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中国防痨杂志 ›› 2025, Vol. 47 ›› Issue (5): 605-612.doi: 10.19982/j.issn.1000-6621.20250039

• 论著 • 上一篇    下一篇

结核抗原特异细胞因子在HIV感染者中诊断结核病的临床价值评估

姚明旭1, 王泽琦1, 宋瑞雪1, 贾红彦1, 孙琦1, 张蓝月1, 杜博平1, 张宗德1, 汪雯2, 吴亮3(), 潘丽萍1()   

  1. 1首都医科大学附属北京胸科医院/北京市结核病胸部肿瘤研究所分子生物学实验室/耐药结核病研究北京市重点实验室,北京 101149
    2首都医科大学附属北京佑安医院感染中心,北京 100069
    3首都医科大学附属北京地坛医院感染性疾病诊疗中心,北京 100015
  • 收稿日期:2025-01-25 出版日期:2025-05-10 发布日期:2025-04-29
  • 通信作者: 潘丽萍,Email:panliping2006@163.com;吴亮,Email:wuliang1109@163.com
  • 基金资助:
    北京市自然科学基金(L234055);高层次公共卫生技术人才建设项目培养计划(学科骨干-03-37);北京市适宜技术推广项目(BHTPP2024084)

The performance of Mycobacterium tuberculosis-specific antigens-induced cytokines in the diagnosis of tuberculosis among HIV-infected individuals

Yao Mingxu1, Wang Zeqi1, Song Ruixue1, Jia Hongyan1, Sun Qi1, Zhang Lanyue1, Du Boping1, Zhang Zongde1, Wang Wen2, Wu Liang3(), Pan Liping1()   

  1. 1Department of Molecular Biology, Beijing Key Laboratory for Drug-Resistant Tuberculosis Research, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
    2Department of Infectious Diseases, Beijing You’an Hospital, Capital Medical University, Beijing 100069, China
    3Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
  • Received:2025-01-25 Online:2025-05-10 Published:2025-04-29
  • Contact: Pan Liping, Email: panliping2006@163.com; Wu Liang, Email: wuliang1109@163.com
  • Supported by:
    Beijing Natural Science Foundation(L234055);High-level Public Health Technical Personnel Construction Project Training Plan(Discipline backbone-03-37);Beijing Health Technologies Promotion Program(BHTPP2024084)

摘要:

目的: 评估HIV感染者中应用结核分枝杆菌(Mycobacterium tuberculosis,MTB)抗原特异细胞因子和趋化因子诊断结核病的临床价值。方法: 前瞻性纳入2021年12月至2024年6月在首都医科大学附属北京地坛医院、首都医科大学附属北京佑安医院就诊的HIV感染者132例,所有患者均采集外周血12ml,完成结核感染T细胞检测,并收集MTB抗原刺激和未刺激的全血,在全自动细胞提取仪完成RNA提取,采用SYBG引物法完成白细胞介素-2(IL-2)、IL-5、IL-18、IL-24、单核细胞趋化蛋白-1(MCP-1)、单核细胞趋化蛋白-2(MCP-2)、单核细胞趋化蛋白-3(MCP-3)、趋化因子CXC配体9(CXCL9)、趋化因子CXC配体10(CXCL10)、CC 基序趋化因子配体 19(CCL19)、巨噬细胞集落刺激因子(CSF-1)和γ-干扰素(IFNG)等基因的qPCR检测,分析上述因子在结核组和非结核组间的表达差异,采用Lasso回归模型筛选特征性指标,并绘制受试者工作特征曲线(receiver operating curve, ROC),评价上述因子及组合在HIV感染者中诊断结核病的临床价值。结果: 根据研究对象临床诊断信息,剔除诊断不明者35例,最终97例纳入分析,其中,结核病患者44例,非结核病患者53例。结核病组MTB抗原特异的IL-18IFNG的ΔΔCt值[中位数(四分位数)]分别为0.5601(-0.0207,1.2880)和1.0130(0.0284,3.9950),与非结核病组[分别为0.0364(-0.6420,0.7438)和0.3727(-0.5992,1.2460)]相比,均明显上调,差异均有统计学意义(Z值分别为-2.284和-1.989,P值分别为0.018和0.028);而结核病组MTB抗原特异的MCP-1MCP-2CXCL9CXCL10的ΔΔCt值[中位数(四分位数)]分别为-1.1660(-1.8920,-0.5699)、-1.4640(-3.5530,0.5763)、-1.7680(-6.3950,-0.2807)、-1.8260(-4.6000,-0.0814),与非结核病组[分别为-0.5803(-1.0040,0.1794)、-0.2367(-1.3010,0.7079)、0.2730(-1.2750,1.8360)、-0.2505(-0.6528,0.9105)]相比,均明显下调,差异均有统计学意义(Z值分别为3.162、2.529、3.745、3.743,P值分别为0.003、0.014、0.001、<0.001)。ROC分析显示,IL-18MCP-1MCP-2CXCL9CXCL10IFNG的曲线下面积范围为0.632~0.724,基于Lasso分析获得的IL18MCP-2CXCL10联合检测的曲线下面积为0.797,均高于任一单一指标。结论: IL18MCP-2CXCL10联合检测在HIV感染者中筛查结核病患者具有一定的潜力。

关键词: 分枝杆菌,结核, HIV, 感染, 细胞因子类, 诊断,鉴别

Abstract:

Objective: To evaluate the clinical value of Mycobacterium tuberculosis (MTB)-specific antigens-induced cytokines in the diagnosis of tuberculosis in HIV-infected individuals. Methods: A total of 132 HIV-infected individuals who visited Beijing Ditan Hospital and Beijing You’an Hospital from December 2021 to June 2024 were prospectively included as study subjects. Twelve milliliters of peripheral blood were collected from each patient, and the interferon-γ release assays were performed on peripheral blood. The whole blood with or without MTB-specific antigens stimulation was collected and the total RNA was extracted automatically, and then the expression levels of cytokines (interleukin-2 (IL-2), IL-5, IL-18, IL-24, monocyte chemoattractant protein-1 (MCP-1), MCP-2, MCP-3, chemokine CXC ligand 9 (CXCL9), chemokine CXC ligand 10 (CXCL10), CC motif chemokine ligand 19 (CCL19), macrophage colony-stimulating factor (CSF-1), and interferon-γ (IFNG)) were tested by SYBG-qPCR. The differences in the expression level of cytokines were analyzed between the TB group and the non-TB group, and the performance of cytokines in differentiating TB was investigated by receiver operating curve (ROC) analysis. Lasso analysis was also performed to evaluate the combined performance of the cytokines in identifying TB patients among HIV-infected individuals. Results: According to the clinical diagnosis information of the subjects, 35 cases with unknown diagnosis were excluded, and 97 cases were finally included in the analysis, including 44 cases of TB patients and 53 cases of non-TB patients. The ΔΔCt values (median (quartile)) of MTB-antigen specific IL-18 and IFNG in the TB group were 0.5601 (-0.0207, 1.2880) and 1.0130 (0.0284, 3.9950), respectively, which were significantly higher than those in the non-TB group (0.0364 (-0.6420, 0.7438) and 0.3727 (-0.5992, 1.2460), respectively), with statistically significant differences (Z values were -2.284 and -1.989, P values were 0.018 and 0.028). The ΔΔCt values (median (quartile)) of MCP-1, MCP-2, CXCL9, and CXCL10 in the TB group were -1.1660 (-1.8920, -0.5699), -1.4640 (-3.5530, 0.5763), -1.7680 (-6.3950, -0.2807), -1.8260 (-4.6000, -0.0814), respectively, which were significantly lower than those in the non-TB group (-0.5803 (-1.0040, 0.1794), -0.2367 (-1.3010, 0.7079), 0.2730 (-1.2750, 1.8360), -0.2505 (-0.6528, 0.9105)), with statistically significant differences (Z values were 3.162, 2.529, 3.745, 3.743, respectively; P values were 0.003, 0.014, 0.001, and <0.001). ROC analysis showed that the area under the curve for IL-18, MCP-1, MCP-2, CXCL9, CXCL10, and IFNG ranged from 0.632 to 0.724. Based on Lasso analysis, the area under the curve for the combined detection of IL18, MCP-2, and CXCL10 was 0.797, which was higher than any single indicator. Conclusion: The combination of IL18, MCP-2, and CXCL10 can assist in identifying TB cases among HIV-infected individuals.

Key words: Mycobacterium tuberculosis, HIV, Infection, Cytokines, Diagnosis, differential

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