湖南省吡嗪酰胺耐药结核病的流行和传播特征分析

Prevalence and transmission of pyrazinamide-resistant Mycobacterium tuberculosis in Hunan Province,China

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,3862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%(566/3862),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。

Objective To 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.Methods The 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 3862 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.Results The rate of PZA-R TB among tuberculosis patients and MDR patients was 14.7%(566/3862)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.Conclusions The 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.