High-dose budesonide for early COVID-19



We were encouraged by the results of the PRINCIPLE trial,1Yu L-M Bafadhel M Dorward J et al.Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform 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 50.1Yu L-M Bafadhel M Dorward J et al.Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. 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.2Daley-Yates P Brealey N Thomas S et al.Therapeutic index of inhaled corticosteroids in asthma: a dose-response comparison on airway hyperresponsiveness and adrenal axis suppression. 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-19.3Strauss R Jawhari N Attaway AH et al.Intranasal corticosteroids are associated with better outcomes in coronavirus disease 2019 (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,2Daley-Yates P Brealey N Thomas S et al.Therapeutic index of inhaled corticosteroids in asthma: a dose-response comparison on airway hyperresponsiveness and adrenal axis suppression.,  4Wilson AM Sims EJ McFarlane LC Lipworth BJ Effects of intranasal corticosteroids on adrenal, bone, and blood markers of systemic activity in allergic rhinitis. 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.References1.Yu L-M Bafadhel M Dorward J et al.Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.Lancet. 2021; 398: 843-8552.Daley-Yates P Brealey N Thomas S et al.Therapeutic index of inhaled corticosteroids in asthma: a dose-response comparison on airway hyperresponsiveness and adrenal axis suppression.Br J Clin Pharmacol. 2021; 87: 483-4933.Strauss R Jawhari N Attaway AH et al.Intranasal corticosteroids are associated with better outcomes in coronavirus disease 2019 (COVID-19).J Allergy Clin Immunol Pract. 2021; 9: 3934-39404.Wilson AM Sims EJ McFarlane LC Lipworth BJ Effects of intranasal corticosteroids on adrenal, bone, and blood markers of systemic activity in allergic rhinitis.J Allergy Clin Immunol. 1998; 102: 598-604Article InfoPublication HistoryPublished: 11 December 2021IdentificationDOI: https://doi.org/10.1016/S0140-6736(21)02440-5Copyright© 2021 Elsevier Ltd. 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Linked ArticlesHigh-dose budesonide for early COVID-19The importance of effective community-based treatments for COVID-19 cannot be overstated. We applaud Ly-Mee Yu and colleagues1 for addressing this issue in the PRINCIPLE trial and would like to share some comments.
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High-dose budesonide for early COVID-19 – Authors’ replyWe thank Ivan Berezowski and colleagues for highlighting the importance of the PRINCIPLE trial finding a safe, effective, and inexpensive community repurposed medication that shortens COVID-19 illness and reduces the need for hospitalisation and use of oxygen.1 Most participants (85%) had up to 10 days’ illness duration (63% fewer than 7 days in the concurrent population). Inclusion of those almost recovered would reduce rather than increase the chance of showing an effect. In addition, if people without obesity incorrectly reported as people with obesity (32% self-reported a body-mass index >35, but only 27·4% of those were eligible on this criterion alone), this would also probably bias the results towards the null because obesity can be associated with worse outcomes.
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Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trialInhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications.
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