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IFNγ/IL10 ratio stratifies corticosteroids therapy for septic shock

ABSTRACT: To stratify hydrocortisone application in septic shock, we investigated an immune sub-study of the CORTICUS trial (Sprung et.al 2008, NEJM) employing machine learning to a panel of 120 parameters of 84 patients (n=24 non-survived, n=60 survived, 28 days) with special emphasis on potentially disadvantageous corticosteroids effects in the context of sepsis including clinical parameters, organ failure scores, lymphocyte counts and plasma protein concentrations of cytokines. We identified the ratio of IFNγ/IL10 in serum before randomization to serve as a valid biomarker for treatment stratification. This was validated with cytokine serum levels of patients (n=49) from the SISPCT study (Bloos et.al 2016, JAMA) and the early arm (n=20) of a hydrocortisone cross-over study (Keh et.al. 2003, Am J Respir Crit Care Med). Integrating these three studies, we yielded an odds ratio of 2.1 and a 95% confidence interval of 0.99-4.52 (P=0.03).In vitro assays revealed IFNγ/Il10 to reflect the burden or severity of systemic infection. Severity was evidencedbyserum levels of these cy-tokines in the patients with septic shock we observed, and also in patients with less severe sepsis. Elucidating the molecular regulation of leukocytes during treatment and placebo by a transcriptomics analysis pointed to induced recovery of immune cell function due to hydro-cortisone treatment, particularly in the predicted hydrocortisone responders. IFNγ/IL10 is a molecular marker with high potential for support of hydrocortisone therapy decision. IFNγ/IL10 is reasonable for this as it reflects the burden and recovery of the immune system which seems to be indicative for corticosteroids treatment of septic shock.

ORGANISM(S): Homo sapiens

PROVIDER: GSE106878 | GEO | 2019/10/01

REPOSITORIES: GEO

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Project description:Goal of the experiment: To identify correlated genes, pathways and groups of patients with systemic inflammatory response syndrome and septic shock that is indicative of biologically important processes active in these patients. Background: We measured gene expression levels and profiles of children with systemic inflammatory response syndrome (SIRS) and septic shock as a means for discovering patient sub-groups and gene signatures that are active in disease-affected individuals and potentially in patients with poor outcomes. Methods: Microarray and bioinformatics analyses of 123 microarray chips representing whole blood derived RNA from controls, children with SIRS, and children with septic shock. Results: A discovery-based filtering approach was undertaken to identify genes whose expression levels were altered in patients with SIRS or septic shock. Clustering of these genes identified 3 Major and several minor sub-groups of patients with SIRS or septic shock. The three groups differed with respect to incidence of septic shock and trended toward differences in mortality. Statistical analyses demonstrated that 6,435 gene probes were differentially regulated between the three patient sub-groups (false discovery rate < 0.001%). Of these gene probes, 623 gene probes within 7 major gene ontologies accounted for the majority of group differentiation. Network analyses of these 623 gene probes demonstrated 5 major gene networks that were differentially expressed between the 3 groups. Statistical comparison of septic shock survivors and non-survivors identified one major gene network that was under expressed in a high fraction of the non-survivors and identified potential biomarkers for poor outcome. Conclusions: This is the first genome-level demonstration of pediatric patient sub-groups with SIRS and septic shock. The sub-groups differ clinically and differentially express 5 major gene networks. We have identified gene signatures and potential biomarkers associated with poor outcome in children with septic shock. These data represent a major advancement in our genome-level understanding of pediatric SIRS and septic shock. Experiment Overall Design: Children < 10 years of age admitted to the pediatric intensive care unit and meeting the criteria for either SIRS or septic shock were eligible for the study. SIRS and septic shock were defined based on pediatric-specific criteria. We did not use separate categories of "sepsis" or "severe sepsis". Patients meeting criteria for "sepsis" or "severe sepsis" were placed in the categories of SIRS and septic shock, respectively, for study purposes. Control patients were recruited from the outpatient or inpatient departments of the participating institutions using the following exclusion criteria: a recent febrile illness (within 2 weeks), recent use of anti-inflammatory medications (within 2 weeks), or any history of chronic or acute disease associated with inflammation. Experiment Overall Design: After obtaining informed consent, blood samples were obtained on Day 1 of the study, and when possible on Day 3 of the study. Blood samples were divided for RNA extraction and isolation of serum. Severity of illness was calculated based on the PRISM III score. Organ failure was defined based on pediatric-specific criteria. Annotated clinical and laboratory data were collected daily while in the intensive care unit. Study patients were placed in the study categories of SIRS or Septic Shock on Day 1 of the study. On Day 3 of the study, patients were classified as SIRS, Septic Shock, or SIRS resolved (no longer meeting criteria for SIRS). All study patients were followed for 28 days to determine mortality or survival. Clinical, laboratory, and biological data were entered and stored using a web-based data base developed locally.

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IFNγ/IL10 ratio stratifies corticosteroids therapy for septic shock

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