微卡与维生素D联合应用对初治涂阳肺结核CD4+ T细胞亚群平衡的影响

doi:10.19982/j.issn.1000-6621.20230078

摘要/Abstract

摘要：

目的: 探讨微卡(母牛分枝杆菌菌苗)联合维生素D辅助治疗对初治涂阳肺结核(pulmonary tuberculosis,PTB)CD4⁺ T细胞亚群平衡的影响,并分析其临床疗效。方法: 采用前瞻性研究方法,于2019年6月至2022年6月,参照入组标准及患者意愿将河南省胸科医院收治的初治涂阳PTB患者分别纳入常规抗结核治疗组(对照组)、常规抗结核+微卡治疗组(微卡组)和常规抗结核+微卡+维生素D辅助治疗组(联合组)。排除中途因各种原因退出或脱落而不能完成6个月治疗方案者,最终以74例为3组不同组别的纳入患者数(共计222例)。检测不同组别PTB患者治疗前及治疗后6个月的外周血辅助性 T细胞1(Th1)、Th2、Th17、调节性 T细胞(Treg细胞)比例及血清γ-干扰素(IFN-γ)、白细胞介素-4(IL-4)、IL-17、IL-10水平,记录不同组别PTB患者治疗6个月的痰菌阴转率、肺部病灶和空洞改善率及综合疗效情况,并进行数据的统计分析。结果: 治疗6个月后,联合组Th1/Th2、Treg/Th17比值和IFN-γ水平[2.32±0.39、0.45±0.03和(16.13±2.67)pg/ml]均明显高于微卡组[2.19±0.25、0.34±0.03和(14.16±3.45)pg/ml;t=2.414,P=0.017;t=22.303,P=0.000;t=3.885,P=0.000]和对照组[2.08±0.37、0.26±0.02和(12.34±1.73)pg/ml;t=3.840,P=0.000;t=45.331,P=0.000;t=10.248,P=0.000],IL-4、IL-17和IL-10水平[(36.54±2.01)pg/ml、(27.10±3.58)pg/ml和(35.46±3.84)pg/ml]均明显低于微卡组[(37.23±1.78)pg/ml、(28.43±2.16)pg/ml和(43.58±4.06)pg/ml;t=2.211,P=0.029;t=2.736,P=0.007;t=12.499,P=0.000]和对照组[(38.89±2.16)pg/ml、(29.40±3.27)pg/ml和(50.24±4.22)pg/ml;t=6.851,P=0.000;t=4.732,P=0.000;t=22.284,P=0.000];痰涂片阴转率[97.30%(72/74)]和总有效率[91.89%(68/74)]均明显优于微卡组[83.78%(62/74)和79.73%(59/74);χ²=7.889,P=0.005;χ²=4.495,P=0.034]和对照组[78.38%(58/74)和77.03%(57/74);χ²=12.397,P=0.000;χ²=6.229,P=0.013]。结论: 常规抗结核联合微卡和维生素D辅助治疗可明显促进患者T细胞亚群Th1/Th2、Th17/Treg平衡恢复,有效改善IFN-γ、IL-4、IL-17和IL-10细胞因子水平,临床疗效显著。

关键词: 结核,肺, 维生素D, 结核菌苗, T淋巴细胞, 干扰素类, 白细胞介素-4

Abstract:

Objective: To evaluate the effect of the combination of microcard (Mycobacterium vaccae vaccine) and vitamin D adjuvant therapy on the balance of CD4⁺ T cell subsets in initially treated patients with smear positive pulmonary tuberculosis (PTB), and to analyze its clinical efficacy. Methods: A prospective study was designed. According to the inclusion criteria and patient’s willing, the initially treated patients with smear positive PTB (PTB group) admitted to Henan Chest Hospital from June 2019 to June 2022 were enrolled into conventional anti-tuberculosis treatment group (control group), conventional anti-tuberculosis with microcard treatment group (microcard group) and conventional anti-tuberculosis combined with microcard and vitamin D adjuvant therapy group (combined group). Excluding those who could not complete the 6-month treatment course due to various reasons, 74 cases in each group were included (222 patients). The proportion of Th1, Th2, Th17, Treg cells and the levels of IFN-γ, IL-4, IL-17, IL-10 in peripheral blood of patients/healthy subjects were detected in each group before treatment and after 6-month treatment, and the sputum negative conversion rate, lesion and pulmonary cavities and comprehensive efficacy were evaluated by the end of 6-month treatment. Results: After six months treatment, the Th1/Th2, Treg/Th17 ratios and IFN-γ levels in the combined group (2.32±0.39, 0.45±0.03 and (16.13±2.67) pg/ml) were significantly higher than those in the microcard group (2.19±0.25, 0.34±0.03 and (14.16±3.45) pg/ml; t=2.414, P=0.017; t=22.303, P=0.000; t=3.885, P=0.000) and control group (2.08±0.37, 0.26±0.02 and (12.34±1.73) pg/ml; t=3.840, P=0.000; t=45.331, P=0.000; t=10.248, P=0.000). The levels of IL-4, IL-17 and IL-10 ((36.54±2.01) pg/ml, (27.10±3.58) pg/ml and (35.46±3.84) pg/ml) in the combined group were significantly lower than those in the microcard group ((37.23±1.78) pg/ml, (28.43±2.16) pg/ml and (43.58±4.06) pg/ml; t=2.211, P=0.029; t=2.736, P=0.007; t=12.499, P=0.000) and control group ((38.89±2.16) pg/ml, (29.40±3.27) pg/ml and (50.24±4.22) pg/ml; t=6.851, P=0.000; t=4.732, P=0.000; t=22.284, P=0.000); the negative conversion rate of sputum smear (97.30% (72/74)) and the total effective rate (91.89% (68/74)) were significantly higher than those in the microgram group (83.78% (62/74) and 79.73% (59/74); χ²=7.889, P=0.005; χ²=4.495, P=0.034) and control group (78.38% (58/74) and 77.03% (57/74); χ²=12.397, P=0.000; χ²=6.229, P=0.013). Conclusion: Conventional anti-tuberculosis combined with microcard and vitamin D adjuvant therapy can significantly promote the balance restoration of T lymphocyte subsets Th1/Th2 and Th17/Treg, and effectively improve cytokines levels of IFN-γ, IL-4, IL-17 and IL-10, and it has a significant clinical benefit.

Key words: Tuberculosis,pulmonary, Vitamin D, Tuberculosis vaccines, T lymphocyte, Interferons, Interleukin-4

中图分类号:

尚耀民, 周晓蕾, 薛运玲, 冷霞. 微卡与维生素D联合应用对初治涂阳肺结核CD4⁺ T细胞亚群平衡的影响[J]. 中国防痨杂志, 2023, 45(6): 575-582. doi: 10.19982/j.issn.1000-6621.20230078

Shang Yaomin, Zhou Xiaolei, Xue Yunling, Leng Xia. Effect of microcard combined with vitamin D on the balance of CD4⁺ T cell subsets in initially treated patients with smear positive pulmonary tuberculosis[J]. Chinese Journal of Antituberculosis, 2023, 45(6): 575-582. doi: 10.19982/j.issn.1000-6621.20230078

图/表 7

表1

不同组别抗结核治疗初治涂阳肺结核患者基本特征比较

组别	性别[例(构成比,%)]		年龄(岁, $x ˉ$ ±s)	体质量指数 ( $x ˉ$ ±s)	吸烟[例 (构成比,%)]	饮酒[例 (构成比,%)]	胸腔积液[例 (构成比,%)]	肺空洞 (个)
组别	男性	女性	年龄(岁, $x ˉ$ ±s)	体质量指数 ( $x ˉ$ ±s)	吸烟[例 (构成比,%)]	饮酒[例 (构成比,%)]	胸腔积液[例 (构成比,%)]	肺空洞 (个)
对照组(74例)	39(52.70)	35(47.30)	41.02±2.80	21.13±1.56	27(36.49)	11(14.86)	18(24.32)	47
微卡组(74例)	36(48.65)	38(51.35)	42.01±3.51	21.56±1.33	24(32.43)	14(18.92)	17(22.97)	40
联合组(74例)	42(56.76)	32(43.24)	41.59±2.86	21.36±1.07	30(40.54)	17(22.97)	23(31.08)	42
统计检验值	χ²=0.976		F=1.937	F=1.922	χ²=1.050	χ²=1.586	χ²=1.447	-
P值	0.614		0.147	0.149	0.592	0.453	0.485	-

表1

表2

不同组别研究对象Th1/Th2和Th17/Treg体系及相关各细胞因子水平检测情况

组别	IFN-γ (pg/ml, $x ˉ$ ±s)	IL-4 (pg/ml, $x ˉ$ ±s)	Th1/Th2 ( $x ˉ$ ±s)	IL-17 (pg/ml, $x ˉ$ ±s)	IL-10 (pg/ml, $x ˉ$ ±s)	Th17/Treg ( $x ˉ$ ±s)
健康组(222例)	32.07±5.33	21.82±3.64	2.34±0.48	10.15±1.86	22.37±2.41	0.50±0.11
PTB组(222例)	9.48±2.08	50.28±5.07	1.55±0.30	35.23±3.89	70.31±8.28	0.11±0.02
t值	58.828	67.941	20.795	86.665	82.830	51.974
P值	0.000	0.000	0.000	0.000	0.000	0.000

表2

表3

不同组别初治涂阳肺结核患者治疗前与治疗6个月后Th1/Th2体系细胞因子的比较

组别	IFN-γ(pg/ml, $x ˉ$ ±s)				IL-4(pg/ml, $x ˉ$ ±s)				Th1/Th2( $x ˉ$ ±s)
组别	治疗前	治疗后	t值	P值	治疗前	治疗后	t值	P值	治疗前	治疗后	t值	P值
对照组	9.15± 2.37	12.34± 1.73	9.352	0.000	50.41± 5.07	38.89± 2.16	17.982	0.000	1.51± 0.32	2.08± 0.37	10.023	0.000
微卡组	9.68± 2.02	14.16± 3.45	9.640	0.000	50.21± 5.06	37.23± 1.78	20.816	0.000	1.55± 0.21	2.19± 0.25	12.941	0.000
联合组	9.61± 1.95	16.13± 2.67	16.964	0.000	50.22± 5.09	36.54± 2.01	21.504	0.000	1.59± 0.28	2.32± 0.39	13.080	0.000
F值	1.363	36.221			0.037	27.283			1.579	9.116
P值	0.258	0.000			0.964	0.000			0.208	0.000
t值^a	1.464	4.057			0.240	5.102			0.899	2.119
P值	0.145	0.000			0.811	0.000			0.370	0.036
t值^b	1.289	10.248			0.228	6.851			1.798	3.840
P值	0.199	0.000			0.820	0.000			0.074	0.000
t值^c	0.214	3.885			0.012	2.211			0.983	2.414
P值	0.830	0.000			0.990	0.029			0.327	0.017

表3

表4

不同组别初治涂阳肺结核患者治疗前与治疗6个月后Th17/Treg体系细胞因子的比较

组别	IL-17(pg/ml, $x ˉ$ ±s)				IL-10(pg/ml, $x ˉ$ ±s)				Th17/Treg( $x ˉ$ ±s)
组别	治疗前	治疗后	t值	P值	治疗前	治疗后	t值	P值	治疗前	治疗后	t值	P值
对照组	35.17± 4.16	29.40± 3.27	9.380	0.000	71.39± 8.25	50.24± 4.22	19.634	0.000	0.10± 0.04	0.26± 0.02	30.777	0.000
微卡组	34.66± 4.34	28.43± 2.16	11.055	0.000	69.68± 6.95	43.58± 4.06	38.341	0.000	0.12± 0.08	0.34± 0.03	22.150	0.000
联合组	35.86± 3.74	27.10± 3.58	14.555	0.000	69.86± 8.29	35.46± 3.84	32.390	0.000	0.11± 0.03	0.45± 0.03	68.938	0.000
F值	1.606	10.510			1.059	248.000			2.494	918.300
P值	0.203	0.000			0.350	0.000			0.085	0.000
t值^a	0.730	2.129			1.364	9.783			1.924	19.087
P值	0.467	0.035			0.175	0.000			0.056	0.000
t值^b	1.061	4.732			1.220	22.284			1.720	45.331
P值	0.290	0.000			0.224	0.000			0.087	0.000
t值^c	1.802	2.736			0.143	12.499			1.007	22.303
P值	0.074	0.007			0.886	0.000			0.316	0.000

表4

表5

表6

表7

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组别	例数	病灶[例(构成比,%)]				空洞[个(构成比,%)]
组别	例数	吸收	明显吸收	不变	恶化	总个数	闭合	缩小	不变	增大
对照组	74	23(31.08)	35(47.30)	12(16.22)	4(5.40)	47	13(27.66)	27(57.44)	6(12.77)	1(2.13)
微卡组	74	30(40.54)	32(43.24)	11(14.86)	1(1.35)	40	23(57.50)	15(37.50)	2(5.00)	0(0.00)
联合组	74	40(54.05)	28(37.84)	6(8.11)	0(0.00)	42	30(71.43)	12(28.57)	0(0.00)	0(0.00)
χ²值^a		2.902					8.699
P值		0.407					0.034
χ²值^b		11.365					19.270
P值		0.010					0.000
χ²值^c		4.166					3.211
P值		0.244					0.201

组别	例数	痊愈	显效	有效	无效	总有效
对照组	74	5(6.76)	18(24.32)	34(45.95)	17(22.97)	57(77.03)
微卡组	74	9(12.16)	21(28.38)	29(39.19)	15(20.27)	59(79.73)
联合组	74	16(21.62)	24(32.43)	28(37.84)	6(8.11)	68(91.89)
χ²值^a		1.132				0.159
P值		0.258				0.690
χ²值^b		3.438				6.229
P值		0.001				0.013
χ²值^c		2.227				4.495
P值		0.026				0.034