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European Sepsis Academy: towards new biomarkers to improve sepsis management

Periodic Reporting for period 2 - ESA -ITN (European Sepsis Academy: towards new biomarkers to improve sepsis management)

Reporting period: 2018-03-01 to 2020-02-29

Sepsis, a severe life-threatening infection with organ dysfunction (affecting ~18 million individuals, with a high mortality rate) initiates a complex interplay of host pro- and anti-inflammatory processes. 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
4) initiation of early targeted treatment

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

1. Describing the pathogenesis of sepsis-induced immune suppression (SIIS) at the level of immune regulatory molecules and DNA methylation
2. Discovery: To identify and validate biomarkers to be used for clinical diagnosis and monitoring of SIIS.
3. Development: To prepare and optimise high-potential diagnostic technology and test innovative clinical trial designs.
ESR1 contributed to defining the role of PTX3 and IL-1R8/TIR8 in specific infection models associated with sepsis and studied mechanisms and potential of innate immunity training in different models of bacteria primary/secondary infections, and H1N1 viral infection. ESR2 evaluated the significance of host derived H2S in using cystathionine gamma lyase (CSE)-deficient animals, and in blood samples of patients with respiratory infections. ESR3 determined the molecular interactions of IRAK-M (a key player in sepsis induced immunosuppression), aimed at identifying target sites for boosting innate immunity as well as a potential biomarker and studied the impact of IRAK-M deficiency in sepsis. ESR4 investigated how gut and lung microorganisms can influence the pathogenesis of sepsis. ESR5 set up the INCLASS study, validated clinical sepsis phenotypes and endotypes through transcriptomic clustering and miRNA profiling, performed cost-effectiveness analysis and implementation of value-based trial design.

WP2 aimed to identify and validate biomarkers that could be used for clinical diagnosis and monitoring of sepsis-induced immune suppression. ESR6/7 collaborated with ESR5 to obtain blood samples from inflammatory and sepsis patients from 4 clinical studies. ESR6 performed high-dimensional immune phenotyping analyses suggesting neutrophilic MDSCs represent a biomarker of sepsis severity, while ESR7 found innate lymphoid cells may represent biomarkers of sepsis. ESR7 collaborated with ICH to decipher the protective role of (sepsis-induced) trained immunity on pneumococcal. ESR8 tested a set of molecules and confirmed the high potential of PTX3 as biomarker for early prognostic stratification of septic patients and developed an automated system to quantify PTX3. ESR9 (with UoA) analyzed metabolic parameters in monocytes from septic and control patients and set up a rat model of faecal peritonitis to test the potential of hormonal intervention to combat sepsis. ESR10 analyzed the impact of fatty acids on the response of blood leukocytes to microbial products and subsequently analysed in a rat model of faecal sepsis. Altogether, collaborative work pinpointed to MDSCs, PTX3 and bioenergetic dysfunctions as promising sepsis biomarkers.

Two prototype assays were developed by ESR11 and 12 and evaluated on European patients admitted to the ICU.
1. An Immune Functional Assay (IFA); developed/optimized to characterize the altered immune status of septic patients, customized (reproducibility), a molecular read out defined and evaluated (allowing stratification) and optimized towards an industrial process.
2. an IPP (immune profiling panel, 12 markers); designed in order to manage sepsis patients based on their immune status. It associated with HAI (hospital acquired infection) and will be assessed in a dedicated clinical cohort.
The MARS-India cohort (ESR13) will allow to evaluate the molecular markers (and gut microbiome composition) previously identified/studied in European cohorts enrolled for the MARS-NL, aimed at quantitating sepsis induced immunosuppression and identifying patients at risk of developing HAI after admission to the ICU. Part of the samples will also be used to validate markers/assays established by ESR11 and 12. ESR14 developed two models for clinical trials: one targeting the sample size determination (including decisions about the recruitment rate), another addressing sequential clinical trial design. ESR15 focused on data-oriented projects; one focusing on rapid identification and treatment of sepsis patients which implies increased antibiotic usage, another designed to reduce antibiotic usage broadly. Also, ESR15 with ESR12 on cost-utility assessments for the new point of care immune profile diagnostic tool.

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 performed. 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.
The ESA-ITN had multiple academic publications and a high presence on conferences and meetings. Furthermore, this team of young scientist formed strong connections, which leaded to multicenter and trans-disciplinary research. This did not only improve the relevance of the current research but also fosters collaboration in the future. This unique approach gives us out-of-the-box ideas that could change the sepsis field. Furthermore, since fast recognition off sepsis saves lives, the ESA-ITN focused strongly on scientific mediation through social media, the presence at the “Science is wonderful” event and non-academic publications.
The availability of an immune profiling (IPP) tool holds great potential in providing patients at high risk with accurate and precise management. Alternatively, immune Functional Assays (IFA), which record a response to a given stimulation, may help to assess the dynamics of immune function in clinical practice. We designed and evaluated a standardized IFA coupled to cutting-edge molecular panel which allow to address the heterogeneity of the immune response of septic shock patients. We achieved several of the key stages of the innovation chain (chemical stimulant, reduced time of stimulation, fully automated system, FilmArray platform) moving from the proof of concept to a prototype IFA which could be industrialized in the future.
Research efforts contribute to define a precision medicine strategy in order to achieve a tailored management of sepsis.