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，成人和儿童哮喘患者可以根据疾病严重程度分为不同的表型。然而，仍然明显需要验证和提高表型指定的保真度，建立其随时间的稳定性，并确定可能有助于“表型进展”的关键变量。我们已经证明，与非严重哮喘患者相比，严重哮喘患者有更广泛的空气滞留。气道成像显示异质区域通气缺陷和空气滞留增加。其中一些缺陷是持续存在的，而另一些缺陷可能是由病毒引起的病情恶化或支气管激发引起的，并且在反复激发后在相同的一般区域复发，这表明局部气道功能障碍。在初步研究中，炎症参数在影像显示通气缺陷的部位往往更为突出。在其他研究中，我们发现反复出现严重喘息的儿童后来肺功能较低，这一观察结果得到了已发表的针对成人和儿童哮喘患者的研究的支持。因此，我们假设某些患者的严重哮喘发作与局部分布的气道炎症细胞的不完全恢复和激活有关。这导致气道损伤加剧，并伴有通气缺陷和空气滞留所反映的气道功能障碍，以及疾病严重程度的普遍增加。为了评估这一假设，我们提出以下具体目标： 1. 使用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；并确定哮喘严重发作对疾病进展的影响。 2. 描述基线时区域阻塞模式的特征及其与肺功能变化的关系；并确定哮喘急性发作恢复后局部气道功能障碍的增量变化如何导致严重哮喘。 3. 确定已建立的和新型生物标志物（YKL-40、vWF 和 P-选择素）在改善严重哮喘表型中的作用，以及炎性细胞在病毒引起的哮喘恶化和随后发生通气缺陷后引起气道损伤中的作用。我们拥有必要的资源、专业知识和承诺来成功执行这些研究，并更好地定义严重哮喘表型，以改善患者的治疗结果。 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分析提供信息，并为探索预防疾病进展的潜在新范式和纳入对患者预后产生积极影响的基于表型的治疗方式铺平道路。