Dampening of the respiratory cytokine storm is promoted by inhaled budesonide in patients with early COVID-19
Jonathan R Baker, Mahdi Mahdi, Dan V Nicolau Jr, Sanjay Ramakrishnan, Peter J Barnes, Jodie L Simpson, Steven P Cass, Richard Ek Russell, Louise E Donnelly, Professor Mona Bafadhel
doi:10.1101/2021.10.26.21265512
Vaccinations against SARS-CoV-2 are effective in COVID-19. However, with limited vaccine access, vaccine hesitancy and variant breakthroughs, there is still a need for effective and safe early treatments. Two community-based clinical trials of the inhaled corticosteroid, budesonide, have recently been published showing and improvement in patients with COVID-19 treated early with budesonide 1,2 . To understand mechanistically how budesonide was beneficial, inflammatory mediators were assessed in the nasal mucosa of patients recruited to the Steroids in COVID (STOIC 1 ) trial and a cohort of SARS-CoV-2 negative individuals. Here we show that in early COVID-19, elevation in viral response proteins and Th1 and Th2 inflammation occurs. Longitudinal sampling in the natural course of COVID-19 showed persistently high interferon levels and elevated concentrations of the eosinophil chemokine, CCL11. In patients who deteriorate, the initial nasal mucosal signal is characterised by a marked suppression of the early inflammatory response, with reduced concentrations of interferon and inflammatory cytokines, but elevated eosinophil chemokines. Systemic inflammation remained altered in COVID-19 patients, implying that even after symptom resolution, changes in immunological mediators do not resolve. Budesonide treatment decreased IL-33 and IFN-γ, implying a reduction in epithelial damage and dampening of the interferon response. Budesonide treatment also increased CCL17 concentrations, suggesting an improved T-cell response; and significantly alters inflammatory pathways giving further insight into how this treatment can accelerate patient recovery. . This finding has now been replicated in a large Phase 3 efficacy trial 2 , but has yet to attract global adoption. The mechanism for how ICS can improve early COVID-19 infection is however currently unknown. Here, we report the nasal mucosal inflammatory response in patients with early COVID-19 disease and examine the evolution of inflammation in the natural course of COVID-19. We also identify how inflammation in the airway can predict illness severity and investigate the effect of inhaled budesonide upon the respiratory mucosa in early COVID-19 disease. Finally, we show using network analysis how inhaled budesonide can resolve the exaggerated inflammatory response seen in early COVID-19 infection and promote resolution to health.
Methods
Study design and participants STOIC was a randomised, open-label, parallel group, phase 2 clinical intervention trial. Participants aged 18 and over with early COVID-19 symptoms (defined as new onset of cough and/or fever and/or anosmia for less than 7 days) were randomised to receive usual care (UC), namely as required anti-pyretics, or inhaled budesonide (BUD) at a dose of 800μg twice a day plus usual care (see supplement figure S1 ). Participants were seen at home at randomisation day 0 (visit 1), day 7 (visit 2), and day 14 (visit 3) by a research nurse to obtain consent, provide inhalers and collect nasal absorption samples and nasopharyngeal swabs which were self-performed. At day 28 (visit 4), whole
Nasal mucosal sampling Nasal mucosal sampling was self-performed by all participants as previously described
37 . Briefly, samples of the nasal mucosal lining fluid were collected by placing a Nasosorption™ FX•I device (Hunt Developments UK Ltd) consisting of a synthetic absorptive matrix strip against the inferior turbinate for a duration of 1 minute. The sample was then eluted in 500 μL of PBS, 1% bovine serum albumin (BSA) (w/v), 1% Triton X-100 (v/v), and 0.05% sodium azide (w/v) (Sigma-Aldrich, UK) and stored at -80°C.
Isolation of serum
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