Progression of Airway Obstruction in Childhood Asthma

描述(申请人提供)：儿童时期持续性哮喘的病程有很大的变异性，对其了解也不完全。NHLBI儿童哮喘管理计划(CAMP)和CAMPCS提供了一个独特的机会来评估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将为每个参与者提供总计18年的观察。在最初10年的随访中，大约1/3的营员出现了严重的呼吸道阻塞。我们确定了两组肺功能类型，导致显著的呼吸道阻塞和高哮喘发病率，并增加了紧急护理就诊和住院的频率：(1)幼儿时期的异常阻塞和仍然异常的(持续性阻塞)和(2)最初正常的肺功能随着时间的推移进展为显著的阻塞(晚期阻塞)。将这两组与另外两组肺功能正常且长期效果良好的组进行比较：(1)最初异常并随着时间的推移而改善(晚期正常)和(2)整个随访过程中正常(持续正常)。持续性和晚期梗阻导致显著梗阻的模式是呼吸道梗阻的一种中间表型，并继续演变。这两种模式都与呼吸道蛋白酶/抗蛋白酶失衡、结构性肺特征以及对口服类固醇治疗的不良反应有关。然而，晚期梗阻组的特点是气道壁厚度增加，过度充气，尿嗜酸粒细胞蛋白X和血浆转化生长因子β降低，弹性酶复合体降低，这表明持续的炎症和受损的气道保护机制。为了探索与这些发展模式相关的显著气道阻塞的机制，包括在这个cAMP队列中肺功能的持续下降，我们将研究诱导痰、尿液、血液和呼出空气中的生物标记物、类固醇敏感性指标、肺生理学和影像。在这一独特的cAMP队列的持续跟踪期间，对这四种不同的肺功能模式进行持续的表征，将为当前和持续的哮喘进展提供信息，并提供一套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，这些研究将导致发现管理营地队列中进展的新策略。他们还将提供对开展研究的方法的洞察，以确定机制并制定战略，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儿童哮喘管理计划期间，在参与10年观察期的轻度至中度哮喘儿童中，发现了不同的肺功能丧失模式。这种肺功能的丧失可能与持续的炎症有关，对当前的治疗没有反应。这项研究将测量与肺结构和生理变化相关的呼吸道炎症指标，并提供对青春期和成年早期哮喘进展机制的洞察。

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.