CAJ | 학술논문

目的分析儿童EB病毒相关性噬血细胞淋巴组织细胞增生症(EBV-HLH)的临床特征,探讨影响其预后的危险因素.方法采用回顾性调查方法 ,对2003年5月至2008年9月收治的62例EBV-HLH患儿临床特征、血清学、病毒载量、病理改变、基因筛查及预后资料进行系统分析.根据随访的生存情况分为生存组和死亡组,采用单因素和多因素Logistic回归分析影响预后的危险因素.结果 (1) 62例患儿中,男36例,女26例,发病年龄2个月～14岁,26例(41.9%)在婴幼儿期发病,38例(61.3%)发病是由于EBV感染再激活所致;(2) 所有患儿均有持续或间断发热,至少有外周血两系减低.伴有肝肿大52例,脾肿大45例,淋巴结病43例.58例患儿血清白蛋白降低,52例血清铁蛋白增高,大部分患儿伴有凝血功能异常和脂质代谢紊乱.48例诊断时骨髓中出现吞噬血细胞现象;31例EBV-HLH患儿中14例血清中EBV-DNA检测阳性,病毒载量拷贝数在5.12×10~2～7.69×10~7/ml之间(平均10~(3.9)/ml);(3) 在3例EBV-HLH的PRF1基因外显子编码区发现3个杂合错义突变,这3个突变均导致氨基酸改变(C102F,S108N和T450M),1例患儿为复合杂合错义突变(S108N和T450M),从遗传学上可明确诊断为家族性噬血细胞淋巴组织细胞增生症亚型2(FHL2);(4) 随访57例病例中35例(61.4%)死亡,其中21例经过HLH-94或04治疗方案.15例是在住院后2个月内死亡.死亡病例相比存活病例白蛋白降低和部分凝血激酶时间延长(P均<0.05).多因素Logistic回归分析显示病程大于1个月、未进行免疫化疗、白蛋白≤25 g/L和深部出血与EBV-HLH的预后呈显著相关性(P均<0.05).结论 EBV-HLH患儿病情严重,预后凶险,病死率高;多数病例由于EBV感染再激活所致;早期诊断并尽早开始化疗可以提高患儿的存活率;病程大于1个月、未进行化疗、白蛋白降低和深部出血是影响其预后的主要危险因素.
목적 분석인동EB병독상관성서혈세포림파조직세포증생증(EBV-HLH)적림상특정,탐토영향기예후적위험인소.방법 채용회고성조사방법 ,대2003년5월지2008년9월수치적62례EBV-HLH환인림상특정、혈청학、병독재량、병리개변、기인사사급예후자료진행계통분석.근거수방적생존정황분위생존조화사망조,채용단인소화다인소Logistic회귀분석영향예후적위험인소.결과 (1) 62례환인중,남36례,녀26례,발병년령2개월～14세,26례(41.9%)재영유인기발병,38례(61.3%)발병시유우EBV감염재격활소치;(2) 소유환인균유지속혹간단발열,지소유외주혈량계감저.반유간종대52례,비종대45례,림파결병43례.58례환인혈청백단백강저,52례혈청철단백증고,대부분환인반유응혈공능이상화지질대사문란.48례진단시골수중출현탄서혈세포현상;31례EBV-HLH환인중14례혈청중EBV-DNA검측양성,병독재량고패수재5.12×10~2～7.69×10~7/ml지간(평균10~(3.9)/ml);(3) 재3례EBV-HLH적PRF1기인외현자편마구발현3개잡합착의돌변,저3개돌변균도치안기산개변(C102F,S108N화T450M),1례환인위복합잡합착의돌변(S108N화T450M),종유전학상가명학진단위가족성서혈세포림파조직세포증생증아형2(FHL2);(4) 수방57례병례중35례(61.4%)사망,기중21례경과HLH-94혹04치료방안.15례시재주원후2개월내사망.사망병례상비존활병례백단백강저화부분응혈격매시간연장(P균<0.05).다인소Logistic회귀분석현시병정대우1개월、미진행면역화료、백단백≤25 g/L화심부출혈여EBV-HLH적예후정현저상관성(P균<0.05).결론 EBV-HLH환인병정엄중,예후흉험,병사솔고;다수병례유우EBV감염재격활소치;조기진단병진조개시화료가이제고환인적존활솔;병정대우1개월、미진행화료、백단백강저화심부출혈시영향기예후적주요위험인소.
Objective To identify the clinical characteristics of and to explore the prognostic factors influencing mortality in children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). Method A retrospective study was conducted on 62 pediatric patients with EBV-HLH who were admitted to our hospital between 2003 and 2008. All their medical records were reviewed and analyzed. For each patient, demographic, clinical and laboratory data, genetic findings and outcome information were collected. The patients were divided into two groups: deceased or survived based on the follow-up results. Comparative analysis of the data was done by using independent-samples t test and Logistic multiple and univariate regression. Result (1) Among the 62 EBV-HLH patients, 36 were male and 26 were female. The age of onset ranged from 2 months to 14 years and most of the patients were between 1 and 3 years of age. EBV-HLH occurred mainly in the setting of reactivation (61.3%). (2) All patients exhibited persistent or intermittent fever and cytopenia≥ 2 cell lines. Most of the patients presented with hepatomegaly (83.9%), splenomegaly (72.6% ) and lymphadenopathy (69.4% ). The main laboratory features showed an elevation of serum ferritin and aminotransfernse levels. A reduction in serum albumin was observed and exhibited coagulopathy with hypofibrinogenemia and hypertriglyceridemia in most of the patients. Forty-eight of patients had hemophagocytosis in bone marrow at diagnosis of EBV-HLH. The serum EBV DNA level in 14 of 31 patients with EBV-HLH was in the range or 5.12×10~2-7.69×10~7 copies/ml with a mean value of 10~(3.9) copies/ml. (3) Three heterozygous mutations in coding region were found, which resulted in amino acid change (C102F, S108N and T450M) in 3 patients. One patient had compound heterozygous mutations (S108N and T450M) in the PRF1 gene as the background defect and documented familial HLH type 2 (FHL2). (4) During the observational period, 35 of 57 patients (61.4%) died 3 months to 3 years after the onset, while 21 of whom died despite aggressive polychemotherapy, 15 of whom died within 2 months after hospitalization. The deceased patients were more likely to have lower albumin level and more prolonged activated partial thromboplasin time than the survived patients (P <0.05 for all comparisons). Multivariate Logistic regression analysis revealed that duration of illness≥1 month, non-chemotherapy, albumin level 25 μg/L and internal organs hemorrhage were related with the prognosis significantly (P <0.05 for all comparisons). Conclusion This study revealed that EBV-HLH infection in pediatric patients had severe clinical courses and prognosis was poor and the majority of cases underwent EBV reactivation. The early diagnosis, prompt and proper chemotherapy can improve the survival rate. The duration of illness≥1 month, non-chemotherapy, decreases in albumin and internal organs hemorrhage were the risk factors related to mortality in children with EBV-HLH.