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：
9061576
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 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9061576
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 resistance in 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 diagnostic assay diagnostic biomarker immune activation improved improved outcome 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）：人们认为儿童至少占全球结核病（TB）的940万例。小儿结核病缺乏准确的诊断会显着阻碍在这种脆弱人群中检测和治疗该疾病的能力。结果，像坦桑尼亚这样的结核病地区的许多儿童都患有晚期疾病，并且遭受了不当的发病率和死亡率。在本应用中提出的项目改善了坦桑尼亚的小儿结核病诊断和管理，将评估一种新的诊断测定法，淋巴细胞上清液中的抗体（ALS），假设未成熟的激活B细胞因响应于TB疾病和非潜伏性TB Intent TB Intection而响应的TB抗原而循环；这些血浆随着结核的分辨率消失。将建立一个预期的队列，由与怀疑TB一起到坦桑尼亚的Haydom Lutheran医院的儿童组成。为了最好地确认儿童使用临床，射线照相和微生物学参数，以最好地确认自己的疾病为“结核病”与“非结核病”，并基于NIH/NIAID标准，并要求具有确认的替代诊断，以归类为非TB患者。通过酸性芽孢杆菌涂片，分枝杆菌培养和分子测试将通过GenExpert MTB/RIF测试进行其他验证性测试。在结核病和非结核病患者中，将评估ALS分析和GenExpert作为结核病诊断测试的性能。此外，将进行一项嵌套的病例控制研究，以检查结核病病例的结果。基于临床，放射学和微生物学参数的变化，儿童将被分类为“正常响应者”或“缓慢反应者”。将在“正常”和“缓慢”的响应者之间比较ALS作为生物标志物的性能。将研究缓慢治疗反应的危险因素，包括对两种最有效的一线结核病药物（Isoniazid和Rifampin），HIV状态，营养状态和并发性腹泻病，包括抗药性结核病，血清药物水平。将增强既定目标的成功的职业发展计划，结合了流行病学，生物统计学和免疫学方面的研究生水平课程，以及有关结核病药物药代动力学的研讨会和结核病诊断方面的患者研究。将追求实验室技能，包括掌握ALS方法论。我的导师团队集体拥有临床结核病，结核病诊断研究，小儿结核病免疫学，结核病药物的药代动力学，国际健康研究和生物统计学方面的专业知识。我的导师的结构性监督和指导将提供科学背景，体验训练以及通过合理的临床设计，执行和解释进行以患者为导向的研究所需的工具，使在资源有限的环境中有肺结核儿童受益。