The Missing Millions: Identification and infectiousness of undiagnosed tuberculosis cases in the community (the MI-TB study)

项目总结/摘要 令人吃惊的是，在结核病流行国家，40%的结核病病例“失踪”（全球仍有约420万病例 未确诊或未报告）！未确诊的病例可能在很大程度上促成疾病传播，因为约30%的病例 涂片阳性，同时具有无症状或轻微症状表现。这些未确诊的病例 结核病在社区中成为一个水库，严重破坏结核病控制工作。 在最近完成的NIH资助的卡斯I研究中，我们对453例咳嗽患者进行了咳嗽气雾剂采样， 新诊断的结核病（通过被动病例发现发现），发现约30%是高传染性结核病 可培养M.可吸入咳嗽气溶胶中的结核杆菌（<10 μ M的感染性可吸入颗粒， 疾病）。多变量分析显示，没有接受结核病治疗的艾滋病毒阴性患者相对健康 并且具有高细菌载量的人更可能具有高传染性。我们还开发了一种新颖的低成本 移动的小型诊所，具备新型结核病诊断和艾滋病毒/CD 4检测能力。使用这个移动的微型诊所， 在开普敦的社区中对4700人进行了筛查，发现了475例疑似结核病病例，其中54例 确诊为肺结核通过结合这两种技术，我们发现令人不安的~17%的未确诊结核病病例是 传染性很强 我们对社区结核病患者传染性和传播的认识存在相当大的差距。我们不 了解社区中未确诊传染性病例的“生物特征”及其传染性程度，以及 我们对病人水平的传染性和结核病传播的理解仍然存在分歧。这些都有影响， 有针对性地开展接触者追踪调查，并开发一种可扩展的筛查工具，以衡量传染性。 在拟议的研究中，我们将采用主动病例发现，使用一种新型的移动迷你诊所来检测“缺失”的结核病病例 并使用咳嗽气溶胶采样（目标1）确定其传染性程度，确定生物特征， 感染性但症状轻微的未确诊个体的生物特征（目标2），并准确建模 使用研究中产生的估计数，评估主动病例发现对疾病传播的影响，从而为政策提供信息。 总之，本项目将阐明在非洲未确诊的最低症状活动性结核病例的生物特征， 社区-“失踪的百万人”，并进一步了解结核病传播的基本生物学， 有可能发现阻断疾病传播的目标。

PROJECT SUMMARY/ABSTRACT A startling 40% of tuberculosis (TB) cases in endemic countries are “missing” (~4.2 million cases globally remain undiagnosed or unreported)! Undiagnosed cases may substantially contribute to disease transmission as ~30% are smear positive while having an asymptomatic or minimally symptomatic presentation. These undiagnosed cases serve as a reservoir in the community and severely undermine TB control efforts. In the recently completed NIH-funded CASS I study we performed cough aerosol sampling on 453 patients with newly diagnosed TB (detected by passive case finding) and found ~30% were highly infectious – containing culturable M. tuberculosis bacilli in their respirable cough aerosols (<10uM infectious inhalable particles that initiate disease). Multivariate analysis revealed relatively healthier, HIV negative patients who were not on TB treatment and had a high bacillary load were more likely to be highly infectious. We have also developed a novel low-cost mobile mini-clinic housing a novel TB diagnostic and HIV/CD4 testing capabilities. Using this mobile mini-clinic we have screened 4700 individuals in the communities of Cape Town and found 475 cases of suspected TB, 54 of which had confirmed TB. By combining these two techniques we found an unsettling ~17% of undiagnosed TB cases are highly infectious. Sizable gaps exist in our knowledge of community-based TB patient infectiousness and transmission. We do not know the ‘bioprofile’ of infectious undiagnosed cases in the community nor their degree of infectiousness, and a chasm remains in our understanding of patient level infectiousness and TB transmission. These have implications for targeting contact tracing investigations and the development of a scalable screening tool to measure infectiousness. In the proposed study we will employ active case finding using a novel mobile-mini clinic to detect ‘missing’ TB cases and establish their degree of infectiousness using cough aerosol sampling (Aim 1), determine a biosignature and bioprofile of infectious but minimally symptomatic undiagnosed individuals (Aim 2), and accurately model the impact of active case finding on disease transmission using estimates generated in the study, thus informing policy. In summary, this project will elucidate the bioprofile of undiagnosed minimally symptomatic active TB cases in the community – ‘the missing millions’, and further our understanding of the fundamental biology of TB transmission, potentially uncovering targets to interrupt disease spread.