mail: zellwegerjp@swissonline.ch
Individuals who are in close contact with a Treatment of latent TB

patient with a transmissible form of
tuberculosis (TB; usually smear-positive As the persons in contact with a case of TB
pulmonary TB) may inhale droplets containing have a much higher risk of developing the
mycobacteria, which settle in the airways and disease in the future than the average
give rise to a local inflammatory reaction. The population, particularly if they have a positive
risk of infection is related to the concentration tuberculin reaction or a positive interferon-c
of mycobacteria in the air and the duration of release assay (IGRA) test, the detection of
contact. Some exposed individuals develop an latent TB among exposed contacts is
active disease (TB) within a couple of weeks important because a preventive treatment can
or months; others will control the incipient reduce this risk. In countries or populations
infection and stay for a prolonged period (up with a low incidence of TB, the search for
to years) in a state of equilibrium called latent infection among contacts and the
latent infection or latent TBor LTBI.
LTBI and risk of TB Key points
Individuals with latent TB have no signs or N The risk of latent TB infection (LTBI)
symptoms of active TB, and only depends on the intensity and duration
immunological markers of a prior contact with of exposure to a source case with
mycobacteria. It is impossible to know if untreated pulmonary TB.
individuals with latent TB still harbour living
mycobacteria. The only gold standard for the N Some infected contacts will develop TB
infection is the development of the disease, at a later time-point. Timely detection
which happens in a minority of exposed of infected contacts and preventive
individuals. Why and how the infected treatment of those at highest risk of
individuals will develop TB is unknown. reactivation is cost-effective and
Estimates are that ,10% of infected reduces the pool of future cases of
individuals may develop TB, half of them active TB.
within 2 yrs after infection, and 90% will N Before prescribing a preventive
never develop the disease. Some infected treatment, active TB should be
individuals have a higher risk of later excluded by a chest radiograph and, if
reactivation than others (for instance abnormal, by a bacteriological
immunocompromised individuals, patients examination of sputum.
receiving immunosuppressive therapy and
small children). As only a minority of contacts N The tests for the detection of latent
develop TB, there is a possibility that most infection are the tuberculin skin test
contacts eradicate the mycobacteria but still and the Interferon-Gamma Release
retain an immunological marker of the Assays (IGRAs). The latter have the
primary contact, even in the absence of living advantage of a greater specificity.
mycobacteria.
Latent tuberculosis 215

prescription of preventive treatment may BCG vaccination or contact with
contribute to the control of the disease by nontuberculous mycobacteria.
reducing the pool of potential future cases.
Detection in low-prevalence countries
The currently recommended preventive
treatments are 9 months of isoniazid, In low-prevalence countries, the search for
4 months of rifampicin or 3 months of an infected individuals is usually performed
association of isoniazid and rifampicin. among persons who recently had a contact
with a patient with pulmonary TB (contact
As the immunological reaction after the investigation), in healthcare workers
contact with mycobacteria needs several days potentially exposed to untreated cases of
or weeks to be complete, the proof of a recent TB and in immunocompromised patients
sensitisation is usually not present before this with a risk of reactivation higher than the
time (the window period). Therefore, the general population. Infected contacts
search for latent infection is usually considered at risk of developing TB in the
performed only 48 weeks after the last future are either followed clinically or
contact. In some cases, where the progression offered a preventive treatment. All contacts
from infection to disease may be rapid with immunological signs of infection
(such as immunocompromised contacts or (positive tuberculin skin test or IGRA)
children aged ,5 yrs), a first testing with a should have at least a chest radiograph for
clinical examination may be performed as detecting signs of past or recent TB. Before
soon as possible after the last contact and prescribing a preventive treatment in contacts
repeated several weeks later, if the results with an abnormal chest radiograph, the
are negative. A test performed immediately presence of an active TB should be
after the last contact will usually indicate a excluded by a bacteriological examination
prior sensitisation and may be observed of sputum. The efficiency of the preventive
among contacts born in a region with high treatment largely depends on the rate of
prevalence of TB and in elderly people, treatment completion.
independently of recent contacts.
Detection in high-prevalence countries
Tests for detection of LTBI
In high-prevalence countries, formal contact
The tests used for the detection of latent investigations are usually not performed, as
infection are all indirect and rely on the most of the contacts may already have
reaction between sensitised lymphocytes and immunological signs of prior infection, but it
antigens from Mycobacterium tuberculosis. is currently recommended to search for the
The traditional test is the tuberculin skin test presence of secondary cases of TB among the
measuring the cutaneous reaction elicited by close relatives and to consider the protection
the intradermal injection of a mixture of of small children with a preventive treatment
antigens from M. tuberculosis cultures. New if one of the parents has a form of
tests have recently been developed and transmissible TB.
introduced on the market, measuring in vitro
Controversies and open questions
the release of cytokines (interferon-c) by
lymphocytes incubated with two or three There are still controversies about the
specific antigens present in M. tuberculosis definition of infectiousness (only smear-
but absent in Mycobacterium bovis bacille- positive cases or all cases with pulmonary TB),
CalmetteGuerin and in most nontuberculous the extent of the contact investigation (only
mycobacteria (IGRAs). The in vitro tests are (at close and prolonged contacts or all contacts)
least) equally sensitive as the tuberculin test and about the indications of preventive
but have the advantage of a greater treatment (only infected contact with a high
specificity, and therefore avoid in practice the risk of reactivation or all contacts or
false-positive skin reactions elicited by prior individuals with a positive tuberculin or IGRA

reaction). Prospective studies on the risk of N Diel R, et al. Predictive value of a whole-blood
reactivation among contacts with a positive IFN-c assay for the development of active TB
immunological reaction will help to clarify disease. Am J Respir Crit Care Med 2008; 15:
these issues. 11641170.
N Ferebee SH. Controlled chemoprophylaxis trials
References in tuberculosis A general review. Adv Tuberc Res
1970; 17: 28106.
N American Thoracic Society, Targeted tuberculin N Landry J, Menzies D. Preventive chemotherapy.
testing and treatment of latent tuberculosis Where has it got us? Where to go next? Int J
infection. Joint Statement of the American Tuberc Lung Dis 2008; 12: 13521364.
Thoracic Society (ATS) and the Centers for N Mack U, et al. LTBI: latent tuberculosis infection
Disease Control and Prevention (CDC). Am J or lasting immune responses to M. tuberculosis?
Respir Crit Care Med 2000; 161: S221S247. A TBNET consensus statement. Eur Respir J
N Andersen P, et al. The prognosis of latent 2009; 33: 956973.
tuberculosis: can disease be predicted? Trends N Moran-Mendoza O, et al. Tuberculin skin test size
Mol Med 2007; 13: 175182. and risk of tuberculosis development: a large
N Cardona PJ. New insights on the nature of latent population-based study in contacts. Int J Tuberc
tuberculosis infection and its treatment. Lung Dis 2007; 11: 10141020.
Inflamm Allergy Drug Targets 2007; 6: 2739. N Pai M, et al. Systematic review: T-cell-based
N Diel R, et al. Cost-effectiveness of isoniazid assays for the diagnosis of latent tuberculosis
chemoprevention in close contacts. Eur Respir J infection: an update. Ann Intern Med 2008;
2005; 26: 465473. 149: 177184.
Latent tuberculosis 217

NONTUBERCULOUS
MYCOBACTERIAL DISEASE
C. Piersimoni
Regional Reference Mycobacteriology Laboratory, United Hospitals,
Ancona, Italy
E-mail: piersim@tin.it
Nontuberculous mycobacteria (NTM) is the The most common clinical manifestation of

term indicating those Mycobacterium species NTM infection is pulmonary disease, but
that are different from Mycobacterium lymphatic, skin/soft tissue, osteoarticular and
tuberculosis complex (MTC) and disseminated disease are also important.
Mycobacterium leprae whose detection in
Pulmonary disease
clinical samples is almost invariably
associated with disease. The most important In immunocompetent subjects, NTM lung
features distinguishing NTM from MTC disease presents as one of the following
include a lower pathogenicity and the lack of clinical forms:
human-to-human transmission. In addition, in
vitro resistance to first-line antituberculous Cavitary lung disease This pattern, which
drugs is another important distinctive issue. closely resembles pulmonary TB, involves the
upper lobes of older males usually affected by
The majority of the .120 NTM species
a pre-existing destructive or obstructive lung
recognised currently has been associated with
condition such as pneumoconiosis, chronic
disease in man or animals.
bronchitis with emphysema (frequently
Epidemiology and pathogenesis associated with long-lasting, heavy smoking)
and bronchiectasis. Thin-walled cavities with
NTM are widely distributed in both natural scarce parenchymal infiltrate and a marked
and man-made environments; organisms can pleural thickening are characteristic. Signs
be found in soil and water with high isolation
rates. Human disease is suspected to be
acquired from environmental exposure and
Key points
pulmonary infection is likely to depend on the
aerosol route. Although much remains to be
understood about the pathogenesis of NTM
N Important features distinguishing NTM
from M. tuberculosis complex include
infections, the following is now well
lower pathogenicity and lack of human-
established:
to-human transmission.
N In HIV-infected patients, disseminated N Disagnosis of NTM disease requires
NTM infections occur only after the CD4+ both clinical and microbiological
T-lymphocyte count has dropped below criteria to be met.
50?mL-1.
N Treatment is disappointing and is
N In HIV-uninfected patients, NTM infections characterised by long duration and
may be associated with specific mutations side-effects, leading to poor
in interferon-c and interleukin-12 synthesis compliance.
and response pathways.

and symptoms include chronic cough with Laboratory diagnosis
sputum production and weakness. With
advanced disease, dyspnoea, fever, weight Mycobacterial culture remains the cornerstone
loss and haemoptysis can also occur. with which to make a definitive diagnosis.
Therefore, appropriate, high-quality specimens
Nodular bronchiectasis This pattern (also properly collected from all patients with
known as Lady Windermeres syndrome) has suspected NTM disease have to be sent to a
been described in slender elderly females with certified laboratory. Due to the ubiquitous
structural chest abnormalities (pectus occurrence of NTM in the environment, the
excavatum, scoliosis and mitral valve prolapse), recognition of disease as opposed to
but no evidence of pre-existing lung disease. contamination of specimens or transient
Indolent productive cough and purulent colonisation may be difficult. While smear-
sputum are the most common presenting positive samples strongly suggest an active
symptoms, while constitutional symptoms and disease, a single positive culture (especially
haemoptysis are not common unless extensive with small numbers of organisms) does not
disease is present. The radiographic findings suffice to set such a diagnosis. In this context,
include small nodular infiltrates and cylindrical the American Thoracic Society has recently
bronchiectasis, predominately located within updated the criteria for the diagnosis of
the middle lobe and lingula. pulmonary disease caused by NTM (table 1).
It is necessary to fulfil all the above elements
Hypersensivity pneumonitis (HP) A to establish a correct diagnosis. Although
syndrome indistinguishable from HP has been these criteria are derived from experience with
reported in subjects exposed to household MAC, it is reasonable to believe they would
water laden with Mycobacterium avium work with other species provided that
complex (MAC) organisms (hot tubs and contamination of clinical specimens and
medicinal baths). Full recovery usually occurs medical devices with environmental NTM
without any specific therapy (simply by avoiding (pseudoinfection) has been excluded. Today,
further contact with contaminated solutions), the combined use of automated liquid culture
but sometimes a combination therapy of for detection and drug susceptibility testing
steroids and antibiotics may be required. (DST) plus the use of genetic probe
technology for identification of mycobacteria
In addition, NTM lung disease may be
associated with the following conditions:
Table 1. American Thoracic Society criteria for diagnosis of
N HIV infection. Although NTM are pulmonary disease caused by NTM
frequently recovered from respiratory Clinical criteria (both required):
specimens of HIV-infected subjects, Pulmonary symptoms, cavitary or noncavitary
lung disease
extrapulmonary or disseminated disease
Appropriate exclusion of other causes for the
are more likely to occur. The most relevant disease
exception to this generalisation is given by
Microbiological criteria (only one required):
Mycobacterium kansasii.
Positive culture results from at least two separate
N Immune reconstitution inflammatory expectorated sputum samples
syndrome. Positive culture results from at least one
bronchial wash or lavage
N Transplantation including both solid-organ A transbronchial or lung biopsy showing
and haematopoietic stem cell transplants. granulomata and/or acid-fast bacilli (AFB) and
positive culture for NTM
N Treatment with tumour necrosis factor-a Biopsy showing granulomata and/or AFB and
antagonists. one or more sputa or bronchial washings that
are culture-positive for NTM
N Cystic fibrosis.
Nontuberculous mycobacterial disease 219

Table 2. Clinical and radiographic features of pulmonary infections caused by the most frequently encountered NTM
Species Pathogenicity; Radiographic findings Treatment (time in months)
outcome
Upper lobe cavitations Clarithromycin, ethambutol,
Mycobacterium rifampin (18)
+ +; poor/fair
avium complex Middle lobe bronchiectasis Clarithromycin, ethambutol,
rifampin (18)
Mycobacterium + + +; good Upper lobe cavitations Rifampin, isoniazid, ethambutol
kansasii (18)
Mycobacterium + + +; fair Upper lobe infiltrates Rifampin, ethambutol
malmoense (24)
Mycobacterium +; poor Upper lobe cavitations and Clarithromycin, rifampin,
xenopi nodules ethambutol, moxifloxacin (18)
Mycobacterium + + +; good Upper lobe cavitations Rifampin, isoniazid, ethambutol,
szulgai pyrazinamide (18)
Mycobacterium +; poor Upper lobe cavitations and Clarithromycin,
simiae nodules moxifloxacin
cotrimoxazole (18)
Mycobacterium + +; poor Multilobar interstitial and Clarithromycin, amikacin, cefoxitin
abscessus nodular lesions (1); surgical resection
+: number of + indicates degree of pathogenicity. Reproduced from PIERSIMONI and SCARPARO (2008), with permission
from the publisher.
is mandatory in all laboratories wishing to N Fujita G, et al. Radiological findings of

perform mycobacteriology. mycobacterial diseases. J Infect Chemother
2007; 13: 817.
Treatment N Glassroth J. Pulmonary disease due to
nontuberculous mycobacteria. Chest 2008; 133:
Treatment regimens for NTM disease are still 243251.
largely undefined and outcome remains N Griffith DE, et al. An official ATS/IDSA
disappointing despite considerable upgrading statement: diagnosis, treatment, and prevention
in mycobacteriology and the availability of of nontuberculous mycobacterial diseases. Am J
some new antimicrobials. Treatment success is Respir Crit Care Med 2007; 175: 367416.
impaired by the long duration of regimens, N Mangione E, et al. Nontuberculous
their side-effects and drug interactions, which mycobacterial disease following hot tub
prevent patients from full compliance exposure. Emerg Infect Dis 2001; 7: 10391042.
(table 2). In addition, although many NTM N National Committee for Clinical Laboratory
Standards. Susceptibility Testing of Mycobacteria,
species may be susceptible in vitro to one or
Nocardiae, and Other Aerobic Actinomycetes.
more antituberculous drugs, correlation M24-A. Wayne, PA, NCCLS, 2003.
between DST results and clinical outcome N Piersimoni C, Scarparo C. Pulmonary infections
is poor. associated with non-tuberculous mycobacteria in
immunocompetent patients. Lancet Inf Dis
References
2008; 8: 323334.
N Clinical and Laboratory Standard Institute. N Prince DS, et al. Infection with Mycobacterium
Laboratory Detection and Identification of avium complex in patients without predisposing
Mycobacteria. M48-A. Forbes, BA, CLSI, 2008. conditions. N Engl J Med 1989; 321: 863868.
N Field SK, Cowie RL. Lung disease due to the N Tortoli E. Impact of genotypic studies on
more common nontuberculous mycobacteria. mycobacterial taxonomy: the new mycobacteria of
Chest 2006; 129: 16531672. the 1990s. Clin Microbiol Rev 2003; 16: 319354.

CHAPTER 9:
AiRwAy diSEASES
CHRoniC RHiniTiS 224

A. Bourdain and P. Chanez
ASTHmA 227
B. Begh and L.M. Fabbri
voCAl CoRd dySfunCTion 236

A.H. Mansur
bRonCHiTiS 240
G. Rohde
gASTRo-oESoPHAgEAl REflux 242

L. Dupont
CoPd And EmPHySEmA 246

bRonCHiECTASiS 252
N. Ten Hacken
CySTiC fibRoSiS 256

A. Bush and J. Davies

CHRONIC RHINITIS
A. Bourdin1 and P. Chanez2
1
Department of Respiratory Disease, CHU Arnaud de Villeneuve,
Montpellier, and 2 Service de Pneumo-Allergologie et Laboratoire
dImmunologie INSERM U600, Universite de la Mediterranee, AP-HM
Marseille, France
E-mail: pascal.chanez@univmed.fr
Rhinitis is one of the commonest human adults and children. It is usually a mild
diseases. Its most important features are disease, but its direct and indirect costs are
inflammation and structural changes of the substantial. Absenteeism at school or at work
nasal mucosa. The causes are heterogeneous is often reported by subjects suffering from
and, if allergy and infections are dominant, it rhinitis. Rhinitis is often associated with other
is often difficult to find a single common IgE-related disease and the continuum linking
aetiology in chronic rhinitis. It is important to upper and lower airways is well represented
consider that rhinitis is often associated with by the association of rhinitis and asthma,
sinusitis and lower airway diseases such as which frequently coexist: asthma is present in
asthma. Rhinitis is a mild disease, but it 2050% of patients with allergic rhinitis.
interferes with sleep quality and daily life. Rhinitis is present in up to 80% of asthma
patients. Whether allergic rhinitis precedes,
Epidemiology
triggers or precipitates asthma is something
Rhinitis is still increasing in prevalence in that requires supportive data. Atopic status
most countries. In some studies, 2530% of plays a potentially prominent role in this
the population is suffering from rhinitis, often relationship, although it is not a prerequisite.
linked to immunooglobulin (Ig)E sensitisation. The risk factors for rhinitis need to be better
It may increase with age, as demonstrated in known and understood in order for preventive
both children and adults, and there is growing measures to be implemented.
evidence that emerging countries are affected Definition and clinical aspects of
by an increase in prevalence. Thus, rhinitis is rhinitis
an important health problem worldwide. It
affects health-related quality of life in both Allergic rhinitis is defined as inflammation of
the nasal mucosa characterised clinically by
nasal discharge, blockage, sneezing and itch,
Key points with two or more symptoms occurring for
.1 h on most days. It can be further
N The prevalence of rhinitis is increasing classified as intermittent (symptoms occurring
in most countries. on ,4 days out of 7 or for ,4 weeks per
N Asthma is present in 2050% of year) or persistent (symptoms occurring on
allergic rhinitis patients, while up to o4 days out of 7 or for o4 weeks per year).
80% of asthma patients have rhinitis. The impact of chronic rhinitis on sleep, daily
activities, work or school is a major
N Treatment is anti-inflammatory and determinant of quality-of-life impairment in
directed according to whether rhinitis is patients. The perception of nasal symptoms is
allergic or nonallergic. highly variable, a fact illustrated in patients
suffering from chronic obstructive pulmonary

Diagnosis of allergic rhinitis
(history skin prick tests or serum-specific IgE)
Allergen avoidance
Intermittent symptoms Persistent symptoms
mild moderate mild moderate

severe severe
intranasal CS
Not in preferred order Not in preferred order
oral H1 blocker oral H1 blocker
intranasal H1 blocker intranasal H1 blocker review the patient
and/or decongestant and/or decongestant after 2-4 weeks
intranasal CS
(chromone) improved failure
in persistent rhinitis step-down review diagnosis

review the patient and continue review compliance
after 2-4 weeks treatment query infections
for 1 month or other causes
if failure: step-up
if improved; continue increase
for 1 month itch/sneeze
intranasal CS add H1 blocker
dose rhinorrhoea blockage add
add ipratropium decongestant
or oral CS
(short term)
failure
surgical referral
Figure 1. Treatment algorithm for allergic rhinitis. Ig: immunoglobulin; CS: corticosteroids. Reproduced from
the ARIA guidelines, with permission from the publisher.
disease, where a discrepancy between nasal antioxidant apparatus are key features of the
inflammation and symptoms has been anatomical barrier of the nasal epithelium.
demonstrated. From a clinical point of view, it The mucosal-associated lymphoid tissue is
is thus difficult to rely on patients reports of developed in the nose. Structural
symptoms as the only way to assess rhinitis. abnormalities including changes of the
basement membrane have been reported in
Nonallergic rhinitis is difficult to differentiate rhinitis. Inflammatory cells such as
clinically from allergic rhinitis. Exacerbations eosinophils, mast cells, T-cells and
are usually associated with infections but macrophages infiltrate the epithelium and
several other triggers, including drugs, may submucosa. Mast cell-derived inflammatory
cause recurrent symptoms. mediators are overexpressed, such as
Pathological and mechanistic aspects histamine, chemokines and cytokines
including interleukin (IL)-5, RANTES, IL-4,
Pseudostratified epithelium and a large highly IL-13, granulocyte macrophage colony-
developed vasculature cover the nasal wall. stimulating factor. Most of these molecules
Tight junctions, peptidases and a large trigger a local eosinophilic inflammatory
Chronic rhinitis 225

process. Allergens, microorganisms and by nasal decongestant and anticholinergic
pollutants are potential triggers that can therapy. Allergic rhinitis should be treated
generate acute and chronic inflammatory according to the ARIA guidelines (fig. 1).
reactions through the epithelium. The release
The term rhinitis covers a heterogeneous
of various mediators is responsible for most of
group of diseases. Allergic rhinitis and its
the clinical symptoms reported by patients.
associated diseases have been well defined
Nasal hypersecretion, sneezing and itching are
and treatment is codified. Mucosal
related to the release of vasoactive and
inflammation is the hallmark of rhinitis. Its
proinflammatory mediators such as histamine
natural history and its relationship with
and sulphido-leukotrienes. Persistent nasal
sinusitis and lower airways diseases need to
obstruction is linked to the perpetuation of
be clarified. New treatments and
inflammatory reactions mostly related, in
management strategies are required,
allergic rhinitis, to eosinophilic infiltration.
especially in the most chronic severe forms.
Effects of anti-inflammatory treatment
References
Intranasal corticosteroids and intranasal or
oral antihistamines, have been shown to have
N Bousquet PJ, et al. ARIA (Allergic Rhinitis and its
Impact on Asthma) classification of allergic
effects on different aspects of inflammation in rhinitis severity in clinical practice in France. Int
allergic rhinitis. Additionally, intranasal Arch Allergy Immunol 2007; 143: 163169.
anticholinergic therapy provides relief for N Carr WW, et al. Managing rhinitis: Strategies for
excessive rhinorrhoea, while leukotriene improved patient outcomes. Allergy Asthma Proc
antagonists block the cysteinyl leukotriene 2008; 29: 349357.
receptor. Nasal obstruction improves N Chanez P, et al. Comparison between nasal and
significantly more with intranasal bronchial inflammation in asthmatic and control
subjects. Am J Respir Crit Care Med 1999; 159:
corticosteroids compared with most of the
588595.
other pharmacological strategies. Specific N Lipworth BJ, White PS. Allergic inflammation in
immunotherapy using sublingual, oral or the unified airway: start with the nose. Thorax
subcutaneous routes has been proven 2000; 55: 878881.
effective and safe in intermittent and N Raherison C, et al. How should nasal symptoms
persistent allergic rhinitis. Allergen avoidance be investigated in asthma? A comparison of
is not effective in persistent allergic rhinitis. radiologic and endoscopic findings. Allergy
Several studies have demonstrated that the 2004; 59: 821826.
effective treatment of rhinitis decreases the N Togias A. Rhinitis and asthma: evidence for
burden of asthma as assessed by unscheduled respiratory system integration. J Allergy Clin
Immunol 2003; 111: 11711183.
visits to physicians and emergency rooms due
to acute exacerbations. Weblink
Treatment should be directed according to the N Allergic Rhinitis and its Impact on Asthma.
cause: nonallergic rhinitis should be treated www.whiar.org.

ASTHMA
B. Beghe and L.M. Fabbri
Dept of Oncology Haematology and Respiratory Diseases, Policlinico di
Modena, University of Modena and Reggio Emilia, Italy
E-mail: leonardo.fabbri@unimore.it
Asthma is a chronic inflammatory disease of the development of asthma rather than its
the airways, characterised clinically by exacerbations remain largely undetermined.
recurrent respiratory symptoms: dyspnoea,
wheezing, chest tightness and/or cough, Asthma is a heterogeneous syndrome that,
almost always associated with reversible over the years, has been divided into many
airflow limitation. Other characteristics of clinical subtypes, e.g. allergic asthma, adult-
asthma are an exaggerated responsiveness of onset asthma that is usually nonallergic,
the airways to various stimuli, and in most cases occupational asthma, asthma in smokers and
asthma in the obese.
a rather specific chronic inflammation of the
airways characterised by an increased number Minimum requirements for the
of CD4+ Th2 lymphocytes, eosinophils and diagnosis of asthma
methacromatic cells in the airway mucosa, and
increased thickness of the reticular layer of the The diagnosis of asthma is based on clinical
epithelial basement membrane. history and lung function tests, particularly
peak expiratory flow (PEF) and spirometry,
Familial predisposition, atopy, and exposure to with assessment of variable and/or reversible
allergens and sensitising agents are important airflow limitation. Allergy tests are also
risk factors for asthma, even though the usually performed during the first assessment
causes of asthma the factors responsible for of a patient with suspected asthma to identify
possible triggers of asthma and to guide their
avoidance.
Key points Asthma clusters in families, and its genetic

determinants appear to be linked to those of
N Asthma is diagnosed based on clinical other allergic immunoglobulin (Ig) E-mediated
history and lung function testing. diseases. Thus, a personal or family history of
asthma and/or allergic rhinitis, atopic
Allergy testing may also have a role.
dermatitis or eczema increases the likelihood
N The differential diagnosis is extensive. of a diagnosis of asthma.
In particular, COPD may be difficult to
Symptoms and medical history
distinguish from asthma.
N The goal of pharmacological asthma Most patients with asthma seek medical
treatment is to achieve and maintain attention because of respiratory symptoms. A
control of symptoms and prevention of typical feature of asthma symptoms is their
exacerbations. variability. One or more of the following
symptoms: wheezing, chest tightness, and/or
N Asthma is a chronic, lifelong disease episodic shortness of breath are reported by
and must therefore be managed in .90% of patients with asthma. However, the
partnership with the patient. presence of these symptoms is not diagnostic,
because identical symptoms may be triggered
Asthma 227
by different stimuli in nonasthmatics, e.g. by Physical examination
acute viral infections. In some asthmatics,
wheezing and chest tightness are absent, and In mild asthma, physical examination is
the only symptom the patient complains of is usually normal under stable conditions but
chronic cough (cough-variant asthma). becomes characteristically abnormal during
asthma attacks and when asthma is more
Symptoms of asthma may be triggered or severe or uncontrolled. Typical physical signs
worsened by several factors, such as exercise, of asthma attacks are wheezing on
exposure to allergens, viral infections and auscultation, cough, expiratory rhonchi
emotions. Recurrent exacerbations of throughout the chest and signs of acute
respiratory symptoms, worsening of lung hyperinflation (e.g. poor diaphragmatic
function requiring change of treatment, excursion at percussion, use of accessory
unscheduled requests for medical assistance muscles of respiration). Some patients,
and sometimes hospitalisation are also particularly children, may present with a
among the characteristic clinical features of predominant nonproductive cough (cough-
asthma. variant asthma). In some asthmatics,
wheezing which usually reflects airflow
Physical activity is an important trigger of limitation may be absent or detectable only
symptoms (wheezing and/or cough) for most on forced expiration, even in the presence of
asthma patients, particularly children. For significant airflow limitation; this may be due
some, it is the only cause. Exercise-induced to hyperinflation or to very marked airflow
asthma usually develops not during exercise limitation. In these patients, however, the
but 510 min afterwards, and it resolves severity of asthma is mostly indicated by other
spontaneously within 3045 min. Prompt signs, such as cyanosis, drowsiness, difficulty in
relief of symptoms after the use of inhaled speaking, tachycardia, hyperinflated chest, use
b2-agonist, or prevention by pre-treatment of accessory muscles and intercostal recession.
with an inhaled b2-agonist before exercise,
supports a diagnosis of asthma. Important Lung function tests
aspects of personal history are exposure to
agents known to worsen asthma in the home Spirometry Lung function tests play a
(some types of heating or cooking system, crucial role in the diagnosis and follow-up of
house dust mites), workplace conditions, air- asthma. Spirometric measurements FEV1
conditioning, pets, cockroaches, environmental and slow vital capacity (VC) or forced vital
tobacco smoke or even the general capacity (FVC) are the standard means for
environment, e.g. diesel fumes in traffic. assessing airflow limitation. Spirometry is
recommended at the time of diagnosis and for
Since the respiratory symptoms of asthma are
the assessment of the severity of both asthma
nonspecific, the differential diagnosis is quite
and chronic obstructive pulmonary disease
extensive. The main goal for the physician is
(COPD). It should be repeated to monitor the
to consider and exclude other possible
disease and when there is a need for
diagnoses (table 1). This is even more
reassessment, such as during exacerbations.
important if the response to a trial of therapy
(bronchodilators) has been negative.
Measurements of residual volume and total
While respiratory symptoms suggest asthma, lung capacity may also be useful in
the sine qua non for the objective diagnosis of determining the degree of hyperinflation and/
asthma is the presence of reversible airflow or enlargement of airspaces. Lung volumes
limitation in subjects with persistent airway may help in the differential diagnosis with
obstruction, and/or airway COPD, but are not necessary for the diagnosis
hyperresponsiveness or increased PEF nor for the assessment of severity of asthma.
variability in subjects without airway In asthma, airflow limitation is usually
obstruction. reversible, either spontaneously or after

Table 1. Differential diagnosis of asthma of asthma and its response to treatment, and
it can help patients to detect early signs of
Localised pathology
asthma deterioration. Diurnal variability is
Inhaled foreign body
Endobronchial tumour calculated as follows:
Vocal cord dysfunction (PEFmax PEFmin) / [(PEFmax + PEFmin) / 2]
Diffuse airway pathology 6 100
Chronic obstructive pulmonary disease
Eosinophilic bronchitis A diurnal PEF variability of .20% is
Post-infectious airway hyperresponsiveness diagnostic of asthma, and the magnitude of
Cystic fibrosis the variability is broadly proportional to
Bronchiectasis disease severity. PEF monitoring may be of use
Left ventricular failure not only in establishing a diagnosis of asthma
Other pathologies and assessing its severity but also in
Gastro-oesophageal reflux uncovering an occupational cause for asthma.
Pulmonary embolism When used in this way, PEF should be
Pulmonary eosinophilia syndromes measured more frequently than twice daily,
Drug-induced airway hyperresponsiveness and special attention should be paid to
changes occurring in and out of the
workplace.
treatment, except for moderate/severe asthma
with fixed airway obstruction (see below). Reversibility to bronchodilators
Reversibility to bronchodilators (i.e. a .12%
An important tool for the diagnosis and reversibility response and .200 mL in FEV1
subsequent monitoring of asthma treatment is after bronchodilator) confirms the diagnosis
the PEF meter. If spirometry does not reveal of asthma. Poorly reversible airflow limitation
airflow limitation, the home monitoring of PEF is usually defined by the absolute reduction of
for 24 weeks may help to detect an post-bronchodilator FEV1/FVC ratios to ,0.7.
increased variability of airway calibre, and However, because this parameter decreases
thus to diagnose. Daily monitoring of PEF (at with ageing, it should be confirmed with
least in the morning at awakening and in the postbronchodilator FEV1/VC values below the
evening hours, preferably after bronchodilator lower limit of normal. Reversibility is often not
inhalation) is also useful to assess the severity present at the time of examination,
Table 2. History, symptoms and results of pulmonary function tests in the differential diagnosis between asthma and
COPD
Asthma COPD
Onset Mainly in childhood In mid to late adult life
Smoking Usually nonsmokers Almost invariably smokers
Chronic cough and Absent Frequent (chronic bronchitis)
sputum
Dyspnoea on effort Variable and reversible to Constant, poorly reversible and
treatment progressive
Nocturnal symptoms Relatively common Relatively uncommon
Airflow limitation Increased diurnal variability Normal diurnal variability
Response to Good Poor
bronchodilator
Airway In most patients, with or with- In most patients with airflow limitation
hyperresponsiveness out airflow limitation
Asthma 229
Table 3. Ancillary tests in the differential diagnosis between stable asthma and COPD
Ancillary test Asthma COPD
Reversibility to bronchodilator and/or Usually present Usually absent
glucocorticosteroids
Lung volumes
Residual volume, total lung Usually normal or, if increased, Usually irreversibly
capacity reversible increased
Diffusing capacity Normal Decreased
Airway hyperresponsiveness Increased Might be increased but
usually not measurable due
to airflow limitation
Allergy tests Often positive Often negative
Imaging of the chest Usually normal Usually abnormal in
advanced stages
Sputum Eosinophilia Neutrophilia
Exhaled nitric oxide Increased Usually normal
particularly in patients on treatment, and thus Arterial blood gases

the absence of reversibility does not exclude
the diagnosis. However, repeated testing of In severe asthma and, more importantly,
reversibility of both clinical features and during acute exacerbations of asthma, the
functional abnormalities may be useful in measurement of arterial blood gases while the
obtaining the best level of asthma control patient is breathing air and/or after oxygen
achievable and/or the best lung function for administration is essential for the diagnosis of
individual patients. Achieving and chronic and/or acute respiratory failure. This
maintaining lung function at the best possible test should be performed in all patients with
level is one of the objectives of asthma clinical signs of acute or chronic respiratory
management. and/or heart failure, and anyway in patients
with a PEF ,50%, those who do not respond
Airway hyperresponsiveness In patients to treatment and those with an arterial
who have symptoms consistent with asthma oxygen saturation f92%.
but who have normal lung function, bronchial Allergy tests
provocation tests with methacholine,
histamine or exercise are helpful in measuring The presence of allergic disorders in a
airway hyperresponsiveness and thereby patients family history should be investigated
confirming or excluding the diagnosis of in all patients with symptoms of asthma. A
active asthma. These measurements are very history provides important information about
sensitive, but poorly specific for a diagnosis of the patients lifestyle and occupation, both of
asthma. This means that while a negative test which influence exposure to allergens and the
can be used to exclude a diagnosis of active time and factors possibly involved in onset
asthma, a positive test does not always mean and in exacerbations of asthma. Skin tests
that a patient has asthma. While the with all relevant allergens present in the
measurement of airway hyperresponsiveness geographic area in which the patient lives are
may be useful to confirm asthma in subjects the primary diagnostic tool in determining
with normal baseline lung function, it is not allergic status. Measurement of specific IgE is
useful in presence of nonreversible airflow not usually more informative than a skin test,
limitation, and thus in the differential and is more expensive. Measurement of total
diagnosis between asthma and COPD. IgE in serum has no value as a diagnostic test

Figure 1. Asthma management approach based on control for children aged .5 yrs, adolescents and adults.
Alternative reliever treatments include inhaled anticholinergics, short-acting oral b2-agonists, some long-acting
b2-agonists, and short-acting theophylline. Regular dosing with short and long-acting b2-agonist is not advised
unless accompanied by regular use of an inhaled glucocorticosteriod. ICS: inhaled corticosteroids; IgE:
immunoglobulin E. #: Preferred controller options are shown in shaded boxes; ": inhaled glucorticosteroids;
+
: Receptor antagonist or symthesis inhibitors. Reproduced from the Global Strategy for Asthma Management
and Prevention, with permission.
for atopy. The main limitation of methods to asthma, it is not required in the confirmation
assess allergic status is that a positive test of the diagnosis and management of asthma.
does not necessarily mean that the disease is The utility of chest radiography is to exclude
allergic in nature or that it is causing asthma, other conditions that may imitate or
as some individuals have specific IgE complicate asthma, particularly acute asthma.
antibodies without any symptoms and it may Examples include pneumonia, cardiogenic
not be causally involved. The relevant pulmonary oedema, pulmonary
exposure and its relation to symptoms must thromboembolism, tumours (especially
be confirmed by patient history. those that result in airway obstruction with
resulting peripheral atelectasis) and
Additional tests pneumothorax.
While the diagnosis and assessment of severity
of asthma and COPD can be fully established Assessment of airway inflammation
on the basis of clinical history and lung function While airway biopsies and bronchoalveolar
tests (including arterial blood gases see lavage may provide useful information in
below), additional tests might be helpful to research protocols, they are considered too
better characterise individual patients. invasive for the diagnosis or staging of
asthma. By contrast, noninvasive markers of
Imaging While chest radiography may be airway inflammation have been increasingly
useful to exclude diseases that may mimic used in research protocols, particularly to
Asthma 231
Table 4. Levels of asthma control
Characteristic Controlled Partly controlled Uncontrolled
(all of the following) (any measure
present in any week)
Daytime symptoms None More than twice per Three or more features
(twice or less per week) week of partly controlled
Limitations of None Any asthma present in any
activities week
Nocturnal symptoms/ None Any

awakening
Need for reliever/ None More than twice per
rescue treatment (twice or less per week) week
Lung function Normal ,80% predicted or per-
(PEF or FEV1)# sonal best (if known)
Exacerbations None o1 per year" One in any week+
PEF: peak expiratory flow; FEV1: forced expiratory volume in 1 s. #: Lung function is not a reliable test for children
aged f5 yrs; ": any exacerbation should prompt a review of maintenance treatment to ensure it is adequate;
+
: by definition, an exacerbation in any week makes that an uncontrolled asthma week. Reproduced from the Global
Strategy for Asthma Management and Prevention, with permission.
differentiate asthma from COPD and measure patient develops poorly reversible airflow
response to treatment. limitation that responds only partially to
treatment. In these cases, symptoms, lung
Exhaled nitric oxide Exhaled nitric oxide function, airway responsiveness, imaging and
(NO) is increased in atopic asthma, but less so even pathological findings may overlap and
in nonatopic asthma. It is reduced by thus may not provide solid information for the
glucocorticosteroids, but not by differential diagnosis. Because the differential
bronchodilators. Measurement of airway diagnosis mainly aims to provide better
inflammation is not required for the diagnosis, treatment, it is important in these cases to
assessment of severity and/or treatment of undertake an individual approach and to
asthma in clinical practice. perform additional tests. Reversibility to
corticosteroids alone or in combination with
Differential diagnosis between asthma long-acting bronchodilators, measurements of
and COPD lung volumes and diffusing capacity, analysis
of sputum and exhaled NO, and imaging of
In most patients, the clinical presentation and the chest may demonstrate whether asthma or
particularly the history provide the strongest COPD is the predominant cause of airflow
diagnostic criteria to distinguish asthma from limitation (table 3). In contrast, reversibility to
COPD (table 2). Pulmonary function tests, bronchodilator and assessment of airway
particularly spirometry, that show a nearly hyperresponsiveness or skin testing may not
complete reversibility of airflow limitation may be useful in these patients.
help to confirm a diagnosis of asthma, and
those that show poorly reversible airflow Comorbidities of asthma
limitation may help to confirm the diagnosis
of COPD (table 2). Differential diagnosis The coexistence of chronic rhinitis, nasal
between asthma and COPD becomes more polyposis and sinusitis may contribute to the
difficult in elderly patients, in whom some severity of asthma.. There is broad evidence to
features may overlap, such as smoking and show that adequate treatment of these upper
atopy and, more importantly, when the airway diseases is beneficial to asthma by

Initial assessment
History, physical examination (auscultation, use of accessory muscles, heart rate, respiratory rate, PEF
or FEV1, oxygen saturation, arterial blood gas if patient in extremis)
Initial treatment
Oxygen to achieve O2 saturation 90% (95% in children)
Inhaled rapid-acting 2-agonist continuously for 1 h
Systemic glucocorticosteroids if no immediate response, or if patient recently took oral
glucocorticosteroid, or if episode is severe
Sedation is contraindicated in the treatment of an exacerbation
Reassess after 1 h
Physical examination, PEF, O2 saturation and other tests as needed
Criteria for moderate episode: Criteria for severe episode:

PEF 60_80% predicted/personal best History of risk factors for near fatal asthma
Physical exam: moderate symptoms, accessory PEF <60% predicted/personal best
muscle use Physical exam: severe symptoms at rest,
Treatment: chest retraction
Oxygen No improvement after initial treatment
Inhaled 2-agonist and inhaled anticholinergic every Treatment:
60 min Oxygen
Oral glucocorticosteroids Inhaled 2-agonist and inhaled anticholinergic
Continue treatment for 1_3 h, provided there is Systemic glucocorticosteroids
improvement Intravenous magnesium
Reassess after 1_2 h
Good response within 1_2 h: Incomplete response within 1_2 h: Poor response within 1_2 h:
Response sustained 60 min Risk factors for near fatal asthma Risk factors for near fatal asthma
after last treatment Physical exam: mild to moderate signs Physical exam: symptoms severe,
Physical exam normal: PEF <60% drowsiness, confusion
No distress O2 saturation not improving PEF <30%
PEF >70% Pa,CO2 >45 mm Hg
O2 saturation >90% Admit to acute care setting Pa,O2 <60mm Hg
(95% children) Oxygen Admit to intensive care
Inhaled 2-agonist anticholinergic
Systemic glucocorticosteroid Oxygen
Intravenous magnesium Inhaled 2-agonist +
Monitor PEF, O2 saturation, pulse anticholinergic
Intravenous glucocorticosteroids
Consider intravenous 2-agonist
Consider intravenous
theophylline
Possible intubation and
mechanical ventilation
Improved: criteria for discharge home
PEF >60% predicted/personal best Reassess at intervals
Sustained on oral/inhaled medication Poor response (see above):
Home Treatment: Admit to intensive care
Continue inhaled 2-agonist
Consider, in most cases, oral glucocorticosteroids Incomplete response in 6_12 h (see above)
Consider adding a combination inhaler Consider admission to intensive care
Patient education: Take medicine correctly if no improvement within 6_12 h
Review action plan
Close medical follow-up Improved (see opposite)
Figure 2. Management of asthma exacerbations in the acute care setting. PEF: peak expiratory flow; FEV1:
forced expiratory volume in 1 s; Pa,CO2: arterial carbon dioxide tension; Pa,O2: arterial oxygen tension.
Reproduced from the Global Strategy for Asthma Management and Prevention, with permission.
Asthma 233
mechanisms not clearly understood. The one Medications to treat asthma can be classified
airway concept developed by the World as controllers or relievers. Medications are
Health Organization ARIA Group has drawn preferably administered by inhalation, as it is
attention to the importance of treating the more efficacious and has fewer side-effects.
whole respiratory tract when managing Controllers (inhaled glucocorticosteroids alone
asthma. Gastro-oesophageal reflux is also or in combination with long-acting b2-agonists)
occasionally associated with asthma, both in are medications to be taken daily, over the long
adults and in children, but treatment of reflux term, to keep asthma under clinical control. In
usually has little overall effect on mild-to- asthma, long-acting b2-agonists should be used
moderate asthma. A frequent and quite only in combination with inhaled
important comorbidity of asthma in adults is corticosteroids when the latter are insufficient
COPD, most probably due to smoking, which is to achieve control, and should be discontinued
quite common in asthmatics. Smoking modifies only when control is maintained for a
the airway pathology of asthmatics to a COPD- sufficiently long time (e.g. o3 months).
like pattern and reduces the response to
treatment. Comorbidities may become Only in patients not controlled by full doses of
important in severe asthma, whereas they play inhaled glucocorticosteroids combined with
a much less important role overall in the clinical long acting b2-agonists may other secondary
manifestations of mild-to-moderate asthma. agents be considered (anti-leukotrienes,
theophylline, systemic steroids, monoclonal
Management anti-IgE antibodies in very specific cases).
Considering its chronic nature and lifelong Relievers (rapid-acting b2-agonists alone or in
duration, asthma can be effectively managed combination in combination with inhaled
only by developing a partnership between the steroids) are medications used on an as-
patient and his or her doctor or health needed basis that act quickly to reverse
professional, that may provide the tools for a bronchoconstriction and relieve its symptoms.
guided self-management (possibly written) plan Ideally, if patients are adequately controlled,
including self-monitoring, and periodic review they should not need rescue medications.
of treatment and level of asthma control.
Education plays a major role in this partnership. Allergen immunotherapy may be considered in
patients with asthma caused by specific
Long-term pharmacological treatment allergens for which there are standardised
The main goal of pharmacological asthma extracts. Only patients with single or two similar
treatment is to achieve and maintain control of allergen sensitivities whose role is confirmed by
symptoms and prevention of exacerbations the history and who have preserved lung
(table 4) using the safest treatment algorithm. function are candidates for this treatment
While the initial treatment should be started (which, however, has limited efficacy and is long
according to the level of severity at the first and relatively expensive). Specific
visit, subsequently treatment should be immunotherapy should be considered only after
adjusted according to the level of control strict environmental avoidance and
achieved (fig. 1). Usually regular treatment is pharmacological interventions, including inhaled
lowered only after a significant period of glucocorticosteroids, have failed to control the
acceptable control, e.g. not ,3 months. This disease. Smoking asthmatics are resistant to anti-
means that monitoring of asthma is essential asthma medications and should be primarily
to maintain control and to establish the lowest treated for smoking addiction. Smokers with
step and dose of treatment. Step-up and step- asthma may develop features of COPD.
down of treatment is not standardised, and Treatment of exacerbations
thus should be tailored to the individual
patient to achieve and maintain control with Shortness of breath, cough, wheezing, and/or
the minimum amount of medication. chest tightness may develop or worsen

recurrently in subjects with asthma even when N Bousquet J, et al. Allergic Rhinitis and its Impact
they are under regular treatment. Milder on Asthma (ARIA) 2008 update (in
exacerbations are usually managed by the collaboration with the World Health
patient with an increased as-needed use of Organization, GA(2)LEN and AllerGen). Allergy
2008; 63: Suppl. 86, 8160.
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combination with inhaled steroids. More
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exacerbations in the emergency department:
severe exacerbations or exacerbations that do summary of the National Asthma Education and
not respond to the increased use of rescue Prevention Program Expert Panel Report 3
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very severe cases with oxygen N Global Strategy for Asthma Management and
supplementation (fig. 2). Severe Prevention, Global Initiative for Asthma (GINA).
Available from: http://www.ginasthma.org 2009.
exacerbations require medical attention or
even hospital admission.
N Global Strategy for Diagnosis, Management,
and Prevention of COPD. Available from: http://
Special considerations www.goldcopd.org 2009.
N Maestrelli P, et al. Mechanisms of occupational
Special considerations are required for asthma. J Allergy Clin Immunol 2009; 123: 531
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comorbidities, e.g. rhino/sinusitis and/or nasal N Reddel HK, et al. An official American Thoracic
polyps, aspirin-induced asthma particularly if Society/European Respiratory Society statement:
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associated with episodes of anaphylaxis,
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occupational asthma or obesity. practice. Am J Respir Crit Care Med 2009; 180:
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Asthma in pregnancy. N Engl J Med 2009; 360:
medical attention in case of smoking
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Asthma 235
VOCAL CORD DYSFUNCTION
A.H. Mansur
Birmingham Heartlands Hospital, Birmingham, UK
E-mail: adel.mansur@heartofengland.nhs.uk
Vocal cord dysfunction (VCD) is characterised Pathogenesis

by paradoxical vocal cord adduction during
inspiration and/or expiration, leading to VCD was seen largely as a conversion disorder
symptoms of breathlessness and wheeze. It is of psychogenic origin. The larynx is innervated
a poorly understood condition that often co- by a complex neurological network, and the
exists with asthma and chronic cough and association between stress and comorbid
shares common triggers such as psychological psychology and VCD attacks strengthened
factors, gastro-oesophageal reflux and this view. More recently it became apparent
rhinosinus disease. The management of that PVCM VCD exists outside the
VCD focuses on establishing the correct conversion disorder prototype. Laryngeal
diagnosis, identification and treatment of closure is a normal physiological reaction to
underlying triggers, and speech therapy. exposure to irritants (e.g. aspiration), but this
Further research is required to define VCD, reaction normally only lasts for few seconds.
establish its natural history and develop Acute (e.g. toxic fume inhalation) or recurrent
evidence-based therapies. irritation (e.g. repeated extreme cold air
exposure) may lead to laryngeal
Terminology hypersensitivity manifesting as vocal cord
adduction and airflow limitation. Laryngeal
Numerous terms have been used to describe hypersensitivity may form part of unified
VCD. These include hysteric croup, allergic airway syndrome with asthma and
Munchausens stridor, pseudo-asthma, rhinitis. The association of laryngeal
factitious asthma, upper airway dysfunction, hypersensitivity with altered autonomic
functional upper airway obstruction, irritable balance status maintained by central brain
larynx syndrome, emotional laryngeal wheeze, activity has been postulated to underlie
laryngeal hyper-responsiveness, and development of VCD.
paradoxical vocal cord movement. Indeed,
there is disagreement of what constitutes Clinical presentation
VCD, with some limiting it to an early
description by CHRISTOPHER et al. (1983) of a VCD presentation varies from cases with
conversion disorder meeting a strict definition predominant throat symptoms, usually
of inspiratory adduction and posterior
chinking of vocal cords, to those who use all Key points
encompassing VCD definition of all cases
demonstrating paradoxical vocal cord N VCD is not well understood, and there
movement (PVCM). is as yet no consensus definition.
Epidemiology N Classically, symptoms appear abruptly,
resolve quickly and do not respond well
While the true prevalence of VCD in the to asthma medication.
general population is unknown, it is more
common in females, athletes, army recruits, N Long-term treatment is based around
and patients with asthma or chronic cough speech therapy and psychotherapy.
(table 1).

Table 1. Vocal cord dysfunction (VCD) prevalence in leading to resolution of the attack or
different patient groups. intubation. If intubated, the airway inflation
pressure is characteristically normal.
Patient group Prevalence %
Refractory asthma 510 Diagnosis
Dyspnoea 2.8 Flowvolume loops may show inspiratory loop
Army recruits with stress- 15 truncation representing extra-thoracic airflow
induced asthma obstruction. The maximal inspiratory flow at
Olympic athletes 5 50% of the forced vital capacity (FVC)/
Childhood acute asthma #
14 maximal expiratory flow at 50% of the FVC
#
ratio can be reduced due to predominant
: presenting to emergency department. The reported inspiratory flow limitation. An abnormally
mean age at VCD diagnosis is 14.5 yrs in children
and 33 yrs in adults. high forced inspiratory flow at 25% of the
FVC/forced inspiratory flow at 75% of the FVC
ratio would indicate an initially normal flow
referred to ear, nose and throat (ENT) followed by rapid flow decline reflecting
specialists, to asthma presenting to respiratory paradoxical vocal cord movement during
clinic, or angio-oedema presenting in an inspiration. However, various studies reported
immunology clinic. Often the diagnosis of the insensitivity of spirometry to diagnose
VCD is made after treatment for asthma has VCD. Sensitivity of spirometry may be
enhanced by histamine or other forms of
not been successful.
airway challenge.
Patients may report rapid onset attacks of
Impulse oscillometry can discriminate
dyspnoea which may be preceded by intense
between central versus peripheral airway
coughing, sensation of strangulation or
obstruction, and may be more sensitive than
breathing through a straw, throat or upper
spirometry. Airway fluoroscopy and colour
chest tightness, dysphonia, or stridor. Classical
Doppler ultrasound imaging of vocal cords
VCD symptoms are of abrupt onset, resolve
movement are other noninvasive tools that
quickly and respond poorly to asthma
have not been standardised against
medication.
laryngoscopy.
Elucidation of triggers of VCD attacks is
Laryngoscopy
important for diagnostic and therapeutic
purposes. Commonly associated triggers VCD diagnosis is established by
include exposure to cold air, exercise, laryngoscopical demonstration of paradoxical
inhalation of strong smells such as perfumes vocal cord movement whilst the patient
or chemical cleaning agents, smoke, cough, experiences spontaneous or induced
reflux, viral infections, allergens and symptoms. Agreed laryngoscopy standards
emotional stress. Psychological morbidity and have not been developed, with some
sexual abuse are experienced in some VCD advocating pre-procedure sedation and
sufferers. The physical examination of patients analgesia, whilst others recommend avoiding
with VCD is usually unremarkable outside these measures. Following short periods of
symptomatic attacks. During symptoms, quiet breathing, specific manoeuvres such as
examination may reveal stridor or wheeze repeating low and high pitched sounds, and
originating at laryngeal level with clear chest forceful inspiration and expiration are
auscultation. The severity of respiratory conducted to induce an attack. Vocal cord
distress varies from mild to severe with movements are timed against respiratory cycle
tachypnoea, but oxygen saturation level is phases by putting a hand on the patients
often normal. Extreme forms of VCD can lead chest. In VCD, the vocal cords adduct
to collapse and loss of consciousness usually anteriorly leaving an open posterior glottic
Vocal cord dysfunction 237

chink (fig. 1). The adduction occurs during Differential diagnosis
inspiration or throughout the respiratory cycle.
False-negative PVCM can be secondary to gag N Laryngeal oedema (angio-oedema).
reflex or coughing. The larynx should also be
inspected for signs of laryngo-pharyngeal
N Allergic laryngitis.
reflux. VCD should be distinguished from N Subglottic stenosis.
vocal cord immobility due to paralysis,
amyotrophic lateral sclerosis, cricoarytenoid
N Laryngomalacia, tracheomalacia.
joint dysfunction and Reinkes oedema. N Vocal cord paralysis.
Laryngeal electromyography may help in
differentiation. Normal laryngoscopy in the
N Systemic disease affecting larynx/upper
absence of symptoms does not exclude VCD. airways (e.g. relapsing chondritis,
The presence of atypical features of asthma Wegeners granulomatosis).
and/or VCD should prompt further Treatment
investigations, such as CT of headneck
thorax and bronchoscopy. The diagnosis and treatment is best
conducted in a multidisciplinary team setting
Investigations of causes of VCD comprised of respiratory physician, speech
A careful history is essential to guide therapist, ENT specialist and psychologist. The
investigations. The presence of concomitant diagnosis is explained to the patient,
rhinitis/asthma or allergic airway disease preferably with support of imaging or
needs to be assessed by lung function, skin illustration. The patients good understanding
allergy testing, blood/sputum eosinophils and of VCD is prerequisite to effective treatment.
exhaled nitric oxide. Gastro-oesophageal A management plan should be formulated
that bear in mind co-existing asthma. Due to
reflux disease symptoms or laryngeal refluxive
VCD under-recognition, patients should carry
changes on laryngoscopy should prompt
an alert card listing medication and treatment
further testing (e.g. oesophageal manometry
strategy.
and pH studies). Underlying psychological
issues should be assessed. Treatment of acute attacks
The treating physician should adopt a

calm reassuring manner and ask patient to
focus on expiration with an S sound that
helps in diverting attention. A panting
manoeuvre can abort acute attacks by
inducing vocal cord abduction. Where
hypoxaemia and hypercapnia has been
excluded, sedation with benzodiazepines may
help patient relaxation. Heliox gas mixture
(e.g. 72% helium and 28% oxygen) can
alleviate symptoms by enhancing upper
airway laminar air flow. Intubation or
tracheostomy should be avoided. In
extreme cases presenting with an
apparent life-threatening attack, the
clinical decision will remain with the
treating physician. If intubation is
contemplated, prior inspection and
Figure 1. Laryngoscopy demonstrating inspiratory documentation of the status of vocal cords
vocal cord adduction and posterior glottic chink. is recommended.

Long-term treatment Conclusion
Speech therapy forms the mainstay of VCD VCD is a relatively uncommon condition that
treatment with the primary aim of teaching mimics and co-exists with asthma, and
patients to relax upper airways and control presents episodically thus making its
laryngeal area. It is conducted in four to six diagnosis challenging and often delayed.
successive sessions to enable the patient to Patients can become frequent healthcare
practice breathing techniques to abort or treat users with substantial morbidity as result of
acute attacks. Patients are taught to exhale erroneous diagnosis and toxic medication use.
gently and avoid forceful inspiration in a Establishing proper diagnosis and treatment
rhythmic manner, followed by introduction of can be effective and rewarding to both the
expiratory resistance by asking patient to patient and healthcare professionals.
produce sounds such as S. The role of
speech therapist extends to making diagnosis, References
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relaxation therapy. and laryngeal hyperresponsiveness: a function of
Psychotherapy should form an integral part of altered autonomic balance? Thorax 2002; 57:
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adverse psychology. Psychotherapy can
N Belafsky PC, et al. Validity and reliability of the
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coping strategies. presenting as asthma. New Engl J Med 1983;
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motion: a sensory-motor laryngeal disorder.
exercise-induced VCD attacks, enhancing Laryngoscope 2008; 118: 367370.
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injection of vocal cords by botulinum toxin A Immunol 2006; 96: 794799.
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resort in intractable cases. dysfunction. Am J Respir Crit Care Med 1995;
152: 13821386.
Prognosis N OConnell M. Vocal cord dysfunction: ready for
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2006; 96: 762763.
VCD prognosis will probably depend on initial
disease severity and associated morbidities. One
N Ruppel GL. The inspiratory flowvolume curve:
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within a 5-yr time frame, with symptoms N Sullivan MD, et al. A treatment for vocal cord
disappearing within 6 months in many who dysfunction in female athletes: an outcome
had good response to speech therapy. However, study. Laryngoscope 2001; 111: 17511755.
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Vocal cord dysfunction 239

BRONCHITIS
G. Rohde
Dept of Respiratory Medicine, Maastricht University Medical Centre,
Maastricht, The Netherlands
E-mail: gernot.rohde@mumc.nl
Definition
Key points
Transient airway inflammation localised to the
respiratory mucosa of the central airways and N Respiratory viral infection is the most
clinically characterised by cough and sputum common cause of acute bronchitis.
production. Fever and dyspnoea can occur.
N Acute bronchitis is usually a
Symptoms self-limiting disease.
Cough is the cardinal symptom and is N The diagnosis of acute bronchitis is
observed in 100% of cases. It usually persists purely clinical and in most cases
for up to 2 weeks but in 26% it can stay for symptomatic treatment is sufficient.
up to 8 weeks. Other symptoms include
sputum production (90%), dyspnoea, N Chronic bronchitis is defined clinically
wheezing (62%), rhonchi, chest pain, fever, as productive cough for 3 months in
hoarseness and malaise. each of 2 successive years.
Epidemiology
Acute bronchitis is one of the most frequent Moraxella catarrhalis. Atypical bacteria (e.g.
human diseases worldwide, with children Mycoplasma pneumoniae, Chlamydia
being most often affected. On average pneumoniae) and Bordetella pertussis also
children contract bronchitis 26 times per play a role.
year, and adults 23 times per year. The
prevalence in UK is 44 cases per 1,000 adults Specific risk factors are not identified and it is
per year. 82% of episodes occur during the currently not clear whether cigarette smoking
cold months. increases the risk of acute bronchitis. There
are epidemiological data showing that the
Aetiology/risk factors frequency of bronchitis is increased after
school holidays, which indicates that crowding
Respiratory infections are the main trigger of
facilitates dissemination of respiratory
acute bronchitis. However, in only 55% of
infections.
cases can pathogens be detected. Respiratory
viruses are the most frequent pathogens. Prognosis
Rhino-, adeno-, echo-, influenza-,
parainfluenza-, entero- and coronaviruses, Acute bronchitis is usually a self-limiting
Coxsackie virus and respiratory syncytial disease. However there are only sparse data
viruses (RSV) represent the usual spectrum. on prognosis and rate of complications. In a
Parainfluenza, entero- and rhinoviruses infect study investigating 653 previously healthy
mainly in the autumn, while influenza, RSV adulty with lower respiratory tract symptoms,
and coronaviruses infect mainly in winter and 20% of patients had persistent sysmptoms. In
early spring. Typical bacteria are Streptococcus 40% of these patients, there was reversible
pneumoniae, Haemophilus influenzae and airway obstruction. In another study, a third of

patients developed asthma or chronic Chronic bronchitis
bronchitis symptoms.
Chronic bronchitis is defined clinically as
Diagnosis chronic productive cough for 3 months in each
of two successive years in a patient in whom
Diagosis is purely clinical. Cough, sputum other causes of productive chronic cough have
production optionally accompanied by been excluded. Cigarette smoking is by far the
dyspnoea and/or wheezing are suggestive. most important and preventable risk factor.
Tachycardia and tachypnoea are usually Chronic bronchitis is a major component of
absent, and vital signs are normal. chronic obstructive pulmonary disease.
Complicated cases show fever; however, in
these cases differential diagnosis like References
pneumonia or systemic influenza should be N American Thoracic Society, Chronic bronchitis,
considered. Clinical signs of pneumonia (rales, asthma, pulmonary emphysema. A statement by
egophony, dullness on percussion) should be the committee on diagnostic standards for non-
absent. Acute bronchitis should be tuberculous disease. Am Rev Respir Dis 1962;
differentiated from asthma, which typically 85: 762768.
presents as progressive cough accompanied N Anto JM, et al. Epidemiology of chronic
by wheezing, tachypnoea, respiratory distress obstructive pulmonary disease. Eur Respir J
2001; 17: 982994.
and hypoxaemia. It should also be
N Boldy DA, et al. Acute bronchitis in the
distinguished from bronchiectasis, a distinct community: clinical features, infective factors,
phenomenon associated with permanent changes in pulmonary function and bronchial
dilatation of bronchi and chronic cough. reactivity to histamine. Respir Med 1990; 84:
Laboratory investigations are not necessary. In 377385.
more severe cases, sputum culture can be N Chesnutt MS, Prendergast TJ. Lung. In: Tierney
considered to guide antibiotic therapy. LM, ed. Current medical diagnosis and
treatment, 41st Edn. New York, McGraw-Hill,
Therapy 2002; pp. 269362.
N Jonsson JS, et al. Acute bronchitis and clinical
Therapeutic goals are reduction of symptoms outcome three years later: prospective cohort
and prevention of complications with as few study. BMJ 1998; 317: 14331440.
side-effects as possible. Antibiotic therapy N Macfarlane JW, et al., Prospective study of the
cannot be recommended generally, but in incidence, aetiology and outcome of adult lower
patients with fever and/or comorbidities, respiratory tract illness in the community. Thorax
2001; 56: 109114.
aminopenicillins or cephalosporins (second
generation) can be administered.
N Wenzel RP, Fowler, III AA, Clinical practice.
Acute bronchitis. N Engl J Med 2006; 355:
Dextromethorpham has been shown to reduce 21252130.
cough efficiently. In patients with dyspnoea N Williamson Jr HA. Pulmonary function tests in
and/or wheezing, short-acting bronchodilators acute bronchitis: evidence for reversible airway
can be beneficial. obstruction. J Fam Pract 1987; 25: 251256.
Bronchitis 241
GASTRO-OESOPHAGEAL
REFLUX
L. Dupont
Dept of Respiratory Medicine, University Hospital Gasthuisberg, KU Leuven,
Belgium
E-mail: lieven.dupont@uz.kuleuven.ac.be
Gastro-oesophageal reflux disease (GORD) is and ear, nose and throat symptoms and
an increasingly prevalent condition that disorders. Respiratory manifestations of GORD
affects up to 20% of the Western population. represent one of the most prevalent and
Transient lower oesophageal sphincter challenging of these extra-oesophageal
relaxations (TLOSRs) are now recognised as a syndromes. The relationship between reflux
major factor in the pathophysiology of GORD. and respiratory symptoms is frequently
Although GORD often causes typical difficult to establish with a high degree of
symptoms such as heartburn or regurgitation, certainty and diagnostic, as well as
it may also present with atypical or extra- therapeutic, management remains largely
oesophageal symptoms, including respiratory empirical. In contrast to oesophageal GORD
manifestations, efficacy of acid-suppressive
therapy in extra-oesophageal GORD
Key points symptoms has not been well established.
N GORD is a common disorder caused by Pathophysiology

the reflux of gastric contents into the
There are a number of potential mechanisms
oesophagus because of impaired func-
whereby GORD may aggravate or trigger
tion of the lower oesophageal sphincter
respiratory disease. Direct aspiration of gastric
and may result in oesophageal and refluxate into the airway occurs as a
extra-oesophageal symptoms. consequence of failure of the normal
N The relationship between reflux and protective mechanisms to foreign material, i.e.
respiratory symptoms or disorders is reflex contraction of the upper oesophageal
frequently difficult to establish with a sphincter and closure of glottis and vocal
high degree of certainty. cords is likely to be relevant in cystic fibrosis
(CF) and rejection after lung transplantation.
N Diagnostic, as well as therapeutic, A vagally mediated oesophageal
management remains largely empirical. tracheobronchial reflex has been postulated
N Treatment with PPI has been shown to to account for the association between acid
improve cough in patients with acid reflux and cough or asthma. Oesophageal
GOR-induced cough but the effect of sensory stimulation can release tachykinins
PPI remains disappointing when treat- into the airways and may increase the
ing GOR in other respiratory diseases. bronchomotor responsiveness to airway
stimuli bronchospasms. It has also been
N Antireflux surgery was associated with postulated that chronic exposure of the
improved allograft function after lung oesophageal mucosa to gastric juices can
transplantation. produce long-lasting hypersensitivity to a
variety of stimuli that can cause the symptom

even in the absence of increased oesophageal recent Cochrane systematic review retrieved
acid exposure or oesophagitis. 13 randomised, controlled trials of GORD
treatment for cough in children and adults.
GOR in asthma and COPD Meta-analysis of the studies comparing PPI
GORD is a common condition among patients treatment (2 or 3 months) with placebo
with obstructive pulmonary diseases. Probably showed no difference between placebo and
one-third of asthmatics present with GORD PPI (odds ratio 0.46, 95% CI 0.191.15) in the
(prevalence range 1084%) and some resolution of cough, although sensitivity
5060% of chronic obstructive pulmonary analyses showed significant changes in cough
disease (COPD) patients have abnormally scores in those receiving PPI in cross-over
high oesophageal acid exposure times, which trials. Further randomised, parallel-design,
is more than the general population. There is placebo-controlled, double-blind trials are
no clear understanding of why this is true but needed.
it may be due to the fact that airway
Based on these data two different
obstruction, diaphragmatic flattening,
management strategies of patients with
b2-agonists and theophylline are able to
suspected reflux-related cough can be
promote oesophageal reflux. Often COPD or
proposed. The empirical strategy with PPI
asthmatic patients with GORD do not have
(usually double dose) given for at least
classic symptoms of GORD.
3 months is probably the most popular one
Recent randomised controlled data suggest but it should be underlined that this strategy
that it is not a useful practice for mild-to- is not supported by strong evidence.
moderate asthmatic patients to treat Appropriate initial selection of potential
asymptomatic GORD with proton pump responders to GORD treatment could be done
inhibitors (PPIs) as it will not improve asthma on the basis of the presence of typical reflux
control. Asthma outcome may only improve to symptoms.
some extent with PPI management among
The second strategy consists of investigations,
patients who present with severe difficult-to-
which should ideally detect both acidic and
control asthma and symptomatic GORD.
nonacidic reflux. Patients who failed to
Reflux symptoms in COPD patients were respond to empirical therapy should be
associated with an increased number of COPD investigated. In well-selected patients,
exacerbations and oxygen desaturation antireflux surgery may be indicated for long-
coincided with episodes of increased term control. This may also be the case for
oesophageal acidity in 40% of patients with patients with refractory acidic or nonacidic
severe COPD and GORD. Uncontrolled data reflux and a well-documented correlation
suggest that PPI treatment may decrease the between reflux episodes and cough.
number of COPD exacerbations.
GOR in advanced lung disease
GOR-induced cough
The prevalence of increased GOR in CF is
Studies have determined GOR to be a cause estimated to be between 35% and 81%. Acid
for chronic cough in up to 43% of patients GOR is most common, but weakly acidic GOR
referred for specialist evaluation. According to may also occur. Patients with CF have a high
published guidelines GORD investigations are risk for gastric aspiration, as demonstrated by
indicated in patients with chronic cough. Only increased bile acids in saliva, sputum or in
a minority of patients with chronic cough and bronchoalveolar lavage fluid. Half of the CF
GORD have typical digestive symptoms and/or patients with increased GOR or gastric
clear evidence of oesophagitis. The treatment aspiration do not present oesophageal
of cough-associated reflux has been evaluated symptoms like heartburn or regurgitation. The
in many uncontrolled and a few controlled characteristics of GOR and material aspirated
trials of drug therapy and antireflux surgery. A depend on the genotype with bile acids
Gastro-oesophageal reflux 243

aspiration being more important in DF508 events might therefore feature as a potential
homozygotes. The causal relationship risk factor for the development of BOS after
between GOR, aspiration and respiratory lung transplantation. Antireflux surgery was
symptoms is not completely elucidated. associated with improved allograft function.
Recent results suggest that patients with
Management of GORD
increased oesophageal acid exposure have
more cough and a positive association In general practice, most cases of GORD are
between GOR and cough is associated with diagnosed on the basis of typical symptoms
poorer lung function. Bile acid levels in and the response to inhibition of gastric acid
sputum is correlated with elastase levels in secretion. Endoscopy, oesophageal
sputum and forced expiratory volume in 1 s. manometry or acid instillation in the
oesophagus (Bernstein test) have limited
GOR may play a role in the pathogenesis and/ sensitivity and specificity for the diagnosis of
or progression of idiopathic pulmonary GORD. 24-h oesophageal pH monitoring can
fibrosis (specifically in acute exacerbation) as provide useful information, in particular
a recurrent inflammatory stimulus. Studies through assessment of the temporal
have found a high prevalence of reflux (36 association between symptoms and reflux
87%) among patients with idiopathic events. The addition of impedance monitoring
pulmonary fibrosis. Pre-transplant patients to pH monitoring further improves GOR
with idiopathic pulmonary fibrosis undergoing diagnosis as it also detects nonacid (weakly
antireflux surgery had reduced supplementary acidic) reflux events and allows testing whilst
oxygen dependence compared with other pre- the patient is on a PPI. Investigations of the
transplant patients with idiopathic pulmonary routine diagnostic value of the measurement
fibrosis. In addition, there are anecdotal cases of pepsin and bile acid concentrations in
of idiopathic pulmonary fibrosis disease saliva, sputum or BALF are in progress.
stability following treatment for reflux. While
it cannot be proven that disease stability was Medications interfering with acid production,
caused by control of reflux, they suggest that especially the PPIs, are the cornerstone of
a subset of patients with idiopathic GORD treatment. Acid-suppressive therapy is
pulmonary fibrosis may benefit from highly effective in the healing and
antireflux therapy. maintenance of oesophagitis, but seems to be
poorly effective when GORD is presumed to
GOR and gastric aspiration have also been underlie extra-oesophageal symptoms.
implicated as a potential nonalloimmune Symptoms that persist during standard acid
cause of lung allograft rejection (bronchiolitis suppressive therapy regimens have also been
obliterans syndrome (BOS)) after lung related to nonacid or weakly acidic reflux.
transplantation. Standard oesophageal pH There is little evidence that further
recordings indicated an increased intensification of acid suppression beyond
oesophageal acid exposure in .70% of lung high-dose PPI twice daily is of any benefit for
transplant patients. Luminal gastric these patients. Several attempts to improve
components such as pepsin and bile acids symptoms in these patients through the
have been demonstrated in bronchial material addition of gastroprokinetic drugs have thus
of lung transplant recipients and were more far not been successful. At present, the only
prevalent in the lungs of patients with BOS. alternative for these patients is a surgical
Aspiration of bile acids was related to weakly fundoplication, but not all patients are
acidic reflux events and especially those eligible for surgery, the intervention is not
occurring during the night were also without complications, and poor responders to
associated with reduced concentration of PPI therapy are also less certain to experience
pulmonary surfactant collectin proteins and symptom relief from surgery. Two classes of
reduced freedom from BOS. Aspiration even in drugs, the c-aminobutyric acid (GABA)-B
the absence of an increased number of GOR agonists and the metabotropic glutamate

receptor-5 antagonists are currently under chronic cough associated with gastro-
evaluation for their ability to reduce TLOSRs oesophageal reflux. BMJ 2006; 332: 1117.
and improve (weakly acidic) reflux and N Dupont LJ, DOvidio F. Emerging risk factors for
symptoms that are refractory to PPI therapy. bronchiolitis obliterans syndrome: gastro-
oesophageal reflux and infections. Eur Respir
Other pathways that are under investigation
Mon 2009; 45: 212225.
include mucosal protective agents, inhibitors N Galmiche JP, et al. Review article: respiratory
of acid-sensitive ion channels, and endoscopic manifestations of gastro-oesophageal reflux
antireflux procedures. disease. Aliment Pharmacol Ther 2008; 27:
449464.
References
N Pashinsky YY, et al. Gastroesophageal reflux
N Asano K, Suzuki H. Silent acid reflux and asthma disease and idiopathic pulmonary fibrosis. Mt
control. N Engl J Med 2009; 360: 15511553. Sinai J Med 2009; 76: 2429.
N Blondeau K, et al. Gastro-oesophageal reflux N Rascon-Aguilar IE, et al. Role of
and aspiration of gastric contents in adult gastroesophageal reflux symptoms in
patients with cystic fibrosis. Gut 2008; 57: exacerbations of COPD. Chest 2006; 130:
10491055. 10961101.
N Chang AB, et al. Systematic review and meta- N Sweet MP, et al. Gastro-oesophageal reflux and
analysis of randomised controlled trials of aspiration in patients with advanced lung
gastro-oesophageal reflux interventions for disease. Thorax 2009; 64: 167173.
Gastro-oesophageal reflux 245

COPD AND EMPHYSEMA
Department of Thoracic Medicine, Medical School, University of Crete,
Greece
E-mail: tzortzaki@med.uoc.gr
Chronic obstructive pulmonary disease enlargement of airspaces, which are

(COPD) is a preventable and treatable disease anatomical hallmarks of emphysema,
with some significant extrapulmonary effects contribute to the loss of elastic recoil and the
that may contribute to its severity in loss of outward traction on the small airways,
individual patients. Its pulmonary component leading to their collapse on expiration. This
is characterised by airflow limitation that is results in airflow obstruction, air trapping and
not fully reversible. The airflow limitation is hyperinflation. In general, the inflammatory
usually progressive and associated with an and structural changes in the airways increase
abnormal inflammatory response of the lungs with disease severity and persist even after
to noxious particles or gases. Cigarette smoking cessation.
smoking is by far the most common risk factor Chronic obstructive bronchitis and/or
for the disease. COPD is a major cause of emphysema
morbidity and mortality worldwide. It affects
,10% of the general population but its COPD is a heterogeneous disease. Two main
prevalence among smokers may reach 50%. phenotypes are recognised: chronic bronchitis
According to an American Thoracic Society/ and emphysema.
European Respiratory Society Task Force,
Chronic bronchitis is characterised by cough
COPD is a preventable and treatable disease
and sputum production for at least 3 months
characterised by airflow limitation that is not
in each of two consecutive years. The
fully reversible. The airflow limitation is
symptoms may precede the development of
usually progressive and is associated with an
abnormal inflammatory response of the
lungs to noxious particles or gases, primarily Key points
caused by cigarette smoking. Although COPD
affects the lungs, it also produces significant N COPD is a heterogeneous disease, with
systemic consequences. The cardinal two main phenotypes: chronic
symptoms of COPD dyspnoea, cough and bronchitis and emphysema.
sputum production are chronic and N A strong genetic component, in
progressive.
conjunction with environmental insult,
COPD comprises pathological changes in four probably accounts for the development
different compartments of the lungs (central of COPD.
airways, peripheral airways, lung parenchyma N Smoking cessation is the single most
and pulmonary vasculature), which are effective intervention in COPD
variably present in people with the disease. prevention and treatment.
Airflow limitation in COPD is caused by the
presence of an abnormal inflammatory N Bronchodilators are central to
cellular infiltrate in the small airways, symptomatic treatment, backed up if
remodelling and thickening of the airway necessary by other interventions.
wall. The destruction of alveoli and

Table 1. Spirometric classification of COPD severity based on post-bronchodilator forced expiratory volume in 1 s (FEV1)
At risk FEV1/FVC .0.70
FEV1 o80% pred
Stage I: mild FEV1/FVC ,0.70
FEV1 o80% pred
Stage II: moderate FEV1/FVC ,0.70
50% fFEV1 ,80% pred
Stage III: severe FEV1/FVC ,0.70
30% fFEV1 ,50% pred
Stage IV: very severe FEV1/FVC ,0.70
FEV1 ,30% pred or FEV1 ,50% pred plus chronic
respiratory failure#
FVC: forced vital capacity; % pred: % predicted. #: respiratory failure is defined as an arterial partial pressure of oxygen
,60 mmHg with or without arterial partial pressure of CO2 .50 mmHg while breathing air at sea level. Respiratory
failure may also lead to effects on the heart such as cor pulmonale (right heart failure). Clinical signs of cor pulmonale
include elevation of the jugular venous pressure and pitting ankle oedema. Patients may have stage IV chronic
obstructive pulmonary disease even if their FEV1 is .30% pred whenever these complications are present. At this
stage, quality of life is significantly impaired and exacerbations may be life threatening. Reproduced from the Global
strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, with permission.
airflow limitation by many years. Stages of severity

Inflammation and secretions provide the
Airflow limitation in COPD is best measured
obstructive component of the disease. In
by spirometry, the most widely available and
contrast to emphysema, chronic bronchitis is
reproducible lung function test. A simple
associated with a relatively undamaged
spirometric classification of disease severity
pulmonary capillary bed. Emphysema is
into five stages has been established by the
present to a variable degree but is usually
Global Initiative for Obstructive Lung Disease
centrilobular rather than panlobular. The body
(GOLD) and the criterion for airflow
responds by decreasing ventilation and
obstruction is a forced expiratory volume in
increasing cardiac output (ventilation/
1 s (FEV1)/forced vital capacity (FVC) ratio
perfusion (V9/Q9) mismatch) leading to
,0.7, regardless of age (table 1). The FEV1/
hypoxaemia, polycythaemia and increased
FVC ratio in normal subjects declines with
CO2 retention, and eventually these patients
age, thus an alternative cut-off for diagnosing
develop signs of right heart failure.
obstruction without over-diagnosing in
The second major COPD phenotype is the younger subjects, is using values outside the
emphysematous patient. Emphysema is 95% confidence intervals for predicted FEV1/
defined by destruction of airways distal to the FVC ratios (below the lower limit of normal).
terminal bronchiole, gradual destruction of Newer publications on reference equations
alveolar septae and of the pulmonary give explicit upper and lower limits of the
capillary bed, leading to decreased ability to normal range, or provide a method for its
oxygenate blood. The body compensates with calculation. Normal values are most difficult
lowered cardiac output and hyperventilation. to predict in older, shorter people, who may
This V9/Q9 mismatch results in relatively not be well represented in the reference
limited blood flow through a quite well- population from which the prediction
oxygenated lung with normal blood gases and equation was derived.
pressures. Eventually, due to low cardiac Risk factors
output, the rest of the body suffers from tissue
hypoxia, pulmonary cachexia, muscle wasting Although smoking is the best-studied COPD
and weight loss. risk factor, it is not the only one and there is
COPD and emphysema 247

consistent evidence from epidemiological 97%, respectively, of the wild-type MM
studies that nonsmokers may develop chronic genotype. ZZ homozygous have the most
airflow obstruction (table 2). Other factors, severe a1-AT deficiency. Emphysema
such as indoor air pollution from burning associated with a1-AT deficiency is typically
biomass fuels for cooking and heating, are panlobular, characterised by uniform
important causes of COPD in many destruction of the pulmonary lobule. Cigarette
developing countries, especially among smoking is the biggest risk factor for the
women. Nevertheless, not all subjects exposed development of emphysema and airflow
to a noxious agent develop COPD. Thus, a obstruction in a1-AT deficiency, and current
strong genetic component in relation with an smokers have an accelerated decline in FEV1,
environmental insult (geneenvironment compared with ex-smokers and never-smokers
interaction) accounts, most probably, for the and a1-AT deficiency. Homozygous Z patients
development of the disease (table 2). Familial have a very low a1-AT and generally show
clustering of COPD has been observed and rapid decline in FEV1 even without smoking.
twin studies have supported the concept of a In homozygous Z smokers, COPD is developed
genetic predisposition to COPD. Different at a younger age. However, this homozygous
strategies have been used to identify genes state is rare in the general population (one in
containing mutations or polymorphisms that 5,000 live births) and thus as genetic risk
contribute to the development of COPD due factor can explain ,1% of COPD.
to smoking. Linkage analysis has revealed
regions suggestive for COPD on chromosomes Recently, epigenetic mechanisms, such as
1, 2 and 12. In addition, linkage of FEV1 and/ acquired somatic mutations, have been
or FEV1/FVC ratio with various loci in the explored in COPD. Somatic mutations are not
genome has been reported (i.e. chromosomes heritable, although the susceptibility to
1, 2q, 4, 6, 8, 12p, 17, 18, 19 and 21). Among acquiring such mutations might be controlled
the candidate genes that have been studied in by inherited genes. In normal conditions, cells
COPD are genes that regulate the production are equipped with a number of repair
of proteases and antiproteases, genes that pathways that remove the damage and
modulate the metabolism of toxic substances restore DNA. However, increased and
in cigarette smoke, genes involved with persistent oxidative stress (e.g. due to
mucociliary clearance and genes that cigarette smoking) may inactivate the human
influence inflammatory mediators. DNA mismatch repair system leading to
acquired mutations. Smoking-induced
However, the genetic risk factor that is best acquired somatic alterations have been
documented is the hereditary deficiency of a1- detected in COPD patients.
antitrypsin (a1-AT), a serum protein made in
the liver that is capable of inhibiting the Management
activity of specific proteolytic enzymes, the The overall approach to managing stable
serine proteases. The a1-AT gene is located COPD is based on an individualised
within the serpin cluster, on the chromosome assessment of disease severity and response to
14q23.1-3. Neutrophil elastase is the main various therapies. The patient who still smokes
target of a1-AT; if not inactivated by a1-AT, should be encouraged to quit. Smoking
neutrophil elastase destroys lung connective cessation is the single most effective
tissue, particularly elastin, and this leads to intervention to reduce the risk of developing
the development of emphysema. .90 COPD and stop its progression, and can
phenotypes of a1-AT have been described. The have a substantial effect on subsequent
common gene variants are M, S and Z. M1, mortality.
M2, M3, M4 are wild types found in 90% of
the population. Different genotypes, ZZ, SZ, The goals of therapy are to prevent and
MZ, SS and MS, cause average serum a1-AT control symptoms, reduce the frequency and
concentration reduced to 16, 51, 83, 93 and severity of exacerbations and improve exercise

Table 2. Risk factors for chronic obstructive pulmonary exacerbations and improve the health status
disease of COPD patients. Recent data, however,
based on a single large study of patients with
Genes
FEV1 ,60% pred, indicate that regular
Exposure to particles treatment with inhaled glucocorticosteroids
Tobacco smoke
can decrease the rate of decline of lung
Occupational dusts, organic and inorganic
Indoor air pollution (heating and cooking with function. Long-term treatment with oral
biomass fuel) glucocorticosteroids should be avoided in
Outdoor air pollution COPD because side-effects such as steroid
Lung growth
myopathy may contribute to muscle weakness,
decreased functionality and respiratory failure
Oxidative stress in patients with advanced COPD. The regular
Sex use of mucolytic and antioxidant agents has
Age been evaluated in COPD patients without
Respiratory infections significant overall benefit, although there has
been a study reporting reduced frequency of
Socioeconomic status
exacerbations. The regular use of antibiotics,
Nutrition other than for treating infectious
Reproduced from the Global strategy for the diagnosis, exacerbations of COPD is not recommended.
management, and prevention of chronic obstructive The regular use of antitussive medications is
pulmonary disease, with permission. also not recommended since cough, although
a troublesome symptom, has a significant
protective role. There has been some recent
tolerance, thus improving overall the quality
evidence regarding the use of statins and
of life (fig. 1). Bronchodilator medications are
long-term macrolide treatment in decreasing
central to the symptomatic management of
COPD exacerbations, but these are not
COPD. These drugs improve emptying of the
standard recommendations.
lungs, tend to reduce dynamic hyperinflation
and improve exercise performance. There is Influenza vaccination is strongly recommended
choice of b2-agonists, anticholinergics and for all COPD patients; it can reduce serious
methylxanthines used either singly or in illness and death by ,50% and should be
combination. Inhaled therapy is preferred and given once a year. Pneumococcal
bronchodilators are prescribed on either an as- polysaccharide vaccine is recommended for
needed or a regular basis, although it is COPD patients who are aged o65 yrs.
evident that regular treatment with long-
acting bronchodilators is more effective and Pulmonary rehabilitation aims at improving
convenient than treatment with short-acting exercise capacity, reducing symptoms and
ones. Treatment with a long-acting inhaled overall improving quality of life. It is a
anticholinergic drug reduces the rate of COPD multidisciplinary programme ideally involving
exacerbations and improves the effectiveness several types of health professionals. COPD
of pulmonary rehabilitation. A combination of patients at all stages of disease appear to
a short-acting b2-agonist and an benefit from exercise training programmes,
anticholinergic produces better and more although benefit decreases after a
sustained improvements in FEV1 than either rehabilitation programme ends. Pulmonary
drug alone. The addition of inhaled rehabilitation improves dyspnoea, improves
glucocorticosteroids is appropriate for quality-of-life scores, reduces the number of
symptomatic patients with COPD stage III and hospitalisations and days in hospital, reduces
IV and repeated exacerbations according to anxiety and depression related with COPD
the guidelines (fig. 1). This treatment does and improves survival. A comprehensive
not modify the long-term decline of FEV1, but rehabilitation programme includes exercise
it has been shown to reduce the frequency of training, education and nutrition counselling.

I: Mild II: Moderate III: Severe IV: Very Severe
FEV1/FVC <0.70
FEV1/FVC <0.70
FEV1/FVC <0.70 FEV1 <30% pred
FEV1/FVC <0.70 or FEV1 <50% pred
FEV1 80% pred 50% FEV1 <80% pred 30% FEV1<50% pred plus chronic respiratory
failure
Active reduction of risk factor(s); influenza vaccination
Add short-acting bronchodilator (when needed)
Add regular treatment with one or more long-acting bronchodilators (when

needed); add rehabilitation
Add inhaled glucocorticosteroids if repeated
exacerbations
Add long-term oxygen if
chronic respiratory failure.
Consider surgical
treatments
Figure 1. Chronic obstructive pulmonary disease (COPD) treatment by severity. FEV1: forced expiratory volume
in 1 s; FVC: forced vital capacity; % pred: % predicted. Reproduced from the Global strategy for the diagnosis,
management, and prevention of chronic obstructive pulmonary disease, with permission.
Nutritional status is an important factor in N Celli B, et al. Effect of pharmacotherapy on rate

determining symptoms, respiratory function of decline of lung function in chronic obstructive
and prognosis in COPD. Both extremes pulmonary disease: results from the TORCH
study. Am J Respir Crit Care Med 2008; 178:
(overweight and underweight) are
332338.
detrimental. A reduction in body mass N Celli BR, et al. Standards for the diagnosis and
index, seen in ,25% of stage III and IV treatment of patients with COPD: a summary of
COPD patients, is an independent risk the ATS/ERS position paper. Eur Respir J 2004;
factor for mortality. Present evidence 23: 932946.
suggests a combination of nutritional N Coventry PA. Does pulmonary rehabilitation
support and exercise regimes, to induce reduce anxiety and depression in chronic
anabolic action. obstructive pulmonary disease? Curr Opin Pulm
Med 2009; 15: 143149.
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deficiency? 2: Genetic aspects of a1-antitrypsin
N Barnes PJ. Molecular genetics of chronic deficiency: phenotypes and genetic modifiers of
obstructive pulmonary disease. Thorax 1999; emphysema risk. Thorax 2004; 59: 259264.
54: 245252. N Global Initiative for Chronic Obstructive Lung
N Blamoun AI, et al. Statins may reduce episodes Disease. Global strategy for the diagnosis,
of exacerbations and the requirement for management, and prevention of chronic
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N Celli BR, et al. Airway obstruction in never N Hersh CP, et al. Attempted replication of
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N Hogg JC. Pathophysiology of airflow limitation N Silverman EK, Speizer FE. Risk factors for the
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N Nici L, et al. Pulmonary rehabilitation: what we deficiency. Lancet 2005; 365: 22252236.
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Rehabil Prev 2009; 29: 141151. pulmonary function and chronic bronchitis. Am
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23: 208214. 315.
N Seemungal TAR, et al. Long term erythromycin N Zheng JP, et al. Effect of carbocisteine on acute
therapy is associated with decreased COPD exacerbation of chronic obstructive pulmonary
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178: 11391147. controlled study. Lancet 2008; 371: 20132018.

EXACERBATIONS OF COPD
A.J. Mackay and J.A. Wedzicha
Academic Unit of Respiratory Medicine, University College London,
London, UK
E-mail: j.a.wedzicha@medsch.ucl.ac.uk
Definition Burden
Chronic obstructive pulmonary disease Exacerbations are important events in the

(COPD) is a chronic inflammatory airway natural history of COPD; they have been
condition associated with episodes of acute shown to drive lung function decline and are
deterioration termed exacerbations. An responsible for much of the morbidity and
exacerbation of COPD is defined as an event mortality associated with this highly prevalent
in the natural course of the disease condition. Exacerbations are also among the
characterised by a change in the patients most common causes of medical admission
baseline dyspnoea, cough, and/or sputum that and are costly to health services.
is beyond normal day-to-day variations, is
Patients hospitalised with exacerbations of
acute in onset, and may warrant a change in
COPD are a particularly vulnerable group with
regular medication in a patient with
a poor long-term outlook, with all-cause
underlying COPD.
mortality approaching 50% at 3 yrs post-
discharge. Advanced age and severe lung
function impairment, in addition to diabetes
and poor health status, are particular risk
factors for mortality. Inpatient mortality of
Key points patients admitted with COPD exacerbations in
the UK is 7.4%, and rises to 25% for those
N Exacerbations are important events; patients with hypercapnic respiratory failure
they drive lung function decline and are treated with noninvasive ventilation. Thus
responsible for much of the morbidity prevention, early diagnosis and prompt,
and mortality associated with COPD. effective management is vital to improve
exacerbation recovery, ameliorate the effects
N The majority of COPD exacerbations are
on quality of life and reduce the risk of
triggered by respiratory viral infections
hospitalisation.
and/or bacterial infections.
Causes
N The frequent exacerbator phenotype
is stable over time and exists across all Exacerbations are associated with increased
GOLD stages. systemic and airway inflammation, and may
N Frequent exacerbators exhibit faster be precipitated by environmental factors.
decline in lung function, have worse However, the majority of COPD exacerbations
quality of life, increased risk of are triggered by bacterial and/or respiratory
viral infections (fig. 1).
hospitalisation and greater mortality.
Infection Bacteria are isolated from sputum
N Both pharmacological and nonpharma- in 4060% of acute exacerbations of COPD
cological therapies exist that can help and respiratory viruses are identified in 40
prevent COPD exacerbations. 60% of exacerbations, rhinovirus being the
most prevalent species identified. Experimental
Exacerbations of COPD e1
Triggers
Bacteria Viruses Pollutants
Effects
Inflamed COPD airway
Greater airway inflammation
Systemic Bronchoconstriction,
inflammation oedema, mucus
Expiratory flow
limitation
Cardiovascular Exacerbation Dynamic

comorbidity symptoms hyperinflation
FIGURE 1. Triggers of chronic obstructive pulmonary disease exacerbations and associated pathophysiological
changes leading to increased exacerbation symptoms. Reproduced from WEDZICHA and SEEMUNGAL (2007) with
permission from the publisher.
infection models provide direct evidence that exacerbation; exacerbation symptoms, forced
the symptomatic and physiological changes expiratory volume in 1 s (FEV1) decline and
seen in acute exacerbations of COPD can be inflammation being more severe in the
precipitated by rhinovirus infection. presence of both bacteria and viruses. These
Furthermore, viral and bacterial infections subjects are discussed further in the chapter
demonstrate a synergistic effect at entitled Infective exacerbations of COPD.
e2 ERS Handbook: Respiratory Medicine

Air pollution Extensive data exists to exhibit faster decline in lung function and
support a role for air pollution in the aetiology may have worse functional status, as
of some COPD exacerbations. The Air measured by time outdoors. Thus, it is vital to
Pollution and Health, a European Approach identify patients at risk of frequent
(APHEA) collaboration examined short-term exacerbations.
effects of air pollution on mortality and
morbidity of COPD in six European cities and Exacerbations become more frequent and
found that increased levels of environmental severe as COPD severity increases. However,
pollutants (sulphur dioxide, nitrogen dioxide, one distinct group of patients appears to be
ozone and particles) were associated with susceptible to exacerbations, irrespective of
elevated relative risks of daily admissions for disease severity. This phenotype of
COPD. susceptibility to exacerbations is stable over
time and the major determinant of frequent
exacerbations is a history of prior
Low temperature COPD exacerbations are exacerbations. This phenomenon is seen
more common and may be more severe in the across all Global Initiative for Chronic
winter months with colder temperatures; small Obstructive Lung Disease (GOLD) stages,
but significant falls in lung function occur including patients with stage 2 disease, of
with reductions in outdoor temperature whom 22% had frequent exacerbations in the
during winter in COPD patients. The first year of the Evaluation of COPD
mechanisms behind these observations are Longitudinally to Identify Predictive Surrogate
not clearly understood but may relate to Endpoints (ECLIPSE) study. Thus suggesting
increasing prevalence of respiratory viruses in that patients with the frequent exacerbator
low temperature winter months and/or phenotype are prone to exacerbations as a
increased susceptibility to upper respiratory result of intrinsic susceptibility, and develop
tract virus infections in cold weather. exacerbations when exposed to particular
triggers, like respiratory viruses.
Frequent exacerbator phenotype
Susceptibility to
Patients with a history of frequent exacerbations Respiratory viruses are more
exacerbations have worse quality of life, likely to be detected in patients with a history
increased risk of hospitalisation and greater of frequent COPD exacerbations, suggesting
mortality (fig. 2). Frequent exacerbators also that frequent exacerbators may be more
Poorer quality of life Higher mortality
Patients with frequent exacerbations
Greater airway Faster decline

inflammation in lung function
FIGURE 2. Effect of chronic obstructive pulmonary disease exacerbations in the group with frequent
exacerbations. Reproduced from WEDZICHA and SEEMUNGAL (2007) with permission from the publisher.
susceptible to respiratory viral infections. Cells (LABAs) also reduce exacerbation frequency
from patients with COPD manifest increased and in the TORCH (Towards a Revolution in
viral titre and copy number following COPD Health) study, in which 6,112 patients
rhinovirus infection compared to controls and were followed over 3 yrs, both inhaled
intercellular adhesion molecule (ICAM)-1, the fluticasone and salmeterol reduced
rhinovirus major group receptor, is exacerbation frequency when administered
upregulated on the bronchial epithelium of separately in comparison to placebo. The
patients with COPD. combination of fluticasone and salmeterol
reduced exacerbation frequency further, in
Frequent exacerbators also have elevated addition to improving health status and lung
airway inflammation when stable, as function in comparison to placebo. The
measured by sputum interleukin (IL)-6 and combination of ICS and LABA also resulted in
IL-8 levels, in addition to a higher incidence of fewer hospital admissions over the study
lower airway bacterial colonisation. period and trended towards a mortality
benefit, although this did not reach statistical
Haemophilus influenzae enhances rhinovirus significance. Reduction in exacerbation
serotype 39-induced protein expression of frequency has been also found with other
IL-8 and epithelial-derived neutrophil LABA/ICS combinations, such as formoterol
attractant-78, chemokines which are increased and budesonide.
in the sputum and airways of patients with
COPD exacerbations. Haemophilus influenzae
Long-acting antimuscarinics (LAMAs) also
also increases expression of ICAM-1 and
reduce exacerbation frequency. In the
Toll-like receptor-3 and augments binding of
Understanding Potential Long-Term Impacts
rhinovirus to cultured cells. Through such
on Function with Tiotropium (UPLIFT) trial,
mechanisms, patients colonised with bacteria
5,993 patients were randomised to tiotropium
may be more susceptible to the development
or placebo for a duration of 4 yrs, with
of virally triggered exacerbations.
concomitant therapy allowed. Although the
Exacerbation prevention primary end-point of the trial (reduction in
rate of decline in FEV1) was negative,
Vaccines In retrospective cohort studies of tiotropium was associated with a reduction in
community-dwelling elderly patients, exacerbation risk, related hospitalisations and
influenza vaccination is associated with a respiratory failure.
27% reduction in the risk of hospitalisation
for pneumonia or influenza and a 48% Phosphodiesterase
reduction in the risk of death. Pneumococcal inhibitors Phosphodiesterase-4 inhibitors
polysaccharide vaccine has been shown to inhibit the airway inflammatory processes
reduce the incidence of community-acquired associated with COPD. Evidence from a
pneumonia in COPD patients under the age pooled analysis of two large placebo-
of 65 yrs and those with severe airflow controlled, double-blind multicentre trials
obstruction, although no mortality benefit revealed a significant reduction of 17% in the
was demonstrated. As a result, influenza and frequency of moderate (glucocorticoid
pneumococcal vaccines are recommended in treated) or severe (hospitalisation/death)
the majority of patients with COPD. exacerbations. However, only patients with an
FEV1 ,50% (GOLD stage 3 and 4), presence
Inhaled corticosteroids and long-acting of bronchitic symptoms and a history of
bronchodilators The ISOLDE (Inhaled exacerbations were enrolled. There are no
Steroid in Obstructive Lung Disease in Europe) comparator studies with ICS. Weight loss was
study showed a 25% reduction in also noted in the roflumilast group, with a
exacerbation frequency with inhaled mean reduction of 2.1 kg after 1 yr, and was
corticosteroids (ICS). Long-acting b-agonists highest in obese patients. Therefore, following

Table 1. Strategies to prevent exacerbations
Pharmacological therapies for exacerbation prevention
Vaccines
Inhaled corticosteroids
Long-acting bronchodilators (LABA and LAMA)
Combinations of LABA and inhaled corticosteroids
Phosphodiesterase-4 inhibitors
Mucolytics
Long-term antibiotics
Nonpharmacological therapies
Pulmonary rehabilitation
Home oxygen therapy
Home ventilatory support
LABA: long-acting b-agonist; LAMA: long-acting antimuscarinics.
treatment with roflumilast, weight needs to Pulmonary rehabilitation and home

be carefully monitored. oxygen and ventilatory support There is
some evidence from clinical trials that
Mucolytics The routine use of these agents pulmonary rehabilitation programmes reduce
is not recommended as only a few patients hospital stay. There is evidence from
with viscous sputum appear to derive some epidemiological studies that home oxygen
small benefit from mucolytics. and ventilatory support may reduce hospital
admission, but controlled trials have not yet
Long-term antibiotics At present there is addressed these issues. These subjects are
insufficient evidence to recommend routine discussed in detail in the chapters entitled
prophylactic antibiotic therapy in the Pulmonary rehabilitation and Oxygen
management of stable COPD, but some therapy and ventilatory support (table 1).
studies have shown promise. Erythromycin
reduced the frequency of moderate and/or References
severe exacerbations (treated with systemic N Anderson HR, et al. Air pollution and daily
steroids, treated with antibiotics, or admissions for chronic obstructive pulmonary
hospitalised) and shortened exacerbation disease in 6 European cities: results from the
length when taken twice daily over 12 months APHEA project. Eur Respir J 1997; 10: 1064
by patients with moderate to severe COPD. 1071.
The macrolide azithromycin has been used as N Calverley PM, et al. Roflumilast in symptomatic
prophylaxis in patients with cystic fibrosis and chronic obstructive pulmonary disease: two
randomised clinical trials. Lancet 2009; 374:
is also suitable for use in COPD patients for
685694.
exacerbation prevention. A large US trial of N Calverley PM, et al. Salmeterol and fluticasone
long-term azithromycin therapy in COPD will propionate and survival in chronic obstructive
report shortly. pulmonary disease. N Engl J Med 2007; 356:
775789.
Furthermore, intermittent pulsed moxifloxacin N Donaldson GC, et al. Relationship between
when given to stable patients has been shown exacerbation frequency and lung function
decline in chronic obstructive pulmonary
to significantly reduce exacerbation frequency
disease. Thorax 2002; 57: 847852.
in a per-protocol population, and in a post hoc N Global Initiative for Chronic Obstructive Lung
subgroup of patients with bronchitis at baseline. Disease (GOLD). Global Strategy for the
However, this reduction did not meet statistical Diagnosis, Management and Prevention of
significance in the intention to treat analysis COPD. GOLD, 2009. Available from: www.
and further work is required in this area. goldcopd.org.
N Hurst JR, et al. Susceptibility to exacerbation in Am J Respir Crit Care Med 2010; 182:
chronic obstructive pulmonary disease. N Engl J 332340.
Med 2010; 363: 11281138. N Seemungal TA, et al. Effect of exacerbation on
N Mallia P, et al. Experimental rhinovirus infection quality of life in patients with chronic
as a human model of chronic obstructive obstructive pulmonary disease. Am J Respir Crit
pulmonary disease exacerbation. Am J Respir Care Med 1998; 157: 14181422.
Crit Care Med 2011; 183: 734742. N Sethi S, et al. Pulsed moxifloxacin for the
N Nichol KL, et al. Effectiveness of influenza prevention of exacerbations of chronic
vaccine in the community-dwelling elderly. N obstructive pulmonary disease: a randomized
Engl J Med 2007; 357: 13731381. controlled trial. Respir Res 2010; 11: 10.
N Roberts CM, et al. Acidosis, non-invasive N Tashkin DP, et al. A 4-year trial of tiotropium in
ventilation and mortality in hospitalised COPD chronic obstructive pulmonary disease. N Engl J
exacerbations. Thorax 2011; 66: 4348. Med 2008; 359: 15431554.
N Sajjan US, et al. H. influenzae potentiates airway N Wedzicha JA, Seemungal TA. COPD
epithelial cell responses to rhinovirus by exacerbations: defining their cause and
increasing ICAM-1 and TLR3 expression. FASEB J prevention. Lancet 2007; 370: 786796.
2006; 20: 21212123. N Wilkinson TM, et al. Early therapy improves
N Schneider D, et al. Increased cytokine response outcomes of exacerbations of chronic
of rhinovirus-infected airway epithelial cells obstructive pulmonary disease. Am J Respir Crit
in chronic obstructive pulmonary disease. Care Med 2004; 169: 12981303.

EXTRAPULMONARY EFFECTS
OF COPD
Y. Nussbaumer-Ochsner and K.F. Rabe
Centre for Pneumology and Thoracic Surgery, Grosshansdorf Hospital,
Grosshansdorf, Germany
E-mail: k.f.rabe@kh-grosshansdorf.de
Chronic obstructive pulmonary disease understanding of COPD has evolved, and it is

(COPD) is an inflammatory disease of the no longer justified to consider COPD as a
lungs that is characterised by a fixed airflow disease restricted to the lungs. COPD has
limitation. Over the past few years, the become a complex and multicomponent
disorder, and the majority of patients die from
cardiovascular diseases or cancer, and not
primarily respiratory diseases. Extrapulmonary
Key points comorbidities significantly complicate the
management of, and influence the prognosis
N There is clear evidence that COPD is of, patients with COPD. The broad range of
not simply a disease limited to the clinical presentations, ranging from chronic
airways but should be considered a bronchitis to hyperinflation and severe
complex and multicomponent emphysema, also illustrates that the term
syndrome. COPD describes patients with very different
clinical phenotypes.
N Forced expiratory volume in 1 s (FEV1)
is not just a lung function parameter for The main recognised extrapulmonary
grading COPD severity, but is also a manifestations include cardiovascular disease
marker for premature death from any and heart failure, musculo-skeletal wasting,
cause. osteoporosis, metabolic syndrome and
depression (table 1). While some of these
N The course of the disease and comorbidities share risk factors with COPD,
the prognosis is influenced by such as cigarette smoking, other frequently
extrapulmonary pathology and observed comorbidities cannot be attributed
accompanying comorbidities. to smoking. There is increasing evidence that
N Patients with COPD show comorbidities chronic inflammation is a key factor in COPD
that are not only related to smoking and is present in many other chronic diseases
but also to other lifestyle factors, associated with COPD. The theory that COPD
including diet and inactivity: chronic could be considered part of a chronic
systemic inflammatory syndrome takes these
systemic inflammation seems to link
different aspects into account.
them and might explain why they often
occur together. Local and systemic inflammation
N Future research has to answer the In industrialised countries of the western
question of whether the successful world, cigarette smoking accounts for most
treatment of comorbidities associated cases of COPD. Smoking triggers a local
with COPD positively influences the inflammatory response throughout the whole
course of the disease itself. tracheobronchial tree. The cellular pattern is
rather heterogenous and inflammatory cells
Extrapulmonary effects of COPD e19

Table 1. Systemic manifestations and comorbidities of conditions often occur together. Systemic
chronic obstructive pulmonary disease inflammation might be the common pathway
leading to these chronic diseases and might
Cardiovascular diseases
Ischaemic heart disease explain the high prevalence of multiple
Hypertension chronic diseases in the same patient.
Pulmonary hypertension
Impact on patient care
Congestive heart failure
"Metabolic" disorders Comorbidities and systemic effects in patients
Osteoporosis with COPD not only have prognostic value but
Skeletal muscle weakness also have implications for medical treatment.
Cachexia: weight loss and muscle wasting Medical care should focus on comorbidities
Diabetes mellitus that are easier to prevent and treat than
Metabolic syndrome
COPD itself. A diagnosis of COPD can easily
Other comorbid diseases be performed by spirometry but the severity of
Lung cancer the disease is clearly dependent on the
Chronic kidney disease presence of comorbidities. Therefore, it has
Depression
been proposed that any patient older than
Obstructive sleep apnoea syndrome
Normocytic anaemia 40 yrs with a positive smoking history
(.10 pack-yrs), symptoms and a lung function
compatible with COPD should be carefully
are found in the proximal and peripheral evaluated for more general disorders
small airways, the lung parenchyma and the associated with the chronic systemic
pulmonary vasculature. Apart from these local inflammatory syndrome (table 2).
effects, smoking may significantly contribute Therapeutical implications
to or cause systemic inflammation. COPD
patients suffering from an acute exacerbation Pharmacological treatment targeting the
or having severe disease show increased lungs has only a minor impact on the course
markers of interleukins (IL-6, IL-8 and tumour of the disease, and the treatment of COPD
necrosis factor-a), acute-phase proteins should no longer be centred just on
(C-reactive protein (CRP) and fibrinogen) and controlling symptoms and reducing
circulating inflammatory cells (monocytes, exacerbations. Large clinical trials have shown
neutrophils and lymphocytes). Whether this that available drugs for COPD
systemic inflammation is the result of a (bronchodilators and inhaled corticosteroids)
spill-over of local inflammation in the lungs, do not significantly influence the long-term
is a systemic inflammatory effect that affects decline in forced expiratory volume in 1 s.
multiple organ systems, or is attributable to Another approach would be to target the
some comorbid conditions that affect the underlying systemic disease itself. A few
lungs, remains debatable (fig. 1). observational studies have shown that the
treatment of extrapulmonary manifestations
Systemic inflammation is actually not only (e.g. muscle weakness) and comorbid diseases
present in patients with COPD, but is also a (e.g. heart disease and peripheral arterial
common feature in various other chronic disease) positively influences morbidity and
diseases. Compared to healthy individuals, mortality in COPD patients. Even though
elevated levels of inflammatory markers such these studies have clear limitations they
as CRP and IL-6 are observed in patients with suggest so far that statins, angiotensin-
stable coronary artery disease, peripheral converting enzyme inhibitors and angiotensin
arterial disease and diabetes. These findings receptor blockers might have dual
have to be taken into account when the cardiopulmonary properties and be able to
causative role of COPD in systemic positively influence the course of the disease.
inflammation is investigated because these However, these findings have to be confirmed

Lung cancer
Peripheral lung
inflammation
"Spill-over"
Acute-phase proteins
Skeletal muscle Systemic
CRP
weakness inflammation
Serum amyloid A
Cachexia IL-6, IL-1, TNF-
Surfactant protein D
Ischaemic Diabetes
Cardiac Normocytic Depression
heart Osteoporosis metabolic
failure anaemia
disease syndrome
Figure 1. Systemic effects and comorbidities of chronic obstructive pulmonary disease (COPD). Peripheral lung
inflammation may cause a spill-over of cytokines, such as interleukin (IL)-6, IL-1b and tumour necrosis factor
(TNF)-a, into the systemic circulation, which may increase acute-phase proteins such as C-reactive protein
(CRP). Systemic inflammation may then lead to skeletal muscle atrophy and cachexia, and may initiate and
worsen comorbid conditions. Systemic inflammation may also accelerate lung cancer. An alternative model is
that systemic inflammation causes several inflammatory diseases, including COPD. Reproduced from BARNES
and CELLI (2009).
in prospective and carefully controlled trials and might be the reason for its overwhelming
before any conclusions regarding the efficacy. Lifestyle interventions in general, and
management of COPD patients can be drawn. pulmonary rehabilitation specifically, are
essential components of patient care and
Assuming that systemic inflammation is a key
should be evaluated in any patient with COPD
factor in COPD and other chronic diseases,
GOLD stage II or higher (Global Initiative for
pulmonary rehabilitation addresses important
Chronic Obstructive Lung Disease).
extrapulmonary components that are not
Appropriate education about the disease
targeted by any pharmacological treatment,
itself, its time course and treatment options,
as well as psychosocial support, including
Table 2. Components of the chronic systemic smoking cessation and nutritional
inflammatory syndrome interventions, are part of a successful
Age older than 40 yrs rehabilitation programme.
Smoking for more than 10 pack-yrs
Conclusions
Symptoms and lung function compatible with
COPD Chronic diseases, including COPD, share
Chronic heart failure common aspects, and chronic systemic
inflammation seems to be one of the linking
Metabolic syndrome
elements. Extrapulmonary effects of COPD not
Increased C-reactive protein only influence the prognosis but also have an
At least three components are required for diagnosis. impact on disease management. The treat-
COPD: chronic obstructive pulmonary disease. ment of patients with COPD must become
Reproduced from FABBRI and RABE (2007) with truly multidisciplinary and has to move from
permission from the publisher.
an organ-specific to a more holistic approach.
Extrapulmonary effects of COPD e21

References N Nijm J, et al. Circulating levels of
proinflammatory cytokines and neutrophil-
N Barnes PJ, Celli BR. Systemic manifestations and platelet aggregates in patients with coronary
comorbidities of COPD. Eur Respir J 2009; 33: artery disease. Am J Cardiol 2005; 95: 452456.
11651185. N Nussbaumer-Ochsner Y, Rabe KF. Systemic
N Fabbri LM, Rabe KF. From COPD to chronic manifestations of COPD. Chest 2011; 139:
systemic inflammatory syndrome? Lancet 2007; 165173.
370: 797799. N van Gestel YR, et al. Effect of statin therapy on
N Mancini GB, et al. Reduction of morbidity and mortality in patients with peripheral arterial
mortality by statins, angiotensin-converting disease and comparison of those with versus
enzyme inhibitors, and angiotensin receptor without associated chronic obstructive
blockers in patients with chronic obstructive pulmonary disease. Am J Cardiol 2008; 102:
pulmonary disease. J Am Coll Cardiol 2006; 47: 192196.
25542560. N Wisniacki N, et al. Insulin resistance and
N Mannino DM, et al. Prevalence and outcomes of inflammatory activation in older patients with
diabetes, hypertension and cardiovascular systolic and diastolic heart failure. Heart 2005;
disease in COPD. Eur Respir J 2008; 32: 91: 3237.
962969. N Young RP, et al. Forced expiratory volume in one
N Mortensen EM, et al. Impact of statins and ACE second: not just a lung function test but a
inhibitors on mortality after COPD marker of premature death from all causes.
exacerbations. Respir Res 2009; 10: 45. Eur Respir J 2007; 30: 616622.

BRONCHIECTASIS
N. ten Hacken
University Medical Center Groningen, Groningen, The Netherlands
E-mail: n.h.t.ten.hacken@long.umcg.nl
Bronchiectasis is a disorder characterised by transmural infection and inflammation with

abnormal bronchial wall thickening and mediator release. The prevalence varies
luminal dilatation of the central and medium- between countries but seems to increase with
sized bronchi due to a vicious circle of age and is more common in females. Frequent
symptoms are chronic cough and production
of mucopurulent sputum. Less frequent are
haemoptysis, pleuritic pain, recurrent fever,
Key points
wheeze and dyspnoea. Exacerbations of
bronchiectasis are characterised by increase in
N Diagnosis of bronchiectasis is based on
symptoms, i.e. increase in cough and change
the presence of daily production of
in purulence and volume of sputum
mucopurulent phlegm and chest associated with increase in malaise. These
imaging that demonstrates dilated and exacerbations are almost always associated
thickened airways. HRCT scan is today with infections of bronchiectasis (table 1).
the gold standard.
Underlying causes of bronchiectasis may be
N The diagnosis of bronchiectasis should
acquired or inherited, and include post-
lead to the investigation and treatment
infective, mechanical obstruction, excessive
of possible causes and associated
immune response, deficient immune response,
conditions. inflammatory pneumonitis, abnormal mucus
N Antibiotics form the mainstay of clearance and fibrosis. Conditions associated
treatment of bronchiectasis. Acute with bronchiectasis include infertility,
exacerbations should be treated promptly inflammatory bowel disease, connective tissue
with short courses of antibiotics. disorders, malignancy, diffuse
panbronchiolitis, a1-antitrypsin deficiency and
N The continuous administration of mercury poisoning. In adults the aetiology is
antibiotics, mucolytics, anti-inflammatory idiopathic in ,50%, and in children 25%;
agents and bronchodilators is not clear, however, these figures may differ in time and
but may be considered on an individual between countries due to the availability of
basis. diagnostics and antibiotics (including
N Bronchopulmonary hygiene physical vaccinations).
therapy techniques are widely used, yet
Work-up
there is not enough evidence to support
or refute them. The work-up of bronchiectasis comprises:
N Surgery may be considered if the area
N blood tests: C-reactive protein, white blood
of the bronchiectatic lung is localised
count;
and if the patients symptoms are
debilitating or life threatening (like N differentiation, immunoglobulin (Ig)G, IgM,
massive haemoptysis). IgA, total IgE, IgG, aspergillus serology, a1-
antitrypsin;

Table 1. Microbiology of bronchiectasis
Bacterial
Haemophilus influenza
Pseudomonas aeruginosa
Moraxella catarrhalis
Streptococcus pneumoniae
Staphylococcus aureus
Mycobacterial
Avium-intracellulare complex
Kansasii
Fortuitum
Fungal
Aspergillus fumigatus
Figure 1. Signet ring sign. Cross-sectional computed
The pattern of microbiology is quite stable; however, tomography scan of the right lung in a patient with
resistance against antibiotics may increase in time.
bronchiectasis. White arrow indicates a signet ring
Pseudomonas is associated with more severe disease.
Nontuberculous mycobacteria associates frequently sign. Taken from OUELLETTE (1999).
with Aspergillus. Taken from ILOWITE et al. (2009).
Management
N specific tests to identify underlying causes Management of bronchiectasis should aim at
or contributing conditions dependent of fast resolution and prevention of infective
the clinical setting; exacerbations, no sputum infections, optimal
bronchial clearance, minimal respiratory
N spirometry; symptoms, normal lung function, high quality
N sputum smear and cultures for bacteria, of life and no treatment-related adverse
mycobacteria and fungi; and effects. Obviously, the prompt recognition and
treatment of the underlying cause(s) and/or
N radiography of chest and sinus, if necessary condition(s) is important for both short- and
a high-resolution computed tomography long-term outcomes. For the specific treatment
(HRCT) scan of the lung. of CF-related bronchiectasis see next chapter
on Cystic fibrosis. Unfortunately, there are
The chest radiograph is abnormal in most only limited high-quality studies on the
patients; however, a normal chest radiograph management of non-CF bronchiectasis. Several
does not exclude bronchiectasis. HRCT is reviews list a large number of treatment
nowadays the gold standard for options; however, due to small study samples,
bronchiectasis. Characteristic findings include different study populations and outcome
internal bronchial diameters 1.5 times greater variables, and other methodological issues, it
than that of the adjacent pulmonary artery is difficult to draw definitive conclusions.
(signet ring sign, fig. 1), lack of bronchial
tapering, visualisation of bronchi within 1 cm Acute exacerbations Antibiotic treatment
of the costal pleura, visualisation of the is the mainstay of acute exacerbations and is
bronchi abutting the mediastinal pleura, and targeted at likely organisms (table 1) or the
bronchial wall thickening. The distribution of results of sputum culture(s). A
bronchiectasis on HRCT scan may give fluoroquinolone is recommended over 710
diagnostic clues for allergic days in outpatients without history of
bronchopulmonary aspergillosis, cystic fibrosis recurrent exacerbations or sputum cultures
(CF), primary ciliary dyskinesia, and idiopathic (Barker, UpToDate; see Weblinks).
bronchiectasis. Severity of bronchiectasis on Hospitalised patients may be treated with two
HRCT scan is poorly correlated with clinical i.v. antibiotics with efficacy for Pseudomonas
indices. (Barker, UpToDate; see Weblinks). Supportive
Bronchiectasis 253
management may consist of inhaled improved sputum production, sputum viscosity
bronchodilators, systemic corticosteroids, and and ease of sputum expectoration; however,
measures to improve bronchial clearance 7% saline was superior to 0.9%. Two
(physical therapy, hydration, mucolytic systematic reviews found insufficient evidence
agents). to either support or refute bronchial hygiene
physical therapy.
Prevention of exacerbations Prolonged
use of antibiotics (.4 weeks) may be Symptoms and quality of life
considered in patients who quickly relapse Haemoptysis is treated with bronchial
(.46 times per year) or demonstrate embolisation; however, surgical resection is
progressive lung function decline. Several sometimes inevitable. Surgical resection may
treatment strategies are described: also be considered if the area of the
bronchiectatic lung is localised and if the
N oral antibiotic 23 times daily, patients symptoms are debilitating or life
N oral macrolide three times weekly, threatening. In this case, surgery can even be
curative if there is absence of an ongoing
N aerosolised tobramycin, gentamycin, colis- underlying cause. Although surgery is widely
tin, ceftazidime, or aztreonam twice daily used, there are no randomised controlled
(aerosoled antibiotics in non-CF bronchiec- trials (RCTs). Inhaled fluticasone improved
tasis are frequently not licensed or stopped dyspnoea, sputum production, days without
because of side-effects), cough, b2-agonist use and health-related
quality of life.
N intravenous antibiotics, 23-week courses
with 12-month intervals (Barker, UpTodate;
Lung function RCTs on short-acting b2-
see Weblinks).
agonists, long-acting b2-agonists,
A Cochrane review concluded that there is a anticholinergic therapy, oral methyl-xanthines,
small benefit on overall clinical response leukotriene antagonists and oral
scores, but not on exacerbation rates. Clearly corticosteroids were not selected in Cochrane
the indication for prolonged use of antibiotics reviews. Nevertheless, bronchodilator therapy
should be based on a benefitrisk evaluation, may be considered if a patient has proven
also taking possible adverse effects into airway obstruction. Macrolides may improve
account. methacholine reactivity, airway obstruction
and carbon monoxide diffusion. However, if
Sputum and bronchial clearance Inhaled macrolides are considered, the presence of
rhDNAse administered to stable non-CF nontuberculous mycobacteria must be
bronchiectasis patients has been associated excluded first, and patients must be warned
with increased exacerbation frequency and about ototoxicity.
greater forced expiratory volume in 1 s
decline and therefore should not be given.
Exercise tolerance Pulmonary
Oral bromhexine improved expectoration,
rehabilitation is effective in improving exercise
quantity and quality of sputum, and
capacity and endurance, whereas simultaneous
auscultatory findings during acute infective
inspiratory muscle training may be important in
exacerbations. Macrolides improved sputum
the longevity of these training effects.
production and sputum inflammatory markers.
12-day inhalation of mannitol improved the
tenacity and hydration of sputum. Inhaled References
fluticasone improved sputum production and N Ilowite J, et al. Pharmacological treatment
sputum inflammation, but not its options for bronchiectasis: focus on
microbiological profile. Nebulised 0.9 and 7% antimicrobial and anti-inflammatory agents.
saline as an adjunct to physiotherapy Drugs 2009; 69: 407419.

N Lynch DA, et al. Correlation of CT findings with N ten Hacken NH, et al. Treatment of
clinical evaluations in 261 patients with bronchiectasis in adults. BMJ 2007; 335: 1089
symptomatic bronchiectasis. AJR Am J 1093.
Roentgenol 1999; 173: 5358.
N Nicotra MB, et al. Clinical, pathophysiologic, Weblinks
and microbiologic characterization of N Cochrane Library. Meta-analyses on
bronchiectasis in an aging cohort. Chest 1995; bronchiectasis: anticholinergic therapy, oral
108: 955961. methyl-xanthines, leukotriene receptor
N Ouellette H. The signet ring sign. Radiology antagonists, short-acting beta-2-agonists, long-
1999; 212: 6768. acting beta-2-agonists, oral steroids, inhaled
N Pasteur MC, et al. An investigation into causative steroids, mucolytics, inhaled hyperosmolar
factors in patients with bronchiectasis. Am J agents, prolonged antibiotics, surgery versus
Respir Crit Care Med 2000; 162: 12771284. non-surgical treatment, bronchopulmonary
N Rosen MJ. Chronic cough due to bronchiectasis: hygiene physical therapy, nurse specialist care,
ACCP evidence-based clinical practice guidelines. and physical training. http://www3.interscience.
Chest 2006; 129: Suppl. 1, 122S131S. wiley.com/cgi-bin/mrwhome/106568753/HOME.
N ten Hacken NH, et al. Bronchiectasis: Clinical N UpToDate. Clinical manifestations and diagnosis
Evidence Handbook (online), 2008. http:// of bronchiectasis. Treatment of bronchiectasis.
clinicalevidence.bmj.com/ceweb/conditions/rdc/ Author: AF Barker. http://www.utdol.com/home/
1507/1507.jsp. index.html.
Bronchiectasis 255
CYSTIC FIBROSIS
A. Bush and J. Davies
Imperial College and Royal Brompton Hospital, London, UK
E-mail: a.bush@rbht.nhs.uk
The autosomal recessive condition cystic

Key points fibrosis (CF) is the most common inherited
disease of white races; the prevalence varies
N Adult pulmonologists need to know across Europe. Although commonest in white
about cystic fibrosis; it is common people, it has been found in virtually every
across Europe, patients are surviving ethnic group. The gene, on the long arm of
into middle age and beyond, and new chromosome 7, encodes a multifunctional
diagnoses are being made even in old protein, cystic fibrosis transmembrane
age. regulator (CFTR), which is active at the apical
membrane of epithelial cells. Different classes
N Cystic fibrosis is now a true multisystem of mutation have been described (fig. 1);
disease; to the well-known severe mutations (classes IIII) are usually
complications of chronic respiratory associated with pancreatic insufficient CF and
infection and malabsorbtion has been a worse prognosis, whereas those with milder
added conditions such as cirrhosis, mutations (IVVI) are more usually pancreatic
insulin deficiency and diabetes, sufficient. The combination of a mild and
osteopenia, stress incontinence and severe gene usually leads to a mild pancreatic
infertility. phenotype; however, there is only a poor
correlation between genotype and pulmonary
N Furthermore, with longevity is phenotype. In many parts of Europe, the most
coming new complications, including common mutation is DF508, but there are
the selection of resistant marked ethnic differences.
microorganisms and antibiotic allergy. CFTR functions as a chloride channel and
Other organ systems will likely be regulates other ion channels, such as the
affected in the aging cystic fibrosis epithelial sodium channel (ENaC). Most of the
population. morbidity and mortality of CF is due to
chronic bronchial infection, but as adults
N Treatment of cystic fibrosis thus survive longer, multisystem complications are
requires a dedicated multidisciplinary becoming more important. The airways of the
team, comprising physicians, newborn with CF are effectively normal at
specialist nurses, physiotherapists, birth, but from an early age, cycles of
dieticians, clinical psychologists and infection and inflammation supervene,
pharmacists. leading ultimately to severe bronchiectasis
and respiratory failure. The most popular
N The increasing knowledge of the hypothesis for the pathophysiology of CF lung
molecular pathophysiology of cystic disease is airway surface liquid dehydration
fibrosis is leading the way in the due to uncontrolled activity of ENaC, possibly
development of genotype specific triggered by viral infection. Median survival is
therapies, which will be a paradigm for predicted to be ,50 yrs, longer for males. In
other diseases. parts of Europe there are now more adult than
paediatric CF patients.

CFTR
CFTR
Class IV Class VI
Accelorated turnover
Class III
Cl-
Golgi complex
Class II Proteosome
Endoplasmic
reticulum
Class I Class V
Nucleus
Figure 1. Classes of cystic fibrosis (CF) mutations. Class I: no cystic fibrosis transmembrane regulator (CFTR)
synthesis (mutation, premature stop codon)(G542X); class II: CFTR processed incorrectly and does not reach
apical cell membrane (DF508); class III: CFTR reaches apical membrane, but channel regulation is abnormal
(G551D); class IV: CFTR reaches apical membrane, but channel open time is reduced (R334W); class V:
reduced CFTR synthesis (R117H); class VI: CFTR reaches apical cell membrane, but has a shortened half-life
due to more rapid turnover (1811+1.6 kb A.G).
Cystic fibrosis 257

Adult physicians will encounter CF patients by Other diagnostic modalities that are employed
two routes: include:
N referral from a paediatric clinic of an N Genetic testing: more than 1,300 variants
already diagnosed patient. Transition to a are described, and rare ones are usually
new and strange adult clinic from the undetected in the routine clinical labora-
familiar staff and surroundings of the tory, so a negative genotype cannot
paediatric clinic may be a difficult time, exclude disease.
and needs to be handled with sensitivity.
Increasingly, young adult handover clinics,
N Nasal transepithelial potential difference
measurement: only available in a few
staffed by paediatricians and adult physi-
centres.
cians, are being set up.
N a new diagnosis made in adult life.
N Ancillary testing: human faecal elastase
(pancreatic insufficiency), high-resolution
CF is usually diagnosed in early childhood, computed tomography for occult bronch-
increasingly by newborn screening, but mild iectasis, scrotal ultrasound or semen ana-
atypical cases may be missed. ,1015% of lysis for congenital bilateral absence of the
CF patients present in adult life (see table 1). vas deferens (CABVD).
Conversely, always consider the possibility
that the diagnosis of CF made in childhood is Management of CF (table 2)
incorrect, and whether a repeat diagnostic CF has now become a true multisystem
work-up should be done. disease. Treatment can only be optimally
Diagnostic testing for CF conducted with the help of a full
multidisciplinary team (CF physician,
Once the diagnosis is suspected, it is usually specialist nurse, physiotherapist, dietician,
easily confirmed by a sweat test, which must clinical psychologist and pharmacist) and the
be performed in an experienced centre. help of ancillary specialists with expert
Table 1. Late presentation of cystic fibrosis (CF; such patients are usually but not invariably pancreatic sufficient)
Recurrent respiratory Consider especially with suggestive microorganisms such as Staphylococcus
infections aureus, Pseudomonas aeruginosa, Burkholderia cepacia
Atypical asthma Especially if chronic productive cough, and a poor response to standard asthma
therapy
Bronchiectasis Especially if any extrapulmonary features, a positive family history, or infection
with atypical microorganisms
Male infertility Azoospermia due to congenital bilateral absence of the vas deferens (CABVD)
Electrolyte Classically as acute heat exhaustion leading to sodium, chloride and potassium
disturbance depletion
Atypical Always consider the possibility of CF if these organisms are isolated from sputum
mycobacterial
infection
Acute pancreatitis Typically seen in pancreatic sufficient CF
CF liver disease Portal hypertension and variceal haemorrhage; liver cell failure is a late
manifestation
Cascade screening Diagnosis made in a relative leading to extended family screening
New diagnoses of CF have been made even in old age; CF diagnosis should always be considered.

Table 2. Management of cystic fibrosis (CF) lung disease
Disease stage Pulmonary status Aim Management
Cystic fibrosis
Early (unusual Pre-infection Mucus clearance Airway clearance techniques (physiotherapy and adjuncts; these
but seen in include exercise and mucolytics, e.g. rhDNase, hypertonic saline)
adults with CF) Intermittent isolation of Pseudomonas Prevent infection Segregation and cohorting to prevent cross-infection.
aeruginosa Prophylactic antibiotics controversial; used against
Staphylococcus aureus in the UK; avoid cephalosporins
Influenza vaccination
Eradication of infection. Energetic High doses of appropriate antibiotics. P. aeruginosa eradication
treatment is essential protocols include both topical (nebulised) and systemic (usually
oral ciprofloxacin). Eradication achieved in 8090%
Intermediate Chronic infection with usual organisms Suppression of bacterial load and thus Depends on organism: P. aeruginosa: nebulised high-dose
(P. aeruginosa: eventually present in 80% of limitation of inflammatory response tobramycin (300 mg b.i.d.) or colomycin
patients; S. aureus (methicillin resistant and Use the new, faster nebuliser devices, for example, e-Flow (PARI)
sensitive), less usually Haemophilus influenzae) and iNeb (Profile Pharma)
Treat infective exacerbations Oral or IV antibiotics (some centres use regular elective courses, but
no evidence to prefer this over symptomatic use)
Culture results usually guide choice, but no evidence that this
improves outcome
259
Table 2. Continued
260
Reduce inflammation (it is controversial No evidence for a role for corticosteroids except in treating ABPA,
whether the CF airway is intrinsically because of efficacy but adverse side-effect profile (oral) or lack of
pro-inflammatory, or there is merely a benefit (inhaled)
greater airway inflammatory response Ibuprofen not much used in most of Europe; beware synergistic
to infection than normal) nephrotoxicity with intravenous aminoglycosides
Azithromycin is useful, but mode of action unknown
Infection with less common organisms Eradication if early; suppression of Confirm diagnosis in a reference laboratory; treat on an
(Burkholderia cepacia complex, bacterial load most commonly individual basis with specialist microbiological advice
Stenotrophomonas maltophilia,
Achromobacter xylosoxidans)
ABPA Reduce allergic response Oral corticosteroids (long course often required), consider pulsed
Prevent bronchiectasis methyl prednisolone
Addition of an antifungal agent common but evidence limited
Nontuberculous Mycobacterial infection Eradication or suppression Diagnosis and management difficult; seek specialist advice,
(Mycobacterium abscessus may be very especially for M. abscessus infection
difficult to eradicate) Prolonged courses of multiple chemotherapies will be needed:
ethambutol, rifampicin, azithromycin, amikacin, ciprofloxacin,
moxifloxacin are among the agents used
Lobar or segmental atelectasis (may be seen Re-inflation of the lung Intensive physiotherapy, with rhDNase and hypertonic saline as
at any stage of CF) appropriate
Intravenous antibiotics
Fibreoptic bronchoscopy, consider endobronchial instillation of
rhDNase if conventional management fails
Late Major haemoptysis (may be seen also in Prevent or halt acute bleeding Admit for intravenous antibiotics and clotting studies; broncho-
those with well preserved lung function) scopy not useful. Bronchial artery embolisation for ongoing
bleeding; can consider the use of tranexamic acid. Lobectomy is a
last resort
Pneumothorax (carries a very bad prognosis) Control air leak, prevent recurrence Conservative management for trivial pneumothoraces, otherwise
tube drainage. Early surgery and pleurodesis if does not respond
rapidly
End-stage respiratory failure Optimise conventional treatment Oxygen therapy (no survival benefit demonstrated, unlike for COPD)
ERS Handbook: Respiratory Medicine

Refer for lung transplant Consider nasal ventilation as a bridge to transplantation
ABPA: allergic bronchopulmonary aspergillosis; COPD: chronic obstructive pulmonary disease.
Table 3. Management of gastrointestinal manifestations of cystic fibrosis (CF) in the adult
Organ Manifestation Management
Pancreas Exocrine insufficiency: High-fat diet
malabsorption, steatorrhoea Supplementation with enteric-coated
microsphere pancreatic enzymes and
fat-soluble vitamins
Fat absorption may be aided by alkaline
environment (H2-blockers or proton pump
inhibitors)
Gastrostomy feeds if in nutritional failure
(parenteral nutrition only rarely required)
Acute pancreatitis (pancreatic sufficient As for other causes; oral pancreatin
patients) powder (anecdotal evidence only)
Oesophagus Gastro-oesophageal reflux Proton pump inhibitors, prokinetic agents
(especially common post-lung transplant) Surgery if refractory symptoms
Small bowel Distal intestinal obstruction Oral gastrografin (Schering) or klean prep
syndrome (Norgine)
Review dose of, and adherence to,
pancreatic enzyme replacement therapy,
perform 3-day faecal fat collection
Consider pro-kinetic agents
Severe acute cases, relieve with
colonoscopy; laparotomy a last resort
Coeliac disease (increased Gluten-free diet, as for isolated coeliac
incidence in CF) disease
Crohns disease (any part of the bowel) Management as for isolated Crohns
disease, seek specialist gastroenterology
advice
Colon Constipation Laxatives, high-fibre diet; must not be
confused with distal intestinal obstruction
syndrome
Rectum Rectal prolapse Rare in adults, usually related to
uncontrolled fat malabsorption
Liver Fatty liver (usually asymptomatic) Liver ultrasound at least every 2 yrs
Macronodular cirrhosis (variceal bleeding, Ursodeoxycholic acid, taurine (seek
splenomegaly, specialist advice)
hypersplenism)
Hepatocellular failure a late Severe cases may need transplantation
manifestation
DIOS: distal intestinal obstruction syndrome.
knowledge of CF (ear, nose and throat Respiratory tract disease The main issues
surgeon, obstetrician and endocrinologist). CF are the prevention of infection where possible
patients should be seen at least every by cohort segregation of patients with
3 months by the core CF team. A large particular infections, and the aggressive use of
number of treatment guidelines have been antibiotics; although conventional teaching is
published. that airway infection occurs with a relatively
Cystic fibrosis 261

Table 4. Treatment of other manifestations of cystic fibrosis (CF) in the adult
Organ Manifestation Management
Upper airway Nasal polyps (can cause obstructive Topical steroids. Long courses of
sleep apnoea) antibiotics
Surgery if medical management fails,
re-operation often needed
Sinusitis Most patients have asymptomatic
changes on radiography or computed
tomography scan, and require no
treatment
Topical steroids. Antibiotics
Surgery if medical management fails, but
results often disappointing. Some use
sinus drainage tubes and repeatedly instil
antibiotics into the sinuses
Endocrine Insulin deficiency, which causes Screen regularly with annual glucose
pancreas reduced lung function and nutrition tolerance test, or continuous glucose
before overt hyperglycaemia monitoring
Frank diabetes; although there may be Have a low threshold for starting insulin
an element of peripheral insulin Continue high-fat diet, adjust insulin
resistance, the main root cause is doses accordingly
diminished insulin secretion Diabetic ketoacidosis is very rare
Oral hypoglycaemic agents not to be used
outside a randomised controlled trial
Sweat gland Electrolyte depletion, often leading to Sodium and potassium chloride
acute collapse supplementation
Bones and joints Osteopenia (cystic fibrosis Measure bone mineral density at least
transmembrane regulator is every 2 yrs
expressed in bones) Prevention: weight bearing exercise, high
Pathological fracture dairy intake, vitamin D and K therapy
Treat with bisphosphonates if severe
CF arthropathy (large or small joint) Nonsteroidal anti-inflammatory agents,
prednisolone; seek specialist
rheumatological advice if more than mild
Male Bilateral absence of vas deferens Sperm aspiration and in vitro fertilisation;
reproductive leading to male infertility genetic counselling prior to procedure
tract
Female Vaginal candidiasis Topical anti-fungal agents
reproductive Stress incontinence Seek gynaecological advice
tract
Pregnancy (not an illness, but may be a Pre-pregnancy genetic counselling
major therapeutic challenge); women advisable
with severe CF may be subfertile, but Continue standard CF medications; close
normal conception is usual collaboration with obstetric unit; may
need regular admissions to hospital for
intravenous antibiotics
Especially beware if low lung function
prior to pregnancy, and CF related
diabetes on insulin

Table 4. Continued
Late iatrogenic Antibiotic allergy Consider desensitisation in hospital
Chronic renal failure Related to multiple courses of intravenous
aminoglycosides; use these agents
appropriately sparingly
Miscellaneous Vasculitis Rare, usually responds to steroids, but
seek specialist rheumatological advice
Epithelial cancer Small but definite increase in risk; careful
clinical surveillance mandatory
narrow spectrum of microorganisms, recent Future developments

work, including the use of molecular
techniques, suggests that anaerobes in A large number of novel therapies are
particular may be more important than currently being trialled in CF. Gene therapy,
previously thought. Sputum clearance using a using as vectors either liposomes, viruses or
choice of many chest physiotherapy nanoparticles, has been the subject of proof of
techniques and the identification and concept trials, and a large therapeutic trial is
aggressive management of late complications about to start. The age of genotype specific
therapy dawned with the use of agents such
are also important. If the patient has poor
as topical aminoglycosides or oral PTC124 to
lung function, early discussion with the local
over-ride premature stop codons (class I
transplant centre is advisable. Routine
mutations). Other approaches include the use
respiratory care at every clinic visit should
of molecular chaperones (correctors) to
include spirometry and pulse oximetry, and
transport abnormal (class II mutations) CFTR
sputum or cough swab culture.
to the apical cell membrane, and potentiators
to improve activity when they reach this site.
Gastrointestinal disease (table 3) The There is ongoing mutation-specific work to
main issues are to ensure optimal nutrition, and increase chloride channel activity of class III
be alert to gastrointestinal causes of weight loss and IV mutations, as well as the use of
that are unrelated to pancreatic insufficiency. compounds that activate alternative epithelial
Bad nutrition is a very poor prognostic feature. chloride channels. There is no doubt that we
CF patients have higher than normal energy are on the verge of a CF treatment revolution.
requirements because of subclinical Most important, however, is to ensure that the
malabsorption and a higher energy consumption basic therapy, which has so greatly improved
secondary to infection. Increased metabolic rate prognosis, is not neglected here and now.
is thought by some to be part of the underlying
defect. Weight should be measured, and body References
mass index calculated, 3-monthly. N Brenckmann C, Papaioannou A.
Bisphosphonates for osteoporosis in people with
Other organ system disease (table 4) It cystic fibrosis. Cochrane Database Syst Rev
is important to be aware that new 2001; 4: CD002010.
complications are being described as CF N Bush A. In: European Lung White Book.
patients survive longer. A full systems review Sheffield, European Respiratory Society, 2003;
pp. 8995.
is essential at each clinic visit. Finally, the
psychological aspects of CF and the effects of
N Colombo C, et al. Liver disease in cystic fibrosis. J
Pediatr Gastroenterol Nutr 2006; 43: Suppl. 1,
chronic illness and the burden of disease and S49S55.
its treatment should not be underestimated; N Dodge JA, et al. Cystic fibrosis mortality and
see the poignant stories and poetry on the survival in the UK: 19472003. Eur Respir J
Breathing Room website. 2007; 29: 522526.
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N Farrell PM, et al. Guidelines for diagnosis of N McKone EF, et al. Effect of genotype on
cystic fibrosis in newborns through older adults: phenotype and mortality in cystic fibrosis: a
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Pediatr 2008; 153: S4S14. 16711676.
N Festini F, et al. Isolation measures for prevention N Nick JA, Rodman DM. Manifestations of cystic
of infection with respiratory pathogens in cystic fibrosis diagnosed in adulthood. Curr Opin Pulm
fibrosis: a systematic review. J Hosp Infect 2006; Med 2005; 11: 513518.
64: 16. N Onady GM, Stolfi A. Insulin and oral agents for
N Flume PA, et al. Cystic fibrosis pulmonary managing cystic fibrosis-related diabetes.
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of lung health. Am J Respir Crit Care Med 2007; N Southern KW, et al. Macrolide antibiotics for
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transmembrane regulator protein mutations: N www.genet.sickkids.on.ca/cftr/.
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Paediatr Drugs 2007; 9: 110. N www.cfgenetherapy.org.uk.

CHAPTER 10:
oCCuPATionAl And
EnviRonmEnTAl lung
diSEASES
woRk-RElATEd And oCCuPATionAl ASTHmA 268

RESPiRAToRy diSEASES CAuSEd by ACuTE 273

inHAlATion of gASES, vAPouRS And duSTS
B. Nemery
HyPERSEnSiTiviTy PnEumoniTiS 278

T. Sigsgaard and A. Rask-Anderson
PnEumoConioSiS 282
R.D. Stevenson
indooR And ouTdooR PolluTion 285

G. Viegi, M. Simoni, S. Maio, S. Cerrai, G. Sarno and S. Baldacci
Smoking-RElATEd diSEASES 291

TREATmEnT of TobACCo dEPEndEnCE 295

HigH-AlTiTudE diSEASE 298

diving-RElATEd diSEASES 302

E. Thorsen
RAdiATion-induCEd diSEASE 304

R.P. Coppes and P. Van Luijk

WORK-RELATED AND
OCCUPATIONAL ASTHMA
Athens Chest Hospital, Asthma Centre and 7th Respiratory Medicine Dept,
Sotiria Hospital, Athens, Greece
E-mail: minagaga@yahoo.com
Definition WRA accounts for 915% of cases of asthma

in adults of working age.
Work-related asthma (WRA) is the most
common form of occupational lung disease, WRA may be categorised into: occupational
causing significant morbidity and disability. asthma (OA), which refers to asthma caused
specifically by exposure to an agent present at
the workplace; and work-aggravated or
work-exacerbated asthma (WEA), in which
Key points
pre-existing asthma is exacerbated by
conditions in the work environment. The
N The burden of work-related asthma American College of Chest Physicians
(WRA) is still very high, accounting for consensus document and British Occupational
one in ten cases of adult asthma, and Health Research Foundation guidelines
causing morbidity, disability and high therefore define WRA to include OA (i.e.
costs. asthma induced by sensitiser or irritant work
N Prevention is very important. Health exposures) and WEA (i.e. pre-existing or
officials, work managers and doctors concurrent asthma worsened by work factors).
must be aware of the problem, strict OA can occur in workers with or without prior
measures for exposures to known asthma and can be subdivided into:
sensitisers should always be followed, 1) sensitiser-induced OA, characterised by a
conditions at work examined and, when latency period between first exposure to a
necessary, amended. respiratory sensitiser at work and the
development of symptoms; and 2) irritant-
N Better education of workers and
induced OA that occurs typically within a few
managerial staff as well as medical
hours of a high-concentration exposure to an
professionals is key to the prevention irritant gas, fume or vapour at work. When the
and prompt diagnosis and management causal exposure consists of a single inhalation
of WRA and occupational asthma (OA). incident, the condition is commonly called
When WRA is diagnosed, prompt reactive airways dysfunction syndrome.
management is required and consists of
removing or reducing exposure through In clinical practice, it is often difficult to
elimination or substitution of causative differentiate between true OA and
agents and, where this is not possible, by aggravation of pre-existing asthma.
effective control of exposure. Conversely, aggravation of symptoms related
to work exposure, even in the absence of new
N Pharmaceutical treatment of OA follows sensitisation, requires individual and collective
the general asthma guidelines. measures at the workplace, similar to OA. A
recent consensus definition therefore is that

OA is defined as asthma induced by burden of OA. However, the relationship
exposure in the working environment to between the levels of exposure and the
airborne dusts, vapours or fumes, with or induction of OA is not always clear and the
without pre-existing asthma (FRANCIS (2007)). methodology of exposure assessment requires
Physicians involved in adult asthma care need standardisation. Atopy increases the risk of
to be aware of the high prevalence of WRA developing OA in workers exposed to various
and the importance of inducing or sensitisers including enzymes, bakery
exacerbating factors at work. allergens, laboratory animals, crab, prawn and
acid anhydrides. The latent interval between
Sensitising and triggering agents first exposure and the onset of symptoms
More than 250 agents causing OA have been varies depending on the agent, the level of
described and are categorised into high exposure/management and biological
molecular weight (HMW) and low molecular variability of exposure. The latent interval can
weight (LMW) agents, according to whether extend to many years; however, the risk of OA
their molecular weight is above or below appears to be highest soon after first exposure
1 kD. HMW agents are usually proteins of to laboratory animal allergens, isocyanates,
animal and vegetal origin such as flour, platinum salts and enzymes. See table 1 for a
laboratory animal proteins and enzymes. LMW list of agents frequently identified by
agents include a wide variety of chemicals, inhalational challenge.
such as acid anhydrides, platinum salts and Diagnosis
reactive dyes. Sensitisation to most HMW and
some LMW factors is through an The clinical presentation and symptoms of OA
immunoglobulin (Ig)E mechanism and can be are no different from non-OA. Patients
tested by skin tests. An immunological experience attacks of breathlessness,
mechanism is suspected for LMW agents but wheezing, cough, chest tightness and
has not been demonstrated, and an antigen- limitations in their daily activities. In any
specific immune response cannot easily be working adult patient presenting with such
tested in most affected workers. symptoms, the diagnosis of WRA should be
considered. In individuals with suspected
The most frequently reported agents of
WRA, the physician should obtain a history of
occupational asthma are: job duties and possible exposures, the use of
N Isocyanates protective devices and the presence of
respiratory disease in co-workers. Table 2
N Flour and grain dust shows examples of occupations/industries
N Colophony and fluxes with sentinel health events for sensitiser-
induced OA.
N Latex
Symptoms may get worse when the patient
N Animal and plant proteins enters the work environment, but very often
the patients experience delayed symptoms
N Aldehydes
and therefore may get worse after leaving
N Wood dust work. A clinically useful approach, therefore, is
not asking whether the patients experience
N Metal salts
worsening of their symptoms when at work
Epidemiological studies have demonstrated but rather whether they feel better after a
that the level of exposure is the most weekend or a holiday away from work.
important determinant of OA. This implies However, this is difficult to describe, as most
that preventive measures should be aimed at people feel rested and happier at the end of a
reducing workplace exposure. Prevention holiday. The diagnosis requires first
through elimination/reduction of exposure is spirometry, with a positive bronchodilation
the most effective approach for reducing the test and/or histamine, methacholine or
Work-related and occupational asthma 269

Table 1. Low molecular weight (LMW) and high molecular measurements and skin tests or IgE assays,
weight (HMW) agents frequently identified by the gold standard for diagnosing sensitiser-
inhalational challenge induced OA is a specific bronchial provocation
LMW agents
test (specific inhalation challenge), which may
demonstrate a direct relationship between
Isocyanates exposure to a test agent and an asthmatic
HDI
response. The response may be early or late
MDI
TDI and may carry a risk to the patient of a severe
Metals reaction. Therefore, these tests should be
Plicatic acid (white or red cedar) performed only when necessary and only in
Wood dust specialised centres under medical supervision.
Hairdresser products
Epoxy Management
Gums Ideally, causal agents should be eliminated
Dyes and fabrics
from the workplace, an option that is not
Chemicals
Perfume often available. The second-best option is to
remove the workers from exposure; however,
HMW agents
many patients cannot quit their job. In such
Flour cases, the early institution of preventive
Plants and grain dust measures, including the replacement of
Seafood/fish specific reagents where possible, the strict
Latex
monitoring of exposure levels, and the use of
Animal-derived allergens
Leather extractor fans and masks, is necessary. The EU
Enzymes has allocated a high priority to safeguarding
Talc the health and safety of workers. Existing EU
health and safety legislation aims to minimise
HDI: hexamethylene diisocyanate; MDI: methylene
the health risks from dangerous substances in
diphenyl diisocyanate; TDI: toluene diisocyanate. Data
derived from DUFOUR (2009). the workplace, placing the emphasis on their
elimination and substitution in order to
protect workers. There are four important
directives in this field, containing the basic
exercise testing of airway hyperresponsiveness provisions for health and safety at work, and
for the confirmation of asthma. Furthermore, further defining the risks related to exposure
the patient should be asked to record to chemical agents, to biological agents and
symptoms, use of medication and peak to carcinogens at work. Medical surveillance
expiratory flow (PEF) measurements when programmes are very important and may
working and off work. PEF should be include symptom questionnaires, spirometry
measured at least four times a day for a and skin prick testing at regular intervals (e.g.
period of a month while times on and off work every 6 or 12 months), as well as monitoring
should be noted (the recommendation is at of exposure levels.
least 2 weeks on and 2 weeks off work). The Once OA has developed, recovery is directly
sequential self-measurements of PEF can be dependent on the duration and level of
complemented by repeated measurements of exposure to the causative agent. Depending
provocative concentration of histamine or on the severity of the case, the condition of
methacholine causing a 20% fall in forced the patient can substantially improve during
expiratory volume in 1 s. Allergic sensitisation the first year after removal from exposure.
to some inducers such as animal proteins can Conversely, asthma may persist even after
be examined by skin prick testing or in vitro removal from exposure to the causative
assays of specific IgE. When the diagnosis workplace agent. The likelihood of
cannot be confirmed by serial PEF improvement or resolution of symptoms or

Table 2. Examples of occupations/industries with sentinel health events for sensitiser-induced occupational asthma
Industry, process or occupation Selected agents
Jewellery, alloy and catalyst makers Platinum
Polyurethane, foam coatings, adhesives production and Isocyanates
end-use settings (e.g. spray painters, and foam and
foundry workers)
Alloy, catalyst, refinery workers Chromium, cobalt
Solderers Soldering flux (colophony)
Plastics industry, dye, insecticide makers, organic Phthalic anhydride, trimetallic anhydride (used
chemical manufacture in epoxy resins)
Foam workers, latex makers, biologists, and hospital and Formaldehyde
laboratory workers
Printing industry Gum arabic, reactive dyes and acrylates
Metal plating Nickel sulphate and chromium
Bakers Flour, amylase and other enzymes
Woodworkers and furniture makers Red cedar (plicatic acid) and other wood dusts
Laboratory workers and animal researchers Animal proteins
Detergent formulators Detergent enzymes such as protease, amylase,
and lipase
Seafood (crab, snow crab and prawn) workers Crab, prawn and other shellfish proteins
Healthcare workers and nurses Psyllium, natural rubber latex, glutaraldehyde,
methacrylates, antibiotics and detergent
enzymes
Laxative manufacture and packing Psyllium
Hairdressers and manicurists Persulphates and acrylates (artificial nails)
Reproduced from TARLO (2008), with permission from the publisher.
preventing deterioration is greater in workers Socioeconomic impact of WRA

who have no further exposure to the causative
The economic impact of WRA is due not only
agent, have relatively normal lung function at
to direct healthcare costs but also to indirect
diagnosis, and those who have shorter
costs from impaired work productivity and
duration of symptoms prior to diagnosis and
compensation/rehabilitation costs, as well as
prior to avoidance of exposure.
to the intangible costs from impaired quality
Trigger avoidance is pivotal in preventing of life. Income loss is more likely when
asthma symptoms and progression of severity. avoidance of exposure leads to a change of
Nevertheless, pharmacological treatment is job and this income loss is not offset by
also required to control symptomatic patients. compensation. In many European countries,
Pharmacological treatment follows the compensation does not include rehabilitation or
general asthma treatment guidelines, and retraining, perhaps accounting for the relatively
inhaled steroids and b-agonists are the high proportion (30%) of workers who continue
cornerstone of management. Treatment to be exposed to the causative agent.
follows a stepwise approach, based on asthma Moreover, when considering the cost of OA and/
control and severity and the approach is or compensation, it is not only lung function
identical to that of non-OA. impairment and optimal asthma treatment that
Work-related and occupational asthma 271

need to be taken into account, but also N Mullan RJ, Murthy LI. Occupational sentinel
psychogenic factors. These can play an important health events: an up-dated list for physician
role in the quality of life of OA patients, and recognition and public health surveillance. Am J
significant prevalence of anxiety and depression Ind Med 1991; 19: 775799.
has been shown in that population.
N Nemery B. Occupational asthma for the
clinician. Breathe 2004; 1: 2532.
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2003; 21: 879885. Eur Respir J 2003; 21: 706712.

RESPIRATORY DISEASES
CAUSED BY ACUTE
INHALATION OF GASES,
VAPOURS AND DUSTS
B. Nemery
Research Unit of Lung Toxicology, Occupational, Environmental and
Insurance Medicine, K.U. Leuven, Leuven, Belgium
E-mail: Ben.Nemery@med.kuleuven.be
Acute inhalation injury may occur in the result from chemical warfare, and from
workplace, but also at home or in the conventional warfare or terrorist actions
community, e.g. as a result of fires and involving explosions, fires and building
explosions, volcanic eruptions, industrial destructions.
disasters, and accidents involving trains or
trucks transporting chemicals. Inhalation The clinical presentation and severity of
accidents may be of catastrophic proportions, inhalation injury range from self-limited
as occurred with the release of methyl inhalation fever to life-threatening chemical
pneumonitis with lung oedema and evolution
isocyanate in Bhopal, India, in 1984. Mass
to acute respiratory distress syndrome (ARDS)
casualties with inhalation injuries may also
and multiorgan failure. Following inhalation
injury, the lesions may heal completely or
Key points there may be persisting structural or
functional sequelae.
N An influenza-like response (inhalation Inhalation fever
fever) may follow the inhalation of
high quantities of zinc fumes (metal Inhalation fever is the name given to a group
fume fever) or organic aerosols of nonallergic, noninfectious flu-like clinical
(organic dust toxic syndrome). syndromes caused by the acute inhalation of
metal fumes, organic dusts or some plastic
N After inhalalation of poorly water- fumes.
soluble agents, such as nitrogen
dioxide, phosgene or cadmium fumes, Metal fume fever is caused by a single
pulmonary oedema becomes clinically exposure to high amounts of some metallic
manifest only 412 h after exposure. fumes, most notably those emitted when
heating zinc. Organic dust toxic syndrome
N Acute inhalation injury may be (ODTS) is caused by the inhalation of large
followed by various structural lesions in quantities of agricultural and other dusts of
the airways, but also by asthma. Such biologic origin (bio-aerosols), which are
asthma induced by a single inhalation generally heavily contaminated with toxin-
injury is called acute irritant-induced producing microorganisms. Polymer fume
asthma, or RADS. fever occurs after exposure to the fumes of
heated fluorine-containing polymers.
Respiratory diseases caused by acute inhalation of gases, vapours and dusts 273
The clinical features of the inhalation fevers compound-specific (table 1). The main agents
are those of a beginning influenza. The actual that may cause acute inhalation injury are as
exposure may or may not have been follows:
experienced as irritant for the eyes and
respiratory tract. 48 h after the exposure, the
subject begins to feel unwell with fever (up to
N Water-soluble irritants, such as ammonia
(NH3), sulphur dioxide (SO2), hydrochloric
40uC), chills, headaches, malaise, nausea and
muscle aches. Respiratory symptoms are acid (HCl), formaldehyde, acetic acid, have
usually mild and consist mainly of cough and/ good warning properties and mainly affect
or sore throat, but occasionally subjects may the upper respiratory tract, unless massive
have more severe responses with dyspnoea. quantities have been inhaled.
The diagnosis of inhalation fever rests N Gases of intermediate water solubility, such
essentially on the recent exposure history and as chlorine (Cl2) and hydrogen sulphide
the clinical condition, and when these clearly (H2S), penetrate deeper into the bronchial
point to inhalation fever, no sophisticated tree. Accidental release of gaseous chlorine
investigations are required. In general, chest is one of the most frequent causes of
auscultation and chest radiograph are normal, inhalation injury, not only in industry, but
but in more severe cases crackles may be also in the community as a result of
heard and there may be transient infiltrates transportation accidents, the use of
on chest radiograph. Pulmonary function is chlorine for disinfecting swimming pools,
often within normal limits; in severe cases or the mixing of bleach (NaClO) with acids;
there may be a decrease in diffusing capacity mixing bleach with ammonia leads to the
and arterial hypoxaemia. Increased peripheral release of volatile and irritant chloramines
blood leukocytosis, with a rise in neutrophils, (including trichloramine, NCl3). Hydrogen
is a consistent finding until 24 h after the sulphide (H2S), which is formed by the
exposure; other blood tests should be normal, putrefaction of organic material in sewage
except for indices of an inflammatory
drains, manure pits or ship holds, and is
response. Bronchoalveolar lavage studies have
also a frequent contaminant in the
shown pronounced and dose-dependent
petrochemical industry, does not only
increases in polymorphonuclear leukocytes on
the day after exposure to zinc fumes or cause mucosal irritation, but it also leads to
organic dust. chemical asphyxia by mechanisms that are
somewhat similar to those of cyanide.
Inhalation fever must not be confused with
other more serious conditions, including N Poorly water-soluble agents, such as
chemical pneumonitis, which in its early nitrogen dioxide (NO2), phosgene (COCl2),
phases could be mistaken for inhalation fever. ozone (O3), mercury vapours (Hg),
A differential diagnosis must also be made cadmium oxide (CdO) fumes, are particularly
with various types of infectious pneumonias hazardous because they cause little sensory
and with acute extrinsic allergic alveolitis. irritation and are, therefore, hardly noticed,
and they reach the distal airways thus
Inhalation fever is a self-limited syndrome and potentially causing noncardiogenic
recovery normally takes place after a nights pulmonary oedema, which develops over
rest. Tolerance exists against re-exposures
the course of several hours.
occurring shortly after a bout of metal fume
fever or ODTS. N Exposure to organic solvents is rarely a
cause of toxic pneumonitis. However,
Acute chemical pneumonitis
exposure to very high concentrations of
Major causes The response to acute solvent vapours in confined spaces (e.g. in
chemical injury in the respiratory tract is rarely chemical tanks) may cause chemical

Table 1. Possible causes of toxic tracheo-bronchitis or morbidity is often the major complication
pneumonitis in burn victims. It may be caused by direct
Irritant gases thermal injury (particularly if hot vapours
High water-solubility: NH3, SO2, HCl, etc. have been inhaled), but more generally the
Moderate water-solubility: Cl2, H2S, etc. lesions are caused by chemical injury. The
Low water-solubility: O3, NO2, COCl2, etc. toxic components of smoke include
Organic chemicals gaseous asphyxiants (CO, HCN) and
Organic acids: acetic acid, etc. irritants, as well as particulates.
Aldehydes: formaldehyde, acrolein, etc.
Isocyanates: methylisocyanate (MIC), toluene Clinical presentation Depending on the
diisocyanate (TDI) circumstances of the accident, there may be
Amines: hydrazine, chloramines, etc. thermal or chemical facial burns. Signs of
Riot control agents (CS) and vesicants mucosal irritation include cough, hoarseness,
(mustard gas) stridor or wheezing, retrosternal pain,
Organic solvents discharge of bronchial mucus, possibly with
Leather treatment sprays
blood, mucosal tissue and soot. Auscultation
Some agrochemicals (paraquat, cholinesterase
inhibitors)
of the chest may or may not be abnormal,
with wheezing, rhonchi or crepitations.
Metallic compounds Mucosal oedema, haemorrhage and
Mercury vapours
ulcerations may be visible in the air passages.
Metallic oxides: CdO, V2O5, MnO, Os3O4, etc.
Halides: ZnCl2, TiCl4, SbCl5, UF6, etc. Victims of inhalation accidents with poorly
Ni(CO)4 soluble agents may feel and look perfectly
Hydrides: B2H5, LiH, AsH3, SbH3 well initially, but then experience progressive
Complex mixtures
dyspnoea, shallow breathing, cyanosis, frothy
Fire smoke pink sputum and eventually ventilatory
Pyrolysis products from plastics failure. A clinical picture of ARDS may thus
Solvent mixtures develop gradually over 472 h, even after a
Spores and toxins from microorganisms period of clinical improvement.
Pulmonary function can be used to monitor

pneumonitis and pulmonary oedema, often ambulatory subjects who have been exposed.
in victims who have been unconscious. Arterial blood gases show varying degrees of
Pneumonia and respiratory distress hypoxaemia and respiratory acidosis,
syndrome caused by loss of alveolar depending on the severity of the injury. The
surfactant may also result from the chest radiograph is usually normal if only the
aspiration of solvents or fuels ingested conducting airways are involved, but there
unintentionally (e.g. from siphoning petrol) may be signs of peribronchial cuffing. After
or intentionally (e.g. by fire eaters). exposure to deep lung irritants the chest
Severe acute respiratory illness may also be radiograph is unremarkable in the first hours
caused by spraying solvent-propelled after presentation, but signs of interstitial and
fluorocarbon-containing water-proofing alveolar oedema may become visible and,
agents and leather conditioners. with time, patchy infiltrates, areas of
atelectasis and even white lungs may
N Some agrochemicals (such as paraquat develop. These changes may be due to tissue
and organophosphate or carbamate damage and organisation or they may reflect
insecticides) may cause toxic pneumonitis superimposed infectious (broncho)pneumonia.
after ingestion or dermal exposure.
In some instances, particularly in the later
N The commonest cause of toxic pneumonitis stages of chemical pneumonitis, there may be
is smoke inhalation caused by domestic, pathological (and radiological) features of
industrial or other fires. Respiratory organising pneumonia with or without
bronchiolitis obliterans. Following resolution of Subacute toxic pneumonitis
the acute pulmonary oedema, a relapse in the
clinical condition may occur after 26 weeks Although the concept of chemical-induced
with dyspnoea, cough, fine crackles, a lung injury is used only for disorders resulting
radiographic picture of miliary nodular from a single, acute exposure to a toxic
infiltrates, arterial hypoxaemia and a restrictive chemical, the term subacute toxic
or mixed impairment, with low diffusing pneumonitis may be used to refer to lung
capacity. This relapse phase has been attributed injury caused by repeated peaks of toxic
to bronchiolar scarring with peribronchiolar and exposures or a more prolonged toxic exposure
obliterating fibrosis of the bronchioli. over weeks to months. This is the case with
exogenous lipoid pneumonitis, which may be
Management At the scene of the accident, caused by inhalation of natural or synthetic
appropriate medical intervention includes mineral oils, and with pulmonary alveolar
removal from exposure, resuscitation and proteinosis, which may be caused by heavy
supportive treatment. In some instances, exposure to silica (acute silico-proteinosis)
emergency personnel must also be protected and possibly by other agents.
from chemicals that remain present on victims
or their clothes and decontamination The Ardystil syndrome is an example of
procedures must be available. For some types subacute toxic pneumonitis. This outbreak of
of exposures asymptomatic persons must severe organising pneumonia occurred in
remain under observation for 24 h; they 1992 in Spain, and involved several workers
should not exercise, nor should they be from factories where textiles were air-sprayed
overfilled by intravenous fluids. Oxygen with dyes.
treatment should be given as required by the Another recently described form of subacute
level of arterial oxygen saturation. toxic lung injury is popcorn workers lung.
This severe lung disease, characterised as
The further management of acute inhalation bronchiolitis obliterans, occurred in subjects
injury will be governed by the severity of the occupationally exposed to vapours of butter
patients condition and will involve intensive flavouring (containing diacetyl) used for
care treatment with intubation and artificial making microwave-popcorn and other food.
ventilation, as required. Antibiotics are only to
Possible sequelae of acute inhalation
be given if there are signs of infection. In
injury
victims of smoke injury, bronchoscopic removal
of soot from the airways may be necessary. The Following acute inhalation injury, there is
administration of (systemic) corticosteroids is often complete recovery. However, this is not
probably justified to prevent complications always the case. Various persistent anatomical
arising from (excessive) inflammation, such as lesions such as constrictive bronchiolitis,
bronchiolitis obliterans, although there are no bronchiectases, bronchial strictures or polyps,
controlled studies on this issue. may be identified by imaging studies or
through bronchoscopy.
Physicians treating victims in the early days
after the incident must document accurately Moreover, even in the absence of such
the clinical condition and all relevant data in structural sequelae or in the absence of
these patients. Documentation of the damage significant defects in basal spirometry, a state
by bronchoscopy and high-resolution computed of permanent nonspecific bronchial
tomography may be justified. Repeated hyperreactivity may be observed. This
measurements of ventilatory function and condition of adult-onset, nonallergic asthma
arterial blood gases must be carried out, and known as "reactive airways dysfunction
victims of acute inhalation injury should never syndrome" (RADS) or acute irritant-induced
be discharged without a comprehensive asthma occurs in a proportion of survivors of
assessment of their pulmonary function. inhalation injury. Observations in fire-fighters

and other personnel involved in rescue N Moya C, et al. Collaborative Group for the Study
operations during and following the collapse of Toxicity in Textile Aerographic Factories.
of the World Trade Center on September 11, Outbreak of organising pneumonia in textile
2001, suggest that RADS may occur even printing sprayers. Lancet 1994; 344: 498502.
without the occurrence of clinically serious
N Nemery B. Late consequences of accidental
exposure to inhaled irritants : RADS and the
injury. Bhopal disaster. Eur Respir J 1996; 9: 19731976.
References N Nemery B. Reactive fallout of World Trade
Center dust. Am J Respir Crit Care Med 2003;
N Blanc P, Boushey HA. The lung in metal fume 168: 23.
fever. Semin Respir Med 1993; 14: 212225. N Nemery B. Toxic Pneumonitis. In: Hendrick DJ, et
N Douglas WW, Colby TV. Fume-related al., eds. Occupational Disorders of the Lung.
bronchiolitis obliterans. In: Epler GR, ed. Recognition, Management, and Prevention.
Diseases of the bronchioles. New York, Raven London, WB Saunders, Harcourt Publishers,
Press, 1994; pp. 187213. 2002; pp. 201219.
N Das R, Blanc PD. Chlorine gas exposure and the N Olson KR, Shusterman DJ. Mixing
lung: a review. Toxicol Indust Health 1993; 9: incompatibilities and toxic exposures. Occup
439455. Med 1993; 8: 549560.
N Kreiss K, et al. Clinical bronchiolitis obliterans in N Shusterman DJ. Polymer fume fever and other
workers at a microwave-popcorn plant. N Engl J fluorocarbon pyrolysis-related syndromes. Occup
Med 2002; 347: 330338. Med 1993; 8: 519531.
HYPERSENSITIVITY
PNEUMONITIS
T. Sigsgaard1 and A. Rask-Andersen2
1
Aarhus University, Aarhus, Denmark
2
Uppsala University, Uppsala, Sweden
E-mail: sigsgaard@dadlnet.dk
Hypersensitivity pneumonitis (HP), also known Regardless of the causative agents or

as allergic alveolitis, is an immunologically environmental setting, the pathogenesis and
mediated inflammatory lung disease in the clinical manifestations of the disease are
lung parenchyma induced by the inhalation of similar. The hallmark of the disease is a
a variety of organic or inorganic antigens and massive lymphocytic inflammation with
characterised by hypersensitivity to the accumulation of activated T-lymphocytes in
antigens. The disease is usually named the lung interstitium.
colourfully after the environment in which it
Epidemiology
occurs (e.g. farmers lung and bird fanciers
lung) and has been reported from over 30 In a large, general-population-based cohort of
different occupations and environments. HP patients from the UK, the overall incidence
rate was approximately one per 100,000
population, and in Japan the summer-type HP
Key points occurs every year in approximately one per
million population. Most other studies have
N Hypersensitivity pneumonitis (HP) is an focused on the risk of developing clinical
immunologically mediated disease among subsets of the population with
inflammatory lung disease in the lung high levels of exposure to particular antigens.
parenchyma induced by the inhalation For example, the incidence of farmers lung in
of a variety of organic or inorganic Sweden in the 1980s was ,20 per
antigens and characterised by 100,000 person-yrs. However, there has been a
hypersensitivity to the antigens, decrease in the incidence of farmers lung due
to changes in farming practice (hay making
N The disease is usually named after the replaced by silage bags). A recent study from
environment in which it occurs. North America showed that the most common
N The main characteristic of HP is a cause was bird or hot-tub exposure.
massive lymphocytic inflammation with Risk factors
accumulation of activated
T-lymphocytes in the lung interstitium. The first reported HP was farmers lung,
caused by inhalation of microorganisms from
N The only treatment for allergic diseases infested crops. The disease was first described
such as HP is to avoid exposure to the among farmers in the Nordic parts of the
offending allergen and if the exposure globe; however, it has since been described in
ceases, the symptoms usually subside a range of farming operations all over the
rapidly, but the lung function world, making farming-like operations with
impairment may persist. decaying organic material one of the
important exposures to look for when

confronted with a case of HP. One of the most feeling, cough, muscle and joint aches and
common appearances of HP is bird fanciers headache. Radiography of the thorax shows
lung, caused by exposure to birds, e.g. pigeons diffuse, fine, nodular shadows, either general
or parakeets. Among pigeon breeders HP, or predominantly in the bases. In the early
intestinal mucin, a high molecular weight stages the changes can be difficult to detect,
glycoprotein, has been identified as a major but widespread patchy opacities may also be
antigen. seen. Lung function is decreased, with a
typical restrictive pattern and a decreased
Host factors
diffusing capacity.
Smoking seems to give protection towards HP, Environmental assessment
although the disease has been described in a
few smokers. The reason behind this protection The origin of the disease is an adverse
might be the downregulation of the immune reaction towards an occupational or
system by tobacco smoke and nicotine. environmental factor, so it is imperative to
search the patients environment for this
Virus infection seems to increase the
exposure, and to minimise further contact to
susceptibility of mice towards the antigens,
the offending agent. Often it is obvious what
and a higher number of virus antigens have
been found in the bronchial lavage of HP the reason might be, e.g. a mouldy hay
patients. problem occurring after a wet harvest season.
In some instances the causal agent might be
Pathological mechanism difficult to find and techniques for the
assessment of microorganisms should be
Although HP is a well known disease, the employed in order to assess the exposure to
pathogenesis is still only partly understood. which the patient is exposed.
When PEPYS (1978) found precipitating
antibodies to mould antigen in many cases, it Diagnosis
was believed for many years that the immune
complexes were the basis of the lung changes. The diagnosis of HP relies on an array of
It is now believed that the cellular immune nonspecific clinical symptoms and signs
response is driving the disease. Following developed in an appropriate setting, with
inhalation of antigen, a complex formed by demonstration of bilateral patchy infiltrates
soluble antigens and immunoglobulin G on chest radiographs, and serum precipitating
antibodies triggers the complement cascade antibodies against offending antigens. Several
and alveolar macrophage activation is different diagnostic criteria for HP have been
induced, resulting in an increase in proposed; all have significant problems that
macrophages. These cells secrete cytokines limit their utility. After studying a total of 661
and chemokines that attract neutrophils in HP patients with a stepwise logistic
alveoli and small airways. The number of T- regression, a panel of clinical experts
lymphocytes is also increased, with a identified six significant predictors of HP.
predominance of the CD8+ T-lymphocytes
subset, resulting in a decrease in the CD4+/ Diagnostic criteria of extrinsic hypersensitivity
CD8+ ratio (in contrast to what is seen in pneumonitis:
sarcoidosis). Different upregulatory
mechanisms result in a stronger interaction
N Exposure to a known offending antigen
between macrophages and T-cells and a more N Symptoms occurring 48 h after exposure
effective antigen-presenting capacity.
N Positive precipitating antibodies to the
Symptoms and findings offending antigen
The predominant symptoms in HP are N Inspiratory crackles on physical
tiredness, dyspnoea, fever, shivering, flu-like examination
Hypersensitivity pneumonitis 279

Table 1. Types of hypersensitivity pneumonitis (HP) and typical causative exposures and antigens
HP type Exposure Antigen
Farmers lung Mouldy hay Saccharopolyspora rectivirgula
Bagassosis Mouldy bagasse Thermoactinomyces sacchari
Mushroom workers lung Mushroom spores, mushroom Thermophilic actinomycetes
compost
Malt workers lung Mouldy barley Aspergillus clavatus, Faenia rectivirgula
Humidifier/ Contaminated water reservoirs Thermophilic actinomycetes
air-conditioner lung
Grain handlers lung Mouldy grain Saccharopolyspora rectivirgula,
Thermoactinomyces vulgaris
Cheese workers lung Cheese mould Penicillium casei
Paprika splitters lung Paprika dust Mucor stolonifer
Compost lung Compost Aspergillus spp.
Peat moss workers lung Peat moss Monocillium spp., Penicillium citreonigrum
Suberosis Mouldy cork dust Penicillium frequentans
Maple bark strippers Mouldy wood bark Cryptostroma corticale
lung
Wood pulp workers lung Mouldy wood pulp Alternaria spp.
Wood trimmers disease Mouldy wood trimmings Rhizopus spp.
Japanese summer-type Indoor air Trichosporon cutaneum
HP
Metal grinding Metalworking fluids Mycobacteria
Hot-tub lung Mist from hot tubs Mycobacteria
Bird breeders lung Pigeons, parakeets, fowl, rodents Avian or animal proteins
Mollusc-shell Sea snail shells Shell dust
hypersensitivity
Chemical workers lung Manufacture of plastics, Trimellitic anhydride, diisocyanate,
polyurethane foam, rubber methylene diisocyanate
N Recurrent episodes of symptoms when the occurrence is sporadic and not part
of the daily work of the patient. However, in
N Weight loss some cases, e.g. farmers, it might be difficult
However, diagnosing HP often poses to avoid the exposure totally for a range of
challenges, even to expert clinicians. different reasons. Under such circumstances
Additional investigations (including surgical respiratory protection can be used to minimise
biopsy) are indicated in patients with the exposure as much as possible.
interstitial diseases in whom the diagnosis It has been discussed whether medical
remains unclear after initial assessment. treatment has an effect on the outcome of HP.
Treatment Cortisone has been found to reduce
interleukin-8 synthesis. Cortisone treatment
The only treatment for allergic diseases is to seems to improve the radiological findings
avoid the exposure to the offending allergen. and should be given to severely ill patients to
This can be done in many circumstances, e.g. ameliorate symptoms, but no apparent benefit

is derived from long-term treatment. The common condition, but the prognosis is good
cortisone treatment should be given for about and most people have recovered totally
2 months. without any sequels after 24 h. No treatment
is required if the exposure is terminated.
Prognosis
References
If the exposure ceases, the symptoms usually
subside rapidly, but the lung function N Ando M, et al. Japanese summer-type
impairment may persist for a longer period hypersensitivity pneumonitis. Geographic
and become permanent, with a restrictive distribution, home environment, and clinical
pattern and decreased diffusing capacity. characteristics of 621 cases. Am Rev Respir Dis
Repeated attacks increase the risk of 1991; 144: 765769.
sequelae. It is therefore important to treat the N Arya A, et al. Farmers lung is now in decline. Ir
Med J 2006; 99: 203205.
patient as soon as possible in order to avoid
more damage to the lung parenchyma than is
N Bourke SJ, et al. Hypersensitivity pneumonitis:
current concepts. Eur Respir J 2001; 18: Suppl.
already the case at the time of diagnosis. 32, 81s92s.
Differential diagnosis N Hanak V, et al. Causes and presenting features
in 85 consecutive patients with hypersensitivity
Infectious lung diseases, both of virological pneumonitis. Mayo Clin Proc 2007; 82: 812
and bacteriological origin, as well as other 816.
lung diseases such as sarcoidosis, have to be N Lacasse Y, et al. Clinical diagnosis of
ruled out. Another differential diagnosis is the hypersensitivity pneumonitis. Am J Respir Crit
organic dust toxic syndrome (ODTS) also Care Med 2003; 168: 952958.
known as inhalation fever or toxic N Malmberg P, et al. Incidence of organic dust
toxic syndrome and allergic alveolitis in Swedish
pneumonitis: acute, febrile, noninfectious,
farmers. Int Arch Allergy Appl Immunol 1988;
flu-like, short-term reactions that can be
87: 4754.
produced by inhalation of bio-aerosols and N Pepys J. Antigens and hypersensitivity
organic dusts as well as plastic hardeners and pneumonitis. J Allergy Clin Immunol 1978; 61:
metal (zinc) fumes. Symptoms are caused by 201203.
the release of inflammatory cytokines from N Solaymani-Dodaran M, et al. Extrinsic allergic
the lungs caused by an inhalatory alveolitis: incidence and mortality in the general
overexposure to aerosols. ODTS is quite a population. QJM 2007; 100: 233237.
Hypersensitivity pneumonitis 281

PNEUMOCONIOSIS
R.D. Stevenson
Glasgow Royal Infirmary and University of Glasgow, Glasgow, UK
E-mail: robstevenson@doctors.org.uk
Asbestos, coal and silica exposures are the

main causes of pneumoconiosis relevant to Key points
current clinical and medico-legal practice.
Although these exposures have greatly N Pleural plaques are benign and do not
diminished in recent years, many patients still predispose to malignancy.
present to pneumologists with disease N Asbestosis is a disappearing disease.
resulting from exposure that occurred in
previous years. This article will consider the N Diffuse pleural thickening is the sequel
effects of dust inhalation both on lungs and to benign asbestos pleurisy and may
pleura. cause restricted ventilation.
Asbestos N New cases of coal workers
pneumoconiosis are still occurring.
The mining and use of amphibole forms of
asbestos, mainly crocidolite and amosite, has N Silicosis increases the risk of both TB
ceased worldwide, but chrysotile, the and lung cancer.
serpentine form, is still used in Africa, South
America and Asia, both because of a lack of
cheaper substitutes and because it is less However in the majority of cases, any such
harmful than the amphiboles. Some ceiling effect is unlikely to be of clinical significance.
boards still contain chrysotile and people who Some studies have suggested that plaques
live near chrysotile mines experience predispose to the development of
environmental exposure. There is a high mesothelioma, but the consensus view is that
incidence of mesothelioma in women who they are not pre-malignant. Until recently in the
lived in the chrysotile mining region of UK, pleural plaques were accepted as justifying
Quebec, Canada, where contamination of compensation. However, in 2007, the House of
chrysotile by the amphibole tremolite Lords ruled that plaques did not constitute an
increases toxicity. injury and that compensation would no longer
be awarded to affected individuals.
Pleural plaques Pleural plaques, which are
discrete areas of thickening on the parietal Benign asbestos pleurisy and diffuse
pleura, are the commonest manifestation of pleural thickening Asbestos pleurisy was
asbestos exposure. They are usually first described in 1964. Many episodes are
discovered incidentally on plain chest asymptomatic but some patients experience
radiographs or computed tomography scans. pain, fever and dyspnoea. Typically the
They do not become evident radiographically pleurisy is associated with a blood-stained
in ,15 yrs from first exposure. Previously, effusion but some cases are of dry pleurisy.
plaques were thought to have no effect on Spontaneous recovery is usual although
lung function, but a recent statement from the recurrence on the other side is common.
American Thoracic Society claimed that studies Asbestos pleurisy may occur after a latency of
of large cohorts showed a reduction in lung ,10 yrs, but in another study the mean
function attributable to pleural plaques. latency was 26 yrs.

Diffuse pleural thickening (DPT) involves the pneumoconiosis (CWP) has fallen consistently
visceral pleura and may be unilateral or as the numbers of coal miners and the dust
bilateral. It is now thought to follow earlier levels in mines have decreased. Nevertheless,
episodes of benign pleurisy. The fibrosis may mining is still a major industry in many parts
be extensive and cause restricted ventilation. of eastern Europe, India, China, South
It may be difficult to distinguish from America and Africa. Increased mechanisation
confluent pleural plaques but in DPT, results in higher dust levels. New cases of
obliteration of the costo-phrenic angle has CWP are still being diagnosed in miners who
usually occurred and this does not happen have worked exclusively under current
with plaques. exposure limits. The risk of CWP depends on
the total dust burden and is also related to
Asbestosis Asbestosis is diffuse interstitial
the coal rank, which is based on carbon
pulmonary fibrosis secondary to severe
content. Anthracite has a higher rank than
asbestos exposure. In the USA, it is becoming
bituminous. Therefore, this disease is not
a disappearing disease because of the great
disappearing as definitely as asbestosis and
reduction in exposure. Disease progression
continued vigilance is necessary in assessing
was a feature of severe disease after heavy
respiratory symptoms in miners.
exposure, but after mild exposure, the disease
tends to become quiescent. It is therefore very
rare nowadays to see patients with severe Clinical features Simple CWP is a
asbestosis. radiological and pathological diagnosis. The
characteristic lesion is the coal macule, which
The relevance of asbestosis in current practice is a centrilobular accumulation of
is almost entirely medico-legal. Patients with macrophages. This lesion causes no signs or
pulmonary fibrosis and a history of asbestos symptoms and dyspnoea in a patient with
exposure seek compensation, but many of simple CWP must prompt a search for another
them had limited exposure and have diagnosis. This may be associated emphysema
coincidentally developed idiopathic due to coal dust or smoking, or the
pulmonary fibrosis of the usual interstitial development of progressive massive fibrosis,
pneumonia (UIP) sub-type. The two important but it may also be a treatable disease
distinguishing features are the more unrelated to CWP.
progressive nature of UIP in terms of
radiographic changes and declining lung It is now accepted that CWP causes bronchitis
function and the presence of pleural plaques due to coal dust resulting in cough and mucus
which occur in ,95% of patients with production. In addition, CWP is recognised as
asbestosis. being associated with airflow obstruction
independent of smoking. Post-mortem
An international meeting was held in Helsinki examination suggests that coal mine dust
in 1997 and criteria for the diagnosis of causes centrilobular emphysema, especially
asbestosis were developed, which in addition when pneumoconiosis is present. In the UK,
to radiological features, included data on chronic bronchitis and emphysema are
analysis of lung tissue for asbestos bodies and classified as an occupational disease for
fibres. which industrial injuries benefit can be paid.
There is agreement that asbestosis increases the
Silicosis
risk of lung cancer but there is still no consensus
about whether asbestos exposure in the absence Prevalence Silicosis is a major worldwide
of asbestosis also increases the cancer risk. disease even in developed countries. It affects
miners and workers in the construction
Coal workers pneumoconiosis industry and foundries. There is some
Populations at risk Over the past 30 yrs, evidence that prevalence in South Africa is
the prevalence of coal workers rising. A recent study claimed that exposure
Pneumoconiosis 283
over a working lifetime to the commonly used environmental mycobacteria and also of
standard of 0.1 mg?m-3 results in significant extrapulmonary tuberculosis.
radiological silicosis with death both from
silicosis and from lung cancer. Chronic obstructive pulmonary
disease Emphysema is a common feature of
long-term silica exposure and along with
Clinical features Like CWP, uncomplicated
bronchitis may develop with or without
silicosis is not associated with signs or
radiological signs of silicosis. Smoking may
symptoms. Dyspnoea usually indicates the
potentiate the effect of silica on airflow
development of progressive massive fibrosis or
obstruction.
tuberculosis but may reflect associated airway
disease or emphysema. Silicosis often
References
continues to progress after exposure has
ceased. N al Jarad N, et al. Bronchoalveolar lavage and
99mTc-DTPA clearance as prognostic factors in
asbestos workers with and without asbestosis.
Lung cancer Traditionally lung cancer was Respir Med 1993; 87: 365374.
not associated with silicosis, but recent N American Thoracic Society Committee of the
authoritative reviews have concluded that the Scientific Assembly on Environmental and
data are sufficient to support an association Occupational Health, Adverse effects of
between silicosis and lung cancer. It remains crystalline silica exposure. Am J Respir Crit Care
Med 1997; 155: 761768.
unclear whether the increased risk derives
from exposure to silica or requires the
N Asbestos, asbestosis, and cancer: the Helsinki
criteria for diagnosis and attribution.:: Scand J
presence of silicosis. Work Environ Health 1997; 23: 311316.
N Coggon D, Newman Taylor A. Coal mining and
chronic obstructive pulmonary disease: a review
Tuberculosis It is well known that silicosis
of the evidence. Thorax 1998; 53: 398407.
predisposes to tuberculosis which may be two- N Copley SJ, et al. Asbestosis and idiopathic
to 30-fold more common than in controls pulmonary fibrosis: comparison of thin-section
without silicosis. HIV status adds a further CT features. Radiology 2003; 229: 731736.
complication. In black South African gold N Corbett EL, et al. HIV infection and silicosis: the
miners, HIV infection increased tuberculosis impact of two potent risk factors on the
incidence by five times, whereas silicosis incidence of mycobacterial disease in South
increased incidence by three times. When HIV African miners. AIDS 2000; 14: 27592768.
and silicosis were both present, the N Martensson G, et al. Asbestos pleural effusion: a
clinical entity. Thorax 1987; 42: 646651.
tuberculosis incidence increased N t Mannetje A, et al. Exposure-response analysis
multiplicatively by 15 times. In addition to and risk assessment for silica and silicosis
tuberculosis, patients with silicosis have an mortality in a pooled analysis of six cohorts.
increased incidence of infection with Occup Environ Med 2002; 59: 723728.

INDOOR AND OUTDOOR
POLLUTION
G. Viegi1,2, M. Simoni1, S. Maio1, S. Cerrai1, G. Sarno1 and S. Baldacci1
1
Pulmonary Environmental Epidemiology Unit, Institute of Clinical
Physiology, National Research Council, Pisa and
2
Institute of Biomedicine and Molecular Immunology A. Monroy, National
Research Council, Palermo, Italy
E-mail: viegig@ifc.cnr.it
Air pollution is a well-established hazard to risk of specific exposures (workers exposed to

human health. Air quality is particularly inorganic dust, wood dust, fumes, gases and
important for subpopulations that are more cleaning agents). Children are particularly
susceptible (i.e. children, the elderly, subjects vulnerable since they inhale a higher volume
with cardiorespiratory diseases or those who of air per body weight than adults, the lungs
are socioeconomically deprived) or at higher are growing, the immune system is
incomplete, and defence mechanisms are still
evolving. Air pollution can affect the cells in
Key points the lung by damaging those that are most
susceptible, and if the damaged cells are
N Recent epidemiological studies have important in the development of new
clearly shown that outdoor and indoor functional parts of the lung, the lung may not
achieve its full growth and function as a child
air pollution affects respiratory health
matures to adulthood. This can lead to
worldwide, causing an increase in the
enhanced susceptibility during adulthood to
prevalence of respiratory symptoms/
the effects of ageing and infections as well as
diseases (i.e. COPD, asthma, hay fever,
to pollutants. Air pollution is mostly produced
lung function reduction) and of by human activities. Other pollutants derive
mortality, both in children and in adults. from natural sources, such as biological
N Rapid industrialisation and allergens (e.g. acarids, house dust mites, pets,
urbanisation have increased moulds), and natural phenomena (e.g.
air pollution and, consequently, the volcanic activity, forest fires).
amount of exposed people. Outdoor pollution
N Conservative estimates show that
The most important outdoor pollutants derive
between 1.5 and 2 million deaths per
from fossil fuel combustion. Primary pollutants
year could be attributed to indoor air
directly emitted into the atmosphere are
pollution in developing countries. carbon monoxide (CO), sulphur dioxide (SO2),
N The abatement of the main risk factors nitrogen dioxide (NO2) and particulates (PM).
for respiratory diseases and the support Ozone (O3) is a secondary pollutant, mainly
of health care providers and general produced by chemical reaction of NO2 and
community to public health policy for hydrocarbons in the presence of sunlight at
improving outdoor/indoor air quality warm temperature. Rapid industrialisation
can achieve huge health benefits. and urbanisation in many parts of the world
have increased air pollution and,
Indoor and outdoor pollution 285

consequently, the number of people exposed of chronic exposure comprise an increase in
to it. In China, for instance, rapid economic morbidity and mortality for cardiovascular and
development has led to severe environmental respiratory diseases, including COPD and lung
degradation, particularly due to coal cancer, and impaired development of the
combustion (it provides 7075% of energy) lungs in children. In COPD patients, continued
and vehicular traffic. Chinese mortality and exposure to noxious agents promotes a more
morbidity associated to outdoor pollution are rapid decline in lung function and increases
very high: more than 300,000 deaths and 20 the risk of repeated exacerbations. Air
million cases of respiratory illnesses annually. pollution can harm the foetus if the mother is
The main effects of the more common exposed to high levels during pregnancy (i.e.
outdoor pollutants are summarised in table 1. intra-uterine growth retardation), and it can
increase respiratory neonatal mortality. PM,
Exposureresponse relationships for outdoor NO2 and O3 are the most important
pollutants, especially PM, have been pollutants today. The health effects of PM are
confirmed by epidemiological studies in more serious for fine (aerodynamic diameter
recent decades. Short-term exposure, due to ,2.5 mm, PM2.5) and ultrafine (aerodynamic
acute increase in air pollution, may cause diameter ,0.1 mm, PM0.1) particles, as they
premature mortality and increase hospital penetrate deeper into the airways of the
admissions for exacerbations of chronic respiratory tract, reaching the alveoli.
obstructive pulmonary disease (COPD) or Vehicular exhausts are responsible for
asthma. Long-term cumulative health effects small-sized airborne PM air pollution in urban
Table 1. Major outdoor pollutants and related health effects

Pollutant Major sources Health effects
Particulate matter Vehicular traffic Lung cancer
Wood stoves Premature death
Organic matter/fossil fuel combustion Mortality from cardiorespiratory diseases
Power plants/industry Reduced lung function
Wind-blown dust from roads, Lower airways inflammation
agriculture and construction Upper airways irritation
Bush fires/dust storms
Nitrogen dioxide Vehicular traffic Exacerbation of asthma
Power plants/industry Airway inflammation
Bronchial hyperresponsiveness
Increased susceptibility to respiratory
infection
Ozone Sunlight: chemical reaction between Lung tissue damage
other pollutants Reduced lung function
Vehicular traffic Reduced exercise capacity
Power plants/industry Exacerbation of asthma
Consumer products Upper airway and eye irritation
Carbon monoxide Organic matter/fossil fuel combustion Death/coma at very high levels
Vehicular traffic Headache, nausea, breathlessness
Wood stoves Confusion/reduced mental alertness
Sulphur dioxide Coal/oil burning power plants Exacerbation of respiratory diseases
Industry/refineries including asthma
Diesel engines Respiratory tract irritation
Metal smelting

areas. A recent Chinese study showed that reduce the efficacy of short-acting b-agonists
long-term exposure to PM2.5 increases the risk in producing bronchodilation.
of mortality from lung cancer by 1521% per
10 mg?m-3 increase. O3 significantly increases Furthermore, European Community Respiratory
annual mortality rates from respiratory causes, Health Survey data suggest that NO2 traffic-
as demonstrated by a very large cohort study related pollution causes asthma symptoms and
performed in the USA (,450,000 subjects possibly asthma incidence in adults.
from 96 metropolitan areas). Even in Sweden, Indoor pollution
with overall low levels of traffic-related air
pollution, adults living near a road with Indoor environments contribute significantly
higher traffic show significantly higher risk for to human exposure to air pollutants. People
diagnosis of asthma (OR 1.40, 95% CI 1.04- spend most of their time indoors: up to 90%
1.89) and COPD (OR 1.64, 95% CI 1.112.40) in industrialised countries. Further, levels of
and for related symptoms. In Italy, the current some pollutants are higher inside than
authors have recently reported that people outside buildings. Even at low concentrations,
living in an urban area show a higher risk of indoor pollutants may have an important
having increased bronchial responsiveness biological impact because of long exposure
(OR 1.41, 95% CI 1.131.76) than people periods (e.g. at home/school, in working
living in a rural area. places). Conservative estimates show that 1.5
2 million deaths per year could be attributed
The role of air pollution in the epidemics of to indoor air pollution. There is consistent
allergies is still debated, even if experimental evidence that exposure to indoor pollutants
studies have suggested that the effects of air increases the risk of several respiratory/allergic
pollutants on the development and worsening symptoms/diseases (table 2). Relevant indoor
of allergies are biologically plausible. Asthma pollution sources are environmental tobacco
shows a strong familial association, but smoke (ETS), a common source of indoor PM,
genetic factors alone are unlikely to account biomass (wood/coal) fuel use and mould/damp.
for the rapid rise in its prevalence seen in
recent decades. The rapid increase in the ETS is associated with increased risk of acute
burden of atopic diseases occurred along with respiratory or irritation symptoms, infectious
rapid urbanisation/industrialisation. Thus, diseases, chronic respiratory illnesses, lung
genetic and environmental factors may function reduction and even lung cancer. It
interact to cause asthma. A growing number has been estimated to be a significant pooled
of studies shows significant associations of risk for chronic cough in never-smokers heavily
traffic with new-onset asthma, or asthma exposed to ETS, both in males (OR 1.60, 95%
symptoms/exacerbations, in children. A recent CI 1.222.10) and females (OR 1.68, 95% CI
study on a very large sample of German 1.172.34). In nonsmoking males, the
children shows significantly higher risk for mortality risk for respiratory diseases is about
asthmatic bronchitis (OR 1.56, 95% CI 1.03 double for those living with smokers than for
2.37), hayfever (OR 1.59, 95% CI 1.112.27) those who do not. A few studies performed
and allergic sensitisation to pollen (OR 1.40, worldwide suggest higher risk for ETS
95% CI 1.201.64), in children living near exposure in females than in males. In China,
busy streets. Another recent study on 70,000 about 80% of the cardiorespiratory burden
children, in the USA, indicates that the risk for caused by ETS exposure concerns women, and
respiratory allergy/hayfever increases with the number of deaths from ETS due to
increasing summer O3 levels (OR 1.20, 95% cardiovascular diseases and lung cancer in
CI 1.151.26 per 10 ppb increment) and women is about two-thirds of that from active
increasing PM2.5 levels (OR 1.23, 95% CI smoking. The induction period of lung cancer
1.101.38 per 10 mg?m-3 increment). A study being long, its risk is probably related to
on asthmatic children in Mexico City suggests cumulative lifetime ETS exposure. Meta-
that recent exposure to NO2 and O3 may analyses on spousal ETS exposure estimated a

Table 2. Major indoor pollutants and related health effects
Pollutant Major sources Health effects
Particulate matter Wood stoves Lung cancer
Organic matter/fossil fuel combustion Premature death
for heating/cooking Mortality from cardiorespiratory diseases
Environmental tobacco smoke Reduced lung function
Lower airways inflammation
Upper airways irritation
Nitrogen dioxide Unvented gas/kerosene appliances Exacerbation of asthma
Airway inflammation
Increased susceptibility to respiratory
infection
Carbon monoxide Organic matter/fossil fuel combustion Death/coma at very high levels
for heating/cooking Headache, nausea, breathlessness
Wood stoves Confusion/reduced mental alertness
Unvented gas/kerosene appliances Low birth weight (foetal exposure)
Environmental tobacco smoke Bronchial hyperresponsiveness
Volatile organic Building materials and products such Lung cancer
compounds as new furniture, solvents, paint, Asthma, dizziness, respiratory and lung
adhesives, insulation diseases
Cleaning activities and products Chronic eye, lung or skin irritation
Office materials Neurological and reproductive disorders
pooled risk for lung cancer of OR 1.23 (95% Based on meta-analyses, building dampness
CI 1.131.34). ETS exposure is a risk factor for and mould are associated with approximately
new-onset asthma among both nonsmoking 3050% increases in respiratory and
adults and children; it exacerbates pre-existing asthma-related health outcomes. In adults, a
asthma and increases symptom burden and pooled risk for cough by indoor mould/
morbidity. In children, ETS also increases the dampness was estimated at OR 2.10, 95% CI
risk of sudden infant death syndrome, middle- 1.273.47. There is also evidence on the
ear disease, lower respiratory tract illnesses, association of mould exposure with new-
wheeze and cough. onset sthma, and worsening of pre-existing
asthma (wheezing, cough, shortness of breath)
About half of the worlds population burns in both children and adults. Allergic
biomass for cooking, heating and lighting, in symptoms are commonly related to mould
open fires or with inefficient stoves, and in exposure (sneezing, nose/mouth/throat
poorly ventilated rooms, especially in irritations, nasal stuffiness/ runny nose, red/
developing countries. There is very high itchy/watery eyes). In children, a population
production of PM and CO. Indoor air pollution attributable risk for asthma of 6.7% has been
from biomass fuels is strongly poverty-related estimated.
and represents an important risk factor for acute
respiratory illness morbidity and mortality, Finally, exposure to VOCs may result in a
especially in children and women. The evidence spectrum of illnesses ranging from mild
that biomass use increases the risk of COPD in (irritations) to very severe effects, including
women is very strong (about threefold higher cancer. Many studies indicate that the effects
risk in those exposed than in those unexposed). are related to very low levels of exposure. VOC
Besides COPD, observed health effects include exposure also seems a significant risk factor
weakening of the immune system, impaired for asthma (especially benzene, ethylbenzene
lung function and lung cancer. and toluene).

Biological mechanisms with asthma seem at higher risk of
exacerbations due to air pollution exposure.
Many recent studies have shown that
oxidative stress, induced by air pollutants, Conclusion
plays a central role in the impact of air
pollution. The first contact of inhaled ambient Outdoor and indoor pollution greatly affect
pollutants is with the fluid layer that covers respiratory health worldwide as shown by
the respiratory epithelium, and the responses many recent epidemiological studies.
following the exposure are mediated through
oxidation reactions occurring within this fluid Patient education about the importance of
airlung interface. These reactions can result good indoor air quality in the home and
in oxidative stress and consequent increased workplace is essential. The support of
production of inflammatory mediators from healthcare providers and the general
human airway epithelial cells. Oxidative stress community for public health policy aimed at
is a situation in which the oxidant improving outdoor air quality through
antioxidant balance is disturbed. This programmes to abate/reduce polluting
imbalance can occur when the generation of emissions is also important. Moreover, there is
oxidant molecules (free radicals) exceeds the evidence that increased antioxidant intake may
available antioxidant defences. protect against the effects of air pollution.
Hopefully, these actions will reduce the
The three pollutants of most concern that can
negative effects of air pollution on the
cause oxidative stress include NO, which is a
respiratory health status and quality of life of
free radical, PM10, and O3. The majority of
the general population, in particular of the
human genetic association studies of air
more susceptible individuals.
pollutants have examined O3 exposure. O3 is
a powerful oxidant and reacts with the References
bronchial epithelium lining fluid to generate
free radicals. It depletes levels of protective N Effects of air pollution on childrens health and
development a review of the evidence. Geneva,
antioxidants and increases the production of
World Health Organization, 2005. Available at:
inflammatory mediators. http://www.euro.who.int/__data/assets/pdf_file/
0010/74728/E86575.pdf.
The size and the surface of PM determine the
potential to elicit oxidative damage. In
N Groneberg-Kloft B, et al. Analysis and evaluation
of environmental tobacco smoke exposure as a
general, the smaller the size of PM the higher risk factor for chronic cough. Cough 2007; 3: 6.
the toxicity through mechanisms of oxidative N Hernandez-Cadena L, et al. Increased levels of
stress and inflammation. Nanoparticles outdoor air pollutants are associated with
(ultrafine particles with diameter ,100 nm) reduced bronchodilation in children with
are more toxic and inflammogenic than fine asthma. Chest 2009; 136: 15291536.
particles. They generate reactive oxygen N Maio S, et al. Urban residence is associated with
species to a greater extent and exacerbate bronchial hyper-responsiveness in Italian general
pre-existing respiratory and cardiovascular population samples. Chest 2009; 135: 434441.
disease, also through a doseresponse effect. N Parker JD, et al. Air pollution and childhood
respiratory allergies in the United States. Environ
Pulmonary impairment related to pollutants Health Perspect 2009; 117: 140147.
exposure may be higher in individuals who N Simoni M, et al. Mould/dampness exposure at
home is associated with respiratory disorders in
are genetically at risk for greater susceptibility
Italian children and adolescents: the SIDRIA-2
to oxidative stress. The formation of reactive Study. Occup Environ Med 2005; 62: 616622.
oxygen species is an important aspect of the N Valavanidis A, et al. Airborne particulate matter
inflammatory process of asthma, and genetic and human health: toxicological assessment and
aberrations associated with antioxidants importance of size and composition of particles
might explain the reason why some people for oxidative damage and carcinogenic

mechanisms. J Environ Sci Health C Environ N Viegi G, et al. Indoor air pollution and airway
Carcinog Ecotoxicol Rev 2008; 26: 33962. disease. Int J Tuberc Lung Dis 2004; 8: 14011415.
N Viegi G, et al. Definition, epidemiology and N Yang IA, et al. Genetic susceptibility to the
natural history of COPD. Eur Respir J 2007; 30: respiratory effects of air pollution. Thorax 2008;
9931013. 63: 555563.

SMOKING-RELATED DISEASES
University of Nancy, Henri Poincare, Nancy, France
E-mail: y.martinet@chu-nancy.fr
Tobacco use is by far the single largest Tobacco smoke

avoidable cause of chronic illness and
premature death worldwide. Smokers die of Almost all tobacco-associated lung cancer and
cancer of the lung and of other organs as well respiratory diseases result from smoke
as of respiratory and cardiovascular diseases. inhalation. In this respect, studies have shown
In the European Union (EU), tobacco use kills that people who only use oral tobacco (such
at least 650,000 people (more than one in as Swedish snus, for example) during their
seven of all deaths) each year. Nearly 50% of lifetime are at no greater risk of developing
these deaths involve diseases of the these diseases than nonsmokers; however, the
use of oral tobacco is related to several health
respiratory system, mainly lung cancer and
problems, such as gum and pancreatic cancer
chronic obstructive pulmonary disease
and, possibly, cardiovascular diseases. Given
(COPD). Given the relatively long period
that cigarette smoking is by far the most
between time of smoking initiation ("first
common method of tobacco consumption, the
puff") and time of onset of smoking-related
following data mainly concern diseases
lung disease (o510 yrs), young people who
related to active cigarette smoking.
start smoking often disregard future health
risks of tobacco use. Unfortunately, while Cigarette smoke is composed of .4,000
male smoking is declining in most European substances, including nicotine, chemical
countries, female smoking rates are still on the poisons, toxic gases, small particles and
rise in some parts of the EU, and in most other carcinogens. The nicotine present in tobacco
countries of the world, due to tobacco leaves is highly addictive but has little toxicity
industry activism. on the respiratory tract. Thus, people smoke for
the psychoactive effects of nicotine, but die
from the high toxicity of the other components
present in smoke. Even if tobacco smoke
composition varies slightly (due to tobacco
Key points type, substances added during manufacturing,
filter type) the health risks and effects of
N Tobacco use is responsible for more tobacco smoking are quite constant from one
than one in seven out of all deaths in cigarette brand to another. Furthermore,
the EU. previously labelled low tar/low nicotine
cigarettes have been shown to be as hazardous
N About 50% of tobacco-related deaths as regular ones. Likewise, hand-rolled
are due to lung cancer and COPD. cigarette, bidi, and water-pipe smoking are at
N Female smoking is still on the rise in least as dangerous as cigarette smoking.
some parts of the EU. Finally, while pipe and cigar smoke is more
toxic than cigarette smoke, cigar and pipe
N Preventing tobacco use and treating smokers are seldom deep inhalers. This explains
tobacco addicts should be given top the lower incidence of respiratory disease in
priority. these noninhaling smokers. Nevertheless, this
rate is still higher than in nonsmokers.
Smoking-related diseases 291

Cannabis smoke 9
8 70
Death/100,000 same age (European standard)

In respect to effects on the respiratory tract,
Males
cannabis smoking is at least as dangerous as 7 60
tobacco smoking. Moreover, since cannabis is
Cigarettes per adult per day

usually smoked mixed with tobacco, young 6

50
people often become addicted to tobacco for 5
life, even occasional users merely seeking to 40
experience the relaxing effects of 4
30

tetrahydrocannabinol. This co-consumption of 3

cannabis and tobacco complicates

20
characterisation of the specific health effects 2
Females
of cannabis smoking. Nevertheless, it has 1

10

been shown that cannabis smoking causes

0 0

lung cancer and COPD.
1900
1925
1950
1975
2000
2006
Lung cancer Years
Lung cancer is the most frequent cause of

Figure 1. Trends in cigarette smoking () and
death due to tobacco use: 8590% of the death by lung cancer (???????) by sex in France,
225,000 lung cancer deaths occurring each 19502006. Modified from HILL et al. (2010).
year in the EU are the consequence of
tobacco smoking. Lung cancer is one of the COPD and asthma
deadliest cancers, with 5-yr survival rates
ranging from 1015%. Lung cancer incidence In 2000, ,30% of the 371,000 deaths from
and mortality increase roughly in proportion nonmalignant respiratory diseases occurring
to the first power of smoking intensity in the EU were caused by cigarette smoking.
(number of cigarettes smoked per day) and, Among these cases, COPD was the most
most importantly, to the second power of frequent cause of death. Nearly two-thirds of
smoking duration (total number of years of these COPD deaths were caused by tobacco
smoking). Tobacco smoking results in all major smoking. The COPD mortality rate is roughly
histological types of lung cancer. Lung cancer 20 times higher among heavy smokers (male
risk is similar in males and females with or female) than nonsmokers. According to
comparable smoking histories. With such a international guidelines for COPD
highly specific cause and terrible prognosis, classification (American Thoracic Society,
the best treatment of lung cancer is to avoid
it through tobacco smoking prevention and Never smoker
100
treatment. Indeed, the relative risk of lung
FEV1 % of value at age 25
cancer steadily decreases when smokers give 75

Stopped at age 45
up smoking. For example, in the UK, for males
who stopped smoking at ages 30, 40, 50 and 50 Regular smoker
60, the risk of lung cancer by age 75 yrs was Disability Stopped at age 65
2, 3, 6 and 10%, respectively; whereas for 25
males who smoked up to 75 yrs of age this Death
cumulative risk reached 16%. In the same 0
25 50 75
way, an increase in overall tobacco Age yrs
consumption by a population is followed by
an increase of lung cancer incidence, while a Figure 2. Loss of forced expiratory volume in 1 s
fall in consumption is followed by a drop in (FEV1) in never-smokers, regular smokers and
lung cancer incidence, as shown for males in smokers giving up at ages 45 and 65 yrs. Modified
France between 1950 and 2006 (fig. 1). from FLETCHER and PETO (1977).

Stopping smoking at age 2534 yrs
100

Stopped smoking
80
% survival from age 35 yrs
Cigarette smokers
60
Nonsmokers
40

20

0
Stopping smoking at age 4554 yrs

100
Stopped smoking

80
% survival from age 35 yrs

Cigarette smokers
60
Nonsmokers

40

20

40 50 60 70 80 90 100
Age yrs
Figure 3. Survival of male doctors who stopped smoking at ages 2534 and 4554 yrs. Modified from DOLL
et al. (2004).
European Respiratory Society), up to 60% of Respiratory infectious diseases

current smokers aged .65 yrs suffer from
COPD. Measurement of forced expiratory Bronchial and lung infectious diseases,
volume in 1 s (FEV1) and of its decline is the including tuberculosis, acute bronchiolitis,
best marker of airflow limitation in COPD, and pneumonia, the common cold, and influenza
FEV1 value is directly related to COPD are more frequent and more severe in smokers.
morbidity and mortality. Physiological decline Interstitial lung diseases
of FEV1 with age is accelerated by tobacco
smoking, whereas, in contrast, smoking Several interstitial lung diseases, namely,
cessation slows lung function decline in respiratory bronchiolitis-associated interstitial
smokers (fig. 2). Cessation also improves lung disease, desquamative interstitial
COPD patient quality of life, and is the only pneumonia, and pulmonary Langerhans cell
measure that definitively improves COPD histiocytosis are strongly associated with
patient survival. Asthmatic patients who cigarette smoking.
smoke have a higher risk of hospitalisation for Passive smoking
their disease and experience more severe
symptoms with poor clinical control and In addition to its direct harmful effects on
poorer quality of life. Finally, active cigarette active smokers, exposure to tobacco
smoking is a direct cause of asthma onset, combustion products from smoking is
and causes more severe symptoms and lung dangerous to nonsmokers, as environmental
function decline. tobacco smoke is highly toxic. In the EU, in
Smoking-related diseases 293

2002, an estimated 79,449 deaths were N Doll R, et al. Mortality in relation to smoking: 50
attributable to passive smoking from various years observations on male British doctors. Br
diseases caused by second-hand smoking, Med J 2004; 328: 15191528.
including lung cancer (13,241 deaths), N Flanders WD, et al. Lung cancer mortality in
relation to age, duration of smoking, and daily
chronic non-neoplastic respiratory disease
cigarette consumption: results from Cancer
(5,275 deaths), ischaemic heart disease Prevention Study II. Cancer Res 2003; 63:
(32,342 deaths), and stroke (28,591 deaths). 65566562.
Furthermore, COPD, asthma, and several N Fletcher C, Peto R. The natural history of chronic
infectious diseases are more severe in airflow obstruction. Br Med J 1977; 1: 1645
1648.
nonsmokers exposed to passive smoking.
N Foulds J, Kozlowski L. Snus what should the
Conclusion public-health response be? Lancet 2007; 369:
19761978.
Since current treatments of lung cancer and N Hill C, et al. Assessment of the Lung Cancer
COPD are poorly efficient, it is obvious that Epidemic Due to Smoking. BEH 1920. Saint
preventing tobacco use through tobacco Maurice (France), Institut de Veille Sanitaire,
control and treating tobacco addiction are by 2010.
far the most efficient means to prevent and N Lifting the smokescreen: 10 reasons for a
cure these respiratory diseases. This smokefree Europe. Brussels, European
conclusion is also true for most other diseases Respiratory Society Journals Ltd, 2006.
related to cigarette smoking. Indeed, the N Mannino DM, et al. The natural history of
chronic obstructive pulmonary disease. Eur
overall impact of smoking cessation on Respir J 2006; 27: 627643.
survival is significant for all smokers at any N Ryu JM, et al. Smoking-related interstitial lung
age, as shown in fig. 3. diseases: a concise review. Eur Respir J 2001; 17:
122132.
References
N Tobacco or health in the European Union. Past,
N Arcavi L, Benowitz NL. Cigarette smoking and present and future. Brussels, Commission of the
infection. Arch Intern Med 2004; 164: 22062216. European Communities, 2004.

TREATMENT OF TOBACCO
DEPENDENCE
Tobacco Free Research Institute, Dublin, Ireland
E-mail: lclancy@tri.ie
Tobacco dependence is a disease that would smoke at work is also a significant

be of little consequence if it were not for occupational hazard. This situation has been
adverse effects of smoking. Instead it causes greatly improved by the enactment of smoke-
3040% of all cancers and is the principal free laws in many countries, especially within
cause of lung cancer. It is the biggest cause of the European Union. Second-hand smoke
preventable respiratory disease, even if lung remains, however, the most significant indoor
and other respiratory cancers are excluded: pollutant, especially in homes and motor cars.
smoking is linked causally or as an important
Treating tobacco dependence is an important
risk factor to chronic obstructive pulmonary
issue for respiratory physicians. An interest in
disease (COPD), emphysema, asthma and
the prevention of dependence through
respiratory infections including tuberculosis.
tobacco control mechanisms should also be a
Nevertheless, to speak of smoking as an priority.
occupational or environmental disease is
perhaps not entirely accurate. Without doubt, Prevention
however, smoking prevalence has a strong
occupational bias. Exposure to second-hand As always, prevention is the primary
intervention to be considered. The
mechanisms for tobacco control are well
established and incorporated in the
Key points Framework Convention for Tobacco Control
(FCTC), which is the first medical treaty of the
N Tobacco dependence is a disease and is World Health Organization (WHO) and has
an important issue for respiratory been ratified by 168 countries. The WHO has
physicians. also proposed a strategy, MPOWER, for these
mechanisms implementation and monitoring.
N The prevention of tobacco dependence
It is clearly stated in the FCTC that price is the
through tobacco control mechanisms is
most effective tobacco control measure but
a priority.
that interventions such as workplace
N Effective and cost-effective treatments restrictions on smoking, protection from
for tobacco dependence exist in the exposure and product regulation by various
form of motivational support and means are important. It is also agreed that
pharmacotherapy. proper information about the dangers of
smoking needs to be made known. The value
N The treatment of tobacco dependence of health warnings, especially graphic image
benefits from knowledge, experience warnings is emphasised and there is a
and training, which is not provided in realisation that packaging and labelling are
medical schools at undergraduate level, important methods of advertising for the
and that should be a priority. tobacco industry. This is especially so in
countries where direct advertising and
Treatment of tobacco dependence 295

promotion and sponsorship are banned. usefulness and consider how they could be
However the role of treating smoking in the made available to our patients.
plan, although regarded as important, is left
Evidence-based treatments
unclear. The reasons for this are many and
include considerations of availability, cost, Effective and cost-effective treatments for
efficacy and efficiency. This is not surprising smoking exist. The two treatment modalities
but is challenging. Even more challenging is proven to be effective consist of motivational
the fact that the costs of other evidence-based support, in the form of counselling, and
interventions are usually much smaller than pharmacotherapy. Present knowledge
those of treatment. This may also be true of suggests that a combination of the two is
some other diseases, for which treatments are more effective than either alone. The duration
much better developed. The cost-effectiveness of counselling seems to be important. Within
of treatment of tobacco dependence as a limits, longer seems better for instance, brief
disease in patients without other diseases may intervention by a general practitioner of some
not be obvious: the time lag between the 3 min increases success rates by ,2.5% when
treatment and the prevention of serious compared with those who did not receive such
physical disease may obscure comparisons advice. Sessions lasting ,10 min and
with the treatments of other diseases. repeated three to four times at intervals
However, effective treatments are available, according to present knowledge seem to be
are very cost-effective and compare very well near optimal, but these considerations need
with treatment of other diseases in this further defining and application.
regard. Despite this, interest in supplying this As regards pharmacological therapies, a
service seems to be low among policymakers. number of preparations have been shown to
Smoking was, and to some extent still is, not have measurable success rates. These include
accepted as a disease by many people. This is nicotine replacement therapy (NRT), which
in no small part due to the tobacco industry. approximately doubles success rate.
For generations, it denied that smoking was Varenicline and buproprion also have
harmful and addictive and emphasised the established success rates. Varenicline seems to
free choice argument and the apparent be more effective than NRT, while
glamour of smoking. It is now becoming buproprions success rate is similar to that of
widely accepted that smoking is a disease and NRT. The use of these preparations and their
that it is based on addiction. It is very difficult safety profiles need to be studied carefully.
to treat but the rewards for treating it They provide the clinician with
successfully are enormous. pharmacotherapy which has proven efficacy
and should be used knowledgably by
One-third of the population of the world physicians. TNNESEN (2009) recently reviewed
smokes. If this disease is to be tackled by the evidence for smoking cessation,
treating all smokers, the implications are concluding that with the most optimal drugs
daunting: treatment alone will probably never and counselling a 1-yr abstinence rate of
become the appropriate response to this ,25% can be expected in smoking cessation.
epidemic, unless much better and cheaper This compares very favourably with the
treatments can be developed to make this treatment of any other chronic relapsing
possible in the future. At present treatment disease. CAPONNETTO and POLOSA (2008)
has a defined role. Its importance in tobacco recently outlined the predictors of success and
control will vary from time to time and from failure in treatment. Factors which influence
country to country depending on the stage of outcomes include degree of nicotine
implementation of tobacco control policies. dependence, age at initiation, how many
Our first responsibility as doctors is probably cigarettes are smoked per day, social support
to know what treatments exist, then to and family circumstances, such as a
examine the evidence base for their nonsmoking partner, sex and comorbidities

such as alcoholism and depression. They also guideline for smoking cessation. JAMA 1997;
point out the complex relationship with 278: 17591766.
previous attempts and of course the N Fagerstrom KO, Jimenez-Ruiz CA.
importance of motivation to quit. Pharmacological treatments for tobacco
dependence. Eur Respir Rev 2008; 17: 192198.
In addition, evidence suggests that quit N Goodman P, et al. Effects of the Irish smoking
attempts are more frequent in subjects with ban on respiratory health of bar workers and air
high baseline body-mass index and low quality in Dublin pubs. Am J Respir Crit Care
weight concerns. Innovative approaches, such Med 2007; 175: 840845.
as brief isometric exercise and the cognitive N Raw M, et al. A survey of tobacco dependence
treatment guidelines in 31 countries. Addiction
technique of body scanning, may be effective
2009; 104: 12431250.
for reducing desire to smoke and withdrawal N Rigotti NA, et al. Smoking cessation
symptoms in temporarily abstaining smokers. interventions for hospitalized smokers: a
Conclusion systematic review. Arch Intern Med 2008; 168:
19501960.
The treatment of tobacco dependence N Tnnesen P, et al. Smoking cessation in patients
benefits from knowledge, experience and with respiratory diseases: a high priority, integral
training. This is not provided in medical component of therapy. Eur Respir J 2007; 29:
schools at undergraduate level. We expect 390417.
that the structure of training for the
N US Department of Health and Human Services.
The health consequences of involuntary
management of this disease and particularly exposure to tobacco smoke: a report of the
its treatment will improve and increase in the Surgeon General. Atlanta: Department of Health
short term. Knowledge of general tobacco and Human Services, 2006.
control principles will also need attention if N Ussher M, et al. Effect of isometric exercise and
we are to succeed in this important body scanning on cigarette cravings and
endeavour. withdrawal symptoms. Addiction 2009; 104:
12511257.
References
Weblink
N Caponnetto P, Polosa R. Smoking cessation: tips
for improving success rates. Breathe 2008; 5: N World Health Organization. WHO Report on the
1624. Global Tobacco Epidemic, 2009: Implementing
N Cromwell J, et al. Cost-effectiveness of the smoke-free environments. www.who.int/tobacco/
clinical practice recommendations in the AHCPR mpower/en/.
Treatment of tobacco dependence 297

HIGH-ALTITUDE DISEASE
Pulmonary Division, University Hospital of Zurich, Switzerland
E-mail: konrad.bloch@usz.ch
Physiological response to altitude breathing, is observed in healthy subjects at

altitudes .2,000 m mostly during sleep. It
The low barometric pressure at altitude results may cause intermittent dyspnoea and sleep
in a reduced inspiratory and arterial oxygen disturbances (figs 1 and 2).
tension. The immediate physiological
response comprises a rise in heart rate and Prolonged altitude exposure triggers various
pulmonary arterial pressure. Chemoreceptor- acclimatisation mechanisms including an
mediated hyperventilation tends to mitigate increased chemoreceptor sensitivity to
hypoxaemia but the associated hypocapnia hypoxia and hypercapnia, enhanced
with an arterial carbon dioxide tension close erythropoesis and alterations in the endocrine
to the apnoeic threshold promotes ventilatory system, metabolism and in fluid balance.
instability with periods of hyperpnoea
The reduced air density at altitude lowers
alternating with central apnoea/hypopnoea.
airflow resistance. Vital capacity is slightly
This pattern, termed high-altitude periodic
reduced due to respiratory muscle weakness
and pulmonary congestion. Oxygen uptake
Key points through the lungs is affected by a reduced
alveolarcapillary oxygen gradient and a
N A low barometric pressure at altitude reduced transit time of blood through
results in reduced inspired and arterial pulmonary capillaries due to increased cardiac
output. This causes diffusion limitation
oxygen partial pressures.
leading to hypoxaemia especially during
N Hypoxaemia triggers adaptive exercise.
physiological repsonses termed
High-altitude-related disease
acclimatisation.
N Respiratory acclimatissation includes Acute mountain sickness (AMS) is the most
common altitude-related illness. It affects
hyperventilation and periodic
1040% of lowlanders ascending to 3,000 m
breathing, which typically prevails
and 4060% at 4,500 m. A lack of prior
?during sleep.
acclimatisation, rapid ascent, high sleeping
N Acute mountain sickness, high-altitude altitude and individual susceptibility
cerebral oedema and high-altitude predispose to AMS. Symptoms start within
pulmonary oedema may affect 612 h after arrival at altitude and include
travellers after rapid ascent to altitude. headache, loss of appetite, nausea or
Chronic mountain sickness occurs in vomiting, weakness, fatigue and insomnia.
long-term residents of high mountain The diagnosis relies on the constellation of
areas. typical symptoms in the setting of altitude
exposure. Different scores (e.g. the Lake
N Treatment of high-altitude related Louise Score) help to establish the diagnosis
illness consists of descent, and to grade AMS severity. If additional
supplemental oxygen and drugs. neurological signs such as ataxia, cognitive
deficits and impaired vigilance develop, a

Pa,CO2
Pa,O2
Arousal
Hypoxia Hyperventilation Central apnoea Hyperpnoea
Pa,CO2
Pa,O2
Figure 1. Mechanisms of high-altitude periodic breathing.
potentially life-threatening high-altitude 3,500 m but occurs in 24% of mountaineers

cerebral oedema (HACE) must be considered. within hours to 4 days after arrival at
Treatments of AMS include descent to lower 4,500 m. It is promoted by rapid ascent,
altitude, analgesics for headache and physical exertion and individual susceptibility.
acetazolamide. More severe forms of AMS and Manifestations of HAPE include excessive
HACE require dexamethasone and oxygen if dyspnoea, dry cough, tachycardia, cyanosis,
available. Inflatable hyperbaric bags pulmonary crackles and low-grade fever. Chest
simulating descent to 1,5002,500 m are also radiography shows interstitial or alveolar
used. opacities but a normal-sized heart. Descent,
supplemental oxygen or both are nearly
High-altitude pulmonary oedema (HAPE) is a always successful in HAPE. If oxygen is not
noncardiogenic and noninflammatory oedema available or descent not possible,
resulting from excessive elevation of pharmaceuticals become necessary (table 1).
pulmonary capillary pressure, uneven Pulmonary vasodilators such as nifedipine or
distribution of blood flow and impaired phosphodiesterase inhibitors (sildenafil) lower
alveolar fluid clearance. HAPE is rare below pulmonary artery pressure. If descent is
Sum 1L
Rib Cage 1L
Abdomen 1L
Heart rate min-1 140
50
Oxygen sat. % 90
50
Figure 2. Periodic breathing associated with oscillations in oxygen saturation and heart rate recorded in a 28-yr-old
women resting after a climb at 6,850 m. Modified from BLOCH et al. (2010), with permission from the publisher.
High-altitude disease 299

Table 1. Prevention and treatment of high-altitude disease
Disease Prevention Treatment
Acute mountain Acclimatisation Analgesics, antiemetics
sickness (AMS) Slow ascent Acetazolamide 26250 mg?day-1
Acetazolamide 26125-250 mg?day-1, More severe forms: descent
starting 24 h before ascent oxygen 26 L?min-1
or dexamethasone 264 mg?day-1 24 h Dexamethasone (initially mg i.v., then
before ascent 464 mg?day-1 p.o.)
Acetazolamide (26250 mg?day-1),
eventually in combination with
dexamethasone
Portable hyperbaric chamber
High-altitude As for AMS Immediate descent. If not possible:
cerebral oedema Oxygen (26 L?min-1),
(HACE) Portable hyperbaric chamber
Dexamethasone (initially 8 mg i.v., then
464 mg?day-1 p.o.)
Check for accompanying HAPE,
acetazolamide if descent delayed
High-altitude Acclimatisation Immediate descent. If not possible:
pulmonary Slow accent Oxygen 26 L?min-1 until oxygen
oedema (HAPE) Avoid overexertion saturation .90% or hyperbaric chamber
Nifedipine 3060 mg?day-1 (extended- Nifedipine 1020 mg initially, switch to
release formulation) an extended-release formulation
(nifedipine 30/60 mg) depending on
blood pressure
Treat accompanying AMS by
dexamethasone
impossible and oxygen unavailable a exchange, arterial oxygen tension may drop to
hyperbaric bag may be life-saving. low levels at altitude so that the use of
supplemental oxygen should be considered. It
Table 1 summarises prevention and treatment seems reasonable that patients with severe
of altitude related diseases. disease (forced expiratory volume in 1 s ,50%
Chronic mountain sickness, a condition predicted) with an arterial oxygen saturation
observed in long-term high altitude residents, ,95% at low altitude should have an
is characterised by severe hypoxaemia, individual assessment before travelling to
excessive erythrocytosis and pulmonary altitude. Acetazolamide should be used with
hypertension. Affected people suffer from caution in patients with severe airflow
fatigue, dizziness, headache and confusion. obstruction since carbon dioxide retention may
Descent to low altitude leads to prompt relief. lead to worsened dyspnoea or respiratory failure.
Patients with lung disease at altitude Asthma A reduced allergen burden with
increasing altitude can be expected at
Little is known about the risks of altitude
.1,500 m. Conversely, inhalation of cold air
exposure in patients with pre-existing lung
disease. Recommendations are largely based may worsen asthma, especially in combination
on anecdotal evidence. with exercise or hypoxia-induced
hyperventilation. Asthma patients with
Chronic obstructive pulmonary controlled disease are advised to take their usual
disease In patients with impaired gas medications when travelling to altitude, to avoid

strenuous exercise in a cold environment and to Rapid ascent, inappropriate time for
treat any exacerbation appropriately. Patients acclimatisation, strenuous physical exertion
with uncontrolled, severe asthma should be and individual susceptibility predispose to
cautioned against travelling to altitude. high-altitude-related illnesses, which may be
prevented with appropriate precautions.
Obstructive sleep apnoea
syndrome Untreated patients residing at sea- References
level and travelling to moderate altitude
(2,500 m) revealed an exacerbation of sleep
N Basnyat B, Murdoch DR. High-altitude illness.
Lancet 2003; 361: 19671974.
apnoea with pronounced hypoxaemia and N Bloch KE, et al. Nocturnal periodic breathing
frequent central events. Sleep quality was during acclimatization at very high altitude at
worse at altitude and daytime testing revealed Mt. Muztagh Ata (7546m). Am J Respir Crit
impaired vigilance and elevated blood Care Med 2010; Epub ahead of print. DOI:
pressure. Combined treatment with continuous 10.1164/rccm.200911-1694O.
positive airways pressure ventilation and N Imray C, et al. Acute mountain sickness:
acetazolamide seems advisable. pathophysiology, prevention, and treatment.
Prog Cardiovasc Dis 2010; 52: 467484.
Pulmonary hypertension In general, N Luks AM, Swenson ER. Travel to high altitude
with pre-existing lung disease. Eur Respir J 2007;
patients with more than mild pre-existing
29: 770792.
pulmonary hypertension should be counselled
against high-altitude travel because pre-
N Maggiorini M. Prevention and treatment of high-
altitude pulmonary edema. Prog Cardiovasc Dis
existing pulmonary hypertension may 2010; 52: 500506.
predispose to HAPE. In patients not on medical N Nussbaumer-Ochsner Y, et al. Exacerbation of
therapy, prophylaxis with nifedipine and sleep apnoea by frequent central events in
supplemental oxygen should be considered. patients with the obstructive sleep apnoea
syndrome at altitude: a randomised trial. Thorax
Conclusions 2010; 65: 429435.
N Nussbaumer-Ochsner Y, Bloch KE. Lessons from
Physiological adaptation allows humans to high-altitude physiology. Breathe 2007; 4:
tolerate exposure to even very high altitudes. 123132.
High-altitude disease 301

DIVING-RELATED DISEASES
E. Thorsen
University of Bergen, Bergen, Norway
E-mail: einar.thorsen@helse-bergen.no
Professional divers are engaged in underwater that of air at atmospheric pressure, maximal
construction and inspection, and compressed expiratory flow rates and maximal voluntary
air workers (Caisson workers) work at ventilation are reduced by 50%. Most
increased ambient pressure in a dry experimental data are close to this theoretical
environment, mostly in tunnel construction. relationship, as illustrated in fig. 1.
Military forces, police and fire brigades have
When diving to depths .50 m, the gas
teams of divers for specialised underwater
breathed is often a mixture of helium and
operations. Recreational divers make up by far
oxygen to compensate for the mechanical
the largest group of divers. The physical
limitations of ventilatory capacity due to gas
environment in which these divers are density. The partial pressure of oxygen in
operating is different, but common to all these gas mixtures is usually 3050 kPa,
groups is exposure to increased ambient corresponding to a fraction of oxygen of
pressure and the exposure factors associated 25% at depths of o100 m.
with pressure.
Physical work under water is demanding. A
Pulmonary limitations at depth normal ventilatory capacity and physical work
Gas density increases proportionately with capacity evaluated by exercise testing are
required. External resistance and static load
ambient pressure when air is used as the gas
related to breathing apparatus and
breathed. Airway resistance is proportional to
submersion adds to the increased load
gas density and maximal expiratory flow rates
imposed by gas density. The gas breathed at
are inversely proportional to the square root
depth has to be dry to prevent icing in the
of gas density. This means that at a depth of
pressure regulators and evaporative heat loss
30 m, when relative gas density is four times
is high. The gas breathed has the temperature
of ambient water and, because of increased
gas density, convective heat loss is increased.
Key points Subjects with bronchial hyperreactivity may
be at increased risk of bronchoconstriction at
N Normal lung function and physical depth. There are, however, no definite studies
work capacity are required for confirming this risk as subjects with asthma
underwater work. traditionally have been excluded from diving.
N Normal lung function is required to Pulmonary barotrauma
reduce the risk of pulmonary
barotrauma. Intra-alveolar gas volume will expand during
decompression. If there is any obstruction to
N Cumulative diving exposure is the free flow of gas out of the alveoli or a
associated with a long-term reduction decrease in lung compliance, there will be an
in lung function of an obstructive increase in intra-alveolar pressure imposing a
pattern, which at some time in the risk for lung rupture or pulmonary
career may preclude further diving. barotrauma. Any processes in the lung
associated with airway obstruction or

6.0 shown to be common with the decompression

procedures routinely used in commercial and
5.0

military diving operations.

4.0
FEV1 L

The venous gas microemboli are filtered in the

3.0 pulmonary circulation and are associated with

2.0

inflammatory responses that add to toxic

effects of hyperoxia. Venous gas microemboli
1.0 may be shunted over to the systemic
1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 circulation through intrapulmonary and
Relative gas density
intracardiac shunts. A patent foramen ovale is
present in 2030% of the general population.
Figure 1. The theoretical relationship between gas
Local circulatory disturbances due to gas
density and forced expiratory volume in 1s (FEV1:
red line), and some experimental data. The relative bubbles that are either formed in situ or
gas density of air at atmospheric pressure is 1. transported by the systemic circulation to
other areas like joints, skin, brain and spinal
decreased compliance locally or generally are cord may cause decompression sickness.
considered to increase the risk. Lung rupture The combination of added static and dynamic
may cause pneumothorax, respiratory load, immersion and exercise
pneumopericardium, mediastinal emphysema results in a large increase in pulmonary
and most seriously arterial gas embolism, arterial pressure. Undue breathlessness after
which may be fatal. A pneumothorax or diving, or even swimming only, may be related
pneumopericardium encountered at depth to pulmonary oedema.
may be fatal because of an increase in the
transpulmonary pressure difference during Long-term effects of diving
decompression that obstructs venous return. The exposure to hyperoxia and the
The lowest pressure drop associated with accumulation of gas microemboli in the lung
diving causing pulmonary barotrauma are associated with inflammatory responses.
described in the literature was ,20 kPa (or Several cross-sectional studies of divers lung
200 cmH2O). The volume expansion for a function indicate that residual effects of
given pressure reduction is larger close to the single dives accumulate to a long-term effect
surface (BoyleMariottes law). characterised by an obstructive spirometric
pattern and a reduction in diffusion capacity.
Pulmonary effects of a single dive
There are only a few longitudinal studies of
A dive is associated with exposure to divers lung function, but these studies
hyperoxia and a decompression stress, and confirm the findings in the cross-sectional
both are related to ambient pressure and studies by demonstrating a negative
time. Hyperoxia at partial pressures of oxygen relationship between cumulative diving
.40 kPa has well known toxic effects on the exposure and maximal expiratory flow rates
lung causing acute reductions in diffusion and forced expired volume in 1 s.
capacity, vital capacity and maximal References
expiratory flow rates. The decompression
stress is related to the amount of inert gas N Lundgren CEG, Miller JN, eds. The Lung at
dissolved in the tissues during the bottom Depth. New York, Marcel Dekker Inc., 1999.
phase of the dive and the rate of N Brubakk AO, Neumann TS, eds. Bennett and
Elliotts Physiology and Medicine of Diving.
decompression. Supersaturation resulting in Edinburgh, Saunders, Elsevier Science Ltd, 2003.
formation of venous gas bubbles has been N Tetzlaff K, Thorsen E. Breathing at depth:
demonstrated when the tension of inert gas in physiologic and clinical aspects of diving while
the tissues exceeds ambient pressure by breathing compressed gas. Clin Chest Med
,30 kPa. Venous gas microemboli have been 2005; 26: 355380.
Diving-related diseases 303

RADIATION-INDUCED
DISEASE
R.P. Coppes and P. van Luijk
University Medical Center Groningen, University of Groningen, Groningen,
the Netherlands
E-mail: r.p.coppes@med.umcg.nl
Radiotherapy plays an important role in the

treatment of tumours located in the thoracic Key points
area. The cure rate for these tumours is,
however, limited by the low radiation dose N Radiotherapy for tumour treatment
that can be tolerated by the lungs. The results in pulmonary complications in
presently set dose already results in about 20% of patients.
pulmonary complications in about one-fifth of N Radiation-induced lung injury develops
patients. from an early, inflammatory phase to a
Radiation-induced lung injury develops in an late fibrotic phase.
early inflammatory phase termed radiation
pneumonitis (RP) followed by a late fibro-
productive phase (fig. 1). These phases lead Several inflammatory responses contribute to
to compromised lung perfusion, increased RP. Acute alveolar and interstitial
vascular resistance, reduced gas-exchange inflammation and loss of type I epithelial
interphase between air and blood, and induces proliferation of type II epithelial cells.
suboptimal blood oxygenation. Symptoms This leads to a cascade of induction of
range from dyspnoea on effort to respiratory inflammatory cytokines (fig. 1), potentially
failure, oxygen dependency, right heart failure aggravated by chemotherapeutic agents.
and death. Subsequently, an influx of inflammatory cells,
0 5 10 15 20 25 30 35 40
Time after irradiation weeks
Figure 1. Radiation-induced lung injury develops in an early inflammatory and late fibrotic phase. Black line:
pneumonitis; red line: fibrosis; blue line: cytokine response.

such as leukocytes, lymphocytes, neutrophils RF is caused by accumulation of collagen
and macrophages, is induced. Though and other extracellular matrix fibres in the
macrophages are a hallmark, T-lymphocytes interstitium under persistent cytokine stimuli
and matured dendritic cells also play an in combination with arterio-capillary sclerosis.
important role in RP.
References
Radiation-induced lung disease is a
consequence of: N Johnston CJ, et al. Inflammatory cell recruitment
following thoracic irradiation. Exp Lung Res
N loss of type I epithelial and endothelial cells 2004; 30: 369382.
N inflammatory responses
N Marks LB, et al. Radiation-induced lung injury.
Semin Radiat Oncol 2003; 13: 333345.
N malfunction of microvasculature N McBride WH, et al. A sense of danger from
radiation. Radiat Res 2004; 162: 119.
N lung fibrosis. N Novakova-Jiresova A, et al. Changes in
In addition, malfunction of the expression of injury after irradiation of
increasing volumes in rat lung. Int J Radiat
microvasculature due to endothelial injury
Oncol Biol Phys 2007; 67: 15101518.
and subsequent increased permeability with N Novakova-Jiresova A, et al. Pulmonary radiation
protein exudation contributes to the injury: identification of risk factors associated
develoment of RP. Depending on the with regional hypersensitivity. Cancer Res 2005;
irradiated region and volume, the 65: 35683576.
inflammatory response may affect only N Rodemann HP, Bamberg M. Cellular basis of
pulmonary blood vessels (low dose, large radiation-induced fibrosis. Radiother Oncol
volumes) or vessels and parachyma (high 1995; 35: 8390.
dose, low volumes) to induce complications. N Rube CE, et al. Increased expression of
pro-inflammatory cytokines as a cause
Following or even without prior symptomatic of lung toxicity after combined
pneumonitis, chronic radiation-induced treatment with gemcitabine and thoracic
pulmonary fibrosis (RF) may develop irradiation. Radiother Oncol 2004; 72:
depending on the irradiated lung volume. 231241.
Radiation-induced disease 305

CHAPTER 11:
inTERSTiTiAl lung diSEASE
SARCoidoSiS 308
U. Costabel
idioPATHiC inTERSTiTiAl PnEumoniAS 311

EoSinoPHiliC diSEASES 319

A. Menzies-Gow
dRug-induCEd RESPiRAToRy diSEASE 322

Ph. Camus

SARCOIDOSIS
U. Costabel
Dept Pneumology/Allergy, Ruhrlandklinik, Essen, Germany
E-mail: ulrich.costabel@ruhrlandklinik.uk-essen.de
Sarcoidosis is a multisystem granulomatous at the time of diagnosis. Symptoms of

disorder of unknown aetiology, which sarcoidosis are largely nonspecific. Low-grade
commonly affects young and middle-aged fever (sometimes up to 40uC), weight loss
adults. The disease frequently presents with (usually limited to 26 kg during the
bilateral hilar lymphadenopathy, pulmonary 1012 weeks before presentation), night
infiltration, and ocular and skin lesions. Any sweats and arthralgias can be found in about
organ of the body may be involved. The 2030% of patients. Sarcoidosis is an
prevalence rates of Sarcoidosis vary widely, important and frequently overlooked cause of
from ,1 case to 40 cases per 100,000 fever of unknown origin. Fatigue and skeletal
population. Sarcoidosis is common in muscle weakness are more common; present
Scandinavia, Central Europe, the USA and in f70% of patients when carefully looked
Japan. It is less frequently seen in other Asian for. According to their initial presentation,
countries, Central and South America, and sarcoidosis patients can be divided into two
Africa. Sarcoidosis in Afro-Americans is more
severe, while Caucasians are more likely to
present with asymptomatic disease. Overall Key points
mortality is 15%.
The cause of sarcoidosis remains unknown. N Sarcoidosis is a multisystem
Available evidence strongly supports the granulomatous disorder of unknown
hypothesis that the disease develops when a aetiology, which commonly affects
specific environmental exposure with young and middle-aged adults.
antigenic properties occurs in a genetically N Prevalence of sarcoidosis varies from
susceptible individual. Potential aetiologic ,1 case to 40 cases per 100,000
agents include mycobacteria and population, and overall mortality is
Propionibacterium acnes. Sarcoidosis
15%.
susceptibility or chronicity has been
associated with a number of human leukocyte N Clinical presentation varies widely,
antigen alleles. Some genetic associations though fever, fatigue and skeletal
have been found with specific disease subsets, muscle weakness are often noted.
most notably with Lofgrens syndrome. A
polymorphism of the BTNL2 gene has been
N Decision to treat should be carefully
assessed based on benefit to the
linked with sarcoidosis. The immunological
abnormalities are characterised by the patient and disease severity; treatment
accumulation of activated T-cells of the should mainly be considered if
T-helper cell type 1 and macrophages at sites symptoms develop or lung function
of ongoing inflammation. deteriorates.
Clinical presentation N The clinical course of sarcoidosis can be

unpredictable, so regular monitoring of
The clinical presentation of sarcoidosis varies signs of disease progression is advised.
widely. 3050% of patients are asymptomatic

distinct subgroups: acute and chronic. The aspiration, which has the highest yield when
acute form can present as classical Lofgrens guided by endobronchial ultrasound, and with
syndrome, which is characterised by fever, biopsy of the bronchial mucosa. Other easily
bilateral hilar lymphadenopathy, ankle accessible sites for biopsy are the skin, lip, or
arthritis and erythema nodosum. The chronic superficial lymph nodes. In patients without
form shows an insidious onset, and organ- biopsy, clinical and/or radiological features
related symptoms predominate, such as alone may be diagnostic in stage I (reliability
cough, dyspnoea, and chest pain. of 98%) or stage II (89%), but are less
accurate in stage III (52%) or stage 0 (23%).
Diagnostic approach
The classical Lofgrens syndrome may not
The criteria of the American Thoracic Society require biopsy proof. Bronchoalveolar lavage
(ATS), European Respiratory Society (ERS), and studies of lymphocyte subpopulations
and the World Association of Sarcoidosis and showing an increase in the CD4/CD8 ratio
Other Granulomatous Disorders (WASOG) for may be helpful. Elevated serum angiotensin-
the diagnosis of sarcoidosis include: converting enzyme and calcium levels may
lend support to the diagnosis.
N The presence of a consistent clinical and
radiological picture The chest radiogram is described in 4 stages
(table 2). Computed tomography scanning
N Histological evidence of non-caseating describes much greater detail of mediastinal
granulomas and parenchymal abnormalities, but is not an
N Exclusion of other conditions capable of essential of baseline study. It is indicated
producing a similar histological or clinical when clinical presentation and/or chest
radiographic findings are unclear or to detect
picture
complications of the lung disease.
The initial diagnostic work-up for patients with
suspected sarcoidosis involves careful baseline Natural history and prognosis
assessment of disease distribution and The disease course is highly variable.
severity by organ, with emphasis on vital Spontaneous remissions occur in nearly two
target organs (table 1). Specifically, the thirds of patients. Serious extrapulmonary
diagnostic assessment should attempt to involvement (cardiac, central nervous system,
accomplish four goals: hepatic) occurs in 47% of patients at time of
presentation. Incidence becomes higher as the
N Provide histological confirmation of the
disease evolves. Adverse prognostic factors
disease
include lupus pernio, chronic uveitis, age at
N Assess the extent and severity of organ onset .40 yrs, chronic hypercalcaemia,
involvement nephrocalcinosis, African ethnic origin,
progressive pulmonary sarcoidosis, nasal
N Assess whether the disease is stable or is mucosal involvement, cystic bone lesions,
likely to process neural sarcoidosis, cardiac sarcoidosis, and
N Determine whether therapy will benefit a chronic respiratory insufficiency.
patient Treatment and follow-up
Granuloma alone are never diagnostic proof
The indication to treat a patient depends on
of sarcoidosis.
many factors, the most important being
An important step is choice of site for a proper whether or not the patients is symptomatic.
biopsy. Transbronchial lung biopsy is the Except for life- and sight-threatening organ
recommended procedure in most cases, with involvement, it should be carefully considered
the diagnostic yield reaching 80%. This can whether the patient might benefit from
be combined with transbronchial needle treatment. For asymptomatic pulmonary
Sarcoidosis 309
Table 1. Initial evaluation for sarcoidosis For patients with chronic disease requiring
years of therapy, alternatives to corticosteroids
History (occupational and environmental
include methotrexate, azathioprine and
exposure, symptoms)
hydrocloroquine, all given usually in
Physical examination combination with low dose corticosteroids. For
Chest radiography refractory sarcoidosis patients, new therapeutic
Pulmonary function tests: vital capacity, FEV1, approaches have begun to emerge through the
carbon monoxide diffusion capacity use of immuno-modulatory agents. Based on
Peripheral blood counts current understanding of pathogenic
mechanisms, these are tumour necrosis factor-
Serum chemistries: calcium, liver enzymes,
creatinine, ACE
a-blocking drugs, such as infliximab,
thalidomide, and pentoxyfyllin.
Urine analysis
Electrocardiography Because the clinical course of sarcoidosis can
Eye investigation
be unpredictable, regular monitoring for signs
of disease progression is necessary, using the
Tuberculin skin test
least invasive and most sensitive tools. For
Selection of site for biopsy pulmonary sarcoidosis, this is spirometry and
FEV1: forced expiratory volume in 1 s; diffusion capacity. For stable stage I disease,
ACE: angiotensin-converting enzyme. follow-up every 612 months is usually
adequate; more frequent evaluations (every
36 months) are advised for stage II, III or IV
sarcoidosis. All patients should be monitored
patients, a watch-and-wait approach is for a minimum of 3 yrs after therapy is
appropriate; treatment should mainly be discontinued. Follow-up needs to be more
considered if symptoms develop or lung vigilant after corticosteroid-induced
function deteriorates. The goal of treatment is remissions, due to the high rate of relapses in
to make the patient asymptomatic and to this context, ranging 1570%.
restore or preserve organ function. Initial
therapy is still based on corticosteroids. For References
pulmonary sarcoidosis, the initial prednisone
dose is 2040 mg; higher doses may be
N Drent M, Costabel U, eds. Sarcoidosis. Eur Respir
Mon 2005; 32.
needed for cardiac or neural sarcoidosis. The N Grutters JC, et al. Sarcoidosis. In: du Bois RM,
dose is slowly tapered to 510 mg per day; Richeldi L, eds. Interstitial lung diseases. Eur
treatment should be continued for a minimum Respir Mon 2009; 46: 126154.
of 12 months. Patients with Lofgrens N Hunninghake GW, et al., ATS/ERS/WASOG
syndrome do not require therapy with statement on sarcoidosis. Sarcoidosis Vasc
corticosteroids. Diffuse Lung Dis 1999; 16: 149173.
Table 2. Chest radiographic stages

Stage Findings Frequency
0 Normal 510%
I BHL 50%
II BHL and parenchymal infiltrates 25%
III Parenchymal infiltrates without BHL 15%
IV Sign of fibrosis 510%
BHL: bilateral hilar lymphadenopathy

IDIOPATHIC INTERSTITIAL
PNEUMONIAS
Cardiopulmonary Dept, Section of Respiratory Diseases, University
Hospital, Parma, Italy
E-mail: dario.olivieri@unipr.it
Idiopathic interstitial pneumonias (IIPs) prevalence ranges between 2729 cases per
represent a heterogeneous group of disorders 100,000 persons. The disease typically affects
with different clinical and histological adults, peaking after the sixth decade of life,
features and prognoses. They are considered with a higher incidence in males and smokers.
as inflammatory disorders of the interstitium There is a familial variant of idiopathic
without extrapulmonary involvement. pulmonary fibrosis (IPF), which accounts for
0.53% of cases of IIPs; this form is
The most recent American Thoracic Society indistinguishable from the nonfamilial forms,
(ATS) and European Respiratory Society (ERS) except that patients tend to be younger in the
classifications of IIPs include seven different former.
diseases identified by a typical histological
pattern; each histological pattern meets Clinical features and treatment
precise clinical and radiological features and The IIPs include IPF, nonspecific interstitial
corresponds to a particular prognosis. pneumonia (NSIP), cryptogenic organising
Epidemiology pneumonia/bronchiolitis obliterans organising
pneumonia (COP/BOOP), acute interstitial
The incidence of IIPs has been estimated at 7 pneumonia (AIP), respiratory bronchiolitis/
11 cases per 100,000 persons while the interstitial lung disease (RB/ILD),
desquamative interstitial pneumonia (DIP)/
alveolar macrophage pneumonia (AMP) and
Key points lymphoid interstitial pneumonia (LIP) (table 1).
Some of these entities have been well
N IIPs represent a heterogeneous group of
identified clinically, as well as the appropriate
disorders with different clinical and
corresponding treatments. In particular, when
histological features and prognoses. the inflammatory component dominates, such
N The most recent ATS and ERS as in DIP/AMP, AIP and COP/BOOP, prompt
classifications of IIPs include seven corticosteroid therapy may lead to a
different diseases identified by a typical significant improvement and sometimes to
histological pattern: NSIP, COP/BOOP, complete resolution of the disease.
AIP, RB/ILD, DIP/AMP and LIP. LIP and AIP require prompt intervention by
N The terms IPF and NSIP should only be the haematology and intensive care units
used for chronic fibrosing interstitial (ICU) respectively, because of their particular
pneumonia of unknown cause limited onset and the necessity of a specific
therapeutical approach.
to the lungs. The prognosis in IPF is
worse with a histological pattern of UIP. Nowadays the terms IPF and NSIP should be
used only for chronic fibrosing interstitial
Idiopathic interstitial pneumonias 311

Table 1. Classification of idiopathic interstitial pneumonias
IPF/UIP Idiopathic pulmonary fibrosis/usual interstitial pneumonia
DIP/AMP Desquamative interstitial pneumonia/alveolar macrophage pneumonia
RB/ILD Respiratory bronchiolitis/interstitial lung disease
AIP Acute interstitial pneumonia
COP/BOOP Cryptogenic organising pneumonia/bronchiolitis obliterans organising pneumonia
NSIP Nonspecific interstitial pneumonia
LIP Lymphoid interstitial pneumonia
pneumonia of unknown cause limited to the Acute interstitial pneumonia

lungs. This distinction is particularly relevant
because of the different clinical aspects and AIP is a rare fulminating form of lung injury,
therapeutic approaches. Moreover, the with clinical and radiological findings similar
prognosis is worse in these forms and to those seen in acute respiratory distress
particularly in IPF with a histological pattern syndrome (ARDS). The disease evolves
of usual interstitial pneumonia (UIP). through three phases. First the exudative
phase (from the onset to the 7th day) showing
Desquamative interstitial pneumonia/ oedema, hyaline membranes and acute
alveolar macrophage pneumonia interstitial inflammation. The proliferative
DIP is characterised by its insidious onset, phase (30th day) is then characterised by
with a worsening dry cough and progressive hyperplasia of type 2 pneumocytes. Finally,
dyspnoea. There is a strong correlation the organising phase shows loose organising
between this disease and cigarette smoking. fibrosis mostly with type II alveolar septa.
The term desquamative originated from the Hypoxaemia develops early and progresses
belief that the principal histological feature rapidly to respiratory failure, which may be
was desquamation of epithelial alveolar cells; refractory to supplemental oxygen, whereby
in fact, intra-alveolar macrophage AIP requires prompt treatment in the ICU.
accumulation and the presence of Cryptogenic organising pneumonia/
hyperplastic epithelial cells seem to be the bronchiolitis obliterans organising
dominant aspects of the disease. Radiological pneumonia
features include ground-glass opacities with a
lower zone predilection. The pathogenesis is COP/BOOP is a rare form of IIP of unknown
unclear and the clinical course may vary: most aetiology. Features of the organising
patients improve with steroid treatment, but pneumonia pattern are organisation within
some may develop fibrosis. alveolar ducts and alveoli, with or without
organisation in bronchioles. The clinical onset
Respiratory bronchiolitis/interstitial
is aspecific and includes dyspnoea, dry cough,
lung disease
fever and inspiratory crackles. Radiological
This form affects primarily current or former aspects are bilateral diffuse alveolar opacities
smokers, especially males. Symptoms are mild with a lower zone predilection and peripheral
and aspecific. The principal histological predominance. The characteristic
aspect is the presence of clusters of brown histopathological lesion includes an excessive
macrophages in the respiratory bronchioles, proliferation of granulation tissue within small
alveolar ducts and peribronchial alveolar airways and alveolar ducts associated with
space. Usually, smoking cessation leads to a chronic inflammation in the surrounding
complete resolution of the lesions. Steroid alveoli. Systemic steroid therapy is the gold
treatment may be necessary. standard treatment when other causes of

bronchiolitis (i.e. infective bronchiolitis) are mediators are the transforming growth factor
excluded. (TGF)-b, tumour necrosis factor (TNF)-a,
platelet-derived growth factor, connective
Lymphoid interstitial pneumonia tissue growth factor, integrin-mediated
LIP is more common in children than adults. intercellular adhesion molecules, proteases
The aetiology is unknown. Up to three and oxygen radicals. Deficiency of interferon-c
quarters of patients present a monoclonal may contribute to activating and perpetuating
increase in gammaglobulin, whereas in the fibroblastic process. As far as the
childhood hypogammaglobulinemia may histological aspect is concerned, the presence
occur. LIP is associated with Sjogrens of fibroblastic foci is typical in UIP; the
Syndrome in a quarter of cases. LIP is defined fibroblastic foci are formed by mesenchymal
as an interstitial lymphoid infiltrate including cells similar to myofibroblasts. Under the
lymphocytes, plasma cells and histiocytes, influence of TGF-b the cells increase the
with associated type II cell hyperplasia and production of collagen, vimentin and actin,
the presence of interstitial mononuclear cells leading to an excessive deposition of
and the formation of noncaseating extracellular matrix.
granulomas. In LIP the infiltrate is In the rare familial form, the transmission
characterised by the presence of polyclonal mode is unknown. It is likely to be autosomal
lymphocytes (T and B); by contrast, in the dominant with variable penetration in two
lymphomas the infiltrate is usually thirds of patients. Familial IPF has been
monoclonal. Radiological aspects are bilateral associated with altered a1-antitrypsin inhibitor
interstitial linear or nodular opacities; alleles on chromosome 14. Genetic
honeycombing may appear in the advanced polymorphism for interleukin (IL)-1 receptor
phase of the disease. Spontaneous resolution antagonists or TNF- a may be involved.
is possible, but steroid and/or
immunosuppressive therapy may be necessary. Physiology The physiological aberrations in
IPF are typical of a restrictive pattern and
Idiopathic pulmonary fibrosis/usual include reduced lung volumes (vital capacity
interstitial pneumonia and nonspecific and total lung capacity), and normal or
interstitial pneumonia increased expiratory flow rates. Transfer factor
of the lung for carbon dioxide (TL,CO) is
Pathogenesis The pathogenetic typically reduced, indicating damage to the
mechanisms of IPF (pattern UIP) and NSIP are interstitium causing impaired gas exchange. A
not completely clear. There are various further consequence of this alteration is
hypotheses relative to the initial stimulus hypoxaemia, which is exacerbated with
responsible for the pathogenetic process, such exercise. Late in the course of the disease
as exposure to toxic substances or viral severe hypoxaemia may be observed also at
infections. Regardless of the initial cause, the rest; hypercapnia may be present as well.
inflammatoryfibrotic process in UIP is
characterised by injury to the alveolar Clinical features and diagnosis The
epithelial cells, destruction of the initial insidious symptoms of IPF/UIP and NSIP
subepithelial basement membrane, and the are an insistent nonproductive cough and
subsequent abnormal cicatrisation with progressive dyspnoea. In most patients,
increased fibroblastic response and excessive physical examination reveals end-inspiratory
deposition of collagen and extracellular matrix. crackles (velcro-type). The course of the
disease may vary, in relation to the types of
The interplay between inflammatory and IIP. As far as UIP is concerned, prognosis is
mesenchymal cells is regulated by a number extremely severe; the course of the disease is
of cytokines produced by fibroblasts and rapid, even if some patients stabilise after an
epithelial cells; the most important of these initial period of decline. Respiratory failure

appears in 38 yrs and mean survival from and objective follow-up of the disease. HRCT
the onset of the disease is approximately 35 scans consistent with IIP represent one of the
yrs. During the late phases of the disease, major ATS/ERS guidelines diagnostic criteria.
patients often show cor pulmonale. In particular, the HRCT scans in the case of
Respiratory failure is the main cause of death, UIP show a heterogeneous distribution with
followed by pulmonary embolism and predilection for the peripheral, especially
heart failure. subpleural and basilar regions of the lung.
The main radiological feature in UIP is
Diagnosis of IPF and NSIP is the result of an honeycombing, that is cystic radiolucencies as
integrated and multidisciplinary process, expression of severe and irreversible fibrotic
requiring cooperation among clinicians, conversion of the parenchyma. Secondary
radiologists and pathologists. International features include coarse reticular opacities,
guidelines state that histology is necessary for thickened bronchial walls, bronchiectasis and
diagnosis. A surgical lung biopsy has a higher bronchioloectasis.
diagnostic value compared to a transbronchial
biopsy or bronchoalveolar lavage. However, it NSIP is characterised by the presence of
is an invasive approach with potential risks, ground-glass areas, signifying an active
and sometimes patients may present clinical inflammatory process. The main aspects to be
and physiological contraindications to surgery. considered for differential diagnosis between
In some cases, an acute exacerbation of the UIP and NSIP are the geographic and
disease follows surgery, leading to a temporal histological and radiological
general decline. heterogeneity, the high concentration of
fibroblastic foci and honeycombing in the
The most recent ATS/ERS guidelines present UIP form.
new clinical diagnostic criteria, which increase
the likelihood of a correct diagnosis of IPF in Natural history and exacerbations The
the immunocompetent adult, in the presence course of the disease is characterised by a
of all the major criteria as well as at least progressive decline in pulmonary function,
three minor criteria, even without histological leading to a worsening general condition and
data (table 2). ultimately death. A subset of patients,
particularly in cases of UIP, develops an
High resolution computed tomography accelerated and usually fatal course, showing
(HRCT) has become a crucial tool for the an extremely rapid decline; this condition is
diagnostic process and allows an accurate known as an acute exacerbation.
Table 2. American Thoracic Society/European Respiratory Society criteria for diagnosis of IPF
Major criteria
Exclusion of other known causes of IIP (environmental/professional exposures, drug toxicities,
connective tissue diseases)
Abnormal lung function: restrictive pattern and impaired gas exchange
Bibasilar reticular abnormalities and ground glass opacities on HRCT scans
Transbronchial lung biopsy or BAL not consistent with other diseases
Minor criteria
Age .50 yrs
Duration of illness .3 months
Insidious onset of dyspnoea on exertion
Bibasilar inspiratory crackles (velcro-type)

The criteria for defining an exacerbation are: which were considered first-line drugs. Later,
cytotoxic and immunosuppressive agents were
N progressive dyspnoea during the last 30 days used, usually in combination with
N new pulmonary infiltrates in chest corticosteroids.
radiographs
The most recent revelations from the
N worsening of hypoxaemia with a reduction pathogenetic field identify the initial phase of
in oxygen partial pressure .10 mmHg the disease as injury to the alveolar epithelial
N absence of pulmonary infection supported cells and destruction of the subepithelial
by negative bronchoalveolar lavage (BAL) basement membrane, leading to abnormal
wound healing with a vigorous fibroblastic
N absence of any other cause, such as heart response and excessive deposition of collagen
failure, pulmonary embolism or conditions and extracellular matrix. This new
which may cause acute lung damage. pathogenetic theory suggests a primary role
Diagnosis of exacerbation may be for fibroblast deregulation. Thus, the
controversial, despite the codification of the fibroproliferative process became the
diagnostic criteria; ground-glass opacities are therapeutic target, and new drugs which
not specific for IPF and NSIP and may be arrest the proliferation of fibroblasts and the
present in cases of infection. Nonintubated depostition of extracellular matrix are being
patients in the acute phase of the disease testing.
often cannot undergo BAL because of their Established treatment Corticosteroids
unstable conditions and they are treated with have been considered the mainstay of IPF
antibiotics for precautionary measure. Lung treatment for decades, although there are no
biopsy shows diffuse alveolar damage, randomised placebo-controlled trials using
however the invasiveness of the procedure is a corticosteroids alone. The ATS/ERS international
limiting factor and only few well-selected consensus statement concludes that existing
patients undergo surgical lung biopsy. It is our therapies are of unproven benefit.
duty to mention the correlation between
surgical lung biopsy or lung resection and
In the past, high doses of prednisone or
acute exacerbation, however unclear, as far as
prednisolone (1 mg?kg-1?day-1), considering
causality is concerned. Risk factors involved in
ideal body weight) for 46 weeks, with a
this accelerated phase may be a high
gradual taper, were used. Given the high risk
concentration of oxygen (100%),
of systemic side-effects and the significant
hyperexpansion of the lung parenchyma and
toxicity, especially when in combination with
the use of mechanical ventilation in the post-
other drugs, the dose has been re-evaluated,
operative phase.
and more recent therapeutic regimens
Generally, the factors responsible for the recommend low doses of prednisone or
exacerbations are still unknown; clinical prednisolone (0.5 mg?kg-1?day-1 for 4 weeks,
presentation in some patients (fever, influenza- followed by 0.25 mg?kg-1?day-1 for 8 weeks,
like symptoms, neutrophilia in BAL) may be then 0.125 mg?kg-1?day-1). The rate of taper
consistent with a viral infection, however the depends on the patients individual
pathogen has not been identified. characteristics. In the case of responders with
clinical and radiological improvement,
Treatment Poor understanding of the prolonged maintenance therapy with low
pathogenetic mechanisms underlies the dose alternate-day prednisone may be
ineffectiveness of the current treatment prescribed to reduce the chance of
options. Initially, a pathogenetic theory recrudescent disease.
considered IPF and NSIP as inflammatory
processes justifying the use of anti- In case of exacerbation, 2 mg?kg-1?day-1 of
inflammatory drugs, such as corticosteroids, methylprednisolone for ,14 days should be

administered, depending on individual clinical is rarely used for IIP treatment and its use is
response. The rapid decline of pulmonary limited for selected patients awaiting a lung
function may lead to important respiratory transplant. There are no clinical trials showing
failure; accordingly, patients require that cyclosporine therapy is beneficial.
supplemental oxygen and noninvasive
positive pressure mechanical ventilation. In Novel therapeutic strategies Interferon
the most severe cases, intubation may be (IFN)-c-1b is a novel biological antifibrotic
necessary. drug with a number of inhibitory effects on
fibroblasts. In the literature there are only few
Azathioprine and cyclophosphamide are the studies relative to the real efficacy of IFN-c,
most frequently used second-line drugs, alone either alone or in combination therapy with
or in combination with corticosteroids. low dose corticosteroids.
Azathioprine is the most frequently used
cytotoxic agent and usually is well tolerated. Colchicine inhibits the synthesis of collagen
Its metabolism leads to the production of and suppresses growth factors that are
mercaptopurine, similar to purine, which necessary for fibroblast proliferation. On the
inhibits DNA synthesis. Azathioprine is basis of these properties, the use of this drug
administered per os, usually in combination is being tested. Data are limited, although
with low-dose corticosteroids; initial dose is there is no evidence that colchicine improves
2550 mg?day-1 (23 mg?kg-1?day-1). If the progression of the disease and survival.
adverse effects do not appear, an increase of
25 mg every 714 days is recommended, until D-Penicillamine is a thiolic compound which
a maximum dose of 150 mg?day-1 is reached. interferes with collagen turnover. Indeed, it
There are no clinical trials which confirm a inhibits collagen synthesis and deposition by
certain benefit of combination interrupting cross-linking of collagen
(corticosteroids+azathioprine) therapy. Given molecules. There are no controlled clinical
the minor toxicity compared to trials showing any benefit of D-penicillamine
cyclophosphamide, azathioprine should be therapy. Given the frequent adverse effects,
administered in patients with symptomatic or D-penicillamine does not appear to be a
progressive disease for 6 months unless treatment choice in IIPs.
adverse effects which suggest interruption or
modification of the treatment appear. Pirfenidone (5-methyl-1-phenyl-2[1H]-
pyridone) attenuates pulmonary fibrosis in
Cyclophosphamide is usually used as a animal models. It reduces synthesis of
second-line drug for patients who have collagen (I and III) and TNF-a, and inhibits
presented adverse effects to high-dose TGF-b-stimulated collagen synthesis.
corticosteroid therapy. The route of Moreover, it decreases synthesis of the
administration is usually oral or intravenous, extracellular matrix and blocks the mitogenic
but it can also be administered by effect of profibrotic cytokines.
intramuscular injection. Generally,
cyclophosphamide is used in combination Experimental models in vitro and in vivo
with low-dose corticosteroids. Scientific showed that angiotensin-converting enzyme
evidence confirming the efficacy of inhibitors (ACEI) and statins possess antifibrotic
cyclophosphamide in the treatment of IPFs is properties. However, there is no evidence of
lacking; no clinical benefit regarding survival improved survival in treated patients.
and progression of the disease has been
There is evidence that the production of
reported.
oxidative agents increases in IIP. In particular,
Cyclosporine is a fungus-derived peptide neutrophils, macrophages and fibroblasts
which exerts potent immunosuppressive release oxidative agents, such as reactive
effects; it inhibits lymphocyte T proliferation oxygen species (ROS), hydrogen peroxide
by inhibiting the release of IL-2. Cyclosporine (H2O2) and superoxide anion. These factors, in

addition to the reduction of antioxidants, The typical fibroproliferative process in IPF
facilitate fibroblast deregulation and deposition seems to be related to inflammation and
of extracellular matrix. N-acetylcysteine (NAC) is vascular injury. Indeed, endothelium damage
derived from the amino acid cysteine. It is causes exposition of the intimale tissue to
considered a precursor of glutathione (GSH) circulation, thereby inducing thrombotic
and it stimulates GSH synthesis. GSH has strong events. Pulmonary embolism is one of the
antioxidative properties, as it removes free most common causes of death in IPF patients
oxygen radicals and decreases H2O2. The route and D-dimer levels often increase during
of administration is oral at a dose of exacerbation of the disease. Recently, the role
1,800 mg?die-1 and only in association with of thrombotic events in the natural history of
conventional therapy with corticosteroids and the disease and survival in IPF patients has
azathioprine. A significant difference in the rate been evaluated. Patients treated with warfarin
of decline of FVC and TL,CO has been described added to corticosteroids had significantly
in patients treated with NAC, even if no higher survival after exacerbation when
difference was observed in mortality. compared to patients treated with
Endothelin (ET)-1 is a potent mitogen for corticosteroids alone. D-dimer levels and
endothelial and smooth muscle cells. ET-1 is number of days free of exacerbation did not
strongly upregulated in patients with IPF and is differ between the two groups. The
mainly expressed in epithelial cells. Some mechanisms underlying increased survival are
studies have suggested that inhibition of ET-1 unclear. Certainly extravascular deposition of
could have antifibrotic effects. Bosentan is a fibrin and thrombotic events play main roles
non-selective ET(A) and ET(B) receptor in the fibroproliferative process and acute
antagonist which is used in patients with lung injury. Hence, anticoagulant therapy may
pulmonary hypertension and it could delay the be considered as an important additional
progression of IPF. However, in the treatment of therapeutic support in IIP treatment.
IPF, clinical trials have been disappointing.
Lung transplantation Lung
TNF-a antagonist etanercept has been found transplantation is the only option which
to be significantly elevated in bleomycin- definitely improves survival in IPF patients
induced pulmonary fibrosis (BIPF). TNF-a and the only option for patients refractory to
stimulates a series of cytokines, such as TGF-b, medical therapy. IIPs represent the second
IL-5 and modifies eosinophil recruitment in the most frequent disease which requires lung
parenchyma. Both antibodies anti-TNF-a and transplantation. It is extremely important to
TNF-a soluble receptor antagonists have been decide when to list a patient for
found to reduce fibrotic processes in animals. transplantation. Given the legal complexity of
Table 3. International Society for Heart and Lung Transplantation guidelines

For referral
Radiographic or histological evidence of UIP irrespective of vital capacity
Histological evidence of fibrotic NSIP
For listing
Radiographic or histological evidence of UIP and any of the following: TL,CO ,39% predicted; .10%
reduction in FVC in the last 6 months; oxygen saturation ,88% during 6MWT; honeycombing on HRCT
(fibrosis score .2)
Histological evidence of NSIP and any of the following: TL,CO , 35% predicted; .10% reduction in
FVC or .15% in TL,CO in the last 6 months
DL,CO: transfer factor of the lung for carbon dioxide; FVC: forced vital capacity; 6MWT: 6-min walk test.

the process, early listing is urged. Recently, the N Hospenthal MA. Diagnosis and management
International Society for Heart and Lung of idiopathic pulmonary fibrosis: implications
Transplantation published guidelines for for respiratory care. Respir Care 2006;
establishing the characteristics and the criteria 51: 382391.
for transplantation and listing (table 3).
N Hyzy R, et al. Acute exacerbation of
idiopathic pulmonary fibrosis. Chest 2007;
132: 16521658.
Unfortunately, many patients die while N Kubo H, et al. Anticoagulant therapy for
awaiting a transplant because of the poor idiopathic pulmonary fibrosis. Chest 2005; 128:
availability of donor organs. Post-operative 14751482.
mortality in transplanted patients is high, N Noble PW, Hormer RJ. Idiopathic pulmonary
because of rejection, infections and other fibrosis: new insights into pathogenesis. Clin
complications. Two- and 5-yr survival rates Chest Med 2005; 25: 749758.
following single lung transplants are
N Noth I, Martinez FJ. Recent advances in
idiopathic pulmonary fibrosis. Chest 2007; 132:
approximately 70% and 50%, respectively. 637650.
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agent for the treatment of pulmonary arterial
N American Thoracic Society, Idiopathic hypertension. Int J Clin Pract 2004; 58: 6973.
pulmonary fibrosis: diagnosis and treatment. N Orens JB, et al. Pulmonary Scientific Council of
International consensus statement. Am J Respir the International Society for Heart and Lung
Crit Care Med 2000; 161: 646664. Transplantation. International guidelines for the
N American Thoracic Society/European Respiratory selection of lung transplant candidates: 2006
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interstitial lung diseases. Respiration 2004; 71: N Raghu G, et al. Azathioprine combined with
209213. prednisone in the treatment of idiopathic
N Coultas DB, et al. The epidemiology of pulmonary fibrosis: a prospective, double-blind
interstitial lung diseases. Am J Respir Crit Care randomized, placebo-controlled clinical trial. Am
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N Demedts M, et al. High-dose acetylcysteine in N Richeldi L, et al. Costicosteroids for idiopathic
idiopathic pulmonary fibrosis. N Engl J Med pulmonary fibrosis. Cochrane Database Syst Rev
2005; 353: 22292242. 2003; 3.

EOSINOPHILIC DISEASES
A. Menzies-Gow
Royal Brompton and Harefield NHS Foundation Trust, London, UK
E-mail: a.menzies-gow@rbht.nhs.uk
The exact role of the eosinophil has yet to be

determined. It is believed to play a role in Key points
combating helminthic parasitic infections and,
in health, eosinophils primarily reside within N Eosinophilic lung disease covers a wide
the gastrointestinal mucosa. Eosinophilic lung spectrum of pathology from airways to
diseases cover a wide spectrum of pathology parachymal lung disease.
ranging from airways disease, such as
eosinophilic bronchitis, to parenchymal
N Always exclude secondary causes of
disease, such as eosinophilic pneumonia, and eosinophilia before diagnosing acute or
also systemic diseases, such as the hyper- chronic eosinophilic pneumonia.
eosinophilic syndrome. N Novel therapies are being introduced
for eosinophilia including tyrosine
Nonasthmatic eosinophilic bronchitis kinase inhibitors and monoclonal
antibodies against interleukin 5.
Eosinophilic bronchitis is a common and
treatable form of chronic cough that was first
identified in 1989. Nonasthmatic eosinophilic
bronchitis is a condition that presents with a
corticosteroid-responsive chronic cough in
nonsmokers. These patients have evidence of
eosinophilic airways inflammation without the bronchitis, mast cells infiltrate the airway
variable airflow obstruction or airways epithelium leading to bronchitis and cough.
hyperresponsiveness characteristic of asthma.
Anti-inflammatory therapy with inhaled
Eosinophilic bronchitis accounts for 1030% corticosteroids is the mainstay for the
of cases of chronic cough referred for treatment of eosinophilic bronchitis. Inhaled
specialist investigation. Eosinophilic bronchitis corticosteroids produce a significant
is defined as a chronic cough in patients with improvement in symptoms as well as a fall in
no symptoms or objective evidence of airflow sputum eosinophilia. There is no evidence to
obstruction, a histamine/methacholine suggest that any one inhaled corticosteroid is
provocative concentration causing a 20% fall more effective. Data is also not available to
in forced expiratory volume in 1 s of guide the dose or duration of inhaled
.16 mg?mL-1 and .3% sputum eosinophilia. corticosteroid therapy. Logically,
antileukotrienes may be of benefit, but this
It is unclear why eosinophilic inflammation hypothesis has not been tested in clinical
leads to asthma in some individuals and trials. In very resistant cases, oral
eosinophilic bronchitis in others. Studies by corticosteroids may be required for symptom
BRIGHTLING (2006) suggest that the key may control.
be mast cell localisation. In asthmatics, mast
cells infiltrate airways smooth muscle, Little is known about the natural history of
resulting in airflow obstruction and the condition, but it can be transient, episodic
hyperresponsiveness. In eosinophilic or persistent unless treated.
Eosinophilic diseases 319

Acute and chronic eosinophilic
pneumonia
Acute eosinophilic pneumonia presents as an
acute febrile illness of ,5 days duration. The
average age at presentation is 30 yrs with
symptoms of dyspnoea, cough, myalgia and
fevers. Patients often present with severe type
I respiratory failure requiring ventilation.
Unlike other pulmonary eosinophilic
syndromes, the blood eosinophil count is
usually normal. The chest radiograph
demonstrates diffuse alveolar and interstitial
infiltrates. The diagnosis is confirmed by the
presence of a bronchoalveolar lavage
eosinophilia of .25% in the absence of
parasitic, fungal or other infections and no
history of drug hypersensitivity. Acute
eosinophilic pneumonia responds quickly to
oral corticosteroids with no relapse after
stopping therapy. Figure 1. Chest radiograph of patient presenting
Chronic eosinophilic pneumonia typically with chronic eosinophilic pneumonia demonstrating
presents in middle-aged asthmatic women, the characteristic peripheral infiltrates.
but it can also develop in nonasthmatic
individuals. The symptoms are gradually investigations are not performed prior to
progressive and include shortness of breath, starting steroids.
cough, fever and weight loss. Clinical Both acute and chronic eosinophilic
examination demonstrates wheezing and pneumonia are idiopathic conditions. It is
hypoxia. Patients usually have a raised blood important to exclude secondary causes of
eosinophil count at the time of an acute eosinophilia before diagnosing either
exacerbation along with elevated condition. In clinical practice, this requires a
inflammatory markers. The majority of careful travel history asking about residence in
patients have infiltrates visible on chest areas of endemic parasitic infection and a
radiograph, and they are peripherally careful drug history including illicit
distributed in about two-thirds of cases substances. The other main causes of a
(fig. 1). pulmonary eosinophilic syndrome are as
High-resolution computed tomography is follows: allergic bronchopulmonary
more sensitive at demonstrating infiltrates aspergillosis, the hypereosinophilic syndrome,
and ,50% of patients also have mediastinal and ChurgStrauss syndrome, which should
adenopathy. Patients respond well to oral also be excluded at the time of diagnosis.
corticosteroids, but tend to relapse on Hypereosinophilic syndrome
discontinuation of therapy. Many patients
require long-term, low-dose oral corticosteroids The hypereosinophilic syndrome (HES) is a
to control the condition; in a small minority, heterogeneous group of disorders
alternative steroid-sparing agents have been characterised by the presence of marked
used. This condition is frequently blood and tissue eosinophilia resulting in a
misdiagnosed as asthma. Blood eosinophilia variety of clinical manifestations. The
and pulmonary infiltrates respond to following criteria are used to define idiopathic
corticosteroids within 2448 h, making it HES: 1) blood eosinophilia .1,500?mm-3 for
easy to miss this condition if the relevant o6 months; 2) absence of an underlying

cause for the eosinophilia; and 3) end-organ had a poor prognosis with poor steroid
damage due to the eosinophilia. responsiveness. The use of the tyrosine kinase
inhibitor, imatinib, in this group of patients
Idiopathic HES can occur at any age, but
has significantly improved their outcome.
tends to develop in the fourth or fifth decade
of life, with a male predominance. Nonspecific The lymphoproliferative variant is a
systemic symptoms are common. More consequence of increased production of
specific symptoms will depend upon which eosinophilopoietic cytokines by clonal
organs are affected. The lungs are involved in populations of phenotypically abnormal,
,40% of patients, leading to cough and activated T-lymphocytes. Identification of
airflow limitation. Pulmonary function tests interleukin-5 (IL-5) as a key mediator of
demonstrate an obstructive pattern in patients eosinophilopoiesis led to the use in clinical
with cough. In patients with cardiac trials of an anti-IL-5 monoclonal antibody
involvement, concomitant pulmonary fibrosis (mepolizumab) for HES. Mepolizumab is an
can occur leading to a restrictive or mixed effective corticosteroid sparing agent in
pattern. The chest radiograph can be normal patients with HES negative for FIP1L1/
or demonstrate spontaneously clearing PDGFRA.
airspace shadowing in early disease. At a later
stage with multi-organ involvement, up to References
one-third of cases will have diffuse, N Allen J. Acute eosinophilic pneumonia. Semin
nonsegmental interstitial infiltrates. Respir Crit Care Med 2006; 27: 142147.
The most important cause of morbidity and N Brightling CE. Chronic cough due to
nonasthmatic eosinophilic bronchitis: ACCP
mortality in idiopathic HES is cardiovascular
evidence based clinical practice guidelines.
involvement. Thromboembolic disease and Chest 2006; 129: 116S121S.
involvement of the nervous system are also N Klion AD, et al. Approaches to the treatment of
common presentations. hypereosinophilic syndromes: a workshop
Until recently, oral corticosteroids have been summary report. J Allergy Clin Immunol 2006;
117: 12921302.
the mainstay of treatment. Better
understanding of eosinophil biology has led
N Marchand E, Cordier JF. Idiopathic chronic
eosinophilic pneumonia. Semin Respir Crit Care
to the use of more logical targeted therapies. Med 2006; 27: 134141.
Distinct HES subtypes are now recognised. N Rothenberg ME, et al. Treatment of patients with
The myeloproliferative variant is associated the hypereosinophilic syndrome with
with the presence of a fusion tyrosine kinase, mepolizumab. N Engl J Med 2008; 358:
FIP1L1/PDGFRA. These patients historically 12151228.
Eosinophilic diseases 321

DRUG-INDUCED
RESPIRATORY DISEASE
Ph. Camus
Dept of Pulmonary & Intensive Care, UMC Dijon Bocage, Dijon, France
E-mail: ph.camus@chu-dijon.fr
Drug-induced and iatrogenic respiratory

Key points disease (DIRD) is a classic, not uncommon
and often unpredictable complication of
N DIRD is not uncommon and is exposure to therapy drugs, including the novel
multifaceted, with involvement of the biological kinase inhibitors gefitinib, erlotinib,
airways, lung, pleura, pulmonary imatinib, dasatinib and monoclonal antibody
circulation and neuromuscular system. therapy, irradiation, abused substances, herbal
therapy and vaccines. The diagnosis of DIRD
N Chemotherapy agents, amiodarone, is one of exclusion (table 1), and aetiologies
ACE inhibitors, NSAIDs and b-blockers other than the drug or drugs must be ruled
in particular pose the risk of adverse out, particularly an infection due to
respiratory effects. Pneumocystis jiroveci or other opportunistic
N The clinical and imaging expression of pathogens. Patients exposed to methotrexate,
DIRD closely resembles that of illnesses anti-tumour necrosis factor (TNF) agents,
of other causes or that occur immunosuppressive drugs, chemotherapy
agents and rituximab are at risk of developing
idiopathically. Pathology is rarely
opportunistic infections, and further tests are
specific for the drug aetiology.
required to rule out an infection in such
N Diagnosing DIRD requires a high patients.
degree of awareness, up-to-date
DIRD is probably under-reported. Incidence is
knowledge and ruling out of other
greater with chemotherapy agents (up to
causes, particularly infection.
40% depending on which drug regimen is
N Stopping the drug is often followed by used and which test is used to diagnose the
improvement in symptoms and condition) or amiodarone or methotrexate
imaging. However, this should be done (12% per year) compared with other drugs.
carefully to avoid relapse of the under- With most of the other 400 or so drugs known
lying condition for which the drug was to cause respiratory injury, DIRD is
given. uncommon.
N Corticosteroid therapy is reserved for The respiratory system includes the lung,
severe cases and where dechallenge airways, pulmonary circulation, pleura,
does not produce measurable haemoglobin and neuromuscular system.
improvement. Duration of corticosteroid Each of these can be the target of drug-
therapy varies with drug and pattern of induced injury, causing varied imaging
patterns of involvement (table 2).
involvement.
N Generally, rechallenge with the drug is Accordingly, DIRD can occur in the form of
discouraged as severe relapse of DIRD interstitial lung disease (ILD), where drugs
may account for 3% of ILD cases, upper
can occur.
airway obstruction (UAO), bronchospasm or

bronchiolitis obliterans, pulmonary management of the airway and of respiratory
hypertension, pleural effusion or thickening, failure and early drug withdrawal are
impaired oxygen carrying capacity of warranted. A maintained list of drugs and
haemoglobin and reduced inspiratory muscle patterns of drug-induced respiratory
force. Potentially severe DIRD includes acute involvement is available on the Pneumotox
angioedema from angiotensin-converting website at www.pneumotox.com.
enzyme (ACE) inhibitors, catastrophic
Pathophysiology: mechanisms
bronchospasm from nonsteroidal
antiinflammatory drugs (NSAIDs), b-blockers Drug-induced ILD is characterised by homing,
or aspirin, acute methotrexate pneumonitis or proliferation and persistence of immune-
minocycline-induced eosinophilic pneumonia, effector cells including eosinophils in lung
pulmonary oedema from tocolytic agents or tissue. This causes pulmonary shadowing,
chemotherapy drugs, anticoagulant-induced increases in bronchoalveolar lavage (BAL)
diffuse alveolar haemorrhage, large-volume cells and hindrance to gas exchange.
pleural effusion and acute Corticosteroid therapy usually quenches drug-
methaemoglobinemia and drug-induced induced pulmonary inflammation and is
neuromuscular acute respiratory failure. These followed by improvement in symptoms and
drug-induced complications portend imaging. Rechallenge with the causal drug
immediate severity and may have fatal often but not always produces relapse of
consequences. In such cases, prompt DIRD. The mechanisms for drug-induced cell
recognition of the drug aetiology, emergent influx are generally unknown.
Table 1 . Checklist for diagnosing drug-induced respiratory disease

1. Maintain a high degree of awareness of drug-induced disease vis a` vis any new respiratory sign and
symptom if not explained otherwise. Use Pneumotox website as needed#
2. Record medical history including history of exposure to drugs, radiation and substances of abuse
3. Evaluate the possibility or likelihood of pulmonary involvement from an underlying condition if present
4. Retrieve pre-therapy imaging and pulmonary function data. Compare with present tests
5. Review timing of exposure to drug versus onset of symptoms (minutes to years, depending on drug and
pattern)
6. Try to define pattern of injury in the most conservative way (lung biopsy can be risky; pathology may
show nonspecific findings)
7. Evaluate drug causality, taking into account each drug taken in isolation. Correlate with pattern of
involvement#
8. Evaluate the likelihood of disease caused by drug versus underlying condition, (an opportunistic
infection, other drugs, or incidental disease) using the above and BAL
9. In vitro tests of mononuclear cell migration are cumbersome and none has yet proved useful
10. Evaluate literature pertaining to the specific drug or pattern of involvement#
11. Dicontinue drug, patient condition permitting. This may not be followed by improvement in patients
with acute disease. Check whether the underlying illness needs a substitute drug
12. Evaluate whether corticosteroid therapy is indicated (depending on drug, severity, pattern and effect of
drug discontinuance)
13. Organise appropriate follow-up including imaging and pulmonary physiology
14. Discuss rechallenge only if no other drug available to treat the patients condition. Otherwise avoid
BAL: bronchoalveolar lavage; #: match drug and pattern using Pneumotox website.
Drug-induced respiratory disease 323

Table 2. Main imaging pathological patterns of drug-induced infiltrative lung disease
Pattern on chest Causal drugs Pathology correlate
radiograph or CT
Diffuse haze or ground-glass Drugs that cause interstitial Interstitial inflammation, cellular
opacity pneumonia# interstitial pneumonia
Chemotherapy agents Early/mild pulmonary oedema, alveolar
haemorrhage or DAD
Localised ground-glass Radiation therapy# Early or mild radiation lung injury
opacity (interstitial oedema, cell sloughing, cell
debris)
Diffuse white-out white Drugs that produce acute ILD, Dense cellular interstitial pneumonia
lungs pulmonary oedema, DAD, with or without tissue eosinophilia.
eosinophilic pneumonia or Acute pulmonary oedema. DAH
DAH#
Disseminated areas of Drugs that cause interstitial Cellular interstitial pneumonia. DIP
ground-glass with a mosaic pneumonia#
pattern of distribution
Bilateral perihilar alveolar Drugs causing pulmonary Pulmonary oedema, DAD, DAH
opacities with a batwing oedema, DAD or DAH#
pattern of distribution
Multiple subpleural areas of Drugs causing pumonary Eosinophilic pneumonia, BOOP
condensation eosinophilia or BOOP. Statins#
Opacities with a Amiodarone# Phosphoilipidosis, organising pneumonia
recognisable segmental or Statins #
BOOP
lobar pattern of distribution
Paraffin# Exogenous lipoid pneumonia
Diffuse miliary pattern BCG therapy, methotrexate, Granulomatous reaction"
sirolimus#
Area of condensation. Drugs causing BOOP or BOOP, eosinophilic pneumonia
A mass eosinophilic pneumonia#
Amiodarone Phospholipidosis, APT features,
amiodaronoma
Paraffin Paraffinoma
Wandering opacities Drugs which cause organising BOOP, eosinophilic pneumonia
or eosinophilic pneumonia#
Irradiation for breast BOOP
carcinoma#
Multiple nodular opacities Amiodarone# APT features
#
Bleomycin BOOP
Areas of nodular fibrosis
Pulmonary fibrosis. Chemotherapy agents. Pulmonary fibrosis. UIP pattern
Low lung volumes Amiodarone. Nitrofurantoin.
Irradiation
CT: computed tomography; DAD: diffuse alveolar damage; ILD: interstitial lung disease; DAH: diffuse alveolar
haemorrhage; DIP: desquamative interstitial pneumonia pattern; BOOP : bronchiolitis obliterans organising
pneumonia; APT: amiodarone pulmonary toxicity; UIP: usual interstitial pneumonia; #: see appropriate pattern on
Pneumotox website; ": interferons and anti-tumour necrosis factor agents may produce a mimic of sarcoidosis.

With some drugs (chemotherapy agents, and the herbicide paraquat can generate reactive
drugs that cause pulmonary oedema or oxygen species, which attack cell constituents
bronchospasm), the respiratory reaction is and deplete reducing equivalents. This may
dose dependent. Above a certain drug lead to cell death and consequent pulmonary
dosage, most patients exhibit some form of inflammation and/or fibrosis. Of note, the
adverse reaction, suggesting a dose-related heterogenous distribution of activating
cytopathic mechanism. Patients on enzymes in the lung may account for the
chemotherapy for haematological selective alveolar or bronchial injury seen with
malignancies or solid tumours may exhibit a a specific agent. The delicate and/or unstable
time- or dose-related decrease in the diffusing architecture of the lung may expose it to
capacity for carbon monoxide, thought to potentially severe consequences of even small
reflect subclinical dose-related pulmonary amounts of tissue damage.
toxicity, without necessarily exhibiting
clinically detectable disease. An immunological reaction is thought to cause
the adverse reaction to some drugs. For instance,
However, most drug reactions are idiosyncratic transfusion-related ALI is caused by the binding
and occur unpredictably in only a few of human leukocyte antigen antibodies of donor
individuals, regardless of dose or time on the origin to circulating blood cells in the recipient,
drug. causing cell activation, endothelial cell injury
and an increase in vascular permeability with
Several drugs in a pharmacological class may
consequent alveolar oedema. The drug-induced
cause the same pattern of injury. Examples
lupus syndrome is characterised by a positive
include the association: of b-blockers or
anti-nuclear and sometimes anti-DNA antibody
NSAIDs and acute bronchospasm; of
test. The antibody may be at the origin of the
chemotherapy agents and pulmonary
adverse pleural reaction that is a hallmark of the
oedema, acute lung injury (ALI), diffuse
drug-induced lupus. Drug-induced asthma is
alveolar damage (DAD) or pulmonary fibrosis;
largely non-immunoglobulin E-dependent.
and of ergots with pleural thickening. This
Nevertheless, small incremental doses of
also suggests that a common pathogenetic
NSAIDs or aspirin can be given to asthmatics
mechanism caused the injury.
who are intolerant to these drugs and thus a
Experimental and clinical evidence suggests state of tolerance can be induced, should such
that drug disposition in lung is a critical factor patients need to be treated with this class of
for toxicity. For instance, amiodarone and its medications.
main metabolite sequester in lung, reaching
Alveolar haemorrhage can complicate
tissue concentrations that are above the
threshold for toxicity to lung cells. This may treatments with variegated anticoagulant
cause cell toxicity despite serum drugs, and overdose is thought to account for
concentrations being within the therapeutic this complication although not all cases
range. The slow efflux of amiodarone and exhibit abnormal coagulation studies. Only a
metabolite from the lung are consistent with few drugs produce pulmonary capillaritis with
for the slow resolution of amiodarone consequent alveolar haemorrhage.
pulmonary toxicity (APT) in the clinic, except Rare cases of drug-induced injury result from
when corticosteroid therapy is added. deposition of the drug excipient in lung tissue,
A few drugs are known to undergo metabolic notably the pulmonary circulation, causing
activation in designated lung cells, leading to reactive foreign body granulomas around
the formation of reactive drug species that pulmonary arterioles.
bind avidly and covalently to cell Clinical presentation
macromolecules, causing injury or cell loss.
Metabolism of nitrofurantoin, A high degree of suspicion must be
cyclophosphamide, mitomycin, bleomycin and maintained at all times, and drugs should be

a diagnostic consideration in any patient with exposed to several causal drugs with each
otherwise unexplained respiratory symptoms, drug having differing delay times for DIRD to
abnormal pulmonary physiology or new present, or they have received chest
radiographic findings while being treated irradiation, or DIRD cannot be confidently
with therapy or other drugs. Some adverse separated from pulmonary involvement of the
reactions to drugs exhibit a short time to underlying disease for which the drug was
onset (e.g. b-blocker-induced bronchospasm, given. Examples include patients with thoracic
chemotherapy-induced pulmonary oedema), malignancies or rheumatoid arthritis, when
and this readily suggests causality. For most they are exposed to corticosteroids and/or
drugs, however, there is a long time delay for novel biological drugs including tyrosine
DIRD to present and thus, consideration of kinase inhibitors or anti-TNF antibody therapy.
the drug aetiology is not always raised in due Similarly, diagnosing DIRD is difficult in
time. Drugs can cause lung injury when patients with autoimmune conditions or
administered by the oral, intravenous or recipients of solid organ or bone marrow
intramuscular, inhaled, pleural or intrathecal transplant who are receiving long-term
route or following delivery in a distant organ treatments with immunosuppressive drugs,
that is situated upstream of the lung (e.g. corticosteroids or sirolimus.
bone, brain or liver).
Imaging
Symptoms of DIRD at presentation may
include a nonproductive cough, dyspnoea, Imaging features of DIRD are diverse, as are
wheezing, cyanosis and rigors. Acute their clinical presentations.
bronchospasm, angio-oedema and shock
Drug-induced bronchospasm may present with
characterise those cases with drug-induced
hyperinflation concomitant with
anaphylaxis. Occasional patients present with
bronchospasm on imaging.
stridor, hoarseness, wheezing, haemoptysis or
acute chest pain. Extrarespiratory signs, On CT, airway narrowing can be documented
symptoms and laboratory features include a in patients with drug-induced angio-oedema
cutaneous rash, lymph-node enlargement and or haematoma and UAO.
hepatitis. Rare patients present with full-blown
systemic reactions resembling lupus Patients with ILD generally present with
erythematosus, ChurgStrauss syndrome, bilateral lung shadowing (table 2) that may
Wegeners granulomatosis or polymyositis. localise in the bases, mid-lung regions or
apices or can be diffuse. Both the density and
The severity of DIRD relates to the acuteness, extent of pulmonary involvement correlate
extent, location and reversibility of the with the degree of respiratory impairment. On
adverse reaction. Life-threatening computed tomography, there is inter- or
presentations are in patients with acute dense intralobular septal thickening and lobular or
ILD, upper airway oedema, massive pleural more widespread alveolar filling, depending
effusion or drug-induced systemic on patient, drug and pattern of involvement.
involvement. Pleural effusions may be present in severe ILD
Drug withdrawal followed by abatement of presentation. APT may cause electron-dense
signs and symptoms is a simple and areas of condensation with, often, pleural
straightforward test to confirm the drug effusion. Chemotherapy lung is in the form of
aetiology. The risk of rechallenge should be basilar opacities or a more diffuse haze or
balanced against the merit of securing the consolidation. In eosinophilic pneumonia, the
diagnosis, as fatal reactions may follow pulmonary opacities tend to predominate in
rechallenge with the causal agent. the lung periphery. Acute nitrofurantoin lung
is in the form of diffuse haze. Chronic
However, many clinical situations are nitrofurantoin lung is with scattered
complex. It is possible that patients are peribronchovascular areas of consolidation.

Bronchiolitis obliterans organising pneumonia Specific reactions
(BOOP) typically presents with migratory
alveolar opacities on serial chest films. Airways Angio-oedema is a well-demarcated
Mediastinal or hilar lymph node enlargement oedema that is classically caused by ACE
characterises those cases with a inhibitors. The condition develops shortly after
granulomatous pattern of reaction. The first exposure to the drug or it occurs later
pulmonary opacities in exogenous lipoid after uneventful weeks or months of
pneumonia typically have low attenuation treatment in the form of rapidly developing
numbers. Radiation pneumonia generally breathing difficulty or asphyxia due to airway
develops in the area of the radiation beam. narrowing. The condition is more common in
Only in severe cases does the shadowing elderly African-American women. About 40%
extend outside the radiation beam. It is very of the cases require admission to intensive
difficult if not impossible to infer pathology care. This complication requires emergent
from the pattern on imaging. identification of the airway, and orotracheal
intubation or tracheostomy are indicated in
Drug-induced pleural effusion is severe cases to stabilise the airway. Even
undistinguishable from an effusion of other though patients tend to improve quickly upon
causes, except when APT is present in drug discontinuance, close patient follow-up is
association. An airfluid level can be present required since a rebound can occur after a few
when the pleural pathology occurs as a hours. Patients should not be rechallenged
complication of chemotherapy in patients with any ACE inhibitor, as severe relapse may
with pulmonary metastases adjacent to the occur in patients so tested.
pleural surface.
Pathology and other diagnostic tests Catastrophic bronchospasm may closely
follow exposure to as little as one tablet of
BAL is used to rule out an infection, and to NSAID, aspirin or a nonselective b-blocker in
evaluate alveolitis by enumerating cell aspirin-sensitive individuals, atopics,
numbers and percentages. Inflammatory cells asthmatics or in a patient known to react
decrease upon drug withdrawal. adversely to these classes of medications.
About 15% of acute asthma attack cases
On pathology, drugs can cause virtually any admitted to intensive care are thought to be
pattern of ILD, including cellular or fibrotic triggered by exposure to drugs. Rechallenge is
interstitial pneumonia, eosinophilic hazardous and leads to severe relapse with
pneumonia, acute lung injury or diffuse consequent anoxic brain damage and death.
alveolar damage, pulmonary granulomas,
DAD, BOOP, desquamative or lymphocytic An annoying cough is a frequent complication
interstitial pneumonia, a usual interstitial of treatments with ACE inhibitors. Incidence
pneumonia pattern or rarely, pulmonary varies according to the drug used and ethnicity.
alveolar proteinosis. These patterns are not The condition remits within days or a few
specific to the drug aetiology and cannot be weeks with cessation of exposure to the drug.
separated reliably from the idiopathic variant.
Thus, while pathology may help eliminate Parenchymal lung disease Methotrexate
conditions other than drugs, lung biopsy is pneumonitis is a form of acute, severe and
rarely used to document drug-induced ILD. reversible ILD. The condition develops
Notable exceptions include APT and unexpectedly in patients on methotrexate
exogenous lipoid pneumonia, which may long term typically rheumatoid arthritis
display characteristic features on pathology. patients. A background of previous ILD is a
risk factor for developing methotrexate lung.
No in vitro test of monocyte cell migration in The disease typically manifests dense diffuse
the presence of the drug has demonstrated pulmonary shadowing and respiratory failure.
diagnostic utility in DIRD. Lymphocytes are the predominant cell type in

the BAL. The main differential diagnosis is mainly observed following exposure to
Pneumocystis jiroveci pneumonia or chemotherapy agents including taxanes,
pneumonia due to other opportunistic gemcitabine, mitomycin and rituximab, blood
microorganisms. These need be ruled out and blood products. There is a spectrum of
confidently using the BAL and molecular severity ranging from transient pulmonary
diagnostic tools. Mild cases of methotrexate infiltrates following each exposure to the drug
lung exist. In rare cases, pulmonary fibrosis to acute pulmonary edema or an acute
follows an episode of otherwise classic respiratory distress syndrome (ARDS) picture.
methotrexate pneumonia. Severe cases may develop at once, or after
several bouts of pulmonary infiltrates,
Eosinophilic pneumonia is a common pattern indicating impending toxicity. Outcome is
of reaction to drugs. Other causes of good in early or mild cases. Severe cases may
pulmonary infiltrates and eosinophilia must evolve to refractory respiratory failure.
be ruled out. The condition shows bilateral Chemotherapy agents may cause a peculiar
shadowing in the context of peripheral and form of acute ILD called chemotherapy lung.
BAL eosinophilia. Acute eosinophilic The condition is in the form of pulmonary
pneumonia is a severe form of ILD with acute infiltrates during or shortly after completion of
respiratory failure and sometimes, pleural treatment with the drug. Bleomycin,
effusion is present. Characteristic causal cyclophosphamide, gemcitabine, nitrosoureas
agents include NSAIDs, antibiotics (e.g. and taxanes are classic causal drugs, with
minocycline), abused drugs and exposure to recent evidence implicating targeted therapies
tobacco smoke of recent onset. Rechallenge is (gefitinib, erlotinib, pemetrexed). On
contraindicated, as relapse will almost pathology, there is moderate interstitial
inevitably occur. Severe systemic presentations interstitial inflammation and oedema, along
can occur and are characterised by a with a reactive epithelium and widespread
cutaneous rash and deep-seated organ areas of acute lung injury or alveolar damage.
involvement. This is called the drug rash with The condition may or may not improve upon
eosinophilia and systemic symptoms (DRESS). drug discontinuance and corticosteroid
APT is a distinctive condition that develops therapy. In more severe cases an ARDS picture
insidiously after months or years on the drug, or an accelerated form of pulmonary fibrosis
in the form of asymmetrical consolidation that develop.
may be electron-dense. Pulmonary function is Drug-induced BOOP resembles BOOP of other
restrictive in nature. Foam cells are present in causes or which occurs idiopathically. It takes
the BAL and are an aid to diagnosis of APT, the form of migratory opacities, fixed opacities
although this does not prove toxicity and is a or masses or diffuse shadowing with
routine finding on the drug. The clinical respiratory failure. Main causal agents include
imagingpathological expression of APT is amiodarone, interferon, methotrexate,
multifaceted and includes ground-glass minocycline, rituximab, statins and radiation
shadowing, lung nodules, pulmonary fibrosis therapy to the breast. Drug withdrawal is
or, rarely, pleural effusion in isolation. indicated in all cases and it is followed by
Amiodarone withdrawal may not suffice for disappearance of signs and symptoms of the
APT to clear, due to the high affinity and condition. Otherwise, sequential relapses may
peristence of amiodarone in lung tissue. occur. Costicosteroid therapy is reserved for
Corticosteroid therapy often is required to severe cases and in those with equivocal
accelerate recovery. Severe APT may occur in effect of drug withdrawal.
the setting of thoracic surgery and can be in
the form of an ARDS picture. Interferons, anti-TNF agents and a few other
drugs may occasion a granulomatous pattern
Several drugs can acutely produce lung of pulmonary and lymph node reaction that
permeability changes. Pulmonary oedema is may closely mimic sarcoidosis. Pulmonary

infiltrates and lymph node enlargement are There is slow improvement with
present on imaging. A confirmatory discontinuance of the ergot.
transbronchial lung biopsy may be required,
Pulmonary vasculopathy This condition
except if granulomas are present on a readily-
mainly is in the form of pulmonary
accessible tissue such as the dermis.
hypertension similar to primary pulmonary
Drug-induced diffuse alveolar haemorrhage is hypertension. Anorectic agents, benfluorex
diagnosed by BAL, which shows a and crushed tablets injected intravenously as
hemorrhagic return. Oral or parenteral a form of drug abuse can effectuate the
anticoagulants, fibrinolytic agents, abciximab, condition.
ticlopidine and clopidogrel can cause the
syndrome. Rarely, alveolar haemorrhage is a Methaemoglobinaemia
manifestation of drug (mainly Methaemoglobinaemia is a drug-induced
propylthiouracil)-induced anti-neutrophil state of oxidation of the iron in haemoglobin,
cytoplasmic antibody vasculitis. and methaemoglobin is a poor oxygen carrier.
The condition is diagnosed by slate-grey
Drug-induced pulmonary fibrosis can occur as
cyanosis, a low pulse oxygen saturation,
a complication of treatments with
normal arterial oxygen tension and calculated
chemotherapy agents, amiodarone and
arterial oxygen saturation, and measurement
irradiation (fibrosis is localised in the latter).
of methaemoglobin in a patient receiving an
Patients present with dyspnoea. On imaging
eligible drug.
there are diffuse linear or streaky opacities
and volume loss. The condition may stabilise
with drug discontinuance. In most patients, References
however, the disease is progressive and N Babu KS, Marshall BG. Drug-induced airways
response to corticosteroid therapy is limited. diseases. Clin Chest Med 2004; 25: 113122.
N Briasoulis E, Pavlidis N. Noncardiogenic
When drug aetiology is considered likely, pulmonary edema: an unusual and serious
corticosteroid therapy is indicated in severe complication of anticancer therapy. The
ILD cases and wherever drug withdrawal is Oncologist 2001; 6: 153161.
not followed by improvement in a few days or N Goldblatt M, et al. Dasatinib-induced pleural
weeks. effusions: A lymphatic network disorder? Am J
Med Sci 2009; 338: 414417.
Pleura Many drugs can injure the pleura, N Khasnis AA, Calabrese LH. Tumor necrosis factor
including the novel targeted agent dasatinib. inhibitors and lung disease: A paradox of
Involvement is in the form of a pleural efficacy and risk. Semin Arthritis Rheum 2010
exudate with or without pleural eosinophilia [Epub ahead of print. DOI: 10.1016/
or a serosanguineous effusion. Lupus-inducing j.semarthrit.2009.09.001].
drugs may cause drug lupus with pleural or
N Lara AR, Schwarz MI. Diffuse alveolar
hemorrhage. Chest 2010; 137: 11641171.
pleuropericardial effusion in the context of N Rubin RL. Drug-induced lupus. Toxicology 2005;
positive antinuclear antibodies (ANA). The 209: 135147.
novel anti-TNF agents infliximab, etanercept N Sondhi D, et al. Airway compromise due to
and adalimumab may cause a form of lupus angiotensin-converting enzyme inhibitor-induced
syndrome with anti-double-strand DNA in angioedema: clinical experience at a large
addition to the ANA antibodies, an unusual community teaching hospital. Chest 2004; 126:
finding in classic drug-induced lupus. 400404.
N Vahid B, Marik PE. Pulmonary complications of
novel antineoplastic agents for solid tumors.
Ergots are notable for the insidious Chest 2008; 133: 528538.
development of diffuse pleural thickening N Foucher P, Camus P. Pneumotox1 Website, 1997.
with or without an effusion causing dyspnoea, www.pneumotox.com Date last updated: June 4,
chest pain and restrictive lung dysfunction. 2010.

CHAPTER 12:
PulmonARy vASCulAR
diSEASES
PulmonARy EmboliSm 332

M. Pistolesi
PulmonARy vASCuliTiS 336

A.U. Wells
PulmonARy HyPERTEnSion 340


PULMONARY EMBOLISM
M. Pistolesi
Section of Respiratory Medicine, Department of Internal Medicine,
University of Florence, FIorence, Italy
E-mail: massimo.pistolesi@unifi.it
Despite the recent advances in prevention and

diagnostic imaging, pulmonary embolism (PE) Key points
remains a major health problem. The
incidence of this pathological condition is N Although early treatment is highly
as high as one in 1,000 per year in the effective, PE is underdiagnosed and
general population. Early diagnosis is therefore it remains a major health
fundamental since early treatment is highly problem.
effective. However, due to the low specificity
of its clinical presentation, this common
N Diagnostic strategy should be based on
disease is still underdiagnosed and it is clinical evaluation of the probablility of
estimated that in the USA ,50,000 people PE.
die each year of PE.
Several points are summarised below
concerning the diagnostic strategies to be Pre-test clinical probability of PE
adopted in patients with clinical suspicion of
PE that have been highlighted and brought to A thorough clinical evaluation is the key step
the attention of the scientific community by in raising the suspicion of the disease and
recent scientific publications, expert reviews, setting-up appropriate diagnostic strategies.
and international guidelines. Although the diagnostic yield of individual
clinical symptoms, signs and common
laboratory tests is limited, the combination of
General rules for the diagnostic work-up these variables, either by empirical assessment
of patients clinically suspected of PE or by a prediction rule, can be used to stratify
patients into an increased risk of PE (low,
N Pre-test clinical probability of PE should be intermediate or high). The results of two
objectively assessed in each patient. broad prospective studies in the 1990s
N D-Dimer should be determined if pre-test (Prospective Investigation of Pulmonary
probability of PE is low or intermediate. Embolism Diagnosis (PIOPED) and Prospective
Investigative Study of Acute Pulmonary
N Diagnostic imaging of the chest should Embolism Diagnosis (PISA-PED)) indicate that
be used to assess post-test probability of physicians estimates of the clinical likelihood
PE in most patients. Further testing is of PE, even if based on empirical assessment,
necessary when post-test probability of do have predictive value.
PE is neither sufficiently low nor
sufficiently high to permit therapeutic Three objective scoring systems have been
decisions. tested prospectively and validated in large-
scale clinical trials: Wells score, Geneva score
N Diagnostic strategies of PE could differ and Pisa score. The three scoring systems
significantly in different clinical contexts perform reasonably well to assess objectively
and special conditions. the clinical probability of PE in outpatients or

emergency room patients. The Pisa score considered according to the determined PE
seems to perform better than other scoring clinical probability and the sensitivity of the
systems in hospitalised patients. It appears particular D-dimer method of measurement
that fully standardised scoring systems, such employed. A negative D-dimer test result,
as Wells and Geneva scores, with no implicit measured by any method, in combination
evaluation of symptoms (e.g. dyspnoea, chest with a low probability clinical assessment,
pain) and simple instrumental findings (ECG, excludes PE with accuracy. An intermediate
chest radiograph) could not perform better clinical probability also would exclude PE with
than subjective clinical judgment of reasonable certainty if D-dimer was measured
experienced physicians, as it was obtained in by a high sensitivity ELISA method. It has
the PIOPED and the PISA-PED studies. been shown that the 3-month risk of PE or
Conversely, interpretation of ECG and chest DVT in untreated patients with a negative D-
radiograph in these patients, as requested by dimer and a low or intermediate clinical
the Pisa score, necessitates a certain level of probability is ,1%. Conversely, if clinical
clinical experience and is hard to be assessment results in high probability for PE, a
standardised. concomitant negative D-dimer test does not
exclude PE.
Nevertheless, several prospective studies have
shown that, whatever scoring method is used, The number of patients with suspected PE in
pre-test clinical probability categorises whom D-Dimer must be measured to exclude
patients into subgroups with a different one PE episode ranges between three in the
prevalence for PE and that the positive and emergency dept and o10 in hospitalised
negative predictive value of various objective patients. It then appears recommendable to
tests is strongly conditioned by the consider D-Dimer measurement in the
independently assessed pre-test clinical diagnostic work-up of PE only in outpatients
probability. Accordingly, recent international or in patients of the emergency dept with low
guidelines recommend that the clinical or intermediate levels of clinical probability.
probability of the disease should be assessed
in each patient with suspected PE before any The sensitivity of D-Dimer testing for
further objective testing occurs. Future research pulmonary embolism increases with the
is needed to develop standardised models, of extent of PE. D-Dimer concentrations are the
varying degree of complexity, which may find highest in patients with PE involving the
application in different clinical settings to pulmonary trunk and lobar arteries and with
predict the probability of PE. perfusion scan defects involving .50% of the
pulmonary circulation.
D-Dimer
Diagnostic imaging of the chest
D-Dimer plasma levels are elevated in the (post-test probability of PE)
presence of simultaneous activation of
coagulation and fibrinolysis. A normal D-dimer The contribution of computed tomography
level has, consequently, a high negative angiography (CTA) in the diagnosis of PE has
predictive value for PE or deep vein in recent years greatly increased as a
thrombosis (DVT). However, fibrin endogenous consequence of the extraordinary
production may be increased in a wide variety advancement in CTA technology.
of conditions including, among others, cancer, Multidetector CTA has become the most
inflammation, infection, pregnancy and widely used technique for the diagnosis or
chronic illnesses. Elevated plasma D-dimer exclusion of PE and has almost replaced lung
levels have, for this reason, a low positive scanning as a screening test and conventional
predictive value for PE and DVT. pulmonary angiography as the reference
standard for the diagnosis of acute pulmonary
The value of D-dimer measurement in the embolism. CTA, however, does not escape the
diagnostic work-up of each patient must be simple rule that the combined use of the
Pulmonary embolism 333

estimated clinical probability and the results PE when featuring wedge-shaped (segmental)
of one noninvasive test substantially increases perfusion defects or not compatible with PE
the accuracy in confirming or ruling out a when featuring defects other than wedge-
disease, as compared with either assessment shaped or normal perfusion. When compared
alone. As shown by the PIOPED II trial, the with the original PIOPED protocol, the PISA-
predictive value of CTA is high with a PED approach has several advantages, as
concordant clinical assessment, but additional follows: 1) Q9 scan either confirms or excludes
testing is necessary when clinical probability the clinical suspicion of PE (thus virtually
is inconsistent with the imaging results. eliminating nondiagnostic examinations);
2) the sensitivity of lung scintigraphy is
Perfusion (Q9) lung scan was introduced greatly increased (86% versus 41%), yet with
40 yrs ago as the first chest imaging method minor reduction of specificity (from 97% to
for the diagnosis of PE. A normal Q9 scan
93%); 3) the combination of clinical probability
excludes PE (high sensitivity and high
and Q9 scan results confirms or excludes PE in
negative predictive value), whatever the pre-
,80% of patients. More recently the
test clinical probability. However, Q9 scanning
diagnostic performance of Q9 scan for PE was
was thought to be poorly specific (low positive
confirmed by examining 889 scans from the
predictive value) for PE because all common
PIOPED II. PIOPED II data were used to test the
pulmonary diseases (infections, neoplasms,
hypothesis that reading Q9 scans without
chronic obstructive pulmonary disease) can
V scans, and categorising the Q9 scan as
produce decreased blood flow to the affected
PE present, PE absent, or nondiagnostic
regions. Ventilation (V9) scan was added to Q9
can result in clinically useful sensitivity and
scan to increase the specificity of scintigraphy.
specificity in a high proportion of patients. The
This diagnostic approach is based on the
study has confirmed that Q9 scan and CTA have
flawed expectation that regions of the lung
comparable positive and negative predictive
excluded from perfusion by emboli maintain
values, with no nondiagnostic readings for the
normal ventilation, thus giving rise to V9/ Q9
Q9 scan (table 1).
mismatch. This criterion to diagnose PE is at
variance with the notion that ventilation is Diagnostic strategies in different
shifted away from embolised lung regions. clinical contexts and special conditions
The concept that dead space ventilation is not
significantly increased in the course of PE was Most clinicians and diagnostic radiologists
widely held in respiratory pathophysiology feel, however, more comfortable with an
before the V9/ Q9 scanning approach was anatomical demonstration of whether a clot is
developed as it was asserted by COMROE present or not as compared to assess a PE
(1966), who foresaw that decrease in wasted probability by looking at V9/ Q9 mismatches
ventilation (ventilation to unperfused or (PIOPED) or to evaluate the shape of a
poorly perfused lung) helps the patient but perfusion defect (PISA-PED). Furthermore,
hinders the physician in diagnosis.. This is in contrary to scintigraphy, in most hospitals,
keeping with the results of the PIOPED trial, in CTA is available 24 h/7 days a week.
which it was shown that the high probability However, CTA cannot be performed in the
V9/ Q9 scan (Q9 defects without matching V9 whole population of patients suspected of PE.
abnormalities) lacks sensitivity in diagnosing As shown in the PIOPED II trial, ,50% of the
PE since it fails to identify 59% of PE patients recruited patients did not undergo CTA for
(sensitivity 41%, specificity 97%). The documented contraindications, such as renal
combination of clinical probability and V9/ Q9 failure, abnormal creatinine levels, allergy to
scan results either confirms or excludes PE in contrast agent, possible pregnancy, critical
,30% of patients. The diagnostic value of illness, requirement of ventilator support, or
the Q9 scan (without V9 imaging) was recent myocardial infarction. In all these
reappraised in the PISA-PED study, in which conditions, Q9 scan could be the preferred
Q9 scans were read either as compatible with alternative approach to the diagnosis of PE.

Table 1. Predictive value of multidetector computed tomography angiography (CTA) and perfusion scintigraphy (Q9) scan
from retrospective evaluation of PIOPED II data
Imaging test Positive predictive Negative predictive Nondiagnostic %
value % value %
Q9 scan 85 96 0
CTA 86 95 6
This approach is particularly important for reduce cost and radiation load with gain in
reproductive-age female patients in whom the diagnostic yield.
breast irradiation dose from CT angiography
can be minimised by using the Q9 scan as the References
first imaging test. N Comroe JH Jr. The main function of the
pulmonary circulation. Circulation 1966; 33:
Under circumstances in which clinical 146158.
probability and imaging test (CTA or N Eisner MD. Before diagnostic testing for
scintigraphy) results are discordant and pulmonary embolism: estimating the prior
further testing, such as lower limb probability of disease. Am J Med 2003; 114:
compression ultrasonography, is required to 232234.
either confirm or exclude the diagnosis. N Miniati M, et al. Value of perfusion lung scan in
Another practical approach could be to image the diagnosis of pulmonary embolism: results of
the pulmonary circulation with CTA if Q9 scan the Prospective Investigative Study of Acute
was the first imaging test used or vice versa. Pulmonary Embolism Diagnosis (PISA-PED). Am
J Respir Crit Care Med 1996; 154: 13871393.
Summary and conclusions N Lucignani G, Pistolesi M. Diagnosing pulmonary
embolism: clinical problem or methodological
The choice of a diagnostic strategy for issue? Eur J Nucl Med Mol Med 2009; 36: 522
pulmonary embolism depends on the pre-test 528.
clinical probability of PE, the condition of the N PIOPED Investigators. Value of the ventilation-
patient, the availability of the necessary test, perfusion scan in acute pulmonary embolism:
the risks of testing, the risk of an inaccurate results of the Prospective Investigation of
positive or negative diagnosis, and the cost. Pulmonary Embolism Diagnosis (PIOPED). JAMA
Clinical evaluation makes it possible to 1990; 263: 27532759.
classify patients into probability categories N Remy-Jardin M, et al. Management of suspected
acute pulmonary embolism in the era of CT
corresponding to an increasing prevalence of
angiography. A statement from the Fleischner
PE, whether assessed by implicit clinical Society. Radiology 2007; 245: 315329.
judgment or by a validated prediction rule. N Sostman HD, et al. Sensitivity and specificity of
Structured models to assess clinical perfusion scintigraphy for acute pulmonary
probability so far developed have different embolism in PIOPED II. J Nucl Med 2008; 49:
performances in patients of the emergency 17411748.
department and those who are hospitalised. N Stein PD, et al. Challenges in the diagnosis of
Exclusion of PE by clinical probability acute pulmonary embolism. Am J Med 2008;
assessment and D-dimer spares the cost and 121: 565571.
radiation of an imaging evaluation. CTA has N Stein PD, et al. Multidetector computed
become the method of choice for imaging the tomography for acute pulmonary embolism. N
Engl J Med 2006; 354: 23172327.
pulmonary vasculature when PE is suspected
in routine clinical practice. Scintigraphy can
N The Task Force for the Diagnosis and
Management of Acute Pulmonary Embolism of
be considered as the preferred alternative the European Society of Cardiology, Guidelines
chest imaging technique for patients with on the diagnosis and management of acute
contraindication to CTA. If scintigraphy is pulmonary embolism. Eur Heart J 2008; 29:
used, eliminating the ventilation scan can 22762315.
Pulmonary embolism 335

PULMONARY VASCULITIS
A.U. Wells
Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK
E-mail: a.wells@rbh.nthames.nhs.uk
The principles of diagnosis and management Antineutrophil cytoplasmic antibodies (ANCA)

are broadly similar across the individual are often present in systemic vasculitides
pulmonary vasculitides, sub-divided into involving the small- and medium-sized vessels,
primary systemic and secondary disorders including CSS, WG and microscopic
(table 1). The main challenges for the polyangiitis. ANCA are subcategorised as
clinician are to recognise that vasculitis is a cytoplasmic, perinuclear or atypical and are
possible diagnosis, to make the diagnosis in directed primarily against proteinase 3 in WG
nonclassical disease and to select a level of (cytoplasmic) and against myeloperoxidase in
treatment appropriate to disease severity. CSS (perinuclear), although all ANCA patterns
Wegeners granulomatosis (WG) and Churg have been reported in both disorders. In vitro
Strauss syndrome (CSS) are the most frequent and animal data suggest that ANCA interact
examples of life-threatening disease. with primed neutrophils, leading to
endothelial damage and further neutrophil
Epidemiology and pathogenesis recruitment. Both diseases are generally
WG is the third most prevalent systemic considered to be triggered by foreign agents,
vasculitis (after giant cell arteritis and including drugs and infections, with the most
vasculitis in rheumatoid arthritis), with an suggestive data relating to chronic nasal
annual incidence of 311 per million, largely carriage of Staphylococcus aureus in WG.
affecting adults aged 3050 yrs. CSS has an Clinical presentation
annual incidence of ,3 per million and
mainly affects adults aged 3050 yrs. In Vasculitis should be suspected in diffuse alveolar
neither disorder is there a strong sex haemorrhage, which may be difficult to
predilection. diagnose as haemoptysis is often absent or
scanty. Diffuse alveolar haemorrhage should be
suspected when unexplained infiltrates on chest
Key points imaging are associated with a fall in
haemoglobin over a day or two or, in chronic
N Haemoptysis is often scanty or absent low-grade haemorrhage, with an iron-deficiency
in disffuse alveolar haemorrhage. anaemia. Bronchoalveolar lavage is usually
N Vasculitis must often be treated diagnostic of haemorrhage. Vasculitis should
also be suspected: 1) in patients presenting with
empirically, in the absence of full
breathlessness on exertion and an unexplained
diagnostic clinical criteria or a
isolated or disproportionate reduction in carbon
histological diagnosis.
monoxide diffusing capacity; and 2) in patients
N Initial treatment should be definitive, with features of an underlying systemic
even when the diagnosis is tentative. vasculitis, such as WG, CSS or a pulmonaryrenal
syndrome (of which Goodpastures disease is the
N Chronic infection and malignancy are
best-known example).
the most frequent differential
diagnosis. Investigations that tend to be useful in
suspected vasculitis are shown in table 2.

Table 1. Classification of pulmonary vasculitis
Primary vasculitides Frequency of lung
(Chapel Hill International Consensus nomenclature) involvement
Large vessel
Giant-cell arteritis Rare
Takayasus arteritis Frequent
Medium-sized vessel
Polyarteritis nodosa Rare
Kawasaki disease No
Small vessel (with variable medium-sized vessel involvement)
Wegeners granulomatosis Frequent
ChurgStrauss syndrome Frequent
Microscopic polyangiitis Frequent
HenochSchonlein purpura No
Essential cryoglobulinaemia No
Secondary vasculitides
Rheumatological
Pulmonaryrenal (e.g. Goodpastures syndrome)
Relapsing
polychronditis
Behcets syndrome
Chronic infection
Lymphoma
Drugs
ChurgStrauss Syndrome p-ANCA is diagnostically definitive, and is no

more than a useful ancillary finding, increasing
The American College of Rheumatology or decreasing the diagnostic likelihood.
definition of CSS requires the satisfaction of at
least four of six criteria (table 3). There is Wegeners granulomatosis
typically a prodrome of rhinitis with nasal
polyps and the eventual development of late- The classic historical WG triad consists of renal,
onset asthma, followed by eosinophilia in lower respiratory tract and upper respiratory
tissue or peripheral blood and, ultimately, tract involvement. Most often, chronic rhinitis,
systemic vasculitis. Other frequent sites of sinusitis or mastoiditis progresses to generalised
involvement include the central nervous disease over months to years with lower
system (especially mononeuritis multiplex in respiratory tract involvement in 6585%,
75%), skin (60%), heart (50%), joints and, including diffuse alveolar haemorrhage, which
less frequently, the kidneys and may be life-threatening. Fever and weight loss
gastrointestinal tract. The classical triad at are frequent. There is a wide range of
lung biopsy is necrotising angiitis, granulomas extrapulmonary organ involvement. Lung
and tissue eosinophilia. Pulmonary infiltrates involvement is asymptomatic in a third of cases.
on chest imaging are more common than The cardinal histological features are
pulmonary nodules (which very seldom granulomatous inflammation and necrotising
cavitate). Pleural disease is present in 50% of vasculitis, affecting small- to medium-sized
cases. The diagnostic role of ANCA continues vessels. Chest imaging may show one or more
to be debated. ANCA, usually p-ANCA, are nodules which can cavitate, localised or diffuse
present in up to two-thirds of patients, but infiltrates (which may represent alveolar
also occur in many other nonvasculitic haemorrhage), or evidence of large and small
autoimmune and infectious conditions. Thus, airway disease. As in CSS, the diagnosis should
neither the presence nor the absence of never be dependent upon ANCA positivity:
Pulmonary vasculitis 337

Table 2. Useful investigations for suspected pulmonary vasculitis
Imaging
Chest radiography, high-resolution computed tomography
Lung function tests
Pulmonary function tests, arterial gases
Renal function
Urine dipstick testing and microscopy for proteinuria, haematuria and cellular casts; estimation of renal
function; consider renal biopsy (if evidence of nephritis)
Immunology
Antineutrophil cytoplasmic antibodies (ANCA), antiglomerular basement membrane (anti-GBM),
immune complexes, rheumatoid factor, antinuclear antibodies (ANA), antiphospholipid antibodies
Bronchoalveolar lavage
Iron-laden macrophages
Biopsy
Renal
Skin
Lung (surgical)
c-ANCA are not present in all cases and are also number of clinical criteria. However, many
found in other vasculitides, chronic bacterial patients with vasculitis have features
infections and cryoglobulinaemia. overlapping between diagnostic entities with
transient or nonfulfilment of diagnostic criteria.
Among vasculitides, microscopic polyangiitis, Thus, a versatile diagnostic approach is
a necrotising vasculitis affecting small to required. When vasculitis is suspected but full
medium-sized vessels, is the main clinical mimic clinical criteria are not satisfied, a histological
of WG. This disorder also often presents with diagnosis should be made, if possible. However,
diffuse alveolar haemorrhage, which can have a a negative biopsy does not exclude vasculitis,
poor prognosis. Necrotising glomerulonephritis, which may be patchy or give rise to nonspecific
mononeuritis multiplex, and skin lesions are inflammatory change (as in upper airway
variably present. The cardinal histological biopsies in WG patients).
distinction is the absence of granulomas, which
are characteristically present in WG. Thus, the diagnosis of a vasculitic syndrome is
sometimes necessarily empirical, with chronic
Diagnosis of vasculitis
infection and malignancy the most frequent
A confident diagnosis requires histological differential diagnoses. In such cases, initial
confirmation or satisfaction of the requisite treatment and monitoring should be as for the
vasculitic syndrome most closely
corresponding to the clinical presentation in
Table 3. ACR diagnostic criteria for CSS (four out of six are
required) that patient. Initial treatment should be
definitive, as a clear response provides
1. Presence of asthma important support for the diagnosis, whereas
2. Peripheral blood eosinophilia (.10%) a tentative therapeutic approach often
3. Evidence of a neuropathy in a vasculitic prolongs diagnostic uncertainty.
pattern (e.g. mononeuritis multiplex)
Prognosis
4. Transient pulmonary infiltrates
5. A history of sinus disease The poor historical outcome of the vasculitic
syndromes has been transformed by more
6. Evidence of extra-vascular eosinophilia on
biopsy aggressive therapy, but also by the increasing
detection of milder disease, including patients

with limited involvement. In localised Following initial treatment, less intense long-
pulmonary WG and CSS alike, the outcome is term therapy is almost invariably required. In
much better than with multi-organ WG, standard maintenance treatment has
involvement. In CSS, the prognosis worsens consisted of azathioprine (2.0 mg?kg-1?day-1),
strikingly with two or more extrapulmonary usually with low-dose corticosteroid therapy,
complications (5-yr survival 54%). Mortality is although no comparison with other agents
largely ascribable to sepsis (as a complication (such as methotrexate and mycophenolate
of treatment) or disease progression. Death mofetil) has been undertaken, either in WG or
from progressive disease is most commonly due other vasculitides. In WG, co-trimoxazole
to renal failure or lung involvement in WG, and therapy has been efficacious in localised
to renal failure, cerebrovascular involvement respiratory tract disease and may have an
and gastrointestinal disease in CSS (with 10% ancillary role in maintaining remission.
of deaths accounted for by lung disease).
Intravenous immunoglobulin and anti-
Treatment thymocyte globulin have been variably
In most patients with WG, and in severe efficacious in resistant WG. Rituximab therapy
vasculitis in general, intense is more promising, based on striking responses
immunosuppression to induce remission is recently reported in patients refractory to
usual. In WG, oral cyclophosphamide standard treatments.
(2.0 mg?kg-1?day-1) and intravenous References
cyclophosphamide (600 mg?m-2 at
34 weekly intervals, depending on disease N Conron M, Beynon HLC. ChurgStrauss
severity) are equally successful in inducing syndrome. Thorax Rare Disease Series. Thorax
remission. Intravenous therapy is associated 2000; 55: 870877.
with a slightly higher relapse rate, but is much N Guillevin L, et al. Prognostic factors in
polyarteritis nodosa and ChurgStrauss
less toxic in the short-term and is much less
syndrome. A prospective study in 342 patients.
likely to provoke haemorrhagic cystitis and Medicine 1996; 75: 1728.
subsequent malignancy, based on long-term N Jayne D, et al. A randomized trial of
systemic lupus erythematosus data. In life- maintenance therapy for vasculitis associated
threatening disease, cyclophosphamide and with antineutrophil cytoplasmic autoantibodies.
intravenous methyl prednisolone should be New Engl J Med 2003; 349: 3644.
administered concurrently. Prophylactic co- N Jennette JC, et al. Nomenclature of systemic
trimoxazole (trimethoprim 160 mg/ vasculitides. Proposal of an international
sulfamethoxazole 800 mg three times a consensus conference. Arthritis Rheumatism
week) is often used with prolonged intense 1994; 37: 187192.
immunosuppression, to reduce the risk of N Keogh KA, et al. Rituximab for refractory
Pneumocystis carinii opportunistic infection. Wegeners Granulomatosis: report of a
prospective, open-label pilot trial. Am J Respir
In less severe vasculitis, a less aggressive Crit Care Med 2006; 173: 180187.
initial approach is justified. In isolated N Lanham JG, et al. Systemic vasculitis with
pulmonary CSS, a good response is usual with asthma and eosinophilia: the clinical approach
oral prednisolone (1 mg?kg-1?day-1, up to to the ChurgStrauss syndrome. Medicine
(Baltimore) 1984; 63: 65681.
60 mg?day-1) or, in more severe disease,
intravenous methylprednisolone (up to 1 g
N Lhote F, Guillevin L. Polyarteritis nodosa,
microscopic polyangiitis and ChurgStrauss
daily on three successive days). In WG without syndrome. Semin Respir Crit Care Med 1998; 19:
major organ involvement, methotrexate 2746.
(0.3 mg?kg-1?week-1) is as effective as daily N Specks U. Pulmonary vasculitis. In: Schwarz MI,
oral cyclophosphamide in the induction of King TE Jr, eds. Interstitial lung disease.
remission, although relapse is more likely with Hamilton, Canada, BC Dekker, 1998; pp. 507
cessation of treatment at 12 months. 534.
Pulmonary vasculitis 339

PULMONARY HYPERTENSION
Univ Paris-Sud, Orsay, Centre National de Reference de lHypertension
Pulmonaire Seve`re, Service de Pneumologie et Reanimation Respiratoire,
Hopital Antoine Becle`re, AP-HP, Clamart, and INSERM U999, Hypertension
Arterielle Pulmonaire, Physiopathologie et Innovation Therapeutique,
Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France
E-mail: gerald.simonneau@abc.aphp.fr
Pulmonary hypertension (PH) is defined as an seen in idiopathic PAH with comparable

increase in mean pulmonary arterial pressure histological findings. Associated PAH account
Ppa o25 mmHg at rest as assessed by right for approximately half of the patients
heart catheterisation. followed at specialised centres. Pulmonary
veno-occlusive disease (PVOD) and pulmonary
Classification capillary haemangiomatosis remain difficult
According to values of pulmonary wedge disorders to classify since they share some
pressure (Ppw), PH can be pre-capillary (Ppw
f15 mmHg) or post-capillary (Ppw Key points
.15 mmHg).
PH can be classified into five groups N PAH is a rare condition characterised by
according to pathological, pathophysiological elevated pulmonary arterial resistance
and therapeutic characteristics. Despite leading to right heart failure and death.
comparable elevations of Ppa in the different
clinical groups, the underlying mechanisms,
N PAH can be sporadic (idiopathic PAH),
heritable, induced by drugs or toxins, or
diagnostic approaches, and prognostic and
associated with other conditions such
therapeutic implications are completely
as connective tissue diseases.
different.
The new clinical classification is shown in
N Doppler echocardiography is the inves-
tigation of choice for noninvasive
Table 1. Group 1 relates to pulmonary arterial
screening but measurement of haemo-
hypertension (PAH), corresponding to
dynamic parameters during right heart
idiopathic, heritable and associated pre-
capillary pulmonary hypertension. The term catheterisation is mandatory to confirm
familial PAH has been replaced by heritable the diagnosis (mean pulmonary artery
PAH because specific gene mutations have pressure o25 mmHg and pulmonary
been identified in sporadic cases with no artery wedge pressure f15 mmHg).
family history. Heritable forms of PAH include N Recent advances in the management of
clinically sporadic idiopathic PAH with PAH include prostaglandins, endothelin
germline mutations (mainly bone receptor antagonists and type 5
morphogenetic protein receptor 2 gene as phosphodiesterase inhibitors.
well as activin receptor-like kinase type-1 gene
or endoglin gene) and clinical familial cases N Lung transplantation is an option for
with or without identified mutation. severe patients deteriorating despite
Associated PAH includes conditions that can medical treatment.
have a similar clinical presentation to that

Table 1. Updated clinical classification of pulmonary hypertension (PH)
1 PAH
1.1 Idiopathic PAH
1.2 Heritable
1.2.1 BMPR2
1.2.2 ALK1, endoglin (with or without hereditary haemorrhagic telangiectasia)
1.2.3 Unknown.
1.3 Drugs and toxins induced
1.4 APAH:
1.4.1 Connective tissue diseases
1.4.2 HIV infection
1.4.3 Portal hypertension
1.4.4 Congenital heart disease
1.4.5 Schistosomiasis
1.4.6 Chronic haemolytic anaemia
1.5 Persistent PH of the newborn
19Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis
2 PH due to left heart disease
2.1 Systolic dysfunction
2.2 Diastolic dysfunction
2.3 Valvular disease
3 PH due to lung diseases and/or hypoxia
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
3.4 Sleep-disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
3.7 Developmental abnormalities
4 Chronic thromboembolic PH
5 PH with unclear and/or multifactorial mechanisms
5.1 Haematological disorders: myeloproliferative disorders, splenectomy.
5.2 Systemic disorders, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyoma-
tosis, neurofibromatosis, vasculitis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis
PAH: pulmonary arterial hypertension; BMPR2: Bone morphogenetic protein receptor, type II; ALK-1: Activin receptor-like
kinase 1 gene; APAH: associated PAH. Reproduced from SIMONNEAU et al. (2009), with permission from the publisher.
characteristics with PAH but also demonstrate attempting to distinguish between proximal
a number of differences. Given the current and distal forms. The most frequent causes of
evidence, these conditions have been PH are those complicating left heart diseases
individualised as a distinct category but not (group 2) and pulmonary diseases (group 3).
completely separated from PAH and have
been designated as clinical group 1. Chronic All forms of PH have some common
thromboembolic pulmonary hypertension pathologic features regardless of their
(CTEPH) is an important subcategory of PH, aetiology: medial hypertrophy of muscular
which may be cured by surgical pulmonary and elastic arteries; dilation and intimal
endarterectomy. It was decided to maintain atheromas of elastic pulmonary arteries; and
only a single category of CTEPH without right ventricular hypertrophy. In addition to
Pulmonary hypertension 341

the aforementioned pathologic changes Diagnosis
common to all forms of PH, PAH is
The diagnostic process starts with the
characterised by constrictive and complex
identification of the more common clinical
arterial lesions involving to varying degrees
groups of PH (group 2 left heart diseases
the pre- and intra-acinar pulmonary arteries
and group 3 pulmonary diseases), to
The plexiform lesion is a focal proliferation of
distinguish group 4 CTEPH and finally to
endothelial channels lined by myofibroblasts,
make the diagnosis and recognise the
smooth muscle cells, and connective tissue
different types of group 1 PAH and the rarer
matrix. The lesion is located within pre- and conditions of group 5.
intra-acinar pulmonary arteries, and is
associated with expansion and partial PAH should be considered in the differential
destruction of the arterial wall with extension diagnosis of exertional dyspnoea, syncope,
of the plexiform lesion into the perivascular angina and/or progressive limitation of
connective tissue. The plexiform lesion is exercise capacity, particularly in patients
often located at an arterial branching without apparent risk factors, symptoms or
point (fig. 1). signs of common cardiovascular and
respiratory disorders. Special awareness
Epidemiology and survival should be directed towards patients with
associated conditions and/or risk factors for
PAH is a rare condition with a prevalence
development of PAH such as family history,
ranging 1550 per million in western Europe.
connective tissue diseases, congenital heart
The prevalence of idiopathic PAH was about 6
diseases, HIV infection, portal hypertension,
per million in the French Registry and its haemolytic anaemia, or a history of drug and
incidence was 2 per million per yr. Median toxin intake known to induce PAH. In
survival of idiopathic PAH was 2.8 yrs in the everyday clinical practice, such awareness may
National Institutes of Health Registry before be low. More often, PH is found unexpectedly
the recent development of PAH-specific on transthoracic echocardiography requested
therapies. Despite improvements in recent for another indication.
years, idiopathic, familial, and anorexigen-
associated PAH remains a progressive, fatal If noninvasive assessment is compatible with
disease in the modern management era. PH, clinical history, symptoms, signs, ECG,
Mortality is most closely associated with male chest radiograph, transthoracic
sex, right ventricular haemodynamic function echocardiogram, pulmonary function tests
and exercise limitation. (including nocturnal oximetry if required) and
high-resolution computed tomography (HRCT)
of the chest are requested to identify the
presence of group 2 left heart diseases or
group 3 pulmonary diseases. If these are not
found or if PH seems out of proportion to
their severity, less common causes of PH
should be sought. Ventilation/perfusion lung
scan should be considered. If ventilation/
perfusion scan shows multiple segmental
perfusion defects, a diagnosis of group 4
CTEPH should be suspected. The final
diagnosis of CTEPH (and the assessment of
suitability for pulmonary endarterectomy)
will require helical computed tomography of
Figure 1. A typical plexiform lesion in a patient with the chest, right heart catheterisation and
idiopathic PAH. The lesion is located at an arterial selective pulmonary angiography. HRCT of
branching point. the chest may also show signs suggestive of

Avoid excessive physical activity (I-C) General measures and supportive therapy Oral anticoagulants:
Supervised rehabilitation (II a-B) IPAH, heritable PAH and PAH due to
Avoid pregnancy (I-C) Expert referral (I-C) anorexigens (IIa-C)
Psychosocial support (IIa-C) APAH (IIb-C)
Influenza and pneumococcal infection Diuretics (I-C)
vaccination (II-C) Acute vasoreactivity test (I-C for IPAH) Oxygen# (I-C)
(IIb -C for APAH) Digoxin (IIb-C)
Pulmonary hypertension
Vasoreactive
Non vasoreactive
WHO-FC I-III Initial therapy

Recommendation Evidence WHO-FC II WHO-FC III WHO-FC IV
CCB (I C) Ambrisentan, Bosentan Ambrisentan, Bosentan Eproprostenol i.v.
I-A Sildenafil Sitaxentan
Sildenafil
Sustained response Epoprostenol IV, Iloprost inhaled
(WHO-FC I-II) Tada lafil Tadalafil
I-B
Treprostinil s.c., inhaled
Sitaxsentan Iloprost IV, Teprostinil IV Ambrisentan, Bosentan
Yes No IIa-C Sitaxentan
Sildenafil, Tadalafil
Iloprost inhaled and i.v.
Continue CCB Treprostinil s.c., i.v., inhaled
Initial combination therapy
IIb-B Beraprost
Inadequate clinical response
se Sequential combination therapy (IIa-B)+

al respon
ate clinic ERA
BAS (I-C) and/or Inadequ
Lung transplantation (I-C) + +
Prostanoids + PDE-5 I
Figure 2. Evidence-based treatment algorithm for pulmonary arterial hypertension (PAH) patients (for group 1 patients only). Level of recommendation and evidence have been
evaluated in the ESC/ERS European Guidelines. IPAH: idiopathic pulmonary arterial hypertension; APAH: associated pulmonary arterial hypertension; WHO-FC: World Health
Organization functional class; CCB: calcium channel blockers; i.v.: intravenous; s.c.: subcutaneous; BAS: balloon atrial septostomy; ERA: endothelin receptor antagonist; PDE5 I:
phosphodiesterase type-5 inhibitor. #: to maintain arterial blood O2 pressure o8 kPa (60 mmHg); ": under regulatory review; +: IIa-C for WHO-FC II.
343
group 19 PVOD. If a ventilation/perfusion associated with anorexigen use are the most
scan is normal or shows only subsegmental likely to exhibit an acute positive response
patchy perfusion defects, a tentative and to profit from high-dose calcium-channel
diagnosis of group 1 - PAH or the rarer blocker therapy. Vasoreactive patients should
conditions of group 5 is made. Performing a be treated with optimally tolerated doses of
right heart catheterisation will be necessary to calcium channel blockers; adequate response
confirm the diagnosis and assess should be confirmed after 34 months of
hemodynamic severity. Additional specific treatment. Nonresponders to acute
diagnostic tests, including haematology, vasoreactivity testing who are in New York
biochemistry, immunology, serology and Heart Association (NYHA) functional class II
ultrasonography, will allow the final diagnosis should be treated with an ERA or a PDE5 I.
to be refined. 6-min walk distance is an Nonresponders to acute vasoreactivity testing,
important marker of exercise limitation with or responders who remain in (or progress to)
prognostic value in PAH. NYHA functional class III should be
considered candidates for treatment with
Treatment
either an ERA or a PDE5 I or a prostanoid. As
A treatment algorithm for PAH patients is head-to-head comparisons among different
shown in figure 2. The grades of compounds are not available, no evidence-
recommendation and levels of evidence for based first-line treatment can be proposed. In
the PAH treatments are derived from this case, the choice of drug is dependent on a
European Guidelines published jointly by the variety of factors, including the approval
European Respiratory Society and the status, the route of administration, the side-
European Society of Cardiology in 2010. Drug effect profile, patients preferences and
classes are listed by alphabetical order (ERA: physicians experience. Some experts still use
endothelin receptor antagonists; PDE5 I: first-line i.v. epoprostenol in NYHA functional
phosphodiesterase type-5 inhibitors; class III patients, because of its survival
prostanoids) and single compounds are listed benefits. Continuous i.v. epoprostenol may be
by alphabetical order within each class. The considered as first-line therapy for NYHA
treatment algorithm does not apply to functional class IV PAH patients because of
patients in other clinical groups, and in the survival benefit in this subset.
particular not to patients with PH associated
with group 2 left heart disease or with In case of inadequate clinical response,
group 3 pulmonary diseases. In addition, the sequential combination therapy should be
different treatments have been evaluated by considered. Combination therapy can either
randomised control trials mainly in idiopathic include an ERA plus a PDE5 I or a prostanoid
PAH, heritable PAH, PAH due to anorexigen plus an ERA or a prostanoid plus a PDE5 I.
drugs and in PAH associated with connective Appropriate protocols for timing and dosing
tissue diseases or with congenital heart to limit possible side-effects of the
diseases (surgically corrected or not). The combination have still to be defined.
grades of recommendation and levels of
Balloon atrioseptostomy and/or lung
evidence for the other PAH subgroups are lower.
transplantation are indicated for PAH with
The suggested initial approach, after the inadequate clinical response despite optimal
diagnosis of PAH, is the adoption of general medical therapy or where medical treatments
measures, the initiation of supportive therapy are unavailable. These procedures should be
and referral to an expert centre. Acute performed only in experienced centres.
vasoreactivity testing with inhaled nitric oxide
or intravenous prostacyclin or adenosine References
should be performed in all patients with N DAlonzo GE, et al. Survival in patients with
group 1 PAH, although patients with primary pulmonary hypertension. Ann Int Med
idiopathic PAH, heritable PAH, and PAH 1991; 115: 343349.

N Galie` N, et al. Guidelines for the diagnosis and N Humbert M, et al. Survival in patients with
treatment of pulmonary hypertension. The task idiopathic, familial, and anorexigen-associated
force for the diagnosis and treatment of pulmonary arterial hypertension in the modern
pulmonary hypertension of the European Society management era. Circulation 2010; 122:
of Cardiology (ESC) and the European Respiratory 156163.
Society (ERS), endorsed by the International N Rich S, et al. Primary pulmonary hypertension: a
Society of Heart and Lung Transplantation national prospective study. Ann Int Med 1987;
(ISHLT). Eur Respir J 2009; 34: 12191263. 107: 216223.
N Humbert M, et al. Pulmonary arterial hypertension N Simonneau G, et al. Updated clinical
in France: results from a national registry. Am J classification of pulmonary hypertension. J Am
Respir Crit Care Med 2006; 173: 10231030. Coll Cardiol 2009; 54: Suppl. 1, S43S54.
Pulmonary hypertension 345

CHAPTER 13:
PlEuRAl, mEdiASTinAl And
CHEST wAll diSEASES
PlEuRAl EffuSion 348

R. Loddenkemper
PnEumoTHoRAx And PnEumomEdiASTinum 352

P. Schneider
mEdiASTiniTiS 358
nEuRomuSCulAR diSoRdERS 361

A. Vianello
CHEST wAll diSoRdERS 366


PLEURAL EFFUSION
R. Loddenkemper
Former Chief of Department of Pneumology II, Lungenklinik Heckeshorn,
HELIOS Klinikum Emil von Behring, Berlin, Germany
E-mail: rloddenkemper@dzk-tuberkulose.de
Pleural effusion is defined as accumulation of

Key points fluid in the pleural space that exceeds the
physiological amounts of 1020 mL. Pleural
N Pleural effusions may present as effusion develops either when the formation
primary manifestations of many of pleural fluid is excessive or when fluid
diseases. However, most often they are resorption is disturbed. Pleural effusions may
observed as secondary manifestations represent a primary manifestation of many
or complications of other diseases. diseases, but most often they are observed as
secondary manifestations or complications of
N Cardiac failure is the main cause of
other diseases.
pleural effusions.
Pleural effusion is found in almost 10% of
N Of noncardiac causes, parapneumonic
patients who have internal diseases and the
effusions are commonest, followed by
main cause in 3040% of these is cardiac
malignant pleural effusions. failure. Among the noncardiac effusions,
N Small pleural effusions can be detected parapneumonic effusions are the most
best by ultrasound (or CT). common at 48%, of which ,75% are of
bacterial and 25% of viral origin. Malignant
N Pleural effusion can in the majority of pleural effusions follow in 24% of cases, half
cases be diagnosed by case history, of which are caused by lung or breast cancer.
clinical presentation, imaging techniques Pleural effusion is secondary to pulmonary
and examination of pleural fluid. embolism in 18% of cases, to liver cirrhosis in
N The most important laboratory 6%, and to gastrointestinal diseases, mainly
parameter of pleural fluid is total pancreatitis, in 3% of cases. Many other
possible causes, albeit extremely rare, play an
protein, distinguishing trans- and
important role in differential diagnosis.
exudates.
N Biopsy procedures such as closed-needle Pleural effusion may result from a number of
pathophysiological mechanisms, all of which
biopsy or medical thoracoscopy/
disturb the physiological balance between the
pleuroscopy may be necessary to
formation and removal of pleural fluid
confirm or exclude malignant or
(normal production estimated at 15 mL?day-1
tuberculous causes. in a 60-kg person). Most effusions develop
N Treatment depends upon the from both an increase in the entry rate of
underlying disease. liquid into the pleural space and a decrease in
the maximal exit rate of liquid from the
N Local treatment options include pleural space. Transudative effusions are
therapeutic thoracentesis, chest-tube caused either by increased hydrostatic
drainage, chemical pleurodesis and, pressure (e.g. in cardiac failure), or by reduced
rarely, surgical interventions. plasma oncotic pressure because of protein
deficiency (e.g. liver cirrhosis, nephrotic

syndrome). The pleura itself remains intact. resolve after appropriate treatment.
Rarely, transudates may arise from the entry Additional biopsy procedures, such as closed
of liquids with low protein concentrations (e.g. needle biopsy or medical thoracoscopy/
urine, cerebrospinal fluid or iatrogenic pleuroscopy, may be necessary to confirm or
intrapleural infusion of fluids). In contrast, exclude malignant or tuberculous causes.
pathological changes in the pleura result in These are performed in a stepwise diagnostic
exudation caused by diffuse increase of approach (fig. 1).
capillary permeability, due to localised
ruptures (e.g. blood vessels, lymphatic vessels, In many cases, evaluation of the pleural fluid
lung abscess, oesophagus) or to disturbed yields valuable diagnostic information or even
absorption (e.g. lymphatic blockage). permits a clear diagnosis. The most important
criteria are appearance, protein content and
Pleural effusion may present at all ages, but is cellular components. In case of more specific
mainly found in adults. Malignant pleural diagnostic questions, routine measurement of
effusions are observed mainly in patients the glucose content is supplemented by
aged .60 yrs; the most common determination of further laboratory
presentations are dyspnoea and chest pain,
and those of the individual underlying
diseases. Physical examination reveals
Diagnostic approach to pleural effusions
dullness on percussion, usually at the base of
the thorax, and decreased breath sounds.
Aetiology unknown Aetiology probable
Pleural effusion may be demonstrated by a (e.g. cardiac/renal)
number of techniques with different
sensitivities. The demonstration by percussion
requires at least 300400 mL of fluid, 1 Thoracentesis
Persistence Improvement
Colour? Protein? with therapy with therapy
whereas at least 200300 mL is necessary for Cells? Others?
standard chest radiography. Smaller amounts
can be recognised by lateral decubitus
radiography, which also demonstrates
Aetiology unknown Positive finding of:
whether the fluid is moving freely. Ultrasound malignant cells
is able to demonstrate small effusions, and bacteria, fungi, etc.
other specific parameter,
the sensitivity is almost 100% for volumes of e.g. amylase (>serum)
o100 mL. Computed tomography and
2 Blind
magnetic resonance imaging have very similar pleural biopsy
sensitivities, but require a more advanced
technology and are therefore much more
expensive.
Aetiology unknown
In the majority of cases, the aetiology is based
on the case history, clinical presentation, Histological finding
of malignancy or
imaging techniques and examination of the tuberculosis
pleural fluid. 3 Thoracoscopy
including biopsy
The presence of a pleural effusion is
established only by thoracentesis. The site Follow-up
should be selected according to the results of
the diagnostic procedures. If the effusion is In single cases
Aetiology unknown
small, thoracentesis can be performed under (<10%) open surgical
ultrasound guidance. Thoracentesis is biopsy
indicated in all cases of pleural effusion of
unknown origin and in effusions that do not Figure 1. Diagnostic approach to pleural effusions.
Pleural effusion 349

Table 1. Investigative parameters of pleural effusion Markedly elevated amylase values are
observed in acute pancreatitis and pancreatic
Obligatory
pseudocysts, oesophageal perforation and
Appearance
Total protein occasionally in malignant effusions.
Cell differentiation (cytology)
Haemothorax is characterised by purely
Optional bloody effusions and haematocrit values that
Glucose (pH) exceed those in peripheral blood by .50%.
Lactate dehydrogenase
Increased triglycerides distinguish chylous
Cholesterol
NT-proBNP
from pseudochylous effusions. Although
Triglycerides nonspecific, adenosine deaminase and T-cell-
Amylase based interferon-c release assays may allow
Bilirubin the diagnosis of tuberculosis as cause of
Creatinine pleural effusion with high sensitivity and
Haematocrit specificity.
Immunocytology
Tumour markers Diagnostic testing for the infecting organisms
Adenosine deaminase that cause pleural effusion is indicated in
Interferon-c release assay empyemas with aerobic and anaerobic
Antinuclear factor, rheumatoid factors, etc. cultures and in suspected tuberculous, fungal
Search for infecting organisms
or parasitic effusions.
Tubercle bacilli
Gram staining Therapeutic aims in patients with pleural
Anaerobic, aerobic bacteria
effusion are palliation of symptoms (pain,
Fungi, parasites
dyspnoea), treatment of underlying diseases,
NT-proBNP: N-terminal pro-B-type natriuretic peptide. prevention of pleural fibrosis with reduction of
pulmonary function, and prevention of
parameters and search for infecting organisms recurrences. The therapeutic approach
(table 1). depends on the availability of options for
causal or only symptomatic treatments.
The most important laboratory parameter is
total protein content in the effusion, for which Empyema usually requires, besides antibiotic
a threshold value of 30 g?L-1 separates a treatment, additional pleural drainage.
transudate from an exudate. However, this Resolution may be further facilitated by
value is not exclusive, and additional instillation of a fibrinolytic agent. In
parameters such as lactate dehydrogenase malignant pleural effusions, therapeutic
(LDH .200 U?L-1) or cholesterol thoracentesis or chest-tube drainage
(.0.55 mmol?L-1 (60 mg?dL-1)) may be combined with chemical pleurodesis or
helpful (table 2). The simultaneous medical thoracoscopy with talc poudrage are
determination of serum values is important, the preferred options for local treatment. In
because these may strongly influence the those resulting from tumours likely to respond
values in the pleura. Low glucose values may to chemotherapy or hormonal treatment,
indicate rheumatoid pleuritis, lupus pleuritis, systemic treatment should be started and may
empyema, tuberculous or malignant effusion be combined with therapeutic thoracentesis or
or oesophageal perforation. pleurodesis.
Table 2. Lights criteria for exudates

TP .3 g?dL-1 TP - pleura/TP - serum .0.5
LDH .200 U?L-1 LDH pleura/LDH serum .0.6
TP: total protein; LDH: lactate dehydrogenase. Sensitivity of ratios 89.5/91.4, accuracy 95.4/94.7.

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Pleural effusion 351

PNEUMOTHORAX AND
PNEUMOMEDIASTINUM
P. Schneider
DRK Kliniken Berlin, Thoracic Surgery, Berlin, Germany
E-mail: p.schneider@drk-kliniken-berlin.de
Introduction and classification In most instances the pneumothorax presents

with minor symptoms without any
Pneumothorax is defined as an accumulation physiological changes. Rarely, a simple
of air in the pleural space with secondary lung pneumothorax progresses and develops with
collapse. This accumulation is of diverse significant haemodynamic and respiratory
derivation, but visceral pleural rupture with air instability, hypoxia and shock. This clinical
leakage is the most common cause. An presentation is accompanied by a tension
original possible ruptured oesophagus with pneumothorax and demands emergency
diminished chest wall integrity can cause free treatment.
air in the pleural space, and more rarely a
gas-forming organism. The pneumothorax can be classified according
to cause or clinical presentation; or of
spontaneous, traumatic or iatrogenic aetiology
Key points (table 1). The first category includes primary
and secondary causes. A primary spontaneous
N The most likely cause of a primary pneumothorax occurs in individuals with no
spontaneous pneumothorax is the known pulmonary disease. A secondary
rupture of small subpleural bulla. pneumothorax occurs in patients with clinical or
radiographic evidence of underlying lung
N Pneumothorax usually present with
disease. Traumatic pneumothorax occurs as a
acute chest pain and dyspnoea.
result of penetrating or blunt trauma with
N Pneumothorax can be complicated by disruption of the bronchus, the lung, or the
persistent air leak .3 days, oesophagus. A traumatic pneumothorax is
pneumomediastinum and defined as open with an associated disruption
haemopneumothorax. of the chest wall. Iatrogenic pneumothorax
includes the diagnostic and therapeutic
N Recurrence is the most common pneumothorax, which are relatively common in
indication for surgery in patients with a the hospital environment but will not be
primary spontaneous pneumothorax. considered in this discussion.
N Surgery is accomplished by a video- Primary spontaneous pneumothorax
assisted thoracoscopy mechanical
abrasion, or by parietal apical Clinical features The most likely cause of a
pleurectomy in association with primary spontaneous pneumothorax is the
resection of the lung. rupture of small subpleural bulla (fig. 1),
occuring at rest or during exercise. It is seen
N In secondary pneumothorax the most often in young, tall male patients with
mortality rate for surgery may reach 10 admitted cigarette or cannabis smoking
percent and the morbidity is significant. habits. Hereditary aspects have been
described.

Table 1. Classification of pneumothorax on the affected side. Percussion of the chest
cavity is hyperresonant and tympanic, and on
Spontaneous
auscultation breath sounds are decreased or
Primary (healthy individuals)
Secondary (underlying pulmonary disease) absent. A pleural friction rub can sometimes
Chronic obstructive pulmonary disease be heard. Tachycardia is found in most
Infection patients.
Neoplasm
Catamenial Diagnosis The clinical diagnosis of a
Miscellaneous pneumothorax is best confirmed by erect
Traumatic posteroanterior and lateral chest radiographs.
Blunt Expiration posteroanterior chest radiography
Penetrating may be useful to demonstrate a small
Iatrogenic pneumothorax not seen on standard film.
Inadvertent
Diagnostic
Therapeutic Computed tomography scanning is generally
not necessary unless abnormalities are noted
on the plain chest radiograph or for further
evaluation (e.g. suspected secondary
In the North American population, incidence pneumothorax), or if an aberrant chest drain
varies from 67 per 100,000 men to 12 per emplacement is suspected.
100,000 women. Bilateral pneumothoraces
occur in ,10% of patients. Recurrences are Complications Air leakage may persist for
observed in 42% of patients, usually within .48 h after the treatment of a
2 yrs. After the second pneumothorax, the pneumothorax. Often the air leak is seen in
chances of having a third episode increase to patients with a secondary pneumothorax, but
.50%. occasionally patients with a primary
spontaneous pneumothorax develop this
The clinical presentation usually relates to the complication. In this instance, surgery must be
degree of pulmonary collapse. Although some considered.
patients have an asymptomatic
pneumothorax, more often they present with
Pneumomediastinum (fig. 2) is secondary to
acute chest pain and dyspnoea.
the dissection of air along the bronchial and
Physical findings may be totally absent if the pulmonary vessel sheets or as a complication
collapse is minimal, while substantial collapse of a spontaneous pneumothorax. It is
is defined in decreased chest wall movement generally of no clinical consequence, but
other causes of pneumomediastinum, such as
injury to major airways or oesophagus
perforation, may be needed to be excluded!
Pneumoperitoneum secondary to a
pneumothorax is rare, and it must be
differentiated from a pneumoperitoneum
associated with a perforated abdominal
organ. Interstitial and subcutaneous
emphysema are usually of no consequence.
Haemothorax (fig. 3) is a rare complication of a
pneumothorax and results more often from the
rupture of a small vessel located in adhesions
between the visceral and the parietal pleura.
Often re-expansion of the lung with a chest
Figure 1. Bulla on the apex. drain helps to tamponade the bleeding point.
Pneumothorax and pneumomediastinum 353

bullectomy with or without pleurodesis by
pleurectomy or gauze abrasion.
Observation Asymptomatic patients in

good health (,20%) with a small
pneumothorax and no evidence of
radiographic progression may be treated per
observation. To ensure no complications
develop, it is recommended that these
patients be observed in hospital for 2448 h.
Before discharge, patients must be warned of
a potential tension pneumothorax
Figure 2. Pneumomediastinum.
development. A weekly follow-up with clinical
examination and chest radiograph is to be
carried out until the pneumothorax has been
Occasionally the patient becomes hypotensive completely resolved. The main inconvenience
and requires emergency surgery. in this form of therapy is the duration, which
Bilateral pneumothorax happens in ,1% of far exceeds what is seen with conventional
cases and can be simultaneous or, more pleural drainage plus the added risk of a
tension pneumothorax development.
commonly, sequential.
Therefore observation only is inappropriate in
Management The different clinical most cases.
situations in spontaneous pneumothorax
require different therapeutic approaches. The Aspiration and small chest tube
nonoperative approach includes observation, drainage Simple aspiration of air with a
simple aspiration, and thoracostomy with 16-gauge intravenous cannula connected to a
ambulatory chest drainage. Chemical three-way stopcock and a 60-mL syringe is an
pleurodesis with tetracycline or talc are option.
options that can be used to reduce the risk of
recurrence. Surgical intervention entails apical Small 9-Fr. chest tubes with or without flutter
valves have also been used as an alternative to
larger and more conventional thoracostomy
tubes. The success rate is high, but problems
associated with kinking and occlusion of the
drains have been described. Treatment is still
controversial. Simple aspiration is recommended
by the British Thoracic Society but not by the
American College of Chest Physicians as first-
line treatment for the primary pneumothorax
requiring intervention. Acceptance by medical
staff is seemingly modest.
Conventional tube
thoracostomy Conventional tube
thoracostomy remains the procedure of choice
for the management of moderate-to-large
pneumothoraces. The drain allows for rapid
and complete evacuation of air from the
pleural space. Although underwater-seal
Figure 3. Haemopneumothorax on the right side. drainage is sufficient for most cases of

pneumothorax, the current author prefers the several sites. Segmentectomy and lobectomy
use of negative intrapleural pressure to are usually unnecessary and are
maintain lung re-expansion over a period of contraindicated.
5 days.
Obliteration of the pleural space is thought to
be necessary to prevent recurrences. It is
Nonsurgical therapy of
recurrences Most surgeons are concerned accomplished by mechanical abrasion, or by
about the routine use of chemopleurodesis in parietal apical pleurectomy (fig. 5), which is
the treatment of spontaneous pneumothorax. performed in association with resection of the
Being a benign disease occurring in young lung during a video-assisted thoracoscopy.
people who may require surgery in later life This operation is carried out under general
(for other disease development) the important anaesthesia with a dual-lumen endotracheal
symphysis which follows chemopleurodesis tube. Only two thoracic incisions are made for
complicates and multiplies the risk in the thoracoscope and dissecting or stapling
association with high morbidity rates, instruments.
especially if lung resection or transplantation
is considered. Chemical pleurodesis should Apical parietal pleurectomy can be performed
therefore be used only in selected cases. easily using this technique with modern endo-
scissors and forceps.
Indications for surgery Surgery may be
Video-assisted surgery is recommended as the
indicated in the first instance, if the
pneumothorax is complicated by a persisting first-line surgical treatment for patients with
air leak over 3 days. Furthermore, recurrent primary spontaneous pneumothorax.
haemothorax development, failure to re- This recommendation is based on its
expand the lung, bilateral involvement and favourable early postoperative course without
tension hazard are indications. Patients with major complication and the long-term
an occupational risk hazard are a classic outcome with 3% recurrence and patient
indication. Some authors have proposed that satisfaction.
all young patients with a diagnosed Secondary pneumothorax
spontaneous pneumothorax should be spared
a drain thoracostomy and proceed directly to Spontaneous pneumothorax can be secondary
surgical intervention. This approach is not to a variety of pulmonary and nonpulmonary
standard treatment, though many patients are disorders.
operated on as a result of complication or
disease recurrence. See table 2 for indications
Table 2. Indications for surgery in primary spontaneous
for surgery in primary spontaneous
pneumothorax
pneumothorax.
First episode
Prolonged air leak
Surgical therapy The principles of surgical Non re-expansion of the lung
intervention for spontaneous pneumothorax Bilateral pneumothoraces
consist of bulla or bleb resection (fig. 4) and Haemopneumothorax
obliteration of the pleural space to prevent Occupational hazard (flight personnel, divers)
recurrence. Absence of medical facilities in isolated area
Tension pneumothorax
Associated single large bulla
Recurrence is the most common indication for
Individual indication
surgery in patients with a primary Second episode
spontaneous pneumothorax. Ipsilateral recurrence
Contralateral recurrence after a first
Multiple wedge resections may also be pneumothorax
required when the disease is present at

Figure 6. Thoracoscopic view of bullous emphysema
with pneumothorax.
Figure 4. Specimen of an apical bulla resected by
stapler. (e.g. hyperresonance on percussion and
diminished breath sounds at auscultation). In
Chronic obstructive pulmonary disease (COPD) most cases, the diagnosis is made by chest
is the most common cause of secondary radiographs, which are also difficult to
pneumothorax (fig. 6, table 3). It occurs interpret because of the increased
typically in patients aged .50 yrs and is the radiolucency of the diseased lung. For these
result of a bulla rupture into the pleural space. difficult cases, computed tomography may be
necessary to confirm the diagnosis, localise
Most patients with COPD and pneumothorax the pneumothorax and facilitate distinction
present with chest pain and acute sudden between a large bulla and a pneumothorax.
respiratory distress. These patients show little
tolerance to even a small pneumothorax The emergency treatment of patients with a
because of their limited pulmonary function. secondary pneumothorax is similar to that
The diagnosis is difficult due to physical described for primary spontaneous
findings associated with COPD pneumothorax, except that observation alone
is seldom justified. If the pleural space is
adequately drained and the lung maintains a
re-expanded state, the air leak eventually
closes. In some patients, however, a
bronchopleural fistula persists for 1015 days,
and surgical repair must be considered.
When surgery is required, the procedure must
be individualised and based on the extent
and disease infiltration, as well as the air leak
location.
Staple resection of the bullae should be
carried out, followed by a subtotal parietal
pleurectomy or pleural abrasion.
The mortality rate for this surgery may reach
10% and morbidity is significant in those
individuals with a poor overall physical
Figure 5. Specimen of apical parietal pleurectomy. condition. Other options, such as chemical

Table 3. Causes of secondary pneumothorax pleurodesis, autologous blood injection and
permanent fistula drainage can be considered
Airway and pulmonary disease
in individual cases.
Chronic obstructive pulmonary disease
(bullous or diffuse emphysema) Summary
Asthma
Cystic fibrosis Primary spontaneous pneumothorax occurs in
Intersitial lung disease young patients with no evidence of coexisting
Pulmonary fibrosis (fig. 7) lung disease while secondary pneumothorax
Sarcoidosis is mostly seen in emphysema patients. Unless
Infectious disease there is a complication, most surgeons will
Tubercular and other mycobacterial
manage the first episode by conventional tube
Bacterial
Pneumocystis carinii
drainage. Recurrences are treated by bulla or
Parasitic bleb resection with apical parietal pleurectomy.
Mycotic Video-assisted surgery is the safest approach
AIDS with excellent long-term results.
Neoplasic
Bronchogenic carcinoma References
Metastatic (lymphoma or sarcoma) N Abolnik IZ, et al. On the inheritance of primary
Catamenial spontaneous pneumothorax. Am J Med Genet
Endometriosis 1991; 40: 155158.
Miscellaneous N Aguinagalde B, et al. Percutaneous aspiration
Marfans syndrome versus tube drainage for spontaneous
EhlersDanlos syndrome pneumothorax: systematic review and meta-
Histiocytosis X analysis. Eur J Cardiothorac Surg 2010; 37:
Scleroderma 11291135.
Lymphangiomyomatosis N Baumann MH, et al. Management of
Collagen disease spontaneous pneumothorax: an American
College of Chest Physicians Delphi consensus
statement. Chest 2001; 119: 590602.
N Ben-Nun A, et al. Video-assisted thoracoscopic
surgery for recurrent spontaneous
pneumothorax: the long-term benefit. World J
Surg 2006; 30: 285290.
N Beshay M, et al. Emphysema and secondary
pneumothorax in young adults smoking cannabis.
Eur J Cardiothorac Surg 2007; 32: 834838.
N Chambers A, Scarci M. In patients with first-
episode primary spontaneous pneumothorax is
video-assisted thoracoscopic surgery superior to
tube thoracostomy alone in terms of time to
resolution of pneumothorax and incidence of
recurrence? Interact Cardiovasc Thorac Surg
2009; 9: 10031008.
N Chen JS, et al. Management of recurrent primary
spontaneous pneumothorax after thoracoscopic
surgery: should observation, drainage, redo
thoracoscopy, or thoracotomy be used? Surg
Endosc 2009; 23: 24382444.
N Henry M, et al. BTS guidelines for the
Figure 7. Severe pulmonary fibrosis with management of spontaneous pneumothorax.
pneumothorax on the left side. Thorax 2003; 58: Suppl. 2, ii39ii52.

MEDIASTINITIS
Universite Louis Pasteur and Ho
pitaux Universitaires de Strasbourg,
Strasbourg, France
E-mail: pierre-emmanuel.falcoz@wanadoo.fr
The majority of acute mediastinal infections

results from oesophageal perforation or Key points
infection following a trans-sternal cardiac
procedure. Occasionally, acute mediastinitis N DNM is a particularly virulent and
results from oropharyngeal abscesses with potentially lethal mediastinal infection.
severe cervical infection spreading along the N Initial presentation is toxic shock and
fascial planes into the mediastinum. This respiratory difficulty, sometimes with
particularly virulent form of mediastinal
other signs such as erythema and
infection is described as descending
oedema of the neck and upper chest.
necrotising mediastinitis (DNM).
DNM is a potentially lethal condition
N DNM is an emergency, and should be
treated with broad-spectrum i.v.
especially if diagnosis or treatment is delayed
antibiotics as well as early and
or inapropriate. Despite the introduction of
aggressive surgical drainage.
modern antimicrobial therapy and computed
tomographic (CT) imaging, DNM has
continued to produce high mortality rates
(reported between 25% and 40%).
WHEATLEY et al. (1990), the most common
Criteria for diagnosis of DNM primary oropharyngeal infection is
Criteria for diagnosis of DNM have been odontogenic (25 of 43 cases) with
accurately defined as follows: mandibular second or third molar abscess.
Route of diffusion
N Clinical manifestations of a severe
infection. Familiarity with the cervical fascial planes is
essential in understanding the propagation
N Establishment of a relationship between an
pathways, symptoms and thoracic
oropharyngeal or cervical infection and
complications of cervical infections. The
subsequent mediastinitis.
infection from neck to mediastinum spreads
N Demonstration of radiographic features along three primary routes: via the
characteristic of DNM. retropharyngeal space, the perivascular space
and the pretracheal space. The
N Documentation of a necrotising retropharyngeal space has been thought to be
mediastinal infection at the time of the most important route by which a cervical
operative debridement or necropsy. infectious disease spreads to the mediastinum
Epidemiology (70% of cases in the series of MONCADA et al.
(1978)). Rapid spread of infection is
Primary sites of infection are peridontal facilitated by tissue necrosis (loose of
abscess, retropharyngeal abscess, and anatomical structure), gravity and negative
peritonsillar abscess. According to intrathoracic pressure.

Pathogens involved often have a nonspecific constellation of
symptoms. Various CT imaging findings are
DNM is a polymicrobial process with increased attenuation of mediastinal fat, air
anaerobic organisms being the most fluid levels, pleural and pericardial effusions,
predominant. FREEMAN et al. (2000) reviewed oesphageal thickening and enlarged lymph
the English literature and found 96 patients nodes. BRUNELLI et al. (1996) found
with DNM between 1990 and 1999. All but cervicothoracic CT imaging to be immediately
four (4%) had mixed aerobic and anaerobic diagnostic in all patients in whom it was used.
infection, with those pathogens acting often
synergistically; in the four exceptions, the sole Treatment
pathogen was b-haemolytic Streptococcus.
Principles of treatment are:
CHOW et al. (1978) reported that anaerobes
had been recovered from 94% of patients N Emergency.
with DNM; 52% had mixed infections and
88% had polymicrobial infections. N Intravenous broad-spectrum antibiotic
therapy: probabilistic and secondarily
Clinical and radiological signs adapted to the pathogen(s).
Anamnesis: N Early and aggressive surgical drainage:
extensive debridement, excision of necrotic
N Phase I: periodontal or peritonsillar abscess tissue, bacteriological sampling,
treated by simple antibiotherapy. mediastinal and pleural irrigation, feeding
N Phase II: erythema and oedema of the neck jejunostomy.
associated with subcutaneous
The decision on the type of surgical drainage
emphysema.
to be employed is a crucial one. Four
N Phase III: acute aggravation of the approaches have been classically reported:
infectious syndrome; onset of cough, transcervical, standard posterolateral
dyspnoea, sternal pain and painful dysphagia. thoracotomy, median sternotomy and
transthoracic via subyphoid or clamshell
Patients with DNM usually present with toxic incision. Thoracoscopic approach and video-
shock and respiratory difficulty. Other assisted mediastinoscopic drainage can also
presenting signs may include erythema and be found. Although each of these techniques
oedema of the neck and upper chest. In offers potential advantages and
severe infections, frank necrosis of skin, fascia disadvantages, the posterolateral thoracotomy
and muscle may be present. In the chest, incision (sometimes bilateral) remains the
DNM may produce abscesses and empyemas, standard by which other transthoracic
pleural and pericardial effusions, intrathoracic approaches should be measured.
haemorrhage and cardiac tamponade, and
frequently results in the death of the patient. The optimal surgical approach for mediastinal
drainage is theoritically dependent on the
Delay of diagnosis is one of the primary level of diffusion of necrotising process.
reasons for high mortality in DNM. Diagnosis Several studies have reported that mediastinal
of DNM from conventional radiographic drainage is best accomplished through a
studies may be difficult, principally because transthoracic approach when the necrotising
the signs appear late in the course of the process extends below the level of the fourth
disease. Cervicothoracic CT imaging is thoracic vertebra posteriorly or the tracheal
currently considered as the diagnostic study of bifurcation anteriorly. However, because of
choice for patients in whom DNM is the rapid spread of this type of infection,
suspected. Indeed, CT scan findings have been other investigators have advocated mandatory
proven to confirmed the diagnosis of DNM transthoracic mediastinal exploration
with high accuracy in these patients who regardless of the level of infection. This latter
Mediastinitis 359
point was confirmed in a meta-analysis, where with persistent symptoms of septicaemia after
a statistically significant difference (p,0.05) being treated for oropharyngeal infections.
in survival was found between patients Prompt surgical drainage of the mediastinum
undergoing transcervical mediastinal should be performed. Optimal mediastinal
drainage (53%) versus those receiving drainage method should be tailored to each
transthoracic mediastinal drainage (81%). patients condition and extension of the
mediastinitis (posterolateral thoracotomy is
Close-watch care Recurrent abscesses and
frequently required). In the postoperative
collections are common after first operative
period, progression of the disease and
drainage (50%) and they should be drained
effectiveness of surgical therapy should be
promptly. CT scan (at best) or ultrasound-
monitered by CT scanning. Further drainage
guided percutaneous drainage (for lack) of
should be carried out if necessary either
recurrent abscesses and collections may
surgically or by percutaneous drainage.
decrease the need for recurrent surgical
procedures in these critically ill patients. References
Surveillance should be continued until no
evidence of progressive infection is found on CT
N Brunelli A, et al. Descending necrotizing
mediastinitis: cervicotomy or thoracotomy? J
imaging and the patient displays no clinical Thorac Cardiovasc Surg 1996; 111: 485486.
signs of infection. Hyperbaric oxygen therapy N Chow AW, et al. Orofacial odontogenic
has not shown any real proof of effectiveness in infections. Ann Intern Med 1978; 88: 392402.
this particular framework, when looking at N Corsten MJ, et al. Optimal treatment of
evidence-based medicine. It should not take the descending necrotizing mediastinitis. Thorax
place or delay surgical treatment. 1997; 52: 702708.
N Devaraj A, et al. Computed tomography findings
Mediastinal fibrosis Fibrosing in fibrosing mediastinitis. Clin Radiol 2007; 62:
781786.
mediastinitis is an uncommon chronic sequela
of prior infectious mediastinal involvement. A
N Estera AS, et al. Descending necrotizing
mediastinitis. Surg Gynecol Obstet 1983; 157:
chronic, noninfectious inflammatory process 545552.
results in progressive mediastinal fibrosis. The N Freeman RK, et al. Descending necrotizing
fibrosis may constrict or obstruct virtually any mediastinitis: an analysis of the effects of serial
of the mediastinal organs (in particular, surgical debridement on patient mortality. J
superior vena cava, oesophagus, pulmonary Thorac Cardiovasc Surg 2000; 119: 260267.
vein or artery). CT scans demonstrate a N Marty-Ane CH, et al. Management of
localised (or less frequently diffuse) mass descending necrotizing mediastinitis: an
infiltrating the mediastinum and constricting aggressive treatment for an aggressive disease.
the structure; extensive calcification is Ann Thorac Surg 1999; 68: 212217.
associated with the fibrotic mass in a vast N Moncada R, et al. Mediastinitis from
odontogenic and deep cervical infection:
majority of the cases. This appearance is anatomic pathways of propagation. Chest 1978;
pathognomonic of the disorder. 73: 497500.
N Shimizu K, et al. Successful video-assisted
Conclusions mediastinoscopic drainage of descending
necrotizing mediastinitis. Ann Thorac Surg
DNM is caused by downward spread of neck 2006; 81: 22792281.
infections and constitutes a highly fatal N Wheatley MJ, et al. Descending necrotizing
complication of oropharyngeal lesions. CT mediastinitis: transcervical drainage is not
imaging should be performed in all patients enough. Ann Thorac Surg 1990; 49: 780784.

NEUROMUSCULAR
DISORDERS
A. Vianello
Respiratory Physiology Division, University-City Hospital of Padova, Padova,
Italy
E-mail: avianello@qubisoft.it
Various neuromuscular diseases (NMD) can

progress to the point where they cause Key points
pulmonary complications (table 1); a careful
respiratory follow-up adapted to the variable N NMD have a range of causes, but
time course of each disease is therefore common principles apply to their
mandatory. Although the diseases have treatment.
different causes and clinical courses, common
principles apply in their management.
N Treatment focuses on ventilatory
assistance and assisted coughing
Evaluation of patients with suspected techniques.
respiratory impairment
Clinical evaluation As the first step, a
Indicators of bulbar muscle involvement
systematic clinical evaluation is essential to
include dysarthria, trouble swallowing liquids,
detect the subtle respiratory symptoms and
aspiration manifesting as a new-onset cough,
signs related to respiratory muscle failure.
or frank choking.
Symptoms are frequently nonspecific,
including fatigue, lethargy, or difficulty in
concentrating. Dyspnoea and orthopnoea are Pulmonary function testing Pulmonary
often late findings in patients with usually function tests (PFT) should be routinely
severe functional impairment due to performed during the evaluation of patients
peripheral muscle weakness. Patients with with NMD. Because of the inadequacy of
sleep-disordered breathing (SDB) often seem inspiratory muscle function, PFT generally
reveals a pattern of restrictive ventilatory
to have symptoms such as an unrefreshed
defect, with the following characteristics:
feeling upon awakening, morning headaches,
disappearance of snoring, daytime tiredness,
and irritability as a result of repeated arousals N preserved total lung capacity until a
and carbon dioxide retention. Physical far-advanced stage of the disease
evaluation is essential and may reveal an
increase in respiratory rate, followed by
N elevated residual volume
alternating abdominal and rib cage breathing N reduced vital capacity (VC)
(respiratory alternans), the absence of
outward excursion of the abdomen during
N preserved functional residual capacity
inspiration or even paradoxical inward When VC falls below 55% of predicted values,
inspiratory movement due to diaphragm the onset of insidiously progressive
weakness (abdominal paradox), accessory hypercapnia is likely. A significant difference
muscle recruitment, and mucous between upright and recumbent lung volumes
encumbrance of upper or lower airways. has been reported frequently for patients with
Neuromuscular disorders 361

Table 1. NMD affecting respiratory function
Site of lesion Specific disorders
Anterior horn cell Amyotrophic lateral sclerosis
Poliomyelitis
Type I SMA, intermediate SMA
Peripheral nerve and/or nerve roots GuillainBarre` Syndrome
CharcotMarieTooth disease
Neuromuscular junction Congenital myasthenia
Muscle Duchenne/Becker muscular dystrophy
Limb-girdle muscular dystrophy (especially types 2C-2F-2I)
Facio-scapolo-humeral muscular dystrophy
Congenital muscular dystrophy
Congenital myotonic dystrophy
Acid maltase deficiency
Congenital myopathy
Mitochondrial myopathy
Bethlem myopathy
SMA: spinal muscular atrophy.
NMD; in particular, a fall in VC of o25% has Sleep study All patients with NMD should
been considered a sensitive indicator of be monitored carefully for the presence of
diaphragmatic weakness. A specific SDB. Nocturnal oximetry alone is inadequate
evaluation of respiratory muscle strength is at detecting sleep apnoea and
mandatory as these tests are both sensitive hypoventilation. In addition, criteria defining
and highly prognostic. A high-negative significant desaturations remain controversial.
maximal inspiratory pressure (MIP) result Overnight polysomnography (PLSG) or
(,-80 cm H2O) or a high positive maximal respiratory polygraphy (RP) is advisable for
expiratory pressure result (.+90 cmH2O) patients who develop symptoms and signs of
excludes clinically relevant inspiratory or
expiratory muscle weakness. Cough peak
expiratory flow (CPEF) is the single most Examinations required in the assessment
important factor in determining whether the of respiratory function in patients with
ability to eliminate bronchial secretions is well NMD are:
preserved. Patients who either alone or with N Checklist of symptoms and signs.
assistance are able to generate a CPEF
.260 L?min-1 can effectively remove N Vital capacity sitting or standing, and
bronchial secretions, whereas those with a lying.
CPEF ,160 L?min-1 usually require tracheal
suctioning at the onset of respiratory
N Maximal inspiratory and expiratory
pressures.
infections. The frequency of pulmonary
function monitoring depends on the rapidity N Cough-peak expiratory flow.
of progression of the neuromuscular syndrome
and may range from every 12 months to
N Arterial blood gases, if symptoms
present.
yearly. Once the VC drops below 4050%
predicted, or MIP below 30% predicted, N PLSG or RP, if symptoms or nocturnal RF
daytime arterial blood gases should be present.
performed.

sleep-wake abnormality or nocturnal Indications for NPPV therapy in chronic NMD
respiratory failure (RF). It has been suggested are:
that PLSG or RP should be performed in all
1. Symptoms (such as fatigue, dyspnoea,
NMD patients as early as possible to take a
morning headache) and one of the following:
baseline recording. It should be repeated
according to the course of the disease to 2. Physiological criteria:
detect abnormalities during sleep and
subsequent indication to long-term ventilatory N Significant daytime CO2 retention (arterial
treatment. CO2 tension . 50 mmHg).
N Nocturnal oxygen desaturation (arterial
Management oxygen saturation ,88% for at least five
consecutive minutes).
Noninvasive positive pressure
ventilation (NPPV) In recent years, the N Forced VC ,50% predicted or MIP
approach of care in neuromuscular RF has ,60 cmH2O, only for rapidly progressive
been revised, due to two new critical disease.
developments: 1) technology has advanced
and several new types of ventilatory aids have The following complications are considered to
been introduced, which deliver effective be contraindications for the noninvasive
mechanical ventilation (MV), even ventilatory approach:
noninvasively. 2) the majority of severely
disabled ventilator users have expressed
N Severely impaired swallowing, leading to
chronic aspiration and repeated pneumonia.
satisfaction with their lives, even though
they are usually unable to achieve some of N Ineffective clearing of tracheobronchial
the goals associated with acceptable quality secretions, despite the use of noninvasive
of life in the "normal" population. manual or mechanical expiratory aids.
As a consequence, increasing numbers of

N The need for around-the-clock (.20 h)
ventilatory support.
NMD patients with advanced respiratory
impairment are now being successfully These conditions usually require an invasive
treated by long-term NPPV usually in the application of MV via tracheostomy. There is
home setting. The non-invasive administration no consensus on the optimal interface to use
of positive pressure ventilation requires a in delivering NPPV: nasal masks are usually
positive pressure ventilator delivering preferable for nocturnal ventilation, due to the
pressurised gas to the lungs through an fact that they are more comfortable and
interface with the nose or mouth, or both. permit better speech; conversely, oronasal
In recent years, manufacturers have developed interfaces may be a suitable alternative for
a new generation of microprocessor-controlled subjects who have excessive air leaking
ventilators that supply both volume- and through the mouth or nose. Mouthpiece
pressure-limited modes. Also, special features interfaces have also been successfully used to
have been incorporated that are designed to deliver NPPV for up to 24 h?day-1. Finally, the
facilitate the application of noninvasive choice of ventilator and interface in most
techniques and are simple, reliable and easy cases is individualised according to patients
for the patient to use. preference and physicians intuition and
experience, rather than based on standardised
Long-term NPPV is required when evidence-based guidelines. Administration of
spontaneous respiratory muscle efforts are NPPV to NMD patients with chronic RF may
unable to sustain adequate alveolar be expected to allow some individuals with
ventilation, causing chronic-stable, or slowly nonprogressive pathology to live to nearly
progressive RF. normal life expectancy, extend survival by

many years in patients with other conditions,
improve physiological lung function and
quality of life (QoL), as well as decrease the
frequency of exacerbations requiring acute
care facilities. Although ineffective for
prolonging survival in patients with rapidly
progressive conditions and advanced bulbar
muscle involvement, such as amyotrophic
lateral sclerosis/motor neurone disease, NPPV
may be added with the aim of improving
some aspects of the QoL, in particular energy,
vitality and symptoms related to SDB, being
Figure 1. Application of mechanical insufflation
considered as an important part of the total exsufflation combined with manually assisted
palliative care plan for terminally ill cases. coughing during respiratory tract infection.
Assisted coughing techniques The onset
of acute RF in patients with advanced stage special competence in the management of
NMD may be caused by airway encumbrance such patients have the responsibility of
with mucous as a result of weakened offering these treatment options, encouraging
respiratory muscles and an inability to cough the patients to decide in advance whether or
effectively. A noninvasive approach to the not these measures would be acceptable.
management of tracheobronchial secretions, References
based on the combination of expiratory
muscle aid and NPPV, has been proposed. This N Bach JR, et al. Prevention of pulmonary
treatment strategy may result in a reduced morbidity for patients with Duchenne muscular
dystrophy. Chest 1997; 112: 10241028.
need for nasal suctioning and conventional
intubation, and/or tracheostomy. Among
N Bourke SC, et al. Effects of non-invasive
ventilation on survival and quality of life in
noninvasive expiratory aids, manually assisted patients with amyotrophiclateral sclerosis: a
coughing (MAC) techniques have been randomised controlled trial. Lancet Neurol
demonstrated to be effective in facilitating 2006; 5: 140147.
the elimination of airway secretions. N Braun NM, et al. Respiratory muscle and
Additionally, mechanical insufflation- pulmonary function in polymyositis and other
exsufflation (MI-E) has been shown to proximal myopathies. Thorax 1983; 38:
effectively mobilise mucous secretions and 616623.
has been proposed as a complement to MAC N Clinical indications for noninvasive positive
pressure ventilation in chronic respiratory failure
techniques in the prevention of pulmonary due to restrictive lung disease, COPD, and
morbidity during respiratory tract infections nocturnal hypoventilation a consensus
(fig. 1). MI-E can be administered by a device conference report. Chest 1999; 116: 521534.
consisting of a two-stage axial compressor N Gomez-Merino E, Bach JR. Duchenne muscular
that provides positive pressure to the airway, dystrophy: prolongation of life by noninvasive
then rapidly shifts to negative pressure, ventilation and mechanically assisted coughing.
thereby generating a forced expiration. Am J Phys Med Rehabil 2002; 81: 411415.
N Hill NS. Ventilator management for
neuromuscular disease. Semin Respir Crit Care
Conclusion Med 2002; 23: 293305.
It is now clear that life can be greatly
N Kohler M, et al. Quality of life, physical disability,
and respiratory impairment in Duchenne
prolonged for most individuals with NMD by muscular dystrophy. Am J Respir Crit Care Med
the availability of noninvasive aids and that 2005; 172: 10321036.
the great majority of severely disabled N Lofaso F, Quera-Salva MA. Polysomnography for
patients submitted to ventilatory assistance the management of progressive neuromuscular
are satisfied with their lives. Clinicians with a disorders. Eur Respir J 2002; 19: 989990.

N Mellies U, et al. Daytime predictors of sleep N Vianello A, et al. Long-term nasal intermittent
disordered breathing in children and positive pressure ventilation in advanced
adolescents with neuromuscular disorders. Duchennes muscular dystrophy. Chest 1994;
Neuromusc Disord 2003; 13: 123128. 105: 445448.
N Polkey MI, et al. Respiratory aspects of N Vianello A, et al. Mechanical insufflation
neurological disease. J Neurol Neurosurg exsufflation improves outcomes for neuromuscular
Psychiatry 1999; 66: 515. disease patients with respiratory tract infections.
N Simonds A, et al. Impact of nasal ventilation on Am J Phys Med Rehabil 2005; 84: 8388.
survival in hypercapnic Duchenne muscular N Vianello A, et al. Non-invasive ventilatory
dystrophy. Thorax 1998; 53: 949952. approach to treatment of acute respiratory
N Simonds AK. Recent advances in respiratory care failure in neuromuscular disorders. A
for neuromuscular disease. Chest 2006; 130: comparison with endotracheal intubation. Int
18791886. Care Med 2000; 26: 384390.

CHEST WALL DISORDERS
Universite de Strasbourg and Hopitaux Universitaires de Strasbourg,
Strasbourg, France
E-mail: pierre-emmanuel.falcoz@chru-strasbourg.fr
There is a large and diverse group of pectus deformities have just started to emerge
congenital abnormalities of the thorax that and hopefully will answer many questions
manifest as deformities and/or defect of the unanswered so far.
anterior chest wall. Depending on the severity
of the case, the cardiopulmonary sphere PE
(tolerance to exercise) as well as the PE is a recessively inherited chest wall
psychological area may be implicated. deformities with an occurrence of 0.3% of all
This diverse group includes pectus excavatum births (9:1 predominance in males). In
(PE), pectus carinatum (PC), Poland syndrome patients with PE, the normal moderately
and cleft sternum. Among them, the two most convex contour of the anterior chest wall is
common chest wall abnormalities are PE replaced by precordial depression. Depending
(funnel chest) and PC (keel chest). on the severity of the anomaly, the sterno-
vertebral space is narrowed, there is a shift of
Pathogenesis the heart into the left hemithorax and
Over the years, the theories concerning the pulmonary expansion is confined.
pathogenesis of pectus deformities evolved The PE indications for surgery may be
from substernal ligament traction to summarised as follows:
overgrowth of the rib cartilage and later to a
stressstrain imbalance. The genetic aspects of N Aesthetic (psychological repercussion)
N Symptom
Key points
N Exercise intolerance; decreased endurance;
N The two most common chest wall exercise-induced asthma
abnormalities are pectus excavatum N Body images issues (computed tomography
and pectus carinatum. (CT) scan)
N The two most common surgical N Pain
procedures for pectus excavatum repair
are the modified Ravitch technique and N Abnormal/low forced vital capacity, forced
the Nuss technique. expiratory volume in 1 s, maximum
voluntary ventilation
N Careful pre-operative evaluation on the
basis of clinical but also psychological N Decreased oxygen pulse, oxygen uptake,
symptoms is required to select potential minute ventilation
candidates for surgical remodelling. N Echocardiogram: compression of right
N The optimal timing of surgical repair atrium/right ventricle (rare)
would be after the main growth has
stopped (late teens or early 20s).
N CT Haller index .3.0
N Calliper measurement depth . 2.5

PC PC The repair of PC, including exposure,
detachment of the pectoralis muscles,
In PC, the clinical aspect includes a variety of transverse osteotomy and resection of the
protrusion deformities of the anterior chest deformed cartilages, is largely identical to
wall. The most common variety consists of that described in PE. Operative correction
anterior displacement of the sternal gladiolus required double bilateral chondrotomy
with the appropriate cartilages in tow. In parasternally and at points of transition to
severe forms, there is also a narrowing of the normal ribs, followed by detorsion of the
transverse diameter of the chest, which seems sternum, retrosternal mobilisation and
to further exaggerate the anomaly. correction of the everted sternum, as well as
of the everted and inverted ribs. After
The PC indications for surgery may be
incomplete wedge osteotomy the
summarised as follows:
mobilised sternum is finally stabilised by
N Aesthetic (psychological repercussion) a temporary support bar anterior to the
sternum and cartilages (in place for at least
N Pain 6 months).
N Frequent injury
Controversies
N Body image issues
Some controversies do need to be mentioned:
N Abnormal pulmonary function testing
First, concerning PE, there has never been a
Surgical treatment randomised controlled trial comparing the
results of the two most common surgical
PE Although there are a number of different procedures (there is currently an ongoing
techniques utilised by surgeons, most repairs evaluation from a multi-centre study).
performed today will be either the modified Secondly, concerning the optimal timing of
Ravitch technique or the Nuss procedure (note surgical repair, it seems that the best time for
that the Wada procedure of sternal turnover repair would be after the main growth has
is no longer realised). stopped (i.e. after adolescence in the late
teens or early 20s), as opposed to an early
repair. Although the operation is more
The Ravitch technique requires the exposition
traumatic after adolescence, the results are far
of the thoraxs anterior region (horizontal
better with minimal recurrence. Thirdly, the
inframammary fold incision preferred) with
goal of such an approach remains elusive. Not
resection of costal cartilages affected
only are we unable to reach an agreement on
bilaterally, the performance of a cross-sternal
such simple issues as how to measure the
osteotomy with the placing of a temporary
clinical or even the anatomical severity of
stabiliser (support bar anterior to the
pectues deformities, but we are still engaged
sternum), and the development of a
in a seemingly endless debate with the
muscular flap.
insurance companies as to whether these
The Nuss technique is an alternative and new often physiologically and psychologically
technique done by means of minimally crippling abnormalities should be even
invasive surgery and based on the skeletons considered a disease at all.
malleability and the remodelling capacity of Conclusions
the thorax. The techique consists in the
implantation of a retrosternal steel bar that Chest wall abnormalities, PE and PC, are a
would modify the concavity of the sternum relatively rare problem, but are commonly
while maintening the contour of the reformed seen in the practice of general thoracic
thorax, all done by means of two small surgery. Careful pre-operative evaluation on
incisions on each side of the thorax. the basis of clinical but also psychological
Chest wall disorders 367

symptoms is required to select potential N Haller JA, et al. Evolving management of pectus
candidates for surgical remodelling. Surgical excavatum based on a single institutional
procedures, based on the surgeons personal experience of 664 patients. Ann Surg 1989;
expertise, are currently relatively well codified 209: 578583.
and provide satisfactory results with a low
N Huddelston CB. Pectus excavatum. Semin Thorac
Cardiovasc Surg 2004; 16: 225232.
rate of complications. N Nuss D, et al. A ten-year review of minimally
References invasive technique for the correction of pectus
excavatum. J Pediatr Surg 1998; 33: 545552.
N Colombani PM. Preoperative assessment of chest N Ravitch MM. The operative treatment of pectus
wall deformities. Semin Thorac Cardiovasc Surg excavatum. Ann Surg 1949; 129: 429444.
2009; 21: 5863. N Robicsek F, Fokin AA. Surgical repair of anterior
N Feng J, et al. The biomechanical, morphologic, chest wall deformities: the past, the present, the
and histochemical properties of the costal future. Introduction. Semin Thorac Cardiovasc
cartilages in children with pectus excavatum. J Surg 2009; 21: 43.
Pediatr Surg 2001; 36: 17701776. N Robiscek F, et al. Surgical repair of pectus
N Fonkalsrud EW, Anselmo DM. Less extensive excavatum and carinatum. Semin Thorac
techniques for repair of pectus carinatum: the Cardiovasc Surg 2009; 21: 6475.
undertreated chest deformity. J Am Coll Surg N Saxena AK, Willital GH. Surgical repair of pectus
2004; 198: 898905. carinatum. Int Surg 1999; 84: 326330.
N Gurnett CA, et al. Genetic linkage localizes an N Shamberger SC, Hardy Hendren W III.
adolescent idiopathic scoliosis and pectus Congenital deformities. In: Pearson FG, et al.,
excavatum gene to chromosome 18 q. Spine eds. Thoracic Surgery. New York, Churchill
(Phila Pa 1976) 2009; 34: E94E100. Livingstone, 1995; pp. 11891209.

CHAPTER 14:
THoRACiC TumouRS
lung CAnCER 372

CHEmoTHERAPy And oTHER AnTi-TumouR 377

THERAPy foR THoRACiC mAlignAnCiES
PRinCiPlES of SuRgiCAl TREATmEnT foR 382

EARly-STAgE nonSmAll CEll lung CAnCER
mETASTATiC TumouRS 388

E. Quoix
PlEuRAl And CHEST wAll TumouRS 392

A. Scherpereel
mEdiASTinAl TumouRS 399

P.E. Van Schil, P. Lauwers and J.M. Hendriks

LUNG CANCER
Respiratory Oncology Unit/Pulmonology, University Hospital Leuven,
Belgium
E-mail: johan.vansteenkiste@uz.kuleuven.ac.be
Lung cancer is the most common cause of Several molecular genetic abnormalities have
cancer-related mortality worldwide for both been described in lung cancer, including
males and females, with an incidence of chromosomal aberrations (e.g. chromosome
about 1.3 million cases per year. The term 3p or 8p deletions), overexpression of
lung cancer, or bronchogenic carcinoma, oncogenes (K-ras, c-MET, Bcl-2, etc.), deletions
refers to malignancies that originate in the and/or mutations in tumour suppressor genes
airways or pulmonary parenchyma. (p53, retinoblastoma gene, genes on
chromosome 3p) or altered telomerase
Epidemiology activity.
Lung cancer occurs through a complex Classification of malignant lung
multistage process that results from the tumours
combination of carcinogen exposure and
genetic susceptibility (fig. 1). The World Health Organization (WHO)
classification of lung tumours is based on
A number of lifestyle and environmental histological characteristics in surgical samples
factors have been associated with the or biopsies and is primarily based on light-
development of lung cancer, of which optic microscopy. The following major
cigarette smoking is the most important. subcategories can be distinguished:
Cigarette smoking accounts for ,8090% of
all lung cancers. Compared with nonsmokers, Pre-invasive lesions: mild, moderate, severe
smokers have an ,20-fold increase in lung squamous dysplasia and carcinoma in situ are
cancer risk, depending on the duration of precursors of squamous cell carcinoma,
smoking and the number of cigarettes smoked atypical adenomatous hyperplasia of
per day. Cigarette smokers can benefit at any adenocarcinoma; and diffuse idiopathic
age from smoking cessation: as the period of pulmonary neuroendocrine cell hyperplasia of
abstinence from smoking increases, the risk of neuroendocrine tumours.
lung cancer decreases, although it remains
Small cell lung cancer (SCLC): carcinoma with
elevated compared with never-smokers. In
typical small cells, closely linked to smoking. A
recent years, an increasing number of never-
smoker patients present with a lung cancer,
often of adenocarcinoma histology. A number Key points
of other factors may also affect the risk of
developing lung cancer, such as underlying N Combined modality treatment has
acquired lung diseases (chronic obstructive improved cure rates for nonmetastatic
pulmonary disease and pulmonary fibrosis) patients.
and environmental exposures, often
synergistically with smoking (asbestos, radon, N Systemic therapy has improved quantity
metals, ionising radiation including previous and quality of life for metastatic
radiotherapy and polycyclic aromatic patients.
hydrocarbons).

Cigarette Metabolic Persistence
smoking activation Mutations and other
Nicotine PAH, NNK and DNA changes: RAS, MYC, Lung
addiction other carcinogens adducts P53, p16, RB, FHIT, cancer
Miscoding and other critical genes
Metabolic
detoxification Repair
Excretion Normal DNA Apoptosis
Figure 1. The multistep process leading from nicotine addiction to lung cancer. PAH: polyaromatic
hydrocarbons; NHK: nicotine-derived nitrosamine ketone. Reproduced from HECHT (1999), with permission
from the publisher.
variant combined type harbours .10% pleural involvement), haemoptysis, chest pain,
nonsmall cell components. dyspnoea, hoarseness (laryngeal nerve
involvement), superior vena cava syndrome
Nonsmall cell lung cancer (NSCLC): (dilated neck veins, facial oedema), Pancoasts
carcinoma with larger cells and a varying syndrome (pain, Horner sign, hand muscle
degree of squamous epithelial or glandular atrophy).
differentiation. Squamous cell carcinoma is a
typically centrally located tumour in smokers. In addition, paraneoplastic effects of lung
Adenocarcinoma is the predominant cancer are common: hypercalcaemia (nausea,
histological subtype and the most prevalent lethargy, dehydration), syndrome of
form of lung cancer in younger males (,50 inappropriate antidiuretic hormone
yrs old) and in females of all ages, in never- (hyponatraemia), hypertrophic osteo-
and former-smokers. Large cell carcinoma and arthropathy (clubbing, periostal proliferation
large cell neuroendocrine carcinoma (LCNEC); of tubular bones), dermatomyositis,
the latter is also described in the spectrum of haematological manifestations (anaemia,
neuroendocrine tumours extending from the leukocytosis, thrombocytosis),
low-grade typical carcinoid over the hypercoagulability, Cushings syndrome,
intermediate-grade atypical carcinoid to high- neurological syndromes (LambertEaton). It is
grade neuroendocrine tumours (LCNEC and important to distinguish paraneoplastic
SCLC). effects from symptoms due to metastasis, as
only the latter impede a radical approach.
Immunohistochemistry (and electron
microscopy) are valuable adjuncts for As for extrathoracic disease, the most frequent
differential diagnosis, e.g. the sites of distant metastasis are the liver (pain,
subclassification of NSCLC, the distinction constitutional symptoms), adrenal glands,
between pleural metastatic adenocarcinoma bones (pain) and brain (headache, paresis,
and mesothelioma (calretinin and seizures). General symptoms such as anorexia,
cytokeratin). They are required for diagnosis of weight loss and asthenia are often also
LCNEC (chromogranin, synaptophysin, neural present.
cell adhesion molecule).
Diagnosis
Clinical manifestations
Bronchoscopy is the appropriate test for
The majority of patients with lung cancer have centrally located tumours, where a
advanced disease at clinical presentation, pathological diagnosis will be obtained in
which reflects the frequent asymptomatic ,90% of cases, by means of forceps biopsy,
course of early stage lung cancer. bronchial brushing or washing.
Symptoms due to the intrathoracic effects of Peripheral lesions, especially solitary
the tumour are cough (central airway or pulmonary nodules, can be a diagnostic
Lung cancer 373

challenge. Noninvasive techniques are cardiopulmonary exercise testing,
positron emission tomography with 18F-2- measurement of left/right distribution of
fluoro-2-deoxy-D-glucose positron emission pulmonary function by, for example,
tomography (FDG-PET: enhanced uptake of scintigraphy, echocardiography, and other
FDG in tumours) or contrast enhanced tests may be appropriate.
computed tomography (CT). For most lesions,
pathological documentation is needed: Performance status (PS), measured by, for
peripheral sampling of tissue by bronchoscopy example, the Karnofsky or WHO scale, is very
(nowadays with help of endobronchial important in patients with advanced disease,
ultrasound), fine needle aspiration by CT where it is strongly related to prognosis and
guidance, sometimes surgical sampling by treatment choices.
video-assisted thoracoscopy. Treatment of NSCLC (table 1)
Staging For fit patients with stage I and II, upfront
A proposal for revision of the Tumour-Node- surgical resection is indicated, followed by
Metastasis (TNM) classification of lung adjuvant cisplatin-based chemotherapy in
tumours was officially adopted for NSCLC, case of lymph node spread or larger-sized
SCLC and carcinoid tumours in 2010. The (.45 cm) primary tumour. Curative
combination of T, N, and M descriptors conformal radiotherapy is to be considered in
determines the overall disease stage: stage I medically inoperable patients.
(localised tumour, no lymph node spread), Stage III is subdivided into stage IIIA
stage II (spread to hilar nodes), stage III (more (ipsilateral mediastinal lymph node spread) or
advanced tumour and/or mediastinal lymph stage IIIB (contralateral). In stage IIIA
node spread) and stage IV (distant patients, assessment of resectability in a
metastasis). The stage defines the prognosis multidisciplinary group is essential. Patients
and guides management. with resectable stage IIIA benefit from
A detailed medical history, physical surgical combined modality treatment
examination, blood testing and contrast- (induction therapy followed by complete
enhanced CT from the adrenal gland to the resection), as this approach improves local
lung apex should be performed. According to control, progression-free survival and overall
symptoms and locoregional spread, a CT or survival if pneumonectomy can be avoided.
magnetic resonnance image of the brain, a For patients with unresectable stage IIIA or
bone scintigraphy or other tests may be stage IIIB, nonsurgical combined modality
appropriate. Patients without evident treatment is preferred (chemotherapy plus
metastatic disease benefit from FDG-PET or radiotherapy). For fit patients, concurrent
fusion FDG-PET-CT, which improve staging administration is preferred; for others, a
of locoregional lymph node and distant sequential approach.
spread. The role of PET for SCLC is less In patients with advanced NSCLC and good
well defined. PS (Karnofsky .80%), two-drug platinum-
Functional assessment based chemotherapy is indicated because of
modest gain in survival and improved
In patients scheduled for radical treatment symptom control and quality-of-life. Recent
(surgical or nonsurgical combined modality data point at the importance of histology for
treatment), an appropriate functional treatment: patients with adenocarcinoma
evaluation is needed. This can be simple (ECG have a superior outcome with cisplatin-
and basic pulmonary function tests) in fit pemetrexed chemotherapy, while the opposite
individuals, but is often more complex is true for squamous cell carcinoma, where
because of co-existing smoking-related gemcitabine, vinorelbine, or a taxane can be
cardiopulmonary disease. Diffusion capacity, added to platinum. Moreover, some

Table 1. Major staging groups, preferred treatment patterns, and expected 5-yr survival rates for nonsmall cell lung cancer
Group Stage Treatment 5-year survival
Surgical resection (adjuvant chemotherapy for
Stage I large tumours) 58-73%
Early stages Radiotherapy if medically inoperable
Surgical resection + adjuvant chemotherapy
Stage II 36-46%
Radiotherapy if medically inoperable
Locally Surgical or nonsurgical combined modality
Stage IIIA 24%
advanced treatment
stages Stage IIIB Nonsurgical combined modality treatment 9%
Advanced ,5%
Stage IV Chemotherapy and/or targeted agents
stage
Data from GOLDSTRAW et al. (2007).
adenocarcinomas harbour activating General treatment measures

mutations in the epidermal growth factor
receptor (EGFR) gene, which predicts a Radiotherapy plays an important role in
sustained tumour control in case of therapy palliation of local problems such as vena cava
with EGFR tyrosine kinase inhibitors. Second- superior syndrome, haemoptysis,
line systemic treatment (docetaxel, postobstructive pneumonia, bone pain and
pemetrexed, erlotinib) also improves disease- brain metastasis. Endobronchial treatment
(cryotherapy, laser resection, endobronchial
related symptoms and survival. Nevertheless,
stenting) may relieve symptoms in patients
quite some patients have a lower PS. They
with major airway obstruction. Overall
may be treated with single-agent
supportive measures, such as analgesics,
chemotherapy or best supportive care.
corticosteroids, biphosphonates in the case of
Treatment of SCLC bone disease, etc., should accompany the
primary tumour treatment, or may be the only
Patients with stages IIII should be treated option in patients with very poor performance
with four to six cycles of cisplatin-etoposide status. A multidisciplinary team including
chemotherapy in combination with thoracic doctors, nurses, psychologists, social workers
radiotherapy. Concurrent administration is and others will have a major role in the latter
preferred if the patient is fit enough and if situation. Smoking cessation should be
the tumour volume is not too bulky. advised to all patients in remission after
Prophylactic cranial irradiation (PCI) should treatment.
be offered to patients with response
following chemoradiotherapy, as it reduces References
the risk of cerebral metastases and improves N Albain KS, et al. Radiotherapy plus
survival. Patients with stage IV should be chemotherapy with or without surgical resection
treated with platinum (cisplatin or for stage III non-small-cell lung cancer: a phase
carboplatin) in combination with etoposide III randomised controlled trial. Lancet 2009;
for four to six cycles. PCI is added in case 374: 379386.
of major response after chemotherapy. N Alberg AJ, et al. Epidemiology of lung cancer:
ACCP evidence-based clinical practice guidelines
Patients with good performance status (2nd edition). Chest 2007; 132: Suppl. 3, 29S
relapsing after response to first-line 55S.
chemotherapy should be considered for N Brambilla E, et al. The new World Health
re-treatment, either with repeat platinum- Organization classification of lung tumours. Eur
etoposide or with topotecan. Respir J 2001; 18: 10591068.
Lung cancer 375

N Brunelli A, et al. ERS/ESTS clinical guidelines on N Mok TS, et al. Gefitinib or carboplatin-paclitaxel
fitness for radical therapy in lung cancer in pulmonary adenocarcinoma. N Engl J Med
patients (surgery and chemo-radiotherapy). Eur 2009; 361: 947957.
Respir J 2009; 34: 1741. N Scagliotti G, et al. Phase III study comparing
N DAddario G, Felip E. Non-small cell lung cancer: cisplatin plus gemcitabine with cisplatin plus
ESMO clinical recommendations for diagnosis, pemetrexed in chemotherapy-naive patients with
treatment and follow-up. Ann Oncol 2009; 20: advanced stage non-small cell lung cancer. J Clin
Suppl. 4, 6870. Oncol 2008; 26: 35433551.
N Goldstraw P, et al. The IASLC Lung Cancer Staging N Sorensen M, Felip E. Small cell lung cancer:
Project: proposals for the revision of the TNM ESMO clinical recommendations for diagnosis,
stage groupings in the forthcoming (seventh) treatment and follow-up. Ann Oncol 2009; 20:
edition of the TNM Classification of malignant Suppl. 4, 7172.
tumours. J Thorac Oncol 2007; 2: 706714. N Toh CK, et al. Never-smokers with lung cancer:
N Hecht SS. Tobacco smoke carcinogens and lung epidemiologic evidence of a distinct disease
cancer. J Natl Cancer Inst 1999; 91: 11941210. entity. J Clin Oncol 2006; 24: 224551.
N The International Adjuvant Lung Cancer Trial N Vansteenkiste JF, et al. Lymph node staging in
Collaborative Group, et al, Cisplatin-based non-small cell lung cancer with FDG-PET scan: a
adjuvant chemotherapy in patients with prospective study on 690 lymph node stations
completely resected non-small cell lung cancer. from 68 patients. J Clin Oncol 1998; 16:
N Engl J Med 2004; 350: 351360. 21422149.

CHEMOTHERAPY AND OTHER
ANTI-TUMOUR THERAPY FOR
THORACIC MALIGNANCIES
Division of Respiratory Medicine, Medizinische Klinik-Innenstadt,
Ludwig-Maximilians-University, Munich, Germany
E-mail: huber@med.uni-muenchen.de
In oncology, chemotherapy involves the use of

Key points substances with nonspecific cytotoxic and
anti-proliferative properties to control tumour
N Due to the interdisciplinary nature of spread and symptoms, improve quality of life
lung cancer treatment, decision-making and lengthen survival.
should take place in structured tumour
Depending on the clinical situation, either a
boards.
single chemotherapeutic agent or a doublet
N SCLC generally responds well to initial may be given. In metastatic lung cancer,
chemotherapy. chemotherapy is palliative; however, in earlier
stages of disease it can be curative when
N Prophylactic cranial irradiation has an combined with local irradation
important role in the treatment of (radiochemotherapy) or surgery.
SCLC. Chemotherapy given after surgery is known as
adjuvant chemotherapy; that administered
N First-line treatment of NSCLC is before surgery is neoadjuvant or induction
generally a platinum-based doublet. chemotherapy. Generally, chemotherapy is
administered intravenously, although some
N Performance status is an important agents may be given orally. There are also
parameter in treatment circumstances in which chemotherapeutic
decision-making. agents may be administered locally
(intrathecally or in the pleural space).
N The individualisation of treatment Although most modern chemotherapeutic
based on histology and molecular agents have milder side-effects than the older
biology is of increasing importance in agents, side-effects remain problematic and
NSCLC. include neutropenia, neuropathy,
nephropathy, fatigue, hair loss and nausea
N The side-effects of chemotherapy vary
and vomiting (table 1).
between agents and should be taken
into account during treatment The decision how to treat a patient is
planning. dependant not only on the diagnosis itself,
but on the patients comorbidities and overall
N Endobronchial techniques are an medical condition, as well as on the overall
important tool in the palliation of lung prognosis and goal of treatment (table 2).
cancer patients. Performance status scales attempt to
standardise the assessment of a patients
Chemotherapy and other anti-tumour therapy for thoracic malignancies 377

Table 1. The major side-effects of chemotherapeutic agents
Nausea and Cisplatin is highly emetogenic
vomiting Prophylactic anti-emetics should be given to all patients receiving
chemotherapy
Delayed nausea and vomiting may occur days after administration
Commonly used anti-emetics include dexamethasone, serotonin antagonists
and neurokinin-1 inhibition
Neutropenia Severe neutropenia refers to peripheral neutrophil counts ,500 cells?mL-1
Reverse isolation in hospitalised patients with severe neutropenia may reduce
the risk of nosocomial infections
Febrile neutropenia refers to elevated oral or axillary temperature (.38uC for
.1 h, or .38.2u C one-time measurement) in the setting of severe
neutropenia, and should be treated with intravenous antibiotics
The prophylactic use of granulocyte colony-stimulating factors can be
considered in those at increased risk of developing febrile neutropenia
Anaemia Consider transfusion in symptomatic patients or those with very low
haemoglobin
The use of erythrocyte-stimulating factors (e.g. erythropoietin) is generally not
recommended; however, it can reduce the number of transfusions and improves
fatigue
Neuropathy Most commonly caused by the taxanes and vinorelbine
Fatigue Multifactorial
Malnutrition, anaemia and depression commonly play a role
general state of health; the Karnofsky scale commonly used but less effective regimen is
and the World Health Organization/Eastern adriamycin, cyclophosphamid, vincristin. In
Cooperative Oncology Group (WHO/ECOG) small cell lung cancer, chemotherapy offers a
scale are commonly used (table 3). clear survival benefit, from 46-week survival
in untreated patients with extensive disease,
In most cases the overall management of lung to 12-month survival in extensive disease with
cancer involves a combination of chemotherapy.
chemotherapy, radiation, bronchoscopic
intervention and surgery. For this reason, Second line The second-line treatment of
interdisciplinary tumour boards are an SCLC has been shown to increase survival and
important forum for discussion and decision quality of life compared with best supportive
making in the care of lung cancer patients. care alone. Here the choice of medications
depends on the length of time since the initial
Chemotherapy in small cell lung cancer remission. For patients whose tumours initially
respond well to chemotherapy and then go on
First line Small cell lung cancer (SCLC) is to recur or progress .36 months later, the
almost always a systemic disease and in most medications used in first-line treatment can be
cases the initial response to chemotherapy is given again. Tumours that progress
quite good. ,3 months after the end of first-line therapy
should be treated with different agents: in this
Cisplatin plus etoposide is a frequently used setting, topotecan monotherapy is a common
first-line combination, although carboplatin choice and can be given intravenously or
can be used instead of cisplatin in patients orally. If the tumour does not respond to first-
with poor prognosis/performance status or line therapies or progresses quickly after
contraindications to cisplatin. Another chemotherapy, second-line treatment is

Table 2. Considerations for individual chemotherapeutic agents
Cisplatin Highly emetogenic (appropriate use of anti-emetics is essential)
Nephrotoxic. Avoid in patients with reduced GFR
Prehydration (o500 mL NaCl 0.9% per 50 mg cisplatin) reduces the risk of
nephrotoxicity
Carboplatin Consider as alternative to cisplatin in elderly patients or those with contraindications to
cisplatin, dosed at AUC
Vinorelbine May cause neuropathy or neutropenia
Available in pill form for oral administration
Gemcitabine 30-min infusion time (more toxicity with slower infusion), avoid combination with
radiotherapy due to increased side-effects
Pemetrexed Short (10-min) infusion time
Effective in patients with nonsquamous cell NSCLC and mesothelioma
The risk of myelosuppression can be significantly reduced by vitamin B12 (1,000 IU
i.m. every 9 weeks) and folate (0.351 mg?day-1)
Paclitaxel Premedication to prevent allergic reaction is required (dexamethasone and
antihistamine)
Docetaxel Premedication to prevent allergic reaction is required (dexamethasone)
GFR: glomerular filtration rate; AUC: area under the curve; NSCLC: nonsmall cell lung cancer; i.m.: intramuscular.
usually recommended. Inclusion in clinical patients who have responded well to

trials or best supportive care alone also are chemotherapy.
also reasonable options.
Prophylactic cranial irradiation has been
Multimodal therapy Studies have shown shown to improve survival in SCLC patients
that adjuvant chemotherapy improves survival who reach good remission after
in SCLC patients with completely resected very chemotherapy, including those with extensive
limited disease. In patients with limited disease at the time of diagnosis.
disease, local radiation is generally combined
Nonsmall cell lung cancer
with chemotherapy. Concurrent
chemoradiation regimens including cisplatin Chemotherapy is the treatment of choice for
are the most effective. In extensive disease nonsmall cell lung cancer (NSCLC) patients
SCLC, thoracic radiation may be considered in with distant metastases or malignant pleural
Table 3. The World Health Organization/Eastern Cooperative Oncology Group (WHO/ECOG) scale
WHO/ECOG Description
Performance status
0 Patient is fully active and unrestricted in daily activities
1 Patient cannot carry out physically strenuous activities, but is able to care for self
and carry out light work
2 Patient is ambulatory and can care for self but is unable to work. Up and about
for .50% of waking hours
3 Patient is limited in self care activities and confined to bed or chair for .50% of
waking hours
4 Completely disabled. Cannot care for self. Totally confined to bed or chair

effusion, although its efficacy is limited. In fit Targeted therapies The role of targeted
patients, first-line treatment should consist of therapies in NSCLC is growing rapidly. Unlike
cisplatin or carboplatin paired with one of traditional chemotherapeutics, which interfere
gemcitabine, docetaxel, paclitaxel, with cell division in all rapidly dividing cells,
pemetrexed or vinorelbine, administered over targeted therapies attempt to inhibit cell
46 cycles. The increase in survival offered by activity more selectively at the level of growth
platinum-based chemotherapy is in the range factor receptors and intracellular signalling
of several months, although some patients cascades.
experience durable remissions, and there is
evidence that chemotherapy improves The epidermal growth factor receptor (EGFR)
patients quality of life and performance is involved in signalling cascades leading to
status. Unfortunately, ,40% of NSCLC cell division and proliferation. In tumour cells,
tumours do not respond to chemotherapy and mutations and overexpression in EGFR or in
only 20% of NSCLC patients experience downstream components of the EGFR
significant regression of their tumours. In pathway increase proliferation, survival and
earlier randomised trials with platinum-based metastasis. Several targeted therapies attempt
chemotherapy doublets (cisplatin/paclitaxel, to interfere with this abnormal EGFR activity:
cisplatin/gemcitabine, cisplatin/docetaxel, erlotinib and gefitinib are both tyrosine kinase
vinorelbin/cisplatin or carboplatin/paclitaxel), inhibitors (TKIs) which inactivate the
there were no significant differences in intracellular portion or EGFR, whereas
response rate or overall survival. More recent cetuximab, as an antibody, binds to the
studies show that histology plays a role in the extracellular domain of the receptor. EGFR
response of NSCLC to various inhibitors do not cause typical chemotherapy
chemotherapeutic medications. In particular, side-effects, but commonly cause clinically
nonsquamous histology (adenocarcinomas significant rash, diarrhoea and liver enzyme
and large cell NSCLC) is predictive for better elevation.
activity of pemetrexed.
There is evidence that EGFR mutations in exon
Patients with poor performance status may 19 and 21 (activating mutations) predict a
not tolerate platinum-based doublet good response to EGFR TKIs, whereas other
chemothrapy, but can often be treated with a mutations such as T790M predict resistance.
single chemotherapeutic agent, for instance Response to EGFR inhibitors is also associated
gemcitabine or paclitaxel, or in some cases with certain clinical characteristics (female
with a carboplatin-based doublet. patients, nonsmokers, adenocarcinoma, Asian
ethnicity). Erlotinib is approved as a second- or
Second-/third-line chemotherapy Second/ third-line therapy in NSCLC. Gefitinib is only
third-line chemotherapy in NSCLC generally approved for use in patients with a
involves monotherapy with a documented activating mutation in EGFR.
chemotherapeutic agent (docetaxel and
pemetrexed are licensed in this setting) or, in Because tumours are dependent on the
selected patients, erlotinib. Participation in growth of new blood vessels, inhibition of
phase II or III clinical trials with newer angiogenesis is of major therapeutic interest.
targeted agents may offer patients the option Bevacizumab is a monoclonal antibody
of treatment with medications not yet against the vascular endothelial growth factor.
available on the market. There is some recent In stage IIIB and IV NSCLC patients, there is
evidence that early second-line or evidence that the addition of bevacizumab to
maintenance therapy may be beneficial, platinum-based doublets is beneficial. The
especially for patients who did not respond combination of bevacizumab with carboplatin
particularly well to first-line chemotherapy + paclitaxel was shown to provide a survival
(stable disease patients compared to partial/ benefit, whereas the combination of
complete responders). bevacizumab with cisplatin + gemcitabine

only showed a benefit in progression-free tumour growth in or around the central
survival. airways, and stents may be used to maintain
airway patency in patients with compression
Bevacizumab can cause severe haemoptysis,
due to tumour.
seen in the randomised phase II trial mostly in
patients with squamous cell histology. Palliative radiation provides symptomatic
Thereafter, most studies have excluded relief in patients with brain and bone
patients with brain metastases, previous metastases. Pleurodesis is an option for
haemoptysis, cavitary lung lesions or patients with recurrent malignant pleural
concurrent anticoagulation. effusions.
Malignant mesothelioma References
If systemic treatment is applied, usually N DAddario G, Felip E Non-small-cell lung cancer.
cisplatin plus pemetrexed are given. Often ESMO Clinical Recommendations for diagnosis,
more than 6 cycles are used. In patients with treatment and follow-up. Ann Oncol 2009; 20:
contraindications to cisplatin, the off-label use Suppl. 4, iv68iv70.
of carboplatin can be considered. There is N Srensen M, Felip E. Small-cell lung cancer:
evidence supporting off-label second-line ESMO Clinical Recommendations for diagnosis,
treatment with vinorelbin, gemcitabine or in treatment and follow-up. Ann Oncol 2009; 20:
some cases with pemetrexed. Suppl. 4, iv71iv72.
N Spiro SG, Huber RM, Janes SM. Thoracic
Palliative treatments Malignancies. Eur Respir Mon 2009; 44.
N Stahel RA, Weder W, Felip E. Malignant pleural
In advanced lung cancer, progressive tumour mesothelioma: ESMO Clinical Recommendations
growth in the central airways can produce for diagnosis, treatment and follow-up. Ann
haemoptysis, cough, and airway obstruction Oncol 2009; 20: Suppl. 4, iv73iv75.
leading to shortness of breath or pneumonia.
In these situations quality of life may primarily Weblinks
be improved through the palliative use of N American Society of Clinical Oncology. www.
endoscopic tumour debulking techniques or ASCO.org.
prosthetic measures. Brachytherapy is also an N American College of Chest Physicians. www.
effective option for the local treatment of chestnet.org.

PRINCIPLES OF SURGICAL
TREATMENT FOR EARLY-
STAGE NONSMALL CELL
LUNG CANCER
Department of Thoracic Surgery, Hopitaux Universitaires de Strasbourg,
Strasbourg, France
E-mail: Gilbert.Massard@chru-strasbourg.fr
Despite the progress made in thoracic advantage in survival, the area under the
oncology over the past 30 yrs, surgical survival curve proves that the most substantial
resection remains the mainstay of curative part of cure is owed to surgery. Contemporary
treatment for nonsmall cell lung cancer alternatives to surgery for small tumours are
(NSCLC). Although combined modality stereotaxic radiotherapy and radiofrequency
treatments based on neoadjuvant or adjuvant ablation; these treatments are not yet
chemotherapy are credited with a slight scientifically validated and ignore lymphatic
spread (see below). In the N2 category,
surgery has been challenged by exclusive
Key points radiochemotherapy in a recent multicentre
trial by VAN MEERBEECK et al. (2007), whose
The following recommendations are conclusions are not acceptable: the surgical
evidence-based: arm comprised an incomplete resection rate of
N Optimal results are obtained by nearly 50%. Most patients nowadays are
subjected to combined treatments, but the
specialised surgeons working in
scientific evidence remains ambiguous and
large-volume units.
controversial. It is unclear whether
N Anatomical resection combined with a neoadjuvant therapies are more beneficial to
complete lymph node dissection is the the N2 population, or to those with incipient
gold standard. disease. Meta-analysis demonstrated a benefit
for patients undergoing adjuvant therapy; the
N Bronchoplastic and angioplastic
latter is of weak clinical relevance for the
lobectomies are viable alternatives to
individual patient, knowing that treatment of
pneumonectomy, provided that a
20 patients is needed to save one at 2 yrs.
complete resection may be achieved.
The result deteriorates in the long term, and
N Segmentectomies could be applied to long-term complications of chemotherapy
high-risk patients with tumours ,2 cm appear in survivors.
in diameter; wedge excisions may be
recommended for very small Work-up of the patient should include a check-
bronchoalveolar carcinoma up of fitness according to European
(ground-glass opacity). Respiratory Society/European Society of
Thoracic Surgeons guidelines.

The aim of this article is to describe the node. Intralobar N1 is credited with 5-yr
quality requirements of contemporary survival close to 55%, whereas in extralobar
oncologic thoracic surgery, based on N1 it reaches only 35% (table 2).
recommendations issued by a working group
of the French Society for Thoracic and For stage IIIA-N2, survival rates at 5 yrs are
Cardiovascular Surgery. considerably lower and range from 1525%.
However, minimal N2 is a subgroup with a
How can we define early-stage lung possible survival rate of 35% at 5 yrs. There is
cancer? a small subset of completely resectable IIIA -
Although there is no clear definition, it seems T4N0 disease (Pancoast tumors, main carina
adequate to restrict this label to patients with involvement) that can achieve a survival of
reasonable chances for survival. Since lymph close to 50% at 5 yrs.
node invasion at the N2 level is a marker of The large majority of patients with stage IIIB
poor prognosis, the medical oncologist would are inoperable, and global survival at 5 yrs is
certainly restrict the definition to stages N0 ,5%.
and N1.
For the surgeon, resectable disease offers an Quality requirements: what depends on
advantage over nonresectable disease. the surgeon and his institution!
Minimal N2, defined as microscopic Thoracic oncologic surgery is a specialised
metastasis to a single N2 node, is credited medical activity. The best results are obtained
with a survival rate of 3035% at 5 yrs, which by well-trained specialised thoracic surgeons,
is comparable to the worst N1. Further,
working in high-volume units.
resectable T4N0 disease, such as selected
cases of Pancoast tumors or main carinal 1. Qualification of the individual
invasion, may achieve a 5-yr survival of surgeon A comparison of the results of lung
.40%. resections performed by either general or well-
trained thoracic surgeons in a cohort of 1,583
Any marginal situation needs to be discussed
cases of resection for lung cancer performed
with a qualified thoracic surgeon, and any
decision not to operate should be validated by between 1991 and 1995 showed that
a qualified thoracic surgeon in a operative mortality was twice as high when
multidisciplinary discussion. resection was performed by general surgeons.
It is remarkable that 75% of general surgeons
What are the usual survival figures? performed fewer than 10 resections during
the observation period.
The following figures drawn from the classic
surgical literature apply to surgical treatment,
regardless of any neoadjuvant or adjuvant 2. Hospital volume and its impact on
treatment. post-operative mortality A review of data
from the Medicare registry between 1994 and
For stage I, the usual figures vary from 55 1999 revealed that operative mortality
75% with a substantial difference between T1 following lobectomy varied from 6.4% in a
and T2. Survival is further influenced by the low-activity centre (,9 cases per year) to
type of resection (lobectomy versus 4.2% in a high-activity centre (.46 cases per
pneumonectomy) and the comorbidity, which year); following pneumonectomy, the range
accounts for half of late deaths (table 1). extended from 17% to 10.6%.
For stage II, reported 5-yr survival rates vary
between 3550%. Besides a difference We may conclude that a high hospital volume
between T1N1 and T2N1, there is a very warrants the necessary routine not only of the
dissimilar survival pattern according to the operating surgeon, but also of the
intralobar or extralobar location of the N1 surrounding team.
Principles of surgical treatment for early-stage nonsmall cell lung cancer 383
Table 1. Survival following stage I disease: independent factors of prognosis
Yes % No % p-value Relative risk
Pneumonectomy 53 62.7 0.031 1.55
Angio-invasion 54.5 61.9 0.029 1.85
Atherosclerosis 46.3 64.3 0.017 1.55
Adapted from THOMAS et al. (2002).
3. Hospital volume and its impact on extent of the tumour. The rule is to privilege
long-term survival It has been confirmed lobectomy whenever it enables a complete
that hospital volume affects not only early resection. Standard lobectomy is not possible
outcome, but also long-term survival, in a study if the tumour extends across the fissure,
that included 2,118 patients operated upon in invades the main pulmonary artery or involves
one of 76 hospitals over a 10-yr period, divided the bronchial tree proximal to the lobar take-
into quintiles according to hospital volume. off; a double location in different lobes is also
Operative mortality ranged from 3% at high- an indication for pneumonectomy.
volume units to 6% at low-volume units;
operative morbidity ranged 2044%. The 5-yr Lobectomy is preferred to pneumonectomy
survival decreased from 44% at high-volume because of a substantially lower operative risk.
units to 33% at low-volume centres. Operative mortality is ,2% following
lobectomy, and ranges from 610 % following
This study suggests that appropriate decision pneumonectomy. Mortality after
making is enhanced by routine. pneumonectomy may be .10% in patients
aged .70 yrs, or in case of extended
Basic principles of surgical treatment: resection. There is an ongoing debate whether
complete anatomic resection and mortality of pneumonectomy is increased
complete lymph node dissection. after induction chemotherapy, especially on
the right side. We have recently demonstrated
The basic principles described here are based a similar risk when compared to standard
on recommendations issued by a working operations, and a survival advantage even if
group of the French Society for Thoracic and the patient remains stage N2. Other
Cardiovascular Surgery. A complete cancer disadvantages of pneumonectomy are
operation requires anatomic resection of the decreased quality of life owing to loss of
primary lesion and complete homolateral respiratory function, and decreased
lymph-node dissection. possibilities of repeated curative resection,
should a metachronous primary cancer occur
1. Complete anatomic
(,10% of stages I and II).
resection Anatomic resection means either
lobectomy or pneumonectomy with precise To resect less than a pulmonary lobe is not
hilar dissection, according to the loco-regional recommended as a routine. The Lung Cancer
Table 2. Comparison of 5-yr survival for intralobar and extralobar N1

First author Patients n 5-yr survival %
Intralobar N1 Extralobar N1
YANO 78 64 39
VAN V ELZEN 391 57 30
R IQUET 256 53 38

Study Group (GINSBERG et al. (1995)) emission tomography (PET) scan matches with
compared lobectomy and segmentectomy (or mediastinoscopy, but the latter is subject to
wedge excision) for T1N0 cancer in a 1015% failures; a positive PET requires
randomised trial. There was a drop of 20% in histologic assessment because the false-
5-yr survival for patients subjected to positive rate is .40%. Furthermore, .30%
segmentectomy, and a 3-fold increase of local of patients with N2 disease have no apparent
recurrence following segmentectomy or disease at the N1 level (so called skip
wedge excision. More recent investigations metastases). Even among patients with T1
from Japan conclude that wedge excisions are disease, 22% have mediastinal lymph node
valuable in small bronchoalveolar carcinoma; involvement.
similarly, segmentectomies could be applied
As such, intraoperative exploration of the
to stage I tumours ,2 cm.
mediastinum is mandatory, and can be
When the tumour is invading surrounding achieved by two different procedures: either
anatomical structures, an enlarged en bloc R-0 random sampling of nodes, or complete node
resection may achieve satisfactory long-term dissection. Obviously, only complete dissection
results; this should be carried out in appears to be serious and reliable. The
specialised institutions so that an excessive arguments are as follows.
operative mortality does not erase the survival In patients with pathological stage I-N0
benefit of resection. disease, survival increases with the number of
2. Complete homolateral lymph node dissected nodes. This demonstrates that the
dissection The goals of lymph node more lymph nodes are harvested, the lower
dissection are: 1) to ascertain staging; and 2) the risk of ignoring an invaded node, and the
to ensure complete resection of the disease. more reliable the staging.
In a cross-sectional analysis, we have
Staging is important on the individual level to compared sampling and dissection in each
set prognosis and to define the most single case of 248 resections. Sampling
appropriate treatment strategy. On the identified 52% of N2; multilevel N2 was
collective level, adequate staging facilitates identified in 42% of events only. Resection
comparison of different treatment modalities, based on sampling alone would have been
or results from different institutions. complete in only 12%.
Leaving unrecognised lymph node metastases The standard lymph node dissection is defined
obviously leads to local recurrence. Medical as an en bloc dissection of all lymphatic tissue
imaging has serious pitfalls. Computed along its anatomical borders
tomography underestimates N2 stage in one (tracheobronchial tree, sheets of major vessels,
patient out of five, and overestimates in one oesophagus). On the right side, it includes
patient out of two. A negative positron lower oesophageal nodes within the
Table 3. Lymph node dissection increases survival! Results of a randomised study

5-yr survival %
268 dissections 264 samplings
Stage I 82.2 57.5
Stage II 50.4 34.0
Stage III 27.0 6.2
Global 48.4 36.9
Reproduced from WU et al. (2002), with permission from the publisher.
Table 4. Survival following bronchoplastic lobectomy
First author Stage I % Stage II % Stage III %
T EDDER 63 37 21
M EHRAN 57 46 0
VAN S CHIL 62 31 31
M ASSARD 70 37 8
I CARD, 60 30 27
T RONC 63 48 8
pulmonary ligament, subcarinal space and margins; this situation is much more frequent
paratracheal space. On the left side, it on the left side for anatomical reasons.
includes pulmonary ligament, subcarinal
space, aortopulmonary window, phrenic The operative risk of bronchoplastic lobectomy
nodes and subaortic nodes up to the left is comparable to standard lobectomy, with a
tracheo-bronchial angle. mortality of f2%. Long-term survival and
rate of local recurrence match with reported
Formal lymph node dissection does not data per stage (table 4). A meta-analysis
increase the postoperative complication rate. published by MA et al. (2007) showed that
There is increasing evidence for a positive mortality was almost half that after
effect on survival. A first, nonrandomised pneumonectomy in experienced teams; 1-year
study compared sampling to dissection in survival was improved after bronchoplastic
stage II and III and concluded that there is a resection.
survival advantage following dissection.
References
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pulmonary resections in patients with early
dissection without relation to a stage
stage lung cancer: initial results of the
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randomized prospective ACOSOG Z0030 trial.
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respectable non-small cell lung cancer with
A meta-analysis concluded that 4-yr survival
(neo)adjuvant chemotherapy: results of a meta-
was increased in patients having undergone
analysis of the literature. Lung Cancer 2005; 49:
node dissection, with a hazard ratio of 0.78. 1323.
Are there alternatives to N Brunelli A, et al. ERS/ESTS guidelines on fitness
pneumonectomy? for radical therapy in lung cancer patients
(surgery and chemo-radiotherapy). Eur Respir J
Given the high operative mortality rate of 2009; 34: 1741.
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alternatives. Bronchoplastic operations (sleeve staging poatients with nonsmall cell carcinoma.
Ann Thorac Surg 2003; 76: 861866.
lobectomy) are indicated: 1) when the tumour
involves the lobar take-off on the
N Ginsberg RJ, et al. Randomized trial of
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endobronchial side; and 2) when positive N1 non-small cell lung cancer. Ann Thorac Surg
nodes with capsular disruption are identified 1995; 60: 615623.
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Angioplastic lobectomies are indicated when not increase the operative risk of
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cannot be divided safely with tumour-free 31: 181185.

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sulcus tumors : experience with 139 cases Ann Thorac Surg 2002; 73: 106570.
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METASTATIC TUMOURS
E. Quoix
University of Strasbourg, University Hospital, Pneumology, Strasbourg,
France
E-mail: elisabeth.quoix@chru-strasbourg.fr
The thorax is a common site of metastasis

from various cancers, which may affect the
hilar or mediastinal lymph nodes, bone (chest
wall and vertebrae), lung, pleura, muscle or
heart, and pericardium. These metastases may
induce mediastinal compression syndromes
(Pancoast, superior vena cava syndrome,
dysphagia etc., just like locoregional extension
of a primary lung cancer).
Pleural metastases
Pleural metastasis occur commonly in patients
with haematological or solid tumours. In an Figure 1. Neoplasic pericardial effusion in a patient
already old series of 133 patients, the most with lung cancer.
common primary sites appear to be breast
carcinoma (35 patients), lung cancer (32),
lymphomas (20), Hodgkins disease (12), Pericardial effusions
ovary carcinoma (9), adenocarcinoma of
Out of 55 patients admitted to an intensive
unknown primary tumour (6) and melanoma
care unit with malignant pericardial effusion,
(4). In women specifically, 37% of malignant
30 had a lung carcinoma as a primary
pleural effusions were due to breast cancer,
tumour, nine breast cancer, five
20% to gynaecological cancers and 15% to
lung cancer. Probably, with the increase of the haematological malignancies and 11 other
frequency of lung cancer in women, there will solid tumours. Figure 1 shows a neoplastic
be a higher percentage of malignant pleural pericardial effusion in a patient with lung
effusions secondary to lung cancer in the cancer.
forthcoming years. Pulmonary metastases
Endothoracic metastases of breast cancer are

Key points essentially pleuropulmonary (figs 2a and b,
and 3). In a review of 660 cases of breast
N The thorax is a common site of cancers followed during a period of 5 yrs
metastasis from several cancers. between 1975 and 1979, 119 endothoracic
N It is sometimes difficult to distinguish metastases were recorded. Among them, 79
between primary lung cancer and were pleural or pleuroparietal, 80 were
pulmonary (lymphangitis 41, multiple nodules
metastases from other primaries.
34, solitary nodules nine, endobronchial
N Prognosis is linked to the underlying seven, tumoral emboli two, alveolar metastasis
primitive. one), 46 hilar or mediastinal, and two
myocardial metastases CHATKIN et al. (2007).

a) a)
b)
b)
Figure 2. a) Multiple micronodules in a woman who

developed chronic cough 2 yrs after a breast cancer.
b) Same patient 6 yrs later with multiple nodules,
some displaying a pneumonic pattern.
Pulmonary metastases were also frequent in

lung cancer and their prognosis appeared to Figure 3. Multiple excavated pulmonary metastases.
be of intermediate value if there is no other
site involved. In fact, they will be classified as quite severe bleeding at biopsy attempt. In
M1a in the new staging classification. fact, cough with haempoptysis is the most
Sometimes, pulmonary metastases may be frequent symptom.
excavated (fig. 4).
Tumoral emboli may provide similar clinical
Endobronchial metastasis is an infrequent and radiological features as cruoric emboli;
feature (table 1), the most frequent primary however, peripheral tumoral micro-emboli are
site being head and neck (although, it might characterised by respiratory failure despite
be difficult to distinguish them from a primary normal imaging. Diagnosis may be obtained
lung cancer) followed by breast and kidney. by transbronchial biopsy or by video-
thoracoscopy with, at histology, multiple
It may be quite difficult, if not impossible, to carcinomatous emboli in distal pulmonary
distinguish a primary lung cancer from arteries, veins and lymphatics.
endobronchial metastasis on a computed
Hilar and mediastinal metastatic lymph
tomography (CT) scan. Endobronchial
nodes
metastases from melanoma are often black.
Endobronchial metastases of a kidney cancer Of course, metastatic hilar and mediastinal
display strong enhancement on the contrast- lymph nodes are usually linked to an
enhanced CT images. Whenever a intrathoracic carcinoma. Among 565 patients,
bronchofibroscopy is performed, there may be only 37 had a history of extrathoracic
Metastatic tumours 389

Table 1. Endobronchial metastases: frequency by primary
site
Primary n (%)
tumour
Head and neck 71 (31)
Breast 32 (14)
Kidney 31 (13)
Colon/rectum 25 (11)
Melanoma 18 (8)
Sarcoma 10 (4)
Thyroid 9 (4) Figure 4. Left scapula osteolytic metastasis of a
Bladder 6 (3) right upperlobe adenocarcinoma.
Ovarian 5 (2)
pooled lesion-based sensitivity of 88% and
Prostate 4 (2)
specificity of 87% in breast cancer was found
Oesophagus 3 (1) for bone scan and a pooled lesion-based
Testis 3 (1) sensitivity of 69% and a specificity of 98%
Pancreas 3 (1) was found for PET scan. With regard to lung
cancer, bone is also a frequent metastatic site
Adrenal gland 2 (1)
(fig. 4). In a recent study of 1,000 patients,
Stomach 2 (1) 105 (10.5%) had bone metastases at
Other 3 (1) diagnosis. Sensitivity of PET-scan and CT was
Modified from SORENSEN (2004).
94.3% compared with 78.1% with bone scan
and specificity was 98.8% and 97.4%,
respectively. Among the 346 bone metastases
carcinoma in a surgical series. Primary cancer detected by PET scan and CT, 55 were in the
was most frequently breast but also kidney, thoracic spine, 28 in the scapula or clavicles
testis, prostate, thyroid and other. Metastasis (fig. 4), 12 in the sternum and 56 in the ribs
of breast cancer to intrathoracic nodes seems (fig. 5); i.e. 44% of the foci were in the chest.
to occur quite frequently. In an autopsy series The main problem of PET scan is poor
of women who had died of disseminated anatomical resolution (fig. 6).
breast cancer, metastatic involvement of
intrathoracic lymph nodes was found in 71%
of cases. Lymph node involvement was more
extensive in the mediastinum ipsilateral to the
primary breast cancer than in the
contralateral mediastinum.
Bone metastases in the chest
Bone metastases in the chest are common
sites of secondary lesions of lung, prostate
and breast cancer in which bone is the most
common metastatic site. Bone metastases
affect 8% of patients with breast cancer. Bone
scans remain the primary means for detection
of bone metastases. In a meta-analysis of six
studies comparing bone scan and positron- Figure 5. Osteolytic metastasis of the second right
emission tomography (PET) scan without CT, a rib.

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pleural effusion. Cancer 1974; 33: 916922. 1979; 40: 540547.
Metastatic tumours 391

PLEURAL AND CHEST WALL
TUMOURS
A. Scherpereel1,2
1
Pulmonary and Thoracic Oncology Dept, Hospital of the University of Lille
pital Calmette
II, Ho
2
INSERM Unit 1019, Pasteur Institute of Lille, Lille, France
E-mail: arnaud.scherpereel@chru-lille.fr
Pleural and chest wall malignancies are quite

common diseases in our practice. Malignant Key points
pleural effusions (MPEs) and pleural
metastases are much more frequent than N MPEs are much more frequent than
primary tumours of these tissues primary pleural or chest wall tumours.
(mesothelioma, sarcoma, lymphoma, etc.). N Diagnostic strategy includes pleural
Primary chest wall tumours are a cytology, but a firm and reliable
heterogeneous group of rare tumours (,2%
diagnosis of cancer is based on
of all primary tumours; 60% of them are
histology usually best obtained by
malignant) developing in the bones and soft
biopsies during thoracoscopy.
tissues of the thoracic cage, but have similar
diagnostic and therapeutic issues. N Talc pleurodesis by thoracoscopy is the
best local treatment of recurrent or
Epidemiology and pathogenesis
massive MPE, but indwelling pleural
Malignant pleural mesothelioma catheter represents an interesting
(MPM) Malignant mesothelioma, a highly alternative.
aggressive tumour involving the pleura in
90% of cases, is a rare tumour but with
N Figures 1 and 2 summarise a proposal
for MPE and MPM management.
increasing incidence. MPM may occur in
subjects up to 40 yrs after occupational
asbestos exposure (found in .80% of male
that increase vascular permeability and
cases but ,40% in female), the main factor
angiogenesis.
involved in MPM pathogenesis.
An MPE is found in up to 6% of patients with
Pleural metastases and MPEs Pleural
malignancy. In half of these cases, MPE may
tumour involvement may result from a direct
reveal the cancer. Neoplasias responsible for
invasion from adjacent structures (lung, chest
pleural metastases and/or MPE are mostly lung
wall, etc.), blood dissemination or more often
cancer (approximately one-third of cases) or
from tumour emboli to the visceral pleura
breast cancer (1015%), but other cancers
with secondary seeding to the parietal pleura
include carcinomas (ovary, stomach, etc.) or
(lung cancer). Effusion may be due to the
noncarcinoma proliferations such as lymphoma,
pleural tumour lesions or to a lymphatic
sarcoma, melanoma, seminoma or thymoma.
blockade at the mediastinal level. MPEs also
depend on interactions between tumour cells Pleural effusion is the main clinical element
and mesothelial cells through growth factors but it is not found in all pleural malignancies.
such as vascular endothelial growth factor Moreover, pleurisy is not systematically

synonymous with MPE in cancer patients include weight loss, anorexia, asthenia,
because it may be induced by other haemoptysis (lung cancer), adenopathy,
mechanisms such as pneumonia and/or peritoneal effusion, etc. However, MPE or
atelectasia due to bronchial obstruction, MPM may be diagnosed in asymptomatic
transudate induced by severe denutrition or patients by routine chest imaging. A diagnosis
cardiac failure, or even drug- or radiotherapy- of MPM should not be based on unspecific
induced effusion. Therefore the diagnostic and usually late clinical signs. However, the
strategy may differ whether the patient has a association of chest pain, thoracic
cancer background or not, but should always shrinkage, and/or a unilateral pleural
rely on cytology or, better still, on histology. effusion or thoracic mass in asbestos-exposed
patients may suggest this diagnosis.
Lymphoma and chest wall
sarcoma Initial thoracic involvement of
lymphoma is common but mostly involves the There are no reliable clinical features for
mediastinum. Lung parenchyma and/or distinguishing benign from malignant chest
pleural localisations are less frequent and wall tumours. A palpable mass and pain
need to be histologically proven because they are common in both groups of tumours.
modify the staging and prognosis of the The final diagnosis is often obtained only
tumour. Primary soft-tissue sarcoma of the after surgery.
chest wall is a rare disease (,10% of the Imaging Pleural metastases usually exhibit a
8,000 new cases per year of soft-tissue moderate-to-large, nonloculated and unilateral
sarcomas in the USA). pleural effusion. MPE may be associated with
an irregular pleural thickening. Typically this
Prognosis large pleural effusion induces a contralateral
mediastinal shift. If not, one should suspect
The prognosis of patients with pleural an obstruction of a main bronchus by lung
metastases or MPM is poor (median 1-yr cancer or metastasis, a fixed mediastinum
survival 13%, and median survival caused by the cancer and/or lymph nodes,
,12 months, respectively). However survival an extensive tumour infiltration of the
may vary according to the primary cancer: ipsilatary lung mimicking a large effusion,
from a few months usually for lung cancer to or MPM.
a potential much longer survival in breast
cancer or lymphoma. In fact, lymphoma is
Chest radiograph or, better, computed
characterised by a good outcome (cure rate
tomography (CT) scan shows typically an
.80%). Sarcomas have a variable prognosis,
unspecific, unilateral (95% of cases) pleural
with a reported 5-yr survival from 15% up to
effusion mediastinal shift in MPM patients.
90%, depending mostly of the localisation,
More rarely, pleural thickening or mass,
the grade and the differentiation the tumour
without pleuresy, may be observed. Pleural
and the possibility to achieve an early wide
plugs are very common (70% of cases); about
resection of the sarcoma.
20% of patients exhibit the association of
Diagnosis asbestos-induced pulmonary interstitial
fibrosis. Definitive diagnosis of MPM is not
Clinical signs Dyspnoea on exertion and possible by CT scan, but is recommended for
dry cough are the most common signs of MPE. diagnosis and staging (after removal of
Dyspnoea is usually progressive and more pleural effusion if applicable). Magnetic
marked as the effusion becomes larger, but it resonance imaging is mostly useful to assess
may be also modulated by other factors: the tumour extent into the diaphragm and
bronchus obstruction, carcinomatous chest wall.
lymphangitis or associated (pulmonary,
cardiac) comorbidities. Chest pain suggests 18-Fluorodeoxyglucose-positron emission
chest wall involvement. Other signs may tomography (18FDG-PET) usually shows
Pleural and chest wall tumours 393

Clinical and/or radiological diagnosis of
unilateral pleural effusion: MPE?
Small effusion, haemostasis disturbancies.....

relative contra-indications for US-guided
procedureby trained physicians
Previous asbestos exposure?
Clinical and/or radiological
suspicion of MPM
Thoracocentesis
for diagnosis and drainage
Proceed to Figure 2 Lights Transudate: seek and

Exudate Criteria treat cause of
transudate
Cytology: tumour cells?
NO Previous diagnosis of
YES malignancy (lung, breast....)?
If no argument
for tuberculosis, NO YES
infection....
Chest CT scan Is pleural histology needed for
mandatory if no contralateral mediastinal shift on diagnostic clarity?
chest X-ray bronchoscopy if main bronchus Otherwise start treatment
stenosis is suspected: trapped lung?
Contra-indications
Thoracoscopy
Thoracoscopy Surgery at risk Pleural symphysis
CT scan or US-guided Mini-thoracotomy

transthoracic biopsies for pleural biopsies
In the same
time if large Histological proof of
effusion and pleural metastases
bulky tumour
lesions of the
pleura
Pleurodesis (Talc poudrage.....) Treatment of the primary cancer

also is recurrent pleural effusion; (chemotherapy and/or hormone therapy
alternatives: talc slurry, undwelled catheter..... and best supportive care (BSC)....)
Figure 1. Proposed management for malignant pleural effusion (MPE). MPM: malignant pleural mesothelioma;
US: ultrasound; CT: computed tomography; BSC: best supportive care.
hypermetabolism of pleural mesothelioma, Pathology and diagnostic procedures In

metastatic adenopathy and metastasis, but patients suspected of malignancy with pleural
should not be currently performed for the effusion, a thoracocentesis is the first
diagnosis of MPM. Pleural hypermetabolism is diagnostic step (American Thoracic Society/
also found after talc pleurodesis. PET may be European Respiratory Society (ERS)
helpful for the staging of pleural malignancies, guidelines). Pleural fluid analysis finds usually
or in the search of primary cancer. an exudate according to Lights criteria, but a

Clinical and/or
radiological suspicion of MPM
Note: avoid unnecessary thoracocentesis
to prevent tumour seeding to the chest wall
High resolution CT scan of chest
and upper abdomen
(after removal of pleural effusion if applicable)
Thoracoscopy
Contra-indications for diagnosis and staging
Thoracoscopy
Surgery at risk Pleural symphysis
CT scan or US-guided Mini-thoracotomy

transthoracic biopsies for pleural biopsies
Histological proof of MPM

(immunohistochemistry)
Staging
History of occupational
asbestsos exposure? Discussion of therapeutic options
(with the patient) by a trained
multidisciplinary team
Reparation
Prophylactic Always best Active treatment?
radiotherapy of supportive care chemotherapy
chest wall tracts surgery radiotherapy?
(NO consensus, multimodal approach?
according to institutional practice) Proposal of clinical trials+++
Figure 2. Proposed management for malignant pleural mesothelioma (MPM). US: ultrasound; CT: computed
tomography.
transudate due to major hypoprotidaemia diagnosis of MPM should not be based on

with cachexia or to malignant pericardial cytology alone because of its poor sensitivity
effusion does not eliminate the diagnosis of (30%) and specificity (potential confusion
MPE. Assessment of the adenosine deaminase with reactive mesothelial cells or
(ADA) pleural level can bring false-positive adenocarcinoma cells).
results in some cases of MPM or lymphoma,
but may be helpful in countries with medium- Closed, percutaneous needle (e.g. Abrams)
to-high prevalence of tuberculosis. The pleural biopsies are quite easy to perform with
diagnostic sensitivity of pleural cytology in local anaesthesia on an outpatient basis.
MPE may vary, depending of the extension of However, due to the potentially scarce and
the pleural lesions and the primary cancer, irregular distribution of the tumour lesions in
from 6290% in series. Thus in a patient with the pleural cavity, a positive yield of blind
a history of cancer, cytology may be enough biopsies is low (3040%), adding little to a
for the diagnosis of pleural metastases. A negative cytology.

Guided biopsies did better than blind biopsies Staging and pre-therapeutic assessment
in series of MPEs (7080% sensitivity), but of MPM
did worse than thoracoscopy, and are not
It is recommended to use the Union
recommended for the diagnosis of MPM
Internationale Contre le Cancer/International
except in patients for whom thoracoscopy (or
Mesothelioma Interest Group 1995 TNM
mini-thoracotomy if pleural symphysis) is
staging system, even if it is inaccurate in
contra-indicated or rejected by the patient. If
describing T and N extent by current imaging
MPM is not clearly suspected, closed needle
procedures. Only a patients performance
biopsies may be first proposed in young
status (PS) and histological subtype are
patients with pleural lesions and exudative,
recognised as prognostic factors for the
cytology-negative pleural effusion from
management of MPM in routine.
countries with a relatively high prevalence of
tuberculosis. To identify candidates for proper treatment,
the 2008 ERS/European Society of Thoracic
Medical (pleuroscopy) or surgical (video- Surgeons (ESTS) experts on MPM proposed a
assisted thoracoscopic surgery (VATS)) simple and sequential three-step pre-treatment
thoracoscopy with multiple pleural biopsies is assessment (see references for full details).
the gold standard to obtain the diagnosis of
MPM or pleural metastasis. Diagnostic Treatment
accuracy is .90% and complications occur in
It includes palliative local therapies, mostly to
,10% of cases. MPM or pleural metastasis improve the patients symptoms, and a
will usually appear as nodules or masses of treatment of primary cancer depending of the
various diameters. Thoracoscopy is also useful nature of the malignancy, the clinical status
for the staging of MPM and may permit talc and the wishes of the patient.
pleurodesis in case of massive and/or
recurrent pleural effusion. Treatment of primary cancer MPM
treatment relies mostly on best supportive
Immunohistochemistry is helpful in the search care (BSC: oxygen, pain relief, nutrition, etc.)
of primary cancer for pleural metastases or to associated with chemotherapy, and has been
obtain an accurate diagnosis of summarised by the 2008 ERS/ESTS
mesothelioma, referring to the international guidelines, as follows.
classification of pleural tumours (World
Health Organization (WHO) 2004). Surgery has very little indication in MPM.
Epithelioid subtype is the most frequent Debulking surgery (pleurectomy/
mesothelioma subtype. decortication) should not be proposed with a
Soluble biomarkers have been searched to curative intent, but can be considered to
obtain an early and reliable diagnosis of obtain symptom control, especially in
pleural malignancies but none was considered symptomatic patients with entrapped lung
as valuable in routine. Soluble mesothelin (or syndrome who cannot benefit from chemical
pleurodesis. There is limited evidence for the
soluble mesothelin-related peptides (SMRPs))
efficacy of radical surgery for mesothelioma,
levels were increased in serum and pleural
except parietal pleurectomy in very early and
fluid of patients with MPM compared with
rare stage Ia disease. Extrapleural
healthy asbestos-exposed subjects or patients
pneumonectomy (EPP), as well as post-
with benign pleural lesions or pleural
operative irradiation, should be performed
metastasis. SMRPs showed interesting
only in clinical trials, in specialised centres, as
sensitivity (7080%) and specificity (80
a part of multimodal treatment.
100%) as diagnostic markers for MPM.
However, SMRPs do not capture sarcomatoid Palliative radiotherapy aimed at pain relief
(and some mixed) mesothelioma subtypes, may be considered in case of painful chest
and should not be used for MPM screening. wall infiltration or nodules. The value of

prophylactic radiotherapy to prevent have become loculated and/or the lung has
subcutaneous metastasis developing along become fixed and is unable to expand fully,
drainage channels or thoracocentesis tracts is but it should not be performed before
questionable after recent studies and did not sufficient tissue for diagnosis has been
permit any recommendation. obtained. Criteria for talc pleurodesis are a
sufficient WHO PS ,2, an estimated survival
When a decision is made to treat patients .3 months, an established diagnosis of the
with chemotherapy, subjects with a good PS tumour, and no arguments for either a
should be treated with first-line chemotherapy trapped lung (suspected if a pneumothorax
combining of platinum and anti-metabolite persists after thoracocentesis) or an
(pemetrexed), or could be included in clinical endobronchial tumour (massive pleural
trials. No drug has been validated in second- effusion without a contralateral mediastinal
line chemotherapy, and patients with a good shift). This may justify a bronchoscopy or a
PS should rather be proposed to enter into pleural manometry before the pleurodesis. To
clinical trials. Patients demonstrating decrease the risk of pleurodesis failure in MPE,
prolonged symptomatic and objective it is recommended to use 4 g of talc after
response with first-line chemotherapy may be complete aspiration of pleural effusion. In a
treated again with the same regimen in the phase III multicentric randomised study,
event of recurrence or relapse. For assessment success rates in TP versus TS in patients with
and follow-up of MPM, only chest CT scan is MPE were respectively 67% versus 56%
recommended. PET scan and biological (p50.045), and 82% versus 67% in the
markers are still under investigation. The subgroup of lung or breast cancers
modified Response Evaluation Criteria In Solid (p50.022). Benign usual side-effects of talc
Tumors (RECIST) criteria are the preferred (fever, chest pain) were observed with both
method of measuring response to treatment. methods, but no acute respiratory distress
Pleural metastases Because of the syndrome and death.
systemic dissemination of the cancer, it relies
on chemotherapy and/or hormone therapy, Alternatives to talc pleurodesis are repeated
associated with BSC. The choice of cytotoxic pleural punctures or indwelling pleural
drugs depends on the nature of the primary catheters. This last ambulatory procedure has
cancer. Mediastinal and/or abdominal to be proposed rather than a second talc
radiotherapy may be combined with pleurodesis in the case of trapped lung, a
chemotherapy for lymphoma. pleuro-peritoneal shunt with a high risk of
complications, or a parietal pleurectomy in
Chest wall sarcomas The treatment of frail patients. Spontaneous pleurodesis may
choice is an early adequate and wide be obtained by indwelling pleural catheter
resection of the sarcoma. Adjuvant radio- and/ without mortality or major morbidity in nearly
or chemotherapy are considered for high/ half of the cases when pleural drainage is
grade sarcomas. done via the catheter every other day, or even
up to 70% in MPE patients fit for pleurodesis.
Local treatment Pleurodesis is useful in References
treating a patients symptoms and in
preventing recurrent effusions. Sterile talc is N Scherpereel A, et al. Guidelines of the European
preferred to other agents and may be Respiratory Society and the European Society of
Thoracic Surgeons for management of
administered in the pleural space through a
malignant pleural mesothelioma. Eur Respir J
chest drain (talc slurry, TS) or better during 2010; 35: 479495.
medical (pleuroscopy) or surgical N Rodriguez-Panadero F. Effusions from
thoracoscopy (VATS) (talc poudrage, TP). malignancy. In: Light RW, Gary Lee YC, eds.
Pleurodesis is most effective when performed Textbook of Pleural Diseases, 2nd Edn. Hodder
early in the disease process before effusions Arnold, London, 2008; pp. 323337.

N Sahn SA. Malignant pleural effusions. In: Bouros N Tremblay A, et al. Use of tunnelled catheters
D, ed. Pleural disease, Vol. 186. Marcel Dekker, for malignant pleural effusions in patients
New York, 2004: pp. 411438. fit for pleurodesis. Eur Respir J 2007; 30:
N Antony VB, et al. Management of malignant 759762.
pleural effusions. ERS/ATS statement. Eur Respir N Grigoriu B, et al. Utility of osteopontin and
J 2001; 18: 402419. serum mesothelin in MPM diagnosis and
N Maskell NA, et al. Standard pleural biopsy versus prognosis assessment. Clin Can Res 2007; 13:
CT-guided cutting-needle biopsy for diagnosis of 29282935.
malignant disease in pleural effusions: a N Travis WD, et al., eds. World Health Organization
randomised controlled trial. Lancet 2003; 361: Classification of tumors. Tumors of the lung,
13261330. pleura, thymus and heart. Lyon, France,
N Janssen JP, et al. Safety of pleurodesis with talc IARC; 2004.
poudrage in malignant pleural effusion: a N Gross JL, et al. Soft-tissue sarcomas of the chest
prospective cohort study. Lancet 2007; 369: wall: prognostic factors. Chest 2005; 127:
15351539. 902908.

MEDIASTINAL TUMOURS
P.E. Van Schil, P. Lauwers and J.M. Hendriks
Department of Thoracic and Vascular Surgery, Antwerp University Hospital,
Belgium
E-mail: paul.van.schil@uza.be
The mediastinum, which is defined as the table 1. Metastases may also occur in the
anatomical compartment between both lungs, mediastinum.
is a fascinating region due to its surprising
Variety of symptoms
complexity and variety.
Mediastinal tumours can grow to a large size
Variety of compartments and organs
before symptoms appear. Pressure on
Although no universal agreement exists, the surrounding structures may result in
mediastinum is commonly divided into a hoarseness, dyspnoea, dysphagia and superior
superior compartment above a straight line vena cava syndrome. Various paraneoplastic
from the sternal angle of Louis to the vertebral syndromes have been described, such as
column, and an inferior part below this myasthenia gravis and pure red cell aplasia in
imaginary line. The latter is composed of an case of thymoma (fig. 1).
anterior compartment in front of the heart, a Variety of diagnostic means
middle compartment at the level of the heart,
and a posterior part lying behind the heart. Chest computed tomography (CT), magnetic
Each compartment contains different organs resonance imaging and positron emission
and structures, varying from heart and great tomography provide exact anatomical
vessels to lymphatic tissue and pluripotent cells. delineation of a tumour and may suggest a
specific entity. To obtain a precise histological
Variety of histological types and diagnosis, CT-guided puncture, endoscopic or
tumours endobronchial ultrasound, mediastinoscopy,
mediastinotomy and video-assisted thoracic
In both young and old patients, a range of surgery are utilised. In the case of suspicion of
primary tumours and cysts is encountered in lymphoma, germ cell tumour or thymoma,
the mediastinum; these are summarised in
Key points
N Mediastinal tumours are characterised

by a wide variation in clinical
presentation, histological features
and treatment options.
N A multidisciplinary approach is
necessary to determine optimal
treatment.
Figure 1. A large thymoma in the right hemithorax
N Surgical treatment should aim at presenting with myasthenia gravis. The tumour was
complete resection. resected by a bilateral anterior thoracotomy (clam-
shell incision).
Mediastinal tumours 399

Table 1. Primary tumours and cysts encountered in the mediastinum
Superior mediastinum Substernal goitre
Ectopic thyroid
Inferior mediastinum Anterior Thymoma
Thymic cyst
Germ cell tumours
Pleuropericardial cysts
Middle Lymphoma
Bronchogenic cyst
Posterior Neurogenic tumours
Enterogenic cysts
large biopsies are required. Well-circumscribed cases, induction therapy may be a valid
tumours in young patients should be excised approach to downstage a locally aggressive
at once so as not to breach the surrounding tumour. Salvage surgery may be attempted in
capsule. tumours that are no longer responsive to
chemo- or radiotherapy. Long-term survival
Variety of therapeutic strategies
depends on histological type and
Operable lesions are treated by surgical completeness of resection.
excision. Minimally invasive and even robotic
techniques can be applied if a complete References
resection can be obtained by this approach. In N Date H. Diagnostic strategies for mediastinal
the case of incomplete resection or capsular tumors and cysts. Thorac Surg Clin 2009; 19:
invasion, adjuvant radio- or chemotherapy 2935.
may be indicated. Inoperable lesions and N Hoffman R, et al., eds. Hematology: Basic
lymphomas are treated by a combination Principles and Practice, 5th Edn. Philadelphia,
of chemo- and radiotherapy. In selected Churchill Livingstone Elsevier, 2009.

CHAPTER 15:
SlEEP-RElATEd diSoRdERS
obSTRuCTivE SlEEP APnoEA/ 404

HyPoPnoEA SyndRomE
W. De Backer
CEnTRAl SlEEP APnoEA 410

K.E. Bloch and T. Brack
HyPovEnTilATion SyndRomES 414

J-F. Muir

OBSTRUCTIVE SLEEP
APNOEA/HYPOPNOEA
SYNDROME
W. De Backer
Dept of Pulmonary Medicine, University of Antwerp, Antwerp, Belgium
E-mail: wilfried.debacker@ua.ac.be
Obstructive sleep apnoea/hypopnoea All patients should have more than five
syndrome (OSAHS) is characterised by obstructed breathing events per hour during
recurrent episodes of partial or complete sleep. An obstructive apnoea or hypopnoea
upper airway collapse during sleep. The can be defined as an event that lasts for
collapse is highlighted by a reduction in, or o10 s and is characterised by an absence or
complete cessation of, airflow despite ongoing a decrease from baseline in the amplitude of
inspiratory efforts. Due to the lack of a valid measure of breathing during sleep that
adequate alveolar ventilation that results from either reaches .50% with an oxygen
the upper airway narrowing, oxygen desaturation of 3% or an arousal
saturation may drop and partial pressure of (alternatively a 30% reduction with 4%
CO2 may occasionally increase. The events are desaturation). These definitions are
mostly terminated by arousals. Clinical recommended by the American Academy of
consequences are excessive daytime Sleep Medicine (AASM). The Task Force of the
sleepiness related to the sleep disruption. AASM also states that there are common
Minimal diagnostic criteria have been defined pathogenic mechanisms for obstructive
for OSAHS. Patients should have excessive apnoea syndrome, central apnoea syndrome,
daytime sleepiness that can not be better sleep hypoventilation syndrome and Cheyne
explained by other factors, or experience two Stokes breathing. It was more preferable to
or more of the following symptoms, again that discuss each of these separately; although,
are not better explained by other factors: they could be placed under the common
choking or gasping during sleep; recurrent denominator of sleep-disordered breathing
awakenings from sleep; unrefreshing sleep; syndrome. The definition of OSAHS using
daytime fatigue; and impaired concentration. two components, daytime symptoms and
breathing pattern disturbances during sleep,
may suggest that there is a tight correlation
Key points between the two. However, unfortunately this
is not the case. The breathing pattern
N OSAHS is characterised by recurrent abnormalities, mostly described by an
episodes or partial or complete upper apnoea/hypopnoea index (AHI), only weakly
airway collapse during sleep. correlate with quantified measures of
N Minimal diagnostic criteria exist for sleepiness, such as the Epworth Sleepiness
Scale (ESS). This probably means that inter-
OSAHS.
individual sensitivity, with some individuals
N Overnight polysomnography is the gold coping better with sleep fragmentation than
standard for OSAHS diagnosis. others, does compromise the relationship
between the AHI and daytime sleepiness

scores. In addition, epidemiological studies airway behaves like a Starling resistor, making
show a broad range of sleepiness in the the collapse independent of the suction force
general population. Obviously, brought about by the diaphragm, but rather
epidemiological studies investigating the dependent on the balance between the upper
prevalence of OSAHS are all biased by the airway pressure and the tissue pressure at the
lack of a uniform definition. The prevalence of collapsible site. The airway remains patent,
an AHI of .5 events?h-1 in a general regardless of the excessive pressure applied as
population (without taking into account long as the critical pressure of positive end-
symptoms of sleepiness) has previously been expiratory pressure (Pcrit) remains low relative
estimated to be 24% in a male population. to Pu (pressure upstream to the collapsible
When symptoms of sleepiness were also taken segment). Closure of the upper airway occurs
into account, the prevalence decreased to 4% when Pu falls below the surrounding tissue
in males and 2% in females. pressure (Pcrit). In the model of the Starling
resistor, maximal flow (V9max) becomes a
Assessment of OSAHS function of the pressure gradient and the
The most widely used gold standard for resistance in the segment upstream to the
diagnosis is overnight polysomnography collapsible segment Ru: V9max5(PuPcrit)/Ru.
including nasal and/or oral airflow, The collapse of the upper airway then finally
thoraco-abdominal movement, snoring, EEG, occurs during expiration when, due to the
EOG, EMG and oxygen saturation. absence of dilator muscle, Pcrit exceeds the
Cardiorespiratory monitoring alone can be upstream pressures. Prolonged expiratory
considered as highly sensitive (78100%) and time, as occurs during central apnoeas,
specific (67100%). Sleepiness is often therefore predisposes to collapse, but other
evaluated using the ESS, which assesses factors may contribute and can be considered
global level of sleepiness and is independent as risk factors (table 1).
of short-term variations in sleepiness. The ESS Central and obstructive events are closely
discriminates between normal and linked. Sometimes a central event with already
pathological sleepiness. partially collapsed upper airway can transit
Pathophysiology towards an obstructive event with ongoing
occlusion of the upper airway despite the
Structural narrowing of the upper airway at resumption of effort. Often, however, with
one specific location is unlikely to be a major resumption of effort at the end of the central
cause. Studies have shown that the upper apnoea, the obstruction of the upper airway
airway collapse is not restricted to one place disappears, presumably due to reactivation of
but is rather a dynamic phenomenon starting the upper airway dilator muscles. However,
at a certain level and spreading caudally. the mechanisms remain unclear and more
Upper airway obstruction involves more than research is needed to understand why central
one specific site of the upper airway in the apnoeas are sometimes followed by
majority of sleep apnoea patients. The upper obstructive apnoeas and in some cases
airway can collapse when insufficient load followed by reopening of the airways. In any
compensation is generated when an case, since central apnoeas can trigger
imbalance between the activation of the classical obstructive apnoeas, the mechanisms
upper airway dilator muscles and the leading to unstable breathing (and thus
diaphragm occurs. When this occurs, the central apnoeas) are also important in the
airway will collapse during inspiration or at genesis of obstructive apnoeas.
least narrow with the development of flow
Consequences
limitation. However, there is increasing
evidence that the collapse of the upper airway Cardiovascular consequences Obstructed
occurs during expiration. Furthermore, it has airways may generate negative intrathoracic
been convincingly shown that the upper pressure that increases left ventricular
Obstructive sleep apnoea/hypopnoea syndrome 405

Table 1. Risk factors for obstructive sleep apnoea: factors transmural pressure and left ventricular
promoting upper airway collapse afterload. The negative pressure also draws
Abnormal anatomy of the upper airway
more blood into the thorax and increases right
ventricular preload. Intermittent hypoxia
Skeletal factors related to obstructive sleep apnoea (OSA) will
Maxillary and/or mandibular hypoplasia or also impair cardiac contractility and diastolic
retroposition relaxation (fig. 1).
Hyoid position (inferior displacement)
Soft tissue factors OSA patients also have attenuated
Increased volume of soft tissues endothelium-dependent vasodilation and
Adenotonsillar hypertrophy
decreased circulating markers of nitric oxide.
These effects, together with increased
Macroglossia
sympathetic vasoconstrictor activity and
Thickened lateral pharyngeal walls inflammation, will predispose to hypertension
Increased fat deposition and atherosclerosis. In addition, platelet
Pharyngeal inflammation and/or activation and aggregability are increased
oedema and predispose to thrombotic disease.
Increased vascular volume
Epidemiological studies indicate that OSA can
initiate or promote cardiovascular disease,
Increased muscle volume
such as hypertension, coronary heart disease,
Pharyngeal muscle factors heart failure, cardiac arrhythmias
Insufficient reflex activation of upper airway (bradyarrhythmias, atrial fibrillation and
dilator muscles ventricular ectopy) and cerebrovascular
Impaired strength and endurance of disease.
pharyngeal dilators
Metabolic consequences OSA is
Pharyngeal compliance
associated with several components of the
Increased upper airway collapsibility metabolic syndrome (MetS), mainly insulin
Sensory function resistance (IR) and abnormal lipid
Impaired pharyngeal dilator reflexes metabolism. Sleep restriction causes IR by
Impaired mechanoreceptor sensitivity inducing a pro-inflammatory state (increased
release of interleukin-6 and tumour necrosis
Lung volume dependence of upper airway
factor-a). Epidemiological studies have shown
cross-sectional area
that sleep-related hypoxaemia is associated
Increased below functional residual capacity with glucose intolerance independent of
Ventilatory control system factors age, sex, body mass index and waist
Unstable ventilatory control circumference. MetS can be triggered by
Increased ventilatory responses and loop gains both intermittent hypoxia and sleep
fragmentation/deprivation. The mechanisms
Sex factors
are shown in figure 2.
Male influences
Centripetal pattern of obesity MetS can be due to the release of free fatty
Absence of progesterone acids, agiotensin II and adipokines by adipose
Presence of testosterone tissue, which may damage the pancreas,
leading to insufficient insulin release and
Weight
apparent IR.
Obesity causing peripharyngeal fat accumulation
Mean and nadir arterial oxygen saturation
Reproduced from VERBRAECKEN et al. (2009), with
permission from the publisher. during sleep is an independent predictor of
MetS in overweight children and adolescents.

Obstructive sleep apnoea
PNA Arousal PO2 PCO2 Intrathoracic pressure
SNA Myocardial Oxidative stress

Catechols O2 delivery Inflammation
Endothelial dysfunction
HP BP Hypertension
Atherosclerosis
Myocardial ischaemia LV wall tension
LV hypertrophy and failure Cardiac O2 demand
Cardiac arrhythmias
Cerebrovascular disease
Figure 1. Cardiovascular consequences of obstructive sleep apnoea. PNA: parasympathetic nerve activity; PO2:
oxygen tension; PCO2: carbon dioxide tension; SNA: sympathetic nerve activity; HR: heart rate; BP: blood
pressure; LV: left ventricle. Modified from BRADLEY et al. (2009).
CPAP treatment been shown to be effective in controlled

studies. nCPAP results in better sleep quality
Therapy with nasal continuous positive with lower arousal index: less stage 1 and
pressure: mode of action Treatment with more stage 3 and 4 sleep in a placebo-
nasal continuous positive pressure (nCPAP) is controlled (using placebo capsules) study. In
perceived by most physicians as a very addition, in milder forms of sleep apnoea
effective treatment for sleep apnoea and has nCPAP improved self-reported symptoms of
Obstructive
sleep apnoea
Intermittent Sleep
hypoxia fragmentation/ Type 2
sleep deprivation diabetes
Oxidative Neurohumoral Obesity

stress changes
Insulin Metabolic
resistance syndrome
Inflammation Hypertension
Dyslipidaemia
Figure 2. Mechanisms linking obstructive sleep apnoea and the metabolic syndrome. Modified from TASALI et
al. (2008).

OSA, including snoring, restless sleep, daytime central apnoeas. However, central apnoeas are
sleepiness and irritability. Neuropsychological often also characterised by (near) occlusion of
tests also improved after nCPAP compared the upper airway; as highlighted earlier, nCPAP
with ineffective nCPAP. Blood pressure can can also presumably be effective in preventing
also be reduced with nCPAP when compared this collapse and its associated local reflexes.
to oral placebo, especially in patients using
nCPAP for o3.5 h?night-1 and in those with nCPAP and the heart nCPAP can
.20 desaturations of 4% per hour. effectively be used to treat acute cardiogenic
pulmonary oedema with shifting volume from
intra- to extrathoracic compartments.
nCPAP and the upper airway Occlusion of
the upper airway can be prevented when either
the resistance of the upper airway upstream, Ru nCPAP may relieve CSA in chronic heart
or Pcrit can be lowered. Regardless of the severity failure patients by increasing the arterial
of the changes in Pcrit and Pu, nCPAP can carbon dioxide tension above the apnoeic
effectively increase (or restore) flow, largely threshold. nCPAP may reduce ventilation by
through its effect on Pu (V9max5(PuPcrit)/Ru). redistributing excess lung water to
Appropriate titration of the CPAP restores flow. extrathoracic compartments thereby reducing
nCPAP can increase Pu much more than local stimulation of pulmonary vagal irritant
interventions, such as uvulopalatopharyngoplasty, receptors. nCPAP may also unload the
can. Therefore, it also explains that overall nCPAP inspiratory muscles by increasing lung
is much more clinically effective than was shown compliance, again due to extrathoracic
in previous controlled studies. redistribution of lung water.
nCPAP may significantly reduce left
nCPAP and control of breathing As ventricular afterload by lowering the
mentioned previously, some clinical transmural pressure in patients with
observations initially indicated that unstable compromised cardiac function. In the normal
breathing is part of OSA syndrome, while heart, where cardiac output is largely preload
more recent systematic analysis confirmed the dependent, CPAP decreases cardiac output by
increased loop gain and instability in the reducing left ventricular preload. In contrast,
breathing pattern in OSA patients. It can be the failing heart is relatively insensitive to
questioned, therefore, whether nCPAP can changes in preload but very sensitive to
influence control of breathing in (obstructive) reductions in afterload. CPAP induced
sleep apnoea patients. One could demonstrate reductions in left ventricular transmural pressure
that prolonged treatment with nCPAP (and afterload) can augment cardiac output.
significantly decreases the slope of the
hypercapnic ventilatory response curve when nCPAP may also attenuate sympathetic
measured during wakefulness, together with nervous activity and increase cardiac vagal
an increase in arterial oxygen tension and a modulation of the heart with favourable
decrease in the arterialalveolar oxygen effects on blood pressure regulation.
tension difference. It is clear that all of these
changes may contribute to lowering of the In a large prospective study severe untreated
gain in the system and promote a more stable OSA patients had more fatal and non-fatal
breathing pattern. Changes in lung volume, cardiovascular events, this difference
although mostly small, can also be observed disappeared with nCPAP treatment.
during nCPAP therapy. nCPAP and metabolic/systemic effects
of OSA nCPAP may improve MetS although
nCPAP has also been demonstrated to be it is not always certain that nCPAP has an
effective in central sleep apnoea. nCPAP can independent effect. nCPAP also lowers tumour
increase carbon dioxide tension above the necrosis factor-a, interleukin-6 and C-reactive
apnoeic threshold and, therefore, eliminate protein.

Non-CPAP treatment N Chan AS, et al. Non-positive airway pressure
modalities: mandibular advancement devices/
Mandibular advancement device positional therapy. Proc Am Thorac Soc 2008; 5:
Mandibular advancement devices (MAD) are 179184.
the most common oral appliances used for the N De Backer WJ, et al. Novel imaging techniques
treatment of OSA and/or snoring. They have using computer methods for the evaluation of
either a one-piece (monobloc) or two-piece the upper airway in patients with sleep-
disordered breathing: a comprehensive review.
(duobloc) configuration while customised
Sleep Med Rev 2008; 12: 437447.
devices have a better retention, tolerance and N Jennum P, Riha RL. Epidemiology of sleep apnoea/
efficacy. MAD are effective if they increase the hypopnoea syndrome and sleep-disordered
volume of the upper airway, which may breathing. Eur Respir J 2009; 33: 907914.
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sites. Therefore, the overall efficacy is and metabolic consequences. Eur Respir J 2009;
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excessive daytime sleepiness, outcomes in men with obstructive sleep apnoea-
neuropsychological function and hypopnoea with or without treatment with
continuous positive airway pressure: an
cardiovascular risk may decrease. It is
observational study. Lancet 2005; 365: 1046
important to try to predict the outcome. 1053.
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for this purpose. positive airway pressure on sleep architecture in
the sleep apnea-hypopnea syndrome: a
Surgical treatment Several techniques randomized controlled trial. Am J Respir Crit
have been performed, all with the aim of Care Med 2001; 164: 14591463.
enlarging the volume of the upper airway and N Sleep-related breathing disorders in adults:
reducing the closing pressure. recommendations for syndrome definition
and measurement techniques in clinical
Uvulopalatopharyngoplasty reduces upper
research. The Report of an American Academy
airway obstruction by shortening the uvula, of Sleep Medicine Task Force. Sleep 1999; 22:
trimming the soft plate and suturing back the 667689.
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Tonsillectomy is performed at the same time if metabolic syndrome: alterations in glucose
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advances the maxilla and mandible to enlarge N Verbraecken JA, De Backer WA. Upper airway
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has recently been tested and found to be N Won CH, et al. Surgical treatment of obstructive
efficient in selected patients, although more sleep apnea: upper airway and
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which patients will benefit most. 2008; 5: 193199.
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References disordered breathing among middle-aged adults.
N Engl J Med 1993; 328: 12301235.
N Bradley TD, Floras JS. Obstructive sleep apnoea N Younes M, et al. Mechanisms of breathing
and its cardiovascular consequences. Lancet instability in patients with obstructive sleep
2009; 373: 8293. apnea. J Appl Physiol 2007; 103: 19291941.

CENTRAL SLEEP APNOEA
K.E. Bloch1 and T. Brack2
1
Pulmonary Division, University Hospital of Zurich, Zurich
2
Cantonal Hospital Glarus, Glarus, Switzerland
E-mail: konrad.bloch@usz.ch
Central sleep apnoea/hypopnoea (CSA) refers mechanics. Subsequently, different forms of

to the cessation or reduction of ventilation CSA will be discussed.
lasting for o10 s (in adults) due to transient
CSR/CSA syndrome in heart failure
loss of neural output to the respiratory
patients
muscles. Many patients with CSA have mild
hypocapnia or normocapnia, but rarely are The prevalence of CSR/CSA with an apnoea/
hypercapnia and hypoventilation also hypopnoea index of .15 events?h-1 has been
observed. A periodic pattern of waxing and found to be very high (1537%) and OSA is
waning of ventilation with periods of even common (1026%) among patients with
hyperventilation alternating with central severe heart failure (left ventricular ejection
apnoea/hypopnoea is termed CheyneStokes fraction f45%) irrespective of a suspicion of
respiration (CSR). sleep apnoea. In some patients CSR/CSA and
OSA may coexist and alternate over the
Prevalence, aetiology and
course of a night. Symptoms attributable to
pathophsiology CSR/CSA are not well defined and may
The prevalence of CSA in the general
population is not known. However, it seems to
Key points
be significantly less common than obstructive
sleep apnoea (OSA), as ,5% of patients
referred to a sleep laboratory revealed
N CSA is the loss or reduction in
ventilation due to transient loss of
predominant CSA. In contrast, a relatively
high prevalence of CSA is observed in neural output to the respiratory
association with various conditions including muscles.
congestive heart failure, pulmonary N A high prevalence of CSA is observed in
hypertension, ischaemic stroke, neuromuscular association with other conditions, such
disease, obesity hypoventilation syndrome as congestive heart failure, pulmonary
and narcotic use, or during initiation hypertension, ischaemic stroke,
of continuous positive airway pressure neuromuscular disease, obesity
(CPAP) therapy in patients with OSA. In hypoventilation syndrome and narcotic
healthy subjects, CSA may occur during use.
hypoxia at altitude. In addition, idiopathic
CSA is not associated with any comorbid N Risk factors for CSA/CSR are age
condition. .60 yrs, male sex, severe heart failure,
hypocapnia and atrial fibrillation.
Pathophysiological mechanisms underlying
CSA include: respiratory control instability, N Treatment includes oxygen,
due to an increased chemical drive that moves acetazolamide and positive pressure
the prevailing arterial carbon dioxide tension ventilation, in particular adaptive
closer to the apnoea threshold; a prolonged servo-ventilation.
circulation time; and altered respiratory

include paroxysmal nocturnal dyspnoea, poor Cardiac resynchronisation by biventricular
sleep quality, excessive daytime sleepiness, pacing and heart transplantation may also
fatigue and poor exercise tolerance. alleviate CSR/CSA. If medical therapy is
CSR/CSA in heart failure patients is associated ineffective, noninvasive ventilation may
with poor prognosis. Several studies have additionally be required. Nocturnal CPAP has
found an increased mortality in patients with been shown to improve nocturnal CSR/CSA,
CSR/CSA even after controlling for the severity oxygen saturation, left ventricular ejection
of heart failure, age, sex and other potential fraction, sympathetic nervous system activity
confounders. Mortality was particularly high and the 6-min walking distance. However,
in patients presenting with CSR during CPAP did not prolong survival without heart
physical activity during the day (fig. 1). transplantation during a 2-yr follow-up in a
large trial (CANPAP), although a post hoc
Sleep-related breathing disturbances should analysis suggested a survival benefit if CPAP
be suspected in all patients with heart failure sufficiently suppressed CSR/CSA. Adaptive
who suffer from nocturnal dyspnoea, servo-ventilation is a mode of bi-level positive
unrefreshing sleep or daytime sleepiness. airway pressure ventilation that continuously
Particular risk factors for CSA/CSR include: adjusts pressure support according to the
severe heart failure, older age (o60 yrs), breathing pattern of the patient in order to
male sex, hypocapnia, atrial fibrillation and stabilise periodic breathing. It is a promising
CSR observed during the day. The diagnosis treatment option for CSR/CSA as it has been
should be evaluated by polysomnography or a shown to improve nocturnal breathing
cardiorespiratory sleep study, since pulse
pattern, daytime vigilance and quality of
oximetry can not make the important
life after treatment for several weeks.
distinction between CSA and OSA.
Studies in larger patient cohorts over longer
Optimised medical therapy of heart failure is time periods are needed to confirm these
the first step in the treatment of CSR/CSA. effects and to evaluate a potentially improved
Sum
Rib cage
Abdomen
Minute ventilation
Sp,O2 95
85 89 89
Heart rate 95 68
Standing Supine 58 min
Sum
Rib cage
Abdomen
132 s 144 s
Figure 1. CheyneStokes breathing in a patient with congestive heart failure. Inductive plethysmographic
signals from rib cage and abdominal sensors showing regular waxing and waning of ventilation with central
hypopnoea and corresponding oscillations of oxygen saturation. The upper panel represents a 58-min daytime
recording, the lower panels show enlarged portions obtained while standing (left) and in the supine position
(right). Sp,O2: arterial oxygen saturation measured by pulse oximetry. Modified from BRACK et al. (2007).
Central sleep apnoea 411

survival. Supplemental oxygen and Idiopathic CSA apnoea syndrome
acetazolamide have also been shown to
Idiopathic CSA syndrome (fig. 2) is, by
alleviate CSR/CSA. Further studies are
definition, not associated with any underlying
required to better define the role of these
disease. CSA causes sleep fragmentation which
adjuncts for the treatment of heart failure in
may be perceived as unrefreshing sleep and
patients with CSR/CSA.
may result in daytime sleepiness. Idiopathic
Complex sleep apnoea syndrome CSA is thought to be much less common than
OSA, although no systematic epidemiological
In some patients diagnosed with OSA a CSR/ studies have been performed. Treatment
CSA breathing pattern may emerge during options include acetazolamide, theophylline,
initial CPAP therapy. The clinical relevance of CPAP and adaptive servo-ventilation.
this phenomenon, referred to as complex
sleep apnoea, is still a matter of debate since CSA in various conditions
studies suggest that CSA disappears in the CSA and ataxic breathing have been observed
majority of OSA patients during prolonged in patients on chronic opioid medication and
CPAP therapy. However, persistent residual can be successfully treated with adaptive
CSA may disturb sleep quality, prevent servo-ventilation, although the relevance of
complete symptomatic improvement and may the breathing disturbances requires further
lead to CPAP intolerance in OSA patients. In study. Patients with stroke and neuromuscular
this setting adaptive servo-ventilation has disease, such as post-polio syndrome, motor
been successfully used to normalise the neuron disease, multiple system atrophy or
breathing pattern and improve sleep quality. with idiopathic central hypoventilation, may
Nasal flow
Sum
Rib cage
Abdomen
Microphone
Heart rate 73 62
48 54 53 54 54
100 99 93
Oxygen saturation 100 89
78 81 66
75 68 73 74
347 348 348 349 349 350 350 351 351 352 352 353 353 354 354 355 355 356 356 357
Figure 2. Idiopathic central sleep apnoea in a 56-yr-old male suffering from unrefreshing sleep. The 5-min
recording shows repetitive central apnoeas of variable duration (2090 s) associated with severe oxygen
desaturation (minimal value of 66%). The absence of excursions in the inductive plethysmographic rib cage
and abdominal signals during cessation of airflow indicates that apnoeas are due to intermittent loss of
neuromuscular drive.

exhibit CSA with or without associated OSA Conclusions
and/or hypoventilation. Depending on the
prevailing breathing disturbance, bi-level In conclusion, CSA/CSR is less common than
positive pressure ventilation, CPAP or adaptive OSA. However, in certain conditions, including
servo-ventilation may improve breathing and congestive heart failure, neuromuscular
alleviate symptoms. disorders, during opioid use and at high
altitude, the prevalence of CSA is high.
High-altitude periodic breathing Treatment for CSA is not as well established
In healthy subjects, hypobaric hypoxia at as that for OSA, and may include oxygen,
altitudes of .2,000 m may induce periodic acetazolamide and positive pressure
breathing with central apnoea/hypopnoea. ventilation, in particular adaptive servo-
Breathing instability is related to an enhanced ventilation.
chemosensitivity (high controller gain) References
causing a tendency for a ventilatory overshoot
and hyperventilation with a reduced CO2 N Brack T, et al. Daytime CheyneStokes
reserve, i.e. the eupneic carbon dioxide respiration in ambulatory patients with severe
congestive heart failure is associated with
tension approaches the apnoeic threshold
increased mortality. Chest 2007; 132:
which promotes apnoea during minor 14631471.
ventilatory alterations. Symptoms may include N Dai Y, Bradley DT. Central sleep apnea and
paroxysmal dyspnoea and poor sleep quality. Cheyne-Stokes respiration. Proc Am Thorac Soc
In some subjects, high-altitude periodic 2008; 5: 226236.
breathing is associated with acute mountain N Eckert DJ, et al. Central sleep apnea. Chest
sickness; a syndrome characterised by 2007; 131: 595-607.
headaches, insomnia, poor appetite, fatigue N Javaheri S, et al. The prevalence and natural
and, in more severe forms, ataxia and altered history of complex sleep apnea. J Clin Sleep Med
consciousness. The diagnosis of high-altitude 2009; 5: 205211.
periodic breathing is based on clinical N Walker JM, et al. Chronic opioid use is a risk
observations in the appropriate context factor for the development of central sleep
apnea and ataxic breathing. J Clin Sleep Med
combined with pulse oximetry or more
2007; 3: 455461.
sophisticated sleep studies if feasible. N Bradley DT, et al. Continuous positive airway
Treatment is often not required but can be pressure for central sleep apnea and heart
performed by altitude descent or the failure. N Engl J Med 2005; 353: 20252033.
administration of supplemental oxygen or N UpToDate for Patients. Central sleep apnea
acetazolamide, which is also effective against syndrome. www.uptodate.com/patients/content/
acute mountain sickness. search.do?search5central+sleep+apnea.
Central sleep apnoea 413

HYPOVENTILATION
SYNDROMES
J-F. Muir
Respiratory Dept and Respiratory Intensive Care Unit, Rouen Hospital,
Rouen, France
E-mail: Jean-Francois.Muir@chu-rouen.fr
Sleep-related hypoventilation syndromes, sleep with dysrythmic breathing and less

together with central and obstructive sleep reduced during non-REM sleep. The result is a
apnoea syndromes, are sleep-related reduction of alveolar hypoventilation by
breathing disorders (table 1). altering minute ventilation and/or dead space
volume/tidal volume.
Sleep-induced hypoventilation is characterised
by elevated levels of arterial carbon dioxide Respiratory mechanics change during sleep
tension (Pa,CO2) of .45 mmHg while asleep and thereby worsen gas exchange, particularly
or disproportionately increased relative to in neuromuscular diseases and obstructive
levels during wakefulness. airways diseases. REM sleep induces skeletal
muscle hypotonia sparing the diaphragm and
Pathophysiology
not the accessory respiratory muscles, with
Nocturnal hypoventilation can be attributed
to decreased ventilatory drive (wont breathe),
which may be due to respiratory dysfunction Key points
(polio sequelae, central hypoventilation,
amyotrophic lateral sclerosis or ArnoldChiari N Sleep-induced hypoventilation is
malformation), or the following: depression characterised by increased
(hypnotics); alteration of respiratory nerve Pa,CO2 levels of .45 mmHg
conduction (GuillainBarre syndrome),
transmission to the respiratory muscles N Nocturnal hypoventilation is associated
(myasthenia) or worsening mechanics (cant with decreased ventilatory drive,
breathe) with respiratory muscle alteration respiratory iatrogenic depression,
(muscular dystrophy); chest wall deformities; alteration of respiratory nerve
or severe obesity. In the latter situations, lungs conductance, chest wall deformities or
are normal and associated hypoxaemia is due severe obesity
to the displacement of oxygen in the alveoli N OHS is the association of obesity and
from increasing CO2 levels, as predicted by sleep-disordered breathing with
the alveolar air equation. If the lungs are daytime hypersomnolence and
abnormal (chronic obstructive pulmonary
hypercapnia in the absence of other
disease (COPD), tuberculous sequelae, cystic
respiratory diseases
fibrosis or diffuse bronchiectasis), hypercapnia
is mainly due to worsening mechanics and N Polysomnographic evaluation is needed
ventilationperfusion inequalities. in order to diagnose OHS
During the night, ventilatory response to N NIV is used as the first-line treatment
hypoxaemia and hypercapnia is largely with supplementary oxygen
reduced during rapid eye movement (REM)

Table 1. Sleep related hypoventilation/hypoxaemic syndromes#
Sleep-related hypoventilation/hypoxaemic syndromes
Sleep-related non-obstructive alveolar hypoventilation, idiopathic congenital central alveolar
hypoventilation syndrome
Sleep-related hypoventilation/hypoxaemia due to a medical condition
Sleep-related hypoventilation/hypoxaemia due to pulmonary parenchymal or vascular pathology
Sleep-related hypoventilation/hypoxaemia due to lower airways obstruction
Sleep-related hypoventilation/hypoxaemia due to neuromuscular or chest wall disorders
#
: according to the International Classification of Sleep Disorders-2 classification.
deleterious effects in conditions where these hypoventilation syndrome (OHS) is defined as

muscles are necessary to maintain normal the association of obesity (body mass index
ventilation. REM sleep also alters upper (BMI) .30 kg?m-2) and sleep-disordered
airways patency and reduces chronic breathing with daytime hypersomnolence and
respiratory failure. hypercapnia (Pa,CO2 .45 mmHg) in the
absence of any other respiratory disease. The
Clinical features prevalence of OHS is 36% in patients with a
Hypoventilation per se generates a clinical BMI of 3540 kg?m-2 and 48% if BMI is
syndrome associated with, in typical cases, o50 kg?m-2.
dyspnoea during activities of daily living in
the absence of paralysis, poor sleep quality, The pathogenesis of OHS involves abnormal
excessive daytime fatigue and sleepiness, pulmonary mechanics with an excessive work
nocturnal or early morning headache, of breathing and altered hypoxic and
cyanosis and evidence of right heart failure. hypercapnic ventilatory responses, linked, in
part, to chronic hypoxaemia and poor sleep
Diagnosis quality, upper airway obstruction and,
possibly, the influence of leptin.
The presence of such symptoms highlights the
need to perform a physical examination, Without adequate treatment, patients with
pulmonary function tests, a chest radiograph OHS develop cor pulmonale, recurrent
as well as measure arterial blood gases and episodes of hypercapnic respiratory failure
recordings of sleep, i.e. arterial oxygen and loss of survival. OHS is one of the many
saturation and transcutaneous carbon dioxide aetiologies of chronic respiratory failure and
tension. The results of this initial investigation has become a growing indication to initiate
will be concluded by full night ventilatory acute and/or long-term noninvasive
polygraphy (respiratory signals only) or mechanical ventilation (NIV). Mechanisms of
polysomnography (respiratory and action include resting of the respiratory
neurological signals; EEG, EOG, EMG). Chronic muscles, an increase in thoracic compliance
daytime hypercapnia is associated with and and resetting of the respiratory centres. In
preceded by sleep-related hypoventilation. OHS, nocturnal NIV has been shown to be
clinically effective because of a rapid and
Aetiology
sustained improvement of daytime arterial
blood gas levels and a net reduction of
Presence of an extrapulmonary daytime sleepiness.
restrictive disorder If obesity is present
the most frequent diagnosis is obesity In order to establish a diagnosis of OHS
hypoventilation syndrome. Previously called polysomnographic evaluation is needed and
the "Pickwickian syndrome", obesity the ventilatory treatment needs to be
Hypoventilation syndromes 415

adapted. The sleep respiratory pattern can Obesity and CFR
present as obstructive apnoeas and (OHS)
hypopnoeas (90% of cases), obstructive
hypoventilation due to increased upper airway
Nocturnal ventilatory
resistance and/or central hypoventilation polygraphy
(10%) (fig. 1).
Hypoventilation Hypoventilation OSAS
Recent data from a large cohort of OHS and OSAS pattern predominant
patients who had been treated with NIV and pattern
pressure-cycled ventilators showed a very Bilevel NIV + O2 Pa,CO2
significant decrease in the number of hospital
stays for cardiac and/or respiratory illness for 50 mmHg <50 mmHg
the 3 yrs following the initiation of NIV, *
compared with the year prior to the start of Bilevel NIV F nCPAP + O2
treatment. A dramatic improvement in arterial + O2
S
blood gases was observed and a good
compliance suggests that this treatment is Reconsider after Continue
cost-effective and improves morbidity and 3 months use of
CPAPO2 if the
mortality in such patients. NIV is used as first- patient has clinically
line treatment with supplemental oxygen; improved with
expiratory airway pressure is titrated to Pa,CO2 <45 mmHg
control hypopnoeas and apnoeas and
inspiratory airway pressure is added to control Figure 2. A ventilator management algorithm in a
Pa,CO2. If pressure pre-set NIV fails, nasal patient with severe obesity hypoventilation (OHS)
volume pre-set ventilation may be used. In presenting with chronic respiratory failure (CRF).
OSAS: obstructive sleep apnoea syndrome; NIV:
patients with OHS and predominant OSA,
noninvasive ventilation; Pa,CO : arterial carbon
2
once hypercapnia has improved using NIV dioxide tension; CPAP: continuous positive airway
(which may take several weeks), NIV may be pressure; F: failure; S: success. #: an alternative is
changed to nasal continuous positive airway assisted control ventilation.
pressure (fig. 2). NIV has also largely
Snoring
40
1mm
Apnoeas and
hypopnoeas
0
100%
Sp,O2
60
160 c/mn
HR
40
0 1 2 3 4 5 6
Time h
Figure 1. A ventilator polygraphy from a patient with severe obesity hypoventilation syndrome. Apnoea/
hypopnoea index: 26 events?h-1; arterial oxygen tension: 9.6 kPa; arterial carbon dioxide tension: 8.5 kPa.
Sp,O2: arterial oxygen saturation measured by pulse oximetry; HR: heart rate.

improved the immediate vital prognosis of mutation in the PHOX2B gene. It results in
OHS and acute respiratory failure. the failure of automatic central control of
breathing in infants who do not breathe
The medical management is mainly orientated spontaneously or who breathe shallowly and
towards weight loss. A reduction of 510% of erratically. Sufferers are generally treated by
body weight can result in a significant decrease mechanical ventilation with tracheostomy
in Pa,CO2. Unfortunately, weight loss by diet and, in less severe situations, by NIV.
alone is difficult to achieve and sustain; thus, Electrostimulation of the phrenic nerves and
bariatric surgery has been advocated. After or the diaphragm is currently being tested as
significant weight reduction surgery patients a new therapeutic option.
with OHS experience long-term improvement of
arterial blood gases and dyspnoea. References
If obesity is absent or not predominant, the N Bannerjee D, Yee BJ, et al. Obesity
most frequent conditions are: neuromuscular hypoventilation syndrome: hypoxemia during
diseases with Duchenne muscular dystrophy; CPAP. Chest 2007; 131: 16781684.
Steiner myotony; polio sequelae; amyotrophic N Casey KR, Contillo KO, et al. Sleep related
hypoxemic/hypoventilation syndromes. Chest
lateral sclerosis; and high spinal injuries with 2007; 131: 19361948.
tetraplegia and respiratory paralysis. Less N Cuvelier A, Muir JF. Obesity hypoventilation
frequent are acid maltase deficiency and syndrome: new insights in the Pickwick papers.
spinal muscular atrophy. Chest 2007; 131: 78.
Chest wall diseases with kyphoscoliosis and
N de Lucas-Ramos P, de Miguel-Diez J, et al.
Benefits at 1 year of nocturnal intermittent
tuberculosis sequelae are a category of diseases positive pressure ventilation in patients with
that represent the best indication for the obesity-hypoventilation syndrome. Respir Med
application of acute and chronic mechanical 2004; 98: 961967.
ventilation mainly with NIV, and in some severe N Guo YF, Sforza E, et al. Respiratory patterns
situations or after failure of NIV with invasive during sleep in OHS patients treated with
mechanical ventilation with tracheostomy. nocturnal pressure support. Chest 2007; 131:
10901099.
Presence of an obstructive disorder N Hill NS. Noninvasive ventilation. Does it work,
for whom, and how? Am Rev Respir Dis 1993;
COPD, diffuse bronchiectasis and cystic 147: 10501055.
fibrosis are the most frequent conditions. N Janssens JP, Derivaz S, et al. Changing patterns
During sleep there is a worsening of awake in long-term noninvasive ventilation: a 7-year
hypoxaemia and hypercapnia, especially pro-spective study in the Geneva Lake area.
during REM sleep. NIV is generally proposed Chest 2003; 123: 6779.
after failure of long-term oxygen therapy in N Kessler, R, Chaouat, A, et al, The obesity-
hypercapnic COPD when frequent episodes of hypoventilation syndrome revisited: a
prospective study of 34 consecutive cases. Chest
acute respiratory decompensation occur and/
2001; 120: 369376.
or when baseline Pa,CO2 progressively worsens. N Mokhlesi B, Tulaimat A, et al. Impact of
COPD patients with obesity must be adherence with positive airway pressure therapy
investigated for possible overlap syndrome, on hypercapnia in OSA. J Clin Sleep Med 2006;
which is associated with obstructive sleep 2: 5762.
apnoea and COPD. N Muir JF, Cuvelier A. Management of chronic
respiratory failure and obesity. In: Ambrosino N,
Congenital central hypoventilation Goldstein R, eds. Ventilatory Support for Chronic
syndrome Respiratory Failure. Vol. 1. New York, Informa
Healthcare, 2008; pp. 433444.
Congenital central hypoventilation syndrome N Nowbar R, Burkart KM, et al. Obesity associated
is a rare disorder of ventilatory control that hypoventilation in hospitalized patients:
typically presents in newborns and mainly prevalence, effects and outcome. Am J Med
results from a polyalanin repeat expansion 2004; 116: 17.
Hypoventilation syndromes 417

CHAPTER 16:
immunodEfiCiEnCy diSoRdERS
And oRPHAn lung diSEASE
PulmonARy diSEASES in PRimARy 420

immunodEfiCiEnCy SyndRomES
Hiv-RElATEd diSEASE 423

M.C.I. Lipman and R.F. Miller
gRAfT versus HoST diSEASE 430

AmyloidoSiS 433
H.J. Lachmann
PulmonARy AlvEolAR PRoTEinoSiS 435

M. Luisetti
AdulT PulmonARy lAngERHAnS 438

CEll HiSTioCyToSiS
lymPHAngiolEiomyomAToSiS 441

PULMONARY DISEASES IN
PRIMARY
IMMUNODEFICIENCY
SYNDROMES
Dept of Clinical Medicine, Reference Centre for Primary
Immunodeficiencies, Sapienza University of Rome, Rome, Italy
E-mail: isabella.quinti@uniroma1.it
The definition of primary immunodeficiencies combined immunodeficiencies and

(PID) includes multiple genetic defects that phagocytic disorders (table 1). In some cases
belong to the group of rare diseases. The there are unique features of lung
World Health Organization recognises more abnormalities in specific defects.
than 70 diseases classified as PID. The risk
and type of infections change according to Severe and recurrent infections with
the main defects of the immune system, and capsulated bacteria, asthma and
are classified as antibody deficiencies, bronchiectasis represent the most important
morbidity and mortality factors of the patients
affected by primary antibody deficiencies. The
common pathogens isolated from the sputum
Key points are Haemophilus influenzae, Streptococcus
pneumoniae and Streptococcus pyogenes,
N Primary immunodeficiencies (PID) with Pseudomonas aeruginosa and Moraxella
include multiple genetic defects that catarrhalis occurring less frequently. Chronic
belong to the group of rare diseases. lung disease (CLD) represents the principal
morbidity factor. In primary antibody
N More than 70 diseases are classified as
deficiencies where the defect is an inability to
PID.
produce an effective antibody response to
N The risk and type of infections change pathogens, only immunoglobin (Ig)G
according to the main defects of the antibodies might be replaced. The substitutive
immune system, and are classified as therapy with Ig reduces the risk of acute
antibody deficiencies, combined respiratory infections, particularly pneumonia,
immunodeficiencies and phagocytic but has low efficacy in reduction of chronic
disorders. lung complications, infective exacerbations
and asthma, which are promoted by vicious
N A PID diagnosis should be considered circle infectioninflammation. Despite i.v. Ig
in patients presenting with severe and treatment, the number of patients with CLD
recurrent respiratory infections, with and bronchiectasis increases with time for
granulomatous diseases or with almost all age groups (prevalence of CLD
life-threatening invasive pulmonary .50% in adults, 3040% in children). The
infections. overall probability of developing CLD reached
,80% after 17 yrs of follow-up. As already

Table 1. Microorganisms in primary immunodeficiencies
Antibody deficiencies Combined Phagocytic defects
immunodeficiencies
Viruses Enteroviruses CMV, respiratory syncytial virus, No
EBV, parainfluenza type 3
Bacteria Streptococcus pneumoniae, As for antibody deficiencies, S. aureus,
Haemophilus influenzae, also: Salmonella typhi, Listeria P. aeruginosa,
Moraxella catarrhalis, monocytogenes, Candida, Nocardia
Pseudomonas aeruginosa, Pneumocysitis carinii asteroides,
Staphylococcus aureus, S. typhi, Aspergillus
Neisseria meningitidis,
Mycoplasma pneumoniae,
Campylobacter
Mycobacteria No Nontuberculous, including BCG Nontuberculous, BCG
CMV: cytomegalovirus; EBV: EpsteinBarr virus; BCG: bacille CalmetteGuerin. Adapted from NOTARANGELO (2010).
demonstrated in patients with cystic fibrosis, immunodeficiency patients with

dyspnoea and sputum production are bronchiectasis. Aside from Ig replacement, a
conditioning factors of increased morbidity. strategy to reduce lung damage should then
Accumulated mucus in the airways is the be approached. Prophylactic antibiotics,
prominent feature of bronchiectasis, leading macrolides as anti-inflammatory agents,
to airway obstruction, bacterial colonisation inhaled corticosteroids, bronchodilators,
and recurrent infections. The events that mucolytics, or mechanical or rehabilitative
define the pathogenesis of an infection respiratory methods need to be considered.
depend on a large range of variables,
In patients with cellular and combined
including the specific infecting organism and
immunodeficiencies and in patients with PID
its virulence and the overall immunological
who require bone marrow transplantation,
state of the host. IgG antibodies are only one
respiratory viral infections are major causes of
player in the complex network of cells and
morbidity and mortality. All viruses might be
mediators required to protect the respiratory
detected, all worsening the clinical outcome
tract against various insults, including
(table 1). Herpes viruses, paramyxoviruses
infections. In support of this evidence, data
and adenoviruses are common, significant
indicate the role of a very low IgA level as a
pathogens in these patients. Aggressive
major independent risk factor for all the main
treatments may reduce viral replication and
PID-associated clinical conditions (pneumonia,
damage. Fungal infections are less frequent
chronic lung disease, acute and chronic
compared with bacterial or viral infections
sinusitis), underlining the well known role of
among patients with PID. However, fungal
IgA antibodies on immune defence against a
infections can result in significant morbidity
variety of potentially pathogenic organisms
and potentially fatal outcome if misdiagnosed
when they are encountered in the respiratory
or not treated correctly. In this context, the
or the intestinal tracts. The generation of
knowledge of fungal pathogens likely to cause
secretory IgA has a basic impact on the
disease as well as of the expected clinical
epithelial barrier, a function lacking in the
presentation of the infection is important.
majority of PID patients. Moreover, low IgA
levels reflect a severely impaired isotype- Noninfectious associated respiratory diseases
switching process. Thus, the loss of function of might also occur in PID patients and should
memory B-cells seems to represent the major be taken into consideration in the differential
cause of PID-associated clinical conditions as diagnosis. Medical imaging, especially
already demonstrated in common variable computed tomography, plays a crucial role in
Pulmonary diseases in primary immunodeficiency syndromes 421

the initial detection and characterisation of N Pilette C, et al. Lung mucosal immunity:
changes and in monitoring the response to immunoglobulin-A revisited. Eur Respir J 2001;
therapy. The spectrum of abnormalities seen 18: 571588.
at thoracic imaging includes noninfectious N Plebani A, et al. Clinical, immunological, and
airway disorders, infections, CLD, chronic molecular analysis in a large cohort of patients
with X-linked agammaglobulinemia: an Italian
inflammatory conditions, and benign and
multicenter study. Clin Immunol 2002; 104:
malignant neoplasms. 221230.
In conclusion, a PID diagnosis should be N Primary immunodeficiency diseases. Report of
considered in patients presenting with severe an IUIS Scientific Committee. International
and recurrent respiratory infections, with Union of Immunological Societies. Clin Exp
Immunol 1999; 118: Suppl. 1, 128.
granulomatous diseases or with life-
threatening invasive pulmonary infections.
N Quinti I, et al. Long-term follow-up and outcome
of a large cohort of patients with common
References variable immunodeficiency. J Clin Immunol
2007; 27: 308316.
N Alachkar H, et al. Memory switched B cell N Sanchez-Ramon S, et al. Memory B cells in
percentage and not serum immunoglobulin common variable immunodeficiency: clinical
concentration is associated with clinical associations and sex differences. Clin Immunol
complications in children and adults with 2008; 128: 314321.
specific antibody deficiency and common N Thickett KM, et al. Common variable immune
variable immunodeficiency. Clin Immunol 2006; deficiency: respiratory manifestations,
120: 310318. pulmonary function and high-resolution CT scan
N Carsetti R, et al. The loss of IgM memory B cells findings. QJM 2002; 95: 655662.
correlates with clinical disease in common N Wood P, et al. Recognition, clinical diagnosis and
variable immunodeficiency. J Allergy Clin
management of patients with primary antibody
Immunol 2005; 115: 412417.
deficiencies: a systematic review. Clin Exp
N Crooks BN, et al. Respiratory viral infections in
Immunol 2007; 149: 410423.
primary immune deficiencies: significance and
relevance to clinical outcome in a single BMT unit.
Bone Marrow Transplant 2000; 26: 10971102. Weblink
N Notarangelo LD. Primary immunodeficiencies. J
Allergy Clin Immunol 2010; 125: Suppl. 2, N Associazione Italiana Ematologia Oncologia
S182S194. Pediatrica. www.aieop.org.

HIV-RELATED DISEASE
M.C.I. Lipman1,2 and R.F. Miller1,3
1
University College Medical School
2
Royal Free Hospital, and
3
London School of Hygiene and Tropical Medicine, London, UK
E-mail: marclipman@nhs.net
Most HIV-infected patients experience at least chapter will focus upon common causes of
one significant episode of respiratory disease HIV-related disease (table 1). It uses blood
during their lifetime. A very wide variety of absolute CD4 counts to categorise the stages
illnesses and pathogens can be encountered, of HIV infection. This is a reasonably accurate
and systematic investigation is vital. This measure of systemic and local immunity (in
HIV-uninfected individuals, the CD4 count is
typically .500 cells?mL-1). In HIV-infected
Key points subjects with reasonably preserved immunity,
typical community-acquired infections occur
N More than 50% of HIV-infected but at greater frequency than in the general
patients suffer a respiratory episode population. With advancing HIV-induced
immunosuppression (CD4 counts
during the course of their HIV disease.
,200 cells?mL-1), the risk of opportunistic
N In populations with access to infections and malignancy increases.
antiretroviral therapy, use of
combination antiretroviral therapy Use of effective combination antiretroviral
(CART) has led to a marked reduction in therapy (CART) leads to 5090% reductions
the incidence of many HIV-associated in the incidence of HIV-associated
opportunistic infections and malignancies.
opportunistic infections.
However, respiratory problems remain a major
N Pneumocystis jirovecii is the new name cause of disease. This results from the
for Pneumocystis carinii, the cause of worldwide limited availability of CART
Pneumocystis pneumonia in humans. (particularly in resource-poor settings), the
The acronym PCP still applies. failure of sustained HIV suppression in almost
half of patients using it, the failure of
N Bacterial infections are more common
prophylaxis for specific opportunistic
in HIV-infected patients than in the
infections, the continuing late presentation of
HIV-negative general population. patients with previously undiagnosed HIV
N In response to starting CART, there may infection and ongoing cofactors such as
be an overexuberant and uncontrolled smoking, which are common in many HIV-
immune response to exogenous infected populations.
antigen. This phenomenon is called
immune reconstitution inflammatory Infections
syndrome.
Bacterial infection Upper respiratory tract
N Tuberculosis may occur at any stage of infections, acute bronchitis and acute and
HIV infection, is common, and is a symptomatic chronic sinusitis occur more
public, as well as personal, health issue. frequently in HIV-infected patients than in the
general population.
HIV-related disease 423

Table 1. Common causes of HIV-associated respiratory disease
Infectious disease Non-infectious disease
Upper respiratory tract infection Malignancy
Acute bronchitis Kaposi sarcoma
Acute sinusitis Lymphoma
Chronic sinusitis Bronchial carcinoma
Bronchiectasis Nonmalignant conditions
Bacterial pneumonia Chronic obstructive pulmonary disease
Streptococcus pneumoniae HIV-associated pneumonitis e.g. NSIP & LIP
Haemophilus influenzae Pulmonary arterial hypertension
Tuberculosis Pneumothorax
Fungal infections HIV therapy causing respiratory symptoms e.g. IRIS
Pneumocystis pneumonia
Histoplasma capsulatum
Cryptococcus neoformans
NSIP: nonspecific interstitial pneumonitis; LIP: lymphocytic interstitial pneumonitis; IRIS: immune reconstitution
inflammatory syndrome.
Bronchiectasis is increasingly recognised in Immunisation with pneumococcal vaccine is

patients with advanced HIV disease. It recommended in all adults and adolescents
probably arises as a consequence of recurrent (at diagnosis of HIV infection and after 5 yrs);
Pneumocystis jirovecii pneumonia or bacterial although humoral responses and clinical
infection. efficacy are probably impaired in those with
CD4 counts ,200 cells?mL-1.
Compared with HIV-negative populations,
bacterial pneumonia is six to ten times more Fungal infection P. jirovecii, formerly called
frequent in HIV-infected subjects not using P. carinii, is the cause of Pneumocystis
highly active antiretroviral therapy. Injecting pneumonia (the acronym PCP still applies:
drug users are particularly vulnerable PneumoCystis Pneumonia). It remains a
(approximately double that of other HIV risk common problem in individuals unaware of
groups). The presentation of community- their HIV serostatus and also among HIV-
acquired bacterial pneumonia in HIV-infected infected patients intolerant of, or nonadherent
individuals is similar to HIV-negative subjects. to, PCP prophylaxis and/or CART.
However, the chest radiograph may be
atypical, and mimic P. jirovecii pneumonia in Patients present with nonproductive cough
up to half of cases. The usual pathogens and progressive exertional breathlessness of
isolated are Streptococcus pneumoniae and several days to weeks duration, with or
Haemophilus influenzae. Infection with without fever. On auscultation the chest is
Staphylococcus aureus and Gram-negative usually clear; occasionally, end-inspiratory
organisms may occur in advanced HIV disease. crackles are audible. In early PCP the chest
Mycoplasma, Legionella and Chlamyida radiograph may be normal (,10% cases). The
species do not appear to be more frequent. most common abnormality is bilateral,
perihilar interstitial infiltrates, which may
Bacteraemia is up to 100 times more common progress to diffuse alveolar shadowing over a
in HIV-infected patients with bacterial period of a few days. Atypical radiographic
pneumonia, irrespective of CD4 count. appearances include upper zone infiltrates
Complications include intrapulmonary resembling tuberculosis (TB), hilar/mediastinal
cavitation, abscess formation and empyema. lymphadenopathy, intrapulmonary nodules
There is a high relapse rate, despite and lobar consolidation (present in up to
appropriate antibiotic therapy. 20%).

Treatment is usually started empirically in within 72 h of starting specific anti-PCP
patients with typical clinical and radiological treatment. A frequently used regimen is
features and a CD4 count of ,200 cells?mL-1, prednisolone, 40 mg b.i.d. for 5 days then
pending diagnosis by cytological analysis of 40 mg daily on days 610 and 20 mg daily
bronchoalveolar lavage (BAL) fluid or induced on days 1121. This has been shown to reduce
sputum samples. mortality.
Several factors present at or soon after Co-trimoxazole, dapsone and primaquine
hospitalisation predict poor outcome from should be avoided in patients with glucose-6-
PCP. These include increasing patient age, a phosphate dehydrogenase deficiency.
second or third episode of PCP, hypoxaemia,
Patients are at increased risk of PCP as their
low haemoglobin, co-existent pulmonary
CD4 count decreases. Recommended
Kaposi sarcoma and medical comorbidity.
regimens for PCP prophylaxis are listed in
Once hospitalised, development of
table 2.
pneumothorax, admission to the intensive
care unit and need for mechanical Indications for primary prophylaxis are:
ventilation are associated with worse
outcome. N blood absolute CD4 count ,200 cells?mL-1
PCP can be stratified clinically as mild (arterial N blood CD4 count ,14% of total
oxygen tension (Pa,O2) .11.0 kPa, arterial lymphocyte count
oxygen saturation (Sa,O2) .96% (breathing N unexplained fever (.3 weeks duration)
air at rest)), moderate (Pa,O2 8.011.0 kPa,
Sa,O2 9196%) or severe (Pa,O2 ,8.0 kPa, N persistent or recurrent oral/pharyngeal
Sa,O2 ,91%). This categorisation is helpful, as Candida
oral therapy may be given to those with mild
disease. First-choice treatment for PCP of all
N history of another AIDS-defining diagnosis
e.g. Kaposi sarcoma
severity is high-dose co-trimoxazole
(sulphamethoxazole 100 mg?kg-1?day-1 with Indications for secondary prophylaxis are:
trimethoprim 20 mg?kg-1?day-1) in two to four
divided doses orally or intravenously for N all patients after an episode of
21 days. Approximately two-thirds of patients Pneumocystis pneumonia
will successfully complete this regimen.
Treatment-limiting drug toxicity is common Indications for discontinuing secondary
and ,10% will not respond to treatment prophylaxis are:
(defined by deterioration after o5 days of N patients on combination antiretroviral
therapy).
therapy with sustained increase in blood
In patients who develop toxicity or do not CD4 count (.200 cells?mL-1) and unde-
respond to co-trimoxazole, alternative therapy tectable plasma HIV RNA for o3 months
in mild/moderate disease includes (note that if CD4 count subsequently falls
clindamycin (450600 mg q.i.d. orally or i.v.) ,200 cells?mL-1 and/or the HIV RNA
plus oral primaquine (15 mg daily), oral load increases, prophylaxis should be
dapsone (100 mg daily) with trimethoprim re-instituted)
(20 mg?kg-1?day-1), or oral atovaquone
suspension (750 mg b.i.d.). In severe disease, Tuberculosis All patients with TB and
alternative therapy is clindamycin with unknown HIV status should be offered an HIV
primaquine or intravenous pentamidine test. Active TB is estimated to occur between
(4 mg?kg-1 daily). 20 and 40 times more frequently in HIV-
infected subjects. Approximately 15% of all
Patients with an admission Pa,O2 f9.3 kPa new TB cases globally occur in HIV-infected
should also receive adjuvant glucocorticoids subjects, and it accounts for ,25% of all HIV-

related deaths. TB is also covered in other specimens from several body sites or fluids if
chapters, so here the focus is on issues of possible, as there is a reasonable yield e.g.
particular relevance to HIV-infected subjects. from early morning urine cultures.
More than two-thirds of patients with TB and If smears or unspeciated mycobacterial

HIV co-infection present with pulmonary cultures are positive, treatment should
disease. When blood CD4 counts are normal initially include a four-drug anti-TB regimen
or only slightly reduced, clinical features are with rifamycin plus isoniazid, pyrazinamide
similar to adult post-primary disease. Chest and ethambutol, until mycobacterial
radiography often shows upper lobe infiltrates identification and drug sensitivities are
and cavitary changes. Sputum and BAL fluid known. TB diagnosis using nucleic acid
are often smear positive. amplification tests is limited by poor
sensitivity, although it can distinguish
In advanced HIV disease, and with a low Mycobacterium tuberculosis from
blood CD4 count (,200 cells?mL-1), the opportunistic mycobacteria and identify
presentation is often with nonspecific malaise, common mutations in the rpoB gene
fatigue, weight loss and fever. Chest associated with rifampicin resistance, as well
radiographic abnormalities may not be as isoniazid (katG and inbA genes).
obvious although they can include diffuse or
miliary shadowing, mediastinal/hilar Response to treatment with a 6-month four-
lymphadenopathy and pleural effusions; drug regimen is generally good, although
cavitation is uncommon. Sputum or BAL fluid patients with disseminated disease are often
is often smear negative but culture positive. treated for 912 months. Given the reported
Extrapulmonary TB is common in patients increased risk of developing drug-resistant
with CD4 counts ,100 cells?mL-1. Local or disease, it is recommended that HIV patients
disseminated infection may involve lymph with high mycobacterial loads (e.g.
nodes and bone marrow; blood cultures may disseminated disease, as seen in patients with
be positive; and it is worth obtaining low blood CD4 counts) receive daily and not
Table 2. Recommended Pneumocystis pneumonia prophylaxis regimens

Drug Dosage Notes
#
First choice Co-trimoxazole 960 mg q.d. Protects against certain bacterial
(sulphamethoxazole + 480 mg q.d. infections and reactivation of
trimethoprim 5:1) 960 mg thrice toxoplasmosis; adverse effects
weekly include nausea (40%), rash (up to
20%), bone marrow suppression
(20%)
Second Aerosolised pentamidine 300 mg once per Use once per fortnight if CD4 count
choice month via jet ,50 cells?mL-1
nebuliser
Dapsone 100 mg q.d. Plus oral pyrimethamine 25 mg once
per week against reactivation of
toxoplasmosis
Third choice Atovaquone Suspension
750 mg b.i.d.
Azithromycin 1250 mg once
per week
#
: the use of lower doses of co-trimoxazole may be associated with fewer adverse effects.

higher-dose (twice- or thrice-weekly) Malignant conditions
intermittent therapy. Compared with non-HIV-
infected individuals, there is a possible greater Kaposi sarcoma Kaposi sarcoma is the
commonest HIV-associated malignancy.
incidence of adverse reactions to anti-TB
Before the advent of CART, 1520% of AIDS
drugs, and an increased risk of death.
diagnoses were due to Kaposi sarcoma. It is
CART reduces short- and long-term mortality in associated with human herpes virus-8 (also
co-infected patients and should be started as called Kaposi sarcoma-associated virus) co-
soon as possible in subjects receiving infection. Pulmonary Kaposi sarcoma is almost
treatment for active TB. However, there are always accompanied by cutaneous or
issues with its early use in patients on anti-TB lymphadenopathic Kaposi sarcoma (palatal
therapy. Generally, the lower the blood CD4 disease strongly predicts the presence of
count, the more pressing is the clinical need pulmonary lesions). Presentation is with
to start CART (i.e. 24 weeks). nonspecific cough and progressive dyspnoea;
haemoptysis is less common.
Issues with early use of combination
antiretroviral therapy (CART) in tuberculosis As Kaposi sarcoma may involve both the
patients: airways and lung parenchyma, radiological
findings include interstitial or nodular
N high pill burden
infiltrates and alveolar consolidation. Hilar/
N overlapping toxicities, e.g. neuropathy mediastinal lymphadenopathy occurs in
,25% of patients and up to 40% have a
N drugdrug interactions, e.g. CART and pleural effusion.
rifamycins
Diagnosis is confirmed at bronchoscopy in
N poor adherence to complex regimen
.50% cases by the appearance of multiple,
N immune reconstitution inflammatory dis- raised or flat, red or purple endotracheal and
ease more likely endobronchial lesions. Biopsy is rarely
performed since cutaneous Kaposi sarcoma is
Multidrug- and extensively drug-resistant TB usually present and diagnostic yield from biopsy
has been associated epidemiologically with is ,20%. CART may induce remission of
HIV infection. This is probably due to the lesions, and is used in addition to chemotherapy.
rapid development of active (and hence
infectious) TB in the HIV co-infected Lymphoma High-grade B-cell non-Hodgkin
population exposed to drug-resistant cases, lymphoma is the commonest HIV-associated
and hence reflects general susceptibility to thoracic lymphoma, and is usually found in
developing mycobacterial disease, rather association with disease elsewhere.
than to infection with specific drug-resistant Presenting symptoms are nonspecific. Chest
strains. radiographic abnormalities include
mediastinal lymphadenopathy, pleural
Given the high risk of latent TB infection masses or effusions. The prognosis is better if
(LTBI) progressing to active disease, the World patients treated with chemotherapy also
Health Organization recommends that HIV- receive CART.
infected patients with LTBI should receive
prophylactic treatment. As, by definition, LTBI Bronchial carcinoma Lung cancer appears
diagnosis requires a positive immune response to be two to four times more common in HIV-
(e.g. tuberculin skin test or blood interferon-c infected smokers. It is now more frequently
release assay) in an asymptomatic individual, diagnosed than in the pre-CART era. Whether
these assessments are hampered by the this reflects the impact of CART protecting
immune dysregulation present in HIV co- patients from other conditions, or some other
infected subjects. mechanism, is uncertain. Presentation is

usually with disseminated disease, and the there may be an overexuberant immune
prognosis is therefore poor. response to exogenous antigen (from a
current or previous opportunistic infection).
Nonmalignant, noninfectious conditions This is well described for many conditions,
although in particular for mycobacterial
Chronic obstructive pulmonary disease disease, and has been given several names
HIV-infected smokers appear to be at including immune reconstitution
increased risk (,60%) of developing chronic inflammatory syndrome and immune
obstructive pulmonary disease. The synergistic reconstitution disease (IRD). Using TB as an
effects of smoking, recurrent bacterial and example, subjects with known TB responding
opportunistic infections, injecting drug use to treatment start CART and within a median
and possibly direct effect of HIV in the lung, of 2 weeks develop new clinical
argue strongly for scaling up smoking manifestations, e.g. peripheral
cessation services. This will also impact on lymphadenopathy, pleural or pericardial
other smoking-related illnesses such as effusions or cerebral disease. There is no
cardiovascular disease, which are increasingly specific diagnostic test and drug resistance,
prevalent in HIV-infected communities. patient nonadherence and other disease
processes must be actively excluded. It is more
HIV-associated pneumonitis Nonspecific likely in subjects with low baseline CD4
pneumonitis mimics PCP but often occurs at counts (,100 cells?mL-1), more rapid
higher blood CD4 counts. Diagnosis requires suppression of HIV viral load and shorter time
transbronchial, video-assisted thoracoscopic or between starting anti-TB therapy and CART. It
open-lung biopsy. Most episodes are self is reported in up to 30% subjects and, while
limiting, but prednisolone may be beneficial. often severe, is rarely fatal. Treatment is
largely symptomatic, and may involve oral
Lymphocytic interstitial pneumonitis is glucocorticoid therapy.
generally seen in HIV-infected children and
clinically resembles idiopathic pulmonary A second form of IRD is the unmasking of
fibrosis. Diagnosis requires biopsy. Treatment TB. Here, a patient with latent, asymptomatic
with CART is often effective. infection will rapidly develop highly
inflammatory active TB at a median of
Pulmonary arterial 40 days after starting CART. Treatment is
hypertension Pulmonary arterial generally directed at the underlying
hypertension is reported to be six to 12 times mycobacterial infection.
more common in HIV-infected populations.
The presentation and management are similar Lactic acidosis, typically due to the
to nonimmunocompromised individuals, (nucleoside analogue) reverse transcriptase
although CART is associated with improved inhibitors didanosine and stavudine, may
haemodynamics and survival. present with progressive breathlessness. Also,
the nucleoside analogue abacavir can cause a
Pneumothorax Pneumothorax occurs more hypersensitivity reaction (in up to 3% of
frequently in HIV-infected patients than in the subjects) with fever, rash and pulmonary
age-matched general medical population. symptoms. In these cases, recovery occurs if
Cigarette smoking and receipt of nebulised the drug is withdrawn.
pentamidine are risk factors. PCP should be
excluded in any patient presenting with a References
pneumothorax.
N Benfield T, et al. Second-line salvage treatment
of AIDS-associated Pneumocystis jirovecii
HIV therapy causing respiratory pneumonia: a case series and systematic review.
symptoms In response to starting CART J Acquir Immune Defic Syndr 2008; 48: 6367.

N Benfield T. Non-infectious conditions (AIDS). In: N Lipman MCI, et al. An Atlas of Differential
Albert R, Spiro S, Jett J, eds. Comprehensive Diagnosis in HIV Disease. 2nd Edn. London,
Respiratory Medicine. 3rd Edn. Philadelphia, Parthenon Publishing, 2004.
Mosby Elsevier, 2008. N Miller RF, Lipman MCI. Pulmonary infections
N Davis JL, Huang L. Pneumocystis pneumonia. In: (AIDS). In: Albert R, Spiro S, Jett J, eds.
Volberding PA, Sande MA, Lange J, Greene WC, Comprehensive Respiratory Medicine. 3rd Edn.
eds. Global HIV/AIDS Medicine. Philadelphia, Philadelphia, Mosby Elsevier, 2008.
Saunders Elsevier, 2008. N Pozniak AL, et al. BHIVA treatment guidelines
N Grogg KL, et al. HIV infection and lymphoma. J for TB/HIV infection 2010. HIV Med 2010;
Clin Pathol 2007; 60: 13651372. in press.
N Kaplan JE, et al. Guidelines for prevention and N Stringer JR, et al. A new name (Pneumocystis
treatment of opportunistic infections in HIV- jirovecii) for Pneumocystis from humans. Emerg
infected adults and adolescents: Infect Dis 2002; 8: 891896.
recommendations from CDC, the National N Walzer PD, et al. Early predictors of mortality
Institutes of Health, and the HIV Medicine from Pneumocystis jirovecii pneumonia in HIV-
Association of the Infectious Diseases Society of infected patients: 19852006. Clin Infect Dis
America. MMWR Recomm Rep 2009; 58: 1207. 2008; 46: 625633.

GRAFT VERSUS HOST
DISEASE
Dept of Clinical Medicine, Reference Centre for Primary
Immunodeficiencies, Sapienza University of Rome, Rome, Italy
E-mail: isabella.quinti@uniroma1.it
Pathogenesis the recipient-conditioning regimen damages

host tissues and causes release of pro-
Graft versus host disease (GVHD) is the inflammatory cytokines; host antigen-
principal complication of allogeneic bone presenting cells mature, acquire adhesion and
marrow transplantation (BMT). The number of co-stimulatory molecules that activate mature
patients at high risk for GVHD is increasing, donor T-cells; these cells proliferate and
as more BMTs are performed from unrelated produce additional cytokines inducing
donors and older patients. Vascular inflammatory and cellular effectors that
endothelial damage and increased secretion amplify the inflammatory responses that
of pro-inflammatory cytokines are involved in cause tissue damage. Obstacles to the
systemic disorders post-BMT, including GVHD improvement of BMT include the linkage
and cytomegalovirus (CMV) infection. The between GVHD toxicity and the beneficial
pathology of acute GVHD can be considered graft-versus-leukaemia effect, as well as the
in a framework of sequential phases. Initially, impairment of immune reconstitution leading
to life-threatening infections.
Key points Treatment
N GVHD is the principal complication of Novel approaches to prevent or treat GVHD

allogeneic BMT. are linked to the generation of new
monoclonal antibodies, immunomodulatory
N Vascular endothelial damage and therapy, innovative strategies that target both
increased secretion of pro-inflammatory soluble and cellular effectors. Among such
cytokines are involved in the agents are sirolimus, anti-tumour necrosis
pathogenesis of lung disorders. factor and antilymphocyte function-associated
N Acute and subacute patterns of lung (LFA)-3 antibodies, extracorporeal
injury include: idiopathic interstitial photopheresis, mesenchymal stem cells and
regulatory T-cells.
pneumonitis, bronchiolitis obliterans
syndrome, organising pneumonia, Noninfectious pulmonary-associated
alveolar haemorrhage, capillaritis, complications
post-transplant lymphoproliferative
disorders. Common pulmonary complications occur in
2550% of BMT recipients and are
N CMV infection is the most frequent viral responsible for 50% of transplant related
complication in patients undergoing deaths (table 1). Acute and subacute patterns
BMT and acute GVHD significantly of lung injury have been recognised. The
affects active CMV infection recurrence. idiopathic pneumonia syndrome occurs within
the first 120 days after BMT with a rapidly

Table 1. Frequency and mortality due to pulmonary complications after bone marrow transplantation
Frequency % Mortality %
Infectious aetiology 34.3 50
CMV pneumonitis 71.4
Tuberculosis 33.4
PCP 0
Aspergillosis 0
Noninfectious aetiology 65.7 30.4
Idiopathic interstitial pneumonitis 14.3
Organising pneumonia 20
Alveolar haemorrhage 100
Capillaritis 100
Post-transplant lymphoproliferative disorders 100
CMV: cytomegalovirus; PCP: Pneumocystis carinii pneumonia. Adapted from WANG et al. (2004)
progressing fulminant course resulting in frequent viral complication in patients

death in 6080% of patients. By contrast, undergoing BMT. Despite advanced
subacute noninfectious lung injury diagnostic methods and pre-emptive antiviral
(alloimmune lung syndromes), including therapy, CMV disease continues to be a life-
idiopathic pneumonia syndrome, bronchiolitis threatening complication. Clinical
obliterans syndrome and bronchiolitis manifestations could vary from an
obliterans with organising pneumonia, can asymptomatic infection, defined as active
occur in the early post-transplant period or in CMV replication in the blood in the absence
the months post-BMT. Although long-term of clinical manifestations, or organ failure
disease-free survival after BMT could exceed abnormalities characterised by CMV infection
60%, pulmonary infiltrates, due to either with clinical symptoms or organ function
inflammatory or infectious pneumonitis, occur abnormalities. Active CMV infection interacts
in 4060% of BMT recipients causing 80% of significantly in several ways with GVHD.
transplant-related deaths. In children Acute GVHD increases the chances of a poor
undergoing BMT, the incidence of pulmonary outcome. CMV prophylaxis or pre-emptive
complications varies from 1025%. Open lung therapy adopted during the last few years in
biopsy has been recommended to make a allogeneic BMT recipients has changed the
definitive diagnosis and the appropriate natural history of the disease. In prophylaxis,
treatment. Idiopathic interstitial pneumonitis antiviral drugs are administered before any
and CMV pneumonitis are the most common evidence of the virus, and in pre-emptive
causes and should be suspected in patients therapy, antiviral drugs are administered
with diffuse interstitial infiltrates. when there is laboratory evidence of an
Epidemiological data suggest that, although active but asymptomatic infection. Acute
GVHD reactions may play an aetiological role, GVHD significantly affects active CMV
the major contributing factor is conditioning- infection recurrence. CMV infection
related toxicity. Moreover, engraftment recurrence is more frequent with short
syndrome, diffuse alveolar haemorrhage and courses of antiviral therapy. The poor
pulmonary veno-occlusive disease are also bioavailability of oral ganciclovir may account
possible complications. for this; drug resistance may also be a
Infectious pulmonary-associated supplementary factor. Knowledge of these
complications complications is now a part of the
contemporary practice of pulmonary
Respiratory virus infections in BMT patients medicine, no longer isolated to the transplant
are seen in 156%. CMV infection is the most pulmonologist.
Graft versus host disease 431

References N Yoshihara S, et al. Bronchiolitis obliterans
syndrome (BOS), bronchiolitis obliterans
N Takatsuka H, et al. Complications after bone organizing pneumonia (BOOP) and other late-
marrow transplantation are manifestations of onset noninfectious pulmonary complications
systemic inflammatory response syndrome. Bone following allogeneic hematopoietic stem cell
Marrow Transplant 2000; 26: 419426. transplantation. Biol Blood Marrow Transplant
N Paczesny S, et al. Acute graft-versus-host disease: 2007; 13: 749759.
new treatment strategies. Curr Opin Hematol N Castagnola E, et al. Cytomegalovirus
2009; 16: 427436. infection after bone marrow transplantation
N Versluys AB, et al. Strong association between in children. Human Immunol 2004; 65:
respiratory viral infection early after 416422.
hematopoietic stem cell transplantation and the N Wang JY, et al. Diffuse pulmonary infiltrates
development of life-threatening acute and after bone marrow transplantation: the role of
chronic alloimmune lung syndromes. Biol Blood open lung biopsy. Ann Thorac Surg 2004; 78:
Marrow Transplant 2010; 16: 782791. 267272.

AMYLOIDOSIS
H.J. Lachmann
UK National Amyloidosis Centre, Dept of Medicine, University College
London Medical School, Royal Free Campus, London, UK
E-mail: h.lachmann@medsch.ucl.ac.uk
Amyloidosis is a group of diseases caused by Systemic amyloidosis complicating

accumulation of protein as insoluble fibrillar respiratory diseases
deposits in the extracellular space. These
progressively disrupt the structure and Amyloid A (AA) amyloidosis This causes
function of affected tissues. Diagnosis is made proteinuric renal failure and is a potential
by biopsy and Congo red staining, and complication of any sustained inflammation.
classification is by the fibril precursor protein. The amyloid fibrils are derived from the acute
Untreated amyloidosis progresses relentlessly, phase reactant, serum amyloid A protein
but deposits can regress if the supply of fibril (SAA). The major respiratory disease underlying
precursors is reduced. AA amyloidosis in the industrialised world is
bronchiectasis. Previously tuberculosis was
Amyloidosis can present to respiratory common and other associations include cystic
physicians in a number of ways: chronic lung fibrosis, sarcoidosis, lung neoplasia and
conditions can give rise to systemic Kartageners syndrome. The prognosis of AA
amyloidosis; systemic amyloidosis may present amyloidosis depends on the degree of renal
with respiratory symptoms; and localised damage and whether the underlying
pulmonary and respiratory tract amyloid inflammatory disease can be completely
deposits may present symptomatically or controlled. Treatment depends on the
incidentally. underlying disease and may involve surgery,
antimicrobials or immunosuppression.
Systemic, amyloid light chain (AL)

amyloidosis This may occur in association
with any B-cell dyscrasia as it is derived from
Key points monoclonal immunoglobulin light chains. A
number of chest-localised conditions can
N Amyloidosis is a protein deposition underlie systemic AL amyloidosis including
disease. Sjogrens syndrome, plasmacytomas and
Castlemans tumours.
N Diagnosis is by biopsy and Congo red
staining.
Respiratory system symptoms arising
N Systemic amyloidoiss usually affects from systemic AL amyloidosis
serveral organs.
Although lung deposits are universal at post
N Localised amyloidosis can present with mortem, symptoms are rare and dyspnoea
obstructive symptoms, haemoptysis or generally reflects amyloid cardiomyopathy.
as an incidental finding on imaging. Chest radiographs are usually normal. Lung
N Treatment depends on the type and function tests may be restrictive and extensive
distribution of amyloid deposits. alveolar deposits can reduce gas transfer.
Persistent pleural effusions are usually due to
Amyloidosis 433
cardiac infiltration by amyloid but can rarely the prognosis is usually excellent and no
be caused by amyloidotic disruption of the treatment is required.
pleura and may require recurrent drainage or
Mediastinal and hilar amyloid
pleurodesis. Treatment of systemic AL
lymphadenopathy
amyloidosis is chemotherapy directed against
the underlying B-cell clone. The lymphadenopathy may be massive and
typically complicates a low-grade lymphoma.
Amyloidosis localised to the respiratory
Disease progression is slow and calcification
tract
frequent. Tracheal compression or superior
This results either from local production of fibril vena caval obstruction occasionally result.
precursors, or from a microenvironment that
Conclusion
favours fibril formation from a widely distributed
protein. The majority of deposits are AL type Amyloidosis can both complicate long-standing
associated with monoclonal B-cells confined to pulmonary disease and be deposited within the
the affected site. Apparently localised amyloid respiratory system. The presentation and
deposits can be manifestations of systemic prognosis of amyloid deposits depend on their
disease and should always be fully investigated aetiology and distribution and can be benign or
to exclude systemic amyloidosis. life threatening. In most cases of localised disease,
management is essentially supportive or involves
Laryngeal amyloidosis
resection of symptomatic deposits. In contrast,
Amyloid represents 0.51% of benign systemic treatment can be extremely effective in
laryngeal disease and the incidence increases patients with generalised AA and AL amyloidosis.
with age. It usually presents as hoarseness
References
and is relatively benign but can be progressive
or recur after treatment. Fatal haemorrhage N Berk JL, et al. Pulmonary and tracheobronchial
has been reported. Endoscopic or laser amyloidosis. Semin Respir Crit Care Med 2002;
excision is the treatment of choice, aiming to 23: 155165.
preserve voice quality and airway patency. N Lachmann HJ, Hawkins PN. Amyloidosis and the
lung. Chron Respir Dis 2006; 3: 203214.
Very rarely apparently localised laryngeal
amyloid deposits can be a feature of
N Lachmann HJ, et al. Natural history and
outcome in systemic AA amyloidosis. N Engl J
hereditary apolipoprotein AL amyloidosis. Med 2007; 356: 23612371.
Tracheobronchial amyloidosis N Linder J, et al. Amyloidosis complicating hairy cell
leukaemia. Am J Clin Pathol 1982; 78: 864867.
This typically presents in the fifth or sixth N Osserman EF, et al. The pathogenesis of
decades with dyspnoea, cough and "amyloidosis". Studies on the role of abnormal
haemoptysis. Airway narrowing may cause gammaglobulins and gammaglobulin fragments
of the Bence Jones (L-polypeptide) types in the
pneumonia or lobar collapse and solitary
pathogenesis of "primary" and "secondary"
nodules can mimic endobronchial neoplasia. amyloidosis associated with plasma cell
There is no proven therapy although myeloma. Semin Hematol 1964; 1: 3.
chemotherapy has been tried in patients with N Pepys MB. Amyloidosis. Annu Rev Med 2006;
progressive disease. Management is dictated 57: 223241.
by symptoms and includes resection, stenting N Shah PL, et al. The importance of complete
or laser ablation. Survival is ,45% at 6 yrs. screening for amyloid fibril type and systemic
disease in patients with amyloidosis in the
Parenchymal pulmonary amyloidosis respiratory tract. Sarcoidosis Vasc Diffuse Lung
Dis 2002; 19: 134142.
This is typically an incidental finding on chest N Travis WD, et al. Non-neoplastic disorders of the
radiography of solitary/multiple nodules or a lower respiratory tract. In: Atlas of Nontumor
diffuse alveolar-septal pattern. Although the Pathology. Washington DC, American Registry
lesions must be differentiated from neoplasia of Pathology, 2002; pp. 873881.

PULMONARY ALVEOLAR
PROTEINOSIS
M. Luisetti
University of Pavia, Clinica Malattie Apparato Respiratorio, IRCCS
Policlinico San Matteo, Pavia, Italy
E-mail: m.luisetti@smatteo.pv.it
Pulmonary alveolar proteinosis (PAP) is a rare

syndrome occurring worldwide with an Key points
estimated prevalence of 0.1 per 100,000
individuals. PAP is characterised by N Pulmonary alveolar proteinosis (PAP) is
accumulation of surfactant within alveolar a rare syndrome caused by surfactant
macrophages in the alveoli and terminal clearance impairment.
airspaces, with impairment of gas transfer,
and by a variable clinical course, ranging from
N More than 90% of PAP cases are
associated with the presence of
spontaneous resolution to progressive
respiratory failure. neutralising autoantibodies anti
GM-CSF (GMAb; primary autoimmune
A surfactant clearance impairment is the likely PAP).
common pathophysiology of PAP, which can
be classified as follows. N Diagnosis of primary autoimmune PAP
is based of the following triad : 1) crazy
Primary PAP is due to disruption of paving pattern at HR CT scan; 2) milky
granulocyte macrophage-colony stimulating appearance and cytology of BALF; 3)
factor (GM-CSF) signalling, either by the elevated serum level of GMAb.
presence in plasma and lungs of high levels of
neutralising anti-GM-CSF autoantibodies N Whole lung lavage is the current standard
(GMAb) (autoimmune PAP, formerly known as of care of PAP, but alternative therapy
idiopathic PAP), or to mutations in the GM- (especially GM-CSF administration) are
CSF receptor a or b chains. under active investigation.
Secondary PAP occurs as a consequence of the
presence of several underlying diseases complaining about progressive exertional
associated with PAP, such as haematologic dyspnoea and cough; interestingly, about one-
disorders (mostly myelodysplatic syndrome), third of a large Japanese PAP series was
immunodeficiency status, dust inhalation, or asymptomatic. Physical examination of PAP
lysinuric protein intolerance. patients is often unremarkable. Pulmonary
function tests may be normal, but usually the
A third group (PAP-like diseases) is
first abnormality is represented by a decrease
characterised by surfactant production
in lung diffusing capacity, and exertional
impairment and includes genetic disorders
increased alveolararterial oxygen tension
due to mutations in the SP-B and SP-C genes,
gradient. The classic chest radiographic
as well as in the ABCA3 gene.
presentation is a diffuse bilateral infiltrate,
According to a recently published meta- with a distribution sometimes similar to
analysis and large cohort report, .90% of pulmonary oedema (fig. 1a). More typical is
immune PAP patients are middle-aged adults, the high-resolution computed tomography
Pulmonary alveolar proteinosis 435

(HRCT) presentation defined as crazy paving The natural history of the PAP has been
(thickening of interlobular and intralobular greatly influenced by the treatment. In the
septa, and ground-glass opacities, with patchy pre-whole-lung lavage (WLL) era, progressive
distribution) (fig. 1b). Although surgical deterioration occurred in ,30% of PAP
biopsy is traditionally considered mandatory patients. Death occurred mostly because of
to establish the diagnosis of PAP, more irreversible respiratory failure and, to a lesser
recently the triad represented by: 1) typical extent, respiratory infection. The latter is a
radiological findings on HRCT; 2) macroscopic typical complication of the clinical course of
appearance of milky fluid and cytology of PAP: pulmonary and systemic infections due
bronchoalveolar lavage (BAL) fluid; and 3) to opportunistic organisms such as Nocardia,
elevated serum level of GMAb (whose mycobacteria and Cryptococcus are often
sensitivity and specificity for diagnosing PAP reported. Increased susceptibility to lung
is approximately 100%) is now considered infections is traditionally attributed to the
sufficient to establish the diagnosis of impairment of alveolar macrophages engulfed
autoimmune PAP. Lung biopsy should be by surfactant, but systemic infections have
considered when one or more of the previous been ascribed more recently to GM-CSF
findings are unclear. Histopathology usually signalling impairment.
shows well preserved alveolar wall
architecture, and alveolar spaces filled with The adoption of WLL, first described in the
lipoproteinaceous, eosinophilic, Periodic Acid mid-1960s has changed the natural history of
Schiff-positive material and foamy PAP, by dramatically reducing the death rate.
macrophages. It is considered the standard care of PAP, and
95% of PAP patients respond positively to the
procedure, although a considerable fraction of
a)
patients may show relapses or incomplete
resolution. GM-CSF administration, based on
the pathophysiology of the disorder, is
considered an attractive alternative to WLL.
Unfortunately, limited experience and, more
importantly, difficult access to the drug have
so far precluded diffusion of this therapeutic
option. Possible alternatives are
plasmapheresis or immunosuppressive agents
such as rituximab, but data are so far
insufficient. Lung transplantation is considered
b) in end-stage disease, but PAP may recur.
References
N Beccaria M, et al. Long-term durable benefit
after whole lung lavage in pulmonary alveolar
proteinosis. Eur Respir J 2004; 23: 526531.
N Inoue Y, et al. Characteristics of a large cohort of
patients with autoimmune pulmonary alveolar
proteinosis in Japan. Am J Respir Crit Care Med
2008; 177: 752762.
N Luisetti M, Trapnell BC. Pulmonary alveolar
proteinosis. In: Schwarz MI, King TE, eds.
Interstitial Lung Disease, 5th Edn. Maidenhead,
McGraw-Hill, 2010.
Figure 1. a) Radiographic and b) high-resolution N Orphanet Series. November 2009, no.1. www.
computed tomography crazy paving presentation orpha.net/consor/cgi-bin/Education_Home.
of pulmonary alveolar proteinosis. php?lng5EN Date last accessed: March 8, 2010.

N Presneill JJ, et al. Pulmonary alveolar proteinosis. N Seymour JF, Presneill JJ. Pulmonary alveolar
Clin Chest Med 2004; 25: 593613. proteinosis: progress in the first 44 years. Am J
N Ramirez-R J, et al. Pulmonary alveolar Respir Crit Care Med 2002; 166: 215235.
proteinosis: a new technique and rationale for N Trapnell BC, et al. Pulmonary alveolar
treatment. Arch Int Med 1963; 112: 419431. proteinosis. N Engl J Med 2003; 349:
N Seymour JF, et al. Efficacy of granulocyte- 25272539.
macrophage colony stimulating factor in N Uchida K, et al. GM-CSF autoantibodies and
acquired pulmonary alveolar proteinosis. N Engl neutrophil dysfunction in pulmonary alveolar
J Med 1996; 335: 19241925. proteinosis. N Engl J Med 2007; 356: 567579.
Pulmonary alveolar proteinosis 437

ADULT PULMONARY
LANGERHANS CELL
HISTIOCYTOSIS
Department of Respiratory Diseases, Ho pital Louis Pradel, Lyon, France
E-mail: jean-francois.cordier@chu-lyon.fr
Langerhans cell (LC) histiocytosis (LCH) in of LCs associated with inflammatory cells
adults may involve especially the lungs, bone, including eosinophils. The LCs do not differ
the skin, and the pituitary gland. The disease from their counterparts in other tissues,
presentation in childhood is different, with exhibiting convoluted irregular nuclei with
acute disseminated disease with a poor characteristic Birbeck granules on electron
prognosis, and in older children and microscopy. These cells stain positive with
adolescents with multifocal involvement anti-CD1a and anti-CD207 antibodies. Some
including bone. Single-system involvement by features of alveolar macrophage pneumonitis
LCH is possible. (desquamative interstitial pneumonia) or
respiratory bronchiolitis with interstitial
Epidemiology lung disease are often associated. The
Pulmonary LCH in adults is a rare disease with progression of the bronchiole-centered
an estimated prevalence ,1 in 200,000. It granulomatous lesions results in fibrosis with
occurs almost exclusively in smokers, with no end-stage stellar fibrotic scars and adjacent
gender predominance, between the ages of cystic cavities.
2040 yrs, and is more common in the white Clinical features
population.
The respiratory manifestations are not
Pathologic features specific, with cough (often overlooked since
Pulmonary LCH is characterised by the patients are smokers), and dyspnoea on
granulomatous bronchiolocentric organisation exercise. Spontaneous pneumothorax is the
first manifestation leading to diagnosis in
,1020 % of patients. A number of patients
Key points have almost no reported symptoms and
diagnosis is made by routine chest
radiography.
N Pulmonary LCH is characterised by
cough, dyspnoea on exercise, and Pulmonary LCH is solitary in a large majority
diffuse pulmonary nodules and cysts on of patients; however, involvement of other
chest imaging in smokers that may systems may be the first manifestation of the
evolve to respiratory failure. disease. These include bone lesions (which are
N Smoking cessation should be obtained. often characteristic, well demarcated and
osteolytic on imaging; rib involvement with
N No medical therapy has demonstrated chest pain is possible), hypothalamicpituitary
efficacy. involvement resulting in diabetes insipidus
(polyuria, polydipsia) and skin lesions.

Imaging decreased, even in patients with relatively few
lesions on imaging. About one-third of
Chest radiography is usually abnormal with patients develop airflow obstruction with
micronodular and reticular opacities sparing inflation, which may progress to severe
the lower lobes. In advanced disease, the obstructive respiratory failure.
nodules are absent and chest radiography
may suggest emphysema. Diagnosis
High-resolution computed tomography The gold standard for diagnosis is lung biopsy
(HRCT) of the chest usually shows showing the characteristic features described
characteristic features in early disease with above. Surgical biopsy is often obtained
disseminated infracentimetric nodules, which during pleurodesis for refractory or relapsing
may show cavitation and may further pneumothorax. Because of the plurifocal
spontaneously disappear. The cavitated distribution of the lesions in the lung, the
nodules may evolve to thick- then thin-walled yield of transbronchial lung biopsy is usually
cysts (figure 1). The cysts may then enlarge limited. Bronchoalveolar lavage (BAL) is
and become confluent with HRCT features currently considered of little if any value for
resembling emphysema. diagnosis. It shows an increase in total cell
The differential diagnoses with other multiple counts with a large predominance of
cystic lung diseases on imaging comprise macrophages with possible slight increase in
especially lymphangioleiomyomatosis, Birt eosinophils. The CD4/CD8 lymphocyte ratio is
HoggDube and spontaneous familial decreased. The identification of Langerhans
pneumothorax related to FLCN mutations, cells in BAL with antibodies against CD1a has
Sjogren syndrome and nonamyloid only poor sensitivity and specificity and their
immunoglobulin deposition disease. Pleural proportion is usually similar to that in smokers
effusion and mediastinal lymphadenopathy is without LCH. Common laboratory tests are
exceptional. Pulmonary artery enlargement is not contributive.
present in patients with pulmonary
A presumptive diagnosis of pulmonary LCH
hypertension.
may be accepted in patients with
Lung function tests characteristic HRCT features and limited
symptoms and impaired lung function. Lung
Lung function tests may be normal or only biopsy is indicated in those patients with
mildly impaired in patients with nodular significant symptoms and deteriorated or
involvement. However transfer factor of the deteriorating lung function who are
lung for carbon monoxide is usually considered for treatment. In patients with
diffuse cystic lesions on HRCT with fixed lung
function impairment, lung biopsy is of limited
benefit especially as it may not show
characteristic granulomatous lesions.
Evolution
About half of patients improve spontaneously

or with corticosteroid treatment (which has
not been evaluated). Poor outcome with
respiratory failure may occur especially in
older patients with systemic involvement and
deteriorating lung function tests. Pulmonary
Figure 1. High-resolution computed tomography of hypertension, occasionally severe, is common
the chest demonstrating numerous thin-walled cysts in advanced disease. Lung cancer may
in a patient with LCH. develop resulting from smoking habits.
Adult pulmonary Langerhans cell histiocytosis 439

Treatment hypertension. Post-transplant survival is rather
good with 10-yr survival .50%; however,
Given the possibility of spontaneous recovery
pulmonary LCH may recur in about one-fifth
in a number of patients and the absence of
of patients.
controlled therapeutic trials, there is no
evidence for efficacy of any treatment. References
However, the strong association between N Allen TC. Pulmonary Langerhans cell histiocytosis
pulmonary LCH and smoking suggests that and other pulmonary histiocytic diseases. Arch
smoking cessation should be obtained (at Pathol Lab Med 2008; 132: 11711181.
least to prevent further development of N Caminati A, Harari S. Smoking-related interstitial
chronic obstructive pulmonary disease and/or pneumonias and pulmonary Langerhans cell
lung cancer). histiocytosis. Proc Am Thorac Soc 2006; 3:
299306.
Corticosteroid treatment is often used in N Dauriat G, et al. Lung transplantation for
patients with symptomatic disease and pulmonary Langerhans cell histiocytosis : a
worsening lung function, starting with multicenter analysis. Transplantation 2006; 81:
prednisone 0.51 mg.kg-1 then tapered over 746750.
612 months. Whether improvement, when it N Fartoukh M, et al. Severe pulmonary
occurs, results from treatment efficiency or is hypertension in histiocytosis X. Am J Respir Crit
spontaneous cannot be established. Care Med 2000; 161: 216223.
N Kiakouama L, et al. Severe pulmonary
Cytotoxic agents (especially vinblastin) have hypertension in histiocytosis X: long-term
occasionally been used with no conclusive improvement with bosentan. Eur Respir J 2010;
efficiency. 2-chloro-deoxyadenosine (cladribin) 36: 13.
has consistently been shown to be efficient in N Lazor R, et al. Progressive diffuse pulmonary
isolated cases, however it may be proposed Langerhans cell histiocytosis improved by
and evaluated only in referral centres. cladribine chemotherapy. Thorax 2009; 64:
274275.
Pulmonary hypertension, when present, may N Mendez JL, et al. Pneumothorax in pulmonary
be improved by pulmonary arterial Langerhans cell histiocytosis. Chest 2004; 125:
hypertension treatment in some patients. 10281032.
N Tazi A. Adult pulmonary Langerhans cell
Lung transplantation (single- or double-lung, histiocytosis. Eur Respir J 2006; 27: 12721285.
or heartlung) may be considered in patients N Vassallo R, et al. Pulmonary Langerhans cell
with end-stage disease. The majority of these histiocytosis. N Engl J Med 2000; 342:
present with moderate-to-severe pulmonary 19691978.

LYMPHANGIOLEIOMYOMATOSIS
National Reference Centre for Rare Pulmonary Diseases, Lyon, France
E-mail: jean-francois.cordier@chu-lyon.fr
Epidemiology and genetics around lymphatic vessels in the lung and

possibly the axial lymphatics and the thoracic
Lymphangioleiomyomatosis (LAM) is a rare duct. LAM cells are stained with antibodies
(so-called orphan) lung disease affecting against smooth muscle actin, desmin, and
about 1 in 400,000 adult women (usually of HMB-45 (detecting characteristic pre-
childbearing age). It may be sporadic, or melanocyte proteins).
associated with tuberous sclerosis complex
(TSC) where it affects 3040% of adult Clinical manifestations and lung
women and, exceptionally, men. function tests
TSC is associated with inherited mutations Dyspnoea on exertion is the most common
of the TSC1 and TSC2 genes, while symptom, and pneumothorax the most
acquired somatic mutations of TSC2 are common mode of presentation (often
associated with sporadic LAM, resulting in relapsing, and may be bilateral). Chylous
constitutive activation of the kinase effusion (chylothorax, chylous ascites) may be
mammalian target of rapamycin (mTOR) present.
signalling pathway. Lung function tests are characterised by
Pathology airflow obstruction and impaired gas transfer
with decrease in transfer factor of the lung for
In LAM, the lung parenchyma is progressively carbon monoxide (TL,CO). Exercise
replaced by cysts associated with a performance and maximal oxygen uptake are
proliferation of immature smooth muscle cells impaired. Hypoxaemia is present in advanced
and perivascular epithelioid cells (LAM cells). disease.
LAM cell proliferation usually develops Imaging
Chest radiography shows reticular opacities
Key points and cysts, with further possible pleural
effusion or pneumothorax.
N LAM is a rare disease occurring in High-resolution computed tomography
women of child-bearing age, (HRCT) of the chest has a major role in
characterised by dyspnoea on exertion, diagnosis. It shows characteristic multiple
relapsing pneumothorax and numerous round cysts involving the whole parenchyma;
thin-walled cysts on chest imaging. these may progressively become confluent
(fig. 1).
N Diagnostic criteria have been proposed
recently. The differential diagnoses with the other
N The disease may slowly progress to multiple cystic lung diseases on imaging
comprise especially BirtHoggDube
respiratory insufficiency.
syndrome and spontaneous familial
N No effective therapy is available. pneumothorax related to folliculin gene
mutations, Langerhans cell granulomatosis,
Lymphangioleiomyomatosis 441
Angiomyolipoma
Angiomyolipomas (AML) of the kidney (which
are benign tumors composed of blood vessels,
smooth muscle, and adipose tissue easily
identified on HRCT) are associated with LAM
in 50% of sporadic LAM and 80% of patients
with TSC (where these are more often
bilateral and larger). AML may enlarge with
time and become prone to bleeding,
especially when .4 cm in size (embolisation
or nephron-sparing surgery is therefore
indicated). Screening for AML in patients with
Figure 1. HRCT of the chest demonstrating
LAM is recommended.
numerous thin-walled cysts in a patient with LAM.
Diagnostic criteria
Sjogren syndrome and nonamyloid
immunoglobulin deposition disease. Diagnostic criteria for LAM have recently been
proposed by a European Respiratory Society
Cysts may be associated with some small Task Force (table 1). The gold standard for
nodules in TSC (corresponding to multifocal diagnosis of LAM is lung biopsy fitting the
micronodular pneumocyte hyperplasia), pathological criteria for LAM. However, the
pleural effusion or pneumothorax. The axial association of characteristic HRCT features
lymphatics in the thorax and the with AML or other characteristic features of
retroperitoneum may be dilated with LAM may obviate the need for biopsy. The
lymphadenopathy, and abdominal cystic differential diagnosis comprises other multiple
lymphatic collections called lymphangiomas cystic lung diseases including especially the
(in up to 20% of patients) that may result in BirtHoggDube syndrome associated with
abdominal discomfort or compression. mutations of the folliculin gene, familial
Table 1. European Respiratory Society diagnostic criteria for lymphangioleiomyomatosis (LAM)

Definite LAM
1. Characteristic# or compatible# lung HRCT and lung biopsy fitting the pathological criteria for LAM
OR
2. Characteristic# lung HRCT and any of the following:
angiomyolipoma (kidney)"
thoracic or abdominal chylous effusion+
lymphangioleiomyoma1 or lymph-node involved by LAM1
definite or probable TSC
Probable LAM
1. Characteristic# HRCT and compatible clinical historye
OR
2. Compatible# HRCT and any of the following:
angiomyolipoma (kidney)"
thoracic or abdominal chylous effusion+
Possible LAM
Characteristic# or compatible# HRCT
#
: characteristic: multiple thin-walled round well-defined air-filled cysts; compatible: only few multiple (.2 and f10)
,30-mm such cysts; ": diagnosed by characteristic computed tomographic features and/or on pathological examination;
+
: based on visual and/or biochemical characteristics of the effusion; 1: based on pathological examination; e: compatible
clinical features include pneumothorax (especially multiple and/or bilateral) and/or altered lung function tests as in LAM.
Reproduced from JOHNSON et al. (2010).

isolated primary spontaneous pneumothorax In patients with end-stage disease LAM,
(also associated with mutations of the same transplantation (single or bilateral) is an
gene), cysts associated with lymphoid efficient procedure with results comparing
interstitial pneumonia, nonamyloid favourably with transplantation for other
immunoglobulin deposition disease, etc. A pulmonary diseases. As many LAM patients
diagnostic work-up for the preceding are rather young, lung transplantation may
alternative causes of multiple cystic lung be proposed in most severe cases with
disease is mandatory in patients with poor prognosis. Recurrence of LAM on
probable and especially possible LAM. transplant is possible but does not affect
Evolution and prognosis survival.
Disease progression is variable with some References

patients remaining relatively stable for long N Avila NA, et al. Pulmonary
periods whereas others deteriorate rapidly with lymphangioleiomyomatosis: correlation of
ensuing respiratory insufficiency. Repeated ventilation-perfusion scintigraphy, chest
measurement of forced expiratory volume in 1 s radiography, and CT with pulmonary function
and TL,CO is used to assess disease progression tests. Radiology 2000; 214: 441446.
with arterial oxygen measurement in advanced N Avila NA, et al. Lymphangioleiomyomatosis:
disease. Pulmonary hypertension, usually mild, abdominopelvic CT and US findings. Radiology
may develop. 10-yr survival was about 7090% 2000; 216: 147153.
in recent large series. N Benden C, et al. Lung transplantation for
lymphangioleiomyomatosis: the European
Management experience. J Heart Lung Transplant 2009; 28:
17.
As LAM occurs in women of childbearing age, N Bissler JJ, et al. Sirolimus for angiomyolipoma in
oestrogens have been suspected to enhance tuberous sclerosis complex or
and progestatives to prevent its development. lymphangioleiomyomatosis. N Engl J Med 2008;
However, hormonal interventions have not 358: 140151.
demonstrated significant advantages. N Johnson SR, et al. European Respiratory Society
Nevertheless, oestrogens (contraceptive pill, guidelines for the diagnosis and management of
hormone replacement) should be avoided. lymphangioleiomyomatosis. Eur Respir J 2010;
35: 1426.
No effective treatment for LAM is available. N Johnson SR, Tattersfield AE. Clinical experience
The mTOR inhibitors, which transiently reduce of lymphangioleiomyomatosis in the UK. Thorax
the volume of AML, may mildly improve or 2000; 55: 10521057.
stabilise pulmonary LAM; however, only N Moss J, et al. Prevalence and clinical
limited evidence is currently available and characteristics of lymphangioleiomyomatosis
tolerance may be poor. (LAM) in patients with tuberous sclerosis
complex. Am J Respir Crit Care Med 2001; 164:
There is a greater risk of pneumothorax and 669671.
chylous effusion during pregnancy. To become N Ryu JH, et al. The NHLBI
pregnant is the patients decision; however, Lymphangioleiomyomatosis Registry:
pregnancy may be discouraged in patients characteristics of 230 patients at enrollment.
with severe disease. Am J Respir Crit Care Med 2006; 173: 105111.
N Urban T, et al. Pulmonary
Influenzal and pneumococcal vaccination lymphangioleiomyomatosis. A study of 69
should be offered to patients with LAM. patients. Groupe dEtudes et de Recherche sur
Inhaled bronchodilators should be prescribed les Maladies "Orphelines" Pulmonaires
to patients with airflow obstruction and (GERM"O"P). Medicine (Baltimore) 1999; 78:
continued if a response is observed. 321337.
Lymphangioleiomyomatosis 443
CHAPTER 17:
PulmonARy REHAbiliTATion
RESPiRAToRy PHySioTHERAPy 446

J. Bott
PulmonARy REHAbiliTATion 451

T. Troosters, H. Van Remoortel, D. Langer and C. Burtin

RESPIRATORY
PHYSIOTHERAPY
J. Bott
London, UK
E-mail: juliabott@aol.com
Respiratory physiotherapy spans a broad Physiotherapists are thus vital to the delivery
range of services, advice and of effective pulmonary rehabilitation (PR).
nonpharmacological interventions used to
Physiotherapy is provided across all
help patients with a variety of respiratory
healthcare settings, from the patients own
conditions. Its use has been documented for
home to the critical care unit. Physiotherapists
over a century: postural drainage (PD) was
are well qualified to provide assessment and
reported for secretion removal in
monitoring of, for example, ventilatory
bronchiectasis in 1901 and, in 1915,
function and cough effectiveness or exercise
breathing exercises and physical exercise for
tolerance, including for ambulatory oxygen
chest injuries.
(O2) assessment. Interestingly, there is wide
General principles of physiotherapy variance in tasks undertaken by
physiotherapists across countries.
Physiotherapy is aimed at treating or
alleviating problems rather than diseases. Airway clearance
Strategies are used to restore, improve or To help the patient better manage their
maintain movement and/or function, and secretions, a range of airway clearance
maximise participation in everyday life. techniques are available, including:
N independent techniques, e.g. the active

Key points cycle of breathing techniques, autogenic
drainage
Physiotherapy is indicated in most
respiratory conditions, both for groups and N mechanical or other devices, e.g. positive
individuals, for: expiratory pressure (PEP)/oscillating PEP
and high frequency chest wall oscillation
N self-management advice and education
on lifestyle modifications related to N PD or modified PD
physiotherapy strategies N nebulised substances, e.g. hypertonic
N breathlessness management saline
N improvement or maintenance of N techniques for cough enhancement or
mobility and function support, e.g. maximum insufflation
techniques and manually assisted
N airway clearance in well-defined cases
coughing
N prescription of exercise and exercise
training Physiotherapists physiological knowledge and
practical skills means they are well placed to
N prescription of walking aids assist in the delivery of pharmacotherapy
(inhalers) and their timing with respect to the

physiotherapy intervention. Physiotherapists
can also help in the delivery and correct
application of O2 therapy, including
ambulatory O2, as well as offering
improvement of poor ventilatory function,
including in the sedated and paralysed
patients.
Strategies to enhance ventilation and
gas exchange
Strategies to enhance ventilation and gas
exchange include:
N positioning
N breathing techniques
Thank you for giving me my life back.
N manual hyperinflation
N intermittent positive pressure breathing
N breathing techniques to help the patient
better control dyspnoea and panic, both at
(IPPB)
rest and during exertion
N continuous positive airway pressure (CPAP)
Physical activity and exercise should be
N noninvasive ventilation (NIV) encouraged throughout the course of the
disease, including during hospital admission
Physiotherapists are considered by many to be where possible and appropriate. When
invaluable in the delivery of an effective NIV supervised and carried out at appropriate
service. intensity these exercises are more effective.
Physiotherapy is commonly helpful for Exercise training programmes are indicated
postural problems and/or musculoskeletal for patients who have symptoms and impaired
dysfunction and pain as well as for improving physical activities in daily life.
continence. With an increased prevalence Selected patients may benefit from inspiratory
compared with that of nonrespiratory muscle training.
populations, this is especially warranted
during coughing and forced expiratory In both the acute and domiciliary settings:
manoeuvres. N Wheeled walking aids (rollator frame)
Disease-specific physiotherapy reduce the ventilatory requirements of
ambulation.
Chronic obstructive pulmonary disease N Wheeled walking aids are especially useful
(COPD) Taking account of the altered for those who are more disabled by
mechanics of breathing in those with COPD is breathlessness and those using ambulatory
essential for effective breathlessness O 2.
management and advice.
N Patients severely disabled by breathlessness
Breathlessness management includes: may find using a high gutter rollator frame
allows some mobility.
N positioning to fix the shoulder girdle
N Along with occupational therapists,
passively
physiotherapists may promote energy
N forward-leaning postures to improve the conservation strategies to minimise the
length tension ratio of the diaphragm work of activities of daily living.
Respiratory physiotherapy 447

Airway clearance techniques should be used individual basis. Regular review is advised to
where indicated and IPPB may be considered ensure continuing effectiveness and
in acute exacerbations of COPD for patients concordance with therapy; appropriate
with retained secretions who are too weak or adjustment of treatment can be made if
tired to generate an effective cough. NIV is necessary.
now the first-line therapy for hypercapnic
respiratory failure and both NIV and O2 N Physiotherapy for patients with CF should
therapy should be delivered according to include assessment and treatment for
current guidance. musculoskeletal and postural disorders.
Asthma Some form of breathing retraining N Physiotherapists need to be scrupulous
using reduced volume and/or frequency with about hygiene for infection control in this
relaxation is indicated to reduce symptoms population.
and improve quality of life, along with
prescribed medication. Several schools N For those with either CF or bronchiectasis
advocate specific techniques, but it is continence problems should be identified
important to stress that these techniques are and treated.
adjunctive to medication and not a N For patients with bronchiectasis, PR is
replacement therapy. indicated when dyspnoea is impacting on
exercise tolerance or functional activities.
Routine or regular airway clearance is rarely
indicated in the asthmatic patient. N Exercise for the patient with CF must be
undertaken individually to reduce risk of
Disordered breathing (hyperventilation
cross-infection.
syndrome) Breathing exercises combined
with relaxation (technique as for asthma) is Interstitial lung diseases There is little
an effective strategy to reduce symptoms once published evidence on physiotherapy for these
the diagnosis is confirmed. conditions. Studies on the effectiveness of
engaging in exercise training are emerging
Cystic fibrosis (CF) and non-CF-related
and patients with interstitial lung diseases
bronchiectasis Physiotherapy is integral to
can gain benefit from PR providing they are
the management of patients with
referred early in the disease process. Patients
bronchiectasis from any cause, including CF,
at a later stage of disease may benefit from
with airway clearance and exercise central to
wheeled walking aids, ambulatory O2,
this therapy. The acceptability of techniques
breathlessness management and energy
and regimes, to enhance concordance with
conservation strategies.
treatment, is vital to the success of therapy.
A variety of airway clearance techniques, Community-acquired pneumonia

including those with and without mechanical (CAP) Traditional airway clearance
assistance if necessary, should be offered, in techniques are rarely indicated.
order to find one that is both acceptable and
effective. The simplest technique that For patients admitted to hospital with
impinges the least on the patients life is a uncomplicated CAP:
good starting point.
N Regular use of PEP may reduce length of
Effective treatment might need to be stay.
supported by inhaled therapies, e.g. N Medical condition permitting, early mobi-
bronchodilators or hypertonic saline, O2 and lisation is indicated.
NIV or IPPB. These supportive therapies and
PD to enhance airway clearance or exercise N Patients should be encouraged to sit out of
tolerance should be assessed for benefit on an bed for at least 20 min on the first day,

increasing the time and general mobility Strategies to enhance maximal insufflation
on each subsequent day. capacity are indicated and include:
CPAP may be helpful for patients in type I N resuscitation bags

respiratory failure who remain hypoxaemic
despite optimum medical therapy and O2, and
N NIV
NIV may be an option for selected patients in N mechanical insufflation, and
type II respiratory failure, especially those
with underlying COPD.
N breath stacking via the above or
Chest wall disorders PR is indicated in a

N glossopharyngeal (frog) breathing
patient with chest wall deformity from any The presence of severe bulbar dysfunction or
cause with reduced exercise capacity and/or paralysis renders breath stacking ineffective.
breathlessness on exertion. The need for Maximal insufflation capacity used regularly
ambulatory O2 or NIV should be assessed is also a means of maintaining range of
before undertaking exercise. Respiratory movement to the lungs and chest wall. These
muscle training may have a role. It has yet to techniques should be used along with
be established whether breathing or thoracic strategies to enhance cough effectiveness:
mobility exercises are helpful in this client manually assisted coughing or mechanical
group. insufflationexsufflation.
Neuromuscular disease and spinal cord Ventilatory function can be improved with
injury (SCI) Respiratory problems are the careful positioning to optimise the effect of
commonest cause of morbidity and mortality gravity on weak muscles, as can the use of
for those with respiratory muscle weakness; abdominal binders for those with SCI.
physiotherapy therefore provides vital
In patients with SCI, exercise should be
assistance with airway clearance. Difficulty
encouraged; respiratory muscle training and
clearing secretions may be due to inspiratory,
functional electrical stimulation may enhance
expiratory and/or bulbar muscle weakness,
muscle strength or vital capacity. Some
depending on the underlying condition and
patients with early neuromuscular disease
stage of disease.
may benefit from respiratory muscle training
but caution is advised in Duchenne muscular
N Regular monitoring of O2 saturation, vital dystrophy.
capacity and peak cough flow can indicate
impending problems with either ventilation Patients with critical illness The
or cough effectiveness. principles of care remain the same;
physiotherapists provide rehabilitation for the
N The use of respiratory aids when these prevention and treatment of the common
measures fall may prevent or reduce complications associated with prolonged bed
complications. rest, immobility and recumbency, including
deconditioning, weakness and dyspnoea.
O2 therapy should be administered with great Physiotherapy is also used to target specific
care in patients with neuromuscular disease respiratory problems, such as retained airway
because of the risk of increasing ventilation/ secretions, atelectasis and weaning failure.
perfusion mismatch and increasing
hypercapnia. NIV should be considered in
References
those at risk of developing hypercapnia. These
actions are done together with the treating N Bott J, et al. Guidelines for the physiotherapy
physician. management of the adult, medical,
spontaneously breathing patient. Thorax 2009;
Traditional physiotherapy techniques are not 64: Suppl. 1, i1- i51. Available at www.brit-
useful in this client group. thoracic.org.uk/Portals/0/
Respiratory physiotherapy 449

Clinical%20Information/Physiotherapy/ obstructive pulmonary disease based on a
PhysiotherapyGuideline. systematic review of available evidence. Clin
N Gosselink R, et al. Physiotherapy for adult Rehabil 2009; 23: 445462.
patients with critical illness: recommendations N National Institute for Health and Clinical
of the European Respiratory Society and Excellence. NICE guideline 83: Rehabilitation
European Society of Intensive Care Medicine after critical illness. www.nice.org.uk/CG83.
Task Force on Physiotherapy for Critically Ill Date last accessed: June 1, 2010.
Patients. Intensive Care Med 2008; 34, 7: N Nici L, et al. American Thoracic Society/
11881199. European Respiratory Society statement on
N Langer D, et al. A clinical practice guideline for pulmonary rehabilitation. Am J Respir Crit Care
physiotherapists treating patients with chronic Med 2006; 173: 13901413.

PULMONARY REHABILITATION
T. Troosters, H. Van Remoortel, D. Langer, C. Burtin,
M. Decramer and R. Gosselink
Respiratory Rehabilitation and Respiratory Division, University Hospital
Leuven, and Faculty of Kinesiology and Rehabilitation Sciences, Department
of Rehabilitation Sciences, Katholieke Universiteit Leuven, Leuven, Belgium
E-mail: Thierry.Troosters@med.kuleuven.be
Pulmonary rehabilitation is a recognised other care plans for chronic obstructive

therapy for patients with respiratory diseases. pulmonary disease (COPD) patients, such as
The European Respiratory Society and the self-management programmes, lung
American Thoracic Society define pulmonary transplantation programmes, noninvasive
rehabilitation as an evidence-based, ventilation or smoking cessation programmes.
multidisciplinary, and comprehensive
intervention for patients with chronic The evidence base for pulmonary
respiratory diseases who are symptomatic and rehabilitation
often have decreased daily life activities. Several reviews have summarised the evidence
Integrated into the individualized treatment of for pulmonary rehabilitation and practice
the patient, pulmonary rehabilitation is guidelines are available. Briefly, pulmonary
designed to reduce symptoms, optimize
rehabilitation improves health-related quality
functional status, increase participation, and
of life and symptoms unequivocally and
reduce health care costs through stabilizing or
clinically significantly in patients with COPD,
reversing systemic manifestations of the
to a degree similar to or even larger than that
disease. Although this is a long definition, it
obtained by pharmacotherapy. When exercise
captures the core elements important in the
training is provided at adequate intensity,
selection and design of pulmonary
exercise tolerance is enhanced and functional
rehabilitation. Importantly, pulmonary
exercise capacity improves. These
rehabilitation may be an integrated part of
improvements are also clinically relevant if an
appropriate exercise stimulus is provided.
Key points Other improvements are also important but
are to date less studied.
N Pulmonary rehabilitation is an
evidence-based treatment that improves A significant proportion of patients referred for
health-related quality of life and pulmonary rehabilitation suffer from psychiatric
symptoms in chronic obstructive morbidity, most commonly anxiety and
depression. A recent meta-analysis showed the
pulmonary disease.
potential small benefit of multidisciplinary
N Programmes should be tailored to the pulmonary rehabilitation on mood status. The
patient in terms of content, location, relatively small effect size may be a result of the
duration, frequency and exercise dilution of depressed patients in the larger
training. patient pool: effects on these variables can only
be expected in patients with symptoms of
N In order for the effects to be durable,
depression and/or anxiety.
patients everyday activity should be
higher after rehabilitation than before. A less studied effect of rehabilitation is
enhanced self-efficacy. Self-efficacy is the
Pulmonary rehabilitation 451

confidence patients have in their ability to carry healthcare resources, most importantly
out a specific task or manage a specific hospital admissions. There is a body of data
condition (e.g. breathlessness). Patients suggesting that pulmonary rehabilitation
confidence that they can manage dyspnoea reduces the number of hospital days. In more
improves after pulmonary rehabilitation, and fragile patients, such as those recently
one seminal study also showed an improvement admitted to hospital and at risk for
in self-efficacy with walking. It is unclear to what readmission, a meta-analysis showed that the
extent this contributes to an effective change in risk for readmission was reduced substantially
behaviour after pulmonary rehabilitation. following pulmonary rehabilitation.
The amount of activity patients carry out in Programme content and maintaining
daily life is an important outcome for effects
rehabilitation. The systemic consequences of As indicated above, programmes need to be
COPD, such as cardiovascular morbidity, individualised and aim at improving the
muscle weakness and osteoporosis, originate systemic consequences (physiological and
largely directly or indirectly from an psychological) of the underlying disease,
inactive lifestyle. When pulmonary guiding patients and their families towards a
rehabilitation aims at achieving a sustained long-term change in physical activity and self-
effect, an inactive lifestyle after rehabilitation management. Several options are possible in
should be avoided. The effect of pulmonary terms of programme content (the disciplines
rehabilitation programmes on physical activity contributing), location, duration and
levels is as yet unclear. Changing physical frequency. These are summarised in table 1.
activity behaviour is a challenging task. Our Studies comparing different modalities of
research group showed that walking time in rehabilitation are scarce and no unequivocal
daily life changed only modestly after preference has been reported. Studies
3 months of pulmonary rehabilitation. After comparing hospital-based outpatient
6 months there was a more significant rehabilitation to rehabilitation at home found
improvement in physical activity levels. no differences on short-term outcomes. More
Changing physical activity may not simply research is needed to evaluate the criteria for
follow increased exercise capacity. Indeed, assigning patients to a specific form of
physical activity levels are a complex rehabilitation. In addition, it remains unclear
integration of exercise capacity and to what extent home rehabilitation results in
willingness to use that capacity. In recent more durable effects.
years, appealing new strategies have been
developed that may help to increase the For the essential exercise training component,
effects of classical rehabilitation on physical the programme needs to be individualised in
activity. Providing real-time feedback with terms of exercise modalities, specificity of
pedometers may, along with setting training, training intensity and specific
achievable goals, enhance daily activity levels inspiratory muscle training. In order to obtain
in- or outside the context of pulmonary significant physiological improvements in
rehabilitation. Walking at home has been skeletal muscle function it is important to
stimulated effectively using modern train patients at an intensity that is high
interfaces such as mobile phone technology, relative to their maximum capacity. In order to
which included paced walking to the combine an effective training programme with
rhythm of music adapted to the capabilities patient comfort, clinicians have the choice of
of the patient. Future research should several exercise training modalities, including
focus on further strategies that may help endurance, interval and resistance training.
to lead to sustainable behavioural change. The duration of an exercise training
programme is o8 weeks and at least three
An important spin-off of pulmonary sessions per week are needed. One of these
rehabilitation may be a decrease in the use of sessions can be conducted outside the

formally supervised setting, provided that the interventions, may yield results more rapidly.
session is comparable in terms of duration Secondly, exercise at home should be
and intensity to the supervised sessions. facilitated. This can be done using feedback
on home exercises, or incentives. Such
There has been much debate as to whether exercises need to be individually tailored to
the effects of a rehabilitation programme can achieve effective intensity in order to provide
be maintained. From earlier studies it is a continued training stimulus. Ideally,
indeed difficult to claim durable effects for exercises should be regularly supervised.
short-term (68 weeks) pulmonary Lastly, specific attention should probably go
rehabilitation programmes. Long-term studies to patients who suffer from exacerbations, as
(using up to 6 months of rehabilitation) did these events acutely reduce muscle force and
find more long-term effects. functional exercise capacity. Prevention of
such events can be done in patients at risk by
Current understanding of the development of
implementing self-management strategies and
systemic consequences of COPD may help in
providing a case manager. There is currently
the design of successful longer-term strategies
little evidence for a short booster
to maintain the effects of pulmonary
programme after a hospital admission to
rehabilitation. First, efforts should be made to
maintain the benefits of rehabilitation.
change the physical activity behaviour of
patients. Physical inactivity is likely to be the Examination of the strategies used to
most important contributor to the maintain the benefits of rehabilitation reveals
development of systemic consequences in that it is important to achieve a durable
COPD. If patients are not more active after the change in physical activity behaviour and that
rehabilitation programme, it is likely that the patients should continue to carry out planned
effects of rehabilitation on enhanced exercise exercises at high intensity to maintain the
capacity and skeletal muscle force will be physiological benefits of rehabilitation.
short lived. Longer programmes are more Interventions that are not regular or are
successful in achieving this goal than short- less structured are not successful in
term programmes, but changes in the maintaining the benefits of rehabilitation.
programme content, for example providing More research is needed to identify optimal
patients with direct feedback on their physical maintenance strategies after pulmonary
activity levels or using structured behavioural rehabilitation.
Table 1. Choices to be made when prescribing pulmonary rehabilitation

Aspects to be individualised Possible choices or options
Programme content Disciplines typically involved: chest physician, physiotherapists, nurse,
exercise specialist, occupational therapist, psychologist, social worker,
dietician, general practitioner
Location Rehabilitation centre: in-patient, out-patient, home based but
supervised from a specialised centre
Community based: out-patient in centre or primary care office
Home based: supervised by primary care team
Duration o8 weeks, but longer is typically more desired
Frequency o3 sessions per week of which 2 are supervised
Exercise training component Exercise modalities (walking, cycling, upper limbs, etc.)
Exercise intensity
Exercise type: interval, endurance, resistance
Additional interventions: inspiratory muscle training, oxygen therapy,
noninvasive mechanical ventilation, neuromuscular electrical stimulation

Diagnosis COPD
Anamnesis
Symptoms
Reduced participation Optimise
Impaired overall function
Frequent excarbations
YES
Medical treatment optimal NO
Systemic consequences? NO No indication for rehabilitation

Exercise intolerance (6MWT)
Psychological problems (HADS) YES
Nutritional status (BMI, FFM) Design programme see table 1
Adaptation in daily life (interview) Location
Exacerbations (chart review) Frequency
Duration
Disciplines
Exercise limitation (CPET) Design exercise programme
(Skeletal) muscle weakness (QF) Intensity?
Training modalities?
Additional interventions (NMES,
IMT)?
Supplements?
Figure 1. Flow chart for referral to pulmonary rehabilitation programmes. It should be emphasised that
patients who are not candidates for pulmonary rehabilitation may still benefit from exercise training as an
intervention to prevent morbidity.
Patient selection: patients with transplantation or lung volume reduction, a

systemic consequences programme of noninvasive ventilatory support
or oxygen therapy. Such programmes do not
Extrapolating from the definition of exclude pulmonary rehabilitation. On the
pulmonary rehabilitation, the ideal candidate contrary, pulmonary rehabilitation is often
for rehabilitation is symptomatic, has strongly recommended for these patients.
impaired functional status and participation, Figure 1 gives an overview of the selection
is a heavy user of healthcare resources and process and the design of the programme for
should suffer from the systemic patients with COPD.
consequences of COPD. Hence patient
selection should not be based on lung Extrapulmonary consequences of
function, but rather on the proper assessment COPD In the context of pulmonary
of the extrapulmonary consequences of COPD rehabilitation, the most important systemic
found to be reversible with rehabilitation, consequence of COPD is skeletal muscle
symptoms, functional status, levels of dysfunction. In clinical practice, this can be
participation in daily life and health-related assessed by skeletal muscle force or local
quality of life. Other factors such as age, skeletal muscle endurance, which is often
gender and smoking status are not important even more affected. Approximately 70% of
predictors of rehabilitation outcome. It is patients referred to an outpatient COPD clinic
important that patients are screened for suffer from skeletal muscle weakness, and
pulmonary rehabilitation after optimal skeletal muscle force is acutely further
pharmacotherapy is established. While being reduced during acute exacerbations. Reversal
screened, patients can also be considered for of skeletal muscle dysfunction is an important
other programmes such as a lung goal of the exercise training component of a

rehabilitation programme and hence patients of fat-free mass, leads inevitably to skeletal
suffering from skeletal muscle weakness are muscle weakness. It is a complex problem and
particularly good candidates for exercise its origin is not yet fully understood. The
training. Improving skeletal muscle strength treatment of cachexia is an important aspect
can be done particularly effectively by of rehabilitation in patients with COPD and
including resistance training exercises in the requires individualised interventions by
exercise training sessions. When successful, nutritional specialists. In order to
muscle force increases and muscle oxidative appropriately assess this aspect, body
capacity is enhanced. composition should be assessed using DEXA-
scan or bio-electrical impedance measures.
More research is needed on pharmacological
Symptoms The most disabling symptom in
interventions that may assist pulmonary
COPD is clearly shortness of breath. Patients
rehabilitation to restore muscle function more
report dyspnoea, particularly during exercise
effectively. The short-term benefit of
or activity, as a significant burden. Another
testosterone supplements in selected
important symptom is fatigue. Symptoms can
hypogonadal patients, in combination with
be assessed during exercise using Borg
resistance training, is an example of how
pharmacotherapy and rehabilitation may have symptom scores or during daily activities
synergistic effects. using specific questionnaires.
Impaired exercise tolerance and functional Physical activity Participation in daily

exercise capacity result from the pulmonary activities is not easily assessed. Several
and systemic consequences of COPD. In the questionnaires have been used, but increasingly
context of pulmonary rehabilitation, exercise activity monitors are preferred. In the future it is
tolerance is best formally assessed before the likely that benchmark values for physical
programme, using an incremental exercise activity will become available for patients with
test. This will help to guide the programmes COPD. As indicated above, patients not
intensity, training modalities and safety. meeting guidelines on healthy physical activity
Functional exercise capacity is best assessed (30 min of moderate intense exercise on
using field tests such as the 6-min walking 5 days of the week) can be considered
test, for which reference values exist and candidates for pulmonary rehabilitation.
benchmark improvements for programme
quality and clinical and statistical importance Severe exacerbations Patients with COPD
have been reported. When a patients exercise
who have been hospitalised with an acute
tolerance is not abnormal, the indication for
exacerbation are particularly good candidates
exercise training is questionable.
for pulmonary rehabilitation programmes.
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body composition. It is important to pick up related quality of life acutely as the result of
and treat both obesity and cachexia in an exacerbation. Physical activity levels are
pulmonary rehabilitation programmes. Obese also dramatically low during hospital
patients may experience less dyspnoea than admission and at least 1 month afterwards.
non-obese patients for a given oxygen Patients admitted to hospital for COPD are
consumption due to a favourable mechanical very likely to face new hospital admissions in
effect of obesity on operating lung volumes. the subsequent year. The risk of readmission is
Nevertheless, obesity (body mass index particularly high in patients who remain
.30 kg?m-2) limits the functional abilities of inactive after a hospitalisation. In these
patients with limited ventilatory capacity as it patients, the rehabilitation programme may
increases the ventilatory needs for exercises need significant modification, with an
against gravity. Cachexia, an involuntary loss emphasis on acquiring appropriate

self-management skills to prevent subsequent adults with chronic obstructive pulmonary
admissions. Exercise training may need to be disease: systematic review and meta-analysis. J
adapted to more severe ventilatory and/or Psychosom Res 2007; 63: 551565.
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exacerbations are very good candidates for chronic obstructive pulmonary disease. Cochrane
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particularly important problem. obstructive pulmonary disease based on a
systematic review of available evidence. Clin
Rehabil 2009; 23: 445462.
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N Nici L, et al. American Thoracic Society/
Pulmonary rehabilitation is an evidence-based European Respiratory Society statement on
intervention for patients with COPD. It is pulmonary rehabilitation. Am J Respir Crit Care
individually tailored to the needs of patients, Med 2006; 173: 13901413.
both in terms of programme structure and its N Pitta F, et al. Activity monitoring for assessment
of physical activities of daily life in patients with
components. The aim of the rehabilitation COPD. Arch Phys Med Rehabil 2005; 86:
programme is to reverse the systemic 19791985.
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use and lead to a durable change in physical changes in 6-minute walk distance in patients
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MEASURING THE
OCCURRENCE AND THE
CAUSATION OF RESPIRATORY
DISEASES
R. Pistelli1 and I. Annesi-Maesano2,3
1
Catholic University, Columbus Hospital, Rome, Italy
2
INSERM, U 707: EPAR
3
Universite Pierre et Marie Curie Paris 6, Medical School Saint-Antoine,
UMR S 707: EPAR, Paris, France
E-mail: isabella.annesi-maesano@inserm.fr
When reduced to the simplest terms, all exposed subjects, whereas interval or ratio
medical research may be defined as the study scales are more frequently used in basic
of relationships (differences or associations) research. However, clinicians should be aware
among variables. A variable is any quality, of the basic methods used to study the
constituent or characteristic of a person, relationships of variables measured using
animal, thing or environment that can be continuous scales, such as lung function, as
measured. A variable is, by definition, well as understanding relationships of
something that changes and the values nominal or ordinal variables. The aim of this
associated with its measurements are usually chapter is to provide basic knowledge about
grouped in a set or scale. There are four measures and methods commonly used to
basic types of scales of which definitions and define the occurrence of clinical conditions,
examples are reported in table 1. and to study the relationships among those
variables and other variables that characterise
Any measurement performed by using an
the individual and the environment. These
interval or a ratio scale (continuous scales)
methods have been mainly developed for
can be translated to a category of an ordinal
epidemiological research, but they should be
or nominal scale (categorical scales). For
the landmark of any clinical reasoning. We
example, body temperature above or under a
hope to improve the skill of the readers of this
defined point of the Celsius or Fahrenheit
book by discussing the relevance of
scale can be used to identify subjects affected
information about the burden of diseases as
or not by fever, in this way translating from an
assessed by their distribution, the panel of
interval to a nominal scale. Another example
is the use of some values of forced expiratory related risk or protective factors, and the
volume in 1 s to identify subjects affected by evaluation of the effectiveness of preventive
different levels of severity of chronic measures and therapies in respiratory
obstructive pulmonary disease (COPD) medicine.
according to a conventional ordinal scale. In Measuring occurrence
general, clinical research is mainly involved
with patient-centred outcomes that are Epidemiology is the study of the distribution
variables measured using nominal or ordinal and determinants of disease frequency in
scales, e.g. dichotomous variables grouping human populations. The application of this
diseased or not diseased, or exposed or not study to determine valid and precise
Measuring the occurrence and the causation of respiratory diseases e7

Table 1. Scales grouping measurements of health outcomes and exposure factors
Nominal scale Uses names or symbols to assign each measure- Race, gender, geographic area,
ment to a limited number of categories that cannot diseased (yes versus no)
be ordered one above the other
Ordinal scale Assigns each measurement to a limited number of Patient status, cancer stage,
categories not equally spaced and ranked in a COPD stage
graded order
Interval scale Assigns each measurement to an unlimited number Body temperature
of categories that are equally spaced without an
absolute zero point
Ratio scale As the interval scale but measurements can be Length, time, mass and all the
referred to a true zero point derived physical units
COPD: chronic obstructive pulmonary disease.
information about the causes, preventions and Incidence and risk Incidence is a measure
treatments for disease in order to control of the risk of developing some new health
health problems is of outstanding clinical condition or outcome within a specified period
relevance. One of the main goals of any of time, expressed as a proportion or a rate.
epidemiological study is to measure the
occurrence or frequency of health outcomes, a The risk, or incidence proportion (also known
disease (asthma, COPD or lung cancer, etc.) or as cumulative incidence), is the number of
the intake of a medication, for instance. new cases within a specified time period
Epidemiological studies allow also estimation divided by the size of the population initially
of the occurrence of exposure (smoking, air at risk, and can be expressed by the following
pollution or occupational hazards, etc.). Risk, formula:
incidence proportion, and incidence and
prevalence rates are popular measures of Risk ~ incidence proportion ~ a=N 1
frequency. They all are proportions and rates
and their values are meaningless if the in which a is the number of subjects
denominator is not clearly and sensibly stated. developing a health outcome out of N people
For example, imagine you read in a followed for a time period. Of course, any
newspaper, reported from an important particular non-communicable disease has a
scientific journal, that men who are 40 yrs old very low risk over a very short time period and
have a more than 5% risk of developing the cumulative risk increases with time.
COPD. Of course, the dimension of this risk However, the risk may change during the
changes according to the time interval used in lifetime of individuals. As an example, many
the denominator: the risk is high or low
chronic respiratory diseases are associated
according to short or long time interval. In
with ageing and their risk is clearly increasing
many similar cases, the undefined
from the first to the last decade of life.
denominator is the entire life span of
individuals, but the reader should understand However, defining risk is not as simple as it
that the life span, which varies between may appear from the above formula. Actually,
individuals and populations, is not the best the value of N may decrease over the time
denominator to produce a broadly valid period for two main reasons: the competing
measure of risk. Unfortunately, reliable figures risk and the loss to follow-up. First, let us
of risk are not available for many health consider a study aiming to define the risk of
problems, including many respiratory death from lung cancer in a cohort of smokers
diseases. (i.e. a group of individuals sharing a particular

demographic characteristic). It is plausible different methods of calculating time for
that, during the follow-up period, many this outcome and that, whichever the choice,
subjects in the cohort will die from many its rationale should be clearly pre-specified in
different diseases and not from lung cancer. clinical trials. The interpretation of incidence
However, some of these subjects may have rate is not as simple as for the incidence
developed lung cancer but, before clinical proportion. The latter is a probability and is
manifestation, die of another disease. If we expressed by a number in the range 01;
include those subjects in the denominator, the however, the incidence rate may assume any
ratio will give an underestimation of the true value from 0 up to infinity. We may represent
risk of death from lung cancer. Secondly, the incidence rate as the instantaneous
suppose that some subjects included in the velocity of a vehicle and the incidence
cohort were lost during the follow-up period proportion as the proportion of a journey
(this is usual in cohort studies in which the covered by the same vehicle in a defined time
individuals are followed up for long periods). period. Using this representation, we may
Those subjects may not develop the outcome suggest that incidence rate and risk for a
we are interested in, and their inclusion in the health outcome may be related by the
denominator will give an underestimation of following formula:
risk. In conclusion, it is sensible to pay the
same attention to measuring both the Risk ~ incidence rate | time 3
numerator and the denominator of a ratio.
We must remember that this formula may
Competing risk or loss to follow-up can be hold for short time intervals but not for longer
managed using a different measure of health intervals, during which the loss to follow-up
outcome occurrence: the incidence rate and the competing risk will complicate the
expressed as the number of new cases during relationship between the two measures of
some time period, according to the following occurrence. It is possible to find a solution to
formula: that complication by dividing a long time into
shorter time intervals, for which equation 3
Incidence rate ~ a=time 2 may hold, and measuring the risk (or
probability) of developing the outcome in
in which a is the number of incident cases in each time interval. The overall probability will
the cohort, as in equation 1, and time is the be equal to the product of probabilities of
total time interval experienced by the subjects developing the outcome through all time
followed. Time is calculated by summing up intervals. This method is what is generally
the time each subject has been at risk to known as a survival analysis, and it can be
develop the outcome. For events that may applied to any outcome with a well-defined
recur during the follow-up period, time is time of appearance during the follow-up of a
calculated by adding the contribution of each cohort. In respiratory medicine, the results of
subject according to one of the following many trials on chronic disease have been
options: the time experienced up to the first analysed using the survival analysis approach.
occurrence (in this case the numerator Prevalence Prevalence is the proportion of
includes only one occurrence per subject) or subjects affected by a disease (or symptom or
all the time intervals the subject was at risk of dysfunction) or, more generally, presenting the
getting any of these occurrences (in this case health outcome in a defined population. Risk
the numerator includes all the occurrences and incidence rate are measures of disease
experienced by each subject). The onset. Prevalence is a measure of disease
exacerbation of COPD is a typical example of status. The value of prevalence is related not
a recurrent event. Readers should be aware only to disease incidence but also to disease
that different results may be produced by the duration. The relationship of prevalence to

incidence and duration of disease is expressed genetic background precedes the
by the following formula: development of the diseases.
P=1{P ~ ID 4 Measuring the effects: types of study

The second major goal of epidemiology is to
in which P is prevalence, I is incidence and D measure the effect of exposure on the health
is the mean duration of the health outcome. outcome and to estimate the associated risk,
The ratio on the left side of equation 4 is i.e. the probability that the health outcome
known as the prevalence odds. (In general, the will occur following the exposure. This is
odds of an event happening is the ratio of the obtained through different types of study
probability that it happens to the probability designs, according to the research question.
that it does not.) For a low prevalence, Epidemiological study design is divided into
equation 4 may be written as: experimental studies, which include clinical or
prevention trials (field trials and community
P & ID 5 trials), and observational studies, which
including cross-sectional studies, cohort
In this case, the prevalence proportion may be studies, casecontrol studies and panel
approximately considered as the product of studies, according to the particular research
incidence and duration. It is clear that question (table 2). In experimental studies,
prevalence is a good measure of the burden the investigator assigns subjects to treatments
of a disease and can be quite useful for public (vaccination, treatment and prevention, etc.)
health research and decision making. and evaluates their effectiveness, whereas in
However, prevalence cannot be used for observational studies, the researcher observes
causal inference about risk factors for a subjects and waits for the outcome to happen.
disease, except in some rare cases. Factors
Each type of study design represents a
that may determine a health outcome or may
different way of harvesting data and
increase its duration can be associated with
information. In experimental studies, the
an increased prevalence. A well-known study population is enrolled on the basis of
example of this situation in respiratory eligibility criteria that reflect the purpose of
medicine is offered by the prevalence studies the prevention or clinical trial, as well as
in asthma published in recent decades. Many scientific, safety, ethical and practical
factors have been found to be associated with considerations. Scientific, safety, ethical and
an increased prevalence of asthma, but for practical considerations are also applied in
most of them the crucial question Is it a observational studies. An example of a cross-
cause or a factor that increases the duration sectional study is given by the prevalence
of asthma and the reporting of symptoms? is studies on asthma published in the past few
still an open debate. Of course, a reliable decades, such as the International Study of
prevalence proportion or ratio depends on Asthma and Allergies in Childhood (ISAAC).
both a satisfactory measurement of Casecontrol design was used to find risk
population and prevalent cases. Sometimes, factors for lung cancer and for all the diseases
the definition of a prevalent case for a specific with a low occurrence frequency. Cohort
health outcome may be different among studies have provided proof of the cause
studies, and this may lead to quite different effect between tobacco smoking and lung
prevalence estimates. Prevalence studies on cancer. Another type of study is represented
COPD using different clinical definitions (e.g. by the panel study. A panel study is defined as
diagnosis of chronic bronchitis or emphysema) an investigation that collects information on
or, more recently, different cut-off values of the same individuals at different points in
spirometric data, are good examples of this time. Panels of asthmatics have been involved
situation. Prevalence can be used for causal in the study of the short-term effects of air
inference in the case of genetic factors, as pollution. A panel study is, therefore, a

Table 2. Main types of epidemiological study
Type of study Description Type of estimation
Experimental studies
Clinical Trial in which subjects are randomly given the Effectiveness of the treatment by
studies treatment or placebo. comparing the two groups (the treat-
ment and control group, respectively)
Intervention Inference study in which individuals receive an Estimation of the effect of the
studies intervention in order to modify a supposed intervention on the health outcome
causal factor for disease incidence
Observational studies
Cross- Descriptive study in which health outcome Prevalence of acute or chronic health
sectional and exposure status are measured simulta- outcomes in a population
studies neously in a given population Relationship between exposure and
It can be thought of as providing a snapshot health outcome; however, since expo-
of the frequency and characteristics of health sure and disease status are measured
and exposure in a population at a particular at the same point in time, it may not
point in time be possible to distinguish whether the
exposure preceded or followed the
health outcome, and thus cause and
effect relationships cannot be estab-
lished
Cohort Longitudinal investigation in which the occur- Incidence of health outcome
studies rence of a particular health outcome is Relationship between exposure and
compared in well-defined groups of people health outcomes
who are alike in most ways but differ by a Causal relationship (through the
certain characteristic, such as (but not relative risk) in the case of prospective
uniquely) an exposure cohorts.
Cohort studies are both retrospective
(backward-looking) or prospective (forward-
looking)
In a prospective investigation, at the begin-
ning the individuals do not present the health
outcome
The prospective cohort design can establish
whether having been exposed is a cause of the
disease development
Casecontrol Investigation that compares two groups of Relationship between the exposure
studies people: those with the disease or condition and the health outcome (through the
under study (cases) and a very similar group of odds ratio)
people who do not have the disease or
condition (controls)
Medical and lifestyle histories including
exposures of the people in each group are
analysed to learn what factors may be
associated with the disease or condition
Casecontrol studies are usually retrospective
but they can be prospective

longitudinal study; it differs from other studies Table 3. Contingency table presenting the association
that collect information over time, such as data from the case of exposure and disease that are
time series and cohort studies, in that it dichotomous variables
studies the same persons longitudinally. All Health outcome Total
these studies are based on individual data for
both health outcomes and exposure. Ecologic Yes No
studies also exist in which the unit of analysis
Exposure
is a population rather than an individual. For
instance, an ecologic study may look at the Exposed a b a+b
association between smoking and lung cancer Not exposed c d c+d
deaths in different countries. The
Total a+c b+d N
geographical information system is a very
useful new tool that improves the ability of a is the number of individuals in the studied sample
ecologic studies to be able to determine a link exposed to the potential risk factor who have
experienced the health outcome; b is the number of
between health data and a source of individuals exposed who have not experienced the
environmental exposure. These ecologic health outcome; c is the number of individuals
studies allow the development of hypotheses unexposed who have experienced the health outcome;
that provide limited information. and d is the number of individuals unexposed who
have not experienced the outcome.
Quantitative assessment of the
relationship between exposure and
health outcome There are two ways to the health outcome and the lowest (b) for
quantitatively measure the effect of a factor individuals that were exposed to the factor
on the health outcome or the condition of and that did not present the health outcome.
interest: the ratio of the measures of disease In addition, the number of unexposed that did
frequency according to the presence or not present the health outcome (d) is more
absence of the exposure to the factor or the elevated than the number of unexposed
difference between these two measures. The presenting the health outcomes (c). All
ratio is the measure of the strength of the these elements support the hypothesis that in
association between a factor and the health this case there is a relationship between the
outcome, whereas the difference is an exposure and the health outcome. The
estimate of the health impact of the factor statistical significance of the relationship can
under the hypothesis that the association is of be determined by applying statistical testing.
causeeffect type and of the consequences of
avoiding or diminishing the exposure to the Ratio In cohort studies where groups of
factor. Specific statistical tests are necessary individuals are identified on the basis of the
to confirm the existence of an effect. In the presence or the absence of exposure to a
case that both the health outcome and the potential risk factor and then followed-up for
exposure are dichotomous variables, their the appearance of the health outcomes, the
relationship can be quantified and its relative risk (RR) is used to investigate
statistical significance can be established by whether such risk factor is related to the
organising a 262 (two columns and two health outcome. RR estimates the ratio of
rows) contingency table, as represented in disease occurrence in the exposed group to
table 3. that in the unexposed group. If it is not
possible to find a completely unexposed
A visual presentation of the relationship group to serve as the comparison, then the
between a factor and a health outcome when least exposed group is used.
both are a dichotomous variable is provided
by figure 1 where, for instance, the highest The principal measure of relative risk is the
number (a) is observed for individuals that risk ratio or cumulative incidence ratio, which
were exposed to the factor and that presented is the ratio of the cumulative incidence in the

Health belong to a confidence interval greater than 1.
outcome present
Exposed
The need to introduce the confidence interval
n is due to the fact that the studied population
is limited and variable due to random errors in
Health
outcome selecting it. Similarly, to be statistically lower
not present a than 1, the RR has to belong to a confidence
Unexposed interval lower than 1. The method used to
calculate the 95% confidence interval for a
d
RR is shown in Appendix 1. The case of a RR
.1 with a 95% confidence interval that does
not include 1 has to be interpreted as a
c positive association between the exposure
b and the health outcome at the 5%
Health outcome Health significance level and a RR ,1 with a 95%
not present outcome present
Exposed Unexposed
confidence interval that does not include 1 as
a negative association between exposure and
Figure 1. Distribution of the individuals according to outcome at the 5% significance level.
the presence or the absence of the health outcomes
In casecontrol studies in which the subjects
and the exposure to the factor respectively. Example
of exposure related to health outcome. n refers to are selected on the basis of disease status and
the total number of individuals included in the the incidence of the health outcome is not
study. available in the exposed and unexposed
groups, the effect of the exposure on the
exposed group (a/(a+b)) to that in the health outcome is measured by the ratio of
unexposed group (c/c+d)) (table 4). the odds of exposure among the individuals
presenting the outcome to that among the
Thereafter, the relative risk is given by the individuals not presenting the outcome. (The
formula: odds of the event is the quotient p/(1-p), in
a=a z b which p is the probability in favour of the
RR ~ 6 event; this value may be regarded as the
c=c z d
relative likelihood that the event will happen.)
This ratio is called the odds ratio (OR) and is
An RR of 1 means there is no difference in risk
generally estimated through the ratio
between the two groups. An RR .1 means
between the odds in exposed and nonexposed
the health event is more likely to occur in the
exposed group than in the unexposed group. individuals:
An RR ,1 means that the health event is less a=a z b=b=a z b a=b
likely to occur in the unexposed group than in OR ~ ~
c=c z d=d=c z d c=d 7
the exposed group. To be statistically
significant greater than 1, the RR has to ~ ad=bc
Table 4. Incidence of the health outcome in exposed and unexposed individuals in cohort studies
Health outcome Total Incidence 5 risk
Yes No
Exposure
Yes a b a+b a/(a+b) 5 incidence in exposed
No c d c+d c/(c+d) 5 incidence in unexposed
Total a+c b+d N

An odds ratio of 1 indicates that the health Appendix 2. They depend on the type of
event under study is equally likely to occur in measurement scales used for the variables.
both groups. An odds ratio .1 with a 95%
confidence interval that does not include 1 Causation
indicates that the event is more likely to occur
in the exposed group at the 5% significance The existence of a statistically significant
level. An odds ratio ,1 with a 95% association between the exposure to a factor
confidence interval that does not include 1 and the health outcome does not imply that
indicates that the condition or event is less the factor is a cause of the health outcome.
likely to occur in the exposed group at the 5% Assessing causation implies several criteria
significance level. It can be shown that there introduced by Austin Bradford Hill (table 6).
exists the following mathematical relationship Of note, none of the proposed criteria can
between the odds ratio and the relative risk: bring indisputable evidence for or against the
cause-and-effect hypothesis and none can be
1 { az a required sine qua non.
b
RR ~ | OR 8 Bias and errors
1 { c zc d
Occurrence of health outcomes and exposure,
As a consequence, when a disease is rare, a measures of associations and causation are
and c are small, and the odds ratio provides challenged by biases and errors. Random error
a valid estimate of the RR. corresponds to imprecision and bias to
inaccuracy. Error is defined as the difference
Difference Several types of differences exist between the true value of a measurement and
between the measures of health outcome the recorded value of a measurement. There
frequency according to the presence or the are many sources of error in collecting clinical
absence of the exposure to the factor. They data. Error can be described as random or
include the attributable risk, preventive systematic. Random error is also known as
fraction and the population attributable risk variability, random variation, or noise in the
(table 5). It must be noted that these system. The heterogeneity in the human
differences have to be computed under the population leads to relatively large random
assumption that the factor is causally related variation in clinical trials. Random error has
to the health outcome, a condition no preferred direction, so we expect that
encountered in prospective cohort studies, averaging over a large number of observations
having assessed causation and disposing of will yield a net effect of zero. The estimate
the entities like incidences and relative risks may be imprecise, but not inaccurate. The
necessary to compute the differences of risks. impact of random error, imprecision, can be
These differences can be estimated in several minimised with large sample sizes. Systematic
ways, the most used are presented in table 5. error, or bias, refers to deviations that are not
due to chance alone. There are several types
Statistical association between of biases: recall bias, selection bias,
exposure and health outcomes The information bias and confounding. Recall
existence of a significant relationship between bias, selection bias and information bias can
exposure and health outcome can be be reduced by good protocol. Confounding
established independently from the occurs when a variable is associated with both
estimation of the associated risk (odds ratio, the exposure and the health outcome that we
relative risk, etc.). The main statistical are studying. When the effect of an exposure
methods that allow the determination of the is mixed with the effect of another variable
existence of a significant statistical (the confounding variable), we may incorrectly
association between a factor and the health conclude that the disease is caused by the
condition of interest are indicated in exposure. We might then attempt to eliminate

Table 5. Parameter estimating differences between risks
Measure Definition Formula
Attributable The rate (excess risk) of the a c

risk (AR) outcome in exposed individuals AR ~ { 9
azb czd
that can be attributed to the
exposure
It is given by the difference of
cumulative incidences or incidence
densities of the disease in the
exposed (IE) and the unexposed
individuals (I0)
AR5(IE-I0)
Preventive The attributable risk in the case c=c z d { a=a z b
fraction that the exposure is preventive, PF ~ 10
c=c z d
(PF) so that a/(a+b) is greater than
c/(c+d)
Attributable The attributable risk divided by AR
risk percent the rate of disease among the AR% ~ | 100 11
a=a z b
or aetiologic exposed
fraction
(AR%) RR {1
AR% ~ | 100 12
RR
Population The incidence of a disease in a azc c
attributable population that is attributable to PAR ~ { 13
azbzczd czd
risk (PAR) the exposure
Given by the difference between
a
the rate of the disease in the PAR ~ AR | 14
entire population (ITOT) and in the azc
unexposed group (I0)
PAR 5 (ITOT) - (I0)
Also by multiplying the product of
the attributable risk by the pro-
portion of exposed individuals in
the population (PE)
PAR 5 AR6PE
Combined The PAR for a combination of risk Combined PAR# ~
PAR factors is the proportion of the 15
disease that can be attributed to 1 { 1 { PAR1 1 { PAR2 1 { PAR3 . . .
any of the risk factors studied
#
: when there is no multiplicative interaction (no departure from multiplicative scale), combined PAR can be manually
calculated by this formula
the exposure in the hope that the disease variables in smoking studies made it difficult
could be prevented. If, however, the to establish a clear causal link between active
association between the exposure and the smoking and lung cancer, unless appropriate
disease is due to confounding and is not methods were used to adjust for the effect of
causal, elimination of the exposure will not the confounders. An example of confounding
have any effect on the incidence of the variable in the relationship between active
disease. The existence of confounding smoking and lung cancer is air pollution that

Table 6. Criteria for assessing evidence of causation (HILL, 1965)
1) Strength
The larger the association, the more likely that it is causal
However, a small association does not mean that there is not a causal effect
2) Consistency
Consistent findings observed by different persons in different places with different samples strengthen
the likelihood of an effect
3) Specificity
The more specific an association between a factor and an effect is, the bigger the probability of a
causal relationship
Causation is likely in case of a very specific population at a specific site and disease with no other likely
explanation.
4) Temporality
The effect has to occur after the cause
5) Biological gradient
Greater exposure should generally lead to greater incidence of the outcome
6) Plausibility
A plausible mechanism between cause and effect is helpful although, very often, knowledge of the
mechanism is limited
7) Coherence
Coherence between epidemiological and laboratory findings increases the likelihood of an effect of the
exposure on the health outcome
Of note, sometimes we lack such laboratory evidence
8) Experiment
Occasionally it is possible to appeal to experimental evidence
9) Analogy
The effect of similar factors may be considered
can cause cancer and is also associated with modifier, a factor that modifies the effect of a
the exposure of interest, smoking. The effect putative causal factor under study. Effect
of a confounder can be taken into account by modification (also known as statistical
adjusting for it with an appropriate statistical interaction) occurs when the effect measure
model, or through a matching of the depends on the level of another factor. For
individuals according to it. example, bacillus Calmette-Guerin (BCG)
immunisation is an effect modifier for the
Bias has a net direction and magnitude so consequences of exposure to the various
that averaging over a large number of strains of mycobacteria responsible for
observations does not eliminate its effect. In tuberculosis (TB) and has to be taken into
fact, bias can be large enough to invalidate account when investigating risk factors for TB.
any conclusions. Increasing the sample size Effect modification is detected by varying the
will not eliminate all the biases. In selected effect measure for the factor under
epidemiological and clinical studies, bias can study across levels of the other factor. In the
be subtle and difficult to detect. A study can previous example, modification effect of BCG
be invalidated by the presence of bias. Thus, immunisation could be estimated by
the design of clinical or epidemiological trials computing the odds ratio between tobacco
has to focus on removing known biases. smoking and TB according to the presence or
Another important element to be introduced the absence of BCG immunisation. The effect
in epidemiological investigations is the effect of a modifier can be taken into account

Table 7. Sensitivity and specificity computation positive specimens, FN is the number of false
negative specimens and TN is the number of
Reference criterion
true negative specimens.
results
Positive Negative Sensitivity ~ TP=TPzFN
New criterion results

Specificity ~ TN=TNzFP
Positive TP FP
Negative FN TN Sensitivity and specificity can be applied to
TP: number of true positive specimens; FP: number of identify and validate biomarkers, for instance.
false positive specimens; FN: number of false negative
specimens; TN: number of true negative specimens.
Conclusion
Epidemiology provides methods for measuring
through a matching of the individual the occurrence and the causation of respiratory
according to different level of the modifier diseases. In assessing occurrence and
(stratification). relationships between exposure and health
outcomes, criteria of relevance should include:
Sensitivity and specificity 1) the representativeness of the studied
samples particularly in studies with samples of
In the ascertainment of the health outcome,
the general population; and 2) clear definitions
sensitivity and specificity can be used.
of both the health outcome (or dependent
Sensitivity is the probability that the criterion
variables) and the exposure (or independent
used to define the case will produce a true
variables) to be included in the models.
positive result when used on a population (as
compared to a reference or gold standard). References
Specificity is the probability that the used
criterion will produce a true negative result N Hill AB. The environment and disease:
association or causation? Proc R Soc Med 1965;
when used on a population (as determined by
58: 295300.
a reference or gold standard). Using a N Rothman KJ. Epidemiology: an Introduction.
contingence table relating reference and new New York, Oxford University Press, 2002.
criterion results (table 7), the following N Swinscow TDV, Campbell MJ. Statistics at Square
formulae are obtained for sensitivity and One. London, BMJ Books, 2002.
specificity, where TP is the number of true N Swinscow TDV, Campbell MJ. Statistics at Square
positive specimens, FP is the number of false Two. London, BMJ Books, 2002.

Suggested free software When there are zeros, a common convention is
to add 1/2 to each cell.
Epi Info. Version 3.5.3 (January 26, 2011).
Atlanta, Centers for Disease Control and In the case of the odds ratio:
prevention, 2011. Available from:
Upper limit logOR ~ logOR z 1:96 | SElogOR
wwwn.cdc.gov/epiinfo/
Lower limit logOR ~ logOR { 1:96 | SElogOR

Appendix 1: 95% confidence intervals
for the relative risk and the odds which become:
ratio
Upper limit OR ~ expupper limit logOR
Given the 262 contingency table relating the
exposure to the health outcome seen before, a
common way to calculate the 95% Lower limit OR ~ explower limit logOR
confidence interval (CI) is as follows.
with SE being the standard error of the natural
In the case of the relative risk (approximate log (OR) 5 (variance logOR), in which
estimate): variance of logOR 5 (1/A) + (1/B) + (1/C) +
(1/D)
Upper limit ~ explogRR z 1:96 | sqrtvlogRR
Appendix 2: Main methods used to
assess the relationship between
Lower limit ~ explogRR { 1:96 | sqrtvlogRR
exposure and health outcome
with sqrt(vlogRR) representing the square We have presented how to assess the
root of the natural log of the risk ratio, as relationship between the health outcome and
defined by logRR 5 log(a/(a+b)/(c/(c+d))), the exposure in the case both variables are
which is asymptotically normal with variance dichotomous. Table 8 introduces the methods
vlogRR 5 1/a - 1/(a+b) + 1/c - 1/(c+d) that can be used in other cases.
Table 8. Main statistical methods for assessing the relationship between health outcomes and exposures
Statistical methods Description
Correlation A single number that describes the degree of relationship between two
continuous variables
Linear regression Approach to modelling the relationship between a continuous variable y
and one or more variables denoted x that may be either continuous or
categorical
Analysis of variance A statistical test of whether or not the means of several groups are all
equal (i.e. are not statistically significantly different)
Logistic regression model Approach to predict the probability of occurrence of an event by fitting
data to a logit function
It makes use of several predictor variables that may be either continuous
or categorical
Usually used to estimate the odds ratio between the exposure and the
health outcome after adjustment for potential confounders

self-assessment
Further self-assessment questions and exclusive online content related to the ERS Handbook of
Respiratory Medicine, can be found at www.ersnet.org/handbook. The code on the back cover
of this book is your personal login.
The ERS Handbook of Respiratory Medicine is accredited by the European Board of
Accreditation in Pneumology (EBAP) for CME credits.
European accreditation is granted by EBAP following the EACCME (European Accreditation
Council for Continuing Medical Education) standards (D9908) in order to allow readers to
validate the credits obtained through this activity in their home European country.
Each chapter has been afforded a maximum of 1 CME credit, which will be awarded once
readers have successfully completed the CME questions relating to each chapter of the
Handbook. A maximum of 17 CME credits for the whole book can be awarded. To take the CME
test, please visit www.ersnet.org/handbook. In accordance with EBAP guidelines, all authors
have declared potential conflicts of interest.
The questions presented here are purely for self-assessment purposes and are not CME accredited.
notes on the questions
1. Always read the entire question and related answers carefully.
2. For type a questions (in red), only one answer is correct.
For type K questions (in blue), more than one answer may be correct.
Q1. Which of the following Q3. Why is alveolar dead space

surfactant protein(s) play(s) an present at rest in young healthy
active role in innate immunity? subjects in the upright posture?
a. SP-A A. Alveoli at the base of the lung are small,
B. SP-B and therefore poorly ventilated
C. SP-C B. Pulmonary capillaries at the base of
D. SP-D the lung may collapse because of low
intravascular pressures
Q2. With regard to the anatomy of C. Alveoli at the top of the lung are large,
the respiratory system, which of the and therefore better ventilated
following statements is incorrect? D. Pulmonary capillaries at the top of
a. The right main bronchus is deep and the lung may collapse because of low
measures about 20 mm in adults intravascular pressures
B. The left main bronchus curves laterally
and measures about 40 mm in adults Q4. a 55-yr-old woman presents
C. The right upper lobe always has three with a 2-yr history of paroxysms of
segments and has a tri-partite division at dry cough when talking or bending.
its origin Which of the following investigations
D. Each segment is a functional independent is mandatory at this stage?
with its own blood supply and envelope a. Spirometry with reversibility
by connective tissue that originates from B. Chest radiography
the parietal pleura C. Full blood count
e. The right middle lobe is a branch from D. Bronchoscopy
the anterior portion of the right main e. FeNO
bronchus
ers_book cme.indd 1 10/08/2010 11:56:31

Q5. Which of the following is the Q10. the increase in functional
most common nonrespiratory residual capacity in airflow
condition associated with chronic obstruction is the result of:
cough? a. A decrease in lung elastic recoil
a. Sinusitis B. Dynamic mechanisms such as an increase
B. Heartburn in breathing frequency and/or expiratory
C. Irritable bowel syndrome flow limitation within the tidal breathing
D. Nasal polyposis range
e. Congestive cardiac failure C. An increase in time constant of the
respiratory system exceeding the
Q6. Which of the following regarding expiratory time
examination of a patient with superior D. A decrease in inspiratory muscle force
vena cava obstruction is/are true?
a. Giant V waves are visible in the JVP Q11. a 68-yr-old male with nonsmall
B. Peri-orbital oedema may be present cell lung cancer presents with
C. Dilated vessels are visible over the lower increasing breathlessness. His
anterior abdominal wall chest radiograph shows complete
D. Signs and symptoms are more noticeable collapse of the left lung and at
at the end of the day bronchoscopy he has a polypoid
Q7. Which of the following tumour obstructing the left main
statement(s) is/are correct bronchus. Which of the following is
with regard to airway resistance the most appropriate intervention?
measurements by whole-body a. Bronchoscopy and endobronchial
sampling
plethysmography?
B. Bronchoscopy with endobronchial tumour
a. Pbox provides an estimate of Palv
ablation with electrocautery or laser
B. Pbox provides an estimate of Ppl
C. Chemotherapy
C. Inspiration increases Pbox
D. Bronchsocopy with insertion of
D. Expiration decreases Pbox
endobronchial stent
Q8. for which type of patients is e. Treatment with antibiotics and steroids
medical thoracoscopy/pleuroscopy Q12. Which of the following
mainly indicated? statement(s) regarding long-term
a. Patients with transudative pleural effusion
oxygen therapy (ltOt) is/are true?
of indeterminate origin
a. LTOT should be prescribed in all COPD
B. Patients with exudative pleural effusion of
patients with Pa,O2 in range 7.3-8.0 kPa
indeterminate origin
B. LTOT should be prescribed in a COPD
C. Patients with localised chest wall lesions
patient with Pa,O2 8.0 kPa and secondary
D. Patients with diffuse lung disease
polycythaemia
Q9. the causes of exercise C. LTOT should be given during the daytime
intolerance are best evaluated by only
the use of: D. LTOT should be accompanied by
a. Walking tests ambulatory O2 in active users
B. Cardiopulmonary exercise testing
C. Resting lung function measurements
D. All the above
ERS Handbook: Respiratory Medicine 459

ers_book cme.indd 2 10/08/2010 11:56:31
Q13. Which of the following Q17. Which of the following
statement(s) regarding home statement(s) about occupational
noninvasive ventilation is/are true? asthma (Oa) is/are true?
a. It can be combined with cough assist a. Inhaled corticosteroids and broncho-
devices in patients with neuromuscular dilators are the preferred medications in
disease and reduced cough efficacy symptomatic patients with OA
B. It increases survival in patients with COPD B. OA may occur in subjects without atopy
C. It improves quality of life in COPD patients C. The diagnosis of OA cannot be excluded
D. It may reduce readmission in COPD in a patient with pre-existing asthma
patients with frequent hypercapnic D. Twice daily peak- flow measurements are
exacerbations (revolving door admissions) the most commonly used diagnostic test
in OA
Q14. In which of the following
patient(s) is/are the risk(s) of Q18. Which are the most
transition from latent tuberculosis investigated indoor pollution
infection to active tuberculosis sources?
increased? a. Fossil fuel
a. Patients with end-stage renal disease B. Biomass fuel, environental tobacco smoke,
B. Patients after lung transplantation mould/dampness
C. Patients after cornea transplantation C. Environmental tobacco smoke
D. Patients with EpsteinBarr virus infection D. Furniture
Q15. Which of the following Q19. Which is the most frequent

diseases must be excluded before aetiology of pleural effusions?
prolonged use of macrolides is a. Infectious
B. Malignant
considered?
C. Immunological
a. Tuberculosis
D. Cardiac
B. Nontuberculous mycobacteria
e. Idiopathic
C. Pseudomonas aeruginosa
D. Aspergillus fumigatus Q20. Which is the most common
e. HIV respiratory complication associated
Q16. a 60-yr-old farmer with with neuromuscular disorders?
moderate asbestos exposure a. Obstructive sleep apnoea
B. Pulmonary embolism
30 yrs ago presents with diffuse
C. Tracheal stenosis
pulmonary fibrosis, predominantly D. Acute respiratory distress syndrome
basal, inspiratory crackles on e. Bronchial asthma
chest examination, no plaques
or pleural thickening on chest
computed tomography and slowly
deteriorating lung function. What is
the likely diagnosis?
a. Asbestosis
B. Sarcoidosis
C. Idiopathic pulmonary fibrosis
D. Hypersensitivity pneumonitis
e. Nonspecific interstitial pneumonia
ers_book cme.indd 3 10/08/2010 11:56:32

Q21. a 72-yr-old Caucasian male Q23. Which of the following
presents with chronic cough. He is symptoms does not necessarily
a retired teacher, enjoys gardening, impede a radical treatment
quit smoking 10 years ago, takes approach?
medications for hypertension and a. Liver metastasis
gastroesophageal reflux, and drinks B. Bone metastasis
12 glasses of wine daily with dinner. C. Vena cava superior syndrome
D. Brain metastasis
Chest radiography shows a mass
e. Axillar lymphadenopathy
in the right upper lobe; a thorax
computed tomography scan confirms Q24. Which of the following
the presence of a mass and shows treatment options will most
that the subcarinal lymph nodes likely improve the left ventricular
are enlarged. Biopsies obtained ejection fraction in a patient
bronchoscopically show nonsmall cell with congestive heart failure and
lung cancer adenocarcinoma. staging Cheynestokes respiration?
investigations reveal metastatic a. Nocturnal oxygen
lesions in the liver. Which initial B. Nocturnal CPAP
therapy would be most appropriate? C. Acetazolamide
a. Neoadjuvant chemotherapy followed by D. Nocturnal CO2 inhalation
lobectomy e. Theophylline
B. Targeted therapy with erlotinib Q25. What has positively
C. Cisplatin-etoposide with concurrent changed the natural history of
radiation therapy
cytomegalovirus infection post-
D. Cisplatin-pemetrexed chemotherapy
bone-marrow transplant?
Q22. metastatic pleural effusions a. Immunosuppressive therapy
are most frequently observed in: B. CMV prophylaxis or pre-emptive therapy
a. Prostate cancer C. Extracorporeal photopheresis
B. Pancreatic cancer D. Immunoglobulins
C. Breast cancer e. Antibiotic therapy
D. Kidney cancer
e. Lymphomas
answers
Q25. B
Q24. B Q16. C Q8. B
Q23. C Q15. B Q7. A,C,D
Q22. C Q14. A,B Q6. B
Q21. D Q13. A,D Q5. C
Q20. A Q12. B,D Q4. B
Q19. D Q11. B Q3. D
Q18. B Q10. A,B,C Q2. C
Q17. A,B,C Q9. B Q1. A,D

ers_book cme.indd 4 10/08/2010 11:56:32
Index
A airway resistance 6364
abacavir 429 measurement 6465
abscess, lung 189190 airway stenosis
N-acetylcysteine, idiopathic pulmonary fibrosis impact of interventional bronchoscopy 120121
therapy 316317 malignant, interventional pulmonology 118,
acidbase disorders 16, 80, 81 120121
arterial blood gas analysis 79, 8081 pulmonary function tests 118120
acquired immune defence 2829, 30 upper see upper airway stenosis (UAS)
acreolin 36 airway stenting 101, 120121
acute bronchitis 240241 airways, drug-induced disease 327
acute chemical pneumonitis 274276 allergen bronchial provocation test 88, 89, 90
acute cough 34 allergen immunotherapy, asthma 234235
acute eosinophilic pneumonia 320 allergic alveolitis see hypersensitivity pneumonitis (HP)
acute exacerbations of chronic obstructive allergic rhinitis 224226
pulmonary disease (AECOPD) 149150 asthma association 224, 226
acute inhalation injury 273277 definition 224
clinical presentation 273 epidemiology 224
inhalational fever 273274 pathophysiology 225226
pneumonitis see toxic pneumonitis treatment 225, 226
sequelae 277 allergic rhinoconjunctivitis 170
acute interstitial pneumonia (AIP) 105, 311, 312 allergy tests, asthma 230231
acute lung injury (ALI) 146147 occupational 270
drug-induced 325 alveolar epithelium 8
inhalation see acute inhalation injury alveolar haemorrhage, drug-induced 324, 325, 329
radiation-induced 304 alveolar hypoventilation 2021
acute mountain sickness (AMS) 298299, 300 see also hypoventilation syndromes
acute-on-chronic respiratory failure 149, 150 alveolar macrophage pneumonia 312
acute oxygen therapy 151 alveolar macrophages (AMs) 2728
acute respiratory distress syndrome (ARDS) 146147 alveolar pressure (PALV) 16, 17, 18, 19, 20
diagnosis 105 alveolar shunt 23
drug-induced 328 alveolar type I (ATI) cells 8
acute respiratory failure (ARF) 148150 alveolar type II (ATII) cells 8
acute silico-proteinosis 276 alveolar volume (VA) 23
acute thyroiditis 170 measurement 69
acute vasoreactivity testing, pulmonary arterial physiological influences 70, 71
hypertension 343, 344 amantadine 192
acute ventilatory support 152 ambulatory oxygen therapy 151
adenocarcinoma, lung 373, 374375 American Society of Anesthesiologists (ASA), pre-
adenosine monophosphate (AMP) bronchial operative risk classification 156, 157
provocation testing 88, 89 amikacin therapy
adenotonsillectomy, obstructive sleep apnoea nontuberculous mycobacterial infections 220
management 409 pulmonary tuberculosis 204, 205
adjuvant chemotherapy amiodarone pulmonary toxicity (APT) 324, 325,
definition 377 326, 327, 328
nonsmall cell lung cancer 382 amoxicillin therapy, infectious COPD exacerbations
small cell lung cancer 379 174, 175
advanced lung disease amoxicillinclavulanate therapy
gastro-oesophageal reflux 243244 infectious COPD exacerbations 174, 175
see also specific diseases pulmonary tuberculosis 206
air pollution 285289 AMP (adenosine monophosphate) bronchial
asthma and 286, 287, 288, 289 provocation testing 88, 89
biological mechanisms 289 amyloid A amyloidosis 433
children and 285, 286 amyloid light chain amyloidosis 433
COPD and 248, 286, 287, 288 amyloidosis 433434
indoor 287289 anaemia
lung cancer and 286, 287288 chemotherapy-induced 378
outdoor 285287 dyspnoea and 43
airway clearance techniques 446447 anaesthesia, preoperative assessment 156158
COPD 448 anatomical barriers 26
neuromuscular disease 449 anatomy 1114
ers_book_index2.indd 1 10/08/2010 10:59:56

see also individual anatomical structures arterial hypoxaemia see hypoxaemia
angina, dyspnoea and 42, 43 arterial oxygen desaturation 85
angio-oedema, drug-induced 323, 326, 327 arterial pH 80
angiomyolipoma (AML) 442 asbestos exposure 282283
angioplastic pneumonectomy 386 asbestos pleurisy 282283
angiotensin-converting enzyme (ACE), serum levels asbestosis 104, 283
in sarcoidosis 5 Aspergillus pneumonia (AP) 184, 185
angiotensin-converting enzyme (ACE) inhibitors, aspiration, pneumothorax 354
respiratory complications 323, 327 aspiration pneumonia 176, 178
Annexin A11 (ANXA11) 3, 4, 5 aspirin, respiratory complications 327
antero-posterior (AP) radiograph 126 assessment
anti-inflammatory therapy pre-operative 156158
rhinitis 225, 226 pulmonary resection 157158
see also corticosteroid therapy; nonsteroidal anti- see also physical examination
inflammatory drugs (NSAIDs) assisted coughing techniques, neuromuscular
anti-tuberculosis drugs disease patients 364, 449
extrapulmonary tuberculosis 210 associated pulmonary arterial hypertension (APAH)
latent tuberculosis 216 340341, 344
nontuberculous mycobacterial infections 220 asthma 227235
pulmonary tuberculosis 204208 altitude effects 300301
resistance 204, 206, 207208 comorbidities 234, 235
HIV association 427 allergic rhinitis 224, 226
antibiotic resistance gastro-oesophageal reflux disease 234, 242, 243
anti-tuberculosis drugs see anti-tuberculosis drugs vocal cord dysfunction 236, 237, 238, 239
pneumonia pathogens 178 COPD vs. 229, 230, 232, 234
antibiotic therapy diagnosis 227234
bronchiectasis exacerbations 253254 allergy tests 230231
bronchitis 241 arterial blood gas analysis 230
community-acquired pneumonia 178179 assessment of airway inflammation 232
cystic fibrosis 259, 262 bronchial provocation testing 90, 230
descending necrotising mediastinitis 359 differential 229, 232, 234
hospital-acquired pneumonia 182 exhaled breath analysis 94, 232
infectious chronic obstructive pulmonary disease imaging 231232
exacerbations 174, 175 lung function tests 228230
lung abscess 189, 190 physical examination 228
pleural infections 188 drug-induced 325, 327
pulmonary tuberculosis 205 eosinophilic bronchitis vs. 319
purulent sputum and 38 genetics 1, 56
tuberculous meningitis 211 induced sputum biomarkers 93
upper respiratory tract infections 170 management
see also specific antibiotics exacerbations 233, 235
anticholinergic therapy pharmacological 231, 234235
COPD 249 physiotherapy 448
rhinitis 225, 226 occupational see occupational asthma
vocal cord dysfunction 239 symptoms 227228
antigen-presenting cells (APCs) 2829 cough 34, 35
antihistamines, rhinitis treatment 225, 226 dyspnoea 42, 44
antineutrophil cytoplasmic antibodies (ANCA) 336 triggers 227, 228
a1-antitrypsin (AT) deficiency see a1-proteinase air pollution 286, 287, 288, 289
inhibitor (PI) deficiency exercise 228
antiviral drugs mould exposure/dampness 288
cytomegalovirus infection prophylaxis, post-bone smoking 292293
marrow transplantation 431 upper respiratory tract infection vs. 170
oseltamivir 192193 atovaquone, Pneumocystis jirovecii pneumonia
anxiety disorder, hyperventilation 42 management 425, 426
apical parietal pleurectomy, pneumothorax auscultation
management 355, 356 breath sounds 4445, 54
apnoea/hypopnoea index (AHI) 404, 405 heart sounds 45
Ardystil syndrome 276 avian influenza 194
arterial blood gas analysis 7781 azathioprine therapy, idiopathic pulmonary fibrosis 316
acidbase status 79, 8081 azithromycin, Pneumocystis jirovecii pneumonia
asthma 230 management 426
pulmonary gas exchange 7780

B bromhexine, bronchiectasis management 254
B-lymphocytes 29, 30 bronchi, anatomy 1213
bacterial infections bronchial-associated lymphoid tissue (BALT) 26, 28
bronchiectasis 253 bronchial biopsy 100
bronchitis 240 bronchial brushings 100
chronic obstructive pulmonary disease bronchial carcinoma see lung cancer
exacerbations 172173 bronchial clearance, bronchiectasis 254
community-acquired pneumonia 177178 bronchial provocation testing (BPT) 8890
diagnosis see microbiological testing clinical relevance 90
hospital-acquired pneumonia 181182 asthma diagnosis 230
immunocompromised hosts 184 methods 8890
HIV-infected patients 423424 bronchial responsiveness (BR), testing see bronchial
with primary immunodeficiency 420, 421 provocation testing (BPT)
lung abscess 189 bronchial washings 100
pleural 186187 bronchiectasis 252254
upper respiratory tract 169 aetiology 252
see also respiratory infections; specific bacteria; associated conditions 252
specific infections primary immunodeficiency 420, 421
bagassosis 280 diagnosis 37, 252253
balloon atrioseptostomy, pulmonary arterial exacerbations 252
hypertension 343 infective see infective exacerbations of
barotrauma, pulmonary 302303 bronchiectasis
barriers, defence 26 management 253254
bedside radiography 127 prevention 254
benzodiazepines, vocal cord dysfunction treatment 238 HIV-infected patients 424
b2-agonists, asthma management 234 management 253254
beta-blocker-induced bronchospasm 326, 327 physiotherapy 448
bevacizumab therapy, nonsmall cell lung cancer nodular 219
380381 symptoms 252
biomass fuels, indoor air pollution 287, 288 haemoptysis 38
biopsy bronchiolitis obliterans organising pneumonia
lung see lung biopsy (BOOP) 105, 312313
percutaneous fine-needle 110111 drug-induced 324, 327, 328
pleural 396 bronchiolitis obliterans syndrome (BOS) 244
biplane fluoroscopy, fine-needle biopsy guidance 110 fume-related 276
bird fanciers lung 278, 279, 280 popcorn workers 277
bleb resection, pneumothorax management 355 bronchitis 240241
bleeding acute 240241
alveolar, drug-induced 324, 325, 329 aetiology/risk factors 240
thoracentesis-induced 117 chronic see chronic bronchitis
blood culture 162, 163 definition 240
body plethysmography 62, 6465 diagnosis 241
bone eosinophilic see eosinophilic bronchitis
metastases 390391 epidemiology 240
tuberculosis 211 prognosis 240241
bone marrow transplantation (BMT), pulmonary symptoms 240
complications 430431 treatment 241
tuberculosis 212, 213, 431 bronchoalveolar lavage (BAL) 100, 103108
bones, cystic fibrosis-related disease 262 cell counts 107108
Bordetella pertussis nonsmokers vs. smokers 108
detection 166 complications 101
infection 169, 170 cytological appearances 104106, 108
Borg scale 43, 44 definition 103
Bornholm disease 50 indications 103, 104106, 108, 439
bosentan, idiopathic pulmonary fibrosis therapy 317 procedure 103, 106107
botulinum toxin A (Botox), vocal cord dysfunction sample processing 107
treatment 239 bronchodilator reversibility testing, asthma
brachytherapy 101, 381 229230
breast cancer, metastasis 388, 389, 390 bronchodilator therapy
breath sounds, auscultation 4445, 54 asthma 231, 234
breathing frequency 16, 19 exacerbations 233, 235
breathing reserve (BR) 85 bronchiectasis 254
breathlessness see dyspnoea COPD 175, 249, 250

lymphangioleiomyomatosis 443 management 408, 411412, 413
bronchogenic carcinoma see lung cancer pathophysiology 410
bronchoplastic lobectomy, nonsmall cell lung cancer prevalence 410
386 cephalosporins
bronchopulmonary segments, anatomy 12 community-acquired pneumonia management 178
bronchoscopy 98102 hospital-acquired pneumonia management 182
advanced diagnostic procedures 101 infectious COPD exacerbation management 174, 175
complications 100101 cerebral oedema, high-altitude 299, 300
equipment 98 cervical lymph nodes, tuberculosis 210
fluorescence 101 cheese workers lung 280
indications 9899 chemical pneumonitis see toxic pneumonitis
lung cancer diagnosis 98, 373 chemical workers lung 280
interventional 101102, 118, 120121 chemokine production 29
patient preparation 99 chemopleurodesis, pneumothorax 355
procedure 99 chemoreceptor response
sampling techniques 99100 carbon dioxide 7274
bronchospasm hypoxia 7476
drug-induced 323, 325, 326, 327 chemotherapy 377381
dyspnoea 42 adjuvant see adjuvant chemotherapy
building dampness 288 administration routes 377
bullae resection, pneumothorax management 355, 356 Langerhans cell histiocytosis 440
bupropion 296 malignant pleural mesothelioma 381, 397
nonsmall cell lung cancer 374375, 379381, 382
C side-effects 378
cachexia, COPD patients 455 respiratory disease 322, 324, 325, 326, 328
calcium channel blockers, pulmonary arterial small cell lung cancer 375, 378379
hypertension management 343, 344 see also specific chemotherapeutic agents
cancer chemotherapy lung 328
genetics 3, 6 chest
lung see lung cancer bone metastases 390391
see also tumours computed tomography indications 131, 132
cannabis smoke 292 drains see chest tube drainage
capreomycin therapy, pulmonary tuberculosis 204, 205 fluoroscopy 129
capsaicin cough challenge 36, 37 pain 4950
carbon dioxide, ventilatory response to inhalation 7274 percussion 52, 54
carbon monoxide (CO) physiotherapy see respiratory physiotherapy
air pollution 285, 286, 288 chest physiotherapy see respiratory physiotherapy
transfer factor see transfer factor of the lung for chest radiography 126129
carbon monoxide (TL, CO) asthma 231232
carboplatin chemotherapy 379 basic techniques 126, 127
nonsmall cell lung cancer 380 bedside 127
small cell lung cancer 375, 378 bronchiectasis 253
cardiac chest pain 49, 50 chest pain investigation 50
cardiac disease see heart disease digital 127, 129
cardiac risk assessment, peri-operative 157 drug-induced respiratory disease 324, 326327
pulmonary resection 157158 indications 126, 128
cardiopulmonary exercise testing see exercise testing inspiratoryexpiratory 127
cardiovascular disease, as consequence of lung abscess 189
obstructive sleep apnoea 406, 407 lymphangioleiomyomatosis 441
cardiovascular response, exercise testing 86 pleural infection 187, 188
catastrophic bronchospasm 323, 327 pneumonia 177
cavity lung disease 218219 eosinophilic 320
cefditoren therapy, infectious COPD exacerbations 175 pneumothorax 353, 354
cefuroxime therapy, infectious COPD exacerbations 175 projections 126127
central airway stenosis, impact of interventional pulmonary alveolar proteinosis 435, 436
pulmonology 120121 pulmonary Langerhans cell histiocytosis 439
central nervous system (CNS), tuberculosis 211 pulmonary tuberculosis 203
central sleep apnoea/hypopnoea (CSA) 410413 sarcoidosis 309, 310
aetiology 410 chest tube drainage
associated conditions 410, 412413 lung abscess 190
complex 412 pleural infections 187, 188
in heart failure patients 408, 410412 pneumothorax 354
idiopathic 412 chest wall compliance 66

chest wall disorders 366368 role of transforming growth factor-b 910
controversies 367 physical activity levels 453, 455
hypoventilation and 417 effects of pulmonary rehabilitation 452
investigation, transthoracic ultrasonography 138139 see also pulmonary rehabilitation
management risk factors 248, 249
physiotherapy 449 air pollution 248, 286, 287, 288
surgical 367, 368 smoking 241, 246, 248, 292293
pathogenesis 366 secondary pneumothorax and 356, 357
pectus carinatum 367 severity classification 247
pectus excavatum 366, 367 silicosis association 284
chest wall pain 4950 symptoms 246, 455
chest wall tumours 392, 393 dyspnoea 41, 46, 455
clinical signs 393 extrapulmonary 454455
prognosis 393 chronic obstructive pulmonary disease (COPD)
treatment 397 exacerbations 42, 172176, 246250
CheyneStokes respiration (CSR) 410 acute 149150
in heart failure patients 410412 aetiology 172173
children infectious see infective exacerbations of COPD
air pollution hazards 285, 286 noninfectious 172, 173
influenza complications 193, 194 definition 172
Langerhans cell histiocytosis 438 frequency 172
Chlamydophilia pneumoniae management 174176, 249
COPD exacerbations 173, 175 infective exacerbations see under infective
detection methods 163, 165, 166 exacerbations of COPD
chronic beryllium disease (CBD) pulmonary rehabilitation 455456
diagnosis 106 see also chronic obstructive pulmonary disease
genetics 2, 3, 5 (COPD) management
chronic bronchitis 241, 246247 outcomes 172, 173
emphysema vs. 241 chronic obstructive pulmonary disease (COPD)
see also chronic obstructive pulmonary disease management 248250
(COPD) bronchodilator therapy 249, 250
chronic cough 3436 corticosteroid therapy 249, 250
aetiology 3435 influenza vaccination 250
diagnosis 35 nutritional support 250
epidemiology 34 oxygen therapy 151, 175, 250, 447, 448
induced sputum biomarkers 93 physiotherapy 447448
management 3637 pulmonary rehabilitation 250, 447, 452, 453,
risk factors 35, 36 454456
environmental tobacco smoke exposure 287 ventilatory support 152
sputum hypersecretion and 3738 see also under chronic obstructive pulmonary
see also cough disease (COPD) exacerbations
chronic eosinophilic pneumonia 320 chronic renal failure, tuberculosis 212, 213
chronic heart failure see heart failure patients chronic respiratory failure (CRF) 148
chronic lung disease (CLD), primary chronic rhinitis see rhinitis, chronic
immunodeficiency-associated 420421 chronic thromboembolic pulmonary hypertension
chronic mountain sickness 300 (CTEPH) 341
chronic obstructive pulmonary disease (COPD) diagnosis 342
altitude effects 300 ChurgStrauss syndrome
asthma vs. 229, 230, 232, 234 clinical presentation 337
chronic bronchitis see chronic bronchitis diagnosis 338
emphysema see emphysema epidemiology 336
exacerbations see chronic obstructive pulmonary pathogenesis 336
disease (COPD) exacerbations prognosis 338339
exercise intolerance 19, 83, 85, 455 treatment 339
exercise testing 86, 87, 455 cigar smoke 291
exhaled breath analysis 94 cigarette smoke 291
gastro-oesophageal reflux disease association 243 cigarette smoking see smoking
genetics 248 ciprofloxacin therapy
HIV association 428 community-acquired pneumonia 178
induced sputum biomarkers 93 hospital-acquired pneumonia 182
management see chronic obstructive pulmonary infectious COPD exacerbations 175
disease (COPD) management pulmonary tuberculosis 205
pathophysiology 246 cisplatin chemotherapy 379

malignant mesothelioma 381 COPD exacerbations 175, 249, 250
nonsmall cell lung cancer 374, 380 drug-induced respiratory disease 323, 328
small cell lung cancer 374, 375, 378 eosinophilic bronchitis 319
clarithromycin therapy eosinophilic pneumonia 320
nontuberculous mycobacterial infections 220 hypereosinophilic syndrome 321
pulmonary tuberculosis 206 hypersensitivity pneumonitis 281
cleft sternum 366 idiopathic pulmonary fibrosis 315316
clofazimine therapy, pulmonary tuberculosis 206 Langerhans cell histiocytosis 440
co-trimoxazole, Pneumocystis jirovecii pneumonia Pneumocystis jirovecii pneumonia 425
management 425, 426 pulmonary vasculitis 339
coal workers pneumoconiosis (CWP) 283 rhinitis 225, 226
colchicine, idiopathic pulmonary fibrosis therapy 316 sarcoidosis 310
colon, cystic fibrosis-related disease 261 severe acute respiratory syndrome 196
combined antiretroviral therapy (CART) 423 costochondritis 4950
respiratory side-effects 428429 cough 34
tuberculosis patients 427, 428 acute 34
common cold 168, 169 assessment 51, 53
community-acquired pleural infection 186 asthmatic 34, 35
community-acquired pneumonia (CAP) 176179 bronchitis-associated 240
clinical features 177 chronic see chronic cough
definition 176 cough challenge 36
diagnosis 177 cough peak expiratory flow (CPEP) measurement,
see also microbiological testing neuromuscular disease patients 362
epidemiology 176 cough reflex 27
management 178179 capsaicin challenge 36, 37
physiotherapy 448449 defective 34
microbial aetiology 177 transient receptor potential 36, 37
microbial resistance 178 cough suppression 37
severity assessment 178 coughing, manually assisted, neuromuscular disease
complex sleep apnoea syndrome 412 patients 364, 449
compost lung 280 counselling, smoking cessation 296
computed tomography (CT) 130132 crackles 42, 45, 54
chest, indications 131, 132 critically-ill patients
descending necrotising mediastinitis 359 respiratory intensive care 154155
drug-induced respiratory disease 324, 326 respiratory physiotherapy 449
fine-needle biopsy guidance 110 cryptogenic organising pneumonia (COP) 105, 312313
high-resolution see high-resolution computed see also bronchiolitis obliterans organising
tomography (HRCT) pneumonia (BOOP)
lung abscess 189, 190 CT see computed tomography (CT)
magnetic resonance imaging vs. 130, 132 culture techniques 162163, 164
malignant pleural mesothelioma 393 pulmonary tuberculosis diagnosis 203
pleural infection 187 CURB65 score 178
positron emission tomography and (PET/CT), lung cyclophosphamide therapy
cancer diagnosis 136, 137, 374 idiopathic pulmonary fibrosis 316
sarcoidosis 309 respiratory side-effects 325, 328
upper airway stenosis 119 Wegeners granulomatosis 339
computed tomography angiography (CTA), cycloserine therapy, pulmonary tuberculosis 206
pulmonary embolism diagnosis 333334, 335 cyclosporine therapy, idiopathic pulmonary fibrosis 316
congenital central hypoventilation syndrome 417 cystic fibrosis (CF) 256264
constant work rate (CWR) tests 84 bronchiectasis 253
continuous positive airway pressure (CPAP) therapy clinical presentations 258
152, 447 diagnosis 258
central sleep apnoea 408, 411, 412 exercise intolerance 83
community-acquired pneumonia 449 exercise testing 86
obstructive sleep apnoea 407408 gastro-oesophageal reflux 242, 243244
continuous-volume computed tomography scanning genetics 2, 34, 256
130, 131 induced sputum biomarkers 93
controllers, asthma 234 management 258263
conventional tube thoracostomy, pneumothorax gastrointestinal disease 261, 263
354355 lung disease 259260, 261, 263
coronary artery disease (CAD), dyspnoea and 42, 43 novel therapies 263
corticosteroid therapy physiotherapy 448
asthma 231, 234, 235 pathophysiology 256257

prognosis 256 airways 327
respiratory infections see under respiratory infections clinical presentation 325326
cystic fibrosis transmembrane regulator (CFTR) 256 diagnosis 105, 323, 324, 326327
cytokine production 29 HIV therapy-associated 428429
cytomegalovirus (CMV) infection, post-bone marrow methaemoglobinaemia 329
transplantation 430, 431 parenchymal 322, 327329
cytomegalovirus pneumonia (CMVP) 185 pathophysiology 323325
post-bone marrow transplantation 431 pleural 329
cytosine methylation 3 pulmonary vasculopathy 329
drug rash with eosinophilia and systemic symptoms
d (DRESS) 328
d-dimer levels drug resistance
idiopathic pulmonary fibrosis exacerbations 317 anti-tuberculosis drugs see under anti-tuberculosis
pulmonary embolism diagnosis 333 drugs
D-penicillamine, idiopathic pulmonary fibrosis oseltamivir 192193
therapy 316 pneumonia pathogens 178
dampness, exposure 288 drug susceptibility testing (DST), anti-tuberculosis
dapsone, Pneumocystis jirovecii pneumonia drugs 204, 206, 208
management 425, 426 Duchenne muscular dystrophy 449
dasatinib, pleural injury 329 see also neuromuscular diseases (NMD),
decompression stress 303 respiratory complications
defence systems 2630 dusts, inhalational injury
acquired 2829, 30 acute 273, 274
anatomical barriers 26 pneumoconiosis 282284
impairment/dysfunction 29 dynamic hyperinflation 85
innate 8, 26, 2728, 30 dyspnoea 4148
mucociliary clearance and fluid homeostasis 27 aetiology 4143
reflex mechanisms 2627 Borg scale 43, 44
Dejours hypoxia-withdrawal test 76 as defence mechanism 27
dendritic cells 28 definition 41
descending necrotising mediastinitis (DNM) 358360 medical history 4344
clinical/radiological signs 359 Medical Research Council scale 43, 44
diagnosis 358, 359 pathophysiology 4548
diffusion route 358 physical examination 4445, 51, 53
epidemiology 358 see also specific diseases
pathogens involved 359
treatment 359360 e
desquamative interstitial pneumonia (DIP) 105, 312 echinacea 170
development of respiratory system 14 electrocardiography (ECG), cardiac chest pain
dextromethorphan, bronchitis therapy 241 investigation 50
diabetes, dyspnoea 4748 embryology, respiratory system 14
diacetyl-related bronchiolitis obliterans 277 emphysema 247
diaphragm, anatomy 14 chronic bronchitis vs. 241
didanosine 429 coal dust-associated 283
diffuse alveolar damage (DAD), drug-induced 324, 325 genetics 3, 4
diffuse alveolar haemorrhage, drug-induced 324, silicosis association 284
325, 329 see also chronic obstructive pulmonary disease
diffuse pleural thickening (DPT) 283 (COPD)
diffusion equilibrium 22 empyema 187
diffusion impairment 2122 chest radiograph 188
diffusion-weighted magnetic resonance imaging CT scan 189, 190
(DW MRI) 133 management 350
diffusiveperfusive conductance ratio 22 end-expiratory lung volume (EELV) 6162
digital radiography (DR) 127, 129 end-inspiratory lung volume (EILV) 62
direct immunofluorescence (DIF), respiratory virus endobronchial metastases 388, 389
detection 165 endobronchial ultrasound-guided transbronchial fine
diving needle aspiration (EBUSTBNA) 101
pulmonary effects 303 endobronchial valves 101102
pulmonary limitations at depth 302 endothelin-1 inhibitors, idiopathic pulmonary fibrosis
diving-related disease 302303 therapy 317
docetaxel chemotherapy 379 endothelin receptor antagonist (ERA), pulmonary
nonsmall cell lung cancer 375, 380 arterial hypertension management 343, 344
drug-induced respiratory disease (DIRD) 322329 Enterobacteriaceae, as cause of hospital-acquired

pneumonia 181 F
environmental assessment, hypersensitivity familial pulmonary fibrosis 4, 5, 313
pneumonitis 279 farmers lung 278279, 280
environmental tobacco smoke (ETS) 287288 fatigue, chemotherapy-induced 378
eosinophilic bronchitis 319 FDG PET (2-[18F]-fluoro-2-deoxy-d-glucose positron
chronic cough 35, 38, 319 emission tomography)
eosinophilic diseases 105, 319321 lung cancer diagnosis 136137, 374
see also specific diseases pleural malignancies 394
eosinophilic pneumonia 320 FDG SUV (2-[18F]-fluoro-2-deoxy-d-glucose
drug-induced 328 standardised uptake value), lung cancer diagnosis
eosinophils 319 136, 137
epidermal growth factor receptor (EGFR) 380 female reproductive tract, cystic fibrosis-related
mutations 375, 380 disease 262
epidermal growth factor receptor (EGFR)-targeted fever, inhalation 273274
therapies 375, 380 fibrosing mediastinitis 360
epigenetics 3 Ficks principle 15
epiglottitis 169 diffusion impairment 21
epithelial barrier 26 fine-needle aspiration biopsy
Epworth Sleepiness Scale (ESS) 404, 405 percutaneous 110111
equal pressure point (EPP) 1920 transbronchial see transbronchial fine-needle
equilibrium coefficient 22 aspiration (TBNA)
ergots, pleural injury 329 flow-volume loop analysis, upper airway stenosis
erlotinib therapy, nonsmall cell lung cancer 380 118119, 121
etanercept therapy, idiopathic pulmonary fibrosis 317 fluid homeostasis 27
ethambutol 205, 220 fluorescence bronchoscopy 101
ethanol, cough challenge 36 2-[18F]-fluoro-2-deoxy-d-glucose positron emission
ethionamide therapy, pulmonary tuberculosis 206 tomography see FDG PET (2-[18F]-fluoro-2-deoxy-d-
eucapnic voluntary hyperventilation (EVH) 8990 glucose positron emission tomography)
exercise-induced asthma 228 2-[18F]-fluoro-2-deoxy-d-glucose standardised uptake
exercise intolerance 83 value (FDG SUV), lung cancer diagnosis 136
COPD 19, 83, 85, 455 fluoroquinolones
exercise testing 8387 hospital-acquired pneumonia management 182
bronchial responsiveness 88, 89, 90 pulmonary tuberculosis management 204, 205
COPD patients 86, 87, 455 treatment of infectious COPD exacerbations 174, 175
evaluation of therapeutic interventions 87 fluoroscopy
indications 84 chest 129
pulmonary rehabilitation 455 fine-needle biopsy guidance 110
protocols 8384 fluticasone, bronchiectasis management 254
response patterns 86 Forced Oscillation Technique 65
variables and indexes 8485 forced residual capacity (FRC) 1617
exercise tolerance, improvement foreign body inhalation 42
bronchiectasis 254 Framework Convention for Tobacco Control (FCTC) 295
see also pulmonary rehabilitation functional residual capacity (FRC) 59, 61
exercise training fungal infections
COPD management 250, 447 bronchiectasis 253
see also pulmonary rehabilitation; respiratory immunocompromised hosts 184
physiotherapy HIV-infected patients 424426
exhaled breath analysis 9495, 229 with primary immunodeficiency 421422
exogenous lipoid pneumonitis 276 lung abscess 189
expiration 1820, 63 see also specific fungal infections
expiratory flow limitation (EFL) 59 funnel chest (pectus excavatum) 366, 367
expiratory reserve volume 59, 6162
extensively drug-resistant tuberculosis (XDR-TB) G
204, 208 gallium-67 scintigraphy 136
HIV association 427 ganciclovir 431
extracellular matrix (ECM) 78 gas dilution techniques 62
extracorporeal membrane oxygenation (ECMO) 147 gas exchange see pulmonary gas exchange
extrapulmonary tuberculosis (EPTB) 209211 gas microemboli, diving-associated 303
diagnosis 210 gas transfer factor see transfer factor of the lung for
sites 209211 carbon monoxide (TL, CO)
treatment 210 gases, inhalational injury see acute inhalation injury
WHO definition 209 gastro-oesophageal reflux disease (GORD) 242245
see also tuberculosis (TB) in advanced lung disease 242, 243244

comorbidities heart sounds, auscultation 45
asthma 234, 242, 243 helical computed tomography scanning 130, 131
COPD 243 heliox gas mixture, vocal cord dysfunction treatment
cough association see gastro-oesophageal reflux- 238
induced cough HendersonHasselbalch equation 16
management 244245 heritable pulmonary arterial hypertension 340,
pathophysiology 242243 341, 343
symptoms 242 high-altitude, physiological response 22, 298
upper respiratory tract infections vs. 170 high-altitude cerebral oedema (HACE) 299, 300
gastro-oesophageal reflux-induced cough 35, 242, 243 high-altitude disease 298301, 413
management 37, 243 high-altitude periodic breathing 298, 299, 413
gastrointestinal disease, cystic fibrosis-related 261, 263 high-altitude pulmonary oedema (HAPE) 299300
gefitinib therapy, nonsmall cell lung cancer 380 high-dependency unit 154155
gemcitabine therapy 379 high molecular weight (HMW) agents, occupational
malignant mesothelioma 381 asthma 269, 270
nonsmall cell lung cancer 374, 380 high-resolution computed tomography (HRCT) 130131
gene mutations 23 bronchiectasis 253
gene therapy, cystic fibrosis 263 idiopathic pulmonary fibrosis 314
genetics 26 lymphangioleiomyomatosis 441, 442
see also specific diseases pulmonary alveolar proteinosis 436
Geneva score 332 pulmonary hypertension 342343
germ cell tumours 399400 pulmonary Langerhans cell histiocytosis 439
graft versus host disease (GVHD) 430431 hila, anatomy 13
grain handlers lung 280 hilar amyloid lymphadenopathy 434
Gram stain, sputum 164 hilar lymph nodes, metastatic tumours 389390
granulocyte macrophagecolony stimulating factor histamine bronchial provocation testing 88, 89, 90
(GMCSF) signalling, disruption in pulmonary histone modifications 3
alveolar proteinosis 8, 435 HIV-related disease 423429
granulomatous lung diseases COPD 428
diagnosis, bronchoalveolar lavage 106 infections 184, 423427
see also specific diseases bacterial 423424
group A streptococcal pharyngitis 169, 170 fungal 424
see also Pneumocystis jirovecii pneumonia (PJP)
H tuberculosis 185, 201202, 203, 212213, 284,
Haemophilus influenzae infection 426427
COPD exacerbations 173, 174, 175 malignant conditions 427428
hospital-acquired pneumonia 181 pneumonitis 428
Haemophilus influenzae type B (HiB) 169 pneumothorax 428
vaccination 170 pulmonary arterial hypertension 428
haemoptysis 38 therapy-associated 428429
fine-needle biopsy-induced 111 see also immunocompromised hosts
haemorrhage HIV therapy see combined antiretroviral therapy
alveolar, drug-induced 324, 325, 329 (CART)
thoracentesis-induced 117 home ventilatory support 152
haemosiderosis, pulmonary 104 Hoovers sign 44
haemothorax 353354 hospital-acquired pleural infection 186, 187
laboratory investigations 350 hospital-acquired pneumonia (HAP) 176, 180182
thoracentesis-induced 117 definition 180
healthcare-associated pneumonia (HCAP) 180 diagnosis 177, 181, 182
see also hospital-acquired pneumonia (HAP) epidemiology 176, 180
heart attack 42 management 179, 182
heart catheterisation, pulmonary hypertension microbial aetiology 178, 181182
diagnosis 340, 343 pathogenesis 181
heart disease risk factors 181
as consequence of obstructive sleep apnoea severity assessment 178
405406, 407 hot-tub lung 278, 280
dyspnoea and 42, 43 hypercapnia 74, 78, 80, 81
pulmonary hypertension and 341, 343 hypercapnic respiratory failure 149, 150
heart failure patients arterial blood gas analysis 78, 79
CheyneStokes respiration/central sleep apnoea hypereosinophilic syndrome (HES) 320321
408, 410412 hyperinflation, dynamic 85
dyspnoea 43, 47 hyperoxia, diving-associated 303
heart rate reserve (HRR) 8485 hyperoxic rebreathing method 72, 7374

hypersensitivity pneumonitis (HP) 219, 278281 imatinib therapy, hypereosinophilic syndrome 321
diagnosis 106, 279280 immune defence 2630
differential 281 acquired 2829, 30
environmental assessment 279 innate 2628, 30
epidemiology 278 immune reconstitution disease (IRD) 428
host factors 279 immunocompromised hosts
pathogenesis 279 nontuberculous mycobacterial infections 219
prognosis 281 pneumonia 176, 177, 178, 183185
risk factors 278279 tuberculosis 184, 185, 201, 212213
symptoms/findings 279 see also HIV-related disease
treatment 280281 immunodeficiency, primary, pulmonary diseases
types 280 420422
hypertension, pulmonary see pulmonary immunoglobulin (Ig) production 29
hypertension (PH) immunosuppression
hyperventilation syndrome 42, 45 infectious complications 184185
physiotherapy 448 types 183, 184
hypocapnia 80 Wegeners granulomatosis management 339
hypotension, thoracentesis-induced 117 immunotherapy, asthma 234235
hypoventilation syndromes 414417 impulse oscillometry, vocal cord dysfunction
aetiology 415417 diagnosis 237
clinical features 415 indoor pollution 287289
diagnosis 415 induced sputum see sputum induction
management 416417 infective exacerbations of bronchiectasis 252, 253
pathophysiology 2021, 414415 treatment 253254
hypoxaemia 16, 22, 23 infective exacerbations of COPD 172176
aetiology 15, 2021, 22, 23, 24 diagnosis 173174
arterial blood gas analysis 77, 78 treatment 174176
oxygen therapy 151 antibiotic 174, 175
hypoxaemic respiratory failure 148149 nonantibiotic 174176
arterial blood gas analysis 7778, 79 inflammatory diseases
hypoxia, ventilatory response 7476 diagnosis, gallium-67 scintigraphy 136
hypoxia-withdrawal test 76 see also specific diseases
hypoxic ventilatory decline 74, 75 influenza 170, 191194
hysteresis 6061 chemoprophylaxis 192
complications 177, 193, 194
I diagnosis 196197
iatrogenic pneumothorax 352, 353 pandemic 193194
idiopathic central sleep apnoea 412 seasonal 191193
idiopathic interstitial pneumonias (IIPs) 311318 treatment 170, 192
classification 311, 312 influenza vaccination 170, 192
clinical features 311 COPD patients 250
epidemiology 311 lymphangioleiomyomatosis patients 443
management 311312 influenza viruses 191
post-bone marrow transplantation 431 detection 165
see also specific forms inhalation fever 273274
idiopathic pulmonary arterial hypertension 340, hypersensitivity pneumonitis vs. 281
341, 342, 343, 344 inhalation injury, acute see acute inhalation injury
idiopathic pulmonary fibrosis (IPF) 311312, 313318 innate immune defence 8, 26, 2728, 30
clinical features 313314 inspiration 1718, 21, 63, 64
diagnosis 105, 314 inspiratory capacity (IC) 59, 61
exacerbations 314315 inspiratory-muscle pressure 1617
genetics 4, 5, 313 inspiratory reserve volume 59, 6162
management 315318 inspiratory squeaks 45
natural history 314 inspiratoryexpiratory radiography 127
pathogenesis 313 insulin resistance (IR), obstructive sleep apnoea
physiology 313 association 406, 407
Ig (immunoglobulin) production 29 intensive care unit 154155
IgA 29 interferon-g, lack of functional receptors 23
IgG 29 interferon-g-1b, idiopathic pulmonary fibrosis
IgM 29 therapy 316
IkBa kinase (IKK) 10 interferon-g release assays (IGRAs) 204, 213, 215, 216
image-guided percutaneous drainage, lung abscess interleukin-12, lack of functional receptors 23
190 interleukin-17 29

intermittent positive pressure breathing (IPPB) 447 detection methods 163, 164, 165, 166
bronchiectasis management 448 Legionnaires disease, diagnosis 164, 165
COPD management 448 leukotriene antagonists, allergic rhinitis treatment 226
interrupter technique 65 levofloxacin therapy
interstitial lung disease (ILD) community-acquired pneumonia 178
diagnosis, bronchoalveolar lavage 103, 105 hospital-acquired pneumonia 182
drug-induced 322, 323, 327329 infectious COPD exacerbations 174, 175
dyspnoea 43, 4647 pulmonary tuberculosis 205
exercise intolerance 83 Lights criteria 350
exercise testing 86 linezolid therapy, pulmonary tuberculosis 206
genetics 45 liver, cystic fibrosis-related disease 261
management, physiotherapy 448 lobectomy, nonsmall cell lung cancer 383, 384, 385
respiratory bronchiolitis associated 105, 312 bronchoplastic 386
smoking and 293 Lfgrens syndrome 308, 309, 310
interventional lung assist (ILA) 147 long-acting b2-agonists, asthma management 231, 234
interventional pulmonology 118 long-term oxygen therapy (LTOT) 151152
bronchoscopy 101102, 118, 120121 lordotic chest radiograph 127
intraoperative interventions, pulmonary low molecular weight (LMW) agents, occupational
complications 157 asthma 269, 270
intrapleural pressure (PIP) 1617, 18, 1920 lower respiratory tract infections (LRTIs)
isocapnic hypoxia 7475 diagnosis
isoniazid therapy bronchoalveolar lavage 104
latent tuberculosis 216 see also microbiological testing
nontuberculous mycobacterial infections 220 see also specific infections
pulmonary tuberculosis 204, 205 lung(s)
anatomy 1112
J imaging
Japanese summer-type hypersensitivity pneumonitis computed tomography see computed
280 tomography (CT)
joints magnetic resonance imaging see magnetic
cystic fibrosis-related disease 262 resonance imaging (MRI)
tuberculosis 211 nuclear medicine scans 50, 135137
see also scintigraphy
K radiography see chest radiography
kanamycin therapy, pulmonary tuberculosis 204, molecular biology 710
205 lung abscess 189190
Kaposi sarcoma 427 lung biopsy
keel chest (pectus carinatum) 367 bronchial 100
percutaneous fine-needle 110111
L pulmonary Langerhans cell histiocytosis diagnosis
lactate threshold 84 439
lactic acidosis, HIV therapy-associated 428429 sarcoidosis diagnosis 309
Lady Windemeres syndrome 219 transbronchial 100, 101
Langerhans cell histiocytosis (LCH) lung cancer 372375
adult, pulmonary see pulmonary Langerhans cell classification 372373
histiocytosis, adult see also specific histologic types
in children 438 diagnosis 373374
large cell carcinoma, lung 373 bronchoscopy 98, 373
large cell neuroendocrine carcinoma (LCNEC), lung 373 percutaneous fine-needle biopsy 111
laryngeal amyloidosis 434 positron emission tomography 136137, 374
laryngitis, symptoms and signs 169 epidemiology 372
laryngoscopy, vocal cord dysfunction diagnosis 237238 functional assessment 374
latent tuberculosis infection (LTBI) 201, 215217 performance status see performance status (PS),
controversies 216217 lung cancer
detection 216 genetics 6, 372
immunocompromised hosts 213 HIV association 428
HIV-infected 427 management see lung cancer treatment
TB risk 215 metastasis 388, 389, 390, 391
treatment 215216 non small cell see nonsmall cell lung cancer
lateral chest radiograph 126, 127 (NSCLC)
lateral decubitus chest radiograph 126127 risk factors 372
Legionella spp. air pollution 286, 287288
as cause of community-acquired pneumonia 177 smoking 287288, 292, 295, 372, 373

silicosis association 284 genetics 441
small cell see small cell lung cancer (SCLC) management 443
staging 374, 375 pathology 441
mediastinal lymph nodes 1314, 374 prognosis 443
medical thoracoscopy/pleuroscopy (MT/P) 114 symptoms 441
transthoracic ultrasonography 141 lymphatic drainage 11, 13
symptoms 373 lymphoid interstitial pneumonia (LIP) 105, 311, 313
lung cancer treatment 374375 lymphoma 393, 399400
brachytherapy 101, 381 HIV-associated 427428
chemotherapy see chemotherapy
nonsmall cell lung cancer see under nonsmall cell M
lung cancer (NSCLC) macrolides
palliative 381 bronchiectasis management 254
radiotherapy see under radiotherapy community-acquired pneumonia management 178
small cell lung cancer 375, 378379 macrophages, alveolar 2728
surgical resection magnetic resonance imaging (MRI) 132133
nonsmall cell lung cancer 374, 375, 382386 computed tomography vs. 130, 132
pre-operative assessment 157158 diffusion-weighted 133
quality requirements 383 indications 132
lung compliance 1617, 6566 male reproductive tract, cystic fibrosis-related
measurement 6566 disease 262
lung disease malignant airway stenosis, interventional
altitude effects 300301 pulmonology 118, 120121
transthoracic ultrasonography 141 malignant pericardial effusions 388
see also specific diseases malignant pleural effusions (MPEs) 348, 349, 388,
lung function 392393
impact of interventional bronchoscopy 120121 clinical signs 393
improvement, bronchiectasis 254 diagnosis 393, 395396
lung function testing management 350351, 394, 397
asthma 228230 medical thoracoscopy/pleuroscopy (MT/P) 114
lymphangioleiomyomatosis 441 transthoracic ultrasonography 139140
neuromuscular diseases 361362 malignant pleural mesothelioma (MPM) 392
pulmonary Langerhans cell histiocytosis 439 clinical signs 393
upper airway stenosis 118120 diagnostic procedures 395396
see also specific tests imaging 133, 141, 393394
lung injury 146147 pre-treatment assessment 396
graft versus host disease 430431 prognosis 393
inhalation see acute inhalation injury staging 396
radiation-induced 304305 treatment 381, 395, 396397
lung transplant rejection, gastro-oesophageal reflux malt workers lung 280
and 242, 244 mandibular advancement device (MAD) 408
lung transplantation mannitol
idiopathic pulmonary fibrosis 317318 bronchial provocation testing 89
Langerhans cell histiocytosis 440 bronchiectasis management 254
lymphangioleiomyomatosis 443 manually assisted coughing (MAC), neuromuscular
pulmonary alveolar proteinosis 436 disease patients 364, 449
pulmonary arterial hypertension 343 maple bark strippers lung 280
lung volumes 5862 matrix metalloproteinases (MMPs) 78
measurement techniques 62 maxillomandibular advancement osteotomy,
lupus, drug-induced 329 obstructive sleep apnoea management 409
lymph nodes maximal incremental exercise testing 8384
benign vs. malignant, transthoracic maximal respiratory pressures, measurement 66
ultrasonography 138139 mechanical insufflationexsufflation (MIE),
dissection, nonsmall cell lung cancer 385386 neuromuscular disease patients 364, 449
mediastinal see mediastinal lymph nodes mechanical ventilation
metastatic tumours 389390 as cause of lung injury 146147
tuberculosis 210 lung injury management 147
lymphadenopathy, mediastinal see mediastinal measurement of respiratory mechanics 66
lymphadenopathy neuromuscular disease patients 363364
lymphangioleiomyomatosis (LAM) 441443 noninvasive see noninvasive ventilation (NIV)
diagnosis 441443 respiratory failure management 150
disease progression 443 respiratory intensive care unit patients 154155
epidemiology 441 mediastinal drainage 359360

mediastinal lymph nodes 1314 multi-drug resistant tuberculosis (MDR-TB) 204,
metastatic tumours 389390 206, 207208
mediastinal lymphadenopathy HIV association 427
amyloid 434 treatment 207208
chest pain 49 mushroom workers lung 280
mediastinal tumours 399400 myasthenia gravis 399
mediastinitis Mycobacterium abscessus 220
aetiology 358 Mycobacterium avium complex (MAC) 219, 220
descending necrotising see descending necrotising Mycobacterium kansasii 219, 220
mediastinitis (DNM) Mycobacterium malmoense 220
fibrosing 360 Mycobacterium simiae 220
mediastinum, anatomy 1314, 399 Mycobacterium szulgai 220
Medical Research Council (MRC) dyspnoea scale 43, 44 Mycobacterium tuberculosis 200
medical thoracoscopy/pleuroscopy (MT/P) 112114 infection see tuberculosis (TB)
contraindications 113 Mycobacterium xenopi 220
indications 113114 Mycoplasma pneumoniae
techniques 112113 community-acquired pneumonia 177
video-assisted thoracic surgery (VATS) vs. 112 COPD exacerbations 173, 175
meningitis, tuberculous 211 detection methods 163, 165, 166
mepolizumab 321 myocardial infarction 42
mesothelioma see malignant pleural mesothelioma
(MPM) n
metabolic acidosis 80, 81 NAC (N-acetylcysteine), idiopathic pulmonary
HIV therapy-associated 428429 fibrosis therapy 316317
metabolic alkalosis 80, 81 nasal cilia 26
metabolic syndrome, obstructive sleep apnoea nasal continuous positive airway pressure (nCPAP)
association 406, 407, 408 central sleep apnoea 408
metacholine bronchial provocation testing 88, 89, 90 obstructive sleep apnoea 407408
metal fume fever 273, 274 nasal mucosa 26
metal grinding, hypersensitivity pneumonitis 280 nausea, chemotherapy-induced 378
metastatic tumours 388391 needles, percutaneous fine-needle biopsy 110111
bone 390391 neuralgic pain 50
hilar and mediastinal lymph nodes 389390 neuraminidase inhibitors 170, 192, 193
malignant pericardial effusions 388 neuromuscular diseases (NMD), respiratory
pleural see pleural metastases complications 361364
pulmonary 388389 clinical evaluation 361
methaemoglobinaemia 329 dyspnoea 46, 47, 361
methotrexate, Wegeners granulomatosis therapy 339 hypoventilation 417
methotrexate lung 327328 management 363364, 449
microbiological testing 162167 pulmonary function testing 361362
culture techniques 162163, 164 sleep-disordered breathing 361, 362363,
pulmonary tuberculosis diagnosis 203 412413
Gram stain 163164 sleep study 362363
nucleic acid amplification tests 163, 166167 neuropathy, chemotherapy-induced 378
rapid antigen tests 163, 164165 neuroventilatory dissociation (NVD) 46
serology 165166 neutropenia, chemotherapy-induced 378
sputum samples 163164 neutrophils 27, 28
pulmonary tuberculosis diagnosis 203 nicotine replacement therapy (NRT) 296
minocycline-induced eosinophilic pneumonia 323, nitrogen dioxide (NO2), air pollution 285, 286,
328 288, 289
miRNAs 3 nocturnal hypoventilation 414415
molecular biology, lung 710 nocturnal noninvasive ventilation 152
mollusc-shell hypersensitivity 280 obesity hypoventilation syndrome 415
Moraxella catarrhalis, COPD exacerbations 173, 175 nodular bronchiectasis 219
mould exposure 288 nonallergic rhinitis 225
mountain sickness treatment 226
acute 298299, 300 nonasthmatic eosinophilic bronchitis 319
chronic 300 noninvasive ventilation (NIV) 152
moxifloxacin therapy bronchiectasis 448
infectious COPD exacerbations 174, 175 COPD 448
nontuberculous mycobacterial infections 220 neuromuscular disease patients 363364, 449
pulmonary tuberculosis 206 obesity hypoventilation syndrome 416417
mucociliary clearance 8, 27 respiratory intensive care unit patients 154, 155

see also continuous positive airway pressure symptoms 269
(CPAP) therapy oesophagus, cystic fibrosis-related disease 261
nonsmall cell lung cancer (NSCLC) 373 opioid therapy, chronic, central sleep apnoea and 412
early-stage, definition 383 opsonins 27, 28
staging 375, 383 organic dust toxic syndrome (ODTS) 273, 274
treatment 374375 hypersensitivity pneumonitis vs. 281
chemotherapy 374375, 379381, 382 oseltamivir 192193
radiotherapy 382 osteolytic metastases 390
surgical 374, 375, 382386 otitis media 193, 194
survival rates and 374, 375, 383, 384, outdoor pollution 285287
385386 ovarian cancer, metastasis 388, 390
see also lung cancer oxidative stress, air pollution 289
nonspecific interstitial pneumonia (NSIP) 311312, oxygen pulse 84
313318 oxygen therapy 151152
clinical features 313314 acute 151
diagnosis 105, 314 asthma exacerbations 233, 235
exacerbations 314315 COPD 151, 175, 250, 447, 448
management 315318 long-term 151152
pathogenesis 313 neuromuscular disease patients 449
nonsteroidal anti-inflammatory drugs (NSAIDs) physiotherapists role 447
respiratory complications 323, 327 ozone, air pollution 285, 286, 289
upper respiratory tract infection management 170
nontuberculous mycobacterial (NTM) infections 218220 P
epidemiology 218 paclitaxel chemotherapy 379
pathogenesis 218 nonsmall cell lung cancer 380
pulmonary 219220 pain, chest 4950
nosocomial pleural infection 186, 187 palliative treatments
nosocomial pneumonia see hospital-acquired lung cancer 381
pneumonia (HAP) malignant pleural mesothelioma 397
nuclear factor-kB 10 palpation 52
nuclear medicine scans 50, 135137 pancreas, cystic fibrosis-related disease 261, 262
see also scintigraphy pandemic influenza 193194
nucleic acid amplification tests (NAATs) 163, 166167 paprika splitters lung 280
Nuss technique 367 paradoxical vocal cord movement (PVCM) 236, 238
nutritional support, COPD 250 parenchymal pulmonary amyloidosis 434
parietal pleurectomy, pneumothorax management
O 355, 356
obesity particulate matter (PM), air pollution 285287,
COPD patients 455 288, 289
dyspnoea and 47 passive smoking 293294
obesity hypoventilation syndrome (OHS) 415417 peak expiratory flow (PEF) measurement, asthma
oblique chest radiograph 127 227, 228
obstructive lung disease occupational 270
dyspnoea 43 peak oxygen uptake 84
hypoventilation 417 peat moss workers lung 280
lung volume changes 59, 61 pectus carinatum (PC) 367
see also specific diseases pectus excavatum (PE) 366, 367
obstructive sleep apnoea/hypopnoea syndrome pemetrexed chemotherapy 379
(OSAHS) 404409, 414, 416 malignant mesothelioma 381, 397
altitude effects 301 nonsmall cell lung cancer 374, 375, 380
consequences 405407 D-penicillamine, idiopathic pulmonary fibrosis
definition 404 therapy 316
diagnosis 405 penicillins
management 407409 community-acquired pneumonia management 178
pathophysiology 405, 406 hospital-acquired pneumonia management 182
prevalence 405 pentamidine, Pneumocystis jirovecii pneumonia
symptoms 404 management 425, 426
occupational asthma 268272 percutaneous drainage
associated occupations/industries 271 lung abscess 190
diagnosis 269270 see also chest tube drainage
management 270271 percutaneous fine-needle biopsy (PFNB) 110111
sensitising/triggering agents 269, 270 performance status (PS), lung cancer 374
socioeconomic impact 271272 World Health Organization/Eastern Cooperative

Oncology Group (WHO/ECOG) scale 378, 379 malignant see malignant pleural effusions (MPEs)
perfusion lung scintigraphy (PLS) management 350351
pulmonary embolism diagnosis 135136, 334, 335 thoracentesis 115, 116, 350, 351
pulmonary hypertension diagnosis 342343 pathophysiology 348349
pericardial effusion symptoms 349
dyspnoea and 42 dyspnoea 43
malignant 388 transudative 348
pericardium, tuberculosis 211 pleural fluid examination
periodic breathing, high-altitude 298, 299, 413 pleural effusion diagnosis 349350
PET (positron emission tomography), lung cancer pleural infections 187
diagnosis/staging 136137, 374, 385 pleural infection 186189
PET/CT (computed tomography/positron emission bacteriology 186187
tomography), lung cancer diagnosis 136, 137, 374 clinical classification 187
pH, arterial 80 diagnosis 187, 188
phagocytosis 2728 epidemiology 186
pharyngeal specimens, antigen tests 164165 management 187188
pharyngitis 169, 170 pathophysiology 186
phosphodiesterase type-5 inhibitors, pulmonary prognosis 188189
arterial hypertension management 343 tuberculosis 210211
phrenic nerve 14 pleural malignancies
physical examination 5154 mesothelioma see malignant pleural
auscultation 4445, 54 mesothelioma (MPM)
cough 51, 53 metastatic see pleural metastases
dyspnoea 4445, 51, 53 transthoracic ultrasonography 141
inspection 52 pleural metastases 388, 392393
palpation 52 diagnosis 393, 395, 396
percussion 52, 54 prognosis 393
physiology see respiratory physiology treatment 397
physiotherapy 446 see also malignant pleural effusions (MPEs)
respiratory see respiratory physiotherapy pleural pain 49
Pickwickian syndrome 415416 pleural plaques 282
picture archiving and communication systems pleural rubs 54
(PACS) 129 pleural tap see thoracentesis
pirfenidone, idiopathic pulmonary fibrosis therapy 316 pleurectomy, pneumothorax management 355, 356
Pisa score 332, 333 pleurisy, asbestos 282283
platinum-based chemotherapy 379 pleurodesis 397
malignant mesothelioma 381 pleuroscopy see medical thoracoscopy/pleuroscopy
nonsmall cell lung cancer 374, 380 (MT/P)
small cell lung cancer 374, 375, 378 pneumococcal vaccination 170, 179
plethysmography, body 62, 6465 HIV-infected patients 424
pleura lymphangioleiomyomatosis patients 443
anatomy 11 pneumoconiosis 282284
drug-induced disease 329 Pneumocystis jirovecii pneumonia (PJP) 178,
pathology 184185, 424426
transthoracic ultrasonography 139140 management 184, 425426
see also specific diseases pneumomediastinum 353, 354
pleural biopsy 396 pneumonectomy, nonsmall cell lung cancer 383, 384
pleural catheters 397 alternatives 386
pleural cavity 11 pneumonia
pleural drainage, pleural effusions 350 Aspergillus 184, 185
pleural effusion 348351 aspiration 176, 178
aetiology 348 clinical features 42, 177
definition 348 community-acquired see community-acquired
diagnosis 349350 pneumonia (CAP)
laboratory investigations 349350 cytomegalovirus see cytomegalovirus pneumonia
medical thoracoscopy/pleuroscopy 113, 114, (CMVP)
349 eosinophilic see eosinophilic pneumonia
thoracentesis 115, 116, 349 epidemiology 176
transthoracic ultrasonography 139140, 141, hospital-acquired see hospital-acquired pneumonia
349 (HAP)
transudate vs. exudate 350 idiopathic interstitial see idiopathic interstitial
drug-induced 327 pneumonias (IIPs)
exudative 349, 350 in immunocompromised hosts 176, 177, 178, 183185

HIV-infected patients 424 primary immunodeficiencies (PID), pulmonary
as influenza complication 177, 193, 194 diseases 420422
investigations and diagnosis 177 primary progressive pulmonary tuberculosis 201
see also microbiological testing primary spontaneous pneumothorax 352353,
management 178179 352355
prevention 179 primary viral pneumonia 193, 194
severity assessment 178 pro-motility agents 37
ventilator-associated 176, 177, 178, 180, 181 prophylactic cranial irradiation (PCI) 375, 379
pneumonia severity index (PSI) 178 Prospective Investigation of Pulmonary Embolism
pneumonitis Diagnosis (PIOPED) study 332, 333, 334, 335
chemical see toxic pneumonitis Prospective Investigative Study of Acute Pulmonary
HIV-associated 428 Embolism Diagnosis (PISAPED) study 332, 333, 334
hypersensitivity see hypersensitivity pneumonitis prostaglandins, pulmonary arterial hypertension
(HP) management 343, 344
post-bone marrow transplantation 431 prostate cancer, metastasis 390
radiation 304, 305 a1-proteinase inhibitor (PI) deficiency 248
pneumotachographshutter system, airway genetics 2, 4
resistance measurement 65 proteinosis, pulmonary alveolar 8, 435436
pneumothorax 42 prothionamide therapy, pulmonary tuberculosis 206
classification 352, 353 proton pump inhibitors (PPIs), gastro-oesophageal
definition 352 reflux disease management 37, 243, 244
HIV association 428 Pseudomonas aeruginosa infection
iatrogenic 352, 353 COPD exacerbations 173, 174
medical thoracoscopy/pleuroscopy 113, 114 hospital-acquired pneumonia 181
spontaneous see spontaneous pneumothorax psychotherapy, vocal cord dysfunction 239
traumatic see traumatic pneumothorax pulmonary alveolar proteinosis (PAP) 8, 435436
Poland syndrome 366 pulmonary amyloidosis 433434
polymer fume fever 273 pulmonary arterial hypertension (PAH) 340
polysomnography diagnosis 342343
central sleep apnoea assessment 411 epidemiology 342
neuromuscular disease patients 362363 HIV association 428
obstructive sleep apnoea assessment 405 prognosis 342
popcorn workers lung 277 treatment 343344
positive end-expiratory pressure (PEEP), lung injury pulmonary barotrauma 302303
management 147 pulmonary capillary haemangiomatosis 340341
positron emission tomography (PET), lung cancer pulmonary complications, post-operative see post-
diagnosis/staging 136137, 374, 385 operative pulmonary complications
positron emission tomography/computed pulmonary diffusive flux, impairment 2122
tomography (PET/CT), lung cancer diagnosis 136, pulmonary embolism (PE) 332
137, 374 diagnosis 332335
post-nasal drip syndrome 34 clinical probability assessment 332333
post-operative interventions, pulmonary computed tomography angiography 333334,
complications 157 335
post-operative pulmonary complications d-dimer measurement 333
intraoperative interventions 157 magnetic resonance imaging 132133
post-operative interventions 157 perfusion lung scintigraphy 135136, 334, 335
pre-operative assessment 156158 ventilation lung scintigraphy 135, 334
pulmonary resection 157158 dyspnoea and 42
pre-operative interventions 157 idiopathic pulmonary fibrosis patients 314, 317
risk factors 156157 pulmonary fibrosis
American Society of Anesthesiologists drug-induced 329
classification 156, 157 idiopathic see idiopathic pulmonary fibrosis (IPF)
postero-anterior (PA) radiograph 126, 127 radiation-induced 304305
postural drainage (PD) 445 pulmonary function see lung function
bronchiectasis 448 pulmonary gas exchange 20
pre-operative assessment 156158 arterial blood gas analysis 7780
pulmonary resection 157158 enhancement strategies 447
pre-operative interventions, pulmonary complications exercise testing 86
157 impairments 20
pregnant women see also transfer factor of the lung for carbon
air pollution hazards 286 monoxide (TL, CO)
influenza complications risk 194 pulmonary haemosiderosis 104
lymphangioleiomyomatosis 443 pulmonary hypertension (PH) 340344

altitude effects 301 R
classification 340342 radiation fibrosis (RF) 304305
diagnosis 342343 radiation-induced lung injury 304305
drug-induced 329 radiation pneumonitis (RP) 304, 305
epidemiology 342 radiography see chest radiography
pathologic features 341342 radiotherapy 304
prognosis 342 lung cancer
treatment 343344 nonsmall cell lung cancer 374, 382
pulmonary Langerhans cell histiocytosis, adult 438440 palliative 381
diagnosis 104, 439 small cell lung cancer 375, 379
epidemiology 438 malignant pleural mesothelioma 397
features 438 rapid-acting b2-agonists, asthma management 231,
outcomes 439 234, 235
treatment 440 rapid antigen tests 163, 164165
pulmonary metastases 388389 rare lung diseases
pulmonary oedema diagnosis, bronchoalveolar lavage 104
drug-induced 324, 328 see also specific diseases
high-altitude 299300 Ravitch technique 367
pulmonary rehabilitation 451456 reactive airway disease, dyspnoea 42
bronchiectasis 254, 448 reactive airways dysfunction syndrome (RADS) 277
chest wall disorders 449 ReadLeigh rebreathing test 7374
COPD 250, 447, 452, 453, 454456 rebreathing test 72, 7374
severe exacerbations 455456 recoil pressure (PREC) 18, 19, 20
definition 451 rectum, cystic fibrosis-related disease 261
evidence base 451452 reflex mechanisms, defensive 2627
maintaining effects 453 reflux cough 35, 36
patient selection 454 see also gastro-oesophageal reflux-induced cough
programmes 452454 regulatory genes 3
see also respiratory physiotherapy relaxation volume 58
pulmonary resection relievers, asthma 234
bronchiectasis 254 reproductive tract, cystic fibrosis-related disease 262
lung cancer see under lung cancer treatment residual volume (RV) 5961
pre-operative assessment 156, 157158 respiratory acidosis 80, 81
pulmonary surfactant see surfactant system respiratory alkalosis 80, 81
pulmonary tuberculosis 200208 respiratory bronchiolitis-associated interstitial lung
aetiology 200 disease 105, 312
clinical features 202 respiratory exchange ratio (RER) 15, 20
diagnosis 136, 203204 respiratory failure (RF) 148150
epidemiology 201202 definition 148
pathogenesis 201 hypercapnic see hypercapnic respiratory failure
primary 202 hypoxaemic see hypoxaemic respiratory failure
secondary 202 idiopathic pulmonary fibrosis 313314
treatment 204208 management 150
see also anti-tuberculosis drugs neuromuscular disease patients 363364
see also tuberculosis (TB) respiratory infections
pulmonary vascular disorders (PVD) bacterial see bacterial infections
drug-induced 329 cystic fibrosis 256, 258
exercise intolerance 83 management 259260, 261, 263
exercise testing 86 HIV-related see under HIV-related disease
see also specific disorders microbiological diagnosis see microbiological
pulmonary vasculature, anatomy 13 testing
pulmonary vasculitis 336339 post-bone marrow transplantation 431
classification 337 primary immunodeficiency-associated 420422
clinical presentation 336338 smoking association 293
diagnosis 338 see also specific infections; specific pathogens
epidemiology 336 respiratory intensive care unit (RICU) 154155
pathogenesis 336 respiratory mechanics 1620, 6366
prognosis 338339 expiration 1820, 63
treatment 339 inspiration 1718, 21, 63, 64
pulmonary veno-occlusive disease (PVOD) 340341, measurement in mechanical ventilation 66
342343 respiratory muscle strength 66
pulmonary ventilation see ventilation respiratory-muscle work (W) 1718
pyrazinamide 204, 205, 220 respiratory physiology 1525

alveolar hypoventilation 2021 diagnosis 5, 106, 309, 310
diffusion impairment 2122 epidemiology 308
pulmonary gas exchange 20 genetics 3, 45, 308
respiratory mechanics see respiratory mechanics induced sputum biomarkers 93
respiratory quotient see respiratory quotient (RQ) natural history 309
ventilationperfusion maldistribution 2325 prognosis 309
ventilatory requirements 1516 serum angiotensin-converting enzyme levels 5
respiratory physiotherapy 446449 treatment 309310
airway clearance techniques 446447 sarcoma, chest wall 393, 397
bronchiectasis 448 scintigraphy 50, 135136
chest wall disorders 449 gallium-67 136
community-acquired pneumonia 448449 perfusion see perfusion lung scintigraphy (PLS)
COPD 447448 ventilation see ventilation lung scintigraphy (VLS)
critically ill patients 449 seasonal influenza 191193
cystic fibrosis 448 secondary bacterial pneumonia 193, 194
hyperventilation syndrome 448 secondary pneumothorax 353, 355357
interstitial lung diseases 448 secretory IgA 29, 30
neuromuscular disease 449 sedation, vocal cord dysfunction treatment 238
spinal cord injury 449 segmentectomy, nonsmall cell lung cancer 385
ventilation-/gas exchange-enhancing strategies 447 self-efficacy enhancement, pulmonary rehabilitation
see also pulmonary rehabilitation 451452
respiratory polygraphy, neuromuscular disease serology 165166
patients 362363 severe acute respiratory syndrome (SARS) 194197
respiratory quotient (RQ) 15, 16 clinical features 195196
reduced 20 diagnosis 196197
respiratory syncytial virus (RSV), detection 165166 epidemiology 194195
respiratory system anatomy 1114 management 196
respiratory viruses virology 196
bronchitis-associated 240 silicosis 284
chronic obstructive pulmonary disease single breath (sb) technique 68
exacerbations 172, 173, 174 sinusitis 169, 170
detection methods 163 Sjrgrens syndrome
antigen tests 164165 diagnosis 106
nucleic acid amplification tests 166167 lymphoid interstitial pneumonia association 313
serologic 165166 skeletal muscle dysfunction, COPD 454455
post-bone marrow transplant infections 431 sleep-disordered breathing (SDB)
primary immunodeficiency-associated 421 neuromuscular disease patients 361, 362363,
upper respiratory tract infections 169 412413
restrictive lung disease see also central sleep apnoea/hypopnoea (CSA);
dyspnoea 43 obstructive sleep apnoea/hypopnoea syndrome
lung volume changes 59, 61 (OSAHS)
see also specific diseases sleep-induced hypoventilation 414415
rhinitis, chronic 224226 Smad proteins 89
asthma association 224, 226 small bowel, cystic fibrosis-related disease 261
clinical aspects 224225 small cell lung cancer (SCLC) 372373
definition 224 genetics 6
epidemiology 224 treatment 375, 378379
pathophysiology 225226 see also lung cancer
treatment 225, 226 smoke inhalation 275, 276
rhinoconjunctivitis, allergic 170 smoking 295
rhinosinusitis 169, 170 air pollution 287288
rifabutin therapy, pulmonary tuberculosis 206 associated diseases see smoking-related diseases
rifampicin therapy cessation see smoking cessation
latent tuberculosis 216 effect on bronchoalveolar lavage cell counts 108
nontuberculous mycobacterial infections 220 prevention 295296
pulmonary tuberculosis 204, 205 protection against hypersensitivity pneumonitis 279
right-to-left shunt 2223 smoking cessation
rimantadine 192 COPD management 248
RoughtonForster equation 6970 impact on survival 293, 294
interventions 296297
S Langerhans cell histiocytosis management 440
sarcoidosis 308310 lung cancer patients 375
clinical presentation 308309 smoking-related diseases 291294

asthma 234, 292293 suberosis 280
COPD 241, 246, 248, 292293 sulphur dioxide (SO2), air pollution 285, 286
desquamative interstitial pneumonia 312 superior vena cava obstruction 52, 54
in HIV-infected patients 428 surfactant system 8
interstitial lung diseases 293 abnormalities 8
Langerhans cell histiocytosis 440 pulmonary alveolar proteinosis 8, 435
lung cancer 287288, 292, 295, 372, 373 surgeons, thoracic, qualifications 383
passive smoking-related 293294 surgical thoracoscopy, medical thoracoscopy/
respiratory infections 293 pleuroscopy (MT/P) vs. 112
pneumonia 179 surgical treatment
sneezing 2627 bronchiectasis 254
soluble mesothelin-related peptides (SMRPs) 396 chest wall disorders 367, 368
speech therapy, vocal cord dysfunction 239 complications see post-operative pulmonary
spinal cord injury (SCI) complications
hypoventilation 417 lung abscess 190
respiratory physiotherapy 449 lung cancer see lung cancer treatment
spiral computed tomography scanning 130, 131 malignant pleural mesothelioma 396397
spirometry mediastinal tumours 400
asthma diagnosis 228229 obstructive sleep apnoea 409
COPD severity classification 247 pleural infection 188
upper airway stenosis detection 119, 121 pneumothorax 355, 356
vocal cord dysfunction diagnosis 237 pre-operative assessment 156158
spontaneous pneumothorax 352357 pulmonary resection see pulmonary resection
clinical features 352353 see also video-assisted thoracic surgery (VATS)
complications 353354 sweat gland, cystic fibrosis-related disease 262
diagnosis 353 swine influenza 194
management 354355, 356357 systemic amyloidosis 433
primary 352355 systemic sclerosis 106
secondary 353, 355357
sputum 3738 T
bloody see haemoptysis T-lymphocytes 28, 29
hypersecretion 3738 talc pleurodesis 397
microbiological testing 163164 targeted therapies, nonsmall cell lung cancer 380381
purulence 37, 38 terizidone therapy, pulmonary tuberculosis 206
sputum induction 9294 tetracycline therapy, infectious COPD exacerbations
disease biomarkers 93 174, 175
procedure 92 thiacetazone therapy, pulmonary tuberculosis 206
pulmonary tuberculosis diagnosis 203 thoracentesis 115117
reproducibility and validity 9394 complications 117
safety issues 9293 contraindications 116117
sputum reduction, bronchiectasis 254 diagnostic 115, 116, 349
sputum smear test, pulmonary tuberculosis procedure 115116, 117
diagnosis 204 set 117
squamous cell carcinoma, lung 373, 374 therapeutic 115, 116, 350, 351
Staphylococcus, pleural infection 186, 187 thoracic surgeons, qualifications 383
Staphylococcus aureus infection thoracic surgery see surgical treatment
COPD exacerbations 173 thoracoscopy 112
hospital-acquired pneumonia 181 medical see medical thoracoscopy/pleuroscopy
Starling resistor 405 (MT/P)
stavudine 429 surgical 112
stenosis see airway stenosis see also video-assisted thoracic surgery (VATS)
stenting, airway 101, 120121 thoracostomy
streptococcal pharyngitis 169, 170 pneumothorax 354355
Streptococcus milleri infection, pleural 186 see also chest tube drainage
Streptococcus pneumoniae infection thorax, normal appearance, transthoracic
community-acquired pneumonia 177 ultrasonography 138, 139
COPD exacerbations 173, 174 thymoma 399400
detection methods 162, 163, 164 thymus gland 13
hospital-acquired pneumonia 181 thyroiditis, acute 170
pleural 186 tidal volume 18, 58, 59
streptomycin therapy, pulmonary tuberculosis 204, 205 Tietzes syndrome 4950
stridor 44 tissue inhibitors of metalloproteinases (TIMPs) 7
subacute toxic pneumonitis 276277 tobacco dependence 295

prevention 295296 tuberculous meningitis 211
treatment 296297 tuberculous pleural effusion, diagnosis, medical
see also smoking thoracoscopy/pleuroscopy (MT/P) 113, 114
tobacco smoke 291 tuberous sclerosis complex (TSC) 443
tolerable limit of exercise (Tlim) 85 tumour necrosis factor-a antagonists
tonsillectomy, obstructive sleep apnoea idiopathic pulmonary fibrosis therapy 317
management 409 respiratory side-effects 326, 328329
total lung capacity (TLC) 16, 19, 5860 tuberculosis risk and 212, 213
toxic pneumonitis 274277 TumourNodeMetastasis (TNM) classification, lung
acute 274276 tumours 137
aetiology 274275 tumours
clinical presentation 275276 chest wall see chest wall tumours
hypersensitivity pneumonitis vs. 281 diagnosis, bronchoalveolar lavage 104
inhalation fever vs. 274 HIV-associated 427428
management 276 lung see lung cancer
subacute 276277 mediastinal 399400
trachea, anatomy 1213 metastatic see metastatic tumours
tracheobronchial amyloidosis 434 pleural
tracheobronchitis 169 mesothelioma see malignant pleural
chest pain 49 mesothelioma (MPM)
tracheostomy ventilation 152 metastatic see pleural metastases
neuromuscular disease patients 363 transthoracic ultrasonography 141
traffic-related air pollution 286287 turbulent flow 17
transbronchial fine-needle aspiration (TBNA) 100
endobronchial ultrasound-guided 101 U
transbronchial lung biopsy 101, 102 ultrasound
transfer coefficient of the lung for CO (KCO) 69 fine-needle biopsy guidance 110
physiological influences 70, 71 pleural infection 187
transfer factor of the lung for carbon monoxide transthoracic see transthoracic ultrasonography
(TL, CO) 21, 6871 upper airway, cystic fibrosis-related disease 262
calculation 6870 upper airway collapse, obstructive sleep apnoea 405
definition 68 upper airway stenosis (UAS)
measurement technique 68 impact of interventional pulmonology 120121
physiological influences 7071 pulmonary function testing 118120
transforming growth factor-b 810 upper respiratory tract infections (URTIs) 168170
transient lower oesophageal sphincter relaxations complications 169
(TLOSRs) 242, 245 diagnosis 169170
transient receptor potential (TRP) 36, 37 HIV-infected patients 423424
transplant patients, tuberculosis risk 212, 213 pathogens 169
transplantation predisposing conditions 168
bone marrow see bone marrow transplantation (BMT) prevalence 168
lung see lung transplantation prevention 170
transthoracic fine-needle biopsy 110111 symptoms and signs 168, 169
transthoracic ultrasonography 138141 cough 34
advantages 138 transmission 168
appearance of normal thorax 138, 139 treatment 170
chest wall pathology 138139 urinary antigen tests 164
pleural pathology 139141 usual interstitial pneumonia (UIP) 283, 312, 313318
pulmonary pathology 141 clinical features 313314
technical aspects 138 diagnosis 314
traumatic pneumothorax 352, 353 prognosis 313, 314
fine-needle biopsy-induced 111 see also idiopathic pulmonary fibrosis (IPF)
thoracentesis-induced 117 uvulopalatopharyngoplasty, obstructive sleep
tuberculin skin test 203, 213, 216 apnoea management 409
tuberculosis (TB) 200
extrapulmonary see extrapulmonary tuberculosis V
(EPTB) vaccination
in immunocompromised hosts 184, 185, 201, Haemophilus influenzae type B (HiB) 169
212213 influenza see influenza vaccination
HIV-infected see under HIV-related disease pneumococcal see pneumococcal vaccination
latent see latent tuberculosis infection (LTBI) vagus nerve 14
pulmonary see pulmonary tuberculosis valves, endobronchial 101102
silicosis association 284 vapours, inhalational injury see acute inhalation injury

varenicline 296 pathogenesis 236
vasculitis see pulmonary vasculitis prognosis 239
venous gas microemboli, diving-associated 303 terminology 236
ventilation treatment 238239
control see ventilatory control vocal fremitus 52, 54
enhancement strategies 447 volatile organic compounds (VOCs), air pollution
magnetic resonance imaging 133 288, 289
ventilation lung scintigraphy (VLS) vomiting, chemotherapy-induced 378
pulmonary embolism diagnosis 135, 334
pulmonary hypertension diagnosis 342343 W
ventilationperfusion maldistribution 2325 walking tests 84
ventilator-associated pneumonia (VAP) 176, 177, Wegeners granulomatosis 170, 336
178, 180, 181 clinical presentation 337338
ventilator-dependent patients diagnosis 338
definition 155 epidemiology 336
see also mechanical ventilation pathogenesis 336
ventilatory control 1516, 7276 prognosis 338339
carbon dioxide responsiveness 7274 treatment 339
hypoxia responsiveness 7476 Wells score 332, 333
ventilatory response wheezing 42, 44, 54
to exercise 85 whispering pectoriloquy (WP) 54
see also ventilatory control whole-body plethysmography 62, 6465
ventilatory support 152 whole-lung lavage (WLL), pulmonary alveolar
see also mechanical ventilation proteinosis 436
video-assisted thoracic surgery (VATS) whooping cough 169, 170
malignant pleural mesothelioma/pleural wood pulp workers lung 280
metastasis 396 wood trimmers disease 280
medical thoracoscopy/pleuroscopy (MT/P) vs. work-exacerbated asthma (WEA) 268
112 work-related asthma (WRA) 268
pleural infection management 188 see also occupational asthma
pneumothorax management 355 World Health Organization (WHO)
videobronchoscope 98, 99 extrapulmonary tuberculosis definition 209
see also bronchoscopy lung tumour classification 372373
vinorelbine chemotherapy 379 pulmonary tuberculosis treatment
malignant mesothelioma 381 recommendations 204, 207
nonsmall cell lung cancer 374, 378 World Health Organization/Eastern Cooperative
viral pneumonia, primary 193, 194 Oncology Group (WHO/ECOG) scale 378, 379
viruses see respiratory viruses
vital capacity (VC) 61 x
vocal cord dysfunction (VCD) 236239 X-ray, chest see chest radiography
asthma association 236, 237, 238, 239
clinical presentation 236237 Z
diagnosis 237238 zanamivir 192
epidemiology 236, 237

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FIRST EDITION 2010

Design by Ian Turpin

All material is copyright to the European Respiratory Society.

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Why an ERS Handbook of Respiratory Medicine? Education is one

Paolo Palange, Anita Simonds

2. SIGNS AND SYMPTOMS

3. PULMONARY FUNCTION TESTING

4. OTHER DIAGNOSTIC TESTS

INFLUENZA, PANDEMICS AND SARS 191

11. INTERSTITIAL LUNG DISEASE

PULMONARY VASCULITIS 336

13. PLEURAL, MEDIASTINAL AND

14. THORACIC TUMOURS

16.IMMUNODEFICIENCY DISORDERS AND

PULMONARY REHABILITATION 451

molECulAR biology of THE lung 7

AnATomy of THE RESPiRAToRy SySTEm 11

immunology And dEfEnCE mECHAniSmS 26

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The extracellular matrix Major features of lung diseases are:

Components of the extracellular matrix (ECM) N altered deposition of extracellular

Molecular biology of the lung 7

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Figure 1. Transforming growth factor-b signalling.

Molecular biology of the lung 9

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Anatomy of the respiratory system 11

The trachea (fig. 1) is 100 mm long and

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Anatomy of the respiratory system 13

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The appropriateness of the ventilatory (V9E) respiratory-muscle work, perfusion and O2

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regions. Hence, reducing r, e.g. by breathing

When V9E is low, expiration can be achieved v9/V 5 1/R?C (12)

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2 generation, dictating the maximum expiratory

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Each day, 10,00015,000 L of air is inhaled

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Immunology and defence mechanisms 27

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Immunology and defence mechanisms 29

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CougH And SPuTum 34

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Cough is a vital protective mechanism measures, such as hand washing and

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Cough and sputum 35

Table 3. Risk factors for chronic cough

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20 moderate amounts of sputum does not alter

55C 43C 33C 30C 25C 17C

TRPV2 TRPV1 TRPV3 TRPV4 TRPM8 TRPA1

VRL1 VR1 VRL3 VR-OAZ CMR1 Coexpressed

Cough and sputum 37