Inhaled corticosteroids and angiotensin-converting enzyme-2 in COPD
Authors: Brian Lipworth, Rory Chan, Chris Kuo
Journal: Journal of Allergy and Clinical Immunology (2020)

Finney et al1Finney 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 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. They go on to postulate that this effect might therefore reduce susceptibility of patients with COPD to coronavirus disease 2019 (COVID-19). The OpenSAFELY cohort showed that among 105,249 patients with COPD taking ICS combination therapy compared with 43,308 patients taking long-acting beta-agonist and long-acting muscarinic antagonist (LABA/LAMA) combination, the adjusted hazard ratio for mortality from COVID-19 was 1.39 (95% CI, 1.10-1.76).2Schultze 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 The risk of death was more pronounced in those patients prescribed triple therapy with ICS/LABA/LAMA than those patients prescribed dual therapy with ICS/LABA, with hazard ratios (vs LABA/LAMA) of 1.43 (95% CI, 1.12-1.83) and 1.29 (95% CI, 0.96-1.74), respectively. Hence, reduced expression of ACE2 associated with ICS use does not appear to be associated with a commensurate reduction in COVID-19–related deaths per se. However, the risk of mortality not related to COVID-19 was also observed to be higher in patients with COPD taking ICS-containing therapy versus LABA/LAMA, with an adjusted hazard ratio of 1.23 (95% CI, 1.08-1.40). This in turn perhaps suggests that other factors such as local immunosuppression due to ICS in the presence of impaired mucociliary clearance and altered microbiome3Singanayagam A, Johnston SL. Long-term impact of inhaled corticosteroid use in asthma and chronic obstructive pulmonary disease (COPD): review of mechanisms that underlie risks [published online ahead of print January 14, 2020]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2019.12.907.Google Scholar may have contributed to increased deaths in patients with COPD, or possibly that patients taking ICS had more severe disease. Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferonJournal of Allergy and Clinical ImmunologyVol. 147Issue 2PreviewThe mechanisms underlying altered susceptibility and propensity to severe Coronavirus disease 2019 (COVID-19) disease in at-risk groups such as patients with chronic obstructive pulmonary disease (COPD) are poorly understood. Inhaled corticosteroids (ICSs) are widely used in COPD, but the extent to which these therapies protect or expose patients to risk of severe COVID-19 is unknown. Full-Text PDF Open AccessReplyJournal of Allergy and Clinical ImmunologyVol. 147Issue 3PreviewWe thank Lipworth et al1 for their correspondence regarding our article recently published in the Journal of Allergy and Clinical Immunology.2 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. Full-Text PDF