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

摘要 据估计，至少15-30%的有症状的结核病（TB）是培养阴性的，其中 大约一半进展为培养阳性结核病。改进痰培养诊断- 因此，阴性结核病是早期干预预防发病的主要机会， 传染性疾病的发展。然而，目前还没有有效的诊断方法。 确认或筛查培养阴性结核病的策略。只是最近，在无痰 基于近患者诊断--包括结核病宿主反应特征的基于诊断的测试 和侧流检测尿液中的结核抗原-已经提供了越来越多的 敏感的结核感染读数独立于痰培养。总之，这些方法具有 作为能够检测结核病患者的补充诊断生物标志物的潜力尚未开发 否则会被缓慢、难以获得的基于痰培养的方法遗漏。长期目标 为培养阴性结核病开发快速可行的诊断方法，我们将评估 最新的，最有前途的尿液LAM平台和结核病宿主反应特征， 一组有症状但培养阴性的个体， 微生物特征超过12个月。我们的核心假设是宿主反应 特征和尿液LAM检测-单独或组合-对于以下各项具有超过70%的AUC ROC： 区分“可能”与“不太可能”培养阴性TB的个体-参考 结核病的纵向临床和扩展微生物学信号。我们将测试我们的假设 通过以下互补目标： 目标1将比较一组先前验证的结核病宿主反应基因表达特征 在培养证实的TB、TB阴性对照和充分表征的培养队列之间， 阴性个体，假设有症状的，文化阴性的读数 个体将落在培养确认的TB和TB阴性对照之间。然后我们将 评价这些特征区分可能与不可能培养阴性的能力 TB.在目标2中，我们将遵循相同的方法，使用现有的 和新的高亲和力尿LAM测定这三个队列之间，并评估个人 以及尿LAM和宿主应答特征的组合值，用于区分可能的 与不太可能培养阴性的结核病相比。 本研究的预期结果是培养阴性的诊断策略的基础。 结核病，以促进早期适当的治疗，从而阻止发展的一个重要的人口 对预防结核病发病和传播具有深远影响。

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.