Exploring the Early Tuberculosis Spectrum Through Highly-Sensitive Mtb DNA Detection

通过高灵敏度 Mtb DNA 检测探索早期结核病谱

• 批准号: 10419579
• 负责人: Yingda Linda Xie
• 金额: $ 2.77万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10419579
• 关键词: Adult; Africa; Biological Markers; Biology; Blood; Clinical; Clinical Microbiology; Communicable Diseases; Containment; DNA; Data; Demographic Factors; Detection; Disease; Funding; Gene Expression Profile; Genetic Transcription; Growth; Individual; Messenger RNA; Microbiology; Morbidity - disease rate; Mycobacterium tuberculosis; Natural History; Parents; Role; Signs and Symptoms; Sputum; Testing; Tuberculosis; curative treatments; detection assay; detection test; diagnostic accuracy; follow-up; mortality; predictive signature; programs; risk stratification; scale up; transmission process

ABSTRACT Tuberculosis (TB, Mtb) remains one of the leading infectious disease killer globally, despite the availability of curative treatment for most individuals. The ability to identify TB which has progressed beyond bacterial containment associated with latency but not yet reached the burden of culture-positive, symptomatic active disease could have far- reaching impact in thwarting transmission and decreasing individual morbidity and mortality. The global scale-up of ultra-sensitive Mtb DNA detection assays, such as the WHO-recommended GeneXpert MTB/RIF Ultra (Ultra), presents a critical opportunity to identify this incipient, pre-cultivatable disease stage. We hypothesize that sputum Mtb DNA-positive/culture-negative individuals are more likely to have incipient TB than Mtb DNA-negative/culture-negative (TB-negative) individuals. To test this hypothesis, we initiated a substudy to an R01-funded Ultra diagnostic accuracy study of adults in Africa with signs/symptoms of TB to evaluate the biology and natural history Ultra Mtb DNA- positive/culture-negative individuals. In Aim 1, we will characterize host clinical and demographic factors associated with sputum Mtb DNA-positive/culture-negative status and characterize these individuals on the spectrum of Mtb infection using pre-validated blood transcriptional signatures predictive of progression to active TB. In Aim 2, we will evaluate and compare microbiologic indicators of TB disease between Mtb DNA positive/culture negative and TB-negative individuals. Specifically, we propose to investigate the presence of Mtb mRNA from sputum and evaluate for differentially culturable Mtb from extended incubation and culture supplemented with growth promoting factors. Finally, we will evaluate the natural history of Mtb DNA- positive/culture-negative individuals with respect to TB-negative controls using longitudinal clinical, microbiologic, and host transcriptional data collected over a 12- month follow-up period in the parent study. Together, these proposed studies will inform the utility of ultrasensitive Mtb DNA detection tests for early TB risk stratification and characterize the natural history and biomarkers of culture-negative TB.

摘要 结核病（TB，Mtb）仍然是全球主要的传染病杀手之一， 尽管对大多数人来说可以获得治愈性治疗。识别能力 结核病已经进展到与潜伏期相关的细菌遏制之外，但 然而，达到培养阳性的负担，症状活动性疾病可能已经远远- 在阻止传播和降低个人发病率方面产生影响， mortality.全球扩大超灵敏结核分枝杆菌DNA检测检测试剂盒的规模，例如 世卫组织推荐的GeneXpert MTB/RIF Ultra（Ultra）提供了一个关键机会， 识别这种早期的、可预培养的疾病阶段。我们假设痰结核分枝杆菌 DNA阳性/培养阴性个体比Mtb更有可能患有早期结核病 DNA阴性/培养阴性（TB阴性）个体。为了验证这个假设，我们 在R 01资助的非洲成人Ultra诊断准确性研究中启动了一项子研究 患有结核病的体征/症状，以评估生物学和自然史Ultra Mtb DNA- 积极/文化消极的个体。在目标1中，我们将表征宿主临床和 与痰结核分枝杆菌DNA阳性/培养阴性状态相关的人口统计学因素 并使用预先验证的 血液转录特征可预测进展为活动性TB。在目标2中，我们将 结核分枝杆菌DNA与结核病微生物学指标的比较 阳性/培养阴性和TB阴性个体。具体而言，我们建议 研究痰中Mtb mRNA的存在，并评估差异 来自延长孵育和补充生长的培养物的可培养Mtb 促进因素。最后，我们将评估结核分枝杆菌DNA的自然历史- 阳性/培养阴性个体相对于TB阴性对照，使用 纵向临床，微生物学和宿主转录数据收集超过12- 在母研究中随访1个月。总之，这些拟议的研究将提供信息， 超灵敏结核分枝杆菌DNA检测试验在早期结核病风险分层中的效用， 描述培养阴性结核病的自然史和生物标志物。