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Background: Large clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may however benefit depending on their individual immune response. Methods: We performed an exploratory analysis of the CORTICUS trial database employing machine learning to a panel of 137 variables collected from 83 patients (60 survivors, 23 non-survivors) including demographic and clinical measures, organ failure scores, leukocyte counts and circulating cytokine levels. The identified biomarker was validated against data collected from patients enrolled into a cohort of the Hellenic Sepsis Study Group (HSSG) (n=162) and two data sets of two other clinical trials. Ex vivo studies were performed on this biomarker to assess a possible mechanistic role. Results: 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 ratio for a decision rule, we found significant improvement in survival in the groups of patients being in compliance with the prediction rule (discovery set: OR=3.03 [95% Cl: 1.05-8.75], P=0.031, validation set: OR=2.01 [95% CI: 1.04-3.88], P=0.026). Applying the rule to two further, smaller datasets showed the same tendency. Mechanistic studies revealed that IFNγ/IL10 was negatively associated with pathogen load in spiked human blood. An in silico analysis of published IFNγ and IL10 values in bacteremic and non-bacteremic SIRS patients supported this association between the ratio and pathogen burden. Conclusion: If confirmed prospectively, the IFNγ/IL10 ratio could be used as a rapidly available theranostic for use of hydrocortisone therapy in septic shock.

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