The diagnostic value of cell-free Mycobacterium tuberculosis DNA test on pleural effusion in early diagnosis of tuberculous pleurisy

doi:10.19982/j.issn.1000-6621.20220064

Abstract

Abstract:

Objective: To evaluate the diagnostic value of cell-free Mycobacterium tuberculosis DNA test (CF.TB) on pleural effusion in detecting tuberculous pleurisy. Methods: A total of 216 patients with unexplained pleural effusion in Beijing Chest Hospital Affiliated with Capital Medical University from July 2016 to December 2018 were enrolled. All patients were given thoracentesis or thoracic catheterization to collect pleural effusion. The CF.TB, SAT-PCR, GeneXpert MTB/RIF and adenosine deaminase (ADA) assay were performed on pleural effusion samples and T-SPOT.TB test was used on blood sample. With a composite reference standard (CRS) as the reference standard, the sensitivity, specificity, positive prediction value and negative prediction value of CF.TB, SAT-PCR, GeneXpert MTB/RIF assay, ADA and T-SPOT.TB were evaluated. Moreover, the diagnostic value of CF.TB alone and CF.TB plus ADA test were assessed. Results: Among those 216 patients, 165 cases were confirmed as tuberculous pleurisy clinically,51 cases were non-tuberculosis pleural effusion. With CRS as the reference standard, the sensitivity of CF.TB, SAT-PCR and GeneXpert MTB/RIF assay, ADA and T-SPOT.TB were 70.30% (116/165), 7.88% (13/165), 12.12% (20/165), 67.27% (111/165) and 87.27% (144/165) respectively. The specificity of five tests were 100.00% (51/51), 100.00% (51/51), 100.00% (51/51), 92.16% (47/51), and 62.75% (32/51) respectively. The positive prediction value were 100.00% (116/116), 100.00% (13/13), 100.00% (20/20), 96.52% (111/115) and 88.34% (144/163) respectively. The negative prediction value were 51.00% (51/100), 25.12% (51/203), 26.02% (51/196), 46.53% (47/101) and 60.38% (32/53) respectively. The sensitivity of CF.TB test was significantly higher than that of SAT-PCR (70.30% vs. 7.88%), GeneXpert MTB/RIF (12.12%) and ADA test (67.27%), the differences were statistically significant (χ² values were 1.350, 1.153 and 1.025, respectively, all P values=0.000). Furthermore, comparing with CF.TB test alone, performing CF.TB plus ADA could significantly improve the sensitivity of detecting tuberculous pleurisy (88.48%, 146/165 vs 70.30%, 116/165), the difference was statistically significant (χ² value was 16.670, P value=0.000). Conclusion: CF.TB test has higher sensitivity than SAT-PCR and GeneXpert MTB/RIF, and higher specificity than ADA and T-SPOT.TB in diagnosing tuberculous pleurisy. Moreover, jointly using CF.TB and ADA can significantly improve its sensitivity. We suggest it should be adopted as an important assisting diagnostic method for detecting tuberculous pleurisy.

Key words: Tuberculosis, pleurisy, Pleural effusion, Nucleic acid amplification techniques, Comparative study

CLC Number:

R521

Zhang Yun, Li Kun, Liang Qingtao, Liu Zichen, Duan Hongfei, Li Xuelian, Guo Ru, Che Nanying, Yang Xinting. The diagnostic value of cell-free Mycobacterium tuberculosis DNA test on pleural effusion in early diagnosis of tuberculous pleurisy[J]. Chinese Journal of Antituberculosis, 2022, 44(8): 835-843. doi: 10.19982/j.issn.1000-6621.20220064

Figures/Tables 4

References 27

[1]	Light RW. Update on tuberculous pleural effusion. Respirology, 2010, 15(3):451-458. doi: 10.1111/j.1440-1843.2010.01723.x. doi: 10.1111/j.1440-1843.2010.01723.x URL
[2]	杨新婷, 关国英, 王亚红, 等. 结核性胸膜炎的临床特征及诊断技术分析. 中国防痨杂志, 2017, 39(11):1162-1168. doi: 10.3969/j.issn.1000-6621.2017.11.003. doi: 10.3969/j.issn.1000-6621.2017.11.003
[3]	高孟秋. 《WS 288—2017肺结核诊断》新标准中关于临床诊断患者判定的解析. 中国防痨杂志, 2018, (3):243-246. doi: 10.3969/j.issn.1000-6621.2018.03.005. doi: 10.3969/j.issn.1000-6621.2018.03.005
[4]	Porcel JM. Advances in the diagnosis of tuberculous pleuritis. Ann Transl Med, 2016, 4(15):282-288. doi: 10.21037/atm.2016.07.23. doi: 10.21037/atm.2016.07.23 pmid: 27570776
[5]	Gopi A, Madhavan SM, Sharma SK, et al. Diagnosis and treatment of tuberculous pleural effusion in 2006. Chest, 2007, 131(3):880-889. doi: 10.1378/chest.06-2063. doi: 10.1378/chest.06-2063 URL
[6]	Porcel JM, Palma R, Valdes L, et al. Xpert(R) MTB/RIF in pleural fluid for the diagnosis of tuberculosis. Int J Tuberc Lung Dis, 2013, 17(9): 1217-1219. doi: 10.5588/ijtld.13.0178. doi: 10.5588/ijtld.13.0178 pmid: 23827859
[7]	Rufai SB, Singh A, Kumar P, et al. Performance of Xpert MTB/RIF Assay in Diagnosis of Pleural Tuberculosis by Use of Pleural Fluid Samples. J Clin Microbiol, 2015, 53(11): 3636-3638. doi: 10.1128/JCM.02182-15. doi: 10.1128/JCM.02182-15 URL
[8]	Krenke R, Korczynski P. Use of pleural fluid levels of adenosine deaminase and interferon gamma in the diagnosis of tuberculous pleuritis. Curr Opin Pulm Med, 2010, 16(4): 367-375. doi: 10.1097/MCP.0b013e32833a7154. doi: 10.1097/MCP.0b013e32833a7154 pmid: 20473171
[9]	Jeon D. Tuberculous pleurisy: an update. Tuberc Respir Dis (Seoul), 2014, 76(4): 153-159. doi: 10.4046/trd.2014.76.4.153. doi: 10.4046/trd.2014.76.4.153
[10]	Gao BA, Zhou G, Guan L, et al. Effectiveness and safety of diagnostic flexi-rigid thoracoscopy in differentiating exudative pleural effusion of unknown etiology: a retrospective study of 215 patients. J Thorac Dis, 2014, 6(5):438-443. doi: 10.3978/j.issn.2072-1439.2014.02.09. doi: 10.3978/j.issn.2072-1439.2014.02.09
[11]	Rozman A, Camlek L, Kern I, et al. Semirigid thoracoscopy: an effective method for diagnosing pleural malignancies. Radiol Oncol, 2014, 48(1):67-71. doi: 10.2478/raon-2013-0068. doi: 10.2478/raon-2013-0068 pmid: 24587782
[12]	Lo YM, Corbetta N, Chamberlain PF, et al. Presence of fetal DNA in maternal plasma and serum. Lancet, 1997, 350(9076):485-487. doi: 10.1016/S0140-6736(97)02174-0. doi: 10.1016/S0140-6736(97)02174-0 pmid: 9274585
[13]	Patel KM, Tsui DW. The translational potential of circulating tumour DNA in oncology. Clin Biochem, 2015, 48(15):957-961. doi: 10.1016/j.clinbiochem.2015.04.005. doi: 10.1016/j.clinbiochem.2015.04.005 pmid: 25889059
[14]	Weerakoon KG, McManus DP. Cell-Free DNA as a Diagnostic Tool for Human Parasitic Infections. Trends Parasitol, 2016, 32(5):378-391. doi: 10.1016/j.pt.2016.01.006. doi: S1471-4922(16)00007-6 pmid: 26847654
[15]	Ullah H, Qadeer A, Giri BR. Detection of circulating cell-free DNA to diagnose Schistosoma japonicum infection. Acta Trop, 2020, 211:105604. doi: 10.1016/j.actatropica.2020.105604. doi: 10.1016/j.actatropica.2020.105604 URL
[16]	Yang J, Han X, Liu A, et al. Use of Digital Droplet PCR to Detect Mycobacterium tuberculosis DNA in Whole Blood-Derived DNA Samples from Patients with Pulmonary and Extrapulmonary Tuberculosis. Front Cell Infect Microbiol, 2017, 7: 369-375. doi: 10.3389/fcimb.2017.00369. doi: 10.3389/fcimb.2017.00369 URL
[17]	Yu SC, Lee SW, Jiang P, et al. High-resolution profiling of fetal DNA clearance from maternal plasma by massively parallel sequencing. Clin Chem, 2013, 59(8):1228-1237. doi: 10.1373/clinchem.2013.203679. doi: 10.1373/clinchem.2013.203679 URL
[18]	Che N, Yang X, Liu Z, et al. Rapid Detection of Cell-Free Mycobacterium tuberculosis DNA in Tuberculous Pleural Effusion. J Clin Microbiol, 2017, 55(5):1526-1532. doi: 10.1128/JCM.02473-16. doi: 10.1128/JCM.02473-16 URL
[19]	赵雁林, 逄宇. 结核病实验室检验规程. 北京: 人民卫生出版社, 2006.
[20]	Shaw JA, Irusen EM, Diacon AH, et al. Pleural tuberculosis: A concise clinical review. Clin Respir J, 2018, 12(5):1779-1786. doi: 10.1111/crj.12900. doi: 10.1111/crj.12900 URL
[21]	Sehgal IS, Dhooria S, Aggarwal AN, et al. Diagnostic Performance of Xpert MTB/RIF in tuberculous Pleural Effusion:Systematic Review and Meta-analysis. J Clin Microbiol, 2016, 54(4):1133-1136. doi: 10.1128/JCM.03205-15. doi: 10.1128/JCM.03205-15 URL
[22]	沙巍, 何娅, 蒋瑞华, 等. 实时荧光核酸恒温放大检测(SAT)法对肺结核诊断价值的研究. 中国防痨杂志, 2012, 34(6):377-379.
[23]	Yu G, Shen Y, Ye B, et al. Diagnostic accuracy of Mycobacterium tuberculosis cell-free DNA for tuberculosis: A systematic review and meta-analysis. PLoS One, 2021, 16(6): e0253658. doi: 10.1371/journal.pone.0253658. doi: 10.1371/journal.pone.0253658
[24]	Yang X, Che N, Duan H, et al. Cell-free Mycobacterium tuberculosis DNA test in pleural effusion for tuberculous pleurisy: a diagnostic accuracy study. Clin Microbiol Infect, 2020, 26(8):1089.e1-1089.e6. doi: 10.1016/j.cmi.2019.11.026. doi: 10.1016/j.cmi.2019.11.026
[25]	To EW, Chan KC, Leung SF, et al. Rapid clearance of plasma Epstein-Barr virus DNA after surgical treatment of nasopharyngeal carcinoma. Clin Cancer Res, 2003, 9(9):3254-3259.
[26]	Disch J, Oliveira MC, Orsini M, et al. Rapid clearance of circulating Leishmania kinetoplast DNA after treatment of visceral leishmaniasis. Acta Trop, 2004, 92(3):279-283. doi: 10.1016/j.actatropica.2004.08.002. doi: 10.1016/j.actatropica.2004.08.002 URL
[27]	Gui X, Xiao H. Diagnosis of tuberculosis pleurisy with adenosine deaminase(ADA): a systematic review and meta-analysis. Int J Clin Exp Med, 2014, 7(10):3126-3135.

临床资料	结核组(165例)	非结核组(51例)	统计检验值	P值
年龄[岁, M(Q₁,Q₃)]	40(26,57)	58(48,66)	Z=4.818	0.001
性别[男性例数,构成比(%)]	126(76.36)	27(52.94)	χ²=10.345	0.001
渗出液[例数,发生率(%)]	160(96.97)	51(100.00)	χ²=1.567	0.594
单侧胸腔积液[例数,发生率(%)]	147(89.09)	49(96.08)	χ²=1.692	0.172
T-SPOT.TB阳性[例数,阳性率(%)]	144(87.27)	19(37.25)	χ²=11.858	0.001

检测方法	临床确诊(例)		敏感度 (%)	特异度 (%)	阳性预测值 (%)	阴性预测值 (%)	符合率 (%)
检测方法	结核 (165例)	非结核 (51例)	敏感度 (%)	特异度 (%)	阳性预测值 (%)	阴性预测值 (%)	符合率 (%)
SAT-PCR			7.88	100.00	100.00	25.12	29.63
阳性	13	0
阴性	152	51
GeneXpert MTB/RIF			12.12	100.00	100.00	26.02	32.87
阳性	20	0
阴性	145	51
CF.TB			70.30	100.00	100.00	51.00	77.31
阳性	116	0
阴性	49	51
分枝杆菌培养			15.15	100.00	100.00	26.70	35.19
阳性	25	0
阴性	140	51

检测方法	临床确诊(例)		敏感度 (%)	特异度 (%)	阳性预测值 (%)	阴性预测值 (%)	符合率 (%)
检测方法	结核 (165例)	非结核 (51例)	敏感度 (%)	特异度 (%)	阳性预测值 (%)	阴性预测值 (%)	符合率 (%)
CF.TB			70.30	100.00	100.00	51.00	77.31
阳性	116	0
阴性	49	51
ADA>40U/L			67.27	92.16	96.52	46.53	73.15
阳性	111	4
阴性	54	47
T-SPOT.TB			87.27	62.75	88.34	60.37	81.48
阳性	144	19
阴性	21	32
CF.TB+ADA			88.48	92.16	97.33	71.21	89.35
阳性	146	4
阴性	19	47

组别	CF.TB					SAT-PCR			GeneXpert MTB/RIF
组别	检测例数		阳性例数	阳性率(%)	检测例数		阳性例数	阳性率(%)	检测例数	阳性例数	阳性率(%)
合并肺结核
有	106		80	75.47	105		9	8.57	106	17	16.04
无	59		36	61.02	57		4	7.02	59	3	5.08
χ²值		3.793				0.002			4.269
P值		0.051				0.964			0.039
呼吸道病原学
阳性	49		36	73.47	48		4	8.33	49	6	12.24
无痰/阴性	116		80	68.97	114		9	7.89	116	14	12.07
χ²值		3.352				0.001			0.001
P值		0.563				0.999			0.975
ADA
≥40U/L	111		81	72.97	108		11	10.19	111	15	13.51
<40U/L	54		35	64.81	54		2	3.70	54	5	9.26
χ²值		1.158				1.265			0.617
P值		0.282				0.261			0.432
年龄(岁)
15~39	81		60	74.07	78		6	7.69	81	8	9.88
40~59	48		34	70.83	48		5	10.42	48	7	14.58
≥60	36		22	61.11	36		2	5.56	36	5	13.89
χ²值		2.015				0.671			0.930
P值		0.365				0.806			0.705
组别	CF.TB					SAT-PCR			GeneXpert MTB/RIF
组别	检测例数		阳性例数	阳性率(%)	检测例数		阳性例数	阳性率(%)	检测例数	阳性例数	阳性率(%)
性别
男性	126		90	71.43	123		11	8.94	126	16	12.70
女性	39		26	66.67	39		2	5.13	39	4	10.26
χ²值		0.323				0.181			0.016
P值		0.571				0.672			0.888