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”.
Funding: We are grateful for the generous support of CVC Capital Partners, the Evelyn Trust (20/75), UKRI COVID Immunology Consortium, Addenbrooke’s Charitable Trust (12/20A) and the NIHR Cambridge Biomedical Research Centre for their financial support. K.G.C.S. is the recipient of a Wellcome Investigator Award (200871/Z/16/Z); M.P.W. is the recipient of Wellcome Senior Clinical Research Fellowship (108070/Z/15/Z); C.H. was funded by a Wellcome COVID-19 Rapid Response DCF and the Fondation Botnar; N.M. was funded by the MRC (CSF MR/P008801/1) and NHSBT (WPA15-02); I.G.G. is a Wellcome Senior Fellow and was supported by funding from the Wellcome (Ref: 207498/Z/17/Z).
Conflict of Interest: The authors declare they have no competing interests.
Bergamaschi, Laura and Mescia, Federica and Turner, Lorinda and Hanson, Aimee and Kotagiri, Prasanti and Dunmore, Benjamin J. and Ruffieux, Helene and de Sa, Aloka and Huhn, Oisin and Wills, Mark R. and Baker, Stephen and Doffinger, Rainer and Dougan, Gordon and Elmer, Anne and Goodfellow, Ian and Gupta, Ravindra K. and Hosmillo, Myra and Hunter, Kelvin and Kingston, Nathalie and Lehner, Paul and Matheson, Nicholas J. and Nicholson, Jeremy K. and Petrunkina, Anna M. and Richardson, Sylvia and Saunders, Caroline and Thaventhiran, James and Toonen, Erik J. M. and Weekes, Michael P. and Group, (CITIID-NIHR) COVID BioResource Collaboration and Toshner, Mark and Hess, Christoph and Bradley, John R. and Lyons, Paul A. and Smith, Kenneth G.C., Early Immune Pathology and Persistent Dysregulation Characterise Severe COVID-19. Available at SSRN: https://ssrn.com/abstract=3757074 or http://dx.doi.org/10.2139/ssrn.3757074
This version of the paper has not been formally peer reviewed.
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