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Identification of biomarkers of response to IFNg during endotoxin tolerance: application to septic shock.

ABSTRACT: The rapid development in septic patients of features of marked immunosuppression associated with increased risk of nosocomial infections and mortality represents the rational for the initiation of immune targeted treatments in sepsis. However, as there is no clinical sign of immune dysfunctions, the current challenge is to develop biomarkers that will help clinicians identify the patients that would benefit from immunotherapy and monitor its efficacy. Using an in vitro model of endotoxin tolerance (ET), a pivotal feature of sepsis-induced immunosuppression in monocytes, we identified using gene expression profiling by microarray a panel of transcripts associated with the development of ET which expression was restored after immunostimulation with interferon-gamma (IFN-?). These results were confirmed by qRT-PCR. Importantly, this short-list of markers was further evaluated in patients. Of these transcripts, six (TNFAIP6, FCN1, CXCL10, GBP1, CXCL5 and PID1) were differentially expressed in septic patients' blood compared to healthy blood upon ex vivo LPS stimulation and were restored by IFN-?. In this study, by combining a microarray approach in an in vitro model and a validation in clinical samples, we identified a panel of six new transcripts that could be used for the identification of septic patients eligible for IFNg therapy. Along with the previously identified markers TNFa, IL10 and HLA-DRA, the potential value of these markers should now be evaluated in a larger cohort of patients. Upon favorable results, they could serve as stratification tools prior to immunostimulatory treatment and to monitor drug efficacy.

SUBMITTER: Allantaz-Frager F

PROVIDER: S-EPMC3708924 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Identification of biomarkers of response to IFNg during endotoxin tolerance: application to septic shock.

Allantaz-Frager Florence F Turrel-Davin Fanny F Venet Fabienne F Monnin Cécile C De Saint Jean Amélie A Barbalat Véronique V Cerrato Elisabeth E Pachot Alexandre A Lepape Alain A Monneret Guillaume G

PloS one 20130711 7

The rapid development in septic patients of features of marked immunosuppression associated with increased risk of nosocomial infections and mortality represents the rational for the initiation of immune targeted treatments in sepsis. However, as there is no clinical sign of immune dysfunctions, the current challenge is to develop biomarkers that will help clinicians identify the patients that would benefit from immunotherapy and monitor its efficacy. Using an in vitro model of endotoxin toleran ...[more]

PMID: 23874546

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Project description:Severe sepsis and septic shock are common in intensive care and carry high mortality rates. In patients with Gram-negative infections, early and extensive removal of endotoxin may limit the inflammatory response that characterizes septic shock. The Alteco® LPS Adsorber (hereafter referred to cited as the lipopolysaccharide (LPS) Adsorber) can be used for endotoxin removal and attenuate the deleterious inflammatory and clinical responses seen in septic shock.The Abdominal Septic Shock - Endotoxin Adsorption Treatment (ASSET) trial is a pilot study investigating the feasibility and safety of LPS Adsorber therapy. This pilot, multicenter, stratified, parallel, double-blinded, randomized, phase IIa, feasibility clinical investigation will be performed in five Scandinavian intensive care units. Thirty-two subjects with early septic shock and organ failure, following adequate resuscitation, will be randomized to receive either: extracorporeal veno-venous hemoperfusion therapy with the LPS Adsorber or veno-venous hemoperfusion therapy with a placebo adsorber (without active LPS-binding peptide). Patients will be stratified by infection focus such that 20 subjects with an abdominal focus (stratum A) and 12 subjects with a urogenital focus (stratum B) will be included in a parallel design. Thereafter, an interim analysis will be performed and an additional 12 patients may be included in the study. The study is designed as adaptive a priori: the patients from this study can be included in a later phase IIb study. The aim of the study is to investigate the feasibility of LPS Adsorber therapy commenced early in the time-course of septic shock. The primary endpoint will be a characterization of all reported unanticipated serious adverse device effects and anticipated serious adverse device effects. Secondary outcomes are decrease in endotoxin plasma concentration, impact on clinical outcome measures and impact on inflammatory response by LPS Adsorber therapy, as well as detailed description of the relevant mediators bound to the LPS Adsorber. Recruitment of patients will start in September 2015.The ASSET trial will give insight into the feasibility and safety of this LPS Adsorber therapy and preliminary data on its potential clinical effects in septic shock. Moreover, this pilot trial will provide with necessary data for designing future studies.ClinicalTrials.gov Identifier NCT02335723 . Registered on 28 November 2014.

Project description:The Protocol-based Care for Early Septic Shock trial found no differences across alternative resuscitation strategies in all-cause mortality. A separate aim was to determine whether differences in resuscitation strategies affected trajectories of biomarkers of key pathways associated with downstream clinical outcomes of sepsis and whether there were differences in survival across treatment arms for patients with different baseline biomarker profiles.Secondary analysis of a large randomized clinical trial.Thirty-one U.S. hospitals.Six hundred twenty-eight patients with septic shock.Two resuscitation protocols versus usual care.We measured a panel of biomarkers representing four pathophysiologic domains: "inflammation" (tumor necrosis factor, interleukin-6, and -10); "coagulation" (D-dimers, thrombin-antithrombin complex); "oxidative stress" (urine isoprostane); and "tissue hypoxia" (lactate) at 0, 6, 24, and 72 hours after treatment. We analyzed whether alternative resuscitation strategies affected biomarker trajectories over 72 hours and whether effects on 90-day hospital mortality varied by baseline (time 0) biomarker profiles-both using regression models with interaction terms for treatment arms. For all baseline biomarkers, higher concentrations were associated with increased risk of death by 90 days. However, there was no significant effect of treatment assignment on subsequent biomarker trajectories. We did find evidence for heterogeneity of treatment effect of protocol-based care on mortality for patients with different baseline [interleukin-6] and [interleukin-6] × [interleukin-10] profiles, whereas patients with the lowest quartiles fared better with protocol-based care (odds ratios, 0.32 [0.13-075]; p = 0.01 and 0.32 [0.14-0.73]; p = 0.01, respectively).In patients with septic shock, alterations in inflammation, coagulation, oxidative stress, and tissue hypoxia are common and associated with adverse outcomes but are not influenced by protocol-based resuscitation compared with usual care. However, contrary to expectation, protocol-based resuscitation appeared to be superior in patients with lower concentrations of inflammatory biomarkers. The mechanisms responsible for this effect are unclear.

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. Keywords: Septic shock, SIRS, pediatrics, outcome, infection, inflammation

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Identification of biomarkers of response to IFNg during endotoxin tolerance: application to septic shock.

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Identification of biomarkers of response to IFNg during endotoxin tolerance: application to septic shock.

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