Multidimensional phenotype classification in grade 3 BPD

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Bronchopulmonary dysplasia (BPD) is a severe chronic lung disease that develops over the first months of life in more than half of infants born less than 30wk of gestation. Infants who develop grade 3 BPD, the most severe disease form (defined as invasive ventilation at 36wk postmenstrual age), are at high risk for life-long deficits in health and cognition and poor quality of life. Unfortunately, rates of grade 3 BPD are increasing, and no therapies have been proven to treat this devastating disease. A key contributor to these care gaps is the nearly singular reliance on the prescribed respiratory support to define BPD presence and severity, select therapeutic interventions, and assess prognosis. Our data and others’ show that this subjective diagnostic approach masks significant heterogeneity in clinical presentation, treatment responsiveness, and outcomes. In other heterogenous chronic respiratory conditions such as COPD, cystic fibrosis, and asthma, evidence- based phenotyping (identification of patient subgroups based on shared characteristics) has become the new gold-standard to objectively classify distinct disease sub-types, improve patient counseling, identify novel disease mechanisms, and discover and implement more effective treatments. Our central hypothesis is that multidimensional phenotyping in grade 3 BPD is feasible, will accurately characterize disease heterogeneity, and will improve outcome prediction. Confirmation of this hypothesis will promote a frameshift towards an objective, systematic diagnostic approach in BPD and first-ever phenotype-specific trials in neonatology. Importantly, our motivating preliminary data support this hypothesis. Using retrospective results from chest CT, cardiac echo, and bronchoscopy, we showed that preterm infants with grade 3 BPD can be classified into phenotypes based on the presence or absence of severe parenchymal lung disease, abnormal large airways, and pulmonary arterial hypertension. This diagnostic approach correlated with pre-discharge outcomes and suggested possible phenotype-specific therapies. However, it relied on investigator chosen phenotypes rather than empirically derived subgroups, used qualitative results from only 3 diagnostic tests, and did not assess longitudinal phenotype stability or post-discharge outcomes. Our recent data indicate that serial quantitative cardiopulmonary imaging and evaluation of proven mechanistic contributors to BPD may improve disease phenotyping and outcome prediction. Our proposal builds on these preliminary data and will employ robust cluster analyses and longitudinal multidimensional imaging, biological, and clinical data in a large, prospective cohort of very preterm infants to accomplish the following Specific Aims: (1) define objective, evidence-based phenotypes in grade 3 BPD, and (2) define the strength of association between grade 3 BPD phenotypes and neurodevelopmental and pulmonary outcomes through 2 years’ corrected age using standardized development testing and validated outcome measures.