Hector R Wong1, Sarah J Atkinson, Natalie Z Cvijanovich, Nick Anas, Geoffrey L Allen, Neal J Thomas, Michael T Bigham, Scott L Weiss, Julie C Fitzgerald, Paul A Checchia, Keith Meyer, Michael Quasney, Mark Hall, Rainer Gedeit, Robert J Freishtat, Jeffrey Nowak, Shekhar S Raj, Shira Gertz, Christopher J Lindsell. 1. 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.
Abstract
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.
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.
Authors: Hector R Wong; Natalie Z Cvijanovich; Geoffrey L Allen; Neal J Thomas; Robert J Freishtat; Nick Anas; Keith Meyer; Paul A Checchia; Scott L Weiss; Thomas P Shanley; Michael T Bigham; Sharon Banschbach; Eileen Beckman; Kelli Harmon; Jerry J Zimmerman Journal: Am J Respir Crit Care Med Date: 2014-04-15 Impact factor: 21.405
Authors: Hector R Wong; Thomas P Shanley; Bhuvaneswari Sakthivel; Natalie Cvijanovich; Richard Lin; Geoffrey L Allen; Neal J Thomas; Allan Doctor; Meena Kalyanaraman; Nancy M Tofil; Scott Penfil; Marie Monaco; Mary Ann Tagavilla; Kelli Odoms; Katherine Dunsmore; Michael Barnes; Bruce J Aronow Journal: Physiol Genomics Date: 2007-03-20 Impact factor: 3.107
Authors: Hector R Wong; Natalie Z Cvijanovich; Nick Anas; Geoffrey L Allen; Neal J Thomas; Michael T Bigham; Scott L Weiss; Julie Fitzgerald; Paul A Checchia; Keith Meyer; Thomas P Shanley; Michael Quasney; Mark Hall; Rainer Gedeit; Robert J Freishtat; Jeffrey Nowak; Raj S Shekhar; Shira Gertz; Emily Dawson; Kelli Howard; Kelli Harmon; Eileen Beckman; Erin Frank; Christopher J Lindsell Journal: Am J Respir Crit Care Med Date: 2015-02-01 Impact factor: 21.405
Authors: Charles L Sprung; Djillali Annane; Didier Keh; Rui Moreno; Mervyn Singer; Klaus Freivogel; Yoram G Weiss; Julie Benbenishty; Armin Kalenka; Helmuth Forst; Pierre-Francois Laterre; Konrad Reinhart; Brian H Cuthbertson; Didier Payen; Josef Briegel Journal: N Engl J Med Date: 2008-01-10 Impact factor: 91.245
Authors: Hector R Wong; Shelia Salisbury; Qiang Xiao; Natalie Z Cvijanovich; Mark Hall; Geoffrey L Allen; Neal J Thomas; Robert J Freishtat; Nick Anas; Keith Meyer; Paul A Checchia; Richard Lin; Thomas P Shanley; Michael T Bigham; Anita Sen; Jeffrey Nowak; Michael Quasney; Jared W Henricksen; Arun Chopra; Sharon Banschbach; Eileen Beckman; Kelli Harmon; Patrick Lahni; Christopher J Lindsell Journal: Crit Care Date: 2012-10-01 Impact factor: 9.097
Authors: Sarah J Atkinson; Natalie Z Cvijanovich; Neal J Thomas; Geoffrey L Allen; Nick Anas; Michael T Bigham; Mark Hall; Robert J Freishtat; Anita Sen; Keith Meyer; Paul A Checchia; Thomas P Shanley; Jeffrey Nowak; Michael Quasney; Scott L Weiss; Sharon Banschbach; Eileen Beckman; Kelli Howard; Erin Frank; Kelli Harmon; Patrick Lahni; Christopher J Lindsell; Hector R Wong Journal: PLoS One Date: 2014-11-11 Impact factor: 3.240
Authors: Hector R Wong; Natalie Z Cvijanovich; Nick Anas; Geoffrey L Allen; Neal J Thomas; Michael T Bigham; Scott L Weiss; Julie C Fitzgerald; Paul A Checchia; Keith Meyer; Michael Quasney; Mark Hall; Rainer Gedeit; Robert J Freishtat; Jeffrey Nowak; Riad Lutfi; Shira Gertz; Jocelyn R Grunwell; Christopher J Lindsell Journal: Crit Care Med Date: 2018-03 Impact factor: 7.598