VOLATILE MARKERS OF PULMONARY TUBERCULOSIS IN THE BREATH

描述（申请人提供）：背景：肺结核（TB）是一个日益严重的公共卫生问题，但在疑似疾病患者中确认诊断通常是昂贵和耗时的。临床医生迫切需要一种更快、更好、更便宜的活动性肺结核筛查测试。理想的肺结核筛查试验应具有高度敏感性和特异性以及快速、廉价和非侵入性。 目前使用的测试没有满足这些标准：抗酸杆菌的痰染色具有高特异性但敏感性差，而分枝杆菌的痰培养具有较高的敏感性，但它昂贵且耗时。然而，一项1期试点研究提供的证据表明，呼吸中挥发性有机化合物（VOC）的呼吸测试可以提供一种临床有用的新标志物。呼吸中氧化应激标志物的模式识别分析以94.1%的灵敏度和95.1%的特异性识别活动性肺结核感染患者。模糊逻辑分析法预测活动性肺结核感染的敏感性为100%，特异性为83.3%。 假设：结合模式识别分析或模糊逻辑分析的呼吸VOC测试可以提供一种新的肺结核筛查测试，该测试具有高度敏感性和特异性以及快速，廉价和非侵入性。 测试假设的计划：我们将在一项大型多中心试验中评估呼吸测试在肺结核检测中的作用。呼气试验的结果将与痰培养的“金标准”进行比较。结核呼吸VOC的模式识别分析和模糊逻辑分析将用于在患者训练集中开发预测模型。这些模型将在一组测试患者中进行评估和比较，以确定呼吸测试作为活动性肺结核标志物的灵敏度、特异性和预测价值。 长期目标： a.科学性：在更大的受试者组中验证I期研究的临床结果。 B.技术：开发一种适用于床旁筛查的相对便宜的小型快速呼吸测试。 C.商业：获得美国食品药品监督管理局（FDA）对器械的批准并上市。 研究的重要性：肺结核的呼吸测试可以通过以低成本快速检测新感染以及监测治疗效果来产生重要的临床影响。此外，它还可能降低肺结核引起的死亡率和发病率。

DESCRIPTION (provided by applicant): Background: Pulmonary tuberculosis (TB) is a growing public health problem, but confirming the diagnosis in patients with suspected disease is often costly and time-consuming. Clinicians urgently need a screening test for active pulmonary tuberculosis that is faster, better and cheaper. An ideal screening test for pulmonary TB would be highly sensitive and specific as well as rapid, inexpensive and non-invasive. No test in current use fulfills these criteria: sputum staining for acid fast bacilli has high specificity but poor sensitivity, and culturing sputum for Mycobacteria has higher sensitivity, but it is expensive and time consuming. However, a Phase 1 pilot study provided evidence that a breath test for volatile organic compounds (VOCs) in the breath could provide a clinically useful new marker. Pattern recognition analysis of oxidative stress markers in breath identified patients with active pulmonary TB infection with 94.1% sensitivity and 95.1% specificity. Fuzzy logic analysis of breath VOCs predicted active pulmonary tuberculosis infection with sensitivity = 100% and specificity = 83.3%. Hypothesis: A test for breath VOCs combined with pattern recognition analysis or fuzzy logic analysis could provide a new screening test for pulmonary TB that is highly sensitive and specific as well as rapid, inexpensive and non-invasive. Plans to test the hypothesis: We will evaluate the breath test in a subset of patients enrolled in a large multicenter trial designed to evaluate antibody-detection assays in the detection of pulmonary TB. Results of the breath test will be compared to the "gold standard" of sputum culture for M. tuberculosis. Pattern recognition analysis and fuzzy logic analysis of breath VOCs will be employed to develop predictive models in a training set of patients. These models will be evaluated and compared in a test set of patients to determine the sensitivity, specificity and predictive value of the breath test as a marker of active pulmonary TB. Long term aims: a. Scientific: To validate the clinical findings of the Phase 1 study in a larger group of subjects. b. Technical: to develop a comparatively inexpensive miniaturized and rapid breath test suitable for point of care screening. c. Commercial: To obtain Food and Drug Administration (FDA) approval of the device and to market it. Importance of the research: A breath test for pulmonary TB could make an important clinical impact by detecting new infections rapidly at low cost, and also by monitoring the impact of therapy. Also, it could potentially reduce the mortality and morbidity caused by pulmonary TB.