Unravelling the mechanisms driving multimorbidity in COPD to develop holistic approaches to patient-centred care

H. Burke; T.M.A. Wilkinson

doi:10.1183/16000617.0041-2021

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FIGURE 1
Conceptual diagram of comorbidity and multimorbidity in COPD. GORD: gastro-oesophageal reflux disease.
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FIGURE 2
Drivers, mechanisms and outcomes for multimorbidity in COPD. EVs: extracellular vesicles; GORD: gastro-oesophageal reflux disease.

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TABLE 1

Prevalence of comorbidities in England compared to patients with COPD

	Prevalence in control population^#	Prevalence in COPD	Reference(s)
Osteoporosis/osteopenia	18–22	50–70	[16, 17]
Hypertension	34–41	40–60	[10, 18]
GORD	33	30–60	[19]
Skeletal muscle dysfunction	9	32	[20]
Depression	7–12	25	[21]
Ischaemic heart disease	15	10–23	[22]
Diabetes	6–10	12–13	[10, 23]
Previous stroke	3	10–14	[18, 23]
Arrhythmia	5–11	11–12	[18]
Congestive heart failure	4	5–19	[18, 24]
Obesity	17–32	18–54	[25]

Data are presented as %. GORD: gastro-oesophageal reflux disease. Adapted from [15]. ^#: control population from the same study(ies) as the COPD comorbidity prevalence reported.

TABLE 2

Summary of current and future treatment strategies for multimorbidity in COPD

	Pulmonary effects	Multimorbid effects
Current strategies
Smoking cessation	Reduction in airway inflammation Improves respiratory symptoms and bronchial hyperresponsiveness Prevents accelerated lung decline	Reduction of risk of cardiovascular disease and lung cancer [180]
Exercise and pulmonary rehabilitation	Delays dynamic hyperinflation Reduces functional breathlessness	Increases exercise capacity Improves quality of life Reduces anxiety and depression [181] Increases BMI, skeletal muscle mass and improves osteoporosis [182]
Inhaled corticosteroids	Limited reduction in airway inflammation: decrease in CD8⁺ T-lymphocytes in airway biopsies [183] Reduction in exacerbations, especially in eosinophilic COPD [131] Increased risk of pneumonia, especially in severe disease [184]	Possible reduction in cardiovascular mortality [185] Possible reduction in systemic inflammation (CRP, TNF-α) [86] Improvement in quality of life (in combination with bronchodilator)
Theophylline	Possible increased inspiratory muscle strength [186] Reduction in neutrophilic inflammation [187]	Not known
PDE4 inhibitors, e.g. roflumilast	Reduction in exacerbations and improvement in lung function in patients with chronic bronchitis, FEV₁ <50% and history of frequent exacerbations	Prevention of bone loss and increase in skeletal muscle mass (in a murine model) [188]
Cardiovascular-targeted treatments
Statins	May reduce exacerbations [189]	Reduction in cardiovascular risk [190] Reduction in oxidative stress and inflammation [191]
ACE inhibitors/ARB	Reduction in exacerbations [192] Decrease in hyperinflation [193]	May improve survival (in those with cardiovascular risk)
β-Blockers	Reduction in exacerbations [194]	Reduction in mortality after myocardial infarction [195] and in heart failure [196] Reduction in oxidative stress [197] Improved exercise capacity [198]
Future strategies
Metformin (targeting PI3K-AKT-mTOR pathway)	May improve respiratory symptoms and reduce hospitalisations [199]	Possible reduction in mortality in COPD patients with diabetes [200]
Resveratrol (plant-based antioxidant)	Anti-inflammatory in lung epithelial cells [201]	Possible cardioprotective effects [202]
Losmapimod (p38 MAPK inhibitor)	No effect on respiratory symptoms or lung function, but a trend towards reduction in exacerbations [203]	Not yet determined; possible effect on arterial inflammation
NF-κB inhibitors, e.g. IκB kinase inhibitors	Not yet determined; possible effects on exacerbations given role in activating inflammatory signalling in the COPD lung [204]	Not yet determined; possible effects on skeletal muscle wasting [205], cardiovascular disease, lung cancer, osteoporosis and diabetes [206]
Antioxidants, e.g. Nrf2 activators, NOX4 inhibitors	Not yet determined; possible reduction in inflammation and reversal of corticosteroid resistance	Not yet determined; issues with side-effect profile
Mesenchymal stem cell EVs	Not yet determined; initial trials failed to show benefit [207]	Not yet determined; possibly neuroprotective [208], cardioprotective [209] and anti-inflammatory [210]

PDE4: phosphodiesterase-4; ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blockers; PI3K: phosphatidylinositol 3-kinase; AKT: also known as protein kinase B; mTOR: mechanistic target of rapamycin; MAPK: p38 mitogen-activated protein kinase; IκB: inhibitor of NF-κB; Nrf2: nuclear factor erythroid 2-related factor 2; NOX: NADPH oxidase; EVs: extracellular vesicles; BMI: body mass index; CRP: C-reactive protein; TNF: tumour necrosis factor; FEV₁: forced expiratory volume in 1 s.