Pediatric Sepsis Biomarker Risk Model-II: Redefining the Pediatric Sepsis Biomarker Risk Model With Septic Shock Phenotype

Abstract

Objective: The Pediatric Sepsis Biomarker Risk Model (PERSEVERE), a pediatric sepsis risk model, uses biomarkers to estimate baseline mortality risk for pediatric septic shock. It is unknown how PERSEVERE performs within distinct septic shock phenotypes. We tested PERSEVERE in children with septic shock and thrombocytopenia-associated multiple organ failure (TAMOF), and in those without new onset thrombocytopenia but with multiple organ failure (MOF).

Design: PERSEVERE-based mortality risk was generated for each study subject (n = 660). A priori, we determined that if PERSEVERE did not perform well in both the TAMOF and the MOF cohorts, we would revise PERSEVERE to incorporate admission platelet counts.

Setting: Multiple PICUs in the United States.

Interventions: Standard care.

Measurements and main results: PERSEVERE performed well in the TAMOF cohort (areas under the receiver operating characteristic curves [AUC], 0.84 [95% CI, 0.77-0.90]), but less well in the MOF cohort (AUC, 0.71 [0.61-0.80]). PERSEVERE was revised using 424 subjects previously reported in the derivation phase. PERSEVERE-II had an AUC of 0.89 (0.85-0.93) and performed equally well across TAMOF and MOF cohorts. PERSEVERE-II performed well when tested in 236 newly enrolled subjects. Sample size calculations for a clinical trial testing the efficacy of plasma exchange for children with septic shock and TAMOF indicated PERSEVERE-II-based stratification could substantially reduce the number of patients necessary, when compared with no stratification.

Conclusions: Testing PERSEVERE in the context of septic shock phenotypes prompted a revision incorporating platelet count. PERSEVERE-II performs well upon testing, independent of TAMOF or MOF status. PERSEVERE-II could potentially serve as a prognostic enrichment tool.

Figure 1. The PERSEVERE-II classification tree

The classification tree includes C-C chemokine ligand 3 (CCL3), interleukin 8 (IL8), heat shock protein 70 kDa 1B (HSPA1B), granzyme B (GZMB), matrix metallopeptidase 8 (MMP8), and admission platelet counts. The biomarker concentrations are shown in ng/ml and platelet counts are shown in number/μl. The root node provides the total number of patients in the derivation cohort, and the number of survivors and non-survivors, with the respective rates. Each daughter node provides the respective decision rule criterion and the number of survivors and non-survivors, with the respective rates. Terminal nodes (TN) TN1, TN 2, TN 5, TN8, and TN9 are low risk terminal nodes (≤1.9% risk of death). TN4, TN6, TN7, and TN10 are intermediate risk terminal nodes (16.7% to 33.3% risk of death. TN3 and TN11 are high risk terminal nodes (≥44.4% risk of death).