Improving TB Diagnosis in Children with and without HIV in Kenya

改善肯尼亚感染和未感染艾滋病毒儿童的结核病诊断

• 批准号: 8690932
• 负责人: Rinn Song
• 金额: $ 13.45万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-05 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690932
• 关键词: 5 year old; Address; Adolescent; Adult; Affect; Africa South of the Sahara; Algorithms; Aspirate substance; Biological Assay; Biometry; Blood; Boston; Center for Translational Science Activities; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Childhood; Clinical; Clinical Investigator; Clinical Research; Clinical Sciences; Cohort Studies; Collaborations; Communicable Diseases; Country; Data; Data Analyses; Detection; Development; Development Plans; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Disease; Early treatment; Electronics; Emerging Technologies; Enrollment; Environment; Epidemic; Epidemiology; Evaluation; Faculty; Feces; Funding; Goals; Gold; Grant; HIV; Health; Household; Infant; Infection; Judgment; Kenya; Laboratories; Lead; Manuscripts; Master of Public Health; Medical Research; Mentors; Methods; Modality; Morbidity - disease rate; Nose; Patients; Pediatric Hospitals; Prevention Research; Preventive; Probability; Protocols documentation; Public Health; Public Health Schools; Radiology Specialty; Recording of previous events; Relapse; Research; Research Activity; Research Institute; Research Personnel; Research Proposals; Resources; Serological; Signs and Symptoms; Source; Specimen; Sputum; Stomach; Symptoms; Techniques; Technology; Testing; Thoracic Radiography; Time; Training; Treatment outcome; Tuberculin Test; Tuberculosis; United States National Institutes of Health; Urine; Vaccines; Vulnerable Populations; Work; base; career development; case finding; catalyst; cohort; cytokine; data management; diagnostic accuracy; didactic education; evidence base; high risk; improved; interest; lymph nodes; mortality; neglect; new technology; novel diagnostics; programs; prospective; protocol development; public health priorities; public health relevance; research study; respiratory; response; screening; tool; tuberculosis treatment

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.

描述（由申请人提供）： 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。我对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特别感兴趣。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，我制定了一项全面的职业发展计划，这将使我能够在肯尼亚实施两项研究，完成公共卫生硕士学位，并在哈佛大学公共卫生学院接受高级生物统计学和流行病学方面的额外教育培训。我将有机会与肯尼亚医学研究所/疾病控制和预防研究及公共卫生合作中心 (KEMRI/CDC) 合作进行两项前瞻性队列研究。我制定了研究的概念提案，并将制定拟议研究的方案。作为首席研究员，我将与凯恩博士合作，监督研究活动的规划和实施。我将负责监督数据管理，进行数据分析并通过手稿和演示文稿传播研究结果。环境：波士顿儿童医院和哈佛大学公共卫生学院以其世界知名的教师而闻名，其中几位将担任我和我的项目的导师和顾问。儿童医院还拥有一个既定的临床研究计划，为临床研究人员在资助和方案制定和实施的各个方面提供支持、美国国立卫生研究院资助的哈佛催化剂计划、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 是撒哈拉以南非洲地区开展公共卫生和临床研究的最大合作机构之一。 KEMRI/CDC 正在开展多项结核病临床研究，包括婴儿疫苗试验、青少年队列研究和艾滋病毒成人强化结核病病例发现研究，并拥有专门的 BSL-3 结核病实验室。研究：我的研究提案解决了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，且幼儿患严重疾病和死亡的风险高于成人，但儿童结核病相对被忽视。儿童结核病的诊断具有挑战性，因为症状不具有特异性，并且只有一小部分感染儿童可以得到明确的微生物学诊断。儿童结核病没有敏感且特异的“金标准”诊断方法。痰、诱导痰或胃吸出物的阳性培养可能非常不敏感，尽管具有特异性。添加淋巴结抽吸培养物可以提高敏感性，但仍然遗漏了许多具有一致放射学和治疗反应的病例。在实践中，诊断往往基于临床判断或不充分 经过验证的诊断算法。此外，关于有前途的新兴结核病诊断工具的诊断效用的儿科数据有限或缺乏，这些工具包括使用实时 PCR 的 Xpert MTB/RIF、电子鼻、基于挥发性化合物检测的非侵入性技术以及改良的基于细胞因子的血清学测定。世卫组织和美国国立卫生研究院将改进感染和未感染艾滋病毒儿童的结核病诊断方法的研究列为高度优先事项。这些研究需求包括开发基于证据的临床结核病筛查和感染和未感染艾滋病毒儿童结核病的诊断算法，可在资源有限的环境中使用。实施敏感的结核病筛查和诊断算法有可能通过在有需要时提供预防性治疗、及早开始治疗和避免不必要的治疗，大幅减少这一弱势群体中可预防的疾病和死亡。我们的目标是通过对多种样本类型和 Xpert MTB/RIF 进行强化检查，确定一种敏感且可行的方法，对感染和未感染 HIV 的儿童进行结核病诊断，并评估电子鼻和改良的基于细胞因子的血清学检测对同一队列中结核感染和结核病的诊断效用。为了实现这些目标，我们将在肯尼亚开展一项前瞻性队列研究，招募经微生物学确诊的结核病预检概率较高的儿童。我们的首要目标是确定哪种来源的检测组合对于结核病诊断的效果最高。一旦确定，我们的第二个目标是推导出用于肯尼亚感染和未感染艾滋病毒儿童的结核病筛查和诊断的临床算法。为此，我们将开展一项前瞻性队列研究，招募结核病高危儿童，包括家庭接触者和艾滋病毒感染者，并使用源自第一项研究的最佳、最可行的诊断方法对所有招募的儿童进行标准化诊断检查。然后，我们将简单、广泛使用的测试的体征、症状和结果与结核病诊断测试的结果进行比较，以得出临床算法。