Epstein-Barr Virus Reactivation After Paediatric Haematopoietic Stem Cell Transplantation: Risk Factors and Sensitivity Analysis of Mathematical Model

Abstract

Epstein-Barr virus (EBV) establishes a lifelong latent infection in healthy humans, kept under immune control by cytotoxic T cells (CTLs). Following paediatric haematopoetic stem cell transplantation (HSCT), a loss of immune surveillance leads to opportunistic outgrowth of EBV-infected cells, resulting in EBV reactivation, which can ultimately progress to post-transplant lymphoproliferative disorder (PTLD). The aims of this study were to identify risk factors for EBV reactivation in children in the first 100 days post-HSCT and to assess the suitability of a previously reported mathematical model to mechanistically model EBV reactivation kinetics in this cohort. Retrospective electronic data were collected from 56 children who underwent HSCT at Great Ormond Street Hospital (GOSH) between 2005 and 2016. Using EBV viral load (VL) measurements from weekly quantitative PCR (qPCR) monitoring post-HSCT, a multivariable Cox proportional hazards (Cox-PH) model was developed to assess time to first EBV reactivation event in the first 100 days post-HSCT. Sensitivity analysis of a previously reported mathematical model was performed to identify key parameters affecting EBV VL. Cox-PH modelling revealed EBV seropositivity of the HSCT recipient and administration of anti-thymocyte globulin (ATG) pre-HSCT to be significantly associated with an increased risk of EBV reactivation in the first 100 days post-HSCT (adjusted hazard ratio (AHR) = 2.32, P = 0.02; AHR = 2.55, P = 0.04). Five parameters were found to affect EBV VL in sensitivity analysis of the previously reported mathematical model. In conclusion, we have assessed the effect of multiple covariates on EBV reactivation in the first 100 days post-HSCT in children and have identified key parameters in a previously reported mechanistic mathematical model that affect EBV VL. Future work will aim to fit this model to patient EBV VLs, develop the model to account for interindividual variability and model the effect of clinically relevant covariates such as rituximab therapy and ATG on EBV VL.

Epstein–Barr Virus Monitoring after an Allogeneic Hematopoietic Stem Cell Transplant: Review of the Recent Data and Current Practices in Canada

“…Of note, PTLD subtypes are inconsistently reported and mostly not within the frame of the most recent WHO classification. Across studies, there is again a wide variability in the reported incidence, ranging from as low as 0% to 3.5% in children [4,[8][9][10][11] and 0% to 14% in adults [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31], falling within the range of previously reported incidences. Again, this variability most likely results from the heterogeneity of the transplant populations studied, GvHD prophylaxis, including the use of ATG or not, conditioning regimen administered, as well as donor EBV status.…”

“…The results of EBV reactivation after HSCT in both adults and children are shown in Table 1. Incidence remains highly variable, ranging from 30% to 68% in children [4,[8][9][10][11] and 19% to 86% in adults [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] (excluding Marinho-Diaz et al, 2018, with an unrepresentative six adults studied). This variability reflects a high level of heterogeneity in the reported patient populations, including conditioning regimens, GvHD prophylaxis, donor type, or sensitivity of diagnostic tests.…”

“…Only three studies have found that myeloablative and reduced intensity conditionings are associated with increased incidence [8,21,28]. On the other hand, the administration of anti-thymocyte globulin (ATG) [4,11,14,[18][19][20][21]24,28,30,32,33], specifically horse ATG [9], is now a well-described risk factor. Interestingly, the administration of alemtuzumab seems to be associated with a lower incidence of reactivation, most likely due to its anti-B-cell properties [29,34].…”

“…Interestingly, the administration of alemtuzumab seems to be associated with a lower incidence of reactivation, most likely due to its anti-B-cell properties [29,34]. In a study comparing ATG and alemtuzumab, the prevalence of EBV reactivation was 100% vs 58%, respectively [4], although not confirmed in another study [35]. These recent data underscore that all T-depletion strategies may not equally influence the risk of EBV reactivation, depending on their impact on decreasing B cells (the EBV reservoir) and on depleting T cells, more particularly EBV-specific memory T cells present in the graft.…”

“…PTLD has been associated with a mortality as high as 84% [2] in the absence of treatments and as low as 30% with appropriate therapy [1]. It is usually caused by the Epstein-Barr virus (EBV) [3], a widespread virus in adult populations worldwide, although some cases of EBV-negative PTLDs have also been reported [1,4]. After initial infection, EBV remains dormant in resting memory B cells [5,6].…”