Early immune pathology and persistent dysregulation characterise severe COVID-19



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This research has not been peer-reviewed, and has been posted on pre-print repository medRxiv. This is a preliminary report that should not be regarded as conclusive, guide clinical practice/health-related behaviour, or be reported in news media as established information.


In a study of 207 SARS-CoV2-infected individuals with a range of severities followed over 12 weeks from symptom onset, we demonstrate that an early robust immune response, without systemic inflammation, is characteristic of asymptomatic or mild disease. Those presenting to hospital had delayed adaptive responses and systemic inflammation already evident at around symptom onset. Such early evidence of inflammation suggests immunopathology may be inevitable in some individuals, or that preventative intervention might be needed before symptom onset. Viral load does not correlate with the development of this pathological response, but does with its subsequent severity. Immune recovery is complex, with profound persistent cellular abnormalities correlating with a change in the nature of the inflammatory response, where signatures characteristic of increased oxidative phosphorylation and reactive-oxygen species-associated inflammation replace those driven by TNF and IL-6. These late immunometabolic inflammatory changes and unresolved immune cell defects, if persistent, may contribute to “long COVID”.

Author list:

Laura Bergamaschi, Federica Mescia, Lorinda Turner, Aimee Hanson, Prasanti Kotagiri, Benjamin J. Dunmore, Helene Ruffieux, Aloka De Sa, Oisin Huhn, Mark R. Wills, Stephen Baker, Rainer Doffinger, Gordon Dougan, Anne Elmer, Ian G Goodfellow, Ravindra K. Gupta, Myra Hosmillo, Kelvin Hunter, Nathalie Kingston, Paul J. Lehner, Nicholas J. Matheson, Jeremy K. Nicholson, Anna M. Petrunkina, Sylvia Richardson, Caroline Saunders, James E.D. Thaventhiran, Erik J. M. Toonen, Michael P. Weekes, Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration, Mark Toshner, Christoph Hess, John R. Bradley, Paul A. Lyons, Kenneth G.C. Smith