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

Wong, Hector R. MD; Cvijanovich, Natalie Z. MD; Anas, Nick MD; Allen, Geoffrey L. MD; Thomas, Neal J. MD; Bigham, Michael T. MD; Weiss, Scott L. MD; Fitzgerald, Julie PhD, MD; Checchia, Paul A. MD; Meyer, Keith MD; Quasney, Michael MD, PhD; Hall, Mark MD; Gedeit, Rainer MD; Freishtat, Robert J. MD; Nowak, Jeffrey MD; Raj, Shekhar S. MD; Gertz, Shira MD; Howard, Kelli BSN; Harmon, Kelli MS; Lahni, Patrick BS; Frank, Erin BS; Hart, Kimberly W. MA; Nguyen, Trung C. MD; Lindsell, Christopher J. PhD

doi: 10.1097/CCM.0000000000001852
Clinical Investigations
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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.

Supplemental Digital Content is available in the text.

1Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center and Cincinnati Children’s Research Foundation, Cincinnati, OH.

2Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.

3UCSF Benioff Children’s Hospital Oakland, Oakland, CA.

4Children’s Hospital of Orange County, Orange, CA.

5Children’s Mercy Hospital, Kansas City, MO.

6Penn State Hershey Children’s Hospital, Hershey, PA.

7Akron Children’s Hospital, Akron, OH.

8The Children’s Hospital of Philadelphia, Philadelphia, PA.

9Texas Children’s Hospital and Baylor College of Medicine, Houston, TX.

10Miami Children’s Hospital, Miami, FL.

11CS Mott Children’s Hospital at the University of Michigan, Ann Arbor, MI.

12Nationwide Children’s Hospital, Columbus, OH.

13Children’s Hospital of Wisconsin, Milwaukee, WI.

14Children’s National Medical Center, Washington, DC.

15Children’s Hospital and Clinics of Minnesota, Minneapolis, MN.

16Riley Hospital for Children, Indianapolis, IN.

17Hackensack University Medical Center, Joseph M. Sanzari Children’s Hospital, Hackensack, NJ.

18Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Dr. Wong conceived and developed the study, obtained funding for the study, directly took part in the analyses, and wrote the article. Drs. Cvijanovich, Anas, Allen, Thomas, Bigham, Weiss, Fitzgerald, Checchia, Meyer, Quasney, Hall, Gedeit, Freishtat, Nowak, Raj, and Gertz enrolled patients, provided biological samples and clinical data for the database, and edited the article. Dr. Howard and E. Frank maintained the clinical database and coordinated all interinstitutional research activity. Dr. Harmon maintained the biological repository and processed all biological samples. P. Lahni conducted all biomarker assays. K. W. Hart assisted with statistical analysis. Dr. Nguyen assisted in the concept and design of the study. Dr. Lindsell developed the study, assisted with analysis, and edited the article.

Supported by National Institutes of Health Grants RO1GM064619, RO1GM099773, and R01GM108025. Supported, in part, by an Institutional Clinical and Translational Science Award, NIH/NCRR 8UL1 TR000077.

Dr. Wong and the Cincinnati Children’s Hospital Research Foundation have submitted a provisional patent application for Pediatric Sepsis Biomarker Risk Model (PERSEVERE) and received support for article research from the National Institutes of Health (NIH). His institution received funding from the NIH RO1GM064619, RO1GM099773, and R01GM108025. Dr. Cvijanovich received support for article research from the NIH and received funding from REACH Air Medical Services (assistant medical director). Her institution received funding from the Cincinnati Children’s Hospital Medical Center (via NIH funding), Boston Children’s Hospital (via National Institute of Allergy and Infectious Diseases 1RO1A1084011-01), and Boston Children’s Hospital (via National Heart Lung and Blood Institute 5U01HL107681-04). Dr. Allen disclosed other support (the overall study has been supported by an NIH grant and his institution has been compensated a fixed dollar amount for each patient enrolled in the study) and received support for article research from the NIH. His institution received funding from Cincinnati Children’s Hospital. Dr. Thomas received funding from CareFusion, Therabron, and the Food and Drug Administration. Dr. Weiss received funding from Thermo-Fisher Scientific. Dr. Fitzgerald and his institution received support for article research from the NIH. Dr. Checchia and received support for article research from the NIH. Dr. Meyer and his institution received support for article research from the NIH. Dr. Quasney received support for article research from the NIH. Dr. Freishtat received support for article research from the NIH. Dr. Raj received support for article research from the NIH and disclosed other support (NIH funding was for Dr. Hector Wong. Through his funding, he paid out institution for participating and enrolling the patient). His institution received funding from the Cincinnati Children’s Hospital. Dr. Gertz received support for article research from the NIH and received funding from Hackensack University Medical Center. Her institution received funding from Genomic Analysis of Pediatric Systemic Inflammatory Response Syndrome/Persevere/Septic Shock (Genomics) NIH 5R01GM099773-02. Dr. Howard and her institution received support for article research from the NIH. Dr. Lahni and his institution received support for article research from the NIH. Dr. Frank received support for article research from the NIH. Dr. Hart and her institution received support for article research from the NIH. Dr. Nguyen received support for article research from the NIH. His institution received funding from the NIH National Institute of General Medical Sciences. Dr. Lindsell received support for article research from the NIH. His institution received funding from the NIH and other (Dr. Lindsell is named as co-inventor and has a patent describing PERSEVERE). Dr. Lindsell is named as a co-inventor in the above patent application. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: hector.wong@cchmc.org

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