Defining the Pulmonary Attributes of Pre-symptomatic Lung Disease in Cystic Fibrosis

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 DESCRIPTION (provided by applicant): The state of the art for quantifying the evolution of lung pathology in patients with CF is the forced expiratory volume in one second (FEV1). However, children younger than 6 years of age cannot perform this test reliably and physicians must depend on chest radiographs or high resolution (HR) CT scans, oropharyngeal cultures, and bronchoalveolar lavage to assess lung disease in this population. Defective mucus clearance from the lungs appears to be an integral step in the pathogenesis of CF. We have reported that mucociliary clearance (MCC) varies significantly between 7-14 year old children with CF who have normal lung function and children who have been infected with Pseudomonas aeruginosa (PA) in the preceding 18 months have slower mucus clearance than children who have not been infected with PA. Nevertheless, it is unknown if MCC is a reliable measurement in children with CF, or if it can serve as a pulmonary attribute to identify children at risk for developing chronic CF lung disease. We will begin to fill-in this information gap in 20 children with CF who are 5 or 6 years old and pre-symptomatic of lung disease. Children will undergo measurements of lung clearance index (LCI) and FEV1, if the child can perform this test reliably, and two measurements of MCC, separated by 2 weeks. MCC will be measured from the total right lung and right lung regions over 90 min and after 24 hrs, using gamma scintigraphy. An HRCT scan and repeat measures of MCC, LCI and FEV1 will be obtained one year later. We will also determine the age of onset of PA, the number of PA+ cultures since birth and the rate of PA+ cultures between the 1st and 2nd year MCC measurements and will perform whole genome sequencing of the children's DNA, measure MUC5B levels in children's sputa and obtain detailed histories of the child's environmental exposures. We hypothesize that MCC will be a reliable biomarker in these children (Aim 1a); slower MCC will be associated with hallmarks of developing chronic lung disease, including increased LCI and HRCT scores and lower FEV1 (Aim 1b); changes in MCC over one year will be associated with changes in lung ventilation homogeneity and FEV1 during the same time frame (Aim 1c); children with slower clearance at the time of the 1st year MCC measurement will have an earlier age of onset of PA and a higher rate of PA positive airway cultures since birth, compared to children with faster MCC values; and children with a greater decline in MCC between the 1st and 2nd year measurements will have more frequent PA+ cultures during that time (Aim 2). We also speculate that genetic variants in CF lung modifier loci, MUC5b levels in sputum and/or environmental factors will be associated with variation in early-life mucus clearance (Aim 3). Results from these experiments will begin to determine if measurements of MCC can serve as a pulmonary attribute that can be used to identify children with CF who are at risk for developing chronic lung disease, leading to early strategic interventions that could potentially delay, or reduce serious lung damage, improve survival, and improve quality of life.