Published: 7 April 2022
Authors: Jonathan R Baker, PhD Mahdi Mahdi, BSc Dan V Nicolau Jr, PhD Sanjay Ramakrishnan, MBBS Prof Peter J Barnes, FRS Jodie L Simpson, PhD et al.
Source: This abstract has been sourced from NZ Respiratory Research Review Issue 200
Background Community-based clinical trials of the inhaled corticosteroid budesonide in early COVID-19 have shown
improved patient outcomes. We aimed to understand the inflammatory mechanism of budesonide in the treatment
of early COVID-19.
Methods The STOIC trial was a randomised, open label, parallel group, phase 2 clinical intervention trial where
patients were randomly assigned (1:1) to receive usual care (as needed antipyretics were only available treatment)
or inhaled budesonide at a dose of 800 μg twice a day plus usual care. For this experimental analysis, we investigated
the nasal mucosal inflammatory response in patients recruited to the STOIC trial and in a cohort of SARS-CoV-2-
negative healthy controls, recruited from a long-term observational data collection study at the University of
Oxford. In patients with SARS-CoV-2 who entered the STOIC study, nasal epithelial lining fluid was sampled at
day of randomisation (day 0) and at day 14 following randomisation, blood samples were also collected at day 28
after randomisation. Nasal epithelial lining fluid and blood samples were collected from the SARS-CoV-2 negative
control cohort. Inflammatory mediators in the nasal epithelial lining fluid and blood were assessed for a range of
viral response proteins, and innate and adaptive response markers using Meso Scale Discovery enzyme linked
immunoassay panels. These samples were used to investigate the evolution of inflammation in the early COVID-19
disease course and assess the effect of budesonide on inflammation.
Findings 146 participants were recruited in the STOIC trial (n=73 in the usual care group; n=73 in the budesonide
group). 140 nasal mucosal samples were available at day 0 (randomisation) and 122 samples at day 14. At day 28, whole
blood was collected from 123 participants (62 in the budesonide group and 61 in the usual care group).
20 blood or nasal samples were collected from healthy controls. In early COVID-19 disease, there was an enhanced
inflammatory airway response with the induction of an anti-viral and T-helper 1 and 2 (Th1/2) inflammatory response
compared with healthy individuals. Individuals with COVID-19 who clinically deteriorated (ie, who met the primary
outcome) showed an early blunted respiratory interferon response and pronounced and persistent Th2 inflammation,
mediated by CC chemokine ligand (CCL)-24, compared with those with COVID-19 who did not clinically deteriorate.
Over time, the natural course of COVID-19 showed persistently high respiratory interferon concentrations and elevated
concentrations of the eosinophil chemokine, CCL-11, despite clinical symptom improvement. There was persistent
systemic inflammation after 28 days following COVID-19, including elevated concentrations of interleukin (IL)-6,
tumour necrosis factor-α, and CCL-11. Budesonide treatment modulated inflammation in the nose and blood and was
shown to decrease IL-33 and increase CCL17. The STOIC trial was registered with ClinicalTrials.gov, NCT04416399.
Interpretation An initial blunted interferon response and heightened T-helper 2 inflammatory response in the
respiratory tract following SARS-CoV-2 infection could be a biomarker for predicting the development of severe
COVID-19 disease. The clinical benefit of inhaled budesonide in early COVID-19 is likely to be as a consequence of its
inflammatory modulatory effect, suggesting efficacy by reducing epithelial damage and an improved T-cell response.
Funding Oxford National Institute of Health Research Biomedical Research Centre and AstraZeneca.
Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
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