By Sally Robertson, B.Sc.Jun 22 2020

A study conducted by UK researchers has found no evidence to support the hypothesis that regular use of inhaled corticosteroids may have a beneficial effect on mortality outcomes among patients with coronavirus disease 2019 (COVID-19).

The team, which included researchers from the University of Oxford, London School of Hygiene and Tropical Medicine and Imperial College London, found no significant evidence to support that inhaled corticosteroids (ICS) protect against COVID-related death or that these drugs should be used to treat COVID-19 patients outside of clinical trials.

The findings do not support making any adjustments to ICS treatment regimens among patients with COVID-19, say Ben Goldacre and colleagues.

A pre-print version of the paper is available on the server medRxiv*, while the article undergoes peer review.

Study: Inhaled corticosteroid use and risk COVID-19 related death among 966,461 patients with COPD or asthma: an OpenSAFELY analysis. Image Credit: Orawan Pattarawimonchai / Shutterstock

What led to speculation that ICS may be beneficial?

Severe COVID-19-related outcomes such as hospitalization or death are more likely among older people and those with underlying health conditions. In many cases, such outcomes are due to complications such as acute respiratory distress syndrome and respiratory failure.

However, some early studies of patients with COVID-19 showed that the prevalence of chronic respiratory conditions was unexpectedly low among hospitalized patients.

This led to some scientists speculating that ICS treatments for conditions such as chronic obstructive pulmonary disorder (COPD) and asthma might protect against the development of severe COVID-19.

Examples of proposed protective mechanisms include suppression of SARS-CoV-2 replication and decreased cytokine production. However, ICS use among people with COPD has also been associated with an increased risk for pneumonia and other severe adverse effects.

Evaluating the association between ICS use and COVID-19 mortality

Now, Ben Goldacre and colleagues have evaluated the association between ICS use and COVID-19-related mortality using the OpenSAFELY platform.

This platform links data from primary care electronic health records and deaths registered with the Office for National Statistics for around 40% of the population in England.

The researchers say they developed OpenSAFELY on behalf of NHS England specifically to help address urgent concerns and questions arising from COVID-19 research.

“The greatest strength of this study was the power we had to look at multiple drug treatments as our dataset included medical records from almost 24 million individuals,” writes the team

The researchers followed the association between current ICS use and COVID-19 outcomes (from the 1^st March to 6^th May 2020) among 148,488 people with COPD and 817,973 people with asthma who had been prescribed respiratory treatments in the four months before 1st March.

The team compared people who were receiving ICS with those on alternative treatments and evaluated the cohorts for the primary outcome of death related to COVID-19.

People with COPD who were using ICS were at a 38% increased risk for death compared with those who were using a long-acting beta-agonist and a long-acting muscarinic antagonist.

Among people with asthma, those on a high-dose of ICS were at a 52% increased risk for death, compared with those using a short-acting beta-agonist (SABA) and people on a low-to-medium dose of ICS were at a 10% increased risk.

No “strong support for a protective effect from ICS”

“Our findings do not provide any strong support for a protective effect from ICS use in these populations, as has been previously hypothesized,” write the researchers.

However, neither do the findings provide evidence that ICS use has a causally harmful effect, they add.

Although the study initially seemed to indicate harmful associations between ICS use and COVID-19 outcomes, Goldacre and colleagues say these associations can be “plausibly explained by unmeasured confounding due to disease severity.”

The team identified a stronger association between ICS and COVID-19 mortality among patients receiving triple versus dual ICS therapy for COPD. However, the ICS content of these two regimens is similar, and any causal effect due to ICS would also be expected to be similar between the groups.

The researchers hypothesized that disease severity rather than ICS use might influence the risk of non-COVID-19-related death and therefore used this as a negative control outcome.

“If any potentially harmful association observed in primary analyses was due to confounding (i.e. people prescribed ICS had more severe underlying respiratory disease than those who did not) we expected to observe a similar association with non-COVID-19 related death in people prescribed ICS.”

Indeed, in the COPD population, the risk of non-COVID-19--related death was 23% higher among individuals who received ICS.

The researchers expect that if they had successfully controlled for between-group differences in disease severity, no association between ICS use and the negative control outcome of non-COVID-19-related mortality would have been observed.

People currently taking ICS should continue taking them as advised

The team says that overall, the study found no evidence of a significant beneficial or harmful effect of regular ICS use on COVID-19-related mortality.

The findings “do not provide evidence to support adjustments in ICS therapy among COVID-19 patients,” write Goldacre and colleagues.

“People currently taking ICS should continue taking them if recommended as part of routine care,” they conclude.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.