Anna Schultze, PhD *Alex J Walker, PhD *Brian MacKenna, MPharm *Caroline E Morton, MBChB *Prof Krishnan Bhaskaran, PhDJeremy P Brown, MScChristopher T Rentsch, PhDElizabeth Williamson, PhDHenry Drysdale, MRCSRichard Croker, MScSeb Bacon, BAWilliam Hulme, PhDChris Bates, PhDHelen J Curtis, DPhilAmir Mehrkar, MB BChirDavid Evans, MPhilPeter Inglesby, MPhilJonathan Cockburn, BScHelen I McDonald, PhDLaurie Tomlinson, PhDRohini Mathur, PhDKevin Wing, PhDAngel Y S Wong, PhDHarriet Forbes, PhDJohn Parry, MRCGPFrank Hester, BSc Sam Harper, MSci Prof Stephen J W Evans, MSc Prof Jennifer Quint, PhD Prof Liam Smeeth, PhD Prof Ian J Douglas, PhD † Ben Goldacre, MRCPsych † for theOpenSAFELY Collaborative
Open AccessPublished:September 24, 2020DOI: https://doi.org/10.1016/S2213-2600(20)30415-X
Summary
Background
Early descriptions of patients admitted to hospital during the COVID-19 pandemic showed a lower prevalence of asthma and chronic obstructive pulmonary disease (COPD) than would be expected for an acute respiratory disease like COVID-19, leading to speculation that inhaled corticosteroids (ICSs) might protect against infection with severe acute respiratory syndrome coronavirus 2 or the development of serious sequelae. We assessed the association between ICS and COVID-19-related death among people with COPD or asthma using linked electronic health records (EHRs) in England, UK.
Methods
In this observational study, we analysed patient-level data for people with COPD or asthma from primary care EHRs linked with death data from the Office of National Statistics using the OpenSAFELY platform. The index date (start of follow-up) for both cohorts was March 1, 2020; follow-up lasted until May 6, 2020. For the COPD cohort, individuals were eligible if they were aged 35 years or older, had COPD, were a current or former smoker, and were prescribed an ICS or long-acting β agonist plus long-acting muscarinic antagonist (LABA–LAMA) as combination therapy within the 4 months before the index date. For the asthma cohort, individuals were eligible if they were aged 18 years or older, had been diagnosed with asthma within 3 years of the index date, and were prescribed an ICS or short-acting β agonist (SABA) only within the 4 months before the index date. We compared the outcome of COVID-19-related death between people prescribed an ICS and those prescribed alternative respiratory medications: ICSs versus LABA–LAMA for the COPD cohort, and low-dose or medium-dose and high-dose ICSs versus SABAs only in the asthma cohort. We used Cox regression models to estimate hazard ratios (HRs) and 95% CIs for the association between exposure categories and the outcome in each population, adjusted for age, sex, and all other prespecified covariates. We calculated e-values to quantify the effect of unmeasured confounding on our results.
Findings
We identified 148 557 people with COPD and 818 490 people with asthma who were given relevant respiratory medications in the 4 months before the index date. People with COPD who were prescribed ICSs were at increased risk of COVID-19-related death compared with those prescribed LABA–LAMA combinations (adjusted HR 1·39 [95% CI 1·10–1·76]). Compared with those prescribed SABAs only, people with asthma who were prescribed high-dose ICS were at an increased risk of death (1·55 [1·10–2·18]), whereas those given a low or medium dose were not (1·14 [0·85–1·54]). Sensitivity analyses showed that the apparent harmful association we observed could be explained by relatively small health differences between people prescribed ICS and those not prescribed ICS that were not recorded in the database (e value lower 95% CI 1·43).
Interpretation
Our results do not support a major role for regular ICS use in protecting against COVID-19-related death among people with asthma or COPD. Observed increased risks of COVID-19-related death can be plausibly explained by unmeasured confounding due to disease severity.