Background: Septic shock is associated with high mortality and there is significant heterogeneity in the host response. The aim of this study was to understand the genome-wide expression transcriptomic signatures in children with septic shock and correlate them with outcomes. Methods: This was a prospective study conducted on children (aged 1 month to 18 years) admitted to the PICU (June–December 2021) with septic shock. Demographic details, clinical details, and administered treatment were collected. Differential gene expression analysis was performed to understand the genes and pathways affecting in different subjects. Results: Fifteen patients were recruited (Septic shock survivors (n = 5), nonsurvivors (n = 5), and non-sepsis controls (n = 5). The median age of the patients in survivors and nonsurvivors was 15 (13, 24) months and 180 (180, 184) months, respectively. The sepsis-survivors vs nonsepsis possessed 983 upregulated and 624 downregulated genes while comparing sepsis nonsurvivors (SNS) with nonsepsis yielded 1,854 upregulated and 1,761 downregulated genes. Further, the lowest number of deregulated genes (383 upregulated and 486 downregulated) were present in SNS compared to sepsis survivors. The major Reactome pathways, found upregulated in SNSs relative to survivors included CD22 mediated B cell receptor (BCR) regulation, scavenging of heme from plasma, and creation of C4 and C2 activators while T cell receptor (TCR) signaling, the common pathway of fibrin clot formation and generation of second messenger molecules were found to be downregulated. Conclusion: Mortality-related gene signatures are promising diagnostic biomarkers for pediatric sepsis.

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