Reactivation of Human Herpes Virus 6 (HHV6) during Hematopoietic Stem Cell Transplantation: Risk Factor Analysis of HHV6 Encephalitis and Survival.
Authors: Shimazu Yutaka , Ishikawa Takayuki , Ichinohe Tatsuo , Kondo Tadakazu , Yamashita Kouhei , Maruyama Wataru , Uchiyama Takashi 
Published: April 2020

Abstract
Backgrounds: Cord blood cell transplantations (CBT) with reduced intensity condition (RIC) regimen have broadened the indication of hematopoietic stem cell transplantation (HSCT). Reactivation of human herpes virus 6 (HHV6) and its encephalitis have emerged as complications in HSCT. We have analyzed the risk factors for reactivation of HHV6 and the development of HHV6 encephalitis in a retrospective manner.
Methods: Between January 2005 and June 2008, 105 cases have received HSCT in our institution. Myeloablative or reduced intensity conditioning were chosen in 52 and 53 patients, respectively. Twenty-eight patients received bone marrow from family, 5 received relative peripheral blood. Transplantation from unrelated donor was done in 72 patients, and 50 received bone marrow and 22 received cord blood. HLA match was defined as 6/6 allele-match at the HLA-A, B, and DRB1 for patients received other than CBT, and more than 5/6 allele-match for CBT recipients. Mismatched transplantation was done in 35 patients. The median age at the transplantation was 46 years old (31% cases showed more than 55 years old). The disease status was considered to be as high risk for relapse in 64 patients. Acute GVHD had occurred in 51 patients. When HHV6 infection was suspected, such as abrupt dissemination of skin rush or the onset of fever of unknown origin, peripheral blood was drawn to detect HHV6 DNA by quantitative PCR. HHV6 encephalitis was diagnosed from the typical clinical symptoms, brain MRI imaging of limbic encephalitis, and the presence of HHV6 DNA in blood or in cerebrospinal fluid.
Results: HHV6 reactivation was detected in 23 of 105 (22%) patients, and 17 cases (74%) occurred within the first 20 days post-HSCT. They were treated with either foscarnet or ganciclovir. Multivariate logistic regression analysis identified HLA mismatch (p=0.014) and CBT (p=0.010) as an independent predictor of HHV6 reactivation. Ten cases manifested encephalitis. Three cases died of encephalitis and 1 case died of the relapse of underlying disease, only 6 cases had totally recovered from encephalitis. The use of steroid to control severe acute GVHD preceded the encephalitis in 6 patients. Multivariate analysis could not identify any significant risk factors for encephalitis. Survival analysis using multivariate Cox proportional hazard models identified higher risk of the disease (p=0.028) and reactivation of HHV6 (p=0.025) as an independent poor risk factor for overall survival. Reactivation of HHV6 correlate with the increased rate of relapse (p=0.0176).
Conclusions: Reactivation of HHV6 and encephalitis have an impact on the prognosis of HSCT. Although the risk factors for developing encephalitis are currently unknown, prophylactic use of foscarnet may be consider to reduce the incidence of encephalitis. In case of HLA mismatch HSCT or CBT, we must pay attention to the reactivation of HHV6.