脑脊液特征指标辅助结核性脑膜炎快速筛查的效果评估

doi:10.19982/j.issn.1000-6621.20230419

摘要/Abstract

摘要：

目的: 探索利用若干脑脊液特征指标辅助提高敏感度,实现结核性脑膜炎(tuberculous meningitis,TBM)的快速筛查和早期治疗控制。方法: 2011—2019年期间,依据纳入排除标准,从江苏省苏州市、四川省自贡市和贵州省贵阳市的结核病定点医疗机构收治的383例疑似TBM患者中,随机筛选100例临床诊断TBM患者,并按年龄、性别1∶1配对抽取100例非TBM患者,收集脑脊液白细胞计数、乳酸盐、蛋白总量、腺苷脱氨酶、葡萄糖等生化指标,并采用超高通量液相色谱法分离患者脑脊液代谢物,通过偏正交最小二乘判别法分析(OPLS-DA)筛选在不同类型患者中分布具有差异的生化和代谢物指标,通过机器学习构建决策树模型(boosted-CART),评估特征指标对于快速筛查各类型TBM患者的效果。结果: 以P<0.05、OPLS-DA模型变量权重值>1和代谢物组间表达量差异倍数>1为标准,利用boosted-CART模型筛选脑脊液L-谷氨酰胺和葡萄糖水平作为特征指标,其cut-off值分别为607.06mmol/L(L-谷氨酰胺)和60.03mg/dl(葡萄糖)。上述两项指标联用,可将检出很可能和可能TBM患者的敏感度从66.7%(95%CI:24.1%~94.0%)提升至83.3%(95%CI:36.5%~99.1%),AUC值从0.667(95%CI:0.444~0.889)提升至0.708(95%CI:0.494~0.923),但效果不明显(Z=0.261,P>0.05)。结论: 脑脊液L-谷氨酰胺和葡萄糖指标可提高TBM快速筛查的敏感度,利于TBM早诊早治和控制结核病传播。

关键词: 结核,脑膜, 脑脊液, 脑部疾病,代谢, 早期诊断, 传染病控制

Abstract:

Objective: To explore the apllication of several cerebrospinal fluid (CSF) indicators to improve the detection sensitivity and achieve rapid screening and early treatment control of tuberculous meningitis (TBM). Methods: From 2011 to 2019, according to the inclusion and exclusion criteria, 100 TBM patients were randomly selected from 383 suspected TBM patients admitted to tuberculosis designated medical institutions in Suzhou of Jiangsu Province, Zigong of Sichuan Province and Guiyang of Guizhou Province. And 100 non-TBM patients were selected based on age and sex matched of 1∶1. The biochemical indicators such as white blood cell count, lactate, total protein, adenosine deaminase, and glucose in CSF were collected. Ultra high-throughput liquid chromatography was used to separate the metabolites of CSF. The metabolic indicators with statistically significant differences in distribution were screened by Orthogonal Projections to Latent Structures-Discriminant Analysis (OPLS-DA). A classification and regression tree (boosted-CART) model was constructed by machine learning. The effect of characteristic indicators on rapid screening of TBM patients with various types was evaluated. Results: Using the criteria of P<0.05, OPLS-DA variable important in projection value >1 and absolute value of Forld Change >1, the above model was combined to screen CSF L-glutamine and glucose levels as characteristic indicators. The cutoff values were 607.06 mmol/L (L-glutamine) and 60.03 mg/dl (glucose), respectively. The combination of the above two indicators improved the sensitivity of detecting probable and possible TBM from 66.7% (95%CI: 24.1%-94.0%) to 83.3% (95%CI: 36.5%-99.1%),AUC increased from 0.667 (95%CI: 0.444-0.889) to 0.708 (95%CI: 0.494-0.923)(Z=0.261, P>0.05). Conclusion: Biochemical and metabolic indicators such as CSF L-glutamine and glucose can improve the sensitivity of rapid TBM screening, which is conducive to the early diagnosis and treatment of TBM and to control the spread of tuberculosis.

Key words: Tuberculosis, meningeal, Cerebrospinal fluid, Brain diseases, metabolic, Early diagnosis, Communicable disease control

中图分类号:

汪晨媛, 王珊珊, 王赛楠, 邵戈, 曹佳颐, 熊海燕, 胡屹. 脑脊液特征指标辅助结核性脑膜炎快速筛查的效果评估[J]. 中国防痨杂志, 2024, 46(3): 311-317. doi: 10.19982/j.issn.1000-6621.20230419

Wang Chenyuan, Wang Shanshan, Wang Sainan, Shao Ge, Cao Jiayi, Xiong Haiyan, Hu Yi. Evaluation of the effectiveness of cerebrospinal fluid characteristics indicators in assisting rapid screening of tuberculous meningitis[J]. Chinese Journal of Antituberculosis, 2024, 46(3): 311-317. doi: 10.19982/j.issn.1000-6621.20230419

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参考文献 18

[1]	Thwaites GE, van Toorn R, Schoeman J. Tuberculous meningitis: more questions, still too few answers. Lancet Neurol, 2013, 12(10):999-1010. doi:10.1016/S1474-4422(13)70168-6. pmid: 23972913
[2]	Thwaites GE, Duc Bang N, Huy Dung N, et al. The influence of HIV infection on clinical presentation, response to treatment, and outcome in adults with Tuberculous meningitis. J Infect Dis, 2005, 192(12):2134-2141. doi:10.1086/498220. pmid: 16288379
[3]	World Health Organization. Global tuberculosis report 2022. Geneva: World Health Organization, 2022.
[4]	Marais S, Thwaites G, Schoeman JF, et al. Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect Dis, 2010, 10(11):803-812. doi:10.1016/S1473-3099(10)70138-9. pmid: 20822958
[5]	World Health Organization. WHO consolidated guidelines on tuberculosis: module 3: diagnosis: rapid diagnostics for tuberculosis detection, 2021 update. Geneva: World Health Organization, 2021.
[6]	中国疾病预防控制中心. 中国结核病防治工作技术指南. 北京: 中国疾病预防控制中心, 2021.
[7]	杨汝铃, 龙晓茹, 张祯祯, 等. 222例儿童结核性脑膜炎的临床特征及其预后影响因素分析. 中国防痨杂志, 2020, 42(10):1053-1060. doi:10.3969/j.issn.1000-6621.2020.10.009.
[8]	Li Z, Du B, Li J, et al. Cerebrospinal fluid metabolomic profiling in tuberculous and viral meningitis: Screening potential markers for differential diagnosis. Clin Chim Acta, 2017, 466:38-45. doi:10.1016/j.cca.2017.01.002. pmid: 28063937
[9]	贾佳, 孙支唐, 葛思慧, 等. 结核性脑膜炎早期诊断相关因素分析. 中西医结合心脑血管病杂志, 2019, 17(14):2205-2208. doi:10.12102/j.issn.1672-1349.2019.14.036.
[10]	Solari L, Soto A, Agapito JC, et al. The validity of cerebrospinal fluid parameters for the diagnosis of tuberculous meningitis. Int J Infect Dis, 2013, 17(12):e1111-e1115. doi:10.1016/j.ijid.2013.06.003.
[11]	李玉明. 结核性脑膜炎患者血清及脑脊液代谢组学研究. 天津: 天津医科大学, 2018.
[12]	Kiran D, Basaraba RJ. Lactate Metabolism and Signaling in Tuberculosis and Cancer: A Comparative Review. Front Cell Infect Microbiol, 2021, 11:624607. doi:10.3389/fcimb.2021.624607.
[13]	Mason S, van Furth AM, Mienie LJ, et al. A hypothetical astrocyte-microglia lactate shuttle derived from a ¹H NMR metabolomics analysis of cerebrospinal fluid from a cohort of South African children with tuberculous meningitis. Metabolomics, 2015, 11(4):822-837. doi:10.1007/s11306-014-0741-z.
[14]	van Zyl CW, Loots DT, Solomons R, et al. Metabolic characterization of tuberculous meningitis in a South African paediatric population using ¹H NMR metabolomics. J Infect, 2020, 81(5):743-752. doi:10.1016/j.jinf.2020.06.078.
[15]	Xhima K, Weber-Adrian D, Silburt J. Glutamate Induces Blood-Brain Barrier Permeability through Activation of N-Methyl-D-Aspartate Receptors. J Neurosci, 2016, 36(49):12296-12298. doi:10.1523/JNEUROSCI.2962-16.2016. pmid: 27927949
[16]	Zhou H, Gao F, Yang X, et al. Endothelial BACE1 Impairs Cerebral Small Vessels via Tight Junctions and eNOS. Circ Res, 2022, 130(9):1321-1341. doi:10.1161/CIRCRESAHA.121.320183. pmid: 35382554
[17]	张新宝, 姚超, 洪青青, 等. T细胞斑点试验在结核性脑膜炎诊断中的应用价值. 中国感染与化疗杂志, 2021, 21(1):32-36. doi:10.16718/j.1009-7708.2021.01.005.
[18]	Cresswell FV, Davis AG, Sharma K, et al. Recent Developments in Tuberculous Meningitis Pathogenesis and Diagnostics. Wellcome Open Res, 2021, 4:164. doi:10.12688/wellcomeopenres.15506.3.

特征	确诊TBM (69例)	很可能和可能 TBM(31例)	非TBM (100例)	统计检验值	P值
年龄[岁,M(Q₁,Q₃)]	30(21,45)	33(23,56)	34(24,48)	U=4224.500	0.267
性别[例,构成比(%)]				χ²=0.219	0.640
男性	52(75.4)	16(51.6)	67(67.0)
女性	17(24.6)	15(48.4)	33(33.0)
地区[例,构成比(%)]				χ²=0.949	0.622
江苏省苏州市	16(23.2)	16(51.6)	39(39.0)
贵州省贵阳市	22(31.9)	15(48.4)	34(34.0)
四川省自贡市	31(44.9)	0(0.0)	27(27.0)
城乡[例,构成比(%)]				χ²=0.044	0.835
农村	54(78.3)	23(74.2)	76(76.0)
城市	15(21.7)	8(25.8)	24(24.0)
患有2型糖尿病[例,构成比(%)]				χ²=0.094	0.759
否	60(87.0)	28(90.3)	89(89.0)
是	9(13.0)	3(9.7)	11(11.0)
脑脊液生化指标
白细胞计数[个/μl,M(Q₁,Q₃)]	381(321,440)	310(173,438)	365(227,531)	U=4515.000	0.718
乳酸[mmol/L,M(Q₁,Q₃)]	7.8(5.6,9.4)	2.9(2.4,3.2)	3.5(3.0,4.4)	U=4337.000	0.412
蛋白总量[g/L,M(Q₁,Q₃)]	1.4(0.8,2.2)	1.0(0.7,1.2)	0.8(0.5,1.2)	U=6141.000	<0.001
腺苷脱氨酶[U/L,M(Q₁,Q₃)]	4.9(3.5,6.2)	3.8(2.8,5.2)	2.7(1.7,3.4)	U=7741.000	<0.001
葡萄糖[mg/dl,M(Q₁,Q₃)]	23.1(18.0,27.5)	84.8(60.6,102.2)	31.9(23.9,37.0)	U=6888.000	<0.001

差异物	AUC值	P值	敏感度(%)	特异度(%)	约登指数
L-异亮氨酸	0.847	<0.001	70.5	90.8	0.613
β-丙氨酸	0.838	<0.001	62.1	89.8	0.519
L-谷氨酰胺	0.848	<0.001	64.2	91.8	0.560
黄嘌呤	0.766	<0.001	88.4	64.3	0.527
D-丙氨酸	0.809	<0.001	93.7	62.2	0.559
L-赖氨酸	0.842	<0.001	89.5	67.3	0.568

指标	TBM组 (例)	非TBM组 (例)	敏感度 (%,95%CI)	特异度 (%,95%CI)	AUC值 (95%CI)	P值
所有TBM患者						0.409
L-谷氨酰胺
>607.06mmol/L	9	0	50.0	100.0	0.750
≤607.06mmol/L	9	12	(26.8~73.2)	(69.9~100.0)	(0.577~0.923)
L-谷氨酰胺+脑脊液葡萄糖
L-谷氨酰胺>607.06mmol/L或脑脊液葡萄糖>60.03mg/dl	10	0	55.6	100.0	0.778
L-谷氨酰胺≤607.06mmol/L且脑脊液葡萄糖≤60.03mg/dl	8	12	(31.3~77.6)	(69.9~100.0)	(0.612~0.943)
确诊的TBM患者						0.500
L-谷氨酰胺
>607.06mmol/L	5	0	41.7	100.0	0.917
≤607.06mmol/L	7	12	(16.5~71.4)	(69.9~100.0)	(0.734~1.000)
L-谷氨酰胺+脑脊液葡萄糖
L-谷氨酰胺>607.06mmol/L或脑脊液葡萄糖>60.03mg/dl	5	0	41.7	100.0	0.917
L-谷氨酰胺≤607.06mmol/L且脑脊液葡萄糖≤60.03mg/dl	7	12	(16.5~71.4)	(69.9~100.0)	(0.734~1.000)
很可能和可能的TBM患者						0.397
L-谷氨酰胺
>607.06mmol/L	4	0	66.7	100.0	0.667
≤607.06mmol/L	2	12	(24.1~94.0)	69.9~100.0	(0.444~0.889)
L-谷氨酰胺+脑脊液葡萄糖
L-谷氨酰胺>607.06mmol/L或脑脊液葡萄糖>60.03mg/dl	5	0	83.3	100.0	0.708
L-谷氨酰胺≤607.06mmol/L且脑脊液葡萄糖≤60.03mg/dl	1	12	(36.5~99.1)	(69.9~100.0)	(0.494~0.923)