Endotype Transitions During the Acute Phase of Pediatric Septic Shock Reflect Changing Risk and Treatment Response

Objective: We previously identified septic shock endotypes A and B based on 100 genes reflecting adaptive immunity and glucocorticoid receptor signaling. The endotypes differ with respect to outcome and corticosteroid responsiveness. We determined whether endotypes change during the initial 3 days of illness, and whether changes are associated with outcomes. Design: Observational cohort study including existing and newly enrolled participants. Setting: Multiple PICUs. Patients: Children with septic shock. Interventions: None. Measurements and Main Results: We measured the 100 endotyping genes at day 1 and day 3 of illness in 375 patients. We determined if endotype assignment changes over time, and whether changing endotype is associated with corticosteroid response and outcomes. We used multivariable logistic regression to adjust for illness severity, age, and comorbidity burden. Among the 132 subjects assigned to endotype A on day 1, 56 (42%) transitioned to endotype B by day 3. Among 243 subjects assigned to endotype B on day 1, 77 (32%) transitioned to endotype A by day 3. Assignment to endotype A on day 1 was associated with increased odds of mortality. This risk was modified by the subsequent day 3 endotype assignment. Corticosteroids were associated with increased risk of mortality among subjects who persisted as endotype A. Conclusions: A substantial proportion of children with septic shock transition endotypes during the acute phase of illness. The risk of poor outcome and the response to corticosteroids change with changes in endotype assignment. Patients persisting as endotype A are at highest risk of poor outcomes. Dr. Wong conceived and developed the study, obtained funding for the study, conducted the analyses, and wrote the initial article. Drs. Cvijanovich, Anas, Allen, Thomas, Bigham, Weiss, Fitzgerald, Checchia, Meyer, Quasney, Hall, Gedeit, Freishtat, Nowak, Lutfi, Gertz, and and Grunwell enrolled subjects at the participating institutions, provided clinical data and biological samples, and provided critical review and approval of the article. Dr. Lindsell collaborated with Dr. Wong in conceiving the study, data analysis, and editing the article. 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://ift.tt/29S62lw). Supported by National Institutes of Health Grants RO1GM099773 and R01GM108025. Drs. Wong, Weiss, Fitzgerald, and Checchia's institutions received funding from the National Institutes of Health (NIH). Drs. Wong, Cvijanovich, Allen, Fitzgerald, Checchia, Meyer, Lutfi, and Lindsell received support for article research from the NIH. Dr. Wong disclosed that The Cincinnati Children's Hospital Research Foundation has submitted a provisional patent application for the temporal endotyping strategy reported in this article. Drs. Wong and Lindsell are named as co-inventors on the patent application. Dr. Cvijanovich received funding from Cincinnati Children's Hospital Medical Center and Boston Children's Hospital. Dr. Allen's institution received funding from a subcontract from Cincinnati Children's from their NIH grant. Dr. Thomas's institution received funding from the University of Cincinnati through an NIH subaward, and he received funding from Therabron, CareFusion, and GeneFluidics. Dr. Weiss received funding from ThermoFisher Scientific and Bristol-Meyers Squibb Company. Dr. Meyer's institution received funding from Cincinnati Children's Medical Center (funds paid to institution for specimen collection). Dr. Quasney received support for article research from the University of Michigan Medical School. Dr. Hall received funding from Bristol-Myers Squibb. Dr. Lutfi's institution receive funding from NIH funding by principal investigator through Cincinnati Children Hospital Medical Center. Dr. Lindsell's institution received funding from NIH/National Institute of General Medical Sciences, and he disclosed he is a co-inventor on invention disclosures and patents in the area of septic shock risk stratification, as disclosed by the lead author. 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 Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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