Large clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results . Subgroups may benefit of hydrocortisone treatment depending on their individual immune response . We performed an exploratory analysis of the database from the international randomized controlled clinical trial Corticosteroid Therapy of Septic Shock (CORTICUS) employing machine learning to a panel of 137 variables collected from the Berlin subcohort comprising 83 patients including demographic and clinical measures, organ failure scores, leukocyte counts and levels of circulating cytokines . The identified theranostic marker was validated against data from a cohort of the Hellenic Sepsis Study Group (HSSG) (n = 246), patients enrolled in the clinical trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT, n = 118), and another, smaller clinical trial (Crossover study, n = 20). In addition, in vitro blood culture experiments and in vivo experiments in mouse models were performed to assess biological plausibility . A low serum IFNγ/IL10 ratio predicted increased survival in the hydrocortisone group whereas a high ratio predicted better survival in the placebo group . Using this marker for a decision rule, we applied it to three validation sets and observed the same trend . Experimental studies in vitro revealed that IFNγ/IL10 was negatively associated with the load of (heat inactivated) pathogens in spiked human blood and in septic mouse models . Accordingly, an in silico analysis of published IFNγ and IL10 values in bacteremic and non-bacteremic patients with the Systemic Inflammatory Response Syndrome supported this association between the ratio and pathogen burden . We propose IFNγ/IL10 as a molecular marker supporting the decision to administer hydrocortisone to patients in septic shock. Prospective clinical studies are necessary and standard operating procedures need to be implemented, particularly to define a generic threshold . If confirmed, IFNγ/IL10 may become a suitable theranostic marker for an urging clinical need.
Index: IFNgamma/IL10, hydrocortisone, immune therapy, machine learning, sepsis, steroids, theranostics