Jonathan R Baker, Mahdi Mahdi,Dan V Nicolau Jr, Sanjay Ramakrishnan, Peter J Barnes, Jodie L Simpson, Steven P Cass, Richard E K Russell, ?Louise E Donnelly, Mona Bafadhel Summary 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.