Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis: a retrospective study of 78 pediatric cases in mainland of China.

BACKGROUND: The clinical characteristics of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) are largely unreported in the pediatric patients in mainland of China. The main aim of this study was to recognize the clinical features of EBV-HLH in children and to explore its prognosis and risk factors. METHODS: A retrospective study was performed on 78 pediatric patients with EBV-HLH who were admitted to Beijing Children's Hospital between 2003 and 2008. All patients' medical records were reviewed and analyzed. For each patient, demographic, clinical, laboratory and outcome information was collected. Statistical analysis was conducted via multivariate and univariate analysis. RESULTS: The age of onset peaked between 1 - 2 years and boys were more likely developed EBV-HLH. EBV-HLH occurred mainly in the serological pattern with EBV nuclear antigen (EBNA) positive (70.5%). The overall fatality of the disease was 56.7%. Twelve of the 39 fatalities (30.8%) died rapidly within 2 months after diagnosis. Multivariate analysis revealed that not receiving chemotherapy (P = 0.002), > or = 4 weeks of illness prior to diagnosis (P = 0.004), and albumin levels < 20 g/L (P = 0.045) significantly predicted an increased fatality risk. CONCLUSIONS: EBV-HLH is a severe disease with a high fatality rate that occurs mainly in the serological pattern with EBNA positive. Early initiation of chemotherapy and timely diagnosis significantly improves survival rate. Practical strategies should focus on reducing the likelihood of early death.

[Clinical analysis and follow-up study of Epstein-Barr virus associated-hemophagocytic lymphohistiocytosis in childhood].

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 aminotransferase 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 of 5.12 x 10(2) - 7.69 x 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 thromboplastin 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 microg/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.

Clinical analysis and follow-up study of chronic active Epstein-Barr virus infection in 53 pediatric cases.

BACKGROUND: Chronic active Epstein-Barr virus infection (CAEBV) has been previously reported to be sometimes associated with an aggressive clinical course. The characteristics of CAEBV in Mainland Chinese pediatric patients are largely unreported. The main aims of this survey were to recognize the clinical features of CAEBV in children and to explore its diagnostic criteria and risk factors. METHODS: A retrospective study was performed on 53 pediatric patients (36 boys and 17 girls) with CAEBV who were admitted to Beijing Children's Hospital between 2003 and 2007. All their medical records were reviewed and analyzed. For each patient, demographic, clinical, laboratory data and outcome were collected. Independent-samples t test was used for statistical analysis. RESULTS: The age at onset of CAEBV was from 2 months to 14.6 years (mean (5.3+/-3.3) years). At the time of onset, 43.4% patients had an infectious mononucleosis-like symptom. Most patients exhibited intermittent fever (92.5%, 49/53), hepatomegaly (81.1%, 43/53) and splenomegaly (77.4%, 41/53). Life-threatening complications including hemophagocytic syndrome (24.5%, 13/53), interstitial pneumonia (24.5%, 13/53), hepatic failure (15.1%, 8/53) and malignant lymphoma (11.3%, 6/53) were also observed. The serum EBV DNA level in 23 patients with CAEBV was in the range of 5.05 x 10(2)-4.60 x 10(6) copies/ml with a mean value of 10(3.7) copies/ml. Many patients with CAEBV generally had continuous symptoms during the observational period. Eleven out of 42 patients (26.2%) died 7 months to 3 years after onset. Deceased patients were more likely to have had lower platelet counts and albumin levels than the living patients (P<0.05 for all comparisons). CONCLUSIONS: The study reveals that CAEBV in Chinese pediatric patients has a severe clinical course and prognosis is poor. Thrombocytopenia and decreases in albumin might potentially be risk factors for a poor prognosis. EBV loads should be measured and tissue should be stained on hybridization probes for EBV-encoded small RNA (EBER) if a patient presents with the known symptoms of CAEBV.

Mutations in the perforin gene in children with hemophagocytic lymphohistiocytosis.

BACKGROUND: Recent studies have reported germline mutations in the perforin gene (PRF1) in some types of hemophagocytic lymphohistiocytosis (HLH). However, the prevalence of PRF1 mutations in HLH in Chinese pediatric patients has not been extensively studied. The aim of this study was to investigate the prevalence of mutations and sequence variations in the PRF1 gene in Chinese pediatric patients with HLH. METHODS: Polymerase chain reaction (PCR) was performed with five pairs of primers for the coding exons and the flanking intron sequences of PRF1. Sequencing of PCR products was subsequently applied in 30 pediatric patients with HLH and in 50 controls. RESULTS: Three heterozygous mutations in a coding region were found, which resulted in amino acid changes (C102F, S108N and T450M) in three patients. These mutations were not detected in control subjects. One patient had compound heterozygous mutations (S108N and T450M) in PRF1 as the background defect, and documented familial HLH type 2 (FHL2). One synonymous sequence variant (Q540Q) was observed in one patient but not in the controls. Two SNPs (A274A, H300H) in the coding region were detected in HLH patients and controls, but without differences in the heterozygosity rate between the two groups (P > 0.05 for all comparisons). CONCLUSIONS: We have identified three patients with three heterozygous missense mutations in PRF1; two of those three mutations (C102F and S108N) have so far been found only from Chinese patients. These findings are useful in evaluating the prevalence of PRF1 mutations in Chinese pediatric patients with HLH, and to correlate their genotype with phenotype. Some patients without familial history probably have primary HLH, which should be suspected even beyond the usual age range.