Washington University AsthmaNet

描述（由申请人提供）：哮喘仍然是美国和世界范围内的重要公共卫生问题，大约6.7%的成年人和8.5%的18岁以下儿童患有哮喘。尽管对哮喘发病机制和治疗策略的理解取得了重大进展，但与哮喘相关的发病率仍在继续。在过去的15年里，美国国立卫生研究院支持的哮喘网络，ACRN和CARE，增加了哮喘诊断和治疗的证据基础，这些证据已被显著纳入国家和国际哮喘管理指南。尽管知识基础不断增长，但哮喘护理中仍存在许多未回答的问题，从基于个体患者特征（个性化药物）的优化护理策略到研究新的治疗方法以改善哮喘控制。该提案包含针对三种不同且未充分研究的哮喘人群的临床试验：轻度-中度持续性症状性哮喘的学龄前儿童，低剂量吸入性皮质类固醇（ICS）控制不佳的哮喘青少年和成人，以及尽管接受最大标准治疗仍无法控制的重度持续性哮喘成人。我们将研究两种治疗学龄前儿童轻中度哮喘的策略，以及是否纳入生物标志物（呼出气一氧化氮的分数浓度）可以预测更有效的治疗策略。我们还建议在哮喘控制不佳和维生素D不足的成人受试者中检查在ICS中添加高剂量维生素D，以评价维生素D是否改善皮质类固醇反应性，并提供比ICS剂量加倍或添加长效β-激动剂的类似对照更好的上级哮喘控制。与本研究一致，我们建议评估维生素D增强皮质类固醇有效性的潜在机制。最后，考虑到与严重哮喘相关的发病率和对当前治疗的反应失败，我们提出了一项试验，检查一种新型免疫调节剂阿巴西普的安全性和有效性，阿巴西普抑制T细胞活化所需的共刺激信号（通过CD 28）的传递，在严重持续性不受控制的哮喘患者中。总之，这些研究解决了目前哮喘治疗决策证据基础的空白，并探索了哮喘控制不足的患者的新治疗策略。

DESCRIPTION (provided by applicant): Asthma remains a substantial public health in the United States and worldwide, with approximately 6.7% of adults and 8.5% of children under 18 years of age affected with asthma. The morbidity associated with asthma continues despite significant advances in the understanding of asthma pathogenesis and treatment strategies. Over the past 15 years, the NIH-supported asthma networks, ACRN and CARE, have added to the evidence base for asthma diagnosis and therapeutics, and this evidence has been prominently incorporated into national and international guidelines for asthma management. Despite this growing knowledge base, there remain numerous unanswered questions in asthma care ranging from strategies to optimize care based upon individual patient characteristics (personalized medicine) to examination of novel therapeutic approaches to improve asthma control. This proposal contains clinical trials directed at three diverse, and understudied asthma populations: preschool children with mild-moderate persistent symptomatic asthma, adolescents and adults with asthma inadequately controlled with low dose inhaled corticosteroids (ICS), and adults with severe persistent asthma which remains uncontrolled despite maximum standard therapy. We will examine two therapeutic strategies for preschool children with mild-moderate asthma and whether the incorporation of a biomarker (fractional concentration of exhaled nitric oxide) allows for prediction of the more effective treatment strategy. We also propose to examine the addition of high dose Vitamin D to ICS in adult subjects with not well-controlled asthma and vitamin D insufficiency to evaluate if the Vitamin D improves corticosteroid responsiveness and provides superior asthma control to doubling the dose of ICS or similar control to the addition of a long-acting p-agonist. In concert with this study, we propose to evaluate the potential mechanisms by which Vitamin D enhances corticosteroid effectiveness. Lastly, given the morbidity associated with severe asthma and failure to respond to current therapy, we propose a trial examining the safety and efficacy of a novel immunomodulatory agent, abatacept, which inhibits the delivery of a co-stimulatory signal (through CD28) required for T-cell activation, in subjects with severe persistent uncontrolled asthma. In summary, these studies address current gaps in the evidence base for asthma treatment decision making as well as explore novel therapeutic strategies in patients in whom inadequate asthma control remains commonplace.