Immune recovery and the risk of CMV/ EBV reactivation in children post allogeneic haematopoietic stem cell transplantation

Abstract

Immune reconstitution was studied prospectively in 86 children who underwent allogeneic haematopoietic stem cell transplantation (HSCT). We analysed the risk of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation in correlation with the kinetics of immune recovery and in relation to other potential risk factors that may influence the reactivation of these viruses including: diagnosis, type of HSCT, source of stem cells, type of conditioning, or the occurrence of graft-versus-host disease (GvHD). The absolute number of lymphocyte subpopulations in peripheral blood was evaluated in seven timepoints following HSCT. Significantly lower values of both CD3+ and CD3+CD8+ lymphocytes on day +14 and significantly higher values of both these subsets on day +168 post-transplant in patients with CMV reactivation were observed. Significantly lower values of CD3+CD4+ subpopulation were noted in patients with CMV reactivation on day +28 post allo-HSCT. Significantly lower lymphocyte values in the group with EBV reactivation comparing with the group without EBV reactivation were confirmed only in the case of pan-B lymphocytes (CD19+) subpopulation on day +21, +28, and +84 post allo-HSCT. We identified the impact of CMV reactivation on occurrence of the intestinal acute GvHD, which occurred more frequently in the group with CMV reactivation compared with patients without reactivation. Higher incidence of chronic GvHD was also observed in patients with CMV reactivation compared to the group without reactivation. EBV reactivation occurred more frequently in patients receiving transplants from matched unrelated donors, in particular after peripheral blood stem cell transplantation and while implementing antithymocyte globulin as GvHD prophylaxis.

Incidence, risk factors, and clinical outcomes associated with Epstein‐Barr virus‐DNAemia and Epstein‐Barr virus‐associated disease in patients after haploidentical allogeneic stem cell transplantation: A single‐center study

“…Additionally, Zallio et al reported that CMV reactivation was the only independent variable associated with EBV reactivation 17 . Furthermore, CMV reactivation leaves a long‐lasting dynamic signature on the speed of immune recovery in HSCT recipients 18‐20 . Therefore, reactivation of CMV itself reflects the severity of immunosuppression, suggesting the potential role of monitoring CMV‐DNAemia for predicting EBV infection.…”

T-lymphocyte subsets and Th1/Th2 cytokines in convalescent patients with Epstein–Barr virus-associated aplastic anemia

“…EBV infection is an important factor influencing the incidence of graft-versus-host disease (GVHD) in SAA patients receiving allogeneic hematopoietic stem-cell transplantation (allo-HSTC) treatment. The serum cytokine levels before transplantation were also associated with EBV infection [9].…”

“…Of note, immunodeficiency is common in AA patients, particularly those who have received immunosuppressive therapy. However, reactivation and primary infection of EBV are associated with abnormal lymphoid proliferation [9]. Cytokine imbalance also exists in patients infected with EBV.…”

Epstein‐Barr virus post‐transplant lymphoproliferative disease (PTLD) after hematopoietic stem cell transplantation

“…The incidence of EBV-PTLD with haplo-identical donor was significantly higher [19] 2+ HLA antigen-mismatched related or unrelated donor had significant higher risks [15] UCBT UCBT could increase the risk of EBV events and EBV-PTLD probably due to the condition and immunosuppression [20,21] EBV-DNA Load Both high and very low level of EBV-DNA load had a higher OS than patients with moderate intermediate EBV-DNA load [23] The very low level of EBV load was indicated as a predictive biomaker of a poor survival [24] GVHD Acute GVHD grades II-IV had a significantly higher risk for EBV viremia [25] Acute GVHD grades III-IV was a risk factor of EBV viremia [26] Both acute and chronic GVHD increased the risk of PTLD [15] Acute GVHD impairs specific immune reconstruction due to pro-inflammatory cytokine storm [3] Constant antigen stimulation occurred in GVHD and profound immunosuppressive treatment could probably contribute the risk for PTLD [14] CMV CMV reactivation reflected recovery speed of immune system in pediatric recipients after HSCT [29] CMV has been confirmed as a risk factor after both solid organ transplantation and HSCT [30][31][32]34] CMV reactivation is strongly connected with EBV reactivation [33] Splenectomy Splenectomy was a risk factor [14,35] CD5+ B cell rely on spleen, its immune regulatory function would be impaired after splenectomy, leading to EBV load explosive growth [14,37] TCD There is a dichotomy of PTLD incidence between patients with or without TCD (≥10% vs <1%) [24,[38][39][40][41][42] Recipients with grafts T-cell depletion highly predicted EBV-PTLD [43,44] The selective T-cell depletion had a strong association with risks higher than other TCD methods [15] Alemtuzu mab Alemtuzumab increased virus infections [17] Alemtuzumab was a risk factor for the arising of PTLD…”

“…27,28 CMV infection is a conspicuous problem as it is connected with a series of complications such as cytopenia, GVHD as well as EBV reactivation. Malgorzata et al 29 proved that CMV reactivation reflected the recovery speed of immune system in pediatric recipients after HSCT.…”