Integrated PERSEVERE and endothelial biomarker risk model predicts MODS in pediatric septic shock: A retrospective observational study

Abstract Background: Multiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of persistent organ dysfunctions is necessary to enrich patients for future trials of sepsis therapeutics. Here, we sought to integrate endothelial and PERSEVERE biomarkers to estimate risk of day 7 MODS and individual organ dysfunctions on day 7 of pediatric septic shock.Methods: We measured endothelial dysfunction markers from day 1 serum among those with existing PERSEVERE data. TreeNet® classification model was derived incorporating 22 clinical and biological variables to estimate risk. Based on relative variable importance, a simplified 6 biomarker model was developed thereafter. Results: Among 502 patients, 173 (34.5%) patients had MODS on day 7. Area under the receiver operator characteristic curve (AUROC) for the newly derived PERSEVEREnce model to predict day 7 MODS was 0.93 (0.91-0.95) with a summary AUROC of 0.80 (0.76-0.84) upon 10-fold cross validation. The simplified model, based on IL-8, HSP70, ICAM-1, Angpt2/Tie2, Angpt2/Angpt1, and Thrombomodulin performed similarly. Interaction between variables – ICAM-1 with IL-8 and Thrombomodulin with Angpt2/Angpt1 contributed to the models’ predictive capabilities. Model performance varied when estimating risk of individual organ dysfunctions with AUROCS ranging between 0.91 to 0.97 and 0.68 to 0.89 in training and test sets respectively. Conclusions: The newly derived PERSEVEREnce biomarker model reliably estimates risk of day 7 MODS and individual organ dysfunctions in pediatric septic shock. If validated, this tool can be used for prognostic enrichment in future pediatric trials of sepsis therapeutics.