Two New Neutrophil Subsets Define a Discriminating Sepsis Signature

Am J Respir Crit Care Med. 2022 Jan 1;205(1):46-59. doi: 10.1164/rccm.202104-1027OC.


Rationale: Sepsis is the leading cause of death in adult ICUs. At present, sepsis diagnosis relies on nonspecific clinical features. It could transform clinical care to have immune-cell biomarkers that could predict sepsis diagnosis and guide treatment. For decades, neutrophil phenotypes have been studied in sepsis, but a diagnostic cell subset has yet to be identified. Objectives: To identify an early, specific immune signature of sepsis severity that does not overlap with other inflammatory biomarkers and that distinguishes patients with sepsis from those with noninfectious inflammatory syndrome. Methods: Mass cytometry combined with computational high-dimensional data analysis was used to measure 42 markers on whole-blood immune cells from patients with sepsis and control subjects and to automatically and comprehensively characterize circulating immune cells, which enables identification of novel, disease-specific cellular signatures. Measurements and Main Results: Unsupervised analysis of high-dimensional mass cytometry data characterized previously unappreciated heterogeneity within the CD64+ immature neutrophils and revealed two new subsets distinguished by CD123 and PD-L1 (programmed death ligand 1) expression. These immature neutrophils exhibited diminished activation and phagocytosis functions. The proportion of CD123-expressing neutrophils correlated with clinical severity. Conclusions: This study showed that these two new neutrophil subsets were specific to sepsis and detectable through routine flow cytometry by using seven markers. The demonstration here that a simple blood test distinguishes sepsis from other inflammatory conditions represents a key biological milestone that can be immediately translated into improvements in patient care.

Keywords: CD123; PD-L1; diagnosis; neutrophils; sepsis.

Publication types

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

MeSH terms

  • B7-H1 Antigen / blood*
  • Biomarkers / blood
  • Case-Control Studies
  • Clinical Decision Rules
  • Diagnosis, Differential
  • Flow Cytometry
  • Humans
  • Interleukin-3 Receptor alpha Subunit / blood*
  • Linear Models
  • Longitudinal Studies
  • Neutrophils / metabolism*
  • Receptors, IgG / blood
  • Sensitivity and Specificity
  • Sepsis / blood
  • Sepsis / diagnosis*
  • Sepsis / immunology
  • Severity of Illness Index


  • B7-H1 Antigen
  • Biomarkers
  • CD274 protein, human
  • IL3RA protein, human
  • Interleukin-3 Receptor alpha Subunit
  • Receptors, IgG