HHV-6 Infection/Reactivation after Allogeneic Stem Cell Transplantation in Pediatric Patients: Epidemiology, Risk Factors and Outcome

Introduction. Hematopoietic stem cell transplantation (HSCT) exposes the recipient to a high risk of developing viral reactivations especially during the first weeks after HSCT. Neutropenia and lymphopenia, together with the breakdown of physical barriers expose patients not only to bacterial and fungal infections but also to viral infection/reactivations. HHV-6 is usually acquired during infancy, and seroprevalence in the adult population may reach 90%. Like other herpesviruses, HHV-6 persists latently within permissive cells and it can reactivate during immunosuppression. A high incidence of HHV-6 reactivation is frequently detected after HSCT, but its clinical relevance is still debated. The objectives of this retrospective study were to estimate the incidence of HHV6 reactivation after pediatric HSCT, analyze the possible risk factors and evaluate the impact on outcome.

Patients and methods. We analyzed 234 pediatric subjects given HSCT from a matched family donor (MFD, 17.5%), a matched unrelated donor (MUD, 43.6%) or a partially matched family donor (PMFD, 38.9%) for malignant (55.2%) or non-malignant hematologic diseases (25.6%) between 2010 and 2017. Data have been analyzed according to patient, donor and transplant characteristics. Risk factors analysis was computed throughout the comparison of the cumulative incidence (CI) of HHV-6 reactivation according to descriptive variables. Kaplan Mayer curves were used to illustrate survival results (OS and EFS), and Log-rank test was used to compare groups. The analysis of outcome was completed by analyzing the CI of neutrophils and platelets engraftment, rejection, acute and chronic GvHD, NRM according to presence or absence of HHV-6 reactivation. Gray-test was used to compare different CI curves. The quantification of HHV-6 exposure was calculated using the area under the curve (AUC) of viremia level over time. AUC expresses the kinetics of the DNA viral load in a time-concentration chart. The stratification of patients according to HHV-6 AUC quartiles (AUCq = each of 4 equal groups into which the HHV6 positive population was divided according to distribution of the value of AUC) allowed to describe the viral burden and the intensity of viral exposure. Risk factors analysis and survival analysis were then performed using the parameter AUC and AUC quartiles.

Results. The cumulative incidence of HHV-6 reactivation was 58%, with onset usually within the first month after transplantation (median 19 days). The peak viral load was detected at an average time of 55 days after onset (median 25 days) with a median of 5850 cp/mL (range 50 - 219^10⁶ cp/mL). In univariate analysis, a diagnosis of malignant disease (p=0.021), transplant from PMFD (p=0.010), the use of a busulfan/TBI-based vs Treo-based conditioning regimen (p=0.020), the use of ex vivo T cell-depletion (p<0.001) and the use of ATG (p<0.001) were risk factors for HHV6 reactivation. In multivariate analysis, only the use of ATG remained statistically significant (p=0.025). The occurrence of HHV-6 infection, considered as a categorical variable, did not affect transplant outcome, in particular neutrophils and platelets engraftment, acute and chronic GvHD, rejection, OS, EFS and NRM. All analysis for risk factors and outcomes were then repeated using the AUC and AUCq parameters. HHV-6 exposure measured as AUC or AUCq again failed to demonstrate any impact on outcome. However, in the PMFD group, OS and EFS were worse, although not statistically significant, for the 3^rd-4^th AUCq compared to negative or 1^st-2^nd AUCq.

Conclusions. Based on the results obtained, HHV-6 infection/reactivation, measured as categorical variable or as viral exposure, does not seem to have an impact on HSCT outcomes. Therefore, routine viral monitoring may not give added benefit in the pediatric HSCT setting. However, in selected populations, early restricted monitoring may identify HSCT recipients at risk of HHV6-related disease.