Hector R Wong1,2, Natalie Z Cvijanovich3, Nick Anas4, Geoffrey L Allen5, Neal J Thomas6, Michael T Bigham7, Scott L Weiss8, Julie C Fitzgerald8, Paul A Checchia9, Keith Meyer10, Michael Quasney11, Mark Hall12, Rainer Gedeit13, Robert J Freishtat14, Jeffrey Nowak15, Riad Lutfi16, Shira Gertz17, Jocelyn R Grunwell18, Christopher J Lindsell19. 1. Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH. 2. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH. 3. UCSF Benioff Children's Hospital Oakland, Oakland, CA. 4. Children's Hospital of Orange County, Orange, CA. 5. Children's Mercy Hospital, Kansas City, MO. 6. Penn State Hershey Children's Hospital, Hershey, PA. 7. Akron Children's Hospital, Akron, OH. 8. The Children's Hospital of Philadelphia, Philadelphia, PA. 9. Baylor College of Medicine, Houston, TX. 10. Miami Children's Hospital, Miami, FL. 11. CS Mott Children's Hospital at the University of Michigan, Ann Arbor, MI. 12. Nationwide Children's Hospital, Columbus, OH. 13. Children's Hospital of Wisconsin, Milwaukee, WI. 14. Children's National Health System, Washington, DC. 15. Children's Hospital and Clinics of Minnesota, Minneapolis, MN. 16. Riley Hospital for Children, Indianapolis, IN. 17. St. Barnabas Medical Center, Livingston, NJ. 18. Children's Healthcare of Atlanta at Egleston, Atlanta, GA. 19. Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.
Abstract
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.
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.
Authors: Jonathan Cohen; Jean-Louis Vincent; Neill K J Adhikari; Flavia R Machado; Derek C Angus; Thierry Calandra; Katia Jaton; Stefano Giulieri; Julie Delaloye; Steven Opal; Kevin Tracey; Tom van der Poll; Eric Pelfrene Journal: Lancet Infect Dis Date: 2015-04-19 Impact factor: 25.071
Authors: Hallie C Prescott; Carolyn S Calfee; B Taylor Thompson; Derek C Angus; Vincent X Liu Journal: Am J Respir Crit Care Med Date: 2016-07-15 Impact factor: 21.405
Authors: Hector R Wong; Derek S Wheeler; Ken Tegtmeyer; Sue E Poynter; Jennifer M Kaplan; Ranjit S Chima; Erika Stalets; Rajit K Basu; Lesley A Doughty Journal: Crit Care Med Date: 2010-10 Impact factor: 7.598
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: Natalie Cvijanovich; Thomas P Shanley; Richard Lin; Geoffrey L Allen; Neal J Thomas; Paul Checchia; Nick Anas; Robert J Freishtat; Marie Monaco; Kelli Odoms; Bhuvaneswari Sakthivel; Hector R Wong Journal: Physiol Genomics Date: 2008-05-06 Impact factor: 3.107
Authors: Kamal Abulebda; 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; Arun Chopra; Sharon Banschbach; Eileen Beckman; Christopher J Lindsell; Hector R Wong Journal: Crit Care Med Date: 2014-02 Impact factor: 7.598
Authors: Thomas P Shanley; Natalie Cvijanovich; Richard Lin; Geoffrey L Allen; Neal J Thomas; Allan Doctor; Meena Kalyanaraman; Nancy M Tofil; Scott Penfil; Marie Monaco; Kelli Odoms; Michael Barnes; Bhuvaneswari Sakthivel; Bruce J Aronow; Hector R Wong Journal: Mol Med Date: 2007 Sep-Oct Impact factor: 6.354
Authors: Katie L Burnham; Emma E Davenport; Jayachandran Radhakrishnan; Peter Humburg; Anthony C Gordon; Paula Hutton; Eduardo Svoren-Jabalera; Christopher Garrard; Adrian V S Hill; Charles J Hinds; Julian C Knight Journal: Am J Respir Crit Care Med Date: 2017-08-01 Impact factor: 21.405
Authors: Jan Bakker; Eduardo Kattan; Djillali Annane; Ricardo Castro; Maurizio Cecconi; Daniel De Backer; Arnaldo Dubin; Laura Evans; Michelle Ng Gong; Olfa Hamzaoui; Can Ince; Bruno Levy; Xavier Monnet; Gustavo A Ospina Tascón; Marlies Ostermann; Michael R Pinsky; James A Russell; Bernd Saugel; Thomas W L Scheeren; Jean-Louis Teboul; Antoine Vieillard Baron; Jean-Louis Vincent; Fernando G Zampieri; Glenn Hernandez Journal: Intensive Care Med Date: 2021-12-15 Impact factor: 17.440
Authors: Kimberley M DeMerle; Derek C Angus; J Kenneth Baillie; Emily Brant; Carolyn S Calfee; Joseph Carcillo; Chung-Chou H Chang; Robert Dickson; Idris Evans; Anthony C Gordon; Jason Kennedy; Julian C Knight; Christopher J Lindsell; Vincent Liu; John C Marshall; Adrienne G Randolph; Brendon P Scicluna; Manu Shankar-Hari; Nathan I Shapiro; Timothy E Sweeney; Victor B Talisa; Benjamin Tang; B Taylor Thompson; Ephraim L Tsalik; Tom van der Poll; Lonneke A van Vught; Hector R Wong; Sachin Yende; Huiying Zhao; Christopher W Seymour Journal: Crit Care Med Date: 2021-05-01 Impact factor: 7.598
Authors: Colin G Walsh; Beenish Chaudhry; Prerna Dua; Kenneth W Goodman; Bonnie Kaplan; Ramakanth Kavuluru; Anthony Solomonides; Vignesh Subbian Journal: JAMIA Open Date: 2020-01-22