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

H. Burke, T.M.A. Wilkinson
European Respiratory Review 2021 30: 210041; DOI: 10.1183/16000617.0041-2021
H. Burke
1School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
2University Hospitals Southampton NHS Foundation Trust, Southampton, UK
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  • For correspondence: H.Burke@soton.ac.uk
T.M.A. Wilkinson
1School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
2University Hospitals Southampton NHS Foundation Trust, Southampton, UK
3NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
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  • FIGURE 1
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    FIGURE 1

    Conceptual diagram of comorbidity and multimorbidity in COPD. GORD: gastro-oesophageal reflux disease.

  • FIGURE 2
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    FIGURE 2

    Drivers, mechanisms and outcomes for multimorbidity in COPD. EVs: extracellular vesicles; GORD: gastro-oesophageal reflux disease.

Tables

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  • TABLE 1

    Prevalence of comorbidities in England compared to patients with COPD

    Prevalence in control population#Prevalence in COPDReference(s)
    Osteoporosis/osteopenia18–2250–70[16, 17]
    Hypertension34–4140–60[10, 18]
    GORD3330–60[19]
    Skeletal muscle dysfunction932[20]
    Depression7–1225[21]
    Ischaemic heart disease1510–23[22]
    Diabetes6–1012–13[10, 23]
    Previous stroke310–14[18, 23]
    Arrhythmia5–1111–12[18]
    Congestive heart failure45–19[18, 24]
    Obesity17–3218–54[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 effectsMultimorbid effects
      Current strategies
       Smoking cessationReduction 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  rehabilitationDelays 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 corticosteroidsLimited 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)
       TheophyllinePossible increased inspiratory muscle strength [186]
      Reduction in neutrophilic inflammation [187]
      Not known
       PDE4 inhibitors, e.g.  roflumilastReduction in exacerbations and improvement in lung function in patients with chronic bronchitis, FEV1 <50% and history of frequent exacerbationsPrevention of bone loss and increase in skeletal muscle mass (in a murine model) [188]
      Cardiovascular-targeted treatments
       StatinsMay reduce exacerbations [189]Reduction in cardiovascular risk [190]
      Reduction in oxidative stress and inflammation [191]
       ACE inhibitors/ARBReduction in exacerbations [192]
      Decrease in hyperinflation [193]
      May improve survival (in those with cardiovascular risk)
       β-BlockersReduction 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 inhibitorsNot 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  inhibitorsNot yet determined; possible reduction in inflammation and reversal of corticosteroid resistanceNot yet determined; issues with side-effect profile
       Mesenchymal stem cell EVsNot 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.

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      Unravelling the mechanisms driving multimorbidity in COPD to develop holistic approaches to patient-centred care
      H. Burke, T.M.A. Wilkinson
      European Respiratory Review Jun 2021, 30 (160) 210041; DOI: 10.1183/16000617.0041-2021

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      Unravelling the mechanisms driving multimorbidity in COPD to develop holistic approaches to patient-centred care
      H. Burke, T.M.A. Wilkinson
      European Respiratory Review Jun 2021, 30 (160) 210041; DOI: 10.1183/16000617.0041-2021
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      • Article
        • Abstract
        • Abstract
        • Overview of multimorbidity in COPD
        • Approaches to understanding complex mechanisms underlying multimorbidity in COPD
        • Towards an understanding of mechanistic drivers to multimorbidity in COPD
        • Multimorbidity in COPD over the life course
        • Pulmonary components of multimorbidity
        • Treatment approaches for multimorbidity in COPD
        • Conclusions
        • Acknowledgements
        • Footnotes
        • References
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      • COPD and smoking
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      • TLR-agonist-based therapies for respiratory viral diseases
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