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

摘要 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。在印度的藏族难民结核病发病率非常高。在2017-18年度，我们观察到一例结核病病例 藏族学童感染率分别为916/10万和~20% 印度的寄宿学校。西藏结核病病例总数的60%以上发生在学校和寺庙。 尽管有这种负担，但对西藏人口中结核病的流行病学和战略的了解有限 为了预防它的发生。 西藏儿童零结核病(ZTBK)是一项由约翰斯夫妇全额资助和建立的公共卫生计划 霍普金斯大学、西藏德勒医院和西藏中央行政管理局卫生司 旨在通过多管齐下的筛查方法消除西藏儿童和青少年的结核病， 治疗和预防性治疗。在持续的支持下，ZTBK现在已扩展到覆盖约40,000人 到2022年，在3个州的学校和修道院。在这个移动项目中，整个机构都是 通过症状、结核菌素皮肤试验、胸部X光和Xpert筛查结核病。所有Xpert阳性和疑似病例 标本被送往孟买的印度支那实验室进行培养和药敏测试。文化阳性 分离株储存在印度支那，用于全基因组测序(WGS)。我将使用来自ZTBK计划的数据 研究儿童、青少年和青少年结核病的流行病学、传播和预防性治疗结果。 印度喜马恰尔邦藏族学校、寺庙和尼姑里的成年人。 对于目标1，我将描述结核病感染和疾病的特征，并研究流行病学危险因素。 对于目标2，我假设大多数结核病在聚集环境中的传播是通过最近的 变速箱。我将通过分析WGS数据中的单核苷酸多态来研究结核病的传播 将基因组簇与流行病学联系起来。使用地理空间分析，我将把传输联系起来 具有空间坐标的数据，以全面了解传输动力学。对于目标3，我将测试 假设在会众环境中接受预防性治疗将导致持续较低的风险 疾病超过五年的随访期。通过AIMS，我将研究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治疗策略和有针对性的治疗提供参考 在设施/社区一级中断传播的干预措施，对儿童具有广泛的适用性 以及全球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，将使 我希望能达到研究的目的。通过这个项目进行指导、培训和研究的机会 获奖将给我知识、经验和专业知识来制定多中心的R01计划书 关于结核病传播和预防治疗的研究，这将使我成为一名独立的研究员。

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.