Epstein-Barr Virus Infections

Primary or reactivated Epstein-Barr virus (EBV) infection occurs in 20 to 50% of liver transplant recipients. Common clinical features are fever, pharyngitis, splenomegaly, lymphadenopathy and maculo-papular rush, even if in several patients the infection may be asymptomatic.
In immunosuppressed patients, EBV infection can induce uncontrolled lymphocyte B proliferation and development of post-transplant lymphoproliferative disease (PTLD). Proliferation, activation and transformation of EBV-infected lymphocytes B and simultaneous inactivation of cytotoxic lymphocytes, favor PTLD. The lymphoproliferative disorder may range from benign hyperplasia (mononucleosis-like syndrome), to malignant lymphoma. The risk of developing PTLD is particularly high in children who contract primary EBV infection after transplantation. The quantitative or semiquantitative monitoring of EBV DNA in circulating EBV-infected lymphocytes can help in identifying patients at risk of developing EBV-related PTLD.
No definitive treatment of symptomatic EBV disease or PTLD have been developed. First line treatment is reduction or withdrawal of immunosuppression to obtain the regression of clinical manifestations and/or reduction of the circulating level of EBV genomes. Acute rejection is the major risk, as its treatment may cause an increase in circulating EBV genome levels and worsening of PTLD. When immunosuppression modulation is not effective, antiviral therapy and/or chemotherapy have been employed. Recently, reconstitution of EBV immunity with in vitro expansion and infusion of EBV-specific autologous cytotoxic lymphocytes have been successfully used to treat PTLD in bone marrow transplant recipients. This method is under evaluation in solid organ transplantation.
In our series of 97 pediatric liver recipients, 41 patients were EBV nuclear antibody (EBNA) negative at the time of liver transplantation and 38 were EBNA positive. Eighteen patients were not considered, 9 because pre-transplant EBV serology was not evaluated and 9 other because of early postoperative death. After transplantation we monitored the circulating EBV-DNA levels by quantitative polymerase chain reaction. Sixteen EBNA-negative patients (39%) showed EBV genome greater or equal to 500/105 circulating leukocytes, and 8 of them developed EBV infection-related symptoms (50%). Polyclonal B cell hyperplasia and high levels of EBV genome in the tissues were detected in 2 of them. Two of the 6 EBNA-positive patients (33%), with more than 500 EBV genome/105 circulating leukocytes, developed similar clinical-pathologic manifestations, the others were asymptomatic. The median time between the transplant and the observed increase in EBV-DNA was 8 months. In 4 out of 10 patients with symptomatic EBV infection, immunosuppressive therapy was withdrawn. Symptoms regressed and EBV-DNA level decreased, but acute rejection occurred. In asymptomatic patients with increased EBV-DNA levels the immunosuppressive therapy was decreased resulting in reduction of viremia.