Human Herpesvirus 6B and Pulmonary Disease after Hematopoietic Cell Transplantation

Background: Human herpesvirus 6B (HHV-6B) DNA is frequently detected in bronchoalveolar lavage fluid (BALF) from immunocompromised subjects with lower respiratory tract disease (LRTD). Whether HHV-6B is a pulmonary pathogen is unclear. Methods: We tested prospectively stored BALF for HHV-6B DNA using PCR in allogeneic hematopoietic cell transplantation (HCT) recipients who underwent a BAL for evaluation of LRTD from 1992-2015. We used multivariable proportional hazards models to evaluate the association of HHV-6B+ BALF with overall mortality, death from respiratory failure, and the effect of anti-HHV-6B antivirals on these outcomes. We used branched chain RNA in-situ hybridization (RISH) to detect HHV-6 messenger RNA (U41 and U57) in lung tissue. Findings: We detected HHV-6B+ BALF from 147 of 553 (27%) individuals. Subjects with HHV-6B+ BALF, with or without copathogens, had significantly increased risk of overall mortality (adjusted hazard ratio [HR], 2.06; 95% CI, 1.33-3.21) and death from respiratory failure (aHR, 2.26; 95% CI, 1.44-3.56) compared to subjects with HHV-6B- BALF. Subjects with HHV-6B+ BALF who received antivirals within 3 days pre-BAL had an approximately 1 log10 lower median HHV-6B BALF viral load and lower risk of overall mortality compared to subjects with HHV-6B+ BALF not receiving antivirals (aHR, 0.44; 95% CI, 0.17-1.11). We detected intraparenchymal HHV-6 gene expression by RISH in lung tissue in all 3 tested subjects with HHV-6B+ BALF and sufficient tissue RNA preservation. Interpretation: These data provide evidence that HHV-6B is a pulmonary pathogen after allogeneic HCT. Definitive evidence of causation will require a randomized prevention or treatment trial. Funding: National Institutes of Health, the American Society for Blood and Marrow Transplantation, the HHV-6 Foundation. Declaration of Interest: J.A.H. served as a consultant for Chimerix, Nohla Therapeutics, Inc., and Amplyx and has received research support from Chimerix, Shire, and Karius, Inc. outside the submitted work. C.E.F. has received a grant from Gilead Sciences outside of the submitted work. L.C. has received research support from Sanofi and Immune Design and is a co-inventor on several patents associated with the development of an HSV-2 vaccine; he has no conflicts in the area of HHV-6. M.B. received grants and/or personal fees from Chimerix Inc. and Microbiotix outside the submitted work. L.K.V-V, H.X., E.L.C., S.S., T.S-A, M-L.H, K.R.J., F.M.S, D.M.Z., and W.M.L declare no competing interests. Ethical Approval: The study was approved by the FHCRC Institutional Review Board.