Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients
Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients
Contributed equally to this work with: Jonathan Youngs, Nicholas M. Provine, Nicholas Lim
ROLES Conceptualization, Investigation, Writing – original draft, Writing – review & editing
AFFILIATIONS Institute for Infection & Immunity, St. George’s University of London, London, United Kingdom, Clinical Academic Group in Infection and Immunity, St. George’s Hospital NHS Trust, London, United Kingdom
https://orcid.org/0000-0001-8781-2615Contributed equally to this work with: Jonathan Youngs, Nicholas M. Provine, Nicholas Lim
ROLES Conceptualization, Investigation, Project administration, Writing – original draft, Writing – review & editing
AFFILIATIONS Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom, Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
Contributed equally to this work with: Jonathan Youngs, Nicholas M. Provine, Nicholas Lim
ROLES Conceptualization, Investigation, Writing – original draft, Writing – review & editing
AFFILIATION Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
ROLES Investigation, Writing – review & editing
‡ HS, AA, Y-LC, and JL also contributed equally to this work.
AFFILIATION Jenner Institute, University of Oxford, Oxford, United Kingdom
ROLES Investigation, Writing – original draft, Writing – review & editing
‡ HS, AA, Y-LC, and JL also contributed equally to this work.
AFFILIATIONS Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom, Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
ROLES Investigation, Writing – review & editing
‡ HS, AA, Y-LC, and JL also contributed equally to this work.
AFFILIATION MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
ROLES Investigation, Writing – review & editing
‡ HS, AA, Y-LC, and JL also contributed equally to this work.
AFFILIATION Respiratory Medicine Unit, and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
ROLES Investigation, Writing – review & editing
AFFILIATION Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
ROLES Investigation, Writing – review & editing
AFFILIATION Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
ROLES Investigation
AFFILIATION Respiratory Medicine Unit, and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
ROLES Investigation, Writing – review & editing
AFFILIATION Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
ROLES Investigation, Writing – review & editing
AFFILIATION Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
ROLES Data curation, Resources, Writing – review & editing
AFFILIATIONS Institute for Infection & Immunity, St. George’s University of London, London, United Kingdom, Clinical Academic Group in Infection and Immunity, St. George’s Hospital NHS Trust, London, United Kingdom
ROLES Investigation, Writing – review & editing
AFFILIATIONS MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, United Kingdom
ROLES Investigation, Writing – review & editing
AFFILIATION Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
ROLES Investigation, Resources, Writing – review & editing
AFFILIATIONS Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America, Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, United States of America
ROLES Resources, Writing – review & editing
AFFILIATION Intensive Care Medicine, St George’s University Hospital NHS Foundation Trust, London, United Kingdom
ROLES Resources, Writing – review & editing
AFFILIATION Intensive Care Medicine, Guy’s and St Thomas’ Hospital NHS Foundation Trust, London, United Kingdom
ROLES Resources, Writing – review & editing
AFFILIATION Intensive Care Medicine, St George’s University Hospital NHS Foundation Trust, London, United Kingdom
ROLES Resources, Writing – review & editing
AFFILIATION Centre for Human & Applied Physiological Sciences, School of Basic & Medical Biosciences, Faculty of Life Sciences, & Medicine, King’s College, London, United Kingdom
Membership of the Oxford Immunology Network Covid-19 response T cell Consortium and Oxford Protective T cell Immunology for COVID-19 (OPTIC) Clinical team are listed in the Acknowledgments.
Membership of the Oxford Immunology Network Covid-19 response T cell Consortium and Oxford Protective T cell Immunology for COVID-19 (OPTIC) Clinical team are listed in the Acknowledgments.
ROLES Resources, Writing – review & editing
AFFILIATION Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
ROLES Resources, Writing – review & editing
AFFILIATIONS Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom, Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom, Jenner Institute, University of Oxford, Oxford, United Kingdom
ROLES Resources, Writing – review & editing
AFFILIATION Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
ROLES Resources
AFFILIATION MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
ROLES Resources, Writing – review & editing
AFFILIATION Jenner Institute, University of Oxford, Oxford, United Kingdom
ROLES Investigation, Writing – review & editing
AFFILIATION Respiratory Medicine Unit, and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
ROLES Investigation, Writing – review & editing
AFFILIATIONS Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America, Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, United States of America
ROLES Investigation, Writing – review & editing
AFFILIATION Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
ROLES Investigation, Writing – original draft, Writing – review & editing
AFFILIATION Respiratory Medicine Unit, and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
ROLES Conceptualization, Resources, Writing – original draft, Writing – review & editing
AFFILIATIONS Institute for Infection & Immunity, St. George’s University of London, London, United Kingdom, Clinical Academic Group in Infection and Immunity, St. George’s Hospital NHS Trust, London, United Kingdom
ROLES Conceptualization, Funding acquisition, Resources, Supervision, Writing – original draft, Writing – review & editing
‡ PG, PK, and TB jointly led this project.
AFFILIATION Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
ROLES Conceptualization, Funding acquisition, Investigation, Resources, Writing – original draft, Writing – review & editing
* E-mail: paul.klenerman@medawar.ox.ac.uk
‡ PG, PK, and TB jointly led this project.
AFFILIATIONS Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom, Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
ROLES Conceptualization, Funding acquisition, Investigation, Resources, Writing – original draft, Writing – review & editing
‡ PG, PK, and TB jointly led this project.
AFFILIATIONS Institute for Infection & Immunity, St. George’s University of London, London, United Kingdom, Clinical Academic Group in Infection and Immunity, St. George’s Hospital NHS Trust, London, United Kingdom
Abstract
Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49–14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08–18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 –a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.
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