儿童EB病毒相关噬血细胞性淋巴组织细胞增生症的预后相关危险因素分析

Analysis of prognostic risk factors of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children

目的探讨儿童EB病毒相关噬血细胞性淋巴组织细胞增生症(Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis,EBV-HLH)患儿的预后相关危险因素。方法回顾性分析2015年9月至2017年1月于首都医科大学附属北京儿童医院血液肿瘤中心收治的EBV-HLH患儿的临床及实验室资料。结果与疾病缓解时相比,疾病活动及爆发时血清铁蛋白(serum ferritin,SF)、血浆EBV-DNA、可溶性IL-2受体(s CD25)、IFN-γ、IL-10的中位数均明显升高(P<0.001)。单因素分析显示,WBC<2×10~9/L、中性粒细胞绝对值(absolute neutrophil count,ANC)<0.5×10~9/L、SF>2 000μg/L、血浆EBV-DNA>1×10~5/ml、IFN-γ升高10倍以上、IL-10升高10倍以上、血清ALB<30 g/L、LDH>2 000 U/L、APTT延长、中枢神经系统受累、化疗2周后血常规不恢复为影响生存率的相关危险因素(P均<0.05)。多因素分析显示,ANC<0.5×10~9/L(HR=0.200,95%CI:0.031~0.789,P=0.029)、SF>2 000μg/L(HR=6.723,95%CI:1.444~31.297,P=0.015)、血浆EBV-DNA>1×10~5/ml(HR=10.582,95%CI:1.424~74.745,P=0.011)、化疗2周后血常规不恢复(HR=9.681,95%CI:1.249~35.034,P=0.006)为独立的预后不良相关危险因素。结论 EBV-HLH是HLH中最常见的类型。SF、可溶性IL-2受体、血浆EBV-DNA、IFN-γ、IL-10是监测HLH病情活动的敏感指标,化疗期间应密切监测。ANC<0.5×10~9/L、SF>2 000μg/L、血浆EBV-DNA>1×10~5/ml、化疗2周后血常规不恢复的患儿预后不良,应根据病情及早调整治疗方案。

Objective To explore the prognostic risk factors of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis（EBV-HLH）in children.Methods The data of clinical characteristics and laboratory findings of pediatric patients with EBV-HLH admitted in the Hematology Oncology Center,Beijing Children’s Hospital from September 2015to January 2017 were retrospectively analyzed.Results Compared with remission group,the median levels of SF,serum EBV-DNA,s CD25 and IFN-γ,IL-10 were significantly higher（P0.001）in patients with active state of HLH and fulminant HLH.Univariate analysis showed that the risk factors of poor survival rate included WBC2×10^9/L,absolute neutrophil count（ANC）0.5×10^9/L,serum ferritin（SF）2 000μg/L,serum EBV-DNA1×10^5/ml,IFN-γincreased by 10times,IL-10 increased by 10 times,serum albumin30 g/L,lactate dehydrogenase2 000 U/L,prolonged activated partial thromboplastin time,central nervous system involvement and the routine blood tests failed to return to normal after chemotherapy in 2 weeks（P0.05）.Multivariate analysis indicated that ANC0.5×10^9/L（95%CI：0.031~0.789,P=0.029）,SF2 000μg/L（95%CI：1.444~31.297,P=0.015）,serum EBV-DNA1×10^5/ml（95%CI：1.424~74.745,P=0.011）and blood cell counts failed to return to normal after 2 weeks of chemotherapy（95%CI：1.249~35.034,P=0.006）were independent risk factors of poor prognosis.Conclusion EBV-HLH is the most common type of HLH.The levels of SF,s CD25,serum EBV-DNA and cytokines（IFN-γ,IL-10）are sensitive indicators for HLH activity and should be thoroughly monitored in the course of chemotherapy.ANC0.5×10^9/L,SF2 000μg/L,serum EBV-DNA1×10^5/ml and blood cell counts failed to return to normal after 2 weeks of chemotherapy suggest poor prognosis and urgent requirement of moving to the next therapeutic approach accordingly as early as possible.