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 大约一半的人进展为培养阳性结核病。改进了对痰培养的诊断- 因此，阴性结核病是早期干预的主要机会，以预防发病率和 传染性疾病的发展。然而，目前还没有经过验证的诊断 确认或筛查培养阴性结核病的策略。就在最近，非痰方面的进展 基于近患者的诊断-包括基于试剂盒的结核病主机响应签名测试 以及从尿液中检测结核抗原的侧向流动分析--已经逐渐提供了更多 不依赖于痰培养的结核病感染的敏感读数。总而言之，这些方法有 未开发的作为补充诊断生物标志物的潜力，具有检测结核病患者的能力 否则就会被缓慢、难以接触到的痰培养方法所遗漏。带着长远的目标 为发展快速和可行的培养阴性结核病诊断方法，我们将评估 最新、最有希望的尿液LAM平台和结核病宿主响应签名 一群有症状但培养阴性的人，他们已经在临床上和 微生物学特征超过12个月。我们的中心假设是宿主反应 签名和尿液LAM检测-单独或合并-将具有超过70%的AUC ROC 区分“可能的”和“不可能的”培养阴性结核病的个体。 他们对结核病的纵向临床和扩展微生物学信号。我们将检验我们的假设 通过以下相辅相成的目标： AIM 1将比较一组先前验证的结核宿主反应基因表达签名 在培养确认的结核病、结核病阴性对照和特征良好的培养队列之间- 阴性个体，假设有症状的、培养阴性的读数 个人将介于培养确认的结核病和结核病阴性对照之间。到时候我们会的 评估这些签名区分可能的和不可能的文化负面的能力 结核病。在目标2中，我们将采用相同的方法来评估是否存在结核LAM 和新的高亲和力尿液LAM分析之间的这三个队列，并评估个人 并结合尿液LAM和宿主反应特征值来区分可能的 与不太可能的培养阴性结核病的对比。 这项研究的预期结果是对培养阴性的诊断策略的基础 结核病促进早期适当治疗，从而阻止大量人口的发展 在预防结核病发病率和传播方面具有深远影响的培养阳性疾病。

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.