摘要

Improved tuberculosis (TB) prevention and control depend critically on the development of a simple, readily accessible rapid triage test to stratify TB risk. We hypothesized that a blood protein-based host response signature for active TB (ATB) could distinguish it from other TB-like disease (OTD) in adult patients with persistent cough, thereby providing a foundation for a point-of-care (POC) triage test for ATB. Three adult cohorts consisting of ATB suspects were recruited. A bead-based immunoassay and machine learning algorithms identified a panel of four host blood proteins, interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF), that distinguished ATB from OTD. An ultrasensitive POC-amenable single-molecule array (Simoa) panel was configured, and the ATB diagnostic algorithm underwent blind validation in an independent, multinational cohort in which ATB was distinguished from OTD with receiver operator characteristic-area under the curve (ROC-AUC) of 0.80 [95% confidence interval (CI), 0.75 to 0.85], 80% sensitivity (95% CI, 73 to 85%), and 65% specificity (95% CI, 57 to 71%). When host antibodies against TB antigen Ag85B were added to the panel, performance improved to 86% sensitivity and 69% specificity. A blood-based host response panel consisting of four proteins and antibodies to one TB antigen can help to differentiate ATB from other causes of persistent cough in patients with and without HIV infection from Africa, Asia, and South America. Performance characteristics approach World Health Organization (WHO) target product profile accuracy requirements and may provide the foundation for an urgently needed blood-based POC TB triage test.

译文

结核病 (TB) 预防和控制的改善关键取决于开发一种简单、容易获得的快速分类测试来分层结核病风险。我们假设基于血液蛋白的活性结核病 (ATB) 宿主反应特征可以将其与其他患有持续性咳嗽的成人患者的结核病样疾病 (OTD) 区分开来。从而为 ATB 的护理点 (POC) 分类测试提供了基础。招募了三个由 ATB 嫌疑人组成的成年同伙。基于珠的免疫分析和机器学习算法确定了一组四种宿主血液蛋白，interleukin-6 (IL-6) 、 IL-8 、 IL-18 和血管内皮生长因子 (VEGF), 将 ATB 与 OTD 区分开来。配置了一个超灵敏的可接受的 POC 单分子阵列 (Simoa) 面板，并且在一个独立的, 在跨国队列中，ATB 与 OTD 区分开来，受试者操作员特征曲线下面积 (ROC-AUC) 为 0.80 [95% 置信区间 (CI)，0.75 至 0.85]，灵敏度为 80%(95% CI，73 至 85%)，和 65% 的特异性 (95% CI，57 至 71%)。当将针对 TB 抗原 Ag85B 的宿主抗体添加到面板中时，性能提高到 86% 的灵敏度和 69% 的特异性。一个由四种蛋白质和一种结核抗原抗体组成的基于血液的宿主反应小组可以帮助区分 ATB 和其他原因的持续性咳嗽患者，包括非洲、亚洲、和南美洲。性能特征方法世卫组织目标产品轮廓准确性要求，并可能为迫切需要的基于血液的 POC TB 分类测试提供基础。