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Epstein-Barr Virus-Induced Hemophagocytic Lymphohistiocytosis and X-Linked Lymphoproliferative Disease: A Mimicker of Sepsis in the Pediatric Intensive Care Unit

Division of Pediatric Critical Care Medicine, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, Michigan 48109, USA.
PEDIATRICS (Impact Factor: 5.3). 05/2007; 119(5):e1212-8. DOI: 10.1542/peds.2006-1534
Source: PubMed

ABSTRACT A rare complication of infection with the Epstein-Barr virus is the development of hemophagocytic lymphohistiocytosis. Although most cases of Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis develop in immunocompetent individuals, the rare immunodeficiency X-linked lymphoproliferative disease is often unmasked by Epstein-Barr virus infection and is clinically indistinguishable from Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis. We describe the clinical course and management of a previously healthy 17-year-old boy who presented with hemodynamic collapse and severe systemic inflammatory response syndrome resulting from overwhelming hemophagocytosis in the setting of X-linked lymphoproliferative disease. A novel therapeutic approach using anti-tumor necrosis factor alpha therapy was instituted, aimed at attenuating the viral-induced hyperinflammatory state. Given the similarity to overwhelming sepsis, yet a substantially different therapeutic approach, this case illustrates the importance of early recognition and prompt treatment that are necessary to reduce the high morbidity and mortality associated with Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis and X-linked lymphoproliferative disease.

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    • "For patients with EBV infection, strong consideration should be given to use of anti- CD20 antibodies, such as rituximab to eliminate mature B cells, which serve as the reservoir for EBV. Indeed, rituximab has been used to prevent or to treat HLH in a limited number of EBV+ patients when used with steroids and/or chemotherapy to curtail T cell and macrophage activation (Balamuth et al, 2007; Milone et al, 2005; Lee et al, 2006b; Mischler et al, 2007). Given that the use of Rituximab can lead to reactivation of hepatitis B, patients should be tested for the presence of this virus prior to initiation of therapy (Ram & Raanani, 2009). "
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    ABSTRACT: X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by the clinical triad of increased susceptibility to primary Epstein-Barr virus (EBV) infection, dysgammaglobulinaemia and lymphoma. Most cases are caused by germline mutations in the SH2D1A gene, which encodes the adaptor molecule Signalling Lymphocytic Activation Molecule (SLAM)-associated protein (SAP). Recently, a subset of patients with an XLP-like phenotype was found to carry mutations in XIAP, the gene encoding the X-linked inhibitor of apoptosis protein (XIAP). Studies of XLP patients and Sap-/- mice reveal that loss of SAP expression impairs immune cell activities, such as natural killer and CD8+ T cell cytotoxicity, T cell cytokine production, activation-induced cell death, germinal centre formation and natural killer T cell development. Efforts to dissect the diverse roles of SAP and XIAP are enhancing our understanding of immune cell biology and defining how genetic defects in these molecules predispose to EBV-specific as well as more general cellular and humoral immune dysfunction. These studies are also highlighting critical signalling pathways that might be amenable to pharmacological targeting to improve the treatment of XLP and other disorders associated with impaired antiviral and antitumour immunity.
    British Journal of Haematology 11/2010; 152(1):13-30. DOI:10.1111/j.1365-2141.2010.08442.x · 4.96 Impact Factor
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    • "There was only one case of XLP involving a family history, specifically a sibling death due to pneumonia at 8 months. XLP has been now recognized as a primary immunological disorder in infants and children (Mischler et al, 2007). The only case of a mutation of the PRF1 gene in this study showed no family history. "
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    ABSTRACT: Haemophagocytic lymphohistiocytosis (HLH) is a fatal haematological disorder with diverse aetiology. This prospective study was undertaken to characterize HLH cases in Vietnamese children. Clinical and laboratory data, genetic analyses and outcome of the HLH patients were analysed. A total of 33 patients were enrolled from March 2007 to December 2008, with a median age of 3 years. Mutations of the SH2D1A (SAP) and PRF1 genes were detected in one patient, respectively. The virus association was high, up to 63.6% (21/33), including Epstein-Barr virus (19/33), cytomegalovirus (2/33) and dengue virus (2/33). Five patients had malignant lymphoma and two had autoimmune diseases. Twenty-eight patients were treated according to the HLH-2004 protocol. The first response rate was 64.3% (18/28), with an early death rate of 35.7% (10/28). High levels of interferon-gamma, interleukin-10, MIG and interferon-inducible protein-10 (IP-10) were associated with early mortality (P < 0.05). Reactivation among the responders was high (9/18) and the uneventful resolution was low (3/18) after a median follow-up of 35 weeks. In conclusion, the majority of HLH cases are associated with virus infections in Vietnamese children. Familial HLH is rare. The frequent reactivation and high mortality demands a more appropriate therapeutic regimen in tropical areas like Vietnam.
    British Journal of Haematology 10/2009; 148(2):301-10. DOI:10.1111/j.1365-2141.2009.07957.x · 4.96 Impact Factor
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    • "For patients with EBV infection, strong consideration should be given to use of anti- CD20 antibodies, such as rituximab to eliminate mature B cells, which serve as the reservoir for EBV. Indeed, rituximab has been used to prevent or to treat HLH in a limited number of EBV+ patients when used with steroids and/or chemotherapy to curtail T cell and macrophage activation (Balamuth et al, 2007; Milone et al, 2005; Lee et al, 2006b; Mischler et al, 2007). Given that the use of Rituximab can lead to reactivation of hepatitis B, patients should be tested for the presence of this virus prior to initiation of therapy (Ram & Raanani, 2009). "
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    ABSTRACT: A major focus of our research is to understand the molecular and cellular basis of X-linked lymphoproliferative disease (XLP), a rare and often fatal immunodeficiency caused by mutations in the SH2D1A gene, which encodes the adaptor molecule SAP. Recently, we observed that SAP is essential for the development of natural killer T (NKT) cells, a lymphocyte population that participates in protection against certain tumors, infections, and autoimmune states. In this review, we describe the approaches that we are taking to understand the role of SAP in immune cells, including NKT cells. By using SAP as the focal point of our studies, we hope to identify novel signaling pathways that could be targeted to improve the treatment for patients with XLP as well as more common disorders, such as autoimmunity and cancer.
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