Epstein-Barr Virus-Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management

Abstract

Posttransplant lymphoproliferative disease (PTLD) is a potentially fatal complication after (solid organ) transplantation, which is highly associated with Epstein-Barr virus (EBV). The EBV-specific cytotoxic T cell response that is essential in controlling the virus in healthy individuals is suppressed in transplant recipients using immunosuppressive drugs. A primary EBV infection in EBV-seronegative patients receiving an EBV-seropositive donor organ or a reactivation in those who are already latently infected pretransplantation can lead to uninhibited growth of EBV-infected B cells and subsequently to PTLD. Effective preventive strategies, such as vaccines and antiviral agents, are lacking. Because not every transplant recipient with increasing EBV viral load develops PTLD, it is hard to decide how intensively these patients should be monitored and how and when a preemptive intervention should take place. There is a need for other tools to help predict the development of PTLD in patients at risk to make timing and strategy of preemptive intervention easier and more reliable. The cornerstone of the treatment of patients with PTLD is restoring the host's immunity by reduction of immunosuppressive drug therapy. American and British guidelines recommend to add rituximab monotherapy or rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisolone, depending on histology and clinical characteristics. Although response to these therapies is good, toxicity is a problem, and PTLD still has a relatively high mortality rate. An evolving therapy, especially in PTLD occurring in allogeneic stem cell transplantation, is restoring the host's immune response with infusion of EBV-specific cytotoxic T cells. This may also play a role in the future in both prevention and treatment of PTLD in SOT.

FIGURE 1

The EBV life cycle. In the oropharynx, epithelial cells and naive B cells can both be infected either directly by Epstein-Barr virions or by each other. Infection of epithelial cells leads to initiation of the lytic phase. At the same time, infection of naive B cells leads to initiation of the latent phase, which exists of 3 successive gene transcription programs: the growth program, the default program, and the latency program, resulting in latently infected memory B cells, in which the virus can persist asymptomatically for life. When these memory cells circulate through Waldeyer's ring, differentiating into plasma cells may lead to reactivation of the virus. The EBV-specific cytotoxic T cells are mostly directed against lymphoblasts expressing the growth program. Decrease in number and function of T cells due to immunosuppressive drugs might lead to uninhibited growth of these cells and eventually to PTLD.