MRI Phenotyping of Early BPD and Prediction of Outcomes

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PROJECT SUMMARY Bronchopulmonary Dysplasia (BPD) is a chronic disease of prematurity that is increasing in prevalence, is responsible for the majority of neonatal intensive care unit (NICU) admissions across the nation (more than $13B/year in the US), and has high mortality and morbidity. Children with BPD have decreased pulmonary function, increased incidence of pulmonary vascular disease, and lifelong respiratory illnesses including asthma and COPD, with no clear link between initial diagnosis and outcomes. Currently, BPD is defined in terms of supplementary oxygen requirement, but this simplistic definition fails to account for the multifactorial complexity of the disease and its progression. Multiple groups have attempted to define BPD based on functional and physiologic information, but these definitions fail to identify those premature infants who develop BPD or how disease will progress. One of the only established outcomes predictors for BPD is pulmonary arterial hypertension (PAH), but the diagnosis of PAH itself is ambiguous and often delayed, because echocardiography can be inaccurate in these hyperinflated patients. The lack of a clinically prognostic definition of BPD severely limits the ability to predict outcomes or evaluate interventions designed to improve short and long term outcomes. To address this unmet need to assess cardio-respiratory pathology, our team pioneered the use of MRI in the NICU to quantify cardiac, pulmonary and airway abnormalities in prematurely-born neonates. Our ultra-short- echo (UTE) techniques yield 3D images at resolutions similar to CT, provide functional information unavailable from CT, require no ionizing radiation or contrast injection, and can be performed on free-breathing neonates without sedation. Further, this MRI provides structural information about the lung parenchyma and vasculature and dynamic physiologic information from the heart and airways that has never before been available in neonates. Based on strong preliminary data and our demonstrated ability to perform clinically relevant cardiopulmonary MRI in neonates, we will define BPD phenotypes derived from structural and functional abnormalities prevalent in patients. In doing so, we will determine for the first time how specific structure-function abnormalities correspond to regional pathophysiology and patient outcomes in BPD. Our overall goal is to characterize the early sequelae of premature birth via MRI phenotyping, determine the timecourse of disease via longitudinal MRI, predict respiratory outcomes at or near NICU discharge, and relate early clinical care and image phenotyping to 1- and 2-year respiratory outcomes. This proposal draws upon strong preliminary data and multidisciplinary clinical and research programs to establish the first image-derived phenotypes of BPD, in the stage of life when the disease forms and changes rapidly. The impact of the research is high and has strong potential for translation—affecting our understanding and definition of disease and its formation, with likely impact on future respiratory support, critical care, and outcomes.