Parvovirus B19-associated hemophagocytic lymphohistiocytosis in a child with precursor B-cell acute lymphoblastic leukemia under maintenance chemotherapy

Development of hemophagocytic lymphohistiocytosis (HLH) is quite rare among acute lymphoblastic leukemia (ALL) patients. We present a 3-year-old boy with precursor B-cell ALL, who was complicated by HLH because of parvovirus B19 infection during maintenance chemotherapy. Remarkable erythroid hypoplasia, giant normoblasts, and hemophagocytosed macrophages in bone marrow were important clues for the diagnosis. The patient was successfully treated with high-dose steroids and intravenous immunoglobulins. To our knowledge, this is the first report describing parvovirus B19-associated HLH in ALL. Our case highlights that parvovirus B19 can cause HLH, a potentially fatal disorder, and prolonged unexpected cytopenia in childhood ALL.     

儿童噬血细胞淋巴组织细胞增生症20例分析

目的了解噬血细胞淋巴组织细胞增生症(HLH)的病因,临床特点,治疗及预后。方法回顾性分析20例HLH患儿的发病相关因素,临床特点,实验室检查指标的变化,治疗效果以及转归。结果所有病例均以持续高热起病,均有肝脾肿大,50%患儿有淋巴结肿大;所有患儿二系以上外周血细胞减少,肝功能异常,凝血功能异常有17例(85%),高甘油三脂血症15例(75%),血清铁蛋白增高13例(65%)。17例(85%)骨髓涂片可见组织细胞增生。12例(60%)和感染因素相关,其中8例(40%)明确与EB病毒感染有关。有6例(3%)按HLH-2004方案正规化疗,达到临床治愈。14例(70%)不规范化疗患儿,8例(40%)仍有肝功能异常和体温波动,5例(25%)死亡。结论HLH起病急重,进展快,病死率高。有明显血象、骨髓细胞学、肝功能改变,高甘油三酯血症以及血清铁蛋白改变。对高度怀疑为HLH的患儿,应及早行诊断性治疗,规范按照HLH-2004方案化疗,改善预后。     

Hemophagocytic Syndrome with Restricted Organ Involvement: Excessive Hemosiderosis and Fibrosis of the Spleen

We report the case history of a 6 1/2-month-old girl with a hemophagocytic syndrome, pancytopenia, and excessive hepatosplenomegaly. Some extraordinary histological features present in this case—restricted organ involvement, excessive hemosiderosis, and fibrosis of the spleen—further contributed to the well-known problem of distinguishing between infection-associated hemophagocytic syndrome and familial hemophagocytic lymphohistiocytosis.     

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.     

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.     

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.     

Pneumocystis carinii pneumonitis in haemophagocytic lymphohistiocytosis

We report on a 10-y-old boy who developed Pneumocystis carinii pneumonitis (PCP) as the dominant symptom at the onset of haemophagocytic lymphohistiocytosis (HLH). PCP is a common infection in patients with combined primary immunodeficiencies or acquired immunodeficiency syndrome but it has rarely been observed at the onset of HLH. Typically, HLH presents as a febrile syndrome associated with cytopenia and hepatosplenomegaly. Repeated bone marrow aspirates, spleen or lymph node biopsies are sometimes required to reveal haemophagocytosis. Because of the significant immunosuppression during treatment of HLH, prophylaxis of PCP with co-trimoxazole is recommended. However, de-arranged immune response in HLH renders the patients susceptible to opportunistic infections, even before the introduction of immunosuppressants. Conclusion: We suggest that in patients with unclear respiratory symptoms, it is worth considering a differential diagnosis of HLH.     

An unusual cause of ascites: hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis is character-ized by fever, hepatosplenomegaly, cytopenia, hyper-triglyceridemia, hypofibrinogenemia, and hemophago-cytosis. Ascites is not mentioned as a symptom of hemophagocytic syndrome. We report a one month-old girl suffering from familial erythrophagocytic lympho-histiocytosis, who presented with ascites.     

Elevated circulating levels of interleukin-1 receptor antagonist but not IL-1 agonists in hemophagocytic lymphohistiocytosis

The familial form of hemophagocytic lymphohistiocytosis (HLH) is an inherited disease with disturbed immunomodulation and characterized by fever, hepatosplenomegaly, cytopenia, hypertriglyceridemia, and coagulopathy, i.e., findings which are similar to many of the reported biological effects of the inflammatory cytokines. Due to the previously shown hypercytokinemia in active HLH with elevated levels of interleukin (IL)-6, tumor necrosis factor-α, and interferon-gamma, it has been suggested that cytokine dysregulation may be of pathophysiological importance. Here we have assayed the serum levels of the members of the IL-1 ligand family, the two agonists IL-1α and IL-1β and the antagonist IL-1 receptor antagonist (IL-1ra), in nine children with HLH and cerebrospinal fluid (CSF) specimens from four children. Serum IL-1ra was elevated in all patients with active disease to a degree which correlated well with disease activity. Furthermore, the levels decreased day by day during treatment of a patient who suffered a relapse. Moreover, high levels of IL-1ra were also detected in CSF during active disease. However, IL-1β levels were all within normal limits and circulating IL-1α levels were normal in all but two patients. © 1996 Wiley-Liss, Inc.     

Hemophagocytic lymphohistiocytosis triggered by Gaucher disease in a preterm neonate

Objective: To present the diagnostic workup in an extremely low birth weight infant patient with signs of both sepsis and hemophagocytosis. Participants: A preterm infant presented with clinical and laboratory signs of early-onset sepsis including hepatosplenomegaly, thrombocytopenia, direct hyperbilirubinemia, and elevated liver enzymes. Methods: Despite extensive septic workup, no underlying infection was detected. Additional hyperferritinemia and other elevated inflammatory parameters raised the suspicion of a primary or secondary hemophagocytic lymphohistiocytosis (HLH). Results: However, further metabolic analysis yielded a positive result for Gaucher disease (GD) type 2, a rare, but possible trigger of HLH. Conclusions: Our case shows that GD may lead to the picture of a secondary HLH and that a metabolic workup should always be performed in patients in whom primary HLH has been excluded.     

Chlamydia pneumoniae infection-related hemophagocytic lymphohistiocytosis and acute encephalitis and poliomyelitis-like flaccid paralysis

A 3-year-old male presented with Chlamydia pneumoniae infection-related hemophagocytic lymphohistiocytosis (HLH). The patient developed an episode of HLH with severe skin eruption following C. pneumoniae pneumonia. Symptoms responded to steroid/cyclosporine A therapy, but the patient slowly lost consciousness and developed systemic flaccid paralysis. He was diagnosed with encephalitis/myelitis by brain and spinal MRI. Neurological symptoms and signs gradually resolved. We thought that the immune response to C. pneumoniae infection triggered the development of HLH, associated with unusual neurological complications. This report describes a novel case of C. pneumoniae-associated HLH and with poliomyelitis like flaccid paralysis.     

Successful treatment of non-familial haemophagocytic lymphohistiocytosis with interferon and gammaglobulin

Two cases of non-familial haemophagocytic lymphohistiocytosis (HLH) are presented in which treatment with interferon alfa and gammaglobulin was associated with complete clinical remission. In one case, serological evidence of recent Epstein-Barr virus infection was found. Natural killer cell activity was within normal limits in both children, compatible with a secondary form of HLH. The combination of interferon alfa and intravenous gammaglobulin requires further evaluation in the treatment of non-familial HLH.     

Successful Engraftment and Survival Following Allogeneic Hematopoietic Stem Cell Transplant in a Child with Familial Hemophagocytic Lymphohistiocytosis

Hemophagocytic syndrome is a rare disorder mainly affecting children. Symptoms include prolonged fever, hepatosplenomegaly and cytopenias. Allogeneic stem cell transplant appears to provide the best overall cure rate in this disease. The authors report a young boy, the second child of consanguineous parents, diagnosed with familial hemophagocytic lymphohistiocytosis (HLH) who underwent allogeneic stem cell transplant form HLA matched father.     

Fulminant neonatal liver failure in siblings: probable congenital hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis (HLH) is an autosomal recessive disorder of immune regulation characterized by fever, splenomegaly, cytopenia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. Although presentation usually occurs during the first 2 years of life, congenital presentation is rare. We report siblings with a presumptive diagnosis of familial HLH who presented with hydrops fetalis and severe hepatic involvement ultimately resulting in their deaths. This report emphasizes the difficulty of confirming the diagnosis of HLH. However, establishing the diagnosis has important implications for genetic counseling and family planning. HLH should be considered in the setting of perinatal liver failure. The immunologic basis of the disease is incompletely understood but testing for natural killer cell function, and perforin defects may be helpful in establishing a diagnosis. HLH can be treated with chemotherapy, immunotherapy, and stem cell transplantation.     

Juvenile myelomonocytic leukemia presenting with features of hemophagocytic lymphohistiocytosis in association with neurofibromatosis and juvenile xanthogranulomas

An association exists among neurofibromatosis 1 (NF1), juvenile xanthogranulomas (JXGs), and juvenile myelomonocytic leukemia (JMML). The authors describe a patient with the triple association of JXG, NF1, and JMML initially presenting with features of hemophagocytic lymphohistiocytosis (HLH). An 18-month old boy had multiple cutaneous and gastrointestinal JXG and NF1. At 3 years of age he developed anemia, thrombocytopenia, and hepatosplenomegaly. A bone marrow biopsy revealed features of HLH. Despite chemotherapy, he went on to develop JMML, which proved fatal.     

A case of rhesus hemolytic disease with hemophagocytosis and severe iron overload due to multiple transfusions

BACKGROUND: A newborn with cholestatic hepatic disease and hemophagocytic lymphohistiocytosis due to rhesus hemolytic disease (RHD) is reported. OBSERVATION: A 34 weeks' gestation baby with RHD, who had received multiple intrauterine transfusions (IUT), developed cholestatic hepatic disease and secondary hemophagocytic lymphohistiocytosis (HLH). Her serum ferritin level increased to 5,527 ng/mL, and liver biopsy showed severe iron overload. Treatment with intravenous desferrioxamine resulted in a marked decrease in serum ferritin levels and normalization of liver function CONCLUSION: We suggest that patients who have undergone IUT be evaluated for hyperferritinemia. If hyperferritinemia is noted, chelation therapy should be considered. As another rare finding, HLH can complicate the course of RHD.     

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.     

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.     

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.