Virus-associated Hemophagocytic Syndrome Research Articles

Biomarker and morphological characteristics of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis.

Viruses may induce primary as well as secondary hemophagocytic lymphohistiocytosis (HLH), but it may not be possible to discriminate between these two in patients with a negative family history. Among these HLH cases, fulminant and fatal virus-associated hemophagocytic syndrome (VAHS) occurs mostly in relation to Epstein-Barr virus (EBV) infection. Although the immunological characteristics of EB-VAHS were previously reported, data on non-EB-VAHS were sporadic and fragmentary. This study has compared the clearly distinguishable groups of EBV-positive vs. EBV-negative HLH cases. Among 26 patients with EBV-related HLH and 12 patients with non-EBV HLH, peripheral blood mononuclear cell (PBMC) subsets and serum concentrations of cytokines at the active phase of the disease were compared. Blood and bone marrow smears were also compared. The frequency of the CD3+HLADR+ subset in PBMC (median 34.3% vs. 4.8%), of serum concentrations of interferon (IFN)-gamma (median 105 U/ml vs. 2.4 U/ml), and of soluble interleukin-2-receptor (sIL-2R) (median 14,700 U/ml vs. 3,412 U/ml) were significantly different between these two groups. Morphological characteristics were noted for EBV-related HLH cases. Mortality also differed between these two groups, 9/26 vs. 0/12 (P = 0.05). Data indicate pronounced immunological imbalance and poor prognosis in EBV-related HLH cases. These parameters could be useful for determining an EBV involvement as well as risk factors in the early care and treatment of HLH patients.

A CASE OF VIRUS-ASSOCIATED HEMOPHAGOCYTIC SYNDROME AFTER CORONARY ARTERY BYPASS GRAFTING

A 69-year-old man who underwent coronary attery bypass grafting (CABG) for effort angina with an uneventful clinical course developed hemoptysis and fever on the 13th postoperative day. Chest X-ray showed interstitial pneumonia. the pneumonia spread quickly over the entire lung fields, and respiratory function worsened. The patient was diagnosed with having acute respiratory distress syndrome (ARDS). Steroid therapy was initiated and the patient responded very well. Remarkable remission in pneumonia and ARDS attained. General condition once improved, but 2weeks later, fever appeared again and reevalution revealed pancytopenia and lymphadenopathy. Bone marrow examination revealed hemophagocytosis by mature histiocytes, therefore he was diagnosed as virus associated hemophagocytic syndrome (VAHS). Steroid therapy was immediately started again, but the patient died of disseminated intravascular coagulation and multiple organ failure. This is a very rare case of VAHS due to surgical stress. It is suggested that VAHS must be recognized as a probable postoperative complication.

ウィルス関連血球貧食症候群例 伝染性単核球症に続発した成人例

An adult case of virus associated hemophagocytic syndrome (VAHS) which developed from infectious mononucleosis (IM) is reported. A 21-year-old-man visited our clinic with complaints of high fever, sore throat, and cervical lymphadenopathy. The palatine tonsils appeared to be swollen with white plugs on the surface. Hematological examination revealed mononucleosis with atypical lymphocytes in the peripheral blood. The serum LDH level was elevated. Serum antibodies to Epstein-Barr virus (EBV) showed a primary infection pattern. The patient, on the basis of these findings, was initially diagnosed with IM. The symptoms and laboratory data subsequently showed transient improvement; however, liver dysfunction, pancytopenia, and interstitial pneumonia ultimately developed. Bone marrow puncture was performed 29 days after admission and revealed inflitration of a number of mature histiocytes with erythrophagia, suggesting that VAHS had developed from IM. Combined chemotherapy with prednisolone, interferon, acyclovir, and VP-16, was not effective, and progressive liver dysfunction and pancytopenia advanced. He died 47 days later of disseminated intravascular coagulopathy.

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Epstein-Barr virus infection and its role in the expanding spectrum of human diseases.

Recent advances of the various laboratory tests to detect Epstein-Barr virus (EBV) infection have clarified the causative role for a spectrum of EBV-associated diseases. They include lymphoproliferative disorders (LPD), which occur in immunologically compromised individuals, Hodgkin's disease (HD), chronic active EBV infection (CAEBV), virus-associated hemophagocytic syndrome (VAHS), certain forms of T cell lymphoma, and some gastric carcinomas, in addition to the classical EBV-associated diseases such as EBV genome-positive Burkitt's lymphoma (BL), undifferentiated nasopharyngeal carcinoma (NPC) and infectious mononucleosis (IM). This review intends to introduce the recent progress of studies on EBV infection mainly from the clinical points of view.

Epstein‐Barr virus infection and its role in the expanding spectrum of human diseases

Recent advances of the various laboratory tests to detect Epstein‐Barr virus (EBV) infection have clarified the causative role for a spectrum of EBV‐associated diseases. They include lymphoproliferative disorders (LPD), which occur in immunologically compromised individuals, Hodgkin's disease (HD), chronic active EBV infection (CAEBV), virus‐associated hemophagocytic syndrome (VAHS), certain forms of T cell lymphoma, and some gastric carcinomas, in addition to the classical EBV‐associated diseases such as EBV genome‐positive Burkitt's lymphoma (BL), undifferentiated nasopharyngeal carcinoma (NPC) and infectious mononucleosis (IM). This review intends to introduce the recent progress of studies on EBV infection mainly from the clinical points of view.

Upregulation of tumor necrosis factor-alpha gene by Epstein-Barr virus and activation of macrophages in Epstein-Barr virus-infected T cells in the pathogenesis of hemophagocytic syndrome.

A potentially fatal hemophagocytic syndrome has been noted in patients with malignant lymphomas, particularly in EBV-infected T cell lymphoma. Cytokines, such as interferon-gamma (IFN-gamma), TNF-alpha, and IL-1alpha, are elevated in patients' sera. To verify whether infection of T cells by EBV will upregulate specific cytokine genes and subsequently activate macrophages leading to hemophagocytic syndrome, we studied the transcripts of TNF-alpha, IFN-gamma, and IL-1alpha in EBV-infected and EBV-negative lymphoma tissues. By reverse transcription PCR analysis, transcripts of TNF-alpha were detected in 8 (57%) of 14 EBV-infected T cell lymphomas, higher than that detected in EBV-negative T cell lymphoma (one of six, 17%), EBV-positive B cell lymphoma (two of five, 40%) and EBV-negative B cell lymphomas (one of seven, 14%). Transcripts of IFN-gamma were consistently detected in T cell lymphoma and occasionally in B cell lymphoma, but were independent of EBV status. IL-1alpha expression was not detectable in any category. Consistent with these in vivo observations, in vitro EBV infection of T cell lymphoma lines caused upregulation of TNF-alpha gene, and increased secretion of TNF-alpha, but not IFN-gamma or IL-1alpha. Expression of TNF-alpha, IFN-gamma, and IL-1alpha was not changed by EBV infection of B cell lymphoma lines. To identify the specific cytokine(s) responsible for macrophage activation, culture supernatants from EBV-infected T cells were cocultured with a monocytic cell line U937 for 24 h. Enhanced phagocytosis and secretion of TNF-alpha, IFN-gamma, and IL-1alpha by U937 cells were observed, and could be inhibited to a large extent by anti-TNF-alpha (70%), less effectively by anti-IFN-gamma (31%), but almost completely by the combination of anti-TNF-alpha and anti-IFN-gamma (85%). Taken together, the in vivo and in vitro observations suggest that infection of T cells by EBV selectively upregulates the TNF-alpha expression which, in combination with IFN-gamma and probably other cytokines, can activate macrophages. This study not only highlights a probable pathogenesis for virus-associated hemophagocytic syndrome, but also suggests that anti-TNF-alpha will have therapeutic potential in the context of their fatal syndrome.

The Use of Cyclosporin-A in the Treatment of Virus-Associated Hemophagocytic Syndrome in Adults

Virus-associated hemophagocytic syndrome (VAHS) is one of the categories of hemophagocytic syndrome (HPS) which is a clinicopathologic entity characterized by systemic proliferation of benign hemophagocytic cells of the monocyte-macrophage-histiocyte lineage, associated with fever, cytopenia, hepatosplenomegaly, lymphadenopathy, and coagulopathy. The disease affects children and adults after infection with various viruses. However, clinical manifestations are quite different between children and adults. Although the etiology of VAHS is not fully understood, accumulating evidence has revealed dysregulation of the immune system. Standard treatment of VAHS has not been established, yet, but successful trials aiming at immunomodulation have been reported. In this report, current concepts and clinical features of VAHS are reviewed, focusing on the recently introduced cyclosporin A therapy in VAHS in adults.

咽頭痛，発熱を主訴とした血球貧食症候群例

A 22-year-old male with a persistant sore throat and fever was admitted to our department of otolaryngology. Physical examination revealed an erythematous pharynx, swollen tonsils with exudate and multiple swollen lymphnodes with tenderness in the neck. Although he underwent medical treatment under a diagnosis of infectious mononucleosis, his fever persisted and the level of transaminases in his blood increased.Futhermore he developed pancytopenia and a pre-DIC state with a bleeding tendency. A bone marrow puncture revealed the proliferation of monocytes and histiocytes and phagocytosis. These pathologic findings as well as a high serum ferrit in level, multiple organ failure and hepatosplenomegaly suggested the diagnosis of hemophagocytic syndrome (HPS).Malignant histiocytosis (MH) and virus-associated hemophagocytic syndrome (VAHS) are classified as define HPS, a type of hemopathy. Abnormal poliferation and infiltration of monocytes and histiocytes with active phagocytosis are noted in various organs such as bone marrow, liver, spleen, lung and lymph nodes. Hemophagocytosis is induced by the excess production of cytokines by activated T-lymphocytes and macrophages. Although the patient underwent chemotherapy (CHOP, MEP) as well as treatment for DIC, hedied of gastrointestinal homorrhage and sepsis caused by methicillin-resistant Staphyjococcus aereus (MRSA) and Pseudomonas aeruginosa.

Epstein-Barr virus-associated hemophagocytic syndrome and fatal infectious mononucleosis.

Virus-associated hemophagocytic syndrome (VAHS) has been thought to be a distinct clinical entity, characterized by intermittent fever, enlarged liver and spleen, and the appearance of hemophagocytosis. Hemopoietic cells are actively ingested by monocytes/macrophages in various organs, including lymph nodes, bone marrow, liver, and spleen. Epstein-Barr virus (EBV) is now thought to be one of the major causes for the development of this unique syndrome. Additionally, VAHS is often associated with fatal infectious mononucleosis (IM). The relationship between EBV-associated VAHS and fatal IM is discussed in this concise review.

Successful treatment of virus‐associated haemophagocytic syndrome in adults by cyclosporin A supported by granulocyte colony‐stimulating factor

Two young adult patients with typical virus-associated haemophagocytic syndrome (VAHS) were treated with cyclosporin A and granulocyte colony-stimulating factor (G-CSF). Clinical symptoms such as high fever and malaise disappeared rapidly with concurrent haematological improvement in both patients. The serum levels of interleukin-6 (IL-6), soluble IL-2 receptor, tumour necrosis factor and macrophage-CSF were all elevated before treatment but that of G-CSF was not. The dramatic effect of cyclosporin A observed implies that it efficiently and rapidly suppresses the cytokine storm caused by dysregulated T cells in VAHS. In addition, G-CSF may promote haematological recovery without syndrome regression. We believe that the combination of cyclosporin A and G-CSF may be effective, at least in selected patients with VAHS. Further studies are required to confirm its role as first-line therapy for adult patients with VAHS.

A Case of Epstein Barr Virus-Associated Hemophagocytic Syndrome Confirmed by mRNA In Situ Hybridization and Polymerase Chain Reaction

A Case of Epstein Barr Virus-Associated Hemophagocytic Syndrome Confirmed by mRNA In Situ Hybridization and Polymerase Chain Reaction

Chronic active Epstein‐Barr virus infection in children in Japan

The patients with chronic active Epstein-Barr virus infection (CAEBV) in childhood in Japan are described. Among 39 registered cases, 20 patients were males and 19 were females. Unlike the X-linked lymphoproliferative syndrome, there was no hereditary background. The incidence of hypersensitivity to mosquito bites was high (31.3%) as a past history. Most patients exhibited hepatomegaly (92.3%), splenomegaly (87.2%) and fever (84.6%). The incidence of absent anti-EB virus nuclear antigen titres was unexpectedly low (17.1%). Lymphoreticular disorders and cardiovascular diseases were major complications. Twenty-four (61.5%) patients died 6 months to 8 years after the onset, mainly of hepatic failure (eight cases), cardiac failure (five cases), virus-associated haemophagocytic syndrome (three cases) and haematological malignancies (two cases). This study reveals the CAEBV in Japan has several clinical features and should be informative for the pathogenesis of EB virus.

Virus-associated haemophagocytic syndrome in previously healthy adults.

The clinical characteristics of 15 adult patients with virus-associated haemophagocytic syndrome (VAHS) were studied. The patients were 3 males and 12 females with a mean age of 39.5 years (range 20 to 67 years). Seven patients (mean age 48.6 years) were immunosuppressed by drugs or as a result of having malignant or autoimmune disease. Eight patients (mean age 31.6 years) had no underlying diseases. The prognosis of the patients with immunosuppression was poor, as previously reported, and 3 of them died. In younger adult patients with this syndrome who had no underlying immunosuppressive diseases, the prognosis was good even without therapy. The sera from the patients in both groups contained extremely high levels of macrophage colony-stimulating factor (M-CSF) and slightly elevated levels of tumour necrosis factor-alpha (TNF-alpha). These findings suggested that VAHS, can occur in presumably healthy adults and that VAHS can be a more benign condition than previously believed. M-CSF and TNF-alpha may play an important role in the development of the syndrome in both groups.

The presence of Epstein-Barr virus in multiple organs in a fatal case of virus-associated haemophagocytic syndrome

We describe a case report of a 21-year-old male with fatal Epstein-Barr virus-associated haemophagocytic syndrome. Virus is detected in multiple organs by polymerase chain reaction and in the tissue-specific cells of those organs by in situ hybridisation. It is suggested that organ failure may be a direct response to infection.

Epstein-Barr virus-associated hemophagocytic syndrome.

A virus-associated hemophagocytic syndrome (VAHS) is a non-neoplastic, generalized histiocytic proliferation with prominent hemophagocytosis associated with a systemic viral infection. Epstein-Barr virus (EBV) is one candidate for this association but serologic and molecular biologic studies have been lacking in many cases. Although VAHS is generally a benign process, EBV-associated hemophagocytic syndrome (EBV-AHS) is often fatal and has a relatively high mortality rate. Therefore, EBV-AHS must be distinguished from VAHS caused by other viruses. Recent evidence indicates that the pathophysiology in EBV-AHS appears to be mediated by the unrestricted release of cytokines produced by the EBV-infected T cells. Clinical and laboratory findings, the differential diagnosis, virology studies, pathophysiology, and treatment in EBV-AHS are reviewed.

Partial albinism with immunodeficiency (Griscelli syndrome)

Partial albinism with immunodeficiency is a rare and fatal immunologic disorder characterized by pigmentary dilution and variable cellular immunodeficiency. To define the phenotype, therapy, and outcome, we retrospectively analyzed seven consecutive patients. Primary abnormalities included a silvery-grayish sheen to the hair, large pigment agglomerations in hair shafts, and an abundance of mature melanosomes in melanocytes, with reduced pigmentation of adjacent keratinocytes. Clinical onset occurred between the ages of 4 months and 4 years and was characterized by accelerated phases (lymphohistiocytic infiltration of multiple organs, including the brain and the meninges), triggered by viral and bacterial infections. Characteristic laboratory features included pancytopenia, hypofibrinogenemia, hypertriglyceridemia, and hypoproteinemia. Consistent immunologic abnormalities were characterized by absent delayed-type cutaneous hypersensitivity and impaired natural killer cell function. Some patients had secondary hypogammaglobulinemia, impaired major histocompatibility complex-mediated cytotoxic effects, a decreased capacity of lymphocytes to trigger a mixed lymphocyte reaction, or various functional granulocytic abnormalities. The disease seems to be invariably lethal without bone marrow transplantation; the mean age at the time of death was 5 years. Bone marrow transplantation has been performed in three cases; two patients died in the immediate posttransplantation period of infectious complications, but one patient is cured after a follow-up of 5 years. We conclude that partial albinism with immunodeficiency (Griscelli syndrome) can be differentiated from Chédiak-Higashi syndrome by pathognomonic histologic features. One of the underlying immunologic defects may be a defective function of natural killer cells, predisposing the patient to virus-associated hemophagocytic syndrome or accelerated phases. The prognosis is very poor unless early bone marrow transplantation is carried out. (J P EDIATR 1994;125:886-95)

Monoclonal proliferation of Epstein-Barr virus-infected T-cells in a patient with virus-associated haemophagocytic syndrome

Virus-associated haemophagocytic syndrome (VAHS) is a non-neoplastic, generalized histiocytic proliferation disorder showing marked haemophagocytosis associated with systemic viral infection. We describe the case of a 1-year-old girl with Epstein-Barr virus (EBV)-related VAHS, in whom Southern blot analysis showed monoclonal proliferation of bone marrow cells with the EBV genome; detected with the Xho-1 fragment of the latent infection membrane protein genome. EBV serology showed anti-Epstein-Barr virus nuclear associated antigen (EBNA), anti-viral capsid antigen (VCA)-IgG, anti-VCA-IgA elevation and positive EBNA of Sheep red blood cells (SRBC)-rosette-forming bone marrow cells in the late period of her clinical course, indicative of EBV infection. DNA analysis of her bone marrow cells showed monoclonal rearrangement of the T-cell receptor-beta and -gamma chain genes but not of the immunoglobulin heavy chain genes. Those results suggest that EBV may infect T-cells, after which the cells proliferate monoclonally. Repeated administration of epipodophyllotoxin VP-16-213 induced remission, but adrenocortical steroid, vincristine, and cyclophosphamide had no effect on the patient's condition. Ours is a first case report of VAHS showing monoclonal proliferation of EBV-infected T-cells.

Virus-associated hemophagocytic syndrome: interest of examination of fresh myeloaspirates [letter

Virus-associated hemophagocytic syndrome: interest of examination of fresh myeloaspirates [letter

Fatal Epstein-Barr Virus–Associated Hemophagocytic Syndrome

A virus-associated hemophagocytic syndrome is characterized by high fever, liver dysfunction, coagulation abnormalities, pancytopenia, and a benign histiocytic proliferation with prominent hemophagocytosis in bone marrow, lymph node, spleen, and liver. We describe six Japanese children with fatal Epstein-Barr virus (EBV)-associated hemophagocytic syndrome. Five of the six patients had serologic evidence of primary EBV infection at the onset of their diseases. EBV genomes were detected in all the patients by Southern blot hybridization or the polymerase chain reaction. Furthermore, clonality analysis of the EBV genome showed that EBV-infected cells proliferated monoclonally or biclonally in three examined patients. In situ hybridization study using EBV-encoded RNA 1 (EBER1) showed that EBER1 was detected in one of two examined liver tissues, which localized in hepatocytes.