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.
Highlights
Sepsis, defined as a dysregulated immune response to an acute infection, confers an extremely high mortality and utilization of health care resources [1,2]
The ORANGES trial was a randomized, double-blinded, placebo-controlled trial assessing the utilization of an ascorbic acid, thiamine, and hydrocortisone treatment bundle for the management of septic and septic shock patients admitted to an ICU and is described in detail elsewhere [12]
We prospectively evaluated host response endotype in 51 consecutive adult patients within 12 h of hospital admission diagnosed with sepsis who were enrolled in the ORANGES trial and consented to have testing for endotype analysis (Table 1) [12,14]
Summary
Sepsis, defined as a dysregulated immune response to an acute infection, confers an extremely high mortality and utilization of health care resources [1,2]. A complex interplay of host response and pathogen dynamics leads to varying outcomes and therapy responsiveness [3,4]. Despite numerous clinical trials, anti-cytokine and targeted immune modulating therapies have failed to improve clinical trials in sepsis [1,5]. Based on pre-clinical and clinical experience there has been great interest in employing the combination of hydrocortisone, intravenous ascorbic acid (AA) and thiamine (known as HAT therapy) in the management of patients with sepsis [6,7]. To date, studies have yielded conflicting results regarding the benefits of HAT therapy on clinical outcomes [6,8]. The landmark study by Marik, a propensity-adjusted observational study, reported a striking decrease in mortality in septic patients treated with HAT [9]
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