Effects of Air Pollution on Childhood Tuberculosis in Viet Nam

空气污染和结核病(TB)是全球范围内的公共健康威胁，全世界有三分之一的人感染结核病，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。越南的儿童暴露在令人担忧的二手烟、烹饪烟雾和交通排放中，但对这些污染物对儿童结核病的影响知之甚少。因此，我们建议研究空气污染物对越南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)的免疫反应改变相关。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，以准确预测越南有结核病风险的儿童暴露于空气污染的情况(目标1)。我的目标2，为了评估空气污染暴露作为结核病感染的危险因素，我们将首先招募90名家庭接触者(最近接触涂阳结核病的家庭成员的儿童)参加一项横断面研究，测量持续的个人PM2.5暴露和尿可替宁水平作为预测因素，并将结核病感染检测(结核菌素皮肤测试)作为主要结果。然后，我们将在前瞻性队列研究中跟踪那些未感染结核病的患者，在COX回归分析中使用结核病感染的时间作为我们的纵向结果。在目标3中，那些被目标2确认为结核病感染的儿童将被纳入另一项横断面研究，以评估PM2.5和尿可替宁对干扰素-γ产生结核分枝杆菌特异性CD_4和CD_8+细胞频率的影响。我已经组建了一个由享誉国际的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Nahid博士和Nung(导师)由CDC和NIH资助的广泛的研究基础设施，并在2019年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，我将在三个领域完善我的专业知识：空气污染测量和分析；免疫学理论和实验室经验；以及高级研究设计、生物统计学和结核病研究方法。我们设计了一种研究策略，通过它，我们可以在三个不同但相关的目标上通过生物相关的免疫学机制来证实观察结果。我们预期的发现将通过激励这一领域的进一步研究和指导公共卫生政策来影响公众健康，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，K23的研究和培训将为我成功应用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生涯。

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.