Prevalence of Chromosomally Integrated Human Herpesvirus 6 (HHV-6) Among Patients with HHV-6-Associated Post-Stem Cell Transplant Acute Limbic Encephalitis

Background: Human herpesvirus 6 (HHV-6) reactivates in 33-48% of hematopoietic stem cell transplant (HCT) recipients and is associated with numerous adverse effects. HHV-6 chronically infects cells after primary infection and has a unique ability to integrate into chromosomal telomeres. If this occurs in germ cell lines, vertical transmission results in individuals with chromosomally integrated HHV-6 (ciHHV-6) in every nucleated cell. Studies have found ciHHV-6 in an average of 0.85% of blood donors and 1.99% of patient groups (Rev. Med. Virol. 2012; 22: 144–155). A few reports suggest that patients with ciHHV-6 can develop in vitro and in vivo HHV-6 replication and disease. The prevalence of ciHHV-6 in patients with HHV-6-associated diseases is unknown and may provide insight into the risk for pathologic HHV-6 reactivation.

Methods: To determine the prevalence of ciHHV-6 in patients with HHV-6 end-organ disease, we identified cases of HHV-6-associated post-stem cell transplant acute limbic encephalitis (HHV-6-PALE) and tested patients and their donors for ciHHV-6. HHV-6-PALE was diagnosed in patients with HHV-6 DNA in cerebrospinal fluid (CSF) and neurologic symptoms with no other explanatory etiology. CiHHV-6 was identified in blood samples by testing extracted DNA for HHV-6 and a reference gene for cell count with droplet digital PCR. Positive samples had a ratio of 1 ± 0.07 HHV-6/genome equivalents.

Results: Among 3,902 patients undergoing allogeneic HCT at our institution from 1998-2012, 37 (0.95%) met criteria for HHV-6-PALE. This cohort had 16 double cord blood, 13 peripheral blood (PBSCT), and 8 bone marrow HCTs. Median maximum CSF HHV-6 viral load (VL) was 10,000 copies/ml (range, 54-450,000). Twenty-six cellular and 11 serum pre-HCT patient samples were tested for ciHHV-6 (Figure). CiHHV-6 was detected in 1 of 37 samples (2.7%; 95% CI, 0.07-14.5%). This patient developed HHV-6-PALE D+12 after PBSCT with maximum CSF VL of 250,000 copies/ml and died on D+40 from complications of autopsy-confirmed encephalitis. Nineteen donor samples (17 cellular, 2 serum) tested negative for ciHHV-6. Late post-engraftment serum samples were tested in cases without available donor samples; 4 of 15 had HHV-6 DNA detected but were indeterminate for ciHHV-6 (Figure).

Conclusions: This is the first epidemiologic study of the prevalence of ciHHV-6 in patients with HHV-6 PALE and included the largest reported cohort of HHV-6-PALE cases to date. CiHHV-6 was identified in one patient, which has never been described in this setting. Sequencing of pre and post-HCT viruses, as well as histopathologic testing of brain tissue, is in process. Although there is no clear evidence of ciHHV-6 enrichment in this cohort, the detection and poor outcome in the described case underscores the need for a large, multi-center study to determine the impact of ciHHV-6 on outcomes.