Increased incidence of EBV‐related disease following paediatric stem cell transplantation with reduced‐intensity conditioning

Abstract

Summary The incidence of Epstein–Barr virus (EBV) viraemia and lymphoproliferative disease (LPD) was studied in a consecutive cohort of 128 paediatric patients undergoing stem cell transplantation (SCT) with reduced‐intensity conditioning (RIC; n = 65) or conventional‐intensity conditioning (CIC; n = 68). Following CIC, six of 68 (8%) developed viraemia; all remained asymptomatic. EBV viraemia (23 of 65 patients = 35%, P < 0·001) and LPD (10 of 65 = 15%, P < 0·001) were significantly more frequent following RIC. Of the 23 RIC patients who developed viraemia, eight remained asymptomatic, five had symptomatic viraemia (fever ± rash), and 10 patients developed LPD, two of whom died. An absolute lymphocyte count of <0·3 × 109/l at the time of onset of viraemia was strongly predictive of development of LPD (P < 0·05) in this group. The incidence of viraemia was significantly higher in patients receiving serotherapy with antithymocyte globulin (ATG; 15 of 43, 35%) than Campath (12 of 73, 16·4%, P < 0·05). Primary immunodeficiency and acute graft‐versus‐host disease were associated with EBV viraemia in univariate analysis, but were not independent risk factors. In conclusion, EBV viraemia and LPD appear to be significantly more common in children following RIC SCT, particularly with selective depletion of recipient T cells relative to B cells following the use of ATG. This probably reflects the profound immunosuppression following RIC SCT, together with the incomplete ablation of recipient‐derived B cells.

Features of EBV reactivation after reduced intensity conditioning unrelated umbilical cord blood transplantation

“…Preemptive treatment with rituximab was started when the EBV-DNA level exceeded 1000 copies per 10 5 cells on more than one occasion as recently described by Blaes et al 15 With this strategy, EBV reactivation, defined as a viral load of 1000 copies per 10 5 cells, was detected in five patients for a cumulative incidence of 9 and 17% at 6 months and 2 years, respectively, after RIC UCBT, which is comparable to the incidence reported after RIC BM and PBSC HSCT. 24,25 This is also comparable with the cumulative incidence of EBV reactivation that we reported for 175 consecutive patients who received RIC allo-HSCT in our institution (15% at 6 months). However, with the strategy of preemptive treatment of EBV reactivation, none of these patients developed EBV-LPD.…”

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.…”

“…Other studies found a correlation between EBVreactivation and several factors, such as the degree of HLA mismatch between donor and recipient, manipulation of the graft to deplete T cells, degree and duration of immunosuppression used to prevent and treat GVHD, and the use of ATG and Campath. 22,23 A recent analysis by Savani et al 45 suggested that EBV reactivation and the possible development of PTLD is reduced in patients with lymphoid malignancies treated with rituximab during the course of their disease before allo-SCT. Though this did not reach statistical significance, in our study there was a fewer number of patients with lymphoid malignancies in the group of patients who experienced an episode of EBV reactivation (Table 2).…”

“…Two recent reports suggested a higher incidence of LPD in pediatric patients who underwent RIC allo-HSCT including anti-thymocyte globulins (ATGs) or Campath. 22,23 The aim of this analysis was to define the incidence and potential risk factors predicting the development of EBV reactivation in the first 6 months following RIC allo-HSCT in 175 consecutive adult patients, and to assess its impact on clinical outcome.…”

Reduced PTLD-related mortality in patients experiencing EBV infection following allo-SCT after the introduction of a protocol incorporating pre-emptive rituximab

“…[1][2][3] Although the incidence of EBV-PTLD is generally below 1% following allo-SCT, it may dramatically increase among recipients of transplants from mismatched or unrelated donors, and if T-cell depletion is used or intensive immune-suppression is given either to prevent or treat graft-versus-host disease (GVHD). [4][5][6] Other risk factors include previous splenectomy and recipient EBV seronegativity. 7 Treatment of EBV-PTLD relies upon improving the immune response and targeting EBV-infected B cells, rather than relying on anti-viral therapies, as these have not been particularly effective.…”