Non-sputum diagnostics and their role in the detection of Mycobacterium Tuberculosis (Mtb).

结核病在多个阶段的诊断具有挑战性，包括缺乏检测服务，难以从患者身上获得样本以及实验室分析能力有限。目前，用于诊断的最常见的样本是痰，然而许多患者，特别是儿童和老年人，无法产生待分析的样本。最近的研究强调，结核病患者通常不会出现传统上公认的症状，因此可能被当前的诊断方法所遗漏。因此，迫切需要基于替代样本类型的诊断测试，以患者为中心，并可以在咨询时收集。虽然目前的检测主要集中在下呼吸道样本，但历史上曾使用过许多不同的样本类型。在世纪早期的欧洲，在接受扁桃体切除术的患者的扁桃体中常规地寻找Mtb，作为感染的标志物并监测TB的流行。发现的发病率在0.44%（Magee，1937）至9%（Mitchel，1916）之间变化，然而，随着结核病发病率的下降，该做法不再使用。没有数据表明这是否是一种可以通过使用现代诊断方法（例如GeneXpert Ultra，液体培养）进行优化的方法，这可能会补充监测感染流行率的监测工作。世纪在欧洲和印度也对喉拭子进行了研究，发现其是洗胃的潜在替代品。最近，世界卫生组织（WHO）开发了一种目标产品概况（TPP），用于改进结核病诊断所需的测试类型。理想的样品是非痰和非侵入性样品，如尿液或粪便，或微创方法（如手指针刺或唾液）。在南非、摩尔多瓦和尼日利亚进行的研究发现，在痰液样本阴性的儿童和患有结核分枝杆菌病的成人中，通过拭子获得的口腔粘膜样本中有很大比例存在结核分枝杆菌。检测口腔中的杆菌将比获得痰液容易得多，因此期望通过优化取样技术和样品处理来努力改善测试的性能。此外，关于检测Mtb组分（例如LAM）的最新发展已经导致基于新鲜尿液（Fujilam）的快速和即时护理测试，其具有比先前LAM原型（在HIV感染者中<40%）更高的灵敏度和特异性（在尼日利亚中为70-80%）。最近的研究报告说，急性期蛋白（C-反应蛋白（CRP））具有90%至95%的灵敏度来识别结核病患者，但特异性要低得多，约为50-60%，并因艾滋病毒合并感染的存在而改变。尽管CRP不符合WHO TPP的要求，但几个研究小组正在探索将其与其他测试结合用于诊断算法，并显着提高效率。使用基于非痰标本的测试组合具有改善当前诊断算法的主要潜力。

Mtb can be challenging to diagnose at multiple stages including lack of access to testing services, difficulty obtaining samples from patients and limited laboratory capabilities for analysis. Currently the most common sample used for diagnosis is sputum however many patients, especially children and the elderly, cannot produce a sample to be analysed. Recent studies have highlighted that often people with Tuberculosis (TB) do not present with traditionally recognised symptoms and can therefore be missed by current diagnostic approaches. For this reason diagnostic tests are urgently needed that are based on alternative sample types, patient centred and can be collected at the time of consultation. Although current testing focuses on samples from the lower respiratory tract, historically, many different sample types have been used. In Europe in the early 20th century Mtb was routinely looked for in the tonsils of patients undergoing tonsillectomy, as a marker of infection and to monitor the prevalence of TB. The incidence found varied between 0.44% (Magee, 1937) to 9% (Mitchel, 1916) however, as the incidence of TB dropped the practice fell out of use. There is no data on whether this is a method that could be optimised by using modern diagnostic methods (e.g. GeneXpert Ultra, liquid culture), which may complement surveillance efforts to monitor the prevalence of infection. Research was also carried out on laryngeal swabs in the 20th century in Europe and India which were found to be a potential alternative to gastric lavage.Recently the World Health Organisation (WHO) has developed a target product profile (TPP) of the type of tests desired to improve the diagnosis of TB. Desirable samples are non-sputum and non-invasive samples, such as urine or stools, or minimally invasive methods (such as finger prick or saliva). Studies in South Africa, Moldova and Nigeria have detected Mtb on oral mucosa specimens obtained by swabbing in a significant proportion of both children with negative sputum specimens and adults with Mtb disease. Detecting the bacilli in the oral cavity would be considerably easier than obtaining sputum and thus efforts to improve the performance of the tests by optimising sampling techniques and sample processing are desirable. Furthermore, recent developments on the detection of Mtb fractions, such as LAM, have resulted in rapid and point of care tests based on fresh urine (Fujilam), which have higher sensitivity and specificity (70-80% in Nigeria) than previous LAM prototypes (<40% in HIV infected). Recent studies have reported that an acute phase protein (C-Reactive Protein (CRP)) has a sensitivity ranging from 90% to 95% to identify people with TB, but that the specificity is much lower, at about 50-60% and modified by the presence of HIV coinfection. Although CRP does not meet the WHO TPP requirements, its use in combination with other tests, in a diagnostic algorithm is being explored by several research groups, with significant efficiency gains. Using combinations of tests based on non-sputum specimens has major potential to improve current diagnostic algorithms.