Tackling COPD: a Multicomponent Disease Driven by Inflammation

Abstract and Introduction

Abstract

In recent years, research has revealed more about the factors underlying the pathogenesis of chronic obstructive pulmonary disease (COPD). In particular, inflammation in the lungs leads to the structural changes observed in COPD, while extrapulmonary symptoms and comorbidities may be systemic manifestations of these inflammatory processes. A new multicomponent disease model is proposed that takes into account all elements that should be considered in treatment decisions. Current monotherapies act on different aspects of COPD and may not address all components. A combination of a long-acting beta2-agonist and an inhaled corticosteroid has complementary effects, addressing a wider range of components of COPD. This combination appears to have greater clinical benefits than either agent alone in reducing the frequency of exacerbations, reducing the number of hospitalizations, and potentially promoting survival. Minimizing the burden of COPD within — and potentially outside — the lung means treating patients early and addressing as many disease components as possible.

Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by inflammation, airflow limitation that is not fully reversible, and a gradual loss of lung function.[1] The latest American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines also note significant systemic consequences.[1] COPD is a common, costly, and preventable disease that presents challenges in primary care. General practice consultation rates for COPD in the United Kingdom are 2 to 4 times the equivalent rate for angina, illustrating the burden of this disease in primary care practices.[2] Nonetheless, in primary care both the impact and importance of COPD seem to be broadly underestimated. Primary care physicians (PCPs) are the first point of contact in the detection and management of the COPD patient, and in the introduction of important preventative interventions such as smoking cessation. Furthermore, PCPs can play a vital role in early detection through “case-finding strategies” — probably the only cost-effective way of detecting COPD at an early stage.[3]

The number of patients with COPD is estimated at 600 million worldwide and is increasing.[4] Between 1990 and 1997, the prevalence in the United Kingdom increased by 25% in men and 69% in women (Figure 1).[5] COPD is the fourth leading cause of death in Europe and the United States[1,6] and represents a major economic burden. In Europe, the total direct and indirect costs of COPD every year are around 50 billion pounds — almost half of the total costs of lung disease.[2] Yet these figures probably do not represent the extent of the challenge because airflow limitation in general — and COPD in particular — may be under-recognized in patients who attend general practices for other reasons.[7,8] COPD can also be misdiagnosed as asthma, or not diagnosed until at a very late stage of disease.[9]

COPD is preventable and treatable, but like asthma or coronary heart disease, it is not curable. Although current treatments such as smoking cessation can slow COPD progression, they cannot alter its irreversible nature. Therefore, when considering new therapies for COPD, it is particularly important to examine the factors involved in the pathophysiology of the disease. The complex pathophysiology of COPD involves multiple components that contribute to inflammation and airflow limitation, both of which are present at all stages of the disease. During the course of the disease, this translates into a decline in lung function and an increase in symptoms and exacerbations that affect patient health and, ultimately, survival.[10] COPD also has a major impact on quality of life.[11] When deciding on the most appropriate approach to management and treatment, it is important to consider the components that contribute to the disease in order to best improve the lives of patients.

Our Current Understanding of COPD and Approaches to Treatment

In COPD, chronic inhalation of irritants causes an abnormal inflammatory response, remodeling of the airways, and restriction of airflow in the lungs. The inhaled irritant is usually tobacco smoke, but occupational dust and environmental pollution are variably implicated.[9] Although symptoms may vary, they include progressive coughing, wheezing, and dyspnea on exertion, and they occur primarily in smokers over 40 years of age.[12] It is important to recognize that such symptoms are not trivial, but warrant consideration of a diagnosis of COPD. In primary care practices, COPD is usually diagnosed by performing a physical examination and obtaining a detailed medical history. Spirometry, which measures vital capacity and forced expiratory volume in 1 second (FEV1), should preferably be used to confirm the diagnosis and assess severity.[10]

Exacerbations — involving a rapid worsening of symptoms that requires medical intervention — are characteristic of COPD. Exacerbations are more common in severe disease, although they may affect individuals at each stage of COPD.[13] Exacerbations are usually triggered by infections or pollutants and result in physiologic deterioration, an increase in airway inflammation,[14] and an increased risk of hospitalization and mortality.[15,16] Moreover, exacerbations are responsible for the highest proportion of the total costs of the disease.[17] Consequently, the aim of therapy for COPD is not only to treat symptoms and complications as early as possible and to improve exercise tolerance, but also to reduce the number and severity of exacerbations in order to prevent progressive deterioration of health status and lung function.[13] In particular, treatment that reduces the frequency of exacerbations can improve quality of life, reduce the number of hospital visits, reduce morbidity, and lower costs. However, in the past, physicians and patients have sometimes approached treatment of “irreversible” COPD with a sense of nihilism. There was a perception that pharmacologic strategies lacked efficacy, which was confounded by the fact that smoking cessation — the most effective intervention - was associated with a low success rate.[18]

In the late 1990s and early 2000s, the efficacy of long-acting bronchodilator therapies in increasing FEV1 and reducing the symptoms of COPD was demonstrated.[19–21] In particular, bronchodilators were shown to be effective in reducing dynamic hyperinflation, which occurs during exercise and ultimately limits the capacity for exercise. At the same time, several large-scale, long-term studies showed that inhaled corticosteroids (ICSs) alone were effective in reducing the number of exacerbations and in reducing the rate of decline in quality of life, but did not slow the long-term decline in FEV1 in patients with COPD.[22–25] Consequently, the efficacy of ICS treatment in COPD was questioned. However, recent studies in patients with COPD or asthma have shown consistent benefits of ICS treatment on exacerbation frequency[26–29] and have suggested that reductions in exacerbations are responsible for an improvement in health status.[30] As a result, updated guidelines now recommend bronchodilator treatment as first-line therapy in COPD, with ICS treatment as an add-on therapy for patients with severe disease and frequent exacerbations (Figure 2).[10,31] Looking to the future, it is likely that new knowledge of the pathophysiology of COPD will point to improvements in treatment strategies. The situation may be comparable to that of asthma management in the late 1980s, when better understanding of asthma pathophysiology resulted in a change in the treatment paradigm with marked improvements in patient management.

Figure 2.

Therapy at each stage of COPD.[10] Reproduced with permission from http://www.goldcopd.com.

COPD: a Multicomponent Disease

As we have entered the 21st century, evidence has increased to support the view that COPD is not only a disease of the airways and lungs, but also affects other sites of the body such as muscles and bones, and body functions such as cognition, mood, and metabolism.[32–35]

In particular, the fact that a high proportion of COPD patients suffer from cardiovascular disease suggests a shared risk factor (such as smoking) as well as a common pathway: inflammation. There appear to be 4 major factors that contribute to COPD and its exacerbations: airway inflammation, airflow limitation, mucociliary dysfunction, and consequent airway structural changes.[9,36–38] To illustrate clearly these factors and the interaction between them, a multicomponent disease model (MCDM) has been developed that can be represented by a nonproportional Venn diagram.[39]

Airway inflammation, the first factor of the MCDM, first occurs during the early stages of COPD and is key to the pathophysiology and symptoms of the disease.[40] Inhaled irritants trigger an abnormal inflammatory response during which inflammatory cells infiltrate the lungs and the airways become thickened and inflamed.[41,42] However, recent research suggests that inflammation is not confined to the lungs: inflammatory cells and mediators generated in the lungs enter the bloodstream and may have systemic effects on other susceptible areas of the body. This may account for the observation that patients with COPD also present with systemic symptoms and comorbid conditions, including muscle weakness, weight loss, cardiovascular disease, osteoporosis, hypertension, depression, cognitive decline, sleep disorders, sexual dysfunction, and possibly diabetes.[32,38,43,44] In recognition of the systemic component of COPD, the 2004 ATS/ERS Standards for Diagnosis and Treatment of Patients with COPD are the first guidelines to acknowledge that assessment of severity should ideally include systemic symptoms such as weight loss and muscle wasting.[1]

Airflow limitation, a defining characteristic of COPD, is the second aspect of the MCDM. Airflow limitation is affected in turn by the other 3 components of COPD: airway inflammation, mucociliary dysfunction, and airway structural changes. Bronchial hyperreactivity, loss of elasticity in the small airways, and smooth muscle contraction are additional factors that contribute to airflow limitation. The third factor in the model is mucociliary dysfunction — whereby cells in the airway secrete excessive quantities of altered viscous mucus that are not cleared efficiently by the morphologically damaged cilia. Potentially, a vicious cycle may ensue: mucociliary dysfunction increases the risk of infection, while damage caused by recurrent respiratory tract infection contributes to mucociliary dysfunction.[45] The final factor in the MCDM is airway structural changes. These changes can be permanent, usually occur as a result of chronic inflammation, and include airway wall fibrosis, an increase in bronchiolar smooth muscle, epithelial metaplasia, destruction of lung parenchyma through emphysema, and remodeling of the pulmonary vasculature.[37]

Inflammation — At the Core of COPD

It is now clear that the inflammatory response in the lungs is central to the structural changes leading to COPD.[41,42] This is because lung inflammation contributes to airflow limitation[46] and hyperinflation,[47] which in turn cause breathlessness on exertion and more frequent exacerbations.[14] Of interest, research suggests that although COPD and asthma both involve chronic, persistent inflammation, the nature of the inflammation and immune cells involved is very different between the two conditions. While inflammation in asthma is characterized by an increase in CD4+ T cells and eosinophils, increased numbers of neutrophils[41] and CD8+ T cells are observed in COPD.[42]

The importance attached to systemic inflammation in COPD is increasing with time.[38] Inflammatory mediators and activated inflammatory cells released into the systemic circulation in COPD include tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6).[32,38] Studies show that reduced lung function is associated with elevated systemic inflammatory factors that increase during exacerbations,[48] and these factors may contribute to the comorbidities observed in patients with COPD.[38] The contribution that chronic, low-grade inflammation makes to the risk of systemic disease is indicated, for example, by the increased risk of atherosclerosis in patients with inflammatory rheumatic diseases.[49] The increase in systemic inflammation triggers elevations in mediators such as C-reactive protein, which may contribute to the increased risk of cardiovascular disease[43] and may be a marker of impaired health status.[50] Elevated TNF-alpha may contribute to muscle wasting and cachexia,[38] and TNF-alpha and IL-6 are both associated with atherosclerosis.[38] Notably, recent research suggests that elevated levels of IL-6 may be related to an increased prevalence of insulin resistance in COPD.[51]

Implications for the Management of COPD in Primary Care Today

As our knowledge increases regarding the processes that contribute to COPD, so must management strategies be reviewed to ensure best patient outcomes. Given the multicomponent nature of COPD, management must not only address airflow limitation, but should also consider all 4 components of the disease. In particular, inflammation — both in the lungs and throughout the body — is central to the pathogenesis of COPD, and for best patient outcomes, inflammation must be addressed in management strategies. Current therapies act on different aspects of COPD, but used alone they vary in their capacity to address all components of the disease. Furthermore, many therapies are not directed at treating inflammation.[52] Below, we review current pharmacologic therapies and their ability to address the MCDM (see Table 1). The majority of large clinical trials studying such therapies have been pharmaceutical company-sponsored studies.

Table 1.

Current Pharmacologic Agents and Their Potential Effects on the Components of COPD When Used as Monotherapy[9,10,100]

Drug Class	Disease Components Affected	Clinical Effects
Short-acting beta2-agonists	Airflow limitation	Immediate, but short-duration improvements in lung function and dyspnea
Short-acting anticholinergics	Airflow limitation	Immediate, but short-duration improvements in lung function (especially hyperinflation) and dyspnea
Long-acting beta2-agonists	Airflow limitation Mucociliary dysfunction Airway inflammation	Limited improvements in dyspnea Improvements in lung function Decreased exacerbation rate Improvements in health status
Long-acting anticholinergics	Airflow limitation	Limited improvements in lung function and dyspnea Decreased exacerbation rate Improvements in health status Limited improvements in lung function, especially hyperinflation
Theophyllines	Airflow limitation Airway inflammation	Improvements in dyspnea Limited improvements in lung function Increased diaphragm contractility
Inhaled corticosteroids	Airway inflammation	Improvements in dyspnea Decreased exacerbation rate Decreased rate of decline of health status

Bronchodilators

International guidelines including the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines[10] and the ATS/ERS guidelines[1,53] recommend short-acting bronchodilators as first-line therapy. Bronchodilators not only dilate the airway, but they also reduce hyperinflation during exercise and are invaluable in the treatment of COPD.

Historically, short-acting beta2-agonists have been one of the most widely-used classes of bronchodilators. The bronchodilatory effect of these agents — along with their effect on hyperinflation — enables brief symptom relief.[54] Short-acting beta2-agonists have a brief (2-4 hours) duration of action and, therefore, multiple daily dosing is required. Another class of commonly used short-acting bronchodilators — short-acting anticholinergics — provide effective bronchodilation.[55,56] Likewise, they too need multiple daily dosing, and there are no data to support their effects on other components of COPD. The therapeutic ratio of bronchodilators administered by inhalation is very beneficial and predictable.[10] However, there is evidence to suggest that short-acting beta2-agonists can precipitate cardiovascular events,[57] which should be a consideration in patients with underlying cardiac conditions.

In recent years, ‘long-acting’ bronchodilators have been introduced. Long-acting bronchodilators have an extended period of action that reduces the need for multiple dosing, and are also more effective than short-acting bronchodilators.[19,21,58] For instance, the long-acting anticholinergic tiotropium bromide has a 24-hour duration of action; therefore, it can be taken once daily[59] and also provides improved bronchodilation compared with short-acting anticholinergics. If prescribed as an add-on treatment to existing therapy, tiotropium reduces the frequency of exacerbations and improves the quality of life.[20,60] The long-acting beta2-agonists (LABAs), such as salmeterol and formoterol, have also been shown to provide long-lasting bronchodilation and anti-hyperinflation effects when compared with short-acting anticholinergics.[19,20] Moreover, they improve quality of life and exercise capacity, and salmeterol was shown to decrease exacerbation rates.[18,19] However, in patients with symptomatic COPD and frequent exacerbations, bronchodilators alone may not elicit the best possible clinical effects and may not target all components of COPD.

Another bronchodilator, theophylline, has proven efficacy and an anti-inflammatory effect in COPD.[61] However, because its action is nonselective, its use is limited by a narrow therapeutic index due to cardiac, neurologic, and gastrointestinal side effects and interactions with other therapies. In addition, long-term theophylline treatment may need drug monitoring. New, more selective phosphodiesterase-4 inhibitors are currently being investigated in clinical trials.

Mucolytics

In a number of countries, such as in Germany, mucolytic agents play a role in the management and self-management of COPD, although data on their efficacy are controversial. Long-term studies with mucolytics have shown little effect on lung function or symptoms, although some have shown a reduction in exacerbations.[62,63] A recent randomized controlled study with the mucolytic N-acetylcysteine concluded that it was ineffective at preventing exacerbations or deterioration of lung function.[64] The GOLD guidelines conclude that the widespread use of mucolytics cannot be recommended on the basis of current evidence.[10]

Inhaled Corticosteroids

Inhaled corticosteroids, such as fluticasone propionate, beclomethasone, budesonide, ciclesonide, flunisolide, mometasone, and triamcinolone, exert a range of anti-inflammatory effects,[65–71] suggesting a possible role in the management of COPD. Studies in patients with moderate-to-severe COPD have shown that treatment with an ICS can induce improvements in dyspnea, decrease exacerbation rates, and reduce the decline in health status.[22,30,71] In patients with mild-to-moderate disease, an ICS may improve airway reactivity and decrease the use of healthcare services.[24] While the use of an ICS is recommended in the GOLD guidelines for patients with severe disease and frequent exacerbations,[9] more research into the effects in patients with moderate COPD is needed. Given the contribution of systemic inflammation to morbidity in COPD, it is notable that ICS therapy may have benefits on serum markers of inflammation: one trial found that treatment with fluticasone propionate reduced serum levels of C-reactive protein.[72] Short-term side effects of ICSs include sore throat, candidiasis, and hoarseness,[73] but more data are needed to determine the long term-safety of ICSs in COPD.

Overall, the data suggest that current therapies for COPD have a beneficial, albeit modest, effect on the components of this disease when used alone. This raises the question of whether combinations of therapies with complementary effects may address an increased number of components in the COPD model.

Combination Therapy

A number of combination therapies have been investigated with a view to addressing more of the components contributing to COPD. Combinations of a short-acting beta2-agonist with an anticholinergic (such as fenoterol/ipratropium or salbutamol/ipratropium)[74,75] LABAs in free combination with anticholinergics (such as tiotropium/formoterol and tiotropium/salmeterol),[76,77] and a LABA with an ICS(such as salmeterol/fluticasone propionate or formoterol/budesonide)[78] have all been shown to be viable alternatives to monotherapy.

In terms of managing additional components of the MCDM, large clinical trials have demonstrated the potential of combination therapy consisting of a LABA and an ICS.[26–28] The anti-inflammatory effects of the ICSs appear to complement the effects of LABAs on bronchodilation and mucociliary dysfunction. Therefore, such combination treatments may address a greater number of factors in the multicomponent model of COPD compared with single agents.

The clinical benefits of adding an ICS to a LABA are supported by a systematic review of published randomized clinical trials, which found that combination treatment with salmeterol/fluticasone propionate or formoterol/budesonide is more effective than either substance alone or placebo for improving exacerbation rates, quality of life, and lung function.[78] Both salmeterol/fluticasone propionate and formoterol/budesonide produce an improvement in FEV1[79] and in patient-reported health status as measured by the St. George's Respiratory Questionnaire.[26–28] Several cohort studies and meta-analyses have suggested further health benefits that may arise from an ICS/LABA combination. A systematic literature review suggested that the combination has beneficial effects on rates of hospitalizations and even has the potential to affect mortality in COPD.[80] Observational data from the UK General Practice Research Database support this, suggesting that combination therapy with salmeterol/fluticasone proprionate in primary care is associated with a reduction in the risk of rehospitalization[81] and improved survival.[82]

What is particularly interesting about combination treatments is that many of the clinical benefits are greater than those seen with the individual agents alone. This effect has been seen with short-acting beta2-agonists in combination with anticholinergics,[74,83] LABAs in combination with anticholinergics,[76,77] and also when combining an ICS with a LABA.[27,84] For example, the anti-inflammatory effect exerted by salmeterol/fluticasone propionate is greater than the additive effect of the two agents, and survival rates seen in general practice are greater than with either therapy alone.[82] Observational data suggest that the improvement in FEV1 and the reduction in exacerbations seen with the combination are both greater than with salmeterol or fluticasone propionate alone.[27] A recent study suggests that salmeterol/fluticasone propionate reduces inflammatory cell markers in sputum and biopsy samples,[85] whereas in other studies the same doses of fluticasone propionate used alone do not have this effect.[65,66] In addition, the safety profile of salmeterol/fluticasone propionate is comparable to that of the individual agents.[27]

Given the irreversible and debilitating nature of COPD, it is vital that the disease is diagnosed and effective management begins as early as possible in the disease process. Currently, GOLD guidelines[10] recommend that people with mild COPD (forced expiratory volume in 1 second [FEV1] ≥ 80%) use short-acting inhaled therapy as needed to control dyspnea or coughing spasms. In people with moderate to very severe COPD (FEV1 < 80%) whose symptoms are not adequately controlled with as-needed short-acting bronchodilators, adding regular treatment with 1 or more LABA, in conjunction with pulmonary rehabilitation, is recommended. Addition of an ICS to LABA therapy is currently only recommended for people at the more severe stages of disease, defined as FEV1 < 50% with a history of repeated exacerbations. Whether this will change to a recommendation of combination treatment earlier in GOLD staging will depend on whether data on the long-term effects of treatment support this position. According to the latest ATS/ERS guidelines, additional parameters, and not only FEV1, should be considered when assessing severity.[1] They also recognize the additional effects of combination LABA/ICS therapy on lung function and symptoms compared with LABA or ICS monotherapy.[1] In addition, because of the increasing mortality rates in COPD, the ultimate goal of treatment has to be improved survival, and this benefit has yet to be confirmed by prospective trials. A large-scale study is under way to address this need. A long-term, randomized, controlled survival study (TOwards a Revolution in COPD Health [TORCH]) is investigating the effects of the salmeterol/fluticasone propionate combination on all-cause mortality in COPD.[27,86] The results of this study will be published later this year.

Nonpharmacologic Therapies Within a Multidisciplinary Approach

Within the management program, it is generally recognized that by far the most effective nonpharmacologic therapy is smoking cessation. Patients should be encouraged to stop smoking to bring about an improvement in COPD symptoms. Oxygen is an important nonpharmacologic therapy option for patients with severe COPD, and, depending on patient needs, can be given as long-term continuous therapy, during exercise, or to relieve acute dyspnea. Long-term continuous oxygen therapy (LTO2T) (>15 hours/day) has long been established to have benefits in patients with hypoxemic COPD, including prolonged survival[87,88] and prevention of progression of pulmonary hypertension.[89] However, the role of LTO2T in addition to new COPD therapies, ie, long-acting bronchodilators and ICSs, is not well studied. PCPs often play an important role in assessing patients' suitability for oxygen therapy and controlling their compliance. Oxygen therapy should be prescribed initially on the basis of the PaO2. Long-term oxygen therapy is recommended for patients with pO2 ≤ 55 mm Hg or SaO2 ≤ 88%, with or without hypercapnia.[10] Oxygen can also be introduced in people with pO2 55-60 mm Hg or SaO2 89% if there is evidence of pulmonary hypertension, peripheral edema suggesting congestive heart failure, or polycythemia.[10] Ambulatory oxygen sources are an important option for active patients, although evidence about the effect of ambulatory oxygen on quality of life is contradictory.[90,91] Recently, concern was raised about the continuing need for LTO2T in all patients, if once indicated.[91]

The burden of COPD affects many aspects of daily living. The symptoms of the disease can cause a reduction in physical activity that affects patient fitness and is further aggravated by systemic symptoms such as muscle weakness. As well as having physical effects, the symptoms of COPD can affect patient confidence and reduce self-esteem. Physical training is an important component of management and can increase exercise capacity and health status while reducing breathlessness.[92] In addition, as many as 30% of people with COPD are malnourished, and nutritional supplements — particularly in combination with exercise — can improve body weight and respiratory muscle function and mortality.[93,94] The influenza vaccine has a small impact on reducing exacerbations and hospitalizations and should be part of standard practice for COPD patients.[95] The antipneumococcal vaccine also appears to have benefits in younger patients with severe airflow obstruction.[96]

Pulmonary rehabilitation programs involving nonpharmacologic as well as pharmacologic therapies can play an important part in the management of people with COPD, although the extent to which they can be implemented clearly depends on resources. Ideally, rehabilitation programs should be multidisciplinary and should encompass exercise training, physiotherapy, educational advice, inhalation training, nutritional counseling, and psychosocial support. Such programs can help patients cope with their disease and may increase quality of life.[97] Thus, all COPD patients with physical deconditioning, malnutrition, social isolation, failure to comply with inhaled medication regimens, and frequent exacerbations despite appropriate treatment are candidates for pulmonary rehabilitation. Research suggests that education on self-management can reduce hospital visits and improve outcomes.[84,98] Hence, the primary care team, which may include physicians, nurses, physiotherapists, and occupational therapists, should work with patients to maintain the highest possible level of physical activity (ie, continuing the exercise training introduced during rehabilitation) and formulate a program of interventions that suits their lifestyle and supports pharmacologic treatment.

A small subset of severe COPD patients with upper lobe emphysema may benefit from lung volume reduction surgery; PCPs should consider referring these patients for evaluation for lung volume reduction or transplantation surgery.[99] Finally, PCPs have an important role in diagnosing and treating the very frequent comorbidities in COPD, such as coronary heart disease, hypertension, diabetes, depression, and osteoporosis.

Conclusion

In summary, it is paramount that we recognize COPD as a disease comprising multiple components that exert a debilitating effect both on the airways and — via systemic inflammation — on other sites in the body. Optimal management must therefore focus not only on airflow limitation, but also on the inflammatory component and systemic nature of the disease in order to improve patient quality of life and, probably, survival. Guidelines recommend long-acting bronchodilators as first-line therapy in patients with moderate and severe COPD. However, when used alone, many current therapies address a limited number of components of the disease and have limited efficacy on inflammation, weight loss, and muscle fatigue. The latest research suggests that combination therapy with an ICS and a LABA offers a route to address the multicomponent aspects of COPD, with efficacy that is greater than that of either drug alone. Nonpharmacologic treatment modalities should be integrated by the PCP into the treatment plan of this systemic disease.

Figure 1.

Prevalence of physician-diagnosed chronic obstructive pulmonary disease in the United Kingdom.[5] Reproduced from Soriano JB, et al. Thorax. 2000;55:789–794, with permission from the BMJ Publishing Group.

Figure 3.

The multicomponent nature of COPD.[39] Reproduced from Agusti AG, et al. Respir Med. 2005;99:670–682. Copyright 2005, with permission from Elsevier.