Critical COVID-19 is associated with distinct leukocyte phenotypes and transcriptome patterns

J Intern Med. 2021 Sep;290(3):677-692. doi: 10.1111/joim.13310. Epub 2021 Jun 3.


Background: Prognostic markers for disease severity and identification of therapeutic targets in COVID-19 are urgently needed. We have studied innate and adaptive immunity on protein and transcriptomic level in COVID-19 patients with different disease severity at admission and longitudinally during hospitalization.

Methods: Peripheral blood mononuclear cells (PBMCs) were collected at three time points from 31 patients included in the Norwegian SARS-CoV-2 cohort study and analysed by flow cytometry and RNA sequencing. Patients were grouped as either mild/moderate (n = 14), severe (n = 11) or critical (n = 6) disease in accordance with WHO guidelines and compared with patients with SARS-CoV-2-negative bacterial sepsis (n = 5) and healthy controls (n = 10).

Results: COVID-19 severity was characterized by decreased interleukin 7 receptor alpha chain (CD127) expression in naïve CD4 and CD8 T cells. Activation (CD25 and HLA-DR) and exhaustion (PD-1) markers on T cells were increased compared with controls, but comparable between COVID-19 severity groups. Non-classical monocytes and monocytic HLA-DR expression decreased whereas monocytic PD-L1 and CD142 expression increased with COVID-19 severity. RNA sequencing exhibited increased plasma B-cell activity in critical COVID-19 and yet predominantly reduced transcripts related to immune response pathways compared with milder disease.

Conclusion: Critical COVID-19 seems to be characterized by an immune profile of activated and exhausted T cells and monocytes. This immune phenotype may influence the capacity to mount an efficient T-cell immune response. Plasma B-cell activity and calprotectin were higher in critical COVID-19 while most transcripts related to immune functions were reduced, in particular affecting B cells. The potential of these cells as therapeutic targets in COVID-19 should be further explored.

Keywords: B cells; COVID-19; T cells; flow cytometry; monocytes; transcriptomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Adult
  • B-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • COVID-19 / genetics*
  • COVID-19 / immunology*
  • Female
  • HLA-DR Antigens / immunology
  • Humans
  • Immunity, Innate
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Interleukin-7 / immunology
  • Leukocyte L1 Antigen Complex / blood
  • Leukocytes, Mononuclear / immunology*
  • Male
  • Middle Aged
  • Monocytes / immunology
  • Phenotype
  • Programmed Cell Death 1 Receptor / immunology
  • SARS-CoV-2
  • Severity of Illness Index
  • T-Lymphocytes, Regulatory / immunology
  • Thromboplastin / immunology
  • Thromboplastin / metabolism
  • Transcriptome*


  • HLA-DR Antigens
  • IL2RA protein, human
  • IL7 protein, human
  • Interleukin-2 Receptor alpha Subunit
  • Interleukin-7
  • Leukocyte L1 Antigen Complex
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Thromboplastin