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

项目摘要/摘要 令人震惊的是，在流行国家，40%的结核病病例“失踪”(全球仍有420万例结核病病例 未诊断或未报告)！未确诊的病例可能在很大程度上促进了疾病传播，约30%是 涂片阳性，但无症状或症状轻微。这些未确诊的病例 成为社区的蓄水池，严重破坏结核病控制工作。 在最近完成的由美国国立卫生研究院资助的CASS I研究中，我们对453名患有哮喘的患者进行了咳嗽气溶胶采样。 新诊断的结核病(通过被动病例发现)，发现~30%的结核病具有高度传染性 可培养结核分枝杆菌在其呼吸性咳嗽气雾剂(&lt；10uM传染性可吸入颗粒)中 疾病)。多变量分析显示，没有接受结核病治疗的HIV阴性患者相对健康 和细菌载量高的人更有可能具有高度传染性。我们还开发了一种新型的低成本 移动迷你诊所拥有新的结核病诊断和艾滋病毒/CD4检测能力。使用这款移动迷你诊所，我们 在开普敦社区筛查了4700人，发现了475例疑似结核病病例，其中54例 已经确诊为结核病。通过将这两种技术结合起来，我们发现令人不安的~17%的未诊断结核病病例是 传染性很强。 我们对以社区为基础的结核病患者的传染性和传播的了解存在相当大的差距。我们不会 了解社区中未确诊的传染性病例的“生物特征”或其传染性程度，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鸿沟。这些都对 有针对性地进行接触者追踪调查，并开发一种可扩展的筛查工具来衡量传染性。 在拟议的研究中，我们将使用一种新型移动微型诊所的主动病例查找来检测丢失的结核病病例 并通过咳嗽气溶胶采样(目标1)确定它们的传染性程度，确定生物特征和 感染但症状最轻的未确诊个人的生物概况(目标2)，并准确地模拟 利用研究中产生的估计，发现活跃病例对疾病传播的影响，从而为政策提供信息。 综上所述，该项目将阐明未诊断的轻微症状活动性结核病病例的生物特征。 社区-‘失踪的数百万人’，并进一步了解结核病传播的基本生物学， 潜在地发现了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.