切换至 "中华医学电子期刊资源库"
高级检索
中华细胞与干细胞杂志(电子版)

中华细胞与干细胞杂志(电子版) ›› 2020, Vol. 10 ›› Issue (02) : 90 -96. doi: 10.3877/cma.j.issn.2095-1221.2020.02.004

所属专题： 文献；

论著

儿童获得性再生障碍性贫血造血干细胞移植后Epstein-Barr病毒血症危险因素及预后分析
章曼蘋1, 覃霞1, 罗成娟1, 王坚敏1, 罗长缨1, 陈静1,†()   
  1. 1. 200127　上海交通大学医学院附属上海儿童医学中心
  • 收稿日期:2019-07-01 出版日期:2020-04-01
  • 通信作者: 陈静
  • 基金资助:
    上海市进一步加快中医药事业发展三年行动计划（2018年-2020年）项目(ZY （2018-2020）-FWTX-3002)

Risk factors and prognosis of Epstein-Barr virus DNAemia in children with aplastic anemia after allogeneic hematopoietic stem cell transplantation

Manpin Zhang1, Xia Qin1, Chengjuan Luo1, Jianmin Wang1, Changying Luo1, Jing Chen1,†()   

  1. 1. Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medcine, Shanghai 200127, China
  • Received:2019-07-01 Published:2020-04-01
  • Corresponding author: Jing Chen
  • About author:
    Corresponding author:Chen Jing, Email:
全文 ( ) 下载PDF ( ) 导出引用
引用本文：

章曼蘋, 覃霞, 罗成娟, 王坚敏, 罗长缨, 陈静. 儿童获得性再生障碍性贫血造血干细胞移植后Epstein-Barr病毒血症危险因素及预后分析[J]. 中华细胞与干细胞杂志(电子版), 2020, 10(02): 90-96.

Manpin Zhang, Xia Qin, Chengjuan Luo, Jianmin Wang, Changying Luo, Jing Chen. Risk factors and prognosis of Epstein-Barr virus DNAemia in children with aplastic anemia after allogeneic hematopoietic stem cell transplantation[J]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2020, 10(02): 90-96.

目的

分析儿童获得性再生障碍性贫血（AA）异基因造血干细胞移植（allo- HSCT）后Epstein-Barr病毒（EBV）血症的危险因素、利妥昔单抗的干预效果及EBV相关疾病的临床转归。

方法

回顾性分析2010年4月至2018年3月于上海儿童医学中心完成allo-HSCT的257例AA患儿，根据是否发生EBV血症分为：EBV血症组（141例，单纯EBV血症组125例和EBV相关疾病组16例）和非EBV血症组（116例）。采用Cox回归分析危险因素，采用Kaplan- Meier法分析累积生存率，定性资料的组间比较采用卡方检验。

结果

（1）257例患儿行allo-HSCT后发生EBV血症为141例，发生率为54.86﹪ （141/257），其中原发感染为5.67﹪（8/257），再激活为94.33﹪（133/141）。EBV血症的中位发生时间为移植后44 d （13 ~ 568 d），单纯EBV血症的移植相关死亡率为6.40﹪（8/125）；EBV相关疾病的病死率为56.25﹪（9/16）。（2）利妥昔单抗抢先治疗EBV血症的有效率为88.73﹪ （63/71）。（3）与单纯EBV血症组比较，EBV相关疾病组患儿生存率降低，差异有统计学意义（Log-rank P < 0.001）。（4）多因素分析结果显示，使用全身照射治疗（TBI）预处理的患儿，发生EBV感染的风险是不使用TBI预处理的患儿1.717倍（95﹪的CI：1.160 ~ 2.542）；患儿移植物中CD34阳性细胞≥3×106个/kg是< 3×106个/kg患儿的1.775倍（95﹪的CI：1.089 ~ 2.894）。

结论

移植后EBV血症的发生和TBI的应用、输注CD34阳性细胞数大于3×106个/kg密切相关，EBV血症进展为EBV疾病后移植相关死亡率升高，对高危患儿应积极予以利妥昔单抗抢先治疗改善预后。

关键词: 异基因造血干细胞移植, 儿童, Epstein-Barr病毒, 利妥昔单抗
Objective

To investigate risk factors of Epstein-Barr virus (EBV) DNAemia, treatment effects of rituximab, and clinical outcomes of Epstein-Barr virus (EBV) diseasesin children with aplastic anemia (AA) after allogeneic hematopoietic stem cell transplantation (allo- HSCT) .

Method

A retrospective analysis was conducted on children with aplastic anemia (AA) who underwent allo-HSCT from April 2010 to March 2018 in Shanghai Children's Medical Center. According to the occurrence of EBV DNAemia, they were divided into: EBV DNAemia group (141cases, including simple EBV DNAemia 125 cases and EBV-relateddiseases group 16 cases) and non-EBV DNAemia group (116 cases) . Cox regression was used to analyze the risk factors, Kaplan-Meier method was used to analyze the cumulative survival rate, and chi-square test was used to compare the qualitative data between groups.

Result

(1) After allo-HSCT in 257 children, 141 cases developed EBV, the incidence was 54.86﹪ (141/257) , the primary infection was 5.67﹪ (8/257) , the reactivation was 94.33﹪ (133/141) . The median time of EBV was 44 days (13 ~ 568 days) after transplantation. The mortality of simple EBV DNAemia and EBV-related diseases were 6.40﹪ (8/125) and 56.25﹪ (9/16) respectively. (2) Approximately 88.73﹪ (63/71) of patients with EBV were successfully treated preemptively with rituximab. (3) Compared with the EBVemia group, the survival rate of children with EBV-related disease group decreased, and the difference was statistically significant (Log-rank P <0.001) . (4) The results of multivariate analysis showed that children with TBI pretreatment had a 1.717-fold higher probability of EBV infection than those without TBI pretreatment (95﹪ CI 1.160-2.542) . The CD34-positive cells in the grafts of patients were≥3×106 cells/kg, which was 1.775 times than children with <3×106 cells/kg (95﹪ CI 1.089-2.894) .

Conclusion

The occurrence of EBVemia after transplantation is related to the whole body irradiation treatment and the number of CD34-positive cells infused greater than 3×106 cells/kg. EBV DNAemia progression to EBV disease increases transplant-related mortality. The usage of rituximab as preemptive prophylaxis may reduce the incidence and mortality.

Key words: Allogeneic hematopoietic stem cell transplantation, Children, Epstein-Barr virus, Rituximab
表1 EBV血症的危险因素分析
因素 例数 EBV感染发生率（﹪） 单因素分析 多因素分析
? HR值 95﹪CI P值 HR值 95﹪CI P值
性别 ? ? 0.935 0.670 ~ 1.304 0.692 0.900 0.633 ~ 1.278 0.555
? 女 116 52.59 ? ? ? ? ? ?
? 男 141 56.74 ? ? ? ? ? ?
年龄 ? ? 1.150 0.790 ~ 1.674 0.465 1.271 0.855 ~ 1.891 0.236
? >5岁 182 57.14 ? ? ? ? ? ?
? ≤5岁 75 49.33 ? ? ? ? ? ?
移植前EBV血清学 ? ? 1.491 0.730 ~ 3.044 0.273 1.716 0.827 ~ 3.562 0.147
? EBV IgG阴性 18 44.44 ? ? ? ? ? ?
? EBV IgG阳性* 238 55.88 ? ? ? ? ? ?
HLA配型 ? ? 1.128 0.809 ~ 1.574 0.478 1.004 0.697 ~ 1.447 0.983
? HLA不全相合 140 56.43 ? ? ? ? ? ?
? HLA全相合 117 52.99 ? ? ? ? ? ?
移植类型 ? ? 1.154 0.968 ~ 1.376 0.111 1.014 0.820 ~ 1.254 0.897
? 非血缘 160 59.38 ? ? ? ? ? ?
? 血缘 97 47.42 ? ? ? ? ? ?
是否使用TBI ? ? 1.865 1.305 ~ 2.665 0.001 1.717 1.160 ~ 2.542 0.007
? 是 156 62.18 ? ? ? ? ? ?
? 否 101 43.56 ? ? ? ? ? ?
急性GVHD ? ? 1.299 0.922 ~ 1.830 0.134 1.288 0.904 ~ 1.837 0.162
? 0 ~ I度 171 52.05 ? ? ? ? ? ?
? II ~ IV度 86 60.47 ? ? ? ? ? ?
移植物中单个核细胞数 ? ? 1.310 0.908 ~ 1.891 0.149 1.218 0.820 ~ 1.808 0.329
? ≤15×108个/kg 171 47.95 ? ? ? ? ? ?
? >15×108个/kg 85 36.47 ? ? ? ? ? ?
移植物中CD34阳性细胞数 ? ? 1.821 1.155 ~ 2.872 0.010 1.775 1.089 ~ 2.894 0.021
? >3×106个/kg 200 59.00 ? ? ? ? ? ?
? ≤3×106个/kg 55 40.00 ? ? ? ? ? ?
移植物中CD3阳性细胞数 ? ? 1.207 0.862 ~ 1.690 0.273 1.102 0.760 ~ 1.596 0.609
? ≤3×108个/kg 140 58.58 ? ? ? ? ? ?
? >3×108个/kg 115 50.43 ? ? ? ? ? ?
移植物中CD19阳性细胞数 ? ? 1.249 0.845 ~ 1.846 0.265 1.441 0.950 ~ 2.184 0.085
? ≤10×107个/kg 55 53.82 ? ? ? ? ? ?
? >10×107个/kg 199 60.00 ? ? ? ? ? ?
图1 63例治疗有效患儿利妥昔单抗应用次数
图2 8例利妥昔单抗治疗无效患儿死亡原因
图3 EBV血症与非EBV血症患儿allo-HSCT的累积生存曲线
图4 单纯EBV血症与EBV相关疾病患儿allo-HSCT的累积生存曲线
[1]
Styczynski J, Van Der Velden W, Fox CP, et al. Management of Epstein- Barr virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: sixth European conference on infections in leukemia (ECIL-6) guidelines[J]. Haematologica, 2016, 101(7):803-811.
[2]
Styczynski J, Gil L, Tridello G, et al. Response to Rituximab- Based therapy and risk factor analysis in epstein Barr Virus-Related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the infectious diseases working party of the European Gro[J]. Clin Infect Dis, 2013, 57(6):794-802.
[3]
Kinch A, Hallböök H, Arvidson J, et al. Long-term outcome of Epstein- Barr virus DNAemia and PTLD with the use of preemptive rituximab following allogeneic HSCT[J]. Leuk Lymphoma, 2018, 59(5):1172-1179.
[4]
Wareham NE, Mocroft A, Sengeløv H, et al. The value of EBV DNA in early detection of post-transplant lymphoproliferative disorders among solid organ and hematopoietic stem cell transplant recipients[J]. J Cancer Res Clin Oncol, 2018, 144(8):1569-1580.
[5]
Uhlin M, Wikell H, Sundin M, et al. Risk factors for Epstein- Barr virus- related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation[J]. Haematologica, 2014, 99(2):346-352.
[6]
Storek J. Anti-thymocyte globulin dosing-per kg or per lymphocyte?[J]. Lancet Haematol, 2017, 4(4):e154-e155.
[7]
Dubey S, Srivastava A, Nityanand S. Induction of apoptosis of peripheral blood mononuclear cells by antithymocyte globulin (ATG) in aplastic anemia: an in vivo and in vitro study[J]. Ann Hematol, 2002, 81(5):249-253.
[8]
Gagelmann N, Ayuk F, Wolschke C, et al. Comparison of different rabbit anti-thymocyte globulin formulations in allogeneic stem cell transplantation:Systematic literature review and network meta- analysis[J]. Biol Blood Marrow Transplant, 2017, 23(12):2184-2191.
[9]
Baron F, Mohty M, Blaise D, et al. Anti-thymocyte globulin as graft- versus-host disease prevention in the setting of allogeneic peripheral blood stem cell transplantation:A review from the acute leukemia working party of the European society for blood and marrow transplantation[J]. Haematologica, 2017, 102(2):224-234.
[10]
Patriarca F, Medeot M, Isola M, et al. Prognostic factors and outcome of Epstein-Barr virus DNAemia in high-risk recipients of allogeneic stem cell transplantation treated with preemptive rituximab[J]. Transpl Infect Dis, 2013, 15(3):259-267.
[11]
Styczynski J. Managing post-transplant lymphoproliferative disorder[J]. Expert Opinion On Orphan Drugs, 2017, 5(1):19-35.
[12]
Czerw T, Labopin M, Schmid C, et al. High CD3+ and CD34+ peripheral blood stem cell grafts content is associated with increased risk of graft- versus-host disease without beneficial effect on disease control after reduced-intensity conditioning allogeneic transplantation from matched unrelated donors for acute myeloid leukemia-an analysis from the acute leukemia working party of the European society for blood and marrow transplantation[J]. Oncotarget, 2016, 7(19):27255-27266.
[13]
Van Esser JW, Van Der Holt B, Meijer E, et al. Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell-depleted SCT[J]. Blood, 2001, 98(4):972-978.
[14]
Burns DM, Rana S, Martin E, et al. Greatly reduced risk of EBV reactivation in rituximab-experienced recipients of alemtuzumab- conditioned allogeneic HSCT[J]. Bone Marrow Transplant, 2016, 51(6):825-832.
[15]
Garcia-Cadenas I, Castillo N, Martino R, et al. Impact of Epstein Barr virus-related complications after high-risk allo-SCT in the era of pre- emptive rituximab[J]. Bone Marrow Transplant, 2015, 50(4):579-584.
[16]
Solano C, Mateo EM, Pérez A, et al. Epstein-barr virus DNA load kinetics analysis in allogeneic hematopoietic stem cell transplant recipients: Is it of any clinical usefulness?[J]. J Clin Virol, 2017, 97:26-32.
[17]
Chiereghin A, Piccirilli G, Belotti T, et al. Clinical utility of measuring epstein-barr virus-specific cell-mediated immunity after hsct in addition to virological monitoring:Results from a prospective study[J]. Med Microbiol Immunol, 2019, 208(6):825-834.
[18]
Sanz J, Andreu R. Epstein-Barr virus-associated posttransplant lymphoproliferative disorder after allogeneic stem cell transplantation[J]. Curr Opin Oncol, 2014, 26(6):677-683.
[1] 张璇, 马宇童, 苗玉倩, 张云, 吴士文, 党晓楚, 陈颖颖, 钟兆明, 王雪娟, 胡淼, 孙岩峰, 马秀珠, 吕发勤, 寇海燕. 超声对Duchenne肌营养不良儿童膈肌功能的评价[J]. 中华医学超声杂志（电子版）, 2023, 20(10): 1068-1073.
[2] 张宝富, 俞劲, 叶菁菁, 俞建根, 马晓辉, 刘喜旺. 先天性原发隔异位型肺静脉异位引流的超声心动图诊断[J]. 中华医学超声杂志（电子版）, 2023, 20(10): 1074-1080.
[3] 韩丹, 王婷, 肖欢, 朱丽容, 陈镜宇, 唐毅. 超声造影与增强CT对儿童肝脏良恶性病变诊断价值的对比分析[J]. 中华医学超声杂志（电子版）, 2023, 20(09): 939-944.
[4] 刘婷婷, 林妍冰, 汪珊, 陈幕荣, 唐子鉴, 代东伶, 夏焙. 超声衰减参数成像评价儿童代谢相关脂肪性肝病的价值[J]. 中华医学超声杂志（电子版）, 2023, 20(08): 787-794.
[5] 周钰菡, 肖欢, 唐毅, 杨春江, 周娟, 朱丽容, 徐娟, 牟芳婷. 超声对儿童髋关节暂时性滑膜炎的诊断价值[J]. 中华医学超声杂志（电子版）, 2023, 20(08): 795-800.
[6] 米洁, 陈晨, 李佳玲, 裴海娜, 张恒博, 李飞, 李东杰. 儿童头面部外伤特点分析[J]. 中华损伤与修复杂志(电子版), 2023, 18(06): 511-515.
[7] 中华医学会烧伤外科学分会小儿烧伤学组. 儿童烧伤早期休克液体复苏专家共识(2023版)[J]. 中华损伤与修复杂志(电子版), 2023, 18(05): 371-376.
[8] 吴少峰, 张轶男, 孙杰. 机器人辅助手术在儿童微创泌尿手术中的应用和展望[J]. 中华腔镜泌尿外科杂志(电子版), 2023, 17(05): 440-444.
[9] 朱良振, 于永刚, 陈杲, 廖松柏. 儿童高级别闭合性肾损伤肾动脉栓塞与手术探查的疗效比较[J]. 中华腔镜泌尿外科杂志(电子版), 2023, 17(05): 461-465,475.
[10] 王蕾, 王少华, 牛海珍, 尹腾飞. 儿童腹股沟疝围手术期风险预警干预[J]. 中华疝和腹壁外科杂志(电子版), 2023, 17(06): 768-772.
[11] 李芳, 许瑞, 李洋洋, 石秀全. 循证医学理念在儿童腹股沟疝患者中的应用[J]. 中华疝和腹壁外科杂志(电子版), 2023, 17(06): 782-786.
[12] 吕垒, 冯啸, 何凯明, 曾凯宁, 杨卿, 吕海金, 易慧敏, 易述红, 杨扬, 傅斌生. 改良金氏评分在儿童肝豆状核变性急性肝衰竭肝移植手术时机评估中价值并文献复习[J]. 中华肝脏外科手术学电子杂志, 2023, 12(06): 661-668.
[13] 卓少宏, 林秀玲, 周翠梅, 熊卫莲, 马兴灶. CD64指数、SAA/CRP、PCT联合检测在小儿消化道感染性疾病鉴别诊断中的应用[J]. 中华消化病与影像杂志(电子版), 2023, 13(06): 505-509.
[14] 刘笑笑, 张小杉, 刘群, 马岚, 段莎莎, 施依璐, 张敏洁, 王雅晳. 中国学龄前儿童先天性心脏病流行病学研究进展[J]. 中华临床医师杂志(电子版), 2023, 17(9): 1021-1024.
[15] 李静, 张玲玲, 邢伟. 兴趣诱导理念用于小儿手术麻醉诱导前的价值及其对家属满意度的影响[J]. 中华临床医师杂志(电子版), 2023, 17(07): 812-817.
阅读次数
全文


摘要

版权所有 中华医学会 中华医学电子音像出版社有限责任公司  京ICP备14006079号-1  网络出版服务许可证：(署)网出证(京)字第075号