Aïda Meghraoui-Kheddar1, Benjamin G Chousterman2,3, Noëlline Guillou1, Sierra M Barone4, Samuel Granjeaud5, Helene Vallet1,6, Aurélien Corneau7, Karim Guessous2, Charles de Roquetaillade2,3, Alexandre Boissonnas1, Jonathan M Irish4,8, Christophe Combadière1. 1. 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. 2. Dispositif Minimum d'Urgence Parabol, Fédération Hospitalo-Universitaire Promice, Service d'Anesthésie et de Soins Intensifs, Centre Hospitalier Universitaire Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France. 3. U942: Marqueurs Cardiovasculaires en Situation de Stress, Université de Paris-Institut National de la Santé et de la Recherche Médicale, Paris, France. 4. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee. 5. U1068/UM 105/UMR7258: Marseille Cancer Research Center, National Institute of Health and Medical Research-Paoli-Calmettes Institute-Aix-Marseille University-National Center for Scientific Research, Marseille, France. 6. Acute Geriatric Unit, Saint Antoine Hospital, Public Assistance-Hospitals of Paris, Paris, France. 7. Cytométrie Pitié-Salpêtrière, UMS037: Production et Analyse de Données en Sciences de la Vie et en Santé, Sorbonne Université, Paris, France; and. 8. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
Abstract
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.
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.
Authors: Brittany P Boribong; Thomas J LaSalle; Yannic C Bartsch; Felix Ellett; Maggie E Loiselle; Jameson P Davis; Anna L K Gonye; Soroush Hajizadeh; Johannes Kreuzer; Shiv Pillai; Wilhelm Haas; Andrea Edlow; Alessio Fasano; Galit Alter; Daniel Irimia; Moshe Sade-Feldman; Lael M Yonker Journal: bioRxiv Date: 2021-12-20