key: cord-0988653-rfh6hhr0
authors: Adir, Yochai; Fireman Klein, Einat; Saliba, Walid
title: Inhaled corticosteroids and COVID-19 outcomes in asthma - the Israeli experience
date: 2022-02-11
journal: ERJ Open Res
DOI: 10.1183/23120541.00014-2022
sha: 8c4637f90ee1990580d6903520bd5180a9265658
doc_id: 988653
cord_uid: rfh6hhr0

Inhaled corticosteroids (ICS) alone or in combination with bronchodilators are widely used in asthma [1]. ICS have potential immunosuppressive effects which may promote viral replication, delayed viral clearance and increased risks of secondary infections [2, 3]. Furthermore, ICS use in asthma is associated with an increased risk of upper respiratory tract infections [2, 3]. Therefore, in the face of the current coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, concerns have been raised whether the use of ICS in asthmatic patients increase the risk of SARS CoV-2 infection and affect COVID-19 severity and mortality.

Tel-972-4-8258342, Fax-972-4-8258342, e-mail: adir-sh@zahav.net.il

Inhaled corticosteroids (ICS) alone or in combination with bronchodilators are widely used in asthma (1) . ICS have potential immunosuppressive effects which may promote viral replication, delayed viral clearance and increased risks of secondary infections (2) (3) . Furthermore, ICS use in asthma is associated with an increased risk of upper respiratory tract infections (2) (3) . Therefore, in the face of the current coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, concerns have been raised whether the use of ICS in asthmatic patients increase the risk of SARS CoV-2 infection and affect COVID-19 severity and mortality.

In the current study, we examined two objectives; i) the association between ICS use and SARS-CoV-2 infection in asthmatic patients, using a test negative case-control study approach, and ii) the association between ICS use in asthmatic patients with PCR positivity for SARS-CoV-2 and COVID-19 severity and mortality, using a retrospective cohort study approach.

The study was approved by the Clalit Health Services (CHS) institutional review board and was exempt from the requirement for informed consent.

We used the computerized database of CHS to retrospectively identify all ≥18-yearold with an asthma diagnosis (ICD-9, 493.xx) who have seen at least twice by a Pulmonologist in the recent 5 years and underwent PCR testing for SARS-CoV-2 between 1 March 2020 and 17 December 2020. All identified patients who underwent PCR testing for SARS-CoV-2 served to assess the association between ICS use and SARS-CoV-2 infection, using a test negative case-control study approach. In this approach positive PCR patients constituted the cases and negative PCR patients constituted the control group. Asthmatic patients with positive PCR for SARS-CoV-2 served to assess the association between ICS use and moderate-severe COVID-19 and with composite of moderate-severe COVID-19 and 90 days all-cause mortality, using a retrospective cohort study approach. COVID-19 severity was defined according to the Israeli Ministry of Health's guidelines, which are in accordance with the WHO definitions (4).

ICS use was determined using the CHS pharmacy records using the Anatomical Therapeutic Chemical (ATC) classification codes. Based on the timing of ICS prescriptions filled in the previous year patients were classified into three categories; none vs. recent (≤90 days) vs former (90-365 days).

Logistic regression models were used to examine the association between ICS and PCR positivity and Cox proportional hazard regression models were used to assess the association between ICS use and COVID-19 severity. Multivariable models were adjusted for; age, sex, ethnicity, diabetes, hypertension, ischemic heart disease, obesity, hospitalization in the prior year, and systemic corticosteroids (SCS) use. Recent studies suggest that ICS suppress SARS-CoV-2 replication and reduced angiotensin converting enzyme 2 (ACE2) receptor, which mediate SARS-CoV-2 cell entry, expression in bronchial epithelial cells (5) (6) (7) (8) . Further, the available data from most of the epidemiological studies generally suggest that ICS are not an independent risk factor for increased SARS-COV-2 infectivity or COVID-19 severity, advising that ICS treatment in patients with asthma is safe and should be continued during the COVID-19 pandemic (9) (10) (11) (12) (13) . However, other studies reported some conflicting results, such the study by Schultze et al (14) that by using the OpenSAFELY platform, reported an increased risk of death from COVID-19 among people with asthma on high-dose ICS. Although, various sensitivity analyses indicated that this increased mortality risk could be explained by unmeasured confounder including disease severity and risk factors for severe COVID-19, the question whether regular ICS therapy for asthma is safe in the current SARS-COv-2 pandemic is still not completely answered. The results of our study suggest that, in asthmatic patients, recent and former use of ICS are not associated with increased risk of SARS-COv-2 infection nor with increased risk of COVID-19 severity or mortality.

The limitations of the study include lack of data about asthma severity, and limitations related to the observational and retrospective nature of the study.

In summary our study adds to the strength of the current evidence and the current recommendation that the use of ICS is safe and asthmatic patients should continue to take their prescribed asthma medication as usual including ICS alone or in combination with long acting beta 2 agonist, during the COVID-19 pandemic. 

Global Initiative for Asthma. Global strategy for asthma management and prevention

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Inhaled corticosteroids and risk of upper respiratory tract infection in patients with asthma: a meta-analysis

Clinical management of COVID-19 World Health Organization

Inhibitory effects of glycopyrronium, formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells

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Asthma in Adult Patients with COVID-19: Prevalence and Risk of Severe Disease Am J Respir Crit Care Med

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Inhaled corticosteroids do not adversely impact outcomes in COVID-19 positive patients with COPD: An analysis of Cleveland Clinic's COVID-19 registry

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