key: cord-0827652-vfkym9xj
authors: Singh, Dave; Halpin, David M G
title: Inhaled corticosteroids and COVID-19-related mortality: confounding or clarifying?
date: 2020-09-24
journal: Lancet Respir Med
DOI: 10.1016/s2213-2600(20)30447-1
sha: 599aafc688ab972ad5baace86da90f4ae609f6dc
doc_id: 827652
cord_uid: vfkym9xj

nan

Inhaled corticosteroids (ICSs) are the mainstay of anti-inflammatory therapy for asthma and chronic obstructive pulmonary disease (COPD). 1,2 Studies have shown worse outcomes in patients with COVID-19 who have been admitted to hospital and have comorbidities including chronic lung diseases. [3] [4] [5] Whether ICSs protect against COVID-19 or contribute to worse outcomes from COVID-19 has been debated. 6,7 ICS use might reduce antiviral immunity and increase the frequency of pneumonia in patients with COPD. 8 However, ICS use reduces the frequency of exacerbations 1 and might even reduce replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 9 supporting the case for protection against COVID-19.

In The Lancet Respiratory Medicine, Anna Schultze and colleagues 10 use UK electronic primary care records to retrospectively interrogate associations between current ICS use (defined as a prescription within 4 months) and COVID-19-related deaths in patients with asthma and COPD. The COPD cohort (n=148 557) consisted of patients currently using ICSs and a long-acting β-agonists (LABA), with or without a long-acting muscarinic antagonist (LAMA), compared with patients using a LABA and LAMA. Although comorbidities were similar between groups, exacerbations in the previous year were more frequent in the ICS combination group, reflecting that ICSs are used in patients with exacerbations. In the asthma cohort (n=818 490), current ICS users were compared with those using short-acting β agonists (SABAs) only. The mean age, number of comorbidities, and number of exacerbations in the past year were lower in non-ICS users, indicating that between-group analyses might be confounded by baseline differences.

In the COPD cohort, ICS use was associated with an increased risk of COVID-19-related death after adjusting for relevant factors, including age and comorbidities (hazard ratio [HR] 1·39 [95% CI 1·10-1·76]). A sensitivity analysis showed that the risk of death in the COPD population was highest with ICS-LABA-LAMA (triple therapy; adjusted HR 1·43 [1·12-1·83]), and lower and non-significant with ICS-LABA (1·29 [0·96-1·74]), a difference that cannot be explained by ICS use. These sensitivity analyses suggest factors driving increased risk in the ICS combination group that are not attributable to ICS itself, including confounding by treatment indication (ie, patients prescribed triple therapy have an increased disease burden and worse prognosis). A negative control analysis supported this hypothesis, with increased risk of non-COVID-19-related death in ICS users.

In the asthma cohort, no increased risk of COVID-19related death was found in low-to-medium dose ICS users compared with non-ICS users (adjusted HR 1·14 [95% CI 0·85-1·54]), suggesting ICS use had no bearing on COVID-19-related mortality. Schultze and colleagues found increased risk of COVID-19-related mortality in high-dose ICS users compared with non-ICS users (1·55 [1·10-2·18]), but no increase in non-COVID-19related deaths. This result might relate to underlying disease characteristics beyond those captured in the health records, such as increased susceptibility to viral infections with more severe asthma.

Patients with asthma and COPD are understandably concerned about developing COVID-19. They are also concerned whether their medication affects their risk of becoming infected or their prognosis if they do develop COVID-19, and they look to their clinicians for answers to these questions. Does this analysis help answer their questions? We think it provides some insights, but not conclusive answers. The negative results for use of lowto-medium dose ICS in asthma and ICS-LABA in COPD argue against the hypothesis that ICS use increases the risk of COVID-19-related mortality. For the hypothesis that ICS use protects against COVID-19-related mortality, the results rule out a benefit large enough to overcome the effects of confounding factors, but do not completely exclude a smaller benefit.

Overall, the analysis is confounded and does not provide definitive answers that patients and clinicians need, although it hints that ICS use does not provide a strong protective effect. Similar to Schultze and colleagues, we believe that had the analysis taken into account clinical factors, such as disease severity and history of exacerbations, which might have influenced the choice of maintenance therapy, it might have reached different conclusions about possible harms.

Fanatic Studio/Gary Waters/SPL ICSs are used to reduce future risk of events including exacerbations and mortality; 1,2 therefore, ICS use inevitably identifies individuals with an increased disease burden associated with increased future risk. Analyses of associations between ICS use and COVID-19-related outcomes in real-life datasets cannot escape this issue, but the comprehensive analysis reported by Schultze and colleagues in a large sample of almost 1 million people is a valiant attempt to provide some clarity despite the confounding by treatment indication observed.

The analysis does not completely resolve whether regular ICS therapy for asthma or COPD either decreases or increases risk of death from COVID-19. This finding is in contrast with the very real harm patients requiring ICS therapy for their asthma or COPD might be at risk if they stop treatment because of unfounded concerns related to their effects in COVID-19. Until more information is available, patients with asthma and COPD who are stable while using ICS must continue on their treatment during the ongoing COVID-19 pandemic.

Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: the GOLD science committee report 2019

GINA 2019: a fundamental change in asthma management: treatment of asthma with short-acting bronchodilators alone is no longer recommended for adults and adolescents

Prevalence, severity and mortality associated with COPD and smoking in patients with COVID-19: a rapid systematic review and meta-analysis

Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series

Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO clinical characterisation protocol: prospective observational cohort study

Inhaled corticosteroids and COVID-19: a systematic review and clinical perspective

Do chronic respiratory diseases or their treatment affect the risk of SARS-CoV-2 infection?

Long-term impact of inhaled corticosteroid use in asthma and chronic obstructive pulmonary disease (COPD): review of mechanisms that underlie risks

Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs

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