Personalized Medicine: From Systems medicine and Immunometabolism to Precision Diagnosis and Stratification for Individualized Therapies

Necrotizing soft tissue infections are rare, acute bacterial infections that spread in connective tissue, muscle tissue or fat tissue. In colloquial speech, such conditions are often called "flesh-eating bacterial infections". The infections are severe, with mortality between 15 and 25%. Prompt surgery can be life-saving, but it can be extensive, including amputation being necessary in around 10-20%. Clinically, the picture is characterized by fever, local pain and strong general effects. Most have organ failure, and then most severely in those with a significant drop in blood pressure (septic shock), which is seen in up to half of the patients. Because of this, almost everyone needs treatment in an intensive care unit. We have previously participated in the world's largest international study of patients with necrotizing soft tissue infections, in an FP7 EU study called INFECT, which ended in 2018. In this we investigated the underlying pathogenic mechanisms. The PerMIT study is an international study with many of the same research groups and hospitals that participated in INFECT. Together, clinicians, basic medical researchers and statisticians have identified new targets for directed treatment aimed at specific disease mechanisms, which vary between different patient groups. We have studied the interaction between patient and bacteria in soft tissue infections. In the studies, we have also examined patients with sepsis, that is, serious infections, most often bacterial, which cause organ failure in the patient. We have studied clinical scoring systems to help identify patients with sepsis, which are suitable for further use in research and perhaps also in clinical everyday life. We have described cellular and metabolic processes that help us categorize sepsis patients. At PerMIT, we have further developed the understanding of both disease causes and treatment effects in both soft tissue infections and sepsis, and the study has taken us a step further in the development of medical treatment for critically ill patients with serious infections. A treatment strategy based on such interactions, with the identification of targets for very specific treatment, is often referred to as personalized medical treatment, and is so far little developed in the field of infectious diseases. At the same time, we have developed data that facilitates integrated data tools for decision support for diagnosis and selecting best treatment.

Vi har bidratt med resultater for skåring av pasienter til identifikasjon av pasienter med sepsis på sengepost med nosokomial sepsis. Vi har identifisert en interleukin-drevet pathway som er et potensielt mål for persontilpasset behandling med eksisterende receptorblokker. Vi har videreutviklet data til bruk i metabolsk basert stratifisering av pasienter med sepsis. Vi har avkreftet at histopatologisk undersøkelse av bløtvevsbiopsier ved mistenkt nekrotiserende bløtdelsinfeksjon har en plass i akutt stratifisering eller diagnostikk av pasienter med mistenkt nekrotiserende bløtdelsinfeksjon. Vi har lansert modell for digital pasientstratifiering, med et verktøy som kan veilede i identifikasjon og dermed rett behandling av pasienter med nekrotiserende bløtdelsinfeksjoner Vi har videreutviklet brobyggingen mellom basalmedisinske studier og kliniske beslutninger for pasienter med nekrotiserende bløtdelsinfeksjoner. Vi er i prosess med utvikling av behandlingsstudie, med tidlig involvering av aktuell LMI-produsent.

The PERMIT project proposes to implement personalised medicine in severe infectious diseases, specifically focusing on the life-threatening necrotizing soft tissue infections (NSTI) as well as the large heterogeneous group of sepsis patients that represent a global health priority. PERMIT builds on the advances and resources created in the FP7-project INFECT, including the world’s largest patient cohort on NSTI with an associated biobank, multi-omics data, strategic data stewardship and pathophysiologic models. With this strong foundation, we now propose to advance to the phase of preclinical validation of disease signatures/underlying mechanisms/biomarkers, and to translate these results into precision diagnosis enabling patient stratification for individualised therapy. One hypothesis to be explored in PERMIT is that immunometabolic processes are dysregulated and contribute to disease; thus, representing potential targets for tailored therapy. Specific aims are to: 1) identify disease signatures and their underlying mechanisms through dissection of multiomics results using computational analyses of integrated heterogeneous data sets, 2) engineer customized organotypic tissue models for validation and intervention studies, 3) validate identified signatures/biomarkers for patient classification through the use of large patient cohorts, 4) develop novel concepts and stratification schemes for tailored therapy, 5) conduct exploratory clinical studies of the new trial concepts, 6) develop and deploy ICT support tools to improve bedside decisions. The activities proposed will demonstrate the clinical feasibility and potential benefit of personalised medicine in acute infectious diseases. Importantly, the advances are likely to benefit patient outcome through improved diagnostics and tailored therapies. To achieve its objective, PERMIT builds on a transnational interdisciplinary consortium of clinicians, experimentalists, bioinformaticians and computational modellers.