CPCCRN PRECISE Supplement

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Project Summary/Abstract The Personalized Immunomodulation in Pediatric Sepsis-induced MODS (PRECISE) study that is currently being conducted by the NICHD’s Collaborative Pediatric Critical Care Research Network (CPCCRN) uses real- time immune phenotyping to assign subjects to treatment or observational cohorts based on their immune status. The 24-site, 1000-subject PRECISE study currently uses the whole blood ex vivo LPS-induced TNFα production capacity (TNFα response) assay to diagnose severe innate immune suppression, termed “immunoparalysis”. An alternative approach to diagnosing immunoparalysis is the measurement of the expression of the antigen-presenting molecule HLA-DR on the surface of circulating monocytes (mHLA-DR) using flow cytometry. The current application proposes the addition of mHLA-DR expression measurement, which is now much more feasible for multi-center use than at the time of the original study design, to the PRECISE immunophenotyping panel. Though mHLA-DR expression will not be used to drive cohort assignment, its addition will allow for the evaluation of mHLA-DR expression as a potential diagnostic tool that could drive treatment in the future. This is important because there are currently no FDA-approved laboratory tests for the diagnosis of immunoparalysis, and if the PRECISE study is positive, there is currently no way to rapidly generalize its results. The addition of mHLA-DR expression to the dataset provides a unique and time- limited opportunity to understand if thresholds of mHLA-DR expression exist that equate to the TNFα response cutoff used in the PRECISE study; and to understand if mHLA-DR expression can serve as a predictor of a favorable response to GM-CSF. If positive, this could greatly accelerate the movement of immunoparalysis diagnostics to the clinical laboratory, to the benefit of critically ill children.