Neutrophil Dysregulation Differentiates Pediatric Septic Shock Biomarker Based Mortality Risk Strata: Insights from Weighted Gene Co-expression Network and Transcriptomic Analyses

BackgroundPediatric sepsis is a leading cause of global mortality, particularly among children, with limited therapeutic options beyond antibiotics and organ support. The Pediatric Sepsis Biomarker Risk Model (PERSEVERE-II) stratifies mortality risk in pediatric septic shock, yet the molecular mechanisms underlying high mortality risk remain incompletely understood.MethodsWe analyzed whole blood transcriptomes collected from 81 children with septic shock on day 1 of meeting study criteria. Patients were stratified into high- and low-mortality risk groups according to the PERSEVERE-II biomarker risk model. Using weighted gene co-expression network analysis (WGCNA) and differential gene expression analyses, we identified molecular pathways and transcription factors (TFs) associated with mortality risk. Cell type differences were inferred using CIBERSORTx and using a reference single-cell dataset inclusive of neutrophils and their subsets.FindingsWe identified distinct molecular profiles with high-risk patients displaying significant overexpression of genes related to neutrophil degranulation and innate immunity, alongside suppressed adaptive immune responses. The predominance of developing neutrophils underscored a major role of emergency granulopoiesis. Key TFs identified, including LTF, FOXM1, KLF1, and CEBPB, were linked to high-risk gene expression signatures. Our findings indicate a pathological shift toward a dysregulated neutrophil-driven hyperinflammation and adaptive immune suppressive state, which together are associated with adverse outcomes.InterpretationOur results suggest that neutrophil dysregulation underpins the high mortality risk conferred by the PERSEVERE-II model. The identified transcriptional regulators may provide potential targets to mitigate neutrophil dysregulation and improve outcomes among high-risk patients.