Review
Chronic obstructive pulmonary disease and comorbidities

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Summary

Results of epidemiological studies have shown that chronic obstructive pulmonary disease (COPD) is frequently associated with comorbidities, the most serious and prevalent 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 ageing contribute to this association. No convincing evidence has been provided to suggest that treatment of COPD would reduce comorbidities, although some indirect indications are available. Clear evidence that treatment of comorbidities improves COPD is also lacking, although observational studies would suggest such an effect for statins, β blockers, and angiotensin-converting enzyme blockers and receptor antagonists. Large-scale prospective studies are needed. Reduction of common risk factors seems to be the most powerful approach to reduce comorbidities. Whether reduction of so-called spill-over of local inflammation from the lungs or systemic inflammation with inhaled or systemic anti-inflammatory drugs, respectively, would also reduce COPD-related comorbidities is doubtful.

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive debilitating disease with high prevalence. It is the fourth most prevalent cause of death and is responsible for very high expenditures in the health-care system. Global economic costs generated by COPD amount to US$2·1 trillion and are expected to increase to $4·8 trillion by 2030.1 A considerable proportion of these costs is due to the fact that this is a complex disease associated with several serious comorbidities.2

Many comorbidities are associated with COPD, and those for which there are the most data include cardiovascular and cerebrovascular disease, lung cancer, diabetes, muscle weakness, osteoporosis, and anxiety and depression. A randomly selected sample of 1522 patients who were enrolled in a health maintenance organisation in 1997, had on average 3·7 comorbid disorders compared with 1·8 in controls.3 These comorbidities contribute substantially to reduced health status, increased health-care utilisation, all-cause hospital admission, and mortality.4, 5 In fact, patients with COPD are more likely to die from comorbidities than from the disease itself. In a well-designed study in which a panel of senior physicians critically studied and adjudicated the causes of death in patients with COPD, only 40% of deaths were definitely or probably related to COPD, whereas 50% were unrelated to COPD, and 9% were unknown.6 A third of the deaths were due to cardiovascular disease.

We will briefly review the evidence for a link between COPD and the major comorbidities of the disease, with a focus on the mechanisms of their association with COPD, and discuss the implications of these links to the treatment of COPD. We only address the major comorbidities, for which mechanistic links with COPD have recently been studied.

Section snippets

Cardiovascular disease

Cardiovascular disease is not a clearly defined disorder. It usually encompasses ischaemic heart disease, congestive heart failure, pulmonary vascular disease, coronary artery disease, peripheral vascular disease, and stroke and transient ischaemic attack. It might also include biomarkers of disease such as lipid abnormalities or inflammatory markers of disease. This section will mainly focus on ischaemic heart disease, because recent mechanistic work has focused on this area.

The association of

Lung cancer

COPD is an independent risk factor for the development of lung cancer and is associated with a lung cancer risk that is two to six times that of smokers without COPD.34, 35, 36, 37, 38 Reduced FEV1 was shown to increase the risk of incident lung cancer independently of smoking history.37 Moreover, COPD was associated with lung cancer in never-smokers;36 hence, the association is not solely due to smoking. Airflow obstruction and emphysema were also shown to be independent risk factors for lung

Osteoporosis, muscle weakness, and cachexia

A third group of comorbidities includes muscle, fat, and bone wasting (figure 5). These changes in body composition cluster together and associate with emphysema or so-called wasting of the lung.66 Sin and colleagues67 used the data from NHANES III to show that airflow obstruction was independently associated with reduced bone mineral density. Prevalence of osteoporosis increased as the severity of airflow obstruction increased. In women with severe COPD, 33% had osteoporosis and nearly all had

Comorbidity and ageing

Ageing is associated with an increased incidence of non-communicable diseases including cardiovascular disease, type 2 diabetes, osteoporosis, cancer, and COPD.94 The cellular equivalent to physiological ageing is senescence.95 Replicative senescence refers to telomere shortening, which, at a specific length, induces stress signals that lead to cell cycle arrest. However, external stressors such as oxidative stress might also induce premature senescence. One implication of senescence is that

Treatment of comorbidities

Comorbidities should be detected in the medical follow-up scheme for patients with COPD, but no clear guidelines on how and when to screen for comorbidities are available. To the best of our knowledge, specific randomised controlled studies into the treatment of comorbidities in patients prospectively identified as having COPD have not yet been done. Nevertheless, common sense suggests that comorbidities should be treated in patients with COPD with proven treatment regimens. Detection and

Search strategy and selection criteria

We searched the Cochrane Library, PubMed, and Embase for papers published between 2008 and 2012 with the terms “COPD and comorbidities”, “COPD and cardiovascular disease”, “COPD and lung cancer”, “COPD and osteoporosis”, “COPD and muscle weakness”, “COPD and statins”, “COPD and angiotensin II converting enzyme inhibitors”, “COPD and angiotensin receptor blockers”, and “lung cancer and statins”. We also searched the reference lists of identified articles for further relevant papers, and we

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