Chronic Obstructive Pulmonary Diseases:Journal of the COPD Foundation

Running Head: Defining COPD Comorbidities

Funding Support: Not applicable

Date of acceptance: February 27, 2014

Abbreviations: health-related quality-of-life, HR-QOL; forced expiratory volume in 1 second, FEV1; National Health and Nutrition Examination Survey, NHANES; relative risk, RR; odds ratio, OR; Global Initiative for chronic Obstructive Lung Disease, GOLD; body mass index, BMI; hazard ratio, HR; C-reactive protein, CRP; tumor necrosis factor, TNF; relative risk, RR; interleukin-6, IL 6; confidence interval, CI; computed tomography, CT;gastroesophageal reflux disease, GERD; atrial fibrillation/flutter, fibrillation; benign prostatic hypertrophy, BPH; coronary artery disease, CAD; congestive heart failure, CHF; chronic renal failure, CRF; cerebrovascular accident, CVA; degenerative joint disease, DJD;gastroesophageal reflux disease, GERD; obstructive sleep apnea, OSA; peripheral artery disease, PAD; pulmonary hypertension and right heart failure, pulmonary HTN/RHF; congestive heart failure, CHD; chronic kidney disease, CK

Citation:Martinez CH, Miguel DJ, Mannino DM. Defining COPD-related comorbidities, 2004-2014. J COPD F. 2014; 1(1): 51-63. doi: http://doi.org/10.15326/jcopdf.1.1.2014.0119

Introduction

JCOPDF-2014-0119-Figure1Over the past 60 years we have witnessed radical transformations in population demographics and the burden of diseases that are shaping health care and which have an immediate and future impact within the field of respiratory diseases. Despite improvements in life expectancy and lower death rates in the United States over this period, COPD rose to the third leading cause of death in 2008, a testament to the growing importance of chronic diseases and disability.1 Refinements in the understanding of the pathophysiology and mechanisms responsible for susceptibility and heterogeneity of COPD (reviewed in other articles in the same issue of this journal) have occurred over the past 10 years. The search for additional ways to modify important outcomes has been enriched by two separate but related concepts that, at the turn of the century, were not always part of the mainstream understanding of the disease. The first one is that the degree of obstruction –which defines the disease and its severity - does not fully correlate with COPD outcomes (exacerbations, death, and health-related quality-of-life [HR-QOL]).2,3 The second is that a bidirectional interplay exists between the persistent inflammatory processes damaging the lungs and other organs. As a result, COPD is a complex disease linked with other comorbidities that influences treatment effectiveness and outcomes. This paper presents a review of the importance of COPD comorbidities in the development, progression, prognosis and therapy of COPD, and identifies the gaps in knowledge and research in this area.

Challenges in the Identification and Interpretation of COPD Comorbidities

In the United States, COPD patients are usually older adults who have a history of tobacco exposure. These traits are shared with other chronic conditions, including cardiovascular disease and cancer. The typical patient with COPD reports, on average, 4 or more additional diseases4 and on any given day one-third of COPD patients use 5-10 different medications.5 There are several different frameworks that can help to decide if the relevance of a coexistent disease could be elevated to that of a significant comorbid interaction: These are either:

  1. When there is a mutual impact of one disease on the other’s outcomes 6 ;
  2. When the frequency and impact on mortality surpasses the expected within the general population 7 ; or
  3. When the presence of the disease is part of unique COPD phenotypes. 8

In keeping with these frameworks, we present those comorbidities which fulfill at least one of the characteristics. There is, however, significant heterogeneity in the definitions of each one of these studied diseases and the source of data used to evaluate the associations between it and COPD. When possible, we describe the source of information, recognizing that each design has the ability to examine different elements of the entire picture. In the absence of controlled intervention studies to determine the ultimate value of finding and treating comorbidities, consistency across research designs is one of the most valuable aspects of observational data. Thus, at this time, the available data allow us to advance only limited therapeutic recommendations. Each section of this review summarizes the evidence in favor of the association between the disease and COPD, the potential mechanisms, the impact of each disease on COPD outcomes, and the therapeutic implications.

Cardiovascular Disease

Longitudinal population-based studies show that low lung function, measured by forced expiratory volume in 1 second (FEV1 ), is associated with cardiovascular mortality. Participants in the National Health and Nutrition Examination Survey (NHANES) Epidemiologic Follow-up Study with the lowest levels of FEV1 showed 5 times higher risk of death by ischemic heart disease. A pooled analysis of similar longitudinal studies determined that for every 10% decline in FEV1, cardiovascular mortality increases by 28% showing a clear relation between overall cardiovascular death and low lung function.9 A similar gradient exists if the analysis is limited to those fulfilling the diagnosis of COPD. Combined data from more than 5,000 participants in 2 cohorts (the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study) showed that while the odds ratio (OR) of having cardiovascular disease is 1.7 (95% confidence interval [CI] 1.5-1.9) for those in the Global Initiative for chronic Obstructive Lung Disease (GOLD) spirometry category 1, it increased to 2.2(95% CI 1.9-2.5) for those in GOLD 2, and 2.4(95% CI 1.9-3.0) in GOLD spirometry stage 3-4 .6 Of note, the association has been shown to be present for the whole spectrum of cardiovascular diseases, including cerebrovascular disease, congestive heart failure and arrhythmias, and is present even in early disease stages.10 For example, heart failure was self-reported among 12.1% of participants with COPD in NHANES 1998-2008 (compared with 3.9% of those without COPD) and among 7% of participants in other large cohort studies.2 In general, most studies of cardiovascular comorbidities have been able to adjust for age, body mass index (BMI) and tobacco exposure.

JCOPDF-2014-0119-Figure2At the individual level, comorbid ischemic cardiovascular disease among COPD patients in stable clinical state is associated with a poorer HR-QOL and more severe dyspnea, as Patel, et al, demonstrated in a cohort of more than 300 individuals.11 In that study, while the frequency of exacerbations was not affected by coexistent ischemic disease, the length of exacerbations was longer. The effect of ischemic heart disease on COPD mortality was confirmed by Divo, et al,7 after following 1,664 patients for more than 4 years (hazard ratio [HR] for mortality –1.3). They also showed an increased risk from congestive heart failure (HR 1.3), and atrial fibrillation (HR 1.6). Putcha, et al,12 in an analysis using NHANES data, detected worse health status due to cardiovascular comorbidities in COPD; the risk of self-rating their health status as poor was higher when individuals had coexistent heart failure (OR 3.8, 95% CI 2.3-6.2) and coronary disease (OR 2.4) (Figure 2). COPD exacerbations are also related to an increase in cardiovascular events, with a risk of myocardial infarction increasing more than 3 times, and the risk of heart failure more than 10 times in the 6 months following an exacerbation.13,14

Multiple mediators and mechanisms are common to COPD and cardiovascular diseases, with evidence pointing to the importance of inflammatory mediators such as C-reactive protein (CRP) or tumor necrosis factor (TNF). Some examples include compromised vasodilation (both flow-enhanced and nitrogen-dependent) in COPD individuals with higher CRP, blood cell count, or with higher emphysema percentage,15-17 and presence of ultrasound-identified atherosclerotic changes among smokers, which are more pronounced when there is established airway obstruction.18 The common mediators hypothesis has led to speculation that appropriate control of cardiovascular-related inflammation could improve outcomes in COPD. Findings from observational studies showing lower mortality among COPD patients using statins 19 motivated divergent and precautionary opinions,20 and led to the design of clinical trials which are still in progress.21 Conversely, beta-blockers, a mainstay of treatment for cardiovascular disease, are frequently denied to COPD patients due to concerns about worsening bronchospasms. This occurs despite support for their use in COPD patients in the cardiovascular literature and guidelines and the absence of studies demonstrating adverse effects.22-24 With both COPD and cardiovascular disease more common in the elderly, the cardiovascular safety of inhaled medications remains a valid question. There is no evidence of increased cardiac risk for participants in recent studies of long-acting beta-agonists25, 26 or long-acting anti-muscarinic agents25-27 , but there is a signal of increased cardiovascular risk shortly after introduction of any long-acting COPD medication in observational studies.28,29

Diabetes and Metabolic Syndrome

Nationally-representative cross-sectional studies in the United States have estimated a prevalence of diabetes of 12.7% to 16.3% among patients with COPD, significantly higher than in the general population.6 Longitudinal studies have confirmed that COPD is a risk factor for incident diabetes ( RR of 1.4-1.8).30,31 The association of the cluster of risk factors known as metabolic syndrome (hypertension, hyperglycemia, hyperinsulinemia, abdominal obesity), an early step in the development of diabetes and vascular disease, with low levels of lung function, has been well established.32 This finding has fostered the search for common mediators, a fertile area in which the role of adipokines is still being defined. For example, in COPD the level of visceral fat is associated with higher levels of interleukin-6 (IL-6) and lower levels of adiponectin,33 and COPD patients have more insulin resistance, whose magnitude is related to the levels of (IL-6) and TNF-α. The use of corticosteroids in COPD and incident diabetes is still a subject of debate, with pooled data from clinical trials showing no significant associations (HR 1.0, 95% CI 0.7-1.5),34 but with analyses of administrative data supporting a risk (RR 1.3, 95% CI 1.3-1.4).35 For those individuals with both COPD and diabetes, the risk of death is higher at 5 years,6 especially when they are recovering from an exacerbation (HR 2.2),36 and the risk of poor health is also higher.12 High dose inhaled corticosteroids have also been associated with a higher frequency of diabetes-related hospital admission, 37and higher glucose levels.38

Both osteopenia and osteoporosis are increased among patients with COPD, with the severity of COPD related to the prevalence of osteoporosis. Analyses of large administrative databases have estimated that a new diagnosis of COPD increases the risk of being diagnosed with osteoporosis threefold.39 Osteoporosis in COPD can also be found among those with less severe airway obstruction. The clinical consequences of osteoporosis, fractures, are also more frequent in COPD individuals, especially in those with more severe obstruction .Interestingly, the associations are as strong or stronger for men than for women and include a rapid progression of bone loss, in particular when vitamin D deficiency coexists.40 The mechanisms of the COPD-osteoporosis association go beyond the effect of age and systemic steroids, as those factors have been appropriately controlled in the available studies. The classic explanation of osteoporosis in COPD as a result of accelerated decline in bone mineral density among users of inhaled corticosteroids is not supported by recent clinical trials with appropriate follow-up.41 The consistent finding of an association, not just between COPD and osteoporosis, but between the severity of radiologic emphysema and low bone mineral density, 42,43 points to a common mechanism of bone and lung destruction. Interesting associations have been made between the activity of markers of osteoclast activation (e.g. matrix metallo proteinases) and lung function. The clinical implications of the high frequency of osteoporosis in COPD are significant. Physicians are not accustomed to screening men for osteoporosis, thus, more than 80% of COPD individuals with osteoporosis are undiagnosed and untreated.39,44 In addition, COPD is a risk factor for death and perioperative complications after hip fracture repair, highlighting the importance of early diagnosis and prevention of bone loss in this population.

Low body mass index (BMI) and weight loss is common in many chronic diseases; however, in COPD the picture is more complex, as low weight is due to a disproportionate loss of fat-free tissue, especially muscle mass. Low fat-free mass indices, below 15 kg/m2 in women and 16 kg/m2 in men, are found in 20%-50% of COPD patients and double the risk of death.45 The mechanisms explaining cachexia in COPD are still unclear,46 but go beyond the classic explanation of an increase in the oxygen cost of breathing,47 or the pro-inflammatory effect of hypoxemia,48 as cachexia can be present in normoxemic individuals and does not have a linear association with measures of respiratory mechanics. Decreased appetite could be an explanation, but the majority of supportive data comes from cross-sectional studies, where cachexia is already established. Similarly, in cachectic individuals, mediators of catabolic state are upregulated.49 Cachexia is associated with the degree of computed tomography (CT)-measured emphysema, but not the severity of the airway involvement.50,51 Biologic plausibility for this association has been strengthened by metabolomic studies showing similar profiles of amino acid metabolism in those with either emphysema or cachexia,52 and an association between cachexia in COPD individuals and specific genetic polymorphisms within genes related to fat mass and obesity.53 Although low BMI is a prognostic factor in COPD, and is part of multidimensional prognostic indices, 54 there is limited information on the management of patients with cachexia, including the potential for drug interactions and abnormal metabolism, 55 and the effect on cost and health service utilization. 56,57 Potential interventions including the use of mechanical ventilation (to decrease the energy expenditure of breathing), nutritional supplementation, 58 anabolic steroids and growth hormone releasing factors such as ghrelin (to counterbalance the switch from catabolism to anabolism), have met with mixed results. 59,60 Fortunately, COPD patients with cachexia improve with pulmonary rehabilitation similar to their well-nourished counterparts. 61, 62 Beta-2 agonists, one of the most widely used treatments for COPD, have proven to have positive effects on skeletal muscle function and structure in animal models studying different muscle-wasting diseases, but at doses beyond that used in clinical practice. 63

Anemia

Anemia has been described with variable frequency in the COPD population, from 3.3% in NHANES to 6.2% among COPD outpatients, and up to 17% among COPD inpatients.64-66 It has been hypothesized that anemia in COPD shares mechanisms with other anemias of chronic disease, 67 with persistently elevated interleukins (especially IL-1) interfering with the response to erythropoietin. A recent cross-sectional study found higher levels of erythropoietin in COPD patients with anemia, compared with those with normal hemoglobin. 68 Different COPD outcomes, including poor functional status64, frequent exacerbations69 and increased health care-related direct and indirect costs 70 have been associated with the presence of anemia. Cohort studies suggest that survival also seems to be affected by the hemoglobin level, being lower in those with anemia than in those with a normal level or polycythemia. 71 No specific treatment recommendations for coexistent anemia in COPD are currently available.

Obstructive Sleep Apnea

Population-based studies have identified sleep apnea among COPD patients with a frequency similar or just slightly higher than the general population: between 8% and 14%.72, 73 The similar frequency and distribution of risk factors has limited the ability to formulate and prove hypotheses about specific mechanistic pathways in the association. However, what is unique about this form of overlap syndrome is the increase in mortality for those with untreated sleep apnea, and the ability to modulate the risk with regular use of therapy for sleep apnea.74 Clinical findings that should prompt an evaluation of sleep apnea include pulmonary hypertension or right heart failure unexplained by or out of proportion to the degree of obstruction.

Gastroesophageal Reflux Disease

Although researchers have used many different definitions of gastroesophageal reflux disease (GERD), including validated questionnaires, 75-77 esophageal pH-monitors, 78 and administrative medical claims data, 79 there is a consistently higher prevalence of the disease among those with COPD than in the general population. The findings are also consistent across different designs and populations, including cross-sectional studies of COPD patients reporting prevalence between 16% and 62%, 80 and population-based representative surveys describing a prevalence of 28%. 79 There is, however, limited evidence concerning the direction of the relation. One study of the United Kingdom General Practice Research Database detected a low frequency of receiving a new diagnosis of COPD after a diagnosis of GERD was established, but a higher frequency of incident GERD diagnosis among those with established COPD. 81 Those findings, plus the identification of GERD more frequently among COPD individuals with predominantly bronchitis phenotypes (33.6% compared to 27.6% in those without chronic bronchitis), 51 have created renewed attention to the role of mechanical factors such as persistent cough, changes in thoracic and abdominal pressures and the development of hiatal hernias (present in 13% of COPD individuals) 82 as explanations for the COPD-GERD association. All of the above theories are still to be explored. Almost all COPD outcomes are impacted by coexistent GERD, including poorer HR-QOL and more severe symptoms. 83, 84 The risk of frequent exacerbations with coexistent GERD has been reported with an OR of 1.7(95% CI 1.4-2.0) 85 in a large cohort study, to an OR of 1.5(95% CI 1.5-1.6) in cross-sectional analysis of administrative databases 79 to a RR of 1.9(95% CI 1.3-2.8) to 2.2 in smaller cohorts. 76, 86 Observational data has shown better HR-QOL in those with treated GERD, 83 and only one clinical trial has addressed the question of treating COPD with proton-pump inhibitor medications and the risk of exacerbations 87; their results (77% reduction of exacerbations) have not been replicated or extended in subsequent analysis or trials; thus, specific therapeutic recommendations are not available.

Anxiety and Depression

The investigation of sensitive aspects of human behavior, such as the presence of anxiety and depression, is challenging when dealing with large population samples. But even when the sample is more limited, such as when participants are clinical patients or volunteers in cohort studies, the multitude of instruments available makes determination of estimates difficult. Still, while the estimates of anxiety and depression in COPD vary widely, the high prevalence of these comorbidities is a consistent finding. In population-based studies, such as NHANES, depression is reported by 20.6% of participants with COPD (compared with 12.5% for those without). 88 An incident diagnosis of COPD increases the risk of being diagnosed with depression (RR 1.8, 95% CI 1.7-2.0), and the risk appears to be higher within the first year after diagnosis. 89 Nationally-representative data from adults 50 years of age and older in the United States have found that up to 40% of those with COPD have depressive symptoms, a proportion higher than what is found in other chronic diseases, such as stroke, diabetes and heart disease. 90 In a series of clinical patients or volunteers the frequency has been reported between 26% 91 and 35%. 92 Depression is more common in women with COPD, and in younger individuals, along with those with lower educational achievements and current smokers. 90, 91 Other effects include shorter 6-minute walk results, 91 lower self-reported HR-QOL, 12 and twice the mortality rate. 94, 95

Anxiety has been reported by 8.6% of NHANES participants with COPD (in contrast with 3.8% for those without COPD), and up to 28% in clinic-based series 88, 96; it has been associated with female gender97 and chronic bronchitis symptoms. Unexpectedly, anxiety in COPD has been associated with more, not less, levels of physical activity at baseline, 98 and previous reports of a lower walking distance in these subpopulations could be mediated just by the low pulmonary function in participants with anxiety. 99 Equally important is that there is an increased risk of being diagnosed with COPD after a diagnosis of anxiety (RR 1.6, 95% CI 1.4-1.9), depression (RR 1.8, 95% CI 1.5-2.0), or both (RR 2.1,95% CI 1.7-2.5). 100 Anxiety increases the risk of death among COPD patients. 7

The role of pharmacologic and other therapies including cognitive and behavioral interventions, for the treatment of anxiety and depression is still unclear. 101 Fortunately, rehabilitation programs could improve symptoms of anxiety and depression, 102 and referral to specific mental health services has demonstrated improved mortality. 103

Clustering Comorbidities Based on Common Mechanisms

COPD is very heterogeneous and multiple mechanisms have been implicated in its pathogenesis. These mechanisms include inflammatory, immune, senescent, and reparative pathways. Cigarette smoke is associated with inflammatory changes, with an intensity and persistence that is more marked in smokers with COPD, and with progression from an initial response, secondary to activation of the innate immunity, to enhancement of the adaptive immune response as the disease progresses, analogous to what happens in autoimmune diseases. 104-106 As a result, multiple mediators, including cytokines and non-specific inflammatory mediators, are elevated, both in the lung, as well as in the systemic circulation. Patients with COPD and comorbidities have higher levels of these mediators. However, it is still difficult to know if the systemic effect of the extrapulmonary disease involves the lung, or if the excess of mediators produced in the lung is spilling over into the circulation. The key COPD comorbidities with inflammatory and immune features include cardiovascular disease, 16, 17 osteoporosis 16 ,17, 107 and the metabolic syndrome and its consequences, including diabetes. 33, 108, 109 Persistent elevation of inflammatory markers (CRP, fibrinogen, and leukocyte count) is also related to COPD exacerbations, even in the absence of an exacerbation history. 110

The description of COPD as an accelerated senescence of the lung 111 has fostered further research into the role of abnormal apoptosis in the pathogenesis of COPD. Abnormal telomere shortening is associated with COPD. 112, 113 Comorbidities associated with abnormal telomere function include accelerated weight loss (fat-free mass and muscle mass loss, in particular), 114 and can be found in early stages of COPD. 115 Osteoporosis 116, 117 and cardiovascular disease 118-120 are other examples of diseases sharing a significant role of accelerated aging mechanisms with COPD.

Abnormal repair and abnormal responses to enhanced oxidative stress are also potential mechanisms for the development of COPD, 121-123 which are shared with pulmonary fibrosis and cancer. While the development of interstitial lung diseases, especially pulmonary fibrosis, was previously seen as diametrically opposite to COPD, findings of large cohorts of COPD patients with detailed imaging evaluation have found that early interstitial abnormalities are common, 124 and that the combination of emphysema and pulmonary fibrosis is a disease with specific clinical characteristics and prognostic implications. 125 Other pathogenic mechanisms, not covered here, including abnormalities in the coagulation pathway, autoimmunity and abnormal cell proliferation, and the recently introduced role of the change in bacterial communities in the lung (microbiome), 126 will continue bringing exciting ideas to the interpretation of clusters of COPD comorbidities.

Comorbidity Clusters in COPD Phenotypes

The improving definition of COPD phenotypes continues to enhance our understanding of COPD-related comorbidities. 8 Burgel, et al, used hierarchical cluster analysis of data from more than 500 patients and detected 3 main groups: one with COPD but low burden of comorbidities; a second one with high risk of comorbidities with severe emphysema, low frequency of cardiovascular comorbidities and low BMI.; and a third with high risk of mortality, mainly due to a high burden of cardiovascular disease, in the presence of less emphysema. 127 Detailed population-based cluster analysis, based on data from the entire population of Switzerland, reported that emphysema clusters with cachexia, and chronic bronchitis clusters with diabetes and obesity.128 This confirms the clinical observation of the phenotypic coexistence of emphysema with low BMI and osteoporosis, and that the chronic bronchitis phenotype tends to present with more diabetes and sleep apnea. Follow-up of a cohort of 342 patients for more than 4 years allowed Garcia-Aymerich, et al, to identify 3 different COPD phenotypes. One of the phenotypes with high frequency of obesity, diabetes and cardiovascular disease had more frequent admissions with cardiovascular problems.129 Another proposed COPD phenotype, the frequent exacerbation phenotype, is also associated with a limited number of diseases including GERD, cardiovascular disease and depression. 85, 130 One final concept that deserves discussion and further research is the role of low physical activity as a common end-pathway of COPD comorbidities. Overall most of the diseases described above are associated with a sedentary lifestyle, and will force the patient to become more inactive, which amplifies the inflammatory effect of COPD and the coexistent diseases. 131, 132 Determining if exercise programs, not just pulmonary rehabilitation, can modulate the inflammatory response is currently the subject of intense research.

JCOPDF-2014-0119-Table1 JCOPDF-2014-0119-Table2

Conclusions

Among COPD patients, there is growing evidence that some coexistent diseases cannot be explained solely by common risk factors (e.g., tobacco exposure in the United States) or aging. These diseases are important comorbidities as demonstrated by having a frequency higher than in the general population (such as cardiovascular disease, diabetes, anemia) and having more severe consequences, including impact on mortality (e.g., depression, anxiety, diabetes), HR-QOL (heart failure, GERD), and exacerbations (GERD). COPD also increases the risk of developing comorbidities (GERD, diabetes) or having a negative impact on some of those diseases (osteoporosis). There are also comorbidities which are more frequent among patients with proposed COPD phenotypes. Osteoporosis and weight loss are more frequent in those with emphysema-predominant COPD, while diabetes, high BMI and cardiovascular disease are more common in airway-predominant disease, and GERD is associated with the frequent exacerbation phenotype. Common inflammatory and immune mechanisms link specific diseases with some steps in COPD pathogenesis (development of emphysema and low bone mineral density) (Table 1)[LINK TO TABLE 1] and phenotypes (e.g., chronic bronchitis and metabolic syndrome). A better understanding of the relevant pathways should provide better guidance for future therapies (Table 2) [LINK TO TABLE 2].

Acknowledgements

All authors contributed equally to the concept, outline, and writing of the manuscript. All authors approved the final version of the manuscript.

Declaration of Interest

CHM and MJD report no conflicts. DMM has received honoraria or consulting fees and served on speaker bureaus for GlaxoSmithKline, Novartis Pharmaceuticals, Pfizer Inc., Boehringer-Ingelheim, AstraZeneca, Forest Laboratories Inc., Merck, Amgen and Creative Educational Concepts. Furthermore, he has received royalties from Up-to-Date and is on the Board of Directors of the COPD Foundation. CHM is supported by funding from NIH/NHLBI Grant # T32 HL007749-20.

1. U.S. Burden of Disease Collaborators. The state of US health, 1990-2010: burden of diseases, injuries,and risk factors. JAMA. 2013; 310(6):591-608. doi: http://dx.doi.org/10.1001/jama.2013.13805.

2. Miller J, Edwards LD, Agusti A, et al. Comorbidity, systemic inflammation and outcomes in the ECLIPSE cohort. Respir Med. 2013; 107(9):1376-1384. doi: http://dx.doi.org/10.1016/j.rmed.2013.05.001.

3. Marzilli M, Merz CN, Boden WE, et al. coronary atherosclerosis and ischemic heart disease: an elusive link! J Am Coll Cardiol.2012; 60(11):951-956. doi: http://dx.doi.org/10.1016/j.jacc.2012.02.082.

4. Vanfleteren LE, Spruit MA, Groenen M, et al. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med.2013; 187(7):728-735. doi: http://dx.doi.org/10.1164/rccm.201209-1665OC.

5. Barr RG, Celli BR, Mannino DM, et al.Comorbidities, patient knowledge, and disease management in a national sample of patients with COPD. Am J Med. 2009; 22(4):348-355. doi: http://dx.doi.org/10.1016/j.amjmed.2008.09.042.

6. Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J.2008; 32(4):962-969. doi: http://dx.doi.org/10.1183/09031936.00012408.

7. Divo M, Cote C, de Torres JP, et al. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med.2012;186(2):155-161. doi: http://dx.doi.org/10.1164/rccm.201201-0034OC.

8. Martinez CH, Han MK. Contribution of the environment and comorbidities to chronic obstructive pulmonary disease phenotypes. Med Clin North Am.2012; 96(4):713-727. doi: http://dx.doi.org/10.1016/j.mcna.2012.02.007.

9. Sin DD, Man SF. Chronic obstructive pulmonary disease as a risk factor for cardiovascular morbidity and mortality. Proc Am Thorac Soc.2005;2(1):8-11. doi: http://dx.doi.org/10.1513/pats.200404-032MS.

10. Lindberg A, Larsson LG, Ronmark E, Lundback B. Co-morbidity in mild-to-moderate COPD: comparison to normal and restrictive lung function. COPD.2011; 8(6):421-428. doi: http://dx.doi.org/10.3109/15412555.2011.629858.

11. Patel AR, Donaldson GC, Mackay AJ, Wedzicha JA, Hurst JR. The impact of ischemic heart disease on symptoms, health status, and exacerbations in patients with COPD. Chest.2012;141(4):851-857.doi: http://dx.doi.org/10.1378/chest.11-0853.

12. Putcha N, Puhan MA, Hansel NN, Drummond MB, Boyd CM.Impact of co-morbidities on self-rated health in self-reported COPD: an analysis of NHANES 2001-2008. COPD.2013;10(3):324-332.doi: http://dx.doi.org/10.3109/15412555.2012.744963.

13. Donaldson GC, Hurst JR, Smith CJ, Hubbard RB, Wedzicha JA. Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest.2010;137(5):1091-1097.doi: http://dx.doi.org/10.1378/chest.09-2029.

14. Halpin DM, Decramer M, Celli B, Kesten S, Leimer I, Tashkin DP. Risk of nonlower respiratory serious adverse events following COPD exacerbations in the 4-year UPLIFT(R) trial. Lung.2011;189(4):261-268.doi: http://dx.doi.org/10.1007/s00408-011-9301-8.

15. Eickhoff P, Valipour A, Kiss D, et al. Determinants of systemic vascular function in patients with stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;178(12):1211-1218.doi: http://dx.doi.org/10.1164/rccm.200709-1412OC.

16. Valipour A, Schreder M, Wolzt M, et al. Circulating vascular endothelial growth factor and systemic inflammatory markers in patients with stable and exacerbated chronic obstructive pulmonary disease. Clin Sci (Lond) . 2008;115(7):225-232. doi: http://dx.doi.org/10.1042/CS20070382.

17. Barr RG, Mesia-Vela S, Austin JH,et al. Impaired flow-mediated dilation is associated with low pulmonary function and emphysema in ex-smokers: theEmphysema and Cancer Action Project (EMCAP) Study. Am J Respir Crit Care Med.2007;176(12):1200-1207. doi: http://dx.doi.org/10.1164/rccm.200707-980OC.

18. Iwamoto H, Yokoyama A, Kitahara Y, et al. Airflow limitation in smokers is associated with subclinical atherosclerosis. Am J Respir Crit Care Med. 2009;179(1):35-40. doi: http://dx.doi.org/10.1164/rccm.200804-560OC.

19.Janda S, Park K, FitzGerald JM, Etminan M, Swiston J. Statins in COPD: a systematic review. Chest. 2009; 136(3):734-743. doi: http://dx.doi.org/10.1378/chest.09-0194.

20. Suissa S. Co-morbidity in COPD: the effects of cardiovascular drug therapies. Respiration.2010; 80(1):3-7.doi: http://dx.doi.org/10.1159/000315387.

21. COPD Clinical Research Network (COPD CRN). STATins in COPD Exacerbations (STATCOPE)study.COPD CRN Web site. http://www.copdcrn.org/statcope.htm . Accessed April 21, 2014.

22. Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev.2005;(4):CD003566.

23. Hawkins NM, Petrie MC, Jhund PS, Chalmers GW, Dunn FG, McMurray JJ. Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology. Eur J Heart Fail.2009; 11(2):130-139.doi: http://dx.doi.org/10.1093/eurjhf/hfn013 .

24. Mentz RJ, Schulte PJ, Fleg JL, et al. Clinical characteristics, response to exercise training, and outcomes in patients with heart failure and chronic obstructive pulmonary disease: findings from Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION). Am Heart J. 2013;165(2):193-199. doi: http://dx.doi.org/10.1016/j.ahj.2012.10.029 .

25. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007; 356(8):775-789. doi: http://dx.doi.org/10.1056/NEJMoa063070 .

26. Feldman G, Siler T, Prasad N, et al. Efficacy and safety of indacaterol 150 microg once-daily in COPD: a double-blind, randomised, 12-week study. BMC Pulm Med. 2010; 10:11. doi: http://dx.doi.org/10.1186/1471-2466-10-11.

27. Celli B, Decramer M, Leimer I, Vogel U, Kesten S, Tashkin DP. Cardiovascular safety of tiotropium in patients with COPD. Chest. 2010; 137(1):20-30. doi: http://dx.doi.org/10.1378/chest.09-0011.

28. Gershon A, Croxford R, Calzavara A, et al. Cardiovascular safety of inhaled long-acting bronchodilators in individuals with chronic obstructive pulmonary disease. JAMA Intern Med. 2013;173(13):1175-1185.doi: http://dx.doi.org/10.1001/jamainternmed.2013.1016 .

29. Jara M, Wentworth C III, Lanes S. A new user cohort study comparing the safety of long-acting inhaled bronchodilators in COPD. BMJ Open. 2012; 2(3).

30. Song Y, Klevak A, Manson JE, Buring JE, Liu S. Asthma, chronic obstructive pulmonary disease, and type 2 diabetes in the Women's Health Study. Diabetes Res Clin Pract.2010; 90(3):365-371.doi: http://dx.doi.org/10.1016/j.diabres.2010.09.010 .

31. Rana JS, Mittleman MA, Sheikh J, et al.Chronic obstructive pulmonary disease, asthma, and risk of type 2 diabetes in women. Diabetes Care.2004; 27(10):2478-2484.doi:http://dx.doi.org/10.2337/diacare.27.10.2478 .

32. Leone N, Courbon D, Thomas F, et al. Lung function impairment and metabolic syndrome: the critical role of abdominal obesity. Am J Respir Crit Care Med.2009; 179(6):509-516. doi: http://dx.doi.org/10.1164/rccm.200807-1195OC .

33. van den Borst B, Gosker HR, Koster A, et al. The influence of abdominal visceral fat on inflammatory pathways and mortality risk in obstructive lung disease. Am J Clin Nutr.2012; 96(3):516-526. doi: http://dx.doi.org/10.3945/ajcn.112.040774 .

34. O'Byrne PM, Rennard S, Gerstein H, et al. Risk of new onset diabetes mellitus in patients with asthma or COPD taking inhaled corticosteroids. Respir Med.2012; 106(11):1487-1493.doi: http://dx.doi.org/10.1016/j.rmed.2012.07.011.

35. Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the risks of diabetes onset and progression. Am J Med.2010;123(11):1001-1006. doi: http://dx.doi.org/10.1016/j.amjmed.2010.06.019.

36. Gudmundsson G, Gislason T, Lindberg E, et al. Mortality in COPD patients discharged from hospital: the role of treatment and comorbidity. Respir Res. 2006; 7:109. doi: http://dx.doi.org/10.1186/1465-9921-7-109 .

37. Caughey GE, Preiss AK, Vitry AI, Gilbert AL, Roughead EE. Comorbid diabetes and COPD: impact of corticosteroid use on diabetes complications. Diabetes Care. 2013; 36(10) : 3009-3014.doi: http://dx.doi.org/10.2337/dc12-2197 .

38. Slatore CG, Bryson CL, Au DH. The association of inhaled corticosteroid use with serum glucose concentration in a large cohort. Am J Med. 2009;122(5):472-478. doi: http://dx.doi.org/10.1016/j.amjmed.2008.09.048.

39. Morden NE, Sullivan SD, Bartle B, Lee TA. Skeletal health in men with chronic lung disease: rates of testing, treatment, and fractures. Osteoporos Int. 2011; 22(6):1855-1862. doi: http://dx.doi.org/10.1007/s00198-010-1423-y .

40. Graat-Verboom L, Smeenk FW, van den Borne BE, et al. Progression of osteoporosis in patients with COPD: a 3-year follow up study. Respir Med. 2012;106(6):861-870. doi: http://dx.doi.org/10.1016/j.rmed.2011.12.020 .

41. Ferguson GT, Calverley PM, Anderson JA, et al. Prevalence and progression of osteoporosis in patients with COPD: results from the Towards a Revolution in COPD Health study. Chest. 2009; 136(6):1456-1465.doi: http://dx.doi.org/10.1378/chest.08-3016 .

42. Bon J, Fuhrman CR, Weissfeld JL, et al. Radiographic emphysema predicts low bone mineral density in a tobacco-exposed cohort. Am J Respir Crit Care Med.2011;183(7):885-890. doi: http://dx.doi.org/10.1164/rccm.201004-0666OC .

43. Romme EA, Murchison JT, Edwards LD, et al. CT-measured bone attenuation in patients with chronic obstructive pulmonary disease: relation to clinical features and outcomes. J Bone Miner Res.2013; 28(6):1369-1377.doi: http://dx.doi.org/10.1002/jbmr.1873 .

44. Graat-Verboom L, van den Borne BE, Smeenk FW, Spruit MA, Wouters EF. Osteoporosis in COPD outpatients based on bone mineral density and vertebral fractures. J Bone Miner Res.2011;26(3):561 568. doi: http://dx.doi.org/10.1002/jbmr.257.

45. Vestbo J, Prescott E, Almdal T. Body mass, fat-free body mass, and prognosis in patients with chronic obstructive pulmonary disease from a random population sample: findings from the Copenhagen City Heart Study. Am J Respir Crit Care Med. 2006; 173(1):79-83. doi: http://dx.doi.org/10.1164/rccm.200506-969OC.

46. Langen RC, Gosker HR, Remels AH, Schols AM. Triggers and mechanisms of skeletal muscle wasting in chronic obstructive pulmonary disease. Int J Biochem Cell Biol. 2013; 45(10):2245-2256. doi: http://dx.doi.org/10.1016/j.biocel.2013.06.015.

47. Donahoe M, Rogers RM, Wilson DO, Pennock BE. Oxygen consumption of the respiratory muscles in normal and in malnourished patients with chronic obstructive pulmonary disease. Am Rev Respir Dis. 1989; 140(2):385-391. doi: http://dx.doi.org/10.1164/ajrccm/140.2.385.

48. Nguyen LT, Bedu M, Caillaud D. Increased resting energy expenditure is related to plasma TNF-alpha concentration in stable COPD patients. Clin Nut.1999; 18(5):269-274. doi: http://dx.doi.org/10.1016/S0261-5614(98)80023-X.

49. Chaiban JT, Bitar FF, Azar ST. Effect of chronic hypoxia on leptin, insulin, adiponectin, and ghrelin. Metabolism. 2008;57(8):1019-1022. doi: http://dx.doi.org/10.1016/j.metabol.2007.02.011.

50. Kurosaki H, Ishii T, Motohashi N. Extent of emphysema on HRCT affects loss of fat-free mass and fat mass in COPD. Intern Med. 2009;48(1):41-48. doi: http://dx.doi.org/10.2169/internalmedicine.48.1102.

51. Kim V, Han MK, Vance GB. The chronic bronchitic phenotype of COPD: an analysis of the COPDGene Study. Chest. 2011;140(3):626-633. doi: http://dx.doi.org/10.1378/chest.10-2948.

52. Ubhi BK, Cheng KK, Dong J, et al. Targeted metabolomics identifies perturbations in amino acid metabolism that sub-classify patients with COPD. Mol Biosyst. 2012;8(12):3125-3133. doi: http://dx.doi.org/10.1039/c2mb25194a.

53. Wan ES, Cho MH, Boutaoui N, et al. Genome-wide association analysis of body mass in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2011;45(2):304-310. doi: http://dx.doi.org/10.1165/rcmb.2010-0294OC.

54. 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;350(10):1005-1012.doi: http://dx.doi.org/10.1056/NEJMoa021322.

55. Trobec K, Kerec Kos M, von Haehling S, Springer J, Anker SD, Lainscak M. Pharmacokinetics of drugs in cachectic patients: a systematic review. PLoS One. 2013; 8(11):e79603.doi: http://dx.doi.org/10.1371/journal.pone.0079603.

56. Chima CS, Barco K, Dewitt ML, Maeda M, Teran JC, Mullen KD. Relationship of nutritional status to length of stay, hospital costs, and discharge status of patients hospitalized in the medicine service. J Am Diet Assoc. 1997;97(9):975-980. doi: http://dx.doi.org/10.1016/S0002-8223(97)00235-6.

57. Lainscak M, von Haehling S, Doehner W, et al. Body mass index and prognosis in patients hospitalized with acute exacerbation of chronic obstructive pulmonary disease. J Cachexia Sarcopenia Muscle. 2011; 2(2):81-86.doi: http://dx.doi.org/10.1007/s13539-011-0023-9.

58. Ferreira IM, Brooks D, White J, Goldstein R. Nutritional supplementation for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;12:CD000998 doi: http://dx.doi.org/10.1002/14651858.CD000998.pub3.

59. Pan L, Wang M, Xie X, Du C, Guo Y. Effects of anabolic steroids on chronic obstructive pulmonary disease: a meta-analysis of randomised controlled trials. PLoS One. 2014; 9(1):e84855.doi: http://dx.doi.org/10.1371/journal.pone.0084855.

60. Wagner PD. Possible mechanisms underlying the development of cachexia in COPD. Eur Respir J. 2008; 31(3):492-501.doi: http://dx.doi.org/10.1183/09031936.00074807.

61. Vogiatzis I, Terzis G, Stratakos G. Effect of pulmonary rehabilitation on peripheral muscle fiber remodeling in patients with COPD in GOLD stages II to IV. Chest.2011;140(3):744-752. doi: http://dx.doi.org/10.1378/chest.10-3058.

62. Berton DC, Silveira L, Da Costa CC, De Souza RM, Winter CD, Zimermann Teixeira PJ. Effectiveness of pulmonary rehabilitation in exercise capacity and quality of life in chronic obstructive pulmonary disease patients with and without global fat-free mass depletion. Arch Phys Med Rehabil. 2013;94(8):1607-1614. doi: http://dx.doi.org/10.1016/j.apmr.2013.02.005.

63. Joassard OR, Durieux AC, Freyssenet DG. Beta2-Adrenergic agonists and the treatment of skeletal muscle wasting disorders. Int J Biochem Cell Biol. 2013;45(10):2309-2321. doi: http://dx.doi.org/10.1016/j.biocel.2013.06.025.

64. Cote C, Zilberberg MD, Mody SH, Dordelly LJ, Celli B. Haemoglobin level and its clinical impact in a cohort of patients with COPD. Eur Respir J. 2007;29(5):923-929. doi: http://dx.doi.org/10.1183/09031936.00137106.

65. Chambellan A, Chailleux E, Similowski T. Prognostic value of the hematocrit in patients with severe COPD receiving long-term oxygen therapy. Chest . 2005;128(3):1201-1208. doi: http://dx.doi.org/10.1378/chest.128.3.1201.

66. Portillo K, Belda J, Anton P, Casan P. High frequency of anemia in COPD patients admitted in a tertiary hospital. Rev Clin Esp. 2007;207(8):383-387. doi: http://dx.doi.org/10.1157/13108755.

67. Weiss G, Goodnough LT.Anemia of chronic disease. N Engl J Med. 2005;352(10):1011-1023.doi: http://dx.doi.org/10.1056/NEJMra041809.

68. Comeche Casanova L, Echave-Sustaeta JM, Garcia Lujan R, Albarran Lozano I, Alonso Gonzalez P, Llorente Alonso MJ. Prevalence of anaemia associated with chronic obstructive pulmonary disease. Study of associated variables. Arch Bronconeumol. 2013; 49(9):383-387. doi: http://dx.doi.org/10.1016/j.arbres.2013.04.007.

69. Ozyilmaz E, Kokturk N, Teksut G, Tatlicioglu T. Unsuspected risk factors of frequent exacerbations requiring hospital admission in chronic obstructive pulmonary disease. Int J Clin Pract. 2013;67(7):691 697. 1212.

70. Ershler WB, Chen K, Reyes EB, Dubois R. Economic burden of patients with anemia in selected diseases. Value Health. 2005;8(6):629-638. doi: http://dx.doi.org/10.1111/j.1524-4733.2005.00058.x.

71. Kollert F, Tippelt A, Muller C, et al. Hemoglobin levels above anemia thresholds are maximally predictive for long-term survival in COPD with chronic respiratory failure. Respir Care. 2013;58(7):1204-12.doi: http://dx.doi.org/10.4187/respcare.01961.

72. Bednarek M, Plywaczewski R, Jonczak L, Zielinski J. There is no relationship between chronic obstructive pulmonary disease and obstructive sleep apnea syndrome: a population study. Respiration. 2005;72(2):142-149.doi: http://dx.doi.org/10.1159/000084044.

73. Krachman S, Minai OA, Scharf SM. Sleep abnormalities and treatment in emphysema. Proc Am Thorac Soc. 2008; 5(4):536-542.doi: http://dx.doi.org/10.1513/pats.200708-134ET.

74. Machado MC, Vollmer WM, Togeiro SM, et al. CPAP and survival in moderate-to-severe obstructive sleep apnoea syndrome and hypoxaemic COPD. Eur Respir J. 2010; 35(1):132-137. doi: http://dx.doi.org/10.1183/09031936.00192008.

75. Niklasson A, Strid H, Simren M, Engstrom CP, Bjornsson E.Prevalence of gastrointestinal symptoms in patients with chronic obstructive pulmonary disease. Eur J Gastroenterol Hepatol. 2008;20(4):335-341.doi: http://dx.doi.org/10.1097/MEG.0b013e3282f2d0ec.

76. Terada K, Muro S, Sato S, et al. Impact of gastro-oesophageal reflux disease symptoms on COPD exacerbation. Thorax.2008;63(11):951-955. doi: http://dx.doi.org/10.1136/thx.2007.092858.

77. Bor S, Kitapcioglu G, Solak ZA, Ertilav M, Erdinc M. Prevalence of gastroesophageal reflux disease in patients with asthma and chronic obstructive pulmonary disease. J Gastroenterol Hepatol.2010; 25(2):309-313. doi: http://dx.doi.org/10.1111/j.1440-1746.2009.06035.x.

78. Casanova C, Baudet JS, del Valle Velasco M, et al.Increased gastro-oesophageal reflux disease in patients with severe COPD. Eur Respir J. 2004;23(6):841-845. doi: http://dx.doi.org/10.1183/09031936.04.00107004.

79. Kim J, Lee JH, Kim Y, et al. Association between chronic obstructive pulmonary disease and gastroesophageal reflux disease: a national cross-sectional cohort study. BMC Pulm Med. 2013;13(1):51.doi: http://dx.doi.org/10.1186/1471-2466-13-51.

80. Martinez CH, Martinez FJ, Okajima Y, et al. Chronic obstructive pulmonary disease and gastroesophageal reflux disease in COPDGene. Am J Respir Crit Care Med. 2011;183:A2991.

81. Garcia Rodriguez LA, Ruigomez A, Martin-Merino E, Johansson S, Wallander MA.Relationship between gastroesophageal reflux disease and COPD in UK primary care. Chest. 2008;134(6):1223-1230.doi: http://dx.doi.org/10.1378/chest.08-0902.

82. Noth I, Zangan SM, Soares RV, et al. Prevalence of hiatal hernia by blinded multidetector CT in patients with idiopathic pulmonary fibrosis. Eur Respir J. 2012; 39(2):344-351. doi: http://dx.doi.org/10.1183/09031936.00099910.

83. Rascon-Aguilar IE, Pamer M, Wludyka P, Cury J, Vega KJ. Poorly treated or unrecognized GERD reduces quality of life in patients with COPD. Dig Dis Sci. 2011;56(7):1976-1980. doi: http://dx.doi.org/10.1007/s10620-010-1542-5.

84. Miyazaki M, Nakamura H, Chubachi S, et al. Analysis of comorbid factors that increase the COPD assessment test scores. Respir Res. 2014;15(1):13.doi: http://dx.doi.org/10.1186/1465-9921-15-13.

85. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010; 363(12):1128-1138. doi: http://dx.doi.org/10.1056/NEJMoa0909883.

86. Rascon-Aguilar IE, Pamer M, Wludyka P, et al. Role of gastroesophageal reflux symptoms in exacerbations of COPD. Chest. 2006;130(4):1096-1101. doi: http://dx.doi.org/10.1378/chest.130.4.1096.

87. Sasaki T, Nakayama K, Yasuda H, et al. A randomized, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patients. J Am Geriatr Soc. 2009;57(8):1453-1457. doi: http://dx.doi.org/10.1111/j.1532-5415.2009.02349.x.

88. Schnell K, Weiss CO, Lee T,et al. The prevalence of clinically-relevant comorbid conditions in patients with physician-diagnosed COPD: a cross-sectional study using data from NHANES 1999-2008. BMC Pulm Med. 2012; 12:26. doi: http://dx.doi.org/10.1186/1471-2466-12-26.

89. Tsai TY, Livneh H, Lu MC, Tsai PY, Chen PC, Sung FC. Increased risk and related factors of depression among patients with COPD: a population-based cohort study. BMC Public Health. 2013;13:976.doi: http://dx.doi.org/10.1186/1471-2458-13-976.

90. Schane RE, Walter LC, Dinno A, Covinsky KE, Woodruff PG. Prevalence and risk factors for depressive symptoms in persons with chronic obstructive pulmonary disease. J Gen Intern Med.2008; 23(11):1757 1762.doi: http://dx.doi.org/10.1007/s11606-008-0749-z.

91. Hanania NA, Mullerova H, Locantore NW, et al. Determinants of depression in the ECLIPSE chronic obstructive pulmonary disease cohort. Am J Respir Crit Care Med.2011; 183(5):604-611.doi: http://dx.doi.org/10.1164/rccm.201003-0472OC.

92. Lou P, Zhu Y, Chen P, et al. Prevalence and correlations with depression, anxiety, and other features in outpatients with chronic obstructive pulmonary disease in China: a cross-sectional case control study. BMC Pulm Med. 2012; 12:53. doi: http://dx.doi.org/10.1186/1471-2466-12-53

93. Rauch SA, Favorite T, Giardino N, Porcari C, Defever E, Liberzon I. Relationship between anxiety, depression, and health satisfaction among veterans with PTSD. J Affect Disord. 2010;121(1-2):165-168.doi: http://dx.doi.org/10.1016/j.jad.2009.05.026.

94. de Voogd JN, Wempe JB, Koeter GH, et al. Depressive symptoms as predictors of mortality in patients with COPD. Chest.2009;135(3):619-625.doi: http://dx.doi.org/10.1378/chest.08-0078.

95. Fan VS, Ramsey SD, Giardino ND, et al. Sex, depression, and risk of hospitalization and mortality in chronic obstructive pulmonary disease. Arch Intern Med.2007;167(21):2345-2353. doi: http://dx.doi.org/10.1001/archinte.167.21.2345.

96. Di Marco F, Verga M, Reggente M,et al. Anxiety and depression in COPD patients: The roles of gender and disease severity. Respir Med. 2006;100(10):1767-1774. doi: http://dx.doi.org/10.1016/j.rmed.2006.01.026.

97. Laurin C, Lavoie KL, Bacon SL,et al. Sex differences in the prevalence of psychiatric disorders and psychological distress in patients with COPD. Chest. 2007;132(1):148-155. doi: http://dx.doi.org/10.1378/chest.07-0134.

98. Nguyen HQ, Fan VS, Herting J, et al.Patients with COPD with higher levels of anxiety are more physically active. Chest. 2013; 144(1):145-151.doi: http://dx.doi.org/10.1378/chest.12-1873.

99. Eisner MD, Blanc PD, Yelin EH, et al. Influence of anxiety on health outcomes in COPD. Thorax. 2010;65(3):229-234.doi: http://dx.doi.org/10.1136/thx.2009.126201.

100. Bhattacharya R, Shen C, Sambamoorthi U. Excess risk of chronic physical conditions associated with depression and anxiety. BMC Psychiatry. 2014;14(1):10. doi: http://dx.doi.org/10.1186/1471-244X-14-10.

101. Fritzsche A, Clamor A, von Leupoldt A.Effects of medical and psychological treatment of depression in patients with COPD--a review. Respir Med.2011;105(10):1422-1433. doi: http://dx.doi.org/10.1016/j.rmed.2011.05.014.

102. Pirraglia PA, Casserly B, Velasco R, Borgia ML, Nici L. Association of change in depression and anxiety symptoms with functional outcomes in pulmonary rehabilitation patients. J Psychosom Res. 2011; 71(1):45-49.doi: http://dx.doi.org/10.1016/j.jpsychores.2011.01.002.

103. Jordan N, Lee TA, Valenstein M, Pirraglia PA, Weiss KB. Effect of depression care on outcomes in COPD patients with depression. Chest. 2009;135(3):626-632. doi: http://dx.doi.org/10.1378/chest.08-0839.

104. Nadigel J, Prefontaine D, Baglole CJ, et al. Cigarette smoke increases TLR4 and TLR9 expression and induces cytokine production from CD8(+) T cells in chronic obstructive pulmonary disease. Respir Res. 2011;12:149.doi: http://dx.doi.org/10.1186/1465-9921-12-149.

105. Freeman CM, Martinez FJ, Han MK, et al. Lung CD8+ T cells in COPD have increased expression of bacterial TLRs. Respir Res.2013;14:13. doi: http://dx.doi.org/10.1186/1465-9921-14-13.

106. Tan HL, Rosenthal M. IL-17 in lung disease: friend or foe? Thorax.2013;68(8):788-790. doi: http://dx.doi.org/10.1136/thoraxjnl-2013-203307.

107. Bolton CE, Stone MD, Edwards PH, Duckers JM, Evans WD, Shale DJ. Circulating matrix metalloproteinase-9 and osteoporosis in patients with chronic obstructive pulmonary disease. Chron Respir Dis.2009;6(2):81-87.doi: http://dx.doi.org/10.1177/1479972309103131.

108. Vondracek SF, Voelkel NF, McDermott MT, Valdez C.The relationship between adipokines, body composition, and bone density in men with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis.2009;4:267-277. doi: http://dx.doi.org/10.2147/COPD.S2745.

109. Bianco A, Mazzarella G, Turchiarelli V, et al. Adiponectin:an attractive marker for metabolic disorders in chronic obstructive pulmonary disease (COPD). Nutrients.2013;5(10):4115-4125. doi: http://dx.doi.org/10.3390/nu5104115.

110. Thomsen M, Ingebrigtsen TS, Marott JL, et al. Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease. JAMA.2013;309(22):2353-2361. doi: http://dx.doi.org/10.1001/jama.2013.5732.

111. Ito K, Barnes PJ. COPD as a disease of accelerated lung aging. Chest. 2009;135(1):173-180.doi: http://dx.doi.org/10.1378/chest.08-1419.

112. Houben JM, Mercken EM, Ketelslegers HB, et al.Telomere shortening in chronic obstructive pulmonary disease. Respir Med. 2009;103(2):230-236. doi: http://dx.doi.org/10.1016/j.rmed.2008.09.003.

113. Amsellem V, Gary-Bobo G, Marcos E, et al: Telomere dysfunction causes sustained inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011;184(12):1358-1366.doi: http://dx.doi.org/10.1164/rccm.201105-0802OC.

114.Meyer A, Zoll J, Charles AL, et al. Skeletal muscle mitochondrial dysfunction during chronic obstructive pulmonary disease: central actor and therapeutic target. Exp Physiol.2013;98(6):1063-1078.doi: http://dx.doi.org/10.1113/expphysiol.2012.069468.

115.Puente-Maestu L, Perez-Parra J, Godoy R, et al. Abnormal mitochondrial function in locomotor and respiratory muscles of COPD patients. Eur Respir J. 2009;33(5):1045-1052. doi: http://dx.doi.org/10.1183/09031936.00112408.

116. Zhao X, Xu D, Li Y, et al. MicroRNAs regulate bone metabolism. J Bone Miner Metab. 2013 Dec 6 [Epub ahead of print].doi: http://dx.doi.org/10.1007/s00774-013-0537-7.

117. Jilka RL, Noble B, Weinstein RS. Osteocyte apoptosis. Bone 2013, 54(2):264-271. doi:10.1016/j.bone.2012.11.038.doi: http://dx.doi.org/10.1016/j.bone.2012.11.038.

118. Domagala-Kulawik J. Effects of cigarette smoke on the lung and systemic immunity. J Physiol Pharmacol. 2008;59(suppl 6):19-34.

119. Hopkins PN. Molecular biology of atherosclerosis. Physiol Rev 2013;93(3):1317-1542. doi: http://dx.doi.org/10.1152/physrev.00004.2012.

120. Borghini A, Cervelli T, Galli A, Andreassi MG. DNA modifications in atherosclerosis: from the past to the future. Atherosclerosis. 2013;230(2):202-209. doi: http://dx.doi.org/10.1016/j.atherosclerosis.2013.07.038.

121. Warburton D, Shi W, Xu B. TGF-beta-Smad3 signaling in emphysema and pulmonary fibrosis: an epigenetic aberration of normal development? Am J Physiol Lung Cell Mol Physiol.2013;304(2):L83-85.doi: http://dx.doi.org/10.1152/ajplung.00258.2012.

122. Xu B, Chen H, Xu W, et al. Molecular mechanisms of MMP9 overexpression and its role in emphysema pathogenesis of Smad3 deficient mice. Am J Physiol Lung Cell Mol Physiol.2012;303(2):L89-96.doi: http://dx.doi.org/10.1152/ajplung.00060.2012.

123. Rennard SI, Wachenfeldt K. Rationale and emerging approaches for targeting lung repair and regeneration in the treatment of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2011;8(4):368-375.doi: http://dx.doi.org/10.1513/pats.201102-019RM.

124. Washko GR, Hunninghake GM, Fernandez IE, et al. Lung volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med.2011;364(10):897-906. doi: http://dx.doi.org/10.1056/NEJMoa1007285.

125. Jankowich MD, Rounds SI. Combined pulmonary fibrosis and emphysema syndrome: a review. Chest.2012; 141(1):222-231.doi: http://dx.doi.org/10.1378/chest.11-1062.

126. Han MK, Huang YJ, Lipuma JJ, et al. Significance of the microbiome in obstructive lung disease. Thorax. 2012;67(5):456-463.doi: http://dx.doi.org/10.1136/thoraxjnl-2011-201183

127. Burgel PR, Paillasseur JL, Peene B, et al.Two distinct chronic obstructive pulmonary disease (COPD) phenotypes are associated with high risk of mortality. PLoS One. 2012; 7(12):e51048.doi: http://dx.doi.org/10.1371/journal.pone.0051048.

128. Baty F, Putora PM, Isenring B, Blum T, Brutsche M.Comorbidities and burden of COPD: a population based case-control study. PLoS One. 2013;8(5):e63285. doi: http://dx.doi.org/10.1371/journal.pone.0063285.

129. Garcia-Aymerich J, Gomez FP, Benet M, et al. Identification and prospective validation of clinically relevant chronic obstructive pulmonary disease (COPD) subtypes. Thorax. 2011;66(5):430-437.doi: http://dx.doi.org/10.1136/thx.2010.154484.

130. Wedzicha JA, Brill SE, Allinson JP, Donaldson GC.Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med. 2013;11:181. doi: http://dx.doi.org/10.1186/1741-7015-11-181.

131. Moy ML, Teylan M, Danilack VA, Gagnon DR, Garshick E. An Index of daily step count and systemic inflammation predicts clinical outcomes in chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2013;11(2):149-157. doi: http://dx.doi.org/10.1513/AnnalsATS.201307-243OC.

132. Moy ML, Teylan M, Weston NA, Gagnon DR, Danilack VA, Garshick E: Daily step count is associated with Plasma CRP and IL-6 in a US cohort with COPD. Chest. 2014;145(3):542-550. doi:10.1378/chest.13-105 .

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