Tuberculosis Transmission and Preventive Therapy in Tibetan Children and Young Adults in India

总结 每年有100万儿童死于结核病，全球25%的结核病病例发生在儿童、青少年和 年轻人在印度的西藏难民结核病发病率非常高。在2017-18年，我们观察到一例结核病病例， 藏族学生感染率为916/10万，感染率约为20% 印度的寄宿学校西藏60%以上的结核病病例发生在学校和寺庙。 尽管有这种负担，但对西藏人群结核病流行病学和策略的了解有限 为了预防它。 西藏儿童零结核病（ZTBK）是约翰的一个完全资助和建立的公共卫生计划 霍普金斯大学、西藏德勒医院、西藏自治区卫生厅 旨在通过多管齐下的筛查方法， 治疗和预防性治疗。在持续的支持下，ZTBK现已扩大到覆盖约40，000人 到2022年，在三个州的学校和修道院里。在这个移动的项目中， 使用症状、结核菌素皮肤试验、胸部X光和Xpert进行结核病筛查。所有Xpert阳性和疑似 样本被送到孟买的Hinduja实验室进行培养和药物敏感性测试。培养阳性 分离物储存在Hinduja用于全基因组测序（WGS）。我将使用ZTBK计划的数据 研究儿童、青少年和年轻人的结核病流行病学、传播和预防性治疗结果 在印度喜马偕尔邦的藏族学校、寺院和尼姑庵中，有许多成年人。 对于目标1，我将描述结核病感染和疾病的特征，并研究流行病学风险因素。 对于目标2，我假设聚集环境中的大多数结核病传播发生在最近的 传输我将通过分析WGS数据中的单核苷酸多态性来研究结核病的传播， 将基因组簇与流行病学联系起来。利用地理空间分析，我将把 具有空间坐标的数据，以全面了解传动动态。对于目标3，我将测试 假设在聚集的环境中接受预防性治疗将导致持续的低风险， 在五年的随访期内，通过本课题的研究，探讨亚临床结核病的特点 疾病及其传染性。研究结果将为结核病预防性治疗策略提供信息， 在设施/社区一级采取干预措施阻断传播，并广泛适用于儿童 以及全球范围内学校和其他环境中的年轻人。 我确定的培训目标包括空间分析和WGS数据分析， 我来完成这项研究的目的。通过这个项目， 该奖项将给我的知识，经验和专业知识，以制定一个多中心的R 01提案 这是一项关于结核病传播和预防性治疗的研究，它将使我成为一名独立的研究人员。

Summary Annually, one million children die of TB and 25% of the global TB cases occur in children, adolescents and young adults. Tibetan refugees in India have extraordinarily high TB rates. In 2017-18, we observed a TB case and infection prevalence of 916/100,000 and ~20%, respectively, for schoolchildren residing in Tibetan boarding schools in India. More than 60% of the total Tibetan TB cases occur in the schools and monasteries. Despite this burden, understanding is limited of the epidemiology of TB in the Tibetan population and strategies for its prevention. Zero TB in Tibetan Kids (ZTBK) is a fully funded and established public health program of the Johns Hopkins University, Tibetan Delek Hospital, and the Department of Health of the Central Tibetan Administration that aims to eliminate TB for Tibetan children and adolescents through a multipronged approach of screening, treatment and preventive therapy. With ongoing support, the ZTBK is now scaled up to cover ~40,000 people in schools and monasteries across 3 states through 2022. In this mobile program, the entire institution is screened for TB using symptom, tuberculin skin test, chest X-ray, and Xpert. All Xpert positive and suspected specimens are sent to the Hinduja Lab, Mumbai, for culture and drug susceptibility testing. Culture positive isolates are stored at the Hinduja for whole genome sequencing (WGS). I will use data from this ZTBK initiative to study TB epidemiology, transmission, and preventive therapy outcomes for children, adolescents, and young adults in the Tibetan schools, monasteries, and nunneries in Himachal Pradesh state of India. For Aim 1, I will characterize TB infection and disease and study the epidemiologic risk factors. For Aim 2, I postulate that most TB transmission in the congregate settings happen through recent transmission. I will study TB transmission by analyzing single nucleotide polymorphisms in the WGS data and relate the genomic clusters with epidemiological links. Using geospatial analysis, I will relate the transmission data with spatial coordinates for a complete understanding of the transmission dynamics. For Aim 3, I will test the postulate that receiving preventive therapy in the congregate settings will lead to a sustained lower risk of disease over five-years of follow-up period. Through the aims, I will study the characteristics of subclinical TB disease and its transmissibility. The results will inform TB preventive therapy strategies and targeted interventions to interrupt transmission at the facility/community levels and have broad applicability to children and young adults in schools and other settings, globally. The training goals I have identified that include spatial analysis and analysis of WGS data will enable me to accomplish the aims of the study. The opportunity for mentorship, training, and research through this award will give me the knowledge, experience, and expertise to develop an R01 proposal for a multicenter study on TB transmission and preventive therapy that will allow me to become an independent investigator.