HHV-6 Reactivation Lowers the Risk of Acute Graft-Versus-Host Disease but Enhances the Risk of Infections Due to Activation of CD4+FoxP3+ Lymphocytes.

Abstract 4653

CMV, EBV, and HHV-6 reactivation was monitored for 20 days to 4 years after allogeneic hematopoietic stem cell transplantation (alloHSCT) with respect to hematological and immunological reconstitution as well as fate in 118 patients (17 children and 101 adults) who received alloHSCT (100 peripheral blood progenitor cell (PBPC) and 18 bone marrow transplants from 53 siblings and 65 unrelated donors, 64 patients receiving reduced intensive conditioning (RIC) and 54 myeloablative conditioning). All patients on RIC and those transplanted from unrelated donors received anti-thymocyte globulin (ATG). Herpes virus DNA copies were measured by quantitative PCR (primers and probes designed according to Kimura 1999, Machida 2000, and Locatelli 2000). This study focused on HHV-6.

It was found that:

1. Multivariate analysis showed that alternative donor (OR=3.06, p=0.038), myeloablative conditioning regimen (OR=0.22, p=0.004), and an HLA-matched (10/10 at allele level) graft (OR=0.14, p=0.011) were risk factors of HHV-6 reactivation. Interestingly, they were different from those of CMV reactivation (acute GvHD grade >=I, OR=2.74, p=0.024).

2. HHV-6 reactivation was found earlier post-transplant than CMV reactivation (19 vs. 47 days, median values, p=0.014) and rather before clinically apparent aGvHD manifestation, in contrast to CMV and EBV infections (percentages of reactivation events prior to aGvHD were 71, 14, and 14 for HHV-6, CMV and EBV, respectively).

3. HHV-6 was associated with an increase in CD4+ lymphocytes (p=0.028, Wilcoxon matched pairs test), in contrast to CMV infection, in which CD4+ cells were rather low.

4. HHV-6 reactivation noted during 100 days post-transplant was associated with a higher fraction of FoxP3+ in CD4+ cells compared with those of counterparts (13% vs. 8.5%, median values, p=0.008).

5. Encephalitis was frequent in HHV-6 (8/14 vs. 26/104, p=0.023) and EBV (9/14 vs. 22/104, p=0.002) positive patients. HHV-6 preceded EBV (14/26 vs. 28/92, p=0.037) but not CMV (9/36 vs. 33/82, p=0.145) reactivation before 100 days after HSCT.

6. HHV-6 positivity in the 100 days post-HSCT was associated with a higher mortality rate early post-transplant (6-month survival rates of HHV-6-positive and -negative cases: 55% vs. 80%, respectively).

In conclusion: HHV-6 reactivation affects patients early post-transplant and associates with an increase in CD4+ lymphocytes in blood which frequently have FoxP3 generation potential. Risk of aGvHD is consequently lower, but there is a higher incidence of infections, including EBV, encephalitis, and sepsis, and survival is poor.