Transcriptomic Signatures in Sepsis and a Differential Response to Steroids. From the VANISH Randomized Trial

Abstract

Rationale: There remains uncertainty about the role of corticosteroids in sepsis with clear beneficial effects on shock duration, but conflicting survival effects. Two transcriptomic sepsis response signatures (SRSs) have been identified. SRS1 is relatively immunosuppressed, whereas SRS2 is relatively immunocompetent.

Objectives: We aimed to categorize patients based on SRS endotypes to determine if these profiles influenced response to either norepinephrine or vasopressin, or to corticosteroids in septic shock.

Methods: A post hoc analysis was performed of a double-blind, randomized clinical trial in septic shock (VANISH [Vasopressin vs. Norepinephrine as Initial Therapy in Septic Shock]). Patients were included within 6 hours of onset of shock and were randomized to receive norepinephrine or vasopressin followed by hydrocortisone or placebo. Genome-wide gene expression profiling was performed and SRS endotype was determined by a previously established model using seven discriminant genes.

Measurements and main results: Samples were available from 176 patients: 83 SRS1 and 93 SRS2. There was no significant interaction between SRS group and vasopressor assignment (P = 0.50). However, there was an interaction between assignment to hydrocortisone or placebo, and SRS endotype (P = 0.02). Hydrocortisone use was associated with increased mortality in those with an SRS2 phenotype (odds ratio = 7.9; 95% confidence interval = 1.6-39.9).

Conclusions: Transcriptomic profile at onset of septic shock was associated with response to corticosteroids. Those with the immunocompetent SRS2 endotype had significantly higher mortality when given corticosteroids compared with placebo. Clinical trial registered with www.clinicaltrials.gov (ISRCTN 20769191).

Keywords: corticosteroids; norepinephrine; sepsis; transcriptomics; vasopressin.

Figure 1.

Recruitment, randomization, treatment allocation, and RNA sampling in the VANISH (Vasopressin vs. Norepinephrine as Initial Therapy in Septic Shock) clinical trial. SRS = sepsis response signature.

Figure 2.

Kaplan-Meier survival curves comparing survival with (A) norepinephrine (red line) and vasopressin (green line) and (B) hydrocortisone (red line) and placebo (green line) in sepsis response signature (SRS) 1 and SRS2. Crosses represent censored patients (n = 2 for SRS1 vasopressin, n = 1 for SRS1 placebo, and n = 1 for SRS1 hydrocortisone; all other patients were censored at death or Day 29).