Investigators in Japan studied 145 patients who developed HHV-6 encephalitis. At 100 days after transplantation, the overall survival rate was just 58.3%, compared with 80.5% for patients who did not develop encephalitis. High-dose antiviral therapy was shown to mitigate high mortality rates in these patients.
T-cell depleted stem cell transplant patients at Memorial Sloan Kettering Cancer Center with HHV-6 viremia, CMV viremia, or 2 or more viremias experienced longer hospital stays and were readmitted more often. HHV-6 was the most commonly reactivated virus, with 61% of patients affected patients .
A higher prevalence of inherited virus was found in patients
Investigators at Fred Hutchinson Cancer Center determined that transplant patients with inherited ciHHV-6 were twice as likely to develop acute graft vs host disease and three times more likely to develop high level CMV viremia. Transplant patients were also significantly more likely to have inherited ciHHV-6 than donors.
CD8+ T cells recover but CD4+ T cells remain low
Investigators in France discovered that monocytes and B lymphocytes recover quickly and become abnormally elevated by day 75 in cord blood patients, while they remain below normal or normal in stem cell patients. Although CD8 T cells recover, CD4+ T cells remain below normal levels for six months in both groups.
Retrospective analysis of transplant patients revealed that low serum sodium levels are associated with HHV-6 encephalitis, but not HHV-6 myelitis. Low sodium is a possible marker for HHV-6 encephalitis post-transplantation.
Over a dozen studies have now found HHV-6 to predict aGVHD, but this is the first to correlate viral reactivation with poor CD4+ cell immune reconstitution.
Two physicians from Texas propose that ciHHV6 status of donors and recipients be determined before solid organ transplantion, using a single pre-transplant qPCR test on whole blood, and that patients with ciHHV-6 or ciHHV-6 donors be carefully monitored for signs of active HHV-6 infection.
A retrospective study of allogeneic hematopoietic stem cell transplant patients at University of Washington found that reactivation of several double stranded DNA viruses significantly increased the risk of overall mortality, as did an increased quantitative burden of viral exposure. HHV-6B conferred a significantly increased risk for overall mortality.
A young woman on rituximab and two other immunomodulatory agents for the treatment of dermatomyositis developed encephalitis with severe anterograde amnesia. As the use of biologic treatments for refractory autoimmune disease has been increasing, physicians are advised to consider HHV-6 and offer prompt antiviral therapy to limit irreversible morbidity.
Only 11% of HHV-6 reactivated patients with poor immune reconstitution survived compared to 63% in patients with higher levels of T cells (or over 200 CD3+ lymphocytes per microliter).
A retrospective analysis out of the Tokyo Metropolitan Cancer and Infectious Diseases Center reviewed 353 consecutive adult allogeneic hematopoietic stem cell transplant (allo-HSCT) cases and identified 17 cases of CNS infection post-transplant. As determined by PCR on cerebrospinal fluid, HHV-6 was found to be the causative agent in 6 cases, or 1.7% of all transplants.
A group from the University of Minnesota studied the T cells of umbilical cord blood transplant patients and found that CD4+ T lymphocytes co-expressing CD134 contained more than twice the level of HHV-6B than cells without CD134 expression. Surprisingly, almost 70% of the CD134 negative cells contained HHV-6.
It has long been a mystery why HHV-6 is preferentially reactivated in drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug induced hypersensitivity syndrome (DIHS). HHV-6 reactivation occurs in over 60% of severe cases and is part of the definition of DIHS in Japan. Investigators in Japan suspect that the explanation may lie with the CD134 receptor on activated CD4 cells.
Another case of drug induced liver injury accompanied by HHV-6 reactivation has been reported in Japan, the second such case without exanthema to be described. An earlier case was reported last year (Fujita 2015). The authors suggest that drug-induced liver injury cases be investigated for HHV-6 reactivation when liver dysfunction begins several weeks after the initiation of a new drug typically associated with hypersensitivity syndromes.
A group from Baylor College of Medicine reviewed the efficacy of treating viral infections in transplant patients with primary immunodeficiencies using their viral-specific T lymphocytes. A total of 36 patients were treated with these immunotherapy infusions before or after undergoing hematopoietic stem cell transplantation, and a complete or partial antiviral response were seen in 86% of patients with CMV, 76% of patients with EBV and all patients with adenovirus or HHV-6.