© SUPPLEMENT TO JAPI • FEBRUARY 2012 • VOL.
60 17
Risk Factors and Pathophysiology of
Chronic Obstructive Pulmonary Disease (COPD)
Bill B Brashier1, Rahul Kodgule2
Introduction
Chronic obstructive pulmonary disease (COPD) is a
progressive inflammatory disease of the lung characterized by
chronic bronchitis, airway thickening and emphysema. Being the
third largest cause of worldwide mortality and showing a steeply
rising trend in global prevalence, COPD is likely to emerge as
the most important disease for the physicians to manage.1,2
Understanding the basic pathophysiology of COPD will be
of great assistance in diagnosing and treating the disease in
circumstances where new mechanisms, diagnostic tests and drug
therapies are emerging at a rapid pace. The pathophysiology of
the disease is complicated and largely undiscovered. However,
with the advent of new technology and widespread advances
in research the thick cloud cover over the pathophysiology of
COPD is rapidly unveiling.
Risk factors
Smoking has traditionally been known to be the most
Table 1 : Risk factors for COPD
• Genes
• Exposure to particles:
1. Tobacco smoke (10 pack Years; 50% smokers develop COPD)
2. Indoor air pollution from heating and cooking with Biomass fuel in
poorly ventilated homes ( at least 25 years of exposures)
3. Occupational dusts, organic and inorganic: ( attributable Risk 15%
in American population)
a. Automobile-drivers, vehicular mechanics , fertilizer manufacturing,
chlorinated organic compounds dyes, explosives, rubber products,
metal etching, plastics, ammonia exposure in refrigeration and
petroleum refining, grain dust and funguses in farmers, textile
mill manufacturing, leather manufacturing, food products
manufacturing and sales, beauty care workers and welders in
automotive industries.
b. Exposures to crystalline silica: cement industry, brick
manufacturing, pottery and ceramic work, silica sand, granite
and diatomaceous earth industries, gold mining, and iron and
steel founding
4. Outdoor air pollution
• Reduced Lung volumes:
1. Lung growth and development
2. Previous Tuberculosis (28-68% cases of post-treated TB; 2.9-6.6
folds increase risk)
3. Early childhood Recurrent Lower Respiratory infections (2-3
fold risk)
4.
Poor Nutrition
• Female Gender ( reason not known)
• Old Age ( physiological obstruction)
• Low-Socioeconomic status( Multi component)
1
Head Molecular and Clinical Research, 2Senior Research Fellow,
Chest Research Foundation, Marigold Complex, Kalyani Nagar,
Pune, Maharashtra
important cause for COPD amounting to almost 85% of the
COPD cases (50% smokers develop COPD),3-5 the rest being
classified as non-smoking COPD (15%).1,2 These estimates were,
however, based on the data generated from limited number of
studies conducted only in developed countries. Subsequent large
scale epidemiology studies have shattered the world not only
with the finding of unusually high prevalence in the developing
countries but also with the realization that the most important
risk factor for COPD could be indoor-air pollution arising from
the use of biomass fuel.6,7 In developing countries such as India
COPD due to non-smoking causes account to 30-50% of all
COPD cases.6 Burning biomass fuel such as wood, cow-dung
and crop-residues leads to release of air pollutants like SO2,
CO, NO2, formaldehyde and particulate matters smaller than
10 micron in size (PM10) in the ambient indoor air.6,7 Chronic
exposure to these pollutants has been shown to lead to COPD.
This is especially worrisome considering the fact that more than
70% of Indian households rely on biomass fuel for domestic
purposes such as cooking and heating. Recent unpublished data
from our institute suggests that the inflammatory load in COPD
caused by exposure to biomass fuel is similar to that caused by
exposure to tobacco smoke.6, 7
Another important risk factor for non-smoking COPD is the
prolonged exposure to occupational smoke/dust. More than
10 occupations have been associated with the development of
COPD (Table 1), the list of which is further increasing every
year. Tuberculosis is increasingly getting recognized as a risk
factor for COPD.1,2,6 It has been seen that tuberculosis patients,
even after adequate anti-Koch’s therapy are 2-6 times more
prone to develop airway obstruction suggested by spirometry
and symptoms suggestive of COPD in due course of time.1,2,6
Recurrent respiratory infections in childhood have also been
shown to be associated with development of COPD in adult
age.1,2,6 Even poorly treated asthma is considered to be a risk
factor for development of irreversible airway obstruction,
characteristic of COPD. Poverty is an important surrogate of
COPD.1,2,6 Physiological lung function decline induced by ageing
can also predispose to COPD.1
Genetics
There has been substantial stride however with negligible
impact in understanding COPD genetics in last 50 years that
primarily arose from epidemiological query that why only a
fraction of smokers develop COPD while others with similar
amount of smoking history do not develop the disease. Till
date the only well-established genetic risk factor identified
for COPD is SERPINA1 gene which codes for serine protease
inhibitor, alfa-1 antitrypsin (AAT).2,8 Perturbation in SERPINA1
gene leads to deficiency of AAT-1, causing uninhibited action
of proteases and culminating in development of emphysema.8
The M allele is associated with normal AAT while Z alleles
constitute AAT deficiency. However, only 1-2% of the population
exhibits anomaly in SERPINA1, suggesting that many other
genetic variations would be responsible for development of
COPD.2,8 Current understanding is that COPD is a polygenic
disease involving complex interactions between various gene
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Table 2 : Candidate genes associated with COPD
• SERPINA1 encoding AAT1
• EPHX1, Microsomal epoxide hydrolase gene
• GST P1, Glutathione S-transferase P1
• MMP12, Matrix metalloproteinase 12
• MMP9, Matrix metalloproteinase 9
• TGFB1, Transforming growth factor B1
• SERPINE 2
• CHRNA3/5, α-nicotinic acetylcholine receptor
• HHIP, hedgehog interacting protein
• BICD1, Bicaudal D Homologu 1
• FAM13A
• HMOX1, heme oxygenase 1
• Vitamin D binding protein (GC)
• ADRB2, Β2-Adrenergic receptor
• TNF-α, tumor necrosis factor- α
• TGFB3, Transforming growth factor B3
polymorphisms. Many genes have been associated with COPD
(Table 2). However, the picture is likely to become less hazy
once the results of presently ongoing genome-wide association
studies (GWAS) are out.9,10
Molecular mechanisms in
pathogenesis of COPD
COPD is a progressive chronic inflammatory disease of the
airways primarily affecting the small airways and alveoli. Two
important and mutually non-exclusive mechanisms implicated
in the pathogenesis of COPD are the presence of perpetual
inflammation and oxidant-antioxidant imbalance leading to
oxidative stress. Unlike asthma inflammation which primarily
involves steroid-responsive eosinophils and mast cells, the
inflammatory cells in COPD refuse to respond to steroids. The
cells primarily involved in COPD inflammation are neutrophils,
macrophages and lymphocytes. These inflammatory cells further
release a battery of inflammatory mediators like cytokines,
chemokines and chemoattractants which perpetuate the
inflammation leading to an uncontrolled cascade. Neutrophils
by releasing chemoattractants like interleukin-8 (IL-8) and
leukotrien B4 (LTB4) further attract neutrophils to the site.11
Proteolytic enzymes such as elastase, proteinase-3, cathepsin
G, cathepsin B and matrix metealoproteinases (MMP) released
by neutrophils cause damage to elastic lung tissue (Figure 1).11
Macrophages release cytokines and chemokines such as
IL-8, IL-6, IL10 TNFα, LTB4 etc and reactive oxygen species
which attract and activate various inflammatory cells, and series
of proteinases, particularly MMPs such as MMP-2, MMP-9,
MMP-12, MMP-14, with tremendous elastolytic potential and
elastinolytic cysteine proteinases such as cathepsin K, L and
S.12 CD8+ lymphocytes release destructive enzymes such as
perforin and granzyme B which have the ability to induce
apoptosis of the alveolar epithelial cells and CD4 Lymphocytes
induce autoimmune response to the lung tissue.13 A series of
COPD related pathological changes have also been attributed to
oxidative stress such as oxidative inactivation of antiproteases
and surfactants, mucus hypersecretion, membrane lipid per-
oxidation, alveolar epithelial injury, remodelling of extracellular
Cigarette and air pollutants
Macrophages
IL8, (LTB4), GRO-alfa, Reduced Phagocytic activity Matrix
MCP-1, MCP-2, Metaloprotienases:
MIG
MMP1,2,9,12,14
Bacterial colonization
CD8 T cells Proteases Neutrophils
Elastase Free Oxidant radicals
Proteinase 3 O2-. H2O2, OH-
Cathepsin
CD4 T cells MMP(1, 3 9, 12)
Steroid resistance
Autoimmune attack
Emphysema Chronic Bronchitis
● Mucus Hypersecretion
● Sub epithelial Fibrosis
● Bronchoconstriction
Fig. 1 : Pathogenesis of COPD
matrix, and apoptosis, reduction in elastin collagen synthesis
and fragmentation of these skeletal proteins and steroid-
unresponsiveness (Figure 1).14
Pathophysiology of COPD
The pathological consequences of the COPD inflammation
induce series of physiological changes which eventually impact
the quality of life and survival in the natural progress of COPD.
Firstly elastin proteolysis results in reduction in elastic recoil
pressures in the lungs, also since the integrity and movement
of air in the bronchioles are primarily reliant on elastic coil
pressures induced by surrounding elastic tissue, the damage
to the elastin in COPD results in significant airway narrowing
with reduction in air-flow in the bronchioles and air-trapping
in lungs; secondly, fibrotic remodelling of the airways results
in fixed airway narrowing causing increased airway resistance
which does not fully revert even with bronchodilators;
thirdly extensive alveolar and bronchiolar epithelial cells and
pulmonary capillary apoptosis in histological feature such as
emphysema and physiological feature such as decreased surface
area of alveoli for gaseous exchange and ventilation- circulation
mismatch (V/Q). Emphysema also reduces lung elastic recoil
pressure which leads to a reduced driving pressure for expiratory
flow through narrowed and poorly supported airways in which
airflow resistance is significantly increased (Figures 1, 3).15-17
Fixed airway obstruction is cardinal to COPD diagnosis
and severity grading which depicts intensity of small airway
inflammation (mucosal edema, airway fibrotic remodeling and
mucous impaction) and possibly increased cholinergic airway
smooth muscle tone. Due to reduced airway caliber and increased
airway resistance there is reduced airflow particularly during
expiration which prolongs the removal of air from the lungs. This
physiological feature of COPD is usually detected with forced
spirometric maneuvers using spirometric lung volume ratio of
volume of air removed in first second (FEV1) and total volume
of air removed (FVC) during forceful expiration after maximal
inhalation as less than 0.7 (FEV1/FVC <0.7). Reduction in FEV1
is hallmark of airway obstruction, and in COPD there is usually
a progressive decline of 50-60 ml in FEV1 every year versus 20-30
ml in normal healthy adults (Figure 2).18
Lung hyperinflation or air-trapping is hallmark of COPD
pathophysiology. Most patients with COPD have some degree
of underlying hyperinflation that needs detailed physiologic
analysis for detection, and which usually remains undiagnosed
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a.
Normal Airway
Alveoli
Obstructed airway Airway
Alveoli
REDUCED AIR VOLUME and REDUCED AIR-FLOW
Fig. 2 : Pathophysiology of Airway Obstruction in COPD
OLD: Obstructive Lung Disease
Elasticity of lung Inadequate elastic
tissue reduced recoil balances the
outward thoracic wall
pressure at higher FRC
Hyperinflation
Narrowed airway
results in airflow
limitations
Alveolar epithelial cell
apoptosis resulting in
reduction in surface area
for gaseous diffusion
Fig. 3 : Pathophysiological Changes occurring in the Lungs of
COPD patients
in routine clinical practice. Hyperinflation is primary cause of
dyspnoea, poor quality of life and advertent disease prognosis
associated with COPD. Damage to elastin and narrowing of
airways are major causes for air-trapping in COPD. The barrel
shaped chest in COPD is attributed to hyperinflation of the lungs.
The inward lung elastic recoil pressures are the primary forces
which drive air out of the small airways and alveoli during tidal
expiration for which it has to counteract outward recoil pressures
generated by thoracic wall. During end tidal expiration both
these forces equally balance each other causing relative airflow
stasis and relaxed lung state. The volume of air trapped in the
lungs at this equi-pressure stage is physiologically termed as
functional residual capacity (FRC). In COPD pathologically
weakening of elastic tissue generates inadequate inward lung
elastic recoil pressures to cause movement of air out of the
lungs. Therefore to counteract the outward recoil pressures of
thoracic cage, the reduced elastic recoil of the lungs generates
equi-pressures states with larger FRC resulting in state of
hyperinflation.15,19 This pushes the equi-pressure point further
away from the alveoli. Body-plethysmography can measure the
extent of hyperinflation by measuring FRC. It is believed that
the symptomatic improvement produced by bronchodilators is
majorly by reduction in lung hyperinflation rather than actual
bronchodilation (Figure 3).19
The hyperinflation is dynamic in nature and is present
in all stages of the disease, which is usually manifested in
8
b.
FEV1/FVC < 70%
FVC
Volume (L)
FEV1
4
FEV1 in OLD
2
5 10 15
Time (s)
Reduced
Inspiratory Capacity (IC)
Normal
Inspiratory Capacity (IC) Increased
Functional residual capacity (FRC)
Normal
Functional residual capacity (FRC)
Fig. 4 : Pathophysiology of dynamic hyperinflation (DH) in COPD
hyperventilation states which are outcome of expiratory flow
limitations, anxiety and ventilation perfusion mismatches related
to COPD exacerbations or any activity which increases oxygen
demand. In hyperventilation during each breath, inhalation
commences before full exhalation is achieved, this results in
air-trapping which enhances with each successive breath. With
every breath FRC increases and capacity to inspire (Inspiratory
capacity) reduces. When the rising FRC encroaches inspiratory
reserve volumes further increase in inspiratory muscle activation
produce little or no additional ventilation (Figure 4). Also, FRC
no longer occurs at the passive point of equilibrium between
chest wall and lung recoil, but occurs at a positive end-expiratory
pressure (PEEP) before exhalation has achieved the relaxation
volume.17 The outcome of this neuromechanical dissociation
when an increasing level of ventilatory drive is associated
with a reduced capacity of the respiratory muscles to develop
force and effective ventilation is the principal mechanism of
breathlessness in COPD patients. The increasing intrinsic-
PEEP during dynamic hyperinflation places diaphragm in
a mechanical disadvantaged position shortens its operating
length and alters the mechanical linkage between its various
parts. This progressively diminishes the tension and resulting
transdiaphragmatic pressure generated by diaphragmatic
contraction.15 These altered actions of diaphragm can potentially
cause disability and impending respiratory failure during COPD
exacerbations. Therefore the physiotherapy paradigms in COPD
management should especially aim to improve diaphragmatic
strength and contractility. Hyperinflated lungs in COPD patients
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V/Q
mismatch Hypercapnic acidosis
Hypoxia Salt water retention in
kidney tubules
+
Secondary
polycythemia Pulmonary capillay Pulmonary
Remodeling Hypertension
Reduction in pulmonary
Hyperinflation vascular bed
Emphysema
Fig. 5 : Pathophysiology of pulmonary hypertension (PH) in COPD
treated with positive-pressure ventilation in intensive care units,
not allowing sufficient time for passive exhalation can result in
progressive hyperinflation which could be catastrophic. Hence,
a regular monitoring of intrinsic-PEEP is necessary for such
patients.
Changes in Respiratory Drive
The destruction of alveoli and pulmonary vasculature in
COPD reduces the surface area for air-diffusion causing chronic
hypercapnic and hypoxic states. The chronic CO2 retention
reduces sensitivity of CO2 brainstem chemo-receptor apparatus
which no longer contributes as the primary mechanism of
respiratory drive in COPD.18 The respiration in this disease
is driven by hypoxia through receptors located in the carotid
arteries and the aortic arch. Hypoxia also causes vasoconstriction
in the pulmonary capillaries which redirects the blood away
from poorly ventilated alveoli.28 Therefore aggressive correction
of hypoxia with high-flow oxygen in COPD especially during
exacerbations reduces physiological respiratory drive in COPD
patients which could be catastrophic, and therefore needs
judicious management.
Pulmonary Artery Hypertension (PAH)
Structural changes in COPD initiate instability in pulmonary
hemodynamics. Most moderate-to-severe COPD patients
develop some degree of mild PAH (25-35 mmHg) over the course
of time, and rarely severe PAH (>45mmHg),20 however, it may be
a rare accompaniment of mild-moderate COPD cases. PAH is a
known independent prognostic marker of COPD. Each episode
of COPD exacerbation increases pulmonary arterial pressure by
20mmHg which can develop into full fledged PAH on recurrent
episodes. PAH primarily depends on pulmonary artery wedge
pressure plus product of cardiac-output and pulmonary-
resistance. Pathophysiological consequences of COPD such
as hypoxia, hyperinflation, emphysema, hypoxia-induced
secondary polycythemias and lung and systemic inflammation
can induce pulmonary capillary muscularization, intimal-wall
thickenings, plexiform lesions, endothelial dysfunctions and
apoptosis which can potentially generate enhanced pulmonary
vascular resistance which predisposes PAH. 20 Increased
intrathoracic pressures in emphysema induce positive pressures
on right ventricle resulting in increased pulmonary artery wedge
pressure. Left ventricular diastolic dysfunction secondary to
cardiovascular morbidities in COPD can also cause back pressure
changes in pulmonary vasculature and right ventricles. Chronic
severe pulmonary hypertension increases right ventricular after-
load and eventually leads to the clinical syndrome of right heart
Osteoporosis
Increased cardiac output
Increased left-atrial pressure Systemic circulation
IL6, CRP, TNFα,
LEPTIN, Oxidant
radicals+
Ischemic Heart Disease .
HYPOXIA Myocardial Infarction
Skeletal Muscle
Insulin resistance weakness
Diabetes mellitus
Depression
Fig. 6 : Systemic inflammation of COPD and its consequences
failure with systemic congestion and inability to adapt right
ventricular output to peripheral vascular demands (Figure 5).
COPD is a Disease of Systemic
Inflammation
COPD has been recently recognized as a multicomponent
disorder associated with systemic inflammation. The origin of
systemic inflammation has been hypothesised to inflammatory
spill from the lungs into the blood through the thin layered
pulmonary vasculature that can potentially predispose
inflammatory affects to other organs of the body (Figure 6).
However, research to identify haplotype of inflammatory
genes which predisposes to systemic inflammation in COPD is
currently underway.21 Various studies have shown enhanced
levels of acute phase proteins like C-reactive protein (CRP)22
and pro-inflammatory cytokines such as tumour necrosis factor
(TNF)-alpha and IL6 in blood of many COPD patients.23
The major systemic co-morbid conditions associated with
COPD are cardiovascular diseases. Cardiovascular disease
(CVD) is an important cause of mortality in COPD. Studies have
shown raised level of myocardial-biomarkers such as NT pro
BNP, troponin-T and platelet-monocyte aggregates in COPD
patients during COPD exacerbations when burden of systemic
inflammation is at peak.24-26 Also, the pressure swings induced
by phenomenon such as air-trapping affect the end diastolic
pressures in the heart and interact with both right and left
ventricular contractility in complex pattern and can stimulate
cardio-vascular events.
Second most important systemic manifestations of COPD
is skeletal muscle dysfunction and wasting especially muscles
of thighs and upper arms. The early fatigue of skeletal mass
has been regarded as one of the causes of increasing dyspnoea
amongst the COPD patients. The biopsy studies have shown
reduction in type I fibers and a relative increase in type II
fibers, accelerated apoptosis, increased oxidative stress and
inflammatory changes in the muscle mass of the COPD patients.27
There is also emerging evidence to show insulin resistance
in COPD patients which is related to systemic inflammation
effects. Recently an association with diabetes and COPD has
been demonstrated. COPD has also been linked to metabolic
syndrome as it predisposes patients to increased cardiovascular
morbidity and diabetes mellitus. Amongst the other systemic
© SUPPLEMENT TO JAPI • FEBRUARY 2012 • VOL. 60 21
manifestations studies have shown nearly 70% of COPD
have underlying osteoporosis and many COPD suffer with
depression.27
Conclusions
With every passing day the understanding about the
pathophysiology of COPD is improving and simultaneously
becoming more complex. The increasing life expectancy all
over the world suggests that COPD would emerge as the most
important disease for the physicians to manage. Understanding
its pathophysiology would just be the right step in that direction.
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