HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis

In HLH-94, the first prospective international treatment study for hemophagocytic lymphohistiocytosis (HLH), diagnosis was based on five criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). In HLH-2004 three additional criteria are introduced; low/absent NK-cell-activity, hyperferritinemia, and high-soluble interleukin-2-receptor levels. Altogether five of these eight criteria must be fulfilled, unless family history or molecular diagnosis is consistent with HLH. HLH-2004 chemo-immunotherapy includes etoposide, dexamethasone, cyclosporine A upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids. Subsequent hematopoietic stem cell transplantation (HSCT) is recommended for patients with familial disease or molecular diagnosis, and patients with severe and persistent, or reactivated, disease. In order to hopefully further improve diagnosis, therapy and biological understanding, participation in HLH studies is encouraged.     

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.     

采用噬血细胞综合征-04方案治疗噬血细胞综合征5例

目的观察噬血细胞综合征(HLH)-04方案治疗儿童HLH 5例的早期疗效。方法回顾性分析确诊为HLH患儿5例的临床特点,总结其对以鬼臼乙叉甙(VP16)为基础的免疫化学方案治疗的反应及转归。结果HLH患儿5例中4例在早期治疗阶段完全缓解(CR),CR时间17~22 d(平均18.8 d);另1例规则采用VP16治疗84 d未CR,改用鬼臼甲叉甙(VM26)于d130 CR;病例均存活9~11个月,目前仍CR。1例治疗14 d时出现手足震颤,怀疑为环孢素(CSA)不良反应,改用骁悉替代后手足震颤消失。结论儿童HLH可通过采用HLH-04方案的免疫化学治疗,早期得以有效控制。     

Myelodysplasia Syndrome Following Epipodophyllotoxin Therapy in Familial Hemophagocyticlymphohistiocytosis

The prognosis for patients with familial hemophagocytic lymphohistiocytosis (FHL) is poor, but the survival of affected children has been markedly prolonged by treatment with the epiipodophyllotoxin derivatives etoposide and teniposide and by bone marrow transplantation. Secondary malignancies following epipodophyllotoxin therapy, including myelodysplasia syndrome (MDS) and acute myelocytic leukemia (AML), have recently been reported. We describe a 9-year-old boy, treated with epipodophyllotoxins for FHL since he was 3 years old, who developed MDS. He was administered etoposide (cumulative doses of 6.9 g/m intravenously and 13.6 g/m orally) and teniposide (3.4 g/m intravenously), but no other systemic antineoplastic drugs. This is, to our knowledge, the first report of a child with FHL developing MDS or AML. Moreover, MDS or AML following administration of epipodophyllotoxins as the sole systemic chemotherapic drug has not been reported previously. Supportive treatments, including the use of immunomodulating drugs, may reduce the risk for secondary leukemia in patients with FHL.     

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.     

Clinical and Genetic Studies of Familial Hemophagocytic Lymphohistiocytosis in Oman: Need for Early Treatment

Hemophagocytic lymphohistiocytosis (HLH) embraces the frequently indistinguishable conditions of familial hemophagocytic lymphohistiocytosis (FHL) and virus-associated hemophagocytic syndrome (VAHS). Without therapy FHL is invariably fatal, but successful therapy, including chemotherapy and immunotherapy followed by bone marrow transplantation (BMT), has been presented. To clarify the outcome of HLH in a developing country, with regard to clinical, laboratory, and genetic features, a nationwide study on all patients diagnosed with HLH in Oman during the 5-year period 1997-2001 was performed. In 5 patients and their families, mutational analysis was made. Thirteen patients with HLH were identified, 5 of whom had clinical manifestations of central nervous system involvement at presentation. In none of the patients could an infectious cause be identified. Ten children were referred late in the disease course, and the concern about starting chemotherapy before exclusion of an acute viral infection resulted in delayed treatment in some patients. Two children were started early on the HLH-94-therapy followed by successful BMT in one child. In the successfully transplanted child, the response to intrathecal hydrocortisone appeared to be better than standard therapy with intrathecal methotrexate. Finally, a novel missense mutation in the perforin gene was identified in 2 patients and their family members, causing a transition of proline to threonine at codon 89. Early diagnosis and treatment is important to improve outcome. Intrathecal corticosteroids may be considered, in addition to intrathecal methotrexate, in certain patients. Since the novel perforin mutation has been reported in only 2 patients from Oman, and since similar polymorphism in the sequencing data of the members of their families has been identified, a founder effect is possible in this population.     

Clinical and genetic studies of familial hemophagocytic lymphohistiocytosis in Oman: need for early treatment

Hemophagocytic lymphohistiocytosis (HLH) embraces the frequently indistinguishable conditions of familial hemophagocytic lymphohistiocytosis (FHL) and virus-associated hemophagocytic syndrome (VAHS). Without therapy FHL is invariably fatal, but successful therapy, including chemotherapy and immunotherapy followed by bone marrow transplantation (BMT), has been presented. To clarify the outcome of HLH in a developing country, with regard to clinical, laboratory, and genetic features, a nationwide study on all patients diagnosed with HLH in Oman during the 5-year period 1997-2001 was performed. In 5 patients and their families, mutational analysis was made. Thirteen patients with HLH were identified, 5 of whom had clinical manifestations of central nervous system involvement at presentation. In none of the patients could an infectious cause be identified. Ten children were referred late in the disease course, and the concern about starting chemotherapy before exclusion of an acute viral infection resulted in delayed treatment in some patients. Two children were started early on the HLH-94-therapy followed by successful BMT in one child. In the successfully transplanted child, the response to intrathecal hydrocortisone appeared to be better than standard therapy with intrathecal methotrexate. Finally, a novel missense mutation in the perforin gene was identified in 2 patients and their family members, causing a transition of proline to threonine at codon 89. Early diagnosis and treatment is important to improve outcome. Intrathecal corticosteroids may be considered, in addition to intrathecal methotrexate, in certain patients. Since the novel perforin mutation has been reported in only 2 patients from Oman, and since similar polymorphism in the sequencing data of the members of their families has been identified, a founder effect is possible in this population.     

Clinical assessment of Mycoplasma pneumoniae-associated hemophagocytic lymphohistiocytosis

Background: Mycoplasma pneumoniae has been reported to be an etiologic pathogen of infection-associated hemophagocytic lymphohistiocytosis (HLH), but few case reports have been available to date.
Methods: The clinical features of four childhood cases of M. pneumoniae -associated hemophagocytic lymphohistiocytosis (Mp-HLH) were retrospectively assessed to obtain data that might be useful for early diagnosis and effective management. The previous English-language literature pertaining to Mp-HLH was also reviewed.
Results: The patients were two boys and two girls, aged between 1 and 11 years of age. One patient was demonstrated to have concurrent infection with rubella. All the patients had typical radiographic features of M. pneumoniae pneumonia, and one patient also had encephalopathy as a complication. All the children underwent bone marrow examination because of antibiotic-refractory fever, mild hepatosplenomegaly, cytopenia, hyperferritinemia and elevated levels of urine β2-microglobulin. Cytopenia and hepatosplenomegaly in the present patients were relatively mild as compared to those in cases of other infection-associated HLH such as Epstein–Barr virus infection-associated HLH. Treatment with corticosteroids resulted in prompt and complete resolution in two cases, and i.v. high-dose gammaglobulin therapy achieved a complete response in another child. Spontaneous resolution under treatment with antibiotics alone was observed in one case.
Conclusion: Although Mp-HLH is a rare complication of M. pneumoniae infection, it should always be considered in patients with antibiotic-refractory M. pneumoniae infections with cytopenia. Mp-HLH might be effectively treated by corticosteroids or high-dose gammaglobulin. To clarify the diverse clinical manifestations of M. pneumoniae infections, immunological interactions between M. pneumoniae and the host immune system should be further investigated.     

Hemophagocytic lymphohistiocytosis in very young infants

We report three cases of hemophagocytic lymphohistiocytosis (HLH) in infants within the first 6 weeks of life. Diagnosis of HLH was made early after symptoms started. All three cases were successfully treated with dexamethasone and none relapsed, indicating that not all cases of HLH in very young infants are familial.     

Ehrlichia-induced hemophagocytic lymphohistiocytosis in two children

Two children presented with a history of fever and rash. Lab values revealed pancytopenia, elevated ferritin, coagulopathy, and elevated triglycerides. Both children quickly developed respiratory distress and hypotension requiring admission to the ICU. Bone marrow biopsies revealed hemophagocytosis. Studies for Ehrlichia returned positive. The patients were started on doxycycline and treated for hemophagocytic lymphohistiocytosis (HLH). Each made a full recovery. In both patients, testing for MUNC and perforin genes were found to have no mutation. These two cases demonstrate the importance of considering Ehrlichiosis as a possible trigger of HLH.     

Sensorineural hearing loss in a case of familial hemophagocytic lymphohistiocytosis

Severe sensorineural hearing loss (bilateral >80 dB) was diagnosed in a case of familial hemophagocytic lymphohistiocytosis (FHL). The female patient developed HLH at 3 months of age and underwent allogeneic cord blood transplantation at 11 months of age following 7 months of immuno-chemotherapy. The type 2 FHL patient had a homozygous perforin gene mutation of 1090-1091delCT, and was noted to have hearing loss at 3.5 years of age. Retrospective evaluation did not clarify the exact causes of hearing loss. Reports on Kawasaki disease, suggesting a correlation between severe inflammatory status in infancy and the development of sensorineural hearing loss, may shed some light on this rare complication in this case of FHL. Considering the markedly improved prognosis of FHL due to recent advances made in the molecular diagnosis and in the management including allogeneic hematopoietic stem cell transplantation, auditor by screening might be warranted for surviving FHL patients.     

Hemophagocytic lymphohistiocytosis associated with necrotizing enterocolitis in premature newborns

Hemophagocytic lymphohistiocytosis (HLH) is a systemic disease resulting from the excessive release of inflammatory cytokines by macrophages under prolonged antigenic stimulation. If untreated, it leads to multiorgan failure and death. Necrotizing enterocolitis (NEC) has not previously been associated with HLH. Here we report four preterm infants who were diagnosed with HLH associated with NEC. Two patients received chemotherapy and one survived. The other two infants succumbed to multiorgan failure. These results suggest that NEC may be a common clinical manifestation of HLH in premature neonates.     

The outcome of hematopoietic stem cell transplantation in Korean children with hemophagocytic lymphohistiocytosis

Yoon HS, Im HJ, Moon HN, Lee JH, Kim H‐J, Yoo KH, Sung KW, Koo HH, Kang HJ, Shin HY, Ahn HS, Cho B, Kim HK, Lyu CJ, Lee MJ, Kook H, Hwang TJ, Seo JJ. The outcome of hematopoietic stem cell transplantation in Korean children with hemophagocytic lymphohistiocytosis.
Pediatr Transplantation 2010: 14:735–740. © 2010 John Wiley & Sons A/S. Abstract: Chemoimmunotherapy‐based treatments have improved the survival of patients with HLH, but outcomes of the patients are still unsatisfactory. We report here the outcome of Korean children with HLH who underwent HSCT, which was analyzed from the data of a nation‐wide HLH registry. Retrospective nation‐wide data recruitment for the pediatric HLH patients diagnosed between 1996 and 2008 was carried out by the Histiocytosis Working Party of the Korean Society of Hematology. Nineteen patients who received HSCT among the total of 148 enrolled children with HLH were analyzed for the transplant‐related variables and events. The probability of five‐yr survival after HSCT was 73.3% with a median follow‐up of 57. Two months compared to 54.3% for the patients who were treated with chemoimmunotherapy only (p = 0.05). The reasons for HSCT were active disease after eight wk of initial treatment (n = 9), relapsed disease (n = 5), and FHL (n = 5). Fourteen patients are currently alive without disease after HSCT, four patients died of treatment‐related events (infection in two and graft failure in two) at early post‐transplant period, and one patient died of relapse at one yr post transplantation. The survival of patients who were transplanted because of active disease after eight wk of initial treatment was worse compared to those patients who had inactive state at that time (60.6% vs. 100%, respectively, p = 0.06). Of the four patients who received transplants using cord blood, three died of graft failure (n = 2) and relapse (n = 1). The five‐yr probability of survival after HSCT according to the donor type was 85.7% for the MRDs (n = 6), 87.5% for the MUDs (n = 8), and 40% for the MMUDs (n = 5) (p = 0.03). Other variables such as age, CNS involvement at the time of diagnosis, the etiology of HLH (familial or secondary), and the conditioning regimens had no influence on the five‐yr OS of the HLH patients who underwent HSCT. HSCT improved the survival of the patients who had familial, relapsed, or severe and persistent SHLH in the Korean nation‐wide HLH registry. Although numbers were small, these results are similar to other reports in the literature. The disease state after initial treatment, the stem cell source of the transplant, and the donor type were the important prognostic factors that affected the OS of the HLH patients who underwent HSCT.     

HLH-2004方案诊断治疗小儿噬血细胞综合征结果分析

目的 了解我国小儿噬血细胞综合征(HLH)的发病情况和治疗效果,并开展HLH的穿孔素(perforin)基因研究.方法 研究对象为符合国际组织细胞协会HLH-2004诊断标准的18例患儿,分析患儿起病时及治疗后的临床资料.用流式细胞仪和基因测序法检测患儿的穿孔素基因.结果 流式细胞仪检测发现1例患儿的穿孔素在CD8+T细胞和NK细胞中的表达几乎完全缺如,而且基因测序发现该患儿的穿孔素基因存在错义突变(G47C),确诊为原发性HLH.14例接受HLH-2004治疗,随访时间2周～39个月,临床缓解4例,复发4例,持续活动4例,失访2例.共死亡7例.结论 HLH-2004是诊断和治疗小儿HLH的有效方案,提高生存率需积极开展造血干细胞移植.为鉴别原发性和继发性HLH应进行相关基因检测.     

噬血性淋巴组织细胞增生症20例

目的 探讨噬血性淋巴组织细胞增生症(HLH)的临床特点.方法回顾性分析2009年4月-2010年5月本院血液科收治的20例HLH患儿临床表现及血常规、肝功能、血液生化、病原学、免疫学检测、血清铁蛋白及骨髓涂片检查等实验室指标,参照HLH-2004治疗方案治疗.结果患儿主要表现为持续发热,肝、脾、淋巴结大,全血细胞减少,肝功能受损,凝血障碍,低纤维蛋白血症,高三酯甘油血症,自然杀伤细胞比例降低.12例中性粒细胞＜1.0×109 L-1,16例Hb<90 g·L-1,18例血小板<100×109 L-1,血细胞二系降低者18例,三系同时降低12例.ALT升高20例,AST升高18例,LDH升高20例,胆碱酯酶升高13例.三酰甘油升高18例,血清铁蛋白＞1 500 μg·L-1 8例,ESR增快9例;CRP增高11例,自然杀伤细胞比例降低12例,骨髓增生活跃17例,增生低下3例,12例骨髓涂片找到噬血细胞.20例发病与感染相关者中,与EB病毒感染相关性噬血细胞综合征3例,巨细胞病毒感染相关4例,铜绿假单胞菌感染1例.治愈3例,好转15例,疗效不佳自动出院2例.结论 HLH临床表现多样,及时诊治可改善预后.     

A CASE OF SYMPTOMATIC IDIOPATHIC THROMBOCYTOPENIC PURPURA DURING MUMPS

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.     

Haemophagocytic lymphohistiocytosis in Malaysian children

OBJECTIVES: To study the clinical presentation, therapy and outcome of children diagnosed with both primary and secondary haemophagocytic lymphohistiocytosis (HLH) at the University of Malaya Medical Centre. METHODS: All patients diagnosed with HLH between 1998 and 2004 were studied. Clinico-pathological data of these patients were prospectively collected and analysed. RESULTS: Thirteen consecutive patients (eight boys) with a median age of 28 months were seen. All patients presented with high-grade unremitting fever and almost all, with hepatosplenomegaly and cytopenias. Neurological manifestations, which ranged from irritability to seizures and coma, were seen in 10 (77%) patients. Other common presenting features include liver dysfunction (46%) and skin rash (38%). All patients were treated using the HLH-94 protocol chemotherapy which consisted of a combination of etoposide, dexamethasone and cyclosporine. Complete response was seen in seven patients while two required bone marrow transplantation and one developed secondary acute myeloid leukaemia. Two patients died before treatment could be commenced. Overall mortality rate in our series was 46%. CONCLUSIONS: Haemophagocytic lymphohistiocytosis is an uncommon disease with a high fatality rate. Due to its protean clinical manifestations, it may be underdiagnosed. Early detection and prompt institution of appropriate therapy is necessary to improve the outcome in affected patients.     

Rapamycin does not control hemophagocytic lymphohistiocytosis in LCMV-infected perforin-deficient mice

Hemophagocytic lymphohistiocytosis (HLH) is an immunodysregulatory disorder for which more effective treatments are needed. The macrolide rapamycin has immunosuppressive properties, making it an attractive candidate for controlling the aberrant T cell activation that occurs in HLH. To investigate its therapeutic potential, we used rapamycin to treat Lymphocytic Choriomeningitis Virus (LCMV)-infected perforin-deficient (Prf1(-/-)) mice according to a well-established model of HLH. At the regimens tested, rapamycin did not improve weight loss, splenomegaly, hemophagocytosis, cytopenias, or proinflammatory cytokine production in LCMV-infected Prf1(-/-) animals. Thus, single agent rapamycin appears ineffective in treating the clinical and laboratory manifestations of LCMV-induced HLH.     

Life-threatening hemophagocytic syndromes: Current outcomes with hematopoietic stem cell transplantation

Abstract:  Life-threatening hemophagocytic syndromes represent a subset of genetic disorders of inflammation. Many are rapidly lethal and can only be definitively treated at the present time with allogeneic hematopoietic stem cell transplantation (HSCT). In this report, current results with allogeneic transplantation for Hemophagocytic Lymphohistiocytosis (HLH) are described. HLH typically presents symptomatically during infancy and early childhood and can be identified by a constellation of numerous physical findings and laboratory tests indicative of overwhelming inflammation. The majority of patients with familial HLH lack natural killer (NK) cell function; in approximately 50% of cases the specific underlying genetic cause can now be discerned. Effective treatment consists of initial combination therapy with proapoptotic chemotherapy (typically etoposide) and anti-inflammatory therapies (principally steroids) in addition to aggressive supportive care, followed by allogeneic HSCT from the best available donor. Over the past 25 yr, through collaborative worldwide efforts, survival of children with HLH and related disorders has improved from 5% at 1 yr after diagnosis to greater than 50% 3–5 yr after diagnosis.     

Salvage therapy for refractory hemophagocytic lymphohistiocytosis: A review of the published experience

Hemophagocytic lymphohistioytosis (HLH) is a severe, life‐threatening hyperinflammatory disorder that requires prompt diagnosis and treatment. Approximately, 25–50% of patients with HLH fail to achieve remission with established regimens that include dexamethasone and etoposide, or methylprednisolone and antithymocyte globulin (ATG). Some of these patients may require salvage or alternative therapeutic approaches. There is a paucity of literature regarding effective salvage therapies for patients with refractory HLH. In this review, we summarize the published experience of four therapeutics reported for using at least two patients with HLH refractory to dexamethasone and etoposide or methylprednisolone and ATG.