Human Herpesvirus-6 (HHV-6) Viremia Is Frequent but the Incidence of Encephalitis Is Low in Double-Unit Cord Blood Transplantation (CBT) Recipients Transplanted without ATG

Background: While CBT is a known risk factor for HHV-6 reactivation, the level of viremia associated with a high risk of HHV-6 encephalitis is not established and the association with CBT outcomes is controversial.

Methods: We analyzed the nature of HHV-6 reactivation in 125 double-unit CB recipients who were transplanted for hematologic malignancies from 2/2006-3/2012. Viremia was measured by quantitative PCR of plasma HHV-6 DNA (lower detection limit 100 DNA copies/ml).

Results: Of 125 patients (median age 42 years, range 1-69), 93 (74%) received myeloablative and 32 (26%) received non-myeloablative conditioning followed by 4-6/6 HLA-A,B antigen, -DRB1 allele matched CBT for the treatment of AML (n = 43, 34%), ALL (n = 24, 19%), MDS/ CML/ other leukemia (n = 12, 10%), or lymphoma/ CLL (n = 46, 37%). No patient received anti-thymocyte globulin (ATG). One-hundred and seventeen (94%) patients reactivated HHV-6 (median peak 7,600 copies/ml, range 100-160,000) at a median of 20 days (range 10-59). The median time to peak viremia was 23 days (range 12-62) and the median viremia duration was 8 days (range 1-60 days). Fifty-one patients (41% of total, 44% of viremic patients) developed HHV-6 > 10,000 copies/ml (median peak 31,200 copies/ml at 20 days, range 12-57). Only 6 patients (5% of total, 5% of viremic patients) had HHV-6 > 100,000 copies/ml (median peak 130,000 copies/ml at 19 days, range 14-29). HHV-6 encephalitis occurred in 2 patients (1.6%, peak viremias 13,000 and 118,000, respectively); 1 died from encephalitis and the other recovered with therapy. Four other viremic patients had HHV-6 isolated from bronchoalveolar lavage but did not meet criteria for HHV-6 pneumonia. Defining high level viremia as > 10,000 copies/ml in days 14-60, viremia was not associated with diagnosis or conditioning, engrafting unit-recipient HLA-match or TNC, CD34⁺, CD3⁺ cell doses. Treating viremia as a time-dependent covariate in Cox regression analysis, no association was found between viremia and neutrophil or platelet engraftment. There was also no association between viremia and CMV reactivation, day 100 grade II-IV aGVHD, day 100 TRM, relapse, or overall survival. If high level viremia was defined as > 25,000 copies/ml (n = 31, the highest peak viremia quartile days 14-60), no associations with CBT outcomes were detected. Finally, 24 patients had a second viremia (median onset day 49, range 100-27,300) without obvious sequelae.

Conclusions: Nearly all our CBT recipients reactivate HHV-6. While the incidence of end-organ disease is low, possibly due to our exclusion of ATG from the conditioning, our understanding of the significance of HHV-6 viremia is incomplete. We are currently evaluating anti-viral treatment responses, and ultimately a prospective trial is needed to better define the causality between HHV-6 viremia and transplantation outcomes, and to investigate the risk-benefits of pre-emptive therapy.