Sepsis remains a major public health problem with no major therapeutic advances over the last several decades. The clinical and biological heterogeneity of sepsis have limited success of potential new therapies. Accordingly, there is considerable interest in developing a precision medicine approach to inform more rational development, testing, and targeting of new therapies. We previously developed the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) to estimate mortality risk and proposed its use as a prognostic enrichment tool in sepsis clinical trials; prognostic enrichment selects patients based on mortality risk independent of treatment. Here, we show that PERSEVERE has excellent performance in a diverse cohort of children with septic shock with potential for use as a predictive enrichment strategy; predictive enrichment selects patients based on likely response to treatment. We demonstrate that the PERSEVERE biomarkers are reliably associated with mortality in mice challenged with experimental sepsis, thus providing an opportunity to test precision medicine strategies in the preclinical setting. Using this model, we tested two clinically feasible therapeutic strategies, guided by the PERSEVERE-based enrichment, and found that mice identified as high risk for mortality had a greater bacterial burden and could be rescued by higher doses of antibiotics. The association between higher pathogen burden and higher mortality risk was corroborated among critically ill children with septic shock. This bedside to bench to bedside approach provides proof of principle for PERSEVERE-guided application of precision medicine in sepsis.

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Background Multiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of death and 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 the composite risk of death or organ dysfunctions on day 7 of 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, 49 patients died before day 7 and 124 patients had persistence of MODS on day 7 of septic shock. Area under the receiver operator characteristic curve (AUROC) for the newly derived PERSEVEREnce model to predict death or day 7 MODS was 0.93 (0.91–0.95) with a summary AUROC of 0.80 (0.76–0.84) upon tenfold 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 from 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 death or persistent organ dysfunctions on day 7 of septic shock. If validated, this tool can be used for prognostic enrichment in future pediatric trials of sepsis therapeutics. Graphical abstract