Increased levels of circulating Epstein-Barr virus (EBV)-infected lymphocytes and decreased EBV nuclear antigen antibody responses are associated with the development of posttransplant lymphoproliferative disease in solid-organ transplant recipients

Abstract

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) is an uncommon but potentially fatal complication of immunosuppression in solid-organ transplant recipients. A semiquantitative DNA polymerase chain reaction assay was developed to amplify a unique 269-bp region of the EBNA-1 gene in peripheral blood lymphocytes (PBL) using the primers described by Telenti et al (J Clin Microbiol 28:2187, 1990). Serial samples were studied from 23 transplant recipients, 12 of whom were diagnosed with PTLD. The majority of transplant recipients who were EBV seropositive at the time of transplant surgery and who did not develop PTLD (5 of 7, 71%) exhibited less than a 10-fold increase in the levels of EBV-infected PBL over the 0.1 to 5 EBV genomes/10(6) PBL observed in immunocompetent EBV seropositive controls. Transplant recipients who were seronegative at the time of transplantation and who underwent a primary EBV infection but did not develop PTLD exhibited a reduced capacity to control viremia because the levels of EBV-infected PBL were up to 400 times greater than the 1.0 to 50 EBV genomes/10(6) PBL observed in individuals undergoing acute infectious mononucleosis (Rocci et al: N Engl J Med 296:132, 1977). However, all transplant recipients who developed PTLD exhibited a marked elevation of EBV-infected PBL independent of their serologic state at the time of transplantation. Six of the 10 transplant recipients with PTLD exhibited > or = 300,000 EBV genomes/10(5) PBL, two exhibited 10,000 to 50,000 EBV-infected genomes/10(5) PBL, and one each exhibited 2,500 and 500 EBV genomes/10(5) PBL. However, the latter two samples were obtained 4 to 5 weeks after the diagnosis of PTLD and may reflect a decrease in viral load resulting from immunomodulation. Marked decreases in the levels of EBV nuclear antigen-1 (EBNA-1), EBNA-2, and EBNA-LP antibodies correlated with the increase in EBV-infected PBL. Hence, a quantitative difference in circulating EBV viral load and EBNA antibody levels is evident between transplant recipients with and without PTLD and may be useful as a noninvasive prognostic marker with which to monitor and/or predict the development of PTLD.

Epstein–Barr Virus Infection and Posttransplant Lymphoproliferative Disorder

“…First an association between loss or absence of antibody against Epstein–Barr nuclear antigens (EBNA) and development of PTLD in infected organ recipients has been noted . Second early reports found a drop in EBV VL to correlate with increasing levels of antibody against EBNA even when the antibody was passively transmitted . In addition, case reports noted successful treatment of PTLD when using IVIG in combination with interferon‐alpha .…”

“…Chemoprophylaxis using antiviral agents, such as acyclovir and ganciclovir, is one possible approach to the prevention of EBV disease and PTLD. Acyclovir and ganciclovir actively block lytic EBV replication in vitro through inhibition of the late phase lytic replication but neither agent has any effect on EBV in its latent state or on the proliferation of EBV‐transformed B cells . Accordingly, if progression from EBV infection to disease is dependent upon expansion of EBV immortalized B cells independent of the lytic phase of EBV replication, the use of these agents is unlikely to prevent the development of EBV disease.…”

Richter syndrome

“…These patients have impaired T‐cell immunity and are unable to control the proliferation of EBV‐infected B cells 79, 80. Peripheral blood Epstein–Barr viral load increases before the development of the disease and decreases with effective therapy 81. Elevation in serum levels of interleukin‐6, which is a B‐cell growth factor, may increase the proliferation of EBV‐infected B cells 82…”

Longitudinal observation of Epstein–Barr virus antibodies in athletes during a competitive season

“…In general, EBV reactivation should be defined precisely whether it is the recurrent transfer from latency into the lytic cycle that increases viral shedding in saliva [Macsween and Crawford, 2003] and whether this is significant in a clinical context such as in immunocompromised patients [Riddler et al, 1994] or in the rare state of chronic active EBV infection [Kimura, 2006]. As positive EBV DNA might be found in healthy individuals [Maurmann et al, 2003], the diagnostic value is limited in immunocompetent subjects.…”