Impact of Inherited Chromosomally Integrated HHV-6 on Central Nervous System Dysfunction and Management after Hematopoietic Cell Transplantation

Background Human herpesvirus 6B (HHV-6B) is the most frequent infectious cause of central nervous system (CNS) dysfunction after hematopoietic cell transplantation (HCT). HHV-6 species are unique among the herpesviruses for their ability to integrate into telomeric regions of chromosomes. If this occurs in a gametocyte, vertical transmission results in individuals with inherited chromosomally integrated HHV-6 (iciHHV-6) in every nucleated cell. Whether iciHHV-6 in HCT recipients or their donors increases risk for CNS dysfunction is unknown. It is also unknown whether HHV-6 detection, without recognition of iciHHV-6, drives unnecessary interventions. Objectives The aims of this study were to compare the incidence of CNS dysfunction and HHV-6-related interventions after HCTs that did and did not involve patients or donors with iciHHV-6. Methods We used a previously identified cohort of 87 allogeneic HCT recipients in which the recipient, donor, or both had iciHHV-6 (iciHHV-6pos). We matched each iciHHV-6pos HCT with two HCTs in which neither recipient nor donor had iciHHV-6 (iciHHV-6neg). Matching criteria were age at HCT, year of HCT, myeloablative conditioning, and advanced disease status. Clinical testing for HHV-6 with PCR in plasma or cerebrospinal fluid was symptom based. We compared the cumulative incidence of CNS dysfunction in the first 100 days after iciHHV-6pos and iciHHV-6neg HCT. We also compared the proportion of patients in each group who had neuroimaging, lumbar puncture (LP), or HHV-6-targeted antiviral therapy. Results There was a similar cumulative incidence of any CNS dysfunction after iciHHV-6pos and iciHHV-6neg HCT (Figure 1). None of the subjects in the iciHHV-6pos group developed CNS dysfunction directly attributable to HHV-6 compared to one subject (0.6%) in the iciHHV-6neg group diagnosed with HHV-6 encephalitis. HHV-6-targeted antiviral therapy was significantly more frequent after iciHHV-6pos HCT (OR, 12.7; 95% CI, 1.8-298.3), and two patients developed antiviral associated toxicities that contributed to their cause of death. IciHHV-6pos recipients also had increased odds of receiving a LP (OR, 1.6; 95% CI, 0.9-2.8) but similar odds of neuroimaging (OR, 1.2; 95% CI, 0.7-2.1). Conclusions The cumulative incidence of CNS dysfunction was similar after allogeneic HCT involving recipients or donors with and without iciHHV-6. However, potential misattribution of HHV-6 detection as active infection after iciHHV-6pos HCT may have resulted in increased healthcare utilization with related adverse events. These findings are likely more pronounced at institutions using routine HHV-6 screening. Reflexive testing for iciHHV-6 may reduce healthcare utilization and improve outcomes after allogeneic HCT.