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.     

Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality

Hemophagocytic lymphohistiocytosis (HLH) is difficult to diagnose and treat. Highly elevated ferritin is strongly associated with HLH and levels may provide a prognostic marker. A comprehensive review of ferritin data from our patients during treatment was analyzed with respect to mortality. A patient was 17 times more likely to die when percent ferritin decrease was less than 50% as compared to a 96% or greater decrease as indicated with multivariate logistic modeling. Higher maximum ferritin levels in the first 3 weeks also contributed to the odds of death (OR = 5.6; 90% CI = 1.2–24.9). Regular ferritin measurements may be useful predicting outcomes in HLH patients. Pediatr Blood Cancer. 2010;56:154–155. © 2010 Wiley‐Liss, Inc.     

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.     

Hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition in children associated with immunodeficiency, life threatening infections and malignancy. Infection associated hemophagocytosis responds well to appropriate antimicrobioal therapy and rarely to steroids when the infective agent is suspected to be of viral origin.     

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.     

Fatal hemophagocytic lymphohistiocytosis in X‐linked chronic granulomatous disease associated with a perforin gene variant

A patient with previously unrecognized X‐linked chronic granulomatous disease (X‐CGD) died of multi‐organ failure, secondary to ongoing infection and hemophagocytic lymphohistiocytosis (HLH). Post mortem histological investigations were compatible with X‐CGD, and a CYBB gene mutation was confirmed. No homozygous mutations in the genes encoding perforin (PRF1), MUNC 13‐4 or syntaxin‐11 (STX11) were found; however, there was a heterozygous alteration c.1471G>A in the PRF1 gene causing a p.Asp491Asn substitution. Although this substitution has not been reported to cause primary or secondary HLH, we speculate that it may have made the patient more susceptible for HLH under the circumstances of ongoing infection associated with X‐CGD. Pediatr Blood Cancer 2009;52:527–529. © 2008 Wiley‐Liss, Inc.     

Incidence in Sweden and Clinical Features of Familial Hemophagocytic Lymphohistiocytosis

ABSTRACT. We retrospectively studied the incidence of familial hemophagocytic lymphohistiocytosis (FHL) in children during the 16-year period 1971–86. First, all departments of pediatrics, pathology, and infectious diseases were enquired for children with FHL or disorders resembling FHL. Secondly, the causes of death of all children who died during the study period in Sweden ( n = 19 542) were also investigated. Files and histological specimens were further studied in selected children. By using a set of inclusion/exclusion criteria, we found 32 children with FHL. The incidence was 1.2/1000000 children per year. One child per 50 000 live borns developed FHL during this period. The sex ratio was close to 1:1. Prominent early clinical signs were fever (91%), splenomegaly (84%), hepatomegaly (90%), rash (43%), and lymph node enlargement (42%). Neurological symptoms, which developed in 47%, could totally dominate the clinical picture and develop prior to other symptoms and signs. Common laboratory findings were pancytopenia, hypertriglyceridemia, hypofibrinogenemia, elevated serum transaminases, hyperbilirubinemia, hyponatremia, hypoalbuminemia, and a moderate spinal fluid pleocytosis. Chest X-ray often revealed mostly discrete pulmonary infiltrates. FHL is an underdiagnosed disease and in only 11/32 children was diagnosis made during their lifetime. It is important to be aware of the disorder as potential therapy now exists.     

Findings in familial haemophagocytic lymphohistiocytosis prior to symptomatic presentation

Familial haemophagocytic lymphohistiocytosis (FHL) is a rare, autosomal recessive disease of infancy and early childhood clinically characterized by fever, hepatosplenomegaly, lymphadenopathy, rash, neurological symptoms and icterus. Common laboratory findings include cytopenia, elevated liver enzymes, hyperbiliriubinaemia, hypofibrinogenaemia and hypertriglyceridaemia. The natural killer cell function is frequently decreased or absent. A diffuse lymphohistiocytic infiltration is seen in the reticuloendothelial system, often with haemophagocytosis. Molecular diagnosis is available in a minority of FHL families. Without adequate treatment and bone-marrow transplantation, the disease is fatal. A 6-wk-old child with FHL is presented. Shortly before the clinical onset of the disease, blood testing and bone-marrow examination had been carried out. All results were considered normal at that time. Conclusion: Blood tests and bone-marrow examination may be normal shortly before the clinical presentation and therefore do not exclude the diagnosis of FHL. There is a need for extended molecular diagnostic possibilities.     

Post‐hematopoietic stem cell transplant hemophagocytic lymphohistiocytosis or an impostor: Case report and review of literature

HLH occurring after HSCT is a relatively rare disease. Many conditions may mimic or trigger HLH in post‐HSCT period (eg, cytokine release syndrome, engraftment syndrome, graft rejection/failure, acute graft‐vs‐host disease, infections systemic inflammatory response syndrome/sepsis, and thrombotic microangiopathy). Moreover, this period is usually marked by febrile illness, cytopenia, and a “cytokine storm” leading to elevation of inflammatory biomarkers like ferritin and sCD25. These parameters overlap with the diagnostic criteria for HLH. Such confounding factors make the management of post‐HSCT HLH quite challenging. We illustrate this critical issue with case report of a patient who was diagnosed with HLH after allogeneic HSCT for tAML. He received MP and CsA for HLH but VP‐16 was not administered due to fear of severe myelosuppression. Fortunately, he responded well to treatment and remains in remission to date. We recommend caution while using HLH‐94/HLH‐2004 guidelines for the diagnosis and management of post‐HSCT HLH. In this article, we pinpoint these issues with a brief review of all the pediatric cases and clinical studies of post‐HSCT HLH along with a critical evaluation of its various diagnostic criteria. Finally, based on the limitations of current diagnostic criteria, we suggest a need for formulating disease‐specific diagnostic criteria for post‐HSCT HLH.     

Allogeneic hematopoietic stem cell transplantation is associated with cure and durable remission of late‐onset primary isolated central nervous system hemophagocytic lymphohistiocytosis

Primary isolated CNS presentation of HLH is exceedingly rare and typically associated with significant morbidity and mortality. We describe an adolescent patient with late‐onset, primary isolated CNS HLH and a compound heterozygous PRF1 mutation (c50delT (p.L17 fs); c.1229G>C (p.R410P)), not previously reported with this phenotype. He was successfully treated with allogeneic HSCT following a reduced‐intensity conditioning regimen, despite a high pre‐HSCT comorbidity index. Two years after transplant, he is alive and in disease remission. While patients with systemic HLH and active CNS disease have relatively poorer outcomes, a high index of suspicion may aid with early diagnosis of primary isolated CNS HLH; prompt treatment with HSCT may be associated with improved cure and durable remission of this rare disease.     

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.     

Immunosuppression: Preliminary results of alternative maintenance therapy for familial hemophagocytic lymphohistiocytosis (FHL)

Hemophagocytic lymphohistiocytosis (HLH) describes a group of disorders with similar clinical features that are associated with a very high mortality rate. Patients with HLH, and particularly the infantile form referred to as familial hemophagocytic lymphohistiocytosis (FHL), are often treated with multiple courses of epipodophyllotoxins, such as etoposide, for prolonged periods of time. Because of the concern regarding the risk of epipodophyllotoxin-induced acute myelogenous leukemia (AML) we have explored the use of immunosuppression as maintenance therapy for patients with FHL while they await the only known definitive treatment, i.e., bone marrow transplantation (BMT). We report 2 infants with FHL who had significant central nervous system involvement at diagnosis. Both were initially treated with etoposide, methotrexate, and glucocorticosteroids. Once clinical improvement was achieved these patients were successfully maintained in clinical remission of FHL on daily cyclosporine A (CSA) and glucocorticosteroids along with intermittent intrathecal methotrexate for 5 months until appropriate unrelated donors could be identified for BMT.     

儿童噬血细胞性淋巴组织细胞增生症175例临床特征及预后分析

目的探讨噬血细胞性淋巴组织细胞增生症(HLH)的临床特征及预后因素。方法回顾分析2015年1月至2020年10月收治的175例HLH患儿的临床资料,比较存活组和死亡组的临床特征,采用log-rank检验及COX比例风险回归模型进行生存分析。结果 175例HLH患儿中男91例、女84例,中位年龄2.0(1.0～8.0)岁,以婴幼儿期起病最常见(54.3%)。原发性HLH 9例,继发性HLH 166例。继发性HLH中以感染相关性HLH最常见(66.9%)。临床以发热、脾大为突出表现,血清乳酸脱氢酶(LDH)升高最为显著。与存活组相比,死亡组患儿白细胞计数和血红蛋白较低,活化部分凝血活酶时间、凝血酶原时间较长,纤维蛋白原(FIB)较低,中枢神经系统受累率较高,差异均有统计学意义(P<0.05)。中枢神经系统受累、FIB≤1.5 g/L是影响患儿总生存期的独立危险因素(P<0.05)。结论 HLH多见于婴幼儿,临床表现以发热最多见,血清LDH大多异常升高。中枢神经系统受累及FIB水平对初诊HLH患儿疗效评估及预后判断具有重要意义。     

Kawasaki disease preceding haemophagocytic lymphohistiocytosis: Challenges for developing world practitioners

Kawasaki disease (KD) is a recognised precipitant of haemophagocytic lymphohistiocytosis (HLH). Although KD has been previously described in the developing world, there are no reported cases of KD preceding HLH. We report a case of a child with a persistent rash and unremitting fever consistent with the diagnosis of KD, who was found to have HLH, after intravenous gamma globulin failed to produce a clinical response. The diagnosis was made using the revised diagnostic criteria for HLH from the Histiocyte Society (1994). She fulfilled six of the eight clinical and laboratory criteria needed to make the diagnosis. Pediatr Blood Cancer 2010;54:1023–1025 © 2010 Wiley‐Liss, Inc.