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，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来评估1000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。在最初10年的随访后，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严重气道阻塞和高哮喘发病率，且急诊就诊和住院频率增加：(1)儿童早期异常阻塞并保持异常（持续性阻塞）；(2)最初正常的肺功能随着时间的推移发展为严重阻塞（晚期阻塞）。这两组与另外两组肺功能正常且长期预后良好的组进行比较：(1)最初异常并随着时间的推移而改善（晚期正常）；(2)整个随访期间正常（持续正常）。持续性梗阻和晚期梗阻导致严重梗阻的模式是气道梗阻的中间表型，并继续演变。这两种模式都与气道蛋白酶/抗蛋白酶失衡、肺结构特征和口服类固醇治疗反应差有关。然而，晚期梗阻组的特征是气道壁厚度增加、过度膨胀、尿嗜酸性蛋白X和血浆TGF - γ，同时弹性蛋白酶复合物降低，提示持续的炎症和气道保护机制受损。为了探索与这些发展模式（包括肺功能持续下降）相关的严重气道阻塞的机制，我们将研究诱导痰、尿液、血液和呼出空气中的生物标志物、类固醇敏感性指标、肺生理学和影像学。在这一独特的CAMP队列的持续随访期间，对这四种不同的肺功能模式的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。他们还将为开展研究的方法提供见解，以确定机制和制定策略，以监测旨在预防儿童早期哮喘进展的研究的疗效。

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.