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Pediatric Sepsis Endotypes Among Adults With Sepsis

Wong, Hector R. MD1,2; Sweeney, Timothy E. MD, PhD3,4; Hart, Kimberly W. MA5; Khatri, Purvesh PhD3,4; Lindsell, Christopher J. PhD5

doi: 10.1097/CCM.0000000000002733
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Objectives: Recent transcriptomic studies describe two subgroups of adults with sepsis differentiated by a sepsis response signature. The implied biology and related clinical associations are comparable with recently reported pediatric sepsis endotypes, labeled “A” and “B.” We classified adults with sepsis using the pediatric endotyping strategy and the sepsis response signature and determined how endotype assignment, sepsis response signature membership, and age interact with respect to mortality.

Design: Retrospective analysis of publically available transcriptomic data representing critically ill adults with sepsis from which the sepsis response signature groups were derived and validated.

Setting: Multiple ICUs.

Patients: Adults with sepsis.

Interventions: None.

Measurements and Main Results: Transcriptomic data were conormalized into a single dataset yielding 549 unique cases with sepsis response signature assignments. Each subject was assigned to endotype A or B using the expression data for the 100 endotyping genes. There were 163 subjects (30%) assigned to endotype A and 386 to endotype B. There was a weak, positive correlation between endotype assignment and sepsis response signature membership. Mortality rates were similar between patients assigned endotype A and those assigned endotype B. A multivariable logistic regression model fit to endotype assignment, sepsis response signature membership, age, and the respective two-way interactions revealed that endotype A, sepsis response signature 1 membership, older age, and the interactions between them were associated with mortality. Subjects coassigned to endotype A, and sepsis response signature 1 had the highest mortality.

Conclusions: Combining the pediatric endotyping strategy with sepsis response signature membership might provide complementary, age-dependent, biological, and prognostic information.

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.

3Stanford Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Palo Alto, CA.

4Division of Biomedical Informatics Research, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA.

5Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.

Current address for Dr. Sweeney: Inflammatix, Burlingame, CA.

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).

Supported, in part, by National Institutes of Health Grants RO1GM099773 and R01GM108025.

Drs. Wong, Hart, and Lindsell’s institutions received funding from the National Institutes of Health (NIH), and they received support for article research from the NIH. Drs. Wong and Lindsell are named as coinventors for a provisional U.S. patent application based on the endotyping strategy reported in the article. Dr. Sweeney received funding from Inflammatix. Dr. Khatri disclosed stock ownership in Inflammatix, and he received support for article research from the NIH and Bill & Melinda Gates Foundation. Dr. Lindsell received funding from Digital Bioscapes (stock options for participating on a scientific advisory board; no relevance to current work).

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

Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.