结核分枝杆菌潜伏感染与活动性结核病的鉴别诊断

中国是结核病及结核分枝杆菌潜伏感染高负担国家。结核分枝杆菌潜伏感染及活动性结核病的治疗管理和预后完全不同，现有潜伏感染诊断技术并不能有效预测和鉴别活动性结核病的进展和发生。因此，需要探索更加准确的生物标志物。本文主要就结核分枝杆菌潜伏感染和活动性结核病鉴别诊断生物标志物研究进展及问题进行总结和归纳，并展望其发展方向。     

结核分枝杆菌潜伏感染相关抗原的研究进展

结核病是全世界范围内危害人类健康的主要传染病之一。结核分枝杆菌潜伏感染者是结核病的主要来源,早期发现、诊断并有效治疗潜伏感染是有效控制结核病蔓延的重要措施之一。目前,结核分枝杆菌潜伏感染抗原主要包括与结核分枝杆菌缺氧、营养缺乏及与结核分枝杆菌复苏、再激活相关的蛋白。有些潜伏感染相关抗原具有良好的T细胞免疫能力,尤其更易在被潜伏感染人群中识别,有望成为新型的结核分枝杆菌潜伏感染诊断标志物及潜伏感染候选疫苗;有些潜伏感染相关抗原对B淋巴细胞具有较强免疫原性,在结核病体液免疫诊断方面有潜在诊断价值。这些潜伏感染相关蛋白在未来结核分枝杆菌潜伏疫苗及诊断试剂开发中具有良好的应用前景。     

基于组学检测的结核病发病风险研究进展

结核病严重威胁着人类健康,防控形势严峻,研究其发病风险的检测有助于结核病的防治。我国结核感染人数众多,绝大多数患者为潜伏结核感染(Latent Tuberculosis Infection,LTBI),是内源性发病的库源,5%~10%的潜伏感染者会在一生中发生结核病。对LTBI患者进行风险性预测和干预治疗,防止其发展为活动性结核病在结核病防治中具有重要作用。目前尚无诊断LTBI的金标准,也没有权威发布用于预测感染后发病风险的生物学预警指标。本文从转录组学、蛋白组学和免疫组学3方面对LTBI进展到活性结核病的研究进展进行综述,并对结核病发病风险的检测研究方向进行了展望。     

不同国家γ干扰素释放试验临床应用指南的概述

γ干扰素释放试验(interferon gamma release assays,IGRAs)是一种新型的快速诊断结核分枝杆菌感染的免疫学方法.目前已经有16个国家制定了IGRAs诊断结核分枝杆菌感染的应用指南.各国IGRAs应用指南主要针对以下情况进行制定的:成人活动性结核病、成人潜伏结核感染、医疗工作者潜伏结核感染...     

儿童结核病的实验室诊断现状与进展

儿童结核病是全球结核病防控工作的重要组成部分,诊断儿童结核病主要依靠实验室检查结果,但由于儿童结核病本身和标本的特殊性,实验室准确、快速地诊断儿童结核病仍面临挑战。病原学诊断作为儿童结核病诊断的金标准,其敏感度不佳;以超敏结核分枝杆菌和利福平耐药基因检测(Xpert MTB/RIF Ultra)为代表的新型分子生物学检测技术因其较高的敏感度和较短的检测时间有其应用前景;结核菌素皮肤试验(TST)被WHO推荐用于中低收入国家;直接抗原检测技术在少菌、肺外结核标本中敏感度高,在儿童结核病的检测中具有独特价值;其他免疫学新方法对于区分潜伏和活动性结核感染方面具有重要意义;此外,目前已有检测结核分枝杆菌感染后基因表达、蛋白质产生和生物标志物变化的新方法投入研究。留取多份标本或不同标本类型、不同检测方法联合检测有助于提高儿童结核病的检出率。提高结核病在现有方法和非侵入性、易获取标本中的检出率,以及评估新的生物标志物和新技术的适用性是未来儿童结核病实验室诊断研究的方向。     

关口前移:结核潜伏感染及其控制

全球有近1/4的人群感染结核分枝杆菌,其中5%~10%可能在一生中发生活动性结核病,潜伏感染人群成为一个庞大的潜在患者库。世界卫生组织相继于2015年和2018年发布和更新《结核潜伏感染管理指南》,指导包括中国在内的中高收入、结核病发病率低于100/10万的国家和地区推广高危人群结核潜伏感染检测和预防性治疗。我国结核潜伏感染控制策略的开发应该紧密结合国情和结核病疫情特点,可以借鉴但不能照搬国外方案。准确界定干预目标人群、探索适宜的干预手段、建立科学的管理和评价体系等,都需要系统性的基础研究和临床研究提供技术支撑。以结核潜伏感染干预为手段探索结核病防控的关口前移将是落实“预防为主”综合防治策略的重要举措。     

尿液代谢组学在结核病研究中的应用及其进展

结核病是一种严重危害人类健康的慢性传染性疾病。目前, 在结核病诊断、抗结核药物代谢、监测抗结核药物不良反应以及治疗效果的考核与判断等方面还存在着不足之处。代谢组学可提供细胞和代谢过程中的下游产物及特定组织或器官健康/疾病状况等关键信息, 在药物研发、疾病诊断、药物代谢、药物不良反应以及治疗效果的监测等方面具有重要价值。近年研究表明, 应用尿液代谢组学对结核代谢生物标志物进行研究, 不仅能区分结核病与潜伏结核感染还能用于鉴别肺结核病与其他肺部疾病, 为结核病的诊断提供重要依据。应用尿液代谢组学研究抗结核药物的代谢以及不良反应发生机制, 为研发新药、监测药物不良反应等提供重要手段。此外, 尿液代谢组学分析对于判断结核病的程度及其治疗转归等也具有重要意义。本文就尿液代谢组学在结核病诊断、抗结核药物代谢、监测抗结核药物不良反应及治疗效果的考核与判断等方面进行综述。     

结核杆菌特异性酶联免疫斑点技术在HIV感染人群中的应用

我国艾滋病病毒(HIV)感染人群中结核病的发病率高,造成了严重的疾病负担。提高潜伏结核和活动性结核的诊断准确性,对控制HIV病人中结核病的治疗和控制至关重要。该文总结了近年来出现、发展并完善的一种新的结核诊断技术,即结核杆菌特异性酶联免疫斑点技术,及其在HIV人群中的相关研究结果,并着重对该技术在潜伏结核和活动性结核的诊断、治疗效果监测以及结核相关性免疫重建炎症反应综合征中的应用进行了评价。     

终止结核病流行须加强结核分枝杆菌潜伏感染高危人群筛查和预防性治疗的管理

当前,全球结核病发病率下降缓慢,给实现终止结核病目标带来了严峻的挑战。2020年估算全球结核分枝杆菌潜伏感染人群近20亿,在无预防性治疗干预情况下,其中有5%~10%的感染者在一生中会发展为活动性结核病,在结核病高危人群中发病率更高。世界卫生组织在全球范围内号召推广结核分枝杆菌潜伏感染(LTBI)的预防干预,以实现结核病发病率快速下降的目标。笔者就LTBI流行和预防性治疗的现状、高危人群发病风险、筛查方法、干预和管理建议等进行论述,为制定我国LTBI干预和管理策略及措施提供参考。     

IL-8 mRNA定量检测在活动性结核病鉴别诊断中的价值

目的研究活动性肺结核患者外周血单个核细胞(PBMCs)经结核特异性抗原刺激后白介素-8(interleukin-8,IL-8)的mRNA表达情况并与结核潜伏感染(latent tuberculosis infection,LTBI)及非结核感染健康对照组进行比较。方法提取研究对象的PBMCs,经特异性抗原肽刺激后,收集细胞并提取总RNA然后经实时荧光定量PCR检测技术比较各组IL-8 mRNA表达情况。然后以敏感性(sensitivity)为纵坐标,1-特异性(1-specificity)为横坐标绘制结核组和LTBI组相比较的ROC曲线。结果经结核特异性抗原刺激后,结核组PBMCs中IL-8基因mRNA的相对表达量明显高于LTBI和健康对照组,差异有统计学意义(P0.05)。ROC曲线下面积为0.72。以3.985为临界值,鉴别活动性结核病和LTBI的敏感性和特异性分别为54.17%和90.00%,此时阳性似然比等于5.42,64.7%的病例诊断准确。结论 IL-8有可能作为新的活动性结核病诊断标志物,有助于活动性结核病与LTBI的鉴别诊断。     

Human lung immunity against Mycobacterium tuberculosis: insights into pathogenesis and protection

The study of human pulmonary immunity against Mycobacterium tuberculosis (M.tb) provides a unique window into the biological interactions between the human host and M.tb within the broncho-alveolar microenvironment, the site of natural infection. Studies of bronchoalveolar cells (BACs) and lung tissue evaluate innate, adaptive, and regulatory immune mechanisms that collectively contribute to immunological protection or its failure. In aerogenically M.tb-exposed healthy persons lung immune responses reflect early host pathogen interactions that may contribute to sterilization, the development of latent M.tb infection, or progression to active disease. Studies in these persons may allow the identification of biomarkers of protective immunity before the initiation of inflammatory and disease-associated immunopathological changes. In healthy close contacts of patients with tuberculosis (TB) and during active pulmonary TB, immune responses are compartmentalized to the lungs and characterized by an exuberant helper T-cell type 1 response, which as suggested by recent evidence is counteracted by local suppressive immune mechanisms. Here we discuss how exploring human lung immunity may provide insights into disease progression and mechanisms of failure of immunological protection at the site of the initial host-pathogen interaction. These findings may also aid in the identification of new biomarkers of protective immunity that are urgently needed for the development of new and the improvement of current TB vaccines, adjuvant immunotherapies, and diagnostic technologies. To facilitate further work in this area, methodological and procedural approaches for bronchoalveolar lavage studies and their limitations are also discussed.     

Latent tuberculosis infection: recommendations for preventive therapy in adults in Germany

The immunologic mechanisms of latent tuberculosis (TB) infection are complex and hitherto not completely understood. The lifelong risk of an immunocompetent individual of developing active TB after infection with M. tuberculosis is 5-10 % and highest during the first two years after infection. Various factors may considerably increase the risk of developing active TB, e. g., immunosuppressive disease or immunosuppressive medication. However, the development of active TB may be avoided by preventive chemotherapy, the therapy of choice being isoniazid over a 9-month period. Alternative treatment regimens may be indicated in special cases, but it must be borne in mind that the efficacy of these regimens has not been studied sufficiently while they seem to be less well tolerated than isoniazid monotherapy. The tuberculin skin test is still the only sufficiently documented method to detect latent infection with M. tuberculosis which is also suitable for routine application. This test today should be performed exclusively as described by Mendel and Mantoux. Its sensitivity and specificity depend on the prevalence of tuberculosis infection. It should therefore be restricted to individuals at increased risk of latent TB infection. When interpreting the tuberculin skin test, it is necessary to know whether an individual belongs to one of the defined risk groups or has an elevated risk of developing active TB. Among the risk groups are individuals who may have been infected recently with M. tuberculosis (contacts of contagious TB patients) or in whom other factors increase their risk of developing active TB. The indication for chemotherapy for latent TB infection must be based on a careful individual risk-benefit analysis and, besides patient compliance, requires full information of the patient and careful monitoring during therapy. Before initiating treatment, active TB must always be excluded by the proven methods.     

Performance of QuantiFERON-TB Gold In-Tube (QFTGIT) for the diagnosis of <Emphasis Type="Italic">Mycobacterium tuberculosis (Mtb)</Emphasis> infection in Afar Pastoralists,Ethiopia

Background  

Currently, T-cell based gamma interferon (IFNγ) release assays (IGRAs) are acknowledged as the best methods available for the screening of latent tuberculosis infection (LTBI) and also as aid for the diagnosis of active tuberculosis (TB). To our information, the performance of these diagnostic tests has not been evaluated in Ethiopia. Therefore, the intent of this study was to evaluate the performance of QuantiFERON-TB Gold In-Tube (QFTGIT) in patients clinically suspected of active pulmonary TB (PTB) as well as in healthy subjects prior to its utilization for the epidemiological study of active TB and LTBI in Afar pastoralists.     

基于流式细胞术诊断结核感染的研究进展

结核病是危害人类健康的一种传染病,快速诊断与合理治疗是控制结核病的关键,然而对于潜伏性结核感染仍缺少诊断的金标准。目前,结核菌素皮试以及IFN-γ释放试验被视为诊断是否感染结核的有效方法,它们通过间接检测受试者对结核分枝杆菌的细胞免疫反应做出评判,但这两种方法均存在缺陷,也无法明确区分潜伏性感染和活动性结核。流式细胞术作为一项高新技术已经在医学临床领域得到广泛应用。近年来,流式细胞术检测胞内细胞因子技术在结核感染的诊断及疗效评价等方面取得了一定进展。本文对应用流式细胞术进行结核感染诊断的进展进行综述。     

Diagnóstico y abordaje terapéutico de la infección tuberculosa latente

Detection and treatment of latent tuberculosis infection (LTBI) is an essential measure for tuberculosis (TB) control in low-incidence countries. However, such strategy is limited by the low predictive ability of the diagnostic tests for the development of active TB among infected people and the long-term and toxic treatment regimens. The in vitro interferon-gamma release assays are more specific and sensitive than the tuberculin skin test (TST), and enable a better selection of cases requiring treatment. Nonetheless, their capacity to predict development of TB is still poor. In addition, treatment regimens for LTBI are long, and compliance rates are low. This review discusses the use of the available diagnostic tests and the new approaches to the diagnosis of LTBI, as well as its management in different clinical scenarios.     

Tuberculosis: Current state of knowledge

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has developed various mechanisms to survive and cause disease in the human host. Incomplete understanding of the complex microbe–host interactions has hindered the identification of suitable biomarkers to expedite the development of diagnostic tools, drugs and vaccines. The field effectiveness of directly observed therapy–short course has been compromised by the intrinsic limitations of sputum microscopy and suboptimal adherence to the long duration of treatment amid the HIV‐TB syndemic and various socioeconomic constraints. While molecular tools are transforming the diagnostic processes, especially for multi‐drug‐resistant (MDR)‐TB, drug development and service provision for MDR‐TB seriously lag behind. Inappropriate management of detected MDR‐TB cases may amplify drug resistance, jeopardizing future control. Targeted screening and treatment of latent infection with M. tuberculosis with the currently available immunodiagnostic tools and treatment regimens aim more for personal protection than major epidemiological impact or elimination. The interferon‐γ release assays (IGRA) are not affected by cross‐reaction to the bacillus Calmette–Guérin (BCG) vaccine and are increasingly used for such screening before initiation of biologics for treatment of rheumatoid arthritis and other autoimmune disorders. BCG offers only partial and unreliable protection against pulmonary TB in adults, the crucial transmission link for this airborne infection. Systems biology and vaccinomics may speed up vaccine research. The successful development of a fully effective TB vaccine that targets both growing bacteria and non‐growing persisters may reflect a major breakthrough, as natural infection does not induce sufficient immunity to prevent reinfection.     

Tuberculosis in patients with human immunodeficiency virus infection

Tuberculosis (TB) is the major opportunistic infection of human immunodeficiency virus (HIV)-infected persons worldwide. Human immunodeficiency virus infection is the most potent known risk factor for reactivation of latent Mycobacterium tuberculosis infection, and TB disease appears to increase the rate of HIV progression. Pulmonary disease is seen in most patients, including a large proportion of those with extrapulmonary disease. Failure to suspect TB and to order the appropriate diagnostic tests is the most common reason for diagnostic delays. With advancing HIV infection, tuberculin skin test reactivity decreases along with reactivity to nonspecific antigens such as mumps, tetanus toxoid, and Candida; anergy testing need not be a routine component of tuberculosis screening of HIV-infected persons. The diagnosis depends on identifying the organism on smears or cultures; direct amplification tests may facilitate rapid identification of M. tuberculosis, but the relatively low sensitivity in smear-negative specimens limits their use. Also, these tests must be used in conjunction with the clinical assessment, and they must always be performed in conjunction with microscopy and standard culture. Shorter courses of combination preventive therapy of patients with latent tuberculous infection are effective, but the potential advantages of improved adherence and reduced costs of shorter courses should be balanced with an increased risk secondary to ongoing TB exposure in areas with a high TB prevalence. Six months of treatment for active tuberculosis is recommended, unless the response of a particular patient is slow or otherwise suboptimal. The use of highly active antiretroviral therapy (HAART) made a remarkable impact on the course or HIV disease, but raises several issues with respect to HIV-related TB. Drug interactions necessitate either a non-rifamycin-based regimen or a rifabutin-based regimen in patients on HAART treated for TB.     

Recent advances in the diagnosis and management of tuberculosis

PURPOSE OF REVIEW: Tuberculosis (TB) remains one of the leading infectious killers of adults in the world today. This paper will review recent advances and understanding in the epidemiology, diagnosis, and management of TB. RECENT FINDINGS: Tuberculosis remains a significant global threat, particularly in regions of the world heavily affected by HIV. Diagnosis of TB infection and disease rely on outdated and problematic methods, but newer immunologic and nucleic acid-based techniques are emerging. Treatment of latent TB infection still relies mainly on the use of isoniazid but several treatment-shortening strategies are being studied. Treatment of active disease has advanced little since the introduction of short-course chemotherapy with rifampin, but several new drugs are being developed and studied. Timely initiation of HIV treatment in co-infected patients is increasingly seen as important and strategies for initiating therapy for both diseases are being refined. The existence of immune reconstitution inflammatory reactions is also becoming more widely appreciated. Other populations at risk for TB such as those receiving TNF-alpha antagonists are being recognized and improved screening and control measures implemented. SUMMARY: The global epidemiology of TB has been shaped in recent decades by HIV, urbanization and poverty. Diagnosis and treatment remain challenging, however, improved screening of at-risk populations and new diagnostic modalities and treatment strategies offer hope to the millions who suffer from tuberculosis.