Project Details

Serial High-Dimensional Immunophenotyping and Functional Testing in Pediatric MODS (PARADIGM-SHIFT)

R. Brad Lindell, MD

Summary

BACKGROUND: Multiple organ dysfunction syndrome (MODS) is the final common pathway of morbidity and mortality in many critically ill and injured children, and patients with immune dysfunction represent a high-risk phenotype of pediatric MODS, with mortality rates that exceed 50%. Transcriptomic analyses have identified global changes in adaptive immune response and glucocorticoid receptors which confer prognostic significance in sepsis-associated MODS but have yielded limited insights into the biology of immune dysfunction in critically ill children. GAP: Our novel proposed translational research methods will overcome a critical knowledge gap by longitudinally defining the state and dynamic trajectory of immune dysfunction in pediatric MODS using blood samples obtained at the time of MODS onset and twice weekly until death or resolution of organ dysfunction. HYPOTHESIS: We hypothesize that novel endotypes identified through longitudinal, comprehensive high-dimensional proteomic analysis and immunophenotyping of leukocyte subsets will predict organ dysfunction and mortality in pediatric MODS, and that disease- and treatment-specific risk factors will be associated with in vitro measures of innate and adaptive immune suppression. METHODS: As a single-center ancillary study to PARADIGM, we will obtain serial blood samples from eligible children with MODS at Children’s Hospital of Philadelphia. We will employ a high-dimensional mass cytometry assay to comprehensively immunophenotype leukocyte subsets by cell surface markers, a multiplexed serum proteomics biomarker assay to assess innate and adaptive immune response, and mitogen stimulation tests to assess in vitro leukocyte function. RESULTS: Specimens will be analyzed in batches at prespecified intervals; we expect to enroll 40 patients at Children’s Hospital of Philadelphia during the study period. IMPACT: These discovery-oriented pilot studies will refine our understanding of immune dysfunction in MODS, identify risk-stratified cohorts of patients based on immune status, define potential targets for personalized pharmacotherapy, and provide preliminary data for ongoing efforts to bring precision medicine to the bedside in the field of pediatric sepsis. Website Link: https://www.chop.edu/doctors/lindell-brad