Simultaneous Occurrence of Viral-Associated Hemophagocytic Syndrome and Langerhans Cell Histiocytosis: A Case Report

Langerhans cell histiocytosis (LCH) is a class I histiocytosis characterized by the presence of the pathologic Langerhans cell, an unique histiocyte. In contrast to LCH, class II histiocytosis is characterized by the proliferation of mononuclear phagocytes other than Langerhans cells and includes sinus histiocytosis with massive lymphadenopathy, viral-associated hemophagocytic syndrome, and familial hemophagocytic lymphohistiocylosis. Until now, these two classes have been considered separate, if related, entities. We report a 10-month-old girl who presented with pyrexia, hepatosplenomegaly, an edematous skin rash, anemia, thrombocytopenia, and a markedly elevated serum IgG and IgM antibody level to cytomegalovirus. Histologic proof of both hemophagocytosis in the liver and bone marrow and LCH in the skin was obtained at presentation. The clinical course and response to treatment over 6.5 years is recorded. Although the etiology of both class I and class II histiocytosis remains unknown, we speculate that the monocytic/macrophage disorder, as well as the LCH, were both triggered by virus or viral-related monokines secreted by activated macrophages.     

Familial hemophagocytic lymphohistiocytosis and viral infections

A retrospective study was performed in 32 children with hemophagocytic lymphohistiocytosis, 16 of whom had affected siblings. Altogether 22 of these children, of whom the majority (13/22) were familial cases, had clinical or laboratory signs of infection. Laboratory analysis demonstrated Epstein-Barr virus in five children, cytomegalovirus in three and human parvovirus in two. Two siblings with onset of familial hemophagocytic lymphohistiocytosis within one month of each other, both of whom demonstrated serological indications of a recent human parvoviral infection at onset, are described. It is concluded that a viral infection cannot serve as the sole criterion for distinguishing a virus-associated hemophagocytic syndrome as an entity separate from familial hemophagocytic lymphohistiocytosis. Instead, it is suggested that viral infections may elicit a bout of the familial hemophagocytic lymphohistiocytosis disorder in genetically predisposed individuals.     

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目的了解穿孔素基因(PRF1)突变和序列变异在中国儿童噬血细胞综合征(HLH)中的发生情况,探讨基因突变型与临床表现之间可能的关系。方法应用聚合酶链反应(PCR)结合直接测序方法,对2006年1月至2008年5月在首都医科大学附属北京儿童医院治疗的临床诊断为HLH的30例患儿(HLH组)及50名新生儿(对照组)PRF1基因外显子编码区进行突变筛查。结果在3例HLH患儿的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),而在对照组中却未发现。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HLH亚型2(FHL2);1个同义序列变异(Q540Q)在1例患儿中发现,而在对照组中未发现;在HLH组和对照组的PRF1基因编码区发现2个单核苷酸多态位点(SNP)(A274A、H300H),但这2个SNP的基因型频率在HLH组和对照组之间的分布差异无统计学意义(P均>0.05)。结论我国HLH患儿中存在PRF1基因突变,而突变位点(C102F和S108N)目前仅在中国患儿中发现。显示了我国HLH患儿PRF1基因突变具有自身的特点...     

Macrophage Activation and Hemophagocytic Syndrome in Langerhans Cell Histiocytosis: Report of 30 Cases

Macrophage activation and secondary hemophagocytic syndrome are rarely reported in association with Langerhans cell histiocytosis (LCH). The authors reviewed their pathology files for cases of LCH in which evidence of macrophage activation coexisted and report 30 such cases indicating that the association is not that rare and may even be underdiagnosed unless specifically sought. Available clinical data were collected and correlated with pathological findings. Of the 30 cases of LCH with varying degrees of macrophage activation, 29 had multisystem disease. The cases were graded from I to V on the basis of evidence for, and severity of, macrophage activation; cases in category I had evidence of fully developed hemophagocytic syndrome whereas those in category V had limited evidence of macrophage activation. There were seven cases with fully developed hemophagocytic syndrome (category I) and an additional five with hemophagocytosis and some but not all of the features of hemophagocytic syndrome (category II). Most of these 12 cases were young children with high-risk LCH and poor prognosis; 4 are known to have died. Coexisting hemophagocytic syndrome in these cases of LCH may have contributed to their poor prognosis. The association of LCH with macrophage activation, though more than coincidental, is of unknown pathogenesis, but the role of T lymphocytes and cytokines is prominent in both disorders and is presumed to link the two. Received September 25, 2001; accepted October 2, 2001.     

病毒相关性噬血细胞综合征的诊断与治疗

目的　提高对病毒相关性噬血细胞综合征的认识。方法　回顾性分析 1 6例病毒相关性噬血细胞综合征患儿的临床资料。结果　临床表现为持续性高热 ,肝脾大 ,血常规二系或三系减少 ;高三酰甘油血症、血清铁蛋白 (SF)增高 ;纤维蛋白原降低 ,凝血功能障碍 ;CD4/CD8下降 ,非杀伤细胞比例降低 ,高细胞因子血症。骨髓中找到噬血细胞。大剂量人血丙种球蛋白、甲泼尼龙治疗后 ,好转 7例 ,死亡 5例 ,4例放弃治疗。结论　早期诊治是提高病毒相关性噬血细胞综合征患儿生存率的关键。     

Hemophagocytic syndrome in a 4-month-old infant with biotinidase deficiency

Hemophagocytic syndromes such as hemophagocytic lymphohistiocytosis (HLH) are life-threatening hyperinflammatory conditions caused by inherited or acquired immune disorders. Awareness of the clinical symptoms and diagnostic criteria for hemophagocytic syndromes is crucial to start timely life-saving therapy. We present a case of a 4-month-old boy presenting with HLH. However, the patient was subsequently diagnosed with biotinidase deficiency and was successfully treated with biotin-replacement therapy, upon which the hemophagocytic syndrome ceased. Subsequent laboratory evaluations revealed normal lymphocyte cytotoxicity and no mutations in genes associated with familial HLH were found. Biotinidase deficiency should be considered as a differential diagnosis of patients fulfilling HLH criteria.     

Hemophagocytic lymphohistiocytosis following dengue hemorrhagic fever in Hb H/Hb Constant Spring patient

Infection‐associated hemophagocytic syndrome (IAHS), a secondary form of hemophagocytic lymphohistiocytosis (HLH), has been found following several types of infections and can be fatal. We report herein a case of IAHS following dengue infection in a 14‐year‐old patient with underlying α‐thalassemia syndrome (non‐deletional Hb H/Hb Constant Spring disease). He developed prolonged fever, thrombocytopenia, and progressive splenomegaly. Further investigations indicated hyperferritinemia, and increased reactive histiocytes with hemophagocytic activity in the bone marrow. He responded promptly to dexamethasone and i.v. immune globulin. Physicians should be aware of this condition, especially in countries where both dengue hemorrhagic fever and thalassemia are prevalent. The fatal outcome of IAHS can be prevented with prompt appropriate treatment.     

Human herpesvirus-6 (HHV-6)-associated hemophagocytic syndrome

Virus-associated hemophagocytic syndrome (VAHS) is characterized by histiocytic proliferation and phagocytosis triggered by virus infections. Viruses in the herpes group, especially the Epstein-Barr virus (EBV), are well known to cause VAHS; however, the relationship between this syndrome and human herpesvirus-6 (HHV-6) infection has rarely been reported. In this study, we describe a 23-month-old girl who exhibited typical manifestations of VAHS associated with HHV-6 infection. To the best of our knowledge, this case is the fifth reported case in the English literature.     

Clinical features of measles in immunocompromised children

Measles is often fatal for immunocompromised hosts. Protective immunity against measles has been studied but is still not completely understood. Recently, five cases of measles were encountered in immunocompromised children. Two of these were allogeneic bone marrow transplanted cases (one common variable immunodeficiency and one severe aplastic anemia) in remission, one Wilms' tumor case in remission, one hepatoblastoma case after cytotoxic therapy at disease onset and one exaggerating hemophagocytic syndrome case with suppressed natural killer cell activity. Clinical symptoms, laboratory findings and the immunologic backgrounds of these five patients were investigated. One of the patients, an 8 year old boy with hemophagocytic syndrome, died of giant cell pneumonia which was confirmed in the section of necropsy lung specimen. Two other patients who received allogeneic bone marrow transplants were not immune to measles, despite their own and their donors' immunizations. Their clinical symptoms were rather severe but both patients recovered and have remained seropositive for as long as 13 months. This fatality from measles is the first reported in a patient with hemophagocytic syndrome. Suppressed natural killer cell activity may be a poor prognostic factor. Also, secondary immunization failure for measles can occur in bone marrow transplanted patients with rather severe clinical symptoms.     

Subcutaneous t-cell Lymphoma Presenting as Panniculitis in Children: Report of Two Cases

Two cases of peripheral T-cell lymphoma with primarily subcutaneous involvement and clinically presenting as panniculitis were reported in two children. One child developed florid hemophagocytic syndrome and was treated by combination chemotherapy but died 14 months later of disseminated fungal infection. The other child had mild systemic symptoms but no histological evidence of hemophagocytosis. Despite a more florid lymphomatous infiltrate, he attained a complete remission after a short course of prednisone and remains symptom-free at 3 years. Our report confirms that subcutaneous T-cell lymphoma is a distinct clinicopathological entity and highlights the two modes of clinical presentation. The development of florid hemophagocytic syndrome indicates a bad prognosis. This entity must be distinguished from other causes of panniculitis and immunophenotypic analysis of the atypical cells is essential in the diagnosis. Combination chemotherapy is the treatment of choice, but in patients who pursue an indolent course the administration of aggressive chemotherapy may be deferred.     

Successful treatment of refractory Langerhans cell histiocytosis by allogeneic peripheral blood stem cell transplantation

We describe a six-yr-old boy who exhibited typical signs and symptoms of LCH with EBV-associated hemophagocytic syndrome from the age of 15 months. Multiple courses of conventional chemotherapy achieved only marginal improvement over the ensuring five yr. During this period, this boy experienced recurrent episodes of hemophagocytic syndrome associated with CMV infection. Five yr after the first diagnosis of LCH, the patient was treated with allogeneic PBSCT from his HLA-identical eight-yr-old brother. PBSCT was performed using a TBI-incorporating conditioning regimen comprising TBI, busulfan, and cyclophosphamide. Diabetes insipidus, typically a permanent consequence of LCH, was well controlled by DDAVP therapy. At the time of writing, this boy is alive and well, and had been disease-free for more than two yr after the PBSCT.     

小儿感染相关性噬血细胞综合征31例检验结果分析

目的分析小儿感染相关性噬血细胞综合征(IAHS)的临床及实验室特点,探讨IAHS早期诊断指标。方法分析2004年5月至2008年6月收治的31例IAHS的临床及实验室资料。结果EB病毒感染者18例(58.1%)、CMV感染4例(12.9%)、细菌感染4例(12.9%)、真菌感染3例(9.7%)、立克次氏体感染1例(3.2%)和HBV感染1例(3.2%);本组病例以持续高热(100%)、肝肿大(74.2%)、脾肿大(71%)为主要表现;外周血细胞白细胞计数减少(93.5%),血小板减少(87.1%),血清甘油三酯高(90.3%),铁蛋白高(96.8%),肝功能异常(67.7%),凝血异常(64.5%),100%骨髓找到噬血细胞;早期IAHS肝功能和凝血功能改变不明显。结论典型IAHSI临床以持续高热,肝、脾肿大为主要表现,实验室检查以白细胞计数降低、血小板低、肝功能及凝血功能异常、甘油三酯及铁蛋白增高,骨髓找到噬血细胞为主要特点。噬血细胞的形态特征、肝功能及凝血功能异常程度有助于分析IAHS早期诊断。     

A teenage boy with late onset hemophagocytic lymphohistiocytosis with predominant neurologic disease and perforin deficiency

Familial hemophagocytic lymphohistiocytosis (FHLH) is an autosomal recessive disorder of cytotoxic cell function that results in abnormal proliferation of benign lymphocytes and histiocytes in response to infectious stimuli. FHLH generally occurs in very young children, and typically presents with fever, cytopenias, coagulopathy, lymphadenopathy, and hepatosplenomegaly. Central nervous system involvement occurs frequently and may precede the development of systemic symptoms by months to years. We report a case of an 18-year-old male with a 2-year history of symptoms attributed to a demyelinating disorder, who succumbed to rapidly progressive hemophagocyte lymphohistiocytosis. Post-mortem, two distinct perforin mutations were identified. We discuss the central nervous system and genetic findings in this unusual presentation of familial hemophagocytic lymphohistiocytosis.     

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.     

感染相关性噬血细胞综合征的临床探讨

目的 探讨感染相关性噬血细胞综合征的临床特点和干预措施。方法 回顾性分析6例感染相关性噬血细胞综合征的临床过程、实验室检查和干预措施。结果EB病毒是感染相关性噬血细胞综合征的常见病原。对于血细胞减少的有些危重病例,临床必须考虑到噬血细胞综合征的可能。骨髓涂片查找噬血细胞有一定困难,临床支持该病,骨髓涂片应反复查找。结论 干预应早于诊断,临床怀疑噬血细胞综合征,不能因等待检查而耽误临床治疗,及早阻止噬血现象是性命攸关的。而预后与所用干预措施直接相关。     

儿童噬血细胞综合征死亡相关因素分析

目的探讨儿童噬血细胞综合征(HPS)死亡的相关因素,以提高临床医师对其认识,为降低病死率提供可借鉴的经验。方法采用回顾性病例对照研究方法,对HPS死亡患儿(死亡组)和存活患儿(存活组)进行分析比较,对可能与HPS死亡相关的危险因素进行分析。结果46例HPS患儿中,死亡11例,存活35例,病死率23.9%。11例死亡病例中,死于多脏器功能衰竭4例,呼吸循环衰竭3例,感染2例,中枢系统浸润1例,弥散性血管内凝血1例。统计学分析显示,HPS患儿死亡危险因素包括年龄(χ2=6.273,P0.05)、中枢神经系统症状(χ2=16.27,P0.01)、骨髓增生低下(χ2=7.232,P0.05)、谷草转氨酶(AST)400 U/L(χ2=4.927,P0.05)、乳酸脱氢酶(LDH)1 000 U/L(χ2=5.855,P0.05)、治疗方案(χ2=11.266,P0.05)。结论HPS患儿死亡与多种因素相关,及早诊断、治疗对提高HPS患儿生存率至关重要。     

Reactive Hemophagocytic Syndrome

Two cases o f reactive hemophagocytic syndrome (RHS) are reported, and the clinical and pathological features are compared with other histiocytic proliferative disorders, including familial hemophagocytic lymphohistiocytosis (FHL) and malignant histiocytosis. RHS can be associated with a variety o f infections, including viral, bacterial, fungal, and parasitic. RHS may also be familial as exemplified by our 2 cases in siblings. The isolation of an effective agent appears t o be the only criterion by which a diagnosis o f RHS can be made.     

Systemic type Epstein-Barr virus-related lymphoproliferative diseases in children and young adults: challenges for pediatric hemato-oncologists and infectious disease specialists

Involvement of Epstein-Barr virus (EBV) has long been known in the development of various tumor-forming proliferating diseases, such as nasopharyngeal carcinoma in adults. However, in children and young adults more attention should be focused on systemic, severe type EBV-related diseases, such as fatal infectious mononucleosis, hemophagocytic syndrome, or chronic active EBV infection (CAEBV). These disorders show the typical clinical features of hemophagocytic lymphohistiocytosis (HLH). Although viral infectious diseases are mostly taken care of by infectious disease specialists, pediatric hemato-oncologists need to intervene in the treatment of this kind of disease because of their clonal and neoplastic disease characteristics and of their hematologically problematic, rapid, and life-threatening clinical courses.