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Immunocompromised patients, such as stem cell transplant patients and solid organ transplant patients, are at risk for Epstein-Barr Virus (EBV) associated with lymphoproliferative disorder. EBV establishes latency in the B lymphocytes following primary infection, which generally occurs in childhood or as a young adult. In an immunocompetent individual, specific cytotoxic T lymphocytes suppress B cell proliferation. However, in an immunocompromised individual, latent EBV infection can reactivate and potentially cause lymphoproliferative disease. This may progress to a malignancy, most likely due to the lack of specific cytotoxic T lymphocytes to control EBV-induced B cell proliferation.
Transplant patients who are EBV-seronegative at the time of transplant are at highest risk for post-transplant lymphoproliferative disorder (PTLD). This disease can manifest itself in various forms ranging from benign polyclonal hyperplasia to malignant lymphoma. If transplant patients acquire a primary EBV infection while being treated with immunosuppressive drugs, the risk of developing PTLD dramatically increases. Primary EBV infections are particularly common in the pediatric transplant population. Additional risk factors for development of PTLD in the hematopoietic stem cell transplantation (HSCT) population are the intensity and duration of immunosuppressive therapy, the use of an unrelated donor, T-cell-depleted allografts, or antithymocyte globulin and immunosuppression to prevent graft-versus-host disease (GVHD). Notably, if lymphoproliferative disease develops in HSCT patients with GVHD, the prognosis is quite poor.
Although studies have suggested that early diagnosis of PTLD will improve patient outcomes, the diagnosis of PTLD has been challenging. EBV antibody assays do not provide useful information for clinicians monitoring EBV seropositive transplant patients. Real-time quantitative PCR has provided a sensitive tool for monitoring EBV loads in peripheral blood. Many early studies used whole blood or buffy coat for EBV molecular testing. While the use of these samples proved sensitive for the detection of EBV replication, the positive predictive value for PTLD was relatively low. Although other studies used plasma for monitoring EBV replication, some experts remained concerned about the sensitivity of EBV detection in plasma.
In an attempt to resolve this question, University of Pennsylvania and ViraCor Laboratories undertook a prospective study to examine the diagnostic utility of plasma versus whole blood EBV testing in transplant patients. In this study, the EBV DNA qPCR plasma assay had a positive predictive value of 100% and a negative predictive value of 86% for detecting EBV-positive PTLD. In contrast, the EBV DNA qPCR whole blood assay had a dramatically lower positive predictive value of 67% and a nearly equivalent negative predictive value of 92% for detection of EBV in cases of PTLD. Although whole blood, PBMC, and plasma are all useful for detection of EBV in immunocompromised patients, a higher positive predictive value for PTLD is achieved through the use of plasma. For this reason, ViraCor Laboratories recommends and routinely tests plasma for EBV by real-time, quantitative PCR in patients being monitored for the development of PTLD.
Selected References
Tsai D.E., Douglas L, Andreadis C, Vogl D.T., Arnoldi S, Kotloff R, Svoboda J, Bloom R.D., Olthoff K.M., Brozena S.C., Schuster S.J., Stadtmauer E.A., Robertson E.S., Wasik M.A., Ahya V.N. EBV PCR in the diagnosis and monitoring of posttransplant lymphoproliferative disorder: Results of a two-arm prospective trial. American Journal of Transplantation. 2008;8(5):1016-1024.
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