Rapid Monitoring and Assessment of Tubercuolosis Treatment at the Point of Care Using Breath

 描述(申请人提供)：问题和意义：根据疾控中心的全球统计，全球近三分之一的人感染了结核病(TB)。2012年，860万感染者生活在一个被认为负担很高的国家。印度、秘鲁、中国、撒哈拉以南非洲和其他国家的结核病流行区域很大，特别是在低收入人口中。这是一个需要解决的重大健康问题。目的：本提案的目的是描述和评估一种基于固态结核病传感器的快速和便携式结核病治疗监测技术，该传感器可以检测引起结核病的分枝杆菌释放的挥发性有机生物标志物(VOB)。VOB通常存在于人类的呼吸中，已知与包括结核病在内的许多慢性和传染性疾病有关。以下VOB与结核病有关：苯乙酸甲酯、对苯甲酸甲酯、烟酸甲酯和邻苯基苯甲醚。我们先前支持的研究(NSF-STTR)表明，我们新开发的传感器能够在受控环境中检测到这些VOB。该传感材料由金属功能化的3D二氧化钛纳米管阵列组成，根据存在的金属类型结合感兴趣的特定VOB。终端用户的读数是一个电子信号，它根据电流的变化(数量级变化)给出快速的是/否答案。该传感器使用简单，完全是无机的，不需要专门的生物试剂来检测(即抗体、荧光标记等)，具有很长的保质期(超过18个月)，使用简单的恒电位器进行操作，并且是便携的。这项技术的预期用途是在护理点(POC)以快速方式监测结核病治疗，以帮助确定治疗是否有效，或帮助确定患者是否受到结核病耐药菌株的影响。此外，这个传感平台集成了一个数据分析平台，该平台利用操作传感器(智能手机、恒电位仪)的电子设备来收集患者的人口统计数据，包括诊断的时间和地理位置，从而使医护人员和卫生部门能够绘制出结核病在人群中的位置以及它可能传播的位置。这种类型的实时信息对于试图在特定区域管理结核病暴发的卫生部门来说可能是非常宝贵的。使用VOBS监测结核病治疗是一种有吸引力的替代传统方法(即痰分析、临床症状)，因为它可以用非侵入性方法快速检测。我们的初步结果表明，VOB的水平与药物治疗结核病感染是否有效之间存在关系(治疗后7-10天，VOB水平似乎有所下降)。理想情况下，如果这种关系成立，医生可以通过简单地在治疗一周后测量VOBS水平来确定患者是否患有耐药结核病菌株，而不是像目前那样等待几周的培养结果出来。然而，由于用于检测VOB的当前技术(气相色谱/质谱仪)昂贵且不适合低资源设置的现场使用，VOB在POC诊断设置中的使用有限。这里介绍的技术成本低，可以通过特定的金属功能化定制来检测感兴趣的VOB，并可以克服与呼气分析相关的传统技术障碍。为了进一步开发这项技术或结核病治疗监测，并向医护人员提供全面的数据分析，必须考虑以下假设和具体目标：假设1：我们假设，如果治疗感染的药物有效，结核病的VOB水平将会下降。假设2：我们还假设，如果给予治疗后VOB水平没有下降，那么这表明存在多药耐药结核病。具体目标1：确定TB呼气分析仪的分析有效性，并参照用于监测TB的“金标准”确定传感器的灵敏度和特异度。假设3：我们假设一个集成的传感器和智能手机套餐将整合到医生的医疗保健流程中，通过一个直观的应用程序进行操作和数据收集，可以快速轻松地完成分析。具体目标2：将传感器集成到智能手机套装中并评估其性能，包括评估与临床医生的用户界面，以确定该技术如何整合到与医生的医疗保健流程中。假设4：将传感器与智能手机控制器集成将允许医疗保健专业人员实时收集有关患者人口统计的数据，这可能为医疗保健组织提供有关疾病流行率、位置、疾病阶段和治疗效果的重要信息。具体目标3：制定实时数据收集、分析和传播信息的方法，以便进行流行病学跟踪。

 DESCRIPTION (provided by applicant): Problem and Significance: According to the CDC global statistics, nearly 1/3 of the world is infected with Tuberculosis (TB). In 2012 8.6 million f peopled infected lived in what is considered a high burden country. Countries such as India, Peru, China, sub Saharan Africa and others have significant regions endemic for TB, particularly among the lower income population. This represents a significant health problem that needs to be addressed. Objective: The objective of this proposal is to characterize and assess a rapid and portable TB treatment monitoring technology based on a solid-state TB sensor that detects volatile organic biomarkers (VOBs) given off by the mycobacterium that cause TB. VOBs are typically found in the breath of human beings and have known associations with many chronic and infectious diseases including TB. The following VOBs are associated with TB: methyl phenylacetate, methyl p-anisate, methyl nicotinate, and o-phenylanisole. Our prior supported research (NSF-STTR) has shown that our newly developed sensor is capable of detecting these VOBs associated in a controlled environment. The sensing material is made up of metal functionalized 3D TiO2 nanotube arrays that bind specific VOBs of interest based on the type of metal present. The readout for the end-user is an electronic signal that gives a rapid, yes/no answer based on change in current (orders of magnitude change). The sensor is simple to use, completely inorganic requiring no specialized biological reagents for sensing (i.e. antibodies, fluorescent tags, etc.), has a long shelf life (over 18 months), uses a simple potentiostat for operation, and is portable. The intended use for this technology is for monitoring TB treatment at the point of care (POC) in a rapid manner to help ascertain if a treatment is working, or help determine if a patient is subject to a drug resistant strain of TB. In addition this sensing platfom integrates a data analytics platform that utilizes the electronics that operate the sensors (smartphone, potentiostat) to collect patient demographics including time and geolocation of the diagnosis to allow health care workers and health departments to map out where TB is located in a population and where it could possibly spread. This type of information in real-time could be invaluable to health departments trying to manage a TB outbreak in a particular region. Using VOBs for monitoring TB treatment is an attractive alternative to traditional methods (i.e. sputum analysis, clinical symptoms), as it is can be detected using non-invasive methods in a rapid manner. Our preliminary results suggest a relationship between levels of VOBs present and if a medication is effective in treating a TB infection (levels appear to reduce in 7-10 days after treatment). Ideally if this relationship holds true, physicians could ascertain if a patient has a drug resistant strain of TB by simply measuring VOBs levels after a week of treatment instead of waiting several weeks for cultures results to get back as is currently done. However, VOBs have seen limited use in POC diagnostics settings since current technology (Gas Chromatography/Mass Spec) for detection of VOBs is expensive and not suitable for low resource setting field use. The technology presented here is low cost and can be tailored to detect VOBs of interest via specific metal functionalization, and can overcome traditional technological hurdles associated with breath analysis. To further develop this technology or TB treatment monitoring and provide comprehensive data analytics to healthcare workers, the following hypothesis and specific aims must be looked at: Hypothesis 1: We hypothesize that the levels of VOBs for TB will decrease if drugs used to treat the infection are effective. Hypothesis 2: We also hypothesize that if the levels of VOBs are not reduced after administering treatment, then this is indicative of multi-drug resistant TB. Specific Aim 1: Determine the analytical validity the TB Breathalyzer device, and determine the sensitivity and specificity of the sensor in reference to the "gold standard" used to monitor TB. Hypothesis 3: We hypothesize an integrated sensor and smartphone package will integrate into the flow of healthcare for physicians and analysis can be done quickly and easily with an intuitive app for operation and data collection. Specific Aim 2: Integrate sensor into a smartphone package and assess its performance including evaluating the user interface with clinicians to determine how the technology integrates into the flow of health care with physicians. Hypothesis 4: Integration of the sensor with a smartphone controller will allow healthcare professionals to collect data about patient demographics in real time which could provide important information for health care organization in regards to disease prevalence, location, stage of diseases, and effectiveness of treatment. Specific Aim 3: Develop methods for real-time data collection, analysis, and dissemination of the information for epidemiological tracking.