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The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality

Joshua A. Hill, Bryan T. Mayer, Hu Xie, Wendy M. Leisenring, Meei-Li Huang, Terry Stevens-Ayers, Filippo Milano, Colleen Delaney, Mohamed L. Sorror, Brenda M. Sandmaier, Garrett Nichols, Danielle M. Zerr, Keith R. Jerome, Joshua T. Schiffer and Michael Boeckh

Key points

  • We demonstrate frequent plasma detection of multiple double-stranded DNA viruses after allogeneic hematopoietic cell transplantation.

  • There was a dose-response relationship of the cumulative burden of virus exposure with early (day 0-100) and late (day 101-365) mortality.

Abstract

Strategies to prevent active infection with certain double-stranded DNA (dsDNA) viruses after allogeneic hematopoietic cell transplantation (HCT) are limited by incomplete understanding of their epidemiology and clinical impact. We retrospectively tested weekly plasma samples from allogeneic HCT recipients at our center from 2007-2014. We used quantitative PCR to test for cytomegalovirus (CMV), BK polyomavirus (BKV), human herpesvirus 6B (HHV-6B), HHV-6A, adenovirus (AdV), and Epstein-Barr virus (EBV) between days 0-100 post-HCT. We evaluated risk factors for detection of multiple viruses and association of viruses with mortality through day 365 post-HCT with Cox models. Among 404 allogeneic HCT recipients including 125 cord blood, 125 HLA-mismatched, and 154 HLA-matched HCTs, detection of multiple viruses was common through day 100: 90% had ≥1, 62% had ≥2, 28% had ≥3, and 5% had 4 or 5 viruses. Risk factors for detection of multiple viruses included cord blood or HLA-mismatched HCT, myeloablative conditioning, and acute graft-versus-host disease (p-values <0.01). Absolute lymphocyte count <200 cells/mm3 was associated with greater virus exposure based on the max cumulative viral load area under the curve (AUC) (p=0.054). The max cumulative viral load AUC was the best predictor of early (day 0-100) and late (day 101-365) overall mortality (aHR, 1.36; 95% CI, 1.25-1.49 and aHR, 1.04; 95% CI, 1.0-1.08, respectively) after accounting for immune reconstitution and graft-versus-host disease. In conclusion, detection of multiple dsDNA viruses was frequent after allogeneic HCT and had a dose-dependent association with increased mortality. These data suggest opportunities to improve outcomes with better antiviral strategies.

  • Submitted October 28, 2016.
  • Accepted February 12, 2017.