Improving Pediatric Tb Diagnosis and Management in Tanzania

改善坦桑尼亚儿童结核病诊断和管理

• 批准号: 8374149
• 负责人: Tania A Thomas
• 金额: $ 12.97万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-20 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8374149
• 关键词: Acid Fast Bacillae Staining Method; Adult; Affect; Antibodies; Antigens; Antitubercular Agents; B-Lymphocytes; Bacillus (bacterium); Biological Assay; Biological Markers; Biometry; Child; Childhood; Clinical; Clinical Research; Collaborations; Complex; Development Plans; Diagnosis; Diagnostic; Diagnostic tests; Diagnostics Research; Disease; Drug Kinetics; Drug Monitoring; Drug Resistant Tuberculosis; Epidemiology; Evaluation; HIV; Health; Hospitals; Immunoglobulin G; Immunoglobulin-Secreting Cells; Immunology; Infection; Infectious Diseases Research; International; Investigation; Laboratories; Laboratory Research; Lymphocyte; Measures; Mentors; Metabolism; Methodology; Modality; Molecular; Monitor; Morbidity - disease rate; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; NAT2 gene; National Institute of Allergy and Infectious Disease; Nature; Nested Case-Control Study; Nutritional status; Optics; Outcome; Patients; Pattern; Performance; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasmablast; Population; Predictive Value; Predisposition; Protocols documentation; Research; Research Institute; Research Priority; Resolution; Resources; Rifampin; Risk Factors; Serum; Severity of illness; Site; Specimen; Structure; Tanzania; Techniques; Testing; Therapeutic; Training; Treatment outcome; Tuberculosis; United States National Institutes of Health; Vulnerable Populations; Weight Gain; Work; World Health Organization; advanced disease; aged; base; career development; clinical care; cohort; density; design; diagnostic accuracy; immune activation; improved; isoniazid; mortality; neglect; novel; novel diagnostics; patient oriented research; prospective; response; skills; sound; success; tool; treatment response; tuberculosis treatment

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.

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。 公共卫生相关性：目前，没有诊断测试可以准确地检测儿童结核病。迫切需要调查淋巴细胞上清液（ALS）测定中的抗体作为疑似患有TB的儿童的诊断以及监测这些儿童对TB治疗的反应的生物标志物的性能，以填补TB领域中未满足的研究优先事项。将该检测方法与标准TB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。儿童结核病的准确检测有可能影响全球的临床护理，并可能允许更及时地开始结核病治疗，可能影响治疗结果。