• Aïda Meghraoui-Kheddar, Benjamin G Chousterman, Noëlline Guillou, Sierra M Barone, Samuel Granjeaud, Helene Vallet, Aurélien Corneau, Karim Guessous, Charles de Roquetaillade, Alexandre Boissonnas, Jonathan M Irish, and Christophe Combadière.
• Sorbonne Université-Institut National de la Santé et de la Recherche Médicale-Centre National de la Recherche Scientifique, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
• Am. J. Respir. Crit. Care Med. 2022 Jan 1; 205 (1): 46-59.

AbstractRationale: 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.

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