In 1992, Yoshikawa first published that 14% of kidney transplant recipients developed HHV-6 viremia in the first 2-4 weeks posttransplant and 55% showed an increase in anti-HHV-6 antibody titer in the first 3 months (Yoshikawa et al., 1992). Since then, Singh and Carrigan (1996), Singh and Patterson (2000), Ljung-man (2002), and Lautenschlager et al. (2000) have reported HHV-6 as an emerging pathogen in solid organ transplantation. HHV-6 is expressed in the early weeks posttransplant, often exacerbating the severity of other diseases in the transplant recipient (Des Jardin et al., 1998, 2001; Dockrell et al., 1997, 1999), including cytomegalovirus (CMV) (Humar et al., 2000; Boeckh and Garret, 2003).
Until the routine availability and use of prophylactic anti-viral medications like ganciclovir in solid organ transplant recipients, CMV was one of the leading causes of morbidity and mortality (Tolkoff-Rubin and Rubin, 1998). Serologically CMV-negative patients receiving an organ from a CMV-positive donor are at greatest risk, although use of potent immunosuppressives like anti-lymphocyte globulin, steroids, and mycophenolate mofetil as well as a history of rejection increases the risk (Abbott et al., 2002). CMV seropositivity therefore confers some protection against CMV disease. Most recipients of a solid organ transplant have previously been infected with HHV-6 and the organ donors are also highly likely to have been infected by the age of two, therefore the probability of a D + /R— combination for HHV-6 is extremely low. If so, what is the explanation for the fact that infections with HHV-6 are estimated to recur in 14-82% of transplanted individuals (Des Jardin et al., 1998, 2001; Dockrell et al., 1997, 1999)? Do these HHV-6 antibodies fail to confer protection as in CMV? In fact, Dockrell et al. (1999) reported that HHV-6 seronegativity was a risk factor for fungal infection in liver transplant recipients. Since HHV-6 seroprevalence is so high, it was hypothesized that these individuals may be "false" negative reflecting that fact that they are already severely suppressed prior to transplant and therefore antibody negative (despite prior infection with HHV-6).
Management of the immunosuppressive regimen of transplant recipients has always required a balancing act to avoid the risks of infection and rejection. HHV-6 clearly poses heightened risks for the transplant recipient that is thoroughly reviewed by Ljungman in Chapter 22 and shown by others (Morris et al., 1989; Robert et al., 1994; and Snydman et al., 1993). In fact, Tong et al. (2002) published that HHV-6 was associated with chronic allograft nephropathy after renal transplantation. In addition, Acott et al. (1996) have reported that failure to use antiviral therapy at the time of pulsed steroid therapy for HHV-6 associated rejection episodes in febrile pediatric kidney transplant recipients resulted in chronic allo-graft rejection. Fortuitously, ganciclovir, which shows some efficacy against HHV-6, may have protected many transplant recipients since CMV anti-viral prophylaxis is now a standard of care in the first months following transplant.
In the transplant community, neurological side effects are common including tremors, cognitive disorders, psychiatric complications, and depression. These sequelae have been described in most of the clinical trials of calcineurin inhibitor clinical trials in transplant recipients. Is it possible that the drugs are not themselves the source of these side effects but the immunosuppressive environment that they are designed to create? If so, reactivation of the herpesviruses, particularly those known to have neurotropisms like HHV-6 may actually be implicated.
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