原发性噬血细胞综合征患者临床和基因突变特征及对预后的影响  

Clinical and genetic mutation characteristics of patients with primary hemophagocytic lymphohistiocytosis and their impact on prognosis

作　　者：窦留瑞 喻明珠 石林 张嘉[1] 吴林[1] 王晶石[1] 王昭[1] Dou Liurui;Yu Mingzhu;Shi Lin;Zhang Jia;Wu Lin;Wang Jingshi;Wang Zhao(Department of Hematology,Beijing Friendship Hospital,Capital Medical University,Beijing 100050,China)

机构地区：[1]首都医科大学附属北京友谊医院血液科,北京100050

出　　处：《中华医学杂志》2024年第23期2160-2166,共7页National Medical Journal of China

基　　金：国家自然科学基金(82370185)

摘　　要：目的探讨原发性噬血细胞综合征(HLH)患者的临床和基因突变特征及对预后的影响。方法回顾性选取2013年1月至2022年12月首都医科大学附属北京友谊医院收治并确诊的63例病历资料完整的原发性HLH患者为研究对象,分析患者的临床及实验室特征、基因突变特征、功能学特征、治疗转归及预后。随访截至2023年6月30日,中位随访时间[M(Q_(1),Q_(3))]为47(21,76)个月。采用Kaplan-Meier生存曲线分析总生存率,采用Cox比例风险回归模型分析预后影响因素。结果63例原发性HLH患者包括男35例,女28例,中位发病年龄[M(Q_(1),Q_(3))]为17(7,27)岁。初诊时临床表现主要为发热(93.7%,59/63)、脾大(87.3%,55/63)、噬血现象(65.1%,41/63)、肝大(52.4%,33/63)及中枢神经系统受累(38.1%,24/63),39例患者(61.9%)初诊时合并EB病毒感染。PRF1和UNC13D基因突变最常见(74.6%,47/63),PRF1基因最常见的变异位点是c.1349C>T,UNC13D基因最常见的变异位点是c.2588G>A。76.2%(48/63)患者自然杀伤细胞活性减低,52.7%(29/55)患者细胞毒细胞脱颗粒功能减低或缺如。脱颗粒相关基因缺陷的原发性HLH患者中,79.2%(19/24)存在脱颗粒功能受损。1年、3年总生存率分别为74.8%、66.7%。多因素Cox比例风险回归模型分析显示,外周血EB病毒拷贝数≥10000拷贝/ml(HR=3.523,95%CI:1.418~8.757,P=0.007)是影响预后的危险因素。结论原发性HLH患者初诊时临床表现主要为发热、脾大、噬血现象、肝大及中枢神经系统受累;PRF1和UNC13D基因是最常见的突变基因;外周血高拷贝数EB病毒感染是影响预后的危险因素。Objective To investigate the clinical and genetic mutation characteristics of patients with primary hemophagocytic lymphohistiocytosis(HLH)and their impact on prognosis.Methods Sixty-three primary HLH patients with complete medical records admitted and diagnosed at Beijing Friendship Hospital of Capital Medical University from January 2013 to December 2022 were selected.The patients′clinical and laboratory features,genetic and rapid immunological indicator characteristics,treatment outcomes and prognosis were retrospectively analyzed.Follow-up was up to June 30,2023,with a median follow-up time[M(Q_(1),Q_(3))]of 47(21,76)months.Overall survival was analyzed using Kaplan-Meier survival curve,and prognostic factors were analyzed using Cox proportional hazards regression model.Results Sixty-three primary HLH patients included 35 males and 28 females,with a median age[M(Q_(1),Q_(3))]of 17(7,27)years.Clinical manifestations at the initial diagnosis mainly included fever(93.7%,59/63),splenomegaly(87.3%,55/63),hemophagocytosis(65.1%,41/63),hepatomegaly(52.4%,33/63)and central nervous system(CNS)involvement(38.1%,24/63).A total of 39 patients(61.9%)were diagnosed with EB virus(EBV)infection at initial diagnosis.PRF1 and UNC13D gene mutations were the most common mutations,and the highest frequency mutation site in the PRF1 gene was c.1349C>T,and that of UNC13D gene was c.2588G>A.A total of 76.2%(48/63)of patients had reduced activity of natural killer(NK)cells.Cytotoxic cell degranulation function was impaired or absent in 52.7%(29/55)of patients,of which 79.2%(19/24)of patients with primary HLH with defects in degranulation-related genes had impaired degranulation function.The 1-year and 3-year overall survival rates were 74.8%and 66.7%,respectively.Cox multivariate analysis suggested that peripheral blood EBV≥10000 copies/ml(HR=3.523,95%CI:1.418-8.757,P=0.007)was the risk factor for prognosis.Conclusions The main clinical manifestations of primary HLH patients at the initial diagnosis include fever,splenomegaly,hem

关 键 词：噬血细胞综合征 基因特征 临床特征 预后 

分 类 号：R551[医药卫生—血液循环系统疾病]