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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.

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

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PRIMER

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

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

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PRIMER

100 cases26. Although the question of whether hetero­zygosity


for the PI*Z allele confers increased COPD risk has
been controversial, several recent studies have strongly
75 suggested that PI*Z heterozygote individuals have a
FEV1 (predicted normal %)

­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
50 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.
25 Normal decline (~20 ml per year) Whole-exome and whole-genome sequencing have the
Normal decline with low initial lung volume potential to identify other rare genetic determinants of
Accelerated decline COPD, and comprehensive genomic analyses of heavy
smokers without COPD might identify genetic determi-
0 nants of COPD resistance. Whole-exome sequencing has
0 25 35 45 55 65 75
recently implicated a coiled-coil domain containing 38
Age (years)
(CCDC38) variant, which is linked to ciliary func-
Progression of symptoms tion, in the resistance to COPD development 31. Given
that the cilia of lung epithelial cells normally play an
Decreased Shortness of Shortness of Respiratory important part in removing inhaled particulates, it is
physical activity breath on exertion breath at rest failure plausible that ciliary abnormalities could contribute to
Figure 2 | Disease progression in COPD.  In healthy individuals, the forced expiratory COPD development.
Nature Reviews | Disease Primers Although many candidate genes have been tested for
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) their association with COPD, most of these results have
experience an accelerated annual decline in lung function (orange line) and the not been consistently replicated32,33. However, genome-
development of symptoms when FEV1 falls below approximately 60% of the predicted wide association studies (GWAS) of COPD have identi-
normal. Symptoms increase as airway obstruction increases from reduced physical fied multiple genomic regions that are associ­ated with
activity, to shortness of breath on exertion and eventually to shortness of breath at rest COPD34 and most of these associations have now been
followed by respiratory failure. Other patients with COPD might start from a lower peak
replicated in other studies. GWAS of lung function
lung volume (as a result of impaired lung development) and develop symptoms with even
a normal decline in FEV1 (green line).
levels in general population cohorts have been per-
formed in the CHARGE35 and SpiroMeta36 consortia,
and >20 genomic regions have been associated with
Genetic risk factors FEV1 and/or FEV1/FVC levels37. Several of these lung
Although COPD risk is strongly related to tobacco function genomic loci, including Hedgehog-interacting
smoking, the variable development of chronic airflow protein (HHIP) and family with sequence similarity 13
obstruction among smokers suggests that other fac- member A (FAM13A), have also been associated with
tors also influence the onset and progression of COPD. COPD susceptibility.
COPD tends to cluster in families, and twin studies22, GWAS have also been performed for several other
pedigree studies23,24 and analysis of unrelated individ­ COPD-related phenotypes, such as emphysema pattern38
uals25 have all suggested that there is significant herit- and nicotine addiction39,40; the results from these studies
ability of COPD, accounting for at least 30% of the suggest that susceptibility loci might influence different
variation in COPD risk. First-degree relatives of patients COPD-related traits (TABLE 1). For instance, several of
with COPD who smoke cigarettes have approximately a the COPD susceptibility loci, including the 15q25 locus
threefold increased risk of developing COPD compared that has been associated with lung cancer 41 and periph-
with smokers from the general population, whereas eral arterial disease42, are associated with nicotine addic-
non-smoking first-degree relatives of patients with tion. An integrative study combining gene expression
COPD have similar (and low) risks for chronic airflow analysis and genetic association analysis implicated iron-­
obstruction compared with non-smokers in the general responsive element-binding protein 2 (IREB2), another
population. These results indicate that there are likely to gene within the 15q25 locus, in COPD susceptibility 43,
be genetic determinants that interact with smoking and mediation analysis suggested that there might be
to increase COPD risk. two genetic loci influencing COPD on 15q25 — one
Several Mendelian syndromes include COPD (typi- related and one unrelated to nicotine addiction44.
cally emphysema) as part of their constellation of clini- Molecular studies and bioinformatic approaches are
cal features, including α1‑antitrypsin deficiency and needed to identify the functional genetic variants within
cutis laxa. α1‑Antitrypsin deficiency is usually caused COPD genetic loci implicated by GWAS, which prob-
by homozygosity for a single and relatively rare non- ably often influence gene regulation. Chromosome con-
synonymous single-nucleotide polymorphism (SNP) formation capture studies have identified a long-range
— namely, the PI*Z allele of the α1‑antitrypsin gene interaction of the COPD genome-wide association study
(SERPINA1). PIZZ α1‑antitrypsin deficiency, which locus upstream from HHIP with the HHIP promoter.
occurs in approximately 1 in 3,000 individuals in the Subsequent studies identified a functional variant within
United States, accounts for approximately 1% of COPD an enhancer in this region that alters binding to the

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PRIMER

transcription factor SP3 (REF. 45). A recent study dem- of irritants, including cigarette smoke, biomass fuel
onstrated that heterozygous gene-targeted Hhip mice smoke and air pollutants, activates pattern recognition
(Hhip+/–) had increased susceptibility to smoke-induced receptors, such as Toll-like receptors, which results in
emphysema and that lymphocyte activation pathways an innate immune response. This immune response
were implicated in this susceptibility 46. then leads to increased numbers of neutrophils and
Additional efforts to integrate genetic variation with macrophages in the lungs as well as activation of air-
gene expression47, epigenetic markers48 and/or other way epithelial cells and mucus secretion55. Activation
‘-omics’ data types are likely to identify more COPD sus- of adaptive immunity occurs later in the course of the
ceptibility genes and provide insight into the network of disease and leads to increased n ­ umbers of T lympho-
interacting genes that increases COPD risk and contrib­ cytes and B lymphocytes in the lungs. These cells might
utes to COPD heterogeneity. Molecular and cellular be organized into lymphoid follicles, which involves an
studies of these susceptibility genes will be n
­ ecessary to increase in the number and activation of dendritic cells.
understand their role in COPD pathogenesis. During this adaptive immune response there is also an
increase in the number of CD8+ cytotoxic T cells and
Pathogenesis CD4+ T helper 1 cells in lung tissue56. The number
Pathology. The main pathological features of COPD of CD4+ T helper 17 cells is also increased in the lungs
are obstructive bronchiolitis, emphysema and, in many and might further amplify neutrophilic inflammation57.
cases, mucus hypersecretion (chronic bronchitis) (FIG. 1), Some patients with COPD have increased numbers of
but the relative contribution of each of these patholo- eosinophils in their airways, increased sputum and
gies to COPD varies between patients49. Even in early share some features with asthma, such as reversibility
or mild COPD, there is evidence of airflow obstruction of the airway obstruction and a greater response to
and a signifi­cant loss (disappearance) of small airways50. ­corticosteroids than patients with typical COPD58.
A novel CT imaging technique for quantifying small The levels of many different inflammatory mediators
airway disease shows that this small airways loss is an are increased in the lungs of patients with COPD, includ-
early feature of disease and might account for the initial ing lipid and peptide mediators, as well as a network of
progression of airway obstruction in COPD51. Structural cytokines and chemokines that maintain inflammation
changes in small pulmonary arterioles are common in and recruit circulating cells into the lungs59. Many of
COPD, with increased intimal thickening and vascular these pro-inflammatory mediators are regulated through
smooth muscle proliferation, and such changes might the activation of the pro-inflammatory transcription fac-
be the result of inflammation in these vessels as well tor nuclear factor‑κB (NF‑κB) and mitogen-activated
as hypoxic vasoconstriction52. However, pulmonary protein kinases (MAPKs), particularly p38 MAPK60,61.
hypertension is usually not marked in COPD, except In addition, several proteases that degrade elastin fibres
for a small group of patients with disproportionate are secreted from airway resident neutrophils, macro­
pulmonary hypertension who might develop right phages and epithelial cells in patients with COPD.
heart failure53. In larger airways, elastase from neutrophils might be an
important stimulator of mucus hypersecretion, whereas
Chronic inflammation. COPD is associated with chronic matrix metalloproteinases (MMP9 and MMP12) in
inflammation that predominantly affects peripheral the lung parenchyma might be more important in the
airways and lung parenchyma, although large airways ­elastolysis that is observed in those with emphysema.
also show inflammatory changes 54. The degree of Even cigarette smokers with normal lung function
inflammation increases — with increased numbers have increased airway inflammation, suggesting that this
of neutrophils, macrophages and lymphocytes in the might be the normal immune response of the respira-
lungs — as the disease progresses49. Chronic inhalation tory mucosa to inhaled irritants. However, this inflam-
mation seems to be amplified in patients with COPD,
30 particularly during acute exacerbations. The amplified
inflammatory response in COPD might be explained
COPD mortality per 100,000

25 Male
Female by the reduced expression of the nuclear enzyme his-
20
tone deacetylase 2 (HD2, encoded by HDAC2) in cells
such as macrophages and epithelial cells in the lungs of
15 those with COPD, resulting in the activation of multi-
ple inflammatory genes62. The inflammation in COPD
10 persists after smoking cessation, suggesting that it is
5
maintained by some autonomous mechanism that is not
yet understood.
0 The lower respiratory tract of patients with COPD
0 100 1,000 10,000 100,000 is often colonized with bacteria, such as Haemophilus
Gross national income per capita (US$ ppp) influenzae and Streptococcus pneumoniae. This chronic
Figure 3 | Poverty is a risk factor for COPD.  There isNature
a strong relationship
Reviews in men
| Disease Primers
bacterial colonization has been linked to a defect in the
and women between chronic obstructive pulmonary disease (COPD) mortality rates uptake (phagocytosis) of bacteria by macrophages63,64,
(mortality from COPD per 100,000 individuals 15–59 years of age) and annual per capita and, particularly with H. influenzae, might be a factor
gross national income. PPP, purchasing power parity. Data obtained from REF. 17. driving chronic airway and systemic inflammation and

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PRIMER

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

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PRIMER

Healthy COPD Pathophysiology. The airway obstruction in COPD is


Alveolar
macrophage 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
Defective upon expiration, resulting in air trapping (FIG. 7). Air
Phagocytosis Efferocytosis Defective efferocytosis trapping causes lung hyperinflation (increased total
phagocytosis
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-
Bacteria Apoptotic cells Bacteria Apoptotic cells ance84. Although the obstruction of the small airways
Bacterial
Resolution of Bacterial Persistence of
due to fibrosis is irreversible, superimposed cholinergic
clearance tone markedly increases airway resistance. This cholin-
inflammation colonization inflammation
(sterile airway)
ergic tone is reversible by muscarinic antagonists and
Figure 4 | Defective phagocytosis in COPD.  In healthy individuals,
Nature Reviews macrophages
| Disease Primers β2-adrenergic receptor agonists (β2-agonists), which
phagocytose bacteria in the lung periphery and respiratory tract to maintain lung results in reduced air trapping and reduced symptoms.
sterility. These macrophages also phagocytose apoptotic cells (efferocytosis), resulting The fixed narrowing of the airways also causes increased
in resolution of inflammation. In chronic obstructive pulmonary disease (COPD), responsiveness to bronchoconstrictors and is primarily a
macrophages are defective at phagocytosing bacteria, which results in chronic consequence of geometric factors. Emphysema results in
bacterial colonization of the lower airways. In addition, these macrophages have an reduced alveolar surface area, resulting in impaired gas
impaired ability to carry out efferocytosis of apoptotic cells, which results in failure
transfer and eventually hypoxia.
to resolve inflammation.
Causes and pathogenesis of exacerbations
HD2 (REF. 78). ROS also reduce the expression and activ- COPD exacerbations are episodes of symptom worsen-
ity of SIRT1, which is markedly reduced in the lungs ing that are usually associated with increased airway
of patients with COPD and has a role in maintaining inflammation and systemic inflammatory effects85
genomic stability, regulating autophagy and protecting (FIG.  8) . Most COPD exacerbations are triggered by
against cellular senescence and ageing 79. There is also respira­tory viral infections, especially rhinovirus, which
evidence for defective endo­genous antioxidant defences is the cause of the common cold and thus more com-
in patients with COPD. The transcription factor nuclear mon in winter. Respiratory viruses can be identified
factor erythroid 2‑related factor 2 (NRF2; also known in the airway by PCR in up to 60% of exacerbations86.
as NFE2L2) plays a key part in the regulation of multi- Exacerbations associated with viruses tend to have more
ple antioxidant and cytoprotective genes in response to airway and systemic inflammation than those without
oxidative stress. NRF2 function is impaired in patients any evidence of viral infection, are more common in the
with COPD80 and is not appropriately activated by oxida- winter months and are associated with a higher risk of
tive stress owing to its increased acetylation as a result of hospital admission87. Pollutants that reach the airways
reduced HD2 activity 81. might also be associated with precipitating exacerba-
Evidence is emerging to indicate that mitochondria tions, especially by interacting with respiratory viruses,
are an important source of ROS in COPD and that there although significant effects of pollution are only seen in
is a disruption of mitochondrial function in patients with regions of high urban pollution88. Airway bacteria are
COPD, which leads to impaired oxidative phosphory­ also involved in causing exacerbations, although their
lation and reduced intracellular ATP. Mitochondria are precise role in triggering exacerbations is controversial.
fragmented in epithelial cells of patients with COPD and Although airway bacterial load increases during exacer-
these changes are mimicked by cigarette smoke exposure bations, it is now considered that bacteria are often not
in vitro, which leads to mitochondrial ROS production the primary infective cause of the exacerbation but are
and cellular senescence82. Cigarette smoke induces the secondary invaders after a viral trigger 85.
autophagic uptake of mitochondria (mitophagy) in Some patients with COPD are susceptible to exacerba-
airway epithelial cells, which results in mitochondrial tions irrespective of disease severity. These patients have
deficiency and cell death (necroptosis) that is mediated been called ‘frequent exacerbators’ and over time their
by the mitophagy regulator phosphatase and tensin exacerbation frequency is relatively stable89–91. The main
homologue-­induced putative kinase protein 1 (PINK1)83. risk of developing frequent exacerbations is a history of
PINK1 shows increased expression in epithelial cells of exacerbations in the previous year. Frequent exacerbators
patients with COPD, and Pink1 knockout in mice pro- have a worse prognosis, more hospital admissions, faster
tects against the development of emphysema and mucus disease progression and worse health status than those
secretion induced by chronic cigarette smoke exposure. who experience infrequent exacerbations.

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PRIMER

100 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.
75 Senile
emphysema
History of exposure to risk factors. COPD, as with
most chronic non-communicable diseases, results
FEV1 (max %)

from the genetic make-up of an individual interacting


50 with their environment. The respiratory system is con-
Oxidative stress leads to:
Telomere shortening stantly exposed to its surroundings through the act of
Cellular senescence breathing. With its large exposure surface and absorp-
DNA damage tive properties, it is surprising that the proportion of
25 Mitochondrial dysfunction
Autophagy individuals exposed to cigarette smoke who develop
Stem cell exhaustion Normal ageing clinical COPD is not >30–50%95. The most important
Anti-ageing molecules COPD risk factors for COPD are the inhalation of particulate
matter from cigarette smoke and the burning of biomass
0
0 40 50 60 70 80 90
for cooking or heating 12. A combination of both types
10 20 30
Age (years)
of exposure significantly increases the risk of develop-
ing COPD96. Other risk factors for COPD development
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
other particulate matter during infancy, socioeconomic
result of ageing) might be seen in the elderly. In those with chronic obstructive
dis­advantage, childhood respiratory symptoms and
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 asthma during the growth period, as discussed above97.
COPD have all of the features of accelerated lung ageing, including telomere shortening, Recent studies have shown that low lung function in
cellular senescence, DNA damage (failure of repair), mitochondrial dysfunction, impaired early adulthood with subsequent normal lung function
autophagy, stem cell exhaustion and reduced levels and activity of anti-ageing decline is as important as rapid lung function decline in
molecules, such as sirtuin 1. 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-
Diagnosis, screening and prevention lation100, is receiving considerable attention, but study
Diagnosis results are currently insufficient to confer the microbiota
The diagnosis of COPD should be suspected in individ­ an ­important pathobiological role.
uals with respiratory symptoms, such as cough, expec-
toration of sputum, shortness of breath upon exertion Clinical presentation. Most individuals with mild dis-
or lower respiratory tract infections occurring more fre- ease have a normal physical examination, including
quently or lasting longer than expected (>2 weeks). The pulse, respiratory rate, chest expansion and breath and
suspicion should increase if the individuals also report heart sounds. However, the use of a standardized func-
risk factors for COPD, such as exposure to cigarette tional grading of dyspnoea, the most important symp-
smoke, environmental or occupational pollutants and/or tom of respiratory compromise, can help to increase
the presence of a family history of obstructive lung dis- the degree of suspicion, direct the health care pro-
eases1,92. Not infrequently, and usually in more-advanced vider to i­ mplement a spirometry test and help to stage
cases, COPD is suspected at the time of a severe respira- disease severity.
tory decompensation due to an acute exacer­bation or One such scale is the Modified Medical Research
following surgery, such as upper abdominal or thoracic Council dyspnoea scale, graded from 0 to 4 with the
procedures. This deterioration is caused by the main lowest grade implying no dyspnoea with any activity
problem of underdiagnosis, as most individuals with and the highest grade implying dyspnoea with mini-
the disease underestimate their symptoms, assuming mal activity 1,92. In patients with more-advanced dis-
that they are the natural consequence of the smoking ease, increased respiratory rate with forced expiratory
habit, ageing or job exposure93. Furthermore, even in efforts, decreased breath sounds on chest auscultation
moderate-­to-advanced stages of COPD, the affected (listening), the presence of rhonchi (rattling sounds),
patients will become ever more sedentary to avoid coarse crackles and wheezes and, in the most advanced
the uncomfortable symptom of exertional dyspnoea. cases, cyanosis (blue skin discolouration, a sign of
Unfortunately, many health care providers fail to con- hypoxaemia) might be present and should be consid-
sider a diagnosis of COPD in patients presenting with ered an important complication that requires therapy
these symptoms, especially if the person is a woman or with oxygen.
relatively young94. The reasons for the failure to suspect Currently, the ease of use of pulse oximetry, which is
COPD in these groups rests on older studies of the epi- a non-invasive method of measuring oxygen saturation,
demiology of COPD that described the disease as being enables the determination of hypoxaemia early, and oxy-
one of older men. As the smoking habit has increased gen should be prescribed for patients with saturations
in younger individuals and the prevalence of COPD in below 88% while breathing room air 1. The presence of
women is now approaching or has surpassed (in some cor pulmonale (failure of the right side of the heart due

8 | 2015 | VOLUME 1 www.nature.com/nrdp

© 2015 Macmillan Publishers Limited. All rights reserved


PRIMER

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

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

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PRIMER

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

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

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PRIMER

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

Management Non-pharmacological treatment. Pulmonary rehabili­


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

More emphysema Less emphysema

Pink puffer Blue bloater


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

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

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PRIMER

Table 2 | Management of stable COPD the acute exacerbation will not only increase the rate of
exacer­bation recovery but will also affect exacerbation
Aim Treatment Considerations
rates and prevent hospital admissions.
Symptom Pulmonary rehabilitation and Suitable for all patients
reduction* physical exercise Exacerbation prevention. Influenza vaccination is
Short-acting inhaled Only for relief of symptoms associ­ated with a 27% reduction in the risk of hospitali-
bronchodilators zation triggered by influenza virus infection in elderly
One long-acting inhaled LABA and LAMA have similar clinical individ­uals151; therefore, influenza vaccination is recom-
bronchodilator (LABA or LAMA) effects mended for the majority of patients with COPD. There
LABA–LAMA combination When a single, long-acting is less evidence to support the use of a pneumo­coccal
bronchodilator is not sufficiently polysacchari­de vaccine in the prevention of COPD
effective exacer­bations, but large studies are currently underway
Risk One long-acting LAMA preferred over LABA with vaccines that have improved immunogenicity.
reduction‡ bronchodilator Use of long-acting bronchodilators reduces the risk
ICS–LABA combination If there is no bacterial colonization and of exacerbations by approximately 25%152,153. The same
the blood eosinophil count is >32% effect size is seen for ICS use, and the mechanisms that
LABA–LAMA combination When bacterial colonization is present underlie the effects of various pharmacological agents on
and the blood eosinophil count is <2% preventing exacerbations are likely to differ as the effect of
Roflumilast Only in patients with concomitant combined treatment with a LABA and ICS is better than
chronic bronchitis that for each drug alone140. Some exacerbations require
ICS, inhaled corticosteroid; LABA, long-acting β2-adrenergic receptor agonist; LAMA, treatment with systemic corticosteroids, and although
long-acting muscarinic antagonist. *Always consider co-morbidities. ‡Patient with two or more the use of an ICS alone reduces exacerbations by approxi-
exacerbations per year and usually with a forced expiratory volume in 1 second of <50% of mately 25%140, monotherapy with an ICS is not recom-
predicted normal.
mended by GOLD1. The use of ICSs should be restricted
to patients who are at high risk of exacerbations, should
COPD exacerbations are a major cause of admissions probably be restricted to patients without lower airway
and readmissions to hospital and are also independent bacterial colonization and, based on post-hoc analyses
predictors of mortality in COPD. Moreover, exacerba- of recent trials, should not be given to patients with <2%
tions drive disease progression, with some studies find- eosinophils in the peripheral blood in stable disease154,155.
ing that up to 25% of the lung function decline in COPD In addition to well-known local adverse effects, such as
is attributable to exacerbations, whereas other studies oral thrush and hoarse voice, ICSs are associated with an
have found that exacerbations contribute significantly increased risk of pneumonia and they might increase the
less to lung function decline144,145. COPD exacerbations risk of osteoporosis130,156.
are a major determinant of health status in COPD, and LAMAs alone also reduce exacerbation frequency 137
any intervention that reduces exacerbation will affect and have a greater effect on exacerbation reduction than
health status89. COPD exacerbations are also associ- LABAs157. LABA–ICS combinations and LAMA have
ated with cardiovascular events, especially myocardial simi­lar effects on exacerbations in patients with severe and
infarction, and this association is most marked in severe very severe COPD (an FEV1 of <50% of predicted normal);
­exacerbations that require hospital admission146,147. therefore, LAMAs can be used as an alternative to LABA–
ICS combinations in these patients158. A LABA–LAMA
Pharmacological treatment. Management of an exacer­ combination (indacaterol and glycopyrronium) has been
bation comprises oral antibiotics, such as amoxicillin evaluated in patients with a FEV1 of <50% of predicted
or doxycycline, if there is evidence of increased sputum normal and a history of exacerbations. The combina-
purulence or volume148. The choice of antibiotic will tion treatment resulted in fewer health care use exacer-
depend on the patient’s history and underlying disease bations than glycopyrronium alone and was marginally
severity. Oral corticosteroids in short courses are also ­better than either glycopyrronium or open-label tiotro-
added, depending on the individual exacerbation sever- pium in the reduction of all exacerbations when mild,
ity, and there is recent evidence to suggest that shorter moderate and severe exacerbations were combined159.
courses (5 days) of corticosteroids might be as beneficial Roflumilast is a PDE4 inhibitor with broad anti-
as longer courses, such as the more conventional 14 day inflammatory activity and inhibits the airway inflam-
courses149. There is some evidence to suggest that oral mation associated with COPD, especially by reducing
corticosteroids are more effective in patients who have the number of airway neutrophils that are key to
increased blood eosinophil numbers during their exacer­ COPD pathogenesis. Evidence from two large placebo-­
bation, but further prospective studies are needed to con- controlled, double-blind multicentre trials has revealed
firm these findings150. There is evidence that, the ­earlier that roflumilast use results in a 17% reduction in the fre-
that therapy is started at the onset of an exacerbation, quency of moderate or severe exacerbations160. However,
the shorter the recovery of the event and the less chance only patients with a FEV1 of <50% of predicted normal
of hospital admission143. Thus, prompt and appropri- (GOLD3 and GOLD4), presence of bronchitis symptoms
ate management of the exacerbation event will have an and a history of exacerbations were enrolled in these stud-
effect on optimizing recovery and will delay the time to ies. A recent study has shown only marginal benefit when
the next event. In summary, optimal management of roflumilast is added to standard triple COPD therapy 161.

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PRIMER

Antibiotics have also been investigated for their effi- careful monitoring of potential auditory and cardio­
cacy in reducing exacerbation frequency. For instance, vascular adverse effects (by monitoring the QTc interval,
a low dose of the macrolide erythromycin reduces the for instance) are necessary.
frequency of exacerbations and shortens exacerbation Mucolytic drugs reduce the viscosity of airway
length in patients with moderate-to-severe COPD162. mucus to improve airflow. Two large Chinese studies
Azithromycin, another macrolide, when added to have shown that mucolytics reduce exacerbation fre-
usual treatment decreases exacerbation frequency quency 165,166. However, it is unclear whether this effect
and improves quality of life in patients with COPD163. is due to the mucolytic or antioxidant effects of these
However, significant rates of hearing decrement (as drugs. Moreover, the drugs were tested in a popula-
measured by audiometry) and antibiotic resistance tion with little concomitant treatment. For this reason,
were reported for azithromycin use164. Further studies ­mucolytic treatment is not widely recommended.
are required to address the issue of antibiotic resistance There has been considerable interest in performing
in long-term antibiotic trials in COPD. Cardiovascular pulmonary rehabilitation, including physical training,
adverse effects have also been reported with macrolides. early in the time course of an exacerbation or shortly
Further studies with non-macrolide antibiotics are after admission to hospital to reduce the frequency or
ongoing and these will also need to assess issues of safety severity of subsequent exacerbations. Although results
and resistance. Before use of any long-term antibiotics, from initial pilot studies were promising, two well-
patients should be treated with an optimum combina- designed studies have shown little benefit of early inter-
tion inhaled therapy for COPD and show evidence of vention with pulmonary rehabilitation courses167,168.
ongoing exacerbations despite therapy. In addition, Finally, pulmonary rehabilitation has been shown to
reduce the length of subsequent exacerbations.

Quality of life
Postganglionic Health status is defined as “the impact of health on a
cholinergic nerve
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
Airway smooth functional status” (REF. 169). Patients with COPD report
muscle cell
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
Cholinergic tone Cholinergic tone
Airway resistance Airway resistance “a process that is essentially similar to a highly struc-
Air trapping Air trapping tured clinical history, although the end product is not a
clinical impression but an objective measurement … It is
M3-receptor Acetylcholine Muscarinic antagonist no more “soft” … than any well taken clinical history”
β2-receptor β2-agonist SABA or LABA SAMA or LAMA (REF. 175). Consequently, GOLD includes health status
as an objective for COPD diagnosis and management 1.
Figure 11 | Effects of bronchodilators in COPD.  Postganglionic cholinergic nerves Owing to the systemic effects of the disease, one
tonically release acetylcholine, activating muscarinic MNature Reviews
receptors | Disease
on airway Primers
smooth study found that 97.7% of patients with COPD had
3
muscle cells, which in turn leads to bronchoconstriction. This activation causes a marked one or more co-morbidity and 53.5% were diagnosed
increase in peripheral airway resistance as the small airways are already structurally with four or more co-morbidities176. Each additional
narrowed in chronic obstructive pulmonary disease (COPD). Muscarinic antagonists co-morbidity increases the chance of worsening of self-
(anticholinergics) block M3-receptors and thus reduce cholinergic tone, resulting in rated health by 43%177. Vanfleteren and colleagues176
reduced airway resistance and reduced air trapping. Muscarinic antagonists can be identified five co-morbidity clusters and showed that
short-acting (SAMA, such as ipratropium bromide) or long-acting (LAMA, such as
clinical characteristics were comparable between these
tiotropium bromide or glycopyrronium bromide). β2-adrenergic receptor agonists
(β2-agonists) activate β2-receptors on airway smooth muscle, which functionally clusters. However, patients differed in terms of health
antagonize cholinergic tone and have the same bronchodilator effect as muscarinic status, with worst health status scores for those in the
antagonists. β2-agonists can be short-acting (SABA, such as salbutamol (albuterol)) or cardiovascular and psychological co-morbidity cluster
long-acting (LABA, such as salmeterol and indacaterol). There are additive than for those with other co-morbidities176. Indeed,
bronchodilator effects when LAMAs and LABAs are given together. cardiovascular diseases are probably the most frequent

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PRIMER

COPD, progressive airflow limitiation of CT results. CT scans are also able to demonstrate
bronchi­ectasis, which is present in almost half of patients
Dyspnoea with COPD and is associated with a worse prog­nosis183.
Other COPD phenotypes relate to predominant co-
Health status
morbidities — particularly cardiovascular disease — that
Exacerbations and have an important influence on disease outcome. Several
hospitalizations attempts have been made to categorize patients into
Dyspnoea clinical clusters based on these phenotypes, but these
have not been validated184. In addition, although asthma
Health status and COPD are distinct diseases, in 10–20% of patients
Exacerbations and with COPD there are also features of asthma, such as
hospitalizations
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.
Increased risk of dying We are also far from defining molecular phenotypes
Figure 12 | Downward spiral of health-related quality or endotypes of COPD that relate to different disease
Nature Reviews | Disease Primers
of life in COPD.  The progressive airflow limitation that mechanisms. However, this is an important future aim
accompanies chronic obstructive pulmonary disease as this is likely to be necessary to provide the most effect­
(COPD) leads to a spiralling decline in health-related ive targeted therapy as part of a personalized medicine
quality of life through a range of mechanisms, including approach. Much of the current research on molecular
increased dyspnoea and increased rates of disease phenotypes is undertaken on advanced disease, in which
exacerbation and hospitalization.
to the discernment of different phenotypes might be
more difficult. Thus, it will be increasingly necessary
and important diseases that coexist with COPD178, and to study early disease before fixed airflow limitation
impaired cardiac function is associated with worse (and symptoms) develop.
survival in patients with COPD179. However, although Currently, the recognition of different phenotypes,
not directly pathophysiologically related to COPD, such as small airway disease and emphysema, does not
symptoms of anxiety and depression are highly preva- substantially alter management strategies, but as more
lent in those with COPD180 and have been shown to be specific therapies are developed it might be beneficial
­associated with poor adherence to treatment strategies181. to target them to specific phenotypes. For example,
Thus, patients with an impaired health status are at asthma–COPD overlap syndrome might respond better
risk of poor outcomes and prognoses, which can then be to corticosteroid therapy and to specific anti-eosinophil
worsened by co-morbidities (FIG. 12). Unfortunately, co- treatments, such as antibodies that block IL‑5, than other
morbidities are often underdiagnosed and consequently COPD phenotypes185.
under-treated, which might consequently worsen
COPD prognosis. Owing to shared risk factors and Biomarkers of disease activity and progression
pathophysio­logical mechanisms, determining whether There is a need to develop easily measured biomarkers
the co-morbidity or COPD itself causes the symptoms that quantify disease activity, susceptibility to exacerba-
at hand remains challenging 182. Nonetheless, establish- tions, co-morbidities and disease progression, as well as
ing the prevalence of co-morbidities and their effect on biomarkers that predict and monitor response to ther-
health status as an essential patient-related outcome apy. So far biochemical, proteomic and lipid biomarkers
remain important targets for COPD studies as well as in the blood, sputum and exhaled breath have not been
for COPD diagnosis and management. found to be useful in predicting clinical outcomes in
COPD, but more research is needed to develop patterns
Outlook of biomarkers118. The most promising blood biomarkers
Considerably more research is needed on all aspects of are pulmonary surfactant-associated protein D, fibrino-
COPD as we still have a relatively poor understanding gen, club cell 16 protein and CC-chemokine ligand 18
of disease mechanisms and natural history. In addition, (also called pulmonary and activation-regulated
we need more-effective pharmacological therapies that chemokine), but the clinical value of these in predicting
target the underlying disease process. future risk and response to therapy is not yet clear 186.

Defining phenotypes Understanding disease susceptibility


As with other complex diseases, there are several clini- Not all chronic smokers develop airflow limitation,
cal phenotypes of COPD, with some patients show- indicating that there are susceptibility factors or per-
ing predominantly small airway disease and little haps, more importantly, mechanisms that prevent these
­emphysema, whereas others have more-predominant individ­uals from developing COPD, but these remain
emphysema. Although air trapping, bronchial wall largely unknown. Identified genetic poly­morphisms
thickening and emphysema can be detected with a CT account for a small proportion (approximately 30%)
scan, CT scans are not undertaken routinely and patients of this susceptibility, and it is likely that there are
in clinical trials are usually not categorized on the basis other determinants and complex gene–environment

16 | 2015 | VOLUME 1 www.nature.com/nrdp

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PRIMER

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

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PRIMER

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

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20 | 2015 | VOLUME 1 www.nature.com/nrdp

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PRIMER

174. Domingo-Salvany, A. et al. Health-related quality of life 185. Barnes, P. J. Therapeutic approaches to asthma– Author contributions
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175. Jones, P. W. Health status measurement in chronic 186. Lock-Johansson, S., Vestbo, J. & Sorensen, G. life (E.F.M.W.); Outlook (P.J.B.); Overview of Primer (P.J.B.).
obstructive pulmonary disease. Thorax 56, 880–887 Surfactant protein D, club cell protein 16, pulmonary
(2001). and activation-regulated chemokine, C‑reactive Competing interests
176. Vanfleteren, L. E. et al. Clusters of comorbidities based protein, and fibrinogen biomarker variation in chronic P.J.B. has served on scientific advisory boards of AstraZeneca,
on validated objective measurements and systemic obstructive lung disease. Respir. Res. 15, 147 (2014). Boehringer Ingelheim, Chiesi, Daiichi Sankyo, GlaxoSmith­
inflammation in patients with chronic obstructive 187. Yang, I. V. & Schwartz, D. A. Epigenetic control of gene Kline, Glenmark, Johnson & Johnson, Merck, Novartis,
pulmonary disease. Am. J. Respir. Crit. Care Med. expression in the lung. Am. J. Respir. Crit. Care Med. Takeda, Pfizer, Prosonix, RespiVert, Sun Pharmaceuticals,
187, 728–735 (2013). 183, 1295–1301 (2011). Teva and UCB, and has received research funding from
177. Putcha, N., Puhan, M. A., Hansel, N. N., 188. Barnes, P. J. New anti-inflammatory treatments for Aquinox Pharmaceuticals, AstraZeneca, Boehringer
Drummond, M. B. & Boyd, C. M. Impact of chronic obstructive pulmonary disease. Nat. Rev. Drug Ingelheim, Chiesi, Daiichi Sankyo, GlaxoSmith­Kline, Novartis,
co‑morbidities on self-rated health in self-reported Discov. 12, 543–559 (2013). Takeda, Pfizer and Sun Pharmaceuticals. He is also a
COPD: an analysis of NHANES 2001–2008. COPD A review of the challenge to new drug development cofounder of RespiVert (now part of Johnson & Johnson),
10, 324–332 (2013). in COPD and a discussion of some of the targets which has discovered novel inhaled anti-inflammatory
178. Mullerova, H., Agusti, A., Erqou, S. & Mapel, D. W. for future therapy. treatments for asthma and COPD. P.G.J.B. has received
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literature review. Chest 144, 1163–1178 (2013). infliximab in moderate-to‑severe chronic obstructive Trust, Public Health England and the British Lung Foundation,
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180. Maurer, J. et al. Anxiety and depression in COPD: kinase reduces plasma fibrinogen in patients with studies in COPD from AstraZeneca. He has also received
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Bidirectional associations between clinically & Vestbo, J. Tolerability and efficacy of inhaled does not have shares or interest in any company, nor does
relevant depression or anxiety and chronic AZD4818, a CCR1 antagonist, in moderate to severe any member of his family. He has not received or had any
obstructive pulmonary disease (COPD): a systematic COPD patients. Respir. Med. 104, 1297–1303 (2010). relationship with the tobacco industry and has not
review and meta-analysis. Chest 144, 766–777 192. Barnes, P. J. & Adcock, I. M. Glucocorticoid resistance participated in promotional talks. E.K.S. has received, in the
(2013). in inflammatory diseases. Lancet 342, 1905–1917 past 3 years, honoraria and consulting fees from Merck and
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impact of major comorbidities in patients with COPD. 193. Hansel, T. T. & Barnes, P. J. New drugs for has received funding for advising and presenting from
Int. J. Chron. Obstruct. Pulmon. Dis. 9, 871–888 exacerbations of chronic obstructive pulmonary AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline,
(2014). disease. Lancet 374, 744–755 (2009). Novartis, Takeda and Teva, and has received research funding
183. Hurst, J. R., Elborn, J. S. & De Soyza, A. COPD– 194. Faner, R., Cruz, T., Lopez-Giraldo, A. & Agusti, A. from GlaxoSmithKline. J.A.W. has received research grant
bronchiectasis overlap syndrome. Eur. Respir. J. 45, Network medicine, multimorbidity and the lung funding from Novartis, Takeda, Johnson & Johnson, Vifor
310–313 (2015). in the elderly. Eur. Respir. J. 44, 775–788 (2014). Pharma and GlaxoSmithKline. She has received honoraria for
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of chronic obstructive pulmonary disease and asthma: Acknowledgements GlaxoSmithKline, Novartis, Boehringer Ingelheim,
recent advances. J. Allergy Clin. Immunol. 131, The authors thank J. Allinson from Imperial College, London, AstraZeneca, Almirall, Pfizer, Chiesi and RespiVert. E.F.M.W.
627–634 (2013). UK, for the design of Figure 8. declares no competing interests.

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