Complementary diagnostic biomarkers of sputum culture-negative TB [R21]

痰培养阴性结核病的补充诊断生物标志物 [R21]

• 批准号: 10433028
• 负责人: ABRAHAM PINTER
• 金额: $ 23.5万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433028
• 关键词: Affinity; Antigens; Bacteria; Biological Assay; Biological Markers; Cell Wall; Clinical; Clinical Microbiology; Control Groups; Detection; Development; Diagnostic; Disease; Disease Progression; Early Diagnosis; Early Intervention; Foundations; Gene Expression Profile; Goals; Growth; Growth Factor; Immune response; Individual; Methods; Microbiology; Morbidity - disease rate; Mycobacterium tuberculosis; Outcome Study; Parents; Patients; Performance; Phenotype; Pilot Projects; Population; Prevalence; ROC Curve; Rapid diagnostics; Reagent; Research; Resources; Signal Transduction; Specimen; Sputum; Symptoms; Technology; Testing; Tuberculosis; Urine; Validation; Work; base; cohort; diagnostic accuracy; diagnostic biomarker; diagnostic strategy; disease transmission; falls; follow-up; genetic signature; improved; lateral flow assay; lipoarabinomannan; nano-string; novel; prevent; respiratory; transmission process; tuberculosis diagnostics

ABSTRACT At least 15-30% of symptomatic tuberculosis (TB) is estimated to be culture-negative, of whom approximately half progress to culture-positive TB. Improved diagnostics for sputum culture- negative TB thus represents a major opportunity for early intervention to prevent morbidity and development of transmissible disease. However, there are currently no validated diagnostic strategies to confirm or screen for culture-negative TB. Only recently, progress in non-sputum based near-patient diagnostics – including cartridge-based tests of TB host response signatures and lateral flow assays to detect TB antigen from urine – have provided progressively more sensitive readouts of TB infection independent of sputum culture. Together, these methods have unexplored potential as complementary diagnostic biomarkers with an ability to detect TB patients otherwise missed by slow, inaccessible sputum culture-based methods. With the long-term goal of developing rapid and feasible diagnostic approach for culture-negative TB, we will evaluate the latest, most promising urine LAM platforms and TB host response signatures among an existing cohort of symptomatic but culture-negative individuals who have been clinically and microbiologically characterized over 12 months. Our central hypothesis is that host-response signatures and urine LAM detection - alone or combined - will have an AUC ROC of over 70% for discriminating individuals with “probable” versus “unlikely” culture-negative TB – referenced by their longitudinal clinical and extended microbiologic signals of TB. We will test our hypothesis through the following complementary aims: Aim 1 will compare a panel of previously validated TB host response gene expression signatures between culture-confirmed TB, TB-negative controls, and the well-characterized cohort of culture- negative individuals, with the hypothesis that readouts of symptomatic, culture-negative individuals will fall between that of culture-confirmed TB and TB-negative controls. We will then evaluate the ability of these signatures to discriminate probable versus unlikely culture negative TB. In Aim 2, we will follow the same approach to evaluate for presence of TB LAM using existing and novel high-affinity urine LAM assays between these three cohorts, and evaluate the individual and combined value of urine LAM and host response signatures for discriminating probable versus unlikely culture-negative TB. The expected outcome of this study is the foundation of a diagnostic strategy for culture-negative TB to facilitate early appropriate treatment, thereby halting development of a significant population of culture-positive disease with far-reaching impact in preventing TB morbidity and transmission.

抽象的 据估计，至少有15-30％的症状结核病（TB）为培养物，其中 大约一半的培养阳性结核病。改进了痰培养的诊断方法 - 因此，负结核病代表了早期干预以防止发病率和 传播疾病的发展。但是，目前尚无诊断 确认或筛选文化阴性结核的策略。直到最近，非投放的进展 基于接近患者的诊断 - 包括基于墨盒的结核病宿主响应签名测试 和横向流量测定以检测尿液的结核病抗原 - 逐渐提供了更多 TB感染的敏感读数与痰培养无关。这些方法在一起 意外潜力作为具有检测结核病患者的能力的完整诊断生物标志物 否则，基于缓慢，无法访问的痰液培养方法错过了。长期目标 通过开发培养 - 阴性结核病快速且可行的诊断方法，我们将评估 现有的最新，最有前途的尿液LAM平台和结核病主机响应签名 有症状但培养阴性个体的队列，这些人一直在临床上和 在12个月内以微生物学表征。我们的中心假设是宿主响应 签名和尿液检测 - 单独或合并 - AUC ROC为70％以上 通过“可能”与“不太可能”文化阴性结核病区分个人 - 由 他们的纵向临床和扩展的结核病信号。我们将检验我们的假设 通过以下互补目标： AIM 1将比较先前验证的TB宿主响应基因表达特征的面板 在培养确认的结核病，结核病阴性控制和培养良好的群体之间 否定的个体，假设有症状，培养性阴性的读数 个体将介于文化确认的结核病和结核病阴性控制之间。然后我们会 评估这些签名区分有问题与不太可能培养的能力 TB。在AIM 2中，我们将采用相同的方法来评估使用现有的TB LAM的存在 和新型的高亲和力尿液LAM在这三个队列之间进行测定，并评估个体 以及尿液LAM和宿主响应签名的合并价值，以区分有问题 相对于不可能的文化阴性结核。 这项研究的预期结果是培养阴性诊断策略的基础 结核病以促进早期适当的治疗，从而停止大量人群的发展 培养阳性疾病，对防止结核病发病率和传播有深远影响。