European Respiratory Society
COPD and Comorbidity

COPD is responsible for considerable morbidity and mortality, and its course is complicated by co-existing comorbidities that worsen prognosis. Understanding the importance of comorbidity and multiple comorbidities in COPD is important in patient assessment and management planning. This Monograph is the first comprehensive collection of up-to-date articles on COPD comorbidity. It includes chapters on epidemiology, cardiovascular disease, diabetes, psychological disease and infection, and covers the importance of including comorbidity in COPD treatment guidelines, as well as the ways in which comorbidity influences clinical COPD management. This Monograph will be of interest to clinicians, healthcare professionals, and those researching this important area.

  • European Respiratory Society Monographs
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  2. Page vii
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  4. Page 1
    Correspondence: D.M. Mannino, Dept of Preventive Medicine and Environmental Health, University of Kentucky, 111 Washington Ave, Lexington, KY 40536, USA. Email:

    COPD, once thought only to be a disease of the lungs, is now established as a common complex multisystem disease with multiple comorbidities that contribute to symptoms, exacerbations, hospital admissions and mortality. The most notable of these comorbidities include cardiac and cerebrovascular disease, diabetes, hypertension, asthma, pneumonia and depression. Estimation of the prevalence of COPD, as well as its comorbidities, is difficult because of the variability in definitions and methods used. However, recent large epidemiological studies have helped us to understand better the prevalence and effects of COPD comorbidities. The pathogenesis behind many of these comorbidities remains a focus of active investigation. Successful management of COPD comorbidities is central to improving overall outcomes in COPD.

  5. Page 13
    Correspondence: P.J. Barnes, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street, London SW3 6LY, UK. Email:

    COPD is associated with chronic inflammation predominantly affecting the lung parenchyma and peripheral airways, which results in largely irreversible and progressive airflow limitation. This inflammation is characterised by increased numbers of alveolar macrophages, neutrophils and T-lymphocytes (predominantly T-cytotoxic type 1, T-helper (Th) type 1 and Th17 cells) that are recruited from the circulation. These cells and structural cells, including epithelial and endothelial cells and fibroblasts, secrete a variety of pro-inflammatory mediators, including cytokines, chemokines, growth factors and lipid mediators. Oxidative stress plays a key role in driving this inflammation, even in ex-smokers, and may result in activation of the pro-inflammatory transcription factor nuclear factor-κB, impaired antiprotease defences, DNA damage, cellular senescence, generation of autoantibodies and corticosteroid resistance though inactivation of histone deacetylase-2. The peripheral inflammation spills over into the circulation, resulting in systemic inflammation that may worsen comorbidities, such as cardiovascular diseases, diabetes and osteoporosis. Treatment of pulmonary inflammation, either by inhaled or oral anti-inflammatory therapies, may therefore have beneficial effects not only on the lung disease but also on associated comorbidities.

  6. Page 28
    Correspondence: W. MacNee, UoE/MRC Centre for Inflammation Research, Queen′s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. Email:

    Cardiovascular disease is common in COPD patients and is associated with poor clinical outcome. These conditions may share common pathogenic mechanisms. Cardiovascular disease should be actively sought, assessed and treated in COPD patients; this may improve clinical outcome in these patients. Prospective studies are needed to determine whether the use of cardiovascular drugs is a useful treatment in COPD patients.

  7. Page 50
    Correspondence: F.H. Rutten, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box 85060, Stratenum 6.101, 3508 AB Utrecht, The Netherlands. Email:

    Heart failure is common in COPD; however, it is often unrecognised. Tobacco smoking is an important cause of COPD and, indirectly, of heart failure. Heart failure and COPD share common pathways, including systemic inflammation, activation of the neurohumoral system and metabolic modulation resulting in muscle wasting and cachexia. Heart failure is an independent predictor of mortality in COPD.

    The left ventricle is mainly affected in heart failure, as well as in patients with heart failure and concurrent COPD. Diagnosing heart failure in the presence of COPD is difficult because of an overlap in symptoms and signs.

    Natriuretic peptides are useful for selecting COPD patients for echocardiography, which is the cornerstone for diagnosing heart failure. Therapy of heart failure in patients with COPD is, in principle, the same as in those without COPD. In patients with COPD and heart failure β2-agonists can be combined with cardioselective β-blockers, but anti-cholinergics seem to be a safer option. Observational data suggest that cardioselective β-blockers and statins could reduce the risk of mortality and exacerbations of COPD. However, confirmation with randomised controlled trials is required.

  8. Page 64
    Correspondence: R. Singh, Centre for Respiratory Medicine, University College London Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. Email:

    COPD is a complex, multidimensional disease with both pulmonary and extrapulmonary comorbidities playing a significant role in the natural history of the disease. Airway infections play a pivotal part in the effects of comorbidities in patients with COPD. Infections may act either directly, worsening the underlying airway inflammation, or indirectly, amplifying the effects of comorbidities through acute exacerbations, lower airway bacterial colonisation, systemic inflammation and cardiovascular manifestations.

    Patients with COPD are at a higher risk of pneumonia and have worse outcomes than patients without COPD, and the risk appears further increased by the use of inhaled corticosteroids (ICS). Similarly, the risk of atypical infections, such as non-tuberculous mycobacteria and Aspergillus spp., may be increased with ICS use. Repeated infections lead to a vicious circle of inflammation, with the risk of subsequent bronchiectasis. Novel treatments are urgently required to improve the far-reaching consequences of this important disease.

  9. Page 80
    Correspondence: E.P.A. Rutten, Program Development Centre, CIRO+, Hornerheide 1, 6085 NM Horn, The Netherlands. Email:

    With regard to the systemic complexity of COPD, differences in body composition are among the most extensively investigated. As such, malnutrition has been widely studied in relation to COPD, and contributes to a decreased performance in addition to worse prognosis. Patients with COPD have higher prevalence of malnutrition compared to non-COPD subjects, and several risk factors have been identified. However, future research should focus on the pathophysiology of the development of malnutrition in COPD, as recent findings show that the progressive decline of lean mass is not disease specific per se. Furthermore, obesity in COPD is increasing as there might be a complex inter-relationship between the adipose tissue and impaired oxygen availability. However, the impact of obesity on exercise capacity in COPD is dependent on the type of exercise, with obesity being associated with decreased tolerance to weight-bearing exercise while having beneficial effects on dynamic ventilatory mechanics during weight-supported exercise. In contrast to early stage COPD, obesity seems to protect against mortality in patients with severe disease. Treatment of malnutrition and obesity in COPD should be multidisciplinary, as is included in a pulmonary rehabilitation programme.

  10. Page 93
    Correspondence: E.A.P.M. Romme, Dept of Respiratory Medicine, Catharina Hospital, P.O. Box 1350, 5602 ZA Eindhoven, The Netherlands. Email:

    COPD is, in addition to progressive airflow obstruction, characterised by extrapulmonary manifestations that contribute to the disease severity in individual patients. Osteoporosis is recognised as one such extrapulmonary manifestation, since the prevalence of osteoporosis is higher in COPD patients than in control subjects matched for age and sex. Osteoporosis is a skeletal disease characterised by low bone mineral density or micro-architectural deterioration, resulting in increased risk of fracture. The high prevalence of osteoporosis in COPD is probably due to common risk factors such as advanced age and smoking, and to COPD-specific risk factors such as systemic inflammation and the use of corticosteroids. Interventions against common risk factors, like smoking cessation, exercise and healthy diet, might reduce the risk of fracture in patients with osteoporosis. In addition to these lifestyle guidelines, pharmacological treatment with calcium and vitamin D supplementation and antiresorptive treatment (e.g. bisphosphonates) have been indicated to prevent fractures in patients with osteoporosis.

  11. Page 105
    Correspondence: J.R. Hurst, Academic Unit of Respiratory Medicine, UCL, Hampstead Campus, London, NW3 2PF, UK. Email:

    Gastro-oesophageal reflux (GOR) and GOR disease (GORD) are common conditions that appear more prevalent in patients with COPD than control subjects. This chapter reviews the epidemiology and potential mechanisms of such associations, explores the impact of GORD on COPD and, in particular, on COPD exacerbations, and outlines the evidence that intervention for GORD may impact on COPD outcomes.

  12. Page 117
    Correspondence: E.H. Baker, Mailpoint J1A, Ist Floor Jenner Wing, Division of Biomedical Sciences, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK. Email:

    Metabolic syndrome is a complex set of interlinked metabolic abnormalities, strongly associated with premature death from cardiovascular disease. Metabolic syndrome increases the risk of type 2 diabetes mellitus, with insulin resistance being central to the pathophysiology of both conditions.

    People with COPD have multiple risk factors predisposing to metabolic syndrome and diabetes. They have an increased risk of obesity, tend to be sedentary, have increased inflammation and oxidative stress and are treated with corticosteroids. Diabetes mellitus and metabolic syndrome are around 1.5-times more common in people with COPD than in the general population.

    Identification and treatment of metabolic syndrome and diabetes mellitus is important in all populations to reduce the lifetime risk of cardiovascular disease. However, in COPD patients, treatment of diabetes may also reduce pulmonary infection and exacerbations. Reversal of insulin resistance may reduce inflammation and skeletal muscle decline. Treatment strategies include exercise, dietary modification, weight loss and insulin-sensitising and lipid-lowering drugs.

  13. Page 135
    Correspondence: W.T. McNicholas, Pulmonary and Sleep Disorders Unit, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland. Email:

    COPD and obstructive sleep apnoea syndrome (OSAS) represent two of the most prevalent chronic respiratory disorders, and cardiovascular diseases are major comorbidities in both. Coexistence of both disorders (known as “overlap syndrome”) has been estimated to occur in 1% of the general adult population, and overlap syndrome patients have worse nocturnal hypoxaemia and hypercapnia than COPD and OSAS patients alone. The severity of obstructive ventilatory impairment and hyperinflation, especially the inspiratory capacity (IC) to total lung capacity (TLC) ratio, correlates with the severity of sleep-related breathing disturbances. Early treatment with continuous positive airway pressure (CPAP) improves survival, reduces hospitalisation and pulmonary hypertension, and also reduces hypoxaemia. Evidence of systemic inflammation and oxidative stress in COPD and sleep apnoea provides insight into potential interactions between both disorders, which may predispose to cardiovascular disease. Long-term outcome studies of overlap patients currently underway should provide further evidence of the clinical significance of overlap syndrome. Studies of overlap syndrome patients at a clinical, physiological and molecular level should provide insight into disease mechanisms and consequences of COPD and OSAS, in addition to identifying potential relationships with cardiovascular disease.

  14. Page 144
    Correspondence: P.A. Frith, Dept of Respiratory Medicine, Repatriation General Hospital, 216 Daws Road, Daw Park, SA 5041, Australia. Email:

    Depression and anxiety are prevalent comorbidities in COPD and often appear together. Numerous theoretical models have been proposed to explain this relationship, with most suggesting bidirectional and complex pathways. Mental health assessment in COPD remains too infrequent and should be integrated into standard practice. Appropriate use of mental health screening tools, diagnostic resources and referral pathways should be implemented for optimal management. There is evidence that depression and anxiety in COPD negatively impacts on important health outcomes, such as COPD symptom burden, physical function, health-related quality of life, adherence with recommended treatments and mortality whilst increasing disability, exacerbation rates, hospitalisations and length of stay. Treatment options for managing depression and anxiety in COPD are less frequently documented. Whilst some evidence exists supporting the efficacy of pulmonary rehabilitation, pharmacological therapy, cognitive behavioural therapy, self-management programmes, relaxation and palliative care interventions in managing depression and anxiety in COPD, there remains a paucity of high-quality studies in the field consequently limiting integration into evidence-based clinical guidelines.

  15. Page 164
    Correspondence: T. Troosters, Respiratory Rehabilitation and Respiratory Division, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. Email:

    Skeletal muscle dysfunction is an important and independent predictor of morbidity and mortality in patients with chronic disease, including COPD. Management of skeletal muscle abnormalities starts with their detection in clinical practice. This can be performed relatively easily using maximum voluntary strength and/or endurance testing. Other techniques exist for the research setting. Prevention of skeletal muscle dysfunction starts in early disease by maintaining weight-bearing physical activity. Once skeletal muscle dysfunction is present, exercise training is the most effective way towards restoration. Pharmacotherapy is in its infancy and for most pharmacological interventions that may potentially enhance muscle function, it has been shown that they work only (or better) when administered in conjunction with an exercise stimulus. Depending on the action of the drug, such programmes may be geared towards resistance or endurance training. Large studies on pharmacological interventions in patients with muscle dysfunction and COPD are, unfortunately, still missing.

  16. Page 174
    Correspondence: S. Spiro, 66 Grange Gardens, Pinner, Middlesex, HA5 5QF, UK. Email:

    COPD and lung cancer are the commonest burdens to many health services throughout the world and, as a consequence, much has been learnt of their interdependence, epidemiology and optimal management. COPD and lung cancer are strongly associated and coexist in a large number of patients. Smoking is still a major public health issue and remains the causal factor for the majority of cases of COPD and lung cancer. Treating lung cancer patients with severe COPD is a clinical challenge for thoracic physicians and warrants a multidisciplinary team approach. In this chapter, we discuss the epidemiological overlap of those two diseases, address the special features of patient management when these two conditions coexist and consider the common underlying link between them.

  17. Page 189
    Correspondence: S.D. Nathan, Advanced Lung Disease and Transplant Program, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA, 22042, USA. Email:

    Pulmonary hypertension (PH) commonly complicates COPD, with an estimated prevalence of 20–63%. Most PH in COPD is mild-to-moderate in severity, although a small proportion of patients develop PH “out of proportion” to their degree of airflow obstruction. The development of PH is associated with worsened functional status and decreased survival. The pathogenesis of COPD-associated PH is incompletely understood but is believed to result from a complex interplay of inflammation, endothelial dysfunction and vascular remodelling due to hypoxia and cigarette smoke, mechanical factors resulting from air-trapping, and host genetic factors. Physical examination, ECG and radiographic findings may be suggestive of PH but are nonspecific. Echocardiography is useful as a screening tool for PH but may over- or underestimate pulmonary pressures. Right heart catheterisation remains the gold standard for diagnosis. Treatment is focused on smoking cessation, optimal therapy of COPD and supplemental oxygen. There is interest in vasodilator therapy for COPD-associated PH, particularly for those with out-of-proportion PH; however, this approach requires further evaluation in clinical trials.

  18. Page 206
    Correspondence: P.K. MacCallum, The Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK. Email:

    Evidence has emerged over the past decade whereby COPD is characterised by changes in molecular markers that are consistent with a systemic inflammatory and prothrombotic state. These changes may in part explain the increasingly recognised associations between COPD and ischaemic heart disease, ischaemic stroke and venous thromboembolism, these clinical manifestations resulting from the pathological process of thrombosis that are collectively the leading causes of death worldwide. Alterations in these markers become more pronounced at the time of acute exacerbations, which are themselves associated with further increases in cardiovascular disease risk. Therefore, COPD provides an informative clinical model to study associations between inflammation, infection and thrombosis. Clinicians need to bear in mind the associations of COPD with both arterial and venous thrombotic disorders and adapt existing strategies for the prevention of such outcomes in their patients.

  19. Page 217
    Correspondence: P.S. Bakke, Institute of Medicine, University of Bergen, Postbox 7804, N-5020 Bergen, Norway. Email:

    Altogether, nine international guidelines on the management of COPD published between 2004 and 2012 were reviewed for their focus on comorbidities. The guidelines differed greatly in their coverage of comorbidities. This related to the number of times the topic was mentioned, in what aspects of COPD management comorbidity were addressed, what type of comorbidities were considered and, finally, what was actually stated about the various comorbidities. There was no time trend in the quantitative and qualitative content of comorbidities in the guidelines. The guideline with the highest coverage of comorbidities was that of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The increasing knowledge of the significance of comorbidities in COPD is likely to be reflected in an enhanced focus on this aspect in future COPD guidelines.