论文标题
对与异尼氏酶抗性点相关的突变的系统综述，降低了对共同突变的诊断敏感性，并增加了结核分枝杆菌临床菌株中不常见突变的发生率
A Systematic Review of Mutations Associated with Isoniazid Resistance Points to Lower Diagnostic Sensitivity for Common Mutations and Increased Incidence of Uncommon Mutations in Clinical Strains of Mycobacterium tuberculosis
论文作者
论文摘要
分子测试迅速成为全球结核病（TB）控制工作不可或缺的一部分。不常见的电阻机制可以通过这些平台逃脱检测，并导致多药抗药性（MDR）菌株的发展。本文是对已发表文章的系统评价，该文章报告了2013年9月至2019年12月之间的以异尼氏菌（INH）抵抗的突变。目的是针对与INH抗性相关的分类突变，估计其全球流行率和同时出现以及它们在分子诊断方面的效用。在本综述中考虑了与INH耐药性，KATG，INHA，FABG1和基因间区域相关的基因。总共包括52篇文章，描述了来自31个国家 /地区的5,632个INHR临床分离株。最常突变的基因座继续是KATG315（4,100），INHA-15（786）和INHA-8（105）。但是，INHA-8的诊断值远低于以前认为的诊断值，仅在前两个基因座缺乏突变的25（0.4％）INHR分离株中出现。重要的是，在先前的系统审查诊断的四个KATG基因座中，在我们的INHR分离株中仅观察到KATG315。这表明INH抗性的持续进化和区域差异。我们已经在三个基因组区域中确定了58个基因座（两个系统评价）是分子诊断的可靠基础。我们还报告了49个与INH抗性相关的新基因座。包括所有观察到的突变的累积灵敏度为85.1％。最令人不安的是剩余的14.9％的分离株具有未知的抗性机制，将逃脱分子检测，并可能转化为MDR-TB，使治疗更加复杂。将本和其他类似研究中分类的信息整合到当前的诊断工具中对于打击MDR-TB的出现至关重要。
Molecular testing is rapidly becoming integral to the global tuberculosis (TB) control effort. Uncommon mechanisms of resistance can escape detection by these platforms and lead to the development of Multi-Drug Resistant (MDR) strains. This article is a systematic review of published articles that reported isoniazid (INH) resistance-conferring mutations between September-2013 and December-2019. The aims were to catalogue mutations associated with INH resistance, estimate their global prevalence and co-occurrence, and their utility in molecular diagnostics. The genes commonly associated with INH resistance, katG, inhA, fabG1, and the intergenic region oxyR-ahpC were considered in this review. In total, 52 articles were included describing 5,632 INHR clinical isolates from 31 countries. The three most frequently mutated loci continue to be katG315 (4,100), inhA-15 (786), and inhA-8 (105). However, the diagnostic value of inhA-8 is far lower than previously thought, only appearing in 25 (0.4%) INHR isolates that lacked a mutation at the first two loci. Importantly, of the four katG loci recommended by the previous systematic review for diagnostics, only katG315 was observed in our INHR isolates. This indicates continued evolution and regional differences in INH resistance. We have identified 58 loci (common to both systematic reviews) in three genomic regions as a reliable basis for molecular diagnostics. We also report 49 new loci associated with INH resistance. Including all observed mutations provides a cumulative sensitivity of 85.1%. The most disconcerting is the remaining 14.9% of isolates that harbor an unknown mechanism of resistance, will escape molecular detection, and likely convert to MDR-TB, further complicating treatment. Integrating the information cataloged in this and other similar studies into current diagnostic tools is essential for combating the emergence of MDR-TB.
