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Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients.
Youngs, Jonathan; Provine, Nicholas M; Lim, Nicholas; Sharpe, Hannah R; Amini, Ali; Chen, Yi-Ling; Luo, Jian; Edmans, Matthew D; Zacharopoulou, Panagiota; Chen, Wentao; Sampson, Oliver; Paton, Robert; Hurt, William J; Duncan, David A; McNaughton, Anna L; Miao, Vincent N; Leaver, Susannah; Wyncoll, Duncan L A; Ball, Jonathan; Hopkins, Philip; Skelly, Donal T; Barnes, Eleanor; Dunachie, Susanna; Ogg, Graham; Lambe, Teresa; Pavord, Ian; Shalek, Alex K; Thompson, Craig P; Xue, Luzheng; Macallan, Derek C; Goulder, Philip; Klenerman, Paul; Bicanic, Tihana.
  • Youngs J; Institute for Infection & Immunity, St. George's University of London, London, United Kingdom.
  • Provine NM; Clinical Academic Group in Infection and Immunity, St. George's Hospital NHS Trust, London, United Kingdom.
  • Lim N; Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • Sharpe HR; Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • Amini A; Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • Chen YL; Jenner Institute, University of Oxford, Oxford, United Kingdom.
  • Luo J; Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • Edmans MD; Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • Zacharopoulou P; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
  • Chen W; Respiratory Medicine Unit, and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
  • Sampson O; Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • Paton R; Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • Hurt WJ; Respiratory Medicine Unit, and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
  • Duncan DA; Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • McNaughton AL; Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • Miao VN; Institute for Infection & Immunity, St. George's University of London, London, United Kingdom.
  • Leaver S; Clinical Academic Group in Infection and Immunity, St. George's Hospital NHS Trust, London, United Kingdom.
  • Wyncoll DLA; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
  • Ball J; Diamond Light Source, Harwell Science and Innovation Campus, Didcot, United Kingdom.
  • Hopkins P; Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • Skelly DT; Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, United States of America.
  • Barnes E; Intensive Care Medicine, St George's University Hospital NHS Foundation Trust, London, United Kingdom.
  • Dunachie S; Intensive Care Medicine, Guy's and St Thomas' Hospital NHS Foundation Trust, London, United Kingdom.
  • Ogg G; Intensive Care Medicine, St George's University Hospital NHS Foundation Trust, London, United Kingdom.
  • Lambe T; Centre for Human & Applied Physiological Sciences, School of Basic & Medical Biosciences, Faculty of Life Sciences, & Medicine, King's College, London, United Kingdom.
  • Thompson CP; Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • Xue L; Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • Macallan DC; Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • Goulder P; Jenner Institute, University of Oxford, Oxford, United Kingdom.
  • Klenerman P; Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • Bicanic T; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
PLoS Pathog ; 17(9): e1009804, 2021 09.
Article in English | MEDLINE | ID: covidwho-1416909
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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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Type of study: Diagnostic study / Etiology study / Incidence study / Observational study / Prognostic study / Risk factors Limits: Female / Humans / Male / Middle aged Language: English Journal: PLoS Pathog Year: 2021 Document Type: Article Affiliation country: Journal.ppat.1009804

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Full text: Available Collection: International databases Database: MEDLINE Main subject: COVID-19 Type of study: Diagnostic study / Etiology study / Incidence study / Observational study / Prognostic study / Risk factors Limits: Female / Humans / Male / Middle aged Language: English Journal: PLoS Pathog Year: 2021 Document Type: Article Affiliation country: Journal.ppat.1009804