Mycobacterium tuberculosis aerobiology and novel tools to assess infectiousness

结核病是导致艾滋病毒携带者死亡的主要原因，是典型的空气传播疾病， 通过吸入雾化杆菌在人与人之间传播。在流行地区，大多数结核病 最近感染结核分枝杆菌(Mtb)的结果，研究支持少数 个人对大多数结核病传播事件负有责任。尽管有重点的结核病控制干预措施，如 由于结核病预防治疗(TPT)对这些高传染性个人的接触是具有成本效益的，检测 准确判断结核病患者的传染性缺失。这项提议的总体目标是 通过开发一种新的基于咳嗽的诊断方法来预防PLHIV中与结核病相关的发病率和死亡率 结核病传染性。我们之前开发了一种测量结核分枝杆菌咳嗽气雾化的研究工具，咳嗽 气溶胶采样系统(CASS)，它预测结核病的传染性。最近，我们调查了咳嗽的频率 作为结核病传染性的标志，识别了独特的与结核病相关的咳嗽特征，并开发了一种移动 隐私保护咳嗽检测系统。在拟议的研究中，我们将招募艾滋病毒阳性和艾滋病毒阴性的患者 使用以下工具评估新诊断为肺结核的肯尼亚成年人的结核病传染性水平 中国社会科学院测量的雾化结核分枝杆菌计数(结果)。在目标1中，我们将调查咳嗽频率和/或 咳嗽谱图(统称“咳嗽特征”)，以评估结核病的传染性和调查影响 HIV合并感染对结核病传染性的影响。在目标2中，我们将确定目标1参与者的家庭联系人 (指示病例)使用干扰素-伽马释放分析(IGRAs)和 确定与结核分枝杆菌气雾剂高计数相关的指示病例咳嗽特征是否与 家庭接触中IGRAs阳性的频率更高。此外，在注册后的6个月内，我们将 重新测试与IGRA的家庭接触者，以了解积极反应的持久性是否与 指征病例咳嗽签名。我们假设结核分枝杆菌气雾剂计数高的个体将有高的 咳嗽频率和独特的咳嗽谱图，而且咳嗽谱图将因艾滋病毒状况而不同 尽管结核分枝杆菌气雾剂计数相似。此外，我们假设家庭接触者索引病例 在基线和6个月的随访中，“高传染性”咳嗽症状更有可能出现IGRAs阳性。 向上。我们的团队已经开发了工具，不仅可以强有力地确定传染性(CASS)，还可以评估 高HIV/TB负担环境下的咳嗽频率和强度(光谱图分析)。通过识别 咳嗽特征可以预测结核病的传染性，我们将为临床医生和公共卫生开发工具 支持针对结核病控制干预措施的方案。

Tuberculosis (TB), the leading cause of death in people living with HIV, is the archetypal airborne disease, spread person-to-person through the inhalation of aerosolized bacilli. In endemic regions, most TB disease results from recently acquired infection with M. tuberculosis (Mtb), and studies support that a minority of individuals are responsible for most TB transmission events. Although focusing TB control interventions, such as TB preventive treatment (TPT), on contacts of these highly infectious individuals is cost-effective, tests that accurately determine the infectiousness of patients with TB are lacking. The overall objective of this proposal is to prevent TB-related morbidity and mortality among PLHIV by developing a novel cough-based diagnostic of TB infectiousness. We previously developed a research tool to measure Mtb cough aerosolization, the cough aerosol sampling system (CASS), that predicts TB infectiousness. Recently, we investigated cough frequency as a marker of TB infectiousness, identified unique TB-related cough signatures and developed a mobile privacy-preserving cough detection system. In the proposed study, we will enroll HIV-positive and HIV-negative Kenyan adults who are newly diagnosed with pulmonary TB to assess their level of TB infectiousness using CASS-measured aerosolized Mtb counts (the outcome). In Aim 1, we will investigate cough frequency and/or cough spectrogram (collectively “cough signature”) to estimate TB infectiousness and investigate the impact of HIV co-infection on TB infectiousness. In Aim 2, we will identify the household contacts of Aim 1 participants (index cases) to investigate for latent TB infection using interferon-gamma release assays (IGRAs) and determine whether index case cough signatures associated with high Mtb aerosol counts are associated with a greater frequency of positive IGRAs in household contacts. Additionally, at 6 months after enrollment we will re-test household contacts with IGRAs to understand if the durability of positive responses is associated with index case cough signatures. We hypothesize that individuals with high Mtb aerosol counts will have high cough frequencies and unique cough spectrograms, and that cough spectrograms will differ by HIV status despite similar Mtb aerosol counts. Furthermore, we hypothesize that household contacts to index cases with “highly infectious” cough signatures are more likely to have positive IGRAs at baseline and at 6-month follow- up. Our team has developed the tools to not only robustly determine infectiousness (CASS), but to evaluate both cough frequency and intensity (spectrogram analyses) in a high HIV/TB burden setting. By identifying cough signatures predictive of TB infectiousness, we will develop tools for clinicians and public health programs to support the targeting of TB control interventions.