Risk factors for post‐transplant Epstein‐Barr virus events in pediatric recipients of hematopoietic stem cell transplants

Abstract

Background Epstein‐Barr virus (EBV) can cause severe disease following hematopoietic stem cell transplant (HSCT), including post‐transplant lymphoproliferative disorder (PTLD). The objective was to analyze risk factors associated with post‐transplant EBV outcomes among pediatric allogeneic HSCT recipients. Methods We used data from 156 pediatric allogeneic HSCT recipients enrolled in the Canadian multicenter TREASuRE study. Cox and Prentice‐Williams‐Petersen models were used to analyze risk factors for post‐transplant EBV events including occurrence and recurrence of EBV DNAemia, increase in EBV viral load (EBV‐VL), and preemptive use of rituximab, an effective therapy against PTLD. Results Females were at higher risk for increasing EBV‐VL (adjusted hazard ratio (HR) = 2.83 [95% confidence intervals (CI): 1.33–6.03]) and rituximab use (HR = 3.08 [1.14–8.30]), but had the same EBV DNAemia occurrence (HR = 1.21 [0.74–1.99]) and recurrence risks (HR=1.05 [0.70–1.58]) compared to males. EBV DNAemia was associated with recipient pre‐transplant EBV seropositivity (HR = 2.47 [1.17–5.21]) and with graft from an EBV‐positive donor (HR = 3.53 [1.95–6.38]). Anti‐thymocyte globulin (ATG) was strongly associated with all EBV outcomes, including the use of rituximab (HR = 5.33 [1.47–19.40]). Mycophenolate mofetil (MMF) significantly decreased the risk of all EBV events including the rituximab use (HR = 0.13 [0.03–0.63]). Conclusion This study in pediatric allogeneic HSCT patients reveals a reduced risk of all EBV outcomes with the use of MMF. Risk factors for EBV events such as EBV‐VL occurrence and recurrence include EBV positivity in the donor and recipient, and use of ATG, whereas risk factors for the most severe forms of EBV outcome (EBV‐VL and the use of rituximab) include female sex and ATG use.

Association Between Cytomegalovirus and Epstein-Barr Virus Co-Reactivation and Hematopoietic Stem Cell Transplantation

“…The reactivation of multiple herpes viruses, especially cytomegalovirus (CMV) reactivation, commonly occurs following HSCT (Hill et al, 2017;Stern et al, 2021). Epstein-Barr virus (EBV) reactivation is also prevalent and can cause serious complications, such as posttransplant lymphoproliferative disorder (PTLD) (Diop et al, 2021;Enok Bonong et al, 2021). The reported incidences of virus reactivation after HSCT fluctuate widely from 0.1% to 63% for EBV (Styczynski et al, 2016b) and from 30% to 70% for CMV (Styczynski et al, 2016a;Ljungman et al, 2019) with ambiguous effects on transplant outcomes (Auger et al, 2014;Teira et al, 2016).…”

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

“…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.…”

“…Several risk factors for EBV reactivation have been reported. Amongst them, some recipients' characteristics, such as being a female recipient [11,21,32] and aged older than 40 years [19], were associated with EBV reactivation. A serostatus mismatch between an EBV-positive donor and an EBV-negative recipient or having an EBV-positive donor have also been described [9,11,14,15,27,31].…”

“…Amongst them, some recipients' characteristics, such as being a female recipient [11,21,32] and aged older than 40 years [19], were associated with EBV reactivation. A serostatus mismatch between an EBV-positive donor and an EBV-negative recipient or having an EBV-positive donor have also been described [9,11,14,15,27,31]. Some transplantation modalities contribute to an increased risk, such as the type of donor and the conditioning regimen.…”

“…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].…”