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

 描述（由申请人提供）：量化CF患者肺部病理演变的最新技术水平是一秒用力呼气量（FEV 1）。然而，小于6岁的儿童不能可靠地进行这项测试，医生必须依靠胸片或高分辨率（HR）CT扫描，口咽培养和支气管肺泡灌洗来评估这一人群的肺部疾病。从肺中清除粘液的缺陷似乎是CF发病机制中不可或缺的一步。我们已经报道了7-14岁的CF儿童之间的粘液纤毛清除率（MCC）差异显着，这些儿童具有正常的肺功能，并且在过去18个月内感染铜绿假单胞菌（PA）的儿童的粘液清除率比未感染PA的儿童慢。然而，目前尚不清楚MCC是否是CF儿童的可靠测量方法，或者它是否可以作为一种肺部属性来识别有发展为慢性CF肺部疾病风险的儿童。我们将开始在20名5或6岁的CF儿童中填补这一信息空白，这些儿童有肺部疾病的前期症状。如果儿童能够可靠地进行该测试，则儿童将接受肺清除指数（LCI）和FEV 1的测量，并接受两次MCC测量，间隔2周。在90分钟内和24小时后，使用伽马射线照相术测量右肺和右肺区域的MCC。一年后将进行HRCT扫描并重复测量MCC、LCI和FEV 1。我们还将确定PA的发病年龄，自出生以来PA+培养物的数量以及第1年和第2年MCC测量之间PA+培养物的比率，并将对儿童的DNA进行全基因组测序，测量儿童粪便中的MUC 5 B水平，并获得儿童环境暴露的详细历史。我们假设MCC将是这些儿童的可靠生物标志物（目标1a）;较慢的MCC将与发展为慢性肺部疾病的标志相关，包括LCI和HRCT评分增加和FEV 1降低（目标1b）;一年内MCC的变化将与同一时间段内肺通气均匀性和FEV 1的变化相关（目标1c）;与MCC值较快的儿童相比，第1年MCC测量时清除较慢的儿童发生PA的年龄较早，且自出生以来PA阳性气道培养率较高;在第1年和第2年测量之间MCC下降幅度较大的儿童在此期间将进行更频繁的PA+培养（目标2）。我们还推测CF肺修饰基因座的遗传变异、痰液中MUC 5 b水平和/或环境因素将与早期粘液清除的变化相关（目的3）。这些实验的结果将开始确定MCC的测量值是否可以作为一个肺部属性，用于识别有慢性肺部疾病风险的CF儿童，从而导致早期战略干预，可能延迟或减少严重的肺损伤，提高生存率，改善生活质量。

 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.