Progression of Airway Obstruction in Childhood Asthma

描述（由申请人提供）：儿童期持续性哮喘的病程变化很大，且不完全清楚。NHLBI儿童哮喘管理项目（CAMP）和CAMP持续研究（CAMPCS）提供了一个独特的机会，可以评估1,000多名参与者从儿童早期到成年早期的持续哮喘进展。正在进行的CAMPCS将为每位参与者提供总计18年的观察。在前10年随访后，大约1/3的CAMP人群有明显的气道阻塞。我们确定了两组肺功能模式导致显著气道阻塞和高哮喘发病率，紧急护理访视和住院频率增加：（1）儿童早期异常阻塞和剩余异常（持续性阻塞）和（2）最初正常的肺功能随时间进展为显著阻塞（晚期阻塞）。将这两组与肺功能正常且长期结局良好的其他两组进行比较：（1）最初异常并随时间改善（晚期正常）和（2）整个随访期间正常（持续正常）。导致严重阻塞的持续性和晚期阻塞模式是气道阻塞的中间表型，并继续演变。这两种模式都与气道蛋白酶/抗蛋白酶失衡、结构性肺特征和口服类固醇治疗反应不良有关。然而，晚期阻塞组的特征是气道壁厚度增加、过度充气、尿嗜酸性蛋白X和血浆TGF？减少，弹性蛋白酶复合物减少，提示持续炎症和气道保护机制受损。为了探索与这些发展模式相关的显著气道阻塞的机制，包括该CAMP队列中肺功能的持续下降，我们将研究诱导痰、尿液、血液和呼出气中的生物标志物、类固醇敏感性指标、肺生理学和成像。在这个独特的CAMP队列的持续随访期间，对这四种不同的肺功能模式进行持续表征，将为当前和持续的哮喘进展提供信息，并提供一组有助于识别有哮喘进展风险的年轻人群的特征。此外，这些研究将产生假设驱动的研究，这将导致发现新的策略来管理CAMP队列的进展。他们还将深入了解进行研究的方法，以确定机制并制定策略，以监测旨在预防儿童早期哮喘进展的研究的有效性。 公共卫生相关性：在NHLBI儿童哮喘管理项目中，在10年的观察期内，轻度至中度哮喘儿童的肺功能丧失有明显的模式。这种肺功能丧失可能与对当前治疗无反应的持续炎症有关。本研究将测量与肺结构和生理变化相关的气道炎症指标，并深入了解青春期和成年早期哮喘进展的机制。

DESCRIPTION (provided by applicant): The course of persistent asthma in childhood is highly variable and incompletely understood. The NHLBI Childhood Asthma Management Program (CAMP) and CAMP Continuation Studies (CAMPCS) afford a unique opportunity to evaluate continuing asthma progression in over 1,000 participants undergoing observation from early childhood into early adulthood. The ongoing CAMPCS will provide a total 18 years observation for each participant. After the first 10 years of follow-up, approximately 1/3 of the CAMP population had significant airway obstruction. We identified two groups with lung function patterns resulting in significant airway obstruction and high asthma morbidity with increased frequency of urgent care visits and hospitalizations: (1) abnormal obstruction in early childhood and remaining abnormal (Persistent Obstruction) and (2) initially normal pulmonary function progressing to significant obstruction over time (Late Obstruction). These two groups were compared to two other groups with normal pulmonary function and favorable long-term outcomes: (1) initially abnormal and improving over time (Late Normal) and (2) normal throughout follow-up (Persistent Normal). The patterns of Persistent and Late Obstruction leading to significant obstruction are an intermediate phenotype of airway obstruction and continue to evolve. Both patterns are associated with airway proteinase/anti-proteinase imbalance, structural lung characteristics and poor response to oral steroid therapy. However, the group with Late Obstruction is distinguished by increased airway wall thickness, hyperinflation, urinary eosinophilic protein X, and plasma TGF¿ with decreased elastase complex, suggesting ongoing inflammation and compromised airway protective mechanisms. To explore the mechanisms of significant airway obstruction related to these developing patterns including ongoing decline in pulmonary function in this CAMP cohort, we will study biomarkers in induced sputum, urine, blood and exhaled air, indicators of steroid sensitivity, pulmonary physiology and imaging. Ongoing characterization of these four distinct patterns of pulmonary function during continued follow-up of this unique CAMP cohort will inform current and continued asthma progression as well as provide a set of characteristics useful in identifying a younger population at risk for asthma progression. Furthermore, these studies will generate hypothesis-driven research that will lead to the discovery of new strategies to manage progression in the CAMP cohort. They will also provide insight into methods to conduct studies to define mechanisms and formulate strategies to monitor efficacy in studies designed to prevent asthma progression in early childhood. PUBLIC HEALTH RELEVANCE: Distinct patterns of loss in pulmonary function were identified in children with mild to moderate asthma participating in a 10-year observation period during the NHLBI Childhood Asthma Management Program. This loss in pulmonary function is likely related to ongoing inflammation unresponsive to current therapy. This study will measure indicators of airway inflammation which are associated with structural and physiologic changes in the lung and provide insight into mechanisms of asthma progression in adolescence and early adulthood.