Inhaled corticosteroids (ICS) are the first line of treatment to counter the inflammatory pathology in several conditions, including asthma and chronic obstructive pulmonary disease (COPD). Now, a new study published in the journal The Lancet Respiratory Medicine in September 2020 reports on the actual role of ICS in reducing COVID-19 mortality.
Higher COVID-19 Risk with Underlying Illness
Earlier studies have demonstrated a clear link between the occurrence of moderate or severe COVID-19, requiring hospitalization, and the presence of underlying diseases like chronic lung disease. The use of ICS may reduce antiviral immune responses in COPD, thus increasing the frequency of pneumonia in these patients, but their use is also linked to a decline in the number of exacerbations.
Is ICS Related to Increased COVID-19-Related Deaths?
The current paper deals with the question as to whether ICS are protective or harmful in COVID-19 by reducing viral replication. The researchers used UK electronic health records from primary care to explore the associations between the current use of ICS, in the sense of their having been prescribed within the last four months, and the number of deaths related to COVID-19, in asthma and COPD.
The study included a group of ~150,000 COPD patients on ICS as well as long-acting β-agonists (LABA) in combination with a long-acting muscarinic antagonist (LAMA), with a control group who were using a LABA-LAMA combination alone. Both groups had a comparable level of comorbidities, but the first group had a higher frequency of exacerbations of ICS in the previous year. This is one of the criteria for the introduction of ICS in this group.
In the group of asthma patients, numbering over 800,000, the comparison was made between those using ICS and those using short-acting β agonists (SABAs) only. There were, however, significant differences in the mean age in both groups, as well as the number of chronic underlying illnesses and the number of exacerbations in the past year. Thus, these groups may not really be comparable at baseline.
Increased Deaths Not Related to ICS Use in COPD
The researchers found that the COPD cohort showed a 39% risk of mortality following COVID-19, even after adjusting for relevant factors like age and other illnesses. The highest risk of death was found to be in the group taking ICS along with both LABA and LAMA, 43% higher than the baseline risk, but lower with the use of ICS and LABA.
The reasons for these differences in mortality are probably not due to the ICS themselves, since both groups are using these therapeutic agents. Instead, this could be due to confounding factors, such as the probability that people with COPD who are on triple therapy already have a high disease burden and a poor outcome compared to those who are on fewer medications.
In order to test this hypothesis, the researchers carried out a negative control analysis, which showed that ICS users were actually at a higher risk of death unrelated to COVID-19.
ICS May Not be Related to COVID-19 Mortality
What about asthma users? The researchers found that the risk of COVID-19-related death was not increased in those using low to medium doses of ICS relative to those not on ICS, again appearing to rule out any direct effect of ICS on COVID-19-related deaths. However, those on high doses of ICS did have a 55% increased risk of COVID-19-related death, but not of non-COVID-19-related deaths. The reasons might be traceable to other characteristics of health – for example, those with more severe asthma might be more vulnerable to viral infections.
The researchers point out that patients with asthma and COPD may not get a clear answer as to whether they are at a higher risk for COVID-19, and whether this risk is increased by the use of medication for these conditions. However, it seems, from this study, that ICS does not increase the risk of death in COVID-19, as seen by the effect on patients using low to medium doses of these medications.
Implications and Future Directions
The lack of obvious benefit on COVID-19-related mortality could be due to the masking effect of confounding factors on a smaller benefit. To provide clear evidence, future studies must take into account the severity of the underlying lung condition, the history of exacerbations, and, therefore the past use of maintenance therapy, all of which may help to show the level of risk for future potential harm.
The primary obstacle, despite the use of a substantial cohort of patients, to arriving at a clear understanding of how ICS use impacts the individual risk of COVID-19-related death is the presence of underlying disease conditions that independently confer a future risk of death.
The obvious conclusion is that while it is not clear whether the use of ICS on a regular basis does confer increased mortality risk as a result of superimposed COVID-19, there is no question that patients with COPD or asthma who need ICS for their condition will experience harm if they discontinue this treatment out of fear linked to COVID-19-related concerns. Thus, until this is resolved, the recommendation is that “patients with asthma and COPD who are stable while using ICS must continue on their treatment during the ongoing COVID-19 pandemic.”