A gene expression-based approach for the precision use of hydrocortisone in septic shock patients; a secondary analysis of the ADRENAL trial

Background

Small observational studies suggest the effect of corticosteroids in patients with vasodilatory shock vary depending on endotypes determined by gene expression. We sought to replicate these findings in a larger cohort from a randomised clinical trial.

Methods

In a cross-sectional substudy of the Adjunctive Glucocorticoid Therapy In Septic Shock (ADRENAL) trial, patients were classified as one of two immune endotypes using predefined gene expression signatures: immune adaptive-prevalent (IA-P) or immune innate-prevalent (IN-P). We compared the outcomes of the two endotypes using a Bayesian analysis. The primary outcome was Day-28 mortality.

Findings

Of 540 patients, 267 (49.4%) were classified as IA-P and 273 (50.6%) as IN-P. In a Bayesian analysis using noninformative priors, there was no difference in the effect of hydrocortisone on 28-day mortality (odds ratio [OR] 1.43, 95% credible intervals [CrI] 0.72–2.87) and OR 1.39, 95% CrI 0.74–2.61, between the IA-P and IN-P groups, respectively. In the subgroup of patients with more severe shock (n = 215/540, 40%), the corresponding figures for IA-P and IN-P were 1.21, 95% CrI (0.31–4.74) and OR 0.72 (95% CrI 0.30–1.67), respectively. In the subgroup of patients with pulmonary sepsis (232/540, 43%), IA-P patients treated with hydrocortisone had increased mortality (OR 5.55, 95% CrI 1.81–21.2).

Interpretation

Gene expression data from patients with septic shock reveal distinct immune endotypes. There was no evidence of a heterogeneity of treatment effect of hydrocortisone on mortality in the 2 endotypes or in the subgroup with severe shock. Patients with the IA-P endotype and pulmonary sepsis appear to be harmed by corticosteroids.