Systemic Manifestations of COPD. Yvonne Nussbaumer-Ochsner, MD ; and Klaus F. Rabe, MD, PhD

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1 CHEST Translating Basic Research Into Clinical Practice Systemic Manifestations of COPD Yvonne Nussbaumer-Ochsner, MD ; and Klaus F. Rabe, MD, PhD 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. CHEST 2011; 139(1): Abbreviations: ACE 5 angiotensin-converting enzyme; ARB 5 angiotensin receptor blocker; BODE 5 BMI, airflow obstruction, dyspnea, and exercise capacity; CRP 5 C-reactive protein; GOLD 5 Global Initiative for Chronic Obstructive Lung Disease 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 FEV 1 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 Manuscript received May 16, 2010; revision accepted July 24, Affiliations: 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; k.f.rabe@lumc.nl. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( site/misc/reprints.xhtml ). DOI: /chest 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 FEV 1 and FVC below 0.7 measured by spirometry. 3 The spirometric severity is graded according to the percentage of FEV 1 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 CHEST / 139 / 1 / JANUARY,

2 cancer, increased arterial stiffness, and osteoporosis 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 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? Local and Systemic Inflammation in COPD 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 1 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 ) 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 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 166 Translating Basic Research Into Clinical Practice

3 Figure 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 5 Global Initiative for Chronic Obstructive Lung Disease; R 5 restrictive lung disease. (Reprinted with permission from Mannino et al. 5 ) Figure 1. A, Relationship between FEV 1, 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 FEV 1, smoking status, and allcause 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 ) protective mechanisms seems to modulate individual susceptibility to common causes of morbidity and mortality in elderly people. COPD: Part of a Systemic Disease? 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 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. 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 FEV However, as outlined above, other risk factors influence mortality in patients with COPD. 5 Celli et al 40 evaluated different, easily measureable variables that independently determined the association with 1-year mortality in patients with COPD. CHEST / 139 / 1 / JANUARY,

4 Table 1 Evidence of Systemic Inflammation in COPD Inflammatory Marker Cytokines IL-6 IL-8 IL-1 b TNF- a Adipokines Acute-phase proteins CRP Fibrinogen Serum amyloid A Surfactant D Circulating cells Monocytes Neutrophils Lymphocytes CRP 5 C-reactive protein; TNF 5 tumor necrosis factor. (Adapted with permission from Barnes and Celli 18 ) They found that apart from FEV 1 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 FEV 1 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 FEV 1 alone. Implementation in Clinical Daily Routine 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 Figure 3. Percentages of COPD severity according to kidney function. GFR 5 glomerular filtration rate in ml/min/1.73 m 2. (Reprinted with permission from van Gestel et al. 38 ) 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 Pulmonary Rehabilitation Physical activity is significantly reduced in patients with COPD and gradually declines with higher 168 Translating Basic Research Into Clinical Practice

5 Table 2 Retrospective Cohort Trials Assessing Morbidity and Mortality in COPD Patients With Non-COPD Drugs Study Medicament Cohort Definition Number Risk Reduction (95% CI) Relative Risk Reduction van Gestel et al 61 Statins Vascular surgery patients with COPD Søyseth et al 62 Mortensen et al 63 Mancini et al 64 Frost et al 65 Blamoun 66 Mancini et al 64 Mortensen et al 63 Mancini et al 64 Mortensen et al 63 ACE inhibitors/ ARB Statin plus ACE inhibitors/arb COPD patients hospitalized for exacerbation COPD patients hospitalized for exacerbation COPD patients with high cardiovascular vs low cardiovascular risk Admitted patients with a diagnosis of COPD Admitted patients with a diagnosis of COPD COPD patients with high cardiovascular vs low cardiovascular risk Patients with COPD hospitalized for exacerbation COPD patients with high cardiovascular vs low cardiovascular risk COPD patients hospitalized for exacerbation 3,371 HR 0.67 ( ) 33% risk reduction for death in patients with COPD undergoing vascular surgery (10-y mortality) 854 HR 0.57 ( ) 43% risk reduction for death after hospital discharge for COPD exacerbation (median follow-up 1.9 y) 11,212 OR 0.49 ( ) 51% risk reduction for death after hospital discharge for COPD exacerbation (90-d mortality) 19,720 RR 0.53 (0.43;0.65) 47% risk reduction for death in cardiovascular high-risk COPD patients 76,232 OR 0.29 ( ) 71% risk reduction for in hospital death for COPD patients hospitalized 185 OR for nonstatin vs statin use: exacerbations OR 9.54 ( ), intubations OR ( ) 19,720 ACE inhibitors: RR 1.04 (0.86;1.25) ARB: RR 0.62 (0.44;0.87) 11,212 ACE inhibitors: OR 0.62 ( ) Roughly a 10-fold advantage for the statin group compared with the nonstatin group ACE inhibitors: no risk reduction. ARB: 38% risk reduction for death in cardiovascular high-risk COPD patients 38% risk reduction for death (90-d mortality) 19,720 RR 0.44 (0.36;0.55) 56% risk reduction for death in cardiovascular high-risk COPD patients 11,212 OR 0.40 ( ) 60% risk reduction for death after hospital discharge for COPD exacerbation (90-d mortality) ACE 5 angiotensin-converting enzyme; ARB 5 angiotensin receptor blockers; HR 5 hazard ratio; RR 5 risk ratio. 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. Pharmacologic Interventions 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 FEV 1, the hallmark of the disease. 55,56 Pharmacologic CHEST / 139 / 1 / JANUARY,

6 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 ß 2 -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 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 ). The effect of statins, angiotensinconverting 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. 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 level 68,69 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. Figure 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 ) 170 Translating Basic Research Into Clinical Practice

7 b-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 b-blockers did not adversely affect the FEV 1 or induce respiratory symptoms compared with placebo, independent of the severity of the COPD. 70 b -blockers also did not affect the FEV 1 response to b 2 -agonists. Given the demonstrated efficacy of b -blockers in treating coronary artery disease and congestive heart failure, and the recent evidence that treatment with b -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. Future Directions 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. Acknowledgments 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 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. References 1. 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 ;30(4): Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause : Global Burden of Disease Study. 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