Objectives: Prognostic and predictive enrichment strategies are fundamental tools of precision medicine. Identifying children with septic shock who may benefit from corticosteroids remains a challenge. We combined prognostic and predictive strategies to identify a pediatric septic shock subgroup responsive to corticosteroids.
Design: We conducted a secondary analysis of 288 previously published pediatric subjects with septic shock. For prognostic enrichment, each study subject was assigned a baseline mortality probability using the pediatric sepsis biomarker risk model. For predictive enrichment, each study subject was allocated to one of two septic shock endotypes, based on a 100-gene signature reflecting adaptive immunity and glucocorticoid receptor signaling. The primary study endpoint was complicated course, defined as the persistence of two or more organ failures at day 7 of septic shock or 28-day mortality. We used logistic regression to test for an association between corticosteroids and complicated course within endotype.
Measurements and Main Results: Among endotype B subjects at intermediate to high pediatric sepsis biomarker risk model-based risk of mortality, corticosteroids were independently associated with more than a 10-fold reduction in the risk of a complicated course (relative risk, 0.09; 95% CI, 0.01–0.54; p = 0.007).
Conclusions: A combination of prognostic and predictive strategies based on serum protein and messenger RNA biomarkers can identify a subgroup of children with septic shock who may be more likely to benefit from corticosteroids. Prospective validation of these strategies and the existence of this subgroup are warranted.
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.
3Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH.
4UCSF Benioff Children’s Hospital Oakland, Oakland, CA.
5Children’s Hospital of Orange County, Orange, CA.
6Children’s Mercy Hospital, Kansas City, MO.
7Penn State Hershey Children’s Hospital, Hershey, PA.
8Akron Children’s Hospital, Akron, OH.
9The Children’s Hospital of Philadelphia, Philadelphia, PA.
10Texas Children’s Hospital and Baylor College of Medicine, Houston, TX.
11Miami Children’s Hospital, Miami, FL.
12CS Mott Children’s Hospital at the University of Michigan, Ann Arbor, MI.
13Nationwide Children’s Hospital, Columbus, OH.
14Children’s Hospital of Wisconsin, Milwaukee, WI.
15Children’s National Medical Center, Washington, DC.
16Children’s Hospital and Clinics of Minnesota, Minneapolis, MN.
17Riley Hospital for Children, Indianapolis, IN.
18Hackensack University Medical Center, Joseph M. Sanzari Children’s Hospital, Hackensack, NJ.
19Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.
*See also p. 1960.
Dr. Wong conceived and developed the study, obtained funding for the study, directly took part in the analyses, and wrote the article. Dr. Atkinson extracted and analyzed clinical data. 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. Lindsell developed the study, assisted with analysis, and edited the article.
Supported, in part, by National Institutes of Health (NIH) (grants numbers: RO1GM099773 and R01GM108025), Institutional Clinical and Translational Science Award, NIH/National Center for Research Resources 8UL1 TR000077, and National Institute of General Medical Sciences (NIGMS).
Dr. Wong disclosed other support (Dr. Wong and the Cincinnati Children’s Hospital Research Foundation have been issued a 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. Dr. Atkinson received support for article research from the NIH. Dr. Cvijanovich disclosed other support (Institutional grant with Children’s Hospital Boston and Institutional grant with Children’s Hospital of Philadelphia); received support for article research from the NIH; and received funding from Cincinnati Children's Hospital Medical Center. Her institution received funding from the Cincinnati Children’s Hospital Medical Center, the Department of Defense, and REACH Air Medical Services. Dr. Allen received support for article research from the NIH. His institution received funding from Cincinnati Children’s Hospital. Dr. Thomas received funding from CareFusion and Therabron. His institution received funding from the NIH (subcontract) and the Food and Drug Administration (RO1 grant). Dr. Weiss received funding from Honoraria from Thermo-Fisher Scientific. His institution received funding from NIGMS K23GM110496 (grant support). Dr. Fitzgerald received support for article research form the NIH. Her institution received funding from the NIH. Dr. Checchia received support for article research form the NIH. His institution received funding from the NIH. Dr. Meyer disclosed other support (institution received grant payments to cover the costs of specimen submission only) and 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 (he did not have any funding for this article). Dr. Gertz received support for article research from the NIH. His institution received funding from the Cincinnati Children’s Hospital. Dr. Lindsell received support for article research from the NIH. His institution received funding (he is named as co-inventor on a patent describing the multi-biomarker model for predicting mortality in pediatric septic shock [PERSEVERE]). 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
