Use of IFNγ/IL10 ratio for stratification of hydrocortisone therapy in patients with septic shock

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.

Targeting Complement C5a Receptor 1 for the Treatment of Immunosuppression in Sepsis

“… 33 Recently, particularly the IFN-γ/IL-10-ratio was described as a marker indicating the host’s control over the immune response and infection. 28 , 29 The increased IFN-γ/IL-10 ratio and cytokine profiles in C5ar1-deficient mice, challenged by the low-dose sepsis model, supports the idea that C5a signaling under the given conditions is fulfilling an immunosuppressive function. Under these immunosuppressive conditions, pathogen-induced organ damage might cause increased mortality of wild-type animals.…”

“…The ratio of IFN-g to IL-10 was previously described as a measure for the general inflammatory response during systemic infections and the ability of the immune cell to control pathogen invasion. 28,29 Figure 4C depicts this ratio for the models with low and high load, indicating protection of C5aR À/À mice from a deregulated host response caused by a mild infection. During severe infection, however, this protection disappears in accordance with a lack of survival benefit ( Figures 1B and 1C).…”

Sepsis therapies: learning from 30 years of failure of translational research to propose new leads

“…Blocking or activating specific pathways may be potentially beneficial when a pathway is over‐ or under‐expressed in patients who fare badly, albeit with the caveat that this may represent an adaptive rather than detrimental response. This may apply to the use of IL‐1 receptor antagonism (Shakoory et al , ), anti‐TNF therapies (Panacek et al , ), or corticosteroids (König et al , ), where post hoc analyses suggest benefit in those with raised ferritin, raised IL‐6 levels and low IFN‐ γ /IL10, respectively (Table ). On the other hand, a post hoc analysis of a clinical trial showed that a transcriptomic signature suggestive of a more immunocompetent profile fared significantly worse with steroid therapy (Antcliffe et al , ).…”

Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock

“…We thank Anne Goessinger for her outstanding support of the CORTICUS sub-study, Katja Dahlke providing animal data for further analysis, Frank Bloos for providing information and discussing about the SISPCT data, and Jürgen Rödel for providing bacterial clinical isolates. This manuscript has been released as a pre-print at bioRxiv ( 40 ).…”