Treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH); update 2010

The clinical features of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH) vary significantly, from mild to severe, at the time of the treatment decision. There are many reports of successful treatments, for example conservative treatment without etoposide, HLH-94/2004-type immunochemotherapy with etoposide, and hematopoietic stem cell transplantation. When considering the treatment of EBV-HLH, the most important factor is the finding that a survival benefit is obtained when etoposide-containing therapy is initiated within 4 weeks of diagnosis. This indicates that there may be a window for observation or conservative corticosteroid/cyclosporine A or intravenous immunoglobulin (IVIG) treatment; however, once the disease is defined as "high risk" and/or refractory to such therapy, prompt introduction of etoposide (ideally within 4 wk) is recommended. In deciding whether the disease is "high-risk," evaluation of clinical staging, EBV genome copy numbers in the serum, cellular EBV tropism, chromosome analysis, and screening for hereditary immuno-deficient diseases such as familial HLH, are required.     

Primary hemophagocytic lymphohistiocytosis in Iran: report from a single referral center

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by fever, hepatosplenomegaly, and cytopenia, and widespread accumulation of lymphocytes and histiocytes, sometimes with hemophagocytosis, primarily involving the spleen, lymph nodes, bone marrow, and liver. HLH can either occur sporadically (secondary HLH) or as part of a familial syndrome (primary HLH), including familial HLH and the distinct immunodeficiency syndromes. Herein the authors report 6 Iranian patients with primary HLH and their outcome from a single tertiary-care center.     

Epstein-Barr virus DNA in lymphocytes of patients with the virus-associated hemophagocytic syndrome

The virus-associated hemophagocytic syndrome (VAHS) is a histiocytic proliferative disorder with bone marrow and liver failure for which the connection with a specific virus is often tenuous. Epstein-Barr virus (EBV) is one candidate for the association, but serologic or culture confirmation may be lacking in a particular case. As a means of directly identifying the presence of EBV in patients' cells, molecular hybridization studies were carried out using a radioactively labeled viral DNA segment. DNA from mononuclear cells of two children with VAHS had specific hybridization to the EBV DNA probe. One of the patients had serologic evidence for EBV infection. Several immunologic deficiencies were found. VAHS may represent one of several hematologic and/or immunologic dysfunctions caused by EBV.     

Familial hemophagocytic lymphohistiocytosis with the MUNC13-4 mutation: a case report

A 44-day-old male infant with familial hemophagocytic lymphohistiocytosis (FHL) associated with the MUNC13-4 mutation is reported. He presented with fever and poor feeding, lymphocytosis with thrombocytopenia and CSF pleocytosis without virological explanation. On the basis of progressive hyperferritinemia (1323 ng/ml), anemia (hemoglobin: 5.2 g/dl), hypertriglyceridemia (547 mg/dl) and increased LDH (1063 IU/l) with hemophagocytosis in the bone marrow, hemophagocytic lymphohistiocytosis was diagnosed. He showed a good response to corticosteroid therapy and the disease was stable for more than 5 months. Thereafter, he suffered from central nervous system complications, and successfully underwent unrelated cord blood stem cell transplantation. A remission was observed for more than 2 years, with mild mental retardation. Genetic analysis revealed that he had a compound heterozygous mutation of MUNC13-4; namely a novel 2163G>A mutation resulting in W721X, and 754-1G>C resulting in a premature stop codon in this gene. Western blot analysis showed the complete loss of the MUNC13-4 protein, whereas other molecules associated with the SNARE systems were detected at normal levels. Conclusion. FHL may have a broad clinical spectrum, and further analysis on its phenotype-genotype association is required to establish an appropriate treatment strategy, including immunochemotherapy and stem cell transplantation in the future.     

Hemophagocytic lymphohistiocytosis (HLH) presenting on the 3rd day of life

Hemophagocytic lymphohistiocytosis (HLH) embraces the frequently indistinguishable conditions, namely familial hemophagocytic lymphohistiocytosis (FHLH), sporadic hemophagocytic lymphohistiocytosis (SHLH) and virus associated hemophagocytic syndrome (VAHS). The disease is very rare and invariably lethal. Evidence suggests that the disease may be due to an inherited defect in immunoregulation that predisposes to an uncontrolled proliferation of activated histiocytes in response to a stimulus such as viral infection. We report here a 3-day-old neonate with confirmed HLH who had a stormy course and a fatal outcome to the disease process, in spite of early chemotherapy. To our knowledge, we believe this is the youngest reported case of HLH from Middle East. No familial or infective cause could be attributed.     

Epstein-Barr virus-associated peripheral T-cell lymphoma and hemophagocytic syndrome arising after liver transplantation: case report and review of the literature

Post-transplantation lymphoproliferative disorders (PTLD) are a well-recognized complication of solid organ transplantation. The vast majority of PTLD are Epstein-Barr virus (EBV)-related infections that manifest as B-cell malignancies. We report an unusual case of an EBV-associated T-cell lymphoma in a 10-year-old boy who had previously undergone liver transplantation at age 4 years. He presented with hemophagocytic syndrome (HPS) and active EBV infection, with positive serum titers and polymerase chain reaction (PCR) for EBV in blood, colon, and antral samples.     

Rapid LightCycler assay for identification of the perforin codon 374 Trp --> stop mutation in patients and families with hemophagocytic lymphohistiocytosis (HLH)

BACKGROUND: Recently, point mutations in the Perforin gene on chromosome 10q21 have been described to be the cause of hemophagocytic lymphohistiocytosis (HLH) in a subset of patients. Small deletions, missense, or nonsense mutations were found in both coding exons of the gene. One mutation was found apparently independently in different families of Turkish origin. This Trp374stop mutation is located within a cystein-rich epidermal growth factor (EGF) precursor type domain in exon 3 of the Perforin gene. PROCEDURE: To detect this mutation, we developed a rapid "fluorescence resonance energy transfer" (FRET) assay on the LightCycler based on the different melting behavior of mutated and wild-type sequences. RESULTS: In seven out of 20 analyzed patients with defined HLH history, this Trp374stop mutation was detectable within the different genotypes. Additionally, one out of 90 alleles tested in 45 healthy Turkish controls had this mutation. DISCUSSION: We present a rapid and reliable test for the most common Perforin (Trp374stop) mutation in HLH suitable for genetic testing and prenatal diagnosis. The mutation was detected in a large proportion of Turkish patients. Furthermore, a rapid and precise diagnosis of HLH will shorten the initiation of therapy in this subset of patients.     

Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis and X-linked lymphoproliferative disease: a mimicker of sepsis in the pediatric intensive care unit

A rare complication of infection with the Epstein-Barr virus is the development of hemophagocytic lymphohistiocytosis. Although most cases of Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis develop in immunocompetent individuals, the rare immunodeficiency X-linked lymphoproliferative disease is often unmasked by Epstein-Barr virus infection and is clinically indistinguishable from Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis. We describe the clinical course and management of a previously healthy 17-year-old boy who presented with hemodynamic collapse and severe systemic inflammatory response syndrome resulting from overwhelming hemophagocytosis in the setting of X-linked lymphoproliferative disease. A novel therapeutic approach using anti-tumor necrosis factor alpha therapy was instituted, aimed at attenuating the viral-induced hyperinflammatory state. Given the similarity to overwhelming sepsis, yet a substantially different therapeutic approach, this case illustrates the importance of early recognition and prompt treatment that are necessary to reduce the high morbidity and mortality associated with Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis and X-linked lymphoproliferative disease.     

Use of rituximab in conjunction with immunosuppressive chemotherapy as a novel therapy for Epstein Barr virus-associated hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis is a rare, life-threatening complication of Epstein Barr virus (EBV) infection. Current treatments are directed at reducing virus-induced immune dysregulation. Addition of agents that eliminate EBV-infected B cells may improve therapeutic efficacy. On the basis of the observations that the anti-CD-20 monoclonal antibody rituximab reduces disease burden in individuals with EBV-associated lymphoproliferative disorders, we treated a patient with severe EBV-hemophagocytic lymphohistiocytosis using a combination of rituximab and chemotherapy. This patient demonstrated a rapid clinical response and an 18-fold reduction in EBV viral load within 24 hours of receiving rituximab. He remains free of disease 8 months after completing treatment.     

Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO)

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a distinctive constellation of features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. We propose two concepts to clarify how HLH is diagnosed and treated: within the broader syndrome of HLH, “HLH disease” should be distinguished from “HLH disease mimics” and HLH subtypes should be categorized by specific etiologic associations, not the ambiguous dichotomy of “primary” and “secondary.” We provide expert‐based advice regarding the diagnosis and initiation of treatment for patients with HLH, rooted in improved understanding of its pathophysiology.     

Secondary hemophagocytic lymphohistiocytosis in pediatric patients: a single center experience and factors that influenced patient prognosis

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome of excessive immune activation. Secondary HLH syndrome develops as a complication of infection, drugs, rheumatologic conditions, or malignancy. The main objectives of this work were to identify the etiology of secondary HLH and prognostic factors associated with mortality. Patients diagnosed with secondary HLH, between January 2011 and December 2016, were retrospectively included in this study. We analyzed clinical and laboratory findings as well as prognostic factors from 24 pediatric patients diagnosed with secondary HLH. The mean age of patients at the time of diagnosis was 79.9?±?68.7?months (range: 2–202) and 54.2% of the patients were male. The most frequent HLH-2004 criterion was fever (100%). Underlying triggers of HLH were as follows: 13 (54.1%) infections, juvenile idiopathic arthritis in 5 patients (20.8%), drugs in 3 patients (12.5%), malignancies in 2 (0.8%), Kawasaki disease in 1 (0.4%) patient, and 1 (0.4%) with unknown triggers. The median time of diagnosis was 3?days (1–67?days). Overall, the mortality rate was 20.8%. In our logistic regression model, factors associated with mortality were decreased albumin levels (OR1?=?2.3[1.48–3.43]) and etoposide usage (OR2?=?1.22 [1.14–1.89]). The patient’s 30-day survival was inferior among patients whose albumin level was 2?g/dL or less compared to those over 2?g/dL. Increased awareness of the underlying condition is critical in HLH patients. Our study emphasizes the prognostic significance of albumin level.     

儿童EB病毒相关噬血细胞淋巴组织细胞增生症NK细胞表面受体和CD107a表达

目的:研究儿童EB病毒相关噬血细胞淋巴组织细胞增生症（EBV-HLH）NK细胞表面受体和CD107a表达,为深入了解EBV-HLH发病机制提供理论依据。方法:选取2009年8月至2011年5月于北京儿童医院确诊为EBV-HLH、未接受过化学免疫治疗的住院患儿为EBV-HLH组,选取年龄、性别与EBV-HLH组1∶1匹配的健康查体儿童为正常对照组。应用流式细胞仪检测NK细胞表面受体、穿孔素及CD107a表达。予IL-2刺激后再次测定CD107a表达情况。结果:EBV-HLH组和正常对照组各8例。①两组NK细胞表面受体NKp30、NKp46、NKG2D、DNAM-1和2B4表达阳性率差异均无统计学意义,CD56+ NK细胞穿孔素表达率和CD8＋ T细胞穿孔素表达率差异均无统计学意义。②两组在IL-2刺激前CD107a、CD107a/K562、CD107a/2B4/P815、CD107a/NKG2D/P815和CD107a/2B4/NKG2D/P815表达率差异均无统计学意义。③EBV-HLH组在IL-2刺激前后CD107a表达差异无统计学意义;正常对照组IL-2刺激前后CD107a、CD107a/K562和CD107a/NKG2D/P815表达率差异有统计学意义。结论:EBV-HLH患儿NK细胞对IL-2的反应出现异常,可能与EBV-HLH的发生有关。     

Further evidence for genetic heterogeneity in familial hemophagocytic lymphohistiocytosis (FHLH)

Familial hemophagocytic lymphohistiocytosis (FHLH; MIM #267700) is an autosomal recessive disorder of immune regulation characterized by fever, hepatosplenomegaly, and cytopenia that is fatal without bone marrow transplantation. Recent studies have suggested the existence of FHLH loci at 9q21.3-22 and t0q21-22 in Asian and European/African/Australian families, respectively. We studied two unrelated Canadian families in which first cousins were affected with FHLH. In an effort to localize the causative gene, we completed a genome-wide screen for homozygosity by descent by using an automated system to genotype 400 highly polymorphic dinucleotide repeat markers covering the genome with an average resolution of 10 centiMorgans (cM). We identified a total of three candidate loci that met the combined criteria for homozygosity by descent in one family and shared maternal alleles in the other family. One of these, D9S1690, had a cytogenetic localization (9q22.33) proximal to a previously reported inversion of chromosome 9 in an FHLH patient. However, additional closely linked flanking markers within 1-2 cM of all three candidates did not conform to the criteria for linkage in either family. Similarly, we excluded the linked 9q21.3-q22 and 10q21-22 regions recently reported in Asian and European/African/Australian families, respectively. The two families were then analyzed independently to encompass the possibility that they were segregating separate genes. Six additional candidate loci were identified on the basis of homozygosity for the same allele in all affected members of one family, but further analysis of closely linked flanking markers did not demonstrate similar homozygosity. Our data provide further evidence of genetic heterogeneity in FHLH and suggest the existence of at least a third locus for this disease.     

儿童噬血细胞综合征合并重症中枢神经系统病变1例救治经验

患儿，男，13岁，因反复发热11 d入院。患儿于11 d前无明显诱因出现发热，弛张高热，热峰40℃，每日2~3次，伴畏寒、寒颤，咽痛，轻咳，服退热药物体温降至正常2~3 h后又反复。到当地医院住院治疗，血常规检查示白细胞计数（WBC）26×10^9/L，中性粒细胞百分比（N%）87.9%，淋巴细胞百分比（L%）8.7%，血红蛋白（Hb）132 g/L，血小板（PLT）205×10⁹/L；C反应蛋白（CRP）111.46 mg/L，降钙素原（PCT）1.29 ng/mL，肺炎支原体抗体1：160。予头孢哌酮舒巴坦、阿奇霉素、奥司他韦等抗感染治疗，复查血常规示：WBC 10×10⁹/L，N% 83.24%，L% 8.7%，Hb 124 g/L，PLT 241×10⁹/L；CRP 39.25 mg/L，PCT 3.03 ng/mL。发热无好转，来我院急诊，予头孢曲松静脉滴注10 min后出现颜面部多发红色皮疹伴瘙痒，停止头孢曲松输注并口服西替利嗪后皮疹消退，以"发热查因"收住院。