Altered neutrophil and granulopoiesis biology underlie a poor outcome sepsis endotype

The maladaptive response to infection leading to the clinical syndrome of sepsis is highly heterogeneous, confounding immunotherapy trials. Here we establish the pathophysiology of a sepsis response endotype informative for immune state, disease severity, outcome and therapy. We applied whole blood single-cell multiomics (272,993 cells, n=39 individuals) and found patients with this endotype had increased IL1R2+ immature neutrophils, confirmed using CyTOF (n=41 samples) and RNA-sequencing (n=677 individuals), and upregulated STAT3 programs with plasma cytokine profiles of emergency granulopoiesis (EG). We characterised sepsis hematopoietic stem cells (29,336 cells, n=27 samples) with multiomics, and demonstrated endotype-specific EG transcriptional skewing together with STAT3 and EG master regulator CEBPB epigenetic signatures. Our findings establish an immunohematopoietic basis for a deleterious sepsis endotype and nominate IL-6/G-CSF as potential therapeutic targets.EGA study EGAS00001006283