Features of Herpesviruses (CMV, EBV, HHV6) Infections and Immune Reconstitution after Allogeneic Stem Cell Transplantation (allo-SCT) Using Alternative Donors: Comparison Between Matched Unrelated Donors (MUD) and Cord Blood (CB) as Stem Cell Source

Features of herpesvirus infections (CMV, EBV, HHV6) and immune reconstitution after CB transplantation (CBT) has been little studied thus far. Here, we report a retrospective comparison between 15 consecutive adult CBT recipients (CBT group) and 40 patients who received allo-SCT using MUD (MUD group).

The 2 groups had no significant differences in terms of gender, age, disease features, transplant characteristics (CB: meloablative conditioning 46% vs. MUD: 35%; P=NS). However, in vivo T-cell depletion was more frequently used in the MUD group (62.5% vs 6%, P=0.0002). As expected, median number of CD34+ stem cells infused was significantly lower in the CBT group (0.15 10*6/Kg vs 8.2 10*6/Kg, P<0.0001). Both groups were stringently monitored through CMV, EBV, and HHV6 DNA quantifications in the blood prior to allo-SCT, and then monthly up to 9 months after allo-SCT. An active infection was defined by the presence of at least one positive PCR during the follow-up period (detection limit at 2 Log/mL blood). Of note, both groups experienced similar incidences of acute grade 2-4 GVHD, chronic GVHD and disease relapses. Immune reconstitution (T4, T8, B and NK lymphocytes ) at 3, 6 and 9 months post transplant was investigated and compared between the two groups.In this cohort, 22, 29 and 29 patients experienced at least one positive PCR for CMV, EBV and HHV6 respectively, with the % of positive samples for CMV, EBV and HHV6 being 14%, 16% and 27% respectively. No correlation in term of incidence could be found between the 3 viruses. The incidence of CMV infection did not differ between the two groups, and the univariate analysis could not identify a significant risk factor for CMV infection.
However, HHV6 positivity was significantly higher in the CBT group as compared to the MUD group (CBT: 80%; MUD: 42.5%; P <0.0001). HHV6 viral loads were also significantly higher in the CBT group (mean, 3.98±0.86 Log/mL, vs. 3.19±0.82 Log/mL, P<0.0001). In multivariate analysis, the use of CB cells as stem cell source in combination with a myeloablative conditioning regimen appeared to be independent parameters associated with an increased risk of HHV6 infection (OR=5.4, 95%CI, 1.2-23.0; P=0.02 and OR=3.5, 95%CI, 1.03-12.05, P= 0.04, respectively). Interestingly, the occurrence of HHV6 infection translated towards delayed engraftment (median time to neutrophils and platelets recovery: 37  vs 16 d.;  P=0.03; and 98 vs. 12 d.;  P=0.0001).
In sharp contrast with HHV6, EBV infections were less frequent in the CBT group as compared to the MUD group (27% vs. 62%; P<0.0001). In multivariate analysis, the use of a MUD for allo-SCT, was the strongest risk factor associated with an increased EBV infection (OR=0.31, 95%CI, 0.07-1.37; P=0.04). At 3, 6 and 9 months post transplant, median B lymphocytes count in the CBT group was significantly higher (P=0.03; P=0.003; P=0.01) whereas median T8 lymphocytes count was significantly lower (P=0.05; P=0.01; P=0.09). We also noticed that median NK lymphocytes count in the CBT group was significantly higher at 3 months (P=0.0006) but this was not linked to HHV6 infections.

Overall, these results show that after allo-SCT, the pattern of HHV6 and EBV infections is dependant on the source of stem cells. A specific relationship is suggested between HHV6 PCR positivity and the use of CB cells. In addition to a potential delayed engraftment, the clinical implications of the latter finding need to be refined and prospective screening and antiviral prophylaxis approaches are warranted in the context of CBT.