Significance of detecting Epstein-Barr-specific sequences in the peripheral blood of asymptomatic pediatric liver transplant recipients.

Stanford University Medical Center, Stanford, CA 94304-1510, USA.
Liver Transplantation (Impact Factor: 3.79). 01/2000; 6(1):62-6. DOI: 10.1002/lt.500060102
Source: PubMed

ABSTRACT Pediatric allograft recipients are at increased risk for Epstein-Barr virus (EBV)-associated illnesses. The early identification and diagnosis of EBV-associated disorders is critical because disease progression can often be curtailed by modification of immunosuppression. We have previously shown that detection of EBV-specific sequences in the circulation by polymerase chain reaction (PCR) correlated well with the clinical symptoms of EBV infection. The purpose of the current study is to determine the significance of detecting EBV-specific sequences by PCR in asymptomatic pediatric liver transplant recipients. Peripheral-blood DNA was analyzed for the EBV genes, coding from the nuclear antigen 1 (EBNA-1) and the viral capsid antigen (gp220) by PCR. Samples from asymptomatic pediatric liver transplant recipients were analyzed from the immediate postoperative period and at 2- to 4-month intervals thereafter. We followed up 13 of these asymptomatic recipients who tested positive for EBV compared with 7 asymptomatic recipients who tested negative for EBV during the early posttransplantation period. Follow-up ranged from 1.5 to 4 years posttransplantation. Nine patients (69%) initially positive for EBV and asymptomatic ultimately developed symptoms of EBV infection, including fever, lymphadenopathy, rash, respiratory and gastrointestinal symptoms, and/or hepatitis. Five of these patients (56%) went on to develop posttransplant lymphoproliferative disorder based on histological examination of biopsied tissue and immunohistochemical identification of the EBV antigen/DNA in tissue. This is the first report suggesting that detection of EBV-specific sequences in the absence of symptoms may herald impending EBV-associated disorders. Thus, routine monitoring for circulating EBV sequences in asymptomatic recipients may be useful in the early identification of those at risk for developing EBV-associated disease and its ultimate prevention.

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    ABSTRACT: Epstein-Barr virus (EBV) has been associated with a variety of both infectious and malignant human diseases. These viruses are characterized by (B-cell) lymphotropism, their ability to establish latent infection in host cells and to induce proliferation of these latently infected cells. Approximately 90% of humans will become infected with EBV, generally without clinical evidence of disease. Primary infection usually occurs asymptomatically in childhood and results in a lifetime carrier state with periodic release of infectious virus into saliva which may cause infection of naive individuals. E.g. during adolescence, the latter type of infection may be referred to as kissing disease or Pfeiffer’s disease. EBV causes various benign syndromes, such as infectious mononucleosis, chronic active EBV infection, X-linked lymphoproliferative disease and oral hairy leukoplakia. EBV has also been associated with malignant diseases including nasopharyngeal carcinoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, and post-transplant lymphoproliferative disease (PTLD). PTLD refer to a range of hyperplastic to neoplastic lymphoid proliferations which occur after solid organ- or bone marrow transplantation, they mostly are of B-cell origin, and commonly (90%) contain EBV. The lack of early and accurate markers of EBV reactivation and disease has long hampered a timely diagnosis of post-transplant EBV lymphoproliferative disease. The introduction of polymerase chain reaction (PCR)-based assays, however, has allowed for sensitive and quantitative monitoring of viral DNA in peripheral blood samples. This thesis has addressed the question whether molecular monitoring of EBV-DNA would accurately predict for EBV-LPD and whether preventive and therapeutic strategies could be developed based on viral load monitoring.
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    ABSTRACT: Posttransplant lymphoproliferative disease (PTLD) is a severe and life-threatening complication after stem cell or solid-organ transplantation, virtually always associated with presence of Epstein-Barr virus (EBV) in the proliferating cells. PTLD is probably caused by the iatrogenically impaired T-cell response allowing outgrowth of EBV-positive B-cells. Quantitative EBV DNA load monitoring is a minimally invasive technique increasingly recognized as a valuable tool in posttransplant patient management. In this review, we focus on the clinical utility of EBV DNA load monitoring in the peripheral blood of transplant recipients using PCR and we discuss the currently most-widely used techniques and their value and limitations in predicting and diagnosing PTLD. Options for EBV DNA load-guided pre-emptive therapy and application of monitoring EBV DNA load dynamics in the prediction of clinical response after therapy are described. Origins of elevated EBV DNA loads in immunosuppressed patients and recent insights in the EBV life cycle in the immuncompromised host are discussed. Finally, a standardization of methodology, clinical specimen type, and cut-off values is proposed. This is essential for comparisons between different institutes and more adequate patient management.
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