The Lung Clearance Index as a Marker of Early Lung Disease in Preschool Children

描述（由申请人提供）：囊性纤维化（CF）与慢性呼吸系统疾病相关，是大多数患者寿命缩短的原因。越来越多的证据表明，CF肺病在出生后不久就开始了，甚至在没有临床体征和症状的情况下也会发展。传统的肺功能测量方法，如肺活量测定法，很难在幼儿中测量，并且无法发现该年龄组的异常。因此，在6岁以下CF患者的临床研究中，需要更灵敏、更容易的肺功能测量。多次呼吸冲洗测试（MBW）测量气体在肺部混合的效率，并已被证明在传统的肺功能测量之前检测肺功能异常。此外，该测试需要最小的合作，因为它是在正常呼吸期间进行的，因此非常适合年龄较小的儿童。目前在北美的中心还没有经过验证的多次呼吸冲洗系统。最近，一个商业系统已经开发出来，但目前缺乏年龄较小的儿童（3-6岁）的数据，这是疾病进展的关键窗口。然而，很少有数据可以定义什么是LCI随时间的显著变化。本提案的总体目标是将肺清除率指数发展成为6岁以下CF患者介入研究和临床护理的工具。这将通过三个具体目标来实现：目标1：根据学龄前儿童的金标准验证氮冲刷法测量的LCI。目标2：在与临床试验相关的时间间隔内定义LCI测量的可重复性。目的3：确定LC作为临床监测工具的效用。目的1中的验证研究对于验证与金标准的一致性以及完善该年龄组的方案至关重要。验证后，我们将利用氮洗净系统来表征LCI在健康和CF中的可重复性，以确定正常测量变化的限制，这些变化在统计上有效，并且与临床相关。这将在一项为期一年的纵向研究中完成，该研究模仿介入性试验的设计。这一信息将直接适用于该年龄组CF患儿临床研究的设计和解释。最后，我们将测试LCI在监测学龄前儿童肺恶化中的临床应用，并评估LCI是否可用于跟踪临床疾病严重程度随时间的变化。这些研究将为后续针对学龄前CF儿童的干预性试验以及LCI在CF婴儿中的应用研究奠定基础。此外，本研究获得的信息将是后续研究其他气道疾病（如哮喘和原发性纤毛运动障碍）的关键一步。（摘要结束）

DESCRIPTION (provided by applicant): Cystic Fibrosis, (CF) is associated with chronic respiratory disease, which is responsible for the shortened life span in most patients. There is increasing evidence that CF lung disease begins shortly after birth and progresses even in the absence of clinical signs and symptoms. Traditional measures of lung function, such as spirometry, are difficult to measure in young children and are not able to detect abnormalities in this age group. Therefore, more sensitive and easier measures of lung function are needed for clinical studies in CF patients younger than 6 years. Multiple breath washout testing (MBW) measures the efficiency with which gas mixes in the lungs, and has been shown to detect abnormalities in lung function before traditional measures of lung function. In addition the test requires minimal cooperation as it is performed during normal breathing and is therefore ideally suited for younger children. There is currently no validated multiple breath washout system available for centers in North America. Recently, a commercial system has been developed, but the data in younger children (aged 3-6 years), a critical window for disease progression, is currently lacking. However, there is minimal data to define what constitutes a significant change in LCI over time. The overall aim of this proposal is to develop the lung clearance index into a tool for interventional studies and for clinical care in CF patients younger than 6 years of age. This will be accomplished through three specific aims: Aim 1: Validation of the LCI measured by nitrogen washout against the gold standard in preschool children. Aim 2: Define repeatability of LCI measurements at time intervals relevant for clinical trials. Aim 3: Determine the utility of LC as a monitoring tool in a clinical setting. The validation study in Aim 1 is essential to verify agreement with the gold standard, and to refine the protocol for this age group. Following validation, we will utilize the nitrogen washout system to characterize the reproducibility of LCI n health and CF, in order to define the limits of normal measurement variation that are both statistically valid, and clinically relevant. This will be done in a one-year longitudinal study tht mimics the design of interventional trials. This information will be directly applicable to the design and interpretation of clinical studies for children with CF in this age group. Finally, we wll test the clinical utility of the LCI to monitor pulmonary exacerbations in preschool children, and to assess whether the LCI can be used to track changes in clinical disease severity over time. These studies will form the basis for subsequent interventional trials in preschool children with CF and for future studies on the utility of LCI in CF infants. Furthermore, the information gained in this study will be a critical step for subsequent studies in other airway diseases such as asthma and primary ciliary dyskinesia. (End of Abstract)