Sepsis, which is characterized by life threatening organ dysfunction caused by an uncontrolled host response to infection, is the leading cause of death in hospitals and is responsible for >250,000 deaths per year in the U.S. at the cost of over $20 billion in patient care. Sepsis has a mortality rate nearing 50% at 2 years, which has profound implications for patients recovering from severe COVID-19, a form of viral sepsis. Because sepsis is a multi-organ disease, the quantification of circulating proteins and metabolites is central to the profiling of sepsis and of its long-term effects, and some such assays (lactate, procalcitonin) have become the standard of care. To date, the majority of studies, and particularly the large number in COVID-19 sepsis, have profiled plasma and serum, which, compared to whole blood is fraught with variability and belies the important roles of the erythrocyte and other cell-types. To this end, biorepositories at Duke University, which are banking samples from COVID- 19 sepsis patients in the intensive care unit (ICU) and in a post-COVID outpatient clinic, have been utilizing volumetric absorptive microsampling (VAMS) on Neoteryx Mitra tips to collect and store whole blood specimens for future ‘omic analyses. The overarching goals of this application are to develop and validate multiomic methods for mass spectrometry-based quantification of proteins and metabolites from Mitra tips that comprehensively profile sepsis pathobiology. In the R21 phase, we will develop and validate mass spectrometry-based methods for the non-targeted quantification of proteins and post-translational modifications (phosphorylation, glycosylation) in whole blood, and for targeted quantification of numerous metabolite classes. We will develop reference materials and standard operating procedures for inter-laboratory translation of these approaches. In the R33 phase, we will analyze proteins, PTMs and metabolites from over 600 patient timepoints from biorepositories containing longitudinal samples in critically ill sepsis and post-COVID-19 cohorts, and we will integrate these data with well-curated clinical datasets. Completion of these aims will establish the utility of blood sampling by VAMS for future sepsis studies and will create a highly curated clinical and deep multiomic dataset for future hypothesis generation.