Evaluation of a novel breath sensor for rapid, low-cost diagnosis of tuberculosis in children

评估用于快速、低成本诊断儿童结核病的新型呼吸传感器

• 批准号: 9901601
• 负责人: Adithya Cattamanchi
• 金额: $ 65.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901601
• 关键词: 3-Dimensional; Acute; Age; Bacteria; Binding; Biological Assay; Biological Markers; Breath Tests; Cause of Death; Chest; Child; Child Health; Childhood; Clinic; Clinical; Collection; Control Groups; Custom; Data; Detection; Device Designs; Devices; Diagnosis; Enrollment; Environment; Evaluation; Exhalation; Failure; Feedback; Genus Mycobacterium; Growth; HIV; Health Priorities; Hour; Individual; Literature; Measures; Metabolic; Metabolism; Metals; Molecular; Morbidity - disease rate; Mycobacterium tuberculosis; Nanotubes; Patients; Pediatric Hospitals; Performance; Phase; Preparation; Rattus; Reagent; Research; Research Infrastructure; Respiratory System; Sampling; Smell Perception; Specificity; Sputum; Standardization; Subgroup; Symptoms; Technology; Testing; Tuberculosis; Uganda; United States National Institutes of Health; Update; Validation; base; candidate marker; clinical infrastructure; commercialization; cost; design; diagnostic accuracy; experience; global health; handheld equipment; improved; interest; mortality; nicotinate; noninvasive diagnosis; novel; pathogen; point of care; prototype; respiratory; sample collection; scale up; sensor; sensor technology; solid state; titanium dioxide; tuberculosis diagnostics; usability; validation studies; volatile organic compound; voltage

PROJECT SUMMARY Improving diagnosis of tuberculosis (TB) is critical to reducing its burden among children. Key challenges include that many children do not produce sputum and, even among those who do, bacillary burden in sputum is often low. Therefore, identification of a non-sputum based test with high accuracy for diagnosing TB in children is a key global health priority. One approach is to evaluate volatile organic compounds (VOCs) in exhaled breath, which is easily collected from children of all ages. Recent research has identified at least two VOCs – methyl nicotinate and methyl p-anisate – that are a byproduct of Mycobacterium tuberculosis metabolism and should therefore be present in anyone with active TB, regardless of age. These VOCs do not appear to be emitted by other bacteria of the respiratory tract; do not appear to be found at high concentrations in the ambient environment; and have been identified at high concentrations in the breath of TB patients but not healthy controls. However, the lack of a technology to easily measure specific VOCs at the point-of-care has been a key barrier to further validation and use of these VOCs as a biomarker for TB diagnosis. The overall objective of this proposal is to validate methyl nicotinate and methyl p-anisate in exhaled breath as biomarkers for diagnosis of intra-thoracic TB in children when detected using a novel, low-cost, handheld device. The device is a solid-state sensor based on metal-functionalized 3D titanium dioxide (TiO2) nanotube arrays that bind specific VOCs when a specific voltage gradient is applied. Binding results in a change in current that is proportional to the concentration of target VOCs present in the breath. The sensor has been customized to specifically bind methyl-nicotinate and methyl p-anisate and has a low limit-of-detection. Furthermore, the detection is fast (on the order of minutes), reagent-free, and requires no sample preparation. Our central hypothesis is that the breath sensor will increase the proportion of confirmed TB diagnoses in children compared to the currently recommended molecular assay (Xpert MTB/RIF, Cepheid, USA). In Aim 1, we will further develop the novel breath sensor into a field-ready childhood TB diagnostic platform by 1) incorporating positive and negative controls into the existing sensor; 2) designing a prototype for direct collection and delivery of a breath sample to the sensor (versus collection of breath in a breath bag and connecting the bag to the sensor, as is currently done); and 3) performing usability testing to refine the device prototypes. In Aim 2, we will validate the accuracy of the two candidate biomarkers and breath sensor device for diagnosis of intra-thoracic TB in children. We will enroll and follow 700-875 children with a clinical suspicion of TB and 25 children in each of four control groups. We will assess diagnostic accuracy of the breath sensor in reference to NIH case definitions for pediatric TB and incorporate data from children in the control groups to verify specificity and evaluate alternate cut-points. Completion of these aims will result in high-quality data on the performance of a novel breath technology for non-invasive diagnosis of TB in children.

项目摘要 改善结核病的诊断对于减轻儿童的负担至关重要。关键挑战 包括许多儿童不产生痰液，即使在产生痰液儿童中，痰液中的细菌负荷 往往很低。因此，找到一种诊断结核病准确性高的非痰检测方法， 儿童是全球卫生的一个关键优先事项。一种方法是评估挥发性有机化合物（VOC）， 呼出气，这是很容易收集的所有年龄段的儿童。最近的研究发现，至少有两个 挥发性有机化合物-烟酸甲酯和对茴香酸甲酯-是结核分枝杆菌的副产品 因此，无论年龄大小，任何活动性结核病患者都应该存在这种情况。这些VOC不 似乎由呼吸道的其他细菌释放;似乎未发现高浓度 在周围环境中;并已确定在结核病患者的呼吸中具有高浓度， 而不是健康的对照组。然而，缺乏一种技术，可以很容易地测量特定的挥发性有机化合物在护理点 一直是进一步验证和使用这些挥发性有机化合物作为结核病诊断的生物标志物的关键障碍。 本提案的总体目标是验证呼出气中的烟酸甲酯和对茴香酸甲酯， 当使用新型、低成本、手持设备检测时， 设备.该器件是基于金属功能化的3D二氧化钛（TiO 2）纳米管的固态传感器 当施加特定的电压梯度时，结合特定VOC的阵列。结合导致 与呼吸中存在的目标VOC的浓度成比例的电流。传感器已被 定制为特异性结合烟酸甲酯和对茴香酸甲酯，并具有低检测限。 此外，检测速度快（大约几分钟），不需要试剂，不需要样品制备。 我们的中心假设是，呼吸传感器将增加确诊结核病的比例， 与目前推荐的分子检测试剂盒（Xpert MTB/RIF，Cepheid，USA）相比， 在目的1中，我们将进一步开发新的呼吸传感器，使其成为一个现场可用的儿童结核病诊断平台， 1)将阳性和阴性对照结合到现有的传感器中; 2）设计用于直接测量的原型; 呼吸样本的收集和输送到传感器（相对于呼吸袋中的呼吸收集， 将袋连接到传感器，如目前所做的）;以及3）执行可用性测试以改进装置 原型在目标2中，我们将验证两个候选生物标志物和呼吸传感器设备的准确性 用于诊断儿童胸内结核病。我们将招募并随访700-875名儿童， 疑似结核病的儿童和四个对照组各25名儿童。我们将评估诊断的准确性， 呼吸传感器参考NIH儿科TB病例定义，并纳入 对照组，以验证特异性并评价替代临界点。实现这些目标将导致 一种新型呼吸技术用于儿童结核病非侵入性诊断的性能的高质量数据。