Evaluation of Use of Epstein-Barr Viral Load in Patients after Allogeneic Stem Cell Transplantation To Diagnose and Monitor Posttransplant Lymphoproliferative Disease

Abstract

Epstein-Barr virus (EBV)-induced posttransplant lymphoproliferative disease (PTLD) continues to be a serious complication following transplantation. The aim of the present study was to evaluate the EBV load as a parameter for the prediction and monitoring of PTLD. The EBV load was analyzed by a quantitative competitive PCR with 417 whole-blood samples of 59 patients after allogeneic stem cell transplantation (SCT). The EBV load was positive for all 9 patients with PTLD and for 17 patients without PTLD. The viral loads of patients with manifest PTLD differed from the loads of those without PTLD (median loads, 1.4 ؋ 10 6 versus 4 ؋ 10 4 copies/g of DNA; P < 0.0001). A threshold value of 10 5 copies/g of DNA showed the best diagnostic efficacy (sensitivity, 87%; specificity, 91%). However, in patients with less than three major risk factors for PTLD, the positive predictive value of this threshold was rather low. One week prior to the manifestation of PTLD, the EBV load was as low in patients who developed PTLD as in patients without disease (median, 2.2 ؋ 10 4 copies/g of DNA; P was not significant). EBV DNA tested positive first at 20 to 71 days prior to the clinical manifestation of PTLD and occurred with the same delay after transplantation regardless of disease (median delay, 52 versus 63 days; P was not significant). EBV DNA was detected earlier in patients with primary infections than in those with reactivations (33 versus 79 days; P ‫؍‬ 0.01), but the peak levels were similar in the two groups. EBV primary infection or EBV reactivation is frequent in patients after allogeneic SCT but results in PTLD only in a subgroup of patients. Although evaluation of the EBV load has limitations, the EBV load represents a valuable parameter to guide therapy.

Monitoring of Epstein‐Barr virus load after hematopoietic stem cell transplantation for early intervention in post‐transplant lymphoproliferative disease

“…In addition, quantitative polymerase chain reaction assay for EBV DNA in peripheral blood is useful in monitoring the efficacy of therapy [Hoshino et al, 2000;Meerbach et al, 2001;Gärtner et al, 2002]. Kenagy et al [1995] diagnosed markedly elevated levels of EBV DNA in post-transplant lymphoproliferative disease during illness as well EBV DNA levels were reduced dramatically due to effective therapy.…”

“…Method: Looking at the method EBV load can be detected by semiquantitative [Lukas et al, 1998], quantitative competitive [Rowe et al, 1997;Baldanti et al, 2000;Yang et al, 2000;Gärtner et al, 2002] or real-time polymerase chain reaction [Hoshino et., 2000;Wagner et al, 2002b;Orentas et al, 2003;Yancoski et al, 2004]. In the presented prospective study, the author's used a semiquantitative nested EBV polymerase chain reaction [Meerbach et al, 2001], which clearly detects 10 viral copies in 10 5 peripheral blood mononuclear cells.…”

“…For protection they were given immunoglobulins after transplantation resulting in high IgG antibody titers against virus capsid antigen and nuclear antigen of EBV. [Kenagy et al, 1995;Martinez et al, 1995;Bai et al, 1997;Rowe et al, 1997;Brengel-Pesce et al, 2002;Gärtner et al, 2002;Sirvent-von Bueltzingsloewen et al, 2002]. High amounts of EBV in peripheral blood mononuclear cells were detected in these patients [Savoie et al, 1994;Rooney et al, 1995;Lucas et al, 1998].…”

EBV reactivation and post transplant lymphoproliferative disorders following allogeneic SCT

“…These cases support previous observations that some patients with PTLD have low EBV-DNA levels just like patients with only EBV reactivation who never proceed to PTLD. 12 It further should be discussed, whether certain thresholds of EBV-DNA levels can be interpreted as a signal for the start of pre-emptive treatment to prevent the progression of reactivation to PTLD. Van Esser et al 13 used rituximab as pre-emptive therapy when the EBV-DNA level wasX1000 Geq/ml which was sufficient to achieve complete viral clearance in nearly all cases.…”

“…Frequent molecular monitoring of the EBV load and anti-CD20 antibody therapy for cases at high risk have been suggested. [12][13][14] To further determine the incidence, outcome, risk profiles and clinical characteristics of EBV reactivations and PTLD in the post transplant period, we here performed a retrospective study in all 854 patients who received allogeneic SCT between January 1999 and June 2007 in the University Hospital of Hamburg, Germany, and performed further characterization of the 11 cases with EBV-associated PTLD and of the 15 cases with EBV reactivation.…”