Jose Iglesias1,2, Andrew V Vassallo3, Oliver Liesenfeld4, Jerrold S Levine5,6, Vishal V Patel3, Jesse B Sullivan7, Joseph B Cavanaugh3, Yasmine Elbaga8, Timothy E Sweeney4. 1. Department of Critical Care, Department of Nephrology, Community Medical Center, Toms River, NJ 08755, USA. 2. Department of Nephrology, Jersey Shore University Medical Center, Hackensack Meridian School of Medicine at Seton Hall Neptune, Nutley, NJ 07110, USA. 3. Department of Pharmacy, Community Medical Center, Toms River, NJ 08755, USA. 4. Inflammatix, Inc., Burlingame, CA 94010, USA. 5. Department of Medicine Section of Nephrology, University of Illinois at Chicago, Chicago, IL 60612, USA. 6. Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA. 7. School of Pharmacy & Health Sciences, Fairleigh Dickinson University, Florham Park, NJ 07932, USA. 8. Department of Pharmacy, Monmouth Medical Center Southern Campus, Lakewood, NJ 08701, USA.
Abstract
BACKGROUND: Retrospective analysis of the transcriptomic host response in sepsis has demonstrated that sepsis can be separated into three endotypes-inflammatory (IE), adaptive (AE), and coagulopathic (CE), which have demonstrated prognostic significance. We undertook a prospective transcriptomic host response analysis in a subgroup of patients enrolled in the Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis (ORANGES) trial. METHODS: Blood was obtained from 51 patients and profiled using a pre-established 33-mRNA classifier to determine sepsis endotypes. Endotypes were compared to therapy subgroups and clinical outcomes. RESULTS: We redemonstrated a statistically significant difference in mortality between IE, AE, and CE patients, with CE patients demonstrating the highest mortality (40%), and AE patients the lowest mortality (5%, p = 0.032). A higher CE score was a predictor of mortality; coronary artery disease (CAD) and elevated CE scores were associated with an increase in mortality (CAD: HR = 12.3, 95% CI 1.5-101; CE score: HR = 15.5 95% CI 1.15-211). Kaplan-Meier (KM) analysis of the entire cohort (n = 51) demonstrated a decrease survival in the CE group, p = 0.026. KM survival analysis of hydrocortisone, ascorbic acid, and thiamine (HAT) therapy and control patients not receiving steroids (n = 45) showed CE and IE was associated with a decrease in survival (p = 0.003); of interest, there was no difference in survival in CE patients after stratifying by HAT therapy (p = 0.18). These findings suggest a possible treatment effect of corticosteroids, HAT therapy, endotype, and outcome. CONCLUSION: This subset of patients from the ORANGES trial confirmed previous retrospective findings that a 33-mRNA classifier can group patients into IE, AE, and CE endotypes having prognostic significance. A novel finding of this study identifying an association between endotype and corticosteroid therapy warrants further study in support of future diagnostic use of the endotyping classifier.
BACKGROUND: Retrospective analysis of the transcriptomic host response in sepsis has demonstrated that sepsis can be separated into three endotypes-inflammatory (IE), adaptive (AE), and coagulopathic (CE), which have demonstrated prognostic significance. We undertook a prospective transcriptomic host response analysis in a subgroup of patients enrolled in the Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis (ORANGES) trial. METHODS: Blood was obtained from 51 patients and profiled using a pre-established 33-mRNA classifier to determine sepsis endotypes. Endotypes were compared to therapy subgroups and clinical outcomes. RESULTS: We redemonstrated a statistically significant difference in mortality between IE, AE, and CE patients, with CE patients demonstrating the highest mortality (40%), and AE patients the lowest mortality (5%, p = 0.032). A higher CE score was a predictor of mortality; coronary artery disease (CAD) and elevated CE scores were associated with an increase in mortality (CAD: HR = 12.3, 95% CI 1.5-101; CE score: HR = 15.5 95% CI 1.15-211). Kaplan-Meier (KM) analysis of the entire cohort (n = 51) demonstrated a decrease survival in the CE group, p = 0.026. KM survival analysis of hydrocortisone, ascorbic acid, and thiamine (HAT) therapy and control patients not receiving steroids (n = 45) showed CE and IE was associated with a decrease in survival (p = 0.003); of interest, there was no difference in survival in CE patients after stratifying by HAT therapy (p = 0.18). These findings suggest a possible treatment effect of corticosteroids, HAT therapy, endotype, and outcome. CONCLUSION: This subset of patients from the ORANGES trial confirmed previous retrospective findings that a 33-mRNA classifier can group patients into IE, AE, and CE endotypes having prognostic significance. A novel finding of this study identifying an association between endotype and corticosteroid therapy warrants further study in support of future diagnostic use of the endotyping classifier.
Entities:
Keywords:
HAT therapy; ascorbic acid; coagulopathic; endotyping; hydrocortisone; sepsis; septic shock; thiamine; vitamin c
Authors: Alpha A Fowler; Jonathon D Truwit; R Duncan Hite; Peter E Morris; Christine DeWilde; Anna Priday; Bernard Fisher; Leroy R Thacker; Ramesh Natarajan; Donald F Brophy; Robin Sculthorpe; Rahul Nanchal; Aamer Syed; Jamie Sturgill; Greg S Martin; Jonathan Sevransky; Markos Kashiouris; Stella Hamman; Katherine F Egan; Andrei Hastings; Wendy Spencer; Shawnda Tench; Omar Mehkri; James Bindas; Abhijit Duggal; Jeanette Graf; Stephanie Zellner; Lynda Yanny; Catherine McPolin; Tonya Hollrith; David Kramer; Charles Ojielo; Tessa Damm; Evan Cassity; Aleksandra Wieliczko; Matthew Halquist Journal: JAMA Date: 2019-10-01 Impact factor: 56.272
Authors: Jose Iglesias; Andrew V Vassallo; Vishal V Patel; Jesse B Sullivan; Joseph Cavanaugh; Yasmine Elbaga Journal: Chest Date: 2020-03-17 Impact factor: 9.410
Authors: Timothy E Sweeney; Thanneer M Perumal; Ricardo Henao; Marshall Nichols; Judith A Howrylak; Augustine M Choi; Jesús F Bermejo-Martin; Raquel Almansa; Eduardo Tamayo; Emma E Davenport; Katie L Burnham; Charles J Hinds; Julian C Knight; Christopher W Woods; Stephen F Kingsmore; Geoffrey S Ginsburg; Hector R Wong; Grant P Parnell; Benjamin Tang; Lyle L Moldawer; Frederick E Moore; Larsson Omberg; Purvesh Khatri; Ephraim L Tsalik; Lara M Mangravite; Raymond J Langley Journal: Nat Commun Date: 2018-02-15 Impact factor: 14.919