人再生胰岛衍生蛋白、可溶性抑瘤因子2、肿瘤坏死因子受体1在儿童异基因造血干细胞移植术后肠道急性移植物抗宿主病诊疗中的价值

The value of regenerating islet-derived protein 3-alpha,soluble tumor suppressor factor 2 and tumor necrosis factor receptor 1 in the diagnosis and treatment of intestinal acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation in children

目的探讨外周血中人再生胰岛衍生蛋白(REG3α)、可溶性抑瘤因子2(sST2)、肿瘤坏死因子受体1(TNFR1)3种生物蛋白标志物表达水平对儿童异基因造血干细胞移植(allo-HSCT)术后肠道急性移植物抗宿主病(aGVHD)诊断和疗效评估的临床应用价值。方法回顾性分析2020年1月至2021年2月在郑州大学第一附属医院儿科接受allo-HSCT患儿50例的临床资料,男39例,女11例;中位年龄8.5(1~13)岁。在移植前,移植后1周、2周、3周、5周、7周、9周、11周、13周,出现肠道aGVHD时,治疗后检测上述3种生物蛋白表达水平,将发生肠道aGVHD患儿作为观察组,无肠道aGVHD患儿作为对照组,分析2组患儿外周血中3种生物蛋白表达水平的差异是否有统计学意义。采用受试者工作特征曲线(ROC)评价上述3种生物蛋白对肠道aGVHD的诊断价值,采用独立样本t检验比较肠道aGVHD患儿治疗前后3种生物蛋白表达差异。结果1.观察组外周血中的REG3α、sST2、TNFR1水平分别为(33985.42±24631.33)ng/L、(139899.66±115825.65)ng/L、(3041.65±2418.72)ng/L,均高于对照组[(7457.39±4547.49)ng/L、(32059.57±23452.85)ng/L、(1944.51±1170.35)ng/L],差异均有统计学意义(t=6.04、5.19、2.17,均P<0.05)。2.REG3α联合sST2诊断肠道aGVHD的ROC曲线下面积(AUC)为0.952(95%CI:0.851~0.992,P<0.001),Youden指数最大值为0.894,对应灵敏度为83%,特异度为99%;其诊断价值优于REG3α、sST2、TNFR1单个指标(Z=1.763、1.332、3.001,均P<0.05);3.肠道aGVHD患儿治疗有效组治疗前外周血中REG3α、sST2、TNFR1水平分别为(31343.01±25364.71)ng/L、(146629.52±110501.04)ng/L、(2489.00±859.70)ng/L,治疗后下降[(12104.37±11704.60)ng/L、(93539.55±81920.93)ng/L、(2048.15±813.47)ng/L],REG3α、sST2表达水平显著降低,差异均有统计学意义(t=-3.23、-2.10,均P<0.05),TNFR1表达水平变化差异无统计学意义(P>0.05)。结论REG3α、sST2可作为临床辅助诊断肠道aGVHD的重要参考指标,具有较好的辅助诊断价值,也可作为评价临床治疗肠道aGVHD疗效的客观指标。

Objective To investigate the clinical value of the expression levels of biological protein markers regenerating islet-derived protein 3-alpha(REG3α),soluble tumor suppressor factor 2(sST2)and tumor necrosis factor receptor 1(TNFR1)in peripheral blood in the diagnosis and efficacy evaluation of intestinal acute graft-versus-host disease(aGVHD)in children after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods Retrospective analysis of 50 children who underwent allo-HSCT,in the Department of Pediatrics,the First Affiliated Hospital of Zhengzhou University from January 2020 to February 2021 were enrolled,including 39 males and 11 females[median age:8.5(1-13)years].The expression levels of above 3 biological proteins were detected before transplantation,1 week,2 weeks,3 weeks,5 weeks,7 weeks,9 weeks,11 weeks and 13 weeks after transplantation,when intestinal aGVHD occured,and after treatment.Children with intestinal aGVHD were taken as the observation group,and children without intestinal aGVHD were taken as the control group.Whether differences in the expression levels of the 3 biological proteins in the peripheral blood of the 2 groups of children were statistically significant was analyzed.The receiver operating characteristic(ROC)curve was used to evaluate the diagnostic value of the above three biological proteins for intestinal aGVHD,and independent sample t test was performed to compare the expression levels of the 3 biological proteins before and after treatment in children with intestinal aGVHD.Results(1)The concentrations of REG3α,sST2,and TNFR1 in the peripheral blood of the observation group were(33985.42±24631.33)ng/L,(139899.66±115825.65)ng/L,(3041.65±2418.72)ng/L,respectively,which were higher than the control group of(7457.39±4547.49)ng/L,(32059.57±23452.85)ng/L,(1944.51±1170.35)ng/L,the difference was statistically significant(t=6.04,5.19,2.17,all P<0.05).(2)The area under ROC curve(AUC)of REG3αcombined with sST2 in the diagnosis of intestinal aGVHD was 0.952(95%CI:0.851-0.992,P<0.001),the maximum Youden index was 0.894,the corresponding sensitivity was 83%,and the specificity was 99%.Its diagnostic value was better than REG3α,sST2 and TNFR1(Z=1.763,1.332,3.001,all P<0.05).(3)The concentrations of REG3α,sST2,and TNFR1 before treatment in the peripheral blood of children having received effective treatment were(31343.01±25364.71)ng/L,(146629.52±110501.04)ng/L and(2489.00±859.70)ng/L,respectively,which were(12104.37±11704.60)ng/L,(93539.55±81920.93)ng/L and(2048.15±813.47)ng/L after treatment,lower than those before treatment.The expression levels of REG3αand sST2 were significantly reduced(t=-3.23,-2.10,all P<0.05),while the difference of the expression level of TNFR1 before and after treatment was not statistically significant(P>0.05).Conclusions REG3αand sST2 can be used as important reference indicators for clinical auxiliary diagnosis of intestinal aGVHD,and have good auxiliary diagnostic value.REG3αand sST2 can be used as objective indicators to evaluate the efficacy of clinical treatment of intestinal aGVHD.