异基因造血干细胞移植后乙型肝炎病毒感染2例临床干预并文献复习

目的加强对造血干细胞移植中HBV感染的重视，注重早期干预，提高移植成功率。方法回顾性分析97例异基因造血干细胞移植患儿的临床资料，通过对2例HBV感染的诊治体会结合文献复习。结果2001年5月至2008年5月在上海交通大学附属上海儿童医学中心接受异基因造血于细胞移植的97例患儿中，2例分别在移植后41d（病例1）、15个月（病例2）发生HBV感染。病例1移植前肝功能正常，乙肝二对半检查阴性，回顾性分析发现该患儿移植时HBV正处于潜伏状态（HBV—DNA1．17×10^6copies·mL^-1）。该患儿乙肝来势凶猛，移植后41～43d出现巩膜明显黄染并伴大量腹水，移植后46d迅速发展至肝、肾功能衰竭，出现少尿，凝血酶原时间38．4S，部分凝血酶原时间〉120S，凝血酶时间〉100s，Cr251μmol·L^-1，ALT3195U·L^-1，血清总胆红素7mg·L^-1，直接鹏红素2．8mg·L^-1，HBV—DNA1，08×10^3copies·mL^-1，经拉米夫定等积极治疗2周后好转。移植后130d随着移植物抗宿主病（GVHD）的复燃和免疫抑制药物的加强应用，HBV再度活跃，HBV—DNA从原已控制的3．50×10^4copies·mL^-1逐升至2．05×10^6copies·mL^-1，移植后315d出现HBVYMDD（＋）变异株，遂予阿德福韦酯联合治疗至今（移植后3．5年），目前肝、肾功能正常。病例2白血病起病初及干细胞移植前均示HBs-Ab（＋）、HBc—Ab（＋）、HBe—Ab（＋），A¨和HBV—DNA正常，移植后12个月发生慢性广泛性GVHD，加强抗排异治疗后于移植后15个月复查发现：ALT168U·L^-1，HBV-DNA升至5×10^8copies·mL^-1，出现HBs-Ag（＋）和HBe-Ag（＋）。予拉米夫定治疗至移植后4．5年，目前ALT40～80U·L^-1，HBV—DNA1×10^3～1×10^4copies·mL^-1。结论乙肝在移植患儿巾并不少见，长期的免疫抑制治疗常使病情反复，加强病毒监测、重视早期干预至关重要；移植前HBVDNA检测有助于发现潜伏期患儿；HBs—Ab（＋）、HBe—Ab（＋）和HBc—Ab（＋）患儿在强烈免疫抑制下仍有HBV复燃的风险。

Experience of treated patient with fulminant hepatitis B after allogenic hematopoietic stem cell transplantation

Objective To intensify the recognition of hepatitis B infection in patient with hematopoietie stem cell transplantation and pay much attention to treatment earlier to enhance event free survival of hematopoietic stem cell transplantation. Methods The clinical data of 97 consecutive patients with allogenic stem cell transplantion in our institute were retrospectively analysed, By view of the experience of successful rescue of 2 patients with HBV infection, the significance of earlier intervention was discussed, Results Since May 2001,97 cases of allogenic stem cell transplantation had been performed in our hospital. Among them 2 cases were accompanied hepatitis B on ＋ 41 d（ case 1 ） and ＋ 14 months （case 2） after transplantation. Case 1 was normal for live and kidney function and negative for HBV seroreaction at the rate of 5/6 to matched unrelated donor hematopoietic stem cell transplantation. But by reviewing the pre-transplantation blood sample we found this patient was in the latency of HBV infection（ HBV-DNA reached to 1.17 × 10^6 copies · mL^-1 ）. The onset of HBV infection was so severe that obvious jaundice and a great deal of ascites occurred within 3 days and it rapidly progressed to liver and kidney failure within 5 days with ALT 3 195 U ·L^-1, PT 38.4 s, KPTr 〉 120 s, TF〉 100 s, TBIL7 mg · L^-1, DBIL 2.8 mg · L^-1, HBV-DNA 1.08 ×10^8 copies · mL^-1 and disuria occurred with Cr 251 μmol·L^ -1. After treatment with lamivudine the patients recovered within 2 weeks. But HBV infection recurred with the amount of HBV-DNA from 3.50 × 10^4 copies·mL^-1 to 2.05 × 10^6 copies · mL^-1 on ＋ 130 d after transplantation accompanied with flare of chronic GVHD and immunosuppressive therapy was added. Unfortunately the emergence of YMDD motif polymerase mutations resulted in lamivudine resistance on ＋ 315 d after transplantation and Adefovir Dipivoxil was given till now （ ＋ 3.5 y after transplantation） to maintain the normal liver and kidney function. In case 2 it was found that anti-HBs（ ＋ ）, anti- HBc（ ＋ ） , anti-HBe（ ＋ ） with normal ALT, HBV-DNA was found during chemotherapy and the first year of 6/6 matched unrelated donor hematopoietic stem cell transplantation. Because of chronic extensive GVHD immunosuppressive therapy was intensified 12 months after transplantation , ALT 168 U ·L^-1 , HBV-DNA 5 × 10^8 copies · mL^-1 and HBs-Ag（ ＋ ） , HBe-Ag（ ＋ ） were found 15 months after transplantation . From that time Lamifudine was given till now （4.5 y post transplant） with ALT fluctuated between 40 -80 U · L^-1 and HBV-DNA 1× 10^3 - 1× 10^4 copies· mL^-1. Conclusions HBV infection was not rare in patients with hematopoietic stem cell transplant. It is important to monitor the virus and to treat it early. Screening HBV-DNA before transplant will contribute to find latency HBV infection. Reverse seroconversion of HBV after HSCT is possible among HBs-Ab（ ＋ ）, HBc-Ab （ ＋ ） recipients.