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      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

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          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.

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          Most cited references 17

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          Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

          The Third International Consensus Definitions Task Force defined sepsis as "life-threatening organ dysfunction due to a dysregulated host response to infection." The performance of clinical criteria for this sepsis definition is unknown.
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            Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure

            Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS).
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              The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C?*.

              The developmental pipeline for novel therapeutics to treat sepsis has diminished to a trickle compared to previous years of sepsis research. While enormous strides have been made in understanding the basic molecular mechanisms that underlie the pathophysiology of sepsis, a long list of novel agents have now been tested in clinical trials without a single immunomodulating therapy showing consistent benefit. The only antisepsis agent to successfully complete a phase III clinical trial was human recumbent activated protein C. This drug was taken off the market after a follow-up placebo-controlled trial (human recombinant activated Protein C Worldwide Evaluation of Severe Sepsis and septic Shock [PROWESS SHOCK]) failed to replicate the favorable results of the initial registration trial performed ten years earlier. We must critically reevaluate our basic approach to the preclinical and clinical evaluation of new sepsis therapies.
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                Author and article information

                Journal
                J Pers Med
                J Pers Med
                jpm
                Journal of Personalized Medicine
                MDPI
                2075-4426
                23 December 2020
                January 2021
                : 11
                : 1
                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; Vishal.Patel@ 123456rwjbh.org (V.V.P.); Joseph.Cavanaugh@ 123456rwjbh.org (J.B.C.)
                [4 ]Inflammatix, Inc., Burlingame, CA 94010, USA; oliesenfeld@ 123456inflammatix.com (O.L.); tsweeney@ 123456inflammatix.com (T.E.S.)
                [5 ]Department of Medicine Section of Nephrology, University of Illinois at Chicago, Chicago, IL 60612, USA; jslevine@ 123456uic.edu
                [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; jsull@ 123456fdu.edu
                [8 ]Department of Pharmacy, Monmouth Medical Center Southern Campus, Lakewood, NJ 08701, USA; Yasmine.Elbaga@ 123456rwjbh.org
                Author notes
                Article
                jpm-11-00009
                10.3390/jpm11010009
                7822486
                33374697
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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