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

PLoS Pathog. 2021 Sep 16;17(9):e1009804. doi: 10.1371/journal.ppat.1009804. eCollection 2021 Sep.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Biomarkers
  • Blood Proteins
  • CD69 antigen
  • Lectins, C-Type