Molecular detection technologies for diagnosing tuberculous meningitis using cerebrospinal fluid

doi:10.3969/j.issn.2096-8493.2021.01.003

Abstract

Abstract:

Tuberculous meningitis (TBM) is a common tuberculosis disease affecting central nervous system. Early diagnosis and timely treatment are key to improve the prognosis of TBM patients. However, traditional detection methods of MTB are usually with poor sensitivity and time-consuming, we lack effective rapid clinic detection methods, thus it is very difficult to make early diagnosis of TBM. In the review, the current situation, latest progress and existing problems of TBM molecular detecting technologies for testing cerebrospinal fluid samples were displayed and discussed, to offer references for clinical practice.

Key words: Tuberculosis, meningeal, Cerebrospinal fluid, Molecular diagnostic techniques

HAN Li-jun, ZHAO Xue-yao. Molecular detection technologies for diagnosing tuberculous meningitis using cerebrospinal fluid[J]. Journal of Tuberculosis and Lung Disease , 2021, 2(1): 8-12. doi: 10.3969/j.issn.2096-8493.2021.01.003

Figures/Tables 1

References 34

[1]	中华医学会结核病学分会结核性脑膜炎专业委员会. 2019中国中枢神经系统结核病诊疗指南. 中华传染病杂志, 2020,38(7):400-408. doi: 10.3760/cma.j.cn311365-20200606-00645.
[2]	Nurwidya F, Handayani D, Burhan E, et al. Molecular Diagnosis of Tuberculosis. Chonnam Med J, 2018,54(1):1-9. doi: 10.4068/cmj.2018.54.1.1. doi: 10.4068/cmj.2018.54.1.1 URL pmid: 29399559
[3]	中华医学会结核病学分会临床检验专业委员会. 结核病病原学分子诊断专家共识. 中华结核和呼吸杂志, 2018,41(9):688-695. doi: 10.3760/cma.j.issn.1001-0939.201 8.09.008.
[4]	Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med, 2010,363(11):1005-1015. doi: 10.1056/NEJMoa0907847. doi: 10.1056/NEJMoa0907847 URL pmid: 20825313
[5]	Patel VB, Theron G, Lenders L, et al. Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous meningitis in a high burden setting: a prospective study. PLoS Med, 2013,10(10):e1001536. doi: 10.1371/journal.pmed.1001536. doi: 10.1371/journal.pmed.1001536 URL pmid: 24167451
[6]	杨元利, 张永峰, 刘元, 等. Gene Xpert MTB/RIF技术对成年人结核性脑膜炎诊断价值的研究. 中国防痨杂志, 2017,39(9):980-984. doi: 10.3969/j.issn.1000-6621.2017.09.016.
[7]	Bahr NC, Tugume L, Rajasingham R, et al. Improved diagnostic sensitivity for tuberculous meningitis with Xpert(®) MTB/RIF of centrifuged CSF. Int J Tuberc Lung Dis, 2015,19(10):1209-1215. doi: 10.5588/ijtld.15.0253. doi: 10.5588/ijtld.15.0253 URL pmid: 26459535
[8]	Bahr NC, Nuwagira E, Evans EE, et al. Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous meningitis in HIV-infected adults: a prospective cohort study. Lancet Infect Dis, 2018,18(1):68-75. doi: 10.1016/S1473-3099(17)30474-7. doi: 10.1016/S1473-3099(17)30474-7 URL pmid: 28919338
[9]	Metcalf T, Soria J, Montano SM, et al. Evaluation of the GeneXpert MTB/RIF in patients with presumptive tuberculous meningitis. PLoS One, 2018,13(6):e0198695. doi: 10.1371/journal.pone.0198695. doi: 10.1371/journal.pone.0198695 URL pmid: 29912907
[10]	Siddiqi OK, Birbeck GL, Ghebremichael M, et al. Prospective Cohort Study on Performance of Cerebrospinal Fluid (CSF) Xpert MTB/RIF, CSF Lipoarabinomannan (LAM) Lateral Flow Assay (LFA), and Urine LAM LFA for Diagnosis of Tuberculous Meningitis in Zambia. J Clin Microbiol, 2019,57(8):e00652-19. doi: 10.1128/JCM.00652-19. doi: 10.1128/JCM.00652-19 URL pmid: 31189584
[11]	张瑞雪, 龙铟, 冯国栋, 等. Xpert MTB/RIF对结核性脑膜炎诊断的临床评价. 中华检验医学杂志, 2016,39(6):442-447. doi: 10.3760/cma.j.issn.1009-9158.2016.06.011.
[12]	金慧芳, 刘鑫. 脑脊液Gene Xpert MTB/RIF检测和结核杆菌快速培养辅助诊断结核性脑膜炎的价值比较. 临床内科杂志, 2018,35(8):529-530. doi: 10.3969/j.issn.1001-9057.2018.08.007.
[13]	World Health Organization. WHO consolidated guidelines on tuberculosis. Module 3: Diagnosis—Rapid diagnostics for tuberculosis detection. Geneva: World Health Organization, 2020.
[14]	王赛赛, 马艳, 刘洋. 脑脊液检测在结核性脑膜炎早期诊断中的研究进展. 中国防痨杂志, 2019,41(1):95-101. doi: 10.3969/j.issn.1000-6621.2019.01.019.
[15]	Kohli M, Schiller I, Dendukuri N, et al. Xpert MTB/RIF Ultra and Xpert MTB/RIF assays for extrapulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev, 2021, 1: CD012768. doi: 10.1002/14651858.CD012768.pub3. doi: 10.1002/14651858.CD011302.pub3 URL pmid: 33461239
[16]	孙雯雯, 肖和平. 环介导等温扩增技术早期诊断结核性脑膜炎的研究. 中国防痨杂志, 2016,38(12):1102-1108. doi: 10.3969/j.issn.1000-6621.2016.12.018.
[17]	Nagdev KJ, Kashyap RS, Parida MM, et al. Loop-mediated isothermal amplification for rapid and reliable diagnosis of tuberculous meningitis. J Clin Microbiol, 2011,49(5):1861-1865. doi: 10.1128/JCM.00824-10. doi: 10.1128/JCM.00824-10 URL
[18]	Modi M, Sharma K, Sharma M, et al. Multitargeted loop-mediated isothermal amplification for rapid diagnosis of tuberculous meningitis. Int J Tuberc Lung Dis, 2016,20(5):625-630. doi: 10.5588/ijtld.15.0741. doi: 10.5588/ijtld.15.0741 URL pmid: 27084816
[19]	樊丽超, 陈宇, 朱雅娟, 等. 脑脊液环介导等温扩增和GeneXpert MTB/RIF在结核性脑膜炎早期诊断中的效能分析. 中国现代医生, 2020,58(17):128-131.
[20]	冉燕, 赵建军, 张建勇, 等. 利福平耐药实时荧光定量核酸扩增检测技术及环介导等温扩增技术在结核性脑膜炎的诊断价值. 实用医学杂志, 2020,36(24):3416-3419. doi: 10.3969/j.issn.1006-5725.2020.24.022.
[21]	刘威, 李奉京, 黄留玉, 等. 基于颜色判定的LAMP方法快速检测结核分枝杆菌. 中国医疗器械信息, 2014,20(10):7-10, 25.
[22]	Pang Y, Dong H, Tan Y, et al. Rapid diagnosis of MDR and XDR tuberculosis with the MeltPro TB assay in China. Sci Rep, 2016,6:25330. doi: 10.1038/srep25330. doi: 10.1038/srep25330 URL pmid: 27149911
[23]	吴剑, 石学萍, 刘艳. 溶解曲线技术在结核性脑膜炎临床诊断中的价值评价. 新疆医学, 2020,50(5):423-425, 428.
[24]	Kaviyil JE, Ravikumar R. Diagnosis of tuberculous meningitis: Current scenario from a Tertiary Neurocare Centre in India. Indian J Tuberc, 2017,64(3):183-188. doi: 10.1016/j.ijtb.2017.01.005. doi: 10.1016/j.ijtb.2017.01.005 URL pmid: 28709486
[25]	Gupta R, Thakur R, Gupta P, et al. Evaluation of Geno Type MTBDRplus Line Probe Assay for Early Detection of Drug Resistance in Tuberculous Meningitis Patients in India. J Glob Infect Dis, 2015,7(1):5-10. doi: 10.4103/0974-777X.150882. doi: 10.4103/0974-777X.150882 URL pmid: 25722613
[26]	张梦瑶, 任建发, 陈亚南, 等. 脑脊液宏基因组二代测序技术及其在中枢神经系统感染性疾病诊断中的应用进展. 山东医药, 2020,60(27):86-90. doi: 10.3969/j.issn.1002-266X.2020.27.024.
[27]	辛子凯, 邹月丽, 范佳, 等. 脑脊液二代测序确诊中枢神经系统李斯特菌感染二例. 中华医学杂志, 2019,99(25):1989-1990. doi: 10.3760/cma.j.issn.0376-2491.2019.25.018.
[28]	赵伟丽, 乌依罕, 李红芳, 等. 伪狂犬病毒脑炎临床观察与脑脊液二代测序鉴定. 中华医学杂志, 2018,98(15):1152-1157. doi: 10.3760/cma.j.issn.0376-2491.2018.15.006.
[29]	Piantadosi A, Kanjilal S, Ganesh V, et al. Rapid Detection of Powassan Virus in a Patient With Encephalitis by Metagenomic Sequencing. Clin Infect Dis, 2018,66(5):789-792. doi: 10.1093/cid/cix792. doi: 10.1093/cid/cix792 URL pmid: 29020227
[30]	Wang S, Chen Y, Wang D, et al. The Feasibility of Meta-genomic Next-Generation Sequencing to Identify Pathogens Causing Tuberculous Meningitis in Cerebrospinal Fluid. Front Microbiol, 2019,10:1993. doi: 10.3389/fmicb.2019.01993. doi: 10.3389/fmicb.2019.01993 URL pmid: 31551954
[31]	Xing XW, Zhang JT, Ma YB, et al. Metagenomic Next-Generation Sequencing for Diagnosis of Infectious Encephalitis and Meningitis: A Large, Prospective Case Series of 213 Patients. Front Cell Infect Microbiol, 2020,10:88. doi: 10.3389/fcimb.2020.00088. doi: 10.3389/fcimb.2020.00088 URL pmid: 32211343
[32]	Gomathi NS, Singh M, Singh UB, et al. Multicentric validation of indigenous molecular test Truenat^TM MTB for detection of Mycobacterium tuberculosis in sputum samples from presumptive pulmonary tuberculosis patients in comparison with re-ference standards . Indian J Med Res, 2020,152(4):378-385. doi: 10.4103/ijmr.IJMR_2539_19. doi: 10.4103/ijmr.IJMR_2539_19 URL pmid: 33380702
[33]	Li Z, Pan L, Lyu L, et al. Diagnostic accuracy of droplet digital PCR analysis of cerebrospinal fluid for tuberculous meningitis in adult patients. Clin Microbiol Infect, 2020,26(2):213-219. doi: 10.1016/j.cmi.2019.07.015. URL pmid: 31336201
[34]	Park JH, Jin CE, Koo B, et al. A Simple Microfluidic Assay for Diagnosing Tuberculous Meningitis in HIV-Uninfected Patients. J Clin Microbiol, 2019,57(5):e01975-18. doi: 10.1128/JCM.01975-18. doi: 10.1128/JCM.01975-18 URL pmid: 30814264

比较项目	GeneXpert	GeneXpert MTB/RIF Ultra	LAMP	熔解曲线技术	线性探针技术
检测原理	实时荧光定量PCR	实时荧光定量PCR	等温扩增技术	探针-熔解曲线技术	探针-反向杂交技术
检测位点	rpoB^[3]	IS6110、IS1081、 ropB^[3]	IS6110、gyrB^[3]	rpoB、katG、inhA、oxyR、abpC、gyrA^[3]	rpoB、katG、inhA^[3]
报告时间	2h^[13]	2h^[13]	1h^[16]	72h^[23]	6h^[25]
检测内容	结核分枝杆菌复合群,利福平耐药性^[3]	结核分枝杆菌复合群,利福平耐药性^[3]	结核分枝杆菌复合群^[3]	结核分枝杆菌复合群,异烟肼、利福平、乙胺丁醇、氟喹诺酮类药品耐药性^[3]	结核分枝杆菌复合群,异烟肼、利福平的耐药性(2代还可检测氟喹诺酮类及二线注射类药品的耐药性)^[13]
敏感度	23%~52%^{[5,6,7,8,9,10,11,12]}	89.40%^[15]	43.2%~82%^{[16,17,18,19,20]}	12.9%^[23](数据较少)	96.15%^[24](数据较少)
特点	需专门的仪器,手动操作简便,可检测利福平耐药性,结果可靠^[13]	需专门的仪器,手动操作简便,可检测利福平耐药性,结果可靠,较GeneXpert检测阈值低^[13]	操作简便,对实验室及检测人员要求低^[13],但不能进行耐药性检测,存在一定假阳性^[16]	可检测多种药物耐药性,但脑脊液相关检测数据较少,难以评价其实用性	可检测多种药物耐药性,操作复杂,对实验室及检测人员要求高^[13],脑脊液相关检测数据较少,难以评价其实用性
WHO是否推荐	是^[13]	是^[13]	推荐应用于痰液检测,肺外结核的检测有待进一步研究^[13]	否	仅推荐应用于痰液检测^[13]