Human herpesvirus 6B (HHV-6B) detection and genome-wide host expression profiles implicate HHV-6B as a pulmonary pathogen after hematopoietic cell transplantation

Limited understanding of the immunopathogenesis of human herpesvirus 6B (HHV-6B) has prevented its acceptance as a pulmonary pathogen after hematopoietic cell transplantation (HCT). We conducted a prospective multicenter study of patients undergoing bronchoalveolar lavage (BAL) for pneumonia after allogeneic HCT. We tested blood and BAL fluid (BALF) for HHV-6B DNA and mRNA transcripts associated with lytic infection and performed RNA-seq on paired blood. Among 116 participants, HHV-6B DNA was detected in 37% of BALs, 49% of which had HHV-6B mRNA detection. We established an HHV-6B DNA threshold (=2.3 log10copies/ml in BALF) that was highly predictive of HHV-6B mRNA detection and increased risk for death from respiratory failure (adjusted HR, 2.35; 95% CI, 1.08-5.11). Participants with HHV-6B DNA in BALF exhibited distinct host gene expression signatures, notable for enriched interferon signaling pathways in participants clinically diagnosed with idiopathic pneumonia. These data implicate HHV-6B as a pulmonary pathogen after allogeneic HCT. Overall design: In this study, we prospectively enrolled adult allogeneic HCT recipients undergoing a BAL for evaluation of LRTD within 120 days of HCT from three centers and followed outcomes for up to 60 days after the BAL. We collected and tested paired blood and BALF samples with multiple molecular diagnostic techniques to comprehensively investigate the role of HHV-6B as a pulmonary pathogen after allogeneic HCT and determine the utility of whole blood gene expression signatures as a complement to pathogen-directed diagnostic testing.