Improving Pediatric Tb Diagnosis and Management in Tanzania

描述（由申请人提供）：儿童被认为占全球每年940万结核病（TB）病例的至少11%。缺乏对儿童结核病的准确诊断大大阻碍了在这一脆弱人群中发现和治疗这种疾病的能力。因此，在坦桑尼亚等结核病流行地区，许多儿童患有晚期疾病，并遭受不应有的发病率和死亡率。本申请中提出的项目“改善坦桑尼亚的儿科结核病诊断和管理”将评估一种新的诊断检测方法--淋巴细胞上清液中的抗体（ALS），假设未成熟的活化B细胞循环响应结核病期间存在的结核抗原，而不是潜伏性结核感染;这些浆母细胞随着结核病的消退而消失。将建立一个前瞻性队列，由坦桑尼亚海顿路德医院疑似结核病的儿童组成。将对儿童进行随访，以便根据世界卫生组织和NIH/NIAID标准，使用临床、放射学和微生物学参数，最好地确认他们的疾病是“结核病”还是“非结核病”，另外还需要有确认的替代诊断，才能被归类为非结核病患者。将通过抗酸杆菌涂片、分枝杆菌培养和GeneXpert MTB/RIF检测的分子检测进行额外的确证性检测。将在TB和非TB患者中评价ALS检测试剂盒和GeneXpert作为TB诊断检测试剂的性能。此外，将进行巢式病例对照研究，以检查结核病例的结局。根据成人的临床、影像学和微生物学参数的变化，将儿童分为“正常反应者”或“缓慢反应者”。将在“正常”和“缓慢”应答者之间比较ALS作为生物标志物的性能。将调查治疗反应缓慢的风险因素，包括耐药结核病、两种最有效的一线结核病药物（异烟肼和利福平）的血清药物水平、艾滋病毒状况、营养状况和并发的肺部疾病。职业发展计划将促进既定目标的成功，将流行病学、生物统计学和免疫学的研究生课程以及结核病药物药代动力学研讨会和结核病诊断中面向患者的研究结合起来。实验室技能，包括ALS方法的掌握，将被追求。我的导师团队共同拥有临床结核病、结核病诊断研究、儿科结核病免疫学、结核病药物的药代动力学、国际卫生研究和生物统计学方面的专业知识。来自我的导师的结构化监督和指导将提供科学背景，经验培训和进行以患者为导向的研究所需的工具，以及合理的临床设计，执行和解释，使资源有限的环境中的结核病儿童受益。

DESCRIPTION (provided by applicant): Children are thought to comprise at least 11% of the 9.4 million annual cases of tuberculosis (TB) worldwide. The lack of accurate diagnostics for pediatric TB significantly hinders the ability to detect and treat the disease in this vulnerable population. As a result, many children in TB-endemic regions like Tanzania present with advanced illness and suffer undue morbidity and mortality. The project proposed in this application, Improving pediatric TB diagnosis and management in Tanzania, will evaluate a new diagnostic assay, the Antibodies in Lymphocyte Supernatant (ALS), with the hypothesis that immature activated B cells circulate in response to TB antigens which are present during TB disease and not latent TB infection; these plasmablasts disappear with the resolution of TB. A prospective cohort will be established, comprised of children presenting to Haydom Lutheran Hospital in Tanzania with suspected TB. Children will be followed forward in order to best confirm their illness as "TB" versus "not-TB" based upon World Health Organization and NIH/NIAID criteria using clinical, radiographic and microbiological parameters, with the added requisite of having a confirmed alternative diagnosis to be classified as a non-TB patient. Additional confirmatory testing will be pursued through acid-fast bacillus smear, mycobacteriologic culture, and molecular testing via the GeneXpert MTB/RIF test. The performance of the ALS assay and GeneXpert as diagnostic tests for TB will be evaluated among TB and non- TB patients. Additionally, a nested case control study will be performed to examine outcomes within TB cases. Children will be classified into "normal responders" or "slow responders" based on changes in clinical, radiographic, and microbiological parameters adapted from adults. The performance of ALS as a biomarker will be compared between "normal" and "slow" responders. Risk factors for slow treatment response will be investigated including drug-resistant TB, serum drug levels to the two most potent first-line TB medications (isoniazid and rifampin), HIV status, nutritional status and concurrent diarrheal illness. The career development plan which will enhance the success of the stated objectives combines graduate level courses in epidemiology, biostatistics, and immunology, as well as seminars on pharmacokinetics of TB medications and patient oriented research in TB diagnostics. Laboratory skills, including mastery of ALS methodology, will be pursued. My team of mentors collectively has expertise in clinical TB, TB diagnostics research, pediatric TB immunology, pharmacokinetics of TB medications, international health research and biostatistics. Structured oversight and guidance from my mentors will provide the scientific background, experiential training, and tools required to conduct patient-oriented research with sound clinical design, execution and interpretation that benefits children with tuberculosis in resource-limited settings.