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
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 hos...
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MDPI AG
2020-12-01
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| Series: | Journal of Personalized Medicine |
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| Online Access: | https://www.mdpi.com/2075-4426/11/1/9 |
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| author | Jose Iglesias Andrew V. Vassallo Oliver Liesenfeld Jerrold S. Levine Vishal V. Patel Jesse B. Sullivan Joseph B. Cavanaugh Yasmine Elbaga Timothy E. Sweeney |
| author_facet | Jose Iglesias Andrew V. Vassallo Oliver Liesenfeld Jerrold S. Levine Vishal V. Patel Jesse B. Sullivan Joseph B. Cavanaugh Yasmine Elbaga Timothy E. Sweeney |
| author_sort | Jose Iglesias |
| collection | DOAJ |
| description | 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%, <i>p</i> = 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 (<i>n</i> = 51) demonstrated a decrease survival in the CE group, <i>p</i> = 0.026. KM survival analysis of hydrocortisone, ascorbic acid, and thiamine (HAT) therapy and control patients not receiving steroids (<i>n</i> = 45) showed CE and IE was associated with a decrease in survival (<i>p</i> = 0.003); of interest, there was no difference in survival in CE patients after stratifying by HAT therapy (<i>p</i> = 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. |
| first_indexed | 2024-03-10T13:50:20Z |
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| institution | Directory Open Access Journal |
| issn | 2075-4426 |
| language | English |
| last_indexed | 2024-03-10T13:50:20Z |
| publishDate | 2020-12-01 |
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| spelling | doaj.art-5fb90bf6a4904c48a95119d52e0dcab52023-11-21T02:14:17ZengMDPI AGJournal of Personalized Medicine2075-44262020-12-01111910.3390/jpm11010009A 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) TrialJose Iglesias0Andrew V. Vassallo1Oliver Liesenfeld2Jerrold S. Levine3Vishal V. Patel4Jesse B. Sullivan5Joseph B. Cavanaugh6Yasmine Elbaga7Timothy E. Sweeney8Department of Critical Care, Department of Nephrology, Community Medical Center, Toms River, NJ 08755, USADepartment of Pharmacy, Community Medical Center, Toms River, NJ 08755, USAInflammatix, Inc., Burlingame, CA 94010, USADepartment of Medicine Section of Nephrology, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Pharmacy, Community Medical Center, Toms River, NJ 08755, USASchool of Pharmacy & Health Sciences, Fairleigh Dickinson University, Florham Park, NJ 07932, USADepartment of Pharmacy, Community Medical Center, Toms River, NJ 08755, USADepartment of Pharmacy, Monmouth Medical Center Southern Campus, Lakewood, NJ 08701, USAInflammatix, Inc., Burlingame, CA 94010, USABackground: 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%, <i>p</i> = 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 (<i>n</i> = 51) demonstrated a decrease survival in the CE group, <i>p</i> = 0.026. KM survival analysis of hydrocortisone, ascorbic acid, and thiamine (HAT) therapy and control patients not receiving steroids (<i>n</i> = 45) showed CE and IE was associated with a decrease in survival (<i>p</i> = 0.003); of interest, there was no difference in survival in CE patients after stratifying by HAT therapy (<i>p</i> = 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.https://www.mdpi.com/2075-4426/11/1/9sepsisseptic shockHAT therapyvitamin cendotypingcoagulopathic |
| spellingShingle | Jose Iglesias Andrew V. Vassallo Oliver Liesenfeld Jerrold S. Levine Vishal V. Patel Jesse B. Sullivan Joseph B. Cavanaugh Yasmine Elbaga Timothy E. Sweeney 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 Journal of Personalized Medicine sepsis septic shock HAT therapy vitamin c endotyping coagulopathic |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | sepsis septic shock HAT therapy vitamin c endotyping coagulopathic |
| url | https://www.mdpi.com/2075-4426/11/1/9 |
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