Treatment of primary Epstein-Barr virus infection in patient with X-linked lymphoproliferative disease using B-cell direct therapy

The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States
Blood (Impact Factor: 10.45). 03/2005; 105(3):994-6. DOI: 10.1182/blood-2004-07-2965
Source: PubMed

ABSTRACT X-linked lymphoproliferative disease (XLP) is a congenital immunodeficiency that is characterized by an abnormal immune response to primary Epstein-Barr virus (EBV) infection. After EBV exposure, affected patients often develop fulminant infectious mononucleosis (FIM), a life-threatening condition marked by the uncontrolled expansion and activation of T and B lymphocytes and macrophages. We hypothesized that the rapid elimination of B cells immediately following EBV exposure might reduce the severity of primary EBV infection in patients with XLP. To test this possibility, we administered the anti-CD20 antibody rituximab to 2 patients who presented with acute infection. Following treatment, both patients exhibited a complete resolution of symptoms and no longer demonstrated detectable EBV DNA within circulating lymphocytes. Moreover, neither patient has developed FIM or lymphoma in more than 2 years of follow-up. These data suggest that the pre-emptive use of B-cell-directed therapy may reduce the morbidity and mortality of primary EBV infection in XLP-affected individuals.

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Available from: Kim E Nichols, Sep 26, 2015
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    • "Control of infectious disease is of similar importance both in primary as well as 'secondary' HLH. EBV-triggered HLH has been treated successfully with rituximab (anti-CD20 antibody) in addition to conventional therapy [27,76-78]. Immunoglobulins, which may act against pathological antigens or cytokines, have been used as an adjunct in infection-triggered HLH [1,27]. "
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    ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages secreting high amounts of inflammatory cytokines. It is a frequent manifestation in patients with predisposing genetic defects, but can occur secondary to various infectious, malignant, and autoimmune triggers in patients without a known genetic predisposition. Clinical hallmarks are prolonged fever, cytopenias, hepatosplenomegaly, and neurological symptoms, but atypical variants presenting with signs of chronic immunodeficiency are increasingly recognized. Impaired secretion of perforin is a key feature in several genetic forms of the disease, but not required for disease pathogenesis. Despite progress in diagnostics and therapy, mortality of patients with severe HLH is still above 40%. Reference treatment is an etoposide-based protocol, but new approaches are currently explored. Key for a favorable prognosis is the rapid identification of an underlying genetic cause, which has been facilitated by recent immunological and genetic advances. In patients with predisposing genetic disease, hematopoietic stem cell transplantation is performed increasingly with reduced intensity conditioning regimes. Current research aims at a better understanding of disease pathogenesis and evaluation of more targeted approaches to therapy, including anti-cytokine antibodies and gene therapy.
    Arthritis research & therapy 06/2012; 14(3):213. DOI:10.1186/ar3843 · 3.75 Impact Factor
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    • "Most patients with sporadic EBV-HLH can achieve remission by immunochemotherapy; however, patients with XLP are usually refractory to this therapy. Recently, B cell-directed therapy using an anti-CD20 mAb (rituximab) was performed in patients with XLP-1 [19]. Two XLP patients who presented with acute EBV infection were successfully treated with rituximab and were free from EBV-HLH and lymphoma for a prolonged period. "
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    ABSTRACT: X-linked lymphoproliferative syndrome (XLP) is a rare inherited immunodeficiency by an extreme vulnerability to Epstein-Barr virus (EBV) infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP are now divided into type 1 (XLP-1) and type 2 (XLP-2), which are caused by mutations of SH2D1A/SLAM-associated protein (SAP) and X-linked inhibitor of apoptosis protein (XIAP) genes, respectively. The diagnosis of XLP in individuals with EBV-associated HLH (EBV-HLH) is generally difficult because they show basically similar symptoms to sporadic EBV-HLH. Although EBV-infected cells in sporadic EBV-HLH are known to be mainly in CD8+ T cells, the cell-type of EBV-infected cells in EBV-HLH seen in XLP patients remains undetermined. EBV-infected cells in two patients (XLP-1 and XLP-2) presenting EBV-HLH were evaluated by in EBER-1 in situ hybridization or quantitative PCR methods. Both XLP patients showed that the dominant population of EBV-infected cells was CD19+ B cells, whereas EBV-infected CD8+ T cells were very few. In XLP-related EBV-HLH, EBV-infected cells appear to be predominantly B cells. B cell directed therapy such as rituximab may be a valuable option in the treatment of EBV-HLH in XLP patients.
    02/2012; 3(1):1. DOI:10.1186/2042-4280-3-1
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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 · 4.71 Impact Factor
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