Changes of Peripheral Blood Lymphocyte Subsets in 212 Active Tuberculosis Patients: A Uni-centered Descriptive Study
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摘要:
目的 基于相对较大的样本数据,探究活动性结核病(active tuberculosis, ATB)患者外周血淋巴细胞亚群特点及其意义。 方法 回顾性收集北京协和医院住院ATB患者(2012年6月—2022年1月)及年龄、性别与其相匹配的健康人群(2019年3月—2022年5月)的临床资料。以健康人群为对照,分析ATB患者外周血淋巴细胞亚群变化特点,并对不同确诊方式及受累部位ATB患者进行组间比较。 结果 共入选符合纳入与排除标准的ATB患者212例、健康人群200例。ATB患者中,临床确诊82例(38.7%)、病原学确诊130例(61.3%, 包括单纯肺结核77例、单纯肺外结核21例、肺结核并肺外结核32例)。相较于健康人群,ATB患者多种外周血淋巴细胞亚群指标计数及其百分比降低(P均<0.05),T淋巴细胞百分比、CD8+T淋巴细胞百分比、记忆CD4+T淋巴细胞/CD4+T淋巴细胞比值、CD38+CD8+T淋巴细胞/CD8+T淋巴细胞比值等均升高(P均<0.05)。相较于临床确诊ATB患者,病原学确诊ATB患者淋巴细胞、B细胞、自然杀伤(natural killer,NK)细胞、T淋巴细胞、CD4+T淋巴细胞、CD8+T淋巴细胞计数等均降低(P均<0.05)。不同结核感染部位的患者记忆CD4+T淋巴细胞、纯真CD4+T淋巴细胞、CD28+T淋巴细胞及活化CD8+T淋巴细胞亚群计数及其百分比无显著差异(P均>0.05)。相较于单纯肺结核患者,肺结核并肺外结核患者B细胞计数[23(10,69)个/μL比73(25,133)个/μL, P=0.003]降低,单纯肺外结核患者NK细胞百分比[16.7%(10.8%,23.6%)比10.6%(5.3%,17.4%), P=0.042]升高。 结论 ATB患者外周血淋巴细胞亚群指标整体呈减低状态,存在明显的免疫功能紊乱。 Abstract:Objective To explore the characteristics and their significance of peripheral blood lymphocyte subsets in patients with active tuberculosis(ATB), based on a relatively large sample. Methods Clinical data were retrospectively collected from patients with ATB hospitalized in Peking Union Medical College Hospital (June 2012-January 2022) and the healthy population matched with age and sex (March 2019-May 2022). The characteristics of changes in peripheral blood lymphocyte subsets in ATB patients were analyzed using the healthy population as controls, and group comparisons were made between ATB patients with different modes of diagnosis and sites of involvement. Results A total of 212 ATB patients and 200 healthy participants were included. ATB patients consisted of 82 cases (38.7%) without etiological evidence and 130 cases(61.3%) with etiological evidence (77 with pulmonary tuberculosis, 21 with extrapulmonary tuberculosis, and 32 with pulmonary and extrapulmonary tuberculosis). Compared to healthy population, ATB patients had significantly lower counts and percentages of multiple peripheral blood lymphocyte subsets indicators, significantly higher percentage in T lymphocyte, CD8+T lymphocyte as well as higher memory CD4+T lymphocyte/CD4+T lymphocyte ratio and CD38+CD8+T lymphocyte/CD8+T lymphocyte ratio(all P < 0.05). Lymphocyte, B-cell, natural killer (NK) cell, T-lymphocyte, CD4+T-lymphocyte, and CD8+T-lymphocyte counts were lower in patients with pathogenetically confirmed ATB than in those with clinically confirmed ATB (all P < 0.05). There were no significant differences in the counts of memory CD4+T lymphocytes, naïve CD4+T lymphocytes, CD28+T lymphocytes and activated CD8+T lymphocyte subpopulations and their percentages in patients with different tuberculosis infection sites (all P > 0.05). Compared to pulmonary tuberculosis alone, patients with pulmonary and extrapulmonary tuberculosis had lower B-cell counts[23(10, 69)cells/μL vs. 73(25, 133)cells/μL, P=0.003] and patients with extrapulmonary tuberculosis alone had higher percentages of NK cells[16.7%(10.8%, 23.6%) vs. 10.6% (5.3%, 17.4%), P=0.042]. Conclusion ATB patients manifested a reduction in peripheral blood lymphocyte subset, indicating remarkable dysfunction of immune system. 作者贡献:谢蓝田负责研究设计、数据分析及论文初稿撰写,阮桂仁、刘晓清、张丽帆、张月秋提出修改意见;邱志峰提供化验结果;侍效春负责论文修改及定稿。利益冲突:所有作者均声明不存在利益冲突 -
表 1 ATB患者与健康人群一般资料比较
指标 ATB患者(n=212) 健康人群(n=200) P值 男性[n(%)] 133(62.7) 125(62.5) 0.961 年龄[M(P25, P75), 岁] 56(33,66) 55(37,65) 0.952 糖尿病[n(%)] 38(17.9) 14(7.0) 0.001 血红蛋白(x±s, g/L) 109±3 145±3 <0.001 血小板计数[M(P25, P75), 个/μL] 242(161,337) 216(186,260) 0.145 白细胞计数[M(P25, P75), 个/μL] 6690(4583,8538) 5465(4595,6715) <0.001 中性粒细胞百分比[M(P25, P75), %] 75.2(68.0,84.0) 58.9(54.1,64.3) <0.001 中性粒细胞计数[M(P25, P75), 个/μL] 4728(3304,6897) 3285(2557,4005) <0.001 CRP*[M(P25, P75), mg/L] 43.60(13.87,99.63) 0.77(0.39,1.59) <0.001 ATB:活动性肺结核;CRP:C反应蛋白;*ATB患者、健康人群分别有38例、13例信息缺失 表 2 ATB患者与健康人群外周血淋巴细胞亚群比较
指标 ATB患者(n=212) 健康人群(n=200) P值 淋巴细胞百分比[M(P25, P75), %] 14.6(9.2,20.5) 30.8(24.7,35.7) <0.001 淋巴细胞计数[M(P25, P75), 个/μL] 916(516,1315) 1668(1352,1953) <0.001 B细胞百分比[M(P25, P75), %] 7.6(4.4,12.7) 11.5(7.9,14.4) <0.001 B细胞计数[M(P25, P75), 个/μL] 62(27,116) 177(123,248) <0.001 NK细胞百分比[M(P25, P75), %] 12.0(7.1,17.9) 15.7(10.6,21.9) <0.001 NK细胞计数[M(P25, P75), 个/μL] 96(48,176) 258(176,368) <0.001 T淋巴细胞百分比[M(P25, P75), %] 77.6(68.8,82.9) 70.9(65.2,76.8) <0.001 T淋巴细胞计数[M(P25, P75), 个/μL] 681(380,999) 1148(882,1474) <0.001 CD4+T淋巴细胞百分比(x±s, %) 39.8±1.7 39.9±1.2 0.892 CD4+T淋巴细胞计数[M(P25, P75), 个/μL] 369(185,531) 665(489,818) <0.001 CD8+T淋巴细胞百分比[M(P25, P75), %] 27.7(20.3,39.6) 24.2(19.2,30.0) <0.001 CD8+T淋巴细胞计数[M(P25, P75), 个/μL] 240(127,399) 384(288,493) <0.001 记忆CD4+T淋巴细胞/CD4+T淋巴细胞比值*(x±s) 68.7±3.1 63.8±2.1 0.008 记忆CD4+T淋巴细胞计数*[M(P25, P75), 个/μL] 208(112,331) 401(313,519) <0.001 CD45RA+CD4+T淋巴细胞/CD4+T淋巴细胞比值*(x±s) 30.8±3.1 36.2±2.1 0.003 CD45RA+CD4+T淋巴细胞计数*[M(P25, P75), 个/μL] 198(30,197) 234(130,364) <0.001 纯真CD4+T淋巴细胞/CD4+T淋巴细胞比值*(x±s) 29.6±3.1 33.9±2.1 0.018 纯真CD4+T淋巴细胞计数*[M(P25, P75), 个/μL] 91(25,187) 219(122,337) <0.001 CD28+CD4+T淋巴细胞/CD4+T淋巴细胞比值[M(P25, P75)] 95.8(90.5,98.7) 97.2(92.8,99.3) 0.009 CD28+CD4+T淋巴细胞计数[M(P25, P75), 个/μL] 345(163,505) 616(448,780) <0.001 CD28+CD8+T淋巴细胞/CD8+T淋巴细胞比值[M(P25, P75)] 46.8(31.4,63.2) 60.4(45.1,76.1) <0.001 CD28+CD8+T淋巴细胞计数[M(P25, P75), 个/μL] 104(50,204) 218(153,296) <0.001 CD8DR+T淋巴细胞/CD8+T淋巴细胞比值[M(P25, P75)] 51.9(32.2,69.1) 39.1(22.4,54.1) <0.001 CD8DR+T淋巴细胞计数[M(P25, P75), 个/μL] 96(48,209) 129(86,232) 0.005 CD38+CD8+T淋巴细胞/CD8+T淋巴细胞比值[M(P25, P75)] 68.4(54.8,84.0) 29.7(20.6,40.0) <0.001 CD38+ CD8+T淋巴细胞计数[M(P25, P75), 个/μL] 162(85,259) 103(66,164) <0.001 CD4+T淋巴细胞/CD8+T淋巴细胞[M(P25, P75)] 1.51(0.88,2.22) 1.66(1.21,2.24) 0.010 ATB:同表 1;NK:自然杀伤细胞;*76例ATB患者信息缺失 表 3 病原学确诊ATB与临床确诊ATB患者外周血淋巴细胞亚群比较
指标 病原学确诊ATB(n=130) 临床确诊ATB(n=82) P值 淋巴细胞百分比[M(P25, P75), %] 12.0(7.6,19.1) 17.5(12.6,23.7) <0.001 淋巴细胞计数[M(P25, P75), 个/μL] 748(459,1129) 1187(737,1599) <0.001 B细胞百分比[M(P25, P75), %] 8.5(4.5,14.1) 6.8(4.4,10.6) 0.063 B细胞计数[M(P25, P75), 个/μL] 56(22,110) 73(37,120) 0.049 NK细胞百分比[M(P25, P75), %] 12.1(6.6,18.4) 10.9(7.3,17.2) 0.647 NK细胞计数[M(P25, P75), 个/μL] 88(32,150) 111(69,196) 0.004 T淋巴细胞百分比[M(P25, P75), %] 75.6(66.3,82.1) 78.8(72.8,85.0) 0.028 T淋巴细胞计数[M(P25, P75), 个/μL] 578(303,876) 890(584,1251) <0.001 CD4+T淋巴细胞百分比(x±s, %) 37.5±2.4 43.4±2.3 0.001 CD4+T淋巴细胞计数[M(P25, P75), 个/μL] 247(140,433) 483(301,683) <0.001 CD8+T淋巴细胞百分比[M(P25, P75), %] 27.7(20.6,40.0) 27.6(19.6,39.1) 0.449 CD8+T淋巴细胞计数[M(P25, P75), 个/μL] 220(107,362) 293(181,471) 0.001 记忆CD4+T淋巴细胞/CD4+T淋巴细胞比值*(x±s) 70.0±3.9 65.7±5.3 0.204 记忆CD4+T淋巴细胞计数*[M(P25, P75), 个/μL] 162(89,285) 320(209,487) <0.001 CD45RA+CD4+T淋巴细胞/CD4+T淋巴细胞比值*(x±s) 29.2±3.7 34.3±5.3 0.121 CD45RA+CD4+T淋巴细胞计数*[M(P25, P75), 个/μL] 66(20,139) 166(93,300) <0.001 纯真CD4+T淋巴细胞/CD4+T淋巴细胞比值*(x±s) 28.3±3.9 32.4±5.3 0.226 纯真CD4+T淋巴细胞计数*[M(P25, P75), 个/μL] 65(18,156) 146(75,296) <0.001 CD28+CD4+T淋巴细胞/CD4+T淋巴细胞比值[M(P25, P75)] 95.3(87.7,98.7) 96.2(91.0,98.6) 0.258 CD28+CD4+T淋巴细胞计数[M(P25, P75), 个/μL] 236(123,407) 452(289,635) <0.001 CD28+CD8+T淋巴细胞/CD8+T淋巴细胞比值[M(P25, P75)] 41.8(27.8,63.0) 51.5(47.1,55.9) 0.058 CD28+CD8+T淋巴细胞计数[M(P25, P75), 个/μL] 86(39,169) 147(79,240) <0.001 CD8DR+T淋巴细胞/CD8+T淋巴细胞比值[M(P25, P75)] 55.3(31.0,73.1) 45.9(33.5,63.0) 0.098 CD8DR+T淋巴细胞计数[M(P25, P75), 个/μL] 90(43,189) 116(60,248) 0.059 CD38+CD8+T淋巴细胞/CD8+T淋巴细胞比值[M(P25, P75)] 72.0(55.2,86.0) 63.8(59.8,67.8) 0.022 CD38+ CD8+T淋巴细胞计数[M(P25, P75), 个/μL] 144(69,224) 184(99,281) 0.008 CD4+T淋巴细胞/CD8+T淋巴细胞[M(P25, P75)] 1.47(0.71,2.10) 1.64(1.05,2.45) 0.061 ATB:同表 1;NK:同表 2;*病原学确诊ATB和临床确诊ATB分别有36例、40例信息缺失 表 4 不同受累部位的病原学确诊ATB患者外周血淋巴细胞亚群比较
指标 单纯肺结核(n=77) 单纯肺外结核(n=21) 肺结核并肺外结核(n=32) P值 淋巴细胞百分比[M(P25, P75), %] 12.7(5.9,19.4) 10.2(8.1,15.4) 11.9(8.8,19.3) 0.757 淋巴细胞计数[M(P25, P75), 个/μL] 910(777,1043) 855(694,1017) 656(473,840) 0.083 B细胞百分比[M(P25, P75), %] 10.0(5.9,15.2) 8.6(4.3,11.5) 4.9(2.3,14.8) 0.066 B细胞计数[M(P25, P75), 个/μL] 73(25,133) 46(34,93) 23(10,69)# 0.004 NK细胞百分比[M(P25, P75), %] 10.6(5.3,17.4) 16.7(10.8,23.6)# 16.0(7.5,17.9) 0.033 NK细胞计数[M(P25, P75), 个/μL] 95(27,146) 132(78,226) 61(30,143) 0.064 T淋巴细胞百分比[M(P25, P75), %] 74.3(71.5,77.1) 71.5(65.7,77.3) 76.1(72.7,79.5) 0.386 T淋巴细胞计数[M(P25, P75), 个/μL] 694(581,806) 601(489,712) 510(360,660) 0.142 CD4+T淋巴细胞百分比(x±s, %) 36.8±3.4 40.0±5.2 37.7±3.4 0.625 CD4+T淋巴细胞计数[M(P25, P75), 个/μL] 269(137,482) 388(189,467) 207(120,361) 0.128 CD8+T淋巴细胞百分比[M(P25, P75), %] 28.1(19.7,41.7) 25.1(20.6,29.0) 29.4(23.5,41.4) 0.408 CD8+T淋巴细胞计数[M(P25, P75), 个/μL] 224(108,418) 224(138,279) 175 (73,287) 0.177 记忆CD4+T淋巴细胞/CD4+T淋巴细胞比值*(x±s) 70.0±5.2 71.2±9.7 69.1±8.6 0.948 记忆CD4+T淋巴细胞计数*[M(P25, P75), 个/μL] 166(89,320) 279(113,323) 154(88,207) 0.253 CD45RA+CD4+T淋巴细胞/CD4+T淋巴细胞比值*(x±s) 28.6±4.8 28.8±9.7 30.9±8.5 0.881 CD45RA+CD4+T淋巴细胞计数*[M(P25, P75), 个/μL] 55(18,170) 99(42,118) 55(12,146) 0.765 纯真CD4+T淋巴细胞/CD4+T淋巴细胞比值*(x±s) 28.3±5.1 27.6±9.8 29.0±8.5 0.975 纯真CD4+T淋巴细胞计数*[M(P25, P75), 个/μL] 55(15,160) 97(36,112) 51(11,121) 0.829 CD28+CD4+T淋巴细胞/CD4+T淋巴细胞比值[M(P25, P75)] 95.3(88.1,98.9) 95.1(86.6,99.1) 95.4(87.8,97.9) 0.900 CD28+CD4+T淋巴细胞计数[M(P25, P75), 个/μL] 260(116,457) 357(184,426) 205(114,282) 0.123 CD28+CD8+T淋巴细胞/CD8+T淋巴细胞比值[M(P25, P75)] 51.7(29.0,71.6) 32.6(26.7,42.3) 41.5 (27.6,59.0) 0.091 CD28+CD8+T淋巴细胞计数[M(P25, P75), 个/μL] 101(49,208) 76(36,109) 74(26,159) 0.096 CD8DR+T淋巴细胞/CD8+T淋巴细胞比值[M(P25, P75)] 52.0(25.2,77.0) 61.0(48.9,69.5) 55.5(34.5,72.3) 0.455 CD8DR+T淋巴细胞计数[M(P25, P75), 个/μL] 83(40,215) 139(83,177) 65(34,157) 0.221 CD38+CD8+T淋巴细胞/CD8+T淋巴细胞比值[M(P25, P75)] 67.7(62.6,72.8) 67.9(59.1,76.2) 74.3(68.9,79.7) 0.289 CD38+ CD8+T淋巴细胞计数[M(P25, P75), 个/μL] 108(64,268) 150(73,180) 132(55,208) 0.788 CD4+T淋巴细胞/CD8+T淋巴细胞[M(P25, P75)] 1.37(0.64,2.19) 1.66(1.32,2.12) 1.23(0.73,1.64) 0.280 ATB:同表 1;NK:同表 2;*单纯肺结核、单纯肺外结核、肺结核并肺外结核分别有20例、4例、10例信息缺失;与单纯肺结核比较,#P<0.05 -
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