Sepsis and COVID-19 are both placing a major burden on societies and populations worldwide. Deregulated host response to infection is the hallmark supporting the routine use of corticosteroids (CS), a low-cost and highly efficient class of immuno-modulators, in sepsis/COVID-19. Stratifying patients based on individual immune response may improve the balance of benefit to risk of CS treatment. This proposal will integrate different approaches to define the CS sensitivity/resistance of individual patients. The partners will elaborate signatures from different characterizations of biological systems in patients with sepsis/COVID-19. Targeted approaches will define whether characteristics at the level of DNA, RNA, proteins such as cytokines and hormones, or metabolite compounds, support predicting individual patient’s CS responsiveness. Methods of artificial intelligence will integrate the high dimensional multi-level data from previous studies of this consortium and from data to be newly generated. An exploratory adaptive trial will include patients with sepsis/COVID-19 in multiple arms based on novel CS responsiveness signatures to be tested. Within each biomarker-defined cohort, patients will be randomized to receive corticosteroids or placebo allowing the evaluation of the efficiency of signatures elaborated by the partners. Signatures of CS responsiveness will be integrated for predictive enrichment of CS sensitivity and resistance of each individual patient defining personalized treatment rules, and thereby improving their chance to survive in good health. We will test the robustness of the personalized corticotherapy across subsets of patients based on gender, social categories and ethnicity. We will also ensure that the proposed personalized corticotherapy for sepsis/COVID-19 can be accessed for routine care of patients in low- and middle-income countries.