Stability of Severe Asthma Phenotypes: Impact of Exacerbations

描述（由申请人提供）：SARP研究表明，成人和儿童哮喘患者可根据疾病严重程度分为不同的表型。然而，仍然有明确的需要，以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，与非重度哮喘患者相比，重度哮喘患者有更广泛的空气潴留。气道成像显示异质性区域通气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诱导的急性加重或支气管激发引起，并在重复激发时在相同的一般区域复发，表明局部气道功能障碍。在初步研究中，炎症参数往往在成像显示通气缺陷的节段中更为突出。在其他研究中，我们发现反复发作严重喘息的儿童后来肺功能较低，这一观察结果得到了成人和儿童哮喘患者的已发表研究的支持。因此，我们推测，在某些患者中，严重哮喘急性发作与气道炎症细胞的不完全恢复和活化有关。这导致增强的气道损伤和气道功能障碍，如通气缺陷和空气滞留所反映的，以及疾病严重程度的更普遍的增加。为了评估这一假设，我们提出了以下具体目标：1。在一个大型纵向患者队列中，使用多个领域的新变量来完善重度哮喘的表型;并确定重度哮喘急性发作对疾病进展的贡献。 2.描述基线时的局部阻塞模式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重度哮喘。3.确定已建立的和新的生物标志物（YKL-40、vWF和P-选择素）在改善严重哮喘表型中的作用，以及炎症细胞在病毒诱导的哮喘急性发作后导致气道损伤并随后发展为通气缺陷中的作用。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，并更好地定义重度哮喘表型，以改善患者预后。 相关性：从这些研究中获得的新信息将为重度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道路，以预防疾病进展并纳入表型知情的治疗方式，这将对患者结局产生积极影响。

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.