Longitudinal Analysis of Blood and Airway Immune Response: Precision Medicine for

PROJECT SUMMARY/ABSTRACT Pediatric acute respiratory distress syndrome (PARDS) is a heterogeneous immune-mediated clinical syndrome that is commonly triggered by lower respiratory tract infections. PARDS affects 6% of intubated children, and ~1/3 of these children have severe PARDS – those with the highest degree of hypoxemia. An additional 4% are at-risk for PARDS, and of those at-risk children, ~1/5 progress to PARDS. Nearly 1/4 of PARDS survivors develop new morbidity at discharge, and ~1/3 of children with severe PARDS die. More than 40% of children who die PARDS-related deaths are previously healthy, very young children. Neutrophils are key drivers of inflammation and PARDS-related lung injury. The transmigration of blood neutrophils across an endothelial and epithelial cell layer into the alveolar space is a critical event in the transformation of a blood to activation results in the release of proteolytic enzymes, reactive oxygen species, and weblike DNA-histone complexes called neutrophil extracellular traps (NETs). NETs are a subset of nucleosomes that are toxic to many cell types, can skew T cells to a Th17 (vs. Treg) state, and contribute to further lung injury in PARDS. The overall objective of this study is to understand how neutrophil death promotes poor clinical outcomes in intubated children with PARDS. This proposal builds on Dr. Grunwell’s experience with airway and blood neutrophils, metabolomics, and transcriptomics in PARDS during her K23 award by expanding the investigation of mechanisms related to neutrophil death . This study will be the first to compare blood and airway samples each obtained at two times in the week following intubation and associate NETs with a longer duration of intubation and/or death. The specific goals are to determine whether markers of neutrophil cell death and/or a higher systemic Th17/Treg ratio are associated with poor clinical outcomes. The third goal is to an airway neutrophil. In inflammatory environments, neutrophil apoptosis is delayed and in intubated children at-risk and with PARDS integrate transcriptomic (RNASeq), metabolomic, and cytokine data with machine learning methods to link phenotypes with endotypes to gain mechanistic insight into the underlying pathobiology of PARDS. The proposal leverages the existing expertise and collaborative infrastructure at Emory University and Children’s Healthcare of Atlanta to strategically investigate newly discovered pathobiological mechanisms important to the onset and progression of PARDS and to identify factors that account for individual differences in pathology and response to treatments – to achieve the main goal of personalized medicine.