PLoS Pathogens (Sep 2021)

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

DOI
https://doi.org/10.1371/journal.ppat.1009804
Journal volume & issue
Vol. 17, no. 9
p. e1009804

Abstract

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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.