**2. Epstein-Barr Virus (EBV)**

EBV is a herpesvirus that is thought to infect up to 95% of the adult population. Primary infection in childhood usually results in mild, self-limiting illness [1, 2]. Asymptomatic carriers in childhood are often seen. Immunocompetent older children and adult patients get sick from infectious mononucleosis with benign lymphoproliferation of B cells under the control of the cytotoxic T cells and cellular immune response consisting of CD4+ and CD8+ T cells, which control both primary infection ant periodic reactivation that occur in all EBV-seropositive persons [1, 3, 4]. The EBV causes nasopharyngeal carcinoma, Burkitt lymphoma, and other lymphoepithelic tumors (non-Hodgkin's lymphoma, B- and T-cellular lymphomas) [5]. Development of these diseases is based on some cellular factors, as well as 14th chromosome translocation. Once infected with EBV, the virus persists latently in a person for life, in B cell lymphocytes, and chronically replicating in the cells of the oropharynx [5, 6]. In patients with HIV and transplanted ones, EBV becomes a main problem because of the inability of the immune system to control B cell proliferation and immortalization. EBV infection is registered in nearly 75% of transplanted recipients as the source usually is the donor. Contagion can also occur after blood transfusion. In the course of the immunosuppression, the latent EBV infection can be reactivated. Clinical disease represent mononuclear syndrome with temperature, lymphadenopathy, hepatosplenomegaly and monocytosis. The central nervous system is rarely involved with symptoms of serous meningitis, encephalitis, Guillen Barre syndrome.

The immunosuppression required to prevent graft rejection post-transplantation impairs T cell immunity, potentially allowing for uncontrolled proliferation of EBV-infected B cells, which may result in a spectrum of B cell proliferations that range from hyperplasia to true lymphoma [7, 8]. In the initial stages of PTLD, prolypheration is polyclonal. With mutation and selective growth, the lesion becomes oligoclonal and later, monoclonal. Lymphocytes from patients treated with cyclosporine do not exhibit an appropriate T cell response to EBV-infected B cells in vitro. The activity of natural killer cells is reduced for several months following transplantation [9, 10].

PTLD is a well-recognized complication of both solid organ transplantation and allogeneic hematopoietic stem cell transplantation (HSCT). It is one of the most common post-transplant malignancies. In most cases, it is associated with EBV infection of B cells, either as a conse‐ quence of post-transplant reactivation of the virus or from primary EBV infection. The median onset of disease in solid organ transplant population is 6 months and in hematopoietic stem cell recipients 70–90 days [11, 12] after transplantation. The frequency of PTLD depends largely on the type of transplant received and the immunosuppression that the particular transplant requires [6, 11, 12]. Primary EBV infection may develop, such as in an EBV seronegative recipient who received an allograft from an EBV-seropositive donor. This is recognized as probably the most significant risk factor for developing PTLD and be higher in pediatric transplant recipients [12]. The incidence ranged from 0.6%–2.1% in adult kidney recipients to 4.4%–6.9% in pediatric kidney recipients [12, 13] at different time after transplantation. Lung and heart transplantation in adult population is associated with a relatively high rate of PTLD with an incidence of approximately 5% or more [14]. After liver transplantation, reported rate of incidence is approximately 1% in adult recipients and pediatric recipients [15]. In the setting of allogeneic hematopoietic stem cell transplantation, PTLD rates vary greatly depending on the conditioning regimen and the amount of T cell depletion. In pediatric recipients, PTLD occurs in less than 1% of non-T-cell-depleted grafts from matched siblings, compared with as high as 30% of patients with unrelated or HLA-mismatched donors when extensive T cell depletion of the donor bone marrow is performed. Treatment of graft versus host disease with antitimocyte globulin or anti-T-cell monoclonal antibodies is another risk factor for PTLD [16]. According to the laboratory data, PTLD is characterized by leukopenia, thrombocytopenia, atypical lymphocytosis, generalized lymphadenopathy. Also B-cell lymphoma, non-Hodg‐ kin's lymphoma (90%), lung lymphoid hyperplasia and lymphoid interstitial pneumonia (after lung transplantation), oral "hairy" leukoplakia (in association with HPV), and malignant transformation are developed. Of note, PTLD may be very difficult to distinguish from episodes of organ rejection and infection. Cell factors take part in the progress of PTLD, as well as co-infection with CMV. Different clinical symptoms can go along with the functional disorder. Mortality rate after solid-organ transplantation is more than 50% and after hemato‐ poietic stem cell transplantation early mortality rate approached 90% [17, 18].

PTLD is an often-fatal complication of transplanted patients. Early diagnosis is important. Good medical practice requires elucidating the serological status of the patients for EBV before transplantation or immunosuppression. ELISA and immunofluorescence are used. Those who have latent infection have positive results for IgG against capsid antigen of the virus (VCA), and in most cases, against nuclear Ag (EBNA). Patients with primary or activated latent infection may have IgM and IgG anti EBV VCA, and high titer against early Ag (EA), usually EBNA are not formed. Other special studies to confirm the diagnosis of PTLD include immunophenotyping by flow cytometry or immunohistochemistry and molecular studies such as fluorescent in situ hybridization for EBV early RNA (EBER). EBV PCR of peripheral blood may be useful at the time of diagnosis and during follow-up as a method of monitoring the patient's response to treatment [18]. Surveillance by monthly PCR for circulating EBV DNA may be appropriate in such high-risk settings as EBV-seromismatched (donor-positive, recipient-negative) solid organ transplants and T cell depleted, HLA-mismatched stem cell transplants [18, 19].

Reduction in immunosuppression remains the primary therapy and often results in permanent disease eradication (19). Antiviral drugs are used (acyclovir, valacyclovir, famcyclovir, gancyclovir) combined with immunotherapy with anti-B-cell antibodies or conventional chemotherapy. Adoptive immunotherapy with EBV-specific donor T cells is highly effective. There is some data for the prophylactic administration of gancyclovir before transplantation and immunosuppression (20).
