儿童肺结核γ-干扰素释放试验假阴性结果影响因素分析

doi:10.12372/jcp.2025.24e0168

摘要/Abstract

摘要：

目的探究γ-干扰素释放试验(IGRA)在儿童肺结核(PTB)中的诊断价值，分析IGRA假阴性结果的影响因素。方法纳入2018年1月至2023年6月住院治疗的77例确诊PTB患儿为研究对象，根据IGRA结果分为阳性组和阴性组，探究IGRA诊断儿童PTB的敏感度，并分析其假阴性结果的影响因素。结果结核菌素皮肤试验(TST)诊断儿童PTB灵敏度为67.53%(52/77)，IGRA灵敏度为77.92%(60/77)，二者一致率为79.22%，Kappa值为0.48，具有中等一致性。TST硬结反应（中度阳性OR=0.07，95%CI：0.009~0.471，P=0.007，强阳性OR=0.02，95%CI：0.002~0.275，P=0.003）和白蛋白-球蛋白比值(OR=17.19，95%CI：2.38~124.25，P=0.005)是IGRA假阴性结果的独立影响因素。结论儿童免疫系统发育不成熟，IGRA阴性反应需警惕假阴性结果的可能，应重视分子生物学和病理学检查，尽早明确诊断，以免延误病情，错过最佳治疗时机。

关键词: 肺结核, γ-干扰素释放试验, 假阴性, 儿童

Abstract:

Objective To investigate the diagnostic value of interferon-gamma release assay (IGRA) in pediatric pulmonary tuberculosis (PTB) and analyze the risk factors of negative IGRA results. Method A total of 77 children with confirmed PTB who were hospitalized in our hospital from January 2018 to June 2023 were included in the study. Based on IGRA results, they were categorized into positive and false-negative groups. The sensitivity of IGRA for diagnosing pediatric PTB was evaluated, and the factors contributing to false-negative results were analyzed. Result The sensitivity of Tuberculin skin test (TST) for diagnosing pediatric PTB was 67.53% (52/77), while that of IGRA was 77.92% (60/77). The agreement rate between TST and IGRA was 79.22%, with a Kappa value of 0.48, indicating moderate consistency. Multivariate analysis revealed that the induration reaction of TST (moderate positive OR=0.066, 95%CI:0.009-0.471, P=0.007, strong positive OR=0.023, 95%CI: 0.002-0.275, P=0.003) and albumin-to-globulin ratio (OR=17.193,95%CI: 2.379-124.247, P=0.005) were independent predictors of false-negative IGRA results. Conclusion Due to the immature development of the immune system, children should be vigilant against the possibility of false negative results of IGRA. Emphasis on molecular biological and pathological examinations is crucial for achieving an early and accurate diagnosis, thereby preventing delayed treatment and missed opportunities for optimal care.

Key words: pulmonary tuberculosis, interferon-gamma release assay, false negative, child

中图分类号:

姜雯雯, 李思彤, 徐勇胜. 儿童肺结核γ-干扰素释放试验假阴性结果影响因素分析[J]. 临床儿科杂志, 2025, 43(7): 519-524.

JIANG Wenwen, LI Sitong, XU Yongsheng. Analysis on risk factors associated with false-negative results of interferon-gamma release assay in children with pulmonary tuberculosis[J]. Journal of Clinical Pediatrics, 2025, 43(7): 519-524.

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参考文献 20

[1]	WHO. World Health Organization; 2021.Licence: CC BY-NC-SA 3.0 IGO; Geneva:2021. Global tuberculosis report 2021 [EB/OL]. [2022-10-27]. https://www.who.int/publications/i/item/9789240037021.
[2]	Ho CS, Feng PI, Narita M, et al. Comparison of three tests for latent tuberculosis infection in high-risk people in the USA: an observational cohort study[J]. Lancet Infect Dis, 2022, 22(1): 85-96.
[3]	Jonas DE, Riley SR, Lee LC, et al. Screening for latent tuberculosis infection in adults: updated evidence report and systematic review for the US preventive services task force[J]. Jama, 2023, 329(17): 1495-1509. doi: 10.1001/jama.2023.3954 pmid: 37129650
[4]	Krutikov M, Faust L, Nikolayevskyy V, et al. The diagnostic performance of novel skin-based in-vivo tests for tuberculosis infection compared with purified protein derivative tuberculin skin tests and blood-based in vitro interferon-γ release assays: a systematic review and meta-analysis[J]. Lancet Infect Dis, 2022, 22(2): 250-264.
[5]	钟旭辉, 丁洁, 周建华, 等. 中国儿童15项常用临床检验指标的生物参考区间研究[J]中华儿科杂志, 2018, 56(11): 835-845.
	Zhong XH, Ding J, Zhou JH, et al. Biological reference interval study of 15 commonly used clinical test indexes in Chinese children[J]. Zhonghua Erke Zazhi, 2018, 56(11): 835-845.
[6]	Ding Y, Zhou L, Xia Y, et al. Reference values for peripheral blood lymphocyte subsets of healthy children in China[J]. J Allergy Clin Immunol, 2018, 142(3): 970-973. doi: S0091-6749(18)30693-6 pmid: 29746882
[7]	Carranza C, Pedraza-Sanchez S, De Oyarzabal-Mendez E, et al. Diagnosis for latent tuberculosis infection: new alternatives[J]. Front Immunol, 2020, 11: 2006. doi: 10.3389/fimmu.2020.02006 pmid: 33013856
[8]	Yang J, Kong W, Xv N, et al. Correlation between the tuberculin skin test and T-SPOT.TB in patients with suspected tuberculosis infection: a pilot study[J]. Exp Ther Med, 2019, 18(3): 2250-2254. doi: 10.3892/etm.2019.7791 pmid: 31410176
[9]	De Visser V, Sotgiu G, Lange C, et al. False-negative interferon-γ release assay results in active tuberculosis: a TBNET study[J]. Eur Respir J, 2015, 45(1): 279-283. doi: 10.1183/09031936.00120214 pmid: 25359336
[10]	Ahmed A, Vyakarnam A. Emerging patterns of regulatory T cell function in tuberculosis[J]. Clin Exp Immunol, 2020, 202(3): 273-287.
[11]	高卫卫, 邓常文, 朱晓萍. 调节性T细胞在结核免疫调控中的研究进展[J]. 临床肺科杂志, 2022, 27(8): 1238-1242.
	Gao WW, Deng CW, Zhu XP. Research progress of regulatory T cells in the regulation of tuberculosis immunity[J]. Linchuang Feike Zazhi, 2022, 27(8): 1238-1242.
[12]	Bond E, Liang F, Sandgren KJ, et al. Plasmacytoid dendritic cells infiltrate the skin in positive tuberculin skin test indurations[J]. J Invest Dermatol, 2012, 132(1): 114-123. doi: 10.1038/jid.2011.246 pmid: 21850028
[13]	Serrano CJ, Castañeda-Delgado JE, Trujillo-Ochoa JL, et al. Regulatory T-cell subsets in response to specific Mycobacterium tuberculosis antigens in vitro distinguish among individuals with different QTF and TST reactivity[J]. Clin Immunol, 2015, 157(2): 145-155. doi: 10.1016/j.clim.2015.02.008 pmid: 25728490
[14]	Gough M, Singh DK, Moodley C, et al. Peripheral blood markers correlate with the progression of active tuberculosis relative to latent control of Mycobacterium tuberculosis infection in macaques[J]. Pathogens, 2022, 11(5): 544.
[15]	Esaulova E, Das S, Singh DK, et al. The immune landscape in tuberculosis reveals populations linked to disease and latency[J]. Cell Host Microbe, 2021, 29(2): 165-178. doi: 10.1016/j.chom.2020.11.013 pmid: 33340449
[16]	Turner NA, Ahmed A, Haley CA, et al. Use of interferon-gamma release assays in children < 2 years old[J]. J Pediatric Infect Dis Soc, 2023, 12(8): 481-485.
[17]	马进宝, 马婷婷, 任斐, 等. 涂阳肺结核患者γ-干扰素释放试验假阴性的影响因素分析[J]. 中国防痨杂志, 2020, 42(12): 1299-1304.
	Ma JB, Ma TT, Ren F, et al. Analysis on risk factors associated with false negative results of interferon-gamma release assay in active tuberculosis[J]. Zhongguo Fanglao Zazhi, 2020, 42(12): 1299-1304.
[18]	彭涛, 如克亚木·阿不都沙拉木, 房珂, 等. 活动性肺结核免疫耗竭及免疫治疗的研究进展[J]. 传染病信息, 2022, 35(1): 90-94.
	Peng T, Ru Ke Ya Mu·ABDSLM, Fang K, et al. Research progress on immune exhaustion and immunotherapy of active pulmonary tuberculosis[J]. Chuanranbing Xinxi, 2022, 35(1): 90-94.
[19]	王丽, 熊坤龙, 朱长太, 等. T淋巴细胞耗竭在耐多药肺结核患者免疫表达中的初步研究[J]. 中国防痨杂志, 2021, 43(8): 808-812.
	Wang L, Xiong KL, Zhu CT, et al. T lymphocyte exhaustion on the expression of immune effect in patients with multidrug-resistant pulmonary tuberculosis[J]. Zhongguo Fanglao Zazhi, 2021, 43(8): 808-812.
[20]	刘珍敏, 赵瑞秋, 许红梅. 结核感染T细胞斑点试验、涂片检查和结核菌素试验在儿童结核病诊断中的价值[J]. 临床儿科杂志, 2019, 37(4): 282.
	Liu ZM, Zhao RQ, Xu HM. Comparison of T-cell spot test, smear test, and tuberculin test in the diagnosis of tuberculosis in children[J]. Linchuang Erke Zazhi, 2019, 37(4): 282.

项目	阳性组(n=60)	阴性组(n=17)	统计量	P
性别（男/女）	28/32	8/9	0.00	0.977
年龄[M(P₂₅~P₇₅]/岁	12.04(9.04~13.83)	3.92(0.54~7.92)	3.19	0.001
<1	4(6.67)	5(29.41)	16.18	0.003
1~<3	3(5.00)	2(11.76)
3~<7	4(6.67)	3(17.65)
7~<10	7(11.67)	4(23.53)
10~<18	42(70.00)	3(17.65)
BMI[M(P₂₅~P₇₅)]/kg·m^-2	16.00(14.76~18.16)	15.42(14.27~16.82)	1.28	0.199
BCG接种史[n(%)]	58(96.67)	16(94.12)	-	0.532¹⁾
结核接触史[n(%)]	26(43.33)	4(23.53)	2.19	0.139
居住地（农村/城市）	49/11	16/1	0.76	0.384
肺外结核[n(%)]	7(11.67)	5(29.41)	1.97	0.161
下呼吸道感染[n(%)]	13(21.67)	9(52.94)	4.91	0.027
发热[n(%)]	38(63.33)	11(64.71)	0.01	0.917
咳嗽咳痰≥2周[n(%)]	51(85.00)	10(58.82)	4.04	0.044
体重减轻[n(%)]	13(21.67)	2(11.76)	0.32	0.573
胸痛[n(%)]	8(13.33)	1(5.88)	0.17	0.667
咯血或痰中带血[n(%)]	6(10.00)	1(5.88)	0.00	0.965

项目	阳性组(n=60)	阴性组(n=17)	统计量	P
TST硬结反应[n(%)]			χ²=19.27	<0.001
阴性	9(15.00)	12(70.59)
一般阳性	3(5.00)	1(5.88)
中度阳性	23(38.33)	3(17.65)
强阳性	25(41.67)	1(5.88)
HGB（$\bar{x}\pm s$）/g·L^-1	122.33±12.70	110.82±17.38	t=3.03	0.003
WBC×10⁹[M(P₂₅~P₇₅)]/L^-1	7.98(6.71~9.75)	10.07(6.83~13.51)	Z=1.84	0.066
N×10⁹[M(P₂₅~P₇₅)]/L^-1	5.02(3.67~6.75)	4.84(2.57~9.15)	Z=0.20	0.839
L×10⁹[M(P₂₅~P₇₅)]/L^-1	1.81(1.47~2.40)	2.84(1.79~4.12)	Z=2.29	0.022
M×10⁹[M(P₂₅~P₇₅)]/L^-1	0.66(0.44~0.92)	0.67(0.53~0.86)	Z=0.31	0.759
E×10⁹[M(P₂₅~P₇₅)]/L^-1	0.09(0.03~0.15)	0.11(0.03~0.28)	Z=0.82	0.410
PLT×10⁹[M(P₂₅~P₇₅)]/L^-1	364.38±86.25	363.94±166.14	t=0.01	0.992
CPR[M(P₂₅~P₇₅)]/mg·L^-1	16.50(3.10~40.65)	7.00(2.50~73.31)	Z=0.28	0.776
NLR[M(P₂₅~P₇₅)]	2.54(1.58~4.54)	1.54(0.84~4.77)	Z=1.52	0.128
LMR[M(P₂₅~P₇₅)]	3.15(1.90~4.57)	4.06(2.60~7.39)	Z=1.82	0.069
PLR[M(P₂₅~P₇₅)]	197.14(133.21~251.71)	104.42(80.07~186.90)	Z=2.49	0.013

项目	阳性组(n=60)	阴性组(n=17)	统计量	P
LDH[M(P₂₅~P₇₅)]/U·L^-1	259.00(211.25~340.00)	305.00(230.50~367.00)	Z=1.17	0.243
PCT[M(P₂₅~P₇₅)]/ng·mL^-1	0.06(0.04~0.12)	0.05(0.04~0.21)	Z=0.51	0.613
IL-6[M(P₂₅~P₇₅)]/pg·mL^-1	17.87(7.00~34.14)	23.98(1.73~50.11)	Z=0.26	0.792
ALB[M(P₂₅~P₇₅)]/g·L^-1	42.30(39.93~45.10)	40.80(36.60~44.55)	Z=1.01	0.314
GLB[M(P₂₅~P₇₅)]/g·L^-1	29.10(25.18~31.48)	23.70(17.95~27.55)	Z=3.04	0.002
A/G（$\bar{x}\pm s$）	1.49±0.34	1.85±0.62	t=2.31	0.033
IgG相对率[M(P₂₅~P₇₅)]	1.08(0.89~1.19)	1.08(0.89~1.16)	Z=0.20	0.844
IgA相对率[M(P₂₅~P₇₅)]	1.27(0.83~1.72)	1.14(0.93~1.81)	Z=0.21	0.835
IgM相对率[M(P₂₅~P₇₅)]	0.87(0.65~1.09)	0.85(0.50~1.65)	Z=0.03	0.976
IgE[M(P₂₅~P₇₅)]/IU·mL^-1	91.92(23.49~250.03)	65.14(16.03~543.60)	Z=0.18	0.854
CD3⁺相对率[M(P₂₅~P₇₅)]	0.75(0.60~1.12)	0.93(0.54~1.38)	Z=0.98	0.326
CD4⁺相对率（$\bar{x}\pm s$）	0.95±0.43	1.09±0.71	t=0.76	0.459
CD8⁺相对率[M(P₂₅~P₇₅)]	0.76(0.51~1.02)	0.91(0.54~1.38)	Z=1.05	0.294
CD4⁺/CD8⁺[M(P₂₅~P₇₅)]	1.54(1.22~1.98)	1.48(1.12~2.41)	Z=0.50	0.619

变量/指标	β	SE	χ²值	df	P	OR	95%CI
TST硬结反应			12.32	3	0.006
一般阳性	2.63	1.74	2.30	1	0.129	0.07	0.002~2.159
中度阳性	2.72	1.00	7.34	1	0.007	0.07	0.009~0.471
强阳性	3.77	1.26	8.89	1	0.003	0.02	0.002~0.275
HGB	0.05	0.03	3.49	1	0.062	0.95	0.901~1.003
A/G	2.85	1.01	7.95	1	0.005	17.19	2.379~124.247