Kinetics of Epstein-Barr Virus DNA Load in Different Blood Compartments of Pediatric Recipients of T-Cell-Depleted HLA-Haploidentical Stem Cell Transplantation

Abstract

Epstein-Barr virus (EBV) DNA levels in whole-blood samples of 54 pediatric patients receiving T-celldepleted haploidentical hematopoietic stem cell transplantation (HSCT) in 2003 to 2007 were retrospectively compared with EBV DNA loads in peripheral blood mononuclear cells (PBMC). Determination of EBV DNA in whole blood missed 1 of 19 patients (5.2%), who tested positive for EBV DNA in PBMC. The analytical sensitivity of EBV DNA detection in whole-blood samples relative to that in PBMC was 94.7%. Regression analysis showed a significant correlation between DNA levels in PBMC and whole blood (r ‫؍‬ 0.81; P < 0.001). Relative to that in PBMC, the appearance of EBV DNA in whole blood was delayed in 9/18 patients (median, 49 days; range, 6 to 226 days), while peak levels and clearance were reached simultaneously. Following peak levels, EBV DNA showed a slower decline in whole blood than in PBMC. In conclusion, (i) EBV DNA levels in PBMC were significantly correlated with those in whole blood; (ii) a differential kinetics of EBV DNA in the two blood compartments was observed; and (iii) monitoring of EBV DNA levels in whole blood appears to be a valuable alternative to PBMC in the follow-up of pediatric recipients of haploidentical T-cell-depleted HSCT.Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorders (PTLD) represent a life-threatening complication for recipients of solid-organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT) (2, 11, 16). The heterogeneous clinical manifestations of PTLD are mostly due to B-lymphocyte proliferation driven and sustained by EBV latency products (5,11,22). In immunocompetent individuals, uncontrolled EBV-driven B-cell proliferation is prevented mainly by virus-specific cytotoxic T lymphocytes (CTL), while in transplant recipients, impaired CTL control of EBV infection due to pharmacological immune suppression or physical removal of T lymphocytes favors the development of PTLD (11,16).Recipients of T-cell-depleted, HLA-haploidentical HSCT are exposed to the highest risk of developing PTLD (8), because they cannot benefit from adoptive transfer of virus-specific CTL, and a timely diagnosis of EBV-driven lymphoproliferation is mandatory for prompt therapeutic intervention in this severe complication. Preemptive treatment of PTLD in HSCT includes infusion of an anti-CD20 monoclonal antibody (MAb), tapering of immune-suppressive regimens (whenever possible), and adoptive infusion of donor-derived EBV-specific CTL in patients at risk for PTLD (6, 26).The EBV DNA load in blood is considered to reflect EBVinduced cell proliferation, and quantitative determination of EBV DNA levels in peripheral blood mononuclear cells (PBMC), plasma, or whole blood has been proposed as a means to identify SOT or HSCT recipients at risk for developing PTLD (1, 4, 7, 10, 12, 14-17, 19-21, 24, 25). While it is accepted that EBV DNA levels in the blood of patients with EBV-related PTLD are significantly higher than those in healthy EBV-seropositive indivi...

Monitoring and managing viral infections in pediatric renal transplant recipients

“…In asymptomatic transplant recipients, EBV DNA identifies patients at high risk of developing PTLD [7,68,70,79], although the correlation between high viral load and PTLD onset after SOT is not as linear as that observed in hematopoietic stem-cell transplantation recipients. Patients belonging to the SOT cohort may persist with high viral loads for many months without developing PTLD.…”

“…As with CMV and BKV, EBV quantitative assays are not standardized [7,[68][69][70]. In addition, as successful therapy is associated with disappearance of detectable EBV DNA, assessment of viral load is useful to monitor treatment response [7,[68][69][70].…”

“…Thus, the parameter universally selected to monitor infections is viral load. The development and implementation of sensitive, specific, and reliable diagnostic assays that allow quantification of viral load has proved to be instrumental in augmenting the clinical utility of viral monitoring [6][7][8]. In addition, as infection control will ultimately depend on the restoration of a protective immune response, evaluation of specific viral immunity has permitted further characterization of subgroups of patients at high risk for disease development [9,10] and the development of therapeutic strategies based on administration of antigenspecific T cells expanded in vitro from the memory pool [10,11].…”

Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines

“…There are no data to support a preference for whole blood, plasma or serum; all are appropriate specimens for monitoring EBV DNAemia. 7,[41][42][43] Screening for EBV DNA-emia should start within the first month after allo-HSCT. However, the incidence of EBV-PTLD during the first month after HSCT is estimated to be below 0.2%.…”

Epstein-Barr Virus DNAemia in Iranian Liver Transplant Recipients and Assessment of Its Variation in Posttransplant Lymphproliferative Disorder Patients by Quantitative Polymerase Chain Reaction Assay

“…[22][23][24][25][26] In 8 PTLD patients who had serial viral loads available, large variation in maximum load (4370 to 286 844 copies/mL) and time of maximum load (13-360 d after transplant) were observed, which is consistent with other studies. 27,28 Infection with EBV causes a wide range of clinical manifestations including a nonspecific viral syndrome, infectious mononucleosis, and PTLD. 27,29 The PTLD, which is the most important EBVassociated disorder, can be prevented by modulation of the immune system, autologous expanded T-cell infusion, and/or use of anti-EBV drugs such as rituximab.…”