Stanford investigators found that high levels of HHV-6 viremia following allogeneic stem cell transplants were associated not only with acute GVHD and delayed engraftment, but also end organ diseases and increased non-relapse mortality. Of 89 patients studied, 34 had HHV-6 reactivation and 14 (16%) developed end organ disease.
Reactivation of HHV-6 following allogeneic stem cell transplants (HCT) is increasingly recognized as a factor involved in the development of several severe complications. Led by Stanford hematologist and oncologist Sandhya Kharbanda, the team monitored HHV-6 viral load and routinely tested affected organ tissues for the presence of HHV-6 DNA by PCR.
Most of the 89 retrospectively studied patients received acyclovir as prophylaxis against HSV, CMV, and VZV, and some patients who were considered at higher risk for CMV reactivation received ganciclovir and valganciclovir as well during conditioning and following engraftment. However, a subset of patients who were seronegative for HSV, CMV, or VZV received no antiviral prophylaxis, and these were found to reactivate with HHV-6 more frequently.
Survival of tissue positive patients with HHV-6 viremia compared to asymptomatic patients with HHV-6 viremia.
In total, 34 (38%) patients developed HHV-6 viremia following transplantation. Of those 34, 14 (41%) developed symptoms and signs indicative of end-organ disease, and HHV-6 was detected in the involved organs. These individuals had peak viral loads in the blood that were higher than in the asymptomatic, HHV-6 positive subgroup, and non-relapse mortality was higher than in both the asymptomatic group and the control (HHV-6 negative) group. Though the association was not significant, those who were tissue-positive were more likely to have had HLA-mismatched donors and cord blood as the stem cell source. HLA-mismatched donors and cord blood have previously been identified as risk factors for HHV-6 reactivation (Illiaquer 2017), higher HHV-6 viral loads in recipients who have gone on to reactivate with HHV-6 (Gotoh 2014, Mutlu 2014, Illiaquer 2017), and HHV-6 encephalitis (Ogata 2017).
Reasons for biopsy or fluid acquisition in the tissue-positive cohort included encephalitis (4), duodenitis (1), colitis (1), gastritis (3), cholecystitis (2), red cell aplasia (1), delayed or failed engraftment (3), pericarditis/pericardial effusion (2), and pneumonitis (3). In two patients with pneumonitis, bone marrow also tested positive for HHV-6, and in one, pericardial fluid was positive as well. HHV-6 was detected by qPCR in the CSF of 4 patients, the bone marrow of 5, bronchoalveolar lavage of 3, pericardial fluid of 3, the GI tract of 5, the liver of 1, and the gallbladder in 2.
While the tissues and fluid samples tested positive for HHV-6, it is important to note that copy numbers in the blood at the time of tissue obtainment were low or below the limit of detection of 1,000 copies in all but one patient. This finding is important to consider on a broader scale; even when HHV-6 is not present at high levels, or at all, in the blood, tissue-specific infection cannot be ruled out. In studying HHV-6 in the clinical setting, the absence of striking HHV-6 infection solely using blood samples may skew results and lead to inaccurate conclusions.
In 4 of the 14 tissue-positive patients, CMV was also detected in tissues. Although the interactions between HHV-6 and CMV are not fully understood, HHV-6 reactivation in HCT recipients has been correlated with a higher incidence of CMV reactivation (Aoki 2015, Quintela 2016). In one recent study, HCT recipients tended to reactivate with HHV-6 about 2 weeks before CMV reactivation occurred, and while 87% of patients with HHV-6 reactivation later reactivated with CMV, only 33% without HHV-6 reactivation developed active CMV infections (Crocchiolo 2016).
Sandhya Kharbanda is a pediatric hematologist/oncologist at UCSF.
Although the relatively small sample size of this study presented a problem when determining statistical significance, the correlation between higher blood HHV-6 viral loads, HHV-6 detection in organs, and the incidence of end-organ disease, as well as non-relapse mortality, adds to the mounting body of evidence indicating that efforts should be made to prevent the reactivation of HHV-6 post-HCT.
Non-relapse mortality was higher in the tissue-positive group even after antiviral treatment. Because tissue samples from patients without organ dysfunction are not generally obtainable, comparing the tissue-positivity of patients with end-organ disease and asymptomatic individuals with HHV-6 reactivation is an obstacle that is difficult to overcome. However, IHC and other molecular techniques can be applied to tissue samples that are available to help determine whether HHV-6 activity is tied to organ dysfunction. Even now, the evidence in favor of a harmful role for HHV-6 in the setting of HCT supports the use of HHV-6-specific antiviral prophylaxis.
Read the full paper here: Winestone 2017.