Dampening of the respiratory cytokine storm is promoted by inhaled budesonide in patients with early COVID-19

  1. Jonathan R Baker
  2. Mahdi Mahdi
  3. Dan V Nicolau
  4. Sanjay Ramakrishnan
  5. Peter J Barnes
  6. Jodie L Simpson
  7. Steven P Cass
  8. Richard EK Russell
  9. Louise E Donnelly
  10. Mona Bafadhel

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Abstract

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.

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    SciScore for 10.1101/2021.10.26.21265512: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: 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.
    IRB: The study was approved by Fulham London Research Ethics Committee (20/HRA/2531) and the National Health Research Authority and was sponsored by the University of Oxford.
    Sex as a biological variablenot detected.
    RandomizationStudy design and participants: STOIC was a randomised, open-label, parallel group, phase 2 clinical intervention trial.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Recombinant DNA
    SentencesResources
    Quantification of virus RNA copies were generated using a standard curve using nCoV-WHO-Control plasmid of known concentration (Eurofins Genomics, Wolverhampton, UK).
    nCoV-WHO-Control
    suggested: None
    Software and Algorithms
    SentencesResources
    Statistical analysis: Statistical analyses used GraphPad Prism v9.0.0 (
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    (GraphPad, La Jolla, California, USA).
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    For image rendering the Gephi package v0.9.2 (Gephi.org.
    Gephi
    suggested: (Gephi, RRID:SCR_004293)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.10.26.21265512v1 on medRxiv