We read with interest the Article by Sanjay Ramakrishnan and colleagues1Ramakrishnan S Nicolau Jr, DV Langford B et al.Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. in The Lancet Respiratory Medicine on the efficacy of inhaled budesonide in the treatment of early COVID-19 illness in people in the community. The use of inhaled corticosteroids might be associated with poor outcomes among people being treated for COVID-19 in hospital.2Choi JC Jung SY Yoon UA et al.Inhaled corticosteroids and COVID-19 risk and mortality: a nationwide cohort study. However, generally, users of inhaled corticosteroid have more comorbidities than non-users, which might have influenced the study's findings. The study by Ramakrishnan and colleagues is important because the selection bias introduced by a non-hospital setting is less than that introduced by a hospital setting, and a non-hospital setting allows researchers to assess independent drug action. Nevertheless, we would like to address several issues regarding primary outcomes, viral load, and asthma prevalence.

First, the primary endpoint of COVID-19-related urgent care visits is vague. In the per-protocol population, the primary outcome occurred in 11 participants, and only one participant was admitted to a respiratory high-dependency unit. The finding that there were no differences in baseline demographics and clinical characteristics between the participants with and without a primary outcome might cause one to question the severity of the primary-outcome events. Indeed, this was an open-label study. Inclusion in the usual care group might have had a substantial effect on a participant's behaviour and willingness to seek urgent care or visit an emergency department.

Second, no difference in the decrease in viral load was observed between the budesonide and usual care groups. This finding does not support the additive inhibitory effect of budesonide against SARS-CoV-2.3Yamaya M Nishimura H Deng X et al.Inhibitory effects of glycopyrronium, formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells. Additionally, considering the early phase of SARS-CoV-2 infection, the viral titres in this study were relatively low.4Temporal dynamics in viral shedding and transmissibility of COVID-19. The best explanation for these results is that the participants had low disease severity and viral replication, and so were theoretically less likely to benefit from budesonide treatment than anticipated.Third, the asthma prevalence was high (14–16%) in both groups. These proportions are surprising because participants were excluded from the study if they had recently used (within 7 days) inhaled or systemic corticosteroids. Antiviral and allergic responses reportedly are reciprocally regulated.5Gonzales-van Horn SR Farrar JD Interferon at the crossroads of allergy and viral infections. Thus, patients with atopic conditions might be less susceptible to COVID-19 or have an increased response to inhaled corticosteroids, which, if not adequately controlled, would introduce a significant bias.

Nevertheless, Ramakrishnan and colleagues should be credited for conducting the first randomised trial in which the therapeutic potential of inhaled corticosteroids in early COVID-19 illness was assessed. Further studies exploring the effects of inhaled corticosteroids in patients with severe COVID-19 using mechanistic evidence are needed.

We declare no competing interests.

References1.Ramakrishnan S Nicolau Jr, DV Langford B et al.

Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial.

Lancet Respir Med. ()2.Choi JC Jung SY Yoon UA et al.

Inhaled corticosteroids and COVID-19 risk and mortality: a nationwide cohort study.

J Clin Med. 934063.Yamaya M Nishimura H Deng X et al.

Inhibitory effects of glycopyrronium, formoterol, and budesonide on coronavirus HCoV-229E replication and cytokine production by primary cultures of human nasal and tracheal epithelial cells.

Respir Investig. 58: 155-1684.

Temporal dynamics in viral shedding and transmissibility of COVID-19.

Nat Med. 26: 672-6755.Gonzales-van Horn SR Farrar JD

Interferon at the crossroads of allergy and viral infections.

J Leukoc Biol. 98: 185-194Article InfoPublication HistoryIdentification

DOI: https://doi.org/10.1016/S2213-2600(21)00217-4

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ScienceDirectAccess this article on ScienceDirect Linked ArticlesInhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial

Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery after early COVID-19.

Full-Text PDF Inhaled budesonide for early treatment of COVID-19

We have thoroughly read the results of the phase 2 randomised clinical trial reported by Sanjay Ramakrishnan and colleagues1 in The Lancet Respiratory Medicine investigating the role of inhaled budesonide compared with usual care in adults within the first 7 days from the onset of mild COVID-19 symptoms.

Full-Text PDF Inhaled budesonide for early treatment of COVID-19 – Authors' reply

We share the enthusiasm of Rafael San-Juan and colleagues, Markus Zeitlinger and Marco Idzko, and Jae Chol Choi and Won-Young Kim in the search for an effective treatment in early COVID-19, and in the findings of the STOIC study.1

Full-Text PDF Inhaled budesonide for early treatment of COVID-19

We read the Article by Sanjay Ramakrishnan and colleagues in The Lancet Respiratory Medicine with great interest.1 The results of their phase 2 randomised clinical trial indicated that early treatment with inhaled budesonide in patients with COVID-19 might prevent clinical deterioration, as determined by a reduced number of urgent care visits.1 The rational for the use of inhaled corticosteroids in patients with COVID-19 was already discussed by Alvar Agusti and colleagues.2 However, we here highlight that the open-label study design and the subjective primary endpoint both introduce an unknown level of bias, making interpretation of data difficult.

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