HHV-6B: an underappreciated cause of hepatitis in HCT

Although HHV-6 infection in solid organ transplant patients has been well documented, the role of HHV-6 in stem cell transplant cases has not been similarly studied. A recent article published in Transplant Infectious Disease describes a case of acute hepatitis in a hematopoietic cell transplant (HCT) recipient likely caused by HHV-6B, and reviews the current literature on HHV-6B associated hepatitis. The article was written by a team from the University of Washington and Fred Hutchinson Cancer Research Center, and concludes that HHV-6-associated hepatitis may be an underappreciated entity in HCT patients. Currently, HHV-6 testing is not part of the initial screening protocol for suspected hepatitis at most HCT centers.

The article describes a 23-year-old male CMV+ patient with severe sickle cell disease who underwent a match-related myeloablative HCT and subsequently developed acute hepatitis. After tests for EBV, CMV HSV1 and 2, adenovirus and HBV DNA were negative, he was tested for HHV-6 and 170,000 DNA copies per ml were found in the plasma. A workup for ciHHV-6 was negative. Immunohistochemistry revealed HHV-6 antigens in the hepatic cells. The patient was started on ganciclovir, and HHV-6 VL steadily decreased to <5000 copies/mL within 7 days of administration. Symptoms slowly resolved following treatment and transitioning to oral valganciclovir on day 25. Abdominal pain was improved, however HHV-6 DNA remained detectable at low levels for several months.

Although the viral load was initially quite high in this acute case, other studies have identified cases of HHV-6 infection with persistently low or undetectable levels of viremia in spite of high viral loads in the tissue biopsy or autopsy specimens. For example, Buyse et al found that 38.5% of 26 liver samples from patients with graft hepatitis had high levels of HHV-6 in the tissue and identified a pattern of periportal confluent necrosis. Of interest, many of these patients did not have evidence of abnormal HHV-6 viremia (Buyse 2013).

In other recent studies of unexplained liver dysfunction, HHV-6 has been quite prominent. In a study of liver dysfunction in patients with blood cancers (some of whom had undergone BMT) HHV-6 viremia was found in 35% of patients, which was markedly increased compared to EBV (14%), CMV (8%), and HHV-7 (3%) (Ito 2013). In one study of explanted livers, 80% were found positive for HHV-6 (Harma 2002).

Only one other case report of HHV-6 liver dysfunction has been well documented (Kuribayashi 2006) and in this case, the patient also responded to antiviral therapy. In both cases, the high viral load was preceded by a course of steroids to treat possible GVHD.

The authors explain that prompt testing and initiation of treatment for HHV-6 after appropriate evaluation were crucial in achieving a good outcome in this case and note that the evaluation of ciHHV-6 is important for HHV-6+ patients suspected of liver dysfunction so that unnecessary treatment is not continued. This group took advantage of the University of Washington’s new ddPCR test for ciHHV-6. This highly accurate cell based assay typically gives a ratio of HHV-6 DNA to cell genomes of 1:1 in a case of ciHHV-6 (Sedlak 2014). In this case the ddPCR testing yielded a ratio of 0.3 DNA copies per cell.

For more information, read the full article, and visit the following HHV-6 Foundation webpages:

HHV-6 & Transplantation

HHV-6 & Liver Disease