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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - ESA -ITN (European Sepsis Academy: towards new biomarkers to improve sepsis management)

Teaser

Summary

Sepsis, a severe life-threatening infection with organ dysfunction, initiates a complex interplay of host pro- and anti-inflammatory processes. It affects ~18 million individuals worldwide and has a very high mortality rate. Sepsis can be considered a race to the death between the pathogen and the host immune system. Key priorities in treating sepsis are 1) recognising \'sepsis\' as such, 2) identification of the source and type of the infection, 3) identification of the stage of disease and 4) initiation of early targeted treatment.

The European Sepsis Academy (ESA-ITN) aims to develop and validate the pathological insights, biomarker diagnostics and clinical trial models that can enable development and implementation of personalised treatment strategies targeted at the immunosuppressive phase of sepsis focusing on:

1. Describing the pathogenesis of sepsis-induced immune suppression at the level of immune regulatory molecules and DNA methylation
2. Discovery: To identify and validate biomarkers that can be used for clinical diagnosis and monitoring of sepsis-induced immune suppression
3. Development: To prepare and optimise high-potential diagnostic technology platforms for use in diagnostic procedures in sepsis and test innovative clinical trial designs.

Work performed

Pathogenesis
ESR1 has performed in vivo and in vitro experiments aimed at defining the role of PTX3 and IL-1R8/TIR8 in specific infection models associated with sepsis. (Streptococcus pneumoniae and Klebsiella pneumoniae). ESR2 will use gene targeted mice to obtain insight into the production of H2S (Hydrogen sulfide, an emerging factor in sepsis) in vivo and use murine sepsis models to study the effect of H2S deficiency or inhibition in sepsis. ESR3 will study the regulation of IRAK-M expression (a key player in sepsis induced immunosuppression), determine molecular interactions of IRAK-M and study the impact of IRAK-M deficiency in sepsis. ESR4 will investigate the role of the microbiome in sepsis from a biomarker development perspective and identify specific targets and markers for the development of immunosuppression in sepsis. ESR5 has set up a multi-center, randomized, double blind, clinical trial of clarithromycin versus placebo in septic patients with multiple organ dysfunction syndrome and hospital-acquired infections (INCLASS study).

Discovery
ESR6 set up a flow cytometry panel and optimized the basic MDSC panel to work with fresh and fixed samples. She developed a panel in a lyophilized antibody tubes for MDSC profiling to make it possible to include a cohort of patients within different hospitals and countries while minimizing inter-institutional variation due to sample processing. ESR7 set up panels for flow cytometry analysis of human and mouse cells and verified that mouse samples could be fixed before analysis without major impact, as long as analysis is performed within one day. ESR8 focuses on a set of molecules to test their potential as biomarkers for early prognostic stratification of septic patients. ESR9 will look at the temporal relationship between hormonal changes, bioenergetics and cellular function and during the time course of sepsis using in vitro and ex/in vivo models. She will assess different organs and organ systems and corresponding cells analyzing organ/cell-appropriate markers of functionality. ESR10 has been collecting plasma from septic and healthy control rats for ex vivo/in vitro experiments.To reduce unnecessary animal usage, she has been focusing on using hepatocyte and cardiomyocyte cell lines and assesses mitochondrial function of these cell lines using respirometry.

Development
To define an Immune functional Assay (IFA) aiming to characterize the altered immune status ESR1 evaluates i) sepsis samples of a 96-gene molecular signature in Nanostring format using conventional stimuli, and ii) a careful selection of a reasonable number of innovative chemical stimuli . To define a whole blood molecular assay to identify and quantitate sepsis-induced immunosuppression, a first set of 24 genes in FilmArray format was evaluated, discriminating healthy and ill patients and addressing reproducibility and repeatability (ESR12).ESR13 investigates whether the â€œat risk endotypesâ€ signatures previously identified with the MARS cohort are robust across various causes of sepsis and single pathogen scenarios. Clinical trial sample size determination using Bayesian value of information techniques (benefits of learning about the performance of a new technology versus the costs of running a trial) was developed (ESR14) and data (treatment patterns for patients with sepsis) examination in R is in exploratory phases (ESR15).

Training
All ESRs have weekly local supervisor meetings. Multiple training events have been organized according to plan to acquire research specific and transferable skills. Secondments at network institutions have been planned for all ESRs and are just about to start for most. For most ESRs the original secondment scheme was not feasible in the reality of the day and/or did not match anymore the requirements and learning goals of the individual ESRs and therefore was altered in order to better reflect the needs for his/her project and career track.

Final results

ESA-ITN goes beyond the state of the art by describing the pathogenesis of sepsis-induced immune suppression at the level of immune regulatory molecules and DNA methylation (Pathogenesis); identifying and validation of biomarkers that can be used for clinical diagnosis and monitoring of sepsis-induced immune suppression (Discovery); and by preparing and optimizing high-potential diagnostic technology platforms for use in diagnostic procedures in sepsis and testing of innovative clinical trial designs in addition to Training and Management (Development).

The organisation of ESA-ITN offers an international research and training network that reflects the entire innovation value chain for sepsis biomarker diagnostics and allows the ESRs to prepare for an academic or business career. ESA-ITN links to various leading networks and infrastructures in the field of sepsis, such as ESCMID, ESICM, ISF and the MARS cohort.

We are well ahead with the training aspect of the program. The ESRs are in close contact with the industrial partners learning about economic considerations in decision-making processes and obtaining an entrepreneurial mindset. The mini-MBA offered by INSEAD (July 2018) will trigger and stimulate the ESRs to think and learn about research commercialisation.

The contribution to the European innovation capacity, including the non-academic sector is high. ESA-ITN has connected top players from preclinical and clinical science, bioinformatics, diagnostics and innovation science with which adds critical mass to each individual participant and through this massive innovation potential we contribute to leap forward in sepsis diagnostics. Valuable novel biomarkers within the ESA-ITN are being evaluated as we speak.

The ESRs will actively participate in patient outreach programmes organized for sepsis survivors (scheduled for Autumn 2018)and ESA-ITN supports World Sepsis Day (WSD). Dissemination of the research results is already well on track (please refer to midterm report for an overview of peer-reviewed books and articles).