Improving Pediatric Tb Diagnosis and Management in Tanzania

描述(申请人提供)：在全世界每年940万结核病病例中，儿童被认为至少占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，在像坦桑尼亚这样的结核病流行地区，许多儿童患有晚期疾病，并遭受不适当的发病率和死亡率。在这项申请中提出的改善坦桑尼亚儿童结核病诊断和管理的项目将评估一种新的诊断方法，即淋巴细胞上清液中的抗体(ALS)，该方法假设未成熟的激活B细胞对结核病期间存在的结核病抗原做出反应，而不是对潜伏的结核病感染做出反应；这些浆母细胞随着结核病的解决而消失。将建立一个预期队列，由到坦桑尼亚海顿·路德医院就诊的疑似结核病儿童组成。将对儿童进行跟踪，以便根据世界卫生组织和NIH/NIAID的标准，使用临床、放射和微生物参数，最好地确认他们的疾病是“结核病”还是“非结核病”，并增加了将确认的替代诊断归类为非结核病患者的必要条件。将通过抗酸杆菌涂片、分枝杆菌培养和通过GeneXpert MTB/RIF测试进行的分子测试进行额外的确证测试。ALS检测和GeneXpert作为结核病诊断试验的表现将在结核病和非结核病患者中进行评估。此外，还将进行嵌套病例对照研究，以检查结核病病例的结果。根据成人的临床、放射学和微生物学参数的变化，儿童将被归类为“正常反应者”或“慢反应者”。肌萎缩侧索硬化症作为生物标志物的表现将在“正常”和“缓慢”反应者之间进行比较。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、营养状况和并发腹泻疾病。职业发展计划将促进所述目标的成功，结合了流行病学、生物统计学和免疫学的研究生课程，以及关于结核病药物药代动力学的研讨会和以病人为导向的结核病诊断研究。实验室技能，包括对肌萎缩侧索硬化症方法学的掌握。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。我的导师的结构化监督和指导将提供所需的科学背景、经验培训和工具，以进行以患者为导向的研究，并进行合理的临床设计、执行和解释，使资源有限的环境中的结核病儿童受益。 公共卫生相关性：目前，还没有能够准确检测儿童结核病的诊断测试。研究淋巴细胞上清液抗体(ALS)检测在疑似结核病儿童中的诊断作用，以及监测这些儿童对结核病治疗反应的生物标志物的表现，是填补结核病领域尚未满足的研究重点的迫切需要。将这一检测方法与标准结核培养和较新的分子检测方法进行比较，将有助于评估各种检测方法的准确性。对儿童结核病的准确检测有可能影响世界各地的临床护理，并可能使结核病治疗更及时地开始，可能会影响治疗结果。

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. PUBLIC HEALTH RELEVANCE: Currently, there is no diagnostic test that can accurately detect TB in children. Investigating the performance of the antibodies in lymphocyte supernatant (ALS) assay as a diagnostic among children suspected to have TB, as well as a biomarker to monitor response of those children on TB treatment is urgently needed to fill an unmet research priority in the field of TB. Comparing this assay to standard TB culture and newer molecular tests will be helpful in evaluating the accuracy of various testing modalities. An accurate test fo pediatric TB has the potential to impact clinical care worldwide and could allow for timelier initiation of TB treatment, possibly affecting treatment outcomes.