Improving Pediatric Tb Diagnosis and Management in Tanzania

改善坦桑尼亚儿童结核病诊断和管理

基本信息

批准号：
8660027
负责人：
Tania A Thomas
金额：
$ 12.86万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
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/8660027
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

项目摘要

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.

描述（由申请人提供）：全世界每年 940 万结核病 (TB) 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极大地阻碍了在这一弱势群体中检测和治疗该疾病的能力。结果，坦桑尼亚等结核病流行地区的许多儿童都患有晚期疾病，并遭受过高的发病率和死亡率。本申请中提出的项目“改善坦桑尼亚儿科结核病的诊断和管理”将评估一种新的诊断测定法，即淋巴细胞上清液中的抗体（ALS），其假设是未成熟的活化 B 细胞在循环中对结核病抗原作出反应。结核病且非潜伏性结核感染；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，由在坦桑尼亚海多姆路德教会医院就诊的疑似结核病儿童组成。将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对儿童进行随访，以便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、分枝杆菌培养以及通过 GeneXpert MTB/RIF 测试进行分子测试来进行额外的验证性测试。 ALS 检测和 GeneXpert 作为结核病诊断测试的性能将在结核病和非结核病患者中进行评估。此外，还将进行巢式病例对照研究，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，儿童将被分为“正常反应者”或“缓慢反应者”。 ALS 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危险因素，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病。该职业发展计划将促进既定目标的成功，结合了流行病学、生物统计学和免疫学的研究生课程，以及结核病药物药代动力学研讨会和结核病诊断中以患者为导向的研究。将追求实验室技能，包括掌握 ALS 方法。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、结核病药物药代动力学、国际健康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科学背景、体验式培训和工具，以开展以患者为导向的研究，并通过良好的临床设计、执行和解释，使资源有限的环境中的结核病儿童受益。