COPD and comorbidities
Marc Decramer and Wim Janssens
Respiratory Division, University of Leuven, Belgium
Address for correspondence:
Professor Marc Decramer
Chief Respiratory Division
University Hospital
University of Leuven
Herestraat 49
3000 Leuven
Belgium
Tel: +32-16-346807
Key Words
COPD, comorbidities, cardiovascular disease, lung cancer, osteoporosis, muscle weakness, inactivity, systemic inflammation, bronchodilators, inhaled corticosteroids
Summary
Epidemiological studies demonstrated that COPD is frequently associated with comorbidities, the most significant being cardiovascular disease, lung cancer, osteoporosis, muscle weakness and cachexia. Mechanistically, environmental risk factors such as smoking, unhealthy diet, exacerbations and physical inactivity or inherent factors such as genetic background and aging contribute to this association. No convincing evidence has been provided that treatment of COPD would reduce comorbidities, although some indirect indications are available. There is also no clear evidence that treatment of comorbidities improves COPD, although observational studies would suggest such effects for statins, ß-blockers and angiotensin converting enzyme blockers and receptor antagonists. At present, we lack large scale prospective studies. Reduction of common risk factors appears the most powerful approach to reduce comorbidities. It remains doubtful whether reducing “spill over” of local inflammation from the lungs or reducing systemic inflammation with inhaled or systemic anti-inflammatory drugs, respectively, would also reduce COPD-related comorbidities.
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Introduction
COPD is a progressive debilitating disease with high prevalence. It is currently the fourth most prevalent cause of death and it is responsible for very high expenditures in the health care system and economic costs. A recent analysis from the Harvard School of Public Health showed that the global economic costs generated by COPD amount to 2.1 trillion US dollar and are expected to increase to 4.8 trillion by 20301. A considerable fraction of these costs is due to the fact that this is a complex disease associated with several significant comorbidities2.
Patients with COPD suffer among others from cardiovascular and cerebrovascular disease, lung cancer, muscle weakness and osteoporosis. Other comorbidities include: hypertension, arrhythmias, metabolic syndrome, diabetes, gastro-esophageal reflux disease, hematological coagulopathy, anemia, polycythemia, sleep apnea, endocrine disturbances, renal dysfunction etc…A randomly selected sample of 1,522 patients who were enrolled in a health maintenance organization in 1997, had on average 3.7 comorbid conditions compared with 1.8 in controls3. These comorbidities contribute significantly to reduced health status, increased health care utilization, all cause hospital admission and mortality4;5. In fact, COPD patients are more likely to die from comorbidities than from the disease itself. In a well-designed study critically studying and adjudicating the causes of death in COPD by a panel of senior physicians, only 40% of the deaths were definitely or probably related to COPD, whereas 50% were unrelated to COPD, while 9% was unknown6. One third of the deaths was due to cardiovascular disease.
The present article will briefly review the evidence for a link between COPD and the major comorbidities of the disease, with focus on the mechanisms of their association with COPD and finally, discuss the implications of these links to the treatment of COPD. We will only address the major comorbidities, of which mechanistic links with COPD have recently been studied.
Search strategy
We searched the Cochrane Library, PubMed, and Embase for papers published in 2008-2012. We used the terms “COPD and comorbidities”, “COPD and cardiovascular disease”, “COPD and lung cancer”, “COPD and osteoporosis”, and “COPD and muscle weakness”, “COPD and statins”, “COPD and Angiotensin II Converting Enzyme inhibitors”, “COPD and Angiotensin Receptor Blockers”, “Lung cancer and statins”. We also searched the reference lists of identified articles for further relevant papers, and we included older widely cited publications. Because of the restriction of the number of references, only a fraction of the retrieved references could be used. We selected original references published in major journals, that demonstrated associations or mechanisms for the first time. We avoided citing articles that were purely confirmatory.
Because of the extent of this field, it was not possible to comprehensively address all comorbidities. Instead, we focused on mechanisms of comorbidities, particularly on those comorbidities on which’s mechanisms significant research was conducted in recent years. Our choice was supported by the number of articles retrieved by a search in PubMed. For each of the comorbidities we performed this search by the term “comorbidity and COPD and mechanisms”. This search yielded 237 articles for “cardiovascular disease”, 125 for “lung cancer”, 53 for “diabetes”, 52 for “osteoporosis and muscle weakness”, 18 for “cerebrovascular disease”, and 13 for “anxiety and depression”.
Cardiovascular disease
Cardiovascular disease is not a clearly defined concept. It usually encompasses ischemic heart disease, congestive heart failure, pulmonary vascular disease, coronary artery disease, peripheral vascular disease, and stroke and /or transient ischemic attack. It may also include biomarkers of disease such as lipid abnormalities or inflammatory markers of disease. The present section will primarily focus on ischemic heart disease, because recent mechanistic work was focused on this area.
The association of COPD with cardiovascular disease is well established3;7. Progressive respiratory failure only accounts for about 1/3 of COPD deaths, indicating that a large number of COPD patients die from other causes8. In a pooled analysis of two large epidemiological studies, the Atherosclerosis Risk in Communities, ARIC, Study and the Cardiovascular Health Study, CHS, involving over 20,000 adults, the prevalence of cardiovascular disease in COPD patients was 20-22% compared to 9% in subjects without COPD7. In the ARIC study, among people with severe COPD (GOLD stage III and IV), 32% of deaths were due to respiratory causes, whereas 24% were due to lung cancer and 13 % were cardiac related. This high prevalence of cardiovascular mortality was confirmed by the adjudicated causes of death found in the TORCH-study6. Among patients with moderate COPD (GOLD stage II) only 4% of the deaths were respiratory related, 25% were due to lung cancer and 28% were cardiac related9. In a recent review, Sin et al. confirmed this relationship between FEV1 and the causes of death (Figure 1)10.Taken together, this shows that particularly in patients with mild and moderate disease a substantial fraction of mortality is due to cardiovascular disease and lung cancer.
An analysis of data from the National Health and Nutrition Examination Survey (NHANES) further corroborated the relationship between reduced pulmonary function and cardiovascular mortality. This was done by the demonstration of increased cardiovascular mortality in patients with reduced pulmonary function, even with small decrements, that strictly still fell within the normal range11. This relationship was also shown in lifetime non-smokers in a meta-analysis of published studies, indicating that exposure to tobacco smoke was not the sole reason for this association11.
Several recent studies further confirmed the links between COPD and incidence of cardiovascular disease. First, a large population based study demonstrated an increased relative risk of comorbid cardiovascular disease and subsequent MI and stroke in patients with COPD12. Second, arterial stiffness, measured non-invasively as aortic pulse wave velocity is a known marker of cardiovascular events and mortality in the general population. COPD patients have been shown to have increased arterial stiffness13 compared to age-matched and smoking-matched controls, and this correlated with the degree of airflow obstruction and CT-quantified emphysema14. Third, two studies showed a relationship between COPD and either previous cerebrovascular events15 or incidence of acute stroke12.
Finally, COPD was shown to be associated with diseases that are known to enhance the cardiovascular risk profile. In the abovementioned combined analysis of the ARIC and CHS population-based studies, including more than 20,000 people, the odds ratio for having hypertension compared to normal subjects was 1.4 in GOLD stage II, and 1.6 in GOLD stage III and IV7. Most studies did not find associations between COPD and dyslipidemia16, or metabolic syndrome17;18. Several studies found an enhanced prevalence of diabetes in COPD patients7;9;17;19;20, , but the odds ratio of having diabetes was reduced in older patients19. The association of COPD with diabetes, however, was not found in a meta-analysis performed by others21.
The mechanistic links between COPD and cardiovascular disease are complex, multifactorial and not entirely understood (Figure 2). The observed association between both diseases is to a large extent explained by the presence of common risk factors. Within these factors distinction can be made between environmental risk factors, most of them being largely modifiable (lifestyle), and inherent risk factors that predispose individuals to disease, but which cannot be altered. Of all combined risk factors, smoking is by far the most important, but the risk attributable to inactivity and unhealthy diet should not be underestimated. Genetic predisposition and aging are inherent factors, but still poorly understood.
In contrast to COPD in which the amount of pack-years smoked is an important risk determinant19, cardiovascular risk is known to steeply increase with very low levels of smoke exposure and to flatten out with high exposure levels22. Especially small inhaled particles (Particulate Matter, PM2.5 and PM0.1 with a respective diameter less than 2.5μm and less than 0.1μm) are of interest as they have the capability to be inhaled deeply into the lungs and to be deposited in the respiratory bronchioles and alveoli. Once lodged in the small airways, these particles may induce pulmonary inflammation and bronchiolitis known to be the earliest lesions seen in COPD23. The progressive accumulation of macrophages, neutrophils and B and T- lymphocytes within and around small airways produces a cocktail of pro-inflammatory mediators (such as TNFα, IL-1, IL-6, IL-8, GM-CSF), proteases (MMP-9, MMP-12 and elastase), and reactive oxygen species. These mediators translocate to the systemic circulation where they activate the vascular endothelium, platelets and liver cells. Eventually, a pro-inflammatory and pro-coagulant state is generated, which results in endothelial dysfunction, enhances plaque formation and promotes arteriosclerosis10;24. Moreover, bone marrow progenitor cells are stimulated to release monocytes and neutrophils which are preferentially attracted to the sites of inflammation particularly the lung16.
Although systemic inflammation accelerates the progression of atherosclerosis, stable plaques do not usually cause acute coronary syndromes. Vulnerable plaques are characterized by a larger lipid core with increased content of oxidized LDL, increased inflammatory cells, smooth muscle proliferation and thinning of the fibrous cap18. In unstable angina the widespread presence of neutrophilic inflammation in the coronary arteries regardless of the culprit stenosis, indicates that bursts of inflammation precede the rupture of a vulnerable plaque21. For COPD in particular, Van Eeden and colleagues hypothesized that acute episodes of lung inflammation should be considered as the main triggers for such events25. This hypothesis was confirmed by the observation that in a large UK general practice database acute respiratory infections had a much stronger association with acute coronary syndrome than urinary tract infections26. Moreover, an acute exacerbation of COPD was shown to be associated with a 5 day transiently increased risk for acute myocardial infarction27. The latter may also be related to the increased fibrinogen levels and the resultant pro-thrombotic state27. Apart from the indirect effects of small particle inhalation to vascular inflammation, it is now well accepted that PM0.1 and PM2.5 also translocate through gaps between alveolar epithelial cells directly into the systemic circulation. Their immediate effect on platelets and endothelial cells results in oxidative stress, vascular dysfunction and peripheral thrombosis28.
It is unclear whether systemic inflammation may catalyze or even perpetuate an ongoing pulmonary inflammatory response. If this would be true, it could mean that other risk factors of systemic and vascular inflammation, such as visceral obesity, diabetes and inactivity may increase the risk for COPD onset or progression. To a certain extent, epidemiological studies support this idea by showing that inactivity, unhealthy diet, obesity and poor glycemic control are associated with reduced pulmonary function, airway hyper-reactivity and eventually COPD29;30. Regardless of a cause or consequence relationship, the high prevalence of these factors in COPD is unequivocally associated with an increased risk of cardiovascular disease within this patient group.
Finally, it should be stressed that mechanisms other than atherosclerosis and plaque rupture may cause acute cardiovascular events in COPD31. Acute hypoxemia, chronic anemia and severe respiratory distress may cause a cardiac event, especially in patients with diffuse coronary lesions. Arrhythmia’s and sudden death may be triggered by the combination of different pro-arrhythmic drugs such as inhaled or oral bronchodilators and antibiotics. Pulmonary vascular remodeling with pulmonary hypertension may lead to acute right heart failure. Hyperinflation and increased falls in intra-thoracic pressure may compromise ventricular preload and afterload leading to left ventricular dysfunction and acute heart failure. As most of these factors cluster together on the moment of an acute exacerbation, it is obvious that these episodes are often associated with major cardiovascular events and high mortality32.
Lung Cancer
COPD is an independent risk factor for the development of lung cancer, increasing lung cancer risk two- to six fold, compared with incidence rates of smokers without COPD33-37. Reduced FEV1 was shown to increase the risk of incident lung cancer independently of smoking history36. Moreover, COPD was also associated with lung cancer in never-smokers35. Hence, the association between COPD and lung cancer was not solely due to smoking. Airflow obstruction and emphysema were also shown to be independent risk factors for lung cancer33;36;37. About 50% of the patients with lung cancer have COPD (Figure 3). This is in line with the studies cited above showing that lung cancer is one of the major causes of death in patients with COPD7;9;38. This risk appears to be greater in patients with mild to moderate disease, than in more severe disease7;9;33;37-39 . In addition, the risk is greater for squamous cell cancer than for adenocarcinoma37 and persists for as many as 20 years after smoking cessation40. In contrast to the exposure-response curve for cardiovascular risk, lung cancer risk gradually increases with increased exposure and becomes proportionally more important at higher total levels of PM2.5 exposure22.
Non-small cell lung carcinoma accounts for 85% of all lung cancer cases in the US and squamous cell carcinoma41, which is most related to COPD39, still represents the most common histological subtype, certainly in men. The origin of squamous lung cancer is complex and subject of intense research. Carcinogenesis in the lung should be seen as a stepwise progression from premalignant alterations in the epithelium (hyperplasia and dysplasia) over the development of carcinoma in situ to cancer. Squamous cell carcinoma results from the accumulation of multiple independent genetic and epigenetic abnormalities, including DNA sequence alterations, copy number changes, promotor hypermethylation and miRNA silencing. These abnormalities result in the activation of oncogenes and the inactivation of tumor suppressor genes, which accumulate in normal histological and premalignant cells where they may persist for years after smoking cessation40;42;43. Lung cancer is identified by its origin, in particularly the first cell type that suffers from oncogenic mutation and uncontrolled cell growth. However, tumors, including lung tumors, are not only clonal expansions of an individual cell but comprise a heterogeneous population of cells. Cancer stem cells (CSC) possess the capacity of self-renewal and multipotent differentiation into a heterogeneous offspring. Epithelial to mesenchymal transition (EMT) is proposed as a mechanism that may attribute stem cell characteristics to well differentiated epithelial cells44.