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Systemic Manifestations of COPD FREE TO VIEW

Yvonne Nussbaumer-Ochsner, MD; Klaus F. Rabe, MD, PhD
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From the Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.

Correspondence to: Klaus F. Rabe, MD, PhD, Department of Pulmonology, Leiden University Medical Center, C3-P, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; e-mail: k.f.rabe@lumc.nl


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;139(1):165-173. doi:10.1378/chest.10-1252
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COPD is characterized by a poorly reversible airflow limitation resulting from chronic inflammation, mainly due to tobacco exposure. Over the past few years, the understanding of COPD has evolved from it being a disease affecting the lungs to it being a complex, heterogeneous, and generalized disorder in an aging population. Extrapulmonary comorbidities significantly complicate the management and influence the prognosis of patients with COPD. Although certain comorbidities like cardiovascular diseases share some risk factors with COPD, such as cigarette smoking, other frequently observed comorbidities, including musculoskeletal wasting, metabolic syndrome, and depression, cannot be easily attributed to smoking. There is increasing evidence that chronic inflammation is a key factor in COPD and that inflammation might be the common pathway linking these comorbidities and explaining why they typically develop together. Physicians treating patients with COPD need to become aware of these extrapulmonary aspects. Any patient with COPD should be carefully evaluated for comorbidities and the systemic consequences of COPD since they not only influence the prognosis but also have an impact on disease management. The treatment of COPD is no longer focused exclusively on inhaled therapy but is taking on a multidimensional approach, especially because the treatment of the comorbidities might positively affect the course of COPD itself.

Figures in this Article

COPD is characterized primarily by the presence of largely fixed airflow limitation, but there is increasing evidence and acceptance that COPD can no longer be defined as a disease restricted to the lungs. COPD has a much wider impact on health status, and FEV1 is not just a lung function parameter for grading COPD severity but also a marker of premature death from any cause (Fig 1).1 COPD is actually the fourth-leading cause of chronic morbidity and mortality worldwide. Mortality from COPD is expected to increase further and to rank at the third position in 2020, after coronary artery disease and stroke.2

Figure Jump LinkFigure 1. A, Relationship between FEV1, smoking status, and OR for cardiovascular mortality for current smoker (dark grey squares), ex-smoker (white squares), and never smoker (light grey squares). B, Relationship between FEV1, smoking status, and all-cause mortality rate for heavy smoker (dark grey squares), moderate smoker (light grey squares), ex-smoker (white squares), and nonsmoker (moderate grey squares). (Reprinted with permission from Young et al.1)Grahic Jump Location

According to the GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines, a diagnosis of COPD can be established by a fixed ratio of postbronchodilator FEV1 and FVC below 0.7 measured by spirometry.3 The spirometric severity is graded according to the percentage of FEV1 predicted (GOLD stage I-IV). This functional definition, based on airflow limitation, has been used to characterize the disease until now, but, obviously, the degree of airflow limitation is only one aspect in the risk assessment of patients with COPD. The clinical severity of COPD is increasingly being recognized as being determined by concomitant comorbidities (Fig 2)4,5 apart from COPD-specific features (ie, hyperinflation and/or the presence of emphysema). The broad range of clinical presentations, ranging from chronic bronchitis to hyperinflation and severe emphysema, illustrates that the term COPD describes patients with very different clinical phenotypes. Hyperinflation reduces functional physical activity, and there is some evidence that hyperinflation itself is an independent risk factor for mortality in patients with COPD.6,7 The presence of emphysema is associated with an increased risk of lung cancer, increased arterial stiffness, and osteoporosis.8-10 Furthermore, the knowledge that specific classes of drugs such as selective phosphodiesterase 4 inhibitors positively affect the course of the disease only in specific COPD populations but not in others supports the theory that COPD is a heterogeneous disease that needs tailored therapeutic approaches.11

Figure Jump LinkFigure 2. Prediction of death within 5 years by modified GOLD categories and the presence of no (light grey squares), one (white squares), two (moderate grey squares), or three (dark grey squares) comorbid diseases (diabetes, hypertension, or cardiovascular disease). Reference group (normal): subjects with normal lung function for each comorbid disease. Models were adjusted for age, sex, race, smoking status, education level, and BMI. GOLD = Global Initiative for Chronic Obstructive Lung Disease; R = restrictive lung disease. (Reprinted with permission from Mannino et al.5)Grahic Jump Location

Patients with COPD exhibit comorbidities related to common risk factors and they are very frequently characterized by impaired physical activity. A common conceptual COPD approach places the diseased lung as the center and generates a widely accepted cause-effect relationship: physical inactivity and clinical consequences due to respiratory limitations favor the generation of comorbidities. Alternatively, the pulmonary manifestations of COPD might be one aspect of expression of a systemic inflammation with several other organic manifestations.12,13 According to this model, systemic inflammation (eg, triggered by physical inactivity or comorbidities) would favor the development of COPD as a syndrome in susceptible subjects. The relevance of this point of view is debatable because it has not been proven and raises a classic chicken and egg question: Is COPD the cause or the consequence of a not yet identified systemic illness?

The airflow limitation in COPD results from airway inflammation due to an abnormal response of the lungs to noxious particles or gases.3 In Western countries, smoking is the main risk factor for the development of COPD, and 90% of patients are current or past smokers. Smoking is the most important risk factor not only for COPD but also for many other chronic diseases and certain cancers. Smoking triggers a local inflammatory response throughout the whole tracheobronchial tree, and pathologic changes characteristic of COPD are found in the proximal large airways, peripheral small airways, lung parenchyma, and pulmonary vasculature.14 The cellular pattern is quite heterogeneous, and macrophages, neutrophils, T lymphocytes (with a preponderance of the CD8+ subtype), B cells, and mast cells are involved.15

Apart from these local effects, smoking may significantly contribute to or cause systemic inflammation. A stimulation of the hematopoietic system with the release of polymorphonuclear leukocytes, the generation of systemic oxidative stress, an activation of coagulation factors, and a direct effect on the endothelial function of peripheral vessels have been attributed to smoking.16,17 These systemic effects of smoking could explain why patients with COPD often concomitantly display other chronic illnesses such as cardiovascular diseases, or metabolic disorders with or without other risk factors such as arterial hypertension, hyperlipidemia, and obesity.

Patients with COPD, in particular those whose disease is severe or who are experiencing exacerbations, show increased markers of systemic inflammation (Table 1).18-20 In stable COPD, plasma concentrations of C-reactive protein (CRP) are related to mortality in mild-to-moderate, but not in severe, disease stages.21,22 The level of CRP concentration is also related to health status and exercise capacity and seems to be a significant predictor of BMI.23 Independent of smoking status, increased levels of cytokines can be found locally in intercostal muscle biopsy specimens from patients with COPD, suggesting that the upregulation of proinflammatory cytokines might also be involved in respiratory muscle dysfunction.24 Whether this systemic inflammation is the result of a “spill-over” of local inflammation in the lungs, a systemic inflammatory effect that affects multiple organ systems, or is attributable to some comorbid conditions that affect the lungs, remains debatable.12,18,25 The origin of this systemic inflammation in COPD is still unknown and it is unclear whether there is a relationship between pulmonary and systemic inflammation.26

Table Graphic Jump Location
Table 1 —Evidence of Systemic Inflammation in COPD

CRP = C-reactive protein; TNF = tumor necrosis factor. (Adapted with permission from Barnes and Celli18)

There is growing evidence that local and systemic oxidative stress, apart from systemic inflammation, is present in patients with COPD.17 However, oxidative stress, although related statistically to lung function impairment, might simply be an epiphenomenon because it represents an archetypical reaction to any form of inflammation.

Systemic inflammation is not only present in patients with COPD, but is also a common feature in various other chronic diseases. Elevated levels of inflammatory markers such as CRP and IL-6 were observed in patients with stable coronary artery disease, peripheral arterial disease, and diabetes, compared with individuals without disease.27,28 These conditions have to be taken into account when the causative role of COPD in systemic inflammation is investigated because these diseases often occur together. Systemic inflammation is potentially the common pathway leading to these chronic diseases and might explain the high prevalence of multiple chronic diseases in the same patient. Almost one-half of all people aged ≥ 65 years have at least three chronic medical conditions, and one-fifth have five or more.29 Aging itself is associated with a chronic low-grade inflammatory status and the theory that systemic inflammation is the common driver of chronic diseases would explain the high prevalence of chronic diseases with increasing age.30 This so-called “inflamm-aging” seems to be the consequence of lifelong antigenic exposure leading to genetic modifications. The individual capability of dealing with this inflammatory burden and developing protective mechanisms seems to modulate individual susceptibility to common causes of morbidity and mortality in elderly people.

The growing evidence that systemic inflammation is a key driver in COPD and is present in many other chronic diseases associated with COPD probably no longer justifies the concept that COPD is a disease restricted to the lungs. The majority of patients with COPD die from cardiovascular disorders or cancer, not respiratory disease.31-34 One can distance COPD from the traditional view, which was basically centered on the presence of chronic airflow obstruction, in that it has been proposed that COPD could be considered as part of a “chronic systemic inflammatory syndrome.”12 This approach seems justified, given the associated comorbidities in patients with COPD. Apart from cardiovascular diseases and lung cancer, patients with COPD are at risk of other extrapulmonary disorders, such as peripheral skeletal muscle dysfunction, nutritional abnormalities, and osteoporosis.35 Large population studies further show that there is an increased prevalence of diabetes among COPD patients and that diabetes is independently associated with reduced lung function.5,36 As with all other comorbid conditions, it is not clear whether inflammation triggers metabolic deterioration or (more likely) whether metabolic signals trigger an inflammatory response.37 COPD is also moderately associated with chronic kidney disease, and moderate to severe COPD stages were independently associated with an increased risk of long-term mortality in patients with peripheral arterial disease and chronic kidney disease (Fig 3).38 Because not all of these comorbidities can be attributed to smoking alone, other reasons for this association have to be taken into account. The systemic inflammation itself may account for these extrapulmonary manifestations in COPD, but so far the evidence is circumstantial and the exact mechanisms responsible for these associations have not yet been totally elucidated.

Figure Jump LinkFigure 3. Percentages of COPD severity according to kidney function. GFR = glomerular filtration rate in mL/min/1.73 m2. (Reprinted with permission from van Gestel et al.38)Grahic Jump Location

The increasing evidence that COPD is a complex disease involving more than airflow obstruction has resulted in the introduction of new descriptors with which to estimate prognosis. The risk of death in patients with COPD was often graded according to the FEV1.39 However, as outlined above, other risk factors influence mortality in patients with COPD.5 Celli et al40 evaluated different, easily measureable variables that independently determined the association with 1-year mortality in patients with COPD. They found that apart from FEV1 and the modified Medical Research Scale estimates, two descriptors of systemic involvement, BMI and the distance walked in 6 min, showed the strongest relation. Compared with the FEV1 alone, BMI, airflow obstruction, dyspnea and exercise capacity (the BODE index) was shown to be a better predictor of the risk of death from any cause and from respiratory cause. The BODE index underscores the fact that mortality is not determined only by respiratory limitations, but also by systemic consequences (covered by the BMI and 6-min walk test). The determination of the BODE could be a useful part of the clinical assessment in each patient with COPD, because it estimates and defines the risk profile in a much better way than the FEV1 alone.

Comorbidities and systemic features present in patients with COPD not only have prognostic value but also result in implications for medical treatment. Until now, the pharmacologic treatment of patients with COPD has been centered mainly on the lungs, specifically the bronchi, and is primarily symptomatic. Considering the different aspects in the pathogenesis of COPD and the evidence that treatment of certain comorbidities positively affects the course of the disease itself, treatment modalities may become more complex.25,41 The treatment of COPD should no longer be centered only on controlling symptoms and reducing exacerbations, but should also be focused on comorbidities. This is particularly relevant for those comorbidities that are easier to prevent and treat than COPD, thus improving health status and prognosis. Pulmonary rehabilitation seems to address several aspects of this complex disease and might be the only approach to cover the broad spectrum of disease variety (see “Pulmonary Rehabilitation”).

A diagnosis of COPD can be carried out easily by performing spirometry, but the assessment of the severity is clearly dependent on the presence of comorbidities. An overarching approach to diagnosis, assessment of severity, and management of COPD with its associated comorbidities has therefore been propagated recently.12 Any patient older than 40 years with a positive smoking history (> 10 pack years), symptoms, and a lung function compatible with COPD should be carefully evaluated for more general disorders associated with chronic systemic inflammation (ie, cardiovascular and metabolic diseases).

Pharmaceuticals are usually developed for individual diseases and targeted toward specific organs. Considering that the comorbidities in COPD range from cardiovascular and metabolic disorders to osteoporosis and depression, each of them requiring its specific therapy, the treatment of patients with COPD would result in polypharmacy and indeed does so in many elderly.42 Assuming that chronic inflammation is the common mechanism for most of these diseases, therapies directed toward chronic inflammation would theoretically be the “solution.” Taking the systemic inflammatory effects of smoking into account, smoking cessation itself is essential because it not only is the leading cause of COPD, but it also positively affects its associated comorbidities. Smoking cessation is associated with a decrease in the risk of myocardial events,43,44 reduces the risk of many types of cancers,45 and increases bone mineral density in postmenopausal women.46 Furthermore, stopping smoking has been shown to slow accelerated progression of renal failure in a small group with primary renal disease.47 Although cigarette smoking is accepted as a risk factor for diabetes,48 its cessation curiously leads to a higher short-term risk that is partially mediated by weight gain and systemic inflammation.49

Physical activity is significantly reduced in patients with COPD and gradually declines with higher GOLD and BODE stages of the disease.50 Reduced physical activity is also an independent predictor of increased levels of high-sensitivity CRP, IL-6, and fibrinogen in COPD patients,51 and there is increasing evidence that persons who are physically inactive have higher levels of systemic inflammatory markers compared with persons who are physically active.52 Assuming that systemic inflammation is the key factor in COPD and other chronic diseases, pulmonary rehabilitation would address important extrapulmonary components that are not targeted by any pharmacologic treatment and might therefore be the reason for its overwhelming efficacy.53 The benefit of pulmonary rehabilitation might still be underestimated and it may be underused in patients with COPD. Lifestyle interventions in general, and pulmonary rehabilitation specifically, are essential components of patient care and should in principle be evaluated in any patient and all GOLD stages.3 Appropriate education about the disease itself, its time course and treatment options, as well as psychosocial support, including smoking cessation and nutritional interventions, are part of a successful rehabilitation program. By taking this holistic approach, pulmonary rehabilitation also addresses the comorbidities associated with COPD and seems to be the only broad therapeutic approach.

Until recently, there have been no specific pharmacologic treatments of COPD; the available therapies are “borrowed” from asthma and adapted to COPD, even though the underlying inflammatory pattern in asthma is very different.54 Most of the large clinical trials have shown that the available drugs for COPD do not significantly modify the long-term decline in FEV1, the hallmark of the disease.55,56 Pharmacologic treatment of COPD is therefore still mainly used to decrease symptoms, reduce the rate of exacerbations, and improve exercise tolerance and general health status.

Bronchodilators and Inhaled Corticosteroids

Bronchodilators play a central role in the management of patients with COPD and are the mainstay of current pharmacologic treatment. The most commonly used inhaled bronchodilators are ß2-agonists and anticholinergics with variable duration of action. These drugs improve health-related quality of life and reduce exacerbations.55,57 Current guidelines recommend treating patients who have moderate to severe COPD with a long-acting bronchodilator.3 In patients with severe COPD and repeated exacerbations, additional inhaled corticosteroids should be evaluated. Inhaled corticosteroids can decrease local inflammation to some extent in steroid-naive patients with moderate to severe COPD, but both fluticasone with or without salmeterol and tiotropium failed to reduce CRP or IL-6 levels in the serum of patients with COPD.58-60 This observation suggests that available drugs can suppress local lung-specific inflammation but they are not able to prevent systemic inflammation questioning the relevance of a spill-over of inflammatory mediators from the lung into the systemic circulation.

Statins

Another approach would be the treatment of systemic diseases associated with COPD. A few observational studies have shown that the treatment of comorbid diseases has some benefit on COPD itself (Table 261-66). The effect of statins, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARB) was analyzed retrospectively in COPD patients with and without concomitant heart disease.64 A reduced rate of hospitalization due to COPD and reduced total mortality was observed in both groups, whereas the risk of a myocardial infarction was reduced only in a high-risk cardiovascular cohort. The largest benefits occurred with the combination of statins and either ACE inhibitors or ARB. Statin use was also associated independently with improved short- and long-term survival in patients with COPD and peripheral arterial disease (Fig 4).61 These studies, however, have clear limitations in their methodology; they suggest that statins or ACE inhibitors/ARB might have dual cardiopulmonary properties and might be able to alter the prognosis of patients with COPD, but these findings need to be confirmed in prospective and carefully controlled trials before any conclusions about the management of COPD can be drawn.

Table Graphic Jump Location
Table 2 —Retrospective Cohort Trials Assessing Morbidity and Mortality in COPD Patients With Non-COPD Drugs

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blockers; HR = hazard ratio; RR = risk ratio.

Figure Jump LinkFigure 4. Long-term mortality according to COPD and statin use in patients with peripheral arterial disease. (Reprinted with permission from van Gestel et al.61)Grahic Jump Location

It is well known that the effect of statins goes far beyond lowering cholesterol and thereby decreasing mortality from cardiovascular disease and stroke. Statins also show antiinflammatory, antioxidant, and immunomodulatory characteristics.67 They are able to reduce CRP levels independent of their effect on the low-density lipoprotein cholesterol level68,69 and their pleiotropic effect is attributed to the inhibition of the hydroxy-methylglutaryl coenzyme A reductase. Given the increasing evidence that COPD is a systemic inflammatory disease, these pleiotropic effects of statins could explain their positive effects on patients with COPD.

β-Blockers

Patients with COPD are at increased risk of coronary artery disease, and ß-blockers play a pivotal role in the management of cardiovascular diseases. There is a general reluctance to use these substances in patients with COPD because of an unfounded fear of inducing bronchospasm. A large Cochrane database review revealed that cardioselective β-blockers did not adversely affect the FEV1 or induce respiratory symptoms compared with placebo, independent of the severity of the COPD.70 β-blockers also did not affect the FEV1 response to β2-agonists. Given the demonstrated efficacy of β-blockers in treating coronary artery disease and congestive heart failure, and the recent evidence that treatment with β-blockers may reduce the risk of exacerbations and improve survival in patients with COPD,71 the benefit of these medicaments outweighs the side effects and they should not be withheld from patients with COPD.

There is consistent evidence that the understanding of COPD has evolved from a disease limited to the airways to a complex and multicomponent syndrome characterized by pulmonary and systemic inflammation. Chronic diseases, including COPD, share common aspects, and chronic systemic inflammation seems to be one of the linking elements. The origin of this systemic inflammation is still unclear. Because smoking itself induces an inflammatory response and therefore interferes with the postulated systemic inflammatory syndrome in the pathogenesis of COPD, future efforts might be centered on nonsmoking COPD phenotypes for a better assessment of the role of inflammation and the associated comorbidities. Because evidence indicates that newer antiinflammatory pharmacotherapeutics (eg, selective phosphodiesterase 4 inhibitors) are effective in only certain clinical subgroups, the different phenotypes of COPD have to be further elucidated if treatment is to be optimized.20,72 Prospective interventional trials should aim to answer the question as to whether the successful treatment of the comorbidities associated with COPD also positively influences the course of the lung disease. Physicians treating patients with COPD have to become aware of this development and need to include the assessment and diagnosis of associated diseases beyond the lungs. Taking extrapulmonary comorbidities into account, the treatment of patients with COPD must become a multidisciplinary approach, and ultimately the development of guidelines directing clinical care must be reflective of these developments moving from an organ-specific to a more holistic approach.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Rabe has consulted for, participated in advisory board meetings with, and received lecture fees from AstraZeneca, Boehringer, Chiesi Pharmaceuticals, Pfizer, Novartis, Nycomed, MSD, and GaxoSmithKline (GSK). The Department of Pulmonology, and, therefore, Dr Rabe, as head of the department, received grants from Novartis, AstraZeneca, Boehringer Ingelheim, Nycomed, Roche, and GSK from 2005 to 2009. Dr Nussbaumer-Ochsner has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

ACE

angiotensin-converting enzyme

ARB

angiotensin receptor blocker

BODE

BMI, airflow obstruction, dyspnea, and exercise capacity

CRP

C-reactive protein

GOLD

Global Initiative for Chronic Obstructive Lung Disease

Young RP, Hopkins R, Eaton TE. Forced expiratory volume in one second: not just a lung function test but a marker of premature death from all causes. Eur Respir J. 2007;304:616-622. [CrossRef] [PubMed]
 
Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet. 1997;3499064:1498-1504. [CrossRef] [PubMed]
 
Global strategy of diagnosis, management and prevention of COPD (updated 2009). www.goldcopd.com. Accessed August 31, 2010.
 
Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: role of comorbidities. Eur Respir J. 2006;286:1245-1257. [CrossRef] [PubMed]
 
Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J. 2008;324:962-969. [CrossRef] [PubMed]
 
Casanova C, Cote C, de Torres JP, et al. Inspiratory-to-total lung capacity ratio predicts mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;1716:591-597. [CrossRef] [PubMed]
 
Moore AJ, Soler RS, Cetti EJ, et al. Sniff nasal inspiratory pressure versus IC/TLC ratio as predictors of mortality in COPD. Respir Med. 2010;1049:1319-1325. [CrossRef] [PubMed]
 
Wilson DO, Weissfeld JL, Balkan A, et al. Association of radiographic emphysema and airflow obstruction with lung cancer. Am J Respir Crit Care Med. 2008;1787:738-744. [CrossRef] [PubMed]
 
McAllister DA, Maclay JD, Mills NL, et al. Arterial stiffness is independently associated with emphysema severity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;17612:1208-1214. [CrossRef] [PubMed]
 
Ohara T, Hirai T, Muro S, et al. Relationship between pulmonary emphysema and osteoporosis assessed by CT in patients with COPD. Chest. 2008;1346:1244-1249. [CrossRef] [PubMed]
 
Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ.M2-124 and M2-125 study groupsCalverley PM.Rabe KF.Goehring UM.Kristiansen S.Fabbri LM.Martinez FJ. M2-124 and M2-125 study groups Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;3749691:685-694. [CrossRef] [PubMed]
 
Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory syndrome? Lancet. 2007;3709589:797-799. [CrossRef] [PubMed]
 
Sevenoaks MJ, Stockley RA. Chronic obstructive pulmonary disease, inflammation and co-morbidity—a common inflammatory phenotype? Respir Res. 2006;7:70. [CrossRef] [PubMed]
 
Halvorsen B, Otterdal K, Tonstad S, Aukrust P. Smoking and inflammation: their synergistic roles in chronic disease. Curr Cardiovasc Risk Rep. 2008;26:446-451. [CrossRef]
 
Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet. 2004;3649435:709-721. [CrossRef] [PubMed]
 
Yanbaeva DG, Dentener MA, Creutzberg EC, Wesseling G, Wouters EF. Systemic effects of smoking. Chest. 2007;1315:1557-1566. [CrossRef] [PubMed]
 
MacNee W. Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;21:50-60. [CrossRef] [PubMed]
 
Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J. 2009;335:1165-1185. [CrossRef] [PubMed]
 
Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax. 2004;597:574-580. [CrossRef] [PubMed]
 
Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;36312:1128-1138. [CrossRef] [PubMed]
 
de Torres JP, Pinto-Plata V, Casanova C, et al. C-reactive protein levels and survival in patients with moderate to very severe COPD. Chest. 2008;1336:1336-1343. [CrossRef] [PubMed]
 
Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;1753:250-255. [CrossRef] [PubMed]
 
Broekhuizen R, Wouters EF, Creutzberg EC, Schols AM. Raised CRP levels mark metabolic and functional impairment in advanced COPD. Thorax. 2006;611:17-22. [CrossRef] [PubMed]
 
Casadevall C, Coronell C, Ramírez-Sarmiento AL, et al. Upregulation of pro-inflammatory cytokines in the intercostal muscles of COPD patients. Eur Respir J. 2007;304:701-707. [CrossRef] [PubMed]
 
Fabbri LM, Luppi F, Beghé B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J. 2008;311:204-212. [CrossRef] [PubMed]
 
Agustí A. Systemic effects of chronic obstructive pulmonary disease: what we know and what we don’t know (but should). Proc Am Thorac Soc. 2007;47:522-525. [CrossRef] [PubMed]
 
Wisniacki N, Taylor W, Lye M, Wilding JP. Insulin resistance and inflammatory activation in older patients with systolic and diastolic heart failure. Heart. 2005;911:32-37. [CrossRef] [PubMed]
 
Nijm J, Wikby A, Tompa A, Olsson AG, Jonasson L. Circulating levels of proinflammatory cytokines and neutrophil-platelet aggregates in patients with coronary artery disease. Am J Cardiol. 2005;954:452-456. [CrossRef] [PubMed]
 
Anderson G, Horvath J. Chronic Conditions: Making the Case for Ongoing Care. 2002; 2010: Princeton, NJ Robert Wood Johnson Foundation’s Partnership for Solutions
 
De Martinis M, Franceschi C, Monti D, Ginaldi L. Inflammation markers predicting frailty and mortality in the elderly. Exp Mol Pathol. 2006;803:219-227. [CrossRef] [PubMed]
 
Hansell AL, Walk JA, Soriano JB. What do chronic obstructive pulmonary disease patients die from? A multiple cause coding analysis. Eur Respir J. 2003;225:809-814. [CrossRef] [PubMed]
 
Mannino DM, Watt G, Hole D, et al. The natural history of chronic obstructive pulmonary disease. Eur Respir J. 2006;273:627-643. [CrossRef] [PubMed]
 
Mannino DM, Doherty DE, Sonia Buist A. Global Initiative on Obstructive Lung Disease (GOLD) classification of lung disease and mortality: findings from the Atherosclerosis Risk in Communities (ARIC) study. Respir Med. 2006;1001:115-122. [CrossRef] [PubMed]
 
McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA.TORCH Clinical Endpoint CommitteeMcGarvey LP.John M.Anderson JA.Zvarich M.Wise RA. TORCH Clinical Endpoint Committee Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax. 2007;625:411-415. [CrossRef] [PubMed]
 
Agustí AG, Noguera A, Sauleda J, Sala E, Pons J, Busquets X. Systemic effects of chronic obstructive pulmonary disease. Eur Respir J. 2003;212:347-360. [CrossRef] [PubMed]
 
Yeh HC, Punjabi NM, Wang NY, et al. Cross-sectional and prospective study of lung function in adults with type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care. 2008;314:741-746. [CrossRef] [PubMed]
 
Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;4447121:860-867. [CrossRef] [PubMed]
 
van Gestel YR, Chonchol M, Hoeks SE, et al. Association between chronic obstructive pulmonary disease and chronic kidney disease in vascular surgery patients. Nephrol Dial Transplant. 2009;249:2763-2767. [CrossRef] [PubMed]
 
Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet. 1997;3499061:1269-1276. [CrossRef] [PubMed]
 
Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;35010:1005-1012. [CrossRef] [PubMed]
 
Barnes PJ. Future treatments for chronic obstructive pulmonary disease and its comorbidities. Proc Am Thorac Soc. 2008;58:857-864. [CrossRef] [PubMed]
 
Boyd CM, Darer J, Boult C, Fried LP, Boult L, Wu AW. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance. JAMA. 2005;2946:716-724. [CrossRef] [PubMed]
 
Goldenberg I, Jonas M, Tenenbaum A, et al; Bezafibrate Infarction Prevention Study Group Bezafibrate Infarction Prevention Study Group Current smoking, smoking cessation, and the risk of sudden cardiac death in patients with coronary artery disease. Arch Intern Med. 2003;16319:2301-2305. [CrossRef] [PubMed]
 
Critchley J, Capewell S. Smoking cessation for the secondary prevention of coronary heart disease. Cochrane Database Syst Rev. 2004;1:CD003041
 
Vineis P, Alavanja M, Buffler P, et al. Tobacco and cancer: recent epidemiological evidence. J Natl Cancer Inst. 2004;962:99-106. [CrossRef] [PubMed]
 
Oncken C, Prestwood K, Kleppinger A, Wang Y, Cooney J, Raisz L. Impact of smoking cessation on bone mineral density in postmenopausal women. J Womens Health (Larchmt). 2006;1510:1141-1150. [CrossRef] [PubMed]
 
Schiffl H, Lang SM, Fischer R. Stopping smoking slows accelerated progression of renal failure in primary renal disease. J Nephrol. 2002;153:270-274. [PubMed]
 
Willi C, Bodenmann P, Ghali WA, Faris PD, Cornuz J. Active smoking and the risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2007;29822:2654-2664. [CrossRef] [PubMed]
 
Yeh HC, Duncan BB, Schmidt MI, Wang NY, Brancati FL. Smoking, smoking cessation, and risk for type 2 diabetes mellitus: a cohort study. Ann Intern Med. 2010;1521:10-17. [PubMed]
 
Pitta F, Troosters T, Spruit MA, Probst VS, Decramer M, Gosselink R. Characteristics of physical activities in daily life in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;1719:972-977. [CrossRef] [PubMed]
 
Watz H, Waschki B, Kirsten A, et al. The metabolic syndrome in patients with chronic bronchitis and COPD: frequency and associated consequences for systemic inflammation and physical inactivity. Chest. 2009;1364:1039-1046. [CrossRef] [PubMed]
 
Wannamethee SG, Lowe GD, Whincup PH, Rumley A, Walker M, Lennon L. Physical activity and hemostatic and inflammatory variables in elderly men. Circulation. 2002;10515:1785-1790. [CrossRef] [PubMed]
 
Nici L, Donner C, Wouters E, et al; ATS/ERS Pulmonary Rehabilitation Writing Committee ATS/ERS Pulmonary Rehabilitation Writing Committee American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation. Am J Respir Crit Care Med. 2006;17312:1390-1413. [CrossRef] [PubMed]
 
Wouters EF, Reynaert NL, Dentener MA, Vernooy JH. Systemic and local inflammation in asthma and chronic obstructive pulmonary disease: is there a connection? Proc Am Thorac Soc. 2009;68:638-647. [CrossRef] [PubMed]
 
Calverley PM, Anderson JA, Celli B, et al; TORCH investigators TORCH investigators Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;3568:775-789. [CrossRef] [PubMed]
 
Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ. 2000;3207245:1297-1303. [CrossRef] [PubMed]
 
Tashkin DP, Celli B, Senn S, et al; UPLIFT Study Investigators UPLIFT Study Investigators A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;35915:1543-1554. [CrossRef] [PubMed]
 
Lapperre TS, Snoeck-Stroband JB, Gosman MM, et al; Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease Study Group Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease Study Group Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2009;1518:517-527. [PubMed]
 
Sin DD, Man SF, Marciniuk DD, et al; ABC (Advair, Biomarkers in COPD) Investigators ABC (Advair, Biomarkers in COPD) Investigators The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;17711:1207-1214. [CrossRef] [PubMed]
 
Powrie DJ, Wilkinson TM, Donaldson GC, et al. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Eur Respir J. 2007;303:472-478. [CrossRef] [PubMed]
 
van Gestel YR, Hoeks SE, Sin DD, et al. Effect of statin therapy on mortality in patients with peripheral arterial disease and comparison of those with versus without associated chronic obstructive pulmonary disease. Am J Cardiol. 2008;1022:192-196. [CrossRef] [PubMed]
 
Søyseth V, Brekke PH, Smith P, Omland T. Statin use is associated with reduced mortality in COPD. Eur Respir J. 2007;292:279-283. [CrossRef] [PubMed]
 
Mortensen EM, Copeland LA, Pugh MJ, et al. Impact of statins and ACE inhibitors on mortality after COPD exacerbations. Respir Res. 2009;10:45. [CrossRef] [PubMed]
 
Mancini GB, Etminan M, Zhang B, Levesque LE, FitzGerald JM, Brophy JM. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol. 2006;4712:2554-2560. [CrossRef] [PubMed]
 
Frost FJ, Petersen H, Tollestrup K, Skipper B. Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins. Chest. 2007;1314:1006-1012. [CrossRef] [PubMed]
 
Blamoun AI, Batty GN, DeBari VA, Rashid AO, Sheikh M, Khan MA. Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study. Int J Clin Pract. 2008;629:1373-1378. [CrossRef] [PubMed]
 
Hothersall E, McSharry C, Thomson NC. Potential therapeutic role for statins in respiratory disease. Thorax. 2006;618:729-734. [CrossRef] [PubMed]
 
Ridker PM, Danielson E, Fonseca FA, et al; JUPITER Trial Study Group JUPITER Trial Study Group Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;3739670:1175-1182. [CrossRef] [PubMed]
 
Ridker PM, Danielson E, Fonseca FA, et al; JUPITER Study Group JUPITER Study Group Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;35921:2195-2207. [CrossRef] [PubMed]
 
Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2005;194:CD003566
 
Rutten FH, Zuithoff NP, Hak E, Grobbee DE, Hoes AW. Beta-blockers may reduce mortality and risk of exacerbations in patients with chronic obstructive pulmonary disease. Arch Intern Med. 2010;17010:880-887. [CrossRef] [PubMed]
 
Han MK, Agusti A, Calverley PM, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med. 2010;1825:598-604. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. A, Relationship between FEV1, smoking status, and OR for cardiovascular mortality for current smoker (dark grey squares), ex-smoker (white squares), and never smoker (light grey squares). B, Relationship between FEV1, smoking status, and all-cause mortality rate for heavy smoker (dark grey squares), moderate smoker (light grey squares), ex-smoker (white squares), and nonsmoker (moderate grey squares). (Reprinted with permission from Young et al.1)Grahic Jump Location
Figure Jump LinkFigure 2. Prediction of death within 5 years by modified GOLD categories and the presence of no (light grey squares), one (white squares), two (moderate grey squares), or three (dark grey squares) comorbid diseases (diabetes, hypertension, or cardiovascular disease). Reference group (normal): subjects with normal lung function for each comorbid disease. Models were adjusted for age, sex, race, smoking status, education level, and BMI. GOLD = Global Initiative for Chronic Obstructive Lung Disease; R = restrictive lung disease. (Reprinted with permission from Mannino et al.5)Grahic Jump Location
Figure Jump LinkFigure 3. Percentages of COPD severity according to kidney function. GFR = glomerular filtration rate in mL/min/1.73 m2. (Reprinted with permission from van Gestel et al.38)Grahic Jump Location
Figure Jump LinkFigure 4. Long-term mortality according to COPD and statin use in patients with peripheral arterial disease. (Reprinted with permission from van Gestel et al.61)Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Evidence of Systemic Inflammation in COPD

CRP = C-reactive protein; TNF = tumor necrosis factor. (Adapted with permission from Barnes and Celli18)

Table Graphic Jump Location
Table 2 —Retrospective Cohort Trials Assessing Morbidity and Mortality in COPD Patients With Non-COPD Drugs

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blockers; HR = hazard ratio; RR = risk ratio.

References

Young RP, Hopkins R, Eaton TE. Forced expiratory volume in one second: not just a lung function test but a marker of premature death from all causes. Eur Respir J. 2007;304:616-622. [CrossRef] [PubMed]
 
Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet. 1997;3499064:1498-1504. [CrossRef] [PubMed]
 
Global strategy of diagnosis, management and prevention of COPD (updated 2009). www.goldcopd.com. Accessed August 31, 2010.
 
Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: role of comorbidities. Eur Respir J. 2006;286:1245-1257. [CrossRef] [PubMed]
 
Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J. 2008;324:962-969. [CrossRef] [PubMed]
 
Casanova C, Cote C, de Torres JP, et al. Inspiratory-to-total lung capacity ratio predicts mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;1716:591-597. [CrossRef] [PubMed]
 
Moore AJ, Soler RS, Cetti EJ, et al. Sniff nasal inspiratory pressure versus IC/TLC ratio as predictors of mortality in COPD. Respir Med. 2010;1049:1319-1325. [CrossRef] [PubMed]
 
Wilson DO, Weissfeld JL, Balkan A, et al. Association of radiographic emphysema and airflow obstruction with lung cancer. Am J Respir Crit Care Med. 2008;1787:738-744. [CrossRef] [PubMed]
 
McAllister DA, Maclay JD, Mills NL, et al. Arterial stiffness is independently associated with emphysema severity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;17612:1208-1214. [CrossRef] [PubMed]
 
Ohara T, Hirai T, Muro S, et al. Relationship between pulmonary emphysema and osteoporosis assessed by CT in patients with COPD. Chest. 2008;1346:1244-1249. [CrossRef] [PubMed]
 
Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ.M2-124 and M2-125 study groupsCalverley PM.Rabe KF.Goehring UM.Kristiansen S.Fabbri LM.Martinez FJ. M2-124 and M2-125 study groups Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;3749691:685-694. [CrossRef] [PubMed]
 
Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory syndrome? Lancet. 2007;3709589:797-799. [CrossRef] [PubMed]
 
Sevenoaks MJ, Stockley RA. Chronic obstructive pulmonary disease, inflammation and co-morbidity—a common inflammatory phenotype? Respir Res. 2006;7:70. [CrossRef] [PubMed]
 
Halvorsen B, Otterdal K, Tonstad S, Aukrust P. Smoking and inflammation: their synergistic roles in chronic disease. Curr Cardiovasc Risk Rep. 2008;26:446-451. [CrossRef]
 
Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet. 2004;3649435:709-721. [CrossRef] [PubMed]
 
Yanbaeva DG, Dentener MA, Creutzberg EC, Wesseling G, Wouters EF. Systemic effects of smoking. Chest. 2007;1315:1557-1566. [CrossRef] [PubMed]
 
MacNee W. Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;21:50-60. [CrossRef] [PubMed]
 
Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J. 2009;335:1165-1185. [CrossRef] [PubMed]
 
Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax. 2004;597:574-580. [CrossRef] [PubMed]
 
Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;36312:1128-1138. [CrossRef] [PubMed]
 
de Torres JP, Pinto-Plata V, Casanova C, et al. C-reactive protein levels and survival in patients with moderate to very severe COPD. Chest. 2008;1336:1336-1343. [CrossRef] [PubMed]
 
Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;1753:250-255. [CrossRef] [PubMed]
 
Broekhuizen R, Wouters EF, Creutzberg EC, Schols AM. Raised CRP levels mark metabolic and functional impairment in advanced COPD. Thorax. 2006;611:17-22. [CrossRef] [PubMed]
 
Casadevall C, Coronell C, Ramírez-Sarmiento AL, et al. Upregulation of pro-inflammatory cytokines in the intercostal muscles of COPD patients. Eur Respir J. 2007;304:701-707. [CrossRef] [PubMed]
 
Fabbri LM, Luppi F, Beghé B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J. 2008;311:204-212. [CrossRef] [PubMed]
 
Agustí A. Systemic effects of chronic obstructive pulmonary disease: what we know and what we don’t know (but should). Proc Am Thorac Soc. 2007;47:522-525. [CrossRef] [PubMed]
 
Wisniacki N, Taylor W, Lye M, Wilding JP. Insulin resistance and inflammatory activation in older patients with systolic and diastolic heart failure. Heart. 2005;911:32-37. [CrossRef] [PubMed]
 
Nijm J, Wikby A, Tompa A, Olsson AG, Jonasson L. Circulating levels of proinflammatory cytokines and neutrophil-platelet aggregates in patients with coronary artery disease. Am J Cardiol. 2005;954:452-456. [CrossRef] [PubMed]
 
Anderson G, Horvath J. Chronic Conditions: Making the Case for Ongoing Care. 2002; 2010: Princeton, NJ Robert Wood Johnson Foundation’s Partnership for Solutions
 
De Martinis M, Franceschi C, Monti D, Ginaldi L. Inflammation markers predicting frailty and mortality in the elderly. Exp Mol Pathol. 2006;803:219-227. [CrossRef] [PubMed]
 
Hansell AL, Walk JA, Soriano JB. What do chronic obstructive pulmonary disease patients die from? A multiple cause coding analysis. Eur Respir J. 2003;225:809-814. [CrossRef] [PubMed]
 
Mannino DM, Watt G, Hole D, et al. The natural history of chronic obstructive pulmonary disease. Eur Respir J. 2006;273:627-643. [CrossRef] [PubMed]
 
Mannino DM, Doherty DE, Sonia Buist A. Global Initiative on Obstructive Lung Disease (GOLD) classification of lung disease and mortality: findings from the Atherosclerosis Risk in Communities (ARIC) study. Respir Med. 2006;1001:115-122. [CrossRef] [PubMed]
 
McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA.TORCH Clinical Endpoint CommitteeMcGarvey LP.John M.Anderson JA.Zvarich M.Wise RA. TORCH Clinical Endpoint Committee Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax. 2007;625:411-415. [CrossRef] [PubMed]
 
Agustí AG, Noguera A, Sauleda J, Sala E, Pons J, Busquets X. Systemic effects of chronic obstructive pulmonary disease. Eur Respir J. 2003;212:347-360. [CrossRef] [PubMed]
 
Yeh HC, Punjabi NM, Wang NY, et al. Cross-sectional and prospective study of lung function in adults with type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) study. Diabetes Care. 2008;314:741-746. [CrossRef] [PubMed]
 
Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;4447121:860-867. [CrossRef] [PubMed]
 
van Gestel YR, Chonchol M, Hoeks SE, et al. Association between chronic obstructive pulmonary disease and chronic kidney disease in vascular surgery patients. Nephrol Dial Transplant. 2009;249:2763-2767. [CrossRef] [PubMed]
 
Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet. 1997;3499061:1269-1276. [CrossRef] [PubMed]
 
Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;35010:1005-1012. [CrossRef] [PubMed]
 
Barnes PJ. Future treatments for chronic obstructive pulmonary disease and its comorbidities. Proc Am Thorac Soc. 2008;58:857-864. [CrossRef] [PubMed]
 
Boyd CM, Darer J, Boult C, Fried LP, Boult L, Wu AW. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance. JAMA. 2005;2946:716-724. [CrossRef] [PubMed]
 
Goldenberg I, Jonas M, Tenenbaum A, et al; Bezafibrate Infarction Prevention Study Group Bezafibrate Infarction Prevention Study Group Current smoking, smoking cessation, and the risk of sudden cardiac death in patients with coronary artery disease. Arch Intern Med. 2003;16319:2301-2305. [CrossRef] [PubMed]
 
Critchley J, Capewell S. Smoking cessation for the secondary prevention of coronary heart disease. Cochrane Database Syst Rev. 2004;1:CD003041
 
Vineis P, Alavanja M, Buffler P, et al. Tobacco and cancer: recent epidemiological evidence. J Natl Cancer Inst. 2004;962:99-106. [CrossRef] [PubMed]
 
Oncken C, Prestwood K, Kleppinger A, Wang Y, Cooney J, Raisz L. Impact of smoking cessation on bone mineral density in postmenopausal women. J Womens Health (Larchmt). 2006;1510:1141-1150. [CrossRef] [PubMed]
 
Schiffl H, Lang SM, Fischer R. Stopping smoking slows accelerated progression of renal failure in primary renal disease. J Nephrol. 2002;153:270-274. [PubMed]
 
Willi C, Bodenmann P, Ghali WA, Faris PD, Cornuz J. Active smoking and the risk of type 2 diabetes: a systematic review and meta-analysis. JAMA. 2007;29822:2654-2664. [CrossRef] [PubMed]
 
Yeh HC, Duncan BB, Schmidt MI, Wang NY, Brancati FL. Smoking, smoking cessation, and risk for type 2 diabetes mellitus: a cohort study. Ann Intern Med. 2010;1521:10-17. [PubMed]
 
Pitta F, Troosters T, Spruit MA, Probst VS, Decramer M, Gosselink R. Characteristics of physical activities in daily life in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;1719:972-977. [CrossRef] [PubMed]
 
Watz H, Waschki B, Kirsten A, et al. The metabolic syndrome in patients with chronic bronchitis and COPD: frequency and associated consequences for systemic inflammation and physical inactivity. Chest. 2009;1364:1039-1046. [CrossRef] [PubMed]
 
Wannamethee SG, Lowe GD, Whincup PH, Rumley A, Walker M, Lennon L. Physical activity and hemostatic and inflammatory variables in elderly men. Circulation. 2002;10515:1785-1790. [CrossRef] [PubMed]
 
Nici L, Donner C, Wouters E, et al; ATS/ERS Pulmonary Rehabilitation Writing Committee ATS/ERS Pulmonary Rehabilitation Writing Committee American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation. Am J Respir Crit Care Med. 2006;17312:1390-1413. [CrossRef] [PubMed]
 
Wouters EF, Reynaert NL, Dentener MA, Vernooy JH. Systemic and local inflammation in asthma and chronic obstructive pulmonary disease: is there a connection? Proc Am Thorac Soc. 2009;68:638-647. [CrossRef] [PubMed]
 
Calverley PM, Anderson JA, Celli B, et al; TORCH investigators TORCH investigators Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;3568:775-789. [CrossRef] [PubMed]
 
Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ. 2000;3207245:1297-1303. [CrossRef] [PubMed]
 
Tashkin DP, Celli B, Senn S, et al; UPLIFT Study Investigators UPLIFT Study Investigators A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;35915:1543-1554. [CrossRef] [PubMed]
 
Lapperre TS, Snoeck-Stroband JB, Gosman MM, et al; Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease Study Group Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease Study Group Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2009;1518:517-527. [PubMed]
 
Sin DD, Man SF, Marciniuk DD, et al; ABC (Advair, Biomarkers in COPD) Investigators ABC (Advair, Biomarkers in COPD) Investigators The effects of fluticasone with or without salmeterol on systemic biomarkers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;17711:1207-1214. [CrossRef] [PubMed]
 
Powrie DJ, Wilkinson TM, Donaldson GC, et al. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Eur Respir J. 2007;303:472-478. [CrossRef] [PubMed]
 
van Gestel YR, Hoeks SE, Sin DD, et al. Effect of statin therapy on mortality in patients with peripheral arterial disease and comparison of those with versus without associated chronic obstructive pulmonary disease. Am J Cardiol. 2008;1022:192-196. [CrossRef] [PubMed]
 
Søyseth V, Brekke PH, Smith P, Omland T. Statin use is associated with reduced mortality in COPD. Eur Respir J. 2007;292:279-283. [CrossRef] [PubMed]
 
Mortensen EM, Copeland LA, Pugh MJ, et al. Impact of statins and ACE inhibitors on mortality after COPD exacerbations. Respir Res. 2009;10:45. [CrossRef] [PubMed]
 
Mancini GB, Etminan M, Zhang B, Levesque LE, FitzGerald JM, Brophy JM. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol. 2006;4712:2554-2560. [CrossRef] [PubMed]
 
Frost FJ, Petersen H, Tollestrup K, Skipper B. Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins. Chest. 2007;1314:1006-1012. [CrossRef] [PubMed]
 
Blamoun AI, Batty GN, DeBari VA, Rashid AO, Sheikh M, Khan MA. Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study. Int J Clin Pract. 2008;629:1373-1378. [CrossRef] [PubMed]
 
Hothersall E, McSharry C, Thomson NC. Potential therapeutic role for statins in respiratory disease. Thorax. 2006;618:729-734. [CrossRef] [PubMed]
 
Ridker PM, Danielson E, Fonseca FA, et al; JUPITER Trial Study Group JUPITER Trial Study Group Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;3739670:1175-1182. [CrossRef] [PubMed]
 
Ridker PM, Danielson E, Fonseca FA, et al; JUPITER Study Group JUPITER Study Group Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;35921:2195-2207. [CrossRef] [PubMed]
 
Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2005;194:CD003566
 
Rutten FH, Zuithoff NP, Hak E, Grobbee DE, Hoes AW. Beta-blockers may reduce mortality and risk of exacerbations in patients with chronic obstructive pulmonary disease. Arch Intern Med. 2010;17010:880-887. [CrossRef] [PubMed]
 
Han MK, Agusti A, Calverley PM, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med. 2010;1825:598-604. [CrossRef] [PubMed]
 
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