How I treat EBV lymphoproliferation

Abstract

Epstein-Barr virus (EBV)- IntroductionEpstein-Barr virus (EBV) lymphoproliferative disease (LPD) is the result of the outgrowth of EBV-infected B cells that would normally be controlled by an effective EBV-specific cytotoxic T-cell response. LPD may occur during both primary and secondary immune deficiencies and even in some persons without documented immunodeficiency. In this article, I focus on EBV type III latency B-cell lymphoproliferation, which occurs during the immunosuppression that follows hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT). To understand the etiology of these lymphoproliferations and how manipulation of the immune system may be a treatment option, it is important to first understand the biology of EBV. Biology of EBVEBV is a latent ␥-herpesvirus that infects more than 90% of the world's population. Primary lytic infection occurs in the oropharynx and may be asymptomatic or present as infectious mononucleosis. 1 EBV is highly immunogenic; and during primary infection, normal persons mount a vigorous humoral and cellular immune response with the cellular component consisting of CD4 ϩ and CD8 ϩ T cells, which control both primary infection and the periodic reactivations that occur in all EBV-seropositive persons. 2 Indeed, analyses using multimers to enumerate EBV-specific T cells have shown that up to 1% to 5% of circulating T cells in a normal EBV-seropositive person may be specific for EBV. 3,4 After clearance of primary infection, EBV persists as an episome in infected B cells, establishing latent infection characterized by the expression of only a limited array of subdominant EBV antigens. There are 4 types of latency, distinguished by the pattern of EBV antigen expression in infected memory B cells (Figure 1).Most infected circulating memory B cells express no viral antigens (type 0 latency), allowing them to remain invisible to the host immune system. 5 EBNA1, which acts on a latent origin of replication, is responsible for coordinating replication of the latent episome in concert with replication of the host cells and is therefore expressed in all types of latency associated with cell division. 6 Type 1 latency is associated with expression of only EBNA-1 and is seen in circulating B cells when they proliferate and in Burkitt lymphoma. In type 2 latency, LMP1 and LMP2 are also expressed in addition to EBNA1, and this pattern of expression is seen in germinal center B cells in healthy tonsils. The most immunogenic form of latency is type 3, in which all nuclear proteins (EBNAs -1, -2, -3A, -3B, -3C, and -LP) and 2 membrane proteins (LMP1 and LMP2) are expressed together with 2 small RNAs (EBERs). Type 3 latency occurs in B cells immortalized in vitro by EBV into permanently growing lymphoblastoid cell lines. Type 3 latency B cells are rarely detected in healthy seropositive persons, but their occurrence can be inferred from the high frequency of T cells specific for the EBNA3 proteins that persist long-term, and it is probable that periodic reactivat...

Features of EBV reactivation after reduced intensity conditioning unrelated umbilical cord blood transplantation

“…20 LPD after HSCT typically occurs within the first 6 months post transplant, before reconstitution of the EBV-specific cytotoxic T-cell response. 7 In the first patient, EBV-LPD occurred late after UCBT (at 9 months post UCBT), highlighting the concern of a relatively slow immune reconstitution after UCBT. 21,22 However, immunosuppressive treatment at the time of the occurrence of EBV-LPD could have altered the specific immune recovery, as previously reported for CMV in the same setting.…”

“…7,28 In addition, an ever growing number of studies suggested that preemptive therapy with rituximab may be highly effective in controlling viral proliferation and avoiding progression into EBV-related LPD. 29,30 Of note, the efficacy of rituximab was mainly observed in the preemptive setting, but to a lesser extent once EBV-related LPD was fully established.…”

“…6 Following allo-HSCT, EBV reactivation and EBV-related proliferation are well recognized complications. 7 EBV reactivation may be associated with a spectrum of clinical presentations, going from fever to lymphoproliferative disease (LPD), which arise as a consequence of an outgrowth of B cells latently infected with EBV in the setting of loss or suppression of normal cytotoxic T-cell surveillance. Risk factors for EBV-related complications include the degree of mismatch between donor and recipient, manipulation of the graft to deplete T cells, and degree and duration of immunosuppression used to prevent and treat GVHD.…”

“…Risk factors for EBV-related complications include the degree of mismatch between donor and recipient, manipulation of the graft to deplete T cells, and degree and duration of immunosuppression used to prevent and treat GVHD. 7 Despite concerns regarding immune reconstitution following UCB transplantation (UCBT), early reports documented the rates of EBV-LPD to be comparable to those documented after HLA-matched unrelated BM or PBSC HSCT. 8 However, a marked increased risk of EBV-LPD has been observed with the use of RIC before UCBT.…”

Manifestations of Fulminant CD8 T-cell Post-transplant Lymphoproliferative Disorder Following the Administration of Rituximab for Lymphadenopathy with a High Level of Epstein-Barr Virus (EBV) Replication after Allogeneic Hematopoietic Stem Cell Transplantation

“…As most cases of PTLD arise among donor-or recipient-derived B-cells, one strategy to prevent the development of PTLD is to eliminate EBVinfected B-cells in the early phase after HSCT. Monitoring the EBV-DNA load in the peripheral blood in addition to administering preemptive rituximab therapy has recently been reported to be a successful approach to preventing the development of B-cell PTLD (1,2). EBV-specific tetramer analyses using flow cytometry can also be useful for detecting EBV-specific cytotoxic T-cells (CTL), the actions of which are negatively associated with the development of PTLD (3).…”