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湖南省吡嗪酰胺耐药结核病的流行和传播特征分析
刘彬彬
胡培磊
陈振华
易松林
张小萍
谭云洪
作者及单位信息
·
DOI： 10.3760/cma.j.cn112147-20211219-00904
Prevalence and transmission of pyrazinamide-resistant Mycobacterium tuberculosis in Hunan Province,China
Liu Binbin
Hu Peilei
Chen Zhenhua
Yi Songlin
Zhang Xiaoping
Tan Yunhong
Authors Info & Affiliations
Liu Binbin
Department of Clinical Laboratory, Hunan Institute for Tuberculosis Control, Hunan Chest Hospital, Changsha 410013, China
Hu Peilei
Department of Clinical Laboratory, Hunan Institute for Tuberculosis Control, Hunan Chest Hospital, Changsha 410013, China
Chen Zhenhua
Department of Clinical Laboratory, Hunan Institute for Tuberculosis Control, Hunan Chest Hospital, Changsha 410013, China
Yi Songlin
Department of Clinical Laboratory, Hunan Institute for Tuberculosis Control, Hunan Chest Hospital, Changsha 410013, China
Zhang Xiaoping
Department of Clinical Laboratory, Hunan Institute for Tuberculosis Control, Hunan Chest Hospital, Changsha 410013, China
Tan Yunhong
Department of Clinical Laboratory, Hunan Institute for Tuberculosis Control, Hunan Chest Hospital, Changsha 410013, China
·
DOI： 10.3760/cma.j.cn112147-20211219-00904
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摘要

目的分析湖南省吡嗪酰胺耐药结核病的流行情况及危险因素，描述相应结核分枝杆菌分离株的基因型分型和成簇特征。

方法收集湖南省胸科医院（湖南省结核病防治所）2016年1月至2018年12月，3 862例完成包括吡嗪酰胺在内的五种一线抗结核药物（吡嗪酰胺、异烟肼、利福平、链霉素、乙胺丁醇）药敏测试的患者基本信息和药敏结果，计算吡嗪酰胺耐药结核病的流行率，并采用单变量和多变量的logistic回归分析对其进行危险因素分析；选取2017年6月至2018年6月212株吡嗪酰胺耐药结核分枝杆菌分离株，对其进行24位点的MIRU-VNTR分型，用遗传差异值（h值）和Hunter-Gaston指数（HGI）进行位点分辨率的评价，运用BioNumerics 5.0软件对MIRU-VNTR结果进行成簇分析；并进一步对簇内的菌株进行 pncA测序分析。

结果湖南省结核病患者的吡嗪酰胺耐药率为14.7%（566/3 862），耐多药结核病（MDR-TB）患者的吡嗪酰胺耐药率为60.5%（511/844）。多变量logistic回归分析结果显示，相比抗结核药物全敏感（异烟肼、利福平、链霉素、乙胺丁醇均为敏感）的结核病患者，单耐异烟肼、MDR-TB患者产生吡嗪酰胺耐药的风险更高，调整OR值（95% CI）分别为：13.08（5.67~30.18）、298.41（164.88~540.08）， P值均<0.01。成簇性分析结果显示：65株菌株形成19个簇，成簇率为30.7%（65/212），8个簇至少存在两株菌株具有相同的 pncA突变类型，其中4号簇的4例患者、6号簇的3例患者和16号簇的2例患者均居住在同一个县。至少有47.6%［101（47例初治患者+54例复治成簇患者）/212］的吡嗪酰胺耐药结核病患者提示是由传播导致的。

结论湖南省吡嗪酰胺耐药结核病的流行形势较严峻，对任意一线抗结核药物耐药的结核病患者，尤其是MDR-TB患者，需尽快进行吡嗪酰胺药敏测试从而确定治疗方案；近一半结核病患者产生吡嗪酰胺耐药是由于传播导致，吡嗪酰胺耐药结核病的防治策略是重点做好患者的规范化治疗和管理的同时，加强对传染源的发现和控制。

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湖南省吡嗪酰胺耐药结核病的流行形势较严峻，对任意一线抗结核药物耐药的结核病患者，尤其是MDR⁃TB患者，需尽快进行吡嗪酰胺药敏测试从而确定治疗方案；近一半结核病患者产生吡嗪酰胺耐药是由于传播导致。
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结核;吡嗪酰胺;结核，抗多种药物性;串联重复序列;基因分型技术
ABSTRACT

ObjectiveTo provide a scientific reference for the prevention and treatment of pyrazinamide-resistant tuberculosis (PZA-R TB), we analyzed the prevalence and risk factors of pyrazinamide-resistant tuberculosis in Hunan province and described the genotyping and clustering characteristics of the pyrazinamide-resistant Mycobacterium tuberculosis (PZA-R MTB) isolates.

MethodsThe drug susceptibility test results of first-line anti-tuberculosis drugs including isoniazid (INH), rifampicin (RFP), streptomycin (SM), ethambutol (EMB) and pyrazinamide (PZA), and the characteristics of patients were collected from 3 862 tuberculosis patients in Hunan Chest Hospital (Institute of Tuberculosis Control and Prevention) from January 2016 to December 2018. The prevalence of PZA-R TB was calculated and risk factors were analyzed by univariate and multivariable logistic regression analysis. Two hundred and twelve Mycobacterium tuberculosis isolates selected from June 2017 to June 2018 were genotyped using the 24-loci MIRU-VNTR system. The genetic difference value (h), and the Hunter-Gaston index (HGI) were used to evaluate the resolution and variation for the 24 loci. MIRU-VNTR results were analyzed using BioNumerics 5.0 software to conduct cluster analysis. Clustered isolates were further analyzed by pncA gene sequencing.

ResultsThe rate of PZA-R TB among tuberculosis patients and MDR patients was 14.7%(566/3 862) and 60.5%(511/844), respectively. Multivariable logistic regression analysis showed that patients who were INH mono-resistance and MDR had a higher risk of developing PZA resistance, compared with TB patients who were pan-sensitive to anti-TB drugs (INH, RFP, SM, and EMB). The adjusted OR value (95% CI) was 13.08(5.67-30.18), 298.41(164.88-540.08), respectively, and P values were all less than 0.01. Clustering analysis showed that 65 strains formed 19 clusters, the clustering rate was 30.7%(65/212). Of 19 clusters, eight clusters had at least two isolates with identical pncA mutation types within each cluster. In eight clusters, cluster 4, 6, 16 had four, three, and two patients who lived in the same county, respectively, thus providing probable epidemiological links for the recent transmission of PZA-R Mycobacterium tuberculosis. At least 47.6%(101/212) of PZA drug-resistant TB patients were suggestive of primary drug resistance caused by transmission.

ConclusionsThe prevalence of PZA-R TB was severe in Hunan province. PZA susceptibility testing should be performed for isolates resistant to any first-line anti-tuberculosis drugs, especially for MDR-MTB isolates. Nearly half of tuberculosis patients were suggestive of primary drug resistance caused by transmission. The prevention and treatment strategy of PZA-R TB should focus on the standardized treatment and management of patients as well as control of the source of infection.

Tuberculosis;Pyrazinamide;Tuberculosis, multidrug-resistant;Tandem repeat sequences;Genotyping techniques
Tan Yunhong, Email: mocdef.qabq0633610221
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刘彬彬,胡培磊,陈振华,等. 湖南省吡嗪酰胺耐药结核病的流行和传播特征分析[J]. 中华结核和呼吸杂志,2022,45(07)：677-685.

DOI:10.3760/cma.j.cn112147-20211219-00904

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吡嗪酰胺是非常重要的治疗结核病的一线药物，因其可以杀死残留在巨噬细胞酸性环境里的处于休眠状态的结核分枝杆菌（ Mycobacterium tuberculosis，MTB），尤其在耐多药结核病（multidrug resistant tuberculosis，MDR-TB）的治疗中有非常好的治疗效果；在世界卫生组织（WHO）制定的MDR-TB/利福平耐药结核病（Rifampicin-resistant tuberculosis，RR-TB）的短程和长程治疗方案中均推荐使用 ［ 1 , 2 ］ 。国内研究结果显示：全国结核病患者的吡嗪酰胺的总耐药率为14.4% ［ 3 ］ ，MDR-TB患者的吡嗪酰胺耐药率为38.8% ［ 4 ］ 。国内外有关结核病吡嗪酰胺耐药的数据均较缺乏，国内对MTB复合群吡嗪酰胺耐药研究较多的地区主要集中在北京、上海、浙江和广东等地区 ［ 5 , 6 , 7 ］ 。因此，对湖南省吡嗪酰胺耐药结核病展开初步的分子流行病学研究，了解湖南省结核病患者中吡嗪酰胺的耐药水平、分析相应分离株的基因型特征和对其进行耐药突变位点的测序，可为追踪传染源、确定传播途径和识别重点人群提供数据参考，对制定吡嗪酰胺耐药结核病的防治策略和合理化的用药方案有很大意义。
目前分枝杆菌散在重复单元-可变串联重复序列（MIRU-VNTR）作为MTB分型的标准方法在全球广泛使用，其具备操作简单、分辨力高、重复性好等特点 ［ 8 ］ ；大多数研究认为MTB对吡嗪酰胺耐药主要与结核菌 pncA基因突变有关，早前有文献报道显示吡嗪酰胺表型耐药与 pncA基因突变的相关性约达85% ［ 9 , 10 ］ 。因此本研究采用MIRU-VNTR进行基因型分型，并对成簇的菌株进行 pncA基因测序，为湖南省吡嗪酰胺耐药结核病的流行和传播提供数据支持。
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备注信息
A
谭云洪，Email： mocdef.qabq633610221
B

刘彬彬：基因分型实验操作、数据整理、统计分析、论文撰写；胡培磊：测序分析、实验指导、论文修改；陈振华，张小萍，易松林：快培药敏测试操作；谭云洪：研究指导、论文修改

C

刘彬彬, 胡培磊, 陈振华, 等. 湖南省吡嗪酰胺耐药结核病的流行和传播特征分析[J]. 中华结核和呼吸杂志, 2022, 45(7): 677-685. DOI: 10.3760/cma.j.cn112147-20211219-00904.

D
所有作者声明无利益冲突
E
湖南省自然科学基金 (2019JJ50299)
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