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Early Th2 inflammation in the upper respiratory mucosa as a predictor of severe COVID-19 and modulation by early treatment with inhaled corticosteroids: a mechanistic analysis.
Baker, Jonathan R; Mahdi, Mahdi; Nicolau, Dan V; Ramakrishnan, Sanjay; Barnes, Peter J; Simpson, Jodie L; Cass, Steven P; Russell, Richard E K; Donnelly, Louise E; Bafadhel, Mona.
  • Baker JR; National Heart and Lung Institute, Imperial College London, London, UK.
  • Mahdi M; National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK; Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Nicolau DV; Nuffield Department of Medicine, University of Oxford, Oxford, UK; UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia; School of Mathematical Sciences, Queensland University of Technology, Brisbane, QLD Australia.
  • Ramakrishnan S; National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK; Nuffield Department of Medicine, University of Oxford, Oxford, UK; School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia.
  • Barnes PJ; National Heart and Lung Institute, Imperial College London, London, UK.
  • Simpson JL; School of Medicine and Public Health, Priority Centre for Healthy Lungs, University of Newcastle, Callaghan, NSW, Australia.
  • Cass SP; National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK; Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Russell REK; National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK; Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Donnelly LE; National Heart and Lung Institute, Imperial College London, London, UK.
  • Bafadhel M; National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK; Nuffield Department of Medicine, University of Oxford, Oxford, UK; School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK. Electronic address: mona.baf
Lancet Respir Med ; 10(6): 545-556, 2022 06.
Article in English | MEDLINE | ID: covidwho-1778526
ABSTRACT

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 (11) 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.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Drug Treatment Type of study: Cohort study / Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Topics: Long Covid / Vaccines / Variants Limits: Humans Language: English Journal: Lancet Respir Med Year: 2022 Document Type: Article Affiliation country: S2213-2600(22)00002-9

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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Drug Treatment Type of study: Cohort study / Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Topics: Long Covid / Vaccines / Variants Limits: Humans Language: English Journal: Lancet Respir Med Year: 2022 Document Type: Article Affiliation country: S2213-2600(22)00002-9