New tricks for an old dog: opportunities for better tuberculosis control.
New tricks for an old dog: opportunities for better tuberculosis control.
复制标题
DOI：
10.1002/jia2.26081
复制
发表时间：
2023-03
影响因子：
6
通讯作者：
中科院分区：
文献类型：
--
作者：
结核病(TB)仍然是一种神秘的疾病。它一直是全球每年死亡的主要原因之一，在少数高负担国家影响最大，其中许多国家的特点是贫穷、严重的内部不平等、社会不稳定，以及自20世纪末以来艾滋病毒的高流行率。结核病是一种古老的疾病，几千年来一直困扰着人类，它往往无法做出明确的诊断，特别是在儿童和艾滋病毒携带者等风险最高的人群中，由于免疫功能不成熟或缺乏免疫功能，这些疾病的表现可能会很复杂。结核病于1993年宣布为全球紧急状态，多年来一直在努力确保在大众意识中占有一席之地(与新冠肺炎形成对比)，并且始终未能吸引到必要的资金来推动预防和治疗干预措施，以及开发创新的新计划所需的研究[1]。结核病的程序化控制和临床管理需要更深入地了解病原体结核分枝杆菌与其专属人类宿主之间的复杂相互作用。结核病控制仍然在很大程度上依赖于活动性疾病的治疗，标准的6个月多药联合疗法给卫生系统带来了一系列挑战，同时患者依从性差。最近的主要发展包括针对药物敏感和耐药疾病的联合疗法的组成和持续时间方面的创新[2]，以及通过适应性临床试验设计加速新方案开发的可能性[3]。此外，通过结核病药物加速器[4]等开创性伙伴关系的努力，新的结核病药物的临床前流水线比以往任何时候都更强大[5]，利用先进技术解决知识差距，如将抗结核病药物分配到不同的解剖隔间[6]，以及优化设计新的组合以缩短治疗持续时间并限制耐药性的发展[7]。有效的治疗取决于对谁患病的了解，发展改进的护理点结核病诊断仍然是一个优先事项。最近的进展包括扩展GeneXpert分子分析来检测多重耐药[8]，使用直接来自临床样本的全基因组测序[9]，以及基于生物标记物的方法来诊断活动性疾病[10]。基于人工智能的计算机辅助检测系统用于快速数字X射线诊断也显示出良好的前景。新技术--尚未准备好广泛实施--包括使用口罩采样[12]和收集呼吸气雾剂[13]。增加新的、非基于痰的诊断方法对于更好地定义结核病疾病状态至关重要。发展新的疫苗，以取代卡介苗预防感染或防止疾病进展，对于在全球结核病控制方面取得实际进展至关重要，根据最近多项雄心勃勃的高调努力的经验，一份全面的路线图概述了如何加快这一进程[14]。与药物开发一样，这些倡议继续从更复杂的结核分枝杆菌感染和结核病模型中受益匪浅，例如使用非人类灵长类动物的模型[15]。那么在不久的将来呢？收复输给新冠肺炎的失地至关重要，但不会轻易实现。然而，有一些令人鼓舞的迹象表明，从那次大流行中吸取的教训可以有效地应用于结核病。例如，新冠肺炎大流行后不久，亚临床SARS-CoV-2感染的概念就被纳入了主流思维。它似乎是…
Tuberculosis (TB) remains an enigmatic disease. Consistently among the leading causes of annual global mortality, its impact is greatest in a limited number of high-burden countries, many of which are marked by poverty, stark internal inequalities, societal instability and, since the late 20th century, high HIV prevalence. An ancient disease which has plagued humanity for millennia, TB often defies definitive diagnosis, especially in those most at risk, such as children and people living with HIV, where presentation can be complicated owing to immature or deficient immune function. Declared a global emergency in 1993, TB struggles perennially to secure a position in the popular consciousness (in contrast to COVID-19), and consistently fails to attract the funds necessary to drive preventative and therapeutic interventions, as well as the research required to develop innovative new programmes [1]. Programmatic control and clinical management of TB require a deeper understanding of the complex interaction between the causative agent, Mycobacterium tuberculosis, and its obligate human host. TB control remains heavily dependent on the treatment of active disease, with the standard 6-month multidrug combination therapy posing a host of challenges for health systems, in conjunction with poor patient adherence. Key recent developments include innovations in composition and duration of combination therapies for both drugsusceptible and drug-resistant disease [2], and the potential to accelerate new regimen development through adaptive clinical trial design [3]. In addition, through the efforts of pioneering partnerships, such as the Tuberculosis Drug Accelerator [4], the pre-clinical pipeline for new TB drugs is stronger than ever [5], harnessing advanced technologies to address knowledge gaps, such as the distributions of anti-TB drugs into diverse anatomical compartments [6], and the optimal design of new combinations to reduce treatment durations and limit the development of drug resistance [7]. Effective therapy depends on knowledge of who is ill, and the development of improved point-of-care TB diagnostics remains a priority. Recent advances include expanding the GeneXpert molecular assay to detect multi-drug resistance [8], the use of whole-genome sequencing direct from clinical samples [9] and biomarker-based approaches to diagnose active disease [10]. Artificial-intelligence-based computer-aided detection systems for rapid digital X-ray diagnosis are also showing promise [11]. Novel technologies—not yet ready for widespread implementation—include the use of face-mask sampling [12] and the collection of breath aerosols [13]. The addition of newer, non-sputum-based diagnostics is critical to better define the TB disease state. Advancing new vaccines, to replace Bacille Calmette-Guérin for the prevention of infection or to prevent progression to disease, is essential to make realistic progress towards global TB control, and a comprehensive roadmap outlines how this might be accelerated, based on recent experience of multiple ambitious, high-profile endeavours [14]. Like drug development, these initiatives continue to benefit greatly from more complex models of M. tuberculosis infection and TB disease, such as those using non-human primates [15]. And what of the immediate future? Regaining ground lost to COVID-19 is critical but will not be easily achieved. There are, however, some encouraging signs suggesting lessons from that pandemic can be usefully applied to TB. For example, it was not long into the COVID-19 pandemic that the concept of subclinical SARS-CoV-2 infection was assimilated into mainstream thinking. It seems …