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Ers Handbook Respiratory Medicine
Ers Handbook Respiratory Medicine
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 Séverin
SUPPORT STAFF
Sharon Mitchell, Veronica Pock, Claire Turner,
Victoria Morton, Matt Heald, Pippa Powell
ISBN 978-1-904097-99-0
PREFACE The mind is not a vessel to be
filled but a fire to be kindled.
Plutarch
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. Schönhofer
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
9. AIRWAY DISEASES
CHRONIC RHINITIS 224
A. Bourdain and P. Chanez
ASTHMA 227
B. Beghé 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
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
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
RESPiRAToRy PHySiology 15
S.A. Ward
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
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 (55–64 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)
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
somatic mutations. As these mutations N Al-Muhsen S, Casanova JL. The genetic
accumulate over years, a growing organism heterogeneity of mendelian susceptibility to
resembles a genetic mosaic rather than a mycobacterial diseases. J Allergy Clin Immunol
unique clone of the germ cell it is derived from. 2008; 122: 1043–1051.
N Biller H, et al. Genotype-corrected reference
Most of these somatic mutations are silent values for serum angiotensin-converting enzyme.
and either do not cause any defect or are Eur Respir J 2006; 28: 1085–1090.
corrected by its respective counterpart. N Bogunia-Kubik K, et al. HLA-DRB1*03,
However, there is a variety of somatic DRB1*11 or DRB1*12 and their respective
mutations that finally cause tumour genesis. DRB3 specificities in clinical variants of
An example of such a somatic mutation sarcoidosis. Tissue Antigens 2001; 57: 87–90.
involved in cancer is a mutation in the MYC N Coakley RJ, et al. Alpha1-antitrypsin deficiency:
biological answers to clinical questions. Am J
gene, leading to the overexpression of c-myc.
Med Sci 2001; 321: 33–41.
c-myc is a regulatory protein inducing histone N Maier LA, et al. Influence of MHC class II in
acetylation (see above). Overexpression of c- susceptibility to beryllium sensitization and
myc leads to histone hyperacetylation and chronic beryllium disease. J Immunol 2003; 171:
subsequently to the transcription of a variety 6910–6918.
of genes. Overexpression of c-myc is an N Postma DS, Koppelman GH. Genetics of asthma:
important factor in the pathogenesis genesis where are we and where do we go? Proc Am
of small cell lung cancer (SCLC). However, no Thorac Soc 2009; 6: 283–287.
single event, like the mutation of c-myc, is N Rowe SM, et al. Cystic fibrosis. N Engl J Med
responsible for tumour genesis. In general, 2005; 352: 1992–2001.
tumours like SCLC or nonsmall cell lung
N Selroos O. Differences in sarcoidosis around the
world: what they tell us. In: Baughman RP, ed.
cancer present with a large variety of genetic Sarcoidosis. New York, Informa, 2006; pp. 47–64.
alterations, like DNA methylation, alternative N Thomas AQ, et al. Heterozygosity for a
splicing, or histone modifications, which all surfactant protein C gene mutation associated
might be involved in oncognesis. with usual interstitial pneumonitis and cellular
nonspecific interstitial pneumonitis in one
As genetic tools become more common, the kindred. Am J Respir Crit Care Med 2002; 165:
analysis of the individual pathways involved 1322–1328.
in the individual cancer pathogenesis might N Turcios NL. Cystic fibrosis: an overview. J Clin
help to develop individual targets for therapy. Gastroenterol 2005; 39: 307–317.
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
Active
TGF-β
Tβ RI Tβ RII
P
SMAD2/3 P
SMAD6/7
SMAD2/3 P
SMAD4
P
SMAD2/3
SMAD4
DNA
Transcriptional regulation
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
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 acid–base 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 acid–base disturbances the alveolar air–liquid 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 V–PTP 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
Respiratory physiology 17
a) b)
1.5
VT L
1.0
0.5
-5
PIP cmH2O
-10
∆ V
-15
2
1
∆ PIP
0
V' L·s-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:
Respiratory physiology 19
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 PA–a,O2
(diffusion limitation, increased right-to-left
Figure 4. Airflow limitation in expiration. An equal shunt and ventilation–perfusion (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 alveolar–arterial O2 tension difference also be seen in severe COPD, consequent to
(PA–a,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
Respiratory physiology 21
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 PA–a,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 PA–a,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,O2–Pv̄,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 PA–a,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,O2–Pc̄,O2) 5 (PA,O2–Pv̄,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 ‘‘diffusive–perfusive 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 PA–a,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’’
Respiratory physiology 23
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 (P̄a,O2) and carbon
dioxide (P̄a,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
ventilation–perfusion 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 P̄a,O2 and P̄a,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 P̄a,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
Respiratory physiology 25
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
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
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
dySPnoEA 41
G. Scano and P. Laveneziana
CHEST PAin 49
M. Hind
PHySiCAl ExAminATion in 51
RESPiRAToRy mEdiCinE
M.R. Partridge
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 0–5 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
0
diagnosis of bronchiectasis becomes
0.5 1 3 10 20 increasingly likely. The presence of sputum
Capsaicin dose µM
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
Figure 2. The thermosensitive transient receptor potential (TRP) channels important in cough reflex sensitivity.
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 Goodpasture’s 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
Haemoptysis presents in two clinical Respir Crit Care Med 2009; 180: 1042–1047.
scenarios. First, the patient may present with N Decramer M, et al. Effects of N-acetylcysteine on
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: 1552–1560.
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 975–979.
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: 794–797.
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
1–2 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.
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 Hoover’s 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.
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 patient’s 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
●
●
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: 1574–1583.
Conclusions N O’Donnell 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: 145–168.
the symptom of dyspnoea. Although N O’Donnell 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: 109–115.
the study of this symptom is to identify the N O’Donnell 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 O’Donnell DE, et al. Sensory–mechanical
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: 1025–1035.
breathing) for exertional dyspnoea in patients N O’Donnell 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: 1804–1811.
N Ofir D, et al. Ventilatory and perceptual
References responses to cycle exercise in obese females. J
Appl Physiol 2007; 102: 2217–2226.
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: 1039–1047. 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. 1709–1747. patients with type I diabetes mellitus under good
N Lanini B, et al. Perception of dyspnea in patients metabolic control. Clin Sci 1999; 96: 499–506.
with neuromuscular disease. Chest 2001; 120: N Scano G, et al. Understanding dyspnoea by its
402–408. language. Eur Respir J 2005; 25: 380–385.
Chest pain 49
pain and tenderness. Bornholm disease tomography scanning has made identification
(epidemic pleurodynia or devil’s 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 277–299.
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
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: ear–nose–throat.
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.
RESPiRAToRy mECHAniCS 63
D. Navajas and R. Farré
ConTRol of vEnTilATion 72
B.J. Whipp
ExERCiSE TESTing 83
P. Palange
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
Pe,m
Lung
TLC % pred
IC
ax
EVC TLC
Volume
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 pressure–volume 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
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) Pressure–volume loops of lung parenchyma and airways on
inspiration and expiration. The area inside the loop is called hysteresis. b) Partial and maximal flow–volume 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.
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'
Respiratory mechanics 65
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 PL–VL 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. 518–624.
Respiratory mechanics 67
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 alveolar–capillary 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 Hb–binding 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 alveolar–plasma 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 (9–11 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
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
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 (97–98% 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 Roughton–Forster 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 (alveolar–capillary membrane resistance) and
calculation of TL,CO is the multiplication of 1/hVc (transfer resistance of red cells).
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.
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 V9E–Pa,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 hypoxic–hypercapnic
‘‘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). ‘‘Read–Leigh’’ 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
V'E L·min-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 L·min-1
Ventilation L·min-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.
Control of ventilation 75
The current degree of a subject’s 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 blood–gas and
inhalation of a hypoxic gas mixture, or noting
acid–base 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: 335–358.
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: 1–11.
CO2 responsiveness. As the nadir of the N Edelman NH, et al. Effects of CNS hypoxia on
response commonly occurs ,20–25 s after breathing. In: Crystal RG, et al. The Lung:
the hypoxic–hyperoxic transition, there is Scientific Foundations. 2nd Edn. New York,
some uncertainty regarding this latter point. Raven Press, 1997; pp. 1757–1765.
Although this test is quite easy to perform and
N Duffin J. Measuring the ventilatory response to
hypoxia. J Physiol 2007; 584: 285–293.
provides a useful qualitative estimate of N Read DJC, Leigh J. Blood–brain tissue PCO2
hypoxic responsiveness, it remains to be relationships and ventilation during rebreathing.
precisely standardised and quantified. J Appl Physiol 1967; 23: 53–70.
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. 745–772.
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, 129–131.
(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. 149–211.
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 acid–base (A–B)
(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 A–B 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 A–B 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 A–B 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 A–B status using Pa,CO2, pH
and, eventually, HCO3- (or BE).
N Mixed A–B 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 A–B Pa,O2 values close to 90–95 mmHg. Pa,O2
disorders. values ,80 mmHg are considered arterial
hypoxaemia and Pa,O2 ,60 mmHg indicates
Table 1. Arterial–alveolar 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
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 acid–base disorders.
Pa,CO2–pH 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,CO2–pH
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.
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
Henderson–Hasselbalch 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 A–B 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 A–B
maintained between 7.38–7.42. In the clinical disorders. A graphical illustration of this
assessment of A–B equilibrium, two main approach is shown in figure 2.
determinants of arterial pH must be taken into
Table 3 displays some examples of simple A–B
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, A–B 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.
Respiratory alkalosis
Anxiety, central nervous system disorders
Hormones/drugs (catecholamine, progesterone, hyperthyroidism, salicylate)
Fever
Hypoxia
Liver diseases
V '/Q' mismatch
Shunt VA
Diffusion
Acidosis Alkalosis
PA-a,O2
O2 challenge Respiratory
Metabolic
Acidosis Alkalosis
Electrolytes Step 3
Figure 3. Comprehensive approach to interpreting arterial blood gases. V/Q: ventilation/perfusion; VA: alveolar
ventilation; PA-a,O2: alveolar–arterial oxygen gradient; Pa,O2: arterial oxygen tension; Pa,CO2: arterial carbon
dioxide tension; AG: anion gap; Cl-: chloride; U: urinary.
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 subject’s maximal aerobic capacity
should last 10–12 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,O2–Cv,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,O2–Cv,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)
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 V9E–V9CO2 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 ,23–25 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 0.5–1.0 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 25–28 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 ,97–98%. 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 subject’s 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 flow–volume loops is also emerging as protocols. In clinical practice, high-intensity
an important tool to assess the degree of (,70–80% 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.
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 l’hyperexcitabilité mannitol and eucapnic voluntary
de l’appareil bronchovasomoteur. Ce processus hyperventilation tests. The indirect tests
essentiel est le substratum pathologique de commonly act by causing mediator or
l’asthma. Pas l’intervention d’un méchanisme transmitter release and their effect on
à seul, le degré de l’excitabilité inflammatory cells and nerves.
bronchomotorice régit la quantité de
mediateurs necessaire (quantum critique) Previously, BPT was done qualitatively by
pour l’effet 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
médiateurs bronchoconstrictifs produits par doubling the concentration/dose of the test
inhalation continue d’allergènes. Pathol Biol substance has been done.
1959; 21: 2293–2310.
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.
bRonCHoSCoPy 98
P.L. Shah
THoRACEnTESiS 115
E. Canalis and M.C. Gilavert
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.
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
Drug-induced eosinophilic pneumonia Eosinophils very high
Other pulmonary eosinophilias
Idiopathic eosinophilic pneumonia Eosinophils very high
Allergic diseases: asthma; Churg–Strauss 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
alveolitis
tissue debris.
Thoracentesis 115
Figure 1. Thoracentesis needle through the intercostal space.
aspirated. Then 20–60 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.
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: 999–1001.
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. 107–121.
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: 948–950.
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: 1315–1320.
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: 201–209.
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: 1120–1123.
by excluding coagulopathies. N Sahn SA. Diagnostic value of pleural fluid
analysis. Clin Chest Med 1995; 16: 269–278.
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: 68–73.
Thoracentesis 117
INTERVENTIONAL
PULMONOLOGY
M. Noppen
University Hospital UZ Brussel, Brussels, Belgium
E-mail: Marc.Noppen@uzbrussel.be
6 ■
4 ■
2 ▲● ■
Flow L·s-1
▲
● ▲
●
0 ●▲ ● ▲ ■
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
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 postero–anterior
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 patient’s body information. In patients who are too ill to
not rotated and the scapulas rotated so that stand up, antero–posterior (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
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).
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
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:
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
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
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.
L
P
PE
R
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.
L Conclusion
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 35–40%.
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
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 alveolar–arterial
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 alveolar–arterial 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 acid–base 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 system’s 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
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 patient’s 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 nurse–patient
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. nurse–patient ratio of 1:3–1:4 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 nurse–patient 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
PnEumoniA 176
M. Woodhead
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 1–2 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 4–5 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 10–20% 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 24–48 h.
pathogens in specific patient
populations are desirable. Sputum Gram stain and culture The most
frequently submitted specimen in cases of
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 ,35–79% 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 3–4 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 65–70% 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 40–50%, whereas for patients with
sputum culture is very low. severe Legionnaires’ disease who need
immediate special medical care, sensitivities
Rapid antigen tests
reach 88–100%.
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 65–100% 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
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 2–4 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,
1–3 days after exposure to a microbial and other infections.
pathogen. The duration of the symptoms is N Diagnosis is usually purely clinical;
typically 7–10 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
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 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
the emergency department or hospital. Family obstructive pulmonary disease. N Engl J Med
and home support is crucial in the first days 1999; 340: 1941–1947.
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: 1114–1121.
48–72 h after initiation of therapy. In mild N Seemungal T, et al. Respiratory viruses,
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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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 0–1 (mortality 1.5%), moderate 2 (9%), severe 3–5 (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
Pneumonia 179
HOSPITAL-ACQUIRED
PNEUMONIA
F. Blasi
Thoracopulmonary and Cardiocirculatory Dept, Università degli Studi di Milano
and IRCCS Fondazione Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
E-mail: francesco.blasi@unimi.it
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 35–39% 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
Pleural infection occurs when micro- Bacteria are ultimately cultured from either
organisms, most commonly bacteria, enter the pleural fluid or blood in 60–70% 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 15–20%. 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 15–20%.
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.
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.
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, 4–10 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 40–100 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 1–2 million deaths each.
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 5–14 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, 9–31% 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 14–46%. 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
Horseshoe bat – coronavirus Palm civet cat – coronavirus with Human SARS-CoV – further
with 87–92% 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
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 2–4 mm long and 0.2–5 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.
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
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.
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.
ASTHmA 227
B. Beghé and L.M. Fabbri
bRonCHiTiS 240
G. Rohde
bRonCHiECTASiS 252
N. Ten Hacken
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 20–50% 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, 25–30% 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 20–50% 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
Allergen avoidance
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
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
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.
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 5–10 min afterwards, and it resolves severity of asthma is mostly indicated by other
spontaneously within 30–45 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 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
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
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
Reassess after 1 h
Physical examination, PEF, O2 saturation and other tests as needed
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 β2-agonist ± anticholinergic
• Systemic glucocorticosteroid • Oxygen
• Intravenous magnesium • Inhaled β2-agonist +
• Monitor PEF, O2 saturation, pulse anticholinergic
• Intravenous glucocorticosteroids
• Consider intravenous β2-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 β2-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
Asthma 235
VOCAL CORD DYSFUNCTION
A.H. Mansur
Birmingham Heartlands Hospital, Birmingham, UK
E-mail: adel.mansur@heartofengland.nhs.uk
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 2–6 times per play a role.
year, and adults 2–3 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
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.
• 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)
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.
Definition Burden
Exacerbations of COPD e1
Triggers
Effects
Inflamed COPD airway
Systemic Bronchoconstriction,
inflammation oedema, mucus
Expiratory flow
limitation
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’’.
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.
Exacerbations of COPD e3
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
Exacerbations of COPD e5
N Hurst JR, et al. Susceptibility to exacerbation in Am J Respir Crit Care Med 2010; 182:
chronic obstructive pulmonary disease. N Engl J 332–340.
Med 2010; 363: 1128–1138. 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: 1418–1422.
Crit Care Med 2011; 183: 734–742. 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: 1373–1381. 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: 43–48. Med 2008; 359: 1543–1554.
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: 786–796.
2006; 20: 2121–2123. 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: 1298–1303.
Peripheral lung
inflammation
"Spill-over"
Acute-phase proteins
Skeletal muscle Systemic
CRP
weakness inflammation
Serum amyloid A
Cachexia IL-6, IL-1β, TNF-α
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.
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
(.4–6 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 2–3 times daily, patient’s 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, 2–3-week courses
with 1–2-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 benefit–risk 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: 407–419.
Bronchiectasis 255
CYSTIC FIBROSIS
A. Bush and J. Davies
Imperial College and Royal Brompton Hospital, London, UK
E-mail: a.bush@rbht.nhs.uk
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).
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. ,10–15% 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.
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 80–90%
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)
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
PnEumoConioSiS 282
R.D. Stevenson
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 4–12 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. 4–8 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 night’s 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
Respiratory diseases caused by acute inhalation of gases, vapours and dusts 275
bronchiolitis obliterans. Following resolution of Subacute toxic pneumonitis
the acute pulmonary oedema, a relapse in the
clinical condition may occur after 2–6 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 worker’s 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
patient’s 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
Respiratory diseases caused by acute inhalation of gases, vapours and dusts 277
HYPERSENSITIVITY
PNEUMONITIS
T. Sigsgaard1 and A. Rask-Andersen2
1
Aarhus University, Aarhus, Denmark
2
Uppsala University, Uppsala, Sweden
E-mail: sigsgaard@dadlnet.dk
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
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: 365–374.
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: 761–768.
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: 311–316.
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: 398–407.
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: 731–736.
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: 2759–2768.
and silicosis were both present, the N Martensson G, et al. Asbestos pleural effusion: a
clinical entity. Thorax 1987; 42: 646–651.
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: 723–728.
pooled risk for lung cancer of OR 1.23 (95% Based on meta-analyses, building dampness
CI 1.13–1.34). ETS exposure is a risk factor for and mould are associated with approximately
new-onset asthma among both nonsmoking 30–50% 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- 1.27–3.47. 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 world’s 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).
8 70
●
50
people often become addicted to tobacco for 5
life, even occasional users merely seeking to 40
experience the relaxing effects of 4 ●
30
● ●●
20
characterisation of the specific health effects 2 ●
Females
of cannabis smoking. Nevertheless, it has 1 ● ●
●
10
●
0 0
●
1900
1925
1950
1975
2000
2006
Lung cancer Years
● ●
Cigarette smokers
60 ● ●
Nonsmokers
40
● ●
20
● ●
0 ●
▲
Cigarette smokers
60 ● ●
Nonsmokers
▲
40
● ●
20
▲
●
0 ●
●
40 50 60 70 80 90 100
Age yrs
Figure 3. Survival of male doctors who stopped smoking at ages 25–34 and 45–54 yrs. Modified from DOLL
et al. (2004).
Arousal
Hypoxia Hyperventilation Central apnoea Hyperpnoea
Pa,CO2
Pa,O2
Sum 1L
Rib Cage 1L
Abdomen 1L
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.
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
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 30–50 kPa,
groups is exposure to increased ambient corresponding to a fraction of oxygen of
pressure and the exposure factors associated 2–5% 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
●
● ● 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 20–30% 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 (Boyle–Mariotte’s 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
Elliott’s 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: 355–380.
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.
SARCoidoSiS 308
U. Costabel
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 6–12 months is usually
adequate; more frequent evaluations (every
3–6 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 15–70%.
restore or preserve organ function. Initial
therapy is still based on corticosteroids. For References
pulmonary sarcoidosis, the initial prednisone
dose is 20–40 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 5–10 mg per day; Richeldi L, eds. Interstitial lung diseases. Eur
treatment should be continued for a minimum Respir Mon 2009; 46: 126–154.
of 12 months. Patients with Löfgren’s 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: 149–173.
Idiopathic interstitial pneumonias (IIPs) prevalence ranges between 27–29 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
0.5–3% 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
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)
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.
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
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 146–158.
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 232–234.
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: 1387–1393.
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: 2753–2759.
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: 315–329.
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 1741–1748.
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: 565–571.
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: 2317–2327.
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 2276–2315.
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
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
Vasoreactive
Non vasoreactive
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 3–4 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 D’Alonzo 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: 343–349.
mEdiASTiniTiS 358
P-E. Falcoz, N. Santelmo and G. Massard
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%). patient’s 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: 485–486.
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: 392–402.
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: 702–708.
N Devaraj A, et al. Computed tomography findings
Mediastinal fibrosis Fibrosing in fibrosing mediastinitis. Clin Radiol 2007; 62:
781–786.
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 545–552.
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: 260–267.
vein or artery). CT scans demonstrate a N Marty-Ané 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: 212–217.
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: 497–500.
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: 2279–2281.
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: 780–784.
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 1–2 months to
N Arterial blood gases, if symptoms
present.
yearly. Once the VC drops below 40–50%
predicted, or MIP below 30% predicted, N PLSG or RP, if symptoms or nocturnal RF
daytime arterial blood gases should be present.
performed.
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
stress–strain 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
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 ,80–90% 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).
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), Pancoast’s
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, Cushing’s syndrome,
intermediate-grade atypical carcinoid to high- neurological syndromes (Lambert–Eaton). 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
Advanced ,5%
Stage IV Chemotherapy and/or targeted agents
stage
Data from GOLDSTRAW et al. (2007).
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 4–6-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 .3–6 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 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
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.
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 20–44%. 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 6–10 % 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
Principles of surgical treatment for early-stage nonsmall cell lung cancer 385
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, aorto–pulmonary 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
A randomised study including .500 patients
demonstrated a survival advantage of node N Allen MS, et al. Mortality and morbidity of major
pulmonary resections in patients with early
dissection without relation to a stage
stage lung cancer: initial results of the
migration effect: it was observed not only
randomized prospective ACOSOG Z0030 trial.
stage by stage, but also when comparing the Ann Thorac Surg 2006; 81: 1013–1019.
two investigated groups as a whole (table 3). N Berghmans T, et al. Survival improvement in
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. 13–23.
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: 17–41.
pneumonectomy, it is meaningful to look for N Cerfolio RJ, et al. The role of FDG-PET scan in
alternatives. Bronchoplastic operations (sleeve staging poatients with nonsmall cell carcinoma.
Ann Thorac Surg 2003; 76: 861–866.
lobectomy) are indicated: 1) when the tumour
involves the lobar take-off on the
N Ginsberg RJ, et al. Randomized trial of
lobectomy versus limited resection for T1N0
endobronchial side; and 2) when positive N1 non-small cell lung cancer. Ann Thorac Surg
nodes with capsular disruption are identified 1995; 60: 615–623.
at the origin of the lobar bronchus. N Mansour Z, et al. Induction chemotherapy does
Angioplastic lobectomies are indicated when not increase the operative risk of
the lobar branches destined to the upper lobe pneumonectomy! Eur J Cardiothorac Surg 2007;
cannot be divided safely with tumour-free 31: 181–185.
Principles of surgical treatment for early-stage nonsmall cell lung cancer 387
METASTATIC TUMOURS
E. Quoix
University of Strasbourg, University Hospital, Pneumology, Strasbourg,
France
E-mail: elisabeth.quoix@chru-strasbourg.fr
b)
b)
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
Figure 1. Proposed management for malignant pleural effusion (MPE). MPM: malignant pleural mesothelioma;
US: ultrasound; CT: computed tomography; BSC: best supportive care.
Thoracoscopy
Contra-indications for diagnosis and staging
Thoracoscopy
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.
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
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 29–35.
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.
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
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).
Obstructive
sleep apnoea
Intermittent Sleep
hypoxia fragmentation/ Type 2
sleep deprivation diabetes
Insulin Metabolic
resistance syndrome
Inflammation Hypertension
Dyslipidaemia
Figure 2. Mechanisms linking obstructive sleep apnoea and the metabolic syndrome. Modified from TASALI et
al. (2008).
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. Cheyne–Stokes 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).
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 (20–90 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.
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.
AmyloidoSiS 433
H.J. Lachmann
lymPHAngiolEiomyomAToSiS 441
J-F. Cordier and V. Cottin
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 50–90% 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.
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 8.0–11.0 kPa,
Sa,O2 91–96%) 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 (450–600 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-
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 0.5–1% 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: 155–165.
preserve voice quality and airway patency. N Lachmann HJ, Hawkins PN. Amyloidosis and the
lung. Chron Respir Dis 2006; 3: 203–214.
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: 2361–2371.
Tracheobronchial amyloidosis N Linder J, et al. Amyloidosis complicating hairy cell
leukaemia. Am J Clin Pathol 1982; 78: 864–867.
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: 223–241.
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: 134–142.
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. 873–881.
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.
20–40 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
,10–20 % 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), hypothalamic–pituitary
efficacy. involvement resulting in diabetes insipidus
(polyuria, polydipsia) and skin lesions.
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 Birt–Hogg–Dubé
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
Sjögren 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 Birt–Hogg–Dubé syndrome associated with
abdominal discomfort or compression. mutations of the folliculin gene, familial
Lymphangioleiomyomatosis 443
ers_chapter pages.indd 34 10/08/2010 11:55:50
CHAPTER 17:
PulmonARy REHAbiliTATion
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 patient’s 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 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.
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
Anamnesis
Symptoms
Reduced participation Optimise
Impaired overall function
Frequent excarbations
YES
Medical treatment optimal NO
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.
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
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 ð1Þ
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
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
Case–control 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
Case–control studies are usually retrospective
but they can be prospective
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
#
: 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
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-Guérin (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 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
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
handbook
handbook
handbook
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The European Respiratory Society (ERS)
Medicine
The European Respiratory Society (ERS)
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Paolo Palange
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ISBN: 978-1-904097-99-0
ISBN:
ISBN: 978-1-904097-99-0
978-1-904097-99-0