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

Publication ,  Journal Article
Wong, HR; Caldwell, JT; Cvijanovich, NZ; Weiss, SL; Fitzgerald, JC; Bigham, MT; Jain, PN; Schwarz, A; Lutfi, R; Nowak, J; Allen, GL; Baines, T ...
Published in: Sci Transl Med
November 13, 2019

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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Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

November 13, 2019

Volume

11

Issue

518

Location

United States

Related Subject Headings

  • Survival Analysis
  • Sepsis
  • Risk Factors
  • Risk Assessment
  • Punctures
  • Prospective Studies
  • Models, Biological
  • Mice, Inbred C57BL
  • Male
  • Ligation
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wong, H. R., Caldwell, J. T., Cvijanovich, N. Z., Weiss, S. L., Fitzgerald, J. C., Bigham, M. T., … Lindsell, C. J. (2019). Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model. Sci Transl Med, 11(518). https://doi.org/10.1126/scitranslmed.aax9000
Wong, Hector R., J Timothy Caldwell, Natalie Z. Cvijanovich, Scott L. Weiss, Julie C. Fitzgerald, Michael T. Bigham, Parag N. Jain, et al. “Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model.Sci Transl Med 11, no. 518 (November 13, 2019). https://doi.org/10.1126/scitranslmed.aax9000.
Wong HR, Caldwell JT, Cvijanovich NZ, Weiss SL, Fitzgerald JC, Bigham MT, et al. Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model. Sci Transl Med. 2019 Nov 13;11(518).
Wong, Hector R., et al. “Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model.Sci Transl Med, vol. 11, no. 518, Nov. 2019. Pubmed, doi:10.1126/scitranslmed.aax9000.
Wong HR, Caldwell JT, Cvijanovich NZ, Weiss SL, Fitzgerald JC, Bigham MT, Jain PN, Schwarz A, Lutfi R, Nowak J, Allen GL, Thomas NJ, Grunwell JR, Baines T, Quasney M, Haileselassie B, Lindsell CJ. Prospective clinical testing and experimental validation of the Pediatric Sepsis Biomarker Risk Model. Sci Transl Med. 2019 Nov 13;11(518).

Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

November 13, 2019

Volume

11

Issue

518

Location

United States

Related Subject Headings

  • Survival Analysis
  • Sepsis
  • Risk Factors
  • Risk Assessment
  • Punctures
  • Prospective Studies
  • Models, Biological
  • Mice, Inbred C57BL
  • Male
  • Ligation