Effects of Air Pollution on Childhood Tuberculosis in Viet Nam

空气污染和结核病是全球性的公共卫生威胁，全世界有三分之一的人感染了结核病，全球近90%的人口生活在污染超过世界卫生组织规定的安全标准的地区。越南儿童暴露在二手烟、烹饪烟和交通废气中，但对这些污染物对儿童结核病的影响知之甚少。因此，我们建议研究越南空气污染物对儿童结核病的临床和免疫学影响。我们的总体假设是，空气污染暴露将与结核病感染风险增加和对结核分枝杆菌（Mtb）的免疫反应改变有关。为了验证这一假设，我们将首先开发并验证一份问卷和空气污染模型，以准确预测生活在越南的结核病风险儿童的空气污染暴露（目标1）。目标2，为了评估空气污染暴露作为结核病感染的危险因素，我们首先将90名家庭接触者（最近接触涂片阳性结核病家庭成员的儿童）纳入横断面研究，测量个人连续PM2.5暴露和尿可替宁水平作为预测因子，并将结核病感染检测（结核菌素皮肤试验）作为我们的主要结果。然后，我们将在一项前瞻性队列研究中跟踪基线时没有结核感染的患者，使用Cox回归分析中的结核感染时间作为我们的纵向结局。在Aim 3中，从Aim 2中确定的结核病感染儿童将被纳入另一项横断面研究，通过流式细胞术评估PM2.5和尿可替宁对IFN-γ产生mtb特异性CD4+和CD8+细胞频率的影响。我已经组建了一个由国际知名科学家组成的导师和科学顾问团队来解决这个至关重要的假设，并将利用dr。Nahid和Nhung的（导师）广泛的CDC和nih资助的研究基础设施，并在2019年之前提供资金来开展这项研究。我还制定了一项全面的培训计划，通过该计划，我将在以下三个方面完善我的专业知识：空气污染测量和分析；免疫学理论和实验室经验；以及先进的研究设计、生物统计学和结核病研究方法。我们设计了一种研究策略，通过这种策略，我们可以在三个不同但相关的目标中通过生物学相关的免疫机制证实观察结果。我们预期的发现将通过推动这一领域的进一步研究和指导公共卫生政策来影响公共卫生，以最好地保护我们的儿童免受空气传播毒素的有害影响。重要的是，这次K23的研究和培训将为我成功申请R01提供必要的工具，并促进我在空气污染健康影响研究方面的职业发展。

Air pollution and tuberculosis (TB) are public health threats of global proportion, with one-third f people worldwide infected with TB and nearly 90% of the global population living in areas where pollution exceeds safe standards set by the World Health Organization. Children in Viet Nam are exposed to concerning levels of secondhand smoke, cooking smoke, and traffic emissions, yet little is known about the effects of these pollutants on childhood TB. We therefore propose to study the clinical and immunologic effects of air pollutants on childhood TB in Viet Nam. Our overall hypothesis is that air pollution exposures will be associated with increased risk for TB infection and altered immunologic responses to Mycobacterium tuberculosis (Mtb). To test this hypothesis, we will first develop and validate a questionnaire and air pollution models that accurately predict air pollution exposures in children at risk for TB living in Viet Nam (Aim 1). I Aim 2, to evaluate air pollution exposures as risk factors for TB infection, we will first enroll 90 household contacts (children recently exposed to a household member with smear positive TB) into a cross-sectional study, measuring continuous personal PM2.5 exposures and urine cotinine levels as predictors and testing for TB infection (tuberculin skin testing) as our primary outcome. We will then follow those without TB infection at baseline in a prospective cohort study, using time to TB infection in Cox regression analysis as our longitudinal outcome. In Aim 3, those children with TB infection identified from Aim 2 will be enrolled into an additional cross sectional study to evaluate the effects of PM2.5 and urine cotinine on frequencies of IFN-γ producing Mtb-specific CD4+ and CD8+ cells by flow cytometry. I have assembled a Mentor and Scientific Advisory Team of internationally acclaimed scientists to address this critically important hypothesis, and will leverage Drs. Nahid and Nhung's (Mentors) extensive CDC- and NIH-funded research infrastructure with funding through 2019 to carry out this research. I have also developed a comprehensive training plan through which I will refine my expertise in three areas: air pollution measurement and analysis; immunology theory and lab experience; and advanced study design, biostatistics, and TB research methodology. We have designed a research strategy by which we can substantiate observational findings through biologically relevant immunologic mechanisms in 3 distinct but related Aims. Our expected findings will impact public health through motivating further research in this area and guiding public health policy to best protect our children from the harmful effects of airborne toxins. Importantly, this K23 research and training will provide me with essential tools for a successful R01 application and to advance my career in air pollution health effects research.