HHV6 and EBV Reactivations Associate with Encephalitis in Patients Post Allogeneic Haematopoietic Stem Cell Transplantation

Herpes viruses reactivation is frequent post HSCT and constitutes a major complication when the reactivation becomes clinically symptomatic. 102 patients at several time points (1058 measurements for each Herpes virus, on average 10 measurements per one patient, from one week to one year post transplant) were investigated with the use of quantitative PCR for the presence of DNA viral copies in blood cells. CMV, EBV and HHV6 DNA copies in blood cells were determined with the use of the real-time PCR technique employing an Opticon 2 thermocycler (MJ Research, Watertown, USA). PCR conditions and the sequences of PCR primers and probes were selected from BALF5 region of EBV, US17 region of CMV and U67 region of HHV6 as described by Kimura et al, (1999), Machida et al, (2000) and Locatelli et al, (2000), respectively.

It was found: CMV and EBV DNA copies (above 100 copies/100 000 cells) were detected in 35% and 23% of patients, respectively. HHV6 reactivation was considered as significant at lower number of copies (above 10 copies/100 000 cells) and was found in 41% of HSCT recipients. Reactivations were more common at early stage post HSCT, with a peak between +31 and +60 day, then at later time. This difference was statistical significant for CMV (p=0.021) and similar trends were also seen when EBV and HHV6 reactivation were analyzed. CMV and EBV reactivations were associated with severe post transplant complications what resulted with poorer 5 year survival (30% vs 72% p=0.015 and 35% vs 65% p=0.016) in patients with CMV and EBV reactivation, respectively. This was not seen when HHV6 was considered. The poorest 5 year survival was seen in patients having aGvHD and presenting reactivation of CMV (23% vs 67%, p= 0.023). Patients with hepatitis were more frequently positive for CMV (0.54 vs 0.30, p=0.071) and EBV (0.41 vs 0.20, p=0.091) reactivation as compared to those lacking clinically apparent hepatitis. Full blown post transplant limbic encephalitis was seen in one case only and was associated with the presence of HHV6 DNA copies in blood (10 copies/100 000 cells) and in spinal fluid (5865 copies/200μl). However, in 11 cases some neurological, psychological and/or psychiatric symptoms were seen. Notably, among these encephalitis cases nine, six and three patients had HHV6, EBV and CMV reactivation, respectively. In five patients with encephalitis reactivation of two Herpes viruses were detected. Separate analysis of investigated Herpes viruses showed the statically significant association of encephalitis with HHV6 (0.75 vs 0.37 p=0.008) and EBV (0.54 vs 0.20 p=0.019) reactivation. Encephalitis was diagnosed in 25% and 21 percentages of pts with EBV and HHV6 reactive respectively. Seven out of 11 patients with encephalitis died. It appears that HHV6 and EBV reactivations may associate with encephalitis that affects the survival post HSCT.