Mycobacterial Lung Diseases in Virginia: sequencing and clinical determinants of relapse and outcome

项目摘要/摘要 非结核分枝杆菌肺部疾病，主要是由鸟分枝杆菌复合体(MAC)引起的，正在增加 这是一个全国性的临床问题，目前在发病率和死亡率方面超过了国内结核病。它也是 尽管药物疗程较长，但更难治疗，结果更差。在这方面，NIH发布了一份 通知AI-17-016申请NTM疾病。在这里，我们提出了一项来自加州大学的提案 弗吉尼亚州，与弗吉尼亚州卫生部和弗吉尼亚理工大学的合作者，解决了许多 所列举的需求。首先，我们将对我们州所有的MAC分离株进行全基因组测序 Mac肺病患者辨别复发与再感染以及获得的环境来源。 第二，我们将利用全州范围内的新的MAC肺病患者队列来将临床结果与 MAC种类、药物敏感性、血清药物水平和生物被膜生物测定。创新包括使用 全州的流行病学队列，精细的分辨率和广泛的全基因组初步数据 用于区分物种和混合感染的测序--全州范围的血清药物监测 计划(就像我们已经为结核病所做的那样)，以及在分子诊断和基因表型方面的专业知识 关联性。综上所述，对于这一最令人烦恼的肺部疾病的临床问题，我们带来了广泛的 初步数据、独特专业知识、创新技术、凝聚力协作和协同目标。

PROJECT SUMMARY / ABSTRACT Nontuberculous mycobacterial lung diseases, primarily due to M. avium complex (MAC), is an increasing clinical problem nationwide and now overtakes domestic TB in terms of morbidity and mortality. It is also harder to treat and results in poorer outcomes despite longer drug regimens. In this context NIH issued a notice AI-17-016 to request applications for NTM diseases. Here we present a proposal from the University of Virginia, with collaborators at the Virginia Department of Health and Virginia Tech, that addresses many of the needs that were cited. First, we will perform whole genome sequencing of MAC isolates from all of our state's MAC lung disease patients to discern relapse versus reinfection and the environmental sources of acquisition. Second we will utilize a state-wide cohort of new MAC lung disease patients to correlate clinical outcomes with MAC species, drug susceptibility, serum drug levels, and biofilm bioassay. Innovation includes the use of a state-wide epidemiological cohort, exquisite resolution with extensive preliminary data of whole genome sequencing to discern species and mixed infections, a comprehensive state-wide serum drug monitoring program (as we have done already for TB), and expertise in molecular diagnostics and genotypic-phenotypic correlations. In sum, for this most vexing clinical problem of MAC lung disease we bring to bear extensive preliminary data, unique expertise, innovative technology, cohesive collaborations, and synergistic aims.