Whole blood transcriptomics reveals sepsis mortality-associated changes in neutrophil degranulation

Transcriptomic analysis of blood cells can reveal key elements of the dysregulated host response in sepsis and spur biomarker and mechanism identification. We hypothesized that sepsis nonsurvivors exhibit a distinct transcriptional signature in whole blood that reflects insights into sepsis mortality. We conducted a prospective observational cohort study of 161 critically ill sepsis patients. Whole blood RNA was collected within 24 hours of intensive care unit admission. Gene expression levels were measured using microarrays, and changes in gene levels were compared between 30-day nonsurvivors and survivors, adjusting for age, sex, and neutrophil count. Pathway overrepresentation analysis and weighted gene co-expression analysis were performed to identify biological pathways and gene co-expression groups, respectively, associated with sepsis mortality. Gene- and pathway-based results were compared to findings in an independent cohort of 479 sepsis patients with 28-day mortality data. Thirty-day mortality in the enrolled sepsis cohort was 37% (60 of 161 patients). We identified 1106 differentially expressed genes in nonsurvivors (Benjamini-Hochberg-adjusted P-value <.05), including several neutrophil-related genes (CEACAM8, ELANE, PRTN3, MPO, CEACAM6, DEFA4, MS4A3) with expression levels over 1.8 times higher in nonsurvivors despite adjusting for neutrophil counts. The neutrophil degranulation pathway was prominent based on its overrepresentation in (1) differentially expressed genes in both cohorts, (2) overrepresentation by gene set enrichment analysis, and (3) 4 of the 6 gene co-expression groups correlated with sepsis mortality. Our findings highlight the involvement of neutrophil degranulation genes in sepsis mortality, prompting further study to better understand whether they constitute a modifiable target.