Stability of Severe Asthma Phenotypes: Impact of Exacerbations

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的不同被分成不同的表型。然而，仍然有明显的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，重度哮喘患者有更广泛的空气滞留。呼吸道成像显示不均匀的区域通风缺陷和空气滞留增加。其中一些缺陷是持续性的，而另一些缺陷可以由病毒引起的恶化或支气管攻击引起，并在相同的一般区域反复攻击而复发，提示局限性的呼吸道功能障碍。在初步研究中，炎症参数倾向于在成像上显示通风缺陷的节段更突出。在其他研究中，我们发现反复发作严重喘息的儿童以后肺功能降低，这一观察结果得到了对成人和儿童哮喘患者的已发表研究的支持。因此，我们假设，在一些患者中，严重的哮喘恶化与区域分布的气道炎性细胞的不完全恢复和激活有关。这会导致呼吸道损伤加重，并伴有呼吸道功能障碍，如通风缺陷和空气滞留所反映的，并导致疾病严重程度的更普遍的增加。为了评估这一假说，我们提出了以下具体目标：1.在大型纵向患者队列中使用来自多个领域的新变量来改进重症哮喘的表型；并确定严重哮喘恶化对疾病进展的贡献。2.确定基线区域阻塞模式的特征及其与肺功能变化的关系；并确定哮喘加重恢复后区域气道功能障碍的渐进性变化如何可能导致严重哮喘。3.确定已建立的和新的生物标志物(YKL-40、vWF和P-选择素)在提炼重症哮喘表型和炎性细胞在病毒诱导的哮喘加重并随后发展为呼吸缺陷后引起呼吸道损伤中的作用。我们有必要的资源、专业知识和承诺来成功地执行这些研究，并更好地定义严重哮喘的表型，以改善患者的预后。 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划分提供信息，并为探索潜在的新范式铺平道路，以防止疾病进展，并纳入将对患者预后产生积极影响的表型知情治疗方式。

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.