UCSF AsthmaNet Clinical Center

描述（由申请人提供）：本提案旨在在nih支持的网络中建立UCSF/儿童医院奥克兰临床中心，负责进行成人和儿童哮喘治疗的临床试验，包括严重哮喘患者。作为该网络可以进行的临床试验的例子，本申请描述了两项研究。一项试验从证据中得出维生素D对支气管上皮先天防御机制的重要性。该试验将比较两种剂量的维生素D对儿童哮喘发作频率的影响：目前推荐的剂量为400 IU/天，而较高但耐受性良好的剂量为2000 lU/天。第二项试验检查了抗生素阿奇霉素治疗哮喘加重的效果。使用这种抗生素是治疗哮喘加重的常见做法，但证据非常薄弱。之前的三项研究中只有一项显示有任何益处，而且那项研究检查了一种不同的抗生素，显示出的效果很小，而且不一致。鉴于广泛使用抗生素对护理成本和耐药生物出现的影响，我们认为阿奇霉素治疗哮喘加重的实际益处需要确定。我们还认为，这样的研究应该检查足够大的人群，以便检查亚组的差异反应，例如那些有化脓性支气管炎或鼻窦炎症状的人，那些培养或PCR检测潜在细菌病原体阳性的人，以及那些通过痰或鼻灌洗液样本PCR检测有呼吸道病毒感染证据的人。该提案还描述了两项关于哮喘机制的“概念”研究，这些研究可以由NIH“哮喘网”网络承担：其中一项应用高度新颖的、不依赖于培养的方法“PhyloChip”来检查哮喘患者经常使用或初次吸入皮质类固醇治疗时支气管微生物群的差异，这些细菌群如何被长期阿奇霉素治疗所改变，以及这些影响是否与这种治疗对哮喘控制标志物的影响有关。第二项“概念”研究将通过应用基于设计的体视学对治疗前后获得的支气管活组织检查来检查1L-4/IL-13受体拮抗剂对气道重塑标志物的影响。这些研究的直接性质，UCSF/CHRCO的资源，以及他们所服务的人群的高度多样性，将确保研究结果在临床实践中的普遍性。

DESCRIPTION (provided by applicant): This proposal is for the establishment of a UCSF/Children's Hospital Oakland Clinical Center in an NIHsupported network charged with conducting clinical trials of therapies for asthma in adults and children, including patients with severe asthma. As examples ofthe Clinical Trials this network could conduct, this application describes two studies. One trial derives from evidence on the importance of vitamin D for innate defense mechanisms in the bronchial epithelium. This trial would compare the effects of two doses of vitamin D on the frequency of asthma exacerbations in children: the current recommended dose of 400 IU/ day vs. the higher but well-tolerated dose of 2000 lU/day. The second trial examines the effects of treatment of asthma exacerbations with the antibiotic, azithromycin. Use of this antibiotic is common practice in treating asthma exacerbations, but rests on an extraordinarily slender body of evidence. Only one of (only) three previous studies showed any benefit, and that study examined a different antibiotic and showed small and inconsistent effects. Given the effects of widespread use of an antibiotic on the costs of care and on the emergence of resistant organisms, we believe the actual benefit of azithromycin treatment of asthma exacerbations needs to be determined. We also believe that such a study should examine a large enough population to allow examination of differential responses in sub-groups, such as those with symptoms of purulent bronchitis or sinusitis, those with positive culture or PCR for potential bacterial pathogens, and those with evidence of respiratory viral infection by PCR testing of sputum or nasal lavage samples. This proposal also describes two "Concept" studies of mechanisms of asthma that an NIH "AsthmaNet" network could undertake: one applying a highly novel, culture-independent method, the "PhyloChip" to examine differences in the bronchial microbiota in asthmatic patients regularly using - or naive to - inhaled corticosteroid treatment, how these bacterial populations are alTected by prolonged azithromycin treatment, and whether these effects are related to the effects of such treatment on markers of asthma control. The second "concept" study will examine the effects of an 1L-4/IL-13 receptor-antagonist on markers of airway remodeling by applying Designed-Based Stereology to bronchial biopsies obtained before and after treatment. The straightforward nature of these studies, the resources of UCSF/CHRCO, and the highly diverse nature of the populations they serve, will ensure generalizability to clinical practice of the findings made.