Role of Epstein-Barr Virus DNA Load Monitoring in Prevention and Early Detection of Post-transplant Lymphoproliferative Disease

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.

Features of Epstein-Barr Virus (EBV) reactivation after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation

“…35 The current study reports a cumulative incidence of EBV reactivation of 15 and 21% at 6 months and 3 years after allo-HSCT, respectively, but none of the patient experienced EBV-related LPD signs or mortality. In this series, the absence of EBV-related severe complications is likely due to both the strict policy of EBV monitoring during the first months after allo-HSCT and the systematic use of pre-emptive rituximab in those patients experiencing a viral load 41000 copies/10 5 cells as recently described by Blaes et al 21 Indeed, numerous studies 17,18,20,22,[36][37][38] already showed that EBV viral load monitoring in the peripheral blood may be of value in high-risk populations after allo-HSCT. Recent evidence-based guidelines recommended weekly screening of EBV-DNA for at least 3 months in high-risk allo-HSCT recipients.…”

Evaluation of a commercial real-time PCR assay for quantitation of Epstein-Barr virus DNA in different groups of patients

“…It is documented that elevated EBV DNA is a common phenomenon for HIV patients, reflecting rather insufficient immune-mediated control of EBV replication then underlying lymphoproliferative disease (Stevens et al, 2002a). In organ transplant recipients, EBV DNA monitoring allows early diagnosis of threatening posttransplant lymphoproliferative disease, which is preceded by high viral load several months before outbreak of disease (Stevens et al, 2001a;Stevens et al, 2002b). Therefore, clinical relevance of increased EBV DNA levels in different groups of immunocompromised patients may be different.…”

Preemptive diagnosis and treatment of Epstein–Barr virus-associated post transplant lymphoproliferative disorder after hematopoietic stem cell transplant: an approach in development

“…Thus, the shedding of infectious virions into the blood is a major component of CMV disease, but does not play a significant role in PTLD. 2,14,15 Type III latency (the same found in lymphoblastoid B-cell lines) predominates in most PTLD, although multiple latency patterns may be present within a single lesion with lytic replication in a fraction of cells. 14 This heterogeneity is likely to further complicate quantitative PCR approaches.…”

“…An excellent review of assay methods used in solid organ transplant and HSCT recipients was recently published. 14 We will focus solely on PCR assays evaluated in HSCT recipients, as the pathogenesis, timing and course of PTLD differ significantly between these patients and solid-organ transplant recipients. 2,15 Sensitive PCR assays can detect low levels of circulating EBV in many healthy individuals, limiting the predictive ability of qualitative assays.…”