A 33-mRNA Classifier Is Able to Produce Inflammopathic, Adaptive, and Coagulopathic Endotypes with Prognostic Significance: The Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis (ORANGES) Trial

Jose Iglesias; Andrew V Vassallo; Oliver Liesenfeld; Jerrold S Levine; Vishal V Patel; Jesse B Sullivan; Joseph B Cavanaugh; Yasmine Elbaga; Timothy E Sweeney

doi:10.3390/jpm11010009

A 33-mRNA Classifier Is Able to Produce Inflammopathic, Adaptive, and Coagulopathic Endotypes with Prognostic Significance: The Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis (ORANGES) Trial

J Pers Med. 2020 Dec 23;11(1):9. doi: 10.3390/jpm11010009.

Authors

Affiliations

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.

Keywords: HAT therapy; ascorbic acid; coagulopathic; endotyping; hydrocortisone; sepsis; septic shock; thiamine; vitamin c.