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09, 2021;17 (9): e1009804.

Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients.

Jonathan Youngs, Nicholas M Provine, Nicholas Lim, Hannah R Sharpe, Ali Amini, Yi-Ling Chen, Jian Luo, Matthew D Edmans, Panagiota Zacharopoulou, Wentao Chen, Oliver Sampson, Robert Paton, William J Hurt, David A Duncan, Anna L McNaughton, Vincent N Miao, Susannah Leaver, Duncan L A Wyncoll, Jonathan Ball, Philip Hopkins, Oxford Immunology Network Covid-19 response T cell Consortium, Oxford Protective T cell Immunology for COVID-19 (OPTIC) Clinical team, Donal T Skelly, Eleanor Barnes, Susanna Dunachie, Graham Ogg, Teresa Lambe, Ian Pavord, Alex K Shalek, Craig P Thompson, Luzheng Xue, Derek C Macallan, Philip Goulder, Paul Klenerman, Tihana Bicanic
Author Information
  1. Jonathan Youngs: Institute for Infection & Immunity, St. George's University of London, London, United Kingdom. ORCID
  2. Nicholas M Provine: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. ORCID
  3. Nicholas Lim: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. ORCID
  4. Hannah R Sharpe: Jenner Institute, University of Oxford, Oxford, United Kingdom. ORCID
  5. Ali Amini: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. ORCID
  6. Yi-Ling Chen: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
  7. Jian Luo: Respiratory Medicine Unit, and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
  8. Matthew D Edmans: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. ORCID
  9. Panagiota Zacharopoulou: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. ORCID
  10. Wentao Chen: Respiratory Medicine Unit, and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
  11. Oliver Sampson: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. ORCID
  12. Robert Paton: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. ORCID
  13. William J Hurt: Institute for Infection & Immunity, St. George's University of London, London, United Kingdom.
  14. David A Duncan: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom. ORCID
  15. Anna L McNaughton: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. ORCID
  16. Vincent N Miao: 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. ORCID
  17. Susannah Leaver: Intensive Care Medicine, St George's University Hospital NHS Foundation Trust, London, United Kingdom.
  18. Duncan L A Wyncoll: Intensive Care Medicine, Guy's and St Thomas' Hospital NHS Foundation Trust, London, United Kingdom. ORCID
  19. Jonathan Ball: Intensive Care Medicine, St George's University Hospital NHS Foundation Trust, London, United Kingdom. ORCID
  20. Philip Hopkins: Centre for Human & Applied Physiological Sciences, School of Basic & Medical Biosciences, Faculty of Life Sciences, & Medicine, King's College, London, United Kingdom. ORCID
  21. Donal T Skelly: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. ORCID
  22. Eleanor Barnes: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  23. Susanna Dunachie: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. ORCID
  24. Graham Ogg: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
  25. Teresa Lambe: Jenner Institute, University of Oxford, Oxford, United Kingdom. ORCID
  26. Ian Pavord: Respiratory Medicine Unit, and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom. ORCID
  27. Alex K Shalek: 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. ORCID
  28. Craig P Thompson: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. ORCID
  29. Luzheng Xue: Respiratory Medicine Unit, and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom. ORCID
  30. Derek C Macallan: Institute for Infection & Immunity, St. George's University of London, London, United Kingdom. ORCID
  31. Philip Goulder: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. ORCID
  32. Paul Klenerman: Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. ORCID
  33. Tihana Bicanic: Institute for Infection & Immunity, St. George's University of London, London, United Kingdom. ORCID
PMID: 34529726 DOI: 10.1371/journal.ppat.1009804

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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Grants

  1. MR/V028448/1/Medical Research Council
  2. 203805/Z/16/Z/Wellcome Trust
  3. /Wellcome Trust
  4. MC_PC_20060/Medical Research Council
  5. 216417/Z/19/Z/Wellcome Trust

MeSH Term

Antibodies, Neutralizing
Antibodies, Viral
Antigens, CD
Antigens, Differentiation, T-Lymphocyte
B-Lymphocytes
Biomarkers
Blood Proteins
COVID-19
Cohort Studies
Critical Illness
Female
Humans
Immunophenotyping
Influenza, Human
Lectins, C-Type
Lymphocyte Activation
Male
Middle Aged
Mucosal-Associated Invariant T Cells
Patient Acuity

Chemicals

Antibodies, Neutralizing
Antibodies, Viral
Antigens, CD
Antigens, Differentiation, T-Lymphocyte
Biomarkers
Blood Proteins
CD69 antigen
Lectins, C-Type
Journal Article Research Support, Non-U.S. Gov't

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