A TARGETED METABOMOLIC APPROACH TO DESIGN A PREDICTIVE MODEL FROM THE MONITORING OF THE INFLAMMATORY MEDIATORS KINETICS IN PATIENTS ADMITTED TO INTENSIVE CARE UNIT WITH COVID-19 PNEUMONIA. – COVID-METAFLAM

Beginning in December 2019, a novel coronavirus, designated SARS-CoV-2, has caused an international outbreak of respiratory illness termed Covid-19, requiring for a small proportion of patients, admission to Intensive Care Unit (ICU). However, despite the urgent needs of therapeutic guidelines, little is known about the exact immune and inflammatory response of patients with COVID-19 and no robust, sensitive and accurate biomarkers are available. The main objective of the present COVID-METAFLAM project is to characterize the kinetic of metabolomic inflammatory profiles associated with the inflammatory-immune response during COVID-19 pneumonia in ICU patients. We also plan to help for the prediction of the successive phases (acute phase, resolution phase) of the inflammatory-immune response; to search for an association between metabolomic profiles and clinical outcome (morbidity, mortality); to focus on metabolomic profiles in patients receiving immunomodulatory, chloroquine and/or anti-inflammatory treatments. We hypothesize that the integration and machine learning modeling of inflammatory targeted metabolomics in addition to cytokine profiles and bio-clinical data should demonstrated that some metabolites highly correlated with the pathogenic phase of the infection, whereas other are associated with the resolution phase. Our project is thus aimed at stratifying COVID-19 patients according to their inflammatory and metabolic status to help the management of this patients and to provide guidelines for patient treatment. This project will benefit from combined expertise of teams of physicians, virologists, medical biologists and biostatistician working on intensive care and metabolomics/lipidomics. We will also pay a particular attention to the ongoing therapeutic assays using anti-viral, steroids, immunomodulators and other drugs such as hydroxychloroquine. The project will last 12 months and will be organized into five tasks: (i) Recruitment of patients and collection usual demographic, anamnestic, clinical, radiological, biological and microbiological data (based on the COVID-ICU Study, REVA); (ii) Collection and transport of biological samples (based on the AP-HP COVID-Biobank); (iii) Biological explorations; (iv) Analysis of results; (v) Project management. It will be supported by existing networks: COVID-ICU Study, a French prospective multicenter (>70 ICUs, 10 ICUs in the Paris area) performed by the REVA network and the AP-HP COVID-Biobank. Over the 3-month period of inclusion, we estimate that 900 COVID-19 pneumonia patients will be admitted to the 10 participating ICUs (30 patients/month/center). We estimated that 80% of these 900 patients will be included in the COVID-ICU Study. Among them, we estimate that 50% will be included in the AP-HP COVID-Biobank. Altogether, we estimate that 360 patients will be included in the COVID-METAFLAM Study. A total of more than 200 molecular species will be quantified using Liquid Chromatography-Mass Spectrometry (LC-MS/MS) and/or Gas Chromatography-Mass Spectrometry (GC-MS) in our certified department of clinical metabolomic at Saint Antoine hospital (Paris). We will combine data a wide variety of origins, clinical and imagery data (qualitative or quantitative data), biological results and metabolomic to provide a statistical model with prognostic and predictive values, as previously made in our laboratory for specific pathologies and anti-doping research. The project coordination will be ensured by URC –EST, the Clinical Research Center (CRC-EST), the Certified BioBank Research Center (CRB) of Sorbonne University, and the Clinical Research Unit. Our project is ambitious and innovative: (i) this is the first European project which propose a metabolomic approach to monitor kinetics of inflammatory mediators in patients with COVID-19 pneumonia; (ii) the short delay to get results will guaranty a short-term impact, with a quick translation into clinical practice and therapeutics.