Relative adrenal insufficiency is a risk factor in pediatric sepsis

Glucocorticoid (GC) therapy had been strongly recommended for pediatric sepsis (grade 1A). However, the recommendation was changed to grade 2C in 2020. Thus, there is an urgent need to determine if GC therapy is beneficial in pediatric sepsis. Relative adrenal insufficiency (RAI) develops in 33.3% of pediatric septic patients. But little is known about the pathogenesis of RAI and whether GC therapy should be based on the status of RAI. In this study, we utilized 21-day-old SF1CreSRBIfl/fl mice as a pediatric RAI mouse model to assess the pathogenesis of RAI and evaluate GC therapy. We found that RAI mice were susceptible to both cecal ligation and puncture (CLP) and cecal slurry induced septic death. SF1CreSRBIfl/fl mice featured persistent inflammatory responses, and they were effectively rescued by GC therapy. RNA-seq analysis revealed that RAI leads to the persistent inflammatory responses mainly due to transcriptional dysregulation of AP-1 and NF-?B. A number of prognostic biomarkers reported in pediatric septic patients were also identified in RAI mice. Our findings support a precision medicine approach to guide GC therapy for pediatric patients - use of GC based on the status of RAI. Overall design: Bulk RNA sequencing of liver from 21-day-old SRBIfl/fl and SF1CreSRBIfl/fl mice (n=3) at CLP 6h