Budesonide/formoterol combination for reducing cough in COVID-19 patients—A case of inflated expectations!

Dear Editor

We came across the original article on effectiveness of budesonide/formoterol fixed-dose combination MDI in reducing cough symptoms in COVID-19 patients by Samajdar et al.[1] The study tries to elucidate benefit of adding ICS-LABA to standard COVID treatment to attain symptomatic relief in cough. Although the study seems to provide evidence of benefit for ICS-LABA, there were certain aspects that remained unanswered.

Firstly, the study, published as an observational study is rather an interventional study, requiring CTRI registration. Clearly, an intervention, in a prospective fashion, in the form of addition of a new drug to the standard of care has been done during the course of the disease to study the final outcome, thereby meeting the definition of an interventional study.[1] Secondly, there is lack of clarity on how patients were assigned into groups A and B. It seems that decision to initiate ICS-LABA was left at the discretion of investigators. This is likely due to lack of randomization which leads to increased risk of selection bias. Thirdly, sampling strategy seems arbitrary. The basis of the sample size taken in the study has not been stated clearly. The recruitment period matches the second wave of COVID-19 pandemic in India which witnessed over four lakh cases per day in India.[2] A higher sample size could have revealed an effect which was not observed in the current study. Fourthly, the patients in both the groups were prescribed anti-cough medications for symptomatic relief. Majority of medicines were prescribed more commonly in group A, albeit statistical significance did not reach. Combining the number of two medicine groups reaches a P < 0.05. Authors should have adjusted for the concomitant medicines while analysing statistical impact of the investigational agent.[1] Additionally, a significant negative correlation was observed between mean latency of MDI initiation and mean cough score reduction in group A. A similar attempt of finding the correlation (between day of illness on study entry and day 3/7) for group B should have been made to highlight if the negative correlation in group A was due to chance or true significance.[1]

Finally, the idea of effectiveness of beta-2-agonist for cough suppression is not physiologically plausible especially in acute viral illnesses. The quoted references also concludes that there is little evidence of these agents in controlling cough and that too in patients who already have a baseline airway constriction, which was not demonstrated in the index study.[2] Lastly, authors mention regarding affinity of formoterol for SARS-CoV PLpro which can play a role in host’s innate immunity, but this also seems farfetched as there is no proof if the interaction between the drug and the target is inhibitory.[3]

Recent developments have discovered neuronal hypersensitivity of ATP receptor P2X3[4] as mechanism of increased cough following viral illnesses and drugs like Eliapixant targeting P2X3 are under trial for alleviation of cough.[5] ICS-LABA are an important pillar (for reactive airway disease) in supportive treatment for COVID-19 but use in unselected population requires caution.[4]

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