Abstract
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.
Abbreviations
- ACTH
- Adrenocorticotropic hormone
- ADRENAL
- Adjunctive corticosteroid treatment in critically ill patients with septic shock
- CI
- Confidence interval
- CORTICUS
- Corticosteroid therapy of septic shock
- HC
- Hydrocortisone
- HSSG
- Hellenic sepsis study group
- NE
- Norepinephrine
- OR
- Odds ratio
- SISPCT
- Sodium selenite and procalcitonin guided antimicrobial therapy in severe sepsis
- SOFA
- Sequential organ failure assessment
- VASST
- Vasopressin and septic shock trial