A retrospective study of 404 allogeneic hematopoietic stem cell transplant (HSCT) patients by the Fred Hutch Cancer Research Center at the University of Washington found that reactivation of a higher number of double stranded DNA (dsDNA) viruses (CMV, BKV, HHV-6B, EBV, and adenovirus) significantly increased the risk of overall mortality, as did an increased quantitative burden of viral exposure. In a model in which each virus was independently considered while adjusting for the presence of other viruses, HHV-6B conferred a significantly increased risk for overall mortality (see figure).
Mortality odds ratio (and confidence interval) for given virus comparing any detection to none. (Note: these patients were treated aggressively for CMV). Source: BLOOD, Supplemental Material, Hill et al February 2017
In this study, 90% of the patients had more than one dsDNA virus detected in plasma, 62% had 2 or more, and 28% had three or more. The highest risk of mortality appeared to correlate with patients who had reactivated HHV-6B, EBV, BKV, and CMV. The authors point out that absence of approved antiviral treatment for dsDNA viruses such as HHV-6, EBV, and adenovirus have limited their antiviral prevention strategies.
The rate of HHV-6 viremia was lower and the CMV rate was higher than what was found in a similar, Japanese study in 2015 that found 60% positivity for HHV-6 and only 10.5% each for CMV and EBV. The Fred Hutch group found that CMV viremia was the most common at 65% compared to 46% for HHV-6B, 10% for adenovirus, and 9% for EBV (Inazawa 2015). The high rate of CMV viremia may be in part due to the fact that the donor or recipient were CMV seropositive in 86% of selected patients, as well as other differences in HCT type and characteristics.
The authors point out that tissue injury by viruses may be underappreciated or misattributed to other causes. HHV-6, for example, can be active in the lung, liver, or heart tissue with little or no trace in the plasma. Only 34 (8.4%) end organ disease events and 8 deaths were clinically attributed to these dsDNA viruses.
The authors also note that viremia by dsDNA viruses may have indirect effects due to increased production of pro-inflammatory and immunomodulatory cytokines, and that viremia has been associated with an increased risk of bacterial and fungal infections, prolonged hospitalization, and death.
To see the full paper and supplementary material, see Hill 2017.