Distinct immunological signatures discriminate severe COVID-19 from non-SARS-CoV-2-driven critical pneumonia

Immunity. 2021 Jul 13;54(7):1578-1593.e5. doi: 10.1016/j.immuni.2021.05.002. Epub 2021 May 9.


Immune profiling of COVID-19 patients has identified numerous alterations in both innate and adaptive immunity. However, whether those changes are specific to SARS-CoV-2 or driven by a general inflammatory response shared across severely ill pneumonia patients remains unknown. Here, we compared the immune profile of severe COVID-19 with non-SARS-CoV-2 pneumonia ICU patients using longitudinal, high-dimensional single-cell spectral cytometry and algorithm-guided analysis. COVID-19 and non-SARS-CoV-2 pneumonia both showed increased emergency myelopoiesis and displayed features of adaptive immune paralysis. However, pathological immune signatures suggestive of T cell exhaustion were exclusive to COVID-19. The integration of single-cell profiling with a predicted binding capacity of SARS-CoV-2 peptides to the patients' HLA profile further linked the COVID-19 immunopathology to impaired virus recognition. Toward clinical translation, circulating NKT cell frequency was identified as a predictive biomarker for patient outcome. Our comparative immune map serves to delineate treatment strategies to interfere with the immunopathologic cascade exclusive to severe COVID-19.

Trial registration: ClinicalTrials.gov NCT04385108.

Keywords: COVID-19; GM-CSF; HLA typing; SARS-CoV-2; biomarker; high-dimensional single cell analysis; immune profiling; immunophenotyping; peptide binding strength; spectral flow cytometry.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Antigen Presentation
  • Biomarkers / blood
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • COVID-19 / immunology*
  • COVID-19 / pathology
  • Female
  • HLA Antigens / genetics
  • HLA Antigens / immunology
  • Humans
  • Immunity, Innate
  • Immunophenotyping
  • Male
  • Middle Aged
  • Natural Killer T-Cells / immunology
  • Pneumonia / immunology
  • Pneumonia / pathology
  • SARS-CoV-2 / immunology
  • SARS-CoV-2 / pathogenicity*
  • Severity of Illness Index
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism


  • Biomarkers
  • HLA Antigens
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2

Associated data

  • ClinicalTrials.gov/NCT04385108