Rare Bronchiectatic Diseases Consortium

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Abstract

ABSTRACT Bronchiectasis (BE) is a disorder of the intrapulmonary bronchi and bronchioles that is, associated with chronic pulmonary infection and inflammation. BE is a final common result of many muco-obstructive diseases with the most prevalent form being “non-cystic fibrosis bronchiectasis” (NCFB). Notably, four rare genetic diseases are also associated with BE, including, primary ciliary dyskinesia (PCD), alpha-1 antitrypsin deficiency (α1ATD), humoral immune deficiency (HID), and STAT3-hyper IgE syndrome (STAT3-HIES). These rare bronchiectatic diseases (RBDs) are caused by different genetic defects, and we hypothesize that each impact different components of the “Vicious Vortex” of mucus accumulation, infection, and inflammation. Performed through the Rare Bronchiectatic Diseases Consortium (RBDC), this project will test the hypothesis that a longitudinal characterization of the clinical phenotype and disease evolution of these RBD, along with patient-related outcome measures, comprehensive pulmonary function, and CT imaging, and coupled to serial collection of biospecimens will yield novel biomarkers that could accelerate therapeutics development for the four RBDs. Importantly, these studies are designed to identify biomarkers shared by the four RBDs, and those that are RBD specific to broadly advance the design and implementation of future therapeutic trials. The project has three Specific Aims. In the first Aim, we will characterize the clinical phenotype and disease trajectory of bronchiectasis in the four RBD through quality-of-life and symptom scores, spirometry and diffusing capacity measures, and standardized thoracic CT imaging with novel analysis to quantify bronchiectasis and mucus plugging. The goals are to define the longitudinal variability of these measures and compare the clinical courses of these four RBDs. In the second Aim, we will collect sputum, exhaled breathe condensate, and blood samples for measurement of novel, pathogenesis-based biomarkers. These biomarkers will be compared to indices of disease trajectory from Aim 1 to assess their sensitivity and reliability as biomarkers of disease status and progression. Aim 2 will also test the accuracy and sensitivity of sputum and exhaled breath condensate (EBC)-based measures of the lower airway environment with reference to bronchoscopy-collected samples. Finally, we will assess and characterize changes in respiratory symptoms, pulmonary measures, and sputum biomarkers during exacerbations in the four RBD to identify reproducible clinical features and marker(s) that can be used as endpoint(s) for clinical trials. Successful completion of this project will provide the longitudinal clinical trajectories for the four RBDs, produce data regarding applicability and performance of novel biomarkers shared between and specific to RBDs, and identify shared and disease-specific treatable traits essential for future therapeutics development and clinical trial design.