Whole-genome sequencing to establish relapse or re-infection with Mycobacterium tuberculosis: a retrospective observational study.
Whole-genome sequencing to establish relapse or re-infection with Mycobacterium tuberculosis: a retrospective observational study.
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DOI：
10.1016/s2213-2600(13)70231-5
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发表时间：
2013-12
影响因子：
76.2
通讯作者：
Bentley, Stephen D.
中科院分区：
文献类型：
--
作者：
Bryant, Josephine M.;Harris, Simon R.;Parkhill, Julian;Dawson, Rodney;Diacon, Andreas H.;van Helden, Paul;Pym, Alex;Mahayiddin, Aziah A.;Chuchottaworn, Charoen;Sanne, Ian M.;Louw, Cheryl;Boeree, Martin J.;Hoelscher, Michael;McHugh, Timothy D.;Bateson, Anna L. C.;Hunt, Robert D.;Mwaigwisya, Solomon;Wright, Laura;Gillespie, Stephen H.;Bentley, Stephen D.
结核病治疗后复发给治疗带来困难，是决定治疗效果的关键因素。两种过程可引起复发：原发感染的复发或外源菌株的再感染。虽然再感染可以而且确实发生，但其对结核病流行病学及其生物学基础的重要性仍存在争议。我们使用了全基因组测序——这比目前使用的传统分型更准确——来评估复发的频率，并深入了解再感染的生物学基础。我们评估了来自REMoxTB试验的患者，这是一项结核病治疗的随机对照试验，招募了来自马来西亚、南非和泰国的未经治疗的结核分枝杆菌感染患者。我们进行了全基因组测序和分枝杆菌穿插重复单位可变数串联重复（MIRU-VNTR）分型对痰取样分离物进行分型：一个来自治疗前，另一个来自治疗失败后17周或更晚或复发感染。我们比较了基线和复发时收集的分离株的snp数量和位置。我们评估了47对分离株。全基因组测序鉴定出33例菌株之间遗传距离很小（0-6个SNPs）的病例为复发，3例遗传距离在1306 - 1419个SNPs之间的病例为再感染。通过全基因组测序和MIRU-VNTR对6例复发和6例混合感染进行分类。我们检测到5个单一阳性分离株（阳性培养后至少两个阴性培养），没有疾病的临床证据。与目前使用的基因分型方法（如MIRU-VNTR）相比，全基因组测序能够以更高的分辨率区分复发和再感染病例，并提供了对复发生物学的见解。全基因组测序提供的额外清晰度可能在确定临床试验终点方面发挥作用。威康信托基金、欧盟、医学研究理事会、全球结核病药物开发联盟、欧洲和发展中国家临床试验伙伴关系。
Recurrence of tuberculosis after treatment makes management difficult and is a key factor for determining treatment efficacy. Two processes can cause recurrence: relapse of the primary infection or re-infection with an exogenous strain. Although re-infection can and does occur, its importance to tuberculosis epidemiology and its biological basis is still debated. We used whole-genome sequencing—which is more accurate than conventional typing used to date—to assess the frequency of recurrence and to gain insight into the biological basis of re-infection. We assessed patients from the REMoxTB trial—a randomised controlled trial of tuberculosis treatment that enrolled previously untreated participants with Mycobacterium tuberculosis infection from Malaysia, South Africa, and Thailand. We did whole-genome sequencing and mycobacterial interspersed repetitive unit-variable number of tandem repeat (MIRU-VNTR) typing of pairs of isolates taken by sputum sampling: one from before treatment and another from either the end of failed treatment at 17 weeks or later or from a recurrent infection. We compared the number and location of SNPs between isolates collected at baseline and recurrence. We assessed 47 pairs of isolates. Whole-genome sequencing identified 33 cases with little genetic distance (0–6 SNPs) between strains, deemed relapses, and three cases for which the genetic distance ranged from 1306 to 1419 SNPs, deemed re-infections. Six cases of relapse and six cases of mixed infection were classified differently by whole-genome sequencing and MIRU-VNTR. We detected five single positive isolates (positive culture followed by at least two negative cultures) without clinical evidence of disease. Whole-genome sequencing enables the differentiation of relapse and re-infection cases with greater resolution than do genotyping methods used at present, such as MIRU-VNTR, and provides insights into the biology of recurrence. The additional clarity provided by whole-genome sequencing might have a role in defining endpoints for clinical trials. Wellcome Trust, European Union, Medical Research Council, Global Alliance for TB Drug Development, European and Developing Country Clinical Trials Partnership.