2094. A prospective multicenter study of HHV-6B genomic DNA and gene transcription in paired bronchoalveolar lavage fluid and blood from HCT recipients
Authors: Hill Joshua A , Lee Yeon Joo , Vande Vusse Lisa K , Xie Hu , Lisa Chung E , Keane-Candib Jacob , Waghmare Alpana , Cheng Guang-Shing , Zhu Haiying , Huang Meei-Li , Hill Geoffrey , Jerome Keith R , Gharib Sina A , Leisenring Wendy M , Zerr Danielle M , Dadwal Sanjeet S , Boeckh Michael J 
Published: December 2022

Abstract

Background
We previously demonstrated frequent detection of HHV-6B DNA in bronchoalveolar lavage fluid (BALF) and its positive association with mortality in HCT recipients from 1992-2015 with lower respiratory tract disease (LRTD). Whether these findings remain pertinent in contemporary patients, the additive value of testing for viral gene transcription, and the correlation of HHV-6 detection in blood and BALF, are unknown.

Methods
We conducted a prospective study of allogeneic HCT recipients undergoing BAL for LRTD within 120 days of HCT at three cancer centers from 2015-2019. We collected and tested paired blood and BALF for HHV-6B DNA by qPCR and HHV-6B mRNA (U38 and U90 gene transcripts) among DNA positive samples using RT-qPCR. We described the detection of HHV-6B DNA and mRNA in blood and BALF, generated receiver operating characteristic (ROC) curves to determine the ability of BALF HHV-6B DNA detection to predict HHV-6B mRNA detection, and analyzed the association of HHV-6B DNA detection with mortality.

Results
We enrolled 116 allogeneic HCT recipients who underwent 125 BALs. HHV-6B DNA was detected in 45 of 122 BALF (37%) compared to 19 of 124 (15%) plasma samples. Among the 45 BALF samples with HHV-6B DNA detected, either HHV-6B mRNA transcript was detected in 22 (49%) (Figure 1). BALF HHV-6B DNA ≥ 218 copies/ml had an area under the curve of 0.93 for predicting detection of BALF viral mRNA (Figure 2). In turn, patients with BALF HHV-6B DNA ≥ 218 copies/mL had increased risk for mortality and death due to LRTD within 60 days after the BAL (Figure 3). This association remained after adjustment for age, oxygen use, and steroid use at the time of BAL in a multivariable Cox model (Figure 3).

Conclusion
HHV-6B was detected more frequently in BALF than plasma, suggesting compartment-specific reactivation. BALF HHV-6B DNA ≥ 218 copies/mL had high sensitivity and specificity for detection of viral gene transcription in BALF and was associated with increased mortality; this viral load is strikingly similar to the BALF viral load threshold of 251 copies/mL associated with mortality in our prior retrospective study. Together, these data suggest transcriptionally active HHV-6B is a clinically impactful pulmonary pathogen in contemporary HCT recipients.

Disclosures
Joshua A. Hill, MD, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Covance/CSL: Advisor/Consultant|CRISPR: Advisor/Consultant|Deverra: Grant/Research Support|Gilead: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck: Grant/Research Support|Octapharma: Advisor/Consultant|OptumHealth: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Pfizer: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant Alpana waghmare, MD, Allovir: Grant/Research Support|Ansun BioPharma: Grant/Research Support|Kyorin Pharmaceutical: Advisor/Consultant|Pfizer: Grant/Research Support|Vir/GSK: Grant/Research Support Geoffrey Hill, M.D., FRACP, FRCPA, Applied Molecular Transport: Grant/Research Support|Compass Therapeutics: Grant/Research Support|Generon Corporation: Advisor/Consultant|Heat Biologics: Grant/Research Support|iTeos Therapeutics: Advisor/Consultant|iTeos Therapeutics: Grant/Research Support|Laevoroc Oncology: Grant/Research Support|NapaJen Pharma: Advisor/Consultant|Neoleukin Therapeutics: Advisor/Consultant|Serplus Technology: Grant/Research Support|Syndax Pharmaceuticals: Grant/Research Support Danielle M. Zerr, MD MPH, AlloVir: Advisor/Consultant Sanjeet S. Dadwal, MD, FACP, FIDSA, AlloVir: Advisor/Consultant|AlloVir: Grant/Research Support|Ansun Biopharma: Grant/Research Support|Aseptiscope: Advisor/Consultant|Aseptiscope: Stocks/Bonds|Astellas: Speaker's Bureau|Cidara: Advisor/Consultant|Gilead: Grant/Research Support|Karius: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Merck: Speaker's Bureau|Takeda: Speaker's Bureau Michael J. Boeckh, MD PhD, Allovir: Advisor/Consultant|Amazon: Grant/Research Support|Ansun Biopharma: Grant/Research Support|EvrysBio: Advisor/Consultant|Gates Ventures: Grant/Research Support|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|Helocyte: Advisor/Consultant|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Kyorin Pharmaceuticals: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Regeneron: Grant/Research Support|ReViral: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Grant/Research Support|Vir Biotechnology: Advisor/Consultant|Vir Biotechnology: Grant/Research Support.