难治性EB病毒相关噬血细胞性淋巴组织细胞增生症患儿治疗中病情暴发3例并文献复习

Refractory Epstein - Barr virus - associated hemophagocytic lymphohistiocytosis in children：3 cases had an outbreak during treatment and literature review

目的总结并探讨难治性EB病毒（EBV）相关噬血细胞性淋巴组织细胞增生症（EBV—HLH）患儿的临床特点和诊治经验，以提高对该病的认识，改善预后。方法总结3例在治疗过程中出现病情暴发的难治性EBV—HLH病例，对患儿的临床资料进行回顾性分析，并复习相关文献。结果3例患儿均为婴幼儿，以反复发热伴肝脾大为主要表现，无家族史，基因学检查未发现有病理意义的已知HLH相关基因突变，诊断时EBV—DNA明显升高、白细胞及中性粒细胞计数明显减低。3例患儿HLH-94化疗方案效果均不佳，治疗过程中反复发热，血浆EBV-DNA持续不转阴或转阴后再次转阳，化疗过程中出现病情暴发，IFN-γ、IL-10呈暴发性升高，病情暴发后进展极快，DEP方案、血浆置换效果均不好，最后合并消化道出血及多脏器衰竭导致死亡。结论低龄、诊断时EBV—DNA明显升高、白细胞及中性粒细胞明显减少的EBV—HLH患儿有可能治疗效果不佳，治疗过程中易出现HLH暴发。EBV-DNA滴度及细胞因子水平对早期判断病情变化具有重要价值，早期识别此类患者，及时行造血干细胞移植是目前唯一有效的根治手段。

Objective To improve the diagnosis and treatment outcomes of refractory Epstein - Barr virus （EBV） associated hemophagocytic lymphohistiocytosis（ EBV -HLH） ,by analyzing and summarizing the clinical mani- festations, diagnosis and treatment of the children with refractory EBV - HLH. Methods The clinical data of 3 refractory EBV - HLH patients were analyzed retrospectively, and the related literatures were reviewed simuhaneously by analyzing and summarizing the clinical data with refractory EBV - HLH. Results Three patients were all young infant, with recurrent fever accompanied with hepatosplenomegaly as primary manifestations, and with a negative family history. No pathologic known HLH related gene mutations were found. EBV - DNA was obviously increased on diagnosis, with leukopenia and neutropenia. Treatment effect of HLH - 94 protocol was not good in these 3 patients. During treatment there were still intermittent fever. And there was an outbreak during chemotherapy, accompanied by sharply increased levels of IFN -γ , and IL - 10. Plasma EBV - DNA was persistent or recurrent positive. HLH progressed rapidly after the out break of the disease. DEP protocol and plasmapheresis therapy was ineffective. Patients died due to the complicated gastrointestinal bleeding and multiple organ failure. Conclusions Treatment outcomes with chemotherapy might be disappointing in patients with refractory EBV - HLH among young infants, with obviously increased EBV - DNA leukopenia and neutropenia on diagnosis. Disease outbreak could occur during treatment. EBV - DNA titer and cytokine levels are of great value to the early diagnosis of HLH activation. Early identification of such patients, and timely hematopoietic stem cell transplantation were really important to improve the prognosis.