Immunological Biomarkers of Fatal COVID-19: A Study of 868 Patients

Front Immunol. 2021 May 3:12:659018. doi: 10.3389/fimmu.2021.659018. eCollection 2021.


Information on the immunopathobiology of coronavirus disease 2019 (COVID-19) is rapidly increasing; however, there remains a need to identify immune features predictive of fatal outcome. This large-scale study characterized immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection using multidimensional flow cytometry, with the aim of identifying high-risk immune biomarkers. Holistic and unbiased analyses of 17 immune cell-types were conducted on 1,075 peripheral blood samples obtained from 868 COVID-19 patients and on samples from 24 patients presenting with non-SARS-CoV-2 infections and 36 healthy donors. Immune profiles of COVID-19 patients were significantly different from those of age-matched healthy donors but generally similar to those of patients with non-SARS-CoV-2 infections. Unsupervised clustering analysis revealed three immunotypes during SARS-CoV-2 infection; immunotype 1 (14% of patients) was characterized by significantly lower percentages of all immune cell-types except neutrophils and circulating plasma cells, and was significantly associated with severe disease. Reduced B-cell percentage was most strongly associated with risk of death. On multivariate analysis incorporating age and comorbidities, B-cell and non-classical monocyte percentages were independent prognostic factors for survival in training (n=513) and validation (n=355) cohorts. Therefore, reduced percentages of B-cells and non-classical monocytes are high-risk immune biomarkers for risk-stratification of COVID-19 patients.

Keywords: COVID-19; SARS-CoV-2; biomarkers; flow cytometry; lymphopenia; outcome; survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Adult
  • Aged
  • Aged, 80 and over
  • B-Lymphocytes / immunology
  • Biomarkers
  • COVID-19 / immunology*
  • COVID-19 / mortality*
  • COVID-19 / pathology
  • Female
  • Humans
  • Immunity, Innate
  • Lymphopenia / immunology
  • Lymphopenia / mortality
  • Lymphopenia / pathology
  • Male
  • Middle Aged
  • Monocytes / immunology
  • Prognosis
  • SARS-CoV-2
  • Survival Analysis
  • Young Adult


  • Biomarkers