噬血细胞综合征-04方案治疗小儿EB病毒相关性噬血细胞综合征

Treatment of EBV-Hemophagocytic Lymphohistiocytosis With Hemophagocytic Lymphohistiocytosis-04 Protocol.

目的观察以噬血细胞综合征(hemophagocytic lymphohistiocytosis,HLH)-04方案为基础治疗儿童EB病毒(epstein-barr virus)相关性噬血细胞综合征(epstein-barr virus hemophagocytic lymphohistiocytosis,EBV-HLH)的疗效。方法采用回顾性分析法分析2005年4月至2008年4月本科12例确诊为儿童EB病毒相关性噬血细胞综合征患儿的临床特点,总结其治疗结果及转归情况。EB病毒感染的诊断,根据EB病毒血清抗体和(或)EB病毒-DNA呈阳性确诊。噬血细胞综合征的诊断依据噬血细胞综合征-04方案。噬血细胞综合征的治疗方法按噬血细胞综合征-04方案,遇效果不佳或有药物不良反应时适当改良,如以表鬼臼毒噻吩甲基苷(VM26)代替噬血细胞综合征-04方案中的鬼臼乙叉苷(VP16),以吗替麦考酚酯(cellcept,骁悉)代替环胞素A(CsA),吗替麦考酚酯+环胞素A代替鬼臼乙叉苷等。结果①临床表现:12例EB病毒相关性噬血细胞综合征患儿均表现为持续高热、脾大、血细胞减少;1例出现抽搐:8例患儿血清铁蛋白≥500 mg/L;6例三酰甘油≥3.0 mmol/L;5例纤维蛋白原≤1.5 g/L;8例外周血自然杀伤(natural killer,NK)细胞数量降低;所有患儿骨髓细胞涂片,均可见噬血细胞现象。②治疗反应:所有患儿中,1例确诊后放弃治疗;对接受治疗的11例患儿的中位随访时间为17个月(10～36个月)。治疗早期阶段:11例患儿完全缓解(complete remission,CR),平均中位随访时间为21 d。其中,10例患儿的完全缓解时间为14 d～42 d。1例采用规则鬼臼乙叉苷治疗后,反复复发,至治疗后的第112天,仍未缓解,改用表鬼臼毒噻吩甲基苷+吗替麦考酚治疗后,于治疗后的第118天完全缓解,其后一直持续缓解(continue complete remission,CCR)。维持治疗阶段:1例于治疗后第11个月复发,后失访;1例完成全部治疗停药后第11个月复发,现仍在治疗中。迄今,其余9例患儿的持续缓解时间为9～32个月。其中,8例患儿已停药观察,停药时间达1～19个月。结论儿童EB病毒相关性噬血细胞综合征大多可通过采用噬血细胞综合征-04方案的免疫化学治疗有效控制,对于使用鬼臼乙叉苷效果不佳的患儿,可改用表鬼臼毒噻吩甲基苷,表鬼臼毒噻吩甲基苷+吗替麦考酚替代,对于不能耐受环胞素A或疗效不佳者是另一可行的选择。

Objective To evaluate the efficiency of HLH-04 protocol on children with EBV- hemophagocytic lymphohistiocytosis （EBV-HLH）. Methods The clinical features, rates of therapeutic response and prognosis of 12 children with EBV-HLH which were diagnosed and treated in the department of Pediatrics, Second Affiliated Hospital, Sun Yat-Sen University during April 2005 to April 2008, were retrospectively analyzed. All patients fulfilled the diagnostic criteria for EBV-HLH according to the HLH-04 protocol, namely, positivity for the EBV genome and positive anti-viral antibody in the blood. The therapeutic protocol was based on the HLH-04 protocol with some changes if the effect was poor or the side effects of drugs were serious, such as teniposide instead of etoposide, cellcept instead of cyclosporine A,or cellcept ＋ cyclosporine A instead of etoposide. Results ①Clinical features： All the 12 EBV-HLH patients had persistent hyperpyrexia, splenomegaly and hematocytopenia. 1 had convulsion. Serum ferritin in 8 cases was over 500 rag/L, triacylglycerol in 6 cases was over 3.0 mmol/L, fibrinogen in 5 cases was less than 1.5 g/L, the amount of the natural killer cell in 8 cases was decreased, and the hemophagocytosis was found in 12 cases of bone marrow biopsy examination. ②Treatment response： 1 patient quit the treatment after final diagnosis, and the median follow-up time of the other 11 patients were 17 months （10- 36 months）. During the early stage of treatment, the median time for complete remission （CR） was 21 days. 10 achieved complete remission at the 14th-42th day, 1 could not achieve remission （NR） after 112 days, but teniposide and cellcept was given and the patient achieved complete remission at day 118 and kept continue complete remission （CCR） finally. During the maintenance stage, 9 patients achieved continue complete remission and their continue complete remission time was 9-32 months. And 8 cases withdrew drus, the time of drug withdrawal were 1-19 months, 1 patient lost follow-up after 11 months of treatment because of relapse. 1 patient relapsed 10 months later after drug withdrawal, who was receiving drug treatment subsequently. Conclusion Most of EBV-HLH children can be effectively controlled by immunochemical therapy based on the HLH-04 protocol. Etoposide can be replaced with teniposide if its effect is bad; and cellcept is another feasible choice for those who are not tolerant CsA or cannot achieve good effect.