People critically ill with COVID-19 exhibit peripheral immune profiles predictive of mortality and reflective of SARS-CoV-2 lung viral burden

Cell Rep Med. 2021 Dec 21;2(12):100476. doi: 10.1016/j.xcrm.2021.100476. Epub 2021 Dec 2.


Despite extensive analyses, there remains an urgent need to delineate immune cell states that contribute to mortality in people critically ill with COVID-19. Here, we present high-dimensional profiling of blood and respiratory samples from people with severe COVID-19 to examine the association between cell-linked molecular features and mortality outcomes. Peripheral transcriptional profiles by single-cell RNA sequencing (RNA-seq)-based deconvolution of immune states are associated with COVID-19 mortality. Further, persistently high levels of an interferon signaling module in monocytes over time lead to subsequent concerted upregulation of inflammatory cytokines. SARS-CoV-2-infected myeloid cells in the lower respiratory tract upregulate CXCL10, leading to a higher risk of death. Our analysis suggests a pivotal role for viral-infected myeloid cells and protracted interferon signaling in severe COVID-19.

Keywords: COVID-19; COVID-19 outcome; gene modules; inflammatory cytokines; inflammatory monocytes; machine learning; severe COVID-19; single-cell RNA-seq; type I interferon.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • COVID-19 / blood
  • COVID-19 / immunology*
  • COVID-19 / mortality*
  • COVID-19 / virology
  • Critical Illness
  • Cytokines / blood
  • Gene Regulatory Networks
  • Humans
  • Inflammation
  • Lung / immunology*
  • Lung / virology
  • Models, Theoretical
  • Monocytes / immunology
  • Myeloid Cells / immunology
  • Reproducibility of Results
  • SARS-CoV-2 / pathogenicity*
  • Viral Load


  • Cytokines