Improving TB Diagnosis in Children with and without HIV in Kenya

候选人：我的目标是成为儿科传染病领域的独立研究者，重点研究国际卫生和儿科结核病。我特别感兴趣的是在资源有限的环境中改善结核病诊断和加强感染和未感染艾滋病毒儿童的结核病病例发现。在我的导师Robert Husson博士、Kevin Cain博士、Kenneth McIntosh博士和Niaz Banaei博士的指导下，我制定了一个全面的职业发展计划，这将使我能够在肯尼亚进行两项研究，并在哈佛大学公共卫生学院完成公共卫生硕士学位，并在高级生物统计学和流行病学方面进行额外的教育培训。我将有机会与肯尼亚医学研究所/疾病预防控制研究和公共卫生合作中心（KEMRI/CDC）合作进行两项前瞻性队列研究。我为这些研究提出了概念建议，并将为拟议的研究制定方案。作为首席研究员，我将与Dr. Cain合作，监督研究活动的计划和实施。我将负责监督数据管理，进行数据分析，并通过文稿和演示文稿传播调查结果。环境：波士顿儿童医院和哈佛公共卫生学院以其世界知名的教师而闻名，其中几位将成为我和我的项目的导师和顾问。儿童医院还有一个已建立的临床研究项目，为临床研究人员提供资助、方案制定和实施的各个方面的支持，还有美国国立卫生研究院资助的哈佛催化剂项目、临床和转化科学中心，以及哈佛公共卫生学院的优秀教学课程。KEMRI/CDC是撒哈拉以南非洲开展公共卫生和临床研究的最大合作项目之一。KEMRI/CDC正在开展关于结核病的多项临床研究，包括在婴儿中进行疫苗试验、一项青少年队列研究和一项在感染艾滋病毒的成人中加强结核病病例发现的研究，并拥有一个专门的BSL-3结核病实验室。研究：我的研究计划涉及全球儿科结核病控制面临的最大挑战，即在感染和未感染艾滋病毒的幼儿中诊断结核病的困难。尽管全球儿童结核病负担沉重，幼儿患严重疾病和死亡的风险高于成人，但儿童结核病一直相对被忽视。儿童结核病的诊断具有挑战性，因为症状不具有特异性，而且只有一小部分受感染儿童能够获得明确的微生物学诊断。儿童结核病没有敏感和特异的“金标准”诊断方法。痰液、诱导痰或胃吸出物培养阳性可能是非常不敏感的，尽管是特异性的。在此基础上加入淋巴结抽吸培养可提高敏感性，但仍遗漏了许多放射学和治疗反应一致的病例。在实践中，诊断往往是基于临床判断或不足

DESCRIPTION (provided by applicant): Candidate: My goal is to become an independent investigator in the field of pediatric infectious diseases, with a focus on research on internationl health and pediatric tuberculosis. I have a particular interest in improving TB diagnosis and intensified TB case-finding among children with and without HIV in resource-limited settings. Under the guidance of my mentors, Dr. Robert Husson, Dr. Kevin Cain, Dr. Kenneth McIntosh and Dr. Niaz Banaei, I have developed a comprehensive career development plan which will allow me to implement two research studies in Kenya, and complete a Master of Public Health degree and pursue additional educational training in advanced biostatistics and epidemiology at the Harvard School of Public Health. I will have the opportunity to conduct two prospective cohort studies in collaboration with the Kenya Medical Research Institute/Center for Diseases Control and Prevention Research and Public Health Collaboration (KEMRI/CDC) in Kenya. I developed the concept proposal for the studies and will be developing the protocols for the proposed studies. As the lead investigator, working with Dr. Cain, I will supervise the planning and the implementation of study activities. I will be responsible for the oversight of the data management, conduct the data analysis and disseminate findings through manuscripts and presentations. Environment: Children's Hospital Boston and Harvard School of Public Health are known for their world renowned faculty, several of whom will serve as mentors and advisors for me and my project. Children's also has an established Clinical Research Program which provides support for clinical investigators in all aspects of grant and protocol development and implementation, the NIH-funded Harvard Catalyst Program, a Clinical and Translational Science Center, and an outstanding didactic curriculum at the Harvard School of Public Health. KEMRI/CDC is one of the largest collaborations in sub-Saharan Africa carrying out public health and clinical research. KEMRI/CDC is conducting multiple clinical research studies on TB, including vaccine trials among infants, an adolescent cohort study and a study on intensified TB case-finding among adults with HIV and has a dedicated BSL-3 TB laboratory. Research: My research proposal addresses the greatest challenge to global pediatric TB control, the difficulty in diagnosing TB among young children with and without HIV. Despite the substantial global burden of pediatric TB and the higher risk of severe disease and death among young children than adults, childhood TB has been relatively neglected. Diagnosis of TB among children is challenging as symptoms are non-specific and definite microbiological diagnosis can be achieved in only a small proportion of infected children. Pediatric TB has no sensitive and specific "gold standard" diagnostic method. A positive culture of sputum, induced sputum, or gastric aspirate is probably grossly insensitive, albeit specific. Adding culture of lymph node aspirates to this improves sensitivity but still omits many cases with consistent radiology and response to treatment. In practice, diagnosis is often based on clinical judgment or insufficiently validated diagnostic algorithms. Moreover, pediatric data on the diagnostic utility of promising emerging diagnostic tools for TB, including the Xpert MTB/RIF using real-time PCR, the electronic nose, a non-invasive technology based on detection of volatile compounds, and a modified cytokine-based serological assay, are either limited or lacking. WHO and NIH identified research on improved diagnostic approaches for TB among children with and without HIV as a high priority. These research needs include the development of evidence-based clinical TB screening and diagnostic algorithms for TB among children with and without HIV that can be utilized in resource-limited settings. The implementation of sensitive TB screening and diagnostic algorithms has the potential to substantially reduce preventable illness and death among this vulnerable population by provision of preventive therapy if indicated, earlier treatment initiation and by avoidance of unnecessary treatment. Our aims are to determine a sensitive and feasible approach for TB diagnosis among children with and without HIV, using an intensified work-up with multiple specimen types and the Xpert MTB/RIF, and to evaluate the diagnostic utility of both the electronic nose and modified cytokine-based serological assay for TB infection and TB disease in the same cohort. To achieve these aims, we will conduct a prospective cohort study in Kenya enrolling children with a high pretest probability of having microbiologic confirmed TB. Our first aim is to determine which combination of tests from which sources have the highest yield for TB diagnosis. Once this is determined, our second aim is to derive clinical algorithms for screening and diagnosis of TB among children with and without HIV in Kenya. To do this, we will conduct a prospective cohort study and enroll children who are at high risk of TB, including household contacts and children with HIV, and apply a standardized diagnostic work-up to all enrolled children by using the best and most feasible diagnostic approach, derived from the first study. We will then compare signs, symptoms, and results of simple, widely available tests to the result of the TB diagnostic testing to derive clinical algorithms.