Facteurs associés à l’infection au virus Epstein-Barr (VEB) post-greffe chez les enfants recevant des greffes de cellules souches hématopoïétiques (GCSH)

Hematopoietic stem cell transplantation (HSC) constitutes a notable therapeutic advance in the treatment of hematological and non-hematological diseases. However, despite saving lives, it is not without risk. Post-transplant lymphoproliferative disease (PTLD) is one of the complications that can occur after this type of transplant with a mortality risk of up to 80% if left untreated. Moreover, the treatments available to limit the development of this disease are not without harmful effects on transplant recipients. PTLD is predominantly a consequence of primary infection or uncontrolled reactivation of Epstein-Barr virus (EBV). At least 90% of adults are carriers of EBV, compared to around 50-70% in the pediatric population. It is important to understand the risk factors for active EBV infection and PLTD in order to better manage transplant recipients. This thesis aims to contribute to knowledge on the determinants of active EBV infection and PTLD in pediatric HSC transplant recipients. A systematic review combined with a meta-analysis was carried out to develop a comprehensive portrait of the known risk factors for EBV and PTLD in adult and pediatric HSC transplant recipients. Then, using a Canadian multicenter prospective cohort study that enrolled 156 pediatric HSC transplant patients, the link between blood product transfusion and post-transplant EBV infection was analyzed. Finally, the multicenter cohort study also explored new risk factors for EBV-related events ranging from EBV DNAemia to suspicion of PTLD. The results of the systematic review and the meta-analysis revealed that the use of anti-thymocyte globulin (ATG) to prevent graft-versus-host disease is the main factor implicated in the post-transplant occurrence of active EBV infection and PTLD. The high heterogeneity between studies limited the comparison of results and very few studies focused exclusively on pediatric patients. On the other hand, statistical analysis within the multicenter cohort did not reveal a significant increase in the risk of post-transplant EBV infection associated with transfusion. However, genotyping analysis of viral strains from blood donors of an EBV-negative patient who received an EBV-negative graft indicated that one of the blood donors was the source of the primary EBV infection in the patient, despite leukoreduction (which virtually eliminates the presence of cell-associated viruses in blood products). Furthermore, our analyses in the multicenter cohort corroborated the association between ATG and post-transplant EBV-related events, and highlighted two new associations. First, mycophenolate mofetil, a drug used to prevent graft-versus-host disease, is believed to reduce the risk of EBV-related events through its antiproliferative action on T and B lymphocytes (including EBV-infected B cells). Second, girls are more at risk of relatively severe forms of post-transplant EBV infection than boys. The rationale behind this latter association is unknown. New research will make it possible to assess the reproducibility of these results.

Keyphrases: Transfusion, Epstein-Barr virus (EBV), Hematopoietic stem cell transplant (HSCT), Pediatric/child, Prospective cohort, Genotyping, Risk factors, Post-transplant lymphoproliferative disease (PTLD)