HHV-6A reactivation in a ciHHV-6A transplant patient with encephalitis

ciHHV-6A found in 2.7% of  patients with HHV-6 CNS dysfunction: larger studies on ciHHV-6 and reactivation proposed

Experts from one of the leading stem cell transplant centers, the Fred Hutchinson Cancer Research Center at the University of Washington, have reported a case of ciHHV-6A reactivation in a patient who developed CNS dysfunction and HHV-6A encephalitis after receiving a hematopoietic cell transplant (HCT). Although the authors were not able to determine with certainty if the HHV-6 was active and causing the encephalitis in the patient, they felt it was the most likely explanation, and emphasized the need for large multicenter collaborations to determine the impact of ciHHV-6 on patient outcomes.

A landmark study published earlier this year demonstrated that ciHHV-6A could activate from its integrated state and result in a symptomatic infection in patients with severe combined immunodeficiency (SCID). In that study, an infant with SCID reactivated with his own strain, and the virus isolated was identical to his family’s integrated strain of ciHHV-6A (Endo 2014). This finding prompted HHV-6 expert Louis Flamand, PhD, to call for screening of transplant organs and cells for ciHHV-6 status (Flamand 2014).

The team led by Michael Boeckh and Joshua Hill was the first to answer this call for further study by examining archived samples from 37 HCT recipients with CNS dysfunction who had tested positive for HHV-6 in a previous study by pediatric infectious disease specialist Danielle Zerr. Using their new ddPCR assay for ciHHV-6, the group found 1 of 37 (2.7%) to have integrated HHV-6. Although the number of patients tested was too small to draw conclusions on whether the prevalence of ciHHV-6 might be elevated in HCT patients with HHV-6 CNS dysfunction compared to the rate in the general population (0.8%), previous studies have suggested that the prevalence of ciHHV-6 may be higher in some patient populations (Pellett 2011).

The ciHHV-6 patient described in the study developed HHV-6 viremia after being transplanted with non ciHHV-6 cells, and developed hallucinations and agitation on day 11, the day after he received methylprednisolone. He was treated with foscarnet after his spinal fluid was found positive for 2500 DNA copies/ mL in semi-quantitative PCR testing. Although the patient responded initially, the patient’s encephalopathy progressed and his viral load was still positive at the same level by semi-quantitative PCR at day 17. The patient continued to receive steroids through day 23 and foscarnet was continued until kidney toxicity caused the therapy to end at day 29. The patient’s bone marrow was negative for HHV-6 DNA by day 29, and his blood was, by then, from the donor. The patient died due to pulmonary disease on day 40 and autopsy revealed findings consistent with possible viral encephalitis.

The authors state that while the encephalitis could have been caused by an infection other than HHV-6, the findings were best explained by ciHHV-6A reactivation, pointing out that it was unlikely that the HHV-6 DNA detected in the CSF came from leukocytes with ciHHV-6 after the successful myeloblative HCT.

One unanswered question is whether it is safe to administer high dose steroids to patients with ciHHV-6, since steroids activate HHV-6 in vitro, and have been shown by a Japanese group to increase HHV-6 DNA viral loads by two orders of magnitude when administered to patients with drug induced hypersensitivity syndrome (Ishida 2014). By contrast, steroid administration had no impact on EBV and only a modest impact on the CMV viral loads. HDAC inhibitors have also been shown to activate integrated HHV-6 in vitro (Arbuckle 2010) and it is not known if these drugs pose a risk for patients with ciHHV-6.

Two other cases of ciHHV-6-associated encephalitis have been reported including a ciHHV-6 patient who developed encephalitis after receiving a regimen that included prednisone and intrathecal methotrexate for acute leukemia. This patient had 6 cells and 21,000 DNA copies per ml in the spinal fluid. His viral load dropped to zero after 30 days on ganciclovir but increased to 10,000 copies per ml 40 days after discontinuation of the drug. A second round of antiviral treatment reduced his viral load to undetectable levels but the viral load increased once again to 5,000 copies after discontinuation of the antiviral. It finally dropped to zero after a third round of consisting of 60 days on valganciclovir (Wittekindt 2009).

An immunocompetent ciHHV-6 patient was also reported to develop encephalomyelitis and appeared to respond to antiviral therapy (with a drop in CSF viral load from 20,000 copies/ml to 4,400 copies per ml after 40 days, but it was difficult to rule out ciHHV-6 contamination from cells in this case because of there were 127 cells in the first CSF sample dropping to 6 cells after antiviral therapy (Troy 2009).

For more information, read the full paper, and read this interview with the authors of the study, Drs. Joshua Hill and Michael Boeckh.