Non-respiratory biomarkers to diagnose and monitor response in pediatric TB

用于诊断和监测儿童结核病反应的非呼吸生物标志物

• 批准号: 8952359
• 负责人: Tania A Thomas
• 金额: $ 18.5万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8952359
• 关键词: 4 year old; 5 year old; Acid Fast Bacillae Staining Method; Address; Adult; Advocate; Affect; Age; Antibodies; Bacillus (bacterium); Bacteria; Bangladesh; Biological Assay; Biological Markers; Blood; Blood Circulation; Blood specimen; Cause of Death; Cells; Centers for Disease Control and Prevention (U.S.); Child; Childhood; Clinical; Collaborations; Communicable Diseases; Consensus; Coupled; DNA; Detection; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic radiologic examination; Diagnostic tests; Disease; Goals; Gold; Hospitalized Child; Immune; Immune response; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunologics; Immunology; Infant; Kidney; Kinetics; Knowledge; Laboratories; Logistic Regressions; Lung; Lymphocyte; Malnutrition; Measurement; Measures; Mediating; Methods; Modeling; Molecular; Monitor; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Nucleic Acids; Organism; Outcome; Pediatrics; Performance; Peripheral Blood Mononuclear Cell; Plasma; Plasma Cells; Plasmablast; Pneumonia; Prospective Studies; Public Health; Pulmonary Tuberculosis; Pulmonology; Reference Standards; Renal Tuberculosis; Research; Sampling; Serum; Signs and Symptoms; Site; Specimen; Sputum; Testing; Treatment outcome; Tuberculosis; UNICEF; USAID; United States National Institutes of Health; Urine; Vulnerable Populations; Work; base; clinical predictors; diagnostic accuracy; experience; immune activation; microorganism; minimally invasive; mycobacterial; pediatric patients; public health relevance; respiratory; response; tuberculosis treatment; urinary

 DESCRIPTION (provided by applicant): Background: Tuberculosis (TB) is the leading cause of death from a bacteria worldwide and infants and young children are disproportionately affected. However, there is currently no single accurate test to diagnose or monitor children with TB disease. Traditional diagnostic methods that rely upon detecting the actual mycobacterial organisms from sputum are insensitive in children. Biomarkers, like the Antibodies in Lymphocyte Supernatant (ALS) assay and the trans-renal TB DNA assay, are available in adults and hold promise for use in children. ALS uses blood (and not serum) to measure TB-specific antibodies which are actively being secreted from immature plasma cells found in circulation among children who are suffering from TB. Concurrently, the immune-mediated breakdown of Mycobacterium tuberculosis (Mtb) from pulmonary TB results in the release of small, cell-free nucleic acids into the plasma which are filtered through the kidney and can be detected as fragments of Mtb DNA in urine. Objectives: Our overall goal is to use non-respiratory specimens to evaluate biomarkers for pulmonary TB in children. We propose to evaluate the ALS and trans-renal TB DNA assays as diagnostic biomarkers of disease activity. The changes in monthly ALS measurements will also be evaluated as a response-predictive biomarker. Methods: This will be a prospective study among 408 young children (<5 years) from Dhaka, Bangladesh who are hospitalized with signs and symptoms of pneumonia are suspected of having pulmonary TB. Children will be followed over 6 months. We will determine the diagnostic accuracy of each biomarker in comparison to a "gold standard" reference of GeneXpert and/or TB culture-positive disease. Secondary analysis will evaluate the diagnostic performance of each biomarker using an NIH-consensus clinical case definition, since many children do not have microbiologically confirmed TB. Logistic regression models will be used to determine whether or not either biomarker contributes additional information to predicting TB in the presence of clinical predictors and confirmatory laboratory tests. Lastly, the kinetics of monthly ALS values will be correlated with clinical response and TB treatment outcome. Impact: Successful completion of these aims will provide much-needed minimally-invasive diagnostic and monitoring strategies for children suspected of having TB, thereby limiting misdiagnosis.

 描述（由申请人提供）： 背景：结核病 (TB) 是全世界细菌死亡的主要原因，婴儿和幼儿受到的影响尤为严重，但是，目前还没有一种准确的测试来诊断或监测患有结核病的儿童。依赖于检测痰中实际分枝杆菌的传统诊断方法对儿童生物标志物不敏感，例如淋巴细胞上清液中的抗体 (ALS) 测定和经肾测定。结核病 DNA 检测可用于成人，并有望用于儿童。 ALS 使用血液（而非血清）来测量结核病特异性抗体，这些抗体是从患有结核病的儿童循环中发现的未成熟浆细胞中主动分泌的。同时，肺结核中结核分枝杆菌 (Mtb) 的免疫介导分解导致小的无细胞核酸释放到血浆中，这些核酸通过肾脏过滤，并可作为尿液中的 Mtb DNA 目标：我们的总体目标是使用非呼吸道样本来评估儿童肺结核的生物标志物，我们建议评估 ALS 和经肾结核 DNA 测定作为疾病活动的诊断生物标志物的变化。 ALS 测量值也将作为反应预测生物标志物进行评估。 方法：这将是一项前瞻性研究，对象为来自孟加拉国达卡的 408 名因疑似肺炎体征和症状而住院的幼儿（<5 岁）。患有肺结核的儿童将被跟踪 6 个月以上，我们将与 GeneXpert 的“金标准”参考和/或结核培养阳性疾病进行比较，确定每种生物标志物的诊断准确性。使用 NIH 共识临床病例定义的生物标志物，因为许多儿童没有微生物学证实的结核病，因此将使用 Logistic 回归模型来确定任一生物标志物是否在存在临床预测因素和确证实验室的情况下为预测结核病提供额外信息。最后，每月 ALS 值的动力学将与临床反应和结核病治疗结果相关：成功完成这些目标将为疑似患有结核病的儿童提供急需的微创诊断和监测策略。限制误诊。