Research ArticleSepsis

Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model

See allHide authors and affiliations

Science Translational Medicine  13 Nov 2019:
Vol. 11, Issue 518, eaax9000
DOI: 10.1126/scitranslmed.aax9000

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Persevering in the face of sepsis

Despite modern therapies, sepsis remains a major clinical problem with a high risk of mortality. Wong et al. validated a tool called PERSEVERE for predicting mortality in the setting of pediatric sepsis and then built on it to compare therapeutic strategies. To enable the use of this approach in experimental models, the authors developed an adapted version of the tool and validated it in a mouse model of sepsis. They then used mice to compare two potential therapeutic strategies, targeting inflammation or focusing on killing bacteria with high-dose antibiotics. The latter approach was much more effective in animals at high risk of death from sepsis.

Abstract

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.

View Full Text