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（由适用提供）：背景：结核病（TB）是全球细菌的主要原因，婴儿和幼儿受到了不成比例的影响。但是，目前尚无单一准确的测试来诊断或监测结核病疾病的儿童。传统的诊断方法依赖于从痰液中检测实际的分枝杆菌的生物对儿童不敏感。像淋巴细胞上清液（ALS）分析和跨肾脏TB DNA分析的生物标志物一样，在成人中可以使用，并有望在儿童中使用。 ALS使用血液（而不是血清）测量TB特异性抗体，这些抗体是从患有TB的儿童中发现的未成熟浆细胞中分泌的。同时，肺结核的免疫介导的结核分枝杆菌（MTB）的分解导致小型无细胞的核酸释放到血浆中，该血浆通过肾脏过滤，可以被检测为尿液中MTB DNA的片段。目标：我们的总体目标是使用非呼吸标本来评估儿童肺结核病生物标志物。我们建议评估ALS和跨肾脏TB DNA分析作为疾病活动的诊断生物标志物。每月ALS测量的变化也将作为响应预测性生物标志物评估。方法：这将是来自孟加拉国达卡的408名幼儿（<5岁）的前瞻性研究，他们怀疑患有肺炎的体征和症状，患有肺结核。儿童将在6个月内遵循。与GenExpert和/或TB培养阳性疾病的“黄金标准”参考相比，我们将确定每个生物标志物的诊断准确性。次级分析将使用NIH-Consensus临床病例定义评估每个生物标志物的诊断性能，因为许多儿童没有微生物学确认的TB。逻辑回归模型将用于确定在存在临床预测因子和确认实验室测试的情况下，是否有生物标志物为预测结核病提供其他信息。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。影响：这些目标的成功完成将为怀疑患有结核病的儿童提供急需的微创诊断和监测策略，从而限制了诊断。