Management of chronic obstructive pulmonary disease beyond the lungs

Review

Management of chronic obstructive pulmonary disease beyond the lungs Lowie E G W Vanfleteren, Martijn A Spruit, Emiel F M Wouters, Frits M E Franssen

Chronic obstructive pulmonary disease (COPD) is an umbrella term that covers many clinical subtypes with clearly different pulmonary and extra-pulmonary characteristics, but with persistent airflow limitation in common. This insight has led to the development of a more personalised approach in bronchodilator therapy, prevention of exacerbations, and advanced treatments (such as non-invasive ventilation and lung volume reduction techniques). However, systemic manifestations and comorbidities of COPD also contribute to different clinical phenotypes and warrant an individualised approach as part of integrated disease management. Alterations in bodyweight and composition, from cachexia to obesity, demand specific management. Psychological symptoms are highly prevalent, and thorough diagnosis and treatment are necessary. Moreover, prevention of exacerbations requires interventions beyond the lungs, including treatment of gastro-oesophageal reflux disease, reduction of cardiovascular risks, and management of dyspnoea and anxiety. In this Review, we discuss the management of COPD beyond the respiratory system and propose treatment strategies on the basis of the latest research and best practices.

Introduction Although chronic obstructive pulmonary disease (COPD) is defined by the presence of chronic airflow limitation, it is considered a complex, heterogeneous, and multicomponent disease in which comorbidities and extrapulmonary manifestations have important contributions to disease expression, disease burden, and survival. Thus, a COPD phenotype is not limited to the expression of the pulmonary disease itself. Because different groups of patients with different health status can be identified on the basis of their comorbidity profile1 and specific treatment of comorbidities can alter the clinical course,2 we can rightfully consider these non-pulmonary issues in the phenotypic complexity of patients with COPD.3 The presence of co-occurring chronic non-communicable diseases and other physical and psychological manifestations needs to be recognised in our approach to characterise and manage individual patients with COPD. Although management of comorbidities is now incorporated in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy document,4 a COPD-specific approach needs to be considered. The complex and multiple dimensions of COPD demand a drug regimen that includes not only inhaler therapy but also systemic treatments, which have potential pharmacological cross-effects between the respiratory system and other systemic compartments. Indeed, coexisting diseases are interlinked beyond simple coincidence, and perturbation of the network of comorbidities could possibly be achieved by selecting and treating highly connected comorbidities.5 Therefore, in-depth knowledge of the underlying biology of these connected comorbidities is necessary.6 At the same time, we should also be mindful of the notion of “primum non nocere” (first do no harm) and recommend therapies that have strong proven effectiveness and that have clear benefits over harm. Here, we review published work on the management of COPD beyond the lungs, taking into account the most important COPD-related systemic

manifestations and comorbidities (figure 1), and provide recommendations and expert opinion.

Cardiovascular disease Diagnosis Cardiovascular comorbidities are the most prevalent and have the most serious consequences in patients with COPD, but these comorbidities are also frequently undiagnosed.7–9 For example, results from one study10 showed that up to one in five patients with COPD have undiagnosed left ventricular dysfunction that affects survival. Patients with COPD are exposed to important cardiovascular risk factors—eg, smoking, physical inactivity, an unhealthy diet, and ageing. Abdominal

Lancet Respir Med 2016 Published Online June 2, 2016 http://dx.doi.org/10.1016/ S2213-2600(16)00097-7 Department of Research and Education, CIRO, Horn, Netherlands (L E G W Vanfleteren PhD, M A Spruit PhD, Prof E F M Wouters PhD, F M E Franssen PhD); and Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, Netherlands (L E G W Vanfleteren, Prof E F M Wouters, F M E Franssen) Correspondence to: Dr Lowie E G W Vanfleteren, Department of Research and Education, CIRO, 6085 NM Horn, Netherlands [email protected]

Key messages • Systemic manifestations and comorbidities of COPD contribute to the different clinical phenotypes, and an individualised approach is needed as part of integrated disease management. • A COPD-specific approach for cardiovascular risk management, optimisation of body composition (including osteoporosis), and treatment of anxiety and depression is required. • Patients with COPD often have several comorbidities and use multiple drug therapies. For each drug prescribed, its effects, side-effects, and interactions with other comorbidities and drugs need to be carefully considered. • Identification of biomarkers representing the underlying endotypes that lead to different comorbidity expressions will provide opportunities for treatment development. • Pulmonary rehabilitation is a good example of COPD management beyond the lungs, with a specific focus on patients’ physical condition (both pulmonary and nonpulmonary) and adaptation. This includes the identification of the patient’s goals, comorbidities, disease knowledge, emotions, and behaviour.

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Comorbidities

Treatment strategies Drug treatment*

Osteoporosis Nutritional counselling and modulation*

Muscle wasting

Cardiovascular disease

Self-management*

Underweight and obesity

Physical activity coaching*

Exercise training* Metabolic disorders Anxiety and depression

Psychological counselling*

Figure 1: Management of COPD beyond the lungs *Part of a comprehensive pulmonary rehabilitation programme.

obesity and the metabolic syndrome are highly prevalent in patients with COPD, and are associated with less daily physical activity and an increased cardiovascular risk.11 However, at the same time, the emphysematous underweight COPD phenotype is also associated with arterial stiffness, subclinical atherosclerosis, and endothelial dysfunction.12–14 Indeed, lung volume reduction surgery for emphysema has been shown to improve endothelial dysfunction and lower systemic blood pressure.15 Hence, patients with COPD need to be considered as at high risk for cardiovascular comorbidities, and optimal risk management is necessary. Although guidelines on COPD-specific cardiovascular risk management are absent, all patients with COPD should receive routine cardiovascular check-ups, and risk factors should be addressed accordingly (table 1). Moreover, during COPD exacerbations, the differential diagnosis or presence of concomitant cardiac involvement needs to be considered, and exacerbations might further increase the cardiovascular risk for several reasons—eg, physical inactivity, hypoxia, tachycardia, increase in arterial stiffness, pulmonary hypertension, alterations in cardiac filling, increased platelet activation, and use of high-dose β2 agonists.16

Recommendations Cardiovascular risk assessment Referral to cardiologist for further assessment when indicated Medical history: disproportionate dyspnoea, orthopnoea, nocturia, weight changes, oedema, palpitations, typical exertional ischaemic chest pain (angina pectoris), or leg pain (claudicatio intermittens) Physical examination: irregular heartbeats, murmurs, abnormal breath sounds (crepitations), fluid homoeostasis, or vascular pulsations

Referral to cardiologist for further assessment when indicated

Hypertension

β1 blockers can potentially improve COPD-specific outcomes, but conclusive evidence is lacking; highly selective β1 blockade is preferred, and caution is needed with high doses Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers can be used when hypertension is persistent with the use of β1 blockers, when contraindications for β1 blockers (bronchial hyper-reactivity and bradycardia) are present, or when the patient has insulin resistance, diabetes, or renal insufficiency Consider thiazide diuretics in cases of oedema

ECG* Evidence of previous ischaemia or left ventricular dysfunction

Review medical charts; consider exercise ECG and echocardiography; refer to cardiologist for further assessment

Evidence of right heart distress (eg, p-pulmonale, right axis, RBBB)

Might indicate pulmonary hypertension (if pulmonary hypertension is disproportionate, further assessment is needed); consider echocardiography

Atrial fibrillation or flutter

Consider rhythm control, heart rate control with β1 blockers, and anticoagulation therapy; refer to cardiologist for further assessment

QTc time >450 ms

Important to assess whether the patient is also receiving certain treatments—eg, neomacrolides

Dynamic ECG changes during exercise ECG (ie, CPET)

Refer to cardiologist for further assessment

Venous blood sample Increase in NT-pro BNP

Further echocardiographic assessment; might indicate both left and right heart stress

Increase in troponin-T (on indication)

Useful to differentiate cardiac involvement in COPD exacerbations; might identify patients at increased cardiovascular risk during exacerbations and guide primary prevention

Abnormal blood lipids (LDL, HDL, and triglycerides)

Consider statins for cardiovascular risk management

Echocardiography

Consider when clinically indicated (Table 1 continues on next page)

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Recommendations (Continued from previous page) Body composition assessment Normal bodyweight

Consider DXA for assessment of fat-free mass and osteoporosis

Low bodyweight

Consider DXA for assessment of fat-free mass and osteoporosis; dietary counselling and nutritional supplementation

Obesity

Dietary counselling; consider the obesity paradox in patients with severe COPD; optimal BMI for patients with COPD is not known Roflumilast can be considered in patients with chronic bronchitis and frequent exacerbations, and might improve insulin resistance Assess obesity-related comorbidities

Low muscle mass

Nutritional supplementation (greater gain in bodyweight if combined with exercise or resistance training) Consider anabolic steroids in selected patients with severe refractory muscle depletion or in men with hypogonadism; always use in conjunction with pulmonary rehabilitation; no conclusive evidence exists for effectiveness of anabolic steroids on functional outcomes in patients with COPD

Low bone mineral density or lateral vertebral fractures

Bisphosphonates, calcium supplementation, and vitamin D

Fasting venous blood sample Renal dysfunction

Avoid nephrotoxic drugs; consider angiotensin-converting enzyme inhibitors or angiotensin receptor blockers if hypertension or proteinuria is present; salt restriction

Increased fasting glycaemia

Assess and eventually treat diabetes; glycaemic monitoring during exacerbations; hyperglycaemia might be related to treatment of acute exacerbations

Anaemia

Further assessment when necessary

Vitamin D deficiency

Vitamin D supplementation can potentially reduce COPD exacerbations, but no conclusive evidence exists yet

Dyspnoea assessment (eg, modified MRC questionnaire) and psychological assessment (hospital anxiety and depression questionnaire) Severe dyspnoea

Benzodiazepines or opioids (carefully consider advantages and disadvantages of both drug classes); consider overlap between dyspnoea and anxiety

Anxiety

Benzodiazepines (might be useful but should be used with caution), SSRIs, cognitive behavioural therapy, or pulmonary rehabilitation; refer to psychiatrist for DSM-IV diagnosis and treatment; carefully consider diagnosis of anxiety disorders and underlying causes

Depression

SSRIs (preferred) or tricyclic antidepressants; consider the role of bupropion as a smoking cessation drug; refer to psychiatrist for DSM-IV diagnosis and treatment

Assessment of other relevant comorbidities (medical history, review of charts, radiology, specialist consultancy) Gastro-oesophageal reflux disease

Proton pump inhibitors might prevent acute exacerbations and might offer gastric protection in patients using one or more of the following—aspirin, non-steroidal anti-inflammatory drugs, or corticosteroids (frequent use)

Degenerative joint disease, osteoporotic vertebral fractures, or (chronic) pain

Paracetamol, non-steroidal anti-inflammatory drugs (use caution when the patient also have heart disease or renal disease or when they are taking aspirin or corticosteroids), and opioids (consider potential benefits in patients with dyspnoea)

ECG=electrocardiogram. RBBB=right bundle branch block. CPET=cardiopulmonary exercise testing. NT-pro BNP=N-terminal prohormone of brain natriuretic peptide. DXA=dual-energy x-ray absorptiometry. BMI=body-mass index. MRC=Medical Research Council. SSRIs=selective serotonin reuptake inhibitors. DSM-IV=Diagnostic and Statistical Manual of Mental Disorders fourth edition. *When ECG is normal, it is important to have the record available as a reference to compare future ECG changes.

Table 1: Recommendations for the diagnosis and management of COPD comorbidities

Treatment and prevention For years, caution has been advocated with the prescription of β blockers in patients with COPD because of the concern that β blockers might trigger bronchoconstriction and worsen lung function. Hence, these drugs are underprescribed in patients with COPD, even in those with established cardiovascular disease in whom these drugs are known to be beneficial.2 With the development of agents with extremely high affinity for β1 adrenergic receptors over β2 adrenergic receptors, β1 blockers are well tolerated in most patients.17 However, having COPD still seems to be a reason not to treat patients with these agents, leading to suboptimal cardiovascular management. Results from several observational studies2,18–22 have shown that the use of β blockers is associated with a

reduction in overall mortality, exacerbation frequency, and improved outcomes during and after hospital admission for exacerbations. The additional strain of an exacerbation could trigger and expose underlying but previously unknown undiagnosed cardiac dysfunction.16 However, the pathophysiological mechanisms underlying the possible preventive effect of β1 blockers on exacerbations and their consequences remain speculative (figure 2). Patients often have high resting heart rates and peripheral, cardiac, and neurohumoral sympathetic stress,23 and these symptoms will be accentuated during exacerbations. Resting heart rate is an independent risk factor for all-cause mortality in apparently healthy populations and in those with known cardiac disease or COPD.24 Although β1 blockers are highly selective for the

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β1 receptor, there is always a possibility that these drugs affect the β2 receptor to some extent; therefore, high-dose β2 agonist inhaler therapy might affect the β1 pathway Selective β1 blocker

Phosphodiesterase-4 inhibitor Chronic bronchitis COPD

Improved outcome in cardiovascular disease

Cardioprotective effect during exacerbations?

Frequent exacerbations

Improved lung function, reduced exacerbations

Asthma

Obesity

Insulin resistance

Synergy in metabolic disease?

Underweight

COPD

Well tolerated in most patients with COPD

Caution: blunted bronchodilator response, worsening of lung function

Weight loss, reduce insulin resistance by increasing glucagon-like peptide-1

Caution: further unwanted weight loss

Figure 2: Two examples of drug therapy with potential benefits and harms on outcomes of both COPD and other comorbidities Intended drug effects are shown in green boxes, considerations in orange boxes, potential beneficial effects on comorbidity in blue boxes, and potential harms in red boxes.

NCT02587351

Intervention

Study design

Hypothesis or aim

Metoprolol vs placebo

Metoprolol will reduce the risk of COPD Randomised, parallel-group, exacerbations compared with placebo double-blind phase 3 trial

and further aggravate tachycardia and sympathetic stress. These drugs are considered safe at standard doses in patients with stable COPD,25 but during exacerbations, higher doses of short-acting rescue drugs are likely to be used. The safety of these high doses has not been established in clinical trials. In comorbid cardiorespiratory disease, high β2 agonist use has been associated with increased hospital admissions and mortality related to heart failure.26 Additionally, high-dose β2 agonist therapy has been linked to cardiovascular mortality in COPD exacerbations.27 A simultaneous blockage of the β1 pathway might protect from the adverse events caused by excessive β2 pathway stimulation. However, there is no conclusive evidence yet to prescribe primarily β1 blockers in patients with frequent exacerbations. Randomised controlled trials to further elucidate beneficial effects of β1 blockers in COPD are ongoing, but results are not yet available (table 2). At present, our recommendations are to optimise the use of selective β1 blockers in patients with a history of cardiovascular disease, to continue the use of β1 blockers during exacerbations, and to consider these drugs in the treatment of hypertension in COPD (table 1). In fact, epidemiological data suggested that β blockers might be the therapy of choice to treat hypertension in COPD.18 Nevertheless, β blockers have

Estimated Sponsor completion date

Primary outcome

Study population

Time to first occurrence of an acute COPD exacerbation

1028 patients with April, 2020 moderate to severe COPD

Clinical and Translational Science Institute, University of Minnesota; University of Alabama; US Department of Defense

December, 18 patients with moderate to severe COPD 2015 with sinus rhythm and without asthma, bronchiectasis, unstable angina, and heart failure NYHA III–IV

University of Dundee

NCT01656005 Carvedilol vs bisoprolol

Randomised, crossover, open-label phase 4 trial

Selective and non-selective types of β blockers have different effects on airway resistance

Change from baseline in airway resistance at 5 Hz (R5) using impulse oscillometry

NCT02380053

Randomised, crossover, open-label phase 4 trial

Proof-of-concept study to assess the differential effects of chronic β blockade (celiprolol vs bisoprolol) on cardiopulmonary outcomes at rest and during exercise

10 patients with COPD The difference from baseline in the change in inspiratory capacity from rest to isotime peak (ie, same timepoint during endurance exercise test) between β blocker treatments at 4 weeks

April, 2016

University of Dundee

Randomised, parallel-group, open-label phase 2 trial

The combination of ticagrelor and aspirin is superior to clopidogrel and aspirin in modulation of platelet reactivity, endothelial dysfunction, and inflammation in patients with COPD receiving percutaneous coronary intervention for stable coronary artery disease

Reduction of the rate 40 patients of apoptosis in human umbilical vein endothelial cells incubated with serum from patients enrolled in the study

June, 2016

University Hospital of Ferrara

Celiprolol vs bisoprolol

NCT02519608 Ticagrelor vs clopidogrel

(Table 2 continues on next page)

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Intervention

Study design

Hypothesis or aim

Primary outcome

Study population

Estimated Sponsor completion date

(Continued from previous page) NCT02416102

Losartan

Interventional, nonrandomised, crossover open-label, exploratory trial

Inhibition of transforming growth factor β NPD measurement with losartan in ex-smokers with COPD and in active and passive smokers without COPD will lead to an increase in chloride conductance through calcium-activated chloride channel, as measured by NPD

40 patients with COPD and chronic bronchitis (20 ex-smokers and 20 active smokers)

October, 2017

University of Miami

NCT02093195

Bosentan

Randomised, parallel-group, open-label phase 2 trial

To assess the safety and efficacy of bosentan Frequency of COPD exacerbation in the treatment of severe COPD patients with pulmonary hypertension detected by echocardiography

40 patients with severe to very severe COPD and pulmonary hypertension detected by echocardiography

December, 2015

Fourth Military Medical University

Randomised, parallel-group, double-blind trial

To examine the potential for tadalafil, a phosphodiesterase-5 inhibitor, to improve functional status by decreasing pulmonary hypertension

Change in 6 min walk test

150 patients with moderate to very severe COPD and group 3 pulmonary arterial hypertension

December, 2017

VA Office of Research and Development

To study the effect of inhaled prostacyclin (iloprost) on lung volumes and dynamic hyperinflation

Dynamic hyperinflation during maximal cardiopulmonary exercise test

24 patients with COPD

May, 2016

Louisiana State University Health Sciences Center in New Orleans

NCT01862536 Tadalafil vs placebo

NCT01941225

Inhaled iloprost vs Randomised, crossover, inhaled placebo double-blind phase 2 trial

NCT02429050 Morphine vs placebo

Randomised, parallel-group, double-blind phase 4 trial

To study the effect of oral administration of sustained-release morphine on health-related quality of life, respiratory adverse effects, and functional capacity; to explore whether description and severity of breathlessness are related to a clinically relevant response to morphine; and to analyse the costeffectiveness of sustained-release morphine

Change in COPD assessment test, PaCO2, PaO2, (nighttime) SpO2, PtcCO2, and respiratory rate in 4 weeks

124 patients with COPD with mMRC dyspnoea grade 3 or 4

December, 2018

Maastricht University Medical Center

NCT01718496 Morphine vs placebo

Randomised, crossover, double-blind phase 3 trial

To study the effect of one dose of morphine on dyspnoea and exercise tolerance in patients with COPD

Dyspnoea (sensory intensity and affective responses) and exercise endurance (CPET)

20 patients with severe to very severe COPD and chronic activity-related dyspnoea

August, 2016

McGill University Health Center

NCT02211118

Intranasal Randomised, dexmedetomidine open-label phase 4 trial

Dexmedetomidine might be an alternative to existing drug therapies for breathlessness; dexmedetomidine produces a dose-dependent sedation, anxiolysis, and analgesia without respiratory depression or cognitive dysfunction

Dose-dependent safety and efficacy of intranasal dexmedetomidine

30 patients with severe COPD

October, 2015

Dayton VA Medical Center

NCT02253121

Dapagliflozin plus sliding-scale insulin vs placebo plus sliding-scale insulin

Randomised, parallel-group, double-blind phase 4 trial

To treat glucocorticoid-induced hyperglycaemia due to glucocorticoid pulse therapy in an efficacious, safe, and convenient way

Glucose control: percentage of time that a patient has glycaemia within 3·9–10·0 mmol/L

46 patients with COPD who were admitted to hospital for acute exacerbation, treated with corticosteroids, and with known type 2 diabetes or hyperglycaemia

March, 2016

Slotervaart Hospital

Nonrandomised, parallel-group, open-label efficacy study

To assess the effects of roflumilast on Changes in insulin insulin sensitivity and metabolic parameters sensitivity in pre-diabetic individuals who are overweight or obese

NCT01862029 Roflumilast

50 overweight and obese September, 2016 men and women who had stable weight and diet, good general health, no serious underlying illnesses, and normal or clinically insignificant results (medical histories, laboratory profiles, physical examination, and electrocardiograms)

US National Heart, Lung, and Blood Institute

(Table 2 continues on next page)

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Intervention

Study design

Hypothesis or aim

Primary outcome

Study population

Estimated Sponsor completion date

(Continued from previous page) NCT02363335

Roflumilast vs sitagliptin vs roflumilast plus sitagliptin vs placebo

Randomised, crossover, double-blind phase 1 trial

To investigate whether phosphodiesterases are involved in the regulation of GLP-1 secretion from L cells in human beings

GLP-1 secretion from L cells

100 healthy volunteers

December, 2016

US National Institute on Aging

NCT01745848

Roflumilast

Open-label efficacy phase 4 study

Roflumilast (500 μg once daily) will significantly decrease surrogate markers of bone metabolism and early cardiovascular disease in individuals with moderate to severe airflow obstruction and a chronic bronchitis phenotype

Systemic markers of bone metabolism

20 patients with COPD

March, 2016

University of Pittsburgh

NCT02122627

Vitamin D

Randomised, parallel-group, double-blind trial

To assess the effect of vitamin D supplementation on exacerbation rate in patients with COPD and vitamin D deficiency

Exacerbation rate

240 patients aged 40 years and older with COPD and vitamin D deficiency who have had a COPD exacerbation

March, 2017 VU University Medical Center

NCT02245932

Resveratrol vs placebo

Randomised, parallel-group, placebocontrolled, phase 3 double-blind trial

To investigate the efficacy of resveratrol in modulating metabolism and cardiovascular disease risk profile in overweight patients with COPD

Change from baseline 52 overweight patients with mild to moderate in high-sensitivity COPD systemic inflammation (C-reactive protein) at 12 weeks

October, 2016

Maastricht University Medical Center

NCT02634268 Behavioural lifestyle intervention focused on healthy eating and physical activity vs usual care

The programme will lead to weight loss, Randomised, parallel-group, improved exercise tolerance, and reduced shortness of breath single-blind trial

Bodyweight and 6 min walking distance

1000 patients with COPD April, 2019 who are overweight or obese

Seattle Institute for Biomedical and Clinical Research

NCT02190461 Early postdischarge pulmonary rehabilitation vs conventional rehabilitation

Randomised, parallel-group, open-label phase 3 trial

Early post-discharge pulmonary rehabilitation reduces the number of exacerbations and hospital admissions in patients with COPD

Exacerbation incidence with or without hospital admission

November, 60 patients with moderate to severe COPD 2015 and two or more hospital admissions per year

Fundació Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau

NCT02471235

Randomised, parallel-group, single-blind, open-label trial

Hospital readmissions 136 patients aged To assess whether a short course of 40 years or older with pulmonary rehabilitation programme with COPD exacerbations periodic reinforcement exercise training and phone call reminders would help to increase physical activity and decrease readmissions for exacerbations

Randomised, parallelassignment, open-label trial

A programme of integrated care—including education, individualised action and care plans, motivational interviews, telemonitoring at home, rehabilitation, smoking cessation counselling, and priority access to ambulatory clinics—is effective in reducing hospital admissions in COPD patients with several comorbidities

Short-course outpatient pulmonary rehabilitation programme vs usual care

NCT01648621 Integrated care management vs usual care

The number of emergency department presentations

July, 2018

470 patients with COPD April, 2016 defined by spirometry results at the lower limit of normal, who had two or more comorbidities and at least one hospital admission in the previous 12 months

Chinese University of Hong Kong

Toronto East General Hospital

Studies were identified on ClinicalTrials.gov on Jan 31, 2016. NYHA=New York Heart Association. NPD=nasal potential difference. PaCO2=partial pressure arterial carbon dioxide. PaO2=partial pressure arterial oxygen. SpO2=oxygen saturation. PtcCO2=transcutaneous carbon dioxide. mMRC=modified Medical Research Council. CPET=cardiopulmonary exercise testing. GLP-1=glucagon-like peptide-1.

Table 2: Ongoing studies assessing comorbidities or drugs beyond the lungs in COPD

substantial side-effects and should be used judiciously. Caution is advocated in patients with a primary diagnosis of asthma or COPD with pronounced bronchial hyper-reactivity. Although selective β1 blockers are better tolerated than are non-selective blockers in asthma, they are not risk-free.28 Moreover, 6

in COPD, appropriate dosage is important: normal doses of selective β1 blockers are well tolerated, but high doses might blunt bronchodilator response.29 Results from retrospective cohort studies30–33 in COPD patients with and without overt cardiovascular disease suggested that statins might reduce the risk of

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exacerbations, hospital admissions, cardiovascular events, cancer, lung function decline over time, and even all-cause mortality. For more than a decade, the pleiotropic effects of statins have been discussed as a possible anti-inflammatory treatment that might prevent exacerbations in patients with COPD. However, the Prospective Randomised Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) was stopped in October, 2013, because of futility.34 In this trial, 885 patients with COPD were randomised to receive placebo or simvastatin 40 mg. The study was well designed to show that, in patients who had no guideline indication for statins, pleiotropic effects on lung-specific processes underlying exacerbations in the short term were absent. Hence, so far, there is no pulmonary-centred indication to prescribe statins in patients with COPD. However, this study intentionally included patients with low cardiovascular risk, defined as the absence of a guideline-based indication for statin use as defined by the Adult Treatment Panel (ATP) III criteria. Results from STATCOPE showed that this guideline effectively identifies patients at low cardiovascular risk. Importantly, these results should not distract from the need to improve total morbidity and mortality over the long term in patients with COPD. Although statins were unable to reduce exacerbation rate in patients with low cardiovascular risk, they have an important role in cardiovascular risk management.34 Because cardiovascular injury during exacerbations is common, another urgent issue is whether antiplatelet therapy might be of preventive value. In a prospective study of 1343 patients with COPD who were admitted to hospital with acute exacerbation,35 thrombocytosis (>400 × 10⁹ cells per mm³) at admission was independently associated with increased in-hospital and 1 year all-cause mortality, and antiplatelet therapy was associated with reduced 1 year all-cause mortality after an acute exacerbation of COPD. Although no randomised controlled trial on the role of antiplatelet therapy in COPD has been done, the conduct of these trials has been advocated.36 In view of the increased cardiovascular risk during exacerbations and the increased platelet activation state in COPD, which is further elevated during exacerbations,37 low-dose aspirin potentially has preventive value. However, there is no conclusive evidence yet to advocate this strategy. Finally, although most cardiovascular risk discussed here concerns coronary or left ventricular disease, pulmonary hypertension and right ventricular dysfunction are also common in patients with advanced COPD and have important effects on clinical outcomes.38 However, treatment of pulmonary hypertension and right ventricular dysfunction in patients with COPD has not led to clinically relevant improvements.39 More studies are being done to further elucidate whether the

treatment of pulmonary hypertension (tadalafil, bosentan, and inhaled iloprost) in patients with COPD can improve outcomes (table 2).

Hyperglycaemia and insulin resistance Hyperglycaemia, diabetes, and the metabolic syndrome are commonly present in patients with COPD.1,40 Even in patients with well controlled diabetes, glycaemia might be dysregulated during COPD exacerbations. Indeed, corticosteroid-induced hyperglycaemia is very common during exacerbations.41 An ongoing randomised placebo-controlled trial will assess the effect on glycaemic control of additional treatment with dapagliflozin in patients with diabetes or hyperglycaemia (induced by glucocorticoid pulse therapy) who were admitted to hospital for acute COPD exacerbation (table 2). However, the presence of hyperglycaemia during exacerbations has not been associated with worse outcome,41 and accelerated metformin therapy during exacerbations in COPD patients without diabetes did not result in clinical benefit.42 Nevertheless, accurate glycaemic control might contribute to the maintenance of pulmonary function. Considering the large vascular network and high collagen and elastin composition of the pulmonary system, it is prone to microvascular damage and nonenzymatic glycation in diabetes. Indeed, the presence of diabetes has been shown to adversely affect respiratory function, resulting in a restrictive lung function pattern.43 In a prospective open-label study of the effects of 6 months of metformin therapy in 17 patients with COPD,44 improvements in respiratory symptoms, health status, and inspiratory muscle function were seen. The changes remained significant after correction for small changes in body-mass index (BMI), arguing against confounding by obesity. Prospective trials are needed to assess the role of optimal glycaemic control on COPDspecific outcomes and to study the potential benefits of specific pharmacotherapies aimed at glucose metabolism. In this context, phosphodiesterase-4 inhibitors (eg, roflumilast) are also of interest. Roflumilast has been shown to effectively reduce exacerbations and hospital admissions in patients with chronic bronchitis who have frequent exacerbations.45,46 Weight loss (about 2 kg in the first 6 months of treatment) is a common side-effect of roflumilast. Additionally, roflumilast improves glucose homoeostasis and metabolism in patients with newly diagnosed type 2 diabetes.47 The effects of roflumilast on insulin sensitivity and glucagon-like peptide-1 secretion are being investigated in healthy and pre-diabetic individuals who are overweight and obese (table 2). These results might help to further identify individuals who might benefit in multiple ways—eg, obese COPD patients with insulin resistance, chronic bronchitis, and frequent exacerbations (figure 2).

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Alterations in bodyweight and composition Low bodyweight, which affects 10–20% of patients with COPD,1,48 is associated with increased gas trapping and reduced diffusing capacity, independent of the degree of airflow limitation.49 Moreover, low BMI is related to low exercise capacity and increased mortality risk compared with COPD patients with normal weight.50 Although weight loss was traditionally considered an epiphenomenon of disease progression, results from a longitudinal population-based study51 suggested that the frequency and trajectory of weight loss in patients with COPD are similar to those in elderly individuals with normal lung function. Thus, low BMI might predispose to the onset of chronic airflow limitation or develop early on in the (pre-clinical) course of the disease. However, irrespective of the pathophysiology of low BMI, low bodyweight can be reversed in patients with COPD, and weight gain is associated with decreased mortality risk in patients with severe disease.52 Indeed, results from a meta-analysis53 showed that patients with stable COPD who received nutritional supplementation have a significant increase in bodyweight compared with those receiving usual care, and the effects are especially pronounced in patients who were underweight. The increase in bodyweight is greater if nutritional supplementation is combined with exercise training.53 In addition to low BMI, alterations in body composition are commonly observed in patients with COPD. The prevalence of low fat-free mass (≤15 kg/m² in women or ≤16 kg/m² in men) ranges from 11% in outpatients with moderate to severe COPD48 to 28% in patients referred for pulmonary rehabilitation.1 Importantly, 10–15% of COPD patients with normal weight have low fat-free mass,54 emphasising the importance of assessing body composition in addition to BMI. Because low fat-free mass is associated with reduced muscle strength, poor quality of life, and increased mortality risk, it is an important therapeutic target in COPD. Indeed, nutritional supplementation promotes gain in fat-free mass in malnourished patients with COPD.53 Nutritional supplementation also results in additional increments in 6 min walk distance and health status, measured by the St George’s Respiratory Questionnaire, in poorly nourished patients.53 Several small studies investigated the additional effect of anabolic steroids in COPD, and these were included in a meta-analysis.55 Although weight, fat-free mass, and health status were significantly improved in patients treated with anabolic steroids compared with placebo, no functional improvements were reported.55 Thus, the role of anabolic steroids in the treatment of COPD is considered limited. Nevertheless, specific subgroups (ie, hypogonadal men with COPD) might benefit from specific anabolic treatments (eg, testosterone in combination with resistance training).56 As the worldwide burden of obesity (BMI >30 kg/m²) continues to rise, management of this condition 8

becomes increasingly important in patients with cooccurring COPD. The effects of high fat mass on outcomes in COPD are divergent. Although obesity is associated with increased dyspnoea57 and reduced 6 min walking distance,58 the effect on weight-bearing exercise tolerance is low.59 In fact, the degree of static hyperinflation60 and the prevalence of low fat-free mass and osteoporosis1 are reduced in obese patients with COPD compared with those with normal weight. Furthermore, in patients with severe airflow limitation, mortality risk is decreased in those who are also obese61—an effect referred to as the obesity paradox. By contrast, in patients with mild to moderate COPD, as in the general population, obesity is associated with increased mortality risk. Nevertheless, increasing evidence supports a role for adipose tissue dysfunction in the pathophysiology of systemic inflammation62 and cardiovascular risk63 in COPD. In view of the diverse effects of obesity on outcomes in COPD, the optimal management of this condition remains to be established. The components of weight management in COPD are likely to be similar to those in the general population, including reduction in dietary intake, increase in physical activity, and behavioural change. However, neither the effects of weight reduction on symptoms, exercise capacity, health status, and longterm health risk, nor the optimal BMI have been established for patients with COPD. A large study of behavioural intervention on weight reduction in patients with COPD is ongoing and might provide answers (table 2). In view of the arguments regarding the obesity paradox, we need to consider accepting a degree of excessive bodyweight in patients with severe COPD (table 1). Although the components of pulmonary rehabilitation are similar in obese patients and in those with normal weight,64 some special considerations might be applicable to obese patients, including the prescription of waterbased instead of land-based exercise training,65 restrictedcalorie meal counselling, psychological support, and training with non-invasive positive pressure ventilation.66 Moreover, the effects of pharmacotherapy and bariatric surgery on patient-related outcomes in obese patients with COPD are unknown. Because the use of phosphodiesterase-4 inhibitors was associated with weight loss and specifically loss of fat mass,67 a potential role for these drugs in adiposity management in patients who have frequent COPD exacerbations warrants further investigation.

Osteoporosis Osteoporosis is common in patients with COPD, irrespective of the degree of airflow limitation.1,68 Vertebral fractures often coexist with COPD, which negatively affect pulmonary function, mobility, physical activity, quality of life, and survival, and increase the need for care in institutions.69 In patients with advanced

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osteoporosis, coughing can lead to rib fractures, further impairing sputum clearance and increasing exacerbation risk.70 Hip fractures are a common complication of osteoporosis and are related to mortality; the mortality risk is further increased in patients with COPD, in whom general anaesthesia and delays to surgery are known to be significant modifiable risk factors.71 From a clinical perspective, osteoporosis is associated with the presence of emphysema, low bodyweight, and low fat-free mass.1 The frequent use of oral corticosteroids, physical inactivity, smoking, and older age (>60 years) are additional risk factors for osteoporosis in COPD.72 These clinical associations might help to identify patients who need assessment of bone mineral density (figure 3). Dual-energy x-ray absorptiometry (DXA) provides detailed information on body composition (fat mass and fat-free mass), bone mineral density, and lateral vertebral assessment. Therefore, the use of DXA needs to be considered in the integrated management of COPD and might help to assess the risk of future bone fractures and guide treatment. When no osteoporosis treatment is necessary, reassessment depends on clinical history—eg, ongoing weight loss, frequent corticosteroid treatment for exacerbations, or a history of vertebral (or other) fractures are indicators of high risk. If high risk persists, patients should be re-assessed after 3 years. After 5 years of treatment for osteoporosis, re-assessment is warranted. When DXA shows persistent low T scores and the clinical

T score of –2·5 or below (female), or T score of –2·8 or below (male)

Patients with COPD and additional risk factors: • Age <60 years: 3 criteria • Age 60–70 years: 2 criteria • Age >70 years: 1 criterion Criteria: • BMI <20 kg/m² • Reduced mobility • Fall in previous year • Comorbidity associated with osteoporosis • Previous fracture

Dual-energy x-ray absorptiometry

All patients with frequent corticosteroid use (≥7·5 mg prednisone once daily or equivalent)

T score between –1·0 and –2·5 (female), or T score between –1·0 and –2·8 (male)

risk is still considered high, it is advisable to continue osteoporosis treatment.

Vitamin D deficiency Vitamin D deficiency has been associated with increased susceptibility to upper respiratory infections74 and is very common in patients with COPD.75 However, in a randomised controlled trial,76 vitamin D supplementation in 91 patients with COPD did not reduce the incidence of exacerbations compared with placebo (n=91), although a decreased exacerbation rate was seen in a post-hoc analysis of a subgroup of patients who were severely deficient (serum 25-hydroxyvitamin D concentration <25 nmol/L). Similarly, in a 2015 multicentre trial (n=240),77 no effect was seen of vitamin D supplementation on the primary outcome (time to first exacerbation or respiratory infection), but vitamin D protected against moderate to severe exacerbations in a prespecified subgroup of participants who were vitamin D deficient (serum 25-hydroxyvitamin D concentration <50 nmol/L).77 Hence, the correction of vitamin D deficiency in patients with COPD might be advisable when conclusive evidence is available. More studies to clarify the role of vitamin D in the prevention of exacerbations are underway (table 2).

Gastro-oesophageal reflux disease Gastro-oesophageal reflux disease is commonly reported by patients with COPD. In fact, more than half of patients with severe disease had pathological reflux, as defined by

Treatment, lifestyle advice, follow-up Vertebral fracture*

Vertebral fracture assessment and radiography of thoracolumbar spine

No vertebral fracture (or no imaging)

High risk

Additional fracture risk factors: • Recent fracture and T score of –2·0 or below • Frequent falls • Comorbidities and use of drugs associated with bone loss† If none of these risk factors are present, assess risk with fracture risk assessment tool‡ Low risk T score of –1·0 or above (both sexes)

No treatment, lifestyle advice, follow-up

Figure 3: Algorithm for diagnosis and treatment of osteoporosis in patients with COPD This treatment algorithm is based on the 2011 Dutch guidelines of the Society of Rheumatology on osteoporosis and fracture prevention and adapted to the COPD situation.73 BMI=body-mass index. *Vertebral fracture is defined as height loss >25% by radiology and height loss >40% by vertebral fracture assessment. When height loss by vertebral fracture assessment is between 25% and 40% (grade 2), radiography results are decisive. †Comorbidities include diabetes, rheumatic disease, inflammatory bowel disease, primary hyperparathyroidism, and hyperthyroidism; drugs include aromatase inhibitors, thiazolidinediones, anti-epileptic drugs. ‡The fracture risk assessment tool is available online.

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For the fracture risk assessment tool see http://www.shef.ac.uk/ FRAX/tool.aspx

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pH monitoring, and most of them did not report any reflux symptoms.78 In the ECLIPSE study,79,80 gastrooesophageal reflux disease or heartburn was independently associated with the frequent exacerbation phenotype. Patients with COPD might be particularly vulnerable to reflux and gastro-oesophageal reflux disease as a result of exaggerated intrathoracic pressure shifts, increased frequency of coughing, diaphragmatic flattening, and the use of β2 agonists.81 Proton pump inhibitors are highly effective acidsuppressing agents because of inhibitory effects on the H+/K+ ATPase in gastric parietal epithelial cells. In a prospective 12 month, observer-blind, randomised controlled trial in 100 Japanese patients,82 lansoprazole significantly reduced the risk of developing frequent common colds (≥3 per year) and COPD exacerbations. Of note, patients with a history of gastro-oesophageal reflux disease or ulcer disease were excluded from this study. Moreover, omeprazole and lansoprazole have been reported to protect human gastric epithelial and endothelial cells against oxidative stress. This effect was abrogated in the presence of the haem oxygenase-1 inhibitor ZnBG. Exposure to either proton pump inhibitor resulted in a strong induction of haem oxygenase-1 mRNA and protein expression, and led to an increased activity of this enzyme.83 Hence, anti-viral and anti-inflammatory effects of proton pump inhibitors might be able to prevent COPD exacerbations, but conclusive evidence is still needed.

Psychological symptoms The prevalence of psychological symptoms, including anxiety and depression, in patients with COPD is high. Psychological symptoms are associated with increased symptom burden, poor physical and social functioning, inadequate drug use, frequent visits to the physician, increased number and duration of hospital admissions, and increased mortality risk.84 Thus, adequate diagnosis and treatment of these conditions have the potential to improve overall outcome of the patient with COPD.

Dyspnoea and anxiety Although dyspnoea is a somatic signal of danger, it might be misinterpreted as life threatening (ie, the feeling of not able to breath), leading to anxiety and panic attacks. This in turn might lead to heightened physiological arousal, followed by increased symptoms of anxiety. This vicious circle of dyspnoea and anxiety is common among patients with COPD. Indeed, when the Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV) criteria were applied to inpatients with COPD, 11 of 20 patients had anxiety disorder, of whom eight were diagnosed with panic disorder with agoraphobia.84 Agoraphobia is characterised as the avoidance of situations from which escape might be difficult or in which help is unavailable. 10

Reduction of agoraphobic avoidance by exposure techniques might lead to increased mobility and improved physical activity, which are important goals for patients with COPD. Because the term COPD covers multiple phenotypes, the nature of exacerbations in patients with COPD is clearly different. After all, a COPD exacerbation is still, by consensus, a self-reported increase of respiratory symptoms. Hence, patients are likely to respond differently to different preventive strategies. Strategies to reduce anxiety and dyspnoea probably contribute to exacerbation prevention in individual patients. High dyspnoea sensation is highly related to anxiety and even panic attacks, which in turn might result in uncontrolled breathing patterns, increasing dynamic hyperinflation, and increased dyspnoea.85 This spiral might even result in hospital admission. Dyspnoea management strategies and cognitive behavioural therapy might be helpful.86 Anxiolytics help to control restlessness, anxiety, and panic. Low-dose opioids have been shown to reduce dyspnoea sensation, although not all patients respond to treatment.87 Both anxiolytics and opioids have been shown to be safe in appropriate doses.88 However, the prescriber should recognise that these are powerful drugs with substantial side-effects and should be used with extreme caution. Randomised controlled trials that assess the safety and efficacy of morphine on dyspnoea reduction are underway (table 2).

Depression In a review of the management of depression and suicidality in COPD, Hegerl and Mergl89 acknowledged that there is a risk of under-treatment for depression in patients with COPD, because depressive symptoms can erroneously be conceptualised as an understandable reaction to COPD and not as signs of an independent disorder. At the same time, considerable symptom overlap exists between COPD and major depression, leading to the risk of over-diagnosis. Thus, a full diagnosis is warranted before any intervention is initiated. A validated anxiety and depression questionnaire might be useful to identify patients at risk.90 The hospital anxiety and depression questionnaire is commonly used in pulmonary rehabilitation, and pulmonary rehabilitation can improve symptoms, as measured with the hospital anxiety and depression score.91 For a definite diagnosis, criteria according to the DSM-IV need to be considered, but symptoms that might be sufficiently explained by COPD (eg, sleep problems) should not be used additionally as a symptom for diagnosing comorbid major depression.89 The efficacy of cognitive behavioural therapy has been shown in patients with COPD in many studies.92 Because the efficacy of pharmacotherapy for depression was not specifically studied in patients with COPD, antidepressants are assumed to be equally effective in these patients as they are in individuals without

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COPD.89 Because of the less problematic side-effect profile and the safety in overdose, selective serotonin reuptake inhibitors should be preferred over tricyclic antidepressants. However, the specific situation of individual patients who need to quit smoking as the first important step in their disease management also needs to be considered. The high prevalence of depressive symptoms among smokers with COPD, and that nicotine might have antidepressant effects and regulate mood, was the rationale to study antidepressants as smoking cessation drugs. Bupropion has been associated with improved smoking abstinence not only in general smokers but also in smokers with diagnosed depression, in whom this might be the therapy of choice among smoking cessation drugs.93

COPD (emphysema)

Obesity Insulin resistance Osteoporosis

Arterial stiffness

COPD (chronic bronchitis)

Dyslipidemia

Atherosclerosis

Underweight

Muscle wasting

Exposure to environmental factors

Endotype 2

Endotype 1

Intervention 2

Intervention 1

Other comorbidities Other prevalent comorbidities in patients with COPD include metabolic comorbidities, anaemia, renal insufficiency, obstructive sleep apnoea, degenerative joint disease, chronic pain, and altered fluid homoeostasis. Although these comorbidities are important, we will not discuss them all in detail in this Review. Of note, we did consider, for example, lung cancer and pulmonary embolism as comorbidities that are not beyond the lungs.

Pulmonary rehabilitation Pulmonary rehabilitation is a comprehensive intervention designed to improve the physical and psychological condition of people with chronic respiratory disease and to promote the long-term adherence to health-enhancing behaviours, by providing patienttailored therapies that include, but are not limited to, exercise training, education, and behavioural change by an interdisciplinary team of health-care professionals.66 Compared with usual care, pulmonary rehabilitation has been shown to be effective in increasing exercise performance, reducing breathlessness, reducing the number of hospital admissions, and improving recovery after hospital admission for an exacerbation in patients with COPD.66 Moreover, self-efficacy improves following pulmonary rehabilitation, which seems necessary to change to a more active lifestyle, with increased physical activity, in patients with COPD.94 Importantly, patients referred to pulmonary rehabilitation often have several comorbidities, but these do not prevent them from benefiting from this intervention.95 Pulmonary rehabilitation even has the potential to improve or even reverse certain comorbidities. Indeed, a significant and clinically relevant reduction in symptoms of anxiety and depression has been reported following pulmonary rehabilitation, particularly in patients who had high anxiety or depression at the start of the programme.96 Additionally, pulmonary rehabilitation can also increase

Endotype X

Figure 4: Constellations of comorbidities and theoretical underlying endotypes in COPD Distinct pathophysiological mechanisms (ie, endotypes) might underlie the occurrence of groups of comorbidities in patients with COPD. Specific interventions targeting the endotype might affect different comorbid expressions.

fat-free mass.97 By contrast, the effects of pulmonary rehabilitation on cardiovascular risk factors (eg, arterial stiffness) in patients with COPD vary between trials and warrant further investigation.98,99 Pulmonary rehabilitation should be part of the integrated care of patients with COPD (and comorbidities) who, despite otherwise optimal medical treatment, still experience daily symptoms and limitations.66 Even though the effects of pulmonary rehabilitation on daily symptoms, exercise performance, and health status seem indisputable, more trials are being done to gain insights into its effectiveness (table 2).

Towards endotype-driven interventions for comorbidities Comorbidities can be considered as treatable traits within the complex COPD syndrome.100 Potential beneficial cross-effects of comorbidity-specific treatment might exist for individual patients or certain phenotypes. For example, β blockers prescribed for the treatment of cardiovascular disease potentially have beneficial effects during COPD exacerbations (figure 2). By contrast, roflumilast, prescribed to reduce exacerbations and improve lung function in patients with frequent exacerbations and chronic bronchitis, might help obese patients to lose weight and improve insulin resistance by modulating the release of the incretin glucagon-like peptide 1.47 These cross-effects suggest common pathophysiological mechanisms for the different disease expressions and require further investigation.

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Search strategy and selection criteria We searched PubMed for articles published from Jan 1, 1990, to Jan 31, 2016, using the term “COPD” combined with the following individual search terms: “comorbidity”, “cardiovascular”, “underweight”, “nutrition”, “obesity”, “osteoporosis”, “bone mineral density”, “body composition”, “fat-free mass”, “muscle wasting”, “anxiety”, “depression”, “beta blocker”, “statin”, “anti aggregants”, “metformin”, “reflux disease”, “dyspnea management”, “exacerbation”, “roflumilast”, and “polypharmacy”. Articles from these searches and relevant references cited therein were reviewed. Articles published in English, French, and German were included.

Indeed, the co-occurrence of different comorbidities in COPD is not random but seem to cluster in subgroups.1 Some of these groups of comorbidities have been repeatedly recognised in association and might even be characteristic for specific COPD phenotypes in which the pulmonary phenotype might also be different.101 Obesity, insulin resistance, and different disease expressions of atherosclerosis have been repeatedly associated with less severe COPD,1,102 whereas low bodyweight, muscle wasting, osteoporosis, and arterial stiffness have been frequently linked to the emphysematic phenotype.14,103 Therefore, efforts to understand the biology of clinical phenotypes of COPD characterised by specific constellations of comorbidities could lead to the identification of specific endotypes6— ie, subtypes of a clinical disorder defined by a distinct pathophysiological mechanism (figure 4).1,104 As described by Woodruff and colleagues6 in 2015, linking of endotypes to clinical phenotypes and to endotypespecific biomarkers will be crucial in the identification of patients who might respond to endotype-directed drug treatments. Given the different networks of comorbidities involved in COPD, some of these endotypes will most probably not be specific to a particular organ or disease, and interventions might have benefits across a disease network.

Conclusion COPD is a complex syndrome. Apart from a detailed assessment of the pulmonary manifestations and their differential treatment, several extra-pulmonary features and comorbidities need to be considered in the individualised management of patients. A detailed assessment of cardiovascular risk factors and body composition, and an active approach towards associated physical and psychosocial comorbidities, might require specific management strategies. Also, optimal (preventive) strategies to reduce comorbid risk might reduce exacerbation risk. Additionally, because the treatment of patients with COPD extends beyond pulmonary-specific drugs, both adverse and synergic interactions and side-effects need to be considered. 12

Adherence to guidelines for individual chronic diseases might lead to complex drug regimens in patients with multiple comorbidities, and thus potential cumulative side-effects, interactions, and difficulties with compliance. In such situations, it might be challenging for clinicians to optimise treatment in individuals, and priorities need to be set. In the future, biomarkerdriven identification of underlying endotypes that might lead to different comorbidity expressions might provide opportunities for treatment. After all, we are not treating single-organ systems, but the human being as a whole. In this Review, we summarised how to assess and approach the most important comorbidities in patients with COPD, and we believe that this knowledge will improve disease management. However, a dedicated chest physician is not expected to keep all the diseases of the patient in his or her portfolio, and we would advise the physician to closely collaborate with and refer patients to other specialists, psychologists, psychiatrists, physiotherapists, and pulmonary rehabilitation centres. Only in a multidisciplinary and interdisciplinary way can the complexities of a patient with COPD be appropriately addressed. Contributors All authors conceived and designed the Review. LEGWV, MAS, and FMEF drafted the manuscript. All authors contributed to the Review for important intellectual content, critically revised the manuscript, and gave final approval of this version to be published. Declaration of interests We declare no competing interests. Acknowledgments We thank Fiona Cleutjens for her help in designing the figures. References 1 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: 728–35. 2 Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med 1998; 339: 489–97. 3 Han MK, Agusti A, Calverley PM, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med 2010; 182: 598–604. 4 Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013; 187: 347–65. 5 Divo MJ, Casanova C, Marin JM, et al. COPD comorbidities network. Eur Respir J 2015; 46: 640–50. 6 Woodruff PG, Agusti A, Roche N, Singh D, Martinez FJ. Current concepts in targeting chronic obstructive pulmonary disease pharmacotherapy: making progress towards personalised management. Lancet 2015; 385: 1789–98. 7 Triest FJ, Franssen FM, Spruit MA, Groenen MT, Wouters EF, Vanfleteren LE. Poor agreement between chart-based and objectively identified comorbidities of COPD. Eur Respir J 2015; 46: 1492–95. 8 Freixa X, Portillo K, Pare C, et al. Echocardiographic abnormalities in patients with COPD at their first hospital admission. Eur Respir J 2013; 41: 784–91. 9 Vanfleteren LE, Franssen FM, Uszko-Lencer NH, et al. Frequency and relevance of ischemic electrocardiographic findings in patients with chronic obstructive pulmonary disease. Am J Cardiol 2011; 108: 1669–74.

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