High-dose budesonide for early COVID-19.

We were encouraged by the results of the PRINCIPLE trial, which in vulnerable individuals showed inhaled budesonide to confer a non-significant –25% (95% CI –45 to 3) relative reduction in the composite coprimary endpoint of hospital admission or death, with the number needed to treat being 50. Notably, the study had 90% power to detect a 50% reduction in the composite endpoint. The investigators appear to have attributed any protective effects of budesonide to its local glucocorticoid activity in the lung.

We were, however, surprised that no mention was made regarding the possibility for appreciable systemic bioavailability of inhaled corticosteroid from the lungs, especially given the high 1600 μg dose of budesonide. For example, in one study of mild asthma patients with a mean forced expiratory volume in 1 s of 86% predicted, treatment for 1 week with 1600 μg budesonide via the same dry powder inhaler device produced –44% (95% CI –47·5 to –40·0) suppression of 24 h serum cortisol relative to placebo. As such, we would welcome comment with regards to the other coprimary endpoint of time to first reported recovery, in particular whether the observed median difference of –2·94 days might be explained by patients feeling better due to a systemic glucocorticoid effect per se rather than a local effect.

Observational health informatics data found that previous use of conventional doses of intranasal corticosteroid were associated with a 22% (95% CI 15–28) reduced risk of hospital admission, a 23% (8–35) reduced need for intensive care, and a 24% (6–39) lower risk of death in hospital for patients with COVID-19. Moreover, these protective effects were replicated when excluding patients with allergic rhinitis and the use of inhaled corticosteroid.

In the meantime, we believe further randomised controlled trials are warranted to investigate whether the use of lower doses of either inhaled budesonide (400 μg) or intranasal budesonide (200 μg), which are devoid of meaningful systemic effects,2, 4 might ameliorate recovery and attenuate disease progression in ambulatory patients with early COVID-19.

BL reports non-financial support (equipment) from GSK; grants, personal fees (consulting, talks, and advisory board), and other support (attending American Thoracic Society and European Respiratory Society [ERS]) from AstraZeneca; grants, personal fees (consulting, talks, and advisory board), and other support (attending ERS) from Teva; personal fees (consulting) from Sanofi; and personal fees (consulting, talks, and advisory board) from Circassia, in relation to this Correspondence; personal fees (consulting) from Lupin, Glenmark, Vectura, Dr Reddy, and Sandoz; grants, personal fees (consulting, talks, and advisory board), and other support (attending British Thoracic Society) from Boehringer Ingelheim; and grants and personal fees (advisory board and talks) from Mylan, unrelated to this Correspondence; and BL's son is an employee of AstraZeneca. RC and RM declare no competing interests.