PRIMER

Chronic obstructive pulmonary disease

Peter J. Barnes1, Peter G. J. Burney2, Edwin K. Silverman3, Bartolome R. Celli4,
Jørgen Vestbo5, Jadwiga A. Wedzicha1 and Emiel F. M. Wouters6
Abstract | Chronic obstructive pulmonary disease (COPD) is a common disease with high global morbidity
and mortality. COPD is characterized by poorly reversible airway obstruction, which is confirmed by
spirometry, and includes obstruction of the small airways (chronic obstructive bronchiolitis) and
emphysema, which lead to air trapping and shortness of breath in response to physical exertion. The most
common risk factor for the development of COPD is cigarette smoking, but other environmental factors,
such as exposure to indoor air pollutants — especially in developing countries — might influence COPD
risk. Not all smokers develop COPD and the reasons for disease susceptibility in these individuals have not
been fully elucidated. Although the mechanisms underlying COPD remain poorly understood, the disease is
associated with chronic inflammation that is usually corticosteroid resistant. In addition, COPD involves
accelerated ageing of the lungs and an abnormal repair mechanism that might be driven by oxidative stress.
Acute exacerbations, which are mainly triggered by viral or bacterial infections, are important as they are
linked to a poor prognosis. The mainstay of the management of stable disease is the use of inhaled
long-acting bronchodilators, whereas corticosteroids are beneficial primarily in patients who have
coexisting features of asthma, such as eosinophilic inflammation and more reversibility of airway
obstruction. Apart from smoking cessation, no treatments reduce disease progression. More research is
needed to better understand disease mechanisms and to develop new treatments that reduce disease
activity and progression.

Correspondence to P.J.B.
e-mail: p.j.barnes@
imperial.ac.uk
Airway Disease Section,
National Heart and Lung
Institute, Imperial College,
Dovehouse Street,
London SW3 6LY, UK.
Article number: 15076
doi:10.1038/nrdp.2015.76
Published online
3 December 2015
Chronic obstructive pulmonary disease (COPD) is
described — but not defined — by the Global Initiative
for Chronic Obstructive Lung Disease (GOLD) as “a
common preventable and treatable disease … [that]
is characterized by persistent airflow limitation that is
usually progressive and associated with an enhanced
chronic inflammatory response in the airways and the
lung to noxious particles or gases. Exacerbations and
co-­morbidities contribute to the overall severity in
individual patients” (REF. 1). However, the failure to use
clear definitions causes confusion and the term COPD
is also used to describe people with a low forced expira-
tory volume, changes on CT scans due to emphysema
or with symptoms of chronic lung disease and a his-
tory of smoking. In most normal individuals, >70% of
the vital capacity is exhaled in the first second a forced
man­oeuvre; airflow limitation (see BOX 1 for a glossary of
clinical terms used in this Primer) is defined by a ratio
of forced expiratory volume in 1 second (FEV1) to forced
vital capacity (FVC) of <0.7 and can be categorized as
mild (so‑called GOLD1; FEV1of >80% of predicted nor-
mal), moderate (GOLD2; FEV1 of 79–50% of p ­ redicted
­normal), severe  (GOLD3; FEV1 of  49–30% of pre-
dicted normal) and very severe (GOLD4; FEV1 of <30%
of predicted normal). The airflow limitation in COPD
is largely irreversible owing to structural changes in the
lungs. These changes include chronic obstructive bron-
chiolitis, due to fibrosis of small airways (<2-mm internal
diameter), and emphysema, characterized by enlargement
of alveoli and destruction of alveolar walls. The airway
obstruction (FIG. 1) in COPD usually progresses slowly
and represents an acceleration of the normal decline in
lung function that occurs with ageing, but can also occur
with near-normal decline if maximal lung volumes are
reduced owing to poor lung growth2 (FIG. 2). Progressive
airway obstruction leads to dyspnoea (shortness of breath
on exertion) and, as a result, exercise limitation.
COPD is a major global health issue that is increasing
in importance as a cause of death3,4. The disease is cur-
rently the third leading cause of death worldwide, is
ranked fifth in terms of disease burden, has a cumula-
tive lifetime risk estimated to be as high as 25% and is
now affecting men and women equally 5. Age-specific
mortality rates from COPD are declining almost every-
where, and the global increase in the number of COPD
deaths is related to the growth and ageing of the popula-
tion, as this disease predominantly affects the elderly 3,
with the peak prevalence at approximately 65 years of
age. In high-income countries, cigarette smoking is the
main risk factor for the development of COPD, but sev-
eral other risk factors are also recognized, particularly in
low-income countries.

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PRIMER
Author addresses
1
Airway Disease Section, National Heart and Lung Institute,
Imperial College, Dovehouse Street, London SW3 6LY, UK.
2
Division of Medical Genetics and Population Health,
National Heart and Lung Institute, Imperial College,
London, UK.
3
Channing Division of Network Medicine and Pulmonary
and Critical Care Division, Brigham and Women’s
Hospital, Harvard Medical School, Boston, Massachusetts,
USA.
4
Pulmonary and Critical Care Division, Brigham and
Women’s Hospital, Harvard Medical School, Boston,
Massachusetts, USA.
5
Centre of Respiratory Medicine and Allergy, Manchester
Academic Science Centre, University Hospital South
Manchester NHS Foundation Trust, Manchester, UK.
6
Department of Respiratory Medicine, Maastricht
University Medical Centre, Maastricht, The Netherlands.
COPD is greatly underdiagnosed and is often diag-
nosed late in its course. Consequently, there are con-
certed efforts to increase awareness of this disease and
to promote spirometry, including screening, to identify
patients more accurately 6. Although there have been
improvements in the management of COPD, there is
enormous unmet need to find therapies that reduce
­disease progression and mortality.
In this Primer, we discuss the epidemiology of
COPD, its underlying pathology and pathophysiology,
including the role of genetic factors, its diagnosis and
current management strategies. We discuss the impor-
tance of exacerbations and co-morbidities and then
speculate about the future directions of COPD research
and therapy.
Box 1 | Glossary of clinical terms
• Airflow limitation: the inability of a patient to increase the flow of air, measured at the
mouth, independent of the effort made
• CT scan of the thorax: a radiological method to obtain detailed imaging of the thorax
and its contents, including the lungs and airways
• Diffusion capacity for carbon monoxide (DLCO): the amount of carbon monoxide
absorbed by the body after the inhalation of a gas containing a minute concentration
of carbon monoxide. DLCO is a highly sensitive method to determine the ability of the
lung itself to perform normal gas exchange
• Forced expiratory volume in 1 second (FEV1): the volume of air expelled at the first
second of a forced vital capacity manoeuvre
• Forced vital capacity (FVC): the volume of air expelled from the lungs when starting
at total lung capacity until the residual volume is reached. This is performed during
a maximally forced manoeuvre
• Functional residual capacity (FRC): the volume of air in the lungs after a regular breath
• Hypoxaemia: a low level of oxygen in the blood, which can be determined directly
by drawing arterial blood or indirectly by using an oximeter
• Plethysmography: a procedure that accurately measures all of the volumes of air in the
thorax above and beyond those that can be measured with a spirometer
• Residual volume (RV): the volume of air left in the lungs at the end of a forceful
exhalation
• Spirometery: a procedure that uses a spirometer to determine the amount (volume)
and time of displacement of air into and out of the lungs
• Total lung capacity (TLC): the volume of air in the lungs at full inspiration
2 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
Epidemiology
By far the most common cause of chronic airflow
obstruction globally is smoking and exposure to
environ­mental tobacco smoke7. The next most potent
risk factor is a history of tuberculosis8,9. There is some
evidence that dusty work environments have a role in
COPD development 9,10, but many attempts to quantify
this role have not taken full account of the strong effects
of poverty and education on disease risk and conse-
quently might have overstated the contribution of high
dust exposure. In Europe, there is much less convinc-
ing evidence that current levels of outdoor air pollution
cause airflow obstruction. However, it is notable that an
association between mortality and pollution from coal
burning weakened and subsequently disappeared in the
years following the introduction of the Clean Air Act in
the United Kingdom11, and regions that still have very
high levels of pollution from similar sources might still
show these effects.
The most comprehensive data on the global distribu-
tion of COPD come from the mortality statistics com-
piled by the WHO and the Global Burden of Disease
programme3. These data show that ‘COPD’ (in which
COPD was listed as the cause of death rather than diag-
nosed using the GOLD standards) was the third-most
common cause of death in 2010. Most deaths from
COPD occur in East and South Asia as this is where the
largest proportion of world’s population lives, but these
two regions also have the highest age-standardized mor-
tality rates from COPD. COPD mortality rates are higher
in men than in women and rise exponentially with age.
It is the ageing of the world’s population over the past
20 years that has had the most influence on changing
the relative importance of COPD as a cause of death4.
There is a problem in interpreting these findings.
The regions with the highest COPD mortality rates are
not those with the highest tobacco consumption, and
this goes against the common assumption that tobacco
is the most common cause of COPD. A hypothesis that
has been proposed to resolve this problem posits that the
excess death from COPD in these low-income countries
might be caused by heavy exposure to smoke from bio-
mass burning 12. This could make sense in terms of the
relative health effects and exposures to different levels
of particulate air pollution from cigarettes, outdoor air
pollution and household air pollution13. Indeed, some
experi­mental evidence supports that interventions to
reduce exposure to indoor pollution reduce the rate
of decline in lung function14,15. Nevertheless, there are
problems with this explanation. First, the largest studies
have failed to find an association between indoor pollu­
tant exposure levels and chronic airflow obstruction, as
measured by spirometry 9,16. Second, there is little evi-
dence to indicate that there are high levels of chronic air-
flow obstruction in the regions with heavy use of biomass
fuels. Moreover, even in these regions, obstruction is
often more common in men than in women, who would
be expected to have higher exposure to indoor biomass17.
The strongest association with mortality from
‘COPD’ (in which COPD is listed as the cause of death)
is with poverty 17 (FIG. 3). Countries with a low per capita
 PRIMER

Healthy COPD

Destruction
of alveolus
Bronchiole

Excess mucus
Alveolus Narrowed
bronchiole

Mucus hypersecretion, Mucosal

exudate (chronic inflammation
bronchitis) and fibrosis
Smooth (chronic
muscle Airway obstructive
wall bronchiolitis)

Airway
lumen
Mucus

Airway held open Disrupted

by alveolar alveolar
attachments attachments
(elastin fibres) (emphysema)

Figure 1 | Airway obstruction in COPD.  In healthy lungs, the small airways (bronchioles)Nature Reviews
are held open by| Disease
alveolarPrimers
wall
attachments that contain elastin fibres. In chronic obstructive pulmonary disease (COPD), the small airways are narrowed
through thickening of the bronchiolar periphery wall by inflammation and fixed narrowing as a result of fibrosis, disruption
of alveolar attachments as a result of emphysema and luminal occlusion by mucus and inflammatory exudate.

gross national income have much higher recorded mor-
tality rates from COPD, which might partially explain
the high COPD mortality rates in East and South Asia.
This trend mirrors the association of COPD mortality
with socioeconomic status in older data from the United
Kingdom — where the socioeconomic gradient was
stronger for COPD than those for lung cancer and even
for tuberculosis18 — and the overall downward trend
in COPD deaths in England and Wales since the first
decade of the twentieth century 19. There is also a strong
association between per capita gross national income
and the prevalence of low FVC17. Although the inter-
pretation of these data is controversial, as the potential
confounding effects of ethnic differences can be inter-
preted in different ways, the association between socio-
economic status and COPD mortality is strongest when
‘European’ populations are excluded from the analysis,
particularly among women for whom smoking is less
of a confounder. As it is European populations that
seem different, the association of COPD mortality with
poverty among the other countries after excluding the
European countries supports the view that the associ­
ation is less likely to be explained on ethnic grounds.
In support of a role for poverty in mortality from lung
disease, this associ­ation is similar to the association
between infant mortality rates from pneumonia and
bronchitis and adult mortality from chronic bronchi-
tis 50 years later, both of which were higher in poorer
areas of England and Wales20. Although it is true that
poor countries have a very low uptake of medications for
COPD21, it is unlikely, given the efficacy of these treat-
ments and the extensive differences in mortality, that
this is the main reason for disparities in COPD-related
mortality between developed and developing countries.
Mechanisms/pathophysiology
Several distinct and overlapping phenotypes comprise
the syndrome designated as COPD, and it is also likely
that there are several underlying mechanisms of disease.
Not all cigarette smokers develop airway obstruction,
indicating that there are susceptibility mechanisms —
which might include genetic, epigenetic and environ-
mental factors — that are currently poorly understood.
A better understanding of the complex cellular mech­
anisms and molecular pathways involved in COPD
might lead to improved therapies in the future.

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 PRIMER
100
75
FEV1 (predicted normal %)
50
25 Normal decline (~20 ml per year)
Normal decline with low initial lung volume
Accelerated decline
0 nants of COPD resistance. Whole-exome sequencing has
0 25 35 45 55 65
Age (years)
Progression of symptoms
Decreased Shortness of Shortness of Respiratory
physical activity breath on exertion breath at rest failure
Figure 2 | Disease progression in COPD.  In healthy individuals, the forced expiratory
Nature Reviews | Disease Primers
volume in 1 second (FEV1) declines slowly with age from a peak at approximately 25 years
of age (blue line). Many patients with chronic obstructive pulmonary disease (COPD)
experience an accelerated annual decline in lung function (orange line) and the
development of symptoms when FEV1 falls below approximately 60% of the predicted
normal. Symptoms increase as airway obstruction increases from reduced physical
activity, to shortness of breath on exertion and eventually to shortness of breath at rest
followed by respiratory failure. Other patients with COPD might start from a lower peak
lung volume (as a result of impaired lung development) and develop symptoms with even
a normal decline in FEV1 (green line).
Genetic risk factors
Although COPD risk is strongly related to tobacco
smoking, the variable development of chronic airflow
obstruction among smokers suggests that other fac-
tors also influence the onset and progression of COPD.
COPD tends to cluster in families, and twin studies22,
pedigree studies23,24 and analysis of unrelated individ­
uals25 have all suggested that there is significant herit-
ability of COPD, accounting for at least 30% of the
variation in COPD risk. First-degree relatives of patients
with COPD who smoke cigarettes have approximately a
threefold increased risk of developing COPD compared
with smokers from the general population, whereas
non-smoking first-degree relatives of patients with
COPD have similar (and low) risks for chronic airflow
obstruction compared with non-smokers in the general
population. These results indicate that there are likely to
be genetic determinants that interact with smoking
to increase COPD risk.
Several Mendelian syndromes include COPD (typi-
cally emphysema) as part of their constellation of clini-
cal features, including α1‑antitrypsin deficiency and
cutis laxa. α1‑Antitrypsin deficiency is usually caused
by homozygosity for a single and relatively rare non-
synonymous single-nucleotide polymorphism (SNP)
— namely, the PI*Z allele of the α1‑antitrypsin gene
(SERPINA1). PIZZ α1‑antitrypsin deficiency, which
occurs in approximately 1 in 3,000 individuals in the
United States, accounts for approximately 1% of COPD
4 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
cases26. Although the question of whether hetero­zygosity
for the PI*Z allele confers increased COPD risk has
been controversial, several recent studies have strongly
suggested that PI*Z heterozygote individuals have a
­moderately increased risk for COPD if they smoke27,28.
Cutis laxa can be caused by mutations in several dif-
ferent genes, including elastin (ELN)29, which is a key
component of the lung extracellular matrix. In addition,
a rare functional ELN variant has been identified in a
family with a high number of individuals with COPD30.
Whole-exome and whole-genome sequencing have the
potential to identify other rare genetic determinants of
COPD, and comprehensive genomic analyses of heavy
smokers without COPD might identify genetic determi-
75
recently implicated a coiled-coil domain containing 38
(CCDC38) variant, which is linked to ciliary func-
tion, in the resistance to COPD development 31. Given
that the cilia of lung epithelial cells normally play an
important part in removing inhaled particulates, it is
plausible that ciliary abnormalities could contribute to
COPD development.
Although many candidate genes have been tested for
their association with COPD, most of these results have
not been consistently replicated32,33. However, genome-
wide association studies (GWAS) of COPD have identi-
fied multiple genomic regions that are associ­ated with
COPD34 and most of these associations have now been
replicated in other studies. GWAS of lung function
levels in general population cohorts have been per-
formed in the CHARGE35 and SpiroMeta36 consortia,
and >20 genomic regions have been associated with
FEV1 and/or FEV1/FVC levels37. Several of these lung
function genomic loci, including Hedgehog-interacting
protein (HHIP) and family with sequence similarity 13
member A (FAM13A), have also been associated with
COPD susceptibility.
GWAS have also been performed for several other
COPD-related phenotypes, such as emphysema pattern38
and nicotine addiction39,40; the results from these studies
suggest that susceptibility loci might influence different
COPD-related traits (TABLE 1). For instance, several of
the COPD susceptibility loci, including the 15q25 locus
that has been associated with lung cancer 41 and periph-
eral arterial disease42, are associated with nicotine addic-
tion. An integrative study combining gene expression
analysis and genetic association analysis implicated iron-­
responsive element-binding protein 2 (IREB2), another
gene within the 15q25 locus, in COPD susceptibility 43,
and mediation analysis suggested that there might be
two genetic loci influencing COPD on 15q25 — one
related and one unrelated to nicotine addiction44.
Molecular studies and bioinformatic approaches are
needed to identify the functional genetic variants within
COPD genetic loci implicated by GWAS, which prob-
ably often influence gene regulation. Chromosome con-
formation capture studies have identified a long-range
interaction of the COPD genome-wide association study
locus upstream from HHIP with the HHIP promoter.
Subsequent studies identified a functional variant within
an enhancer in this region that alters binding to the

transcription factor SP3 (REF. 45). A recent study dem-
onstrated that heterozygous gene-targeted Hhip mice
(Hhip+/–) had increased susceptibility to smoke-induced
emphysema and that lymphocyte activation pathways
were implicated in this susceptibility 46.
Additional efforts to integrate genetic variation with
gene expression47, epigenetic markers48 and/or other
‘-omics’ data types are likely to identify more COPD sus-
ceptibility genes and provide insight into the network of
interacting genes that increases COPD risk and contrib­
utes to COPD heterogeneity. Molecular and cellular
studies of these susceptibility genes will be n
­ ecessary to
understand their role in COPD pathogenesis.
Pathogenesis
Pathology. The main pathological features of COPD
are obstructive bronchiolitis, emphysema and, in many
cases, mucus hypersecretion (chronic bronchitis) (FIG. 1),
but the relative contribution of each of these patholo-
gies to COPD varies between patients49. Even in early
or mild COPD, there is evidence of airflow obstruction
and a signifi­cant loss (disappearance) of small airways50.
A novel CT imaging technique for quantifying small
airway disease shows that this small airways loss is an
early feature of disease and might account for the initial
progression of airway obstruction in COPD51. Structural
changes in small pulmonary arterioles are common in
COPD, with increased intimal thickening and vascular
smooth muscle proliferation, and such changes might
be the result of inflammation in these vessels as well
as hypoxic vasoconstriction52. However, pulmonary
hypertension is usually not marked in COPD, except
for a small group of patients with disproportionate
pulmonary hypertension who might develop right
heart failure53.
Chronic inflammation. COPD is associated with chronic
inflammation that predominantly affects peripheral
airways and lung parenchyma, although large airways
also show inflammatory changes 54. The degree of
inflammation increases — with increased numbers
of neutrophils, macrophages and lymphocytes in the
lungs — as the disease progresses49. Chronic inhalation
30
COPD mortality per 100,000
25 Male
Female
20
15
10
5
0 The lower respiratory tract of patients with COPD
0 100 1,000 10,000 100,000
Gross national income per capita (US$ ppp)
Figure 3 | Poverty is a risk factor for COPD.  There isNature
a strong relationship
Reviews in men
| Disease Primers
and women between chronic obstructive pulmonary disease (COPD) mortality rates
(mortality from COPD per 100,000 individuals 15–59 years of age) and annual per capita
gross national income. PPP, purchasing power parity. Data obtained from REF. 17.
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 5
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
of irritants, including cigarette smoke, biomass fuel
smoke and air pollutants, activates pattern recognition
receptors, such as Toll-like receptors, which results in
an innate immune response. This immune response
then leads to increased numbers of neutrophils and
macrophages in the lungs as well as activation of air-
way epithelial cells and mucus secretion55. Activation
of adaptive immunity occurs later in the course of the
disease and leads to increased n ­ umbers of T lympho-
cytes and B lymphocytes in the lungs. These cells might
be organized into lymphoid follicles, which involves an
increase in the number and activation of dendritic cells.
During this adaptive immune response there is also an
increase in the number of CD8+ cytotoxic T cells and
CD4+ T helper 1 cells in lung tissue56. The number
of CD4+ T helper 17 cells is also increased in the lungs
and might further amplify neutrophilic inflammation57.
Some patients with COPD have increased numbers of
eosinophils in their airways, increased sputum and
share some features with asthma, such as reversibility
of the airway obstruction and a greater response to
­corticosteroids than patients with typical COPD58.
The levels of many different inflammatory mediators
are increased in the lungs of patients with COPD, includ-
ing lipid and peptide mediators, as well as a network of
cytokines and chemokines that maintain inflammation
and recruit circulating cells into the lungs59. Many of
these pro-inflammatory mediators are regulated through
the activation of the pro-inflammatory transcription fac-
tor nuclear factor‑κB (NF‑κB) and mitogen-activated
protein kinases (MAPKs), particularly p38 MAPK60,61.
In addition, several proteases that degrade elastin fibres
are secreted from airway resident neutrophils, macro­
phages and epithelial cells in patients with COPD.
In larger airways, elastase from neutrophils might be an
important stimulator of mucus hypersecretion, whereas
matrix metalloproteinases (MMP9 and MMP12) in
the lung parenchyma might be more important in the
­elastolysis that is observed in those with emphysema.
Even cigarette smokers with normal lung function
have increased airway inflammation, suggesting that this
might be the normal immune response of the respira-
tory mucosa to inhaled irritants. However, this inflam-
mation seems to be amplified in patients with COPD,
particularly during acute exacerbations. The amplified
inflammatory response in COPD might be explained
by the reduced expression of the nuclear enzyme his-
tone deacetylase 2 (HD2, encoded by HDAC2) in cells
such as macrophages and epithelial cells in the lungs of
those with COPD, resulting in the activation of multi-
ple inflammatory genes62. The inflammation in COPD
persists after smoking cessation, suggesting that it is
maintained by some autonomous mechanism that is not
yet understood.
is often colonized with bacteria, such as Haemophilus
influenzae and Streptococcus pneumoniae. This chronic
bacterial colonization has been linked to a defect in the
uptake (phagocytosis) of bacteria by macrophages63,64,
and, particularly with H. influenzae, might be a factor
driving chronic airway and systemic inflammation and
PRIMER

immune responses in these patients65. This defect in
phagocytosis might also apply to a defective uptake of
apoptotic inflammatory cells (efferocytosis) and there-
fore might contribute to the impairment in resolution
of lung inflammation in individuals with COPD64,66
(FIG. 4). Autoimmune mechanisms might also have a
role in the persistence of bacterial infection, and there
is evidence of the presence of autoantibodies, such
as endothelial cell antibodies and antibodies against
carbonyl-modified proteins, in the lungs of those with
COPD, at least in severe disease67. Finally, the peripheral
lung inflammation observed in COPD might also ‘spill
over’ into the systemic circulation and contribute to the
systemic inflammation in COPD that is associated with
various co-morbidities, such as cardiovascular disease
and metabolic diseases68. However, not all patients with
COPD have evidence of systemic inflammation69 and co-­
morbidities might be part of multimorbidity with similar
mechanisms, such as accelerated ageing, affecting several
organs at the same time.
Accelerated ageing. COPD is largely a disease of the
elderly and there is increasing evidence to indicate that
emphysema is caused by accelerated ageing of the lung
parenchyma owing to defective endogenous anti-ageing
mechanisms, such as those that involve sirtuins70, with
the activation of pathways leading to telomere short-
ening and cellular senescence71 (FIG. 5). Cellular senes-
cence and decreased activity and expression of sirtuin 1
(SIRT1) have also been found in circulating endothelial
progenitor cells of patients with COPD. These cells are
less effective at vascular repair than endothelial progeni-
tor cells from age-matched healthy individuals; there-
fore, patients with COPD are predisposed to develop­ing
cardio­v ascular disease and other co-morbidities 72.
Indeed, stem cell senescence might be a common mech-
anism in COPD and its co-morbidities, with consequent
failure to repair tissue damage73. Autophagy, a process in
which cells keep their cytoplasm clean by removing dam-
aged organelles and proteins, is also impaired with age-
ing 74. Accumulating evidence indicates that autophagy is
defective in COPD, which leads to the accumulation of
damaged proteins and organelles, such as mitochondria,
and in accelerated cellular senescence and death75.
Oxidative stress. Increased oxidative stress is a key
driving mechanism in the pathophysiology of COPD
and accounts for many of the features of the disease76.
Oxidative stress is increased in patients with COPD
from cigarette smoke exposure, but also endogenously
from the activation of inflammatory cells, particularly
neutrophils and macrophages. Reactive oxygen species
(ROS) contribute to COPD pathophysiology in several
ways (FIG. 6). For instance, ROS activate NF‑κB and p38
MAPK, resulting in increased expression of inflam-
matory genes and proteases. ROS also inhibit endo­
genous antiproteases, such as α1‑antitrypsin, resulting
in increased elastolysis. Furthermore, oxidative stress
leads to DNA damage, which is normally repaired
by the efficient DNA repair machinery. However, in
patients with COPD, there might be a failure to repair
double-stranded DNA breaks, which might also lead
to an increased risk of developing lung cancer 77. ROS
induce carbonylation of proteins, which, particularly in
severe COPD, might lead to the generation of circulat-
ing autoantibodies that might perpetuate inflamma-
tion and lung injury 67. ROS also activate transforming
growth factor‑β (TGFβ), leading to fibrosis. In addition,
oxidative stress reduces corticosteroid responsiveness
through a reduction in the activity and expression of

Table 1 | Top genomic regions conferring susceptibility to COPD and COPD-related phenotypes based on GWAS
Chromosomal Representative COPD* Lung function levels in the Emphysema Nicotine addiction||
region gene(s) within region general population‡ pattern§
4q31 HHIP Genome-wide Genome-wide significance¶ Genome-wide Not reported as having
significance¶ significance¶ genome-wide significance#
15q25 CHRNA3–IREB2 Genome-wide Nominal significance** Genome-wide Genome-wide
significance¶ significance¶ significance¶
4q22 FAM13A Genome-wide Genome-wide significance¶ Nominal Not reported as having
significance¶ significance** genome-wide significance#
11q22 MMP12 Genome-wide Not reported as having Genome-wide Not reported as having
significance¶ genome-wide significance# significance¶ genome-wide significance#
14q32 RIN3 Genome-wide Not reported as having Nominal Not reported as having
significance¶ genome-wide significance# significance** genome-wide significance#
1q41 TGFB2 Genome-wide Genome-wide significance¶ Genome-wide Not reported as having
significance¶ significance¶ genome-wide significance#
6p21 AGER Nominal Genome-wide significance¶ Nominal Not reported as having
significance** significance** genome-wide significance#
19q13 CYP2A6–EGLN2– Nominal Not reported as having Genome-wide Genome-wide
ADCK4 significance** genome-wide significance# significance¶ significance¶
ADCK4, aarF domain-containing kinase 4; AGER, advanced glycosylation end product-specific receptor; CHRNA3, cholinergic receptor nicotinic-α3 (neuronal);
COPD, chronic obstructive pulmonary disease; CYP2A6, cytochrome P450 family 2 subfamily A polypeptide 6; EGLN2, Egl‑9 family hypoxia-inducible factor 2;
FAM13A, family with sequence similarity 13 member A; GWAS, genome-wide association studies; HHIP, Hedgehog-interacting protein; IREB2, iron-responsive
element-binding protein 2; MMP12, matrix metalloproteinase 12; RIN3, RAS and RAB interactor 3; TGFB2, transforming growth factor‑β2. *See REF. 34 for details.
‡
See REF. 37 for details. §See REF. 38 for details. ||See REF. 40 for details. ¶P < 5 × 10−8. #P >5 × 10−8. **P < 0.05.

6 | 2015 | VOLUME 1 www.nature.com/nrdp

© 2015 Macmillan Publishers Limited. All rights reserved


Healthy COPD
Alveolar
macrophage
Defective
Phagocytosis Efferocytosis Defective efferocytosis
phagocytosis
Bacteria Apoptotic cells Bacteria Apoptotic cells
Bacterial
Resolution of Bacterial Persistence of
clearance
inflammation colonization inflammation
(sterile airway)
Figure 4 | Defective phagocytosis in COPD.  In healthy individuals,
Nature Reviews macrophages
| Disease Primers
phagocytose bacteria in the lung periphery and respiratory tract to maintain lung
sterility. These macrophages also phagocytose apoptotic cells (efferocytosis), resulting
in resolution of inflammation. In chronic obstructive pulmonary disease (COPD),
macrophages are defective at phagocytosing bacteria, which results in chronic
bacterial colonization of the lower airways. In addition, these macrophages have an
impaired ability to carry out efferocytosis of apoptotic cells, which results in failure
to resolve inflammation.
HD2 (REF. 78). ROS also reduce the expression and activ-
ity of SIRT1, which is markedly reduced in the lungs
of patients with COPD and has a role in maintaining
genomic stability, regulating autophagy and protecting
against cellular senescence and ageing 79. There is also
evidence for defective endo­genous antioxidant defences
in patients with COPD. The transcription factor nuclear
factor erythroid 2‑related factor 2 (NRF2; also known
as NFE2L2) plays a key part in the regulation of multi-
ple antioxidant and cytoprotective genes in response to
oxidative stress. NRF2 function is impaired in patients
with COPD80 and is not appropriately activated by oxida-
tive stress owing to its increased acetylation as a result of
reduced HD2 activity 81.
Evidence is emerging to indicate that mitochondria
are an important source of ROS in COPD and that there
is a disruption of mitochondrial function in patients with
COPD, which leads to impaired oxidative phosphory­
lation and reduced intracellular ATP. Mitochondria are
fragmented in epithelial cells of patients with COPD and
these changes are mimicked by cigarette smoke exposure
in vitro, which leads to mitochondrial ROS production
and cellular senescence82. Cigarette smoke induces the
autophagic uptake of mitochondria (mitophagy) in
airway epithelial cells, which results in mitochondrial
deficiency and cell death (necroptosis) that is mediated
by the mitophagy regulator phosphatase and tensin
homologue-­induced putative kinase protein 1 (PINK1)83.
PINK1 shows increased expression in epithelial cells of
patients with COPD, and Pink1 knockout in mice pro-
tects against the development of emphysema and mucus
secretion induced by chronic cigarette smoke exposure.
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 7
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
Pathophysiology. The airway obstruction in COPD is
predominantly in the small airways of the lung periph-
ery and results in a reduction in FEV1 and the FEV1/FVC
ratio, which progresses over time. An acceleration of the
normal FEV1 decline with age can be observed in most
patients, although poor lung function might result from
the normal decline in lung function of developmentally
impaired lungs. The fixed narrowing of small airways
and the loss of alveolar attachments due to emphysema
result in the premature closure of the small airways
upon expiration, resulting in air trapping (FIG. 7). Air
trapping causes lung hyperinflation (increased total
lung capacity) and an increase in resting lung volume
(functional residual capacity). Air trapping worsens in
response to exercise (dynamic hyperinflations), result-
ing in exertional dyspnoea and reduced exercise toler-
ance84. Although the obstruction of the small airways
due to fibrosis is irreversible, superimposed cholinergic
tone markedly increases airway resistance. This cholin-
ergic tone is reversible by muscarinic antagonists and
β2-adrenergic receptor agonists (β2-agonists), which
results in reduced air trapping and reduced symptoms.
The fixed narrowing of the airways also causes increased
responsiveness to bronchoconstrictors and is primarily a
consequence of geometric factors. Emphysema results in
reduced alveolar surface area, resulting in impaired gas
transfer and eventually hypoxia.
Causes and pathogenesis of exacerbations
COPD exacerbations are episodes of symptom worsen-
ing that are usually associated with increased airway
inflammation and systemic inflammatory effects85
(FIG.  8) . Most COPD exacerbations are triggered by
respira­tory viral infections, especially rhinovirus, which
is the cause of the common cold and thus more com-
mon in winter. Respiratory viruses can be identified
in the airway by PCR in up to 60% of exacerbations86.
Exacerbations associated with viruses tend to have more
airway and systemic inflammation than those without
any evidence of viral infection, are more common in the
winter months and are associated with a higher risk of
hospital admission87. Pollutants that reach the airways
might also be associated with precipitating exacerba-
tions, especially by interacting with respiratory viruses,
although significant effects of pollution are only seen in
regions of high urban pollution88. Airway bacteria are
also involved in causing exacerbations, although their
precise role in triggering exacerbations is controversial.
Although airway bacterial load increases during exacer-
bations, it is now considered that bacteria are often not
the primary infective cause of the exacerbation but are
secondary invaders after a viral trigger 85.
Some patients with COPD are susceptible to exacerba-
tions irrespective of disease severity. These patients have
been called ‘frequent exacerbators’ and over time their
exacerbation frequency is relatively stable89–91. The main
risk of developing frequent exacerbations is a history of
exacerbations in the previous year. Frequent exacerbators
have a worse prognosis, more hospital admissions, faster
disease progression and worse health status than those
who experience infrequent exacerbations.
 PRIMER
100
75 Senile
emphysema
FEV1 (max %)
50
Oxidative stress leads to:
Telomere shortening
Cellular senescence
DNA damage
25 Mitochondrial dysfunction
Autophagy
Stem cell exhaustion Normal ageing
Anti-ageing molecules COPD
0
0 40 50 60 70 80
10 20 30
Age (years)
Figure 5 | Accelerated ageing in COPD.  Forced expiratory Naturevolume
Reviews | Disease (FEV
in 1 second Primers
)
1 include second-­hand exposure to cigarette smoke or
values decline with age in healthy individuals (blue line), and senile emphysema (the
result of ageing) might be seen in the elderly. In those with chronic obstructive
pulmonary disease (COPD), lung ageing seems to be accelerated (green line) as a result
of oxidative stress caused by cigarette smoking and other inhaled stimuli. Patients with
COPD have all of the features of accelerated lung ageing, including telomere shortening,
cellular senescence, DNA damage (failure of repair), mitochondrial dysfunction, impaired
autophagy, stem cell exhaustion and reduced levels and activity of anti-ageing
molecules, such as sirtuin 1.
Diagnosis, screening and prevention
Diagnosis
The diagnosis of COPD should be suspected in individ­
uals with respiratory symptoms, such as cough, expec-
toration of sputum, shortness of breath upon exertion
or lower respiratory tract infections occurring more fre-
quently or lasting longer than expected (>2 weeks). The
suspicion should increase if the individuals also report
risk factors for COPD, such as exposure to cigarette
smoke, environmental or occupational pollutants and/or
the presence of a family history of obstructive lung dis-
eases1,92. Not infrequently, and usually in more-advanced
cases, COPD is suspected at the time of a severe respira-
tory decompensation due to an acute exacer­bation or
following surgery, such as upper abdominal or thoracic
procedures. This deterioration is caused by the main
problem of underdiagnosis, as most individuals with
the disease underestimate their symptoms, assuming
that they are the natural consequence of the smoking
habit, ageing or job exposure93. Furthermore, even in
moderate-­to-advanced stages of COPD, the affected
patients will become ever more sedentary to avoid
the uncomfortable symptom of exertional dyspnoea.
Unfortunately, many health care providers fail to con-
sider a diagnosis of COPD in patients presenting with
these symptoms, especially if the person is a woman or
relatively young94. The reasons for the failure to suspect
COPD in these groups rests on older studies of the epi-
demiology of COPD that described the disease as being
one of older men. As the smoking habit has increased
in younger individuals and the prevalence of COPD in
women is now approaching or has surpassed (in some
8 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
developed countries) that of men, COPD is now preva-
lent in younger individuals and particularly in women,
who might actually develop the disease at an earlier age
than men.
History of exposure to risk factors. COPD, as with
most chronic non-communicable diseases, results
from the genetic make-up of an individual interacting
with their environment. The respiratory system is con-
stantly exposed to its surroundings through the act of
breathing. With its large exposure surface and absorp-
tive properties, it is surprising that the proportion of
individuals exposed to cigarette smoke who develop
clinical COPD is not >30–50%95. The most important
risk factors for COPD are the inhalation of particulate
matter from cigarette smoke and the burning of biomass
90
for cooking or heating 12. A combination of both types
of exposure significantly increases the risk of develop-
ing COPD96. Other risk factors for COPD development
other particulate matter during infancy, socioeconomic
dis­advantage, childhood respiratory symptoms and
asthma during the growth period, as discussed above97.
Recent studies have shown that low lung function in
early adulthood with subsequent normal lung function
decline is as important as rapid lung function decline in
normal-sized lungs in the development of COPD2,98,99.
The role of the microbiota, which differs in smokers and
in patients with COPD from that of the general popu-
lation100, is receiving considerable attention, but study
results are currently insufficient to confer the microbiota
an ­important pathobiological role.
Clinical presentation. Most individuals with mild dis-
ease have a normal physical examination, including
pulse, respiratory rate, chest expansion and breath and
heart sounds. However, the use of a standardized func-
tional grading of dyspnoea, the most important symp-
tom of respiratory compromise, can help to increase
the degree of suspicion, direct the health care pro-
vider to i­ mplement a spirometry test and help to stage
disease severity.
One such scale is the Modified Medical Research
Council dyspnoea scale, graded from 0 to 4 with the
lowest grade implying no dyspnoea with any activity
and the highest grade implying dyspnoea with mini-
mal activity 1,92. In patients with more-advanced dis-
ease, increased respiratory rate with forced expiratory
efforts, decreased breath sounds on chest auscultation
(listening), the presence of rhonchi (rattling sounds),
coarse crackles and wheezes and, in the most advanced
cases, cyanosis (blue skin discolouration, a sign of
hypoxaemia) might be present and should be consid-
ered an important complication that requires therapy
with oxygen.
Currently, the ease of use of pulse oximetry, which is
a non-invasive method of measuring oxygen saturation,
enables the determination of hypoxaemia early, and oxy-
gen should be prescribed for patients with saturations
below 88% while breathing room air 1. The presence of
cor pulmonale (failure of the right side of the heart due
 PRIMER

to hypoxaemia and increased intrapulmonary vascular
resistance) is characterized by severe dyspnoea, impaired
exercise capacity, leg oedema and, in the most severe
cases, generalized oedema.
Use of unsupervised cluster analysis, including
many clinical variables as well as results of a CT scan of
the thorax and biomarkers, has confirmed that COPD is
a complex heterogeneous disease in which the majority
of patients combine features of the classic subgroups of
the ‘pink puffer’ and the ‘blue bloater’ phenotypes101,102.
These studies have also confirmed the association of
these classic phenotypes with clinical, radiological and
biomarker profiles103. Thus, pink puffers have lower
muscle mass, more emphysema and fewer cardio­
vascular and metabolic co‑morbidities than blue bloaters
who have higher body mass index with less emphy-
sema and more metabolic co‑morbidities and ­cardiac
compromise (FIG. 9).
Confirming the diagnosis. A diagnosis of COPD is con-
firmed by the documentation of expiratory airflow limi-
tation during a forced expiratory manoeuvre from total
lung capacity to residual volume. This measurement is
easily achieved using a simple spirometer and recording
the timed FVC following standard recommendations104.
As mentioned previously, >70% of the vital capacity is
exhaled in the first second of the manoeuvre in most
healthy individuals. The FEV1 is characteristically low in
patients with COPD as well as in patients with restric-
tive pulmonary diseases. Accordingly, the diagnosis of
COPD requires a decrease in the ratio of FEV1/FVC to a
value that is usually <0.7. The spirometry test should be
repeated after the administration of inhaled broncho-
dilators to distinguish the presence of poorly reversible
airflow limitation of COPD from the large reversibility
that characterizes airflow obstruction in patients with
asthma. The actual definition of what confirms an abso-
lute diagnosis of COPD remains controversial because
older, otherwise healthy, individuals might have values
of FEV1/FVC of <0.7. To address this issue, using the
lower limit of normal for the FEV1/FVC ratio rather
than the fixed ratio reduces the overdiagnosis of airway
obstruction in the elderly 105. Thus, there should be not
only a decreased FEV1/FVC but also a low FEV1 com-
pared with reference values obtained from population
studies106. The current GOLD scale classifies the severity
of airflow obstruction as a percentage of normal FEV1 as
discussed on page 1.
Other lung function studies might complement the
evaluation of patients with COPD. Many patients, and
more so in advanced disease stages, will have increased
lung volumes and air trapping that are measured by body
plethysmography using a sealed body box. The hyper-
inflation will worsen with exercise and this increase in
air trapping relates well to the degree of dyspnoea. The
capacity of the lungs to allow gas transfer across the
alveoli is assessed using the diffusion capacity for car-
bon monoxide into the blood. Low diffusion capacity
values raise suspicion of the presence of emphysema or
pulmonary vascular compromise and can be helpful in
diagnosing early phases of the disease.
Global assessment and co-morbidities. COPD is not just
a lung disease, and many patients will have compromise
of other body systems with important prognostic and
therapeutic implications107. Most notably, patients with
COPD have exercise limitation due to skeletal muscle
dysfunction, which is probably due to a combination of
disuse atrophy and sarcopaenia (loss of muscle fibres
usually associated with ageing). Indeed, a decreased
functional capacity is a hallmark of COPD and helps to
stage its severity because it predicts mortality better than
the FEV1. A decreased capacity to exercise and a paral-
lel decrease in activity is seen even in milder stages of
COPD108. Thus, it is recommended that the functional
capacity be measured with tests such as the timed walk
distance, gait speed or the formal cardiopulmonary exer-
cise test. Whether from disuse atrophy or from organic
compromise, the functional capacity can be improved
using rehabilitation109.

NRF2 NOX1–NOX4 MPO SOD

Oxidative stress

NF-κB p38 MAPK Autoantibodies SIRT1 DNA damage HD2 Antiproteases TGFβ
Steroid
Inflammation Ageing and cancer resistance Fibrosis and emphysema

Figure 6 | Increased oxidative stress in COPD.  Oxidative stress might be increased inNature
chronic obstructive
Reviews pulmonary
| Disease Primers
disease (COPD) due to a reduction in the expression of the transcription factor nuclear factor erythroid 2‑related factor 2
(NRF2; also known as NFE2L2), NADPH oxidases (NOXs), myeloperoxidase (MPO), superoxide dismutase (SOD) and other
antioxidants, which might be triggered by inflammatory stimuli. Oxidative stress is a key mechanism that drives the
development and progression of COPD through the activation of the pro-inflammatory transcription factor nuclear
factor‑κB (NF‑κB) and p38 mitogen-activated protein kinase (MAPK), the generation of autoantibodies to carbonylated
proteins, reduced expression of sirtuin 1 (SIRT1), DNA damage, reduced histone deacetylase 2 (HD2) expression, reduced
activity of antiproteases and increased release of transforming growth factor-β (TGFβ). Figure from REF. 188, Nature
Publishing Group.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 9

© 2015 Macmillan Publishers Limited. All rights reserved

PRIMER

Healthy COPD

Airway narrowing
Mucosal
inflammation
Smooth and
muscle peribronchiolar
Airway
wall fibrosis

Inspiration
Airway
lumen
Mucus

Airway held open Disrupted

by alveolar alveolar
attachments attachments
(elastin fibres)

Airway closure
Air trapping and
hyperinflation
Expiration

Alveolar
gas exhaled Dynamic Dyspnoea
Quality of life
hyperinflation Exercise
Health status
capacity

Figure 7 | Air trapping in COPD.  In healthy individuals, the airways narrow but do notNatureclose because
Reviewselastin fibres
| Disease in
Primers
alveolar attachments hold them open, thereby allowing alveolar gas to be expired. In those with chronic obstructive
pulmonary disease (COPD), the airways are narrowed and alveolar attachments are disrupted as a result of emphysema,
leading to airway closure upon expiration. This closure results in trapping of alveolar air, which worsens on exercise
(dynamic hyperinflation), resulting in exertional dyspnoea and reduced exercise tolerance, and leads to marked
impairment in quality of life and health status.

A significant proportion of patients have a low body
mass index, with values below 21 kg per m2 associated
with increased risk of death107. A low muscle strength as
a surrogate of muscle mass can be measured by tests such
as the hand grip or quadriceps force tests to complement
determination of the overall compromise in COPD110.
In acknowledgement of the multiple dimensions of
COPD, several proposals for its comprehensive assess-
ment have been developed. The most widely evaluated
of these assessments is the body mass index, degree of
obstruction, dyspnoea and exercise capacity (BODE)
index and its variants, such as the BODEx (in which the
exercise is substituted by the rate of exacerbations)107.
Other assessments include the age, dyspnoea and obstruc-
tion (ADO) index 111, and the dyspnoea, obstruction,
smoking and exacerbation (DOSE) index 112. All of these
indices predict mortality better than the simple measure
of FEV1. Finally, GOLD has proposed a grading system
that includes obstruction, symptoms and exacerbations
that places patients into groups labelled A, B, C or D.
However, initial studies using mortality as the outcome
have shown that this grading system offers no advantage
over the old system based simply on the FEV1 (REF. 113).
Several co‑morbidities also occur more frequently in
patients with COPD than in patients without the disease
and increase the risk of death114. These co-morbidities
include coronary artery disease, arrhythmias including
tachycardia, hypertension and congestive heart failure.
Of particular importance are the increased risks of lung
cancer, depression and anxiety, metabolic syndrome
and osteoporosis114. As all of these are potentially treat-
able, the health care provider treating a patient with
COPD should actively look for them and help guide
their treatment.
Imaging. The presence of cough, sputum or dys­
pnoea is not specific for COPD and can be present in
many other diseases. Thus, the evaluation of a patient

10 | 2015 | VOLUME 1 www.nature.com/nrdp

© 2015 Macmillan Publishers Limited. All rights reserved

 PRIMER

suspected of having COPD frequently includes a
chest X‑ray. Although not confirmatory of COPD,
a chest X‑ray helps eliminate other diagnoses, such as
interstitial lung diseases, congestive heart failure, pleural
effusions and most pulmonary infections. CT scanning
can estimate the degree of emphysema and its distribu-
tion and identify bronchial wall thickening, bronchi-
ectasis (widening of the airway) and gas trapping (on
expiration views). Several computerized automatic quan-
titative techniques have been applied to measure these
parameters, but they have not become routine in clini-
cal practice owing to the complex and time-­consuming
nature of the quantitative analysis. Furthermore, in most
studies, the visual interpretation of an expert radiologist
provides similar information to automatic techniques115.
The proven benefit of lung cancer screening by inter-
mittent serial CT scans in smokers >50 years of age has
made chest CT a valuable tool for the integral evaluation
Triggers COPD airway Therapy
Antibiotics
Viruses
of patients with COPD. Such screening efforts are very
important, as the presence of airflow limitation as meas-
ured by spirometry and of emphysema as evaluated by
CT significantly increases the risk of lung cancer 116 and
worsening of lung function over time117.
Biomarkers. Although desirable, several studies have
failed to find a routine clinically useful biomarker that
helps to grade or follow disease severity or activity in
either sputum, exhaled air condensate, broncho­alveolar
lavage or serum118. Markers of inflammation such a
C‑reactive protein (CRP) and several cytokines have pre-
dictive power for mortality and hospitalization when used
singly or in combination with others, but only margin­ally
improve the prediction when used in addition to clinical
variables119. Several other biomarkers are associ­ated with
certain disease characteristics; the levels of uteroglobin
(also called club cell 16 protein) in serum are inversely
related to FEV1 decline117, as are the serum levels of the
soluble receptor for activated glycosylation end products
(sRAGEs) to emphysema120. Pilot studies using high-
throughput technologies (proteomics and metabolomics)
have shown some promise in identifying biomarkers121,
and several ongoing studies will help to clarify their value
in patients with COPD. However, to date, none can be
recommended for clinical use.

Screening
Baseline state Screening asymptomatic individuals is not recom-
Steroids
mended as there are currently no data showing that out-
comes improve among individuals identified as having
Bacteria
COPD before developing symptoms122. There are also
no data to support that early treatment provides any
Bronchodilators benefit in asymptomatic individuals or that screening is
cost effective122. Nevertheless, all guidelines recommend
screening symptomatic individuals at risk for COPD.
Pollutants
A schematic algorithm to approximate individuals with
possible COPD is shown in FIG. 10.
Pulmonary
Heightened inflammation rehabilitation
(oxidative stress, bronchoconstriction, Prevention
oedema and mucus) The most effective way to combat the worldwide
epidemic of COPD is the implementation of social,
economic and educational programmes aimed at
Physiology decreasing the uptake of cigarette smoking 1,92. This
Physiological change primary prevention effort should be particularly aimed
■ Airway resistance
■ Airway trapping at teenagers, as this is the group in which addiction
begins and is the target of large tobacco corporations123.
Educational campaigns and implementation of smoke-
Compensation Adaptation free spaces should be accompanied by socioeconomic
■ Musculoskeletal ■ Behavioural
■ Respiratory centre ■ Cognitive
initiatives, such as heavy taxation of tobacco products.
■ Cardiac ■ Psychosocial The uptake of these programmes by society is possible,
as has been shown by the marked decrease in smok-
ing prevalence in the United States124. For smokers of
all ages, secondary prevention with active use of edu-
Quality Risk of future Disease cational material, behaviour modification and substi-
Symptoms Hospitalization of life exacerbation progression Death tutive nicotine therapy has also proven to be effective
Patient outcomes and to result in improved outcomes. The arrival of the
Figure 8 | Mechanisms and effects of COPD exacerbations.  Increased inflammation electronic cigarette that can deliver inhaled doses of
Nature Reviews | Disease Primers nicotine approaching that of cigarettes is under cur-
caused by bacteria, viruses or pollutants results in inflammation of the airways that
causes further airway narrowing and systemic inflammation. COPD, chronic obstructive rent research because the consequences of that habit
pulmonary disease. remain unknown125.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 11

© 2015 Macmillan Publishers Limited. All rights reserved

PRIMER

The other considerable risk factor that can be con-
trolled is that of exposure to biomass combustion par-
ticles1. Improvement in working environments and the
construction of dwellings with gasoline, gas or electric
stoves have been shown to result in decreases in the
preva­lence and/or consequences of respiratory ill-
nesses126. A concerted effort from all members of soci-
ety should bring this scourge under control. As poverty
is a major risk factor, general improvement in living
­conditions and diet might also be efficacious.
effect on future disease progression and mortality as
well as on symptoms130. However, as COPD is the result
of cumulative exposures, with biomass fuel exposure
playing a major part globally, exposure reduction must
be viewed in a broader context. Reduction of indoor
pollution, such as through improving biomass stoves
and kitchen ventilation, affects symptoms and future
decline in lung function14,15. Management of symptoms
and future risk includes both non-pharmacological and
­pharmacological treatment.

Management Non-pharmacological treatment. Pulmonary rehabili­

A good patient–doctor relationship and proper follow‑
­up of treatment is needed for optimal management 1.
Focus on both non-pharmacological and pharmaco-
logical treatment is required, as is a focus on patient
behaviour, not least adherence to treatment 127. Self-
management plans have become widespread, but caution
is warranted as trials of self-management have produced
conflicting results128. Similarly, the use of telehealth as
part of COPD management is increasing, despite the
lack of firm evidence of its effectiveness129; more-robust
studies of this approach are clearly needed.
Stable disease
Management of stable (non-exacerbating) disease can
be divided into the following categories: reducing expo-
sure to harmful substances, relief of symptoms and
redu­cing risk, mainly the risk of exacerbations (TABLE 2).
Most regional and national COPD guidelines follow,
to some extent, the recommendation outlined in the
GOLD strategy 1. Smoking cessation has a substantial
tation can be defined as “an interdisciplinary pro-
gramme of care for patients with chronic respiratory
impairment that is individually tailored and designed to
optimize each patient’s physical and social performance
and autonomy. Programmes comprise individualised
exercise programmes and education” (REFS 131–133).
Pulmonary rehabilitation improves exercise capacity,
reduces breathlessness, improves health status, improves
physical activity and activities of daily living and
improves psychological status133. Advice on increased
physical activity has not been proven to be efficacious in
this context but seems logical given the general benefits
of physical activity 1,134.
Pharmacological treatment. Treatment with broncho­
dilators is the mainstay of pharmacological management
of symptoms and primarily addresses breathless-
ness. Bronchodilators include β2-agonists and mus-
carinic receptor antagonists (anticholinergics) (FIG. 11).
Inhaled long-acting bronchodilators of 12–24 hours

More emphysema Less emphysema

Pink puffer Blue bloater

■ Lower body mass index
■ Fewer cardiovascular co-morbidities
■ Fewer metabolic co-morbidities
■ Less muscle mass
■ Hyperinflation
■ Low diffusion capacity for CO
■ More dyspnoea
■ Decreased exercise capacity
■ Worst health status
■ Lower serum levels of sRAGEs
■ Higher body mass index
■ More metabolic co-morbidities
■ Cardiac compromise
■ OSA–COPD overlap
■ Less hyperinflation
■ More chronic bronchitis
■ Increased exacerbations
■ More normal diffusion capacity
■ Higher serum levels of inflammatory
markers (IL-6 and CRP)

Figure 9 | Clinical and radiological characteristics of the classic phenotypes of patients with COPD.
Nature Reviews | Disease Primers
The ‘pink puffer’ and ‘blue bloater’ are two classic phenotypes (traits) of chronic obstructive pulmonary disease (COPD).
Although hypothesis-free studies have confirmed their presence in cohorts of patients with COPD, most patients will have
a combination of these classic characteristics. CO, carbon monoxide; CRP, C-reactive protein; OSA, obstructive sleep
apnoea; sRAGE, soluble receptor for activated glycosylation end product.

12 | 2015 | VOLUME 1 www.nature.com/nrdp

© 2015 Macmillan Publishers Limited. All rights reserved

 PRIMER

Person at risk
Cough, sputum production and family history

Spirometry

FEV1/FVC: <0.7 FEV1/FVC: <0.7

FEV1: >80% FEV1: <80%

Evaluate severity
FEV1 during exercise, dyspnoea, co-morbidities and exacerbations

Moderate (GOLD2) Severe (GOLD3) Very severe (GOLD4)

Mild (GOLD1)
Treat obstruction, educate Treat obstruction, educate Educate patient,
Educate patient
patient, manage risk patient, manage risk manage risk, and assess
and manage risk
and monitor response and monitor response and treat hypoxaemia

Lung reduction
Consider rehabilitation Rehabilitation
or transplantation

Figure 10 | Algorithm for the diagnosis, staging and management programme for COPD.  COPD, chronic obstructive
Nature
pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; Reviews
GOLD, Disease Primers
Global |Initiative
for Chronic Obstructive Lung Disease.

of duration are preferred and, of these, long-acting
β 2-agonists (LABAs) and long-acting muscarinic
antago­nists (LAMAs) are equally effective1. Long-acting
bronchodilators improve lung function, reduce breath-
lessness, improve exercise capacity and improve health
status. There are only minor differences between indi-
vidual bronchodilators, and the choice of drug for an
individ­ual patient will often depend on patient prefer­
ence, availability and cost. The symptomatic effect of
long-acting bronchodilators is due to their effect on
operating lung volumes rather than on decreased air-
flow limitation135 and, for this reason, there is a limi­
ted correlation between effect on FEV1 and symptoms
in the individual patient. The symptomatic effect of a
long-­acting broncho­dilator cannot be predicted by the
response a patient has to a short-acting bronchodilator.
Patients with a history of exacerbations and/or low lung
function are at particular risk of future exacerbations90.
Several drug classes reduce the risk of exacerbations,
including long-acting bronchodilators, inhaled corti-
costeroids (ICSs), macrolides, phosphodiesterase type 4
(PDE4) inhibitors and mucolytics, as discussed below 1.
Adverse effects are mainly limited to dryness of the
mouth for anticholinergics, and tremor and hypokalae-
mia for β2-agonists. The cardiovascular safety of long-
acting bronchodilators has been debated, but recent
trials indicate that they are safe in patients who have
stable cardiovascular disease136–138. The two classes of
long-acting bronchodilators can be combined, but the
symptomatic effects of combined treatment are less
impressive than the almost additive effect they have
on lung function 139. ICSs also improve lung func-
tion and reduce breathlessness140; however, the ratio
between benefits and adverse effects is insufficient
for recommending ICSs for symptomatic treatment.
Finally, long-term oxygen therapy, usually interpreted
as oxygen for at least 15 hours per day, has, in two rela-
tively old ­trials, been shown to reduce mortality over
subsequent years, presumably through protecting the
right side of the heart from hypoxia-induced secondary
pulmonary hypertension1.
Surgical intervention. Lung volume reduction surgery
and transplantation are evidence-based interventions
that can improve survival and quality of life in highly
selected patients, usually those with very severe disease.
Valves and coils placed in the segmental bronchi during
bronchoscopy are still at an experimental stage141.
Exacerbations
The main symptoms of a COPD exacerbation are
increases in dyspnoea, sputum purulence and cough,
but other symptoms might include increased wheezing
and symptoms of a cold142. Although changes in lung
function also occur during a COPD exacerbation, falls
in FEV1 values are small and are not generally useful in
predicting or monitoring exacerbations. Exacerbations
generally last for several days but as long as 12 weeks can
elapse before returning to baseline status.
COPD exacerbations are defined in the GOLD
strategy in terms of health care use as “an acute event
characterized by a worsening of the patient’s respiratory
symptoms that is beyond normal day‑to‑day variations
and leads to a change in medication” (REF. 1). However,
there is now considerable evidence to indicate that
more than half of all COPD exacerbations identified
by symptom worsening are not reported to health care
professionals and are left untreated143. In addition, these
untreated COPD exacerbations, although generally less
severe than those that are treated, might affect health
status143. Accordingly, patients must be encouraged to
report exacerbations for review by their physicians.

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PRIMER
Table 2 | Management of stable COPD
Aim Treatment Considerations
Symptom Pulmonary rehabilitation and Suitable for all patients
reduction* physical exercise
Short-acting inhaled Only for relief of symptoms
bronchodilators
One long-acting inhaled LABA and LAMA have similar clinical
bronchodilator (LABA or LAMA) effects
LABA–LAMA combination When a single, long-acting
bronchodilator is not sufficiently
effective
Risk One long-acting LAMA preferred over LABA
reduction‡ bronchodilator
ICS–LABA combination If there is no bacterial colonization and
the blood eosinophil count is >32%
LABA–LAMA combination When bacterial colonization is present
and the blood eosinophil count is <2%
Roflumilast Only in patients with concomitant
chronic bronchitis
ICS, inhaled corticosteroid; LABA, long-acting β2-adrenergic receptor agonist; LAMA,
long-acting muscarinic antagonist. *Always consider co-morbidities. ‡Patient with two or more
exacerbations per year and usually with a forced expiratory volume in 1 second of <50% of
predicted normal.
COPD exacerbations are a major cause of admissions
and readmissions to hospital and are also independent
predictors of mortality in COPD. Moreover, exacerba-
tions drive disease progression, with some studies find-
ing that up to 25% of the lung function decline in COPD
is attributable to exacerbations, whereas other studies
have found that exacerbations contribute significantly
less to lung function decline144,145. COPD exacerbations
are a major determinant of health status in COPD, and
any intervention that reduces exacerbation will affect
health status89. COPD exacerbations are also associ-
ated with cardiovascular events, especially myocardial
infarction, and this association is most marked in severe
­exacerbations that require hospital admission146,147.
Pharmacological treatment. Management of an exacer­
bation comprises oral antibiotics, such as amoxicillin
or doxycycline, if there is evidence of increased sputum
purulence or volume148. The choice of antibiotic will
depend on the patient’s history and underlying disease
severity. Oral corticosteroids in short courses are also
added, depending on the individual exacerbation sever-
ity, and there is recent evidence to suggest that shorter
courses (5 days) of corticosteroids might be as beneficial
as longer courses, such as the more conventional 14 day
courses149. There is some evidence to suggest that oral
corticosteroids are more effective in patients who have
increased blood eosinophil numbers during their exacer­
bation, but further prospective studies are needed to con-
firm these findings150. There is evidence that, the ­earlier
that therapy is started at the onset of an exacerbation,
the shorter the recovery of the event and the less chance
of hospital admission143. Thus, prompt and appropri-
ate management of the exacerbation event will have an
effect on optimizing recovery and will delay the time to
the next event. In summary, optimal management of
14 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
the acute exacerbation will not only increase the rate of
exacer­bation recovery but will also affect exacerbation
rates and prevent hospital admissions.
Exacerbation prevention. Influenza vaccination is
associ­ated with a 27% reduction in the risk of hospitali-
zation triggered by influenza virus infection in elderly
individ­uals151; therefore, influenza vaccination is recom-
mended for the majority of patients with COPD. There
is less evidence to support the use of a pneumo­coccal
polysacchari­de vaccine in the prevention of COPD
exacer­bations, but large studies are currently underway
with vaccines that have improved immunogenicity.
Use of long-acting bronchodilators reduces the risk
of exacerbations by approximately 25%152,153. The same
effect size is seen for ICS use, and the mechanisms that
underlie the effects of various pharmacological agents on
preventing exacerbations are likely to differ as the effect of
combined treatment with a LABA and ICS is better than
that for each drug alone140. Some exacerbations require
treatment with systemic corticosteroids, and although
the use of an ICS alone reduces exacerbations by approxi-
mately 25%140, monotherapy with an ICS is not recom-
mended by GOLD1. The use of ICSs should be restricted
to patients who are at high risk of exacerbations, should
probably be restricted to patients without lower airway
bacterial colonization and, based on post-hoc analyses
of recent trials, should not be given to patients with <2%
eosinophils in the peripheral blood in stable disease154,155.
In addition to well-known local adverse effects, such as
oral thrush and hoarse voice, ICSs are associated with an
increased risk of pneumonia and they might increase the
risk of osteoporosis130,156.
LAMAs alone also reduce exacerbation frequency 137
and have a greater effect on exacerbation reduction than
LABAs157. LABA–ICS combinations and LAMA have
simi­lar effects on exacerbations in patients with severe and
very severe COPD (an FEV1 of <50% of predicted normal);
therefore, LAMAs can be used as an alternative to LABA–
ICS combinations in these patients158. A LABA–LAMA
combination (indacaterol and glycopyrronium) has been
evaluated in patients with a FEV1 of <50% of predicted
normal and a history of exacerbations. The combina-
tion treatment resulted in fewer health care use exacer-
bations than glycopyrronium alone and was marginally
­better than either glycopyrronium or open-label tiotro-
pium in the reduction of all exacerbations when mild,
moderate and severe exacerbations were combined159.
Roflumilast is a PDE4 inhibitor with broad anti-
inflammatory activity and inhibits the airway inflam-
mation associated with COPD, especially by reducing
the number of airway neutrophils that are key to
COPD pathogenesis. Evidence from two large placebo-­
controlled, double-blind multicentre trials has revealed
that roflumilast use results in a 17% reduction in the fre-
quency of moderate or severe exacerbations160. However,
only patients with a FEV1 of <50% of predicted normal
(GOLD3 and GOLD4), presence of bronchitis symptoms
and a history of exacerbations were enrolled in these stud-
ies. A recent study has shown only marginal benefit when
roflumilast is added to standard triple COPD therapy 161.

Antibiotics have also been investigated for their effi-
cacy in reducing exacerbation frequency. For instance,
a low dose of the macrolide erythromycin reduces the
frequency of exacerbations and shortens exacerbation
length in patients with moderate-to-severe COPD162.
Azithromycin, another macrolide, when added to
usual treatment decreases exacerbation frequency
and improves quality of life in patients with COPD163.
However, significant rates of hearing decrement (as
measured by audiometry) and antibiotic resistance
were reported for azithromycin use164. Further studies
are required to address the issue of antibiotic resistance
in long-term antibiotic trials in COPD. Cardiovascular
adverse effects have also been reported with macrolides.
Further studies with non-macrolide antibiotics are
ongoing and these will also need to assess issues of safety
and resistance. Before use of any long-term antibiotics,
patients should be treated with an optimum combina-
tion inhaled therapy for COPD and show evidence of
ongoing exacerbations despite therapy. In addition,
Postganglionic
cholinergic nerve
Airway smooth
muscle cell
Cholinergic tone Cholinergic tone
Airway resistance Airway resistance
Air trapping Air trapping
M3-receptor Acetylcholine Muscarinic antagonist
β2-receptor β2-agonist SABA or LABA SAMA or LAMA
Figure 11 | Effects of bronchodilators in COPD.  Postganglionic cholinergic nerves
tonically release acetylcholine, activating muscarinic MNature Reviews
receptors | Disease
on airway Primers
smooth
3
muscle cells, which in turn leads to bronchoconstriction. This activation causes a marked
increase in peripheral airway resistance as the small airways are already structurally
narrowed in chronic obstructive pulmonary disease (COPD). Muscarinic antagonists
(anticholinergics) block M3-receptors and thus reduce cholinergic tone, resulting in
reduced airway resistance and reduced air trapping. Muscarinic antagonists can be
short-acting (SAMA, such as ipratropium bromide) or long-acting (LAMA, such as
tiotropium bromide or glycopyrronium bromide). β2-adrenergic receptor agonists
(β2-agonists) activate β2-receptors on airway smooth muscle, which functionally
antagonize cholinergic tone and have the same bronchodilator effect as muscarinic
antagonists. β2-agonists can be short-acting (SABA, such as salbutamol (albuterol)) or
long-acting (LABA, such as salmeterol and indacaterol). There are additive
bronchodilator effects when LAMAs and LABAs are given together.
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 15
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
careful monitoring of potential auditory and cardio­
vascular adverse effects (by monitoring the QTc interval,
for instance) are necessary.
Mucolytic drugs reduce the viscosity of airway
mucus to improve airflow. Two large Chinese studies
have shown that mucolytics reduce exacerbation fre-
quency 165,166. However, it is unclear whether this effect
is due to the mucolytic or antioxidant effects of these
drugs. Moreover, the drugs were tested in a popula-
tion with little concomitant treatment. For this reason,
­mucolytic treatment is not widely recommended.
There has been considerable interest in performing
pulmonary rehabilitation, including physical training,
early in the time course of an exacerbation or shortly
after admission to hospital to reduce the frequency or
severity of subsequent exacerbations. Although results
from initial pilot studies were promising, two well-
designed studies have shown little benefit of early inter-
vention with pulmonary rehabilitation courses167,168.
Finally, pulmonary rehabilitation has been shown to
reduce the length of subsequent exacerbations.
Quality of life
Health status is defined as “the impact of health on a
person’s ability to perform and derive fulfilment from
the activities of daily life. A patient’s self-reported health
status thus includes health-related quality of life and
functional status” (REF. 169). Patients with COPD report
an impaired health status, irrespective of the severity of
the disease170. An improvement in health status is associ-
ated with starting polymedication, pulmonology visits,
balanced diet, completing a rehabilitation programme,
smoking cessation and a reduction in the number of
exacerbations. By contrast, a decline in health status is
associated with worsening respiratory symptoms and
increased hospitalizations171. However, vice versa, the
health status of patients with COPD has been shown
to independently predict polypharmacy 172, future
exacer­bations, hospitalizations173 and survival174. This
bi­directional association underlines the importance of
the routine monitoring of health status in these patients.
Indeed, health status measurement can be defined as
“a process that is essentially similar to a highly struc-
tured clinical history, although the end product is not a
clinical impression but an objective measurement … It is
no more “soft” … than any well taken clinical history”
(REF. 175). Consequently, GOLD includes health status
as an objective for COPD diagnosis and management 1.
Owing to the systemic effects of the disease, one
study found that 97.7% of patients with COPD had
one or more co-morbidity and 53.5% were diagnosed
with four or more co-morbidities176. Each additional
co-morbidity increases the chance of worsening of self-
rated health by 43%177. Vanfleteren and colleagues176
identified five co-morbidity clusters and showed that
clinical characteristics were comparable between these
clusters. However, patients differed in terms of health
status, with worst health status scores for those in the
cardiovascular and psychological co-morbidity cluster
than for those with other co-morbidities176. Indeed,
cardiovascular diseases are probably the most frequent
PRIMER
COPD, progressive airflow limitiation
Dyspnoea
Health status
Exacerbations and
hospitalizations
Dyspnoea
Health status
Exacerbations and
hospitalizations
Increased risk of dying
Figure 12 | Downward spiral of health-related quality
Nature Reviews | Disease Primers
of life in COPD.  The progressive airflow limitation that
accompanies chronic obstructive pulmonary disease
(COPD) leads to a spiralling decline in health-related
quality of life through a range of mechanisms, including
increased dyspnoea and increased rates of disease
exacerbation and hospitalization.
and important diseases that coexist with COPD178, and
impaired cardiac function is associated with worse
survival in patients with COPD179. However, although
not directly pathophysiologically related to COPD,
symptoms of anxiety and depression are highly preva-
lent in those with COPD180 and have been shown to be
­associated with poor adherence to treatment strategies181.
Thus, patients with an impaired health status are at
risk of poor outcomes and prognoses, which can then be
worsened by co-morbidities (FIG. 12). Unfortunately, co-
morbidities are often underdiagnosed and consequently
under-treated, which might consequently worsen
COPD prognosis. Owing to shared risk factors and
pathophysio­logical mechanisms, determining whether
the co-morbidity or COPD itself causes the symptoms
at hand remains challenging 182. Nonetheless, establish-
ing the prevalence of co-morbidities and their effect on
health status as an essential patient-related outcome
remain important targets for COPD studies as well as
for COPD diagnosis and management.
Outlook
Considerably more research is needed on all aspects of
COPD as we still have a relatively poor understanding
of disease mechanisms and natural history. In addition,
we need more-effective pharmacological therapies that
target the underlying disease process.
Defining phenotypes
As with other complex diseases, there are several clini-
cal phenotypes of COPD, with some patients show-
ing predominantly small airway disease and little
­emphysema, whereas others have more-predominant
emphysema. Although air trapping, bronchial wall
thickening and emphysema can be detected with a CT
scan, CT scans are not undertaken routinely and patients
in clinical trials are usually not categorized on the basis
16 | 2015 | VOLUME 1 www.nature.com/nrdp
© 2015 Macmillan Publishers Limited. All rights reserved
of CT results. CT scans are also able to demonstrate
bronchi­ectasis, which is present in almost half of patients
with COPD and is associated with a worse prog­nosis183.
Other COPD phenotypes relate to predominant co-
morbidities — particularly cardiovascular disease — that
have an important influence on disease outcome. Several
attempts have been made to categorize patients into
clinical clusters based on these phenotypes, but these
have not been validated184. In addition, although asthma
and COPD are distinct diseases, in 10–20% of patients
with COPD there are also features of asthma, such as
eosinophilic inflammation, more airway reversibility
and a better therapeutic response to cortico­steroids than
those with classic COPD. This ‘asthma–COPD overlap
syndrome’ is poorly defined and characterized58.
We are also far from defining molecular phenotypes
or endotypes of COPD that relate to different disease
mechanisms. However, this is an important future aim
as this is likely to be necessary to provide the most effect­
ive targeted therapy as part of a personalized medicine
approach. Much of the current research on molecular
phenotypes is undertaken on advanced disease, in which
to the discernment of different phenotypes might be
more difficult. Thus, it will be increasingly necessary
to study early disease before fixed airflow limitation
(and symptoms) develop.
Currently, the recognition of different phenotypes,
such as small airway disease and emphysema, does not
substantially alter management strategies, but as more
specific therapies are developed it might be beneficial
to target them to specific phenotypes. For example,
asthma–COPD overlap syndrome might respond better
to corticosteroid therapy and to specific anti-eosinophil
treatments, such as antibodies that block IL‑5, than other
COPD phenotypes185.
Biomarkers of disease activity and progression
There is a need to develop easily measured biomarkers
that quantify disease activity, susceptibility to exacerba-
tions, co-morbidities and disease progression, as well as
biomarkers that predict and monitor response to ther-
apy. So far biochemical, proteomic and lipid biomarkers
in the blood, sputum and exhaled breath have not been
found to be useful in predicting clinical outcomes in
COPD, but more research is needed to develop patterns
of biomarkers118. The most promising blood biomarkers
are pulmonary surfactant-associated protein D, fibrino-
gen, club cell 16 protein and CC-chemokine ligand 18
(also called pulmonary and activation-regulated
chemokine), but the clinical value of these in predicting
future risk and response to therapy is not yet clear 186.
Understanding disease susceptibility
Not all chronic smokers develop airflow limitation,
indicating that there are susceptibility factors or per-
haps, more importantly, mechanisms that prevent these
individ­uals from developing COPD, but these remain
largely unknown. Identified genetic poly­morphisms
account for a small proportion (approximately 30%)
of this susceptibility, and it is likely that there are
other determinants and complex gene–environment
 PRIMER

interactions that contribute to COPD risk. Epigenetic
mechanisms such as DNA methylation and histone
modification, including acetylation and methylation, that
are influenced by environmental factors, such as diet, are
also likely to be important and are currently being eluci-
dated187. It is important to better understand the molecu-
lar mechanisms for susceptibility, as this would provide
potential new therapeutic targets and might also lead to
diagnostic tests to quantify this susceptibility.
Novel therapeutic targets and treatments
Although we now have effective long-acting broncho­
dilators that provide considerable symptomatic benefit
for patients with COPD, these drugs do not target the
underlying disease process and as such do not reduce dis-
ease progression or mortality. Unlike asthma, there are
no safe and effective anti-inflammatory treatments for
COPD. Because of the high economic impact of COPD,
there is now extensive investment in the search for novel
anti-inflammatory therapies. Several novel therapeutics
are currently being investigated188 (FIG. 13). These drugs
include specific mediator antagonists and cytokine block-
ers as well as a broad range anti-­inflammatory therapies,
such as kinase and PDE inhibitors, all of which have so
far proved to be disappointing in clinical trials, because
they are too specific, are dose-limited by adverse effects
or have not been targeted to responsive patients189–191.
Another important reason for drug failure may be that
only approximately half of patients with COPD have
accelerated decline in lung function, and the remaining
patients have normal decline starting from a reduced
peak function owing to small lungs2.
The PDE4 inhibitor roflumilast is the only anti-
inflammatory treatment so far approved for COPD,
but it has little clinical impact, as the dose that can be
administered is limited by adverse effects161. Another
future approach is to reverse the molecular mechanisms
of cortico­steroid resistance in COPD with existing

Smoking cessation
Nicotine antagonists
and vaccination Cigarette smoke and biomass burning

Oxidative Antioxidants
TLR blockers TLR Inflammasome stress
Inflammasome Reversal
Corticosteroid of steroid
inhibitors resistance resistance

Epithelial cells
Alveolar Defective
macrophage phagocytosis
Bacterial
colonization

Chemotactic Chemokine Antibiotics

Fibroblast Dendritic factors antagonists Phagocytosis
cell

Inflammation

Anti-inflammatory
TH1 cell CD8+ cytotoxic TH17 cell Neutrophil Monocyte treatments
T cell ■ PDE4 inhibitors
Antiproteases ■ Epigenetic
Proteases ■ NE inhibitors modulators
■ MMP9 inhibitors Kinase inhibitors
Antifibrotic agents
■ Anti-TGFβ
■ PPARγ agonists

Regeneration
■ Retinoic acid Mucoregulators
■ Stem cells EGFR inhibitors

Small airway fibrosis Emphysema Mucus hypersecretion

Nature Reviews | Disease Primers

Figure 13 | Potential targets for novel COPD therapy.  Potential strategies and new therapies for chronic obstructive
pulmonary disease (COPD) treatment are shown in the green boxes. EGFR, epidermal growth factor receptor;
MMP9, matrix metalloproteinase 9; NE, neutrophil elastase; PDE4, phosphodiesterase type 4; PPARγ, peroxisome
proliferator-activated receptor-γ; TGFβ, transforming growth factor-β; TH, T helper; TLR, Toll-like receptor. Figure from
REF. 188, Nature Publishing Group.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 17

© 2015 Macmillan Publishers Limited. All rights reserved

PRIMER

treatments, such as theophylline, or novel inhaled thera-
pies192. As oxidative stress is an important driving mech-
anism in COPD, there is also a search for more-effective
antioxidants76. If effective and safe anti-­inflammatory
therapy can be developed, it might be used at a much
­earlier stage in disease progression as a preventive treat-
ment to reduce the risk of future events, such as exacerba-
tions, disease progression, co-­morbidities and mortality.
An effective anti-inflammatory treatment might also be
useful in the acute management of an exacer­bation,
either to prevent the need for ­hospitalization or to more
rapidly resolve the episode193.
COPD as part of multimorbidity
As discussed above, COPD is commonly associated
with co-morbidities, particularly cardiovascular and
metabolic diseases and lung cancer, which have a sub-
stantial effect on its clinical course and prognosis. There
is increasing evidence to indicate that COPD is a com-
ponent of multimorbidity, and a network analysis has
identi­fied important links between these diseases194.
These linked diseases share molecular pathways of
acceler­ated ageing, including cellular senescence,
stem cell exhaustion, mitochondrial defects, impaired
autophagy and reduced levels and activity of anti-ageing
mol­ecules, such as sirtuins73. This interaction suggests
that it might be possible to develop novel therapies that
target these common pathways and thus treat COPD and
its co‑morbidities­simultaneously.
Increasing awareness
Despite the high prevalence, morbidity and mortality
of COPD, this disease remains poorly recognized by
the general public, general practitioners and special-
ists outside pulmonary medicine. This lack of aware-
ness is partly because the disease name is not well
understood and the disease itself is not well defined,
as there might be several diseases leading to the syn-
drome of fixed airway obstruction. It is important to
increase the diagnosis of COPD in general practice by
spirometry measurements in patients at risk, including
smokers and the elderly. However, there is also a need
for more research to understand the underlying disease
mechanisms and disease endotypes, as well as to iden-
tify useful biomarkers and develop new therapeutic and
management approaches.

1. Vestbo, J. et al. Global strategy for the diagnosis,
management and prevention of chronic obstructive
pulmonary disease, GOLD executive summary.
Am. J. Respir. Crit. Care Med. 187, 347–365 (2013).
This strategy document is often regarded as
the COPD standard and is the basis for most
national guidelines.
2. Lange, P. et al. Lung-function trajectories leading to
chronic obstructive pulmonary disease. N. Engl. J. Med.
373, 111–122 (2015).
3. Lozano, R. et al. Global and regional mortality from
235 causes of death for 20 age groups in 1990 and
2010: a systematic for the Global Burden of Disease
Study 2010. Lancet 380, 2095–2128 (2013).
4. Burney, P. G., Patel, J., Newson, R., Minelli, C.
& Naghavi, M. Global and regional trends in COPD
mortality, 1990–2010. Eur. Respir. J. 45, 1239–1247
(2015).
This paper demonstrates that the cross-sectional
association found between mortality from chronic
lung disease and gross national income is also
reflected in an association between the change in
mortality from chronic lung disease and the change
in gross national income. The association is less
prone to confounding by other large differences
between regions.
5. Gershon, A. S., Warner, L., Cascagnette, P., Victor, J. C.
& To, T. Lifetime risk of developing chronic obstructive
pulmonary disease: a longitudinal population study.
Lancet 378, 991–996 (2011).
6. Yawn, B. et al. Prevalence of COPD among
symptomatic patients in a primary care setting.
Curr. Med. Res. Opin. 25, 2671–2677 (2009).
7. Buist, A. S. et al. International variation in the
prevalence of COPD (the BOLD study): a population-
based prevalence study. Lancet 370, 741–750 (2007).
8. Menezes, A. M. et al. Tuberculosis and airflow
obstruction: evidence from the PLATINO study in Latin
America. Eur. Respir. J. 30, 1180–1185 (2007).
9. Hooper, R. et al. Risk factors for COPD spirometrically
defined from the lower limit of normal in the BOLD
project. Eur. Respir. J. 39, 1343–1353 (2012).
10. Blanc, P. D. et al. Further exploration of the links
between occupational exposure and chronic
obstructive pulmonary disease. J. Occup. Environ.
Med. 51, 804–810 (2009).
11. Chinn, S., Florey, C. D., Baldwin, I. G. & Gorgol, M.
The relation of mortality in England and Wales
1969–1973 to measurements of air pollution.
J. Epidemiol. Commun. Health 35, 174–179 (1981).
12. Salvi, S. & Barnes, P. Chronic obstructive pulmonary
disease in non-smokers. Lancet 374, 733–743
(2009).
13. Burnett, R. T. et al. An integrated risk function for
estimating the global burden of disease attributable
to ambient fine particulate patter exposure.
Environ. Health Persp. 122, 397–403 (2014).
14. Romieu, I. et al. Improved biomass stove intervention
in rural Mexico: impact on the respiratory health of
women. Am. J. Respir. Crit. Care Med. 180, 649–656
(2009).
15. Zhou, Y. et al. Lung function and incidence of chronic
obstructive pulmonary disease after improved cooking
fuels and kitchen ventilation: a 9‑year prospective
cohort study. PLoS Med. 11, e1001621 (2014).
16. Smith, M. et al. Prevalence and correlates of airflow
obstruction in 317,000 never-smokers in China.
Eur. Respir. J. 44, 66–77 (2014).
17. Burney, P. et al. Chronic obstructive pulmonary
disease mortality and prevalence: the associations
with smoking and poverty — a BOLD analysis. Thorax
69, 465–473 (2014).
This paper shows that the prevalence of airflow
obstruction is strongly associated with the
prevalence of smoking, as judged by the mean pack
years smoked, and that the prevalence of a low FVC
is strongly associated with poverty. The prevalence
of a low FVC is most closely associated with
mortality rates.
18. Office of Population Censuses and Surveys.
Occupational Mortality: The Registrar General’s
Decennial Supplement for Great Britain, 1979–80,
1982–1983 (Her Majesty’s Stationery Office, 1986).
19. Marks, G. & Burney, P. in The Health of Adult Britain
1841–1991 Vol. 2 (eds Charlton, J. & Murphy, M.)
93–113 (Her Majesty’s Stationery Office, 1997).
20. Barker, D. J. & Osmond, C. Childhood respiratory
infection and adult chronic bronchitis in England and
Wales. BMJ (Clin. Res. Ed.) 293, 1271–1275 (1986).
This is an early paper from Barker and Osmond
showing that mortality rates from chronic airway
disease later in adult life is associated with
mortality in the same areas from bronchitis and
pneumonia among children half a century earlier.
This association was not true for lung cancer rates,
and Barker and Osmond suggest that this is
evidence that the environment encountered during
early life has an important impact on subsequent
lung health.
21. Gnatiuc, L. et al. Gaps in using bronchodilators,
inhaled corticosteroids and influenza vaccine among
23 high- and low-income sites. Int. J. Tuberc. Lung Dis.
19, 21–30 (2015).
22. Ingebrigtsen, T. et al. Genetic influences on chronic
obstructive pulmonary disease — a twin study.
Respir. Med. 104, 1890–1895 (2010).
23. McCloskey, S. C. et al. Siblings of patients with severe
chronic obstructive pulmonary disease have a
significant risk of airflow obstruction. Am. J. Respir.
Crit. Care Med. 164, 1419–1424 (2001).
24. Silverman, E. K. et al. Genetic epidemiology of severe,
early-onset chronic obstructive pulmonary disease:
risk to relatives for airflow obstruction and chronic
bronchitis. Am. J. Respir. Crit. Care Med. 157,
1770–1778 (1998).
25. Zhou, J. J. et al. Heritability of chronic obstructive
pulmonary disease and related phenotypes in
smokers. Am. J. Respir. Crit. Care Med. 188,
941–947 (2013).
26. Silverman, E. K. & Sandhaus, R. A. Clinical practice.
Alpha1-antitrypsin deficiency. N. Engl. J. Med. 360,
2749–2757 (2009).
27. Sorheim, I. C. et al. α1-Antitrypsin protease inhibitor
MZ heterozygosity is associated with airflow
obstruction in two large cohorts. Chest 138,
1125–1132 (2010).
28. Molloy, K. et al. Clarification of the risk of chronic
obstructive pulmonary disease in α1‑antitrypsin
deficiency PiMZ heterozygotes. Am. J. Respir. Crit.
Care Med. 189, 419–427 (2014).
29. Rodriguez-Revenga, L. et al. A novel elastin gene
mutation resulting in an autosomal dominant form of
cutis laxa. Arch. Dermatol. 140, 1135–1139 (2004).
30. Kelleher, C. M. et al. A functional mutation in the
terminal exon of elastin in severe, early-onset chronic
obstructive pulmonary disease. Am. J. Respir. Cell.
Mol. Biol. 33, 355–362 (2005).
31. Wain, L. V. et al. Whole exome re‑sequencing
implicates CCDC38 and cilia structure and function
in resistance to smoking related airflow obstruction.
PLoS Genet. 10, e1004314 (2014).
32. Castaldi, P. J. et al. The COPD genetic association
compendium: a comprehensive online database
of COPD genetic associations. Hum. Mol. Genet. 19,
526–534 (2010).
33. Smolonska, J., Wijmenga, C., Postma, D. S.
& Boezen, H. M. Meta-analyses on suspected chronic
obstructive pulmonary disease genes: a summary
of 20 years’ research. Am. J. Respir. Crit. Care Med.
180, 618–631 (2009).
34. Cho, M. H. et al. Risk loci for chronic obstructive
pulmonary disease: a genome-wide association study
and meta-analysis. Lancet Respir. Med. 2, 214–225
(2014).
This collaborative genome-wide association study
identifies four genetic loci for moderate-to‑severe
COPD and two additional loci for severe COPD.
Although highly significant, these genetic loci are
of modest effect size.

18 | 2015 | VOLUME 1 www.nature.com/nrdp

© 2015 Macmillan Publishers Limited. All rights reserved


35. Hancock, D. B. et al. Meta-analyses of genome-wide
association studies identify multiple loci associated with
pulmonary function. Nat. Genet. 42, 45–52 (2010).
36. Repapi, E. et al. Genome-wide association study
identifies five loci associated with lung function.
Nat. Genet. 42, 36–44 (2010).
37. Soler Artigas, M. et al. Genome-wide association and
large-scale follow up identifies 16 new loci influencing
lung function. Nat. Genet. 43, 1082–1090 (2011).
38. Castaldi, P. J. et al. Genome-wide association identifies
regulatory loci associated with distinct local histogram
emphysema patterns. Am. J. Respir. Crit. Care Med.
190, 399–409 (2014).
39. Siedlinski, M. et al. Genome-wide association study
of smoking behaviours in patients with COPD. Thorax
66, 894–902 (2011).
40. Thorgeirsson, T. E. et al. Sequence variants at
CHRNB3–CHRNA6 and CYP2A6 affect smoking
behavior. Nat. Genet. 42, 448–453 (2010).
41. Amos, C. I. et al. Genome-wide association scan of tag
SNPs identifies a susceptibility locus for lung cancer
at 15q25.1. Nat. Genet. 40, 616–622 (2008).
42. Thorgeirsson, T. E. et al. A variant associated with
nicotine dependence, lung cancer and peripheral
arterial disease. Nature 452, 638–642 (2008).
43. DeMeo, D. L. et al. Integration of genomic and genetic
approaches implicates IREB2 as a COPD susceptibility
gene. Am. J. Hum. Genet. 85, 493–502 (2009).
44. Siedlinski, M. et al. Dissecting direct and indirect
genetic effects on chronic obstructive pulmonary
disease (COPD) susceptibility. Hum. Genet. 132,
431–441 (2013).
45. Zhou, X. et al. Identification of a chronic obstructive
pulmonary disease genetic determinant that regulates
HHIP. Hum. Mol. Genet. 21, 1325–1335 (2012).
With a COPD genome-wide association study
region, chromatin interaction studies followed by
functional analyses identified a likely functional
genetic variant. This is one of the first examples
of functional variant identification with a complex
disease genome-wide association study locus.
46. Lao, T. et al. Haploinsufficiency of Hedgehog
interacting protein causes increased emphysema
induced by cigarette smoke through network rewiring.
Genome Med. 7, 12 (2015).
47. Castaldi, P. J. et al. Genetic control of gene expression
at novel and established chronic obstructive
pulmonary disease loci. Hum. Mol. Genet. 24,
1200–1210 (2015).
48. Qiu, W. et al. Variable DNA methylation is associated
with chronic obstructive pulmonary disease and lung
function. Am. J. Respir. Crit. Care Med. 185,
373–381 (2012).
49. Hogg, J. C. & Timens, W. The pathology of chronic
obstructive pulmonary disease. Annu. Rev. Pathol. 4,
435–459 (2009).
50. McDonough, J. E. et al. Small-airway obstruction and
emphysema in chronic obstructive pulmonary disease.
N. Engl. J. Med. 365, 1567–1575 (2011).
51. Galban, C. J. et al. Computed tomography-based
biomarker provides unique signature for diagnosis
of COPD phenotypes and disease progression.
Nat. Med. 18, 1711–1715 (2012).
52. Peinado, V. I., Pizarro, S. & Barbera, J. A. Pulmonary
vascular involvement in COPD. Chest 134, 808–814
(2008).
53. Seeger, W. et al. Pulmonary hypertension in chronic
lung diseases. J. Am. Coll. Cardiol. 62, D109–D116
(2013).
54. Barnes, P. J. Cellular and molecular mechanisms of
chronic obstructive pulmonary disease. Clin. Chest
Med. 35, 71–86 (2014).
55. Brusselle, G. G., Joos, G. F. & Bracke, K. R. New
insights into the immunology of chronic obstructive
pulmonary disease. Lancet 378, 1015–1026 (2011).
56. Barnes, P. J. Immunology of asthma and chronic
obstructive pulmonary disease. Nat. Immunol. Rev. 8,
183–192 (2008).
57. McAleer, J. P. & Kolls, J. K. Directing traffic: IL‑17
and IL‑22 coordinate pulmonary immune defense.
Immunol. Rev. 260, 129–144 (2014).
58. Barrecheguren, M., Esquinas, C. & Miravitlles, M.
The asthma–chronic obstructive pulmonary disease
overlap syndrome (ACOS): opportunities and
challenges. Curr. Opin. Pulm. Med. 21, 74–79 (2015).
59. Barnes, P. J. Cytokine networks in asthma and chronic
obstructive pulmonary disease. J. Clin. Invest. 118,
3546–3556 (2008).
60. Di Stefano, A. et al. Increased expression of NF‑κB
in bronchial biopsies from smokers and patients with
COPD. Eur. Respir. J. 20, 556–563 (2002).
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 19
61. Renda, T. et al. Increased activation of p38 MAPK
in COPD. Eur. Respir. J. 31, 62–69 (2008).
62. Ito, K. et al. Decreased histone deacetylase activity
in chronic obstructive pulmonary disease. N. Engl.
J. Med. 352, 1967–1976 (2005).
This study demonstrates that COPD lungs have
decreased expression and activity of the nuclear
enzyme HD2, which is required for corticosteroids
to switch off inflammatory genes. This result
explains the amplified inflammation and
corticosteroid resistance in patients with COPD.
63. Taylor, A. E. et al. Defective macrophage phagocytosis
of bacteria in COPD. Eur. Respir. J. 35, 1039–1047
(2010).
64. Donnelly, L. E. & Barnes, P. J. Defective phagocytosis
in airways disease. Chest 141, 1055–1062 (2012).
65. Singh, R. et al. Inflammatory thresholds and the
species-specific effects of colonising bacteria in stable
chronic obstructive pulmonary disease. Respir. Res.
15, 114 (2014).
66. Mukaro, V. R. & Hodge, S. Airway clearance of
apoptotic cells in COPD. Curr. Drug Targets 12,
460–468 (2011).
67. Kirkham, P. A. et al. Oxidative stress-induced
antibodies to carbonyl-modified protein correlate with
severity of COPD. Am. J. Respir. Crit. Care Med. 184,
796–802 (2011).
68. Barnes, P. J. Chronic obstructive pulmonary disease:
effects beyond the lungs. PLoS Med. 7, e1000220
(2010).
69. Agusti, A. et al. Persistent systemic inflammation
is associated with poor clinical outcomes in COPD:
a novel phenotype. PLoS ONE 7, e37483 (2012).
70. Ito, K. & Barnes, P. J. COPD as a disease of
accelerated lung aging. Chest 135, 173–180 (2009).
71. Mercado, N., Ito, K. & Barnes, P. J. Accelerated ageing
in chronic obstructive pulmonary disease: new
concepts. Thorax 70, 482–489 (2015).
A review of the accelerated ageing process in
COPD and the molecular mechanisms involved;
this article also identifies novel targets for
future therapies.
72. Paschalaki, K. E. et al. Dysfunction of endothelial
progenitor cells from smokers and COPD patients due
to increased DNA damage and senescence. Stem Cells
31, 2813–2826 (2013).
73. Barnes, P. J. Mechanisms of development of
multimorbidity in the elderly. Eur. Respir. J. 45,
790–806 (2015).
74. Madeo, F., Zimmermann, A., Maiuri, M. C.
& Kroemer, G. Essential role for autophagy in life span
extension. J. Clin. Invest. 125, 85–93 (2015).
75. Mizumura, K., Cloonan, S. M., Haspel, J. A. &
Choi, A. M. The emerging importance of autophagy in
pulmonary diseases. Chest 142, 1289–1299 (2012).
76. Kirkham, P. A. & Barnes, P. J. Oxidative stress in
COPD. Chest 144, 266–273 (2013).
77. Caramori, G. et al. Unbalanced oxidant-induced DNA
damage and repair in COPD: a link towards lung
cancer. Thorax 66, 521–527 (2011).
78. Barnes, P. J. Corticosteroid resistance in patients with
asthma and chronic obstructive pulmonary disease.
J. Allergy Clin. Immunol. 131, 636–645 (2013).
79. Nakamaru, Y. et al. A protein deacetylase SIRT1 is
a negative regulator of metalloproteinase‑9. FASEB J.
23, 2810–2819 (2009).
80. Malhotra, D. et al. Expression of concern: decline in
NRF2 regulated antioxidants in COPD lungs due to
loss of its positive regulator DJ‑1. Am. J. Respir. Crit.
Care Med. 178, 592–604 (2008).
81. Mercado, N. et al. Decreased histone deacetylase 2
impairs Nrf2 activation by oxidative stress. Biochem.
Biophys. Res. Commun. 406, 292–298 (2011).
82. Hara, H. et al. Mitochondrial fragmentation in
cigarette smoke-induced bronchial epithelial cell
senescence. Am. J. Physiol. Lung Cell. Mol. Physiol.
305, L737–L746 (2013).
83. Mizumura, K. et al. Mitophagy-dependent necroptosis
contributes to the pathogenesis of COPD. J. Clin.
Invest. 124, 3987–4003 (2014).
84. Guenette, J. A., Webb, K. A. & O’Donnell, D. E. Does
dynamic hyperinflation contribute to dyspnoea during
exercise in patients with COPD? Eur. Respir. J. 40,
322–329 (2012).
85. Wedzicha, J. A. & Seemungal, T. A. COPD
exacerbations: defining their cause and prevention.
Lancet 370, 786–796 (2007).
This paper provides an excellent insight into
the nature of exacerbations of COPD, their
importance, clinical consequences and prevention
of their occurrence.
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
86. Seemungal, T. et al. Respiratory viruses, symptoms,
and inflammatory markers in acute exacerbations
and stable chronic obstructive pulmonary disease.
Am. J. Respir. Crit. Care Med. 164, 1618–1623
(2001).
87. George, S. N. et al. Human rhinovirus infection
during naturally occurring COPD exacerbations.
Eur. Respir. J. 44, 87–96 (2014).
88. Peacock, J. L. et al. Outdoor air pollution and
respiratory health in patients with COPD. Thorax 66,
591–596 (2011).
89. Seemungal, T. A. et al. Effect of exacerbation on
quality of life in patients with chronic obstructive
pulmonary disease. Am. J. Respir. Crit. Care Med.
157, 1418–1422 (1998).
90. Hurst, J. R. et al. Susceptibility to exacerbation
in chronic obstructive pulmonary disease. N. Engl.
J. Med. 363, 1128–1138 (2010).
91. Wedzicha, J. A., Brill, S. E., Allinson, J. P.
& Donaldson, G. C. Mechanisms and impact of
the frequent exacerbator phenotype in chronic
obstructive pulmonary disease. BMC Med. 11, 181
(2013).
92. Celli, B. R. & MacNee, W. Standards for the diagnosis
and treatment of patients with COPD: a summary
of the ATS/ERS position paper. Eur. Respir. J. 23,
932–946 (2004).
93. Barr, R. G. et al. Physician and patient perceptions
in COPD: the COPD Resource Network Needs
Assessment Survey. Am. J. Med. 118, 1415 (2005).
94. Cote, C. G. & Chapman, K. R. Diagnosis and treatment
considerations for women with COPD. Int. J. Clin.
Pract. 63, 486–493 (2009).
95. Lundback, B. et al. Not 15 but 50% of smokers
develop COPD? — Report from the Obstructive Lung
Disease in Northern Sweden studies. Respir. Med. 97,
115–122 (2003).
96. Sood, A. et al. Wood smoke exposure and gene
promoter methylation are associated with increased
risk for COPD in smokers. Am. J. Respir. Crit. Care
Med. 182, 1098–1104 (2010).
97. Celli, B. R., Halbert, R. J., Nordyke, R. J. & Schau, B.
Airway obstruction in never smokers: results from
the Third National Health and Nutrition Examination
Survey. Am. J. Med. 118, 1364–1372 (2005).
98. Stern, D. A., Morgan, W. J., Wright, A. L., Guerra, S.
& Martinez, F. D. Poor airway function in early infancy
and lung function by age 22 years: a non-selective
longitudinal cohort study. Lancet 370, 758–764
(2007).
99. Sanchez-Salcedo, P. et al. Disease progression in
young patients with COPD: rethinking the Fletcher
and Peto model. Eur. Respir. J. 44, 324–331 (2014).
100. Erb-Downward, J. R. et al. Analysis of the lung
microbiome in the ”healthy” smoker and in COPD.
PLoS ONE 6, e16384 (2011).
101. Burgel, P. R. et al. Clinical COPD phenotypes: a novel
approach using principal component and cluster
analyses. Eur. Respir. J. 36, 531–539 (2012).
102. Garcia-Aymerich, J. et al. Identification and
prospective validation of clinically relevant chronic
obstructive pulmonary disease (COPD) subtypes.
Thorax 66, 430–437 (2011).

103. Rennard, S. et al. Identification of five chronic
obstructive pulmonary disease subgroups with
different prognoses in the ECLIPSE cohort using
cluster analysis. Ann. Am. Thorac. Soc. 12, 303–312
(2014).
104. Miller, M. R. et al. Standardisation of spirometry.
Eur. Respir. J. 26, 319–338 (2005).
105. Swanney, M. P. et al. Using the lower limit of normal
for the FEV1/FVC ratio reduces the misclassification
of airway obstruction. Thorax 63, 1046–1051
(2008).
106. Hankinson, J. L., Odencrantz, J. R. & Fedan, K. B.
Spirometric reference values from a sample of the
general U. S. population. Am. J. Respir. Crit. Care
Med. 159, 179–187 (1999).
107. Celli, B. R. et al. The body-mass index, airflow
obstruction, dyspnea, and exercise capacity index
in chronic obstructive pulmonary disease. N. Engl.
J. Med. 350, 1005–1012 (2004).
This work provides the first objective evidence of
the importance of non-pulmonary involvement in
patients with COPD. In addition, it prospectively
validates the measurement of a multidimensional
index to prognosticate outcome in patients
with COPD.
108. Watz, H. et al. An official European Respiratory
Society statement on physical activity in COPD.
Eur. Respir. J. 44, 1521–1537 (2014).
PRIMER
109. Nici, L., ZuWallack, R. & American Thoracic Society
Subcommittee on Integrated Care of the COPD
Patient. An official American Thoracic Society
workshop report: the Integrated Care of the
COPD Patient. Proc. Am. Thorac. Soc. 9, 9–18
(2012).
110. Maltais, F. et al. An official American Thoracic Society/
European Respiratory Society statement: update on
limb muscle dysfunction in chronic obstructive
pulmonary disease. Am. J. Respir. Crit. Care Med.
189, e15–e62 (2014).
111. Puhan, M. A. et al. Expansion of the prognostic
assessment of patients with chronic obstructive
pulmonary disease: the updated BODE index and
the ADO index. Lancet 374, 704–711 (2009).
112. Jones, R. C. et al. Derivation and validation of a
composite index of severity in chronic obstructive
pulmonary disease: the DOSE index. Am. J. Respir.
Crit. Care Med. 180, 1189–1195 (2009).
113. Marin, J. M. et al. Multicomponent indices to predict
survival in COPD: the COCOMICS study. Eur. Respir. J.
42, 323–332 (2013).
114. Divo, M. et al. Comorbidities and risk of mortality
in patients with chronic obstructive pulmonary
disease. Am. J. Respir. Crit. Care Med. 186, 155–161
(2012).
115. Gietema, H. A. et al. Quantifying the extent of
emphysema: factors associated with radiologists’
estimations and quantitative indices of emphysema
severity using the ECLIPSE cohort. Acad. Radiol. 18,
661–671 (2011).
116. de Torres, J. P. et al. Lung cancer in patients with
chronic obstructive pulmonary disease — incidence
and predicting factors. Am. J. Respir. Crit. Care Med.
184, 913–919 (2011).
117. Vestbo, J. et al. Changes in forced expiratory volume
in 1 second over time in COPD. N. Engl. J. Med. 365,
1184–1192 (2011).
118. Barnes, P. J. et al. Pulmonary biomarkers in chronic
obstructive pulmonary disease. Am. J. Respir. Crit.
Care Med. 174, 6–14 (2006).
119. Kelly, E., Owen, C. A., Pinto-Plata, V. & Celli, B. R.
The role of systemic inflammatory biomarkers to
predict mortality in chronic obstructive pulmonary
disease. Expert Rev. Respir. Med. 7, 57–64 (2013).
120. Coxson, H. O. et al. The presence and progression
of emphysema in COPD as determined by CT scanning
and biomarker expression: a prospective analysis from
the ECLIPSE study. Lancet Respir. Med. 1, 129–136
(2013).
121. Pinto-Plata, V. et al. Profiling serum biomarkers
in patients with COPD: associations with clinical
parameters. Thorax 62, 595–601 (2007).
122. Qaseem, A. et al. Diagnosis and management of
stable chronic obstructive pulmonary disease:
a clinical practice guideline update from the American
College of Physicians, American College of Chest
Physicians, American Thoracic Society, and European
Respiratory Society. Ann. Intern. Med. 155, 179–191
(2011).
This document reviews the evidence for the
diagnosis and management of patients with stable
COPD. It was signed by all of the major medical
societies interested in clinical practice.
123. Wright, A. A. & Katz, I. T. Tobacco tightrope
— balancing disease prevention and economic
development in China. N. Engl. J. Med. 356,
1493–1496 (2007).
124. Ng, M. et al. Smoking prevalence and cigarette
consumption in 187 countries, 1980–2012. JAMA
311, 183–192 (2014).
125. Pisinger, C. & Dossing, M. A systematic review of
health effects of electronic cigarettes. Prev. Med. 69,
248–260 (2014).
126. Accinelli, R. A. et al. Adherence to reduced-polluting
biomass fuel stoves improves respiratory and sleep
symptoms in children. BMC Pediatr. 14, 12 (2014).
127. Vestbo, J. et al. Adherence to inhaled therapy,
mortality and hospital admission in COPD. Thorax 64,
939–943 (2009).
128. Wedzicha, J. A. & Vestbo, J. Can patients with COPD
self-manage? Lancet 380, 624–625 (2012).
129. Ure, J. et al. Piloting tele-monitoring in COPD: a mixed
methods exploration of issues in design and
implementation. Prim. Care Respir. J. 21, 57–64
(2012).
130. Dransfield, M. T. et al. Once-daily inhaled fluticasone
furoate and vilanterol versus vilanterol only for
prevention of exacerbations of COPD: two replicate
double-blind, parallel-group, randomised controlled
trials. Lancet Respir. Med. 1, 210–223 (2013).
20 | 2015 | VOLUME 1 www.nature.com/nrdp
131. O’Reilly, J., Jones, M. M., Parnham, J., Lovibond, K.
& Rudolf, M. Management of stable chronic
obstructive pulmonary disease in primary and
secondary care: summary of updated NICE guidance.
BMJ 340, c3134 (2010).
132. Casaburi, R. & ZuWallack, R. Pulmonary rehabilitation
for management of chronic obstructive pulmonary
disease. N. Engl. J. Med. 360, 1329–1335 (2009).
133. Bolton, C. E. et al. British Thoracic Society guideline
on pulmonary rehabilitation in adults. Thorax
68 (Suppl. 2), ii1–ii30 (2013).
134. Spruit, M. A. et al. An official American Thoracic
Society/European Respiratory Society statement: key
concepts and advances in pulmonary rehabilitation.
Am. J. Respir. Crit. Care Med. 188, e13–e64 (2013).
135. Parker, C. M., Voduc, N., Aaron, S. D., Webb, K. A.
& O’Donnell, D. E. Physiological changes during
symptom recovery from moderate exacerbations
of COPD. Eur. Respir. J. 26, 420–428 (2005).
136. Calverley, P. M. et al. Cardiovascular events in patients
with COPD: TORCH study results. Thorax 65,
719–725 (2010).
137. Tashkin, D. P. et al. A 4‑year trial of tiotropium
in chronic obstructive pulmonary disease. N. Engl.
J. Med. 359, 1543–1554 (2008).
138. Wise, R. A. et al. Tiotropium Respimat inhaler
and the risk of death in COPD. N. Engl. J. Med. 369,
1491–1501 (2013).
139. Singh, D. New combination bronchodilators for COPD:
current evidence and future perspectives. Br. J. Clin.
Pharmacol. 79, 695–708 (2015).
140. Calverley, P. M. et al. Salmeterol and fluticasone
propionate and survival in chronic obstructive
pulmonary disease. N. Engl. J. Med. 356, 775–789
(2007).
141. Gompelmann, D., Eberhardt, R. & Herth, F. J. Novel
endoscopic approaches to treating chronic obstructive
pulmonary disease and emphysema. Semin. Respir.
Crit. Care Med. 36, 609–615 (2015).
142. Seemungal, T., Harper-Owen, R., Bhowmik, A.,
Jeffries, D. J. & Wedzicha, J. A. Detection of
rhinoviruses in induced sputum at exacerbations of
chronic obstructive pulmonary disease. Eur. Respir. J.
16, 677–683 (2000).
143. Wilkinson, T. M., Donaldson, G. C., Hurst, J. R.,
Seemungal, T. A. & Wedzicha, J. A. Early therapy
improves outcomes of exacerbations of chronic
obstructive pulmonary disease. Am. J. Respir. Crit.
Care Med. 169, 1298–1303 (2004).
144. Donaldson, G. C., Seemungal, T. A., Bhowmik, A.
& Wedzicha, J. A. Relationship between exacerbation
frequency and lung function decline in chronic
obstructive pulmonary disease. Thorax 57, 847–852
(2002).
145. Kanner, R. E., Anthonisen, N. R. & Connett, J. E. Lower
respiratory illnesses promote FEV1 decline in current
smokers but not ex‑smokers with mild chronic
obstructive pulmonary disease: results from the lung
health study. Am. J. Respir. Crit. Care Med. 164,
358–364 (2001).
146. Donaldson, G. C., Hurst, J. R., Smith, C. J.,
Hubbard, R. B. & Wedzicha, J. A. Increased risk of
myocardial infarction and stroke following exacerbation
of COPD. Chest 137, 1091–1097 (2010).
147. McAllister, D. A. et al. Diagnosis of myocardial
infarction following hospitalisation for exacerbation
of COPD. Eur. Respir. J. 39, 1097–1103 (2012).
148. Anthonisen, N. R. et al. Antibiotic therapy in
exacerbations of chronic obstructive pulmonary
disease. Ann. Intern. Med. 106, 196–204 (1987).
149. Leuppi, J. D. et al. Short-term versus conventional
glucocorticoid therapy in acute exacerbations of
chronic obstructive pulmonary disease: the REDUCE
randomized clinical trial. JAMA 309, 2223–2231
(2013).
150. Bafadhel, M. et al. Blood eosinophils to direct
corticosteroid treatment of exacerbations of chronic
obstructive pulmonary disease: a randomized placebo-
controlled trial. Am. J. Respir. Crit. Care Med. 186,
48–55 (2012).
151. Nichol, K. L., Nordin, J. D., Nelson, D. B.,
Mullooly, J. P. & Hak, E. Effectiveness of influenza
vaccine in the community-dwelling elderly. N. Engl.
J. Med. 357, 1373–1381 (2007).
152. Kew, K. M., Mavergames, C. & Walters, J. A.
Long‑acting beta2‑agonists for chronic obstructive
pulmonary disease. Cochrane Database Syst. Rev. 10,
CD010177 (2013).
153. Karner, C., Chong, J. & Poole, P. Tiotropium versus
placebo for chronic obstructive pulmonary disease.
Cochrane Database Syst. Rev. 7, CD009285 (2014).
© 2015 Macmillan Publishers Limited. All rights reserved
154. Pascoe, S., Locantore, N., Dransfield, M. T.,
Barnes, N. C. & Pavord, I. D. Blood eosinophil counts,
exacerbations, and response to the addition of inhaled
fluticasone furoate to vilanterol in patients with
chronic obstructive pulmonary disease: a secondary
analysis of data from two parallel randomised
controlled trials. Lancet Respir. Med. 3, 435–442
(2015).
155. Siddiqui, S. H. et al. Blood eosinophils: a biomarker
of response to extrafine beclomethasone/formoterol in
chronic obstructive pulmonary disease. Am. J. Respir.
Crit. Care Med. 192, 523–525 (2015).
156. Festic, E. & Scanlon, P. D. Incident pneumonia
and mortality in patients with chronic obstructive
pulmonary disease. A double effect of inhaled
corticosteroids? Am. J. Respir. Crit. Care Med. 191,
141–148 (2015).
157. Vogelmeier, C. et al. Tiotropium versus salmeterol
for the prevention of exacerbations of COPD. N. Engl.
J. Med. 364, 1093–1103 (2011).
158. Wedzicha, J. A. et al. The prevention of chronic
obstructive pulmonary disease exacerbations by
salmeterol/fluticasone propionate or tiotropium
bromide. Am. J. Respir. Crit. Care Med. 177, 19–26
(2008).
159. Wedzicha, J. A. et al. Analysis of chronic obstructive
pulmonary disease exacerbations with the dual
bronchodilator QVA149 compared with
glycopyrronium and tiotropium (SPARK):
a randomised, double-blind, parallel-group study.
Lancet Respir. Med. 1, 199–209 (2013).
160. Calverley, P. M. et al. Roflumilast in symptomatic
chronic obstructive pulmonary disease: two
randomised clinical trials. Lancet 374, 685–694
(2009).
161. Martinez, F. J. et al. Effect of roflumilast on
exacerbations in patients with severe chronic
obstructive pulmonary disease uncontrolled by
combination therapy (REACT): a multicentre
randomised controlled trial. Lancet 385, 857–866
(2015).
162. Seemungal, T. A. et al. Long-term erythromycin
therapy is associated with decreased chronic
obstructive pulmonary disease exacerbations.
Am. J. Respir. Crit. Care Med. 178, 1139–1147
(2008).
163. Albert, R. K. et al. Azithromycin for prevention
of exacerbations of COPD. N. Engl. J. Med. 365,
689–698 (2011).
164. Serisier, D. J. Risks of population antimicrobial
resistance associated with chronic macrolide use for
inflammatory airway diseases. Lancet Respir. Med. 1,
262–274 (2013).
165. Zheng, J. P. et al. Effect of carbocisteine on acute
exacerbation of chronic obstructive pulmonary disease
(PEACE study): a randomised placebo-controlled
study. Lancet 371, 2013–2018 (2008).
166. Zheng, J. P. et al. Twice daily N‑acetylcysteine 600 mg
for exacerbations of chronic obstructive pulmonary
disease (PANTHEON): a randomised, double-blind
placebo-controlled trial. Lancet Respir. Med. 2,
187–194 (2014).
167. Eaton, T. et al. Does early pulmonary rehabilitation
reduce acute health-care utilization in COPD
patients admitted with an exacerbation?
A randomized controlled study. Respirology 14,
230–238 (2009).
168. Greening, N. J. et al. An early rehabilitation
intervention to enhance recovery during hospital
admission for an exacerbation of chronic respiratory
disease: randomised controlled trial. BMJ 349,
g4315 (2014).
169. Curtis, J. R. & Patrick, D. L. The assessment of health
status among patients with COPD. Eur. Respir.
J. Suppl. 41, 36s–45s (2003).
170. Jones, P. W. et al. Health-related quality of life
in patients by COPD severity within primary care
in Europe. Respir. Med. 105, 57–66 (2011).
171. Monteagudo, M. et al. Factors associated
with changes in quality of life of COPD patients:
a prospective study in primary care. Respir. Med. 107,
1589–1597 (2013).
172. Franssen, F. M., Spruit, M. A. & Wouters, E. F.
Determinants of polypharmacy and compliance with
GOLD guidelines in patients with chronic obstructive
pulmonary disease. Int. J. Chron. Obstruct. Pulmon.
Dis. 6, 493–501 (2011).
173. Yorgancioglu, A., Havlucu, Y., Celik, P., Dinc, G.
& Saka, A. Relation between quality of life and
morbidity and mortality in COPD patients: two-year
follow‑up study. COPD 7, 248–253 (2010).

174. Domingo-Salvany, A. et al. Health-related quality of life
and mortality in male patients with chronic obstructive
pulmonary disease. Am. J. Respir. Crit. Care Med.
166, 680–685 (2002).
175. Jones, P. W. Health status measurement in chronic
obstructive pulmonary disease. Thorax 56, 880–887
(2001).
176. Vanfleteren, L. E. et al. Clusters of comorbidities based
on validated objective measurements and systemic
inflammation in patients with chronic obstructive
pulmonary disease. Am. J. Respir. Crit. Care Med.
187, 728–735 (2013).
177. Putcha, N., Puhan, M. A., Hansel, N. N.,
Drummond, M. B. & Boyd, C. M. Impact of
co‑morbidities on self-rated health in self-reported
COPD: an analysis of NHANES 2001–2008. COPD
10, 324–332 (2013).
178. Mullerova, H., Agusti, A., Erqou, S. & Mapel, D. W.
Cardiovascular comorbidity in COPD: systematic
literature review. Chest 144, 1163–1178 (2013).
179. Macchia, A. et al. Unrecognised ventricular
dysfunction in COPD. Eur. Respir. J. 39, 51–58
(2012).
180. Maurer, J. et al. Anxiety and depression in COPD:
current understanding, unanswered questions,
and research needs. Chest 134, 43S–56S (2008).
181. Atlantis, E., Fahey, P., Cochrane, B. & Smith, S.
Bidirectional associations between clinically
relevant depression or anxiety and chronic
obstructive pulmonary disease (COPD): a systematic
review and meta-analysis. Chest 144, 766–777
(2013).
182. Smith, M. C. & Wrobel, J. P. Epidemiology and clinical
impact of major comorbidities in patients with COPD.
Int. J. Chron. Obstruct. Pulmon. Dis. 9, 871–888
(2014).
183. Hurst, J. R., Elborn, J. S. & De Soyza, A. COPD–
bronchiectasis overlap syndrome. Eur. Respir. J. 45,
310–313 (2015).
184. Carolan, B. J. & Sutherland, E. R. Clinical phenotypes
of chronic obstructive pulmonary disease and asthma:
recent advances. J. Allergy Clin. Immunol. 131,
627–634 (2013).
NATURE REVIEWS | DISEASE PRIMERS VOLUME 1 | 2015 | 21
185. Barnes, P. J. Therapeutic approaches to asthma–
chronic obstructive pulmonary disease overlap
syndromes. J. Allergy Clin. Immunol. 136, 531–545
(2015).
186. Lock-Johansson, S., Vestbo, J. & Sorensen, G.
Surfactant protein D, club cell protein 16, pulmonary
and activation-regulated chemokine, C‑reactive
protein, and fibrinogen biomarker variation in chronic
obstructive lung disease. Respir. Res. 15, 147 (2014).
187. Yang, I. V. & Schwartz, D. A. Epigenetic control of gene
expression in the lung. Am. J. Respir. Crit. Care Med.
183, 1295–1301 (2011).
188. Barnes, P. J. New anti-inflammatory treatments for
chronic obstructive pulmonary disease. Nat. Rev. Drug
Discov. 12, 543–559 (2013).
A review of the challenge to new drug development
in COPD and a discussion of some of the targets
for future therapy.
189. Rennard, S. I. et al. The safety and efficacy of
infliximab in moderate-to‑severe chronic obstructive
pulmonary disease. Am. J. Respir. Crit. Care Med.
175, 926–934 (2007).
190. Lomas, D. A. et al. An oral inhibitor of p38 MAP
kinase reduces plasma fibrinogen in patients with
chronic obstructive pulmonary disease. J. Clin.
Pharmacol. 52, 416–424 (2011).
191. Kerstjens, H. A., Bjermer, L., Eriksson, L., Dahlstrom, K.
& Vestbo, J. Tolerability and efficacy of inhaled
AZD4818, a CCR1 antagonist, in moderate to severe
COPD patients. Respir. Med. 104, 1297–1303 (2010).
192. Barnes, P. J. & Adcock, I. M. Glucocorticoid resistance
in inflammatory diseases. Lancet 342, 1905–1917
(2009).
193. Hansel, T. T. & Barnes, P. J. New drugs for
exacerbations of chronic obstructive pulmonary
disease. Lancet 374, 744–755 (2009).
194. Faner, R., Cruz, T., Lopez-Giraldo, A. & Agusti, A.
Network medicine, multimorbidity and the lung
in the elderly. Eur. Respir. J. 44, 775–788 (2014).
Acknowledgements
The authors thank J. Allinson from Imperial College, London,
UK, for the design of Figure 8.
© 2015 Macmillan Publishers Limited. All rights reserved
PRIMER
Author contributions
Introduction (P.J.B.); Epidemiology (P.G.J.B.); Mechanisms/
pathophysiology (E.K.S. and P.J.B.); Diagnosis, screening and
prevention (B.R.C.); Management (J.A.W. and J.V.); Quality of
life (E.F.M.W.); Outlook (P.J.B.); Overview of Primer (P.J.B.).
Competing interests
P.J.B. has served on scientific advisory boards of AstraZeneca,
Boehringer Ingelheim, Chiesi, Daiichi Sankyo, GlaxoSmith­
Kline, Glenmark, Johnson & Johnson, Merck, Novartis,
Takeda, Pfizer, Prosonix, RespiVert, Sun Pharmaceuticals,
Teva and UCB, and has received research funding from
Aquinox Pharmaceuticals, AstraZeneca, Boehringer
Ingelheim, Chiesi, Daiichi Sankyo, GlaxoSmith­Kline, Novartis,
Takeda, Pfizer and Sun Pharmaceuticals. He is also a
cofounder of RespiVert (now part of Johnson & Johnson),
which has discovered novel inhaled anti-inflammatory
treatments for asthma and COPD. P.G.J.B. has received
grants from the Medical Research Council, the Wellcome
Trust, Public Health England and the British Lung Foundation,
and serves on an advisory board for Novartis. B.R.C. has
received grants to the Pulmonary and Critical Care Division
of the Brigham and Women’s Hospital to complete research
studies in COPD from AstraZeneca. He has also received
compensation for advisory board participation and/or
consultancy from GlaxoSmithKline, Boehringer Ingelheim,
Almirall, AstraZeneca, MedImmune, Takeda and Novartis. He
does not have shares or interest in any company, nor does
any member of his family. He has not received or had any
relationship with the tobacco industry and has not
participated in promotional talks. E.K.S. has received, in the
past 3 years, honoraria and consulting fees from Merck and
grant support and consulting fees from GlaxoSmithKline. J.V.
has received funding for advising and presenting from
AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline,
Novartis, Takeda and Teva, and has received research funding
from GlaxoSmithKline. J.A.W. has received research grant
funding from Novartis, Takeda, Johnson & Johnson, Vifor
Pharma and GlaxoSmithKline. She has received honoraria for
lectures and/or advisory boards before January 2015 from
GlaxoSmithKline, Novartis, Boehringer Ingelheim,
AstraZeneca, Almirall, Pfizer, Chiesi and RespiVert. E.F.M.W.
declares no competing interests.