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

结核分枝杆菌在多个阶段的诊断可能具有挑战性，包括缺乏获得检测服务的机会、难以从患者身上获取样本以及实验室分析能力有限。目前用于诊断的最常见样本是痰，但许多患者，特别是儿童和老年人，无法提供样本进行分析。最近的研究强调，结核病患者往往没有传统上公认的症状，因此可能被目前的诊断方法遗漏。因此，迫切需要基于替代样本类型、以患者为中心并可在会诊时收集的诊断测试。虽然目前的检测主要集中在下呼吸道的样本上，但从历史上看，已经使用了许多不同的样本类型。在20世纪初的欧洲，人们经常在接受扁桃体切除术的患者的扁桃体中寻找结核分枝杆菌，以此作为感染的标志并监测结核的流行情况。发病率从0.44% （Magee， 1937年）到9% （mitchell， 1916年）不等，然而，随着结核病发病率的下降，这种做法已不再使用。目前还没有数据表明这种方法是否可以通过使用现代诊断方法（例如GeneXpert Ultra，液体培养）来优化，这可能会补充监测感染流行的监测工作。在20世纪的欧洲和印度也对喉拭子进行了研究，这被发现是洗胃的潜在替代品。最近，世界卫生组织（世卫组织）制定了一份旨在改善结核病诊断的检测类型的目标产品概况（TPP）。理想的样本是非痰和非侵入性样本，如尿液或粪便，或微创方法（如手指刺破或唾液）。在南非、摩尔多瓦和尼日利亚的研究中，在痰标本呈阴性的很大一部分儿童和患有结核分枝杆菌病的成年人中，通过擦拭获得的口腔黏膜标本中发现了结核分枝杆菌。检测口腔内的杆菌比获取痰液要容易得多，因此需要通过优化采样技术和样品处理来改进测试的性能。此外，最近在检测结核分枝杆菌组分（如LAM）方面取得的进展导致了基于新鲜尿液（Fujilam）的快速和护理点检测，其灵敏度和特异性（在尼日利亚为70-80%）高于以前的LAM原型（在艾滋病毒感染者中<40%）。最近的研究报告称，一种急性期蛋白（c反应蛋白（CRP））在识别结核病患者方面具有90%至95%的敏感性，但特异性要低得多，约为50-60%，并因HIV合并感染而发生改变。虽然CRP不符合世卫组织TPP的要求，但几个研究小组正在探索将其与其他检测结合使用，用于诊断算法，效率显著提高。使用基于非痰标本的检测组合具有改进当前诊断算法的重大潜力。

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.