Stability of Severe Asthma Phenotypes: Impact of Exacerbations

严重哮喘表型的稳定性：恶化的影响

• 批准号: 8496108
• 负责人: NIZAR N JARJOUR
• 金额: $ 63.26万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-08 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496108
• 关键词: Acute; Adult; Adult asthma; Air; Area; Asthma; Biological Markers; Cells; Child; Childhood; Childhood Asthma; Defect; Development; Disease Progression; Environmental air flow; Event; Exercise; Functional disorder; Goals; Image; Imaging Techniques; Inflammatory; Injury; Lead; Magnetic Resonance Imaging; Medicine; Modality; Outcome; P-Selectin; Patients; Pattern; Phenotype; Properdin; Publishing; Recovery; Recurrence; Resources; Respiratory physiology; Role; Severities; Severity of illness; Testing; Time; Up-Regulation; Virus; Wheezing; cohort; eosinophil; improved; injured airway; methacholine; neutrophil; novel; premature; prevent; pulmonary function; von Willebrand Factor

DESCRIPTION (provided by applicant): Studies in SARP have shown that adult and pediatric asthma patients can be grouped into different phenotypes on a spectrum of disease severity. However, there remains a clear need to validate and improve the fidelity of phenotype designation, establish its stability over time, and determine the critical variables that may contribute to "phenotype progression". We have shown that patients with severe asthma have more extensive air trapping compared to those with non-severe asthma. Airway imaging has shown increased heterogeneous regional ventilation defects and air trapping. Some of these defects are persistent, while others can be provoked with virus-induced exacerbations or bronchial challenge and recur in the same general areas on repeated challenge, suggesting localized airway dysfunction. In preliminary studies, inflammatory parameters tended to be more prominent in segments that showed ventilation defects on imaging. In other studies, we showed that children with recurrent severe wheezing episodes have lower lung function later on, an observation supported by published studies on adult and pediatric patients with asthma. Therefore, we hypothesize that severe asthma exacerbations, in some patients, are associated with incomplete recovery and activation of airway inflammatory cells in a regional distribution. This leads to enhanced airway injury with airway dysfunction as reflected by ventilation defects and air trapping, and a more generalized increase in disease severity. To evaluate this hypothesis we propose the following specific aims: 1. To refine phenotyping of severe asthma using new variables from multiple domains in a large longitudinal patient cohort; and to determine the contribution of severe asthma exacerbations to disease progression. 2. To characterize regional obstructive patterns at baseline and their relationship to changes in pulmonary function; and to determine how incremental changes in regional airway dysfunction after recovery from asthma exacerbation may contribute to severe asthma. 3. To determine the contribution of established and novel biomarkers (YKL-40, vWF, & P-selectin), in refining the severe asthma phenotypes and the role of inflammatory cells in causing airway injury following virus-induced asthma exacerbations with subsequent development of ventilation defects. We have the necessary resources, expertise and commitment to successfully execute these studies and to better define severe asthma phenotypes with the goal of improving patient outcomes. RELEVANCE: The novel information gained from these studies will inform new definitions and phenotyping of severe asthma, and pave the way for exploring potential new paradigms for preventing disease progression and incorporating phenotype-informed treatment modalities that would positively impact patient outcome.

描述（由申请人提供）：SARP的研究表明，成年和小儿哮喘患者可以在各种疾病严重程度上分为不同的表型。但是，仍然需要显然需要验证和提高表型名称的保真度，随着时间的推移确定其稳定性，并确定可能有助于“表型进展”的关键变量。我们已经表明，与非重度哮喘的患者相比，严重哮喘患者的空气诱捕更大。气道成像表明，异质的区域通风缺陷和空气捕获增加。其中一些缺陷是持续存在的，而另一些缺陷可以被病毒引起的加重或支气管挑战，并在相同的一般领域重复挑战中重复出现，这表明局部气道功能障碍。在初步研究中，炎症参数在显示成像的通风缺陷的细分市场中往往更为突出。在其他研究中，我们表明患有重复喘息发作的儿童后来的肺功能较低，这是对成人和小儿哮喘患者的发表研究支持的观察结果。因此，我们假设在某些患者中，严重的哮喘恶化与区域分布中气道炎症细胞的不完全恢复和激活有关。这会导致通风缺陷和空气捕获反映的气道功能障碍，导致气道损伤增强，疾病严重程度的增加。为了评估这一假设，我们提出了以下特定目的：1。使用来自大型纵向患者队列中多个领域的新变量来完善严重哮喘的表型；并确定严重哮喘加剧对疾病进展的贡献。 2。表征基线时区域阻塞模式及其与肺功能变化的关系；并确定从哮喘加重中恢复后区域气道功能障碍的增量变化可能导致严重的哮喘。 3。确定已建立和新型生物标志物（YKL-40，VWF和P-选择蛋白）的贡献，在完善严重的哮喘表型以及炎症细胞在病毒引起的哮喘病毒后引起气道损伤的作用以及随后的频风化缺陷的发展。我们拥有成功执行这些研究并更好地定义严重哮喘表型的必要资源，专业知识和承诺，以改善患者预后。 相关性：从这些研究中获得的新信息将为严重哮喘的新定义和表型提供信息，并为探索潜在的新范式铺平了防止疾病进展的新范式，并纳入了表型信息，对患者结果产生积极影响。