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Early Immune Pathology and Persistent Dysregulation Characterise Severe COVID-19

105 Pages Posted: 29 Dec 2020 Publication Status: Published

See all articles by Laura Bergamaschi

Laura Bergamaschi

University of Cambridge - Department of Medicine

Federica Mescia

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease

Lorinda Turner

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease

Aimee Hanson

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease

Prasanti Kotagiri

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease

Benjamin J. Dunmore

University of Cambridge - Department of Medicine

Helene Ruffieux

University of Cambridge - MRC Biostatistics Unit

Aloka De Sa

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease

Oisin Huhn

University of Cambridge - Department of Medicine

Mark R. Wills

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease; University of Cambridge - Department of Medicine

Stephen Baker

University of Cambridge - Department of Medicine

Rainer Doffinger

NIHR Cambridge Clinical Research Facility

Gordon Dougan

University of Cambridge - Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)

Anne Elmer

NIHR Cambridge Clinic Research Facility - Addenbrooke's Hospital

Ian Goodfellow

University of Cambridge - Division of Virology

Ravindra K. Gupta

Cambridge Institute of Therapeutic Immunology & Infectious Disease; University of Cambridge - Department of Medicine

Myra Hosmillo

Addenbrooke's Hospital - Division of Virology

Kelvin Hunter

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease

Nathalie Kingston

NIHR Cambridge Biomedical Research Centre - NIHR BioResource

Paul Lehner

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease

Nicholas J. Matheson

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease

Jeremy K. Nicholson

Murdoch University - The Centre for Computational and Systems Medicine

Anna M. Petrunkina

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease

Sylvia Richardson

University of Cambridge - MRC Biostatistics Unit

Caroline Saunders

NIHR Cambridge Clinic Research Facility - Addenbrooke's Hospital

James Thaventhiran

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease

Erik J. M. Toonen

Hycult Biotech - R&D Department

Michael P. Weekes

Cambridge University Hospitals NHS Foundation Trust

(CITIID-NIHR) COVID BioResource Collaboration Group

Independent

Mark Toshner

Royal Papworth Hospital; University of Cambridge - Heart and Lung Research Institute

Christoph Hess

University Hospital Basel - Immunobiology Laboratory

John R. Bradley

University of Cambridge - Department of Medicine

Paul A. Lyons

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease

Kenneth G.C. Smith

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease

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Abstract

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.

Suggested Citation

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.

Laura Bergamaschi (Contact Author)

University of Cambridge - Department of Medicine ( email )

Box 157
Hills Rd
Cambridge, CB2 0QQ
United Kingdom

Federica Mescia

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease ( email )

United Kingdom

Lorinda Turner

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease ( email )

United Kingdom

Aimee Hanson

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease ( email )

United Kingdom

Prasanti Kotagiri

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease ( email )

United Kingdom

Benjamin J. Dunmore

University of Cambridge - Department of Medicine ( email )

Box 157
Hills Rd
Cambridge, CB2 0QQ
United Kingdom

Helene Ruffieux

University of Cambridge - MRC Biostatistics Unit ( email )

Cambridge
United Kingdom

Aloka De Sa

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease ( email )

United Kingdom

Oisin Huhn

University of Cambridge - Department of Medicine

Box 157
Hills Rd
Cambridge, CB2 0QQ
United Kingdom

Mark R. Wills

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease ( email )

Cambridge CB2 0AW
United Kingdom
441223 336862 (Phone)

University of Cambridge - Department of Medicine ( email )

Cambridge CB2 0AW
United Kingdom
441223 336862 (Phone)

Stephen Baker

University of Cambridge - Department of Medicine

Rainer Doffinger

NIHR Cambridge Clinical Research Facility ( email )

Cambridge
United Kingdom

Gordon Dougan

University of Cambridge - Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID) ( email )

Cambridge
United Kingdom

Anne Elmer

NIHR Cambridge Clinic Research Facility - Addenbrooke's Hospital ( email )

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Ian Goodfellow

University of Cambridge - Division of Virology ( email )

Ravindra K. Gupta

Cambridge Institute of Therapeutic Immunology & Infectious Disease ( email )

Cambridge CB2 0AW
United Kingdom
441223331491 (Phone)

University of Cambridge - Department of Medicine

Cambridge CB2 0AW
United Kingdom

Myra Hosmillo

Addenbrooke's Hospital - Division of Virology ( email )

Trinity Ln
Cambridge, CB2 1TN
United Kingdom

Kelvin Hunter

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease ( email )

United Kingdom

Nathalie Kingston

NIHR Cambridge Biomedical Research Centre - NIHR BioResource ( email )

Paul Lehner

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease ( email )

United Kingdom

Nicholas J. Matheson

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease ( email )

United Kingdom

Jeremy K. Nicholson

Murdoch University - The Centre for Computational and Systems Medicine ( email )

South Street
Murdoch 6150, Western Australia
Australia

Anna M. Petrunkina

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease ( email )

United Kingdom

Sylvia Richardson

University of Cambridge - MRC Biostatistics Unit ( email )

Cambridge, CB2 OSR
United Kingdom

Caroline Saunders

NIHR Cambridge Clinic Research Facility - Addenbrooke's Hospital ( email )

Cambridge Biomedical Campus
Hills Road
Cambridge, CB2 0QQ
United Kingdom

James Thaventhiran

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease ( email )

United Kingdom

Erik J. M. Toonen

Hycult Biotech - R&D Department ( email )

Michael P. Weekes

Cambridge University Hospitals NHS Foundation Trust ( email )

Mark Toshner

Royal Papworth Hospital ( email )

Papworth Everard
Cambridge, England CB23 3RE
United Kingdom

University of Cambridge - Heart and Lung Research Institute ( email )

Cambridge
United Kingdom

Christoph Hess

University Hospital Basel - Immunobiology Laboratory

Switzerland

John R. Bradley

University of Cambridge - Department of Medicine ( email )

Box 157
Hills Rd
Cambridge, CB2 0QQ
United Kingdom

Paul A. Lyons

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease ( email )

United Kingdom

Kenneth G.C. Smith

University of Cambridge - Cambridge Institute for Therapeutic Immunology and Infectious Disease ( email )

United Kingdom

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