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

 描述(由申请人提供)：用于量化CF患者肺部病理演变的最新技术状态是一秒用力呼气量(FEV1)。然而，6岁以下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发病过程中不可或缺的一步。我们曾报道肺功能正常的7-14岁CF儿童和前18个月感染过铜绿假单胞菌(PA)的儿童的粘液清除(MCC)明显慢于未感染PA的儿童。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患慢性CF肺部疾病的风险的儿童。我们将开始在20名5岁或6岁的有肺部疾病前期症状的CF儿童中填补这一信息空白。如果孩子可以可靠地进行这项测试，他们将接受肺清除指数(LCI)和FEV1的测量，并进行两次MCC测量，间隔2周。在90分钟和24小时后，使用伽马闪烁照相术测量右肺和右肺的总MCC。一年后行HRCT扫描，复查MCC、LCI和FEV1。我们还将确定PA的发病年龄、出生以来PA+培养的数量以及第一年和第二年MCC测量之间PA+培养的比率，并将对儿童的DNA进行全基因组测序，测量儿童痰中MUC5B的水平，并获得儿童环境暴露的详细历史记录。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特征相关，包括LCI和HRCT评分增加以及FEV1降低(目标1b)；MCC在一年以上的变化将与同一时间段(目标1c)内肺通气性和FEV1的变化相关；与MCC值较快的儿童相比，第一年MCC测量时清除较慢的儿童将有较早的PA发病年龄和较高的PA阳性呼吸道培养比率；在第一年和第二年之间，MCC下降较大的儿童在这段时间内将有更频繁的PA+培养(目标2)。我们还推测，CF肺修饰基因、痰中MUC5B水平和/或环境因素的遗传变异将与早期粘液清除的变化相关(目标3)。这些实验的结果将开始确定MCC的测量是否可以作为一种肺部属性，用于识别有患慢性肺部疾病风险的CF儿童，从而导致可能延迟或减少严重肺损伤、提高存活率和生活质量的早期战略干预。

 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.