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Authors: Hugo Farne, Aran Singanayagam
Journal: Journal of Allergy and Clinical Immunology (2020)

We thank Lipworth et al1Lipworth B. Chan R. Kuo C. Inhaled corticosteroids and angiotensin-converting enzyme-2 in COPD.J Allergy Clin Immunol. 2021; 147: 1117Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar for their correspondence regarding our article recently published in the Journal of Allergy and Clinical Immunology.2Finney LJ, Glanville N, Farne H, Aniscenko J, Fenwick P, Kemp SV, et al. Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon [published online ahead of print October 15, 2020]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.09.034.Google Scholar We agree that it is currently unclear whether inhaled corticosteroid (ICS) use in chronic obstructive pulmonary disease (COPD) imparts an overall protective or detrimental effect on susceptibility to coronavirus disease 2019 (COVID-19). Theoretically, any potentially beneficial effects of ICS related to COVID-19, such as angiotensin-converting enzyme 2 attenuation and/or suppression of inflammation, could be offset by detrimental effects. For example, we have previously reported that ICSs suppress type I interferon, leading to secondary bacterial infections and mucus hypersecretion during respiratory viral infections.3Singanayagam A. Glanville N. Girkin J.L. Ching Y.M. Marcellini A. Porter J.D. et al.Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations.Nat Commun. 2018; 9: 2229Crossref PubMed Scopus (136) Google Scholar It should also be noted that, in animal models, angiotensin-converting enzyme 2 has a protective functional role against acute lung injury4Imai Y. Kuba K. Rao S. Huan Y. Guo F. Guan B. et al.Angiotensin-converting enzyme 2 protects from severe acute lung failure.Nature. 2005; 436: 112-116Crossref PubMed Scopus (2019) Google Scholar and thus the suppressive effect of ICSs may have adverse consequences in the context of active infection. Lipworth et al cite the increased risk of death in patients with COPD taking any ICS combination therapy versus those on dual bronchodilators without ICS identified in the OpenSAFELY cohort.5Schultze A. Walker A.J. MacKenna B. Morton C.E. Bhaskaran K. Brown J.P. et al.Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform.Lancet Respir Med. 2020; 8: 1106-1120Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar It is worth noting that the increased risk for patients with COPD prescribed ICS/long-acting beta-agonist did not reach significance (adjusted hazard ratio, 1.29; 95% CI, 0.96-1.74), suggesting that the increased risk ascribed to triple ICS/long-acting beta-agonist/long-acting muscarinic antagonist therapy (1.43; 95% CI, 1.12-1.83) may not be solely related to the ICS component but possibly due to increased disease severity. This is supported by a negative control analysis showing an increase in deaths not related to COVID-19 in patients with COPD prescribed ICS (1.23; 95% CI, 1.08-1.40).5Schultze A. Walker A.J. MacKenna B. Morton C.E. Bhaskaran K. Brown J.P. et al.Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform.Lancet Respir Med. 2020; 8: 1106-1120Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar Unmeasured disease severity is thus likely to be an important confounder in OpenSAFELY, a retrospective observational study with the power to reveal associations and generate hypotheses, but which cannot define causal relationships. For this, randomized controlled trials are needed and several are under way (NCT04416399 [UK]; NCT04355637 [Spain]; NCT04377711 [USA]; NCT04330586 [South Korea]). The results from these studies will be informative for disentangling whether the beneficial effects of these commonly prescribed inhalers outweigh any potential adverse effects. Inhaled corticosteroids and angiotensin-converting enzyme-2 in COPDJournal of Allergy and Clinical ImmunologyVol. 147Issue 3PreviewFinney et al1 elegantly showed in mice that inhaled corticosteroid (ICS) down-regulated the severe acute respiratory syndrome coronavirus-2 entry receptor angiotensin-converting enzyme 2 (ACE2) via suppression of type 1 interferon. It was also found that in 36 patients with chronic obstructive pulmonary disease (COPD), the use of ICS was associated with reduced expression of ACE2 compared with non-ICS users, whereas ACE2 expression is increased in cultured bronchial epithelial cells from patients with COPD and in turn suppressed by fluticasone propionate. Full-Text PDF