Primer

Chronic obstructive pulmonary disease

  • Nature Reviews Disease Primers 1, Article number: 15076 (2015)
  • doi:10.1038/nrdp.2015.76
  • Download Citation
Published online:

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.

Introduction

Chronic obstructive pulmonary disease (COPD) is described — but not defined — by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as “a common preventable and treatable disease … [that] is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and co-morbidities contribute to the overall severity in individual patients” (Ref. 1). However, the failure to use clear definitions causes confusion and the term COPD is also used to describe people with a low forced expiratory volume, changes on CT scans due to emphysema or with symptoms of chronic lung disease and a history of smoking. In most normal individuals, >70% of the vital capacity is exhaled in the first second a forced manoeuvre; airflow limitation (see Box 1 for a glossary of clinical terms used in this Primer) is defined by a ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of <0.7 and can be categorized as mild (so-called GOLD1; FEV1 of >80% of predicted normal), moderate (GOLD2; FEV1 of 79–50% of predicted normal), severe (GOLD3; FEV1 of 49–30% of predicted normal) and very severe (GOLD4; FEV1 of <30% of predicted normal). The airflow limitation in COPD is largely irreversible owing to structural changes in the lungs. These changes include chronic obstructive bronchiolitis, due to fibrosis of small airways (<2-mm internal diameter), and emphysema, characterized by enlargement of alveoli and destruction of alveolar walls. The airway obstruction (Fig. 1) in COPD usually progresses slowly and represents an acceleration of the normal decline in lung function that occurs with ageing, but can also occur with near-normal decline if maximal lung volumes are reduced owing to poor lung growth2 (Fig. 2). Progressive airway obstruction leads to dyspnoea (shortness of breath on exertion) and, as a result, exercise limitation.

Box 1: Glossary of clinical terms
  • Airflow limitation: the inability of a patient to increase the flow of air, measured at the mouth, independent of the effort made

  • CT scan of the thorax: a radiological method to obtain detailed imaging of the thorax and its contents, including the lungs and airways

  • Diffusion capacity for carbon monoxide (DLCO): the amount of carbon monoxide absorbed by the body after the inhalation of a gas containing a minute concentration of carbon monoxide. DLCO is a highly sensitive method to determine the ability of the lung itself to perform normal gas exchange

  • Forced expiratory volume in 1 second (FEV1): the volume of air expelled at the first second of a forced vital capacity manoeuvre

  • Forced vital capacity (FVC): the volume of air expelled from the lungs when starting at total lung capacity until the residual volume is reached. This is performed during a maximally forced manoeuvre

  • Functional residual capacity (FRC): the volume of air in the lungs after a regular breath

  • Hypoxaemia: a low level of oxygen in the blood, which can be determined directly by drawing arterial blood or indirectly by using an oximeter

  • Plethysmography: a procedure that accurately measures all of the volumes of air in the thorax above and beyond those that can be measured with a spirometer

  • Residual volume (RV): the volume of air left in the lungs at the end of a forceful exhalation

  • Spirometery: a procedure that uses a spirometer to determine the amount (volume) and time of displacement of air into and out of the lungs

  • Total lung capacity (TLC): the volume of air in the lungs at full inspiration

Figure 1: Airway obstruction in COPD.
Figure 1

In healthy lungs, the small airways (bronchioles) are held open by alveolar 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.

Figure 2: Disease progression in COPD.
Figure 2

In healthy individuals, the forced expiratory volume in 1 second (FEV1) declines slowly with age from a peak at approximately 25 years of age (blue line). Many patients with chronic obstructive pulmonary disease (COPD) experience an accelerated annual decline in lung function (orange line) and the development of symptoms when FEV1 falls below approximately 60% of the predicted normal. Symptoms increase as airway obstruction increases from reduced physical activity, to shortness of breath on exertion and eventually to shortness of breath at rest followed by respiratory failure. Other patients with COPD might start from a lower peak lung volume (as a result of impaired lung development) and develop symptoms with even a normal decline in FEV1 (green line).

COPD is a major global health issue that is increasing in importance as a cause of death3,4. The disease is currently the third leading cause of death worldwide, is ranked fifth in terms of disease burden, has a cumulative lifetime risk estimated to be as high as 25% and is now affecting men and women equally5. Age-specific mortality rates from COPD are declining almost everywhere, and the global increase in the number of COPD deaths is related to the growth and ageing of the population, as this disease predominantly affects the elderly3, with the peak prevalence at approximately 65 years of age. In high-income countries, cigarette smoking is the main risk factor for the development of COPD, but several other risk factors are also recognized, particularly in low-income countries.

COPD is greatly underdiagnosed and is often diagnosed late in its course. Consequently, there are concerted efforts to increase awareness of this disease and to promote spirometry, including screening, to identify patients more accurately6. Although there have been improvements in the management of COPD, there is enormous unmet need to find therapies that reduce disease progression and mortality.

In this Primer, we discuss the epidemiology of COPD, its underlying pathology and pathophysiology, including the role of genetic factors, its diagnosis and current management strategies. We discuss the importance of exacerbations and co-morbidities and then speculate about the future directions of COPD research and therapy.

Epidemiology

By far the most common cause of chronic airflow obstruction globally is smoking and exposure to environmental tobacco smoke7. The next most potent risk factor is a history of tuberculosis8,9. There is some evidence that dusty work environments have a role in COPD development9,10, but many attempts to quantify this role have not taken full account of the strong effects of poverty and education on disease risk and consequently might have overstated the contribution of high dust exposure. In Europe, there is much less convincing evidence that current levels of outdoor air pollution cause airflow obstruction. However, it is notable that an association between mortality and pollution from coal burning weakened and subsequently disappeared in the years following the introduction of the Clean Air Act in the United Kingdom11, and regions that still have very high levels of pollution from similar sources might still show these effects.

The most comprehensive data on the global distribution of COPD come from the mortality statistics compiled by the WHO and the Global Burden of Disease programme3. These data show that ‘COPD’ (in which COPD was listed as the cause of death rather than diagnosed using the GOLD standards) was the third-most common cause of death in 2010. Most deaths from COPD occur in East and South Asia as this is where the largest proportion of world's population lives, but these two regions also have the highest age-standardized mortality rates from COPD. COPD mortality rates are higher in men than in women and rise exponentially with age. It is the ageing of the world's population over the past 20 years that has had the most influence on changing the relative importance of COPD as a cause of death4.

There is a problem in interpreting these findings. The regions with the highest COPD mortality rates are not those with the highest tobacco consumption, and this goes against the common assumption that tobacco is the most common cause of COPD. A hypothesis that has been proposed to resolve this problem posits that the excess death from COPD in these low-income countries might be caused by heavy exposure to smoke from biomass burning12. This could make sense in terms of the relative health effects and exposures to different levels of particulate air pollution from cigarettes, outdoor air pollution and household air pollution13. Indeed, some experimental evidence supports that interventions to reduce exposure to indoor pollution reduce the rate of decline in lung function14,15. Nevertheless, there are problems with this explanation. First, the largest studies have failed to find an association between indoor pollutant exposure levels and chronic airflow obstruction, as measured by spirometry9,16. Second, there is little evidence to indicate that there are high levels of chronic airflow obstruction in the regions with heavy use of biomass fuels. Moreover, even in these regions, obstruction is often more common in men than in women, who would be expected to have higher exposure to indoor biomass17.

The strongest association with mortality from ‘COPD’ (in which COPD is listed as the cause of death) is with poverty17 (Fig. 3). Countries with a low per capita gross national income have much higher recorded mortality rates from COPD, which might partially explain the high COPD mortality rates in East and South Asia. This trend mirrors the association of COPD mortality with socioeconomic status in older data from the United Kingdom — where the socioeconomic gradient was stronger for COPD than those for lung cancer and even for tuberculosis18 — and the overall downward trend in COPD deaths in England and Wales since the first decade of the twentieth century19. There is also a strong association between per capita gross national income and the prevalence of low FVC17. Although the interpretation of these data is controversial, as the potential confounding effects of ethnic differences can be interpreted in different ways, the association between socioeconomic status and COPD mortality is strongest when ‘European’ populations are excluded from the analysis, particularly among women for whom smoking is less of a confounder. As it is European populations that seem different, the association of COPD mortality with poverty among the other countries after excluding the European countries supports the view that the association is less likely to be explained on ethnic grounds. In support of a role for poverty in mortality from lung disease, this association is similar to the association between infant mortality rates from pneumonia and bronchitis and adult mortality from chronic bronchitis 50 years later, both of which were higher in poorer areas of England and Wales20. Although it is true that poor countries have a very low uptake of medications for COPD21, it is unlikely, given the efficacy of these treatments and the extensive differences in mortality, that this is the main reason for disparities in COPD-related mortality between developed and developing countries.

Figure 3: Poverty is a risk factor for COPD.
Figure 3

There is a strong relationship in men and women between chronic obstructive pulmonary disease (COPD) mortality rates (mortality from COPD per 100,000 individuals 15–59 years of age) and annual per capita gross national income. PPP, purchasing power parity. Data obtained from Ref. 17.

Mechanisms/pathophysiology

Several distinct and overlapping phenotypes comprise the syndrome designated as COPD, and it is also likely that there are several underlying mechanisms of disease. Not all cigarette smokers develop airway obstruction, indicating that there are susceptibility mechanisms — which might include genetic, epigenetic and environmental factors — that are currently poorly understood. A better understanding of the complex cellular mechanisms and molecular pathways involved in COPD might lead to improved therapies in the future.

Genetic risk factors

Although COPD risk is strongly related to tobacco smoking, the variable development of chronic airflow obstruction among smokers suggests that other factors also influence the onset and progression of COPD. COPD tends to cluster in families, and twin studies22, pedigree studies23,24 and analysis of unrelated individuals25 have all suggested that there is significant heritability of COPD, accounting for at least 30% of the variation in COPD risk. First-degree relatives of patients with COPD who smoke cigarettes have approximately a threefold increased risk of developing COPD compared with smokers from the general population, whereas non-smoking first-degree relatives of patients with COPD have similar (and low) risks for chronic airflow obstruction compared with non-smokers in the general population. These results indicate that there are likely to be genetic determinants that interact with smoking to increase COPD risk.

Several Mendelian syndromes include COPD (typically emphysema) as part of their constellation of clinical features, including α1-antitrypsin deficiency and cutis laxa. α1-Antitrypsin deficiency is usually caused by homozygosity for a single and relatively rare non-synonymous single-nucleotide polymorphism (SNP) — namely, the PI*Z allele of the α1-antitrypsin gene (SERPINA1). PIZZ α1-antitrypsin deficiency, which occurs in approximately 1 in 3,000 individuals in the United States, accounts for approximately 1% of COPD cases26. Although the question of whether heterozygosity for the PI*Z allele confers increased COPD risk has been controversial, several recent studies have strongly suggested that PI*Z heterozygote individuals have a moderately increased risk for COPD if they smoke27,28.

Cutis laxa can be caused by mutations in several different genes, including elastin (ELN)29, which is a key component of the lung extracellular matrix. In addition, a rare functional ELN variant has been identified in a family with a high number of individuals with COPD30. Whole-exome and whole-genome sequencing have the potential to identify other rare genetic determinants of COPD, and comprehensive genomic analyses of heavy smokers without COPD might identify genetic determinants of COPD resistance. Whole-exome sequencing has recently implicated a coiled-coil domain containing 38 (CCDC38) variant, which is linked to ciliary function, in the resistance to COPD development31. Given that the cilia of lung epithelial cells normally play an important part in removing inhaled particulates, it is plausible that ciliary abnormalities could contribute to COPD development.

Although many candidate genes have been tested for their association with COPD, most of these results have not been consistently replicated32,33. However, genome-wide association studies (GWAS) of COPD have identified multiple genomic regions that are associated with COPD34 and most of these associations have now been replicated in other studies. GWAS of lung function levels in general population cohorts have been performed in the CHARGE35 and SpiroMeta36 consortia, and >20 genomic regions have been associated with FEV1 and/or FEV1/FVC levels37. Several of these lung function genomic loci, including Hedgehog-interacting protein (HHIP) and family with sequence similarity 13 member A (FAM13A), have also been associated with COPD susceptibility.

GWAS have also been performed for several other COPD-related phenotypes, such as emphysema pattern38 and nicotine addiction39,40; the results from these studies suggest that susceptibility loci might influence different COPD-related traits (Table 1). For instance, several of the COPD susceptibility loci, including the 15q25 locus that has been associated with lung cancer41 and peripheral arterial disease42, are associated with nicotine addiction. An integrative study combining gene expression analysis and genetic association analysis implicated iron-responsive element-binding protein 2 (IREB2), another gene within the 15q25 locus, in COPD susceptibility43, and mediation analysis suggested that there might be two genetic loci influencing COPD on 15q25 — one related and one unrelated to nicotine addiction44.

Table 1: Top genomic regions conferring susceptibility to COPD and COPD-related phenotypes based on GWAS

Molecular studies and bioinformatic approaches are needed to identify the functional genetic variants within COPD genetic loci implicated by GWAS, which probably often influence gene regulation. Chromosome conformation capture studies have identified a long-range interaction of the COPD genome-wide association study locus upstream from HHIP with the HHIP promoter. Subsequent studies identified a functional variant within an enhancer in this region that alters binding to the transcription factor SP3 (Ref. 45). A recent study demonstrated that heterozygous gene-targeted Hhip mice (Hhip+/−) had increased susceptibility to smoke-induced emphysema and that lymphocyte activation pathways were implicated in this susceptibility46.

Additional efforts to integrate genetic variation with gene expression47, epigenetic markers48 and/or other ‘-omics’ data types are likely to identify more COPD susceptibility genes and provide insight into the network of interacting genes that increases COPD risk and contributes to COPD heterogeneity. Molecular and cellular studies of these susceptibility genes will be necessary to understand their role in COPD pathogenesis.

Pathogenesis

Pathology. The main pathological features of COPD are obstructive bronchiolitis, emphysema and, in many cases, mucus hypersecretion (chronic bronchitis) (Fig. 1), but the relative contribution of each of these pathologies to COPD varies between patients49. Even in early or mild COPD, there is evidence of airflow obstruction and a significant loss (disappearance) of small airways50. A novel CT imaging technique for quantifying small airway disease shows that this small airways loss is an early feature of disease and might account for the initial progression of airway obstruction in COPD51. Structural changes in small pulmonary arterioles are common in COPD, with increased intimal thickening and vascular smooth muscle proliferation, and such changes might be the result of inflammation in these vessels as well as hypoxic vasoconstriction52. However, pulmonary hypertension is usually not marked in COPD, except for a small group of patients with disproportionate pulmonary hypertension who might develop right heart failure53.

Chronic inflammation. COPD is associated with chronic inflammation that predominantly affects peripheral airways and lung parenchyma, although large airways also show inflammatory changes54. The degree of inflammation increases — with increased numbers of neutrophils, macrophages and lymphocytes in the lungs — as the disease progresses49. Chronic inhalation of irritants, including cigarette smoke, biomass fuel smoke and air pollutants, activates pattern recognition receptors, such as Toll-like receptors, which results in an innate immune response. This immune response then leads to increased numbers of neutrophils and macrophages in the lungs as well as activation of airway epithelial cells and mucus secretion55. Activation of adaptive immunity occurs later in the course of the disease and leads to increased numbers of T lymphocytes and B lymphocytes in the lungs. These cells might be organized into lymphoid follicles, which involves an increase in the number and activation of dendritic cells. During this adaptive immune response there is also an increase in the number of CD8+ cytotoxic T cells and CD4+ T helper 1 cells in lung tissue56. The number of CD4+ T helper 17 cells is also increased in the lungs and might further amplify neutrophilic inflammation57. Some patients with COPD have increased numbers of eosinophils in their airways, increased sputum and share some features with asthma, such as reversibility of the airway obstruction and a greater response to corticosteroids than patients with typical COPD58.

The levels of many different inflammatory mediators are increased in the lungs of patients with COPD, including lipid and peptide mediators, as well as a network of cytokines and chemokines that maintain inflammation and recruit circulating cells into the lungs59. Many of these pro-inflammatory mediators are regulated through the activation of the pro-inflammatory transcription factor nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs), particularly p38 MAPK60,61. In addition, several proteases that degrade elastin fibres are secreted from airway resident neutrophils, macrophages and epithelial cells in patients with COPD. In larger airways, elastase from neutrophils might be an important stimulator of mucus hypersecretion, whereas matrix metalloproteinases (MMP9 and MMP12) in the lung parenchyma might be more important in the elastolysis that is observed in those with emphysema.

Even cigarette smokers with normal lung function have increased airway inflammation, suggesting that this might be the normal immune response of the respiratory mucosa to inhaled irritants. However, this inflammation seems to be amplified in patients with COPD, particularly during acute exacerbations. The amplified inflammatory response in COPD might be explained by the reduced expression of the nuclear enzyme histone deacetylase 2 (HD2, encoded by HDAC2) in cells such as macrophages and epithelial cells in the lungs of those with COPD, resulting in the activation of multiple inflammatory genes62. The inflammation in COPD persists after smoking cessation, suggesting that it is maintained by some autonomous mechanism that is not yet understood.

The lower respiratory tract of patients with COPD is often colonized with bacteria, such as Haemophilus influenzae and Streptococcus pneumoniae. This chronic bacterial colonization has been linked to a defect in the uptake (phagocytosis) of bacteria by macrophages63,64, and, particularly with H. influenzae, might be a factor driving chronic airway and systemic inflammation and immune responses in these patients65. This defect in phagocytosis might also apply to a defective uptake of apoptotic inflammatory cells (efferocytosis) and therefore might contribute to the impairment in resolution of lung inflammation in individuals with COPD64,66 (Fig. 4). Autoimmune mechanisms might also have a role in the persistence of bacterial infection, and there is evidence of the presence of autoantibodies, such as endothelial cell antibodies and antibodies against carbonyl-modified proteins, in the lungs of those with COPD, at least in severe disease67. Finally, the peripheral lung inflammation observed in COPD might also ‘spill over’ into the systemic circulation and contribute to the systemic inflammation in COPD that is associated with various co-morbidities, such as cardiovascular disease and metabolic diseases68. However, not all patients with COPD have evidence of systemic inflammation69 and co-morbidities might be part of multimorbidity with similar mechanisms, such as accelerated ageing, affecting several organs at the same time.

Figure 4: Defective phagocytosis in COPD.
Figure 4

In healthy individuals, macrophages phagocytose bacteria in the lung periphery and respiratory tract to maintain lung sterility. These macrophages also phagocytose apoptotic cells (efferocytosis), resulting in resolution of inflammation. In chronic obstructive pulmonary disease (COPD), macrophages are defective at phagocytosing bacteria, which results in chronic bacterial colonization of the lower airways. In addition, these macrophages have an impaired ability to carry out efferocytosis of apoptotic cells, which results in failure to resolve inflammation.

Accelerated ageing. COPD is largely a disease of the elderly and there is increasing evidence to indicate that emphysema is caused by accelerated ageing of the lung parenchyma owing to defective endogenous anti-ageing mechanisms, such as those that involve sirtuins70, with the activation of pathways leading to telomere shortening and cellular senescence71 (Fig. 5). Cellular senescence and decreased activity and expression of sirtuin 1 (SIRT1) have also been found in circulating endothelial progenitor cells of patients with COPD. These cells are less effective at vascular repair than endothelial progenitor cells from age-matched healthy individuals; therefore, patients with COPD are predisposed to developing cardiovascular disease and other co-morbidities72. Indeed, stem cell senescence might be a common mechanism in COPD and its co-morbidities, with consequent failure to repair tissue damage73. Autophagy, a process in which cells keep their cytoplasm clean by removing damaged organelles and proteins, is also impaired with ageing74. Accumulating evidence indicates that autophagy is defective in COPD, which leads to the accumulation of damaged proteins and organelles, such as mitochondria, and in accelerated cellular senescence and death75.

Figure 5: Accelerated ageing in COPD.
Figure 5

Forced expiratory volume in 1 second (FEV1) values decline with age in healthy individuals (blue line), and senile emphysema (the result of ageing) might be seen in the elderly. In those with chronic obstructive pulmonary disease (COPD), lung ageing seems to be accelerated (green line) as a result of oxidative stress caused by cigarette smoking and other inhaled stimuli. Patients with COPD have all of the features of accelerated lung ageing, including telomere shortening, cellular senescence, DNA damage (failure of repair), mitochondrial dysfunction, impaired autophagy, stem cell exhaustion and reduced levels and activity of anti-ageing molecules, such as sirtuin 1.

Oxidative stress. Increased oxidative stress is a key driving mechanism in the pathophysiology of COPD and accounts for many of the features of the disease76. Oxidative stress is increased in patients with COPD from cigarette smoke exposure, but also endogenously from the activation of inflammatory cells, particularly neutrophils and macrophages. Reactive oxygen species (ROS) contribute to COPD pathophysiology in several ways (Fig. 6). For instance, ROS activate NF-κB and p38 MAPK, resulting in increased expression of inflammatory genes and proteases. ROS also inhibit endogenous antiproteases, such as α1-antitrypsin, resulting in increased elastolysis. Furthermore, oxidative stress leads to DNA damage, which is normally repaired by the efficient DNA repair machinery. However, in patients with COPD, there might be a failure to repair double-stranded DNA breaks, which might also lead to an increased risk of developing lung cancer77. ROS induce carbonylation of proteins, which, particularly in severe COPD, might lead to the generation of circulating autoantibodies that might perpetuate inflammation and lung injury67. ROS also activate transforming growth factor-β (TGFβ), leading to fibrosis. In addition, oxidative stress reduces corticosteroid responsiveness through a reduction in the activity and expression of HD2 (Ref. 78). ROS also reduce the expression and activity of SIRT1, which is markedly reduced in the lungs of patients with COPD and has a role in maintaining genomic stability, regulating autophagy and protecting against cellular senescence and ageing79. There is also evidence for defective endogenous antioxidant defences in patients with COPD. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2; also known as NFE2L2) plays a key part in the regulation of multiple antioxidant and cytoprotective genes in response to oxidative stress. NRF2 function is impaired in patients with COPD80 and is not appropriately activated by oxidative stress owing to its increased acetylation as a result of reduced HD2 activity81.

Figure 6: Increased oxidative stress in COPD.
Figure 6

Oxidative stress might be increased in chronic obstructive pulmonary 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.

Evidence is emerging to indicate that mitochondria are an important source of ROS in COPD and that there is a disruption of mitochondrial function in patients with COPD, which leads to impaired oxidative phosphorylation and reduced intracellular ATP. Mitochondria are fragmented in epithelial cells of patients with COPD and these changes are mimicked by cigarette smoke exposure in vitro, which leads to mitochondrial ROS production and cellular senescence82. Cigarette smoke induces the autophagic uptake of mitochondria (mitophagy) in airway epithelial cells, which results in mitochondrial deficiency and cell death (necroptosis) that is mediated by the mitophagy regulator phosphatase and tensin homologue-induced putative kinase protein 1 (PINK1)83. PINK1 shows increased expression in epithelial cells of patients with COPD, and Pink1 knockout in mice protects against the development of emphysema and mucus secretion induced by chronic cigarette smoke exposure.

Pathophysiology. The airway obstruction in COPD is predominantly in the small airways of the lung periphery and results in a reduction in FEV1 and the FEV1/FVC ratio, which progresses over time. An acceleration of the normal FEV1 decline with age can be observed in most patients, although poor lung function might result from the normal decline in lung function of developmentally impaired lungs. The fixed narrowing of small airways and the loss of alveolar attachments due to emphysema result in the premature closure of the small airways upon expiration, resulting in air trapping (Fig. 7). Air trapping causes lung hyperinflation (increased total lung capacity) and an increase in resting lung volume (functional residual capacity). Air trapping worsens in response to exercise (dynamic hyperinflations), resulting in exertional dyspnoea and reduced exercise tolerance84. Although the obstruction of the small airways due to fibrosis is irreversible, superimposed cholinergic tone markedly increases airway resistance. This cholinergic tone is reversible by muscarinic antagonists and β2-adrenergic receptor agonists (β2-agonists), which results in reduced air trapping and reduced symptoms. The fixed narrowing of the airways also causes increased responsiveness to bronchoconstrictors and is primarily a consequence of geometric factors. Emphysema results in reduced alveolar surface area, resulting in impaired gas transfer and eventually hypoxia.

Figure 7: Air trapping in COPD.
Figure 7

In healthy individuals, the airways narrow but do not close because elastin fibres in 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.

Causes and pathogenesis of exacerbations

COPD exacerbations are episodes of symptom worsening that are usually associated with increased airway inflammation and systemic inflammatory effects85 (Fig. 8). Most COPD exacerbations are triggered by respiratory viral infections, especially rhinovirus, which is the cause of the common cold and thus more common in winter. Respiratory viruses can be identified in the airway by PCR in up to 60% of exacerbations86. Exacerbations associated with viruses tend to have more airway and systemic inflammation than those without any evidence of viral infection, are more common in the winter months and are associated with a higher risk of hospital admission87. Pollutants that reach the airways might also be associated with precipitating exacerbations, especially by interacting with respiratory viruses, although significant effects of pollution are only seen in regions of high urban pollution88. Airway bacteria are also involved in causing exacerbations, although their precise role in triggering exacerbations is controversial. Although airway bacterial load increases during exacerbations, it is now considered that bacteria are often not the primary infective cause of the exacerbation but are secondary invaders after a viral trigger85.

Figure 8: Mechanisms and effects of COPD exacerbations.
Figure 8

Increased inflammation caused by bacteria, viruses or pollutants results in inflammation of the airways that causes further airway narrowing and systemic inflammation. COPD, chronic obstructive pulmonary disease.

Some patients with COPD are susceptible to exacerbations irrespective of disease severity. These patients have been called ‘frequent exacerbators’ and over time their exacerbation frequency is relatively stable89,​90,​91. The main risk of developing frequent exacerbations is a history of exacerbations in the previous year. Frequent exacerbators have a worse prognosis, more hospital admissions, faster disease progression and worse health status than those who experience infrequent exacerbations.

Diagnosis, screening and prevention

Diagnosis

The diagnosis of COPD should be suspected in individuals with respiratory symptoms, such as cough, expectoration of sputum, shortness of breath upon exertion or lower respiratory tract infections occurring more frequently or lasting longer than expected (>2 weeks). The suspicion should increase if the individuals also report risk factors for COPD, such as exposure to cigarette smoke, environmental or occupational pollutants and/or the presence of a family history of obstructive lung diseases1,92. Not infrequently, and usually in more-advanced cases, COPD is suspected at the time of a severe respiratory decompensation due to an acute exacerbation or following surgery, such as upper abdominal or thoracic procedures. This deterioration is caused by the main problem of underdiagnosis, as most individuals with the disease underestimate their symptoms, assuming that they are the natural consequence of the smoking habit, ageing or job exposure93. Furthermore, even in moderate-to-advanced stages of COPD, the affected patients will become ever more sedentary to avoid the uncomfortable symptom of exertional dyspnoea. Unfortunately, many health care providers fail to consider a diagnosis of COPD in patients presenting with these symptoms, especially if the person is a woman or relatively young94. The reasons for the failure to suspect COPD in these groups rests on older studies of the epidemiology of COPD that described the disease as being one of older men. As the smoking habit has increased in younger individuals and the prevalence of COPD in women is now approaching or has surpassed (in some developed countries) that of men, COPD is now prevalent in younger individuals and particularly in women, who might actually develop the disease at an earlier age than men.

History of exposure to risk factors. COPD, as with most chronic non-communicable diseases, results from the genetic make-up of an individual interacting with their environment. The respiratory system is constantly exposed to its surroundings through the act of breathing. With its large exposure surface and absorptive properties, it is surprising that the proportion of individuals exposed to cigarette smoke who develop clinical COPD is not >30–50%95. The most important risk factors for COPD are the inhalation of particulate matter from cigarette smoke and the burning of biomass for cooking or heating12. A combination of both types of exposure significantly increases the risk of developing COPD96. Other risk factors for COPD development include second-hand exposure to cigarette smoke or other particulate matter during infancy, socioeconomic disadvantage, childhood respiratory symptoms and asthma during the growth period, as discussed above97. Recent studies have shown that low lung function in early adulthood with subsequent normal lung function decline is as important as rapid lung function decline in normal-sized lungs in the development of COPD2,98,99. The role of the microbiota, which differs in smokers and in patients with COPD from that of the general population100, is receiving considerable attention, but study results are currently insufficient to confer the microbiota an important pathobiological role.

Clinical presentation. Most individuals with mild disease have a normal physical examination, including pulse, respiratory rate, chest expansion and breath and heart sounds. However, the use of a standardized functional grading of dyspnoea, the most important symptom of respiratory compromise, can help to increase the degree of suspicion, direct the health care provider to implement a spirometry test and help to stage disease severity.

One such scale is the Modified Medical Research Council dyspnoea scale, graded from 0 to 4 with the lowest grade implying no dyspnoea with any activity and the highest grade implying dyspnoea with minimal activity1,92. In patients with more-advanced disease, increased respiratory rate with forced expiratory efforts, decreased breath sounds on chest auscultation (listening), the presence of rhonchi (rattling sounds), coarse crackles and wheezes and, in the most advanced cases, cyanosis (blue skin discolouration, a sign of hypoxaemia) might be present and should be considered an important complication that requires therapy with oxygen.

Currently, the ease of use of pulse oximetry, which is a non-invasive method of measuring oxygen saturation, enables the determination of hypoxaemia early, and oxygen should be prescribed for patients with saturations below 88% while breathing room air1. The presence of cor pulmonale (failure of the right side of the heart due to hypoxaemia and increased intrapulmonary vascular resistance) is characterized by severe dyspnoea, impaired exercise capacity, leg oedema and, in the most severe cases, generalized oedema.

Use of unsupervised cluster analysis, including many clinical variables as well as results of a CT scan of the thorax and biomarkers, has confirmed that COPD is a complex heterogeneous disease in which the majority of patients combine features of the classic subgroups of the ‘pink puffer’ and the ‘blue bloater’ phenotypes101,102. These studies have also confirmed the association of these classic phenotypes with clinical, radiological and biomarker profiles103. Thus, pink puffers have lower muscle mass, more emphysema and fewer cardiovascular and metabolic co-morbidities than blue bloaters who have higher body mass index with less emphysema and more metabolic co-morbidities and cardiac compromise (Fig. 9).

Figure 9: Clinical and radiological characteristics of the classic phenotypes of patients with COPD.
Figure 9

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.

Confirming the diagnosis. A diagnosis of COPD is confirmed by the documentation of expiratory airflow limitation during a forced expiratory manoeuvre from total lung capacity to residual volume. This measurement is easily achieved using a simple spirometer and recording the timed FVC following standard recommendations104. As mentioned previously, >70% of the vital capacity is exhaled in the first second of the manoeuvre in most healthy individuals. The FEV1 is characteristically low in patients with COPD as well as in patients with restrictive pulmonary diseases. Accordingly, the diagnosis of COPD requires a decrease in the ratio of FEV1/FVC to a value that is usually <0.7. The spirometry test should be repeated after the administration of inhaled bronchodilators to distinguish the presence of poorly reversible airflow limitation of COPD from the large reversibility that characterizes airflow obstruction in patients with asthma. The actual definition of what confirms an absolute diagnosis of COPD remains controversial because older, otherwise healthy, individuals might have values of FEV1/FVC of <0.7. To address this issue, using the lower limit of normal for the FEV1/FVC ratio rather than the fixed ratio reduces the overdiagnosis of airway obstruction in the elderly105. Thus, there should be not only a decreased FEV1/FVC but also a low FEV1 compared with reference values obtained from population studies106. The current GOLD scale classifies the severity of airflow obstruction as a percentage of normal FEV1 as discussed on page 1.

Other lung function studies might complement the evaluation of patients with COPD. Many patients, and more so in advanced disease stages, will have increased lung volumes and air trapping that are measured by body plethysmography using a sealed body box. The hyperinflation will worsen with exercise and this increase in air trapping relates well to the degree of dyspnoea. The capacity of the lungs to allow gas transfer across the alveoli is assessed using the diffusion capacity for carbon monoxide into the blood. Low diffusion capacity values raise suspicion of the presence of emphysema or pulmonary vascular compromise and can be helpful in diagnosing early phases of the disease.

Global assessment and co-morbidities. COPD is not just a lung disease, and many patients will have compromise of other body systems with important prognostic and therapeutic implications107. Most notably, patients with COPD have exercise limitation due to skeletal muscle dysfunction, which is probably due to a combination of disuse atrophy and sarcopaenia (loss of muscle fibres usually associated with ageing). Indeed, a decreased functional capacity is a hallmark of COPD and helps to stage its severity because it predicts mortality better than the FEV1. A decreased capacity to exercise and a parallel decrease in activity is seen even in milder stages of COPD108. Thus, it is recommended that the functional capacity be measured with tests such as the timed walk distance, gait speed or the formal cardiopulmonary exercise test. Whether from disuse atrophy or from organic compromise, the functional capacity can be improved using rehabilitation109.

A significant proportion of patients have a low body mass index, with values below 21 kg per m2 associated with increased risk of death107. A low muscle strength as a surrogate of muscle mass can be measured by tests such as the hand grip or quadriceps force tests to complement determination of the overall compromise in COPD110.

In acknowledgement of the multiple dimensions of COPD, several proposals for its comprehensive assessment have been developed. The most widely evaluated of these assessments is the body mass index, degree of obstruction, dyspnoea and exercise capacity (BODE) index and its variants, such as the BODEx (in which the exercise is substituted by the rate of exacerbations)107. Other assessments include the age, dyspnoea and obstruction (ADO) index111, and the dyspnoea, obstruction, smoking and exacerbation (DOSE) index112. All of these indices predict mortality better than the simple measure of FEV1. Finally, GOLD has proposed a grading system that includes obstruction, symptoms and exacerbations that places patients into groups labelled A, B, C or D. However, initial studies using mortality as the outcome have shown that this grading system offers no advantage over the old system based simply on the FEV1 (Ref. 113).

Several co-morbidities also occur more frequently in patients with COPD than in patients without the disease and increase the risk of death114. These co-morbidities include coronary artery disease, arrhythmias including tachycardia, hypertension and congestive heart failure. Of particular importance are the increased risks of lung cancer, depression and anxiety, metabolic syndrome and osteoporosis114. As all of these are potentially treatable, the health care provider treating a patient with COPD should actively look for them and help guide their treatment.

Imaging. The presence of cough, sputum or dyspnoea is not specific for COPD and can be present in many other diseases. Thus, the evaluation of a patient suspected of having COPD frequently includes a chest X-ray. Although not confirmatory of COPD, a chest X-ray helps eliminate other diagnoses, such as interstitial lung diseases, congestive heart failure, pleural effusions and most pulmonary infections. CT scanning can estimate the degree of emphysema and its distribution and identify bronchial wall thickening, bronchiectasis (widening of the airway) and gas trapping (on expiration views). Several computerized automatic quantitative techniques have been applied to measure these parameters, but they have not become routine in clinical practice owing to the complex and time-consuming nature of the quantitative analysis. Furthermore, in most studies, the visual interpretation of an expert radiologist provides similar information to automatic techniques115. The proven benefit of lung cancer screening by intermittent serial CT scans in smokers >50 years of age has made chest CT a valuable tool for the integral evaluation of patients with COPD. Such screening efforts are very important, as the presence of airflow limitation as measured by spirometry and of emphysema as evaluated by CT significantly increases the risk of lung cancer116 and worsening of lung function over time117.

Biomarkers. Although desirable, several studies have failed to find a routine clinically useful biomarker that helps to grade or follow disease severity or activity in either sputum, exhaled air condensate, bronchoalveolar lavage or serum118. Markers of inflammation such a C-reactive protein (CRP) and several cytokines have predictive power for mortality and hospitalization when used singly or in combination with others, but only marginally improve the prediction when used in addition to clinical variables119. Several other biomarkers are associated with certain disease characteristics; the levels of uteroglobin (also called club cell 16 protein) in serum are inversely related to FEV1 decline117, as are the serum levels of the soluble receptor for activated glycosylation end products (sRAGEs) to emphysema120. Pilot studies using high-throughput technologies (proteomics and metabolomics) have shown some promise in identifying biomarkers121, and several ongoing studies will help to clarify their value in patients with COPD. However, to date, none can be recommended for clinical use.

Screening

Screening asymptomatic individuals is not recommended as there are currently no data showing that outcomes improve among individuals identified as having COPD before developing symptoms122. There are also no data to support that early treatment provides any benefit in asymptomatic individuals or that screening is cost effective122. Nevertheless, all guidelines recommend screening symptomatic individuals at risk for COPD. A schematic algorithm to approximate individuals with possible COPD is shown in Fig. 10.

Figure 10: Algorithm for the diagnosis, staging and management programme for COPD.
Figure 10

COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

Prevention

The most effective way to combat the worldwide epidemic of COPD is the implementation of social, economic and educational programmes aimed at decreasing the uptake of cigarette smoking1,92. This primary prevention effort should be particularly aimed 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-free spaces should be accompanied by socioeconomic initiatives, such as heavy taxation of tobacco products. The uptake of these programmes by society is possible, as has been shown by the marked decrease in smoking prevalence in the United States124. For smokers of all ages, secondary prevention with active use of educational material, behaviour modification and substitutive nicotine therapy has also proven to be effective and to result in improved outcomes. The arrival of the electronic cigarette that can deliver inhaled doses of nicotine approaching that of cigarettes is under current research because the consequences of that habit remain unknown125.

The other considerable risk factor that can be controlled is that of exposure to biomass combustion particles1. Improvement in working environments and the construction of dwellings with gasoline, gas or electric stoves have been shown to result in decreases in the prevalence and/or consequences of respiratory illnesses126. A concerted effort from all members of society should bring this scourge under control. As poverty is a major risk factor, general improvement in living conditions and diet might also be efficacious.

Management

A good patient–doctor relationship and proper follow-up of treatment is needed for optimal management1. Focus on both non-pharmacological and pharmacological treatment is required, as is a focus on patient behaviour, not least adherence to treatment127. Self-management plans have become widespread, but caution is warranted as trials of self-management have produced conflicting results128. Similarly, the use of telehealth as part of COPD management is increasing, despite the lack of firm evidence of its effectiveness129; more-robust studies of this approach are clearly needed.

Stable disease

Management of stable (non-exacerbating) disease can be divided into the following categories: reducing exposure to harmful substances, relief of symptoms and reducing risk, mainly the risk of exacerbations (Table 2). Most regional and national COPD guidelines follow, to some extent, the recommendation outlined in the GOLD strategy1. Smoking cessation has a substantial effect on future disease progression and mortality as well as on symptoms130. However, as COPD is the result of cumulative exposures, with biomass fuel exposure playing a major part globally, exposure reduction must be viewed in a broader context. Reduction of indoor pollution, such as through improving biomass stoves and kitchen ventilation, affects symptoms and future decline in lung function14,15. Management of symptoms and future risk includes both non-pharmacological and pharmacological treatment.

Table 2: Management of stable COPD

Non-pharmacological treatment. Pulmonary rehabilitation can be defined as “an interdisciplinary programme of care for patients with chronic respiratory impairment that is individually tailored and designed to optimize each patient's physical and social performance and autonomy. Programmes comprise individualised exercise programmes and education” (Refs 131,132,133). Pulmonary rehabilitation improves exercise capacity, reduces breathlessness, improves health status, improves physical activity and activities of daily living and improves psychological status133. Advice on increased physical activity has not been proven to be efficacious in this context but seems logical given the general benefits of physical activity1,134.

Pharmacological treatment. Treatment with bronchodilators is the mainstay of pharmacological management of symptoms and primarily addresses breathlessness. Bronchodilators include β2-agonists and muscarinic receptor antagonists (anticholinergics) (Fig. 11). Inhaled long-acting bronchodilators of 12–24 hours of duration are preferred and, of these, long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are equally effective1. Long-acting bronchodilators improve lung function, reduce breathlessness, improve exercise capacity and improve health status. There are only minor differences between individual bronchodilators, and the choice of drug for an individual patient will often depend on patient preference, availability and cost. The symptomatic effect of long-acting bronchodilators is due to their effect on operating lung volumes rather than on decreased airflow limitation135 and, for this reason, there is a limited correlation between effect on FEV1 and symptoms in the individual patient. The symptomatic effect of a long-acting bronchodilator cannot be predicted by the response a patient has to a short-acting bronchodilator. Patients with a history of exacerbations and/or low lung function are at particular risk of future exacerbations90. Several drug classes reduce the risk of exacerbations, including long-acting bronchodilators, inhaled corticosteroids (ICSs), macrolides, phosphodiesterase type 4 (PDE4) inhibitors and mucolytics, as discussed below1.

Figure 11: Effects of bronchodilators in COPD.
Figure 11

Postganglionic cholinergic nerves tonically release acetylcholine, activating muscarinic M3 receptors on airway smooth muscle cells, which in turn leads to bronchoconstriction. This activation causes a marked increase in peripheral airway resistance as the small airways are already structurally narrowed in chronic obstructive pulmonary disease (COPD). Muscarinic antagonists (anticholinergics) block M3-receptors and thus reduce cholinergic tone, resulting in reduced airway resistance and reduced air trapping. Muscarinic antagonists can be short-acting (SAMA, such as ipratropium bromide) or long-acting (LAMA, such as tiotropium bromide or glycopyrronium bromide). β2-adrenergic receptor agonists (β2-agonists) activate β2-receptors on airway smooth muscle, which functionally antagonize cholinergic tone and have the same bronchodilator effect as muscarinic antagonists. β2-agonists can be short-acting (SABA, such as salbutamol (albuterol)) or long-acting (LABA, such as salmeterol and indacaterol). There are additive bronchodilator effects when LAMAs and LABAs are given together.

Adverse effects are mainly limited to dryness of the mouth for anticholinergics, and tremor and hypokalaemia for β2-agonists. The cardiovascular safety of long-acting bronchodilators has been debated, but recent trials indicate that they are safe in patients who have stable cardiovascular disease136,​137,​138. The two classes of long-acting bronchodilators can be combined, but the symptomatic effects of combined treatment are less impressive than the almost additive effect they have on lung function139. ICSs also improve lung function and reduce breathlessness140; however, the ratio between benefits and adverse effects is insufficient for recommending ICSs for symptomatic treatment. Finally, long-term oxygen therapy, usually interpreted as oxygen for at least 15 hours per day, has, in two relatively old trials, been shown to reduce mortality over subsequent years, presumably through protecting the right side of the heart from hypoxia-induced secondary pulmonary hypertension1.

Surgical intervention. Lung volume reduction surgery and transplantation are evidence-based interventions that can improve survival and quality of life in highly selected patients, usually those with very severe disease. Valves and coils placed in the segmental bronchi during bronchoscopy are still at an experimental stage141.

Exacerbations

The main symptoms of a COPD exacerbation are increases in dyspnoea, sputum purulence and cough, but other symptoms might include increased wheezing and symptoms of a cold142. Although changes in lung function also occur during a COPD exacerbation, falls in FEV1 values are small and are not generally useful in predicting or monitoring exacerbations. Exacerbations generally last for several days but as long as 12 weeks can elapse before returning to baseline status.

COPD exacerbations are defined in the GOLD strategy in terms of health care use as “an acute event characterized by a worsening of the patient's respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication” (Ref. 1). However, there is now considerable evidence to indicate that more than half of all COPD exacerbations identified by symptom worsening are not reported to health care professionals and are left untreated143. In addition, these untreated COPD exacerbations, although generally less severe than those that are treated, might affect health status143. Accordingly, patients must be encouraged to report exacerbations for review by their physicians.

COPD exacerbations are a major cause of admissions and readmissions to hospital and are also independent predictors of mortality in COPD. Moreover, exacerbations drive disease progression, with some studies finding that up to 25% of the lung function decline in COPD is attributable to exacerbations, whereas other studies have found that exacerbations contribute significantly less to lung function decline144,145. COPD exacerbations are a major determinant of health status in COPD, and any intervention that reduces exacerbation will affect health status89. COPD exacerbations are also associated with cardiovascular events, especially myocardial infarction, and this association is most marked in severe exacerbations that require hospital admission146,147.

Pharmacological treatment. Management of an exacerbation comprises oral antibiotics, such as amoxicillin or doxycycline, if there is evidence of increased sputum purulence or volume148. The choice of antibiotic will depend on the patient's history and underlying disease severity. Oral corticosteroids in short courses are also added, depending on the individual exacerbation severity, and there is recent evidence to suggest that shorter courses (5 days) of corticosteroids might be as beneficial as longer courses, such as the more conventional 14 day courses149. There is some evidence to suggest that oral corticosteroids are more effective in patients who have increased blood eosinophil numbers during their exacerbation, but further prospective studies are needed to confirm these findings150. There is evidence that, the earlier that therapy is started at the onset of an exacerbation, the shorter the recovery of the event and the less chance of hospital admission143. Thus, prompt and appropriate management of the exacerbation event will have an effect on optimizing recovery and will delay the time to the next event. In summary, optimal management of the acute exacerbation will not only increase the rate of exacerbation recovery but will also affect exacerbation rates and prevent hospital admissions.

Exacerbation prevention. Influenza vaccination is associated with a 27% reduction in the risk of hospitalization triggered by influenza virus infection in elderly individuals151; therefore, influenza vaccination is recommended for the majority of patients with COPD. There is less evidence to support the use of a pneumococcal polysaccharide vaccine in the prevention of COPD exacerbations, but large studies are currently underway with vaccines that have improved immunogenicity.

Use of long-acting bronchodilators reduces the risk of exacerbations by approximately 25%152,153. The same effect size is seen for ICS use, and the mechanisms that underlie the effects of various pharmacological agents on preventing exacerbations are likely to differ as the effect of combined treatment with a LABA and ICS is better than that for each drug alone140. Some exacerbations require treatment with systemic corticosteroids, and although the use of an ICS alone reduces exacerbations by approximately 25%140, monotherapy with an ICS is not recommended by GOLD1. The use of ICSs should be restricted to patients who are at high risk of exacerbations, should probably be restricted to patients without lower airway bacterial colonization and, based on post-hoc analyses of recent trials, should not be given to patients with <2% eosinophils in the peripheral blood in stable disease154,155. In addition to well-known local adverse effects, such as oral thrush and hoarse voice, ICSs are associated with an increased risk of pneumonia and they might increase the risk of osteoporosis130,156.

LAMAs alone also reduce exacerbation frequency137 and have a greater effect on exacerbation reduction than LABAs157. LABA–ICS combinations and LAMA have similar effects on exacerbations in patients with severe and very severe COPD (an FEV1 of <50% of predicted normal); therefore, LAMAs can be used as an alternative to LABA–ICS combinations in these patients158. A LABA–LAMA combination (indacaterol and glycopyrronium) has been evaluated in patients with a FEV1 of <50% of predicted normal and a history of exacerbations. The combination treatment resulted in fewer health care use exacerbations than glycopyrronium alone and was marginally better than either glycopyrronium or open-label tiotropium in the reduction of all exacerbations when mild, moderate and severe exacerbations were combined159.

Roflumilast is a PDE4 inhibitor with broad anti-inflammatory activity and inhibits the airway inflammation associated with COPD, especially by reducing the number of airway neutrophils that are key to COPD pathogenesis. Evidence from two large placebo-controlled, double-blind multicentre trials has revealed that roflumilast use results in a 17% reduction in the frequency of moderate or severe exacerbations160. However, only patients with a FEV1 of <50% of predicted normal (GOLD3 and GOLD4), presence of bronchitis symptoms and a history of exacerbations were enrolled in these studies. A recent study has shown only marginal benefit when roflumilast is added to standard triple COPD therapy161.

Antibiotics have also been investigated for their efficacy in reducing exacerbation frequency. For instance, a low dose of the macrolide erythromycin reduces the frequency of exacerbations and shortens exacerbation length in patients with moderate-to-severe COPD162. Azithromycin, another macrolide, when added to usual treatment decreases exacerbation frequency and improves quality of life in patients with COPD163. However, significant rates of hearing decrement (as measured by audiometry) and antibiotic resistance were reported for azithromycin use164. Further studies are required to address the issue of antibiotic resistance in long-term antibiotic trials in COPD. Cardiovascular adverse effects have also been reported with macrolides.

Further studies with non-macrolide antibiotics are ongoing and these will also need to assess issues of safety and resistance. Before use of any long-term antibiotics, patients should be treated with an optimum combination inhaled therapy for COPD and show evidence of ongoing exacerbations despite therapy. In addition, careful monitoring of potential auditory and cardiovascular adverse effects (by monitoring the QTc interval, for instance) are necessary.

Mucolytic drugs reduce the viscosity of airway mucus to improve airflow. Two large Chinese studies have shown that mucolytics reduce exacerbation frequency165,166. However, it is unclear whether this effect is due to the mucolytic or antioxidant effects of these drugs. Moreover, the drugs were tested in a population with little concomitant treatment. For this reason, mucolytic treatment is not widely recommended.

There has been considerable interest in performing pulmonary rehabilitation, including physical training, early in the time course of an exacerbation or shortly after admission to hospital to reduce the frequency or severity of subsequent exacerbations. Although results from initial pilot studies were promising, two well-designed studies have shown little benefit of early intervention with pulmonary rehabilitation courses167,168. Finally, pulmonary rehabilitation has been shown to reduce the length of subsequent exacerbations.

Quality of life

Health status is defined as “the impact of health on a person's ability to perform and derive fulfilment from the activities of daily life. A patient's self-reported health status thus includes health-related quality of life and functional status” (Ref. 169). Patients with COPD report an impaired health status, irrespective of the severity of the disease170. An improvement in health status is associated 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 polypharmacy172, future exacerbations, hospitalizations173 and survival174. This bidirectional association underlines the importance of the routine monitoring of health status in these patients. Indeed, health status measurement can be defined as “a process that is essentially similar to a highly structured clinical history, although the end product is not a clinical impression but an objective measurement … It is no more “soft” … than any well taken clinical history” (Ref. 175). Consequently, GOLD includes health status as an objective for COPD diagnosis and management1.

Owing to the systemic effects of the disease, one study found that 97.7% of patients with COPD had one or more co-morbidity and 53.5% were diagnosed with four or more co-morbidities176. Each additional co-morbidity increases the chance of worsening of self-rated health by 43%177. Vanfleteren and colleagues176 identified five co-morbidity clusters and showed that clinical characteristics were comparable between these clusters. However, patients differed in terms of health status, with worst health status scores for those in the cardiovascular and psychological co-morbidity cluster than for those with other co-morbidities176. Indeed, cardiovascular diseases are probably the most frequent and important diseases that coexist with COPD178, and impaired cardiac function is associated with worse survival in patients with COPD179. However, although not directly pathophysiologically related to COPD, symptoms of anxiety and depression are highly prevalent in those with COPD180 and have been shown to be associated with poor adherence to treatment strategies181.

Thus, patients with an impaired health status are at risk of poor outcomes and prognoses, which can then be worsened by co-morbidities (Fig. 12). Unfortunately, co-morbidities are often underdiagnosed and consequently under-treated, which might consequently worsen COPD prognosis. Owing to shared risk factors and pathophysiological mechanisms, determining whether the co-morbidity or COPD itself causes the symptoms at hand remains challenging182. Nonetheless, establishing the prevalence of co-morbidities and their effect on health status as an essential patient-related outcome remain important targets for COPD studies as well as for COPD diagnosis and management.

Figure 12: Downward spiral of health-related quality of life in COPD.
Figure 12

The progressive airflow limitation that accompanies chronic obstructive pulmonary disease (COPD) leads to a spiralling decline in health-related quality of life through a range of mechanisms, including increased dyspnoea and increased rates of disease exacerbation and hospitalization.

Outlook

Considerably more research is needed on all aspects of COPD as we still have a relatively poor understanding of disease mechanisms and natural history. In addition, we need more-effective pharmacological therapies that target the underlying disease process.

Defining phenotypes

As with other complex diseases, there are several clinical phenotypes of COPD, with some patients showing predominantly small airway disease and little emphysema, whereas others have more-predominant emphysema. Although air trapping, bronchial wall thickening and emphysema can be detected with a CT scan, CT scans are not undertaken routinely and patients in clinical trials are usually not categorized on the basis of CT results. CT scans are also able to demonstrate bronchiectasis, which is present in almost half of patients with COPD and is associated with a worse prognosis183. Other COPD phenotypes relate to predominant co-morbidities — particularly cardiovascular disease — that have an important influence on disease outcome. Several attempts have been made to categorize patients into clinical clusters based on these phenotypes, but these have not been validated184. In addition, although asthma and COPD are distinct diseases, in 10–20% of patients with COPD there are also features of asthma, such as eosinophilic inflammation, more airway reversibility and a better therapeutic response to corticosteroids than those with classic COPD. This ‘asthma–COPD overlap syndrome’ is poorly defined and characterized58.

We are also far from defining molecular phenotypes or endotypes of COPD that relate to different disease mechanisms. However, this is an important future aim as this is likely to be necessary to provide the most effective targeted therapy as part of a personalized medicine approach. Much of the current research on molecular phenotypes is undertaken on advanced disease, in which to the discernment of different phenotypes might be more difficult. Thus, it will be increasingly necessary to study early disease before fixed airflow limitation (and symptoms) develop.

Currently, the recognition of different phenotypes, such as small airway disease and emphysema, does not substantially alter management strategies, but as more specific therapies are developed it might be beneficial to target them to specific phenotypes. For example, asthma–COPD overlap syndrome might respond better to corticosteroid therapy and to specific anti-eosinophil treatments, such as antibodies that block IL-5, than other COPD phenotypes185.

Biomarkers of disease activity and progression

There is a need to develop easily measured biomarkers that quantify disease activity, susceptibility to exacerbations, co-morbidities and disease progression, as well as biomarkers that predict and monitor response to therapy. So far biochemical, proteomic and lipid biomarkers in the blood, sputum and exhaled breath have not been found to be useful in predicting clinical outcomes in COPD, but more research is needed to develop patterns of biomarkers118. The most promising blood biomarkers are pulmonary surfactant-associated protein D, fibrinogen, club cell 16 protein and CC-chemokine ligand 18 (also called pulmonary and activation-regulated chemokine), but the clinical value of these in predicting future risk and response to therapy is not yet clear186.

Understanding disease susceptibility

Not all chronic smokers develop airflow limitation, indicating that there are susceptibility factors or perhaps, more importantly, mechanisms that prevent these individuals from developing COPD, but these remain largely unknown. Identified genetic polymorphisms account for a small proportion (approximately 30%) of this susceptibility, and it is likely that there are other determinants and complex gene–environment interactions that contribute to COPD risk. Epigenetic mechanisms such as DNA methylation and histone modification, including acetylation and methylation, that are influenced by environmental factors, such as diet, are also likely to be important and are currently being elucidated187. It is important to better understand the molecular mechanisms for susceptibility, as this would provide potential new therapeutic targets and might also lead to diagnostic tests to quantify this susceptibility.

Novel therapeutic targets and treatments

Although we now have effective long-acting bronchodilators that provide considerable symptomatic benefit for patients with COPD, these drugs do not target the underlying disease process and as such do not reduce disease progression or mortality. Unlike asthma, there are no safe and effective anti-inflammatory treatments for COPD. Because of the high economic impact of COPD, there is now extensive investment in the search for novel anti-inflammatory therapies. Several novel therapeutics are currently being investigated188 (Fig. 13). These drugs include specific mediator antagonists and cytokine blockers as well as a broad range anti-inflammatory therapies, such as kinase and PDE inhibitors, all of which have so far proved to be disappointing in clinical trials, because they are too specific, are dose-limited by adverse effects or have not been targeted to responsive patients189,​190,​191. Another important reason for drug failure may be that only approximately half of patients with COPD have accelerated decline in lung function, and the remaining patients have normal decline starting from a reduced peak function owing to small lungs2.

Figure 13: Potential targets for novel COPD therapy.
Figure 13

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.

The PDE4 inhibitor roflumilast is the only anti-inflammatory treatment so far approved for COPD, but it has little clinical impact, as the dose that can be administered is limited by adverse effects161. Another future approach is to reverse the molecular mechanisms of corticosteroid resistance in COPD with existing treatments, such as theophylline, or novel inhaled therapies192. As oxidative stress is an important driving mechanism in COPD, there is also a search for more-effective antioxidants76. If effective and safe anti-inflammatory therapy can be developed, it might be used at a much earlier stage in disease progression as a preventive treatment to reduce the risk of future events, such as exacerbations, disease progression, co-morbidities and mortality. An effective anti-inflammatory treatment might also be useful in the acute management of an exacerbation, either to prevent the need for hospitalization or to more rapidly resolve the episode193.

COPD as part of multimorbidity

As discussed above, COPD is commonly associated with co-morbidities, particularly cardiovascular and metabolic diseases and lung cancer, which have a substantial effect on its clinical course and prognosis. There is increasing evidence to indicate that COPD is a component of multimorbidity, and a network analysis has identified important links between these diseases194. These linked diseases share molecular pathways of accelerated ageing, including cellular senescence, stem cell exhaustion, mitochondrial defects, impaired autophagy and reduced levels and activity of anti-ageing molecules, such as sirtuins73. This interaction suggests that it might be possible to develop novel therapies that target these common pathways and thus treat COPD and its co-morbidities simultaneously.

Increasing awareness

Despite the high prevalence, morbidity and mortality of COPD, this disease remains poorly recognized by the general public, general practitioners and specialists outside pulmonary medicine. This lack of awareness is partly because the disease name is not well understood and the disease itself is not well defined, as there might be several diseases leading to the syndrome of fixed airway obstruction. It is important to increase the diagnosis of COPD in general practice by spirometry measurements in patients at risk, including smokers and the elderly. However, there is also a need for more research to understand the underlying disease mechanisms and disease endotypes, as well as to identify useful biomarkers and develop new therapeutic and management approaches.

References

  1. 1.

    et al. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, GOLD executive summary. Am. J. Respir. Crit. Care Med. 187, 347–365 (2013). This strategy document is often regarded as the COPD standard and is the basis for most national guidelines.

  2. 2.

    et al. Lung-function trajectories leading to chronic obstructive pulmonary disease. N. Engl. J. Med. 373, 111–122 (2015).

  3. 3.

    et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic for the Global Burden of Disease Study 2010. Lancet 380, 2095–2128 (2013).

  4. 4.

    , , , & Global and regional trends in COPD mortality, 1990–2010. Eur. Respir. J. 45, 1239–1247 (2015). This paper demonstrates that the cross-sectional association found between mortality from chronic lung disease and gross national income is also reflected in an association between the change in mortality from chronic lung disease and the change in gross national income. The association is less prone to confounding by other large differences between regions.

  5. 5.

    , , , & Lifetime risk of developing chronic obstructive pulmonary disease: a longitudinal population study. Lancet 378, 991–996 (2011).

  6. 6.

    et al. Prevalence of COPD among symptomatic patients in a primary care setting. Curr. Med. Res. Opin. 25, 2671–2677 (2009).

  7. 7.

    et al. International variation in the prevalence of COPD (the BOLD study): a population-based prevalence study. Lancet 370, 741–750 (2007).

  8. 8.

    et al. Tuberculosis and airflow obstruction: evidence from the PLATINO study in Latin America. Eur. Respir. J. 30, 1180–1185 (2007).

  9. 9.

    et al. Risk factors for COPD spirometrically defined from the lower limit of normal in the BOLD project. Eur. Respir. J. 39, 1343–1353 (2012).

  10. 10.

    et al. Further exploration of the links between occupational exposure and chronic obstructive pulmonary disease. J. Occup. Environ. Med. 51, 804–810 (2009).

  11. 11.

    , , & The relation of mortality in England and Wales1969–1973 to measurements of air pollution. J. Epidemiol. Commun. Health 35, 174–179 (1981).

  12. 12.

    & Chronic obstructive pulmonary disease in non-smokers. Lancet 374, 733–743 (2009).

  13. 13.

    et al. An integrated risk function for estimating the global burden of disease attributable to ambient fine particulate patter exposure. Environ. Health Persp. 122, 397–403 (2014).

  14. 14.

    et al. Improved biomass stove intervention in rural Mexico: impact on the respiratory health of women. Am. J. Respir. Crit. Care Med. 180, 649–656 (2009).

  15. 15.

    et al. Lung function and incidence of chronic obstructive pulmonary disease after improved cooking fuels and kitchen ventilation: a 9-year prospective cohort study. PLoS Med. 11, e1001621 (2014).

  16. 16.

    et al. Prevalence and correlates of airflow obstruction in 317,000 never-smokers in China. Eur. Respir. J. 44, 66–77 (2014).

  17. 17.

    et al. Chronic obstructive pulmonary disease mortality and prevalence: the associations with smoking and poverty — a BOLD analysis. Thorax 69, 465–473 (2014). This paper shows that the prevalence of airflow obstruction is strongly associated with the prevalence of smoking, as judged by the mean pack years smoked, and that the prevalence of a low FVC is strongly associated with poverty. The prevalence of a low FVC is most closely associated with mortality rates.

  18. 18.

    Office of Population Censuses and Surveys. Occupational Mortality: The Registrar General's Decennial Supplement for Great Britain, 1979–80, 1982–1983 (Her Majesty's Stationery Office, 1986).

  19. 19.

    & in The Health of Adult Britain 1841–1991 Vol. 2 (eds Charlton, J. & Murphy, M.) 93–113 (Her Majesty's Stationery Office, 1997).

  20. 20.

    & Childhood respiratory infection and adult chronic bronchitis in England and Wales. BMJ (Clin. Res. Ed.) 293, 1271–1275 (1986). This is an early paper from Barker and Osmond showing that mortality rates from chronic airway disease later in adult life is associated with mortality in the same areas from bronchitis and pneumonia among children half a century earlier. This association was not true for lung cancer rates, and Barker and Osmond suggest that this is evidence that the environment encountered during early life has an important impact on subsequent lung health.

  21. 21.

    et al. Gaps in using bronchodilators, inhaled corticosteroids and influenza vaccine among 23 high- and low-income sites. Int. J. Tuberc. Lung Dis. 19, 21–30 (2015).

  22. 22.

    et al. Genetic influences on chronic obstructive pulmonary disease — a twin study. Respir. Med. 104, 1890–1895 (2010).

  23. 23.

    et al. Siblings of patients with severe chronic obstructive pulmonary disease have a significant risk of airflow obstruction. Am. J. Respir. Crit. Care Med. 164, 1419–1424 (2001).

  24. 24.

    et al. Genetic epidemiology of severe, early-onset chronic obstructive pulmonary disease: risk to relatives for airflow obstruction and chronic bronchitis. Am. J. Respir. Crit. Care Med. 157, 1770–1778 (1998).

  25. 25.

    et al. Heritability of chronic obstructive pulmonary disease and related phenotypes in smokers. Am. J. Respir. Crit. Care Med. 188, 941–947 (2013).

  26. 26.

    & Clinical practice. Alpha1-antitrypsin deficiency. N. Engl. J. Med. 360, 2749–2757 (2009).

  27. 27.

    et al. α1-Antitrypsin protease inhibitor MZ heterozygosity is associated with airflow obstruction in two large cohorts. Chest 138, 1125–1132 (2010).

  28. 28.

    et al. Clarification of the risk of chronic obstructive pulmonary disease in α1-antitrypsin deficiency PiMZ heterozygotes. Am. J. Respir. Crit. Care Med. 189, 419–427 (2014).

  29. 29.

    et al. A novel elastin gene mutation resulting in an autosomal dominant form of cutis laxa. Arch. Dermatol. 140, 1135–1139 (2004).

  30. 30.

    et al. A functional mutation in the terminal exon of elastin in severe, early-onset chronic obstructive pulmonary disease. Am. J. Respir. Cell. Mol. Biol. 33, 355–362 (2005).

  31. 31.

    et al. Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction. PLoS Genet. 10, e1004314 (2014).

  32. 32.

    et al. The COPD genetic association compendium: a comprehensive online database of COPD genetic associations. Hum. Mol. Genet. 19, 526–534 (2010).

  33. 33.

    , , & Meta-analyses on suspected chronic obstructive pulmonary disease genes: a summary of 20 years' research. Am. J. Respir. Crit. Care Med. 180, 618–631 (2009).

  34. 34.

    et al. Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis. Lancet Respir. Med. 2, 214–225 (2014). This collaborative genome-wide association study identifies four genetic loci for moderate-to-severe COPD and two additional loci for severe COPD. Although highly significant, these genetic loci are of modest effect size.

  35. 35.

    et al. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat. Genet. 42, 45–52 (2010).

  36. 36.

    et al. Genome-wide association study identifies five loci associated with lung function. Nat. Genet. 42, 36–44 (2010).

  37. 37.

    et al. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. Nat. Genet. 43, 1082–1090 (2011).

  38. 38.

    et al. Genome-wide association identifies regulatory loci associated with distinct local histogram emphysema patterns. Am. J. Respir. Crit. Care Med. 190, 399–409 (2014).

  39. 39.

    et al. Genome-wide association study of smoking behaviours in patients with COPD. Thorax 66, 894–902 (2011).

  40. 40.

    et al. Sequence variants at CHRNB3CHRNA6 and CYP2A6 affect smoking behavior. Nat. Genet. 42, 448–453 (2010).

  41. 41.

    et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat. Genet. 40, 616–622 (2008).

  42. 42.

    et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452, 638–642 (2008).

  43. 43.

    et al. Integration of genomic and genetic approaches implicates IREB2 as a COPD susceptibility gene. Am. J. Hum. Genet. 85, 493–502 (2009).

  44. 44.

    et al. Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility. Hum. Genet. 132, 431–441 (2013).

  45. 45.

    et al. Identification of a chronic obstructive pulmonary disease genetic determinant that regulates HHIP. Hum. Mol. Genet. 21, 1325–1335 (2012). With a COPD genome-wide association study region, chromatin interaction studies followed by functional analyses identified a likely functional genetic variant. This is one of the first examples of functional variant identification with a complex disease genome-wide association study locus.

  46. 46.

    et al. Haploinsufficiency of Hedgehog interacting protein causes increased emphysema induced by cigarette smoke through network rewiring. Genome Med. 7, 12 (2015).

  47. 47.

    et al. Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci. Hum. Mol. Genet. 24, 1200–1210 (2015).

  48. 48.

    et al. Variable DNA methylation is associated with chronic obstructive pulmonary disease and lung function. Am. J. Respir. Crit. Care Med. 185, 373–381 (2012).

  49. 49.

    & The pathology of chronic obstructive pulmonary disease. Annu. Rev. Pathol. 4, 435–459 (2009).

  50. 50.

    et al. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N. Engl. J. Med. 365, 1567–1575 (2011).

  51. 51.

    et al. Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression. Nat. Med. 18, 1711–1715 (2012).

  52. 52.

    , & Pulmonary vascular involvement in COPD. Chest 134, 808–814 (2008).

  53. 53.

    et al. Pulmonary hypertension in chronic lung diseases. J. Am. Coll. Cardiol. 62, D109–D116 (2013).

  54. 54.

    Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin. Chest Med. 35, 71–86 (2014).

  55. 55.

    , & New insights into the immunology of chronic obstructive pulmonary disease. Lancet 378, 1015–1026 (2011).

  56. 56.

    Immunology of asthma and chronic obstructive pulmonary disease. Nat. Immunol. Rev. 8, 183–192 (2008).

  57. 57.

    & Directing traffic: IL-17 and IL-22 coordinate pulmonary immune defense. Immunol. Rev. 260, 129–144 (2014).

  58. 58.

    , & The asthma–chronic obstructive pulmonary disease overlap syndrome (ACOS): opportunities and challenges. Curr. Opin. Pulm. Med. 21, 74–79 (2015).

  59. 59.

    Cytokine networks in asthma and chronic obstructive pulmonary disease. J. Clin. Invest. 118, 3546–3556 (2008).

  60. 60.

    et al. Increased expression of NF-κB in bronchial biopsies from smokers and patients with COPD. Eur. Respir. J. 20, 556–563 (2002).

  61. 61.

    et al. Increased activation of p38 MAPK in COPD. Eur. Respir. J. 31, 62–69 (2008).

  62. 62.

    et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N. Engl. J. Med. 352, 1967–1976 (2005). This study demonstrates that COPD lungs have decreased expression and activity of the nuclear enzyme HD2, which is required for corticosteroids to switch off inflammatory genes. This result explains the amplified inflammation and corticosteroid resistance in patients with COPD.

  63. 63.

    et al. Defective macrophage phagocytosis of bacteria in COPD. Eur. Respir. J. 35, 1039–1047 (2010).

  64. 64.

    & Defective phagocytosis in airways disease. Chest 141, 1055–1062 (2012).

  65. 65.

    et al. Inflammatory thresholds and the species-specific effects of colonising bacteria in stable chronic obstructive pulmonary disease. Respir. Res. 15, 114 (2014).

  66. 66.

    & Airway clearance of apoptotic cells in COPD. Curr. Drug Targets 12, 460–468 (2011).

  67. 67.

    et al. Oxidative stress-induced antibodies to carbonyl-modified protein correlate with severity of COPD. Am. J. Respir. Crit. Care Med. 184, 796–802 (2011).

  68. 68.

    Chronic obstructive pulmonary disease: effects beyond the lungs.PLoS Med. 7, e1000220 (2010).

  69. 69.

    et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS ONE 7, e37483 (2012).

  70. 70.

    & COPD as a disease of accelerated lung aging. Chest 135, 173–180 (2009).

  71. 71.

    , & Accelerated ageing in chronic obstructive pulmonary disease: new concepts. Thorax 70, 482–489 (2015). A review of the accelerated ageing process in COPD and the molecular mechanisms involved; this article also identifies novel targets for future therapies.

  72. 72.

    et al. Dysfunction of endothelial progenitor cells from smokers and COPD patients due to increased DNA damage and senescence. Stem Cells 31, 2813–2826 (2013).

  73. 73.

    Mechanisms of development of multimorbidity in the elderly. Eur. Respir. J. 45, 790–806 (2015).

  74. 74.

    , , & Essential role for autophagy in life span extension. J. Clin. Invest. 125, 85–93 (2015).

  75. 75.

    , , & The emerging importance of autophagy in pulmonary diseases. Chest 142, 1289–1299 (2012).

  76. 76.

    & Oxidative stress in COPD. Chest 144, 266–273 (2013).

  77. 77.

    et al. Unbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancer. Thorax 66, 521–527 (2011).

  78. 78.

    Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 131, 636–645 (2013).

  79. 79.

    et al. A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9. FASEB J. 23, 2810–2819 (2009).

  80. 80.

    et al. Expression of concern: decline in NRF2 regulated antioxidants in COPD lungs due to loss of its positive regulator DJ-1. Am. J. Respir. Crit. Care Med. 178, 592–604 (2008).

  81. 81.

    et al. Decreased histone deacetylase 2 impairs Nrf2 activation by oxidative stress. Biochem. Biophys. Res. Commun. 406, 292–298 (2011).

  82. 82.

    et al. Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence. Am. J. Physiol. Lung Cell. Mol. Physiol. 305, L737–L746 (2013).

  83. 83.

    et al. Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J. Clin. Invest. 124, 3987–4003 (2014).

  84. 84.

    , & Does dynamic hyperinflation contribute to dyspnoea during exercise in patients with COPD? Eur. Respir. J. 40, 322–329 (2012).

  85. 85.

    & COPD exacerbations: defining their cause and prevention. Lancet 370, 786–796 (2007). This paper provides an excellent insight into the nature of exacerbations of COPD, their importance, clinical consequences and prevention of their occurrence.

  86. 86.

    et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 164, 1618–1623 (2001).

  87. 87.

    et al. Human rhinovirus infection during naturally occurring COPD exacerbations. Eur. Respir. J. 44, 87–96 (2014).

  88. 88.

    et al. Outdoor air pollution and respiratory health in patients with COPD. Thorax 66, 591–596 (2011).

  89. 89.

    et al. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 157, 1418–1422 (1998).

  90. 90.

    et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N. Engl. J. Med. 363, 1128–1138 (2010).

  91. 91.

    , , & Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med. 11, 181 (2013).

  92. 92.

    & Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur. Respir. J. 23, 932–946 (2004).

  93. 93.

    et al. Physician and patient perceptions in COPD: the COPD Resource Network Needs Assessment Survey. Am. J. Med. 118, 1415 (2005).

  94. 94.

    & Diagnosis and treatment considerations for women with COPD. Int. J. Clin. Pract. 63, 486–493 (2009).

  95. 95.

    et al. Not 15 but 50% of smokers develop COPD? — Report from the Obstructive Lung Disease in Northern Sweden studies. Respir. Med. 97, 115–122 (2003).

  96. 96.

    et al. Wood smoke exposure and gene promoter methylation are associated with increased risk for COPD in smokers. Am. J. Respir. Crit. Care Med. 182, 1098–1104 (2010).

  97. 97.

    , , & Airway obstruction in never smokers: results from the Third National Health and Nutrition Examination Survey. Am. J. Med. 118, 1364–1372 (2005).

  98. 98.

    , , , & Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study. Lancet 370, 758–764 (2007).

  99. 99.

    et al. Disease progression in young patients with COPD: rethinking the Fletcher and Peto model. Eur. Respir. J. 44, 324–331 (2014).

  100. 100.

    et al. Analysis of the lung microbiome in the “healthy” smoker and in COPD. PLoS ONE 6, e16384 (2011).

  101. 101.

    et al. Clinical COPD phenotypes: a novel approach using principal component and cluster analyses. Eur. Respir. J. 36, 531–539 (2012).

  102. 102.

    et al. Identification and prospective validation of clinically relevant chronic obstructive pulmonary disease (COPD) subtypes. Thorax 66, 430–437 (2011).

  103. 103.

    et al. Identification of five chronic obstructive pulmonary disease subgroups with different prognoses in the ECLIPSE cohort using cluster analysis. Ann. Am. Thorac. Soc. 12, 303–312 (2014).

  104. 104.

    et al. Standardisation of spirometry. Eur. Respir. J. 26, 319–338 (2005).

  105. 105.

    et al. Using the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction. Thorax 63, 1046–1051 (2008).

  106. 106.

    , & Spirometric reference values from a sample of the general U. S. population. Am. J. Respir. Crit. Care Med. 159, 179–187 (1999).

  107. 107.

    et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N. Engl. J. Med. 350, 1005–1012 (2004). This work provides the first objective evidence of the importance of non-pulmonary involvement in patients with COPD. In addition, it prospectively validates the measurement of a multidimensional index to prognosticate outcome in patients with COPD.

  108. 108.

    et al. An official European Respiratory Society statement on physical activity in COPD. Eur. Respir. J. 44, 1521–1537 (2014).

  109. 109.

    , & American Thoracic Society Subcommittee on Integrated Care of the COPD Patient. An official American Thoracic Society workshop report: the Integrated Care of the COPD Patient. Proc. Am. Thorac. Soc. 9, 9–18 (2012).

  110. 110.

    et al. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 189, e15–e62 (2014).

  111. 111.

    et al. Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated BODE index and the ADO index. Lancet 374, 704–711 (2009).

  112. 112.

    et al. Derivation and validation of a composite index of severity in chronic obstructive pulmonary disease: the DOSE index. Am. J. Respir. Crit. Care Med. 180, 1189–1195 (2009).

  113. 113.

    et al. Multicomponent indices to predict survival in COPD: the COCOMICS study. Eur. Respir. J. 42, 323–332 (2013).

  114. 114.

    et al. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 186, 155–161 (2012).

  115. 115.

    et al. Quantifying the extent of emphysema: factors associated with radiologists' estimations and quantitative indices of emphysema severity using the ECLIPSE cohort. Acad. Radiol. 18, 661–671 (2011).

  116. 116.

    et al. Lung cancer in patients with chronic obstructive pulmonary disease — incidence and predicting factors. Am. J. Respir. Crit. Care Med. 184, 913–919 (2011).

  117. 117.

    et al. Changes in forced expiratory volume in 1 second over time in COPD. N. Engl. J. Med. 365, 1184–1192 (2011).

  118. 118.

    et al. Pulmonary biomarkers in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 174, 6–14 (2006).

  119. 119.

    , , & The role of systemic inflammatory biomarkers to predict mortality in chronic obstructive pulmonary disease. Expert Rev. Respir. Med. 7, 57–64 (2013).

  120. 120.

    et al. The presence and progression of emphysema in COPD as determined by CT scanning and biomarker expression: a prospective analysis from the ECLIPSE study. Lancet Respir. Med. 1, 129–136 (2013).

  121. 121.

    et al. Profiling serum biomarkers in patients with COPD: associations with clinical parameters. Thorax 62, 595–601 (2007).

  122. 122.

    et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann. Intern. Med. 155, 179–191 (2011). This document reviews the evidence for the diagnosis and management of patients with stable COPD. It was signed by all of the major medical societies interested in clinical practice.

  123. 123.

    & Tobacco tightrope — balancing disease prevention and economic development in China. N. Engl. J. Med. 356, 1493–1496 (2007).

  124. 124.

    et al. Smoking prevalence and cigarette consumption in 187 countries, 1980–2012. JAMA 311, 183–192 (2014).

  125. 125.

    & A systematic review of health effects of electronic cigarettes. Prev. Med. 69, 248–260 (2014).

  126. 126.

    et al. Adherence to reduced-polluting biomass fuel stoves improves respiratory and sleep symptoms in children. BMC Pediatr. 14, 12 (2014).

  127. 127.

    et al. Adherence to inhaled therapy, mortality and hospital admission in COPD. Thorax 64, 939–943 (2009).

  128. 128.

    & Can patients with COPD self-manage? Lancet 380, 624–625 (2012).

  129. 129.

    et al. Piloting tele-monitoring in COPD: a mixed methods exploration of issues in design and implementation. Prim. Care Respir. J. 21, 57–64 (2012).

  130. 130.

    et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir. Med. 1, 210–223 (2013).

  131. 131.

    , , , & Management of stable chronic obstructive pulmonary disease in primary and secondary care: summary of updated NICE guidance. BMJ 340, c3134 (2010).

  132. 132.

    & Pulmonary rehabilitation for management of chronic obstructive pulmonary disease. N. Engl. J. Med. 360, 1329–1335 (2009).

  133. 133.

    et al. British Thoracic Society guideline on pulmonary rehabilitation in adults. Thorax 68 (Suppl. 2), ii1–ii30 (2013).

  134. 134.

    et al. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am. J. Respir. Crit. Care Med. 188, e13–e64 (2013).

  135. 135.

    , , , & Physiological changes during symptom recovery from moderate exacerbations of COPD. Eur. Respir. J. 26, 420–428 (2005).

  136. 136.

    et al. Cardiovascular events in patients with COPD: TORCH study results. Thorax 65, 719–725 (2010).

  137. 137.

    et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N. Engl. J. Med. 359, 1543–1554 (2008).

  138. 138.

    et al. Tiotropium Respimat inhaler and the risk of death in COPD. N. Engl. J. Med. 369, 1491–1501 (2013).

  139. 139.

    New combination bronchodilators for COPD: current evidence and future perspectives. Br. J. Clin. Pharmacol. 79, 695–708 (2015).

  140. 140.

    et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N. Engl. J. Med. 356, 775–789 (2007).

  141. 141.

    , & Novel endoscopic approaches to treating chronic obstructive pulmonary disease and emphysema. Semin. Respir. Crit. Care Med. 36, 609–615 (2015).

  142. 142.

    , , , & Detection of rhinoviruses in induced sputum at exacerbations of chronic obstructive pulmonary disease. Eur. Respir. J. 16, 677–683 (2000).

  143. 143.

    , , , & Early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 169, 1298–1303 (2004).

  144. 144.

    , , & Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 57, 847–852 (2002).

  145. 145.

    , & Lower respiratory illnesses promote FEV1 decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study. Am. J. Respir. Crit. Care Med. 164, 358–364 (2001).

  146. 146.

    , , , & Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest 137, 1091–1097 (2010).

  147. 147.

    et al. Diagnosis of myocardial infarction following hospitalisation for exacerbation of COPD. Eur. Respir. J. 39, 1097–1103 (2012).

  148. 148.

    et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann. Intern. Med. 106, 196–204 (1987).

  149. 149.

    et al. Short-term versus conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA 309, 2223–2231 (2013).

  150. 150.

    et al. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Am. J. Respir. Crit. Care Med. 186, 48–55 (2012).

  151. 151.

    , , , & Effectiveness of influenza vaccine in the community-dwelling elderly. N. Engl. J. Med. 357, 1373–1381 (2007).

  152. 152.

    , & Long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst. Rev. 10, CD010177 (2013).

  153. 153.

    , & Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst. Rev. 7, CD009285 (2014).

  154. 154.

    , , , & Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir. Med. 3, 435–442 (2015).

  155. 155.

    et al. Blood eosinophils: a biomarker of response to extrafine beclomethasone/formoterol in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 192, 523–525 (2015).

  156. 156.

    & Incident pneumonia and mortality in patients with chronic obstructive pulmonary disease. A double effect of inhaled corticosteroids?Am. J. Respir. Crit. Care Med. 191, 141–148 (2015).

  157. 157.

    et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N. Engl. J. Med. 364, 1093–1103 (2011).

  158. 158.

    et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am. J. Respir. Crit. Care Med. 177, 19–26 (2008).

  159. 159.

    et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir. Med. 1, 199–209 (2013).

  160. 160.

    et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 374, 685–694 (2009).

  161. 161.

    et al. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet 385, 857–866 (2015).

  162. 162.

    et al. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am. J. Respir. Crit. Care Med. 178, 1139–1147 (2008).

  163. 163.

    et al. Azithromycin for prevention of exacerbations of COPD. N. Engl. J. Med. 365, 689–698 (2011).

  164. 164.

    Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases. Lancet Respir. Med. 1, 262–274 (2013).

  165. 165.

    et al. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE study): a randomised placebo-controlled study. Lancet 371, 2013–2018 (2008).

  166. 166.

    et al. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir. Med. 2, 187–194 (2014).

  167. 167.

    et al. Does early pulmonary rehabilitation reduce acute health-care utilization in COPD patients admitted with an exacerbation? A randomized controlled study. Respirology 14, 230–238 (2009).

  168. 168.

    et al. An early rehabilitation intervention to enhance recovery during hospital admission for an exacerbation of chronic respiratory disease: randomised controlled trial. BMJ 349, g4315 (2014).

  169. 169.

    & The assessment of health status among patients with COPD. Eur. Respir. J. Suppl. 41, 36s–45s (2003).

  170. 170.

    et al. Health-related quality of life in patients by COPD severity within primary care in Europe. Respir. Med. 105, 57–66 (2011).

  171. 171.

    et al. Factors associated with changes in quality of life of COPD patients: a prospective study in primary care. Respir. Med. 107, 1589–1597 (2013).

  172. 172.

    , & Determinants of polypharmacy and compliance with GOLD guidelines in patients with chronic obstructive pulmonary disease. Int. J. Chron. Obstruct. Pulmon. Dis. 6, 493–501 (2011).

  173. 173.

    , , , & Relation between quality of life and morbidity and mortality in COPD patients: two-year follow-up study. COPD 7, 248–253 (2010).

  174. 174.

    et al. Health-related quality of life and mortality in male patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 166, 680–685 (2002).

  175. 175.

    Health status measurement in chronic obstructive pulmonary disease. Thorax 56, 880–887 (2001).

  176. 176.

    et al. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 187, 728–735 (2013).

  177. 177.

    , , , & Impact of co-morbidities on self-rated health in self-reported COPD: an analysis of NHANES 2001–2008. COPD 10, 324–332 (2013).

  178. 178.

    , , & Cardiovascular comorbidity in COPD: systematic literature review. Chest 144, 1163–1178 (2013).

  179. 179.

    et al. Unrecognised ventricular dysfunction in COPD. Eur. Respir. J. 39, 51–58 (2012).

  180. 180.

    et al. Anxiety and depression in COPD: current understanding, unanswered questions, and research needs. Chest 134, 43S–56S (2008).

  181. 181.

    , , & Bidirectional associations between clinically relevant depression or anxiety and chronic obstructive pulmonary disease (COPD): a systematic review and meta-analysis. Chest 144, 766–777 (2013).

  182. 182.

    & Epidemiology and clinical impact of major comorbidities in patients with COPD. Int. J. Chron. Obstruct. Pulmon. Dis. 9, 871–888 (2014).

  183. 183.

    , & COPD–bronchiectasis overlap syndrome. Eur. Respir. J. 45, 310–313 (2015).

  184. 184.

    & Clinical phenotypes of chronic obstructive pulmonary disease and asthma: recent advances. J. Allergy Clin. Immunol. 131, 627–634 (2013).

  185. 185.

    Therapeutic approaches to asthma–chronic obstructive pulmonary disease overlap syndromes. J. Allergy Clin. Immunol. 136, 531–545 (2015).

  186. 186.

    , & Surfactant protein D, club cell protein 16, pulmonary and activation-regulated chemokine, C-reactive protein, and fibrinogen biomarker variation in chronic obstructive lung disease. Respir. Res. 15, 147 (2014).

  187. 187.

    & Epigenetic control of gene expression in the lung. Am. J. Respir. Crit. Care Med. 183, 1295–1301 (2011).

  188. 188.

    New anti-inflammatory treatments for chronic obstructive pulmonary disease. Nat. Rev. Drug Discov. 12, 543–559 (2013). A review of the challenge to new drug development in COPD and a discussion of some of the targets for future therapy.

  189. 189.

    et al. The safety and efficacy of infliximab in moderate-to-severe chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 175, 926–934 (2007).

  190. 190.

    et al. An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease. J. Clin. Pharmacol. 52, 416–424 (2011).

  191. 191.

    , , , & Tolerability and efficacy of inhaled AZD4818, a CCR1 antagonist, in moderate to severe COPD patients. Respir. Med. 104, 1297–1303 (2010).

  192. 192.

    & Glucocorticoid resistance in inflammatory diseases. Lancet 342, 1905–1917 (2009).

  193. 193.

    & New drugs for exacerbations of chronic obstructive pulmonary disease. Lancet 374, 744–755 (2009).

  194. 194.

    , , & Network medicine, multimorbidity and the lung in the elderly. Eur. Respir. J. 44, 775–788 (2014).

Download references

Acknowledgements

The authors thank J. Allinson from Imperial College, London, UK, for the design of Figure 8.

Author information

Affiliations

  1. Airway Disease Section, National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK.

    • Peter J. Barnes
    •  & Jadwiga A. Wedzicha
  2. Division of Medical Genetics and Population Health, National Heart and Lung Institute, Imperial College, London, UK.

    • Peter G. J. Burney
  3. Channing Division of Network Medicine and Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Edwin K. Silverman
  4. Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Bartolome R. Celli
  5. Centre of Respiratory Medicine and Allergy, Manchester Academic Science Centre, University Hospital South Manchester NHS Foundation Trust, Manchester, UK.

    • Jørgen Vestbo
  6. Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands.

    • Emiel F. M. Wouters

Authors

  1. Search for Peter J. Barnes in:

  2. Search for Peter G. J. Burney in:

  3. Search for Edwin K. Silverman in:

  4. Search for Bartolome R. Celli in:

  5. Search for Jørgen Vestbo in:

  6. Search for Jadwiga A. Wedzicha in:

  7. Search for Emiel F. M. Wouters in:

Contributions

Introduction (P.J.B.); Epidemiology (P.G.J.B.); Mechanisms/pathophysiology (E.K.S. and P.J.B.); Diagnosis, screening and prevention (B.R.C.); Management (J.A.W. and J.V.); Quality of life (E.F.M.W.); Outlook (P.J.B.); Overview of Primer (P.J.B.).

Competing interests

P.J.B. has served on scientific advisory boards of AstraZeneca, Boehringer Ingelheim, Chiesi, Daiichi Sankyo, GlaxoSmithKline, Glenmark, Johnson & Johnson, Merck, Novartis, Takeda, Pfizer, Prosonix, RespiVert, Sun Pharmaceuticals, Teva and UCB, and has received research funding from Aquinox Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Chiesi, Daiichi Sankyo, GlaxoSmithKline, Novartis, Takeda, Pfizer and Sun Pharmaceuticals. He is also a cofounder of RespiVert (now part of Johnson & Johnson), which has discovered novel inhaled anti-inflammatory treatments for asthma and COPD. P.G.J.B. has received grants from the Medical Research Council, the Wellcome Trust, Public Health England and the British Lung Foundation, and serves on an advisory board for Novartis. B.R.C. has received grants to the Pulmonary and Critical Care Division of the Brigham and Women's Hospital to complete research studies in COPD from AstraZeneca. He has also received compensation for advisory board participation and/or consultancy from GlaxoSmithKline, Boehringer Ingelheim, Almirall, AstraZeneca, MedImmune, Takeda and Novartis. He does not have shares or interest in any company, nor does any member of his family. He has not received or had any relationship with the tobacco industry and has not participated in promotional talks. E.K.S. has received, in the past 3 years, honoraria and consulting fees from Merck and grant support and consulting fees from GlaxoSmithKline. J.V. has received funding for advising and presenting from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Takeda and Teva, and has received research funding from GlaxoSmithKline. J.A.W. has received research grant funding from Novartis, Takeda, Johnson & Johnson, Vifor Pharma and GlaxoSmithKline. She has received honoraria for lectures and/or advisory boards before January 2015 from GlaxoSmithKline, Novartis, Boehringer Ingelheim, AstraZeneca, Almirall, Pfizer, Chiesi and RespiVert. E.F.M.W. declares no competing interests.

Corresponding author

Correspondence to Peter J. Barnes.