Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model
- 13 November 2019
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 11 (518)
- https://doi.org/10.1126/scitranslmed.aax9000
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.Keywords
Funding Information
- National Institute of General Medical Sciences (R35GM126943)
This publication has 29 references indexed in Scilit:
- Chemokines and Chemokine Receptors: Positioning Cells for Host Defense and ImmunityAnnual Review of Immunology, 2014
- The pediatric sepsis biomarker risk modelCritical Care, 2012
- Biomarker discovery and development in pediatric critical care medicine*Pediatric Critical Care Medicine, 2011
- Stratification is the key: Inflammatory biomarkers accurately direct immunomodulatory therapy in experimental sepsis*Critical Care Medicine, 2009
- Role of the chemokine decoy receptor D6 in balancing inflammation, immune activation, and antimicrobial resistance in Mycobacterium tuberculosis infectionThe Journal of Experimental Medicine, 2008
- Genome-level expression profiles in pediatric septic shock indicate a role for altered zinc homeostasis in poor outcomePhysiological Genomics, 2007
- A rapid, simple, and humane method for submandibular bleeding of mice using a lancetLab Animal, 2005
- Refining clinical diagnosis with likelihood ratiosThe Lancet, 2005
- International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics*Pediatric Critical Care Medicine, 2005
- A method of comparing the areas under receiver operating characteristic curves derived from the same cases.Radiology, 1983